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LIBRARY l

Michigan State
University

 

 

This is to certify that the
dissertation entitled

CHLORINATIVE REARRANGEMENTS OF BICYCLIC AND
MONOCYCLIC CARBINOLS VIA THE ACTION OF BLEACH
AND VINEGAR

presented by

Erik L. Ruggles

has been accepted towards fulfillment
of the requirements for the

Doctoral degree in ChemistrL

 

 

 

Em WM fi-

 

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( /2Q/o 3
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6/01 c:/CIFiC/Dat90ue.p65op. 15

CHLORINATIVE REARRANGEMENTS OF BICYCLIC AND MON OCYCLIC
CARBINOLS VIA THE ACTION OF BLEACH AND VINEGAR

By

Erik L. Ruggles

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY
Department of Chemistry

2003

ABSTRACT
CHLORINATIVE REARRANGEMENTS OF BICYCLIC AND MONOCYCLIC
CARBINOLS VIA THE ACTION OF BLEACH AND VINEGAR
By

Erik L. Ruggles

Investigation into a NaOCl/ACOH induced exo-olefin insertion/ring expansion of
bicyclic vinyl carbinols led to a systematic study of this rearrangement. This ring
expansion/elimination reaction proceeds first through a chlorinative ring enlargement to
form a B-chloroketone. Elimination of HCl follows to produce exocyclic enones in good
yields and regioselectivity. Interestingly in the bicyclic [2.2.2] chlorinative ring
expansions, each diastereomeric starting carbinol rearranges stereospecifically to produce
bicyclic B-chloroketones. Other issues addressed include substrate scope, as well as the
chemo-, regio-, and diastereoselectivity of these chlorinative ring expansions.
Subsequent experimentation with other non—vinylogous carbinols led to the observation
of a number of other chlorinative rearrangements. The information gleaned from this
methodology is an important addition to the database of rearrangements in bicyclic and

monocyclic carbinols.

To Me, Myself and I

iii

ACKNOWLEDGMENTS

I would like to thank Professor Robert E. Maleczka, Jr. for his patience, guidance
and encouragement during my studies at Michigan State. I could not have asked for a
better mentor. I hope I can be as understanding and wise with my own students. I would
also like to thank Professors Greg Baker, John McCracken, and Merlin Bruening for
serving on my guidance committee. I wish to thank Professors William Reusch, Ned
Jackson, and Babak Borhan for their helpful discussions over the years.

On a personal note, upon my arrival at MSU, I had only one family but upon my
departure I have been blessed with a lovely wife, Ali, and son, Sayler. You both are the
love of my life. I am forever grateful for Ali’s gentle prodding over the years and her
understanding of late nights and endless work, I will make it up. Also my heart sings for
Sayler, whose smile, laughter, and antics have always lifted my spirits immeasurably. I
must thank my family for their love and support throughout my long academic studies.
In particular I thank my parents, Ed and Bev, for encouraging me to follow my dreams
and my sister and brother, Whitney and Seth, for their encouragement and friendship.
Last but not least, I want to also express thanks to my Mammaw Ruggles, Mammaw and
Pappaw Morehead, Snook and Glenn, and Michael Riordan whom always have lent a
compassionate ear and were always there to help out in any way. My family has been the
wind behind my sails on this long voyage and I thank you all.

I also thank my colleagues from the Maleczka group for their friendship and help,
especially Lamont Terrell, Joe Ward, Bill Gallagher and Andrea Pellerito. I also thank
Lee Kelepouris, John Asara and the Woodworth brothers, Mike, Elliot, Shawn, and

Adam, for all our many adventures and comic relief over the past six years.

TABLE OF CONTENTS

TABLE OF CONTENTS .................................................................................................... v
LIST OF TABLES ........................................................................................................... viii
LIST OF FIGURES ............................................................................................................ ix
LIST OF SCHEMES ........................................................................................................... x
LIST OF ABBREVIATIONS ........................................................................................... xii
Chapter 1. Introduction of Ideas ......................................................................................... 1
Chapter 2. Radical Oxy-Cope Attempts ............................................................................. 4
2.1. Introduction to the Radical oxy-Cope ..................................................................... 4
2.2. Prior Art ................................................................................................................... 5
2.3. Substrate Synthesis .................................................................................................. 6
2.4. Radical oxy—Cope .................................................................................................... 9
2.4.1. Lead ................................................................................................................ 10
2.4.2. Manganese ...................................................................................................... 1 1
2.4.3. Sulfenate Ester ................................................................................................ 12
2.4.4. Hypoiodites .................................................................................................... 14
2.4.5. Hypochlorites ................................................................................................. 15

2.5. Conclusions ........................................................................................................... 16
Chapter 3. NaOCl/ACOH Promoted Ring Expansions .................................................... 18
3.1. Introduction ........................................................................................................... 18
3.2. Understanding the Reaction Conditions ................................................................ 20
3.3. Proposed Mechanism ............................................................................................ 24
3.4. Chlorinative [2.2.1] Ring Expansions ................................................................... 25
3.4.1. Results and Structural Assignment ................................................................ 26
3.4.2. Mechanistic Considerations ........................................................................... 27

3.5. Further Unsaturated [2.2.2] Substrate Synthesis ................................................... 28
3.6. Chlorinative Ring Expansions of “Vinyl” [2.2.2] Carbinols ................................ 29
3.6.1. Results and Structural Assignment ................................................................ 29
3.6.2. Mechanistic Considerations ........................................................................... 32
3.6.3. Rotomeric Carbinol Investigation .................................................................. 36
3.6.4. Summary of Chlorinative [2.2.2] Bicyclic Expansions .................................. 37

3.7. Chlorinative Ring Expansions of Monocyclic Vinyl Carbinols ........................... 37
3.7.1. Results and Structural Assignment ................................................................ 38
3.7.2. Mechanistic Considerations ........................................................................... 39
3.7.3. Summary of Chlorinative Monocyclic Expansions ....................................... 39

3.8. Exo-Olefin Insertion/One Carbon Ring Expansions ............................................. 4O

3.9. Saturated [2.2.1] and [2.2.2] Substrate Synthesis ................................................. 41

3.10. [2.2.2] and [2.2.1] Exo-Olefin Insertion/One Carbon Ring Expansions ............. 42
3.10.1. Results and Structural Assignment .............................................................. 42
3.10.2. Mechanistic Considerations ......................................................................... 42

3.1 1. Influence of Bridgehead Methyl Group in [2.2.2] Expansion ............................ 45
3.11.1. Substrate Synthesis ....................................................................................... 45
3.1 1.2. Results .......................................................................................................... 46
3.11.3. Mechanistic Considerations ......................................................................... 47
3.1 1.4. Summary of Bicyclic Exo-Olefin Insertion/One Carbon Expansions ......... 48

3.12. Monocyclic Exo—Olefin Insertion Ring Expansions ........................................... 48
3.12.1. Results and Discussion ................................................................................. 48
3.12.2. Dilution Experiments ................................................................................... 50

3.13. Conclusions ......................................................................................................... 50

Chapter 4. Additional N aOCl/AcOH Promoted Chlorinative Rearrangements ............... 52

4.1. Introduction ........................................................................................................... 52

4.2. Substrate Preparation ............................................................................................. 52

4.3. Rearrangement of Secondary Carbinols ................................................................ 53
4.3.1. Results and Structural Assignment ................................................................ 53
4.3.2. Mechanistic Considerations ........................................................................... 56

4.4. Rearrangement of Methyl Substituted Tertiary Carbinols .................................... 56
4.4.1. Results and Structural Assignment ................................................................ 57
4.4.2. Mechanistic Considerations ........................................................................... 58
4.4.3. Summary of Methyl Carbinols ....................................................................... 59

4.5. Rearrangements of Ethynyl Substituted Tertiary Carbinols ................................. 60
4.5.1. Results and Structural Assignment ................................................................ 60
4.5.2. Mechanistic Considerations ........................................................................... 61

4.6. Conclusions ........................................................................................................... 62

Chapter 5. Theoretical Investigation ................................................................................ 64

5.1. Introduction ........................................................................................................... 64

5.2. Theoretical Investigation of Chlorinative Ring Expansion ................................... 65

5.3. Theoretical Investigation of Chlorinative Transition State ................................... 68

5.4. Conclusions ........................................................................................................... 69

Chapter 6. Future Synthetic Investigations ...................................................................... 70

6.1. Nucleophilic Addition to Ring Expanded Enones ................................................ 70

6.2. Patchoulenes .......................................................................................................... 70

6.3. Pinocarvone ........................................................................................................... 72

6.4. Enone DieIs-Alder Cycloadditions ....................................................................... 73

6.5. Increase in Substrate Scope ................................................................................... 75

6.6. Final Thoughts ....................................................................................................... 75

vi

Experimental Details ......................................................................................................... 77

Materials and Methods: ................................................................................................. 77
General Procedures: ...................................................................................................... 78
Specific Procedures and Spectral Data: ........................................................................ 82
REFERENCES AND NOTES ........................................................................................ 173

vii

LIST OF TABLES

Table 1. Temperature and Sequence of Reagent Addition Experiments23 ....................... 20
Table 2. Mechanistic Experiments23 ................................................................................ 22
Table 3. Chlorinative Ring Expansions of [2.2.2] Bicyclics23 ......................................... 31

Table 4. Chlorinative Ring Expansions of Saturated [2.2.2] Isopropenyl Carbinols23 36

Table 5. Chlorinative Expansions of Monocyclics23 ........................................................ 38
Table 6. Bicyclic Exo-Olefin Insertion One Carbon Expansion Results” ....................... 43
Table 7. [2.2.2] Backside Methyl Ring Expansion/Eliminations23 .................................. 46
Table 8. Monocyclic Exo-Olefin Insertion One Carbon Expansion Results23 ................. 48
Table 9. Secondary Carbinol Rearrangements23 .............................................................. 55
Table 10. Methyl Substituted 3°~Carbinol Rearrangements23 .......................................... 58
Table 11. Ethynyl Substituted 3°-Carbinol Rearrangements23 ........................................ 61
Table 12. Select Bicyclic Strain Energies (SE) and Heats of Formation (AI—If) ............... 66
Table 13. Chloroketone Carbinol ASE and AAHf Values ................................................ 67

viii

LIST OF FIGURES

Figure 1. Methods for Generating Oxygen Centered Radicals .......................................... 9
Figure 2. Sulfenate Ester Homolysis ................................................................................ 12
Figure 3. Possible Radical Cyclizations ........................................................................... 16
Figure 4. React-Ir Analysis of Irradiation ........................................................................ 23
Figure 5. lD-NOE Support of Johnson’s Products .......................................................... 26
Figure 6. 1D-NOE Support of Chlorinative Diastereoselectivities .................................. 30
Figure 7. Rotomeric Constraints ...................................................................................... 33
Figure 8. Mechanistic Arguements .................................................................................. 34
Figure 9. lD—NOE Support of Methyl B-Chlorocyclohexanones 95:96 .......................... 39
Figure 10. Predictive Diastereoselective Pneumonic ....................................................... 39
Figure 1 1. lD-NOE Support of 110, 112, and 113 .......................................................... 42
Figure 12. Molecular Orbital and Newman Representations ........................................... 44
Figure 13. lD-NOE Support of 167:168 .......................................................................... 54
Figure 14. lD-NOE Support of 176 and 177 ................................................................... 57
Figure 15. lD-NOE Support of 183 ................................................................................. 60
Figure 16. Regio and Diastereo Discrepancies ................................................................ 64
Figure 17. Singe Point Energies (SPE) of Chloronium Transition States ........................ 68
Figure 18. Patchoulenes ................................................................................................... 70
Figure 19. Possible Substrates .......................................................................................... 75

ix

LIST OF SCHEMES

Scheme 1. General Carbinol Cation Ring Expansion ........................................................ 1
Scheme 2. One Carbon Expansion Impetus ....................................................................... 2
Scheme 3. Johnson and Paquette Expansions .................................................................... 2
Scheme 4. Radical Oxy-Cope Rearrangement ................................................................... 5
Scheme 5. Bulliard’s Reaction ........................................................................................... 6
Scheme 6. Carvone Derived Substrates ............................................................................. 7
Scheme 7. Anionic oxy-Cope Controls23 ........................................................................... 8
Scheme 8. Pb(OAc)4 Attempts ......................................................................................... 10
Scheme 9. Mn(pic)3 and Mn(OAc)3 Attempts ................................................................. 1 1
Scheme 10. Nitrophenyl Sulfenate Attempts23 ................................................................ 13
Scheme 11. Phenyl Sulfenate Attempts23 ......................................................................... 14
Scheme 12. Hypoiodite Attempts .................................................................................... 15
Scheme 13. Hypochlorite Attempts23 ............................................................................... 16
Scheme 14. Proposed Radical Mechanism ...................................................................... 18
Scheme 15. Johnson’s [2.2.1] Chlorinative Ring Expansion ........................................... 19
Scheme 16. Standard Set of Conditions23 ........................................................................ 23
Scheme 17. Proposed Cationic and Concerted Mechanisms ........................................... 24
Scheme 18. Synthesis of 923 ............................................................................................. 25
Scheme 19. t-BuOCl vs. NaOCl in Johnson’s System23 .................................................. 25
Scheme 20. Johnson Regio and Diastereoselectivity ....................................................... 27
Scheme 21. Secondary Cationic Mechanism ................................................................... 28
Scheme 22. “Vinyl” Substrate Synthesis23 ....................................................................... 28

Scheme 23.

Scheme 24.

Scheme 25.

Scheme 26.

Scheme 27.

Scheme 28.

Scheme 29.

Scheme 30.

Scheme 31.

Scheme 32.

Scheme 33.

Scheme 34.

Scheme 35.

Scheme 36.

Scheme 37.

Scheme 38.

Scheme 39.

Scheme 40.

Scheme 41.

Iso—propenyl Carbinol Secondary Mechanism ............................................. 35
Synthesis of Saturated 80 and 8123 ............................................................... 36
Exo—Olefin Insertion/One Carbon Ring Expansion ...................................... 40
Saturated [2.2.1] and [2.2.2] Substrate Synthesis” ...................................... 41
Synthesis of Paquette’s [2.2.2] Backside Methyl System23 .......................... 45
Ketal Carbinol Synthesis23 ............................................................................ 46
Possible Mechanism for 129 ......................................................................... 47
Preparation of H(D), Me, and Alkynyl Carbinols23 ...................................... 53
Secondary Carbinol Cationic Mechanism .................................................... 56
Anticipated 3°-Carbinol Rearrangement ...................................................... 57
Methyl Substituted 3°-Carbinol Cationic Mechanisms ................................ 59
Ethynyl Substituted 3°-Carbinol Cationic Mechanism ................................ 62
Differing Mechanistic Pathways .................................................................. 63
McNelis Expansion of [2.2.1] Alkynyl Carbinols ........................................ 63
Vinyl Grignard Addition of 8 ....................................................................... 70
Proposed Synthetic Routes to [3- and 8-Patchoulenes .................................. 71
Proposed Synthetic Route to (+/-)-Pinocarvone ........................................... 72
Diels—Alder Diene Participation of Enone 9023 ............................................ 74
Diemerization of Enones .............................................................................. 74

xi

AcOH
CH3CI3
CCh
CI
DAID
DHF
DHP
DMF

DMSO

HDA
HMPA
HPLC
H 20
HRMS
IR

LRMS

LIST OF ABBREVIATIONS
acetic acid
dichloromethane
carbon tetrachloride
chemical ionization
diacetoxyiodobenzene
dihydrofuranyl
dihydropyranyl
N,N-dimethylformamide
dimethyl sulfoxide
electric ionization
diethyl ether
equafion
fast atom bombardment
gram
hour
hetero Diels-Alder
hexamethyl phosphoramide
high performance liquid chromatography
water
high resolution mass Spectrometry
infrared spectroscopy

low resolution mass spectrometry

xii

LiAID4
min
mL
mmol
MS
NaBH4
N aOCl
NBS
NMR
NOE
PhH
i-PrgEtN
RCM
r.t.

THF

lithium aluminum deuteride
minute

milliliter

millimole

molecular sieves

sodium borohydride
sodium hypochlorite
N-bromosuccinimide
nuclear magnetic resonance spectroscopy
nuclear Overhauser effect
benzene

di-iso-propyl ethyl amine
ring closing metathesis
room temperature

tetrahydrofuran

xiii

Chapter 1. Introduction of Ideas

The ring enlargement of organic molecules by one carbon atom is a powerful
transformation.l A common feature among the classic Pinacol,2 Tiffeneau-Demjanov,3
and diazo methods,4 is the formation of a carbinol cation, 4, accompanying ring
expansion, 2-—>4 (Scheme 1). These [1,2]-Shifts can be broadly termed as Wagner-
Meerwein rearrangements.5 Within this broad classification, the chemo-, regio-, and

stereoselectivities observed are often dependent on various issues. Ring size, substitution

Scheme 1. General Carbinol Cation Ring Expansion

'- R R R T R
HO x HO + H0 +'. HO 0
—o—d~o~.
n n n

1 2 2 4 5

 

 

OH Pinnacol Rearrangement

x: NH2 Titteneau-Demjanov Rearrangement

+
NEN Diazo Rearrangement

pattern, and/or reagents often dictate the observed selectivities.6 That being said, there
are generalities among ring enlargements: (l) the ability to expand increases (a) as the
donor ability of electrons adjacent to the carbocation increases, (b) as the size of the
expanding ring decreases, and (c) as the ease of carbonium ion formation decreases; (2)
upon examination of the migrating termini, the higher degree of alkyl substitution
normally produces the regioselectivity observed.

During experimentation, originally aimed at the development of a radical oxy-
Cope rearrangement, an interesting one-carbon ring expansion was observed (Scheme 2).
Contrary to the aforementioned processes that expand via a leaving group, in our case

(Scheme 2), the vinyl group attacks an electrophilic source prior to expansion. Both

Scheme 2. One Carbon Expansion impetus
OMe OMe

AcOH, NaOCI EtsN. 50:
’ OH H202CCI4 , Hexanes /

 

,/’

6:7 8

Johnson7 and Paquette8 have observed similar rearrangements in vinyl [2.2.1] carbinols
(equations 1 and 2 respectively, Scheme 3). Johnson uses t-BuOCl as a source of
electrophilic chlorine and proposes that it is the preferential orientation of the iso-
propenyl substituent that imparts the observed diastereoselectivity, with bridgehead
migration being favored. Paquette employs protonation of a vinyl group to evoke a

similar ring expansion of hydrofuranyl carbinols. In this case, bridgehead migration is

Scheme 3. Johnson and Paquette Expansions

 

 

 

 

 

 

 

 

 

 

Johnson
c: of
(1) r-euoCI, 8 hr, dark J
*v +
CHCI3. 55 °c C,
(DH (D (D (DH
9 10:11 12:13
(64%; 1821.0) (36%; 2.3:10)
Paqueue
+
C) O
(2) \ TSOH, CHCI3, TI t \
overnight brie»
(DH (DH
14 15

(83%)

absolute. The observed diastereoselectivity arises from a proposed anti relationship
between the hydroxyl and furanyl oxygens (Scheme 3).
As a result of the interesting nature of these rearrangements, it was decided to

further examine the expansion of vinyl carbinols to understand the scope, mechanism and

synthetic utility of this reaction. The chapters that follow will delve into the chemo-,
regio-, and diastereoselectivity observed in the NaOCl/ACOH mediated Chlorinative ring
expansion on a variety of substrates. However as the impetus of this ring expansion rests
in our labors toward a radical oxy-Cope rearrangement, a discussion of these studies shall

be presented first in Chapter 2.

Chapter 2. Radical Oxy-Cope Attempts
2.1. Introduction to the Radical oxy-Cope

Concerted rearrangements of organic molecules have long been exploited for their
simplicity and ability to impart high levels of stereo and regiocontrol during
transformations. As an example the oxy-Cope rearrangement has been used extensively
for ring expansions as well as the elaboration of polycyclic backbones.9 The oxy-Cope is
highly valued in these endeavors as a result of its ability to impart chirality at one or more
centers during the concerted rearrangement. Although most radical carbon-carbon bond
forming processes occur in a stepwise fashion, it is possible for the bond reorganization
of such a sequence to resemble those observed in concerted reactions. Radical
cyclizations do have the ability to impart regio- and stereoselectivity during the course of
a reaction,10 and radical reactions have mimicked thermal concerted processes.l ”1'3“”
However, the use of an oxygen-centered radical for the acceleration and/or genesis of an
oxy-Cope rearrangement has, to the best of our knowledge, not yet been investigated. '6

The proposed radical oxy-Cope rearrangement requires first the formation of a
suitable oxygen bond that could cleave homolytically under the right conditions, 16.'7
The envisioned process begins with homolytic cleavage of the O-X bond to form alkoxy
radical 17. Subsequent B-cleavage during carbonyl formation produces allylic radical
18a, and its resonance contributor 18b. Literature precedent would have the allylic
radical to add from the least substituted carbon, 18b——)19, in order to form the more
substituted olefin center.l8 After which, recombination produces an oxy-Cope product,

20, via a radical rearrangement.

This type of stepwise radical promoted oxy-Cope rearrangement could potentially

Scheme 4. Radical Oxy-Cope Rearrangement

 

 

7
Li H H H
3 0 § 0 ? O x' i O
/ —> / o —* <——> —> t—.
O\X O m m m mx
/ / H H
16 17 188 18b 19 20

complement its thermal and anionic counterparts. For example in contrast to a concerted
reaction, a stepwise process may be stereoselective but independent of stereochemistry in
the starting bicyclic vinyl alcohol. As illustrated above, upon reaching radical 18a, the
stereochemistry in the starting substrate is inconsequential (Scheme 4). So either
diastereomeric alcohol can be employed. This is quite unlike the thermal/anionic
counterpart in which only one diastereomeric alcohol has the proper orbital alignment for
sigmatropic rearrangement. Thus the vinyl Grignard addition can be non-selective in a
radical initiated oxy-Cope. Secondly, radical rearrangements are considered neutral
processes; hence substrates with base or thermal sensitive substituents could now be
employed. There have also been theoretical estimates opening up the possibility of rate
enhancement under these neutral conditions.19 Finally there is also the prospect of a
stereo outcome opposite that produced by traditional means. That is formation of 20
may, based on related radical cyclization, afford the trans fused product.20 Given these
possibilities and questions, the radical oxy-Cope was viewed as an intriguing complement
to the traditional [3,3] sigmatropic rearrangement.
2.2. Prior Art

In the late 80’s, Bulliard and coworkers published a, rearrangement of carbinol
21.2| Upon treatment with SOgClg, 21 reportedly rearranged to give chloroketones, 22

and 23 as a 1:1 mixture (Scheme 5). Both products are described to be the product of

alkoxy fragmentation after hypochlorite formation followed by cyclization in either an
em, 22, or endo, 23, fashion. This literature report is troublesome, since product 23 is
not what would be expected from endo cyclization. The expected product, 24, would
have both the carbonyl and chloro substituents juxtaposed by one carbon. Moreover 24
could be viewed as arising from the first radical oxy-Cope rearrangement. However this
was never claimed, nor were spectral data for the products detailed in the letter. Whether
ketone 23 was truly constructed or merely a typo led us to try and reproduce Bulliard’s
work. However upon subjecting 21 to their conditions only ketone 22 was observed
along with a number of other products. Attempts at reaching any of the three authors did
not help in the elucidation of whether this truly was a radical oxy-Cope rearrangement.
Our inability to repeat the reaction and less than clear correspondence with the authors

led to the conclusion of this route.

Scheme 5. Bulliard’s Reaction

 

 

0 o
H

O O or c:

\ \ ,

/ CH2C12. 50 °c ~. .~’ /

4 n
21 22 23
Cl

 

24

 

 

 

2.3. Substrate Synthesis

The beginning of the second-generation radical oxy-Cope investigation entailed
the construction of a suitable carbinol that would undergo the standard oxy-Cope
rearrangement. A [2.2.2] bicyclic construct was chosen since only one diastereomer has

the proper orbital alignment for thermal or anionic rearrangement while under radical

conditions either diastereomer should react in the same fashion. Also, [2.2.2] carbinol
systems can be somewhat sluggish toward [3,3]-sigmatropic rearrangement and often
need to be transformed into their potassium salt prior to rearrangement making base

22 . . .
Furthermore even under anionic acceleration, heat

sensitive substitutions problematic.
is often necessary for the rearrangement to proceed. It was hoped that radical conditions
would provide a neutral way to accelerate such reactions and also be stereoconvergent
with both carbinol diastereomers being able to rearrange similiarly. Thus the [2.2.2]

system emerged as one of the most suitable substrates to address such questions.

. 23
Scheme 6. Carvone Derived Substrates

 

 

 

OMe R, R2
Br
N85. 012% MeOH (3:1) t-BuOK. t-BuOH, THF
4' $ /
0°C,1.5h 0°C.10min
0 rt, 10 n 0 n, 18 n o
carvone 25:26 27 (R,=Me, R2=OMe; 409/0)
28 (R,=0Me. R2=Me; 28%)
R1 R2
fiMgBr
> / OH
THF. 0 9C. 30 min
9
80 C. 3 h /

6:7 (R,=Me. R,=OMe; 70-90%; 4:1)
29:30 (R1=0Me. R2=Me; 60-80%; 1:1)

A short route to [2.2.2] systems has been developed by Srikrishna,24 which
utilizes carvone as a chiral starting synthon (Scheme 6). Use of N—bromosuccinimide
(NBS) and methanol (MeOH) generates bromomethoxy carvone 25:26. Treatment with
base then provides the [2.2.2] core via an intramolecular substitution reaction. Vinyl
Grignard addition provides the desired oxy-Cope precursors, 6:7 and 29:30. Another
easily accessible oxy-Cope substrate is 21,25 which is available from successive vinyl

. . 26
addition across Ot-chlorocyclohexanone.

To establish the Spectroscopic and chemical properties of the starting materials
and rearranged products, the starting carbinols were subjected to the Standard oxy-Cope
conditions (Scheme 7). First, the diastereomeric bicyclic carbinols, 6 and 7 were
thermalized. After heating at either 80 °C or 180 °C for 24 hrs only starting material was
recovered (equations 1 and 2, Scheme 7). Upon treatment with KH, all carbinols
rearranged smoothly at 80 °C in 12 hrs to provide the predicted [4.4.0] bicycles, 31 and
32, along with recovered endo carbinols 7 and 30 (equations 3 and 4, Scheme 7). With
the desired products isolated and identified spectroscopically the radical oxy-Cope could

be investigated.

Scheme 7. Anionic oxy-Cope Controls23

OMe
OM
THF 0
(1) 3i 20H ___. .. 6,7
80 °C. 24 h (86%; 1:1)
/

(1 :1) (not observed)

0)
.5

U
.15

(not observed)

OMe
OM
decann
(2) I OH —. + 6
180 °C, 24 h (quant)
/
6
OMe
%OH

OMe
KH, THF OM O
(3) 18-c-6 /
___—_._> 4.
80 °C, 12 h \
OH
: 31 7
(1 :1 ) (52%) (21%)
M90 MeO
KH, THF M60“- 0
18-c-6
(4) / OH _____. + / \
80 °C, 12 h
/ OH
29:30 32 30
(1 ;1) (47%) (34%)

2.4. Radical oxy-Cope

The literature provides many ways to produce alkoxy radicals directly (Figure 1).
The photolysis of nitrites;27 carbinol oxidation via Pb(OAc)4,28 Pb(OAc)4/Cu(OAc)3,39
Pb(OAc)g/Og,30 Mn(2—pyridinecarboxylato)3,3| and Mn(OAc)3;3'C‘f'g irradiation of
sulfenates;32 action of FeCl3 on fused cyclopropylsiloxanes;33 treatment of alcohols with
sulfuryl chloride;2| hypochlorite34 and hypoiodite fragmentation;35 as well as the tin

7 pyridinyl thiones,38 thiazole

hydride reduction of iodoepoxides,36 nitrate esters,3
thiones,39 and phthalimides40 are all methods for the generation of such radicals.

Figure 1. Methods for Generating Oxygen Centered Radicals

m o _
/)\ I _N02
4k /
R1 R3 R1 R R

3

 

 

 

R2 2
Pb(OAc)4
[TMS cyclopropanolsJ
$0202
TMS
/
RO-Cl, hv 0

4k —— H90, 12. hv ———>

Phl(OAc)2. 12, hv

A carbinol
directl Pb(OAc)4. 12 NO
0/ 2
Ph|=O. '2. M Bugan + -m

0 410)\\
8 R1

o’N I
N N /
1 R2 3 /)\ +
R, R3 R1 R3

R2 R2
phthalimides ‘
I thiazole thionesl l pyridinyl thionesl

 

 

 

 

 

 

Though the ways of alkoxy radical generation are numerous. not all cater to the

allylic-homoallylic nature of the starting tertiary bicyclic carbinol. Pyridinyl and thiazole

thiones as well as phthalimides rely on substitution chemistry for their construction. The
bicyclic tertiary nature of the system would require a SN] process, allowing for the
possibility of products derived via cationic bicyclic rearrangements.4| As a result, these
methods were not attempted. Generation of nitrate esters and their subsequent reduction
was thought promising, however early attempts resulted in complete decomposition of
the starting substrates. Thus further study of nitrate esters was avoided.
2.4.1. Lead

The use of Pb(OAc)4 for decarboxylation and oxidative cyclization is well

8c

known.2 It also has been used to create oxygen radicals from secondary bicyclic and

Scheme 8. Pb(OAc)4 Attempts

 

 

 

OMe
Pb(OAc)4 Pb(OAc).
(1) 6 + number of oleiinic products ‘———-—— ’ 0H myriad of olefinic products
PhH, rt. 10 h PhH, 90 °C
/ 2.5 h
6
OMe
Pb(OAc)4 Pb(OAc)4
(2) 7 + number of olefinic products ¢———— ’ \ ————> myriad of olelinic products
PhH, rt, 10 h PhH, 90 °C
OH 2.5 h
7
OMe
Pb(OAc).
Cu(OAc)2 (cat)
(3) ’ 0H myriad of olefinic products
PhH, 90 °C
/ 30 min
6:7
(1 :1)
pyridine
M90 ethyl acrylate
Pb(OAc)2 (cat)
4A Ms, 02
(4) ’ 30
\ PhH. 90 °C (92%)
OH 26h

10

30

- . 2s b
monocyclic carbinols as well. “

Unfortunately, with our substrates clean reactions were
not observed when Pb(OAc)4 mediated rearrangements were attempted at ambient or
reflux temperatures (equations 1 and 2, Scheme 8). Recently, Rigby has shown that use
of Cu(OAc)2 as a catalytic additive can oxidize carbinols as well.29d However these
conditions proved even more harsh than Pb(OAc)4 alone, rapidly providing a myriad of
molecules (equation 3, Scheme 8). Lead (11) was studied next as the use of Pd(OAc)2 in
an oxygen atmosphere has triggered the oxidative ring cleavage of cyclobutanols.30
However, as before, exposure of our substrate to standard Pb(II) conditions gave no
reaction (equation 4, Scheme 8). This prompted the dismissal of lead based reagents.
2.4.2. Manganese

Tris-(2-pyridinecarboxylato)manganese(III) or Mn(pic)3 has been used to

generate alkoxy radicals of carboxylic acids,3”"g as well as with cyclopropanols.“'C'C‘g‘j

Scheme 9. Mn(pic)3 and Mn(OAc)3 Attempts

CL
I / \
N CO;H |

_______. O /

(1) Mn(acac)3
EtOH, 1 h M“ N

(50%)

OMe
BU3an

MeO

(3) / OH

29:30

Mn(OAc)3

DMF, 0 °C
3 h

8113an
Mn(piC)a

 

DMF, 0 °C
3 h

11

(31%)

29:30
(96%)

This reagent can be easily synthesized from the readily available Mn(acac)3 (equation 1,
Scheme 9).3 1" Trisacetoxymanganese(III) or Mn(OAc)3 has been used to generate
carboxylic radicals as well, and also to produce alkyl radicals of [3-ketoesters.3”“5”h
Bicyclic carbinol 6 did not undergo the desired rearrangement and was recovered in low
yield (equation 2. Scheme 9). Use of Mn(pic)3 resulted in high recovery of starting
material (equation 3, Scheme 9). Like the lead-based reagents, this method was
abandoned.
2.4.3. Sulfenate Ester

The use of a sulfur-oxygen bond for the generation of oxygen-centered radicals
began with Beckwith in the late 80’s (Figure 2).”3 The ability to cleave a sulfur-oxygen
bond homolytically makes sense since related peroxide bonds can be cleaved in this
manner. Also it is known that Bu3SnH can be used as an initiation reagent for alkyl
radicals upon treatment with alkyl halogens (Cl, Br, I) and dialkyl chalcogenides (S. Se,

Te),42 It naturally followed that the sulfur-oxygen bond could be cleaved in a homolytic

fashion as well.

Figure 2. Sulfenate Ester Homolysis

 

Beckwrth
s Bu-SnH AIBN [ O
\O 3 . PhS—SnBu A
(r-Bu)c.,H5, 80 °c, 30 min [ 3 -o HO
major
Pasto

O
R 0 Ar R O ' /Ar R\ ,Ar
X \S/ hv (>300 nm) X 'S )J\ S
PhH

major

Soon after Beckwith’s work, Pasto discovered that sulfur-oxygen bonds not only
cleave under Bu3SnH conditions, but also by light when the S—O bearing groups are
properly substituted (Figure 2)."2b'd Electron withdrawing groups, such as nitro, located

on the aromatic ring enhance this desired homolytic fission.

Scheme 10. Nitrophenyl Sulfenate Attempts23

 

OMe 0M6 OMe
Et3N
/ OH MEL / oxone / OH
CHQC|2 -78QC 0” MeOH/H20 o
/ 4 h C, PH=4 Cl 11
S N02 g N02
0
6 33 34
(480/0) (239/0)

OMe OMe
Et3 N Cl 0
/ p(NOZ)PhSCl oxone / g
\ CHzClzh 78°C 028mm MeOH/H20 ”O
NO

- 0
OH pH“ OH
2
7 36
(32%) (27%)

Unfortunately, in our hands, formation of the S-O bond was never observed
(Scheme 10). Carbinol treatment with p-nitrophenylsulfenyl chloride and base43 only

44.45 - - .
This addition was

resulted in addition across the vinylic portion of the substrate.
thought to be a result of the enhanced polarization of the sulfur-chlorine bond due to the
electron withdrawing nitro substituent. To rule out the poSsible sulfenate [2.3]-
sigmatropic rearrangement,46 both 33 and 35 were oxidized via oxone to produce
sulfones 34 and 36 in low yield. In hopes to avoid the addition problem, unsubstituted
phenyl sulfenyl chloride was used (equations 1 and 2, Scheme 11).47 Treatment of the
readily available diphenyl disulfide with sulfuryl chloride produced phenyl sulfenyl

chloride in good yield.48 However, as observed in the nitro case, addition across the vinyl

olefin was the only observable product when Et3N was used as the base.” Use of n-BuLi

13

as a base produced the [2,3]-sigmatropic product, 38, even at -78 °C. As a result. the

sulfenate avenue for oxygen centered radical formation was abandoned.

Scheme 11. Phenyl Sulfenate Attemptsz3

s Q 802012, Et3N S\C(
\ ——.—’
O 5 con, 0 °C. 1 h

(70%)

MeO M90
EtaN
PhSCI
(1) I OH ———_. ’ OH
CH2012 -78°C
/ 4 h C|
S
29 37
(33%)
MeO M90
n-BuLi
PhSCl
(2) / OH _. ’ (3‘
CH2C12 -78°C \ saph
/ 4 h
29:30 38

2.4.4. Hypoiodites

There are a number of ways to generate alkoxy radicals by way of hypoiodites.
Heterolytic cleavage by HgO/Iz was originally pioneered by Petrov and later by Barton,
who developed methods for homolytic cleavage.35“‘b‘50 Hypoiodite fragmentation has
also been observed with Pb(OAC)4/Ig,5| and hypervalent iodine species have been used
extensively by Suare’z and Suginome for the generation of anomeric alkoxy radicals in
hemiacetals and other systems as well. 35C" The reaction of HgO/Iz with carbinol 7 did
not generate the oxy-Cope like product. Nor was the iodoepoxide observed, despite such
species being previously reported to come from the hypoiodination of allylic alcohols.36

Besides starting material the only product isolated, was believed to be iodo 39 (Scheme

14

12).52 Treatment with Pb(OAC)4/Iz provided a complex reaction mixture. as expected
from the previous results (Scheme 8). Lastly, use of hypervalent iodines such as
diacetoxyiodobenzene (DIAD)53 and iodosylbenzene,54 which is readily available from

DIAD,55 was uneventful with only starting material recovered (Scheme 12).

Scheme 12. Hypoiodite Attempts

 

 

 

 

 

 

OMe OMe
H90. 12
/ A /
\ » ' 7
001,, 87 °C. 75 min \ (52%)
OH
I
7 39
(43%)
OM
I I
©/ \OAC NaOH. H20 : ©/ \\0
(DAIB) (88%)
F Pth. 12
*7 6:7
OMe CHZCIQ. rt, 24 h (quant)
DAID, l2
/ OH < ¢ 6:7
PhH, rt, hv, 48 h (quant)
/
DAID, 12
' K PhH, 45 °C. hv. 19 h (72%)

2.4.5. Hypochlorites

In conjunction with hypoiodites, hypochlorites have been extensively used for
alkoxy radical generation.34 The reaction conditions can be quite simple with bleach
(NaOCI) and vinegar (AcOH) being among the common reactants.56 The first attempt at
hypochlorite formation and fragmentation yielded enone 8 regardless of carbinol
stereochemistry, albeit in low yield (Scheme 13). Importantly, as predicted earlier, the
presumed stepwise sequence was selective with respect to product formation, but this

selectivity was independent of the starting carbinol stereochemistry. The hypochlorite

15

conditions only yielded one product resultant from a 7-exo cyclization, 42, even though

there are other more favorable cyclization modes (Figure 3). The fact that there were no

Scheme 13. Hypochlorite Attempts23

OMe OMe

1) AcOH. NaOCl
H2000, 0 °C. 3 h

 

 

/ OH /
2) PhH, rt. hv. 10 h 0
/
6 8
(28%)
OMe OMe
1) AcOH, NaOCl
/ HZO:CCI., 0 °C. 3 h
J: /
\ 2) PhH, rt, hv. 10 h 0
OH
7 8

(26%)

products isolated from reaction by the allylic resonance form, including the “favored” 5-
exo cyclization was surprising. If this reaction is proceeding via free radicals it would

appear that after C-C homolysis, the vinyl sector is in an excellent position for attack by
the newly formed radical center.

Figure 3. Possible Radical Cyclizations

 

 

OMe
I’M. OMe
7-exo S-exo
/ «— ——> O
0
Cl ”I,” OMe 0 ll".- OMe O H CI
42 11.31 [3.31 4‘
—_ H —__l
. / - /
OMe In, OMe
O 188 18b " O
8-endo 6-endo
«—
Cl Cl
H
43 45

2.5. Conclusions

Given the interesting features of the bleach/vinegar induced rearrangement,

namely (1) the single mode of cyclization coupled with ready loss of HCI to produce an

exacyclic enone, and (2) the inexpensive and environmentally friendly, or “green”,

reagents used a more in-depth study of this reaction was undertaken.57

17

Chapter 3. NaOCI/AcOH Promoted Ring Expansions
3.1. Introduction

The ability of simple reagents like NaOCl and AcOH to promote an eta—olefin
ring expansion regardless of carbinol geometry was intriguing. Given the possible
synthetic utility of such a transformation, studies aimed at optimization of the observed
ring expansion/exo-olefin insertion were undertaken. In conjunction with these studies,
mechanistic insight into this process was sought.

Initially the observed expansion was thought to be radical in nature (Scheme 14),
as the conditions employed were those that have generated alkoxy radicals in the past.58
One can envision after alkoxy radical formation and B-fragmentation, allylic radical 48

undergoing a 7-ex0 cyclization to generate radical 49. Subsequent propagation of the

Scheme 14. Proposed Radical Mechanism

OMe OMe OMe
1) AcOH, NaOCl
/ OH H20:CC14,0 °C. 3 h: / OI‘ 2) PhH. rt, hv, 10 h t / O‘ B-lrag.
u Cl L4
\ \ /
46 47

 

 

 

OMe OMe OMe
7-exo HCl
____. / __, / _, /
0 Co\ 0 0
Cl R
. V CI
43 49 42 8

(28%)

radical chain, and loss of HCl would generate the observed enone 8. The above Scheme
is somewhat counter intuitive given what is known about free radicals. Generally allylic
radicals add to give the more thermodynamically stable product, which was not observed,
and 7-ex0 radical cyclizations are not favored when compared to 5—ex0 or even 6-emlo

cyclizations.

l8

Scheme 15. Johnson’s [2.2.1] Chlorinative Ring Expansion

o)
M t-BuOCl, dark Me
Me 8 h. 55 9C CI Me
OH CHCI3 Me O O 0 Me 0
C1 or
10 11 12 13

(41%) (23%) (25%) (1 1%)

 

The generation of B—chloroketones via a ring expansion of vinyl substituted
carbinols are known. Johnson has described the Chlorinative ring homologation of simple
cyclobutanes, -pentanes, and ~hexanes and isopropenyl [2.2.1]-heptanol, 9.59 As
reported, treatment of a warm, dark solution of 9 with t-BuOCl afforded a mixture of
[3.2.1]-B-chloroketones (Scheme 15). Though several mechanistic pictures were
described for this rearrangement, both concerted and free radical sequences were ruled
out. Since the experimental conditions were not free radical, i.e. running the reaction in
the dark, it was argued that if 9 was being transformed into a hypochlorite prior to a
concerted intramolecular rearrangement, a higher degree of diastereoselectivity would
have been observed. Thus, Johnson surmised that a cationic mechanism was the most
probable. Despite the relatively mild nature of the Chlorinative rearrangement,
experimentation with bicyclic substrates beyond the [2.2.1] system was not undertaken
by Johnson or others.

It is interesting that Johnson observed ring expansion in the dark, conditions that
should not allow for free radical formation while we observed similar enlargement, albeit
without isolation of the pre—supposed Chloroketone, under conditions that form free
radicals. The ability for these bicyclic systems to undergo Similar ring expansions in

different environments, light vs. dark, while being subjected to hypochlorite forming

19

conditions led us to further investigate the necessary reagents and conditions for this
reaction.
3.2. Understanding the Reaction Conditions

Refinement of the initial rearrangement and workup conditions allowed for
significant improvement in enone isolated yield. It was assumed that the reaction was
producing a B-chloroketone, 42, which was subsequently undergoing elimination. This
process significantly simplified the rearrangement by avoiding the issue of the a-keto
stereochemistry of 42. Use of triethylamine (Et3N) buffered silica allowed for major

strides in case of purification, as well as helping the elimination process.

Table 1. Temperature and Sequence of Reagent Addition Experiments23

R, R2 F11 F12
1) NaOCl (1.19 eq). AcOH (1.95 eq)

H20 (0.6 M). CC|4 (0.6 M). dark

 

 

’ 0H 2) PhH (0.14 M), hv, rt. 10h. ’
3) 1% Eth/hexanes. SiO2 O
\
Entry Carbinol Procedure Product (yield)"
(1) 6 A e (28%)
exo-OH; R,=Me; R2=OMe R,=Me; R2=OMe
(2) 7 A 8 (26%)

endoOH; R,=Me; R2=OMe

(3) 7 e 8 (26%)
(4) 6 C 8 (35%)
(5) 6 o e (28%)
(6) 6 E a (60%)

 

Procedure A: Addition of room temperature AcOH/substrate/CCI4 solution
to chilled (0 °C) NaOCl/H20 solution. Procedure 8: Addition of room
temperature substrate/CCI. solution to chilled (0 °C) AcOH/NaOCI/H20
solution. Procedure C: Addition of chilled (0 °C) substrate/CCI. solution to
chilled (0 °C) AcOH/NaOCl/HzO solution. Procedure 0: Simultaneous
addition of chilled (0 °C) substrate/COL, solution and AcOH to chilled (0 °C)
NaOCl/HZO solution. Procedure E: Addition of chilled (0 °C)
AcOH/substrate/CCI. solution to chilled (0 °C) NaOCl/H20 solution.

‘ Isolated yield.

20

Screening of the reagents revealed that the AcOH and NaOCl were absolutely
necessary for the reaction to take place. If water (H20) or carbon tetrachloride (CCls)
were excluded sharp decreases in yields were observed. With knowledge of the
necessary ingredients, the temperature and sequence of addition were investigated, still
under the presumption that a hypochlorite intermediate needed to be formed and
irradiated (Table 1). We hypothesized, if reaction conditions were found to enhance
hypochlorite formation then an increase in enone should also be observed. These data
showed that the media of this biphasic reaction needed to be chilled prior to their
combination (entries 1, 2, and 3 vs. entries 4 and 6, Table 1). Even if one of the
components was not chilled, a decrease in yield was observed (entry 5, Table l). The
best yield of enone 8 thus far occurred when a chilled solution (0 0C) of substrate (1.00
eq) and AcOH (1.95 eq) in CCl4 (0.6 M with respect to substrate) was added to a chilled
solution (0 0C) of NaOCl (1.19 eq), in H20 (0.6 M with respect to substrate) after
irradiation and purification via Eth buffered silica chromatography (entry 6, Table 1).

The improvement is isolated enone yield was dependent on the temperature and
sequence of reagent addition in the hypochlorite-forming first step of the three step
sequence. The next set of experiments involved the use of free radical and non-free
radical forming conditions to get an understanding of what intermediates, hypochlorite
vs. cationic, were involved. It was believed that the stereochemistry of the methoxy
bearing carbon was inconsequential to the rearrangement and both 6:7 and 29:30 were
used interchangeably. The first experiment was to run the bleach/vinegar conditions in
the presence of normal room light. The reaction proceeded without the formation of a

large body of byproducts (entries 1 and 2, Table 2). The second set of experiments

21

enlisted a radical scavenger, di-tert—butylhydroxytoluene (BHT). The isolated yields
were lower when BHT was an additive, however the reaction took place regardless of
whether BHT was present in the first or second step (entries 3 and 4, Table 2). Ring

expansion in ambient light and a radical scavenger points toward a reaction that is not

Table 2. Mechanistic Experiments23

 

 

 

R1 R2 R, R2
1) Reagents and Conditions
I OH 2) 1°/oEt3N/hexanes, SD; > / O
\

Entry Substrate Conditions Product (yielda)
(1)b 6:7 A 8 (37%)
(2)b 29:30 A 50 (48%)

(3) 6:7 8 8 (41%)
(4)b 29:30 C 50 (33%)
(5)b 6 D 8 (45%)
(6)b 7 D 8 (48%)
(7)b 6:7 D 8 (53%)
(8) 6:7 E 6 (62%)

 

Reagents and Conditions: A: NaOCl (1 .19 sq). AcOH (1.95 eq.), H20 (06 M),
CCI4 (0.6 M). 0 °C. 2.5 h. B: 1) NaOCI (1.19 eq), ACOH (1 .95 eq), H20 (0.6 M).
CCI‘ (0.6 M). 0 °C. dark. 3 h. 2) BHT (1.6 eq), PhH (0.14 M), rt. hv. 8 h. C: 1)
BHT (1.6 eq). NaOCI (1 .19 eq), AcOH (1.95 eq). H20 (0.6 M), CC|4 (0.6 M). 0
°C. dark, 3 h. 2) PhH (0.14 M).rt,hv.10 h. D: NaOCI (1 .19 eq), AcOH (1.95
eq), H20 (0.6 M). CC|4 (0.6 M). 0 °C. dark, 3 h. E: 1) NaOCl (1 .19 eq). AcOH
(1.95 eq), H20 (0.6 M), CCI. (0.6 M), 0 °C. dark, 3 h. 2) PhH (0.14 M), rt, hv. 10
h.

‘ Isolated yields. b Recovered starting material.

under free radical control. As a result, the likelihood of a hypochlorite intermediate
seemed small. We became curious if there was any chemistry occurring during the
irradiation step. Use of NMR and React-IRTM techniques , Figure 4, to follow the
irradiation of the reaction suggests that very little chemistry was occurring at this stage of

the process. Removal of the irradiation step provided proof that the rearrangement

22

Figure 4. React-Ir Analysis of Irradiation

Value

 

 

0.3500 -_ -_ - ..__.._——— -w -— Cchl‘

A

0.3000

0.3500

 

__ - CH2C12

 

0.3000

0.1500

0.1000

‘ ; A _ ‘

0.0500 _ ‘-_

v V i v v v t w t .

100.0 200.0 300.0 400.0 500.0

 

 

 

 

Time (min)

was occurring during the biphasic portion of the reaction, albeit in somewhat lower
isolated yield (entries 5, 6, and 7, Table 2). The lower isolated yields when compared to
entry 8 (Table 2), and recovery of starting carbinols were interpreted to be the result of
not letting the reaction run to completion. Residual chlorinating agents in the irradiation
step would explain why there was a slightly better yield for entry 8, Table 2. Indeed
when the reaction time was extended to 6 hrs, yields improved from 37% to 92%

(Scheme 16). The excellent isolated yield led to the understanding that the

Scheme 16. Standard Set of Conditions”

AcOH (1 .95 eq)

 

OMe 1 NaOCl (1 .19 eq) OMe
) H20 (0.6 M), cei, (0.6 M)
0 °C. 6 h
’ OH = /
2) 1% Et3N/hexanes. SiO2 O
\
6:7 8

(92%; trial 1)
(95%; trial 2)

rearrangement was occurring during the biphasic portion, or step 1. of this multistep
reaction and that these reactions could be run in the presence of normal laboratory
lighting. AS a result we adopted this set of conditions, as our “standard set of conditions"

for all subsequent substrates studied.

23

3.3. Proposed Mechanism

The previous experiments also gave some additional insight into the mechanism
of this rearrangement. The fact that the product composition is not affected by the
addition of radical scavenger nor by the presence or absence of light discredits the
proposed radical mechanism (Scheme 14). Given these observations and other reports, a
mechanism involving cationic character appears the most probable and is illustrated in
Scheme 17.59'60‘6l The combination of NaOCl and AcOH is a source of Cl’. After Cl+
capture by the vinyl portion of the carbinol, a Wagner—Meerwein shift of the bridgehead
produces carbinol cation 53. Loss of H+ would generate 42 and again, loss of HCl. One
other possible mechanism would be the concerted rearrangement of an in-situ generated
hypochlorite. Though possible, this mechanism seems unlikely since a concerted
rearrangement should impart a higher level of stereoselectivity than that was observed in
the products (Scheme 15). Also when hypochlorites are reacted in the presence of light,
at least trace amounts of oxy-radical derived products are expected.58 None were
observed. Moreover, attempts to purposely prepare hypohalites of 6 or 7 by alternative

methods (Chapter 2) never afforded enone 8 or its haloketone analogues. Lastly, use of
Scheme 17. Proposed Cationic and Concerted Mechanisms

OMe OMe
AcOH, NaOCI
H20:CCI4, 0 °C. 6 h Wagner—Meerwein
/ OH > / OH >
\ C1’ +
Cl
51
OMe
OH

OMe

 

 

OH
Cl

52 'H/ 53

OMe OMe OMe
AcOH. NaOCl
H20:CCI., o ”C. 6 h Concerted ~ HCI
: / o\ ______. / —_. /
C, uj O O
\ Cl
46

42 8

 

v

/
\
6

 

24

React- IRTM showed no formation of an oxygen chlorine bond.“ These facts all support a
cationic rearrangement.

3.4. Chlorinative [2.2.1] Ring Expansions

Scheme 18. Synthesis 01923

4% 2H,... 2
O THF. 0 ”C. 30 min then 80 °C. 3 h Me

OH

 

norcamphor 9
(64%; 50:1)

As stated in Chapter 1, a related Chlorinative ring enlargement has been reported
by Johnson in a number of iso-propenyl carbinols.59 Given the similarities of both ring
expansions, namely the vinyl carbinol substrate and use of a hypochlorite reagent, it was

thought prudent to submit isopropenyl [2.2.1] carbinol 9 to both Johnson’s and our

Scheme 19. t-BuOCl vs. NaOCI in Johnson’s System23

 

Cl
10 54
(1) (BUOCI dark (340°) (2300) (2010)
Me 8 h 55 “C
OH each
9
(219%) (71%)
Me 0 O O
NaOCl, AcOH Cl Cl
H20: CCI. (1 1) 54
(2) (36°/ 28% 1%
Me 0 °C 6 h o) ( 1 (< )
OH
9 Cl
OH
55
(119%) (6%) (109/6)

25

conditions. Also with the advances in structural elucidation since the time of the original
report, the structures of chloroketones 10-13 could be more firmly established. In
addition, a preparative method needed to be developed so as to ascertain the isolated
yields of these products.63
3.4.1. Results and Structural Assignment

Isopropenyl carbinol 9 is readily available from Grignard addition across
norcamphor in a ratio of 50:1 (Scheme 18). Treatment of 9 with Johnson’s conditions
gave a ratio of products similar to that described in the original report, plus the formation
of a dichloro product, 54."4 Johnson reported Six products whose yields were obtained

from gas-liquid phase chromatography (GLC). Only four of these products, 10-13, were

Figure 5. 1D-NOE Support of Johnson’s Products

86% 6.7% 0.4%

0mm “Wm (mm
| 0.5°/o 0 CI 0.4°/o
H H H

I
o C o C'L 1.0% 0 CL 0.2%
H H H. b H H 3‘ HI 3‘ Hb
0.2% 0.1% Me 0.2% Me 1 3%
H H

   

     

O
0.5% 0‘2” 4.0%

   

26

isolated. It is likely that one of the two unidentified products in Johnson’s study was
dichloroketone 54. Exposure to the standard NaOCl/AcOH conditions derived above
produced the same compounds that were observed under Johnson’s conditions, plus a
chlorinated carbinol, 55 (Scheme 19). All structural data, high-field NMR and one-
dimensional nuclear Overhauser enhancement (lD-NOE), were in good agreement with
the original assigned structures (Figure 5).59‘65 Johnson used aromatic solvent-induced
shifts, observed previously in methylcyclohexanones, to distinguish the stereochemical
configurations of 10-13. Use of lD-NOE experiments also confirmed that 55 still
retained the same carbinol geometry as 9. Dichloro product 54 was ascertained by
comparison with the other [3.2.1]—ketones with the diagnostic downfield shift of the
methylenic protons adjacent to the carbonyl observed in 10 and 11.

3.4.2. Mechanistic Considerations

Both reactions are slightly regioselective with the bridgehead carbon ‘a’ bond
preferentially migrating vs. ‘b’ bond cleavage (Scheme 20). The diastereoselectivity
results from the reacting rotomeric isopropenyl conformer. Orientation of the methylene

in an em fashion is preferred by ~2:1 over the endo.

Scheme 20. Johnson Regio and Diastereoselectivity

V18 3 1 yia 'p'

 

._.‘

Cl
Cl
OH Me 0
1O 12
9X0 (41%)) (2510/0)

Me Me
.__—. Me
a Cl’ O
OH O
V CI
1 1

13
(23%) (1 1%)

— .

 

 

 

 

 

27

There also appears to be a secondary pathway to products 54 and 55. The initial
Cl+ capture occurs to generate cation 56, which undergoes loss of H+ and generates 55.
Wagner-Meerwein shift occurs after a second abstraction of electrophilic Cl+ to produce
dichloroketone 54.

Scheme 21. Secondary Cationic Mechanism

d Ci Ci Ci
Cl’ -H‘ 1) Wagner-Meerwein
——. + ——-> ——> + A, 54
OH Me OH OH CI. OH 2) -H.

9 56 55 57

 

3.5. Further Unsaturated [2.2.2] Substrate Synthesis

The conditions derived above mimicked Johnson’s relatively well. Examination
of the literature reveals little regarding cationic rearrangements of vinyl substituted
[2.2.2] carbinols. To more fully appreciate the selectivity, scope and mechanism of this
Chlorinative rearrangement, a series of carvone-derived “vinyl” [2.2.2]-bicyclocarbinols

were subjected to NaOCI and AcOH.

Scheme 22. “Vinyl” Substrate Synthesis23

Li

OMe OMe OMe
2L / 0
/ MgBr / /
OH —* OH
THF THF
0 °C. 30 min 0 -78 °C. 15 min
80°Ceh 0°C, 45min 0 \
58:59 27 ‘78 °C 5 “

 

 

(81 %; 4:1)
60:61
(75%; 10:1)
Li
MeO MeO MeO
A / °
/ MgBr / /
OH
OH THF THF
0 °C. 30 min 0 -78 °C. 15 min
80°C3h 0°C. 45min 0 \
62.63 28 ‘78 QC 5 h
(78 /o; 2.521) 64:65
(60%; 2.511)

28

The substrate synthesis was fairly straightforward. Iso-propenyl, dihydropyranyl
(DHP), and dihydrofuranyl (DHF) anions all added, rather cleanly, across Srikrishna’s
ketones 27 and 28 and the addition products were all isolated in reasonable yield (Scheme
22).66 It should be noted that the methoxy group blocks the em attack to some degree in
58 through 61, achieving modest diastereoselectivity. The methyl group shields the em
face only slightly to yield some diastereomeric favoritism, 62 through 65. The resultant
allylic alcohols (58 through 65) were then subjected to the standard bleach and acetic acid
Chlorinative ring expansion conditions (Table 3).

3.6. Chlorinative Ring Expansions of “Vinyl” [2.2.2] Carbinols
3.6.1. Results and Structural Assignment

All vinyl carbinols investigated, Table 3, rearranged smoothly and surprisingly in
a diastereoselective manner. The stereochemistry of the exo-carbinol vinyl, iso-propenyl,
DHP and DHF rearrangement products, 8, 66, 68, 72, 74, and 75, were assigned on the
basis of lD-NOE experiments (Figure 6). In the Chlorinative ring expansions the through
space effects of note are between the CH2CI or CHCl protons and their interaction with
hydrogens on the top face of the ring (Figure 6). The stereochemistry of the other
diastereomeric chloroketones was assigned by default, since by lH-NMR all these species
possessed the signature a-keto methylene protons thus establishing the regiochemistry of
their rearrangement.

The vinyl carbinol set (entries 1-2, Table 1) revealed that the rearrangement is
also diastereospecific. The exo-carbinol produced the exo-chloroketone, 66, selectively

while the endo-carbinol yields the endo-chloroketone, 67 (entries 1 and 2 respectively,

29

Table 3). The B-chloroketones, 66:67, were prone to eliminate HCl, as can be seen from

of enone 8. It is possible that in both cases the minor chloromethyl diastereomers

Figure 6. 1D-NOE Support of Chlorinative Diastereoselectivities

OMe

 

66 66 8

  

75 74

are produced but not observed due to this elimination. Crude lH-NMR analysis of both
exo- and endo-carbinols, 6 and 7, showed that these rearrangements were not completely
diastereoselective with observed 66:67 ratios of 16:1 and 1:14 respectively. Iso-propenyl
bearing substrates (entries 3-4, Table 3) were then studied since the rearrangement
products of these species cannot eliminate. Like the vinyl bearing carbinols, 6 and 7, the
iso-propenyl carbinols, 58:59 and 62:63, rearranged in a diastereospecific manner. Both

diastereomers were isolated, supporting the previous notion of facile HCl

30

Table 3. Chlorinative Ring Expansions of [2.2.2] Bicyclics23

 

 

 

     

         

 

   

Entry Substrate Products (yield'; ratio)b
OMe OMe
(0° fiat ’
o
\
5 8 (48%) 66 (32% )
OMe OMe
mag I
\
OH O
7
R R'
(3)° / OH
\
Cl
53 (new: Rz=0Mel 68:69 (86%: 20:1) 72 (10%)
62 (Rt=OMe: Rz=Mei 70:71 (78%; 15:1)
R R' OMe
/ -.
(M'fi OH
OH Cl
59 (HEW: F12=0M91 66:69 (82%; 1:12) 73 (16%)
63 (Rt=OMe: 82=Mei 70:71 (76%; 1:11)
OMe
/
(5) OH
0 \
60 74 (90%)
MeO MeO
(6) ’ OH
o \
64 75:76 (43%; 7:1)

 

Reagents and conditions: 1) NaOCl (1 .19 eq), AcOH (1 .95 eq). CCl. (0.6 M). H20 (0.6 M). 0 °C. 6 h.
‘ Isolated yields. b Ratios determined by ‘H-NMR. ‘ Crude ‘H-NMR shows a 16:1 mixture of 66:67.
d Crude ‘H-NMR shows a 1:14 mixture 0166:67. ° Analagous [4.2.1]-carbinols were not isolated for

62 and 63.

31

elimination masking the diastereoselectivity of the rearrangements of 6 and 7. The iso-
propenyl exo-carbinols, 58 and 62, were more selective than their enda counterparts, 59
and 63. The exo-carbinols generate Ot—exo-chloroketones, 68 and 70 preferentially, and
vice versa for the endo-set, 69 and 71 (entries 3 and 4, Table 3).

3.6.2. Mechanistic Considerations

The greater selectivity observed by exo-carbinols 58 and 62 is believed to be a
consequence of sterics. The iso-propenyl unit of 58 and 62, has a large degree of
rotomeric freedom, with its exo- and endo-olefinic rotomers being nearly equivalent in
energy (Figure 7). This freedom enables 58 to adopt the reactive cisoid conformer and
achieve enhanced selectivity. On the other hand, 59 and 63 have a number of
substituents to accommodate and thus the exo- and endo-olefinic species have
significantly different environments. A constriction of rotomeric freedom allows for the
reaction of the transoid conformer and the observed loss in selectivity. Accompanying
each Chloroketone was a [3.2.1]-bicyclocarbinol, 72 and 73, with the migrating carbon
stereochemistry remaining intact. Surprisingly no other vinyl substrate investigated
rearranged to produce this bicyclic Skeleton. DHP and DHF carbinols were also
investigated (entries 5-6, Table 3). They also follow this trend with both exo-carbinols
resulting in the chlorocarbon em to the ring.

Data on the rearrangements presented in Table 3 suggest that, in contrast to 10
(equation 1, Figure 8),59 the [2.2.2]-bicycles rearrange via conformers that place the
olefin and the hydroxyl syn to each other. Paquette has described a similar relationship
during proton mediated ring expansions of DHF substituted [2.2.1]-carbinols.“) pointing

to a

32

Figure 7. Rotomeric Constraints

0M6 OMe

 

33

Figure 8. Mechanistic Arguements

Johnson

C1 C1
(1) M per on.)7 A

Paquene

+
(2) M per LAP” 4
OH H

 

 

(3) -

(”We
(4) ‘\ :
/ (3\ ,_
L H“‘
g l by
/_) or some other

“~‘ (3 (31
‘Cl conjugate base“

68

 

 

preferred anti relationship between the ring oxygen and the hydroxyl (equation 2, Figure
8). However entries 1-4 (Table 3) suggest that, in our reactions, the heteroatom may not
be the primary stereocontrol element. Furthermore, the resultant stereochemistry of the
chlorine-bearing carbons in entries 5 and 6 (Table 3) indicates that the same conformer
undergoes both chlorination and ring expansion. For reasons stated earlier it seems
unlikely that the [2.2.2] systems are being converted to their hypochlorites prior to a
concerted rearrangement (equation 3, Figure 8). It is possible that the Wagner-Meerwein
shift is in concert with, or via a late transition state, chlorination by a hypochlorite species

(equation 4, Figure 8). The rotomeric preference is possibly the result of hydrogen

34

bonding between the carbinol and hypochlorite, allowing for a predisposition of the
reactive site to be on the exterior of the ring. In either event the facile nature of
electrophilic 0“ capture and Wagner-Meerwein shift would explain the observed
diastereoselectivities.

Lastly, the generation of secondary rearrangement products, albeit only in the iso-
propenyl case, via a subsequent alkyl [1,3]—shift points toward a cationic intermediate, 77

(Scheme 23). All these observations lead to the conclusion that this rearrangement,

Scheme 23. Isa-propenyl Carbinol Secondary Mechanism

OMe

 

OMe

 

72

like Johnson’s, is cationic in nature. Chlorination occurs via acetyl hypochlorite, or some
other conjugate hypochlorite,"7 and the carbinol’s cisaid rotomeric geometry (equation 4,
Figure 8). Wagner-Meerwein rearrangement ensues to produce the observed [3-
chloroketones. Furthermore, in terms of chemoselectivity, ether oxygens did not interfere
with the expansion and, to reiterate, no reaction with the bridging olefin was observed

during the rearrangement.

35

3.6.3. Rotomeric Carbinol Investigation
The observed diastereoselectivity of unsaturated [2.2.2] iso-propenyl carbinols
was hypothesized to be the result of a preferred, more reactive iso-propenyl rotomer. The

iso-propenyl unit of exo-carbinol 58 has more rotomeric freedom, than diastereomer
Scheme 24. Synthesis of Saturated 80 and 81"3
OMe OMe
1) H2. Pd/C. EtOAc.12 hrs

0 A
2) MgBr

27 THF, 0 °C. 30 min. 80 °C 3 hrs 30:31
(81%; 2.5:1.0)

 

59. As a result, 58 can easily access the more reactive rotomer allowing for better
diastereoselectivity. In order to explore this hypothesis, the internal olefin was saturated
to produce compounds 80 and 81. Hydrogenation of 27 followed by addition of iso-
propenyl Grignard produced the saturated iso-propenyl carbinols in good yield and

reasonable diastereoselectivity (Scheme 24). If the diastereoselectivity was a result of the

Table 4. Chlorinative Ring Expansions of Saturated [2.2.2] Isopropenyl Carbinols23

 

Entry Carbinol Products (yield\; ratio)

 

OMe

 

(1) OH
80 82 83
(82% 10:1)
OMe
(2) 32 83
(79%; 1:14)
OH
81

 

Reagents and conditions: 1) NaOCl (1 .19 eq). AcOH (1 .95 eq), COL. (0.6
M). H20 (0.6 M). 0 °C. 6 h. ‘ Isolated yield. ° Ratio determined by ‘H-NMR.

36

aforementioned rotomeric constraint, then a loss of selectivity would be observed in
carbinol 80, as a result of the new hydrogen substituents, while a similar ratio of
diastereomers would be observed for 81.

Upon treatment with the standard NaOCl/ACOH conditions, both exa- and enda-
carbinols rearranged smoothly to produce chloroketones 82:83 in a diastereoselective
manner (Table 4). Indeed, a loss of selectivity in the rearrangement of 80 was observed,
while similar diastereoselectivity to that of 59 was observed with 81. These data provide
support for a preferred rotomeric carbinol and that the rotomeric environment can dictate
the observed selectivity. This issue of rotomeric constriction could be explored further
by submitting other alkyl substituted vinyl moieties to our standard set of conditions.
3.6.4. Summary of Chlorinative [2.2.2] Bicyclic Expansions

These examples establish bleach and acetic acid as effective promoters of
Chlorinative one-carbon ring expansions of [2.2.1]- and [2.2.2]—bicyclic molecules.
Rearrangement of vinyl-, iso-propenyl-, DHF-, and DHP-substituted [2.2.2]-bicyclo-
carbinols were chemo-, regio-, and stereoselective, affording B-chloro-[3.2.2]-
bicycloketones in respectable yields. The selectivity of these rearrangements appears to
be derived from reaction of a preferred conformer in which the hydroxyl and the reacting
vinyl groups are in a syn orientation.

3.7. Chlorinative Ring Expansions of Monocyclic Vinyl Carbinols

To emphasize the generality of this rearrangement, a set of simple vinyl
cycloalkanols were selected and subjected to standard conditions. The substrates were
readily available via vinyl Grignard addition across commercially available

cyclopentanone, cyclohexanone and cycloheptanone with little product purification.

37

3.7.1. Results and Structural Assignment

Table 5. Chlorinative Expansions of Monocyclicsza

 

 

Entry Carbinol‘ Products (yieldb)
o o
HO
(1 ) Cl
34 89 90
(98% (69%) (10%)

Q0

l Cl CI
HO HO
Cl
(2)
85 91 92

(quant) (65%) (12%)

Cl
Cl
HO HO Cl
(3)
94

.fi

   

86 93
(97%) (62%) (18%)
O O
\ HO,’
3‘ \\C| '.
(4)6 ,.m\
"0,,
87:88 95:96 97 98
(86%; 101) (71%; 5:1) (10%) (<2%)

 

Reagents and conditions: 1) NaOCI (1 .19 eq). AcOH (1 .95 eq). CCI, (0.6 M), H20 (0.6 M).
0 °C. 6 hrs. ' CH,=CHMgBr.0 °C. 30 min. 80 °C. 1 hr. ” Isolated yields. ‘ Major isomer
shown.

Indeed, all carbinols underwent expansion to produce their respective B-
chloroketones in reasonable yield (Table 5). Unfortunately accompanying the ring
expansion in this series were chlorinated carbinols 92 and 94. Methyl vinyl cyclohexanol
87 rearranged smoothly to provide the B-chlorocyclohexanones, 95:96, in respectable
yield and diastereoselectivity (entry 4, Table 5). The stereochemistry of 95 and 96 were

determined by lD-NOE experiments (Figure 9).

38

   

Figure 9. 1D-NOE Support of Methyl B-Chlorocyclohexanones 95:96
1.2%
o 8.4%
H

     
 

  

1.1%
1.0°/
l
C 11., 0 Cl
H :
I ' H
H a
m,,\)\ W 1.1%
2.8% "’

95 96

3.7.2. Mechanistic Considerations

Importantly, the mneumonic, described previously (Figure 10), holds true in this
monocyclic case. The cisaid geometry, of the hydroxy and vinyl moiety, is again favored
(5:1) in this simple system. There was also a small amount of elimination that had
occurred prior to column chromatography to produce 97. A minute amount of
dichlorocarbinol 98 was also observed, however this compound was never cleanly

isolated so its structure remains tentative.

Figure 10. Predictive Diastereoselective Pneumonic

 

OMe
(1) ‘\ ;
/ O
Q. \”‘~‘
‘O’R

 

(2)

 

 

3.7 .3. Summary of Chlorinative Monocyclic Expansions
These examples show how commercially inexpensive and environmentally benign

NaOCI and AcOH can chlorinatively ring expand a variety of “vinyl” substituted

39

carbinols with excellent chemoselectivity, in reasonable regio and diastereoselectivity
and in good yield. The B-chloroketones isolated can be transformed into a variety of
species making this process synthetically attractive. One such process, which is quite
facile for the vinyl carbinols, is the elimination of HCl to produce exocyclic enones.
3.8. Exo—Olefin Insertion/One Carbon Ring Expansions

Enones are found in a number of biologically active compounds.68 Their
chemical prowess has long been exploited as these compounds can be manipulated at
either the CL, B, or y—positions. The construction of exocyclic enones can be accomplished
in a number of ways. Eliminations of oxalates,69 pyrrolidines,70 B-selenyl ketones,7l 0t-
methoxymethyl ketones,72 B-metallo ketones,73 as well as dehydrosulfenylation,74 and 0t-
methenylation,75 are all suitable methods. However these methods can suffer from a lack
of regioselectivity, low yields, or intricate synthetic procedures. To the best of our
knowledge a synthetic route to exacyclic enones via a one-carbon expansion protocol has
not been established.76 Thus we sought to optimize not only the observed Chlorinative
rearrangement, but also the facile elimination of the B-chloroketones, 66:67, to generate
an exocyclic enone, 8, (Scheme 25). In doing so we also aimed to address other
questions. Can this facile elimination be observed in other bicyclic and monocyclic

systems? Exocyclic enones 8 and 50 could not internalize their olefinic moiety per

Scheme 25. Exo-Olefin Insertion/One Carbon Ring Expansion

OMe OMe OMe
CI‘ Et3N
——> ——>
/ OH / Sl02 /
o o
\ H
Ci
5=7 66:67 8

4O

Bredt’s rule. Will this internalization occur in suitably substituted substrates? Both
questions needed to be addressed.
3.9. Saturated [2.2.1] and [2.2.2] Substrate Synthesis

The vinyl [2.2.1] bicyclics were readily available from their respective
commercially available ketones (Scheme 26). Quick purification via an alumina plug
provided the substrates in good yield. The selectivity of the 1,2-addition observed in the
[2.2.1] constructs complements the literature with the norcamphor and fenchone bicycles
yielding primarily endo-carbinols, 100 and 102 respectively. The internally saturated
[2.2.2] series mimicked what was previously observed (Scheme 6, Chapter 2) with the
methoxy substituent being able to shield the exo—face of the carbonyl. However, the
saturated bridging carbons block endo attack to some degree resulting in a loss of

selectivity (6:7; 4:1 vs. 105:106; 2.4:1).

Scheme 26. Saturated [2.2.1] and [2.2.2] Substrate Synthesis23

 

 

 

R, R) R
3 flMgBr
R :
3 THF, 0 °C. 30 min. 80 °C. 2.5 hrs
R2 0
99:100 (R,=R2=R3=H; 49%; 115.7)
101:102 ( R,=H, R2=R3=Mez 52%; 1:10)
103:143 (R1=R2=Me. R3=H; 83%; pure 98)
R, R2 R, R2
I 1) H2. Pd/C. EtOAc. 12 hrs : OH
O 2) finger \
THF. 0 °C. 30 min. 80 °C. 2.5 hrs
27 or 28 105:106 (R,=Me, R2=OMe; 85%; 24:1)

107:108 (R1=OMB, R2=Me; 700/0, 1.11)

41

3.10. [2.2.2] and [2.2.1] Exo-Olefin Insertion/One Carbon Ring Expansions
3.10.1. Results and Structural Assignment

All vinyl [2.2.1] and [2.2.2] carbinols examined rearranged smoothly to produce
[3.2.1]- and [3.2.2]-bicycloenones respectively (entries 1-11, Table 6), with the
regioisomeric enones being assigned by lD-NOE through space couplings (Figure 11).
The lack of regioselectivity observed in the [2.2.1] substrates was nominal, but not

59606l

surprising considering similar rearrangements (entries 1-3, Table 6). Investigation

into the homologous [2.2.2] systems (entries 4-5, Table 6) revealed complete

regioselectivity, as observed by its unsaturated predecessor (entries 6-1 1, Table 6).

Figure 11. 1D-NOE Support of 110, 112, and 113

27%:

fi1 .00/0 Hfl 1.40/0
{EEE}:\§r/H Me (3
LR)— PH

00%: 32%:

 

00%;

 

110 112 113

3.10.2. Mechanistic Considerations

The lack of regioselectivity observed in the [2.2.1] system has been attributed to
anchimeric assistance following carbocation formation, as well as bond angle distortion
present in both the substrate and intermediate.77 The anchimeric assistance available to
the cationic intermediate can be seen upon examination of the antibonding molecular
orbitals found in the two possible migrating carbon-carbon bonds (Cl-C2 and C1-C3;

Figure 12). This cationic intermediate can effectively interact with either

42

Table 6. Bicyclic Exo-Olelin Insertion One Carbon Expansion Results23

 

Entry Carbinol

<1) 5%
\

OH
100

(2) 6%
0H \
102

(3)
103

O

\

OM

(4) O
\

105:106
(1:1)

M90
(5) OH
\

107:108
(1:1)

H
e
H

Products (yield'; ratio”)

LEA/EA

109:110
(82%; 1.0:1.6)

9%. 9%:

111:112
(86%; 101.5)

EVER

113:114
(96%; 3.0210)

OMe
O
1 15
(90%)
M90
0
116
(88%)

 

Product (yielda)
OMe

(92%)

(88%)

MeO

50
(95%)

50
(8792,)

8
(95%)

50
(91%)

 

Reagents and conditions: 1) NaOCI (1.19 eq). AcOH (1 .95 eq). CCI4 (0.6 M). H20 (0.6 M). 0 °C. 6 h. 2) 1%

Et3N/hexanes. SiOZ. ‘ Isolated yields. b Ratios determined by ‘l-l-NMR.

antibonding orbital as depicted in I. Newman projections II and III, depict eclipsing
interactions along the C1-C3 bond axis while a gauche interaction is present along the
C l-C2 bond (Figure 12). This interaction can induce preferential migration of the C 1 -C3
bond to relieve this eclipsing strain. This influence is observed with both the norcamphor

and fenchone derived carbinols, 100 and 102 (entries 1 and 2, Table 6). In these cases the

43

Figure 12. Molecular Orbital and Newman Representations

3

 

OH
95
CI / .51
OH
\>
I \
H H .C'
H
\\
n
H H OHH I

electronics slightly favor migration of the bridgehead carbon (hydro dialkyl vs. dihydro
alkyl and methyl dialkyl vs. dimethyl alkyl). Yet the C1-C3 bond preferentially migrates.
The camphor substrate, 103, enhances the migratory aptitude of the bridgehead carbon
(methyl dialkyl vs. dihydro alkyl) which was observed preferentially (entries 3, Table 6).
These examples demonstrate that the simple mneumonic of nucleophilicity and migration
might not hold true for other ring systems and does not hold for the [2.2.1] bicyclic
system (entries 1-3, Table 6).

To see if the loss of regioselectivity observed in the [2.2.1] system was an artifact
of the missing internal olefin, the homologous [2.2.2] saturated system was explored
(entries 4 and 5, Table 6). This system, though a diastereomeric mixture, rearranged with
excellent regioselectivity. Selective migration of the bridgehead was observed in both
cases with the ethereal unit surviving the reaction and workup conditions. Lastly, the
original control substrates, 6:7 and 26:27, (entries 6-1 1, Table 6) were investigated under
the optimized standard conditions. Again, as expected, both the em and endo

diastereomeric carbinols produce the same exocyclic enone with absolute regioselectivity.

44

3.11. Influence of Bridgehead Methyl Group in [2.2.2] Expansion
3.11.1. Substrate Synthesis

In order to test the electronics of migration further, the bridgehead methyl group
needed to be transposed to the back-bridging olefin. Fashioning this in a simple system is
not trivial, while the converse is true for a more complicated structure. Following a
procedure of Paquette and Maleczka,78 tandem aldol/michael condensation generates 117
(Scheme 27).79 Subsequent Sakurai reaction, ozonolysis and another aldol generates the
[2.2.2] skeleton, 121.80 Protection of the hydroxyl ensues followed by hydrazone

formation and Shapiro reaction to install the olefin moiety with the backside

Scheme 27. Synthesis of Paquette's [2.2.2] Backside Methyl System23

 

 

 

 

 

 

 

 

 

 

O T1C|4
T MS
0 1) piperidine. K2003 : _ :N 1) EVK 0 9C to rt. 20 h W
: ‘H o 9C (4.5 hr)——>45 9C (8 hr) H 2) 15 % HCI. rt, 20 h -78 °C—i-30 °C
CH2012
117 118
(78%) (60%)
O
1) 03 -78 °C
2) PPh3.rt o AcOH, THF Hunig's. MOMCI
GHQCI2 l 80 °C. 16 h THF, 0 9’C to rt. 10 h
0
OH
119 120 121
(65%) (99%) (75%)
HQNNHTos BuLi HCl
/ ——
MeOH rt. T HNN EtZO 78 °C MeOH. 75 °C
0 cs
OMOM 16 h 3 5 h OMOM 7 h
122 123 124
(75%) (Quant) (67%)
[0) finger
/ _—' / .4' /
THF. 0 °C. 30 min OH
80 °C. 3 h
OH O /
‘25 ‘26 127:128
(72%) CrO3 pyr (36%; 34% SM) (76%; 3:1)
DessMartin (38°/ /;o 35% SM)
Swern (42%; 27% SM)

45

methyl substituent in place, 124.8| Deprotection, oxidation, and vinyl Grignard addition
produces carbinols 127:128 in a 3:1 mixture. The somewhat more manly ketal complex
130:131 was obtained by an intramolecular Diels—Alder reaction of masked

benzoquinones in moderate yield and diastereoselectivity (Scheme 28).82

Scheme 28. Ketal Carbinol Synthesis23

 

 

 

 

 

 

1) DAlB o 0
OH 2) p-cresol ”MgBr
W CH2Cl2. rt . 48 n ’ 0M9 THF, 0 °c. 30 min ’ 03MB
80 °c. 3 n
0 /
129 130:131
(73%) (56%; 10:1)

3.11.2. Results

The expansion of vinyl carbinols 127:128 results in a 5:1 mixture of
regioisomeric exocyclic enones, with no internalization of the olefin observed. It appears
that the bridgehead methyl substituent is the important factor for the complete

regioselective ring expansion of the [2.2.2] systems investigated thus far. The electronics

Table 7. [2.2.2] Backside Methyl Ring Expansion/Eliminations”3

 

 

Entry Substrate Products (yield'; ratio”)
+
O
/ 0
127:128 1 32 133
(3:1) (81%; 5:1)
0 \
M60
(2) / OMe
OH
/ \
/ 0“
O
130 134
(42%)

 

Reagents and conditions: 1) NaOCI (1 .19 eq), AcOH (1 .95 eq).
CCI. (0.6 M). H20 (0.6 M). 0 °C. 6 h. 2) 1% Eth/hexanes. 8102.
‘ Isolated yield. b Ratios determined by ‘H-NMR.

46

of the internal olefin do favor bridgehead migration, though somewhat less than the
previous [2.2.2] examples. The rearrangement of 130 was very difficult to discern. After
in-depth analysis of IH, l3C, DEPT, and mass spectroscopy, structure 134 was deemed
most consistent with the data. This structure is tentative due to our inability to obtain 1D-
NOE spectral data. It is believed that tetracycle 134 arises from Cl+ abstraction via the
internal olefin (Scheme 29).
3.11.3. Mechanistic Considerations

Rearrangement of vinyl carbinol 130 is the first example where the bridging
double bond prefers to capture Cl+. This olefin is more electron rich as a result of the
methyl substituent, however this reaction path was not observed in carbinols 127:128. It
is possible that the ketal portion of the molecule is having some effect here. Wagner-
Meerwein shift of 135 generates cation 136, which is captured by the hydroxyl
substituent to produce 137. Subsequent loss of a proton followed by loss of HCl

generates 134.

Scheme 29. Possible Mechanism for 129

C) + C) C) C)
0' Cl CI
/ OMe i G OMe _> OMe _. OOMe
OH \~/ OH OH + H
// // // //
130 135 136 137
\\ CI Cl
MeO -HCI MeO -H’ MeO
‘— ‘-—-—
/ I / l
/ (SJ O_/ O_/
O 0 3°
H

134 138 137

47

3.11.4. Summary of Bicyclic Exo-Olefin Insertion/One Carbon Expansions

These examples emphasize how this chemistry allows for an unselective Grignard
addition prior to the selective rearrangement. As observed earlier, this rearrangement is
generally chemoselective, with no observable products derived from the bridging olefinic
moiety, except possibly 134. For [2.2.2] systems a bridgehead substitution is necessary
for complete regioselectivity, while the internal olefin is inconsequential. Lastly, [2.2.1]
constructs tend to be only moderately selective, if selective at all.
3.12. Monocyclic Exo-Olefin Insertion Ring Expansions
3.12.1. Results and Discussion

Earlier in the monocyclic Chlorinative ring expansion of 84, enone 90 was
observed with no internalization of the olefinic moiety. To expand the scope of this
rearrangement/elimination and to address the possibility of internalization a variety of
homologous monocyclic carbinols were investigated. The ketone precursors for entries
1-7 (Table 8), are all commercially available. All carbinol substrates were obtained via
vinyl Grignard addition across a suitable carbonyl in respectable yields with no
purification necessary. The carbinols investigated rearranged to give their respective
enones with moderate yields. The ring expansions and elimination of five, six, and seven
membered carbinols (entries 1-3, Table 8) were facile, albeit they gave lower isolated
yields than expected. The lower isolated yields, when compared to their chlorinated
analogues (Table 5), may be a result of the enone’s volatility. This would explain why
the five to six expansion affords lower yields than both the six to seven, and seven to
eight transformations. The expected ring size trend is observed in the larger ring systems

(entries 4-6, Table 8). Of synthetic importance, there was no internalization of the

Table 8. Monocyclic Exo-Olefin Insertion One Carbon Expansion Results:23

48

 

Entry Carbinol Products (Condition A yield“; Condition 8 yield“)

 

   

O O
HO \
84 90
(Condition A: 56%) (Condition A: 12%)
(Condition 8: 67%) (Conditoion B: 0%)
0 CI Cl
HO \ HO
(2)
85 142
(Condition A: 62%) (Condition1 A: 10%) (Condition A: 16%)
(Condition B: 72%) (Condition 8: 0%) (Condition 8: 3%)
CI
Cl Cl
0
HO \ 0 HO
(3)
86 94
(Condition A: 60%) (Condition A: 14%) (Condition A: 19% )
(Condition B: 70%) (Condition 8: 0%) (Condition 8: 4%)
OH
\ O O
(4) ‘\ C i : f ‘OHCL/C
Cl
139 144 145 146
(Condition A: 42%) (Condition A: 0%) (Condition A: 18% )
(Condition B: 63%) (Condition 8: 0%) (Condition 8: 6%)
HO \
OH
O O
(5) Cl
Cl
140 147 149
(Condition A: 28%) (Condition A: 27%) (Condition A: 5%)
(Condition B: 53%) (Condition 8: 3%) (Condition 8: 3%)
O 0 CI
HO \ HO
CI
(6)
141 150 151 152
(Condition A: 26%) (Condition A: 31%) (Condition A: 8%)
(Condition 8: 45%) (Condition 8: 4%) (Condition 8: 4%)
Q 0 Cl
Cl
(7) .n‘“ . .
”I” w”
: 98
37 (Condition A: -.., (Condition A: ---) (Condition A: ---)
(Condition 8: 79%) (Condition 8: 0%) (Condition 8: ~2%)

 

Reagents and conditions: Conditions A: NaOCI (1 .19 6(1). AcOH (1 .95 eq). CCI. (0.6 M). H20 (0.6 M). 0 °C. 6
h. 2) 1% EtaN/hexanes. $102. Conditions A: NaOCI (1 .19 eq). AcOH (1 .95 eq). CCI‘ (0.6 M). H20 (0 3 M), 0
°C. 6 h. 2) 2-3% EtaN/hexanes. 8102. ‘ Isolated yields.

49

olefinic moiety during the reaction or upon purification. The regioselectivity of this
rearrangement still held when a methyl group was added to the five membered case
(entry 7, Table 8). Only the enone from migration of the more nucleophilic carbon was
isolated. This level of regioselectivity has been observed in [2.2.2] bicyclic systems
(Table 3, entries 4-11 Table 6), but not in simple five membered arrays (entries 1-3,
Table 6).
3.12.2. Dilution Experiments

As observed previously (Table 5), the monocyclic systems produced an intrusive
amount of chlorinated carbinol resultant from C12 addition across the substrate’s vinyl
portion. The chlorine addition is a bimolecular reaction, resulting first from its
production from bleach and second, its subsequent addition across the olefin. Dilution of
the aqueous phase could slow the production of Clz and thus circumvent the byproduct
chlorocarbinol’s formation. Treatment under standard conditions, augmented by a two-
fold dilution of the aqueous layer, resulted in a significant decrease in the production of
chlorocarbinols in all ring sizes (all entries, Conditions B, Table 8). These monocyclic
examples demonstrate that the tandem chlorinative ring expansion/elimination sequence
is a general reaction of vinyl-substituted cyclocarbinols.
3.13. Conclusions

In summary; a one-carbon expansion of ‘vinyl’ bicyclocarbinols has been
developed to yield B-chlorobicyclocarbinones in respectable yield. Utilizing a facile
elimination to produce exocyclic enones has furthered this process. Bond migration in
these ring expansions can be regioselective, but data suggest this is substrate dependent,

e.g. [2.2.1] vs. [2.2.2]. The [2.2.2] system investigated was not only regioselective but

50

also diastereoselective. This diastereoselectivity results from the population of a
preferred “vinyl” rotomeric species prior to the Wagner-Meerwein shift. In these cases a
cisaid rotomer, between “vinyl” and hydroxyl, is preferred. This geometry seems to be
optimal for rearrangement and can even be observed in simple ring systems. Clearly the
scope of the rearrangement and synthetic utility of the products, be they Chloroketone or
enone, coupled with the inexpensive reagents all contribute to this reaction’s synthetic

appeaL

51

Chapter 4. Additional NaOCI/AcOH Promoted Chlorinative Rearrangements
4.1. Introduction

Treatment of vinyl carbinols with NaOCI and AcOH promoted a one-carbon
expansion to produce exocyclic enones (Chapter 3). To see how non-vinyl substitution at
the carbinol carbon would affect its reactivity with the standard set of NaOCI/AcOH
conditions, a series of secondary (2°), methyl-substituted tertiary (3°), and alkynyl
substituted 3°-carbinols were constructed. These substrates would address a number of
questions: 1) Without a vinyl substituent, would hypohalite formation result followed by
free radical processes? 2) The chemoselectivity observed in substrate carbinols 6:7 and
29:30 was interesting in that reaction at the vinyl portion of the molecule superseded any
at the bridging olefin. Would reactivity of the bridging olefin be observed? 3) Would the
same chlorinative ring expansion, with or without elimination, be observed with alkynyl-
substituted substrates?
4.2. Substrate Preparation

The necessary substrates were easily prepared via the carvone pipeline.83
Srikrishna’s ketones 27:28 were again treated with the appropriate nucleophiles. The 2°-
carbinols, 153 through 158, were produced by hydride and deuteride reduction. Both
reductions occurred in moderate yield to afford equal amounts of diastereomeric
carbinols (Scheme 30). Treatment of 27 with ethynyl Grignard generated alkynyl
carbinols, 161:162, in good yield with slight diastereoselectivity. The methyl carbinols,
159:160, were more diastereoselective and similarly available via methyl Grignard
addition. These three nucleophilic additions demonstrate nicely how the selectivity of the

Grignard reaction with 27 can increase as size of the nucleophile increases.

52

Scheme 30. Preparation of H(D), Me, and Alkynyl Carbinols:23

 

  
  

M60 M60 OMe OMe
NaBH. NaBH,
/ ._____ / / /
OH
EtOH (95%) EtOH (95%)
H 0 °C. 30 min 0 O 0 °C. 30 min H
rt. 12 h rt. 12 h
155:156 28 27 153:154
79%; 1:1 7°/; :
( ) LiAiH, (5 ° 1 1)
EMQB! EIOH (9570)
MeMgBr 0 °C. 30 min
THF THF rt, 16 h
0°C. 10 min O°C.2h
80 °C.2.5h rt, 5h
OMe OMe
OMe
/ OH / OH
II ’ 0“ °
157:158
161:162 (49%; 1:1)
(68%; 2.8:1) 159:160
(73%; 35:1)

4.3. Rearrangement of Secondary Carbinols
4.3.1. Results and Structural Assignment

The 2°~carbinols, 153:154, 155:156 and 157:158, were treated with NaOCI and
AcOH. These experiments showed that, despite our earlier results, the bicyclic olefin
was not inert to the reaction conditions as the starting substrates were transformed into 7-
chloro-[3.2.l]-ketones in moderate yields and diastereoselectivities (Table 9). There was
no elimination of HCl after Et3N buffered chromatography, which supports a bridging
chlorocarbon. The stereochemistry at the chlorocarbon was determined by IH-NMR.
There is a slight downfield shift of this proton upon comparison of 163 (4.37 ppm) to 165
(4.74 ppm). This results from the difference in the orientation of the methoxy
substituent. If the stereochemistry at this position were reversed, there would be little if
any change in these 6-values given their similar environments. The stereochemistry (1 to
the ketone was also determined initially by lH-NMR. This methyl group in both 163

(0.96 ppm) and 165 (0.97 ppm) appear to be in similar environments. It has been

53

established that cyclohexanones with OL-methyl substituents show distinct 5—values for
axial and equatorial protons. This had been exemplified previously with the chlorinative
ring expansions of Johnson’s substrate, isopropenyl-[2.2.1]-cycloheptanol (Scheme 19,

Section 3.4).84 NMR data suggested that the carbonyl’s a—methyl group was

Figure 13. 1D-NOE Support of167:168

0.2%

1 .8°/o
1 . 1%
1 5%

   

1 .6%

167 168

oriented in an up or equatorial position. Chloroketones 167 and 168 were also subjected
to lD—NOE experiments to further support the stereochemical assignment of the
chlorocarbon (Figure 13).85 Clearly the chlorocarbon’s proton displays a through-space
interaction with the left half of the bicyclic molecule but lacks interaction with the
carbonyl’s (31-protons. Both observations support the stereochemical assignment.

At first it was unclear whether or not the reaction conditions were producing a
hypochlorite. First, the reaction was run in ambient light (entries 1-3, Table 9). The
reaction proceeded without a large body of byproducts to generate the [3.2.1]-ketones in
good yield and modest diastereoselectivity, after lengthening the reaction time to 6 h.
Similar yields, entry 1 vs. entries 4-6 (Table 9), were obtained when the first step of the
reaction, NaOCI/AcOH, was carried out in a dark room followed by subsequent
irradiation (entries 4-6, Table 9). However, only one diastereomer was isolated. Again,

as in the vinyl ring expansions, we questioned whether irradiation was necessary.

54

Table 9. Secondary Carbinol Rearrangements23

R2 R3 R2 R3

bleach/vinegar

 

 

OH
O
R. C' R.
Entry Carbinol Conditions Products Recovered Substrate
(yield‘;ratio°) (yield‘: ratio”)

(1) 153:154 A 163:164 (35%; 3:1) 153:154(39%;1:2.3)

R1=H; R2=Me, R3=OMe R‘=H; R2=Me; R3=OM9
(2) 155:156 B 165:166 (52%; 3:1) 155:156 (12%; 122.3)

R(=H; R2=OMe; Rat—Me R,=H; R2=OMe; R3=Me
(3) 157:158 8 167:168 (60%; 2:1) 157:158 (7%; 1:1)

R.=D; R2=Me; R3=OMe R,=D; R2=Me; R3=OMe
(4)c 153:154 C 163 (45%) 153:154 (36%; 1:3)
(5)c 155:156 C 165 (33%) 155:156 (42%; 1:2.4)
(6) 157:158 C 167 (37%) 157:158 (32%; 123.2)
(7) 157:153 0 167:168 (58%; 1.2:1) 157:158 (36%; 1:1)
(8) 157:158 E 167:168 (45%; 1.5:1) 157:158 (26%; 1:1)

 

Reagents and Conditions: A: NaOCI (1 .19 eq). AcOH (1 .95 eq). H20 (0.6 M), CCI. (0.6 M), 0 °C. 3 h.

B: NaOCI (1 .19 eq). AcOH (1.95 eq). H20 (0.6 M). CCI. (0.6 M), 0 °C. 6 h. C: 1) NaOCI (1 .19 eq), AcOH
(1.95 eq). H20 (0.6 M). CCI, (0.6 M). 0 °C. dark. 3 h. 2) PhH (0.03 M). hv. rt. 7 h. D: NaOCI (1 .19 eq).
AcOH (1 .95 eq). H20 (0.6 M). CCI, (0.6 M). 0 °C. dark, 6 h. E: BHT (1.10 eq). NaOCI (1 .19 eq). AcOH (1 .95
eq). H20 (0.6 M). CCI4 (0.6 M). 0 °C. 6 h.

‘ Isolated yields. b Ratios's determined by ‘H-NMR. ° Minor product not isolated.

Upon subjection of 157:158 to the reaction conditions in the absence of light, no loss of
isolated yield was observed (entry 7, Table 9).

The lower diastereoselectivity observed with conditions A, B, D and E is believed
to arise from the prolonged reaction time. From the ratio of recovered starting material it
appears that the exo-carbinol reacts in a more facile nature than its diastereomer though
both rearrange. Interestingly, this rearrangement is somewhat hindered by the addition of

BHT and a slight loss of stereoselectivity is observed when the reaction is carried out in

55

the dark. In both these cases there was also significant recovery of starting material
(entries 8 and 7 respectively, Table 9). Furthermore, the stereochemistry or to the ketone
goes from a 2:1 to a 1.221 mixture when the reaction is run dark (entry 3 vs. entry 7.
Table 9). Thus, the mechanistic nature of this rearrangement is not completely
understood.
4.3.2. Mechanistic Considerations

Even though there is not a full understanding of all the mechanistic paths, a
cationic pathway is proposed for the formation of the [3.2.1] chloroketones. A cationic
mechanism is apparent due to the ability of this rearrangement to proceed whether the
reaction is run in the dark or in the presence of a radical scavenger. As with the vinyl

substrates, electrophilic chlorine (Cl+) is likely captured by the double bond to generate

Scheme 31. Secondary Carbinol Cationic Mechanism

OMe OMe OMe OMe
( ‘ (1.2] (1.2] -H’
p / OH _. OH _._. OH —. + ——~ 163:164
. OH
C. H ( H Cl H CI H
169 170

C1+

153:154 171

species 169 (Scheme 31). This initiates a [1,2] shift of the front bridging carbon to
produce cation 170. A subsequent [1,2] shift of a hydrogen or deuterium atom generates
carbinol cation 171 and loss of a proton generates the observed y-chloro-[3.2.1]-
bicycloketones 163:164.
4.4. Rearrangement of Methyl Substituted Tertiary Carbinols

In order to further explore possible involvement of the bicyclic olefin the 2°-
carbinol was changed to a methyl substituted 3°-alcohol. This substrate lacks any

protons for the putative [1,2]-shift. However a [1,2]-methyl migration would be

56

available. Thus, capture of Cl+ followed by two sequential [1,2] shifts would produce

Chloroketone 175. This was not the case.

Scheme 32. Anticipated 3°-Carbinol Rearrangement

OMe OMe OMe OMe
( [1.2] [1.2] - H’
159:160 —* OH —> OH —> + —~>
( c1 Ci 0“ CI 0
172 173

Cl+
174 175

4.4.1. Results and Structural Assignment

The formation of 175 or any ketonic structure was not observed. Instead one of
two rearranged products, 176 and 177, were observed depending on which diastereomeric
carbinol was subjected to the standard conditions (Table 10). The structures of the
proposed rearrangement products were not easy to ascertain. Use of l3C-NMR coupled
with DEPT spectroscopy elucidated the two 3°-carbons present in the oxetane
substructure of 176. Similarly the 2°- and 3°-carbons of epoxide 177 were deduced. The
use of lD-NOE also supported the structure assignments. The stereochemistry of
chlorocarbon 176 was also ascertained by the observation of through space interactions

with the left half of the tricycle. There was also a strong methyl-methyl interaction

Figure 14. 1D-NOE Support 01176 and 177

3.5% 0
13% 0.2 /.

   

Cl
Me
0.5% M [Me 0.6%
O
, 0.3%
k: 0
1 .7%
176 176

57

indicative of the 1,3-diaxial orientation. Analysis of bicycle 177 also showed through
space interactions that support the proposed structure. Carbinol 159 yielded an ethereal
tricycle 176, which was accompanied by bicycle 177. Diastereomeric carbinol 160 also

produced 177, but did not generate the tricyclic ether 176.

Table 10. Methyl Substituted 3°-Carbinol Rearrangements”

 

 

Entry Substrate Products (yield‘; ratio”)
OMe C' OMe
Cl
1 M
( ) / OH 0 e \
O
O
159 176 177
(34%) (28%)
Cl
(2)1: / 0MB
‘0
OH O
160 1 76 177
(not observed) (57%)

 

Reagents and conditions: NaOCI (1.19 eq). AcOH (1.95 eq). CCI. (0.6 M). H20 (0.6 M). 0 °C. 6 h. ‘
Isolated yields. ° Ratios determined by ‘H-NMR. ‘ Recovery of 180 (6%).

4.4.2. Mechanistic Considerations

The ability of both carbinols to produce the same rearranged epoxide, 176,
coupled with the observation that only one of the alcohols produced tricycle 177 is
interesting. This implies the operation of two mechanisms, one of which is stereospecific
in relation to the hydroxyl carbon.

Tricycle 176 is envisioned to form via abstraction of Cl+ by the olefin (Scheme
33). Cation 178 undergoes an alkyl [1,2]-shift to produce 180 by way of a three
coordinate non-classical cation. The 3°-cation 180 is in close proximity to the lone pair
of electrons residing on the hydroxyl, and subsequent attack of the hydroxyl followed by

loss of H“ produces 176. This sequence cannot occur with enda-carbinol 160 since

58

Scheme 33. Methyl Substituted 3°-Carbinol Cationic Mechanisms

OMe OMe OMe OMe H CI
01‘
k Cl CI +1.
I R1 R1 R, + R( OMe -—_’ 176
U
R2 R2 Cod

R2
159 or 160 173 179 130 130

J

OMe OMe OMe
CI' CI Cl .H‘
k. , —’ —* ——e 177
+ \
OH pOH

160 181 182

  

I—O

 

R,=OH. R2=Me
or vice versa

 

 

 

the hydroxyl is on the bottom face of the bicycle and the oxygen’s lone pair is to far
removed from the cation. The putative mechanism shared by both carbinols is
interesting, in that this sequence involves loss of H20. This has not been observed upon
reaction of any other carbinol studied. Loss of H20 followed by hydroxide capture
would generate carbinol 160, which can undergo electrophilic capture of Cl+ to produce
181. Capture of the cation by the hydroxyl ensues, followed by loss of H+ to generate
177.
4.4.3. Summary of Methyl Carbinols

The ability of cations to undergo different rearrangement pathways is not new.86
So it is not surprising that diastereomeric carbinols could rearrange via different routes.
This makes the rearrangement of carbinol 159 unattractive since products from each
pathway are formed. This prohibits the use of the convenient protocol of subjecting a
diastereomeric mixture of carbinols, as in the case of the vinyl carbinols, to the conditions

since mixtures would result. Thus separation is necessary at the carbinol stage. The

59

ability of endo-carbinol 160 to generate the chloroepoxide diastereomericall y is appealing
even with the modest yield. To further explore the cationic rearrangement that
NaOCI/AcOH can evoke, alkynyl carbinols were next subjected to the standard
conditions.
4.5. Rearrangements of Ethynyl Substituted Tertiary Carbinols
4.5.1. Results and Structural Assignment

Alkynyl substituted carbinols were employed to see if a ring expansion related to
those observed previously with vinyl substituted alcohols, or another rearrangement
would operate. Upon exposure to the standard conditions, a 1:1 diastereomeric mixture
of 161:162 produced the familiar tricyclic ether 183 along with recovered enda- carbinol
162 (entry 1, Table 11). The geometry of 183 was established via NOE interactions with
the left or cyclopentyl portion of the tricycle, while the aliphatic methyl substituents also
showed a strong diaxia] through-space interaction. This was reminiscent of the methyl
carbinols, in that it appeared that only the exa-carbinol was rearranging to produce the
four-membered ethereal unit. Treatment of 161 gave solely 183 in moderate yield with a
small recovery of starting material. Exposure of 162 to NaOCl/AcOH only resulted in

the recovery of starting material (entries 2 and 3, Table 11).

Figure 15. 1D-NOE Support of 183

1 0%
0.5%

3.0%

0.2%
Ci %
Me

0.2%

//

 

183 183

60

Table 11. Ethynyl Substituted 3°-Carbino| Rearrangements23

 

 

Entry Substrate Products (yield‘)
OMe Cl OMe
1 / OH \\ OMe I //
I 1 O OH
161:162 ‘33 ‘52
(1.1) (39%) (36%)

183 162
(63%) (2%)

OMe
£011

161
OMe

, // 183 162
(not observed) (76%)
OH
162

Reagents and conditions: NaOCI (1 .19 eq). AcOH (1 .95 eq). CCl4
(0.6 M). H20 (0.6 M), 0 °C. 6 h.
‘ Isolated yields.

2
3

 

4.5.2. Mechanistic Considerations

The fact that 162 is inert to the conditions is not completely understood. In all
carbinol cases to this point, there was some rearrangement observed whether the alcohols
were exo or endo. Be that as it may, the ability of 161 to produce only one product is
synthetically appealing. Again, as in the methyl case, separation of the carbinols
becomes an issue. However, the “other” carbinol does not taint the product composition,
and the ether is easily separated from the unreactive alcohol.

The mechanism envisioned would be similar to that proposed for the methyl exo-
carbinol (Scheme 33). Carbinol 161 undergoes Cl+ abstraction followed by an alkyl

[1,2]—shift to generate cation 186. Attack of the hydroxyl followed by loss of a proton

61

generates the tricyclic 183. Again, the hydroxyl geometry present at carbocation 163 is
essential for heterocyclic ring closure.
Scheme 34. Ethynyl Substituted 3°-Carbino| Cationic Mechanism

OMe OMe
CI’ CI
\— / OH OH _T
L/
| | l |
161 134

OMe
+ O\H
| |

185 186

 

 

 

H C1 H CI
\ OMe \ OMe
H
183 186

4.6. Conclusions

The examples discussed above demonstrate that the internal olefin present in the
carbinol substrates is not chemically inert to the reaction conditions as observed in the
vinyl substrates. The aforementioned rearrangements appear to be primarily cationic in
nature. This double bond’s reactivity and subsequent alkyl [1,2]-shift is sensitive to the
nature of the hydroxyl’s substitution. When there is no substitution, i.e. only hydrogen or
deuterium, then migration of the ‘a’ bond is preferred due to abstraction of Cl+ from the
bottom face of the olefin (Scheme 35). Conversely, with the methyl or ethynyl
substitution migration of the ‘b’ bond is preferred. Now Cl+ abstraction occurs from the
top face of the substrate followed by an alkyl [1,2]-shift of the ‘b’ bond. The mode of Cl”
abstraction seems to be influenced by the sterics of the bottom face of the bicycle. It
appears that C1+ capture occurs via the least sterically hindered face followed by

rearrangment. In all the above rearrangements the preferred

62

Scheme 35. Differing Mechanistic Pathways

OMe OMe
via a , ——— —>
b 0.. 0..
CI' H (

——’ 1632164

 

 

CI‘ H
153:154 169 137
OMe OMe
CI‘ CI’
Ci
via b _. C , 176 R=Me
K’gm U 0” 133 R=CzH
R R
159 R=Me 1“ 179 R=Me
161 R=CzH 135 R=C2H

migratory bond is the antiperiplanar one. It was somewhat surprising that the alkynyl
substrates did not undergo the ring expansion observed previously in the vinyl series.

Ethynyl carbinols have been ring expanded in [2.2.1] systems via suggested bromonium

and iodium ion intermediates (Scheme 36).87 These examples however lacked the

Scheme 36. McNelis Expansion of [2.2.1] Alkynyl Carbinols

12. HTIB
/ Br —————>
/ CchN
OH / 0
Br
I
HTIB:[hydroxy(tosyloxy)iodo]benzene (60%)

internal unsaturation present in the substrates above and can be rationalized upon
examination of the cation intermediates. The 2°-cationic intermediate (via olefin) is more
stable than the disubstituted vinyl carbocation (via alkyne) and as a result the alkene
portion of the substrate is far more reactive than the alkyne.

These examples demonstrate the ability of the simple NaOCI/AcOH conditions to
evoke a number of cationic rearrangements as long as there is an olefinic moiety present
in the substrate and that such cationic intermediates can rearrange in a regio and

diastereoselective manner.

63

Chapter 5. Theoretical Investigation
5.1. Introduction

The ring expansions of vinyl-substituted carbinols have been shown to be chemo-
regio- and diastereoselective (Chapter 3). However there have been some discrepancies.
Most notable is the preferred anti orientation in Johnson’s [2.2.1] bicycle while the
carvone derived [2.2.2] bicycles prefer syn. As a result the ability to predict the stereo-
outcome of these chlorinative ring expansions is not absolute. Another discrepancy of
note is the ability for the [2.2.2] system to expand in a completely regioselective manner

while the [2.2.1] constructs respond unselectively. It is obvious that these differences

Figure 16. Regio and Diastereo Discrepancies

 

 

 

 

 

 

Diastereo
OMe
+
Cl JCI n
. _______ / CI+ .___.
OH OH
O
10 15 58
major
Regio
OMe OMe
¢————— / ——-———-—>
a \ a \
O OH OH
110 100 7
major both 'a' and 'b' observed only 'a’ observed

 

 

 

could be the result of the different systems, [2.2.1] vs. [2.2.2]. However it would be
advantageous to be able to predict the regioselectivity of these ring expansions along with
the diastereoselectivity as well.

Molecular force field calculations were made to estimate the relative strain

88

energies (SE) present in these systems. It was hoped that the difference in strain

energies (ASE) between the substrate and products, and also between the regio- and

diastereomeric products would be predictive. All calculations were conducted using a
Spartan program package (version 5.0, Wavefunction Inc.) on a SGI Indigo 11 machine.
The minimum energy conformers were located with the Osawa searching method and
were found within 3.0 kcal/mol of the global minimum.89
5.2. Theoretical Investigation of Chlorinative Ring Expansion

The theoretical study began with the analysis of a few select vinyl substituted
carbinols at the MMFF94 level (Table 12).88 The starting substrate’s SE was compared
to that of both regio and diastereomeric chloroketones. It would not be prudent to
compare the carbinol to that of the enone, as it is the product of elimination and not
expansion. In conjunction with the molecular mechanics study, a semi—empirical
calculation was performed at the AMI level on the MMFF94 conformers to get an idea of
these compounds heat of formation (AHf).

An interesting trend surfaces upon comparison of the starting substrates with the
regiochemistry of the product ketones. It was observed previously that norcamphor.
fenchone, and camphor derived vinyl carbinols were regiochemically unselective, when
subjected to our standard set of bleach/vinegar conditions (entries 1-3, Table 6, Section
3.10.1). Analysis of the ASE and AAHf energies reveal that there is not a significant
difference in ASE (>4.0 kcal/mole) between the two regiochemistries, which supports
what was observed experimentally (entries 1-3, Table 13). The AAHf energies for the
most part complement the ASE calculated. The ASE of entries 1 and 2, Table 13, favor
migration of the ‘b’ bond which is what observed. In the camphor case, entry 3 Table I3,

migration of the ‘a’ bond was preferred by 3:1 experimentally, but the ASE and AAHr

energies favor ‘b’ bond migration. It appears in this case that the electronics of the ring

65

Table 12. Select Bicyclic Strain Energies (SE) and Heats of Formation (AHi)

 

Substrate

Product (Migration 01 a)

Product( (Migration ol 0')

 

LR LRR LR

100

SE:+33.04
AH,=-27.99

LR LR R LR

102

SE=+62.94
AH,=- -.31 44

3% RR; R

103

SE=+62.48
AH,=-29.63

/

6 201 202
SE=+83.63 SE=+89.16 SE=+61.12 SE=+57.89 SE=+69.44 SE:+73 36
AH,=-54.26 AH,=-47.69 AH.=-73.18 AH,=-73.39 AH.=-73.11 AH,=-74.88

Cl $0 k0,,
OH
\O
9 10 11
SE:+36.59 SE=+29.83 SE=+29.42 SE:+132297 SE=+13385
AH,=-32.21 AH,=-60.08 AH,=-60.41 AH,:-65.50 AH,=-63.38
OMe OMe OMe OMe OMe OMe
Cl
0 CI
’ OH ’ _ -.
”I\ o 0
OH = Cl
58 59 68 69 203 204
SE=+98.46 SE=+92.72 SE=+74.43 SE=+71.63 SE=+82.90 SE=+86 35
AH'='50.87 AH1='52.00 AH'='6717 AH'='70.31 AH'='74.24 AHg='73.40

189
SE=+16.94
AH'=‘64.25

193
SE=+42.36
AH'=‘66 81

1'97

SE=+47.15
AH,=-64.19

  

190
SE=+17.80
AH'=’64.04

194
SE=+44.29
AH,=- -.65 99

SE=+499.93
AH,=-62.90

191
SE=+1680
AH,=-64.05

195
SE=+4169

199

SE=+43.99
AH'='68.68

CI
192

SE=+16.85
AH,=-63 38

C1
196
SE:+45 71
AH,=- -62 71

200 9'
SE=+45.14
AH(=‘66.70

OMe OMe OMe OMe OMe OMe
Cl
0 0 CI
/ /
OH
\ ""I\
OH O 0
CI CI
7 7

 

66

expansion are dictating migration and not the release of strain energy. The vinyl carbinol
ASE calculations, entries 4 and 5 Table 13, clearly favor migration of the ‘a’ bond by 2 8
kcal/mol, which was observed experimentally. Analyses of the isopropenyl substrates.

entries 6 through 8 Table 13, also show preference for migration of the ‘a’ bond. In the

Table 13. Chloroketone Carbinol ASE and MH: Values

 

Entry Substrate Product ASE AAH. Product ASE AAH, Product ASE AAH, Product ASE AAH,

 

(1) 100 189 -16.10 -36.26 190 45.24 -36.05 191 -16.24 -36.06 192 -16.19 -35.39
(2) 102 193 -20.58 -35.37 194 -18.65 -34.55 195 -21.25 -3474 196 -17.23 -31.27

(3) 103 197 -15.33 -34.56 198 -12.55 -33.27 199 -18.49 -39.05 200 -17.34 -37.07

(4) 6 66 -22.51 -18.92 67 -25.74 -19.13 201 -14.19 23.85 202 -10.27 -27.19
(5) 7 66 -28.04 -25.49 67 -31.27 -25.70 201 -19.72 -30.42 202 -15.80 -27.19
(6) 9 10 -6.76 -27.87 11 -7.17 -28.20 12 -3.62 -33.29 13 -2.74 -31.17
(7) 58 68 -24.03 -16.30 69 -26.83 -19.44 203 -15.56 -23.37 204 -12.11 -22.53
(8) 59 68 48.29 -15.17 69 -22.41 48.31 203 -18.48 -22.24 204 49.32 -21.40

 

A = Chloroketone Energy - Substrate Energy (kcal/mol)

case of Johnson’s substrate 9, the ASE is not as great as in the [2.2.2] bicycles. This
would predict a mixture of regioisomers with the ‘a’ bond migration predominating,
which was indeed observed experimentally. The AAHf energies in entries 4 though 8,
Table 13, do not complement the ASE energies calculated. This demonstrates that these
ring expansions seem to be influenced by the release of strain energy coupled with the
electronics of migration and not necessarily by the heats of formation. These examples
demonstrate that the ASE at the MMFF94 level can be used to predict whether a ring
expansion will give a mixture of regioisomers (< 4 kcal/mol) or be more selective (> 8
kcal/mol). However, such calculations are not exact in predicting which regiochemical

isomer will predominate, entry 3 (Table 13).

67

5.3. Theoretical Investigation of Chlorinative Transition State

When considering the regioselectivities of these bicyclic ring expansions, the
calculations can be predictive of whether the ring expansions will be regioselective or
not. That being said, the actual diastereoselectivities observed experimentally do not
agree with the calculations, upon comparison of the ASE or AAHf energies (entries 4
through 8, Table 13). This is understandable since the diastereoselectivity is likely
derived from a transition structure. Thus the difference in energies of the transition states
needed to be calculated. Though there is the question of the exact nature of the transition
state, it was assumed to involve a Chloronium ion. The single point energy (SPE)
calculation on this transition state mimicked the diastereoselectivities observed. In every
example the observed diastereoselectivity matches the minimum SPE calculation for the
Chloronium ion transition state. Of course this mneumonic relies on the assumption that a
Chloronium ion is being formed. With this assumption in mind, it does predict that

Johnson’s substrate should adopt a transoid conformation in this transitions state to orient

1., 4»
Mon

Figure 17. Singe Point Energies (SPE) of Chloronium Transition States

In”,

     

OH OH CL
9—TS-antl 9-TS-syn 58-TS-antl 58-TS-syn 59-TS-antl 59-TS-syn
SPE=+82.89 SPE=+84.57 SPE=+140.98 SPE=+132.70 SPE=+141.76 SPE=+138.45

 

OMe OMe
/ + +
Cl / Cl
OH OH
6-TS-anti Bits-syn 7-Ts-anti 7-TS-syn
SPE=+107.82 SPE=+103.27 SPE=+114.21 SPE=+112.35

68

the chloromethyl substituent in an up position, which was observed (~2: l ). The ASPE for
9-TS-anti and 9-TS-syn is only 1.68 kcal/mol. This small difference predicts a mixture
of diastereomers, which is observed by the small (~2:l) ratio. Analysis of the i—Pr and
vinyl transitions states, 58-TS-anti vs. 58-TS-syn and 59-TS-anti vs. 59-TS-syn; 6-TS-
anti vs. 6-TS-syn and 7-TS-anti vs. 7-TS-syn, reveal that now a cisoid geometry is
favored, which is also observed experimentally. The ASPE is much greater for the exo-
carbinols 58 and 7 which carries over to the observed diastereoselectivities, 58 (20:1) vs.
59 (1:12) and 6 (16:1) vs 7 (1:14). Even though this pneumonic is based on certain
assumptions it does mimic the observed diastereoselectivities by predicting the favored
diastereomer.
5.4. Conclusions

The above calculations support what was observed in Chapter 3, though this
theoretical investigation is just that, theoretical. It does however allow the chemist an
idea of whether the desired chlorinative ring expansion will be regioselective or not, and
also which diastereomer will be preferred. In the end of course, one needs to perform the

reaction to determine the actual regio- and diastereoselectivity.

69

Chapter 6. Future Synthetic Investigations
6.1. Nucleophilic Addition to Ring Expanded Enones

Nucleophiles can add into enones in a variety of ways. Additions can occur in
either a 1,2- or 1,4-manner. While electrophilic processes can occur the 01,8, or 7

positions.90 This enables enones to be transformed into a myriad of chemically

Scheme 37. Vinyl Grignard Addition of 8
OMe OMe

flMgBr

 

THF, 0 °C. 30 min, 80 °c 3 hrs;

6 205

substituted species. To probe the reactivity of our rearrangement products, enone 8 was
subjected to vinyl Grignard addition (Scheme 37). Interestingly the vinyl addition
occurred in a 1,4-manner as opposed to a 1,2-addition. Additional effort should be
expended to induce these exocyclic enones to undergo a 1,2-addition, since it appears that
1,4-additons are very facile.

6.2. Patchoulenes

Figure 18. Patchoulenes

RRRRR

a—patchoulone y-patchoulene norpatchoullone fl-patchoulene b-patchoulene

The ease of 1,4 addition may make these rearrangement useful in the synthesis of
natural bicyclics. One such class of compounds are the patchoulenes (Figure 18). For
over the past 130 years, the patchoulenes have been of interest, largely due to their

importance in the perfume industry. As such they have been the subject of total synthesis

70

I The patchoulenes are also prized as key synthetic intermediates to

and derivitization.9
other more complex natural products.92 The two earliest synthetic routes have begun
with homocamphor, which already has the desired [3.2.1] construct installed. Our ring

expansion would provide the [3.2.1] bicyclic core via the ring expansion of (+)-camphor.

Vinyl addition across (+)-camphor generates 103, which subsequently provides the

Scheme 38. Proposed Synthetic Routes to B- and 5-Patchoulenes

/\Mger NaOH, AcOH
THF 0 mo °c OH H20 ; cc:4 (1:1)
0 6 hrs 0 °c 0
/ O
103

113 114

I . .
"‘11:? 51' .V.' ?_“.".".'f’f‘-- 0H
113:114 \
Bng
2) \l/ HO

: M 206 207
l Bng \ :

 

 

 

: 5 RCM
i i
OH OH
' HO ‘ H0
210 211 208 209
: E 1) H2. Pd/C
RCM 2) acetic anhydride. A
i i
1) H2. Pd/C
OH 2) acetic anhydride. A
....................... ’
-Itl|l
212 B-patchoulene b-patchoulene

 

 

 

71'

[3.2.1]—bicyclic enones 113:114 after ring expansion/elimination (entry 3, Table 6,
Chapter 3). Subsequent transformations would allow for both B- and 5—patchoulenes to
be realized. It has been previously observed that the [3.2.2] enones undergo facile 1,4-
addition (Scheme 37). This type of reaction followed the addition of isopropenyl
Grignard would produce ketones 206:207 in a mixture of diastereomers. Ring closing
metathesis (RCM), followed by hydrogenation and elimination of H20 would produce the
desired patchoulenes after separation (Scheme 38). If a 1,2-addition could be optimized
than use of chiral Grignard reagent would allow for the installation of either stereogenic
center present in the fused cyclopentyl substructure. After carbinol separation,
compound 210 would be subjected to RCM, followed by hydrogenation and elimination
of H20, as in the first route, to produce either of the desired natural products.93
6.3. Pinocarvone

Another natural product to be targeted is pinocarvone (Scheme 39).94 Though
commercially available through Interbioscreen Ltd. of Russia, pinocarvone is quite

expensive ($250/50 mg; $390/100 mg; $490/150 mg). The synthesis of this deceivingly

Scheme 39. Proposed Synthetic Route to (+/-)-Pinocarvone

O MgBr hv. 150 °C
N {Y ....... - I / §92texe9M§9, I / .‘3‘.’E¥'?I‘f’:.5_d.'-
\ THF O—H'l, 4 hrs.
OH O

O

 

213 214 215
o 1 flMgBr E
) THF :
‘. ................... J
2) NaOCI, AcOH
H90 / CCI.. 0 °C
(+/-) pinocarvone

 

 

 

72

simple molecule could begin with allyl Grignard addition across 3-methyl-2-butenal .
followed by oxidation to produce ketone 214 in reasonable yield. Irradiation of the
ketone at high temperature should produced (+/-)-[2.l.1]-bicycle 215. Subsequent 1,2-
vinyl addition followed by use of the standard NaOCl/AcOH conditions, with basic
purification, should produce (+/-)—pinocarvone. It is hoped that the rearrangement will be
selective and occur via the bridgehead bond (‘a’-route). The strained nature of the
bicyclic substrate however, could produce poor regioselectivity.

6.4. Enone Diels-Alder Cycloadditions

Diels-Alder reactions have long been exploited for their ability to produce
carbocyclic structures from relative simple alkene starting materials.95 While a Wittig
reaction could transform the ring expanded exocyclic enone into a suitable s-cis-diene for
cycloaddition, s-cis enones themselves have been used as dienophiles or dienes as well.
This flexibility to react in a variety of ways allows our method for the construction of s-
cis—enones to be synthetic starting point for a variety of carbo- and heterocyclic ring
systems.

In conjunction with the Diels—Alder, the standard set of ring expansion/exa-olefin
insertion conditions were explored. In order to obtain the desired exocyclic enones in a
more rapid manner deviations in reaction time and workup were implemented. A shorter
reaction time resulted in slightly lower isolated yields, however streamlined the workup
and allowed for quick and clean isolation of the desired enone. In these examples,
Scheme 40, workup consisted of addition of a cold aqueous solution 3% K3C03 to the
reaction followed by stirring for 5 min. Standard separation and concentration allowed

for the enone to be quickly purified via a short silica plug while eluting with 1%

73

Eth/hexanes. The enone elutes first, compared to the Chloroketone precursor, and was
used directly in the Diels-Alder. These modifications allowed for the rapid

transformation of simple cyclic vinyl carbinols into more complex moieties.

Scheme 40. Diels-Alder Diene Participation of Enone 9023

l NaOCI. AcOH O
HO 1) H20:CCI.(2:1)
0°C, 1 h A
2) Et3N. sno2 PhH 80°C 8h

84 90 216 217
(40%) (not observed) (32%)

 

 

 

NaOCI. AcOH
1) H20: CC|4 (2:1)
84 0 °Cv 3 " ¢ so 217
2) EtaN. SiOz (55%) PhH 80 °c 8 h (88%)
hyroquinone

\
NaOCI. AcOH
H20: col, (2:1) MeO

84 0 °C. 3.75 h _ 90
2

218
(not observed)

d
v

: 217

EtaN. sro2 ' (58%) PhH, 80 °C. a n (85%)
hydroquinone

 

V

OMe

219
(not observed)

In preliminary investigations 2-methylenecyclohexanone, 90, was exposed to a
dienophile. The anticipated intramolecular hetero Diels-Alder (HAD) was not observed
for 90. Instead enone 90 diemerized, in the presence of either norbomylene or styrene,
via HAD to generate spiral 217 (Scheme 40). This type of thermal dimerization of
enones has been observed in the literature.96 Given the inherent resonance structures of

enones it was thought that an electron rich dienophile might aid in achieving the desired

Scheme 41. Diemerization of Enones

03‘5.—~c5¥3—»c633

217

74

cycloaddition. However, use of p-methoxystyrene was unsuccessful. Though these are
not promising results there is still much room for experimentation.
6.5. Increase in Substrate Scope

There is always room for broadening of the substrate scope. This study involved
simple monocyclic, as well as [2.2.1] and [2.2.2] bicyclic systems. There are a number of
other bicyclic systems, for example 224 and 225, which also could be investigated. More
in-depth study of the chemoselectivity could be achieved by the addition of olefins, 222
and 223. Also study of sp2 vs. sp3 migration could be achieved with substrates like 221,
226 and 227. Initial studies with 226 show that arene migration is preferred over sp3-

hybridized methylene. A few of these substrates are shown below (Figure 19).

Figure 19. Possible Substrates

OMe OMe
I OH I OH
£3; ’ OH ’ OH
R R R R
220 221

222 223

HO R “0
OH OH
R R
224 225 226 227

6.6. Final Thoughts

The research described herein has completed a broad investigation into the ability
for bleach and vinegar to be able to generate a number of cationic rearrangements, which
are often selective in some manner. A good understanding of the chemo-, regio-, and

diastereoselectivity of the chlorinative ring expansion/elimination were gained along side

75

observations of other interesting rearrangements. The ability to ring expand general vinyl
carbinols via simple conditions, coupled with the ability to transform the resultant
chloroketones into more complex materials adds to the synthetic prowess of this protocol.
Certainly this body of research has made a contribution to the area of cationic chemistry.
Developing an understanding of these rearrangements and their synthetic subtleties has

been most rewarding to myself.

76

Experimental Details
Materials and Methods:

All air or moisture sensitive reactions were carried out in oven- or flame-dried
glassware under a nitrogen atmosphere unless otherwise noted. All commercial reagents
were used without purification. All solvents were reagent grade. Diethyl ether (Et30)
and tetrahydrofuran (THF) were freshly distilled from sodium/benzophenone under
nitrogen. Benzene (PhH), dimethyl sulfoxide (DMSO) and diisopropylethylamine (i-
PrzEtN) were freshly distilled from calcium hydride under nitrogen. Except as otherwise
noted, all reactions were magnetically stirred and monitored by thin-layer
chromatography with 0.25-mm precoated silica gel plates or capillary GC with a fused
silica column. Flash chromatography was performed with silica gel 60 A (particle size
230-400 mesh ASTM) or basic alumina (particle size ~150 mesh). High performance
liquid chromatography (HPLC) was performed with Ranin component analytical/
semiprep system. Yields refer to chromatographically and spectroscopically pure
compounds unless otherwise stated. Melting points were determined on a
Thomas-Hoover Apparatus, uncorrected. Infrared spectra were recorded on a Nicolet
IR/42 spectrometer. Proton and carbon NMR spectra were recorded on a Varian
Gemini-300, VXR 500 or INOVA 600 spectrometer. Chemical shifts for 1H-NMR and
l3C-NMR are reported in parts per million (ppm) relative to CDC13 (6 = 7.24 ppm for IH-
NMR or 5 = 77.0 ppm for l3C-NMR). Optical rotations were measured with a
Perkin-Elmer Model 341 polarimeter. High resolution mass spectra (HRMS) data were
obtained at either the Michigan State University Mass Spectrometry Service Center or at

the Mass Spectrometry Laboratory of the University of South Carolina, Department of

77

Chemistry & Biochemistry. GC/MS were performed with a fused silica column (30 m by
0.25 mm id).

General Procedures:

General Procedure 1: Preparation of Bicyclic Vinyl and Isa-propenyl carbinols.

A vinyl or isopropenyl magnesium bromide/T HF (1.0 M and 0.5 M respectively,
3.00 eq) solution was chilled to 0 °C prior to the dropwise addition of 27, or 28, (1.00
eq), in THF (~20 M). After complete addition the reaction was stirred at 0 °C for 0.5 hrs
and then warmed to reflux (80 °C). Reflux was maintained for 3 hrs The reaction was
then cooled to 0 °C and quenched with an aqueous solution of NH4C1(53.). After
partitioning with 320 and separation, the ethereal layer was washed two times with an
aqueous solution of NH4Cl(sa,) and once with H20. The combined aqueous layers were
extracted two times with EtzO. The combined ethereal layers were dried over MgSO4,
filtered, and concentrated. The crude residue was purified via flash alumina
chromatography with hexanes/EtOAc as the eluent (30 g basic alumina per 1 g
compound; Activity III).

General Procedure 11: Preparation of Bicyclic DHF and DHP Carbinols.

A solution of (5.00 eq) dihydrofuran or dihydropyran in 15 mL THF (1.8 M) was
chilled to —78 °C prior to the dropwise addition of (5.05 eq) a t-BuLi/pentane (1.7 M)
solution. After 15 min the reaction temperature was raised to 0 °C for 45 min
Subsequent cooling to —78 °C was followed by the dropwise addition of 27, or 28, (1.00
eq) in THF (1.1 M). After 15 min the reaction temperature was raised to 0 °C and stirred
for 5 hrs The reaction was quenched with the addition of an aqueous solution of

NH4Cl(sa,j and partitioned with Eth. After separation, the ethereal layer was washed two

78

times with an aqueous solution of NmClmj. The combined aqueous layers were
extracted two times with Et20. The combined ethereal layers were washed once with
brine and then dried over MgSO4, filtered, and concentrated. The residue was purified
via flash alumina chromatography with hexanes/EtOAc as the eluent (30 g basic alumina
per 1 g cmpd; Activity 111).

General Procedure III: Preparation of Monocyclic Vinyl Carbinols.

A vinyl magnesium bromide/T HF (1.0 M, 3.00 eq) solution was chilled to 0 °C
prior to the dropwise addition of ketone (1.00 eq) in THF (~2.0 M). After complete
addition the reaction was stirred at 0 °C for 0.5 hrs and then warmed to reflux (80 °C).
Reflux was maintained until the reaction was judged complete by TLC (1-3 hrs). The
reaction was then cooled to 0 °C and quenched with an aqueous solution of NH4C1(,m,.
After partitioning with B20 and separation, the ethereal layer was washed two times with
an aqueous solution of NH4Cl(sm, and once with H20. The combined aqueous layers were
extracted two times with Et20. The combined ethereal layers were dried over Mg804,
filtered, and concentrated. If necessary the crude residue was purified via flash alumina
chromatography with hexanes/EtOAc as the eluent (30 g alumina per 1 g compound;
basic Activity HI).

General Procedure IV: Preparation of Bicyclic 2°-Carbinols.

A solution of 27, or 28, (1.00 eq) in 30 mL 95% EtOH (0.37 M) was cooled to 0
°C, afterwhich NaBH4 or LiAlD4 (4.00 eq), was added in one portion. The reaction was
kept at 0 °C for 30 min, then warmed to room temperature and stirred for 16 hrs The
reaction was then quenched with an aqueous solution of NH4Cl(sm, and further partitioned

with Et20. After separation the ethereal phase was washed two consecutive times with

79

an aqueous solution of NH4Cl(sm). The combined aqueous layers were extracted two
consecutive times with Et20. The combined ethereal layers were dried over MgSOi.
filtered, and concentrated to afford a ~1 :1 mixture carbinols.

General procedure V: Rearrangements Induced by NaOCI and AcOH.

A solution of bicyclocarbinol (1.00 eq) in CCl4 (0.6 M) was chilled to 0 °C. After
10 min at 0 °C, AcOH (1.95 eq) was added rapidly to the CCl4 solution. This solution
was stirred at 0 °C for an additional 5 min and then added rapidly to a 0 °C solution of
NaOCl (0.75 M 1.19 eq) in H20 (same volume as CCl4). The biphasic reaction was
vigorously stirred for 6 hrs at 0 °C. The reaction was then poured into a cold solution of
3% K2C03 in H20 and partitioned with the addition of room temperature CH2C12. After
separation the organic layer was washed three times with a cold solution of 3% K2C03 in
H20. The combined aqueous washes were extracted three times with ambient CH2C12.
The combined CH2C12 layers were then dried over MgSO4, filtered, and concentrated.
The residual was purified via flash silica chromatography with hexanes/EtOAc
(chlorinative ring expansion) or 1% Eth/hexanes (ring expansion/exo-olefin insertion) as
the eluent (10 g Si02 per 1 g cmpd).

General Procedure VI: Preparation of oxy-Cope Products.

A 35% wt/wt KH/oil suspension (1.37 eq) was washed three consecutive times
with 1 mL hexanes prior to the dropwise addition of a solution containing a 1:1 mixture
of 1:2, or 29:30, (1.00 eq) in 20 mL THF. After complete addition the reaction was
heated to reflux (80 °C) and maintained overnight. Subsequent cooling to 0 °C and

quenching with 25 mL NH4Cl resulted in a biphasic solution. After partitioning with

B20 and separation, the ethereal layer was washed two times with an aqueous solution of

80

NH4C1(Sa., and once with H20. The combined aqueous layers were extracted two times
with Et20. The combined ethereal layers were dried over Na2804, filtered, and
concentrated. The crude residue was purified via flash alumina chromatography as the
eluent (30 g basic alumina; Activity 11; 30%Et20/hexanes).

General Procedure VII: Preparation of Chlorosulfides (sulfenate attempts).

The following experiments were carried out in a darkened hood and an aluminum
wrapped round bottom flask. To a chilled (-78 °C) solution of 1, or 2, or 29 (1 .00 eq) in
5.0 mL CH2C12 (0.24 M) was added Et3N (2.00 eq). The reaction was stirred for 15 min,
afterwhich p-N02PhSCl (1.11 eq) in 0.40 mL CH2Cl2 (4.0 M), was added dropwise via
syringe. The reaction was stirred at -78 °C for 4 hrs and then partitioned with 10 mL
CH2C12 and 10 mL 3% aqueous HCl. After separation the CH2C12 layer was washed once
with 10 mL 3% aqueous HCl and two times with 10 mL H20. The CH2C12 layer was
then dried over Na2SO4, filtered, and concentrated. After concentration the yellow oil
was purified via prep-HPLC (Rainin si-80-l99-C5 column; 10:1 hexanes/EtOAc, 60
min).

General Procedure VIII: Preparation of Sulfones (sulfide oxidation).

0xone® (2.09 eq) in 2 mL H20 (0.21 M), was buffered to a pH = 4 by addition of
Na2HP04 and subsequently chilled to 0 °C. Addition of 33, or 35, (1.00 eq) in lmL
MeOH (0.20 M) followed, with an additional 1 mL MeOH added to facilitate stirring of
the resultant slurry. The reaction was warmed to room temperature and agitated for 12
hrs The reaction was partitioned with 15 mL CH2C12 and separated. The aqueous layer
was extracted three times with 15 mL CH2C12. The combined CH2Cl2 layers were

washed two times with 15 mL H20 and one time with 15 mL brine. The CH2C12 layer

81

was then dried over Na2SO4, filtered, and concentrated to afford a brown oil. The oil was
purified via prep-HPLC (Rainin si-80-199-C5 column; 100% hexanes, 45 min; 10%
Et0Ac/hexanes, 60 min; 16% EtOAc/hexanes, 60 min).

Specific Procedures and Spectral Data:

OMe

25 26
(5R*)-5-[(1R*)-1-bromomethyl-1-methoxyethyl]-2-methylcyclohexa-Z-enone (25)
and (5R*)-5-[(1S*)-1-bromomethyl-l-methoxyethyl]-2-methylcyclohexa-Z-enone
(26).

A solution of 20.00 g (133.1 mmol, 1.00 equivalent) (R)-(—)—carvone in 200 mL of
a 3:2 CH2Cl2/Me0H solvent system was charged with N2 and chilled to 0 °C. Over a
period of 4 hrs, 29.36 g (164.9 mmol, 1.24 eq) of N-bromosuccinimide was added portion
wise. Upon complete NBS addition the reaction was allowed to come to room
temperature and stir for 16 hrs The reaction was then partitioned with 100 mL CH2CI2
and 100 mL 2% NaOHaq. The phases were separated, and the organic CH2Cl2 phase was
subject to two more 100 mL 2% NaOHaq washes and one subsequent 75 mL brine wash.
The CH2C12 phase was dried with Na2SO4, filtered, and concentrated to afford an orange
viscous oil. The epimeric oil was purified via flash silica chromotography (300 g; 10:1
hexanes/EtOAc) to quantitative yield a 1:1 mixture of 25:26.
25: Rf = 0.24 (10:1 hexanes/EtOAc); 'H-NMR (300 MHz, c1303) 5 6.75 (m, 1 H), 3.43
(ABq, J = 11.1, 4.2 Hz, 2 H), 3.22 (s, 3 H), 2.34 (series of m, 4 H), 1.75 (p, J = 1.2 Hz. 3

H), 1.24 (S, 3 H); l3C-NMR (75 MHZ, CDCl3) 5 199.2 (C), 145.0 (CH), 135.0 (C), 75.8

82

(C), 49.5 (CH2), 40.8 (CH2), 38.9 (CH3), 36.5 (CH3), 26.0 (CH2), 17.9 (CH3), 15.5 (CH);
LRMS (E1) m/z 260.1 (M+), 262.2 (Ma), 228.1 (M+ -Me0H), 230.1 (M+2 -Me0H).

26: Rf = 0.24 (10:1 hexanes/EtOAc); 1H-NMR (300 MHz, CDC13) 5 6.70 (m, l H), 3.40
(ABq, J = 10.9, 4.9 Hz, 2 H), 3.19 (s, 3 H), 2.48 ( m, 2 H), 2.23 (m, 2 H), 1.72 (m, 3 H),
1.21 (s, 3 H); LRMS (E1) m/z 260.1 (M+), 262.1 (Mtz).

25:26: IR (CH2C12) 3250 (m), 3190 (s), 2950 (s), 1720 (s), 1670 (m). 1410 (s), 1395 (s),
1280 (s), 1150 (s), 930 (s), 780 (s), 590 (s) cm".

For original synthesis see: Srikrishna, A.; Sharma, V. R.; Danieldoss, J .; Hemamalini, P.

J. Chem. Soc. Perkin Trans. 1 1996, 1305-131 1.

; :Me MeOi g
/ l
O O
27 28

(15*, 45*, 8R*)-1,8-dimethyl-8-methoxybicyclo[2.2.2]oct-5-en-2-one (27) and (15*,
45*, 85*)-1,8-dimethyl-8-methoxybicyclo[2.2.2]oct-S-en-Z-one (28).

A solution containing 28.98 g (133.1 mmol) bromocarvone 25:26, in 300 mL
tBu0H and 350 mL THF was chilled to 0 °C, and 17.50 g (155.9 mmol, 1.17 eq.) of
lBu0K was added in portons. Upon complete addtion of the base, the reaction was
stirred at 0 °C for 10 min and then warmed to room temperature and stirred for 18 hrs
The reaction was then poured into 300 mL of acidic brine (150 mL 3% HClaq/ 150 mL
brine). The aqueous mixture was partitioned with 150 mL Et20 and separated. The
ethereal solution was washed two additional times with 300 mL acidic brine. The
ethereal layer was dried with Na2504, filtered and concentrated. The resultant brown oil

was purified via flash silica chromotography (180 g; 4:1 hexanes/EtOAc) to yield 9.67 g

83

(40%) of 27, 6.67 g (28%) of 28 and 4.79 g (20%) of 27:28, as a 1:5 mixture of

diastereomers, as a clear oils.
27: Rf:0.53 (4:1 hexanes/EtOAc); [at];0 = -383.8 (c 1.49, CHC13); lH-NMR (300 MHz,

CDC13) 5 6.41 (1, J = 7.5 Hz, 1 H), 5.81 (d, J = 8.1 Hz, 1 H), 3.15 (s, 3 H), 2.88 (m. 1 H).
2.50 (dd, J = 18.0, 3.3 Hz, 1 H), 1.84 (dt, J = 18.3.3.3 Hz, 1 H), 1.73 (dd, J = 13.5, 3.3
Hz, 1 H), 1.42 (dd, J = 13.8.3.3 Hz, 1 H), 1.23 (s, 3 H), 1.12 (s, 3 H); l3C-NMR (75
MHz, CDC13) 5 212.9 (C), 135.7 (CH), 134.4 (CH), 78.8 (C), 50.2 (C), 49.6 (CH3), 45.9
(CH2), 41.5 (CH), 34.6 (CH2), 24.8 (CH3), 17.1 (CH3); IR (neat) 3090 (w), 2970 (m),
2930 (m), 2828 (w), 1724 (s), 1454 (w), 1371 (w), 1082 (m), 754 (w) cm"; LRMS (131)
m/z 180.6 (M+).

28: Rf: 0.33 (4:1 hexanes/EtOAc); [a]? = -3779 (c 1.72, CHC13); 'H-NMR (300 MHz.
CDC13) 5 6.42 (1, J = 8.1 Hz, 1 H), 5.88 (d, J = 8.1 Hz, 1 H), 3.13 (s, 3 H), 2.97 (m, 1 H).
2.05 (m, 2 H), 1.61 (ABq, J = 15.0 Hz, 2 H), 1.32 (s, 3 H), 1.14 (s, 3 H); I3C-NMR (75
MHz, CDC13) 5 212.8 (C), 135.7 (CH), 134.4 (CH), 78.8 (C), 50.2 (C), 49.6 (CH3), 45.9
(CH2), 41.5 (CH), 34.6 (CH2), 24.8 (CH3), 17.2 (CH3); IR (neat) 3090 (w), 2970 (m),
2933 (m), 2826 (w), 1724 (s), 1452 (w), 1375 (w), 1132 (m), 1080 (m), 1012 (w), 920
(w), 848 (w), 748 (m) cm“; LRMS (131) m/z 180.0 (M‘).

For original synthesis see: Srikrishna, A., Sharma, V. R., Danieldoss, 1., Hemamalini, P.

J. Chem. Soc. Perkin Trans. I 1996, 1305-131 1.

OMe OMe

a,
q

84

(15*, 25*, 45*, 8R*)-1,8-dimethyl-2-ethenyl-8-methoxybicyclo[2.2.2]oct-S-en-2-ol (6)
and (15*, 2R*, 45*, 8R*)-1,8-dimethyI-2-ethenyl-8-methoxybicyclo[2.2.2]oct-5-en-2-
ol (7).

Following general procedure I, the reaction of 1.2 g (6.7 mmol) of starting ketone
27, afforded 0.98 g (70%) of 6:7 as a 4:1 diastereomeric mixture after purification via
flash alumina chromatography (60 g; 100:1 hexanes/EtOAc).

6: Rf: 0.42 (5:1 hexanes/EtOAc); [at];0 = -40.0 (c 1.19, CHC13); lH-NMR (300 MHz,

CDC13) 5 6.17 (1, J = 6.9 Hz, 1 H), 5.86 (d, J = 8.1 Hz, 1 H), 5.53 (dd, J = 16.8, 10.5 Hz.
1 H), 5.17 (dd, J = 17.1, 2.1 Hz, 1 H), 4.92 (dd, J = 10.8, 2.1 Hz, 1 H), 3.17 (s, 3 H), 2.85
(s, 1 H), 2.61 (m, 1 H), 1.92 (d, J = 14.1 Hz, 1 H), 1.82 (dd, J = 13.8.3.0 Hz. 1 H), 1.47
(dd, J = 14.1, 2.4 Hz, 1 H), 1.09 (s, 3 H), 0.98 (d, J = 13.5 Hz, 1 H) 0.94 (s, 3 H); ”C-
NMR (75 MHz, CDC13) 5 144.2 (CH), 139.7 (CH), 133.5 (CH), 110.8 (CH2), 78.4 (C),
75.5 (C), 49.6 (CH3), 45.7 (CH2), 43.2 (C), 40.7 (CH2), 40.1 (CH), 24.5 (CH3), 18.8
(CH3); IR (neat) 3439 (br s), 3092 (w), 3042 (w), 2934 (s), 2831 (m), 1650 (w), 1454 (m),
1367 (m), 1116 (s), 1062 (s), 1003 (m), 918 (m), 844 (w), 740 (w-m) cm"; HRMS (E1)
m/z 208.1465 [(Mt), calcd. for C13H2002: 208.1463].

7: 121:0.33 (5:1 hexanes/EtOAc); [a]? = -97.3 (c 1.25, CHC13); 'H-NMR (300 MHz,

CDC13) 5 6.37 (t, J = 7.8 Hz, 1 H), 6.07 (dd, J = 17.7, 11.1 Hz, 1 H), 5.89 (d, J = 7.8 Hz,
1H), 5.31 (dd, J = 17.7, 2.1Hz, l H), 5.11 (dd, J = 10.5, 1.5 Hz, 1H), 3.14 (s, 3 H), 2.57
(m, l H), 2.34 (dd, J = 13.8, 2.1 Hz, 1 H), 1.60 (d, J = 13.8 Hz, 1 H), 1.51 (s, l H), 1.19
(dd, J = 13.5, 3.3 Hz, 1 H), 1.09 (s, 3 H), 1.01 (d, J = 14.4 Hz, 1 H), 1.00 (s, 3 H); l3C-

NMR (75 MHz, CDC13) 5 140.7 (CH), 137.9 (CH), 134.5 (CH), 113.2 (CH2), 79.6 (C),

85

78.9 (C), 49.3 (CH3). 44.3(CH2), 43.4 (C), 40.3 (CH), 39.4 (CH2), 24.7 (CH3), 18.1

(CH3); HRMS (E1) m/z 208.1461 [(M+), calcd. for C13H2002: 208.1463].

MeO M60
/ OH /
\
/ OH
29 30

(15*, 25*, 45*, 85*)-1,8-dimethyl-2-ethenyl-8-methoxybicyclo[2.2.2]oct-5-en-2-ol
(29) and (15*, 2R*, 45*, 8S*)-l,8-dimethyl-2-ethenyl-8-methoxybicyclo[2.2.2]oct-5-
en-2-ol (30).

Following general procedure I, the reaction of 0.8 g (4.6 mmol) of starting ketone
28, afforded 0.61 g (63%) of 29:30 as a 1:1 diastereomeric mixture after purification via

flash alumina chromatography (60 g; 100:1 hexanes/EtOAc).

29: Rf = 0.25 (5:1 hexanes/EtOAc); [013)O = -69.3 (c 1.45, CHC13); 1H-NMR (300 MHz,
CDCl;) 5 6.25 (ABq, J = 8.1, 1.8 Hz, 1 H), 5.93 (d, J = 8.4 Hz, 1 H), 5.77 (dd, J = 17.3,
10.8 Hz, 1H), 5.12 (dd, J=17.1,1.2 Hz, 1H), 4.97 (dd, J: 10.8, 1.2 Hz, 1 H), 3.13 (s, 3
H), 2.66 (m, 1 H), 2.00 (d, J = 13.5 Hz, 1 H), 1.69 (dd, J = 14.4, 2.4 Hz, 1 H), 1.60 (dd, J
= 14.4, 3.3 Hz, 1 H), 1.58 (s, 1 H), 1.43 (s, 3 H), 1.17 (d, J = 13.5 Hz, 1 H), 0.95 (s, 3 H);
l3C-NMR (75 MHz, CDC13) 5 146.2 (CH), 136.5 (CH), 133.4 (CH), 110.3 (CH2), 79.1
(C), 77.7 (C), 48.9 (CH3), 44.1 (CH2), 43.0 (C), 40.2 (CH), 39.6 (CH2), 21.9 (CH3), 18.5
(CH2); IR (neat) 3470 (m br), 3070 (w) 3020 (w), 2963 (s), 2936 (s), 2874 (s), 1726 (s),
1462 (s), 1371 (s), 1286 (s), 1147 (s), 1078 (s), 1001 (s), 918 (s), 733 (s) cm"; HRMS
(EI) m/z 208.1461 [(M+), calcd. for C(3H2002: 208.1463].

30: Rf: 0.11 (5:1 hexanes/EtOAc); [or];O = -125.4 (c 1.24, CHC13); lH-NMR (300 MHz,

CDC13) 5 6.41 (ABq, J = 6.6, 1.5 Hz, 1 H), 5.98 (d, J = 8.4 Hz, 1 H), 5.87 (dd, J = 17.1,

86

10.8 Hz, 1 H), 5.32 (dd, J = 17.4, 1.8 Hz, 1 H), 5.14 (dd, J = 10.5, 1.5 Hz, 1 H), 3.09 (s, 3
H), 2.67 (m, 1 H), 1.94 (dd, J = 15.3, 1.8 Hz, 1 H), 1.67 (s, 1 H), 1.43 (d, J = 13.8 Hz, 1
H), 1.42 (d, J = 15.3 Hz, 1 H), 1.29 (s, 3 H), 1.28 (d, J: 13.2 Hz, 1 H), 1.03 (s, 3 H); ”C—
NMR (75 MHz, CDC13) 5 139.7 (CH), 136.3 (CH), 134.3 (CH), 114.2 (CH2). 79.1 (C).
77.1 (C), 49.1 (CH3), 44.9 (CH2), 43.4 (C), 40.7 (CH2), 39.9 (CH), 22.0 (CH3), 18.4
(CH3); IR (neat) 3470 (m br), 3070 (w) 3020 (w), 2963 (s), 2936 (s), 2874 (s), 1726 (s),
1462 (s), 1371 (s), 1286 (s), 1147 (s), 1078 (s), 1001 (s), 918 (s), 733 (s) cm"; HRMS

(EI) m/z 208.1463 [(M+), calcd. for C13H2002: 208.1463].

’11,, 0M8
m0

:1
(8R*, 9R*, 105*)-6,8-dimethyl-8-methoxybicyclo[4.4.0]dec-5-en-2-one (31).

Following general procedure VI, the reaction of 0.49 g (2.4 mmol) of starting
carbinols 1:2, as a 4:1 mixture, afforded 0.23 g (47%) of 31 after purification via flash
alumina chromatography (30 g; neutral, Activity 11, 30% Et20/hexanes).

31: Rf = 0.33 (4:1 hexanes/EtOAc); 1H-NMR (300 MHz, CDC13) 5 5.27 (s, 1 H),
2.72 (br s, 1 1H), 2.40-1.86 (series of m, 12 H), 1.63 (s, 3 H), 1.09 (s, 3 H); l3C-NMR (75
MHz, CDC13) 5 211.9 (C), 132.9 (C), 122.8 (CH), 75.6 (C), 42.6 (CH2), 48.7 (CH), 40.5
(CH3), 37.9 (CH2), 37.5 (CH3), 30.6 (CH), 30.4 (CH3), 23.1 (CH2), 21.3 (CH2); IR (neat)

3015 (w), 1713 (s), 1580 (w), 1068 (s), 841 (m) cm"; HRMS (EI) m/z 208.1471 [(M+),

M 801,,
m0

32

calcd. for C13H2002: 208.1463].

87

(85*, 9R*, 105 *)-6,8-dimethyl-8-methoxybicyclo[4.4.0]dec-5-en-2-one (32).
Following general procedure VI, the reaction of 0.47 g (2.3 mmol) of starting
carbinols 29:30, as a 1:1 mixture, afforded 0.24 g (50%) of 32 after purification via flash
alumina chromatography (30 g; neutral, Activity 1, 30% Et20/hexanes).
32: Rf = 0.26 (4:1 hexanes/EtOAc); lH-NMR (300 MHz, CDC13) 5 5.09 (s, 1 H), 3.13 (s,
3 H), 2.44 (m, 2 H), 2.40-1.60 (series of m, 8 H), 1.67 (s, 3 H), 1.17 (s, 3 H); l3C-NMR
(75 MHz, CDC13) 5 212.8 (C), 134.2 (C), 122.1 (CH), 75.4 (C), 48.1 (CH), 42.4 (CH2),
39.2 (CH3), 38.8 (CH2), 37.4 (CH3), 33.3 (CH3), 30.9 (CH), 23.3 (CH2), 22.0 (CH2); IR
(neat) 3010 (w), 1714 (s), 1680 (m), 1060(8), 910 (m); HRMS (E1) m/z 208.1455 [(M+),

C31Cd. f01' C13H20022 208.1463]

OMe

OH

C1
3 N02

33
(15*, 25*, 45*, 8R*)-2-[1-ch1oro-2-(4-nitro-phenylsulfanyl)-ethyl]-8-methoxy-1,8-
dimethyl-bicyclo[2.2.2]oct-5-en-2-ol (33).

Following general procedure VII, the reaction of 0.30 g (1.4 mmol) of starting
carbinol l, afforded 0.22 g (48%) of 33 as one isomer after purification via prep-HPLC
(Rainin si—80-199-C5 column; 10:1 hexanes/EtOAc, 60 min).

33: ‘H-NMR (300 MHz, CDCl;) 5 8.14 (d, J = 9.3 Hz, 2 H), 7.49 (d, J = 9.0 Hz, 2 H).
6.09 (t, J = 7.5 Hz, 1 H), 6.02 (d, J = 7.8 Hz, 1 H), 4.24 (dd, J = 14.8, 7.5 Hz, 1 H), 4.03
(br s, 1 H), 3.70 (dd, J = 14.8, 7.2 Hz, 1 H), 3.68 (s, 1 H), 3.23 (s, 3 H), 2.74 (m, l H),
1.99 (d, J =13.8 Hz, 1 H), 1.81 (dd, J: 14.1, 3.6 Hz, 1 H), 1.52 (dd, J: 13.8, 3.1 Hz,1

H), 1.14 (s, 3 H), 1.06 (s, 3 H), 0.97 (d, J = 13.5 Hz, 1 H); l3C-NMR (75 MHz. CDCl;) 5

88

146.1 (C), 145.5 (C), 141.5 (CH), 130.4 (CH), 127.9 (CH), 123.9 (CH), 78.4 (C), 77.3
(C), 55.3 (CH), 49.8 (CH3). 47.9 (CH2), 47.1 (CH2), 44.2 (C), 39.9 (CH), 37.5 (CH2),
24.5 (CH3), 17.7 (CH3); IR (NaCl, neat) 3431 (br s), 3047 (w), 2963 (s), 1577, (w), 670

(s); HRMS (FAB) m/z 397.1955 [(M+), calcd. for C19H24C1N04S: 397.1 1 15].

OMe

9
(0:0

(15*, 25*, 45*, 8R*)-2-[1-chloro-2-(4-nitro-benzenesulfonyl)-ethyl]-8-methoxy-1,8-

:0

dimethyl-bicycIo[2.2.2]oct-5-en-2-ol (34).

Following general procedure VIII, the reaction of 40.0 mg (0.10 mmol) of starting
sulfide 33, afforded 11.8 mg (27%) of 34 after purification via prep-HPLC (Rainin si-80-
199-C5 column; 100% hexanes, 45 min; 10% Et0Ac/hexanes, 60 min; 16%
Et0Ac/hexanes, 60 min).

34: 1H-NMR (300 MHz, CDC13) 5 8.39 (d, J = 9.0 Hz, 2 H), 8.08 (d, J = 9.3 Hz, 2 H),
6.29 (t, J = 7.8 Hz, 1 H), 6.18 (d, J = 8.4 Hz, 1 H), 4.22 (dd, J = 13.2, 1.5 Hz, 1 H), 4.05
(s, 1 H), 3.66 (dd, J = 12.9, 5.7 Hz, 1 H), 3.52 (dd, J = 4.5, 1.5 Hz, 1 H), 3.22 (s, 3 H),
2.75 (m, l H), 2.37 (dd, J = 14.4, 1.8 Hz, 1 H), 2.07 (d, J = 14.4 Hz, 1 H), 1.81 (dd, J =
13.8, 3.3 Hz, 1 H), 1.40 (s, 3 H), 1.16 (s, 3 H), 1.08 (d, J = 14.1 Hz, 1 H); LRMS (El) m/z

429.1 (M+).

OMe

/ S
OH O
NO

35

2

89

(15*, 2R*, 45*, 8R*)-2-[1-chloro-2-(4-nitro-phenylsulfanyl)-ethyl]-8-methoxy-1,8-
dimethyl-bicyclo[2.2.2]oct-S-en-2-ol (35).

Following general procedure VII, the reaction of 0.30 g (1.4 mmol) of starting
carbinol 2, afforded 0.11 g (32%) of 35 as one isomer after purification via prep-HPLC
(Rainin si-80-199-C5 column; 10:1 hexanes/Et0Ac, 60 min).

35: 1H-NMR (300 MHz, CDC13) 5 8.09 (d, J = 9.0 Hz, 2 H), 7.54 (d, J = 9.0 Hz, 2 H),
6.37 (t, J = 6.6 Hz, 1 H), 5.81 (d, J = 7.5 Hz, 1 H), 4.32 (dd, J = 11.7 Hz, 3.0 Hz, 1 H),
3.93 (dd, J = 8.4, 3.0 Hz, 1 H), 3.75 (dd, J = 11.7, 8.7 Hz, 1 H), 3.23 (s, l H), 3.03 (s, 3
H), 2.55 (m, 1 H), 2.00 (d, J = 14.4 Hz, 1 H), 1.36 (dd, J = 13.8, 3.9 Hz, 1 H), 1.25 (s, 3
H), 1.22 (d, J = 14.7 Hz, 1 H), 1.13 (d, J = 14.7 Hz, 1 H), 1.09 (s, 3 H); l3C-NMR (75
MHz, CDC13) 5 147.6 (C), 145.4 (C), 139.3 (CH), 135.2 (CH), 128.0 (CH), 123.9 (CH),
79.5 (C), 78.8 (C), 59.8 (CH), 49.4 (CH3), 47.9 (CH2), 44.9 (C), 44.4 (CH2), 40.8 (CH),
39.9 (CH), 24.6 (CH3), 20.5 (CH3); 11R (NaCl, neat) 3440 (br s), 3035 (w), 2980 (s), 1575,

(w), 665 (s); HRMS (FAB) m/z 397.2003 [(M+), calcd. for C19H24C1N04S: 397.1 1 15].

OMe

OH O
NO

36

\
0:0):0

2

(15*, 2R*, 45*, 8R*)-2-[1-chloro-2-(4-nitro-benzenesulfonyl)-ethyl]-8-methoxy-1,8-
dimethyl-bicyclo[2.2.2]oct-5-en-2-ol (36).

Following general procedure VIII, the reaction of 80.5 mg (0.20 mmol) of starting
sulfide 35, afforded 19.5 mg (23%) of 36 after purification via prep-HPLC (Rainin si-80-
199-C5 column; 100% hexanes, 45 min; 10% Et0Ac/hexanes, 60 min; 16%

Et0Ac/hexanes, 60 min).

90

36: 1H-NMR (300 MHZ, CDC13) 5 8.40 (d, J = 9.0 Hz, 2 H), 8.16 (d, J = 9.0 Hz, 2 H),
6.34 (t, J = 6.9 Hz, 1 H), 5.79 (d, J = 7.8 Hz, 1 H), 4.38 (dd, J = 14.1, 1.2 Hz, 1 H), 4.06
(dd, J = 6.3, 1.2 Hz, 1 H), 3.84 (dd, J = 14.4, 6.3 Hz, 1 H), 3.17 (s, 1 H), 3.07 (dd, J =
14.1, 2.4 Hz, 1 H), 2.95 (s, 3 H), 2.59 (m, 1 H), 1.58 (d, J = 14.7 Hz, 1 H), 1.42 (dd. J =
14.1, 3.3 Hz, 1 H), 1.35 (s, 3 H), 1.15 (d, J = 14.1 Hz, 1 H), 1.09 (s, 3 H); LRMS (EI) m/z

429.1 (M+).

MeO

37
(15*, 25 *, 45*, 85*)-2-(1-chloro-2-phenylsulfanyl-ethy|)-8-methoxy-l,8-dimethyl-
bicyclo[2.2.2]oct-5-en-2-ol (37).

Following general procedure VII, the reaction of 0.10 g (0.51 mmol) of starting
carbinol 29, afforded 53.7 mg (33%) of 37 after purification via prep-HPLC (Rainin si-
80-199-C5 column; 10:1 hexanes/EtOAC, 60 min).

37: 'H-NMR (300 MHz, CDCl;) 5 7.47 (m, 2 H), 7.28 (m, 3 H), 6.22 (ABq, J = 7.8, 1.2
Hz, 1 H), 5.96 (dd, J = 7.8, 1.2 Hz, 1 H), 3.95 (dd, J = 11.7, 5.7 Hz, 1 H), 3.53 (dd, J =
7.2 Hz, 1 H), 3.39 (dd, J = 5.4 Hz, 1 H), 3.12 (s, 3 H), 2.70 (m, 1 H), 2.14 (d, J = ,lH),
1.82 (dd, J = 14.7, 2.1 Hz, 1 H), 1.66 (dd, J = 5.3, 4.5 Hz, 1 H), 1.62 (s, 1 H), 1.45 (s, 3
H), 1.22 (s, 3 H), 1.05 (d, J = 13.2 Hz, 1 H); l3C-NMR (75 MHz, CDCl;) 5 136.9 (CH),
135.5 (C), 132.9 (CH), 131.6 (CH), 131.6 (CH), 129.1 (CH), 127.5 (CH), 78.7 (C), 77.6
(C), 48.9 (CH3), 46.1 (CH), 46.0 (CH2), 44.3 (CH2), 40.3 (CH), 37.7 (C), 21.5 (CH3),
19.2 (CH3); IR (NaCl, neat) 3425 (br s), 3010 (w), 2988 (s), 1590, (w), 675 (s); HRMS

(FAB) m/z 352.1483 [(M+), calcd. for C19H25C102S: 352.1264].

91

MeO

38
Preparation of (15*, 45*, 55*)-7-(2-benzenesulfinyl-ethylidene)-5-methoxy-1,5-
dimethyl-bicyclo[2.2.2]oct-2-ene (38).

The following experiment was carried out in a darkened hood, and an aluminum
wrapped round bottom flask. To a chilled (-78 °C) solution of 0.10 g 29 (0.48 mmol,
1.00 eq) in 10.0 mL THF was added 0.28 mL of a 1.7 M n-BuLi/hexanes solution (2.00
eq). The reaction was stirred for 30 min, afterwhich 0.07 g PhSCl (0.50 mmol, 1.1 1 eq)
in 5 mL THF was added dropwise via syringe. The reaction was stirred at -78 °C for 2
hrs, then warmed to 0 °C and quenched with aqueous NH4C1(,m,. The aqueous was
extracted two times with 20 mL 320. The combined ethereal layers were then dried over
Mg504, filtered, and concentrated. After concentration the yellow oil was purified via
prep-HPLC (Rainin si-80-199-C5 column; 10:1 hexanes/EtOAC, 60 min) to afford 39.5
mg (26%) of 38.

38: 'H-NMR (300 MHz, CDC13) 5 7.54 (m, 2 H), 7.48 (m, 3 H), 6.21 (m, 1 H), 5.87 (d, J
= 8.1 Hz, 1 H), 5.06 (tt, J = 7.8, 2.4 Hz, 0.5H), 4.93 (tt, J = 7.8, 2.4 Hz, 0.75H), 3.48 (pd,
J = 8.1 Hz, 1 H), 3.09 (s, 3 H), 2.71 (m, l H), 2.16 (dt, J = 16.8 Hz, 1 H), 1.82 (dd, J =
10.9, 3.3 Hz, 1 H), 1.79 (dt, J = 16.2 Hz, 1 H), 1.47 (d, J = 12.9 Hz, 1 H), 1.21 (d, J =
13.2 Hz, 1 H), 1.15 (s, 3 H), 1.12 (s, 3 H); l3C-NMR (75 MHz, CDCl;) 5 151.9 (C), 135.4
(CH), 135.3 (C), 132.9 (CH), 131.0 (CH), 128.9 (CH), 124.4 (CH), 104.5 (CH), 78.9 (C),

56.5 (CH2), 50.0 (CH3), 49.1 (CH2), 41.7 (C), 39.8 (CH), 29.6 (CH2), 22.6 (CH3), 21.2

92

(CH3); IR (NaCl, neat) 3047 (w), 2963 (s), 1577, (w), 1180 (s); HRMS (FAB) m/z

316.11587 [(M+), calcd. for C19H2402S: 316.1497].

OMe

(15*, 55*, 9R*)-1,9-dimethyl-9-methoxy-2-methylenebicyclo[3.2.2]non-6-en-3-one
(8).

Following general procedure V, the reaction of 0.11 g (0.52 mmol) of starting
carbinols 1:2, as a 4:1 mixture, afforded 0.10 g (93%) of 8 after purification via flash

silica chromatography (1.2 g; 1% Et3N/hexanes).
8: Rf = 0.40 (5:1 hexanes/EtOAC); [at];O = —53.5 (c 1.05, CHC13); lH—NMR (300 MHz,

CDC13) 5 6.21 (ABq, J = 8.1, 1.2 Hz, 1 H), 5.82 (d, J = 0.9 Hz, 1 H), 5.77 (d, J = 8.7 Hz,
1 H), 5.15 (d, J = 0.6, Hz, 1 H), 3.16 (s, 3 H), 2.99 (dd, J = 18.0.3.6 Hz, 1 H), 2.59 (m, 1
H), 2.27 (dd, J = 18.3, 4.2 Hz, 1 H), 1.99 (d, J = 14.4 Hz, 1 H), 1.57 (d, J = 14.1 Hz, 1
H), 1.25 (s, 3 H), 1.23 (s, 3 H); For l-D NOE correlations see figure shown above; l3C-
NMR (75 MHz, CDC13) 5 202.2 (C), 154.4 (C), 137.4 (CH), 132.6 (CH), 116.9 (CH2),
78.1 (C), 49.6 (CH2), 49.3 (CH3), 42.2 (CH2), 40.0 (CH), 38.2 (C), 26.8 (CH3), 26.4
(CH3); IR (neat) 3040 (m), 2970 (s), 2965 (s), 2860 (m), 1710 (m), 1684 (s), 1599 (s),
1450 (s), 1371 (s), 1136 (s), 1064 (s), 960 (m), 765 (m) cm"; HRMS (E1) m/z 206.1298

[(M+); calcd. for C13H1302: 206.1307].

93

M60

50
(15*, 5S*, 9S*)-1,9-dimethyl-9-methoxy-Z-methylenebicyclo[3.2.2]non-6-en-3-one
(50).
Following general procedure V, the reaction of 0.12 g (0.57 mmol) of starting
carbinols 29:30, as a 1:1 mixture, afforded 0.10 g (91%) of 50 after purification via flash

silica chromatography (1.2 g; 1% Et3N/hexanes).

50: Rf: 0.26 (5:1 hexanes/EtOAC); [61120 = -84.6° (c 1.57 ,CHC13); lH-NMR (300 MHz,
CDC13) 5 6.22 (ABq, J = 6.9, 0.24 Hz, 1 H), 5.84 (d, J = 8.7 Hz, 1 H), 5.78 (d, J = 0.9 Hz,
1 H), 5.15 (d, J: 0.6 Hz, 1 H), 3.11 (s, 3 H), 2.70 (d, J = 16.2, 3.6 Hz, 1 H), 2.67 (m, 1
H), 2.41 (d, J: 14.7 Hz, 1 H) 1.87 (d, J: 15.3 Hz, 1 H), 1.74 (d, J: 14.7 Hz, 1 H), 1.28
(s, 3 H), 1.27 (s, 3 H); l3C-NMR (75 MHz, CDC13) 5 202.4 (C), 154.5 (C), 136.3 (CH),
131.9 (CH), 117.0 (CH2), 78.7 (C), 49.7 (CH2), 49.3 (CH3), 43.6 (CH2), 38.3 (CH), 37.]
(C), 26.3 (CH3), 23.8 (CH3); IR (neat) 3070 (w), 2970 (s), 2937 (s), 2830 (m), 1695 (w),
1682 (s), 1510 (m), 1435 (m), 1375 (s), 1128 (s), 1080 (s), 940 (m), 758 (m-s) cm":
HRMS (EI) m/z 206.1304 [(M”); calcd. for C13H1302: 206.1307].

M

OH
9

(+/-)-(1R*, 2R*, 45 *)-2-isopropenyl-bicyclo[2.2.1]heptan-2-ol (9).
Following general procedure I, the reaction of 5.1 g (46.3 mmol) of norcamphor,
afforded 4.5 g (64%) of 9, as a 50:1 mixture of diastereomers, after purification via flash

alumina chromatography (120 g; basic, Activity 111; 100:1 hexanes/EtOAC).

94

9: Rf=0.40 (5:1 hexanes/EtOAC); 1H-NMR (300 MHz, CDC13) 54.85 (s, l H), 4.72 (d, J
= 3.9 Hz, 1 H), 2.35 (m, 1 H), 2.14 (m, 1 H), 1.98 (d, J = 0.9, Hz, 1 H), 1.86 (m, 2 H),
1.76 (s, 3 H), 1.46 (d, J = 9.9 Hz, 1 H), 1.37-1.18 (series of m, 4 H), 1.12 (dd, J = 13.2,
3.3 Hz, 1 H); I3C-NMR (75 MHz, CDC13) 5 149.8 (C), 108.8 (CH2), 80.8 (C), 44.6 (CH),
43.7 (CH2), 38.7 (CH3), 36.8 (CH), 28.6 (CH2), 21.9 (CH2), 18.4 (CH2); IR (neat) 3366
(br s), 2088 (w), 2968 (s), 2872 (s), 1643 (m), 1454 (s), 1373 (m), 1307 (s), 1163 (s),
1147 (s), 1026 (s), 993 (s), 897 (s), 868 (m), 734 (m) cm"; HRMS (E1) m/z 152.1198
[(M+) calcd. for ClonO: 152.1201].
For previous synthesis see: Johnson, C. R.; Herr, R. W. J. Org. Chem. 1973, 38, 3153-
3159.
Rearrangement of i-propenyl[2.2.1]heptanol via Johnson’s conditions.

A solution of 0.58 g (3.8 mmol, 1.00 eq) 9 in 19 mL (0.2 M) CHC13 was heated to
55 °C, in a dark room, prior to the addition of 0.45 mL (4.0 mmol, 1.05 eq) t-BuOCl.
The reaction was heated (55 °C) for 8 h in a dark room. The reaction was concentrated
and the crude oil was purified via flash silica chromatography (18 g; 50:1
hexanes/EtOAC) to afford 0.24 g (34%) 10, 0.16 g (23%) 11, 0.21 g (29%) 12, 0.05 g

(7%) 13, 0.01 g (2%) 54.

8.6% 6.7%

061% "WW
O 0' 0.5% 0 CI 0.4%
H H H. H H Ht:
""Me 0.2% ""Me 0.1%
H H

10 10

(+/-)-(1R*, 25*, 55*)-2-chloromethyl-2-methyl-bicyclo[3.2.l]octan-3-one (10).

95

Following general procedure V, the reaction of 0.52 g (3.4 mmol) of starting
carbinol 9, afforded 0.23 g (36%) of 10 after purification via flash silica chromatography
(20 g; 50:1 hexanes/Et0Ac).

10: Rf = 0.73 (5:1 hexanes/EtOAC); IH-NMR (500 MHz, CDC13) 5 3.71 (d, J = 6.6 Hz, 1
H), 3.52 (d, J = 6.6 Hz, 1 H), 2.49 (m, 2 H), 2.36 (m, 1 H), 2.21 (dm, J = 15.0 Hz, 1 H),
2.13 (d, J = 12.5 Hz, 1 H), 1.72-1.63 (series of m, 3 H), 1.52 (m, 1 H), 1.39 (m, 1 H),
1.15 (s, 3 H); For l-D NOE correlations see figure shown above; l3C-NMR (125 MHz,
CDCl;) 5 212.0 (C), 54.9 (C), 50.7 (CH2), 47.7 (CH2), 43.6 (CH), 36.0 (CH2), 33.7
(CH2), 28.5 (CH), 25.0 (CH2), 18.7 (CH3); IR (neat) 2957 (s), 2878 (s), 1709 (s), 1462
(s), 1377 (s) , 1290 (s), 1084 (m), 1041 (m), 964 (w), 916 (w), 881 (m), 733 (s) cm";

HRMS (EI) m/z 186.0807 [(M+)ca1cd. for C10H15035C1: 186.0811].

0.4%

0. 27%
\—H.
§’ 0. 2°/o } 1. 3° /0

(+/-)-(1R*, 2R*, 55*)-2-chloromethyl-2-methyl-bicyclo[3.2.1]octan-3-one (11).
Following general procedure V, the reaction of 0.52 g (3.4 mmol) of starting

carbinol 9, afforded 0.18 g (28%) of 11 after purification via flash silica chromatography

(20 g; 50:1 hexanes/EtOAC).

11: Rf = 0.61 (5:1 hexanes/EtOAC); lH-NMR (500 MHz, CDC13) 5 3.78 (d, J = 7.2 Hz, 1

H), 3.68 (d, J = 6.9 Hz, 1 H), 2.61 (dm, J = 9.6 Hz, 1 H), 2.51 (series of m, 2 H), 2.12

(series of m, 2 H), 1.77-1.52 (series of m, 4 H), 1.23 (m, 1 H), 1.26 (s, 3 H); 1H-NMR

(500 MHz, C6D6) 5 3.86 (d, J = 11.7 Hz, 1 H), 3.66 (d, J = 11.7 Hz, 1 H), 2.30 (t, J = 4.4

96

Hz, 1 H), 2.10 (dd, J = 12.6, 4.4 Hz, 1 H), 1.91 (t, J = 4.4 Hz, 1 H), 1.86 (d, J = 3.8 Hz, 1
H), 1.56 (d, J = 12.0 Hz, 1 H), 1.28 (m, 3 H), 1.04 (m, 1 H), 1.00 (m, 1 H), 0.96 (d, J =
0.9 Hz, 3 H); For l-D NOE correlations see figure shown above; l3C-NMR (125 MHz.
CDC13) 5 214.3 (C), 53.0 (C), 50.1 (CH), 47.3 (CH2), 41.7 (CH), 35.6 (CH), 33.6 (CH2),
28.2 (CH2), 24.8 (CH2), 22.0 (CH3); IR (neat) 2953 (s), 2878 (ms), 1703 (s), 1460(m),
1288 (m), 1066 (m), 981 (w), 887 (w), 713 (m) cm"; HRMS (EI) m/z 186.0808 [(M”)

calcd. for C10H15O35C1: 186.081 1].

0.40/O 1.10/0 0 90/0
j H. Hb/T .

\Me C1 \Me
H .\ O .\

12 12

(+/-)-(1R*, 3R*, 55*)-3-chloromethyl-3-methyl-bicyclo[3.2.1]octan-2-one (12).

Following general procedure V, the reaction of 0.52 g (3.4 mmol) of starting
carbinol 9, as a 4:1 mixture, afforded 0.12 g (19%) of 12 after purification via flash silica
chromatography (20 g; 50:1 hexanes/EtOAC).
12: Rf: 0.61 (5:1 hexanes/Et0Ac); 1H-NMR (500 MHz, CDC13) 5 3.82 (d, J = 6.3 Hz, 1
H), 3.10 (d, J = 6.3 Hz, 1 H), 2.77 (t, J = 3.0 Hz, 1 H), 2.49 (m, l H), 2.32 (dd, J = 8.4,
2.7 Hz, 1 H), 1.94 (series of m, 4 H), 1.69 (series of m, 2 H), 1.58 (dt, J = 8.4, 1.5 Hz, 1
H), 1.20 (s, 3 H); For l-D NOE correlations see figure shown above; l3C-NMR (125
MHz, CDC13) 5 214.8 (C), 53.1 (CH2), 50.8 (CH), 47.7 (C), 40.8 (CH2), 34.7 (CH), 34.3
(CH2), 28.7 (CH2), 28.3 (CH3), 28.1 (CH2); IR (neat) 2955 (s), 2876 (s), 1709 (s), 1448
(s), 1288 (s), 1068 (m), 960 (m), 918 (m), 736 (s) cm"; HRMS (EI) m/z, 186.0801 [(M+)

calcd. for C10H15035C1: 186.0811].

97

Cl—‘V M8

I," i O

13
(+/-)-(1R*, 3S*, SS *)-3-chloromethyl-3-methyl-bicyclo[3.2.1]octan-2-one (13).
Following general procedure V, the reaction of 0.52 g (3.4 mmol) of starting
carbinol 9, afforded 0.03 g (6%) of 19, based on lH-NMR. Compound 13 was never
isolated in pure form and as a result spectral information is not available. It’s isolation as
a mixture with other regio and diastereomers allowed for its identification due to its
inherent signature lH-NMR signals and 1-D NOE correlations. See Johnson, C. R.; Herr,

R. W. J. Org. Chem. 1973, 38, 3153—3159.

0
Cl

Cl

54
(+/-)-(1R*, 5S*)-2,2-bis-chloromethyl-bicyclo[3.2.l]octan-3-one (54).

Following general procedure V, the reaction of 0.52 g (3.4 mmol) of starting
carbinol 9, as a 4:1 mixture, afforded 6.1 mg (~1%) of 54 after purification via flash
silica chromatography (20 g; 50:1 hexanes/EtOAC).

54: Rf: 0.59 (5:1 hexanes/EtOAC); |H-NMR (500 MHz, CDC13) 5 4.18 (d, J = 7.5 Hz, 1
H), 4.00 (dd, J = 6.9, 0.9 Hz, 1 H), 3.85 (d, J = 6.9 Hz, 1 H), 3.64 (dd, J = 7.2, 0.9 Hz, 1
H), 2.59 (m, 3 H), 2.24 (dt, J = 8.7, 1.8 Hz, 1 H), 2.13 (d, J = 7.5 Hz, 1 H), 1.71 (m, 2
H), 1.58 (m, 2 H), 1.40 (m, 1 H); l3C-NMR (125 MHz, CDC13) 5 209.1 (C), 57.7 (C),
47.8 (CH2), 45.0 (CH2), 44.8 (CH2), 40.9 (CH), 36.4 (CH), 33.6 (CH3), 27.6 (CH2), 25.2

(CH2); IR (neat) 2959 (s), 2880 (m), 1714 (s), 1460 (m), 1439 (m), 1288 (m), 1190 (w),

98

1097 (w), 870 (w), 787 (s), 761 (s) cm"; HRMS (EI) m/z 220.0426 [(M+) calcd. for

C10H14O35C12: 220.0422].

 

0.5% 4 o /
0.2%
H
H H I Hf 1.7%
H OH Cl
55 55

(+/-)-(1R*, 2S*, 4R*)-2-(1-chloromethyl-vinyl)-bicyclo[2.2.1]heptan-2-ol (55).
Following general procedure V, the reaction of 0.52 g (3.4 mmol) of starting
carbinol 9, as a 4:1 mixture, afforded 0.06 g (10%) of 55 after purification via flash silica
chromatography (20 g; 50:1 hexanes/EtOAC).
55: Rf = 0.45 (5:1 hexanes/EtOAC); 1H-NMR (500 MHz, CDC13) 5 5.33 (s, 1 H), 5.26 (s,
1 H), 4.24 (d, J = 12.5 Hz, 1 H), 4.20 (d, J = 12.5 Hz, 1 H), 2.44 (m, 1 H), 2.38 (br s, 1
H), 2.23 (m, 1 H), 2.04 (dm, J = 5.1 Hz, 2 H), 1.60 (series of m, 2 H), 1.42 (dt, J = 7.5,
2.7 Hz, 1 H), 1.36 (m, 1 H), 1.30 (dp, J = 6.0, 1.2 Hz, 1 H), 1.22 (dd, J = 7.8, 2.1 Hz, 1
H); For 1-D NOE correlations see figure shown above; l3C-NMR (125 MHz, CDC13) 5
150.22 (C), 114.2 (CH2), 81.0 (C), 45.7 (CH), 45.0 (CH2), 44.8 (CH2), 38.7 (CH3), 37.0
(CH), 28.6 (CH2), 21.9 (CH2); IR (neat) 3428 (br m), 2959 (s), 2872 (m), 1690 (w), 1610
(w), 1454 (m), 1309 (m), 1163 (m), 1026 (m), 958 (m), 912 (m), 788 (s), 761 (s) cm";

HRMS (E1) m/z 186.0815 [(M“) calcd. for C.OH,so35c1: 186.0811].

OMe OMe

0H

58 59

99

(15*, 2R*, 4S*, 8R*)-1,8-dimethyl-2-isopropenyI-8-methoxybicyclo[2.2.2]oct-5-en-2-
01 (58) and (13*, 2S*, 4S*, 8R*)-1,8-dimethyl-2-isopropenyl-8-
methoxybicyclo[2.2.2]oct-5-en-2-ol (59).

Following general procedure I, the reaction of 1.00 g (5.5 mmol) of starting
ketone 27, afforded 0.91 g (81%) of 58:59, as a 4:1 diastereomeric mixture, after
purification via flash alumina chromatography (25 g; basic Activity 111, 50:1
hexanes/EIOAC).

58: Rf = 0.42 (5:1 hexanes/EtOAC); [at/1226 = -50.1 (c 0.63, CHC13); 1H-NMR (300 MHz,

CDC13) 5 6.11 (t, J = 6.6 Hz, 1 H), 5.94 (d, J = 7.2 Hz, 1 H), 5.11 (d, J = 2.4 Hz, 1 H),
4.78 (ABq, J = 2.4, 1.2 Hz, 1 H), 3.19 (s, 3 H), 2.68 (m, 1 H), 2.24 (d, J = 13.8 Hz, 1 H),
1.98 (d, J = 13.8 Hz, 1 H), 1.76 (dd, J = 14.4, 3.3 Hz, 1 H), 1.66 (dd, J = 13.8, 2.4 Hz, 1
H), 1.58 (s, 3 H), 1.38 (s, 1 H), 1.11 (s, 3 H), 0.94 (s, 3 H); l3C-NMR (75 MHz, CDC13) 5
148.7 (C), 141.5 (CH), 131.7 (CH), 111.6 (CH2), 78.7 (C), 77.6 (C), 49.8 (CH3), 47.3
(CH2), 43.7 (C), 40.6 (CH), 30.3 (CH2), 24.7 (CH3), 21.5 (CH3), 18.7 (CH3); IR (neat)
3493 (m), 3040 (w), 2961 (s), 2872 (m), 1680 (w), 1620 (w), 1452 (s), 1371 (s), 1101 (s),
1062 (s), 918 (m), 904 (m), 879 (w), 736 (m) cm"; HRMS (EI) m/z 222.1622 [(M+)
calcd. for C14H2202: 222.1620].

59: Rf = 0.21 (5:1 hexanes/EtOAC); [6:1336 = -81.0 (c 0.65, CHC13); ‘H-NMR (300 MHz,

CDC13) 5 6.33 (t, J = 6.9 Hz, 1 H), 5.83 (d, J = 7.8 Hz, 1 H), 5.20 (d, J = 1.8 Hz, 1 H),
4.99 (t, J = 1.8 Hz, 1 H), 3.10 (s, 3 H), 2.54 (m, l H), 2.53 (d, J = 12.6 Hz, 1 H), 1.86 (d,
J = 14.1 Hz, 1 H), 1.82 (s, 3 H), 1.21 (s, 1 H), 1.14 (d, J =14.4 Hz, 1 H), 1.12 (d, J =
13.8 Hz, 1 H), 1.07 (s, 3 H), 1.00 (s, 3 H); l3C-NMR (75 MHZ, CDC13) 5 147.1 (C), 138.0

(CH), 135.0 (CH), 114.0 (CH2), 79.8 (C), 79.4 (C), 49.2 (CH3), 45.8 (C), 41.4 (CH3),

100

41.0 (CH), 40.9 (CH2), 24.9 (CH3). 22.1 (CH3), 19.5 (CH3); IR (neat) 3501 (br m), 3090
(w), 2966 (s), 2932 (s), 2878 (m), 2826 (m), 1697 (m), 1664 (s), 1454 (s), 1367 (s), 1 101
(s), 1072 (s), 939 (m), 810 (w), 690 (w) cm"; HRMS (E1) m/z 222.1624 [(M+) calcd. for

C|4H22022 222L620]

MeO MeO

OH

62 63

(1S*, 2R"‘, 4S *, 8S*)-1,8-dimethy1-2-isopropenyl-8-methoxybicyclo[2.2.2]oct-5-en-2-
01 (62) and (1S*, 2S*, 45*, 8S*)-1,8-dimethyl-2-isopropenyl-8-
methoxybicyclo[2.2.2]oct-5-en-2-ol (63).

Following general procedure I, the reaction of 2.00 g (11.1 mmol) of starting
ketone 28, afforded 1.93 g (78%) of 62:63, as a 2.521 diastereomeric mixture, after
purification via flash alumina chromatography (60 g; basic Activity 111, 50:1
hexanes/EtOAC).

62: R. = 0.64 (5:1 hexanes/EtOAC); (mg; = -64.2 (c 0.80, CHC13); 'H-NMR (300 MHz,

CDC13) 5 6.19 (ABq, J = 6.3, 1.8 Hz, 1 H), 5.96 (d, J = 7.8 Hz, 1 H), 4.99 (d, J = 1.2 Hz,
1 H), 4.81 (t, J = 1.5 Hz, 1 H), 3.13 (s, 3 H), 2.69 (m, l H), 2.06 (d, J = 12.9 Hz, 1 H),
1.73 (dd, J: 14.1, 3.3 Hz, 1 H), 1.63, (d, J = 0.6 Hz, 3 H), 1.62 (dd, J = 13.8, 3.0 Hz, 1
H), 1.46 (s, 3 H), 1.22 (s, 1 H), 1.10 (d, J = 12.9 Hz, 1 H), 0.947 (s, 3 H); l3C-NMR (75
MHZ, CDC13) 5 151.2 (C), 137.5 (CH), 132.2 (CH), 111.3 (CH2), 79.1 (C), 78.9 (C), 48.8
(CH3), 45.7 (CH2), 43.3 (C), 40.6 (CH), 39.2 (CH2), 22.5 (CH3), 21.6 (CH3), 18.7 (CH3);

IR (neat) 491 (br m), 3040 (m), 2932 (s), 2824 (s), 1726(5), 1710 (w), 1454 (s), 1373 (s).

101

1 134 (s), 1080 (s), 991 (m), 897 (m), 733 (s) cm"; HRMS (EI) m/z 222. 1624 [(M+) calcd.
fOf C|4H23022 222.1620].

63: R. = 0.52 (5:1 hexanes/EtOAC); [0113. = -76.0 (c 0.25, CHC13); 'H-NMR (300 MHz,

CDC13) 5 6.45 (A3,, J = 6.3 Hz, 1 H), 5.91 (d, J = 7.2 Hz, 1 H), 5.04 (1, J = 1.5 Hz, 1 H),
4.87 (s, 1 H), 3.15 (s, 3 H), 2.99 (m, 1 H), 2.09 (d, J = 13.5 Hz, 1 H), 1.86 (d, J = 0.6 Hz,
3 H), 1.69 (dd, J = 14.7, Hz, 1 H), 1.42 (dd, J = 11.1, 2.1 Hz, 1 H), 1.34 (s, 3 H), 1.33 (s,
1 H), 1.22 (d, J = 12.9 Hz, 1 H), 1.16 (s, 3 H); l3C-NMR (75 MHz, CDC13) 5 136.8 (C),
135.4 (CH), 132.5 (CH), 113.0 (CH2), 79.2 (C), 77.2 (C), 49.4 (CH3), 46.3 (CH2), 41.2
(CH), 40.5 (C), 36.2 (CH2), 22.3 (CH3), 19.8 (CH3), 17.2 (CH3); IR (neat) 3491 (s), 3090
(w), 2932 (s), 2824 (s), 1701 (s), 690 (w), 1454 (s), 1336 (s), 1115 (s), 1080 (s), 1010
(m), 897 (s), 680 (m-s) cm"; HRMS (E1) m/z 222.1708 [M+) calcd. for CmHggOg:

222.1620].

OMe OMe

(15*, 2R*, 4S *, 8R*)-2-(2,3)-dihyropyranyl-S-methoxy-1,8-dimethyl-
bicyclo[2.2.2]oct-5-en-2-ol (60) and (1S*, 25*, 4S*, 8R*)-2-(2,3)-dihyr0pyranyl-8-
methoxy-1,8-dimethyl-bicyclo[2.2.2]oct-5-en-2-ol (61).

Following general procedure II, the reaction of 1.99 g (11.08 mmol) of starting
ketone 27, afforded 2.19 g (75%) of 60:61, as a 10:1 diastereomeric mixture, after
purification via flash alumina chromatography (60 g; basic Activity 111, 50:1

hexanes/EtOAC).

102

60: Rf = 0.50 (5:1 hexanes/Et0Ac); [a133, = -510 (c 0.19, CHC13); 'H-NMR (300 MHz,

CDC13) 5 6.07 (t, J = 7.5 Hz, 1 H), 5.93 (d, J = 7.8 Hz, 1 H), 4.96 (t, J = 3.6 Hz, 1 H),
3.88 (m, 2 H), 3.61 (s, 1 H), 3.21 (s, 3 H), 2.64 (m, 1 H), 2.02 (m, 2 H), 1.96 (d, J = 13.8
Hz, 1 H), 1.74 (m, 4 H), 1.12 (s, 3 H), 0.96 (s, 3 H), 0.95 (d, J = 13.8 Hz, 1 H); l3C-NMR
(75 MHz, CDC13) 5 152.7 (C), 138.2 (CH), 132.3 (CH), 98.8 (CH), 79.5 (C), 78.1 (C),
65.9 (CH2), 49.1 (CH3), 44.4 (C), 42.1 (CH2), 40.6 (CH), 37.4 (CH2), 24.9 (CH3), 22.1
(CH2), 20.2 (CH2), 19.4 (CH3); IR (neat) 3543 (br S), 3050 (w), 2937 (s), 2874 (m), 2830
(m), 1714 (s), 1458 (m), 1369 (m), 1284 (w), 1105 (s), 1066 (s), 796 (m), 680 (m) cm":
HRMS (E1) m/z 264.1719 [M+) calcd. for C16H24O3: 264.1725].

61: Rf = 0.30 (5:1 hexanes/EtOAC); 1H-NMR (300 MHz, CDC13) 5 6.25 (t, J = 7.8 Hz, 1
H), 5.82 (d, J = 7.8 Hz, 1 H), 5.19 (t, J = 3.9 Hz, 1 H), 3.95 (t, J = 5.4 Hz, 2 H), 3.15 (s,
3 H), 2.52 (m, 1 H), 2.40 (dd, J = 14.4, 1.8 Hz, 1 H), 2.04 (m, 2 H), 1.85 (d, J = 13.8 Hz,
1 H), 1.77 (m, 2 H), 1.37 (s, 1 H), 1.30 (dd, J = 14.4, 3.3 Hz, 1 H), 1.08 (s, 3 H), 0.98 (s,
3 H), 0.82 (d, J = 13.8 Hz, 1 H); l3C-NMR (75 MHz, CDC13) 5 155.6 (C), 140.2 (CH),
134.5 (CH), 95.8 (CH), 80.1 (C), 78.6 (C), 66.4 (CH2), 49.2 (CH3), 45.3 (C), 42.2 (CH3),
40.8 (CH), 37.6 (CH2), 25.3 (CH3), 22.9 (CH2), 20.3 (CH2), 19.9 (CH3); IR (neat) 3439
(br s), 3044 (w), 2934 (s), 2872 (s), 2826 (m), 1709 (s), 1458 (s), 1365 (s), 1255 (m),

1085 (s), 1066 (s), 987 (w), 846 (w), 734 (m) cm'l; HRMS (131) m/z 264.1739 [M+) calcd.

MeO MeO
/ OH / \
O \ OH
64 65

for C16H24O3: 264.1725].

103

(1S’", 2R*, 4S*, 8S*)-1,8-dimethyl-2-(2,3)dihydrofuryl-8-methoxybicyclo[2.2.2]oct-
5-en-2-ol (64) and (18*, 2S*, 45*, 8S*)-1,8-dimethyl-2-(2,3)-dihydrofuryl-8-
methoxybicyclol2.2.2]oct-S-en-Z-ol (65).

Following general procedure 11, the reaction of 0.97 g (5.3 mmol) of starting
ketone 28, afforded 0.79 g (75%) of 64:65, as a 25:1 diastereomeric mixture, after
purification via flash alumina chromatography (40 g; neutral Activity 111, 30:1

hexanes/EtOAC).
64: Rf = 0.15 (4:1 hexanes/EtOAC); [61136 = -67.0 (c 0.32, CHC13); |H-NMR (300 MHz.

CDC13) 5 6.39 (ABq, J = 8.1, 1.5 Hz, 1 H), 5.97 (d, J = 8.1 Hz, 1 H), 4.92 (1, J = 2.4 Hz,
1 H), 4.32 (1, J = 9.6 Hz, 2 H), 3.09 (s, 3 H), 2.68 (m, 1 H), 2.62 (td, J = 9.3, 2.7 Hz, 2
H), 2.23 (dd, J = 15.0, 1.5 Hz, 1 H), 2.04 (s, 1 H), 1.82 (d, J = 14.1 Hz, 1 H), 1.35 (s, 3
H), 1.21 (d, J = 9.3 Hz, 1 H), 1.13 (d, J = 9.3 Hz, 1 H), 1.09 (s, 3 H); l3C-NMR (75
MHz, CDC13) 5 159.4 (C), 136.1 (CH), 133.9 (CH), 97.2 (CH), 79.5 (C), 76.5 (C), 70.2
(CH2), 48.9 (CH3), 43.7 (CH2), 43.4 (C), 39.9 (CH), 38.6 (CH2), 29.9 (CH2), 21.1 (CH3),
19.3 (CH3); IR (neat) 3466 (br m), 3090 (w), 2936 (s), 2872 (s), 2824 (m), 1707 (m),
1680 (w), 1456 (s), 1136 (s), 1080(8), 970(5), 941 (s), 830 (w), 731 (s) cm"; HRMS (131)
m/z 250.1568 [(M+), calcd. for C,5szo,: 250.1569].

65: R. = 0.31 (4:1 hexanes/EtOAC); 'H-NMR (300 MHz, CDC13) 5 6.30 (1, J = 7.2 Hz, 1
H), 5.85 (d, J = 8.1 Hz, 1 H), 5.08 (1, J = 2.4 Hz, 1 H), 4.32 (dt, J = 9.3, 3.3 Hz. 2 H),
3.17 (8,3 H), 2.65 (series of m, 2 H), 2.55 (m, 1 H), 2.49 (dd, J = 13.8, 2.1 Hz, 1 H), 1.86
(d, J = 13.8 Hz, 1 H), 1.63 (d, J = 14.7 Hz, 1 H), 1.38 (dd, J = 14.4, 3.3 Hz, 1 H), 1.22 (s,
1 H), 1.11 (s, 3 H), 1.07 (s, 3 H); l3C-NMR (75 MHz, CDC13) 5 158.7 (C), 137.6 (CH),

133.0 (CH), 97.7 (CH), 79.3 (C), 76.1 (C), 69.8 (CH3), 49.2 (CH3), 44.0 (CH3), 42.5

104

(CH), 40.4 (CH2), 38.5 (C), 30.5 (CH2), 24.8 (CH3). 19.4 (CH3); IR (neat) 3468 (br 5).
3061 (m), 2974(5), 1710 (m), 1651 (s), 1456(8), 1365 (s), 1163 (s), 1070(5), 1008 (s),

939 (s), 852, (m), 733 (s) cm'l; HRMS (EI) m/z 250.1572 [(M+), calcd. for C15H2203:

250.1569].

 

(15*, 2S*, 5S*, 9R*)-2-chloromethyl-1,9-dimethyl-9-methoxybicyclo[3.2.2]non-6-en-

3-one (66). 9
Following general procedure V, the reaction of 0.35 g (1.4 mmol) of starting

carbinol 1, afforded 0.11 g (32%) of 66 after purification via flash silica chromatography

(3 g; 75:1 hexanes/EtOAC).
66: Rf: 0.33 (5:1 hexanes/EtOAC); [01133, = -49.4 (c 0.68, CHC13); lH-NMR (300 MHz,

CDC13) 5 6.28 (ABq, J = 7.8, 1.2 Hz, 1 H), 5.83 (d, J = 9.0 Hz, 1 H), 3.74 (dd, J = 11.4,
4.2 Hz, 1 H), 3.49 (dd, J = 11.4, 8.4 Hz, 1 H), 3.15 (8,3 H), 2.79 (dd, J = 15.9, 5.4 Hz, 1
H), 2.64 (m, 1 H), 2.59 (dd, J = 8.4, 4.2 Hz, 1 H), 2.19 (dd, J = 13.2, 2.4 Hz, 1 H), 1.94
(d, J = 14.4 Hz, 1 H), 1.43 (d, J = 15.0 Hz, 1 H), 1.23 (s, 3 H), 1.17 (5,3 H); For l-D
NOE correlations see figure shown above; l3C—NMR (75 MHz, CDC13) 5 208.5 (C),
136.] (CH), 133.6 (CH), 78.5 (C), 66.6 (CH), 49.7 (CH2), 49.3 (CH3), 42.6 (CH2), 41.3

(CH2), 40.3 (CH), 36.5 (C), 29.6 (CH3). 26.9 (CH3); IR (neat) 3070 (w), 2961 (s), 2928

105

(s), 2855 (m), 1684 (s), 1599 (m), 1462 (s), 1371 (s), 1257 (m), 1134 (s), 1064 (s), 765

(m) cm"; HRMS (E1) m/z, 242.1163 [(M+); calcd. for CI3H190335C1: 242.1074].

OMe
I
e". E O

H
C1

67
(1S*, 2R*, 53*, 9R*)-2-chloromethyl-l,9-dimethyl-9-methoxybicyclo[3.2.2]non-6-en-
3-one (67).

Following general procedure V, the reaction of 0.12 g (0.57 mmol) of starting
carbinol 2, afforded 0.05 g (36%) of 67 after purification via flash silica chromatography

(3.5 g; 5:1 hexanes/EtOAC).
67: Rf = 0.26 (5:1 hexanes/EtOAC); [afiflb = -20.0 (c 0.14, CHC13); lH-NMR (300 MHz,

CDC13) 5 6.28 (ABq, J = 8.7, 1.1 Hz, 1 H), 5.84 (d, J = 9.3 Hz, 1 H), 3.74 (dd, J = 11.5,
3.9 Hz, 1 H), 3.50 (dd, J = 11.5, 8.2 Hz, 1 H), 3.16 (s, 3 H), 2.78 (dd, J = 15.3, 4.9 Hz, 1
H), 2.65 (m, 1 H), 2.60 (dd, J = 7.7, 3.3 Hz, 1 H), 2.19 (dd, J = 15.9, 2.7 Hz, 1 H), 1.93
(d, J = 14.2 Hz, 1 H), 1.35 (d, J = 14.3 Hz, 1 H), 1.18 (s, 3 H), 1.17 (s, 3 H); l3C-NMR
(125 MHz, CDC13) 5 224.1 (C), 136.8 (CH), 132.2 (CH), 78.3 (C), 78.0 (CH), 50.0
(CH3), 49.7 (CH2), 41.0 (CH), 34.5 (CH2), 29.9 (CH2), 28.0 (CH3), 24.3 (C), 22.6 (CH3);
IR (neat) 3023 (w), 2918 (s), 2849 (s), 1724 (w), 1603 (w), 1462 (m), 1379 (m). 1120
(ms), 1074 (m), 935 (w), 844 (w), 758 (m) cm"; HRMS (EI) m/z 242.1087 [(M+); calcd.

for CI3H190235C1: 242.1074].

106

     

, 0.3%
/
Me c' 0 Me .
Me‘ Me“
H. Hb
0.8/o

. 1.4%
so as
(15*, 2S*, 58*, 9R*)-2-chloromethyl-1,2,9-trimethyl-9-methoxybicyclo[3.2.2]non~6-
en-3-one (68).
Following general procedure V, the reaction of 67.8 mg (0.30 mmol) of starting
carbinol 58, afforded 67.2 mg (86%) of 68:69, as a 20:1 diastereomeric mixture, and 7.8
mg (10%) of 72 after purification via flash silica chromatography (1.0 g; 50:1 to 5:1

hexanes/EtOAC).
68: Rf = 0.83 (5:1 hexanes/Et0Ac); [0713, = -60.0 (c 0.10, CHC13); 1H-NMR (500 MHz,

CDC13) 5 6.20 (ABq, J = 8.8, 1.3 Hz, 1 H), 5.82 (d, J = 8.8 Hz, 1 H), 3.87 (d, J = 11.0
Hz, 1 H), 3.77 (d, J = 11.4 Hz, 1 H), 3.17 (s, 3 H), 2.94 (dd, J = 15.9, 3.9 Hz, 1 H), 2.63
(d, J = 15.4 Hz, 1 H), 2.54 (m, 1 H), 2.32 (dd, J = 15.9, 3.9 Hz, 1 H), 1.25 (d, J = 15.4
Hz, 1 H), 1.19 (s, 3 H), 1.15 (s, 3 H), 1.06 (s, 3 H); For l-D NOE correlations see figure
shown above; l3C-NMR (125 MHz, CDC13) 5 209.9 (C), 139.8 (CH), 132.7 (CH), 78.3
(C), 58.1 (C), 49.3 (CH3), 47.2 (CH2), 45.9 (CH2), 40.8 (CH2), 40.0 (CH), 39.4 (C), 27.1
(CH3), 24.6 (CH3), 21.2 (CH3); IR (neat) 3034 (m), 2932 (s), 2828 (m), 1701 (s), 1458
(s), 1371 (s), 1277 (m), 1140 (s), 1064 (s), 916 (m), 738 (s), 680 (s) cm"; HRMS (E1) m/z

256.1238 [(M“); calcd. for C14H210235C1: 256.1230].

107

 

(1S*, 2R*, 5S*, 9R*)-2-chloromethyl-1,2,9-trimethyl-9-methoxybicyclo[3.2.2]non-6-
en-3-one (69).

Following general procedure V, the reaction of 0.14 g (0.65 mmol) of starting
carbinol 59, afforded 0.13 g (82%) of 68:69, as a 1:12 diastereomeric mixture, and 26.9
mg (16%) of 73 after purification via flash silica chromatography (1.0 g; 50:1 to 5:1

hexanes/EtOAC).
69: R. = 0.42 (5:1 hexanes/EtOAC); [0113, = -48.0 (c 0.02, CHC13); 1H-NMR (300 MHz,

CDC13) 5 6.29 (ABq, J = 8.7, 0.9 Hz, 1 H), 5.90 (d, J = 9.0 Hz, 1 H), 3.64 (d, J = 3.0 Hz,
2 H), 3.15 (s, 3 H), 2.82 (dd, J = 15.6, 5.1 Hz, 1 H), 2.57 (m, 1 H), 2.37 (dd, J = 15.6, 2.7
Hz, 1 H), 2.06 (d, J =15.3 Hz, 1 H), 1.16 (s, 3 H), 1.15 (s, 3 H), 1.12 (d, J = 15.6 Hz, 1
H), 1.07 (s, 3 H); l3C-NMR (125 MHz, CDC13) 5 212.3 (C), 135.7 (CH), 134.4 (CH),
78.8 (C), 56.9 (C), 50.3 (CH3), 49.6 (CH2), 45.9 (CH2), 41.6 (CH), 40.8 (CH3), 34.6 (C),
29.6 (CH3), 24.8 (CH3), 22.6 (CH3); IR (neat) 3093 (w), 2986 (s), 2804 (s), 2777 (s),
1728 (s), 1705 (m), 1458 (s), 1383 (s), 1298 (m), 1116 (s), 1076 (s), 935 (m), 844 (m),

752 (m) cm"; HRMS (E1) m/z 256.1233 [(M”); calcd. for CI4H210235C1: 256.1230].

 

70

(15*, 2S*, 5S*, 9S*)-2-chloromethyl-1,2,9-trimethy1-9-methoxybicyclo[3.2.2]non-6-

en-3-one (70).

108

Following general procedure V, the reaction of 0.30 g (1.3 mmol) of starting
carbinol 62, afforded 0.27 g (78%) of 70:71, as a 15:1 diastereomeric mixture, after
purification via flash silica chromatography (1.0 g; 50:1 to 5:1 hexanes/EtOAC).

70: R. = 0.25 (4:1 hexanes/EtOAC); [1113, = -720 (c 0.15, CHC13); ‘H-NMR (300 MHz,

CDC13) 5 6.28 (ABq, J = 7.2, 1.5 Hz, 1 H), 5.87 (d, J = 9.0 Hz, 1 H), 3.91 (d, J = 11.4 Hz,
1 H), 3.57 (d, J = 12.0 Hz, 1 H), 3.08 (s, 3 H), 2.96 (m, l H), 2.57 (d, J = 15.6 Hz, 1 H),
2.48 (d, J: 13.8 Hz, 1 H), 1.72 (d, J: 14.7 Hz, 1 H), 1.56 (d, J: 15.3 Hz, 1 H), 1.21 (s,
3 H), 1.19 (s, 3 H), 1.03 (s, 3 H); I3C-NMR (75 MHz, CDC13) 5 211.1 (C), 138.2 (CH),
132.5 (CH), 79.2 (C), 58.1 (C), 49.4 (CH3), 46.3 (CH2), 46.1 (CH2), 41.2 (CH), 37.7 (C),
36.2 (CH2), 23.9 (CH3), 23.1 (CH3), 17.2 (CH3); IR (neat) 3090 (w), 2972 (s), 2934 (s),
2826 (m), 1724 (s), 1697 (s), 1454 (m), 1375 (m), 1134 (s), 1082 (s), 848 (w), 750 (s),

682 (m) cm": HRMS (131) m/z 256.1240 [(Mt); calcd. for CI4H210235C1: 256.1230].

 

(18*, 2R*, 58*, 98*)-2-chloromethyl-l,2,9-trimethy1-9-methoxybicyclo[3.2.2]non-6-
en-3-one (71).

Following general procedure V, the reaction of 0.32 g (1.4 mmol) of starting
carbinol 63, afforded 0.28 g (76%) of 70:71, as a 1:11 diastereomeric mixture, after
purification via flash silica chromatography (1.0 g; 50:1 to 5:1 hexanes/Et0Ac).

71: Rf = 0.42 (5:1 hexanes/EtOAC); [1213, = -530 (c 0.06, CHC13); 'H-NMR (300 MHz.

CDC13) 5 6.44 (ABq, J = 6.3, 1.8 Hz, 1 H), 5.90 (d, J = 7.2 Hz, 1 H), 3.45 (d, J = 12.6 Hz,

1 H), 3.38 (d, J = 12.0 Hz, 1 H), 3.14 (s, 3 H), 2.96 (m, 1 H), 2.56 (d, J = 17.4 Hz, 1 H),

109

2.45 (d, J: 14.1 Hz, 1 H), 1.33 (s, 3 H), 1.21 (s, 3 H), 1.18 (d, J=16.2 Hz, 1 H), 1.15 (s.
3 H), 1.11 (d, J = 15.6 Hz, 1 H); l3C-NMR (75 MHz, CDC13) 5 212.3 (C), 135.4 (CH),
131.8 (CH), 79.3 (C), 69.3 (C), 65.8 (CH2), 49.1 (CH3), 46.8 (CH2), 41.9 (CH2), 38.3
(CH), 35.0 (C), 22.3 (CH3), 22.0 (CH3), 15.2 (CH3); IR (neat) 3090 (w), 2972 (s), 2934
(s), 2826 (m), 1724 (s), 1697 (s), 1454 (m), 1375 (m), 1134 (s), 1082 (s), 848 (w), 750

(s), 682 (m) cm"; HRMS (E1) m/z 256.1248 [(M+); calcd. for C14H210235Cl: 256.1230].

3.1% 1.1%

 

(1R*, 2R*, 6R*, 9R*)-2-chloromethy|-2,9-dimethyl-9-methoxy-3-methy1ene-
bicyclo[4.2.l]non-4-en-1-ol (72).

Following general procedure V, the reaction of 67.8 mg (0.30 mmol) of starting
carbinol 58, afforded 67.2 mg (86%) of 68:69, as a 20:1 diastereomeric mixture, and 7.8
mg (10%) of 72 after purification via flash silica chromatography (1.0 g; 50:1 to 5:1
hexanes/Et0Ac).

72: Rf = 0.35 (5:1 hexanes/Et0Ac); [a]? = -15.9 (C 0.33, CHC13); lH-NMR (300 MHz,
CDC13) 5 6.24 (t, J = 7.7 Hz, 1 H), 5.98 (d, J = 7.7 Hz, 1 H), 5.34 (d, J = 1.1 Hz, 1 H),
5.29 (s, 1 H), 4.17 (dd, J: 13.2, 1.1 Hz, 1 H), 4.05 (dd, J: 13.2, 1.1 Hz, 1 H), 3.52 (s, 1
H), 3.22 (s, 3 H), 2.72 (m, 1 H), 1.99 (d, J = 13.7 Hz, 1 H), 1.97 (dd, J = 14.3.3.3 Hz, 1
H), 1.79 (dd, J = 13.7, 2.2 Hz, 1 H), 1.14 (s, 3 H), 0.98 (s, 3 H), 0.97 (d, J = 13.7 Hz, 1

H); For l-D NOE correlations see figure shown above; l3C-NMR (75 MHz, CDC13) 5

110

150.1 (C), 140.3 (CH), 133.4 (CH), 115.4 (CH2), 78.5 (C), 76.8 (C), 49.7 (CH3), 46.9
(CH2), 45.5 (CH2), 44.6 (C), 43.4 (CH2), 40.7 (CH), 24.6 (CH3), 18.8 (CH3); IR (NaCl,
neat) cm'l 3560 (br m), 3015 (w), 2961 (s), 2934 (s), 2871 (m), 1728 (s), 1630 (w), 1590
(w), 1462 (m), 1379 (m), 1286 (s), 1124 (s), 1124 (s), 1072 (s), 962 (w), 918 (w), 742

(m); HRMS (EI) m/z 256.1219 [(M+); calcd. for CMHZICIOZ: 256.7680].

OMe

, OH
on

73
(1R*, 28*, 6R*, 9R*)-2-chloromethy1-2,9-dimethyl-9-methoxy-3-methy1ene-
bicyclo[4.2.1]non-4-en-1-ol (73).

Following general procedure V, the reaction of 0.14 g (0.65 mmol) of starting
carbinol 59, afforded 0.13 g (82%) of 68:69, as a 1:12 diastereomeric mixture, and 26.9
mg (16%) of 73 after purification via flash silica chromatography (1.0 g; 50:1 to 5:1
hexanes/EtOAC).

135b: Rf = 0.42 (5:1 hexanes/EtOAC); [a]? = -14.0 (C 0.17, CHC13); 1H-NMR (300

MHz, CDC13) 5 6.40 (t, J = 7.7 Hz, 1 H), 5.89 (d, J = 8.2 Hz, 1 H), 5.71 (s, 1 H), 5.60 (s,
1 H), 4.33 (d, J = 12.6 Hz, 1 H), 4.20 (d, J = 12.6 Hz, 1 H), 3.18 (s, 3 H), 2.62 (m, 1 H),
2.57 (d, J: 14.8 Hz, 1 H), 1.77 (d, J: 14.8 Hz, 1 H), 1.56 (s, 1 H), 1.40 (dd, J: 14.8, 3.8
Hz, 1 H), 1.12 (s, 3 H), 1.02 (s, 3 H), 0.92 (d, J = 14.8 Hz, 1 H) l3C-NMR (75 MHz,
CDC13) 5 147.2 (C), 137.6 (CH), 135.2 (CH), 118.6 (CH2), 80.1 (C), 79.4 (C), 49.3
(CH3), 46.3 (CH2), 45.2 (C), 42.0 (CH2), 41.7 (CH2), 41.0 (CH2), 24.9 (CH3), 19.2 (CH3);

IR (NaCl, neat) cm'1 3544 (br w), 3015 (w), 2980 (s), 2932 (s), 2860 (s), 1706 (w), 1623

111

(w), 1458 (s), 1383 (s), 1350 (s), 1278 (m), 1124 (s), 1072 (s), 933 (m), 844 (m), 724 (m);

HRMS (131) m/z 256.3248 [(M"); calcd. for C14H21C102: 256.7680].

 

74

(18*, 2R*-(3R*), 58*, 9R*)-2-(3-chloro)-spiropyrany1-1,9-dimethyl-9-
methoxybicyclo[3.2.2]non-6-en-3-one (74).

Following general procedure V, the reaction of 0.12 g (0.48 mmol) of starting
carbinol 60, afforded 0.13 g (90%) of 74, after purification via flash silica

chromatography (1.0 g; 50:1 to 5:1 hexanes/EtOAC).
74: Rf = 0.08 (5:1 hexanes/Et0Ac); [01133, = +240 (6' 0.20, CHC13); 'H-NMR (500 MHz,

CDC13) 5 6.16 (t, J = 6.6 Hz, 1 H), 6.02 (d, J = 6.6 Hz, 1 H), 4.96 (dd, J = 8.7, 3.8 Hz, 1
H), 3.65 (t, J = 5.5 Hz, 2 H), 3.21 (s, 3 H), 2.75 (m, 1 H), 1.95 (dd, J = 13.7, 3.3 Hz, 1
H), 1.93 (d, J = 14.2 Hz, 1 H), 1.86-1.75 (series of m, 4 H), 1.70 (dd, J = 13.7, 2.7 Hz, 1
H), 1.62 (m, 1 H), 1.13 (s, 3 H), 0.97 (s, 3 H), 0.94 (d, J = 14.2 Hz, 1 H); For l-D NOE
correlations see figure shown above; l3C-NMR (125 MHz, CDC13) 5 208.0 (C), 140.1
(CH), 131.3 (CH), 82.3 (C), 78.3 (C), 61.9 (CH2), 57.4 (C), 49.7 (CH3), 46.2 (CH2), 43.7
(C), 42.2 (CH2), 40.3 (CH), 29.1 (CH2), 29.0 (CH2), 24.4 (CH3), 18.5 (CH3); IR (neat)
3049 (w), 2932 (s), 1724 (s), 1643 (w), 1460 (s), 1367 (s), 1334 (s), 1286 (s), 1224 (s),
1169 (s), 1105 (s), 1062 (s), 910 (s), 846 (m), 756 (m), 731 (m), 704 (m), 667 (s) cm";

HRMS (E1) m/z 298.1244 [(M+); calcd. for C16H23O335C1: 298.8047].

112

 

74

(18*, 2R*, 58*, 98*)-2-(3-chloro)-spirofuranyl-1,9-dimethyI-9-
methoxybicyclo[3.2.2]non-6-en-3-one (75).

Following general procedure V, the reaction of 0.35 g (1.4 mmol) of starting
carbinol 64, afforded 0.17 g (43%) of 75:76, as a 7:1 diastereomeric mixture, after

purification via flash silica chromatography (1.0 g; 50:1 to 5:1 hexanes/EtOAC).
75: R. = 0.56 (4:1 hexanes/Et0Ac); [01136 = -910 (c 0.16, CHC13); 1H-NMR (300 MHz,

CDC13) 5 6.32 (ABq, J = 8.3, 1.9 Hz, 1 H), 5.82 (d, J = 7.3 Hz, 1 H), 4.06 (m, 2 H), 3.03
(s, 3 H), 3.00 (t, J = 5.8 Hz, 1 H), 2.71 (dd, J = 7.3, 2.9 Hz, 2 H), 2.65 (m, 1 H), 2.42 (dd,
J: 14.1, 7.3 Hz, 1 H), 2.33 (dd,J =15. 1, 2.44 Hz, 1 H), 1.91 (d,J = 14.6 Hz, 1 H), 1.33
(d, J = 14.6 Hz, 1 H), 1.29 (s, 3 H), 1.06 (s, 3 H); For l-D NOE correlations see figure
shown above; l3C-NMR (75 MHz, CDC13) 5 208.5 (C), 135.2 (CH), 133.4 (CH), 111.6
(C), 85.4 (CH), 67.9 (C), 65.7 (CH2), 43.8 (CH3), 38.4 (CH2), 37.2 (CH2), 34.9 (C), 33.7
(CH), 25.9 (CH2), 24.4 (CH3), 19.0 (CH3); IR (neat) 3110 (w), 2932 (s), 1721 (m), 1705
(m), 1454 (s), 1369 (s), 1300 (s), 1242 (s), 1217 (s), 1174 (s), 1082 (s), 925 (s), 879 (s),
781 (m), 756 (m), 734 (mw), 677 (mw) cm"; HRMS (EI) m/z 284.1205 [(M“); calcd. for

C15H210335C1: 284.1 179].

113

; éOMe Meoi \;
O O
78 79

(18*, 4R*, 8R*)-1,8-dimethyl-8-methoxybicyclo[2.2.2]octan-2-one (78) and (18*,
4R*, 8S*)-l,8-dimethyl-8-methoxybicyclo[2.2.2]octan-Z-one (79).

A solution containing 1.01 g (5.6 mmol, 1.00 eq) 27:28 and a spatula tip of Pd/C

in 150 mL EtOAc was purged via an aspirator and subsequently charged with H2. The
reaction was stirred at room temperature for 16 hrs The reaction was then gravity filtered
through celite and concentrated. The resultant oil was purified via flash silica
chromatography (15 g; 4:1 hexaneletOAc) to afford 0.52 g (51%) of saturated 78 and
0.47 g (47%) of saturated 79 both as clear oils.
78: Rf = 0.75 (4:1 hexanes/Et0Ac); ‘H-NMR (300 MHz, CDC13) 5 3.01 (s, 3 H), 2.2—1.2
(series of m, 9 H), 1.04 (s, 3 H), 0.72 (s, 3 H); l3C-NMR (75 MHz, CDC13) 5 216.1 (C),
74.6 (C), 49.1 (CH3), 45.9 (CH2), 43.5 (C), 40.7 (CH), 35.9 (CH2), 28.8 (CH2), 22.7
(CH3), 20.5 (CH2), 19.6 (CH3); IR (neat) 2934 (s), 2820 (m), 1720 (s), 1454 (s), 1454 (s),
1346 (s), 1134 (s), 1076 (s), 981 (w), 844 (w), 790 (m) cm"; HRMS (E1) m/z 182.1302
[(M+), calcd. for C11H1802Z 182.1307].

79: Rf = 0.50 (4:1 hexanes/EtOAC); [0113," = -8.0 (c 0.12, CHC13); ‘H-NMR (300 MHz,
CDC13) 5 2.93 (s, 3 H), 2.40 (dt, J = 18.9, 2.7 Hz, 1 H), 2.01 (1, J = 3.0 Hz, 1 H), 1.77
(dd, J = 18.6, 2.7 Hz, 1 H), 1.48 (d, J = 13.8 Hz, 1 H), 1.34 (d, J = 14.4 Hz, 1 H), 1.7-1.4
(series of m, 4 H), 1.14 (s, 3 H), 0.71 (s, 3 H); l3C-NMR (75 MHz, CDC13) 5 215.5 (C),
74.3 (C), 48.7 (CH3), 45.6 (CH2), 43.2 (CH2), 40.3 (CH), 35.6 (C), 28.5 (CH3), 22.3

(CH3), 20.2 (CH3), 19.3 (CH3); IR (116211) 2930 (s), 2828 (m), 1722 (s), 1456 (m), 1375

114

(m), 1174 (m), 1086 (s), 981 (w), 947 (w), 868 (w) cm'l; HRMS (EI) m/z 182.1310

[(M+), C31Cd. fOI‘ CHngOZ: 182.1307].

OMe OMe

OH

80 81
(18*, 2R*, 48*, 8R*)-2-isopropenyl-5-methoxy-1,5-dimethyl-bicyclo[2.2.2]octan-2-ol
(80) and (18*, 28*, 48*, 8R*)-2-isopropeny1-5-methoxy-1,5-dimethyl-
bicyclo[2.2.2]octan-2-ol (81).

Following general procedure I, the reaction of 2.2 g (12.3 mmol) of starting
ketone 78, afforded 0.91 g (81%) of 80:81, as a 2.5:] diastereomeric mixture, after
purification via flash alumina chromatography (25 g; basic Activity III, 50:1
hexanes/EtOAC).

80: Rf = 0.42 (5:1 hexanes/EtOAC); lH-NMR (300 MHz, CDC13) 5 5.07 (d, J = 2.0 Hz, 1
H), 4.74 (d, J = 2.0, Hz, 1 H), 3.15 (s, 3 H), 2.64 (m, 1 H), 2.20 (d, J = 13.4 Hz, 1 H),
1.93 (d, J = 13.4 Hz, 1 H), 1.78 (dd, J = 14.2, 3.5 Hz, 1 H), 1.62 (dd, J = 13.4, 2.0 Hz, 1
H), 1.60 (s, 3 H), 1.40 (s, 1 H), 1.13 (s, 3 H), 1.11 (s, 1 H), 1.05 (series of m, 4 H), 0.98
(s, 3 H); l3C-NMR (75 MHz, CDC13) 5 148.0 (C), 110.5 (CH2), 77.9 (C), 77.4 (C), 50.0
(CH3), 47.8 (CH2), 43.3 (C), 41.2 (CH), 30.8 (CH2), 30.6 (CH2), 25.7 (CH3), 22.1 (CH3),
21.9 (CH2), 17.9 (CH3); LRMS (131) m/z 224.1 (M+ 35C1), 226.1 (M+ 37C1).

81: R, = 0.21 (5:1 hexanes/EtOAC); 'H-NMR (300 MHz, CDC13) 5 4.98 (d, J = 1.7 Hz, 1
H), 4.80 (t, J = 1.7 Hz, 1 H), 3.12 (s, 3 H), 2.69 (m, 1 H), 2.14 (d, J = 12.2 Hz, 1 H), 1.69
(d, J =14.4 Hz, 1 H), 1.65 (s, 3 H), 1.55 (m, 1 H), 1.48 (8,3 H), 1.17 (s, 1 H), 1.15 (d, J

= 14.4 Hz, 1 H), 1.10 (series of m, 4 H), 1.09 (d, J = 12.8 Hz, 1 H), 0.96 (s, 3 H): '3C-

115

NMR (75 MHz, CDC13) 5 146.2 (C), 115.3 (CH2), 79.6 (C), 79.1 (C), 49.8 (CH3), 46.1
(C), 42.1 (CH2), 40.9 (CH), 40.6 (CH2), 24.9 (CH2), 23.9 (CH3), 22.9 (CH3), 22.7 (CH3),
19.3 (CH3); LRMS (EI) m/z 224.1 (M’), 226.1 (M+ 37C1).

202:203: IR (neat) 2958 (s), 2880(8), 1720 (s), 1620 (w), 1452 (s), 1371 (s), 1110 (s),

1064 (s), 920 (m), 899 (m), 856 (w), 720 (m) cm".

 

82

(18*, 28*, 58*, 9R*)-2-chloromethyl-1,2,9-trimethyl-9-methoxybicyclo[3.2.2]non-3-
one (82).

Following general procedure V, the reaction of 80.5 mg (0.35 mmol) of starting
carbinol 80, afforded 74.0 mg (82%) of 82:83, as a 10:1 diastereomeric mixture, after
purification via flash silica chromatography (1.0 g; 50:1 to 5:1 hexanes/EtOAC).

82: Rf = 0.65 (5:1 hexanes/EtOAC); 1H-NMR (300 MHz, CDC13) 5 3.85 (d, J = 10.7 Hz,
1 H), 3.75 (d, J = 10.7 Hz, 1 H), 3.19 (s, 3 H), 2.76 (dd, J = 16.0, 4.0 Hz, 1 H), 2.64 (d, J
= 14.4 Hz, 1 H), 2.55 (m, 1 H), 2.34 (dd, J = 16.0, 4.0 Hz, 1 H), 1.27 (d, J = 14.4 Hz, 1
H), 1.20 (s, 3 H), 1.18 (series of m, 4 H), 1.17 (s, 3 H), 1.08 (s, 3 H); l3C-NMR (75 MHz,
CDC13) 5 209.7 (C), 78.5 (C), 58.4 (C), 49.7 (CH3), 47.6 (CH2), 46.2 (CH2), 40.6 (CH3),
40.1 (CH), 39.8 (C), 28.2 (CH2), 27.6 (CH3), 24.9 (CH2), 24.8 (CH3), 21.6 (CH3); IR
(neat) 3034 (m), 2932 (s), 2828 (m), 1701 (s), 1458 (s), 1371 (s), 1277 (m), 1140 (s),
1064 (s), 916 (m), 738 (s), 680 (s) cm"; HRMS (EI) m/z 258.6305 [(M”); calcd. for

C14H230235C1: 258.7842].

116

 

(18*, 2R*, 58*, 9R*)-2-chloromethyl-l,2,9-trimethyl-9-methoxybicycIo[3.2.2]non-3-
one (83).

Following general procedure V, the reaction of 81.2 mg (0.36 mmol) of starting
carbinol 81, afforded 73.4 mg (79%) of 82:83, as a 14:1 diastereomeric mixture, after
purification via flash silica chromatography (1.0 g; 50:1 to 5:1 hexanes/EtOAC).
83: Rf: 0.38 (5:1 hexanes/EtOAC); 1H-NMR (300 MHz, CDC13) 5 3.62 (d, J = 2.8 Hz, 2
H), 3.17 (s, 3 H), 2.85 (dd, J = 15.4, 5.0 Hz, 1 H), 2.59 (m, 1 H), 2.39 (dd, J = 14.9, 3.0
Hz, 1 H), 2.08 (d, J = 14.9 Hz, 1 H), 1.51 (dd, J = 15.2, 4.9 Hz, 1 H), 1.39 (dd, J = 8.9,
4.9 Hz, 1 H), 1.18 (s, 3 H), 1.14 (s, 3 H), 1.12 (series of m, 3 H), 1.09 (s, 3 H); l3C-NMR
(75 MHz, CDC13) 5 210.9 (C), 78.4 (C), 57.0 (C), 51.1 (CH3), 49.8 (CH3), 45.7 (CH3),
41.3 (CH), 41.2 (CH2), 34.9 (C), 29.9 (CH3), 29.7 (CH2), 25.5 (CH2), 25.1 (CH3), 23.0
(CH3); IR (neat) 3093 (w), 2986 (s), 2804 (s), 2777 (s), 1728 (s), 1705 (m), 1458 (s),
1383 (s), 1298 (m), 1116 (s), 1076 (s), 935 (m), 844 (m), 752 (m) cm"; HRMS (E1) 211/:
258.7513 [(M+);ca1cd. for C14H230235C1: 258.7842].

“8
84

l-vinyl-cyclopentanol (84).

Following general procedure 111, the reaction of 2.10 mL (23.8 mmol) of

cylcopentanone, afforded 2.61 g (98%) of 84 with no need of purification.

117

84: Rf = 0.48 (5:1 hexanes/EtOAC); lH-NMR (300 MHz, CDC13) 5 6.00 (dd, J = 17.1,
10.5 Hz, 1 H), 5.24 (dd, J: 17.4, 1.5 Hz, 1 H), 5.00 (dd, J: 10.8, 1.2 Hz, 1 H), 1.80 (m,
3 H), 1.65 (series of m, 6 H); l3C-NMR (75 MHz, CDC13) 5 144.4 (CH), 111.0 (CH3),
82.1 (C), 40.2 (2 CH2), 23.6 (2 CH2); IR (neat) 3372 (br s), 3088 (w), 2961 (s), 2874 (s),
1641 (m), 1439 (m), 1415 (m), 1321 (m), 1228 (m), 1192 (m), 1064 (m), 993 (s), 916 (s)
cm"; LRMS (EI) m/z 112.1 (M‘).

For previous syntheses see: (a) Johnson, C. R.; Cheer, C. J.; Goldsmith, D. J. Org.
Chem. 1964, 29, 3320-3323. (b) Marcou, A.; Normant, H. Bull. Soc. Chim. France

1965, 3491-3494.

H0

85

l-vinyl-cyclohexanol (85).

Following general procedure 111, the reaction of 1.06 mL (10.1 mmol) of
cylcohexanone, afforded 1.28 g (quantitative) of 85 with no need of purification.
85: Rf = 0.42 (5:1 hexanes/EtOAC); 1H-NMR (300 MHz, CDC13) 5 5.94 (dd, J = 17.4,
10.6 Hz, 1 H), 5.24 (dd, J = 17.1, 1.2 Hz, 1 H), 5.02 (dd, J = 10.8, 1.5 Hz, 1 H), 1.53
(series of m, 11 H); l3C-NMR (75 MHz, CDC13) 5 l3C-NMR (75 MHz, CDC13) 5 145.9
(CH), 111.4 (CH2), 71.5 (C), 37.5 (CH2), 25.4 (2 CH2), 21.9 (2 CH2); IR (neat) 3385 (br
s), 3086 (m), 3007 (m), 2934 (s), 2858 (s), 1652 (m), 1448 (s), 1352 (m), 1265 (m), 1175
(m), 1053 (s), 993 (s), 962 (s), 922 (s), 852 (m) cm"; LRMS (EI) m/z 126.0 (M).
Commerically available or for original synthesis see: Marcou, A.; Normant, H. Bull.

Soc. Chim. Fr. 1965, 3491—3494.

118

l-vinyl-cycloheptanol (86).

Following general procedure HI, the reaction of 1.50 mL (12.7 mmol) of
cylcoheptanone, afforded 1.72 g (97%) of 86 with no need of purification.
86: Rf: 0.57 (5:1 hexanes/EtOAC); 1H-NMR (300 MHz, CDC13) 5 5.93 (ddd, J = 17.4,
10.8, 1.8 Hz, 1 H), 5.09 (dd, J: 17.4, 1.5 Hz, 1 H), 4.87 (dd, J: 10.8, 1.5 Hz, 1 H), 1.95
(m, 1 H), 1.60 (series of m, 6 H), 1.39 (series of m, 6 H); l3C—NMR (75 MHz, CDC13) 5
146.4 (CH), 109.9 (CH2), 75.3 (C), 40.8 (2CH2), 29.3 (2CH2), 21.9 (2CH2); IR (neat)
3379 (br s), 3084 (w), 3007 (w), 2939 (s), 2858 (s), 1625 (w), 1460 (s), 1415 (m), 1344
(m), 1203 (m), 1089 (m), 1030 (s), 995 (s), 954 (m), 918 (s), 844 (m) cm"; LRMS (E1)
m/z 140.2 (M+).

For original synthesis see: Marcou, A.; Normant, H. Bull. Soc. Chim. Fr, 1965, 3491-

1-10,“ 1 HO,” 1
87 as

(18*, 28*)-2-methyl-l-vinyl-cyclopentanol (87) and (1R*, 28*)-2-methy1-l-vinyl-

3494.

cyclopentanol (88).

Following general procedure 111, the reaction of 2.00 g (20.3 mmol) of
methylcyclopentanone, afforded 2.21 g (86%) of 87:88, as a 10:1 mixture of
diastereomers, after purification via flash alumina chromatography (60 g; basic Activity

III, 50:] hexanes/EtOAC).

119

87: Rf: 0.43 (4:1 hexanes/Et0Ac); 1H-NMR (500 MHz, CDC13) 5 5.78 (dd, J = 17.2,
10.6 Hz, 1 H), 5.19 (d, J: 17.2 Hz, 1 H), 5.01 (d, J: 11.0 Hz, 1 H), 1.71 (series of m, 4
H), 1.58 (m, 1 H), 1.43 (m, 2 H), 0.80 (d, J: 6.6 Hz, 3 H); ”C-NMR (75 MHz, CDC13) 5
143.7 (CH), 111.9 (CH2), 82.4 (C), 43.4 (CH), 40.2 (CH2), 31.5 (CH2), 21.3 (CH2). 11.7
(CH3); IR (neat) 3453 (br s), 3088 (w), 2963 (s), 2974 (s), 1722 (s), 1456 (s), 1375 (m),
1155 (m), 1045 (m), 999 (m), 947 (m), 916 (m), 734 (m) cm'l; LRMS (E1) m/z 126.1
(M+).

88: Rf: 0.67 (4:1 hexanes/EtOAc); lH-NMR (500 MHz, CDC13) 5 5.63 (dd, J = 17.2,
10.6 Hz, 1 H), 5.05 (dd, J: 17.2, 1.7 Hz, 1 H), 4.85 (dd, J = 11.0, 1.3 Hz, 1 H), 1.84 (m,
2 H), 1.54 (series of m, 4 H), 1.05 (m, 1 H), 0.62 (d, J = 7.0 Hz, 3 H); l3C-NMR (75
MHz, CDC13) 5 141.1 (CH), 111.6 (CH2), 82.0 (C), 44.7 (CH), 37.5 (CH2), 31.2 (CH3),
20.5 (CH2), 15.9 (CH3); IR (neat) 3447 (br s), 3092 (w), 2961 (s), 2874 (s), 1732 (m),
1456 (m), 1375 (m), 1109 (m), 995 (s), 949 (s), 918 (s), 734 (m) cm"; LRMS (E1) m/z
126.1 (M+).

For original synthesis see: Battioni, J. P.; Capmau, M. L.; Chodkiewicz, W. Bull. Soc.

Chim. Fr. 1969, 976-981.

0

6A..

2-chloromethy1 cyclohexanone (89).
Following general procedure V, the reaction of 0.25 g (2.2 mmol) of 84, afforded

0.23 g (69%) of 89, and 0.025 g (10%) 90 after purification via flash silica

chromatography (12 g; 10:1 hexanes/EtOAC).

120

89: Rf: 0.46 (5:1 hexanes/EtOAC); ‘H-NMR (500 MHz, CDC13) 5 3.84 (dd, J = 11.5.4.9
Hz, 1 H), 3.41 (dd, J = 11.5, 7.6 Hz, 1 H), 2.62 (d1, J = 7.6, 4.9 Hz, 1 H), 2.37 (m, 2 H),
2.28 (m, 1 H), 2.07 (m, 1 H), 1.90 (m, 1 H), 1.65 (m, 2 H), 1.42 (m, 1 H); l3C—NMR (75
MHz, CDC13) 5 222.8 (C), 56.8 (CH), 39.2 (CH2), 38.6 (CH2), 36.1 (CH2), 26.3 (CH3),
20.2 (CH2); IR (neat) 3056 (w), 2930 (s), 2860 (s), 1707 (s), 1448 (s), 1373 (m), 1267
(m), 1130 (m), 1074 (m), 974 (w), 951 (w), 734 (m) cm"; HRMS (131) m/z 146.0508

[(M+); calcd. for C7H..35C1o: 146.0498].

For original synthesis see: Portnyagin, Y. M.; Chemysh, O. N. Zh. Org. Khim. 1974, 10,

2117-2119.

0

ii”

90

2-methylene-cyclohexanone (90).

Following general procedure V, the reaction of 0.51 g (4.6 mmol) of 84, afforded
0.28 g (56%) of 90 after purification via flash silica chromatography (15 g; 1%
Et3N/hexanes).
90: Rf = 0.67 (5:1 hexanes/Et0Ac); 1H-NMR (500 MHz, CDC13) 5 5.80 (d, J = 1.5 Hz, 1
H), 5.10 (d, J = 1.5 Hz, 1 H), 2.55 (t, J = 6.0 Hz, 1 H), 2.42 (t, J = 6.5 Hz, 1 H), 1.87 (t, J
= 6.5 Hz, 1 H), 1.83 (m, 1 H), 1.74 (t, J: 6.5 Hz, 1 H), 1.70 (m, 1 H), 1.59 (m, 1 H), 1.50
(m, 1 H); l3C-NMR (125 MHz, CDC13) 5 211.9 (C), 145.3 (C), 120.1 (CH2), 40.7 (CH2),
34.6 (CH2), 32.8 (CH2), 25.2 (CH2); IR (neat) 3012 (w), 2932 (s), 2862 (s), 1718 (s),
1654 (m), 1446 (m), 1377 (m), 1269 (m), 1120 (s), 1068 (s), 1047 (m), 999 (m), 960 (m),

906 (m), 887 (m) cm"; HRMS (E1) m/z 110.0726 [(M+) calcd. for C7HIOO: 110.0732].

121

For previous syntheses see: (a) Muehlstaedt, M.; Herzschuh, R. J. Prakt. Chem. 1963,
20, 20-34. (b) Muehlstaedt, M.; Zach, L.; Becwar-Reinhardt, H. J. Prakt. Chem. 1965,
29, 158-172. (c) Ksander, G. M.; McMurry, J. E.; Johnson, M. J. Org. Chem. 1977, 42,

1180-1185.

0

601
91

2-chloromethy1 cycloheptanone (91).

Following general procedure V, the reaction of 0.36 g (2.9 mmol) of 85, afforded
0.30 g (65%) of 91 and 68.6 mg (12%) of 92 after purification via flash silica
chromatography (14 g; 10:1 hexanes/EtOAC).
91: R; = 0.52 (5:1 hexanes/EtOAC); IH-NMR (500 MHz, CDC13) 5 3.76 (dd, J = 10.9,
6.0 Hz, 1 H), 3.45 (dd, J = 10.9, 7.1 Hz, 1 H), 2.86 (m, 1 H), 2.48 (m, 2 H), 1.85 (m, 4
H), 1.64 (m, 2 H), 1.43 (m, 2 H); I3C-NMR (125 MHz, CDC13) 5 212.8 (C), 53.8 (CH),
45.2 (CH2), 43.7 (CH2), 29.2 (CH2), 29.0 (CH2), 28.8 (CH2), 23.6 (CH2); IR (neat) 2930
(s), 2855 (s), 1699 (s), 1452 (m), 1331 (w), 1221 (w), 1143 (w), 1107 (w), 939 (w), 835
(w) em"; HRMS (EI) m/z 160.0652 [(M+) calcd. for C3H1335C1O: 160.0655].
For original synthesis see: Ryu, I.; Ogawa, A.; Sonoda, N. Nippon Kagaku Kaishi 1985,

442-444

Cl

? ,Cl
H0

92

1-(1,2-dichloro-ethyl)-cyclohexanol (92).

122

Following general procedure V, the reaction of 0.36 g (2.9 mmol) of 85, afforded
0.30 g (65%) of 91 and 68.6 mg (12%) of 92 after purification via flash silica
chromatography (14 g; 10:1 hexanes/EtOAc).
92: Rf = 0.40 (5:1 hexanes/EtOAC); 1H-NMR (500 MHz, CDC13) 5 4.06 (dd, J = 11.9,
3.0 Hz, 1 H), 3.98 (dd, J = 8.8, 3.0 Hz, 1 H) 3.66 (dd, J = 11.9, 8.8 Hz, 1 H), 2.01 (s, 1
H), 1.75 (d, J = 12.8 Hz, 2 H), 1.68 (d, J = 13.2 Hz, 2 H), 1.55 (m, 6 H); l3C-NMR (125
MHz, CDC13) 5 73.3 (C), 72.3 (CH), 45.8 (CH2), 34.8 (CH2), 34.0 (CH2), 25.3 (CH3),
21.6 (CH2), 21.4 (CH2); IR (neat) 3456 (br s), 2936 (s), 2858 (s), 1448 (m), 1377 (m),
1319 (m), 1261 (m), 1149 (m), 1041 (m), 981 (m), 902 (m), 852 (w), 765 (m), 727 (m)

cm"; HRMS (EI) m/z 196.0425 [(M+)ca1cd. for C3H1435C120: 196.0422].

8..

93

2-chloromethyl cyclooctanone (93).

Following general procedure V, the reaction of 0.42 g (3.2 mmol) of 86, afforded
0.35 g (62%) of 93 and 0.12 g (18%) of 94 after purification via flash silica
chromatography (15 g; 10:1 hexanes/Et0Ac).
93: Rf = 0.56 (5:1 hexanes/Et0Ac); 1H—NMR (300 MHz, CDC13) 5 3.70 (dd, J = 10.4,
8.7 Hz, 1 H), 3.33 (dd, J = 10.4, 5.4 Hz, 1 H), 3.04 (m, 1 H), 2.39 (ddd, J = 14.8, 7.1, 3.2
Hz, 1 H), 2.29 (ddd, J: 14.8, 10.9, 3.2 Hz, 1 H), 2.01 (m, 1 H), 1.83 (ddd, J: 13.7, 6.5.
3.2 Hz, 1 H), 1.72 (m, 1 H), 1.60 (m, 1 H), 1.48 (m, 4 H), 1.34 (m, 1 H), 1.00 (m, 1 H):
13C-NMR (125 MHz, CDC13) 5 216.5 (C), 51.4 (CH), 44.8 (CH2), 44.0 (CH3), 31.9

(CH2), 27.8 (CH2), 24.5 (CH2), 24.3 (CH2), 23.3 (CH2); IR (neat) 2928 (s), 2856 (s), 1701

123

(s), 1484 (s), 1448 (s), 1332 (m), 1199 (m), 1084 (m), 962 (w), 850 (w), 717 (s) cm":

HRMS (E1) m/z 174.0853 [(M+) calcd. for C9H1535C10: 174.081 1].

Cl Cl
H0

94

1-(1,2-dichloro-ethyl)-cycloheptanol (94).

Following general procedure V, the reaction of 0.42 g (3.2 mmol) of 86, afforded
0.35 g (62%) of 93 and 0.12 g (18%) of 94 after purification via flash silica
chromatography (15 g; 10:1 hexanes/Et0Ac).
94: Rr = 0.44 (5:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDC13) 5 4.02 (dd, J = 5.7, 3.9
Hz, 1 H), 3.96 (d, J = 6.1 Hz, 2 H), 2.33 (s, l H), 1.97 (dd, J = 14.5, 9.7 Hz, 1 H), 1.81
(dd, J = 14.1, 9.2 Hz, 1 H), 1.65 (m, 4 H), 1.56 (m, 4 H), 1.40 (m, 2 H); l3C-NMR (125
MHz, CDC13) 5 77.3 (C), 72.6 (CH), 64.0 (CH2), 38.3 (CH2), 38.3 (CH2), 29.5 (CH3),
29.4 (CH2), 22.2 (CH2), 22.2 (CH2); IR (neat) 3449 (br m), 2928 (s), 2858 (s), 1460 (s),
1317 (m), 1253 (m), 1192 (m), 1120 (m), 1049 (m), 929 (m), 707 (m) cm"; HRMS (E1)

771/: 210.0563 [(M+)ca1cd. for C9H.635C12o: 210.0578].

1.20/o 1’10/0
. °/
8.4% 1 0
O H CI 0 Cl
’ H. t H
H I
"17,, \_)\ "I 1 .1 °/o
2.8% ”I

95 96

 

2-chloromethy1-3-methyl-cyclohexanone (95).

124

Following general procedure V, the reaction of 0.90 g (7.1 mmol) of 87, afforded
0.81 g (71%) of 95:96, as a 5:1 diastereomeric mixture, 88.6 mg (18%) of 97, and (<2%)
98 after purification via flash silica chromatography (20 g; 10:1 hexanes/EtOAC).
95: Rf = 0.67 (5:1 hexanes/EtOAc); 1H-NMR (300 MHz, CDC13) 5 3.78 (dd, J = 11.5,
6.0 Hz, 1 H), 3.37 (dd, J = 11.5, 8.7 Hz, 1 H), 2.79 (dt, J = 8.7, 5.4 Hz, 1 H), 2.61 (m, 1
H), 2.25 (m, 2 H), 1.86 (m, 2 H), 1.68 (m, 1 H), 1.01 (m, 1 H), 0.74 (d, J = 7.1 Hz, 3 H);
l3C-NMR (75 MHz, CDC13) 5 208.2 (C), 57.7 (CH), 41.0 (CH2), 39.9 (CH2), 35.7 (CH3),
33.3 (CH2), 24.8 (CH), 19.9 (CH3); IR (neat) 2932 (s), 2870 (s), 1709 (s), 1456 (s), 1377
(m), 1267 (w), 1155 (m), 1126 (w), 1080 (w), 1047 (w), 1016 (w), 991 (w), 951 (w), 736

(m) cm“: HRMS (151) m/z. 160.0655 [(M+) calcd. for C8H1335C120: 160.0655].

0

(if

97

3-methyl-2-methylene-cyclohexanone (97).

Following general procedure V, the reaction of 0.90 g (7.1 mmol) of 87, afforded
0.81 g (71%) of 95:96, as a 5:1 diastereomeric mixture, 88.6 mg (18%) of 97, and (<2%)
98 after purification via flash silica chromatography (20 g; 10:1 hexanes/Et0Ac).
97; Rf = 0.61 (5:1 hexanes/EtOAC); ‘H-NMR (300 MHz, CDC13) 5 5.66 (s, 1 H). 5.01 (s,
1 H), 2.45 (m, 1 H), 2.38 (dt, J = 16.8, 5.4 Hz, 1 H), 2.25 (ddd, J = 5.9, 10.2, 5.1 Hz, 1
H), 1.74 (series of m, 4 H), 1.02 (d, J = 6.6, 3 H); l3C-NMR (75 MHz, CDC13) 5 202.3
(C), 151.0 (C), 117.5 (CH2), 40.3 (CH2), 36.3 (CH), 32.3 (CH2), 21.7 (CH2), 19.1 (CH3):
IR (neat) 3055 (w), 2932 (s), 2868 (s), 1707 (s), 1635 (m), 1458 (s), 1377 (s), 1265 (s).
1188 (s), 1124 (s), 1051 (s), 1018 (s), 968 (s), 920 (s), 736 (s) cm’l; HRMS (E1) m/z

124.0890 [(M+) calcd. for CnggO: 124.0888].

125

2%

OH
100

(+/-)-(1R*, 2R*, 48 *)-2-vinyl-bicyclo[2.2.l]heptan-2-ol (100).

Following general procedure I, the reaction of 2.15 g (19.5 mmol) of norcamphor,

afforded 0.93 g (49%) of 99:100, as a 125.7 diastereomeric mixture, after purification via
flash alumina chromatography (60 g; basic, Activity III; 20:1 hexanes/EtOAC).
100: Rf = 0.44 (5:1 hexanes/EtOAc); 1H-NMR (300 MHz, CDC13) 5 5.97 (ddd, J = 17.4,
10.8, 0.9 Hz, 1 H), 5.10 (dt, J: 17.4, 1.2 Hz, 1 H), 5.91 (dt, J = 10.8, 1.2 Hz, 1 H), 2.16
(br s, 1 H), 2.03 (br s, 1 H), 1.97 (m, l H), 1.86 (br s, 1 H), 1.79 (dABq, J: 13.2, 4.5, 1.5
Hz, 1 H), 1.49 (dq, J: 13.9, 8.1 Hz, 1 H), 1.47 (d, J: 10.2 Hz, 1 H), 1.40-1.18 (series of
m, 3 H), 1.12 (dd, J = 12.9, 3.6 Hz, 1 H); l3C-NMR (75 MHz, CDC13) 5 145.4 (CH),
110.1 (CH2), 79.0 (C), 47.1 (CH), 44.6 (CH2), 38.1 (CH2), 37.0 (CH), 28.7 (CH2), 21.7
(CH2); IR (neat) 3370 (br s), 3070 (w), 2955 (s), 2872 (s), 1630 (w), 1454 (m), 1410 (m),
1307 (s), 1163 (m), 1072 (m), 1054 (m), 993 (s), 981 (s), 916 (s), 881 (w), 844 (w), 734
(m) cm“; HRMS (131) m/z 138.1042 [(M“) calcd. for C,H,,o: 138.1045].

For previous synthesis see: Sundararaman, P.; Fallis, A. G. J. Org. Chem. 1977, 42,

9%

OH

813-819.

102

(+/-)-(1R*, 28 *, 48 *)-l,3,3-trimethyl-2-vinyl-bicyclo[2.2.1]heptan-2-ol (102).

126

Following general procedure I, the reaction of 2.02 g (13.2 mmol) of fenchone,
afforded 1.14 g (52%) of 101:102, as a 1:10 diastereomeric mixture, after purification via
flash alumina chromatography (60 g; basic, Activity 111; 50:1 hexanes/EtOAC).

102: Rf = 0.67 (5:1 hexanes/Et0Ac); 1H-NMR (300 MHz, CDC13) 5 5.91 (dd, J = 17.1,
10.8 Hz, 1 H), 5.10 (dd, J: 17.1, 1.8 Hz, 1 H), 4.95 (dd,J: 10.5,1.8 Hz, 1 H), 1.90 (m,
l H), 1.66 (d, 1 H), 1.64 (m, 2 H), 1.42—1.30 (series of m, 2 H), 1.10 (d, J = 9.0 Hz, 1 H),
0.95 (dd, J = 12.9, 3.9 Hz, 1 H), 0.88 (s, 3 H), 0.85 (s, 3 H), 0.84 (s, 3 H); '3015%: (75
MHz, CDC13) 5 142.7 (CH), 110.0 (CH2), 82.2 (C), 52.0 (C), 48.3 (CH), 44.2 (C), 40.5
(CH2), 29.1 (CH2), 28.5 (CH3), 25.4 (CH2), 21.8 (CH3), 17.1 (CH3); IR (neat) 3507 (br
w), 3086 (w), 2961 (s), 2934 (s), 2876 (m), 1670 (w), 1460 (m), 1385 (m), 1319 (w),
1261 (w), 1169 (w), 1134 (m), 1099 (m), 1080 (m), 1022 (w), 995 (m), 912 (m) cm";
HRMS (EI) m/z 180.1355 [(M+) calcd. for CrszoO: 180.1514].

For previous synthesis see Keegan, D. 8.; Midland, M. M.; Werley, R. T.; McLoughlin, J.

I. J. Org. Chem. 1991, 56, 1185-1191.

OH

/

1113

(+/-)-(1R*, 2R*, 4R*)-l,7,7-trimethyl-2-vinyl-bicyclo[2.2.1]heptan-2-ol (103).
Following general procedure I, the reaction of 11.2 g (0.07 mol) of camphor,

afforded 11.0 g (83%) of 103 after purification via flash alumina chromatography (300 g;

basic, Activity HI; 100:1 hexanes/EtOAC).

103: Rf = 0.59 (5:1 hexanes/EtOAC); 1H-NMR (300 MHz, CDC13) 5 6.01 (dd, J = 17.1.

10.8 Hz, 1 H), 5.19 (dd, J: 17.4, 1.2 Hz, 1 H), 5.03 (dd, J = 10.8, 1.5 Hz, 1 H), 2.31 (dt,

127

J = 18.3, 3.6 Hz, 1 H), 1.92 (m, 2 H), 1.89 (d, J = 18.6 Hz, 2 H), 1.47 (s, 1 H), 1.32 (m, 2
H), 1.10 (s, 3 H), 0.79 (s, 3 H), 0.78 (s, 3 H); ”C-NMR (75 MHz, CDC13) 5 143.8 (CH),
112.0 (CH2), 81.4 (C), 60.3 (C), 42.9 (C), 31.1 (CH2), 29.8 (CH), 26.9 (CH3). 19.7 (CH3),
14.1 (CH3), 9.6 (CH3), 9.2 (CH3); IR (neat) 3508 (br s), 3058 (w), 2972 (s), 1625 (m).
1454 (s), 1398 (s), 1371 (s), 1325 (m), 1275 (s), 1069 (s), 999 (m), 972 (m), 918 (s), 736
(s) cm"; LRMS (E1) m/z 180.1 (M).

For previous synthesis see: Capman, M. L.; Chodkiewicz, W.; Cadiot, P. Tetrahedron
Lett. 1965, 1619-1624. Keegan, D. 8.; Midland, M. M.; Werley, R. T.; McLoughlin, J. I.
J. Org. Chem. 1991, 56, 1185-1191.

OMe OMe

OH
\
/ OH

105 108

(18*, 28*, 4R*, 8R*)-l,8-dimethyl-2-ethenyl-8-methoxybicyclo[2.2.2]octan-2-ol (105)
and (18*, 2R*, 4R*, 8R*)-1,8-dimethy1-2-ethenyl-8-methoxybicyclol2.2.2]octan-2-ol
(106).

Following general procedure I, the reaction of 0.52 g (2.8 mmol) of starting
ketone 78, afforded 0.51 g (85%) 105:106, as a 2.5:] diastereomeric mixture, after
purification via flash alumina chromatography (3 g; basic, Activity 111; 100:1
hexanes/Et0Ac).

105: Rf = 0.37 (5:1 hexanes/EtOAC); lH-NMR (300 MHz, CDC13) 5 5.88 (dd, J = 17.1,
10.8 Hz, 1 H), 5.27 (dd,J: 17.4, 2.4 Hz, 1 H), 5.05 (dd, J: 10.8, 2.1 Hz, 1 H), 3.18 (s, 3
H), 1.89 (m, 1 H), 1.80 (dd, J: 12.9, 1.8 Hz, 1 H), 1.79 (m, 1 H), 1.73 (m, 1 H), 1.63 (dd,

J = 14.4, 2.1 Hz, 1 H), 1.48 (series of m, 3 H), 1.29 (br s, 1 H), 1.22 (s, 3 H), 1.10 (d, J =

128

15.0 Hz, 1 H), 0.69 (s, 3 H); l3’C-NMR (75 MHz, CDC13) 5 141.2 (CH), 112.4 (CH3),
76.5 (C), 73.5 (C), 49.3 (CH3), 45.3 (CH2), 39.3 (CH2), 36.8 (C), 33.8 (CH), 29.2 (CH3),
23.5 (CH2), 22.2 (CH3), 21.3 (CH3); IR (NaCl, neat) 3458 (br m), 3015 (w), 2949 (s),
2870 (m), 2829 (w), 1740 (w), 1450 (m), 1373 (m), 1140 (m), 1064 (s), 989 (m), 945 (w),
920 (m) cm"; HRMS (131) m/z 210.1629 [(M+), calcd. for C13H2202: 210.1620].

106: Rf = 0.25 (5:1 hexanes/EtOAc); IH-NMR (300 MHz, CDC13) 5 6.10 (dd, J = 17.4,
10.8 Hz, 1 H), 5.16 (dd, J=17.1,1.5 Hz, 1 H), 5.01 (dd, J: 10.8, 1.5 Hz, 1 H), 3.09 (s, 3
H), 2.14 (dt, J=14.1,3.0 Hz, 1 H), 1.76 (m, 2 H), 1.59 (dd, J: 14.2 Hz, 2 H), 1.51 m, 1
H), 1.31 (s, 1 H), 1.25 (dd, J: 14.4, 3.3 Hz, 1 H), 1.21 (5,3 H), 1.10 (d, J: 14.4 Hz, 1
H), 0.88 (s, 1 H), 0.64 (s, 3 H); l3C-NMR (75 MHz, CDC13) 5 143.7 (CH), 111.2 (CH3),
76.0 (C), 74.7 (C), 48.6 (CH3), 46.0 (CH2), 38.2 (CH2), 36.7 (C), 33.8 (CH), 27.6 (CH3),
23.9 (CH3), 22.3 (CH2), 20.9 (CH3); IR (NaCl, neat) 3466 (br s), 3084 (w), 2947 (s), 2826
(m), 1722 (m), 1639 (w), 1450 (m), 1373 (m), 1271 (m), 1167 (m), 118 (m), 1066 (m),

991 (m), 945 (w), 918 (m) cm'l; HRMS (EI) m/z 210.1614 [(M+), calcd. for C(3H3203:

MeO MeO
OH
9Q
/ OH
107 1 08

(18*, 28*, 4R*, 88*)-1,8-dimethyl-2-etheny1-8-methoxybicyclo[2.2.2]octan-2-ol (107)

210.1620].

and (18*, 2R*, 4R*, 88*)-1,8-dimethy1-2-ethenyl-8-methoxybicyclo[2.2.2]octan-2-ol
(108).
Following general procedure 1, the reaction of 0.75 g (4.1 mmol) of starting

ketone 79, afforded 0.61 g (70%) 107:108, as a 1.1:1 diastereomeric mixture, after

129

purification via flash alumina chromatography (3 g; basic, Activity 111; 100:1
hexanes/EtOAC).

107: Rf = 0.44 (4:1 hexanes/EtOAC); lH—NMR (300 MHz, CDC13) 5 5.95 (dd, J = 17.1,
10.8 Hz, 1H), 5.13 (dd, J: 16.5, 1.5 Hz, 1 H), 4.97 (dd, J=11.1, 1.5 Hz, 1H), 3.07 (s, 3
H), 2.20-1.23 (series of m, 9 H), 1.22 (s, 3 H), 1.13 (s, 1 H), 0.61 (s, 3 H); l3C-NMR (75
MHz, CDC13) 5 143.9 (CH), 111.4 (CH2), 75.5 (C), 74.8 (C), 48.7 (CH3), 45.5 (CH3),
40.3 (CH2), 36.4 (C), 34.2 (CH), 28.6 (CH2), 22.6 (CH3), 21.0 (CH3), 20.4 (CH2); HRMS
(131) m/z 210.1615 [(M+), calcd. for C13H2202: 210.1620].

108: Rf: 0.37 (4:1 hexanes/EtOAC); 1H-NMR (300 MHz, CDC13) 5 5.87 (dd, J = 16.8,
10.8 Hz, 1 H), 5.13 (dd, J: 16.5, 0.9 Hz, 1 H), 4.97 (dd, J: 10.8, 1.5 Hz, 1 H), 3.08 (s, 3
H), 2.20-1.23 (series of m, 9 H), 1.12 (s, 3 H), 0.82 (s, 1 H), 0.59 (s, 3 H); ”C-NMR (75
MHz, CDC13) 5 143.1 (CH), 111.7 (CH2), 75.7 (C), 75.0 (C), 49.1 (CH3), 44.0 (CH2),
39.9 (CH2), 36.1 (C), 33.8 (CH), 27.4 (CH2), 22.8 (CH3), 21.1 (CH3), 19.7 (CH3); HRMS
(E1) m/z 210.1622 [(M+), calcd. for 03szng 210.1620].

107:108: IR (neat) 3460 (br s), 3084 (w), 2934 (s), 2826 (m), 1637 (m), 1456 (s), 1373

(s), 1246 (s), 1076 (s), 995 (s), 920 (s) cm".

0 ° \

109 110
(+/-)-(1R*, 58*)-2-methylene-bicyclo[3.2.1]octan-3-one (109) and (+/-)-(1R*, 58*)-3-
methylene-bicyclo[3.2.l]octan-2-one (110).
Following general procedure V, the reaction of 0.51 g (3.6 mmol) of 100,

afforded 0.41 g (82%) 109:110, as a 1:1.6 regiomeric mixture, after purification via flash

silica chromatography (15 g; 1% Et3N/hexanes).

130

109: Rf = 0.56 (5:1 hexanes/EtOAC); 'H-NMR (300 MHz, CDC13) 5 5.94 (s, 1 H), 5.15
(s, 1 H), 2.75 (1, J = 2.7 Hz, 1 H), 2.51 (m, 1 H), 2.39 (series of m, 2 H), 1.93-1.45 (series
of m, 6 H); l3C-NMR (75 MHz, CDC13) 5 203.1 (C), 142.4 (C), 122.5 (CH3), 49.7 (CH),
39.2 (CH2), 35.6 (CH2), 34.1 (CH), 28.8 (CH2), 28.2 (CH2); IR (neat) 3092 (w), 2955 (s),
2874 (s), 1697 (s), 1612 (m), 1450 (m), 1286 (m), 1188 (m), 1107 (s), 1057 (m), 981 (w),
939 (m), 916 (m), 734 (s) cm": LRMS (ED m/z 136.0 (M‘).

110: R. = 0.57 (5:1 hexanes/EtOAC); 'H-NMR (500 MHz, CDC13) 5 5.66 (d. J = 2.0 Hz,
1 H), 4.98 (d, J = 1.5 Hz, 1 H), 3.04 (1. J = 4.5 Hz, 1 H), 2.51 (d, J = 2.5 Hz, 1 H), 2.43
(m, 1 H). 2.38 (dd, J = 7.5, 4.0 Hz, 1 H), 1.85 (m, 2 H), 1.77 (d, J = 12.0 Hz, 1 H), 1.71
(m, 1 H), 1.55 (m, 1 H), 1.49 (m, 1 H); l3C-NMR (75 MHz, CDC13) 5 201.6 (C), 151.4
(C), 117.1 (CH2), 49.3 (CH), 42.7 (CH), 37.3 (CH2), 34.0 (CH2), 31.4 (CH3), 29.3 (CH3);
IR (neat) 3092 (w), 2955 (s), 2874(8), 1697(5), 1612 (m), 1450 (m), 1286 (m), 1188 (m),
1107 (s), 1057 (m), 981 (w), 939 (m), 916 (m), 734 (s) cm"; HRMS (E1) m/z 136.0887
[(M”) calcd. for CanO: 136.0888].

For original synthesis of 105 see: Keenan, M.; Rocco, V. P.; Takeuchi, K.; Tupper, D.

E.; Vixien, V. Patent GB2367554. 2002.

51. .

O
111 112

(+/-)-(1R*, 58*)-1,4,4-trimethyl-2-methylene-bicyclo[3.2.1]octan-3-one (111) and

(+/-)-(1R*, SS *)-1,4,4-trimethy1-3-methylene-bicyclo[3.2.1]octan-3-one (112).
Following general procedure V, the reaction of 0.50 g (3.0 mmol) of 102,

afforded 0.43 g (86%) 111:112, as a 121.5 regiomeric mixture, after purification via flash

silica chromatography (15 g; 1% Et3N/hexanes).

131

111: Rf = 0.71 (5:1 hexanes/EtOAC); 1H-NMR (300 MHz, CDC13) 5 5.74 (s, 1 H), 5.09
(s, 1 H), 1.98 (d, J = 12.6 Hz, 2 H), 1.83 (series of m, 2 H), 1.55—1.27 (series of m, 3 H),
1.10 (s, 3 H), 1.07 (s, 3 H), 0.98 (s, 3 H); l3C—NMR (125 MHz, CDC13) 5 205.4 (C),
173.5 (C), 114.4 (CH2), 57.5 (C), 42.6 (C), 40.0 (CH), 35.0 (CH2), 34.3 (CH3), 30.3
(CH2), 21.8 (CH3), 19.8 (CH3), 19.3 (CH3); 1R (NaCl, neat) 3081 (w), 2968 (s), 2874 (s),
1695 (s), 1610 (m), 1462 (s), 1385 (m), 1267 (m), 1051 (s), 1030 (m), 935 (m), 908 (m),
736 (s) cm"; LRMS (BI) m/z 178.2 (M’).

112; Rf = 0.74 (5:1 hexanes/EtOAC); 1H-NMR (500 MHz, CDC13) 5 5.54 (d, J = 1.5 Hz,
1 H), 5.02 (d, J = 1.5 Hz, 1 H), 2.02 (m, 1 H), 2.00 (s, 1 H), 1.98 (d, J = 11.7 Hz, 1 H).
1.77 (series of m, 2 H), 1.51 (m, 2 H), 1.24 (s, 3 H), 1.10 (s, 3 H), 1.04 (s, 3 H); l3C-NMR
(125 MHz, CDC13) 5 207.9 (C), 154.8 (C), 114.5 (CH2), 48.7 (C), 46.8 (C), 45.5 (CH),
41.5 (CH2), 37.4 (CH2), 26.5 (CH2), 26.4 (CH3), 23.2 (CH3), 23.1 (CH3); IR (NaCl, neat)
3081 (w), 2968 (s), 2874 (s), 1695 (s). 1610 (m), 1462(5), 1385 (m), 1267 (m), 1051 (s),

1030 (m), 935 (m), 908 (m), 736 (s) cm'l; HRMS (131) m/z 178.1358 [(MI) calcd. for

i \‘\O 0 \\
113 114

(1R*, 5R*)-l,8,8-trimethyl-2-methy1ene-bicyclo[3.2.1]octan-3-one (113) and (1R*,

C12H1302 178.1358].

5R*)-l,8,8-trimethyl-3-methylene-bicyclo[3.2.1]octan-2-one (114).
Following general procedure V, the reaction of 0.50 g (2.7 mmol) of 103.
afforded 0.47 g (96%) 113:114, as a 3:1 regiomeric mixture, after purification via flash

silica chromatography (15 g; 1% Et3N/hexanes).

132

113: R. = 0.63 (5:1 hexanes/EtOAc); [a];0 = -46.8 ° (c 1.40); ‘H-NMR (500 MHz,
CDC13) 5 5.63 (m, 1 H), 4.86 (m, 1 H), 2.46 (dm, J = 9.6 Hz, 1 H), 2.01 (dq, J = 11.1, 1.8
Hz, 2 H), 1.78 (1, J = 2.7 Hz, 2 H), 1.50-1.30 (series of m, 2 H), 0.66 (s. 3 H), 0.59 (s. 3
H), 0.53 (s, 3 H); l3C-NMR (125 MHz, CDC13) 5 203.9 (C), 141.8 (C), 121.1 (CH2), 46.0
(C), 44.6 (C), 42.5 (CH2), 42.4 (CH), 29.2 (CH2), 26.4 (CH2), 19.1 (CH3), 18.5 (CH3), 8.6
(CH3); IR (NaCl, neat) 3098 (m), 2910 (s), 2868 (s), 1615 (m), 1462 (s), 1387 (s), 1282
(s), 1236 (s), 1130 (s), 1086 (s), 1016 (s), 995 (s), 960 (s), 918 (s), 740 (m) cm": HRMS
(E1) m/z 178.2701 [(M+) calcd. for CHngO: 178.2707].

114: R. = 0.58 (5:1 hexanes/EtOAC); 'H-NMR (500 MHz, CDC13) 5 5.48 (d, J = 0.9 Hz,
1 H), 4.79 (d, J = 0.6 Hz, 1 H), 2.36 (ddd, J = 11.1, 2.7. 1.5 Hz, 1 H), 2.10 (d1,] = 9.6,
0.6 Hz, 2 H), 1.63 (1, J = 2.3 Hz, 2 H), 1.20-1.09 (series of m, 2 H), 0.71 (s, 3 H), 0.67 (s,
3 H), 0.59 (s, 3 H); l3C-NMR (125 MHz, CDC13) 5 201.1 (C), 154.2 (C), 115.2 (CH3),
56.8 (C), 45.9 (C), 44.5 (CH), 36.2 (CH2), 35.4 (CH2), 34.3 (CH2), 23.5 (CH3), 16.5
(CH3), 12.9 (CH3); IR (NaCl, neat) 3098 (m), 2910 (s), 2868 (s), 1615 (m), 1462 (s),
1387 (s), 1282 (s), 1236(5), 1130 (s), 1086 (s), 1016(8), 995 (s), 960 (s), 918 (s), 740 (m)

cm"; LRMS (EI) m/z 178.1 (M).

OMe

115

(18*, 5R*, 9R*)-1,9-dimethyl-9-methoxy-2-methy1enebicyclo[3.2.2]nonan-3-one

(115).

133

Following general procedure V, the reaction of 0.10 g (0.48 mmol) of starting
carbinols 105:106, as a 1:1 mixture, afforded 90.3 mg (90%) of 115 after purification via

flash silica chromatography (3 g; 1% Et3N/hexanes).
115: R. = 0.38 (5:1 hexanes/EtOAC); [or];O = -243 (c 0.38); 'H-NMR (300 MHz,

CDC13) 5 5.75 (d, J = 0.9 Hz, 1 H), 5.17 (d, J = 0.9 Hz, 1 H), 3.17 (s, 3 H), 3.15 (d. J =
12.0 Hz, 1 H), 2.66 (dt, J: 18.9, 3.3 Hz, 1 H), 2.53 (dd, J: 19.5, 4.8 Hz, 1 H), 2.11 (m, 1
H), 1.87 (dd, J = 15.0, 3.6 Hz, 1 H), 1.75 (dd, J = 15.3, 0.9 Hz, 1 H), 1.52 (dd, J = 17.1,
1.5 Hz, 1 H), 1.50 (m, 1 H), 1.49 (dd, J=17.4,2.4 Hz, 1 H), 1.17 (s, 3 H), 1.12 (s, 3 H);
l3C-NMR (75 MHz, CDC13) 5 205.1 (C), 158.1 (C), 118.4 (CH2), 75.0 (C), 49.0 (CH3).
46.5 (CH2), 46.4 (CH2), 34.7 (C), 34.3 (CH), 33.4 (CH2), 29.4 (CH3), 23.7 (CH2), 29.4
(CH3); IR (neat) 3090 (w), 2928 (s), 2826 (m), 1722 (s), 1684 (s), 1464 (s), 1375 (s),
1118 (s), 1078 (s), 981 (w), 943 (m), 916 (m), 823 (w) cm"; HRMS (EI) m/z 208.1468

[(M+); calcd. for 031121)ng 208.1463].

MeO

11s
(18*, 5R*, 98*)-1,9-dimethyl-9-methoxy-2-methylenebicyclo[3.2.2]nonan-3-one
(116).

Following general procedure V, the reaction of 0.13 g (0.63 mmol) of starting
carbinols 107:108, as a 1:1 mixture, afforded 0.11 g (88%) of 116 after purification via
flash silica chromatography (3 g; 1% Et3N/hexanes).

116: Rf = 0.44 (4:1 hexanes/EtOAC); 1H-NMR (300 MHz, CDC13) 5 5.89 (d, J = 1.2 Hz,

1 H), 5.17 (d, J = 0.9 Hz, 1 H), 3.11 (d, J = 14.4 Hz, 1 H), 3.06 (s, 3 H), 2.95 (dd, J =

134

18.3.5.7 Hz, 1 H), 2.31 (dd, J = 18.3, 2.4 Hz, 1 H), 2.10 (p, J = 2.7 Hz, 1 H), 1.72 (d, J =
15.0 Hz, 1 H), 1.68 (d, J = 16.2 Hz, 1 H), 1.54 (series of m, 2 H), 1.45 (d, J = 14.4 Hz, 1
H) 1.23 (s, 3 H), 1.12 (s, 3 H); l3C-NMR (75 MHz, CDC13) 5 202.5 (C), 156.2 (C), 118.1
(CH2), 76.1 (C), 48.8 (CH3), 46.4 (CH2), 44.3 (CH2), 37.4 (CH), 34.7 (C), 32.5 (CH3),
29.6 (CH2), 24.7 (CH3), 24.6 (CH3); IR (neat) 3090 (w), 2928 (s), 2826 (s), 1722 (s),
1684 (m), 1597 (w),1464 (s), 1375(3), 1118 (s), 1078(8), 981 (m), 943 (m), 916 (m), 823
(w) cm"; HRMS (E1) m/z 208.1463 [(M“); calcd. for C13H2002: 208.1463].
H
>13
117

1-(2-methyl-propenyl)-piperidine (117).

To a stirring chilled, 0 °C, heterogeneous solution of 12.04 g K2CO3 (87.1 mmol,
35 mol%) in 58 mL piperidine (586.4 mmol, 2.36 eq), was added 22.6 mL iso-
butryaldehyde (248.8 mmol, 1.00 eq) in a dropwise manner over 1.5 hrs After complete
addition the reaction was stirred at 0 °C for 3 hrs, then warmed to room temperature and
agitated an additional 8 hrs The reaction was gravity filtered, dried over MgSO4, filtered,
and concentrated to produce a yellow oil. The oil was purified via short path distillation
at room temperature under aspirator pressure. To prevent severe foaming, 5 mL silicon
oil was added to the distillation mixture. The distilation produced 27.12 g (78%) of the
desired piperidine enamine, 117, as a water white oil.
117: bp = 22 °C (15 mmHg); 1H-NMR (300 MHz, CDC13) 5 5.30 (q, J = 1.2 Hz, 1 H),
2.75 (t, J = 5.1 Hz, 2 H), 2.50 (t, J = 5.1 Hz, 2 H), 1.62 (s, 3 H), 1.55 (d, J = 1.2 Hz, 3 H),
1.52-1.36 (series of m, 6 H); I3C-NMR (75 MHz, CDC13) 5 136.1 (CH), 120.8 (C), 54.0

(CH2), 47.2 (CH2), 27.0 (CH2), 25.7 (CH2), 24.0 (CH2), 22.2 (CH3), 17.3 (CH3): IR (neat)

135

3010 (w), 2932 (s), 2853 (m), 27m), 1089 (m), 2737 (m), 1678 (w), 1441 (m), 1386 (m),
1269 (w), 1180 (m), 1111 (m), 1035 (m), 987 (w), 862 (m) cm"; LRMS (E1) m/z 139.2

(M+), 140.2 (M+ +H), 124.1 (M+ -Me).

O

9:“

118

(2, 4, 4)-trimethyIcyclohexanes-Z-en-l-one (118).

Enamine 117 was chilled to 0 °C and 25.0 mL ethyl vinyl ketone (251.1 mmol,
1.01 eq) was added dropswise via addition funnel over a period of 45 min After
complete addition the reaction was warmed to room temperature and stirred for 24 hrs
The addition of 300 mL of an aqueous 15% HCl solution followed with aggitation for an
additional 48 hrs at room temperature. The reaction was then brought to reflux (110 °C)
for 1 hr and then cooled to room temperature. The reaction was partitioned with brine
and the reaction mixture was extracted four times with 50 mL Eth. The combined
ethereal layers was dried over MgSO4, filtered, and concentrated to produce a yellow oil.
The oil was distilled via the short-path at aspirator pressure (15 mmHg) with heating to
produce 20.92 g (60%) of 118 as a water-white oil.
118: bp = 74-76 °C (15 mm Hg); 1H-NMR (300 MHz, CDC13) 5 6.32 (s, 1 H), 2.36 (t, J
= 6.6 Hz, 2 H), 1.74 (t, J = 6.6 Hz, 2 H), 1.64 (d, J = 1.5 Hz, 3 H), 1.04 (s, 6 H); l3C-
NMR (75 MHz, CDC13) 5 199.6 (C), 155.0 (CH), 132.3 (C), 36.2 (CH3), 34.3 (CH3), 32.8
(C), 27.8 (CH3), 15.8 (CH3); IR (neat) 3300 (w), 2926 (s), 2868 (s), 1716 (m), 1678 (s),
1448 (s), 1361 (s), 1176(5), 1087 (s), 1023 (s), 981 (w), 916 (m), 883 (m) cm", 752 (w):
LRMS (E1) m/z 139.0 (M+'), 138.0 (M+); HRMS (EI) m/z 138.1044 [(M+), calcd. for

C9H14O: 138.1045].

136

For previous synthesis see: Paquette, L. A.; Oplinger, J. A. Tetrahedron 1989, 45, 107-

124.

119

(+/-)-(28*, 3S *)-3-ally1-(2, 4, 4)-trimethylcyclohexanone (119).

A solution of 13.30 g 118 (96.2 mmol, 1.00 eq) in 180 mL CH2C12 was chilled to
-78 °C. To this solution, 15.0 mL TiC14 (136.7 mmol, 1.42 eq) was added in a dropwise
manner slowly turning the solution from clear to dark red and finally to a bright yellow
slurry. After the complete addition of TiCl4 the reaction was kept at —78 °C for an
additional 10 min To this, 14.77 mL allyltrimethylsilane (92.9 mmol, 0.96 eq) in 20 mL
CH2C12 was added dropwise turning the solution a ruddy red The reaction temperature
was kept at -78 °C after the silanes complete addition for 3 hrs The reaction was warmed
to 0 °C, quenched with H20 and partitioned with 100 mL E120. After separation the
aqueous layer was extracted two times with 100 mL 320. The combined ethereal layers
were washed once with 100 mL H20 and once with 150 mL brine. The organics were
dried over MgSO4, filtered, and concentrated to afford a clear oil. The oil was purified
via flash silica chromotography (400 g; 30:1 hexanes/EtOAC) to provide 11.27 g (65%)
of racemic diastereomer 119 as a transparent oil.
119: 1H-NMR (300 MHz, CDC13) 5 5.71 (ABsext, J = 17.1, 10.2, 6.9 Hz, 1 H), 4.91 (dd.
J = 17.1, 1.5 Hz, 1 H), 4.84 (dd, J = 10.2, 1.5 Hz, 1 H), 2.35 (td, J = 14.1, 6.6 Hz, 1 H),
2.23 (dq, J: 14.6, 6.3 Hz, 1 H), 2.18 (m, 2 H), 1.98 (dt, J = 15.3, 6.9 Hz, 1 H), 1.55 (dd, J

= 6.3, 3.0 Hz, 1 H), 1.50 (dd, J =13.8, 4.8 Hz, 1 H), 1.19 (dt, J = 11.4.5.1 Hz, 1 H), 0.96

137

(s, 3 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.90 (s, 3 H); '3C-NMR (75 MHz, CDC13) 5 212.8 (C),
138.4 (CH), 115.0 (CH2), 52.9 (CH), 46.2 (CH), 41.1 (CH2), 37.8 (CH2), 34.4 (CH2), 34.1
(C). 29.4 (CH3), 19.8 (CH3), 12.5 (CH3); IR (neat) 3076 (m-w), 2970 (s), 2937 (s), 2872
(s), 1714 (s), 1678(8), 1639(m), 1469(8), 1437 (m), 1390 (m), 1369 (m), 1311 (m), 1248
(w), 1153 (m), 1010 (m), 995 (m), 910 (s) cm"; HRMS (EI) m/z 180.1507 [(M’"), calcd.
for CIZHZOO: 180.1514].

For previous synthesis see: Paquette, L. A.; Oplinger, J. A. Tetrahedron 1989, 45, 107-

124.

—O

120
(+/-)-(28*, 3S*)-(2,2,6-trimethyl-5-oxo-cyclohexyl)-acetaldehyde (120).

A solution of 1 1.8162 g 119 (65.5 mmol, 1.00 eq) in 250 mL CH2C12 was charged
with N2 at —-78 °C. Ozone was bubbled into the reaction until a clear blue solution was
produced, ~2 hr. Nitrogen was then bubbled through the reaction, to removing excess
ozone, until a water white solution was generated. The reaction was worked up in a
reductive manner by the dropwise addition of 51.95 g Ph3P (198.0 mmol, 3.02 eq) in 200
mL CH2C12. After overnight stirring, 12 hrs, at room temperature the yellow green
heterogeneous solution was gravity filtered and concentrated to afford a yellow white
solid. The solid was taken up in 200 mL 320 and gravity filtered onto a silica column
and purified via flash silica chromotography (200 g; 20%EtOAc/hexanes) to provide
1 1.81 g (98%) of the desired aldehyde 120 as a white solid.

120: mp = 115-120 °C; 1H-NMR (300 MHz, CDC13) 5 9.75 (dd, J = 2.1, 0.9 Hz, 1 H),

2.90-2.15 (series of m, 4 H), 2.05-1.95 (series of m, 1 H), 1.80-1.60 (series of m, 2 H),

138

1.04 (S, 3 H), 0.97 (d, J = 6.3 HZ, 1 H), 0.94 (S, 3 H), 0.92 (d, J = 6.6 HZ, 3 H); l3C-NMR
(75 MHZ, CDC13) 5 211.6 (C), 201.3 (CH), 45.4 (CH), 40.9 (CH), 40.6 (CH2), 38.0
(CH2), 35.8 (CH2), 33.7 (C), 29.4 (CH3), 19.6 (CH3), 12.6 (CH3); HRMS (E1) 711/:
182.1302 [(M+), calcd. for CHHrgOz: 182.1307].

For previous synthesis see: Maleczka, Jr., R. E. Ph.D. Dissertation, Ohio State

University , 1992.

OH
121

(+/-)-(1R*, 3R*, 48*, 6S*)-6-hydroxy-3,8,8-trimethylbicyclo[2.2.2]oct-2-one (121).

A solution of 98.0 mL AcOH (1.7 mols, 26.1 eq) in 125 mL THF was prepared, to
which 11.94 g 120 (major) (65.5 mmol, 1.00 eq) was added. The reaction was refluxed
(95 °C) for 10 hrs and then partitioned with 75 mL EtzO and 75 mL of an aqueous 1 M
NaOH solution. After separation the ethereal layer was washed two times with 75 ml. of
an aqueous 1 M NaOH solution. The combined aqueous layers were extracted two times
with 50 mL 320. The combined ethereal layers were dried over MgSO4, filtered, and
concentrated to produce a white solid. The solid was purified via alumina
chromatography (300 g; basic Activity III; 30:1 hexanes/EtOAC) to yield 8.9486 g (75%)
of racemic diasteromer 121 as a white solid.

121: mp = 92-94 °C; IH-NMR (300 MHZ, CDC13) 5 4.22 (dt, J = 9.3, 3.6, 1 H), 2.61
(ABq, J = 7.2, 5.1, 2.1 Hz, 1 H), 2.40 (dABq, J = 9.3, 2.1, 1.2 Hz, 1 H), 2.30 (q, J = 3.0
Hz, 1 H), 1.63 (br s, 1 H), 1.60 (q, J = 2.4 Hz, 1 H), 1.52 (dd, J = 6.6, 3.0 Hz, 2 H), 1.48

(q, J = 3.0 HZ, 1 H), 1.17 (d, J = 7.5 HZ, 3 H), 1.09 (s, 3 H), 1.05 (s, 3 H); I3C-NMR (75

139

MHZ, CDC13) 5 219.2 (C), 69.0 (CH), 53.1 (CH), 45.0 (CH), 42.7 (CH), 36.0 (CH2), 30.6
(C), 30.5 (CH3), 29.3 (CH3), 28.0 (CH2), 12.9 (CH3); IR (neat) 3431 (br s), 2966 (s), 2872
(s), 1724 (s), 1452 (s), 1388 (s), 1294 (m), 1170 (m), 1103 (s), 1032 (s), 1005 (m), 916
(m), 733 (s) cm"; HRMS (EI) m/z 182.1307 [(M+), calcd. for CnHrgOzz 182.1307].

For previous synthesis see: Paquette, L. A.; Maleczka, Jr., R. E.; Qiu, F. J. Org. Chem.

1991, 56, 2455-2461.

OMOM

122

(+/-)-(1R*, 3R*, 48*, 6S*)-6-methoxymethoxy-3,8,8-trimethy1bicyclo[2.2.2]oct-2-one
(122).

A solution of 8.9486 g 121 (49.0 mmol, 1.00 eq) in 30 mL THF was cooled to 0
°C. To this chilled solution, 9.40 mL {PerEt (54.0 mmol, 1.01 eq) was added in a
dropwise manner. After complete addition the reaction was stirred at 0 °C for 15 min
which was followed by addition of 4.3 mL methoxymethylchloride (56.6 mmol, 1.15 eq)
in 20 mL THF. Upon complete addition the reaction was warmed to room temperature
and stirred for 30 hrs The reaction was taken up in 30 mL EtzO and partitioned with 30
mL H20. After separation the ethereal layer was washed three times with 30 mL H20.
The combined aqueous layers were extracted once with 30 mL Eth. The combined
organics were dried over MgSO4, filtered, and concentrated to provide a pale yellow oil.
The oil was purified via flash silica chromatography (250 g; 4:1 hexanes/EtOAC) to yield

8.31 g (75%) of 122.

140

122: Rf = 0.57 (4:1 hexanes/EtOAC); 1H—NMR (300 MHZ, CDC13) 5 4.43 (d, J = 6.6 Hz,
1 H), 4.42 (d, J = 6.6 Hz, 1 H), 3.87 (m, 1 H), 3.15 (s, 3 H), 2.44 (m, 1 H), 2.28 (m, 1 H),
2.21 (m, l H), 1.54 (dt, J: 9.0, 1.8 Hz, 1 H), 1.37 (dd, J: 11.7, 1,8 Hz, 1 H), 1.32 (m, 2
H), 1.00 (d, J = 4.5 Hz, 3 H), 0.95 (s, 3 H), 0.89 (s, 3 H); 13C—NMR (75 MHZ, CDC13) 5
216.2 (C), 94.5 (CH2), 73.7 (CH), 54.9 (CH3), 49.6 (CH), 44.7 (CH), 42.2 (CH), 36.3
(CH2), 30.5 (CH3), 30.2 (C), 29.0 (CH3), 26.1 (CH2), 12.8 (CH3); IR (neat) 2963 (s), 2824
(m), 2788 (w), 1724 (s), 1456 (m), 1369 (m), 1217 (m), 1145 (s), 1101 (s), 1037 (s), 918
(m), 883 (w), 733 (m), 648 (m) cm"; HRMS (EI) m/z 226.1568 [(MI), calcd. for
C13H2203: 226.1569].

For previous synthesis see: Paquette, L. A.; Maleczka, Jr., R. E.; Qiu, F. J. Org. Chem.
1991, 56, 2455-2461.

,1, /

Tos N
OMOM

123

(+/-)-(1R*, 3R*, 48*, 6S*)-6-methoxymethoxy-3,8,8-trimethylbicyclo[2.2.2]oct-2-one
tosylhydrazone (123).

To a room temperature stirring solution of 8.31 g 122 (36.7 mmol, 1.00 eq) in 50
mL MeOH, was added 8.26 g tosylhydrazide (44.3 mmol, 1.21 eq). The reaction was
stirred at room temperature for 36 hrs After concentration and PhH azeotrope, the
residue was taken up consecutively in cold (0 °C) ether and filtered. The filtrate was then
concentrated to produce 14.45 g (quantitative yield) of 123 as a white gel like material.

Only one isomer was observed via NMR.

141

123: 1H-NMR (300 MHz, CDC13) 5 8.47 (br s, 1 H), 7.80 (d, J = 8.1 Hz, 2 H), 7.23 (d, J
= 7.8 Hz, 2 H), 4.46 (ABq, J = 4.5, 6.0 Hz, 2 H), 3.80 (m, l H), 3.22 (s, 3 H), 3.01 (q, J =
3.0 Hz, 1 H), 2.38 (s, 3 H), 2.12 (m, 1 H), 1.35 (m, 2 H), 1.29 (dd, J = 5.1, 2.4 Hz, 1 H),
1.25 (dd, J = 4.8, 2.4 Hz, 1 H), 1.20 (m, 1 H), 1.02 (s, 3 H), 1.01 (s, 3 H), 0.98 (d, J = 6.0
Hz, 3 H); l3C-NMR (75 MHz, CDC13) 5 165.5 (C), 143.2 (C), 135.7 (C), 128.9 (CH),
128.1 (CH), 97.1 (CH2), 78.7 (CH), 54.8 (CH3), 44.8 (CH), 37.4 (CH), 36.1 (CH2), 35.3
(CH), 30.5 (CH3), 30.4 (C), 29.1 (CH3), 26.4 (CH2), 21.5 (CH3), 16.0 (CH3); IR (neat)
3500 (br m), 3123 (s), 2966 (s), 1915 (w), 1736 (s), 1645 (s), 1599 (s), 1495 (s), 1334 (s),
l 163 (s), 943 (s), 814 (s), 760 (s), 730 (s), 705 (s) cm]; HRMS (E1) m/z 394.1918 [(M+),
calcd. for C20H30NZO4S: 394.1926].

For previous synthesis see: Paquette, L. A.; Maleczka, Jr., R. E.; Qiu, F. J. Org. Chem.

1991, 56, 2455—2461.

OMOM
1 24

(+/-)-(1R*, 48*, 6S*)-6-methoxymethoxy-3,8,8-trimethylbicyclo[2.2.2]oct-2-ene
(124).

To a cold (0 °C) magnetically stirred solution of 3.51 g 123 (8.9 mmol, 1.00 eq) in
40 mL PhH, 22.3 mL n-BuLi (1.6 M/hexanes, 4.01 eq) was added in a dropwise manner.
After complete addition the reaction was stirred at 0 °C for 3 hrs The reaction was
quenched with an aqueous solution of NH4Cl(sa., and stirred at room temperature for 2 hrs
The reaction was separated and the aqueous layer extracted once with 50 mL Eth. After
separation the ethereal layer was washed three times with 40 mL of an aqueous soluton of

NH4C1(,.,.,. The combined aqueous layers were extracted once with 50 mL Eth. The

142

combined organics were was washed once with 30 mL brine, then dried over MgSO4,
filtered, and concentrated to produce an oil. The oil was purified via flash silica
chromatography (25 g; 10%EtOAc/hexanes) to yield 1.2496 g 124 (67%) as an oil.

124: R. = 0.61 (4:1 hexanes/EtOAc); lH-NMR (300 MHZ, CDC13) 5 5.68 (d, J = 6.3 Hz,
1 H), 4.62 (d, J = 6.9 Hz, 1 H), 4.58 (d, J = 6.9 Hz, 1 H), 3.82 (dt, J = 8.7, 3.3 Hz, 1 H),
3.31 (s, 3 H), 2.59 (sextet, J: 2.7 Hz, 1 H), 2.27 (ddd, J: 13.8, 8.4, 3.0 Hz, 1 H), 1.83 (s,
3 H), 1.81 (m, 1 H), 1.12 (m, 2 H), 1.03 (m, 1 H), 0.95 (s, 3 H), 0.79 (s, 3 H); l3C-NMR
(75 MHZ, CDC13) 5 145.0 (C), 120.3 (CH), 94.7 (CH2), 75.5 (CH), 55.1 (CH3), 47.7
(CH), 39.6 (CH2), 36.8 (CH), 31.8 (CH2), 31.5 (C), 31.0 (CH3), 29.3 (CH3), 22.0 (CH3);
IR (NaCl, neat) cm'l 3015 (w), 2930 (s), 2864 (m), 2822 (w), 1464 (w), 1444 (w), 1363
(w), 1143 (m), 1101 (s), 1043 (s), 1027 (In), 991 (w), 945 (w), 918 (m), 802 (w); HRMS
(CI) m/z 228.1976 [(M+ NH4), calcd. for C13H2202: 228.1964].

For previous synthesis see: Paquette, L. A.; Maleczka, Jr., R. E.; Qiu, F. J. Org. Chem.

1991, 56, 2455-2461.

OH

125
(+/-)-(1R, 28, 4S)- 5,8,8-trimethy1-bicyclo[2.2.2]oct-S-en-Z-ol (120).

To a stirring solution of 0.5575 g 124 (2.6 mmol, 1.00 eq) in 30 mL MeOH was
added three drops of an aqueous 12 M HCl solution. The reaction was heated at 70 °C for
5 hrs, afterwhich the reaction was cooled to room temperature and concentrated. The
residue was purified via flash chromotography (5 g; 5% EtOAc/hexanes) to provide 0.32

g (72%) of 125 as a white solid.

143

125: mp = 58-60 °C Rf = 0.32 (4:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 5.64
(dd, J = 6.3, 1.2 HZ, 1 H), 3.84 (m, l H), 2.49 (sext, J: 3.0 Hz, 1 H), 2.32 (ddd, J = 19.5,
8.1, 2.7 Hz, 1 H), 1.82 (d, J: 1.8 Hz, 3 H), 1.79 (m, 1 H), 1.38 (br s, 1 H), 1.09 (m, 2 H),
0.93 (s, 3 H), 0.85 (dt, J = 14.1, 3.0 Hz, 1 H), 0.78 (s, 3 H); l3C-NMR (75 MHZ, CDC13) 5
146.5 (C), 119.6 (CH), 70.2 (CH), 48.0 (CH), 39.8 (CH), 39.2 (CH2), 34.7 (CH3), 32.0
(C). 30.9 (CH3), 29.2 (CH3), 22.0 (CH3): IR (KBr) cm“1 3356 (br s), 3038 (m), 2945 (s),
2864 (s), 1623 (m), 1444(5), 1361 (s), 1155 (m), 1130 (m), 1082 (s), 1060(8), 1035 (m),
962 (m), 814 (m), 802 (m); HRMS (E1) m/z 166.1353 [(M+), calcd. for CHngoi
166.1358].

For previous synthesis see: Paquette, L. A.; Maleczka, Jr., R. E.; Qiu, F. J. Org. Chem.

1991, 56, 2455-2461.

0
126

(+/-)-(1R, 4S)- 5,8,8-trimethyl-bicyclo[2.2.2]oct-S-en-Z-one (126).

Crpryridine Oxidation: To a stirring solution of 0.395 mL pyridine (4.8
mmol, 1.20 eq) in 25 mL CHzClz, 0.2497 g CrO3 (2.4 mmol, 61 mol%) was added. The
reaction was stirred for 15 min afterwhich, 0.6758 g 125 (4.0 mmol, 1.00 eq) in 6 mL
CH2C12 was added dropwise. The reaction was stirred for an additional 15 min, then
partitioned with the addition of 30 mL of an aqueous 1 M NaOH solution. After
separation the CHzClz phase was washed once with 30 mL of an aqueous 1 M NaOH
solution, two times with 30 mL of an aqueous 1 M HCl solution, and two times with 30
mL of an aqueous solution of NaHCO3.,...,,. The CH2C12 phase was dried over MgSOs,

filtered and concentrated. The residue was purified via flash chromotography (7 g;

144

5%EtOAc/hexanes) to provide 0.2403 g (36%) of 126 as well as 0.2302 g (34% recovery)
of 125.

Bess-Martin Oxidation: To a stirring solution of 48.3 mg 125 (0.29 mmol, 1.00
eq) in 2.5 mL CHzClz, was added 0.1519 g Dess-Martin periodinane (0.35 mmol, 1.23
eq). The reaction was stirred at room temperature for 7 hrs and then partitioned with 5
mL CHzClz and 6 mL of a 1:1 10% aqueous solution of Na28203/NaHCO3.,a.,. The
biphasic reaction was stirred for 1 hr. After separation the aqueous layer was extracted
twice with 15 mL CH2C12. The combined CH2C12 layers was dried over MgSO4, filtered
and concentrated to afford an oil. The oil was purified via flash chromotography (l g;
5% EtOAc/hexanes) to provide 17.8 mg (38%) of 126 as well as 16.9 mg (35% recovery)
of 125.
Dess-Martin Periodinane: (a) Martin, J. C.; Dess, D. B. J. Org. Chem. 1983, 48. 4155-
4156. (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.

Swern Oxidation: A solution of 0.051 mL oxalyl chloride (0.5 mmol, 1.20 eq) in
2 mL CHzClz was chilled to -78 °C, afterwhich 0.076 mL DMSO (1.0 mmol, 2.20 eq)
was added in a dropwise manner. The reaction was stirred for 15 min before the
dropwise addition of 81.0 mg 125 (0.48 mmol, 1.00 eq) in 1 mL CH2C12. After complete
addition the reaction was stirred an additional 15 min before the dropwise addition of
0.34 mL iPrzEtN (2.4 mmol, 5.00 eq). After its complete addition the reaction was
warmed to room temperature and partitioned with the addition of 10 mL EtzO and 10 mL
H20. After separation the ethereal layer was washed two times with 10 mL H20. The
combined aqueous layers were washed two times with 20 mL 320. The combined

ethereal layers were dried over MgSO4, filtered and concentrated. The residue was

145

purified via flash chromotography (1 g; 5% EtOAc/hexanes) to provide 33.6 mg (42%) of
the desired 126 as well as 22.2 mg (27% recovery) of 125.

Swern Oxidation: Swern, D.; Mancuso, A. J. Synthesis 1981, 165-184.

126: R. = 0.56 (4:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 5.69 (d, J = 3.0 Hz,
1 H), 2.87 (p, J = 2.4 Hz, 1 H), 2.29 (dd, J = 18.3, 2.1 Hz, 1 H), 2.15 (m, 1 H), 1.89 (dd, J
= 18.6, 3.0 HZ, 1 H), 1.85 (d, J = 1.8 HZ, 3 H), 1.56 (dd, J: 13.2, 2.4 Hz, 1 H), 1.40 (dd,
J = 13.2, 3.3 Hz, 1 H), 1.06 (s, 3 H), 0.94 (s, 3 H); l3C-NMR (75 MHZ, CDC13) 5 213.6
(C), 147.7 (C), 118.5 (CH), 49.9 (CH), 49.5 (CH), 38.7 (CH2), 36.2 (CH2), 33.5 (C), 31.1
(CH3), 28.4 (CH3), 22.1 (CH3); LRMS (BI) m/z 164.0 (M*), 165.1 (M“).

For previous synthesis see: Paquette, L. A.; Maleczka, Jr., R. E.; Qiu, F. J. Org. Chem.

I I
OH fl
/ OH
127 128

(+/-)-(1R*, 2R*, 48*)-2-ethenyl-5,8,8-trimethyl-bicyclo[2.2.2]oct-5-en-2-ol (127) and

1991, 56, 2455-2461.

(1R*, 28 *, 4S*)-2-ethenyl-5,8,8-trimethyl-bicyclo[2.2.2]oct-5-en-2-ol (128).

Following general procedure I, the reaction of 0.12 g (0.76 mmol) of starting
ketone 126, afforded 0.11 g (76%) of 127:128, as a 3:1 diastereomeric mixture, after
purification via flash silica chromatography (1.5 g; basic Activity 111; 5%
EtOAc/hexanes).

127: R. = 0.60 (4:1 hexanes/EtOAc); 1H-NMR (300 MHz, CDC13) 5 5.88 (dd, J = 17.4.
10.5 Hz, 1 H), 5.67 ((11, J = 6.6, 1.5 Hz, 1 H), 5.08 (dd, J: 17.4, 1.5 Hz, 1 H), 4.87 (dd, J

= 10.5, 1.5 Hz, 1 H), 2.18 (dt, J= 6.6.2.7 HZ, 1 H), 1.92 (dd, J = 12.6, 2.4 Hz, 1 H), 1.83

146

(dd, J = 17.7.2.4 Hz,1H),1.81(s,1H),1.76(d,J=1.5 Hz, 3 H), 1.41 (dd, J =17.1,2.4
Hz, 1 H), 1.39 (d, J =11.1Hz,1H),1.14(s,3 H), 0.92 (d, J =12.6 Hz, 1 H), 0.81 (s, 3
H): l3C-NMR (75 MHz, CDC13) 5 147.9 (CH), 144.1 (C), 122.8 (CH), 109.2 (CH2), 75.6
(C), 48.7 (CH), 43.7 (CH), 36.7 (CH2), 35.3 (CH2), 32.3 (C), 31.7 (CH3), 28.0 (CH3),
21.8 (CH3); HRMS (BI) m/z 192.1521 [(M+);ca1cd. for C13HzoO: 192.1514].

128: Rf = 0.48 (4:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 6.09 (dd, J = 17.0,
10.4 HZ, 1 H), 5.79 (d1, J = 6.0, J = 1.6 HZ, 1 H). 5.35 (dd, J = 17.5 Hz, 1.6 Hz, 1 H),
5.12 (dd, J = 10.9 HZ, 1.6 Hz, 1 H), 2.35 (m, 1 H), 2.22 (dd, J = 14.9 Hz, 2.2 Hz, 1 H),
1.84 (d, J = 1.6 Hz, 3 H), 1.37 (dd, J = 14.2 Hz, 1.6 Hz, 1 H), 1.22 (br s, 1 H). 1.21 (dd. J
= 14.8, 2.7 Hz, 1 H), 1.11 (d, J = 7.1 Hz, 1 H), 0.99 (s, 3 H), 0.96 (d, J = 8.7 Hz, 1 H),
0.81 (s, 3 H); l3C-NMR (75 MHZ, CDC13) 5 146.7 (CH), 142.7(C), 121.4 (CH), 113.3
(CH2), 75.3 (C), 48.7 (CH), 37.9 (CH), 36.2 (CH2), 36.1 (CH2), 34.7 (C). 32.5 (CH3),

31.3 (CH3), 28.1 (CH3); HRMS (E1) m/z 192.1521 [(M+); calcd. for C13HgoO: 192.1514].

129
(+/-)-(18*, 3R*, 68*, 7R*)-3-methoxy-8-methyl-4-oxa-tricyclo[4.3.1.03’7]dec-8-en-2-
one (129).

A solution of 4.92 mL 2-propenol (72.3 mmol, 5.00 eq), 5.59 g
diacetoxyiodobenzene (17.3 mmol, 1.20 eq) in 25 mL CHzClz was stirred at room
temperature for 10 min afterwhich 1.83 mL p-cresol (14.4 mol, 1.00 eq) in 25 mL CH3C13
was added dropwise over the course of an hour. After complete addition the reaction was

stirred at room temperature for 48 hrs The reaction was then concentrated and the

147

residual purified via flash silica chromatography (80 g; 30% EtOAc/hexanes) to provide
2.0552 g (73%) of 129 as a clear oil.

129: Rf = 0.19 (4:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 5.86 (dt, J = 6.9, 1.8
Hz, 1 H), 4.05 (dd, J = 7.8, 3.6 Hz, 1 H), 3.70 (d, J: 7.8 Hz, 1 H), 3.44 (s, 3 H), 3.09 (dd,
J = 4.2, 2.1 Hz, 1 H), 3.00 (dt, J = 6.6, 2.7 Hz, 1 H), 2.45 (m, 1 H), 1.83 (d, J = 1.5 Hz, 3
H), 1.70-1.80 (series of m, 2 H); '3C-NMR (75 MHz, CDC13) 5 201.7 (C), 139.1 (C).
122.5 (CH), 100.7 (C), 73.8 (CH2), 51.0 (CH3), 47.1 (CH), 45.1 (CH), 34.9 (CH), 31.2
(CH2), 21.1 (CH3); IR (NaCl, neat) em‘1 3090 (w), 2947 (m), 1743 (s), 1442 (m), 1375
(m), 1298 (m), 1246 (s), 1167 (m), 1087 (ms), 1049 (ms), 1006 (m), 960 (ms), 916 (m),
827 (m), 765 (m), 733 (ms); HRMS (EI) m/z 194.1021 [(M"); calcd. for CHH14O3:
194.0943].

For previous synthesis see: Liao, O; Chu, C.; Lee. T.; Rao, P. D.; Song, L. J. Org.

O 0
8M6 , OMe
\
OH
131

’ o
/
130

Chem. 1999, 64, 4111-4118.

(+/-)-(1S*, 28*, 3R*, 68*, 7R*)-3-methoxy-8-methyl-2-vinyl-4-oxa-
tricyclo[4.3.1.03’7]dec-8-en-2-ol (130) and (+/-)-(18*, 2R*, 3R*, 68 *, 7R*)-3-methoxy-
8-methyl-2-vinyl-4-oxa-tricyclo[4.3.1.0”]dec-8-en-2-ol (131).

Following general procedure I, the reaction of 2.05 g (10.5 mmol) of starting
ketone 129, afforded 1.32 g (56%) of 130:131, as a 10:1 diastereomeric mixture, after
purification via flash silica chromatography (80 g; basic Activity 111; 25:1

hexanes/EtOAc).

148

130: Rf = 0.35 (4:1 hexanes/EtOAc); IH-NMR (500 MHZ, CDC13) 5 6.27 (dd, J = 17.4,
10.8 Hz, 1 H), 5.97 (dt, J: 6.6, 1.8 Hz, 1 H), 5.48 (dd, J: 17.4, 2.4 Hz, 1 H), 5.18 (dd, J
= 10.8, 2.1 Hz, 1 H), 3.98 (dd, J = 7.5, 3.3 Hz, 1 H), 3.64 (d, J = 7.5 Hz, 1 H), 3.38 (s, 3
H), 2.81 (dd, J = 4.2, 1.2 HZ, 1 H), 2.72 (s, 1 H), 2.48 (dt, J = 6.6, 2.7 Hz, 1 H), 2.17 (m,
1 H), 1.85 (d, J = 1.5 HZ, 3 H), 1.61-1.51 (series of m, 2 H); l3C-NMR (125 MHz.
CDC13) 5 138.1 (CH), 133.6 (C), 127.0 (CH), 113.1 (CH2), 109.6 (C), 79.0 (C), 72.0
(CH2), 50.9 (CH3), 46.3 (CH), 41.8 (CH), 34.6 (CH), 30.6 (CH2), 20.5 (CH3); LRMS (El)
m/z 222.0 (M+), 223.2 (MH); HRMS (EI) m/z 222.1260 [(M+); calcd. for C.3ngO3:
222.1256].

131: Rf: 0.19 (4:1 hexanes/EtOAc); 1H-NMR (500 MHZ, CDC13) 5 5.87 (m, 2 H), 5.37
(dd, J = 17.2, 2.2 Hz, 1 H), 4.94 (dd, J = 10.6, 2.2 Hz, 1 H), 3.97 (dd, J = 7.5, 3.5 Hz, 1
H), 3.84 (s, 1 H), 3.67 (d, J = 7.5 Hz, 1 H), 3.25 (s, 3 H), 2.84 (d, J = 5.7 Hz, 1 H), 2.19
(m, 1 H), 2.16 (m, 1 H), 1.77 (d, J = 1.7 HZ, 3 H), 1.46-1.28 (series of m, 2 H); l3C-NMR
(125 MHz, CDC13) 5 140.0 (CH), 138.9 (C), 127.4 (CH), 111.6 (CH2), 108.50 (C), 80.0
(C), 72.9 (CH2), 50.6 (CH3), 47.1 (CH), 43.9 (CH), 35.7 (CH), 29.8 (CH2), 21.0 (CH3):
LRMS (E1) m/z 222.0 (M+), 223.2 (M+'); HRMS (E1) m/z 222.1249 [(M+); calcd. for
C13HigO3: 222.1256].

130:131: IR (neat) 3550 (br m), 3500 (br m), 3091 (w), 3020 (m), 2945 (s), 2874 (s),
1675 (w), 1625 (w), 1439 (s), 1329(5), 1284 (s), 1253 (s), 1149(5), 1081 (s), 1037 (s).

999 (s), 958 (s), 920 (s), 825 (s), 733 (s) cm".

C)

132 133

149

(+/-)-(18*, 5R*)-6,9,9-trimethyl-2-methylene-bicyclo[3.2.2]non-6-en-3-one (132) and
(+/-)-(18*, 5R*)-6,9,9-trimethyl-3-methylene-bicyclo[3.2.2]non-6-en-2-one (133).
Following general procedure V, the reaction of 0.50 g (2.6 mmol) of starting
carbinols 127:128, as a 3:1 mixture, afforded 0.40 g (81%) of 132:133, as a 5:1
regiomeric mixture, after purification via flash silica chromatography (4.5 g; 1%
Et3N/hexanes).
132: Rf = 0.52 (4:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 5.86 (m, 1 H), 5.58
(d, 7.1 Hz, 1 H), 5.20 (m, 1 H), 3.01 (t, J: 7.6 Hz, 1 H), 2.91 (dd, J: 17.0, 4.4 Hz, 1 H),
2.82 (dd, J = 17.2, 4.4 Hz, 1 H), 2.54 (q, J = 2.7 Hz, 1 H), 1.91 (d, J = 7.7 Hz, 1 H), 1.83
(d, J = 1.6 Hz, 3 H), 1.20 (d, J = 7.1 Hz, 1 H), 1.13 (s, 3 H), 0.94 (s, 3 H); l3C—NMR (75
MHZ, CDC13) 5 213.8 (C), 154.2 (C), 147.9 (C), 118.8 (CH), 116.0 (CH2), 50.0 (CH),
48.3 (CH), 39.2 (CH2), 36.8 (CH2), 34.2 (C), 30.1 (CH3), 28.9 (CH3), 21.2 (CH3); HRMS
(EI) m/z 190.1347 [(M“); calcd. for C13ngO: 190.1358].
133: R. = 0.48 (4:1 hexanes/EtOAc); lH-NMR (300 MHz, CDC13) 5 5.77 (d, J = 7.1 Hz,
1 H), 5.72 (d, J = 2.2 Hz, 1 H), 5.03 (d, J = 2.2 HZ, 1 H), 3.10 (t, J = 7.1 Hz, 1 H), 2.48
(q, J = 2.7 Hz, 1 H), 2.31 (dd, J = 19.2, 3.8 Hz, 1 H), 1.89 (d, J = 7.7 Hz, 1 H), 1.81 (d, J
= 1.6 Hz, 3 H), 1.66 (dd, J: 19.5, 3.8 Hz, 1 H), 1.01 (d, J = 7.1 Hz, 1 H), 1.04 (s, 3 H),
0.96 (s, 3 H); l3C-NMR (75 MHZ, CDC13) 5 215.1 (C), 153.1 (C), 148.2 (C), 119.1 (CH),
116.4 (CH2), 54.0 (CH), 52.7 (CH), 39.5 (CH2), 35.9 (CH2), 31.5 (C), 29.4 (CH3), 22.5
(CH3), 20.5 (CH3); LRMS (EI) m/z 190.1 (M+).
132:133: IR (neat) 3041 (m), 2975 (s), 2962 (s), 1715 (s), 1680 (m), 1448 (s), 1373 (s),

1130 (s), 958 (m), 760 (m) cm".

150

(+/-)-(18*, 2R*, 7R*, 88*, 108*)-(2, 10)-epoxy-7-methoxy-9-methylene-10-vinyl-6-
oxa-tricyclo[5.2.l.0l’m]dec-3-en-10-ol (134).

Following general procedure V, the reaction of 0.14 g (0.65 mmol) of starting
carbinols 130, afforded 60.4 mg (90%) of 134 after purification via flash silica
chromatography (3 g; 1% Et3N/hexanes).

134: R. = 0.48 (4:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 6.29 (dd, J = 17.4,
10.8 Hz, 1 H), 5.44 (dd, J: 17.1, 1.8 Hz, 1 H), 5.42 (s, 1 H), 5.29 (s, 1 H), 5.26 (m, 1 H),
5.21 (dd, J = 11.1, 1.5 Hz, 1 H), 3.95 (dd, J: 7.2, 3.0 Hz, 1 H), 3.58 (d, J = 7.5 Hz, 1 H),
3.35 (s, 3 H), 3.06 (m, 1H), 2.83 (d, J = 4.2 Hz, 1 H), 2.63 (m, 1 H), 2.46 (dm, J = 10.8
Hz, 1 H), 2.11 (q, J: 3.0 Hz, 1 H) l3C-NMR (125 MHz, CDC13) 5 142.8 (C), 137.7 (CH),
118.6 (CH2), 114.2 (CH2), 107.9 (C), 78.7 (C), 74.1 (CH2), 56.4 (CH), 49.8 (CH3), 44.8
(CH), 43.4 (CH), 36.0 (CH), 23.6 (CH2); HRMS (EI) m/z 220.1186 [(M+); calcd. for
C.3H..,O3: 220.2643].

HO I

139

l-vinyl-cyclooctanol (139).
Following general procedure 111, the reaction of 2.0 g (15.8 mmol) of
cyclooctanone, afforded 2.19 g (90%) of 139 after purification via flash silica

chromatography (60 g; basic Activity III; 20:1 hexanes/EtOAc).

151

139: R.= 0.25 (9:1 hexanes/EtOAc); 1H-NMR (500 MHZ, CDC13) 5 5.94 (dd, J = 17.5,
10.5 HZ, 1 H), 5.15 (dd, J = 17.5, 1.5 Hz, 1 H), 4.94 (dd, J = 10.5, 1.5 Hz, 1 H), 2.33 (m.
l H), 1.80 (m, 1 H), 1.70 (m, 2 H), 1.58 (m, 6 H), 1.44 (m, 4 H); 13C-NMR (75 MHZ,
CDC13) 5 145.8 (CH), 111.1 (CH2), 125.0 (C), 41.7 (CH2), 36.0 (2CH2), 28.1 (2CH3),
21.8 (2CH2); IR (neat) 3420 (br s), 3065 (w), 3015 (w), 2926 (s), 2856 (s), 1693 (m),
1473 (m), 1448 (m), 1414 (m), 1334 (w), 1242 (w), 1161 (w), 1093 (w), 995 (s), 918 (s),
734 (m) cm"; LRMS (E1) m/z 152.2 (M+).

Commerically available or for original synthesis see: Marcou, A.; Normant, H. Bull. Soc.

Chim. Fr. 1965, 3491-3494.

H0

140
l-vinyl-cyclododecanol (140).

Following general procedure HI, the reaction of 2.0 g (10.9 mmol) of
cyclododecanone, afforded 2.03 g (88%) of 140 after purification via flash silica
chromatography (60 g; basic Activity 111; 20:1 hexanes/EtOAc).

140: R.= 0.12 (95:5 hexanes/EtOAc); 1H-NMR (500 MHz, CDC13) 5 5.93 (dd, J = 17.5,
11.0 Hz, 1 H), 5.17 (dd, J: 17.5, 1.5 Hz, 1 H), 4.97 (dd, J: 11.0, 1.5 Hz, 1 H), 1.59 (m,
2 H), 1.40 (m, 4 H), 1.31 (m, 17 H); l3C-NMR (75 MHZ, CDC13) 5 145.3 (CH), 111.0
(CH2), 73.3 (C), 34.6 (2CH2), 26.3 (2CH2), 25.9 (2CH2), 22.5 (2CH2), 22.1 (2CH3), 19.5
(CH2); IR (neat) 3414 (br s), 3092 (w), 2939 (s), 2853 (s), 1620 (m), 1471 (s), 1448 (s),

1348 (m), 1365 (m), 1170 (m), 1062 (s), 997 (s), 918 (s), 738 (s) cm"; LRMS (EI) m/z

152

210.0 (M+). For original synthesis see: Marcou, A.; Normant, H. Bull. Soc. Chim.

France 1965, 3491-3494.

H0

141
l-vinyl-cyclopentadecanol (141).

Following general procedure 111, the reaction of 2.0 g (8.9 mmol) of
cyclopentadecanone, afforded 1.75 g (78%) of 141 after purification via flash silica
chromatography (60 g; basic Activity 111; 20:1 hexanes/EtOAc).

141: R.: 0.50 (9:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDC13) 5 5.96 (dd, J = 17.5,
11.0 Hz, 1 H), 5.21 (d, J: 17.5 HZ, 1 H), 5.03 (d, J: 11.0 Hz, 1 H), 1.51 (m, 4 H), 1.36
(m, 25 H); l3C-NMR (75 MHZ, CDC13) 5 145.4 (CH), 111.4 (CH2), 75.1 (C), 38.2
(2CH2), 27.7 (2CH2), 26.9 (2CH2), 26.7 (2CH2), 26.7 (2CH2), 26.3 (2CH2), 21.8 (2CH3);
IR (neat) 3377 (br m), 3084 (w), 301 l (w), 2932 (s), 2858 (s), 1639 (w), 1458 (m), 1412
(w), 1350 (w), 1280 (w), 1155 (w), 1133 (w), 995 (m), 918 (s), 734 (s) cm"; HRMS (E1)

m/z 252.2453 [(M+) calcd. for C17H3ZO: 252.2453].

0

d)”

142

2-methylene-cycloheptanone (142).
Following general procedure V, the reaction of 0.21 g (1.6 mmol) of starting
carbinol 80 and afforded 0.15 g (72%) of 142 after purification via flash silica

chromatography (3 g; 2% Et3N/hexanes).

153

142: R. = 0.53 (5:1 hexanes/EtOAc); lH-NMR (300 MHZ, CDC13) 5 5.92 (d, J = 2.1 Hz,
1 H), 5.22 (d, J = 2.1 Hz, 1 H), 2.57 (d, J: 11.1 Hz, 2 H), 2.46 (d, J = 9.6 Hz, 2 H), 1.66
(series of m, 6 H); 13C--NMR (75 MHZ, CDC13) 5 203.6 (C), 148.3 (C), 122.4 (CH3), 43.4
(CH2), 33.8 (CH2), 31.2 (CH2), 30.4 (CH2), 25.2 (CH2); IR (neat) 3065 (w), 2928 (s),
2858 (s), 1703 (s), 1610 (w), 1452 (s), 1317 (w), 1230 (m), 1167 (m), 1135 (m), 1105
(m), 1049 (m), 978 (m), 943 (m), 748 (w) cm"; HRMS (EI) m/z 124.0890 [(M+) calcd.
for CanO: 124.0888].

For previous syntheses see: (a) Muehlstaedt, M.; Herzschuh, R. J. Prakt. Chem. 1963,
20, 20—34. (b) Muehlstaedt, M.; Zach, L.; Becwar—Reinhardt, H. J. Prakt. Chem. 1965,

29, 158-172. (c) Ksander, G. M.; McMurry, J. E.; Johnson, M. J. Org. Chem. 1977, 42,

143

1180-1185.

2-methylene-cyclooctanone (143).

Following general procedure V, the reaction of 0.25 g (1.7 mmol) of starting
carbinol 81 and afforded 0.15 g (70%) of 143 after purification via flash silica
chromatography (3 g; 2% Et3N/hexanes).

143: R. = 0.51 (5:1 hexanes/EtOAc); lH-NMR (300 MHZ, CDC13) 5 5.75 (d, J = 2.4 Hz,
1 H), 5.12 (d, J = 2.1 Hz, 1 H), 2.48 (m, 2 H), 1.67 (m, 2 H), 1.50 (series of m, 6 H), 1.35
(m, 2 H); l3’C—NMR (75 MHZ, CDC13) 5 206.6 (C), 148.4 (C), 121.8 (CH2), 39.2 (CH2),
31.0 (CH2), 30.5 (CH2), 28.8 (CH2), 28.9 (CH2), 25.2 (CH2); IR (neat) 2928 (s), 2856 (s),
1701 (s), 1466 (s), 1373 (m), 1240(8), 1172 (w), 1128 (s), 1087 (w), 1047 (m), 935 (w),

910 (w), 733 (w) cm"; HRMS (E1) m/z 138.1055 [(M+) calcd. for C9H14O: 138.1045].

154

For previous syntheses see: (a) Muehlstaedt, M.; Herzschuh, R. J. Prakt. Chem. 1963,
20, 20—34. (b) Muehlstaedt, M.; Zach, L.; Becwar-Reinhardt, H. J. Prakt. Chem. 1965,
29, 158-172. (c) Ksander, G. M.; McMurry, J. E.; Johnson, M. J. Org. Chem. 1977, 42,

1180-1185.

0

Q5:

144

2-methylene-cyclononanone (144).

Following general procedure V, the reaction of 0.29 g (1.4 mmol) of starting
carbinol 139 and afforded 0.19 g (53%) of 144 and 26.5 mg (6%) 146 after purification
via flash silica chromatography (3 g; 2% Et3N/hexanes).

144: R. = 0.74 (4:1 hexanes/EtOAc); 1H-NMR (500 MHZ, CDC13) 5 5.43 (d, J = 0.8 Hz,
1 H), 5.34 (d, J = 0.8 Hz, 1 H), 2.59 (m, 2 H), 2.42 (td, J = 6.1, 0.8 Hz, 2 H), 1.79 (p, J =
6.1 Hz, 2 H), 1.49 (series of m, 4 H), 1.36 (series of m, 4 H); l3C-NMR (125 MHz,
CDC13) 5 210.8 (C), 152.2 (C), 118.5 (CH2), 41.5 (CH2), 32.6 (CH2), 26.7 (CH2), 26.1
(CH2), 24.3 (CH2), 24.2 (CH2), 22.4 (CH2); IR (neat) 3088 (w), 3065 (w), 2932 (s), 2874
(m). 1682 (s), 1620 (w), 1469 (m), 1444 (m), 1361 (w), 1298 (w), 1267 (w), 1205 (w),
1147 (w), 1113 (w), 1089 (w), 1039 (w), 922 (m), 908 (m), 736 (m) cm"; HRMS (El)
m/z 152.1201 [(M+) calcd. for C10H..,O: 152.1201].

For previous syntheses see: (a) Muehlstaedt, M.; Herzschuh, R. J. Prakt. Chem. 1963,
20, 20-34. (b) Muehlstaedt, M.; Zach, L.; Becwar—Reinhardt, H. J. Prakt. Chem. 1965,
29, 158-172. (c) Ksander, G. M.; McMurry, J. E.; Johnson, M. J. Org. Chem. 1977,42,

1180-1185.

155

1-(1,2-dichloro-ethyl)-cyclooctanol (146).

Following general procedure V, the reaction of 0.29 g (1.4 mmol) of starting
carbinol 139 and afforded 0.19 g (53%) of 144 and 26.5 mg (6%) 146 after purification
via flash silica chromatography (3 g; 2% Et3N/hexanes).

146: R. = 0.42 (4:1 hexanes/EtOAc); 1H-NMR (500 MHZ, CDC13) 5 4.04 (m, 2 H), 3.67
(ABq, J = 12.8, 3.0 Hz, 1 H), 1.90 (m, 3 H), 1.77 (m, 1 H), 1.60 (series of m, 7 H), 1.35
(series of m, 4 H); l3C-NMR (125 MHZ, CDC13) 5 76.4 (C), 71.7 (CH), 46.1 (CH3), 34.5
(CH2), 33.9 (CH2), 28.6 (CH2), 27.1 (CH2), 25.0 (CH2), 22.1 (CH2), 22.0 (CH2); IR (neat)
3462 (br m), 2924(5), 2856 (m), 1471 (m), 1367 (m), 1251 (m), 1068 (m), 1016 (m), 939

(m), 734 (In) em": HRMS (B1) m/z 224.0721 [(M") calcd. for C.0H..o35C12: 224.0735].

0

147

2-methylene-cyclotridecanone (147).

Following general procedure V, the reaction of 0.29 g (1.4 mmol) of starting
carbinol 140 and afforded 0.15 g (53%) of 147, 10.4 mg (3%) 148 and 11.9 mg (3%) 149
after purification via flash silica chromatography (3 g; 3% Et3N/hexanes).

147: R. = 0.78 (5:1 hexanes/EtOAc); lH-NMR (300 MHz, CDC13) 5 5.93 (s, 1 H), 5.68
(s, 1 H), 2.70 (m, 1 H), 2.31 (m, 1 H), 1.95 (m, 2 H), 1.65 (m, 2 H), 1.53 (m, 2 H), 1.24

(series of m, 14 H); l3C-NMR (75 MHz, CDC13) 5 204.2 (C), 149.4 (C), 125.3 (CH3),

156

37.1 (CH2), 31.0 (CH2), 26.6 (CH2), 26.3 (CH2), 26.2 (CH2), 26.0 (CH3), 25.8 (CH3), 25.3
(CH2), 24.7 (CH2), 24.5 (CH2), 24.1 (CH2); IR (neat) 2932 (s), 2862 (s), 1716 (m), 1672
(m), 1462 (m), 1444 (m), 1360 (w), 1267 (w), 1111 (w), 1070 (w), 933 (w), 733 (m)
cm"; LRMS (B1) m/Z 208.1 (M’).
For previous syntheses see: Muehlstaedt, M.; Remane, H.; Graefe, J. Z. Chem. 1969, 9,
303-305. (b) Muehlstaedt, M.; Koehler, H. J.; Porzig, D.; Scholz, M. J. Prakt. Chem.
1970, 312, 292-299. (c) Marshall, J. A.; Audia, v. H. J. Org. Chem. 1985, 50, 1607-

1611.

C1

148

2-chloromethyl-cyclotridecanone (148).

Following general procedure V, the reaction of 0.29 g (1.4 mmol) of starting
carbinol 140 and afforded 0.15 g (53%) of 147, 10.4 mg (3%) 148 and 11.9 mg (3%) 149
after purification via flash silica chromatography (3 g; 3% Et3N/hexanes).

148: R. = 0.80 (5:1 hexanes/EtOAc); lH-NMR (500 MHZ, CDC13) 5 3.67 (dd, J = 1 1.0,
9.2 Hz, 1 H), 3.39 (dd, J = 10.6, 5.3 HZ, 1 H), 2.88 (m, 1 H), 2.72 (ddd, J = 18.1, 10.1,
3.0 HZ, 1 H), 2.37 (ddd, J = 18.1, 6.6, 3.5 Hz, 1 H), 1.94 (m, 1 H), 1.51 (m, 2 H), 1.26
(series of m, 17 H); l3C—NMR (125 MHz, CDC13) 5 212.1 (C), 54.1 (CH), 44.4 (CH2),
42.7 (CH2), 30.1 (CH2), 26.3 (CH2), 26.2 (CH2), 26.1 (CH2), 24.8 (CH2), 24.4 (CH3),
24.0 (CH2), 23.8 (CH2), 23.4 (CH2), 21.6 (CH2); IR (neat) 2930 (s), 2858 (s), 1709 (s),
1462 (s), 1410 (s), 1371 (m), 1286 (m), 1168 (m), 1115 (m), 1087 (m), 1030 (m), 916

(m), 733 (s) cm"; HRMS (E1) m/z 244.1623 [(M’”) calcd. for CMH3535C1O: 244.1594].

157

Cl

1
HO C

149

1-(1,2-dichloro-ethyl)-cyclododecanol (149).

Following general procedure V, the reaction of 0.29 g (1.4 mmol) of starting
carbinol 140 and afforded 0.15 g (53%) of 147, 10.4 mg (3%) 148 and 11.9 mg (3%) 149
after purification via flash silica chromatography (3 g; 3% Et3N/hexanes).

149: R. = 0.35 (5:1 hexanes/EtOAc); 1H-NMR (500 MHz, CDC13) 5 4.09 (dd, J = 13.2,
6.1 Hz, 1 H), 3.96 (m, 2 H), 2.33 (br s, 1 H), 1.78 (m, 2 H), 1.54 (dt, J = 11.9, 4.8 Hz, 1
H), 1.34 (series of m, 19 H); l3C-NMR (125 MHz, CDC13) 5 77.5 (C), 70.8 (CH), 64.1
(CH2), 33.3 (CH2), 31.7 (CH2), 26.4 (CH2), 26.2 (CH2), 25.9 (CH2), 22.5 (CH2), 22.4
(CH2), 22.1 (CH2), 22.0 (CH2), 19.6 (CH2), 19.1 (CH2); IR (neat) 3372 (br s), 2930 (s).
2862 (s), 1471 (s), 1444 (m), 1348 (w), 1265 (w), 1161 (w), 1076 (m), 1032 (m), 736 (m)

cm"; HRMS (B1) m/z 280.1360 [(M+) calcd. for C.,H2.o35C12: 280.1361].

0

150

2-methyIene-cyclohexadecanone (150).

Following general procedure V, the reaction of 0.35 g (1.4 mmol) of starting
carbinol 136 and afforded 0.16 g (45%) of 150, 16.1 mg (4%) 151 and 18.1 mg (4%) 152
after purification via flash silica chromatography (3 g; 3% Et3N/hexanes).

150: R. = 0.53 (5:1 hexanes/EtOAc); lH-NMR (300 MHZ, CDC13) 5 5.92 (s, 1 H), 5.69

(s, 1 H), 2.72 (ddd, J = 18.6, 10.2, 3.0 HZ, 1 H), 2.62 (m, l H), 2.32 (m, 1 H), 1.92 (m, l

158

H), 1.65 (series of m, 3 H), 1.51 (series of m, 3 H), 1.25 (series of m, 18 H); l3C-NMR
(75 MHz, CDC13) 5 204.2 (C), 149.4 (C), 125.3 (CH3), 42.7 (CH2), 37.1 (CH3), 30.9
(CH3), 25.8 (CH2), 25.3 (CH2), 24.8 (CH2), 24.7 (CH2), 24.5 (CH2), 24.4 (CH3), 24.1
(CH2), 24.0 (CH2), 23.8 (CH2), 23.4 (CH2), 21.6 (CH2); IR (neat) 3056 (w), 2943 (s),
2868 (s), 1720(5), 1675 (w), 1478 (s), 1442 (s), 1364 (m), 1262 (m), 1105 (m), 1072 (m),
928 (w), 744 (s) cm"; LRMS (BI) m/z 250.1 (M).

For previous syntheses see: (a) Muehlstaedt, M.; Koehler, H. J.; Porzig, D.; Scholz, M.
J. Prakt. Chem. 1970, 312, 292-299. (b) Marshall, J. A.; Audia, v. H. J. Org. Chem.

1985, 50, 1607-1611

0

& 0'
151
2-methylene-cyclohexadecanone (151).

Following general procedure V, the reaction of 0.35 g (1.4 mmol) of starting
carbinol 136 and afforded 0.16 g (45%) of 1150, 16.1 mg (4%) 151 and 18.1 mg (4%) 152
after purification via flash silica chromatography (3 g; 3% Et3N/hexanes).

151: R. = 0.43 (95:5 hexanes/EtOAc); 1H-NMR (500 MHZ, CDC13) 5 3.66 (d, J = 10.5
Hz, 1 H), 3.43 (dd, J = 11.0, 6.0 Hz, 1 H), 2.90 (m, 1 H), 2.55 (m, l H), 2.41 (m, 1 H),
1.74 (m, 1 H), 1.63 (m, 2 H), 1.47 (m, 4 H), 1.26 (series of m, 19 H); l3C-NMR (125
MHz, CDC13) 5 211.9 (C), 53.8 (CH), 44.3 (CH2), 43.0 (CH2), 30.3 (CH3), 27.8 (CH2),
27.5 (CH2), 27.3 (CH2), 27.0 (CH2), 26.6 (CH2), 26.5 (CH2), 26.4 (CH2), 26.2 (CH2),

26.1 (CH3), 26.1 (CH2), 25.6 (CH2). 21.8 (CH2); IR (neat) 2928 (s), 2855 (s), 1716 (s).

159

1458 (s), 1369 (w), 1284 (w), 1091 (w), 908 (m), 733 (s) cm"; HRMS (EI) m/z 287.2145

[(M") calcd. for C.7H3.O35Cl: 286.2063].

C1 Cl
H0

152

1-(1,2-dichloro-ethyl)-cyclopentadecanol (152).

Following general procedure V, the reaction of 0.35 g (1.4 mmol) of starting
carbinol 136 and afforded 0.16 g (45%) of 150, 16.1 mg (4%) 151 and 18.1 mg (4%) 152
after purification via flash silica chromatography (3 g; 3% Et3N/hexanes).

152: R. = 0.26 (95:5 hexanes/EtOAc); 1H-NMR (500 MHZ, CDC13) 5 4.03 (m, 2 H), 3.70
(t, J: 10.0 Hz, 1 H), 1.78 (br s, 1 H), 1.65 (m, 2 H), 1.62 (m, 1 H), 1.50 (m, l H), 1.34
(m, 24H); l3C-NMR (125 MHZ, CDC13) 5 223.8 (C), 76.4 (C), 71.2 (CH), 46.0 (CH3),
37.3 (CH2), 34.8 (CH2), 27.5 (CH2), 27.4 (CH2), 26.8 (CH2), 26.5 (CH2), 26.5 (CH2), 26.4
(CH2), 26.3 (CH2), 25.9 (CH2), 25.8 (CH2), 21.7 (2 CH2); IR (neat) 3464 (br w), 2934 (s),
2858 (s), 1460 (m), 1350 (w), 1259 (w), 1151 (w), 1091 (w), 1047 (w), 908 (s), 734 (s)

cm"; HRMs (B1) m/z 322.1855 [(M”) calcd. for C17H32035C12: 322.1830].
OMe OMe
.5 .5
OH
153 154

(18*, 2R*, 48*, 8R*)-8-methoxy-l,8-dimethylbicyclo[2.2.2]oct-5-en-2-ol (153) and

(18*, 28 *, 48 *, 8R*)-8-methoxy-l,8-dimethylbicyclo[2.2.2]oct-5-en-2-ol (154).

160

Following general procedure IV, the reaction of 2.02 g (11.2 mmol) of starting
ketone 27, afforded 1.16 g (57%) of 153:154, as a 1:1 diastereomeric mixture, with no
purification necessary.

153: R. = 0.45 (5:1 hexanes/EtOAC); [ali‘,', = -26.2 (c 0.36, CHC13); 'H-NMR (300 MHz.
CDC13) 5 6.11 (t, J = 8.1 Hz, 1 H), 5.69 (d, J = 7.8 Hz, 1 H), 3.33 (dm, J = 9.3 Hz. 1 H),
3.09 (s, 3 H), 2.43 (m, 1 H), 2.09 (br s, l H), 1.79 (d, J = 13.8 Hz, 1 H), 1.61 (dd, J =
13.5, 2.7 Hz, 1 H), 1.21 (d, J = 13.5 Hz, 1 H), 1.09 (s, 3 H), 1.02 (s, 3 H), 0.80 (dt, J =
13.5, 3.0 Hz, 1 H); l3C-NMR (75 MHz, CDC13) 5 134.9 (CH), 134.0 (CH), 78.8 (C), 71.4
(CH), 49.3 (CH3), 42.3 (CH2), 40.5 (C), 39.2 (CH), 32.9 (CH2), 24.5 (CH3), 21.2 (CH3);
IR (neat) 3439 (br s), 3040 (m), 2930 (s), 2828 (m), 1579 (w), 1516 (w), 1456 (s), 1365
(s) 1323 (m), 1259 (m), 1194 (m), 1165 (m), 1089 (s), 1070 (s), 995 (w), 922 (w), 846
(w), 723 (m), 704 (s) cm"; LRMS (E1) m/z 150.0 (M+ -MeOH); HRMS (E1) m/z
182.1303 [(M+); calcd. for C..H.8Oz: 182.1307].

154: R. = 0.36 (5:1 hexanes/EtOAc); 151:. = -98.0 (c 0.14, CHC13); 'H-NMR (300 MHz,
CDC13) 5 6.25 (t, J = 8.1 Hz, 1 H), 5.76 (d, J = 8.1 Hz, 1 H), 3.54 (dm, J = 8.4 Hz, 1 H),
3.05 (8,3 H), 2.45 (m, l H), 2.09 (br s, 1 H), 1.79 (d, J: 13.8 Hz, 1 H), 1.53 (dt, J: 13.8,
2.7 Hz, 1 H), 1.21 (d, J = 13.5 Hz, 1 H), 1.04 (s, 3 H), 1.00 (s, 3 H), 0.88 (dd, J = 13.5,
1.5 Hz, 1 H); l3C-NMR (75 MHZ, CDC13) 5 138.6 (CH), 133.9 (CH), 78.7 (C), 73.4
(CH), 49.3 (CH3), 46.6 (CH2), 40.7 (C), 39.4 (CH), 33.9 (CH2), 24.2 (CH3), 21.0 (CH3);
IR (neat) 3441 (br s), 3042 (m), 2934 (s), 2826 (m), 1579 (w), 1516 (w), 1460 (m), 1367
(m), 1325 (w), 1246 (w), 1196 (w), 1159 (w), 1101 (m), 1066 (s), 995 (w), 902 (w), 843
(w), 727 (m), 704 (w), 677 (w) cm"; LRMS (E1) m/z 149.8 (M+ -MeOH): HRMS (E1)

m/z 182.1312 [(M+); calcd. for CnHigOg: 182.1307].

161

MeO MeO
£0“ 66
OH
155 156

(18*, 2R*, 48*, 88*)-8-methoxy-l,8-dimethylbicyclo[2.2.2]oct-5-en-2-ol (155) and
(18*, 28 *, 48*, 88 *)-8-methoxy-1,8-dimethylbicyclo[2.2.2]oct-5-en-2-ol (156).
Following general procedure IV, the reaction of 2.07 g (11.4 mmol) of starting
ketone 28, afforded 1.66 g (79%) of 155:156, as a 1:1 diastereomeric mixture, with no
purification necessary.
155: R. = 0.12 (25:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 6.21 (ABq, J = 6.3,
2.1 Hz, 1 H), 5.88 (d, J = 8.1 HZ, 1 H), 3.45 (dt, J = 9.9, 2.4 Hz, 1 H), 3.10 (s, 3 H), 2.56
(m, l H), 2.00 (s, 1 H), 1.83 (d, J: 13.2 Hz, 1 H), 1.79 (d, J: 13.2 Hz, 1 H), 1.37 (s, 3
H), 1.30 (dt, J: 14.1, 2.7Hz, 1 H), 1.13 (dd, J: 13.5Hz, J: 1.5 HZ, 1 H), 1.09 (s, 3 H);
l3C-NMR (75 MHZ, CDC13) 5 136.0 (CH), 133.9 (CH), 79.5 (C), 48.9 (CH3), 41.5 (CH3),
40.3 (C), 39.4 (CH), 32.8 (CH2), 25.5 (CH2), 21.9 (CH3), 21.1 (CH3); IR (neat) 3445 (br
s). 3040 (m), 2970 (s), 2824 (m), 1550 (m), 1460 (s), 1371 (s) 1325 (m), 1259 (m), 1190
(m), 1126 (s), 1099 (s), 1074 (s), 997 (m), 968 (m), 918 (s), 897 (m), 702 (s), 677 (m)
cm"; HRMS (B1) m/z 182.1302 [(M+); calcd. for CHH1302: 182.1307].
156: R. = 0.22 (25:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 6.38 (ABq, J = 6.6,
1.8 Hz, 1 H), 5.88 (d, J = 5.1 HZ, 1 H), 3.49 (m, 1 H), 3.09 (s, 3 H), 2.62 (m, l H), 2.17
(ddd, J = 4.94, 3.29, 1.09 Hz,, 1 H), 1.39 (d, J = 13.5 Hz, 1 H), 1.26 (s, l H), 1.25 (s, 3
H), 1.19 (s, 3 H), 1.07 (d, J = 13.8 Hz, 1 H), 0.98 (dt, J = 14.7, 3.3 HZ, 1 H); l3C-NMR
(75 MHZ, CDC13) 5 134.2 (CH), 133.4 (CH), 78.9 (C), 74.2 (CH), 49.3 (CH3). 47.2

(CH3), 40.9 (C), 39.3 (CH), 35.9 (CH2), 22.8 (CH3), 21.2 (CH3); IR (neat) 3437 (br s),

162

3034 (s), 2932 (s), 2831 (s), 1610 (w), 1454 (s), 1369 (s), 1344 (s), 1307 (s), 1273 (s),
1192 (s), 1136 (s), 1076 (s), 955 (s), 881 (m), 850 (s), 819 (m), 756 (s), 731 (s), 657 (w)
cm": HRMS (El) m/z 182.1301 [(M+); calcd. for CHngOzI 182.1307].
OMe OMe
£011 £0
0 OH
157 158

(18*, 2R*, 48*, 8R*)-8-methoxy-l,8-dimethylbicyclo[2.2.2]oct-5-en-2-ol (157) and
(18*, 28 *, 48 *, 8R*)-8-methoxy-l,8-dimethylbicyclo[2.2.2]oct-5-en-2-ol (158).
Following general procedure IV, the reaction of 2.00 g (11.1 mmol) of starting
ketone 27, afforded 1.00 g (49%) of 157:158 as a 1:1 diastereomeric mixture, with no
purification necessary.
157: 1H NMR (300 MHZ, CDC13) 5 6.19 (ABq, J = 8.1 Hz, J = 1.2 Hz, 1 H), 5.77 (d, J =
8.1 HZ, 1 H), 3.17 (s, 3 H), 2.53 (m, l H), 2.48 (d, J = 14.4 Hz, 1 H), 1.87 (s, 1 H), 1.67
(m, l H), 1.61 (dd, J = 13.5, 2.7 HZ, 1 H), 1.16 (s, 3 H), 1.10 (s, 3 H), 0.86 (dd, J = 13.5,
2.7 HZ, 1 H); l3C NMR (75 MHZ, CDC13) 5 134.9 (CH), 134.5 (CH), 78.9 (C), 77.5 (CD),
49.4 (CH3), 42.7 (CH2), 40.5 (C), 39.4 (CH), 33.5 (CH2), 24.6 (CH3), 21.2 (CH3); IR
(neat) 3433 (br s), 3040 (m), 2934 (s), 2870 (s), 2826 (m), 1458 (s), 1385 (s), 1325 (m),
1280 (m), 1221 (m), 1145 (s), 1109 (s), 1076(5), 947 (m), 920 (m), 890 (m), 723 (s), 700
(m), 673 (m) cm"; HRMS (EI) m/z 183.1342 [(M+); calcd. for CHHnDOg: 183.1369].
158: lH NMR (300 MHZ, CDC13) 5 6.33 (t, J = 7.2 HZ, 1 H), 5.85 (d, J = 7.8 Hz, 1 H),
3.13 (s, 3 H), 2.53 (m, l H), 1.83 (s, l H), 1.72 (m, 1 H), 1.61 (dd, J = 13.5, 2.7 Hz, 1 H),
1.29 (d, J = 13.5 Hz, 1 H), 1.12 (s, 3 H), 1.08 (s, 3 H), 0.97 (d, J = 13.5 HZ, 1 H): ”C

NMR (75 MHZ, CDC13) 5 138.8 (CH), 134.3 (CH), 78.8 (C), 76.4 (CD), 49.5 (CH3), 46.6

163

(CH2), 40.8 (C), 39.5 (CH), 34.0 (CH2), 24.3 (CH3). 21.1 (CH3); HRMS (E1) 711/:

183.1378 [(M+); calcd. for CHHnDOZ: 183.1369].

OMe

163

(1R*, 28*, 58*, 68*, 8R*)-2-8-chloro-6-methoxy-2,6-dimethyl-bicyclo[3.2.l]octan-3-
one (163).

Following general procedure V, the reaction of 0.93 g (5.1 mmol) of 153:154, as a
1:1 diastereomeric mixture, afforded 0.49 g (45%) of 158 after purification via flash
silica chromatography (15 g, 1% Et3N/hexanes).
163: R. = 0.31 (4:1 hexanes/EOtAc); 1H-NMR (300 MHz. CDC13) 5 4.37 (td, J = 4.5, 1.2
Hz, 1 H), 3.08 (s, 3 H), 2.93 (m, 1 H), 2.68 (ddd, J = 16.2, 3.6, 0.9 Hz, 1 H), 2.46 (ddd, J
= 15.9, 2.7, 1.2 HZ, 1 H), 2.39 (m, 1 H), 2.28 (m, 1 H), 1.77 (d, J: 14.7 HZ, 1 H), 1.60
(ddd, J = 9.3, 6.9, 1.5 Hz, 1 H), 1.29 (s, 3 H), 0.97 (d, J = 6.9 Hz, 3 H); l3C-NMR (75
MHZ, CDC13) 5 209.5 (C), 80.6 (C), 61.1 (CH), 51.0 (CH), 50.8 (CH3), 45.5 (CH), 43.8
(CH), 38.4 (CH2), 37.5 (CH2), 25.7 (CH3), 11.8 (CH3); IR (neat) 2974 (s), 2939 (s), 2874
(m), 2829 (m), 1714 (s), 1690 (w), 1450 (m), 1412 (m), 1379 (s), 1323 (m), 1215 (m),
1161 (s), 1149 (s), 1086 (s), 1053 (s), 912 (s), 819 (m), 805 (m), 785 (m), 733 (s) cm":

HRMS (E1) m/z 216.0913 [(M+); calcd. for CHHnClOg: 216.0917].

M60

0

165

164

(1R*, 28*, 58*, 6R*, 8R*)-8-chloro-6-methoxy-2,6-dimethyl-bicyclo[3.2.1]octan-3-
one (165).

Following general procedure V, the reaction of 1.00 g (5.4 mmol) of 155:156, as a
1:1 diastereomeric mixture, afforded 0.38 g (33%) of 165 after purification via flash
silica chromatography (13 g, 1% Et3N/hexanes).
165: R. = 0.36 (4:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 4.74 (td, J = 6.3, 1.5
Hz, 1 H), 3.11 (s, 3 H), 3.08 (m, 1 H), 2.89 (ddd, J = 15.0, 4.2, 1.2 Hz, 1 H), 2.50 (m, l
H), 2.32 (m, 1 H), 2.22 (dq, J: 15.9, 1.5 Hz, 1 H), 1.95 (dd, J: 14.4, 6.9 Hz, 1 H), 1.46
(d, J = 14.7 Hz, 1 H), 1.17 (s, 3 H), 0.96 (d, J = 6.6 Hz, 3 H); l3C-NMR (75 MHZ,
CDC13) 5 210.9 (C), 82.1 (C), 62.0 (CH), 49.6 (CH3), 49.4 (CH), 45.5 (CH), 44.2 (CH),
39.7 (CH2), 38.1 (CH2), 20.0 (CH3), 11.8 (CH3); IR (neat) 2970 (s), 2941 (s), 2750 (m),
1710(8), 1462 (m), 1421 (m), 1379(8), 1325 (m), 1209 (m), 1147 (m), 1095 (s), 1086 (s),
1053 (m), 908 (s), 890 (s), 829 (m), 788 (m), 760 (m), 733 (s) cm"; LRMS (EI) m/z 216.0
(M+), 218.0 (Ma); HRMS (E1) m/z 216.0918 [(M"); calcd. for C . .H.7C102: 216.0917].

Me OMe
L496
Oifié
(1895
H

0.20/0 0.10/0

    

1696

 

167 188
(1R*, 28 *, 58*, 68*, 8R*)-2-deutero-8-chloro-6-methoxy-2,6-dimethyl-
bicyclo[3.2.l]octan-3-one (167) and (1R*, 2R*, 58*, 68*, 8R*)-2-deutero-8-chloro-6-

methoxy-2,6-dimethyl-bicyclo[3.2.l]octan-3-one (168).

165

Following general procedure V, the reaction of 0.18 g (0.98 mmol) of 157:158, as
a 1:1 diastereomeric mixture, afforded 0.12 g (60%) of 167:168, as a 2:1 diastereomeric
mixture, after purification via flash silica chromatography (5 g, 10:1 hexanes/EtOAc).

167: R. = 0.56 (4:1 hexanes/EtOAc); [0.13, = +400 (0 0.23, CHC13); 'H—NMR (300

MHZ, CDC13) 5 4.40 (dt, J = 4.5, 1.5 Hz, 1 H), 3.12 (s, 3 H), 2.71 (dd, J = 15.9, 3.9 HZ, 1
H), 2.51 (ddd, J = 16.2, 3.0, 1.5 Hz, 1 H), 2.43 (m, 1 H), 2.31 (m, 1 H), 1.81 (d, J = 14.4
HZ, 1 H), 1.64 (dd, J = 14.4, 6.6 Hz, 1 H), 1.32 (s, 3 H), 1.00 (s, 3 H); For l-D NOE
correlations see figure shown above; l3C-NMR (75 MHZ, CDC13) 5 209.7 (C), 80.7 (C),
61.2 (CH), 51.] (CH), 50.9 (CH3), 48.5 (CD), 45.5 (CH), 38.6 (CH2), 37.6 (CH2), 25.8
(CH3), 11.8 (CH3); IR (neat) 2974 (s), 2937 (s), 1714 (s), 1450 (s), 1412 (m), 1379 (s),
1323 (In), 1226 (s), 1153 (s), 1078 (s), 918 (s), 852 (m), 798 (m), 733 (s) cm"; HRMS
(B1) m/z 217.7186 [(M+); calcd. for C1 .H16D0235C1: 217.7192].

168: R. = 0.31 (5:1 hexanes/EtOAc); [01336 = +180 (0 0.08, CHC13); 1H-NMR (500

MHZ, CDC13) 5 4.26 (t, J = 3.3 Hz, 1 H), 3.14 (s,3H), 2.78 (dd, J = 10.8, 2.7 Hz, 1 H),
2.68 (ddd, J = 10.8, 1.5, 0.6 Hz, 1 H), 2.45 (m, 1 H), 2.39 (m, 1 H), 1.83 (m, 2 H), 1.34
(s, 3 H), 1.32 (s, 3 H); For l-D NOE correlations see figure shown above; l3C-NMR (125
MHZ, CDC13) 5 208.5 (C), 80.0 (C), 59.4 (CH), 50.9 (CH3), 50.4 (CH), 49.3 (CD), 45.0
(CH2), 44.6 (CH), 37.1 (CH2), 26.0 (CH3), 19.8 (CH3); IR (neat) 2970 (s), 2937 (s), 1709
(s), 1454 (In), 1377 (m), 1325 (m), 1226 (m), 1167 (m), 1084 (m), 1064 (s), 929 (m), 790

(In) em"; HRMS (BI) m/z 217.7190 [(M“); calcd. for C1 .H..,D0235C1: 217.7192].

OMe OMe
£011 g
OH
159 160

166

(18*, 2R*, 48*, 8R*)-8-methoxy-l,2,8-trimethyl-bicyclo[2.2.2]oct-5-en-2-ol (159) and
(18*, 28*, 48*, 8R*)-8-methoxy-1,2,8-trimethyl-bicyclo[2.2.2]oct-5-en-2-ol (160).

To 5.3 mL (27.7 mmol, 5.00 eq) of a chilled (0 °C) 3.0 M methyl magnesium
bromide/T HF solution was added, 0.99 g (5.2 mmol, 1.00 eq) 27 in 5 m1 THF dropwise.
After complete addition, the reaction was stirred at 0 °C for 2 hrs and then at room
temperature for 5 hrs. Upon cooling back to 0 °C, the reaction was quenched with an
aqueous solution of NH4C1.,.,.), warmed to room temperature and then stirred for 2 hrs.
After separation the ethereal layer was washed two times with an aqueous solution of
NHzClm), afterwhich the combined aqueous layers were extracted once with 20 ml 15th.
The combined organics were dried over MgSO4, filtered, and concentrated to afford a
yellow oil. The residual was purified via flash alumina chromatography (30 g; basic,
Activity 111; 50:1 Hex/EtOAc) to 0.74 g (73%) of 159:160 as a 1:1 mixture.

159: R. = 0.26 (5:1 hexanes/EtOAc); lH-NMR (300 MHZ, CDC13) 5 6.17 (t, J = 8.1 HZ,
1 H), 5.92 (d, J = 7.8 Hz, 1 H), 3.23 (s, 3 H), 2.78 (br s, l H), 2.63 (m, l H), 1.93 (dd, J =
13.9, 3.0 Hz, 2 H), 1.32 (dd, J: 13.5, 2.1 HZ, 1 H), 1.15 (s, 3 H), 1.09 (s, 3 H), 1.08 (s, 3
H), 1.02 (d, J = 14.1 Hz, 1 H); l3C-NMR (75 MHZ, CDC13) 5 140.1 (CH), 133.1 (CH),
78.7 (C), 72.5 (C), 49.6 (CH3), 46.2 (CH2), 43.5 (C), 41.6 (CH2), 40.2 (CH), 26.9 (CH3),
24.5 (CH3), 18.1 (CH3); IR (neat) 3512 (br s), 3043 (m), 2970 (s), 2936 (s), 2874 (s),
2828 (m), 1610 (w), 1452 (s), 1363 (s), 1286 (s), 1159 (s), 1109 (s), 1093 (s). 1086 (s),
906 (m), 885 (s), 744 (s), 680 (s) cm"; LRMS (131) m/z 196.1 (M,), 197.2 (M+1); HRMS
(E1) m/z 196.1462 [(M”); calcd. for C12H20022 196.2860].

160: R. = 0.10 (5:1 hexanes/EtOAc); 'H-NMR (300 MHZ, CDC13) 5 6.32 (1, J = 7.0 Hz,

1 H), 5.84 (d, J = 8.0 HZ, 1 H), 3.11 (s, 3 H), 2.49 (m, 1 H), 2.19 (s, 1 H), 2.15 (dd, J =

167

14.0, 2.0 Hz, 1 H), 1.58 (d, J = 14.5 HZ, 1 H), 1.23 (dd, J = 13.5, 2.5 HZ, 1 H), 1.22 (s, 3
H), 1.09 (s, 3 H), 1.07 (s, 3 H), 1.04 (d, J = 14.0 HZ, 1 H); l3C-NMR (125 MHZ, CDC13)
5 138.0 (CH), 134.6 (CH), 79.2 (C), 74.7 (C), 49.3 (CH3), 44.8 (CH3), 43.6 (C), 40.8
(CH2), 40.4 (CH), 24.6 (CH3), 22.3 (CH3), 18.2 (CH3); IR (neat) 3445 (br s), 3095 (m),
2964 (s), 2934 (s), 2874 (m), 1512 (w), 1460 (s), 1365 (s), 1251 (m), 1147 (s), 1099 (s),

1070 (s). 925 (m), 841 (m), 744 (s), 680 (m) cm".

   

17a 176 177
(1R*, 38*, 5R*, 6R*, 7R*, 88*)-7-chloro-5-methoxy-l,3,5-trimethyI-1-oxa-
tricyclo[4.2.1.0”]nonane (176) and 6-chloro-4-methoxy-1,2,4-trimethyl-8-oxa-
tricyclo[3.3.1.02’7lnonane (177).

Following general procedure V, the reaction of 98.5 mg (0.50 mmol) of 159,
afforded 39.3 mg (34%) of 177 and 32.3 mg (28%) of 176 after purification via flash
silica chromatography (5 g, 10:1 hexanes/EtOAc).

176: R. = 0.33 (5:1 hexanes/EtOAc); 1H-NMR (500 MHZ, CDC13) 5 4.15 (t, J = 4.4 Hz, 1
H), 3.18 (s, 3 H), 2.38 (m, 1 H), 2.35 (d, J = 15.3 Hz, 1 H), 2.24 (d, J = 13.7 Hz, 1 H),
1.96 (t, J: 4.9 HZ, 1 H), 1.81 (dd, J: 15.3, 6.5 Hz, 1 H), 1.38 (dd, J: 13.7.7.1 Hz, 1 H),
1.31 (s, 3 H), 1.30 (s, 3 H), 1.22 (s, 3 H); For l-D NOE correlations see figure shown
above; l3C-NMR (125 MHz, CDC13) 5 78.9 (C). 62.8 (C), 60.8 (CH), 58.6 (C), 50.7

(CH2), 48.5 (CH3), 46.0 (CH), 36.3 (CH), 27.7 (CH2), 27.1 (CH3), 21.6 (CH3), 19.9

168

(CH3); IR (neat) 2930 (s), 2855 (m), 1458 (m), 1379 (m), 1321 (w), 1234 (w), 1132 (w),
1066 (m), 910 (w), 893 (m), 787 (m) cm"; HRMS (EI) m/z 231.1152 [(M”); calcd. for
C.2H.gOz35C1: 230.1074].

177: R. = 0.12 (5:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 4.93 (d, J = 1.1 Hz,
1 H), 4.22 (s, 1 H), 3.91 (d, J = 4.4 HZ, 1 H), 3.25 (s, 3 H), 2.74 (In, 1 H), 2.03 (d, J =
15.4 Hz,1H),1.89(t,J=1.65 Hz, 1 H), 1.81 (d,J=14.8 Hz, 1 H), 1.41 (s, 3 H), 1.13 (d,
J = 1.1 HZ, 3 H), 0.90 (s, 3 H); For l-D NOE correlations see figure shown above; 13C-
NMR (125 MHZ, CDC13) 5 77.6 (C), 75.0 (C), 63.0 (CH), 60.0 (CH), 49.3 (CH3), 47.6
(C), 44.8 (CH2), 44.7 (CH), 41.6 (CH2), 27.8 (CH3), 25.1 (CH3), 19.0 (CH3); IR (neat)
3424 (br s), 2987 (s), 2934 (s), 2874 (s), 1608 (m), 1462 (s), 1379 (s), 1257 (ms), 1230
(ms), 1172 (s), 1115 (s), 1066 (s), 952 (ms), 925 (s), 893 (s), 871 (ms), 781 (ms) cm";

HRMS (BI) m/z 231.1163 [(M+ +H); calcd. for C.2H.90235Cl: 230.1074].

OMe OMe

’ OH ’ fi

11 O”
161 162
(18*, 28*, 48*, 88*)-1,8-dimethyl-2-ethyny1-8-methoxybicyclo[2.2.2]oct-5-en-2-ol
(161) and (18*, 2R*, 48*, 88*)-l,8-dimethyl-2-ethynyl-8-methoxybicyclo[2.2.2]oct-5-
en-2-ol (162).

To 55.5 mL (27.7 mmol, 5.00 eq) of a chilled (0 °C) 0.5 M ethynyl magnesium
bromide/THF solution, was added 1.00 g 27 (5.54 mmol, 1.00 eq) in 10 mL THF
dropwise via syringe. The reaction was kept at 0 °C for 10 min and then heated to reflux
(80 °C), which was maintained for 2.5 hrs The reaction was cooled to 0 °C and quenched

with an aqueous solution of NH4C1.,,,., and then partitioned with 30 mL Eth. After

169

separation the ethereal layer was washed two times with 30 mL of an aqueous solution of
NH4C1.,.,.,. The combined aqueous layers were extracted three times with 20 mL 320.
The combined ethereal layers were washed once with 30 mL brine, dried over MgSO4,
filtered, and concentrated to afford a yellow oil. The oil was purified via flash alumina
chromatography (30 g; basic, Activity 111; 30:1 hexanes/EtOAc) to afford 0.77 g (68%) of
161:162 in a 2.8: 1.0 mixture.

161: R. = 0.33 (4:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 6.23 (t, J = 7.5 HZ,
1 H), 5.90 (d, J = 8.1 Hz, 1 H), 3.14 (s, 3 H), 2.74 (s, 1 H), 2.57 (m, l H), 2.34 (s, l H),
2.12 (dd, J = 13.8, 2.7 Hz, 1 H), 1.90 (d, J = 13.8 Hz, 1 H), 1.88 (dd, J = 13.5, 2.7 Hz, 1
H), 1.22 (s, 3 H), 1.09 (s, 3 H), 0.99 (d, J = 14.1 Hz, 1 H); l3C-NMR (75 MHZ, CDC13) 5
138.5 (CH), 133.8 (CH), 88.2 (C), 78.4 (C), 72.7 (C), 71.0 (CH), 49.5 (CH3), 43.8 (CH).
43.2 (CH2), 41.6 (CH2), 40.9 (C), 24.5 (CH3), 19.0 (CH3); HRMS (EI) m/z 206.1308
[(M”), calcd. for C.3H.302: 206.1307].

162: R. = 0.29 (4:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 6.30 (t, J = 7.2 HZ,
1 H), 5.78 (d, J = 7.8 HZ, 1 H), 3.13 (s, 3 H), 2.69 (dd, J = 13.8, 2.4 Hz, 1 H), 2.51 (m, 1
H), 2.44 (s, 1 H), 2.07 (s, l H), 1.40 (dd, J: 13.8, 3.3 Hz, 1 H), 1.23 (s, 3 H), 1.15 (d, J:
14.1 Hz, 1 H), 1.07 (s, 3 H), 1.02 (d, J = 13.8 HZ, 1 H): l3C-NMR (75 MHZ, CDC13) 5
135.4 (CH), 134.2 (CH), 85.9 (C), 78.7 (C), 72.7 (C), 71.1 (CH) 49.3 (CH3), 41.0 (CH),
40.8 (C), 40.2 (CH2), 39.6 (CH2), 24.5 (CH3), 18.9 (CH3); HRMS (E1) m/z 206.1306
[(M+), calcd. for C13H1302: 206.1307].

161:162: IR (KBr) 3400 (br s), 3300 (s), 3090 (m), 2998 (s), 2990(5), 2975 (s), 2670 (m).
2620 (m), 2030 (w), 1699 (w), 1420 (m), 1345 (s), 1110 (m), 1080 (s), 1015 (m), 920

(m), 910 (m), 850 (m). 760 (s) cm".

170

3.0%

 

183 183
(1R*, 3R*, 4R*, 68*, 7R*, 8S*)-6-chloro-1-ethynyl-4-methoxy-2,4-dimethyl-8-oxa-
tricyclo[3.3.l.Ol’zlnonane (183).

Following general procedure V, the reaction of 0.30 g (1.4 mmol) of 156,
afforded 0.14 (39%) of 183 after purification via flash silica chromatography (3.5 g. 1%
Et3N/hexanes).

140: R. = 0.44 (4:1 hexanes/EtOAc); lH-NMR (300 MHZ, CDC13) 5 4.15 (1, J = 4.8 Hz,
1 H), 3.16 (s, 3 H), 2.65 (d, J = 15.6 Hz, 1 H), 2.50 (t, J = 5.7 HZ, 1 H), 2.18 (dd, J =
15.6, 6.6 HZ, 1 H), 2.16 (d, J: 13.8 Hz, 1 H), 2.01 (t, J: 5.1 HZ, 1 H), 1.49 (s, 3 H), 1.37
(dd, J = 13.5, 7.2 Hz, 1 H), 1.26 (d, J = 15.9 Hz, 1 H), 1.22 (s, 3 H); For l—D NOE
correlations see figure shown above; l3C-NMR (75 MHZ, CDC13) 5 82.5 (C), 78.6 (C),
71.8 (C), 64.2 (C), 59.4 (CH), 52.8 (C), 50.6 (CH3), 48.1 (CH), 45.2 (CH), 36.1 (CH3),
27.1 (CH3), 27.0 (CH2), 22.8 (CH3); IR (neat) 3300 (m), 3090 (w), 3966 (s), 2939 (s),
2810 (m), 2100 (w), 1498 (m), 1379 (m), 1319 (m), 1234 (m), 1188 (m), 1159 (m), 1136

(s), 1064 (s), 895 (s), 814 (m), 738 (s), 679 (m) cm'l; HRMS (EI) m/z 240.0919 [(M+);

Preparation of Diels-Alder Adduct (217).

calcd. for C.3H.735C102: 240.7256].

171

A typical ring expansion/exo-olefin insertion procedure, reaction time shortened
to 1 hr, was performed on 0.50 g (4.5 mmol) 84 and afforded 0.19 g (40%) of 90. Enone
90 was immediately dissolved in 6.5 ml (0.28 M) PhH. To this solution was added 0.85 g
(9.1 mmol, 5.00 eq) norbomylene. The reaction was refluxed (80 °C) for 12 hrs, cooled
to room temperature and concentrated. The oil was purified via flash silica
chromatography (4 g, 20:1 hexanes/EtOAc) to afford 0.32 g (82%) 217.

217: R. = 0.57 (5:1 hexanes/EtOAc); 1H-NMR (300 MHZ, CDC13) 5 2.70 (td, J = 12.0,
5.4 HZ, 1 H), 2.22 (dt, J = 12.6, 5.4 Hz, 1 H), 2.09 (m, 2 H), 1.98 (series of m, 5 H), 1.80
(m, 3 H), 1.58 (series of m, 8 H); l3C-NMR (75 MHz, CDC13) 5 211.9 (C), 144.5 (C),
104.7 (C), 80.4 (CH2), 39.5 (CH2), 38.7 (CH2), 28.8 (CH2), 28.3 (CH2), 27.6 (CH2), 27.4
(CH2), 23.0 (CH2), 22.7 (CH2), 22.7 (CH2), 20.7 (CH2); IR (neat) 2960 (s), 2949 (s), 1710
(s), 1555 (m), 1498 (m), 1322 (m), 1244 (In), 1180 (m), 1161 (m), 1136(8), 1068 (s),

895(m), 758 (s), cm"; HRMS (E1) m/z 220.2156 [(M+); calcd. for C .4H2.)ng 220.1463].

172

REFERENCES AND NOTES

 

10

Ring enlargement review: (a) Gutsche, C. D.; Redmore, D. Carbocyclic Ring
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Diazo review: (a) Gutsche, C. D. Org. React. 1954, 8, 364-429. (b) Gutsche, C.;
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Wagner-Meerwein review: (a) Pocker, Y. Molecular Rearrangements, ed. Mayo P.
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Selectivity of cation rearrangements reviews: (a) Berson, J. A. in Molecular
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173

 

ll

l6

l7

18

19

20

21

22

Cation-radical Diels-Alder: (a) Bauld, N. L.; Bellville, D. J.; Harirchian, B.;
Lorenz, K. T.; Pabon, R. A.; Reynolds, D. W.; Wirth, D. D.; Chiou, H-S.; Marsh,
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Cation-radical Claisen: Dhanalekshmi, S.; Venkatachalam, C. 8.;
Balasubramanian, K. K. J. Chem. Soc. Chem. Commun. 1994, 511-512.
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Cation-radical sigmatropic reactions: Bauld, N. L. Tetrahedron, 1989, 45, 5307-
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Anion-radical [3,3] sigmatropic: (a) Enholm, E. J .; Moran, K. M.; Whitley, P. E.;
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One oxy-Cope product via radicals has been found in the literature. However there
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1961, 83, 3877-3844.

(a) Murdoch, J. R. J. Am. Chem. Soc. 1983, 105, 2660-2667. (b) Curran, D. P.;
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174

 

23

24

25

26

27

29

3O

31

The structure assigned to each new compound is in accordance with its infrared,
300 or 500 MHz 1H NMR, and 75 or 125 MHz 13C NMR spectral data, as well as
appropriate ion identification by high-resolution mass spectrometry. Stereochemical
assignments were supported by NOE NMR experiments. See Experimental
Appendix for details.

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175

 

32

33

34

35

36

37

Sulfenates: (a) Beckwith, A. L. J.; Hay, B. P.; Williams, G. M. J. Chem. Soc.
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T. J. Chem. Soc. Perkin Trans. I 1992, 3119-3124. (0) Suarez, E.; Armas, P.;
Francisco, C. G. Tetrahedron Lett. 1993, 34, 7331-7334. (p) Lusztyk, J .;
Courtneidge, J. 1...; Page’, D. Tetrahedron Lett. 1994, 35, 1003-1006. (q) Suarez, E.;
Francisco, C. G.; Freire, R.; Gonzalez, C. C.; Leon, E. I. J. Org. Chem. 2000, 66,
1861-1866. (r) Suarez, E.; Gonzalez, C. C.; Kennedy, A. R.; Leon, E. 1.; Riesco-
Fagundo, C. Angew. Chem. Int. Ed. Engl. 2001, 40, 2326-2328. (s) Suarez, E.;
Francisco, C. G.; Freire, R.; Gonzalez, C. C.; Leon, E. I.; Riesco-Fagundo, C. J.
Org. Chem. 2001, 66, 1861-1866.

Iodoepoxides: Galatsis, P.; Millan, S. D.; Faber, T. J. Am. Chem. Soc. 1993, 58,
1215-1220.

Nitrate esters: Fraser-Reid, B.; Vite, G. D. Synth. Commum. 1988, 18, 1339-1342.

176

 

38

39

4O

41

42

43

44

45

46

47

48

Pyridinyl thiones: (a) Barton, D. H. R.; Togo, H.; Zard, 8. Z. Tetrahedron 1985,
41, 5507-5516. (b) Barton, D. H. R.; Crich, D.; Kretzschmar, G. J. Chem. Soc.
Perkin Trans. I 1986, 39-53. (c) Beckwith, A. L. J .; Hay, B. P. J. Am. Chem. Soc.
1988, 110, 4415-4416. (d) Beckwith, A. L. J .; Davison, I. G. E. Tetrahedron Lett.
1991, 32, 49-52. (e) Barton, D. H. R.; Jaszberenyi, J. C.; Morrell, A. I.
Tetrahedron Lett. 1991, 32, 31 1-314.

Thiazole thiones: Hartung, J .; Schwarz, M. Synlett. 1997, 848-850.

Phthalamides: (a) Kim, S.; Lee, T. A.; Song, Y. Synlett. 1998, 471-472. (b)
Newcomb, M.; Crich, D.; Huang, X. Org. Lett. 1999, I , 225-227.

Bicyclic cationic rearrangements: (a) Berson, J. A. Molecular Rearrangements,
Mayo, P., Ed.; Interscience Publishers: New York, 1963, pp 1 l l-232. (b) Bartlett,
P. D. Nonclassical Ions, W. A. Benjamin, New York, 1965. (c) Gutsche, D.:
Redmore, D. Carbocyclic Ring Expansion Reactions, Hart, H. and Karabatsos, G. J.
Ed.; Academic Press, New York, 1968, pp 1-95. (d) Hesse, M. Ring Enlargement
in Organic Chemistry, VCH Publishers, New York, 1991 pp 1-34.

Radicals via Bu3SnH: Giese, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds; Pergamon Press, New York, 1986.

Sulfenate procedure (p-NO2): Pasto, D. J .; Cottard, P.; Horgan, S. J. Org. Chem.
1993,58, 4110-4112.

Polar S-Cl addition across olefins: Fallis, A. G.; Tuladhar, S. M. Tetrahedron Lett.
1987, 28. 523-526.

In the isolation of sulfides 33, 35, and 37, only one diastereomer was isolated in
each case. Due to the unsatisfactory results the more in depth question of
diastereoselectivity was not pursued.

Sulfenate [2,3]-sigmatropic rearrangement: (a) Mislow, K, Rayner, D. R., Miller.
E. G., Bickart, R, Gordon, A. J. J. Am. Chem. Soc. 1966, 88, 3138-3139. (b)
Mislow, K., Miller, E. G., Rayner, D. R. J. Am. Chem. Soc. 1966, 88, 3139-3140.
(C) Baldwin, J. E., Hackler, R. E., Kelly, D. P. J. Chem. Soc. Chem. Commun. 1968,
538-539. (d) Mislow, K., Tang, R. J. Am. Chem. Soc. 1970, 92, 2100-2104. (g)
Brown W. L., Fallis, A. G. Can. J. Chem. 1987, 1828-1837.

PhSCl: Zelc'ans, G. Encyclopedia of Reagents for Organic Synthesis, Paquette, L.
A., Ed.; Wiley, New York, 1995; Vol. 1, pp 272-277.

Phenyl sulfenyl chloride procedure: Hursthouse, M. B.; Malik, K. M. A.; Hibbs, D.
E.; Roberts, 3. M.; Seago, A. J. H.; Sik, v.; Storer, R. J. Chem. Soc. Perkin Trans.
I 1995, 2419-2425.

177

 

49

50

51

52

53

54

55

56

57

58

59

6O

61

62

Sulfenate procedure (phenyl): Guindon, Y.; Denis, R. C. Tetrahedron Lett. 1998,
39, 339-342.

HgO/I2: Iwasa, S.; Rawal, V. H. Encyclopedia of Reagents for Organic Synthesis,
Paquette, L. A., Ed.; Wiley, New York, 1995; Vol. 5, pp 3261-3263.

Pb(OAc)4/12: Mihailovic’, M. L.; Cekovié, 2. Encyclopedia of Reagents for
Organic Synthesis, Paquette, L. A., Ed.; Wiley, New York, 1995; Vol. 5, 2956-
2958.

Since the desired radical oxy-Cope product was not observed, compound 39 was
not fully characterized as a result of other possible avenues of investigation.

DAID: Moriarty, R. M.; Chany II, C. J.; Kosmeder II, J. W. Encyclopedia of
Reagents for Organic Synthesis, Paquette, L. A., Ed.; Wiley, New York, 1995; Vol.
2, 1479-1484.

Iodosylbenzene: Moriarty, R. M.; Kosmeder II, J. W. Encyclopedia of Reagents for
Organic Synthesis, Paquette, L. A., Ed.; Wiley, New York, 1995; Vol. 4, 2846-
2850.

PhIO synthesis: Sharefkin, J. G.; Saltzman, H. Organic Syntheses Coll. Vol. V,
1973, 658. 00

NaOCI: Glavin, J. M.; Jacobsen, E. N. Encyclopedia of Reagents for Organic
Synthesis, Paquette, L. A., Ed.; Wiley, New York, 1995; Vol. 7, 4580—4585.

The optimization of this reaction can be found in Chapter 3.

Hypochlorite formation: (a) Greene, F. D.; Savitz, M. L.; Osterholtz, F. D.; Lau, H.
H.; Smith, W. N.; Zanet, P. M. J. Org. Chem. 1963, 28,55-64. (b) Walling, C.;
Thaler, W. J. Am. Chem. Soc. 1961, 83, 3877-3884. (c) Walling, C.; Clark, R. T. J.
Am. Chem. Soc. 1974, 96, 4530-4534.

Chlorinative ring expansions: (a) Johnson, C. R.; Herr, R. W. J. Org. Chem. 1973,
38, 3153-3159. (b) See also Johnson, C. R.; Cheer, C. J .; Goldsmith, D. J. J.
Org.Chem. 1964, 29, 3320-3323.

Dihydrofuranyl ring expansions: Paquette, L. A.; Andrews, J. F. P.; Vanucci, C.;
Lawhom, D. E.; Negri, J. T.; Roger, R. D. J. Org. Chem. 1992, 5 7, 3956-3965.

Bridged bicyclic ring expansion of ketones: (a) Krow, G. R. Tetrahedron 1987 , 43,
3-38. (b) Djuardi, E.; Bovonsombat, P.; McNelis, E. Tetrahedron Lett. 1994, 50,
11793-11802.

The oxygen chlorine bond vibration was deduced from the IR spectrum of t-BuOCl.

178

 

63

64

65

66

67

68

69

7O

71

72

73

74

Johnson and Herr (reference 7) reported GC yields.

Johnson and Herr report this reaction generates six products by GC analysis. Only
the four present in Scheme 15 were identified.

This analysis also supports Johnson’s conclusion of a preferred CH2C1 rotomer
present in [3.2.1]-ketone 10. The methyl substituent appears as a doublet (J = 0.6
Hz), resultant from W-coupling with the CHzCl protons making two conformers
possible. Johnson used aromatic solvent induced shifts of 10 to deduce the
preferred conformer shown below. NOE data is consistent with this model. (For
aromatic solvent induced shifts see Bhacca, N. S., Williams, D. H. In Applications
of NMR Spectroscopy in Organic Chemistry, Holden-Day: San Francisco, CA,
1964, Chapter 7.)

Me Me
H, C: 0 Cl H, 0
HI I
10 10
preferred

Srikrishna’s ketones: Srikrishna, A.; Sharma, V. R.; Danieldoss, J .; Hemamalini, P.
J. Chem. Soc. Perkin Trans. I 1996, 1305-1311.

Hypohalite review: Anbar, M.; Ginsburg, D. Chem. Rev. 1954, 54, 925-958.

Biologically active enones: Miller, J. A.; Ullah, G. M.; Welsh, G. M.; Mallon, P.
Tetrahedron Lett. 2001, 42, 2729-2731.

McMurry, J. E.; Ksander, G. M.; Johnson, M. J. Org. Chem. 1977,42, 1180-1185.

(a) Tamura, R.; Watabe, K.; Hatayama, H.; Suzuki, H.; Yamamoto, Y. J. Org.
Chem. 1990, 55, 408-410. (b) Tamura, R.; Watabe, K.; Ono, N.; Yamamoto, Y. J.
Org. Chem. 1992, 5 7, 4895-4903.

Liotta, D.; Zima, G.; Barnum, C. J. Org. Chem. 1980,45, 2737-2739.

Shono, T.; Nishiguchi, 1.; Komamura, T.; Sasaki, M. J. Am. Chem. Soc. 1979, 10],
984-987.

(a) Ryu, 1.; Murai, S.; Sonoda, N. J. Org. Chem. 1986, 51, 2391-2393. (b)
Nakahira, H.; Ryu, 1.; Ikebe, M.; Oku, Y.; Ogawa, A.; Kambe, N.; Sonoda, N.;
Murai, S. J. Org. Chem. 1992, 57, 17-28.

Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98, 4887-4902.

179

 

75

76

77

78

79

80

81

82

83

84

85

86

(a) Gras, J. L. Tetrahedron Lett. 1978, 21 11-2114; 2955-2958. (b) Kellog, R. M.;
Kruizinga, W. H. J. Am. Chem. Soc. 1981, 103, 5183-5189.

This type of elimination has been suggested by, Johnson, C. J .; Cheer, C. J .;
Goldsmith, D. J. J. Org. Chem. 1964,29, 3320-3323.

Notion of anchimeric assistance and bond angle distortion: Berson, J. A.; Willner,
D. J. Am. Chem. Soc. 1964, 86, 609-616.

Synthetic route to 126: (a) Paquette, L. A.; Oplinger, J. A. Tetrahedron 1989,45,
107. (b) Paquette, L. A.; Maleczka, Jr., R. E.; Qiu, P.; J. Org. Chem. 1991, 56,
2455-2461. (c) Maleczka, Jr., R. E. Ph.D. Dissertation, Ohio State University ,
1992.

Compound 117: Yanagita, M.; Inayama, S. J. Org. Chem. 1954, 19, 1724-1733.

Sakurai Reaction: Sakurai, H.; Hosomi, A. J. Am. Chem. Soc. 1977, 99, 1673-
1675.

For Shapiro reaction: (a) Shapiro, R. H.; Heath, M. J. J. Am. Chem. Soc. 1967, 89,
5734—5735. (b) Barrett, A. G. M.; Adlington, R. M. Acc. Chem. Res. 1983, I6, 55-
59.

Intramolecular Diels-Alder reaction of masked benzoquinones: Liao, O; Chu, C .;
Lee. T.; Rao, P. D.; Song, L. J. Org. Chem. 1999, 64, 4111-4118.

Srikrishna’s ketones: Srikrishna, A.; Sharma, V. R.; Danieldoss, J .; Hemamalini, P.
J. Chem. Soc. Perkin Trans. I 1996, 1305-1311.

lH-NMR comparison of OL-methylcyclohexanones: Johnson, C. R.; Cheer, C. J .;
Goldsmith, D. J. J. Org. Chem. 1964, 29, 3320-3323.

The structure of 167 was also verified via X-ray crystallography.

Bicyclic cationic rearrangements: (a) Berson, J. A. Molecular Rearrangements,

Mayo, P., Ed.; Interscience Publishers: New York, 1963, pp 111-232. (b) Bartlett,
P. D. Nonclassical Ions, W. A. Benjamin, New York, 1965. (c) Gutsche, D.;
Redmore, D. Carbocyclic Ring Expansion Reactions, Hart, H. and Karabatsos, G. J.
Ed.; Academic Press, New York, 1968, pp 1-95. ((1) Hesse, M. Ring Enlargement
in Organic Chemistry, VCH Publishers, New York, 1991, pp 1-34.

Ethynyl carbinol ring expansions: Djuardi, E.; Bovonsombat, P.; McNelis, E.
Tetrahedron 1994, 50, 11793-11802.

Halgren, T. A. J. Comput. Chem. 1996, I 7, 490-519 and references cited therein.

180

 

89

9O

91

92

93

94

95

96

(a) Osawa, E.; Goto, H. J. Chem. Soc. Perkin Trans. 2 1993, 187-198. (b) Osawa,
E.; Goto, H. Tetrahedron 1993, 49, 387-396.

Nucleophilic enone chemistry: (a) Boyd, G. V. The Chemistry of Enones, Patai, S.;
Rappoport, 2., Ed.; Wiley, New York, 1989, pp 282-291. (b) Duval, D.; Géribaldi,
S. The Chemistry of Enones, Patai, S.; Rappoport, Z., Eds.; Wiley, New York,
1989, pp 356-456.

(a) Buchi, G.; Erickson, R. E.; Wakabayashi, N. J. Am. Chem. Soc. 1961, 83, 927-
938. (b) Bates, R. B.; Slagel, R. C. J. Am. Chem. Soc. 1962, 84, 1307-1308. (c)
Buchi, G.; MaCLeod Jr, W. D. J. Am. Chem. Soc. 1962, 84, 3205-3206. ((1) Buchi,
G.; MaCLeod Jr, W. D.; Padilla O, J. J. Am. Chem. Soc. 1964, 86, 4438-4444. (e)
Tsubaki, N.; Nishimura, K.; Hirose, Y. Bull. Chem. Soc. Jpn. 1967, 40, 597-600.
(f) Leriverend, P.; Conia, J. M. Bull. Soc. Chim. Fr. 1970, 1060-1066. (g)
Paknikar, S. K.; Veeravalli, J. Indian J. Chem. Sect. B 1980, 19B, 432.

Holton, R. A.; Juo, R. R.; Kim, H. B.; Williams, A. D.; Harusawa, S.; Lowenthal,
R. E.; Yogai, S. J. Am. Chem. Soc. 1988, 110, 6558-6560

Separation necessary since carbinol 212 places the methyl substituent at the wrong
position after ring Closing metathesis.

(a) Banthorpe, D. V.; Whittaker, D. Chem. Rev. 1966, 66, 643-656. (b) Bessfere-
Cheetien, Y. Bull. Soc. Chim. Fr. 1971, 2591. (C) Jefford, C. W.; Boschung, A. F.;
Moriarty, R. M.; Rimbault, C. G.; Laffer, M. H. Helv. Chim. Acta. 1973, 56, 2649-
2659.

(a) Woodward, R. B.; Katz, T. J. Tetrahedron 1959, 5, 70-89. (b) Sustmann, R.;
Sauer, J. Angew. Chem. Int. Ed. Engl. 1980, I 9, 779-807. (C) Craig, D. Chem. Soc.
Rev. 1987, 16, 187-238. ((1) Kagan, H. B.; Riant, 0. Chem. Rev. 1992, 92, 1007-
1019.

Thermal diemerization of acrolein: Smith, C. W.; Norton, D. G.; Ballard, S. A. J.
Am. Chem. Soc. 1951, 73, 5267-5272.

181