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LIBRARY
Michigan State
University

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                                 

 

 

 

 

This is to certify that the
dissertation entitled
Approaches to the Synthesis of Guaianolide and
Pseudoguaianolide Natural Products via Furan
Terminated Cationic Cyclizations

presented by

Gary Michael Johnson

has been accepted towards fulfillment
of the requirements for

P oh 0 D odegfee in ChemiStry

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Date MW 88

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APPROACHES TO THE SYNTHESIS OF GUAIANOLIDE
AND PSEUDOGUAIANOLIDE
NATURAL PRODUCTS m FURAN TERMINATED CATIONIC
CY CLIZATIONS

By

Gary Michael Johnson

A THESIS

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

DOCTOR OF PHILOSOPHY
Department of Chemistry

December, 1988

ABSTRACT

APPROACHES TO THE SYNTHESIS OF GUAIANOLIDE
AND PSEUDOGUAIANOLIDE
NATURAL PRODUCTS _\_/_I_A_ FURAN TERMINATED CATIONIC
CY CLIZATIONS

by

Gary Michael Johnson

The guaianolides and pseudoguaianolides are members of a class of natural
products which possess a bicyclo(5.3.0)decane skeleton. These functionally
and stereochemically complex natural products have exhibited a broad and
potent spectrum of biological activities; and as a result have been the targets
of extensive synthetic studies.

As part of a general program in furan chemistry, we have examined and
demonstrated the utility of furans as di-anions in annulation sequences.
When coupled with the ability of the furan nucleus to serve as the
operational equivalent of a variety of acyclic, carbocyclic, and heterocyclic
systems, this methodology should serve well in the synthesis of complex
systems such as those represented by the guaianolides and pseudo-
guaianolides.

We will describe general and flexible approaches to guaianolide precursors,
utilizing furan terminated cationic cyclizations to form the crucial
bicyclo(5.3.0)decane ring system. Pseudoguaianolides are obtainable through a

simple modification of these precursors.

For Vita

iv

I wish to thank Dr. Rhoda Craig, Kalamazoo College, for her guidance,
friendship, and a P.R.F. supported internship, which motivated me to pursue
a career in organic chemistry.

I thank Dr. Steven Tanis, formerly of M.S.U., for his support, guidance,
patience, and friendship throughout this project. Through his persistance, I
was fortunate to be able to join his group and complete this work, despite the
untenable circumstances which occurred during this time frame.

Financial support for this project, from the National Institutes of Health
(GM-33947), for the period January, 1986 through December, 1988 is greatfully
acknowledged. A teaching assistantship from September, 1984, to December,
1985 was provided by Michigan State University.

I would like to acknowledge certain members of the faculty and staff for
their assistance and advice, and all the past and present secretaries for their
assistance throughout this project. Special thanks to my fellow students for
their advice and friendship, especially Yousef, Tutul, and Vinod.

I thank the Grand Wazoo (Dr. Reusch) for his advice, friendship, and help
in smoothing out the constant technicalities. Thanks also to Dr. Tanis and
Dr. Reusch for many fine Cabernet and Zinfandels.

I give my Love to my family, for their comfort and support throughout
this travail. Special thanks to Bill and Melinda, who had more to do with the
completion of this endeavour than they realize.

Most importantly, thank you Linda for your Love, support, and patience,

without which, this work would not have been possible.

vi

W

List of Figures ......................................................................................... vii
List of Schemes ...................................................................................... viii
Introduction ............................................................................................ 1
Results and Discussion ......................................................................... 10
Conclusions ............................................................................................. 24
Experimental ........................................................................................... 26

Bibliography ............................................................................................. 53

Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
Figure 6.
Figure 7.
Figure 8.
Figure 9.

Figure 10.

Figure 1 1.
Figure 12.

Figure 13.

vii

Early Transformations to Tricyclic (5.7.5) System
Perillene and Dendrolasin

Furan Substitution Patterns

A General Furan Terminated Cationic Cyclization
Fused, Bridged, and Spirocyclic Systems
Aphidicolin and Perhydrohistrionicotoxin
Depiction of Possible Biosynthetic Transformations
Depictions of Possible Biogeneses

Estafiatin, Compressanolide, Damsin, Ambrosin,
and Parthenin

Furan Terminated Cationic Cyclization Sequence
Type A Cyclization: Path A and B
Olefin to Ketone Conversion (Direct or 2 Step)

Preparation of Bis-Olefin Intermediate

oxoxUlth-WWNH

\l

11
13
21

viii

LI T F EMES

Scheme 1. Cyclization Types and Target Structures

Scheme 2. First Generation Synthesis of a Type A System
Scheme 3. Alternative Approaches to the Type A System
Scheme 4. Alternative Type A Cyclization Sequence (1)
Scheme 5. Alternative Type A Cyclization Sequence (11)
Scheme 6. Deoxygenation of Keto-dithiolane

Scheme 7. Attempted Deprotection of Olefin-dithiolane
Scheme 8. Deprotection-Olefination of Keto-dithiolane
Scheme 9. Guaianolide Route from Keto-Olefin Intermediate
Scheme 10. Pseudoguaianolide Route (I) from Keto-Olefin

Scheme 11. Pseudoguaianolide Route (H) from Keto-Olefin

10
12
14
15
16
17
18
18
20
21
23

W

For close to a decade, our group has been actively pursuing new synthetic
methodology applicable to the total synthesis of a wide array of biologically
active natural productsl. The thrust of our research has centered around the
preparation of these natural products via heteroaromatic precursors, utilizing
a strategy which employs the heterocycle as an integral part of the bioactive
molecule.

This approach might be contrasted to many prior synthetic endeavors,
directed toward furan or butyrolactone containing natural products, which
involved the generation of complex carbocyclic intermediates to which the
heteroaromatic ring was then appended (Figure 1). For example, consider
the numerous syntheses of bicyclo(5.3.0)decane containing natural products.

<1)
Guy fi"
47..
O f» T...
CO

Figure 1: Early Transformations To Tricyclic 5.7.5 Systems

The approach most often followed (8 syntheses)2 began with a cyclopentane
ring, and appended on a cycloheptane; with the butyrolactone being added
last. Several syntheses based on a trans-annular cyclization3 of a cyclodecane
precursor have been reported, as well as several others, proceeding by
rearrangement of a hydronapthalene precursor4 to provide the five-seven
ring system directly. The final method which has been used is the
construction of a five membered ring onto a preformed seven membered
rings.

Our group has developed a novel approach, which employs unique
heterocyclic chemistry as a profitable way to construct the core nuclei of a
number of bioactive moleculesl. Toward this end, the heterocycle furan was
found to possess functional and structural features which would judiciously
lend themselves to chemical exploitation, and allow the preparation of
several diverse classes of complex natural products. We will illustrate this
approach within the context of preparing a furan-containing bicyclo(5.3.0)-
decane ring system.

Early successful syntheses in our group1a produced the simple natural
products Perillene 1, and Dendrolasin 2, from readily available furan
precursors in a concise and high yield approach (Figure 2). With these results

\ \ \
/\ /\

Figure 2: Perillene (1) and Dendrolasin (2)

in hand, we next examined methodology that would effect a practical
approach to more complex molecules, possessing the framework and
substitution patternslb‘g found in Figure 3. This protocol would lend itself
well to the recognized ability of a furan to undergo electrophilic substitution

 

 

O
A B
Figure 3: Furan Substitution Patterns

at the alpha position; allowing access to substructures with framework A, or B
in the event that the alpha position was first blocked.

The postulated cationic cyclization (Figure 4), in which the furyl moiety
was the cyclization terminator, was not well precedented in the literature.
However we hoped to avail ourselves of the extensive body of knowledge
accumulated in this field through the elegant studies6 of Johnson, Van
Tamelen, Goldsmith, and a number of other workers. It seemed likely that

Q7—~ m ——— m

R R R

 

 

 

 

Figure 4: Furan Terminated Cationic Cyclization

the absence of literature precedent involving furans as cyclization
terminators was due to a combination of factors, including the inaccessability
of suitable starting substrates, the poor nucleophilic character. of the furyl
residue relative to standard terminator functions, and the increased acid
lability of a disubstituted product furan relative to the starting material.1C It
therefore became a goal of our group to solve these problems, and to
demonstrate the ability of a furan to act as a terminator in cationic
cyclizations. In addition, the furan in a cyclic framework, might then stabilize

a specific conformation of the cyclized product, allowing the development of
peripherial stereocenters via standard cyclic strategy. Roberts7 has shown that
a double bond in the seven membered ring. will place it in a chair
conformation; thus a furan should provide an equivalent control element,
allowing the use of established cyclic methodology. After serving this
purpose, the furyl substituent might then be unravelled to a variety of useful
functionalities.

We have now successfully incorporated a furan into the framework of a
number of fused, Spirocyclic, and bridged ring systemslc'i (Figure 5). Among
the compounds prepared in the early studies were Pallescensin-AIC 3a, and

 

FUSED (3a)

\

 

BRIDGED (3b)

   

Figure 5: Fused, Bridged, and Spirocyclic Ring Systems

N akafuran-91d 3b. More recent successes, utilizing a furan as a terminator,
have included the formal total syntheses of the potent antiviral agent (i)
Aphidicolin1i 4, via an epoxide initiated cationic cyclization, and the
neurotoxic alkaloid (2t) Perhydrohistrionicotoxin” 5, via a regiospecific n-
acyliminium ion initiated cationic cyclization (Figure 6). These successes

 

Figure 6: Aphidicolin (4) and Perhydrohistrionicotoxin (5)

encouraged us to concurrently pursue several other classes of
stereochemically complex bioactive natural products that contained within
their framework, five membered, oxygenated, heterocyclic rings, in various
states of oxidation8. These classes included guaianolides9a,
pseudoguaianolidesga’c, tiglaneslo, daphnaneslo, and ingenaneslo. These
classes of natural products, available in small quantities from their plant
sources, have served as synthetic targets as a result of their broad and potent
biological activities“, which include anti-tumor, anti-neoplastic, anti-
leukemic, allergenic, anti-helmenthic, anti-feedant, analgesic, contraceptive,
molluscicidal, and anti-inflammatory properties. Many members of these
classes of compounds have been prepared; however, most of the more
complex pseudoguaianolides, daphnanes, ingenanes, and tiglanes have not
yet yielded to total chemical synthesis. Many of the natural guaianolides and

_ =20...

PPO

Figure 7: Biosynthetic Transformation From trans-Farnesyl Pyrophosphate

pseudoguaianolides possess bicyclo(5.3.0)decane nuclei to which is fused a
butyrolactone ring. These sesquiterpene lactones are thought to be derived
biosynthetically9b (Figure 7) from trans-farnesyl pyrophosphate.
Furthermore, the pseudoguaiane skeleton is thought to result from a

 

Figure 8: A. Biogenesis Of cis-Fused Guaianolides From A Germacrolide-4,5—
Epoxide In A Chair Like Transition State

 

Figure 8: B. Biogenesis Of A trans-Fused Pseudoguaianolide From A
Germacrolide-4,5-Epoxide In A Chair Like Transition State

migration of the C-4 methyl moiety to C-5 during biogenesis. While these
transformations have yet to be experimentally proven, possible routes12 are
depicted in Figure 8. The pseudoguaianolide depicted in Figure 8 is further
categorized as an ambrosanolide, which contains the C-10 methyl in the beta
orientation; as opposed to the helenanolides, which have the C-10 methyl in
the alpha orientation. The ambrosanolides are further differentiated from
the helenanolides in that the former has a lactone ring closed predominently
toward C-6, with the C-6 oxygen moiety in the beta orientation, and the latter
has the lactone ring closed toward C-8, with the C-8 oxygen moiety having
both alpha and beta orientations.

Representative guaianolides chosen for this study were Estafiatin13 6, and
Compressanolide14 7, which possess a cis ring fusion, and a butyrolactone

 

Figure 9: Estafiatin (6), Compressanolide (7), Damsin (8), Ambrosin (9), and
Parthenin (10)

ring moiety fused to a seven membered ring (Figure 9). The
pseudoguaianolide targets chosen were Damsin15 8, Ambrosin16 9, and

Parthenin17 10; all ambrosanolides containing a trans fused 5 - 7 ring
junction and a pendant butyrolactone moiety.

Having previously demonstrated the ability of the furyl moiety to
successfully participate in annulation sequences, resulting in a
regiocontrolled furan terminated cationic cyclizationlcrd, it was decided to
approach compounds 6 - 10 via a similiar pathway. As illustrated in Figure
10, the coupling of a hypothetical cyclopentane di-cation equivalent,
selectively at the beta position, with a furyl di-anion equivalent would lead to
the substituted cyclopentane 13, which after cyclization by a Friedal-Crafts type
process, would afford 14. For this sequence to succeed, the reactivities of the

R
H P)
‘. +)
O /

11 12 13 14

 

 

 

Figure 10: Furan Terminated Cationic Cyclization Sequence

di-anion and di-cation equivalents would need to be adjusted such that only
one regioisomer results from the initial carbon-carbon bond formation. With
respect to the furyl moiety, selectivity could be guaranteed by relying on the
vastly different levels of reactivity displayed by a side chain furyl
organometallic and the neutral furan with regard to an electrophile. In order
to assure regiochemical integrity in the initial carbon-carbon bond forming
sequence, we anticipated utilizing a cyclopentane di-cation equivalent in
which the second site of electron deficiency was developed as a result of the
chemistry employed in the first carbon-carbon bond formation. In such a
fashion 14 could be produced possessing a variety of R functions, eventually
leading to Estafiatin 6, and Compressanolide 7.

A second and important consideration that heightened our interest in 14,
was the possibility of introducing the requisite, ring junction methyl moiety
as part of the starting cyclopentane equivalent, or via alkylation of the
putative thermodynamic enolate of 14; which would constitute entry into the
pseudoguaianolides, perhaps affording eventually the ambrosanolides 8 - 10.
Finally, alteration of the nature of the di-cation and di-anion equivalents
could also provide access to more highly oxygenated compounds, and yield
products of annulation sequences with alternate furan placement; thus
furnishing assorted helenanolides and tiglane diterpenes.

10

As part of our general program in furan chemistry, we envisioned the
construction of the substituted bicyclo(5.3.0)decane ring systems via furan
terminated cationic cyclizations as is shown in Scheme 1. The placement of
the furan terminator relative to the preformed five membered ring dictates

 

 

Type A Furan Estafiatin (R - H)
Closure Manipulation Compressanolide (R - H)
+ ———’ . ' Ambrosin (Fl - Me)
I Damsin (R - Me)
R
/
R
Type 3 Furan
+ Closure Manipulation Contertin (R- B-Me)
/ O —'—’ Fastigilin-C (R - a-Me)
/

 

Scheme 1: Cyclization Types and Target Structures

that the Type A closure will provide us with a route towards the desired
substrates of this study. This Type A closure might be accomplished by either
of the two paths described in Figure 11. In path a , the initiating function is
held exo to the forming cycle; whereas, in path b , the initiator is part of the

11

I X X
- -/+ thA
09 + — —~ .
O
H R H R O / \

 

I x X /
+/- -/+ Path 8
Q + ——> —>
Y O Y Y 0

Figure 11 : Type A Cyclization; Path A and Path B

forming seven membered ring. Having successfully utilized vinyl-spiro
epoxides18 as cyclohexane di-cation equivalents in the past, we chose to
initially examine path a. These sequences, employing the vinyl-spiro
epoxides prepared from cyclopentenone and 2-methyl-cyclopentenone, are
shown in Scheme 2. The depicted scheme suggests that guaianolides and
pseudoguaianolides might be readily approached by simply altering X=H to
X=Methyl in the spiro epoxide 15. In practice we were unable to realize this
goal, for although we were able to prepare methyl substituted 15, every
attempt to react the compound in Snz' fashion with Grignard reagent19 16a
(Cul) resulted in epoxide opening and addition of the organometallic to the
beta-gamma unsaturated aldehyde. However, 15 (X=H) reacted smoothly
with organometallics 16 to afford allylic alcohols 17 (Scheme 2, 69-85% yields).
Utilization of CuBr'SMez20 in the sequence (16b => 17b) was found to be
crucial to its success, as CuCN provided only dimerization of the vinyl
Grignard. Moreover, the use of the vinyl Grignard MgBrz-EtzOZI, (16b, =>
17b) rather than the initially produced vinyl lithium, was found to be

12

important as the lithium derivative afforded less than 20% of the desired
alcohol 17b.

Our next task was the cyclization of the product primary allylic alcohols, an
endeavour which we had examined previously in model systems without
success. We exposed alcohols 17 to a variety of reaction conditions to no
avail. We were unable to obtain even trace quantities of the desired tricyclic
products. Our model structure suggested the utility of secondary allylic
alcohols as initiators for furan terminated cyclizations, therefore we treated
alcohols 17 with PCC to give the related aldehydes 18, which were coupled

R R R
CuBr'SMez ”PCC 23°“
+ Meflm _. _._. 4512.
X 0 2pm ”so“
H

HO Fl'
Rt
15X=H 1611 M 178 rats: 198 B field 203 B field
a) H Mg 3) H 35% a) H Me 84% a) H Me 95%
b) =cr-12 Li. M931, ”=01, 69% b) H Ph 64% b) H Fh 87%

e) HpMeOPh63% c) HpMeOPh74‘is
”5012 Me 69% djaou, Me 72%

 

1) ThexleHz; 1) LDA.
H20,.Na0H (21) H MoOPH (23) Nate,
_—’ —> _._>
2) 900 (22) R' 2) LAH (24) R' O
O OH / H
2 2 R mu 2 4 E m1 2 5 field 2 B E m:
3) Me 42% pMeOPh 60% 35% WeOPh 51%
b) Pb 45%
c)pMeOPh 40%

Scheme 2: First Generation Svnthesis of TvDe-A Svstem

with several organometallic reagents to provide the corresponding secondary
allylic alcohols 19 (63-84% yields, 2 steps). These secondary alcohols were
readily cyclized upon exposure to a two phase mixture of cyclohexane-formic

13

acid, followed by a catalytic amount of tosic acidzz, providing olefins 20 (74-
95% yields). During the course of this reaction we observed, via TLC,
intermediate formate esters, which have been isolated and identified. The
addition of catalytic tosic acid, a stronger acid, serves to either surpress the
formation of allylic formates and facilitate cyclization, or to induce the allylic
formates to cyclize. In the absence of tosic acid we obtain only 50 - 70% of 20,
along with 20 - 40% of the corresponding formate esters.

With 20a readily in hand, we next studied its conversion to our desired
common intermediate ketone 25 by either a direct cleavage, or via a two step
sequence (Figure 12). Toward that end, we submitted 20a (R=H, R'=Me) to a
variety of reagents designed to vicinally hydroxylate the double bond or
directly cleave the olefin. These included: a) (i) catalytic or stochiometric
050423, (ii) NaIO424; b) KMnO425; c) catalytic and stochiometric RuO426; d)
0327; e) MCPBA followed by acidic aqueous periodate. With the exception of
condition e (3%) we were unable to obtain 25.

 

Figure 12: Olefin to Ketone Conversion (Direct or 2 Step)

Given these difficulties, we elected to examine the multi-step approach
outlined in Scheme 2. Olefins 20 uneventfully afforded ketones 22 (40 - 45%
overall yield for the three steps depicted). At this point, a number of
alternatives were examined including Baeyer-Villager oxidation28 and enol
ether ozonolysi529, all to no avail. In each of these cases we observed either
no reaction, or destruction of the starting substrate. However, smooth
hydroxylation (MoOPH30) of the enolate of 22c (R'=pMeOH) led to diol 24

14

after LAH reduction (60% yield two steps, stereochemistry not determined).
Cleavage of 24 occured upon exposure to N a104, affording an unoptimized
mixture of desired ketone 25 (35% yield) and a pinacol-type rearrangement
product 26 (51% yield).

While the path a route described in Scheme 2 does provide 25, it is
altogether too long, and the overall yield is an unacceptable 3%. This
prompted us to examine the alternate path b (Figure 11) Type A cyclization,

 

Scheme 3: Alternative Approaches to the Synthesis of the Type A System

as is outlined in Scheme 3. As shown, we had a choice of two intersecting
approaches, an allylic alcohol mediated closure, and an enone initiated
closure, both of which were available from the same starting materials. In
this sequence, we hoped to avoid the troublesome C=C cleavage by carrying
the necessary A-ring carbonyl center into the sequence either directly, or in a
protected form. Both the allylic alcohol and enone substrates were available
from 3-(3-furyl)propanal31, and a substituted cyclopentene synthon which
was prepared by the procedures32 of Swenton and Piers.

The dithioketal 27, synthesized from 1,3-cyclopentanedione32, was
metallated (n-BuLi, THF, -78°) and reacted with 3-(3-furyl)propanal to provide

15

the desired allylic alcohol 28 in 78% yield (Scheme 4). Exposure of 28 to our
"standard" allylic alcohol cyclization conditions (formic acid/cyclohexane;
tosic acid) led exclusively to the Spirocyclic 29 in 86% yield. A rationale for
this unexpected observation is the formation of a sulfur stabilized allylic
cation resulting from the rupture of the dithioketal sulfur - carbon bond.

 

 

27 28 (90%) Eli”

3O (82%)

Scheme 4: AltemativeType A Cyclization

An alternative procedure”, to eliminate this unwanted competative
process via specific C - 0 bond activation, involved treating 28 with mesyl
chloride and triethyl amine. The resulting product was found to be 30 (82%
yield), in which the double bond was observed to have migrated from the 1,10
position into the ring juncture. This event, though troublesome, would not
necessarily doom the approach. Based upon the assumption that the derived
enone (dithiolane deprotection) might be readily realized, we considered the
likelihood that a "thermodynamic" enolization would provide access to the
needed carbon-10 position vs formation of a homoannular cyclopentadiene-
type dienolate.

16

Support for this rational came from calculations using the Dahlinger MM2
protocol34 which suggested that the desired "thermodynamic" dienolate
should be more stable by ca. 1.4 kcal/ mole With this supporting evidence,
we attempted to generate the requisite enone 25 (with 1,5 unsaturation) from
the dithiolane 30. However, under a wide variety of reaction conditions,35
we were unable to effect this transformation. This difficulty added to the
uncertainty resulting from the stranding of the double bond in the 1,5
position caused us to consider the enone initiated path b closure shown in
Scheme 5.

 

BF3 (0512 )

 

S I
K/SO/

31 (61%) 32 (64%)

   

Scheme 5: AltemativeType A Cyclization

Allylic alcohol 28 was oxidized with PCC to provide enone 31 in 61% yield.
Having previously studied enone initiated cyclizations,1CrC1 we treated 31 with
BF3-Et20 to provide the trans fused product 32 in 64% yield (Scheme 5) with
minimal amounts of the cis and Spirocyclic fused isomers. Support for the
trans configuration in 32 comes from a comparison of the cis and trans
isomers with literature data, and is in agreement with MM2 calculations,34
which suggest that the trans isomer is more stable than its cis adduct by about
2 kcal/ mole.

With ketone 32 in hand, we next needed to examine the introduction of
two carbon atoms for entry into the pseudoguaianolide manifold, and one

carbon atom to prepare the guaianolide nucleus. However, we thought it

17

would be prudent to initially compare the product of Scheme 6 to the hard
won ketone 25 of Scheme 2. Toward that end, we reduced 32 with LiBH4

1) Red'n (91%) _

2) Barton (86%)'
deoxygenafion

 

   

Scheme 6: Deoxygenation, of Keto-dithiolane

(91%) to furnish a single alcohol of unknown configuration. Using Barton
deoxygenation methodology,36 we prepared the corresponding xanthate ester
(86%), which was cleaved using HSnBu3 to provide dithiolane 33. Finally, we
sought to deprotect 33 to provide ketone 34 for a direct comparision to
compound 25. Again, despite using a variety of reagents and conditions,35 we
were unable to obtain 34 in yields greater than 5%. We concluded that 34 and
25 were identical, based on NMR, MS, and IR data, and next considered the
introduction of the needed exo-methylene carbon and the angular methyl
moiety.

To effect the requisite ketone - olefin transposition of substrate 32, we had
available to us a number of synthetic techniques, namely Wittig chemistry,37
Lombardo's reagent,38 Peterson olefination,39 or the Tebbe reagent,40 among
others. An examination of half a dozen variations37 on the Wittig
technology failed to provide the desired conversion with reproducible results
or in good yields. The use of Lombardo's reagent, ZnCHzBrz-TiCl4, (8-10
equivelents) provided olefin 36 in quantitative crude yield (94% purified). In
addition, Peterson olefination, TMSCHzLi followed by KH, also provided
olefin 36 in 87% yield for the two steps (Scheme 7). This latter result would

18

1) TMSCHZU
2) KH (98%) '

 

   

Scheme 7: Attempted Deprotection of Olefin-dithiolane

later turn out to be fortuitous since we were once again frustrated in our
attempt to deprotect dithiolane 36 to keto-olefin 37. Under a variety of
reagents and conditions,35 we were unable to deprotect dithiolane 36
(Scheme 7) to obtain ketone 37 in more than 17% yield (grossly contaminated
with mercury). We reasoned that many of the standard dithiolane
deprotection protocols such as those involving HgH, AgII, tetrafluoroboric
acid, NBS, etc., were likely to attack not only sulfur, but also possibly react
with the exocyclic olefin or the disubstituted furan. Given these additional
concerns, along with the previously indicated failures, we opted for a
"simplified" substrate, i.e. the tertiary silylmethylcarbinol intermediate 35
(Scheme 8), for deprotection studies.

 

Scheme 8: Deprotection-Olefination of Keto-dithiolane

19

After a number of unsuccessful deprotection attempts, tertiary carbinol 35
was treated with NCS and AgNO3, according to the procedure of Corey,41. To
our delight, intermediate 35 underwent deprotection with concomminent
hydrolysis to provide keto-olefin 37 directly in 94% yield. We believe that the
ring juncture in 37 is trans, as would be expected via the synthesis of 37 from
trans 32. Further evidence for this configuration is given by Gonzalez.42 He
finds that the olefin resonances in the proton N MR for trans compounds
similar to 37 appear as two distinct singlets, whereas in the cis compounds
only one singlet is seen for both exo methylene protons.

The AgNO3/NCS deprotection procedure failed when attempted on the
substrates 30, 31, 33, and 36. Introduction of these substrates to the aqueous
acetonitrile solution of AgN03 and NCS resulted in a black heterogeneous
reaction mixture that provided either none or trace (<1 %) amounts of the
deprotected products. However, addition of substrate 35 to the reaction
solution resulted in a pale yellow mixture, which became a snow white
heterogeneous mixture over the course of the reaction. To date, we have not
examined in detail the hydrolysis of dithiolane 35 in the presence of the by-
products assumed to result from NCS, AgNO3 catalyzed olefin formation.
An observation which might be relevent is the complete absence, by TLC, of
olefin 36 in the reaction mixture leading to 37. We hope to examine these
questions in more detail at a later date.

With tricyclic ketone 35 in hand (39% overall yield from 27) we could now
progress toward the preparation of both guaianolide and pseudoguaianolide
natural products. The initial projected routes to Estafiatin 6 and
Compressanolide 7 are shown in Scheme 9. Treatment of the trans ketone 37
with MeLi would give a tertiary alcohol which might be dehydrated to
provide enone 38 after furan manipulation according to our previously
published conditions.43 Epoxidation, lithium/ammonia reduction, and
lactonization should yield the desired intermediate 39, which has previously
been converted to Compressanolide by Vanderwalle.44 Estafiatin13 should
also be readily available from 37, via the corresponding A 3 - 4 olefin after
dehydration and epoxidation as precedented in the literature.45

Our initial attempts to prepare 38 have not met with success. Alkyl-
lithium addition to the ketone 37 was moderately successful, resulting in a 30
- 40% yield of tertiary alcohol, and 40 - 50% recovered ketone. This result was

1) H202/base:
2) Li/NH3;

3) H"

 

 

 

   

Scheme 9: Guaianolide Route from Keto-Oletin 37

likely due to the enolization of the cyclopentanone. Attempts to add TMS-
methyl-lithium resulted in almost quantitative recovery of starting substrate.
We again examined Wittig chemistry37 in an attempt to convert this ketone
to an olefin, in a slight modification of our projected route. Once again, we
were rebuffed, realizing gross mixtures of products in less than 50% recovered
yields. Success was finally achieved by the treatment of ketone 37 with
Lombardo's reagent38, ZnCHzBroniCl4. Utilization of 8 - 10 equivalents,
added in one portion provided the bis olefin 40 in 95% yield (Figure 13) as a
6/1 mixture of exocyclic/endocyclic olefins. We are presently working to
unravel the furan in compound 40 to provide a lactone as in compound 39.
Initial attempts via direct silylation1e (n-BuLi, TMSCl) or indirect silylation11
(bromination, followed by n-BuLi, TMSCl) have not proved fruitful, but we
are continuing to examine these procedures at present. In addition we still
have the option of utilizing a ketone intermediate like substrate 38, which
should ultimately provide us with 39.

21

Lombardo's Reagent
anHzBr2°nCl4

 

   

Figure 13: Preparation of Bis-Olefin

Our projected route to the pseudoguaianolides from ketone 37 is shown in
Scheme 10. Alkylation of the thermodynamic enolate of 37 should provide
substrate 41, for which models suggest that a cis fusion might be favored.
There appears to be a large degree of configurational freedom in the seven
membered ring in the cis configuration, while the trans configuration is a

 

1) Isomerize: RC“. 1) Furan
2) Reduce, Man'p.

3) Protect 2) H2

42

   

Scheme 10: Pseudoguaianolide Route from Keto-Olefin 37

22

rigidly locked, seven membered chair. Should this be the case, there is
established literature procedures46 for isomerizing the olefin in 41 to provide
intermediate 42 after carbonyl reduction and protection. Manipulation of the
furyl moiety, followed by hydrogenation should then lead to 45, which has
previously been transformed15‘17 into Damsin 8, Ambrosin 9, and Parthenin
10.

Our initial attempts to prepare 41, via LDA or KDA, followed by Mel
resulted in mixtures of mono, bis, and tri methylated products in relatively
low yields. However, the use of KH, followed by Mel provided 52%
(unoptimized yield) of a single isomer, along with 35% of what appears to be a
mixture of mono, di and/or tri substituted product. After literature
comparison47, and extensive proton, carbon, and 2D, studies48, we have
determined to the best of our knowledge that the adduct we obtained in 52%
yield, 41, has the desired trans ring juncture configuration. We believe the
35% mixture to contain the cis isomer along with di and tri methylated
products, which are not separable.

With pseudoguaianolide intermediate 41 (trans ring juncture) in hand, we
next attempted to reduce the seven membered ring olefin with Pd/ C and
hydrogen. At atmospheric and elevated pressures 35 - 100 psi (1-24 hours), we
recovered almost exclusively starting material. However, using PtOz/C‘l'9
and hydrogen (atmospheric, 1 hour), we obtained a single product 43, in 86-
93% yields (Scheme 11). Once again, via literature comparison47, and
extensive proton, carbon, and 2D NMR,48 we concluded that we have
obtained adduct 43, with both methyl groups in the cis conformation.
Protection of ketone 43 as its ethylene ketal, 44, was attempted with
N oyori's50 kinetic ketalization conditions. Initial results provided a mixture
of a rearranged product, (methyl migration), and ketal 44. We are presently
working to improve these conditions, and unravel the furan, which should
lead to compound 45, and thus a formal total synthesis of our
pseudoguaianolides Damsin, Ambrosin, and Parthenin.

Protect
-——>

 

4 3 (93%)

 

Scheme 11: Pseudoguaianolide Route to Ketone 45

24

The bicyclo(5.3.0)decane products prepared during the course of this work
have demonstrated that the furan terminated cationic cyclization sequences
are viable routes for the preparation of functionally and stereochemically
complex natural product precursors. The cyclization intermediates are readily
available in concise high yield sequences from suitably functionalized furyl
precursors. These materials should serve well as substrates for completing
the preparation of both the guaianolide and pseudoguaianolide classes of
natural products.

The unexpected difficulties encountered in the modification of the tri-cyclic
intermediate prepared by our initial path a, Type A cyclization, proved to be
only a minor annoyance, as our flexible furan methodology allowed us to
circumvent the problems via our path b Type A cyclization. Starting from a
dithiolane protected bromo—enone, the path b sequence provided a single
precursor 37 for both guaianolides and pseudoguaianolides in five steps and
39% overall yield; after a tedious but successful search for a ketal deprotection
protocol.

As previously discussed, vide infra, initial attempts to convert precursor 37
into our guaianolide targets have not met with success, i.e. the failure to
unravel the furan to a butyrolactone ring. This may have been due to an
over-abundance of olefinic sites in compound 40, which causes interference
with the normal reaction processes that have been used on past substratesl.
Overcoming this difficulty might be accomplished by hydrolysis of compound

37, followed eventually by olefin incorporation; or by the

preparation/ manipulation of a tri-substituted furan in which a silicon, sulfur,
or selenium substituent has been incorporated into the molecule.

Incorporation of a methyl group into the ring juncture of adduct 37,
followed by olefin reduction, has provided us with an advanced
pseudoguaianolide intermediate 43. To complete the synthesis of our
pseudoguaianolide targets, the final obstacle is again the unraveling of the
furan moiety to a butyrolactone ring, or butenolide equivalent. It has become
increasingly apparent through this work, and that of co-workers using
similiar methodology, that furan hydrolysis/oxidation is a substrate
dependant phenomenon. We are confident in this case however, that our
previously published methodologylerk should result in the conversion of the
furyl moiety in compound 43 to a lactone containing adduct. The presence of
oxygen, and lack of olefinic sites should aid in this transposition, and
hopefully remove the obstacles which are currently present in the
guaianolide sequence.

In summary, this work has utilized furan as a terminator in cationic
cyclization methodology to prepare tri-cyclic intermediates suitable for the
synthesis of guaianolide and pseudoguaianolide natural products.
Transformation of these intermediates to the desired bioactive products
remains to be accomplished, with the hydrolysis/ oxidation of the furyl

moiety being the final major task.

26

EXEERIMENIAL

General: Tetrahydrofuran, ethyl ether, benzene, and hexane were dried by
distillation under argon from sodium benzophenone ketyl. Di-isopropyl
amine, collidine, and methylene chloride were dried by distillation from
calcium hydride. N,N dimethyl formamide was dried by distillation from
phosphorous pentoxide. N -butyl-, sec-butyl-, and t-butyl lithium in hexane
were purchased from Aldrich Chemical Co., Milwaukee, Wis., and were
titrated by the method of Watson and Eastham.51 Magnesium metal was
activated by successive washings with 0.1N aq. HCl, distilled water, acetone,
and anhydrous ether respectively, and then dried in a dessicator over
phosphorous pentoxide at reduced pressure.

Chromatography was performed using the flash technique of Still et. al.52,
using the silica gel and solvents mentioned. The column outer diameter
(o.d.) is listed in millimeters. Thin layer chromatography used Merck SIL
G/ UV precoated glass plates. Spots were visualized by dipping into one of the
following: 1) a solution of vanillin (1.5 g) in absolute ethanol (100. ml) and
conc. sulfuric acid (0.5 ml), 2) a solution of phosphomolybdic acid (5.0 g) in
absolute ethanol (100. ml); and then heating the plate.

Proton magnetic resonance spectra were recorded at 60 MHz (Varian T-60),
80 MHz (Varian FT-80), and 250 MHz (Bruker WM-250) as solutions in
deuterochloroform unless otherwise indicated. Chemical shifts are reported
in parts per million on the 8 scale relative to a tetramethylsilane internal
standard. Data are reported as follows: chemical shift (multiplicity (s=singlet,
d=doublet, t=triplet, q=quartet, m=mu1tiplet, brs=broad singlet), coupling
constant (Hz), integration). 13C magnetic resonance spectra were recorded on
a Bruker WM-250 spectrometer (68.9 MHz) and are reported in parts per
million from tetramethylsilane on the 5 scale.

High resolution mass spectra were performed by the M. S. U. Regional Mass
Spectroscopy Facility; Dept. of Biochemistry, East Lansing, Michigan 48824.
Electron impact (EI/ MS) and chemical ionization (CI/ MS) mass spectra were
recorded on a Finnigan 4000 utilizing an INCOS 4021 data system. A Pye-
Unicam SP-1000 infrared spectrophotometer was used to record infrared
spectra using polystyrene as a standard. Melting points were obtained on a
Thomas-Hoover capillary melting point apparatus and are uncorrected.

27

All reactions, unless otherwise stated, were carried out under a blanket of
argon in flame dried glassware, with the rigid exclusion of moisture from all
reagents. Base washed glassware was prepared as follows: washing in an
KOH/EtOH base bath, followed by distilled water, ammonium hydroxide,
distilled water, absolute ethanol, and flame drying. Syringes, cannulas,
needles, and spin bars employed with base washed glassware were also
prepared in the same manner.

The preparation of 3-bromocyclopentenone and its dithiolane derivative
were prepared according to the procedures of Piers32a or Swenton32b.

MW” (153), - To a solution of triphenyl-phosphine
(25.99 g, 99.2 mmol) in CHzClz (600. ml), cooled in an ice water bath, was

added 3-(2-furyl)-propan-1-ol12h (10.0 g, 79.4 mmol), followed by addition of
NBS (17.66 g, 99.2 mmol) in 4 portions over ten minutes. After stirring at 0°C
for four hours, the solution was warmed to RT and stirred one hour further.
The solution was concentrated in vacuo: cast into hexane (350. ml), and
stored overnight in a freezer. The precipitated Ph3PO was removed by
filtration through a pad of celite, the filter cake washed with hexane, and the
combined filtrates were washed with N aHCO3, and brine (250. ml ea.), dried
(MgSO4), and concentrated in vacuo to provide the crude product as a
pleasant smelling, pale yellow liquid. Distillation (BP24 93-97°C) provided
11.0 g, (73.3%) of 16a. Rf=0.68 in hex/ ether (1 /1).

 

--1 9|.Ill‘t ----42 -0- -- 00‘1‘1‘ -(A)Toa
solution of 1-((dimethylsulfonio)methyl)cyclopent-Z-en-1-011h, (3.78 g, 13.23
mmol) in THF (150 ml) in a 250 ml base washed round bottom flask, was
added N aH (0.480 g, 15.87 mmol) in one portion. The mixture stirred for five
and one half hours and was then cooled in a dry ice-isopropanol bath (~78°C).
(B) To activated Mg metal (0.50 g, 20.6 mmol), in a 500 ml base washed round
bottom flask with condenser, is added 10% of a solution of 3-(3 furyl)-propyl
bromide19 16a (3.00 g, 15.87 mmol) in THF (10. ml). After reaction began, the
remaining 90% of the bromide solution was diluted with THF (85. ml) and
added over one half hour, followed by gentle refluxing for two hours. The
mixture was cooled in a dry ice—isopropanol bath, and CuCN (1.42 g, 15.87
mmol) was added in one portion. After stirring at -78°C for one hour, the

28

mixture was warmed to -45°C (dry ice-acetonitrile) for one half hour, then
cooled to -78°C for one quarter hour. The spiroepoxide (A) at -78°C, was then
added via cannula over one half hour. After stirring at -78°C for three hours,
the mixture was warmed to RT over one and one half hours. The solution
was then quenched with sat. aq. NH4C1 (100 ml) and NH40H/H20 (220 ml,
1:1). The mixture was saturated with NaCl, separated, and the aqueous phase
was extracted with ether (3 x 100 ml). The combined organic layers were
washed with N aHCO3, and brine (200 ml ea.), dried (MgSO4), and
concentrated in vacuo. The crude product was purified by chromatography
on a column of silica gel (50 mm o.d., 200. g, 230-400 mesh, packed
hexane/ ether (4/1), run hexane/ ether (2/1), 100 ml fractions) using the flash
technique. Fractions 11-23 provided 2.089 g (76.6%) of 27a. Rf=0.28 in (1/1)
hexane/ ether) as a pale yellow viscous liquid.

EI/MS (70 eV): 206(M+, 8.8), 188(14.9), 17509.3), 159(5.5), 147(3.5),131(6.6),
123(8.6), 106(14.8), 95(47.3), 79(base), 67(83.3),53(56.3), 41 (86.7)

1H-NMR(250 MHZ): 5 : 7.31(t, I=1 Hz, 1), 7.18(brs, 1), 6.26(brs, 1), 5.06(m, 1),
4.16(s, 2), 2.67(m, 1), 2.40(t, I=7.5 Hz, 2),2.30(m, 2), 2.10(m, 1), 1.65-1.20(m, 5)

IR (Neat): 3640—3100, 2980-2880, 2860, 1500, 1450, 1430, 1380, 1160, 1020(w), 875,
775, 720 cm-1

----t.a_-H - 00‘1----'1'-.-0.-.-.‘10.' 1‘411‘91‘51-
To a solution of alcohol 17a (1.00 g, 4.854 mmol) in CHzClz (400 ml), in a 1L
base washed round bottom flask, was added celite (25. g), followed by PCC (1.57
g, 7.28 mmol). After stirring two hours at room temperature, ice cold hexane
(200 ml) was added and the mixture was filtered through a plug of celite/ silica
gel. The filtrate was dried (MgSO4), and concentrated i_n vacuo, to give the
crude aldehyde as a viscous yellow liquid. The crude product was purified by
chromatography on a column of silica gel (50 mm o.d., 100. g, 230-400 mesh,
hexane/ ether (5 / 1), 30 ml fractions) using the flash technique. Fractions 10-16
afforded 0.667 g. (67.4%) of intermediate aldehyde 18a. Rf=0.48 in (1/ 1)
hexane/ ether.

Irn

29

E1] MS (70 em: 204(M+, 30.2), 186(3.2), 175(7.7), 14703.1), 133(5.0), 122(base),
10903.2), 95(34.0), 81(74.1), 67(55.5), 53(45.6)

lH-NMRQSO MHZ): 8 : 9.73(s, 1), 7.31(m, 1), 7.20(brs, 1), 6.75(m, 1), 6.26(brs,
1), 2.89(m, 1), 2.55(m, 2), 2.450, I=6.3 Hz, 2),2.18(m, 1), 2.00-1.35(m, 5)

IR (Neat): 2980-2880, 2860, 2710, 1675, 1610, 1500, 1430, 1350, 1255, 1160, 1020,
870, 770, 720 cm-1

--1-_0.‘1 ----.a -.1. --u 01‘1'1' H-Toasolution
of the intermediate aldehyde 18a (1.151 g, 5.642 mmol) in ether (500. ml), in a
1L base washed round bottom flask cooled in a dry ice-isopropanol bath to -
78°C, is added MeLi (1.4M, 7.6 ml, 10.64 mmol), and the mixture stirred for
one hour. Additional MeLi (0.33 equiv.) was then added and the mixture
stirred for one additional half hour until no starting material was observed by
TLC. The solution was warmed to room temperature over one half hour,
and was quenched with sat. aq. NH4C1 (200 ml). After separation, the aqueous
phase was extracted with ether (3 x 150 ml). The combined organic layers
were dried (MgSO4), and concentrated in vacuo. The crude product was
purified by chromatography on a column of silica gel (50 mm o.d., 125. g, 230-
400 mesh, hexane/ ether (2.5/1), 40 ml fractions) using the flash technique.
Fractions 14-35 afforded 1.161 g (94%) of 19a. Rf=0.20 in (1/ 1) hexane/ ether.

EILMS (70eV): 220(M+, 3.0), 202(7.4), 1870.1), 175(3.0), 159(2.5), 147(2.4),
133(2.4), 120(9.9), 111(4.4), 9505.4), 8108.5), 6705.3) 5302.8), 43(base)

lH-NMRQSO MHz): 8 : 7.34(t, I=1.5 Hz, 1), 7.19(brs, 1), 6.23(brs, 1), 5.51 (brs, 1),
4.39(q, I=6.3 Hz, 1), 2.64(m, 1), 2.40(t, I=8.4 Hz,2), 2.28(m, 2), 2.09(m, 1), 1.66-
1.30(m, 6), 1.27(d of d, I=5.4, 1 Hz, 3)

IR (Neat): 3700-3100, 3000-2820, 1500, 1450-1430, 1370, 1160, 1060, 1020, 870, 840,
770 cm-1

WWW - To a solution of the alcohol 19a (0.100 g, 0.4545

mmol) in cyclohexane (40 ml), in a 100 ml base washed round bottom, was
added formic acid (10 ml) in one portion. After stirring twenty minutes,
stOH (two crystals) was added and the mixture was heated gently (50°) for
five minutes. After stirring twenty five minutes, the mixture was diluted
with cyclohexane (25 m1) and carefully quenched with sat. aq. NaHCO3 (60
ml). This was followed by solid NaHCO3 until pH 9.0 was obtained. The
aqueous phase was extracted with ether (3 x 50 ml), and the combined organic
layers were washed with brine (75 ml), dried (MgSO4), and concentrated i_n
mg. The crude product was purified by chromatography on a column of
silica gel (40 mm o.d., 30. g, 230-400 mesh, hexane/ether 05/1), 10 ml
fractions) using the flash technique. Fractions, 5-10 afforded 0.089 g (95%) of
20a. Rf=0.64 in (10/ 1) hexane/ ether.

EIlMS (70eV): 202(M+, base), 187(47.3), 173(62.8) 15909.4), 14506.3),131(23.8),
11706.8), 10504.9), 91(37.5), 77(28.8), 65(24.9)

1H-NMR(250 MHz): 8: 7.20(d, 1:1.5 Hz, 1), 7.17(d, ]=1.5 Hz, .33), 6.19(d, I=1.5
Hz, .33), 6.15(d, I: 1.5 Hz, 1), 5.26(t, 1:1 Hz, .33), 4.88 (d of q, 1:6, 4 Hz, 1), 3.78(m,
1), 2.8-1.2(m, 13)

[R (Neat): 3000-2800, 1505, 1460-1420,1150, 890, 830, 790, 725, 690 cm-1

- - - - - - - - To a solution of 3-furylmethy-tri-n-
butylstannanelczd (12.0 g, 32.42 mmol) in THF (75. ml), in a 250 ml base
washed round bottom flask, cooled in a dry ice-isopropanol bath, was added
n-BuLi (2.4M, 17.6 ml, 1.3 eq.) over fifteen minutes. After stirring for one
hour at -78°C, CuCN (3.78 g, 42.2 mmol, 1.3 eq.) was added in one portion and
the reaction stirred one hour further. The mixture was warmed (-45°) in a dry
ice-acetonitrile bath for one half hour, and then cooled again to - 8°C. To the
cuprate was added a solution of 2,3-dibromopropene19d (8.43 g, 42.2 mmol) in
THF (15. ml) by cannula over one half hour. After stirring at -78°C for three
hours, the reaction was quenched with sat. aq. NH4Cl (100 ml) and the
organic phase separated. The aqueous phase was extracted with ether (3 x 250
ml), and the combined organic layers were then dried (MgSO4) and
concentrated in vacuo (NO HEAT). The crude product was purified by

31

chromatography on a column of silica gel (60 mm o.d., 500. g., 230-400 mesh,
(99/ 1) hex. / ether, 250 ml fractions) using the flash technique. Fractions 23-40
gave 5.15 g. (79%) of the pure product 16b. Rf=0.19 in hexane.

EI/MS (70 eV): 202(M++1, 4.9), 200(5.11), 121 (66.9), 103(5.59), 9105.2), 81(base),
53(57.6), 39(42.7)

lH-NMR (250MHz): 5 : 7.28 (m, 2), 6.28 (m,2), 5.58 (In, 1), 5.42 (m, 1), 2.70(s, 4)

IR (Neat): 3000-2860, 1630, 1570, 1500, 1450, 1430, 1385, 1190, 1160, 1115, 1070,
1035, 890, 875, 780, 725 cm-1

--1!0.411'1 - ‘- La --.‘1---- 1--1-1-A--(A)Toa
solution of 1-((dimethylsulfonio)methyl)-cyclopent-2-en-1-ol1h (0.10 g, 0.350
mmol) in THF (4.0 ml), in a 25 ml base washed round bottom flask, was
added NaH (0.01 g, 0.420 mmol, 85%) in one portion. After stirring at room
temperature for three hours, the mixture was cooled to -78°C, in a dry ice-
isopropanol bath. (B) To a solution of 2—bromo-4-(3-furyl)-butene (0.211 g, 1.05
mmol) in ether (4.0 ml) in a 25 ml base washed round bottom flask cooled in
a dry ice-isopropanol bath was added n-BuLi (1.3M, 1.05 mmol, 0.81 ml). After
stirring for one hour at -78°C, the mixture was warmed to -45°C (dry ice-
acetonitrile bath) and the reaction stirred for one hour. The solution was
then cooled to -78°C once more, and was added via cannula to 1.10 mmol of
MgBrz at -78°C; prepared in situ from 1.10 mmol of ethylene dibromide and
1.25 mmol of magnesium metal in 5.0 ml of ether.

After addition was complete, the mixture was warmed to -45°C for one half
hour, and then cooled back to -78°C, and copper bromide dimethyl sulfide
(0.108 g, 0.525 mmol) was added in one portion. After stirring one half hour
at -78°C, the in situ generated spiroepoxide (A), at -78°C, was added m
cannula over fifteen minutes. The reaction stirred at -78°C for three hours
and was then allowed to warm to room temperature and quenched with
N aHC03 (10 m1). This solution was diluted with ether (200 m1), and cast into
NaHCO3/ sat. aq. NH4C1/ H20 (90/ 60/ 40 ml). After separation, the aqueous
phase was extracted with ether (3 x 100 ml), and the combined etheral layers
were washed with N aHCO3, brine, (200 m1 ea.), dried (MgSO4), and

 

32

concentrated in vacuo. The crude product was purified by chromotography
on a column of silica gel (30. mm o.d., 30. g., 230-400 mesh, packed in
hexane/ ether (6/1), run in hexane/ ether (3/1),10 ml fractions) using the flash
technique. Fractions 20-72, gave 0.0525 g (68.9%) of pure 17b. Rf=0.25 in (1 / 1)
hexane / ether.

EI/MS (70eV): 218(M+, 3.7), 200(2.4), 187(2.6), 1710.5), 162(2.8), 149(5.5),
137(base), 11909.9), 105(22.2), 96(41.9), 81 (88.6), 67(84.9)

lH-N MR (250MHz): 5 :7.33(t, I=2 Hz, 1), 7.21(m, 1), 6.28(m, 1), 5.56(m,1),
4.81(m, 1), 4.73(m, 1), 4.21 (hrs, 2), 3.35(m, 1), 2.59 (t, I=7.4 Hz, 2), 2.27(m, 5), 1.76-
1.35(m, 2)

IR (Neat): 3640-3100, 3000-2800, 1630, 1500, 1450, 1430, 1380, 1150,1020(w), 890,
870, 780, 720 cm-1

--l.1| ---.'1--A 00‘1--‘1'-- . 00.; 1‘10.‘ 1‘911'91'3! -
To a solution of the alcohol 17b (0.375 g, 1.72 mmol) in CHzClz (150. ml), in a
500 ml base washed round bottom flask, is added celite (10 g) followed by PCC
(0.593 g, 2.75 mmol) in one portion. After stirring for one and one half hours,
ice cold hexane (75 ml) was added and the mixture filtered through a plug of
celite/ silica gel. The solution was dried (MgSO4), and concentrated in vacuo
to provide the aldehyde as a viscous yellow liquid. The crude product was
purified by chromatography on a column of silica gel (30 mm o.d., 30. g, 230-
400 mesh, hexane/ ether (5/1), 10 ml fractions) using the flash technique.
Fractions 12-27 afforded 0.240 g (65%) of intermediate aldehyde 18d. Rf=0.51
in (1 / 1) hexane/ether.

EIZMS (70 eV): 217(M++1, 2.3), 216(M+, 15.6), 201(2.1), 18702.7), 1720.94),
145(3.9), 135(24.9), 12202.9), 10706.1), 9501.8), 81(base), 67(21.6), 53(36.6),
41(25.6)

lH-NMRQSOMHZ): 5 : 9.71(s, 1), 7.34(t, ]=2.1 Hz, 1), 7.21(m, 1), 6.73(m, 1),
6.28(brs, 1), 4.85(brs, 1), 4.81 (brs, 1), 3.53(m, 1), 2.71-2.0(m, 7), 1.79(m, 1)

33

IR (Neat): 3000-2880, 2850, 2700, 1720, 1670, 1620, 1500, 1450, 1430,1380, 1350,
1300-1250(w), 1160-1100(w), 1015, 890, 780 cm-1

- -1 1.0. ‘ 1 - --l-1t ---- ‘1-- 0-‘1 ‘1‘ ,‘1 - Toasolution
of the intermediate aldehyde, 18d, (0.0438 g, 0.203 mmol) in ether (25. ml) in a
50 m1 base washed round bottom cooled in a dry ice-isopropanol bath, was
added MeLi (1.1M, 0.304 mmol, 0.19 ml), and the mixture stirred for one half
hour. Additional MeLi (0.5 equiv.) was added, and the mixture stirred one
half hour further until no starting material was seen by TLC. The solution
was slowly warmed to 0°C, quenched with sat. aq. NH4C1 (35 ml), and
extracted with ether (3 x 50 ml). The ether layers were combined, washed
with brine (75 m1), dried (MgSO4), , and concentrated in vacuo. The crude
product was purified by chromatography on a column of silica gel (10 mm
o.d., 10.0 g, 230-400 mesh, packed hexane/ ether (4/1), run hexane/ ether (2/1),
6 ml fractions) using the flash technique. Fractions 8-18 provided 0.042 g
(89%) of 19d. Rf=0.18 in (1 / 1) hexane/ ether.

Ell MS (70eV): 232(M+, 2.8), 2140.6), 189(2.7), 1710.2), 162(3.0) 151(23.6),
133(4.14), 121(4.9), 107(24.2), 9308.3), 81 (51.1), 6702.5), 43(base)

1H-NMR(250MHz): 5 : 7.12(t, I=2 Hz, 1), 7.06(brs, 1), 6.09(brs, 1), 5.45(m, 1),
4.90(brs, 1), 4.77(brs, 1), 4.15(m, 1), 3.25(m,1), 2.49(t, I=8.5 Hz, 2), 2.20(m, 2),
2.02(m, 1), 1.57(m, 1), 1.4-1.15(m, 3), 1.13(d of d, I=6.3 Hz, 1 Hz, 3)

IR (Neat): 3660-3100, 3000-2840, 1630, 1500, 1450, 1430, 1370, 1160, 1065, 1020,
890, 870, 780 cm-1

W951) - To a solution of the alcohol 19d (0.058 g, 0.250

mmol) in cyclohexane (10 ml) in a 25 ml base washed round bottom was
added formic acid (2.5 ml, 98%) in one portion . After one half hour the
mixture was cast into cyclohexane (50 ml), and carefully quenched with sat.
aq. N aHC03 (50 ml). After separation, the aqueous phase was extracted with
ether (3 x 40 ml), and the combined organic layers were washed with brine (75
ml), dried (MgSO4), and concentrated in vacuo. The crude product was

purified by chromatography on a column of silica gel (30 mm o.d., 30. g, 230-
400 mesh, packed hexane/ ether (15/1), run in hexane/ ether (10/1), 8-10 ml
fractions) using the flash technique. Fractions 5-9 and 11-22, respectively,
resulted in 0.0271 g (51 %) of the cyclized product 20d, and 0.0355 g (49%) of the
formate ester of 19d. Rf=0.7 (20d), and 0.21 (formate ester) in (10/1)
hexane / ether.

EIZ MS (70eV): (cyclized): 214(M+, base), 199(43.7), 185(48.0), 17109.2), 157(24.7),
14303.0), 12907.7), 11505.1), 105(9.1), 91(24.1), 7704.9), 6500.5), 55(8.3)

lH-NMR (250 MHZ): 5 : (cyclized): 7.23 (d, ]=1 Hz, 1), 6.14(d, ]=2 HZ, 1), 5.01(d
of q, I=6.4, 2.1 HZ, 1), 4.86(brs, 1), 4.78(m, 1), 3.83(m, 1), 2.98(q, I=6 Hz, 1), 2.52(t,
2), 2.54-2.16(m, 5), 1.92(m, 1), 1.58(d of d, I=8.3, 1 HZ, 3)

IR (Neat): (cyclized): 3000-2820, 1630, 1505, 1460-1420, 1260, 1180-1000(w), 890,
830-790(w), 725 cm-1

EI/MS (70eV): (formate): 260(M+, 12.8), 214(37.4), 19900.8), 18504.9), 172(35.7),
15703.6), 145(8.81), 133(base), 119(23.4), 105(22.3), 91(39.8), 81(55.6), 6500.3),
5309.2)

1H-NMR1250 MHz): 5 : (formate): 7.76(brs, 1), 7.70(s, .57), 7.22(m, 1), 7.18 (m,
1), 6.2(m, 1), 5.65(m, 1), 5.58(m, 1), 4.98(s, .58), 4.95(s,l), 4.85(t, I=1 Hz, 1),
4.55(brs, .57), 3.25(m, 1), 2.49(m, 2), 2.20(m, 2), 2.02(m, 1), 1.57(m, 1), 1.143, 3),
1.15(d of d, I=6.3, 2.4 Hz, 1.57)

IR(Neat): (formate): 3000-2820, 1720, 1630, 1500, 1450, 1380, 1200- 1150(w),
1050(w), 890, 870, 830, 780, 730 cm-1

W: The combined reagents were allowed to stir at RT
for twenty minutes. PISA (2 crystals) was then added and the solution heated
gently (50°) for two minutes, and after stirring for twenty minutes further, the
reaction was diluted with cyclohexane (20 ml). The aqueous phase was
separated, diluted with cyclohexane (20 ml), quenched with NaHC03 (20 ml
sat. aq. and then solid), saturated with NaCl, and extracted with ether (3 x 50

35

ml). The combined organic layers were washed with N aHCO3 and brine (50
m1 ea.), dried (MgSO4), and concentrated i_n vacuo. The cyclized product 20d
was obtained in 72% yield after purification by flash chromatography.

--11.1.\--111‘.10.\0‘1-,,- - -,.,,a --.‘1---- H‘ ‘1‘ ‘ -
To Mg metal (0.233 g, 9.59 mmol) was added ten percent of a solution of p-
bromoanisole (1.570 g, 8.400 mmol) in THF (10 ml). After the reaction began
the remaining bromide was diluted with THF (90 m1) and then added over
one quarter hour. After two hour of gentle reflux, the solution was cooled in
a dry-ice isopropanol bath (-78°), and a solution of the intermediate aldehyde
18a, (0.979 g, 4.799 mmol) in THF (25 ml) was added over one half hour. After
stirring for three hours at -78°, the mixture was warmed to RT and stirred
overnight until no further starting material could be seen by TLC. The
mixture was quenched with sat. aq. NH4C1 (25 ml), separated, and the
aqueous phase was extracted with ether (3 x 50 ml). The combined organic
layers were dried (MgSO4), and concentrated in vacuo. The crude product
was purified by chromatography on a column of silica gel (50. mm o.d., 100. g,
230-400 mesh, 200. ml forerun, hexane/ether(2.5/1), 50 ml fractions) using the
flash technique. Fractions 8-18 provided 1.305 g. (87.%) of 19c. Rf=0.21 in
(1/1) hexane/ ether.

EI/ MS (70 eV): 312(M+, 1.1), 2410.1), 17102.2), 1610.1), 147(2.2), 129(base),
11108.9), 101(8.9), 83(200), 71 (34.4), 55(94.4)

Iii-NMR (250 MHz): 5 : 7.34(brs, 1), 7.24(d, I=8.4 Hz, 2), 7.18(brs, 1), 6.85(d,]=8.4
Hz, 2), 6.75(d, I=1 Hz, 1), 6.24(brs, 1), 5.63(m, 1), 5.22(brs, 1), 3.8(s, 3), 3.75(s, 1),
2.66(brs, 1), 2.4(t, 1:105 Hz, 2), 2.1(m, 3), 1.83(brs, 1), 1.64-1.22 (m, 5)

IR (NEAT): 3640-3080, 2930, 2850, 1610, 1585, 1510, 1460, 1440, 1305, 1250, 1175,
1105, 1025, 875, 830, 780, 735 cm-1

High Res. EIZMS: calculated for C20H2403: 312.1725; observed: 312.1724

WM - To a solution of the alcohol 19c (1.300 g, 4.170

mmol) in cyclohexane (500 ml) was added formic acid (35 ml, 98%) in one
portion. After stirring ten minutes, the mixture was separated and the
organic phase washed twice with sat. aq. N aHCO3 (150 ml). The solution was
dried (MgSO4), and concentrated in vacuo. The crude product was purified
by chromatography on a column of silica gel (50 mm o.d., 50. g., 230-400 mesh,
(8/ 1) hexane/ ether, 25 ml fractions) using the flash technique. Fractions 5-8
gave 0.9063 g. 74% of 20c. Rf=0.77 in (1 / 1) hexane/ ether.

EI/MS (70eV): 294(M+ base), 264(8.4), 251(3.6), 2356.0), 18605.4), 173(59.1),
147(44.9), 121(34.9), 10504.1), 91(30.6), 7708.9) ‘

lH-NMR (250 MHz): 5 : 7.26(d, 1:1 Hz, 1), 7.2(d, ]= 8.4 Hz, 2), 6.81(d, I=8.4 Hz,
1), 6.19(d, 1=1 Hz, 1), 5.73(m, 1), 3.941111, 1), 3.78 (s, 3), 2.65(m, 2), 2.58-1.18(m, 9)

IR (Neat): 2920, 2840, 1740(w), 1605, 1510, 1460, 1440, 1295, 1245, 1175,1150, 1125,
1060, 1035, 900, 860, 820, 735, 690 Crn-l

High Res. EIZMS: calculated for C20H2203: 294.1620; observed: 294.1614

WWW: To a THF solution of borane-dimethyl
sulfide21 (2.0 M, 0.272 ml, 0.544 mmol) cooled to -10°C in a ice-salt water bath,

was added 2,3-dimethyl-2-butene (64.7 ul, 0.544 mmol) dropwise. The
mixture was warmed to 0°C, stirred one hour, warmed to room temperature,
and stirred one hour further. A solution of cyclized product 20c (64.0 mg.,
0.218 mmol) in THF (1.0 ml) was added dropwise and the mixture stirred 20
hours at room temperature. The mixture was cooled to 0°C, quenched with
water (1.0 ml), followed by 3N N aOH (2.0 ml), and 30% hydrogen peroxide (3.0
ml). The solution stirred at 0°C for one hour, warmed to RT over one hour,
and was cast into sat. aq. NH4C1 (30 ml) and ether (50 ml). The organic layer
was separated and washed with 10% sodium bisulfite, and sat. aq. N aHCO3 (30
ml ea.). The aqueous phases were combined, saturated with sodium chloride,
and extracted with ether (3 x 50 ml). The combined organic phases were
washed with brine (50 m1), dried (MgSO4), and concentrated in vacuo. The
crude alcohols were purified by chromotagrophy on a column of silica gel (10

37

mm o.d., 1.5 g., 230-400 mesh, hexane/ ether (2/1), 2 m1 fractions) using the
flash technique. Fractions 2,3 gave 5.4 mg. (8.%) recovered starting material
20c. Fractions 8-14 gave 40.6 mg. (59.8%) of intermediate 21c.

EIZMS (70 eV): 312(M+, 6.5), 294(24.4), 186(3.9), 17607.0), 147(36.7),137(base),
121 (26.6), 10902.7), 91(22.3), 77(20.9), 5500.0)

1 fl-NMR (250 MHZ): 5 : 7.28(d, I=1.2 HZ, 1), 7.21(d, ]=8.9 HZ, 1.3), 6.83(d, I=1.2
Hz, 1.3), 6.19(d, ]=8.9 HZ, 1), 4.39(d, I=10.1 Hz, 1), 3.78, 3.79(s, s, 3.7), 3.580, I=15.6
Hz, 1), 2.62(m,4), 2.30(m, 2), 2.15-1.15(m, 7)

IR (Neat): 3600-3320, 3080-2800, 1730(w), 1610, 1580, 1510, 1465, 1450, 1380, 1305,
1250, 1175, 1105, 1025, 895, 830, 735, 690 cm-1

F_Iigh Res. EI/ MS: calculated for C20H2403: 312.1725; observed: 312.1728

W: To the intermediate alcohol 21c (0.038 g, 0.1218 mmol) in
CH2C12 (10. ml) was added celite (0.5 g), followed by PCC (0.066 g, 0.305 mmol)
in one portion. After stirring 2.5 hours another 15 mg. (0.075 mmol) of FCC
was added, and the mixture stirred one half hour further. The mixture was
then diluted with ice cold hexane (30 ml), and filtered through a plug of
celite/ silica gel. The filter cake was rinsed with hexane/ ether (200 ml, 95/5),
and the combined organic phase was dried (MgSO4) and concentrated i_r__1_
Egg. The crude product was purified by chromatography on a column of
silica gel (10. mm o.d., 2. g., 230-400 mesh, hexane/ ether (2/1), 1 ml fractions)
using the flash technique. Fractions 2-5 gave 0.0221 g. (58.5%) of the products
22c as a (6-8):1 mixture (alpha R'/ beta R') which could be further separated by
flash chromatography. Mp (major isomer): 93-94°, Mp(mixture):78-81°, Minor
isomer: oil.

EIZMS (70eV): (major isomer): 310(M+, 47.1), 17403.3), 163(74.8), 149(43.2),
135(base), 11906.3), 10508.4), 91(37.7), 77(37.9), 55(60.4)

lH-NMR (150MHz): 5 : (major isomer) :7.79(dd, I=8.9, 1 Hz, 2), 6.80(dd, I=8.9,

1 Hz, 2), 6.74(d, 1:1 Hz, 1) 5.74(d, 1:1 Hz, 1), 4.24(m, 1), 3.82(s,1), 3.71 (m, 1), 2.60-
1.21(m, 11)

IR (neat): (major isomer): 3010-2860, 1760(w), 1670, 1605, 1580, 1515, 1460, 1450,
1420, 1375, 1260, 1235, 1190—1170, 1118, 1070, 1030, 920, 850, 820,790, 750, 700, 690
cm-1

High Res. EIZMS (main: 139mg): calculated for C20H2203: 310.1569;
observed: 310.1566

EIZMS (70eV): (minor isomer): 310(M+, 24.0), 293(4.89), 202(5.01), 17406.6),
16306.7), 14807.3), 135(base), 107(8.81), 9109.8), 77(25.2)

Ifl-NMR (250MHz): 5 :(minor isomer): 7.80(dd, I=8.9, 1 Hz, 2), 6.96(d, 1 Hz,
1), 6.86(dd, I: 8.9, 1 Hz, 2), 6.03(d, I=1 Hz, 1), 3.92(m, 1), 3.84(s, 1), 3.80(m,1), 2.60-
1.40(m, 11)

IR (Neat): (minor isomer): 3010-2820, 1725(w), 1670, 1600, 1580, 1510, 1455,
1420, 1365, 1310, 1260, 1215, 1170, 1070, 1030, 900, 840, 740, 695 cm-1

WWW: To a solution of the major ketone
22c, (0.1467 g, 0.4732 mmol) in THF (6. ml) at -78°c was added LDA (1.5 M, 1.5

eq., 0.47 ml) dropwise. The mixture stirred for one half hour, was warmed to
-45°c (dry-ice/acetonitrile) for one half hour, and then cooled back to -78°c .
MoOPh.HMPA.PYR30 (0.410 g, 0.710 mmol, 2 eq.) was then added in one
portion, and the mixture was allowed to warm from -78° to RT over 2.5
hours. The mixture was diluted with ether (50 ml), and washed with sodium
sulfite (20 ml) and citric acid (30 ml). The aqueous layers were salted and
extracted with ether (3 x 50 ml), and the combined organic layers were dried
(MgSO4) and concentrated in vacuo. The crude was purified via
chromatography on a column of silica gel (30 mmm o.d., 20. g. 230-400 mesh,
(10/ 1) hexane/ ether for fract. 1-36, (3/1) hexane/ ether for fract. 37-72, 8 ml
fractions, 30 ml forerun) using the flash technique. Fractions 2-15 gave 35.2
mgs (24%) recovered 22c, and fractions 30-68 gave 111. mgs (72%) of the
intermediate alpha hydroxy ketone 23. Rf = 0.32 in (1 / 1) hexane/ ether.

39

EIZMS (25eV): 308(M-18, base), 191(4.1), 179(53.4), 148(22.5), 135(71.2), 11903.9),
10501.5), 91 (8.4), 84(27.4)

CI] MS (25eV): 367(M+41, .98), 355(M+29, 1.97), 327(M+1, 17.3), 309(79.7),
191(22.4), 163(2.95), 147(22.4), 135(base), 12103.4)

lH-NMR (250MHz): 5: (C6D6): 8.24, 8.2,(d, J=8.9 Hz, 2), 6.79 (d, 1:1 Hz, 1), 6.65,
6.61(d, I=8.9 Hz, 2), 5.80(d, 1:1 Hz, 1), 3.65(d, I=8.9 Hz, 1), 3.25(d, I= 6.5 Hz,1),
3.18(s, 3), 2.88(brs, 1), 2.72(d of 1, 13.4, 8. Hz, 1), 2.6-1.2(m, 9)

IR (neat): 3620-3200, 3080-2800, 1710(w), 1670, 1600, 1510, 1450, 1420, 1370, 1300,
1245, 1170, 1030, 860-780, 735, 685 cm-1.

High Res. EleS: calculated for C20H2204: 326.1518; observed: 326.1546

12191124): To a solution of LAH (12.4 mg., 0.326 mmol) in ether (1.5 ml) at 0°C
was added a solution of intermediate alpha hydroxy ketone 23 (0.1061 g.,
0.3255 mmol) in ether (1.5 ml). The mixture was stirred for one half hour at
0°C, and then warmed to RT over 1.5 hours. LAH (6.2 mgs, 0.5 eq.) was added
and the mixture stirred one hour further. The mixture was quenched with
water (1 ml), diluted with ether (50 ml), and washed with 15% NaOH (25 ml).
The aqueous layers were saturated with salt and extracted with ether (3 x
50.ml), and the combined organic layers were dried (MgSO4), and
concentrated in vacuo to give 88.6 mgs. (83%) of the crude diol 24, which was
used without further purification.

EIlMS (25eV): 310(M-18, 2.65), 190(25.2), 163(35.9), 147(base), 137(52.1), 12105.1),
109(8.13), 91(27.1), 77(26.7), 55(45.7)

CIZMS (25eV): 369(M+41, .50), 355(M+29, 3.65), 339(M+11, 4.92), 329(M+1, 11.7),
311(M-18, base), 29301.3), 19003.3), 175(21.2), 147(43.4), 137(29.3), 12102.0),
85(25.6)

40

1[_-_I-NMR (250MHz): 5 : (C6H6): 7.29, 7.26,(d, ]=8.9 Hz, 2), 7.10 (d, I=1 Hz, 1),
6.74, 6.70(d, I=8.9 Hz, 2), 5.93(d, I=1 Hz, 1), 4.31(d, I=4.4 Hz, 1), 3.82(d, I: 6.7
Hz,1), 3.31(s, 3), 2.55-0.90(m, 13)

IR (neat): 3700-3100, 3020-2810, 1735(w), 1620, 1520, 1460, 1300, 1250,1190, 1100-
1000, 970, 910, 840, 810, 750 cm-1

_I-_Iigh Res. EI/MS: calculated for C20H2404: 328.1675; observed: 328.1671

WE): To diol 24 (0.0886 g., 0.2701 mmol) in t-BuOH (3.5 ml) was added
N aIO4 (0.145 g., 0.675 mmol) in H20 (3.5 ml). The mixture was stirred for 1.5
hours, diluted with ether (50 ml), and separated. The aqueous layer was
diluted with brine (6.5 ml), and extracted with ether (3 x 50 ml). The
combined organic layers were dried (MgSO4), and concentrated in vacuo. The
crude product was purified by chromatography (30 mm o.d., 40. g 230-400
mesh, 50 ml fractions, fract. 1-20 (10/ 1) Hexane/ ether, fract. 21-40 (8/ 1)
hexane/ ether, fract. 41-60 (5/ 1) hexane/ ether, fract. 61-80 (2/1) hexane/ ether,
fract. 81-100 (ether), 200. ml forerun) using the flash technique. Fractions 7-40
gave 25.8 mg. (49%) of a 3/1 mixture of compound 25 and anisaldehyde.
Fractions 41-70 gave 62.0 mg. of a compound (26) M.W. 310 (CI/ MS). The
anisaldehyde/ product mixture was taken up in ethanol (50 ml) and washed
with cold sat. aq. N aHCO3. The aqueous was extracted with ether (3 x 10 ml),
and the combined organic phases were dried (MgSO4) and concentrated in
vacuo to provide 17.7 mg. (35%) of ketone 25.

EIZMS (25eV): 190(M+,13.6), 163(7.14), 149(37.1), 134(base), 11908.6), 105(7.14),
9600.0), 91(20.0), 7700.0), 69(7.14), 55(25.7)

lH-NMR (250MHz): 5 : 7.28(d, I=1 Hz, 1), 6.15(d, I=1 HZ, 1), 3.66(d, I=6.6 Hz, 1),
2.6-1.0(m, 11)

IR (neat): 3080-2800, 1730, 1600, 1515, 1460, 1385, 1340-1230, 1125, 1075, 905,
880, 840, 740, 700 cm-1

High Res. EI/ MS: calculated for C12H1402: 190.0999; observed: 190.0979

41

W - Prepared according to the method of Piers/

Swenton32 with the following modifications: To a solution of 1,3-
cyclopentanedione (10.0 g., 102.0 mmol) in CHC13 (250 ml) is added
phosphorus tribromide (19.37 ml, 204.0 mmol) in one portion. The mixture
was stirred at reflux for 18 hours, cooled, and 50 ml of ice/ water was added.
The aqueous layer was separated and extracted with CHC13 (3 x 75 ml). The

combined organic extracts were passed through a four inch plug of
celite/ silica gel , and the filter cake was rinsed with CHC13. The combined
solutions were dried (MgSO4) and concentrated in vacuo (NO HEAT) to
provide 9.42 g (57.7 %) of the haloenone.

EIZMS (25eV): 161(M+1 ,189), 81 (6.42), 53(base)

lH-N MR (60MHZ): 5 : 6.4(m, 1), 3.0(m, 2), 2.45(m, 2)

W32 - To a solution of the bromoenone
(5.80 g., 36.0 mmol) in CHC13 (175 ml) was added vacuum dried, crushed, 4A

molecular sieves (12 g), followed by ethane dithiol (3.81 ml, 45.03 mmol) in
one portion via syringe. BF3-OEt2 (0.9 ml, 7.31 mmol) was then added
dropwise, and the mixture stirred for 18 hours. The solid residue was
removed by filtration through celite, washed with sat'd. NH4Cl, NaHCO3,
and brine (2 x 50 ml each), dried (MgSO4), and carefully concentrated in vacuo
(NO HEAT). The crude product was purified by chromatography on a
column of silica gel (50 mm o.d., 200 g., 230-400 mesh, packed hexane/ ether
(99/1), run hexane/ ether (35/1), 400 ml forerun, 50 ml fractions) using the
flash technique. Fractions 5-12 provided 5.42 g (64%) of 27. Rf=.73 in (1/1)
hexane / ether.

EIZMS (25eV): 238(M+,23.1), 210(77.3), 178(46.6), 157(6.79), 14604.2), 129(56.6),
97(base), 85(9.16)

lH-N MR (60MHZ): 5 : 5.84(brs, 1), 3.33(s, 4), 2.66(5, 4)

- - - - To oil free NaH (17.2 g., 0.5491 mmol,) covered
with dry ether (IL) was added trimethyl phosphonoacetate (100.0 g., 0.5491

42

mmol) in dry ether (250 ml), dropwise over two hours. After stirring an
additional 4.5 hours, a solution of 3-furylaldehyde (50.0 g., 0.520 mmol) in dry
ether (200 ml) was added dropwise over one hour. After stirring overnight,
the reaction was carefully quenched with brine (400 m1), and cast into
hexane/ water (1L, 1:1). The organic phase was separated, washed with water
and brine (0.5L each), dried (MgSO4), and concentrated in vacuo to provide
77.88 g, (99%) of product as a fluffy white solid, which was used without
further purification. Rf=0.59 in hexane/ ether (1:1).

EIZMS (25eV): 152(M+,80.97), 121 (base), 10901.5), 93(49.0), 8103.3), 65(52.6)

1 fl-NMR (60MHZ): 5 : 7.62(rn, 2), 6.65(s, 1), 6.33(s, 1), 6.08(s, 1), 3.78(s, 3)

W311 - To a solution of Ni(OAc)2-4(H20) (9.92 g.,
40.0 mmol) in 95% EtOH (400 ml) was added NaBH4 (72 ml, 1M in

EtOH/NaOH, prepared by addition of 4.0 g N aBH4 to 95 ml abs. EtOH and 5
ml 2N N aOH)53. After one hour, hydrogen evolution was complete, and 3-
(3-furyl)-2-methylacrylate (107.0 g., 0.7070 mmol) in 95% EtOH (300 ml) was
added in one portion. The mixture was hydrogenated at 100 psi for 18 hours,
the catalyst removed by filtration through a pad of celite, and the filter cake
was rinsed with EtOH. The solution was cast into brine (1.5L) and extracted
with hexane/ ether (4/ 1, 4 x 500 ml). The combined organic layers were dried
(MgSO4), and concentrated in vacuo to provide 99.6 g (91.5%) of product as a
colorless oil, used without further purification. Rf=0.62 in hexane/ ether (1:1).

EI/ MS (JZSeV): 154(M+,71.3), 123(34.3), 11502.4), 95(base), 81(90.2), 67(32.9),
53(26.2)

ILI-NMR (60MHZ): 5 :7.27(m, 2), 6.21(m, 1), 3.61(s, 3), 2.8-2.0(m, 4)

W19 - To a solution of LAH (29.5 g., 0.776 mol) in dry ether
(1.2L) cooled to 0°C in an ice/ water bath was added the propionate (99.6 g.,
0.647 mmol) in ethanol (200 ml) over one hour. The solution was warmed to
room temperature and stirred overnight (15 hrs.). The reaction was cerefully
quenched with water (75 ml), 2N NaOH (125 ml), and again with water (300

43

ml), in sequence. After separation, the aqueous phase was extracted with
ether (4 x 500 ml). The combined organic layers were dried (MgSO4),
concentrated in vacuo. Distillation, BP5 122-128°, provided 57.1 g (70%) of the

alcohol as a water white oil.

EIZMS (25eV): 126(M+,14.4), 107(4.98), 9503.4), 82(base), 67(38.5), 54(26.8),
41(32.1)

lH-NMR (60MHz): 5 : 7.30(m, 2), 6.25(brs, 1), 3.6(m, 2 ), 2 42(m, 2), 1.9(m, 2)

AW - To a solution of the the protected bromoenone 27 (3.60
g., 15.8 mmol) in THF (225 ml), cooled to -78°C in a Dry Ice/isopropanol bath,
was added n-BuLi (2.4M, 11.90 ml, 28.4 mmol) dropwise via syringe over
fifteen minutes. After stirring at -78°C for two hours, 3-(3-furyl)-propanal
(1.77g., 14.3 mmol) in THF (50 m1) at -78°C is added via cannula over fifteen
minutes. The reaction mixture is stirred at -78°C for 2.5 hours, allowed to
warm to 0°C over one hour, and quenched with sat'd. N a2CO3 (50 ml). The
aqueous phase was separated, and extracted with Tl-IF (3 x 100ml). The
combined organic phases were washed with brine (100 ml), dried (MgSO4),
and concentrated in vacuo. The crude product was purified by
chromatography on a column of silica gel (50 mm o.d., 200 g, 230-400 mesh,
packed in hexane/ether (9:1), 1.5L forerun in hexane/ether (7:1), then 1.0L
forerun in hexane/ ether (4:1), followed by 125 ml fractions) using the flash
technique. Fractions 4-16 provided 3.12 g (78%) of 28 as a clear viscous oil.
Rf=0.19 in hexane/ ether (1:1).

EI/MS (25e\fl: 282(M+, 2.90), 2640.68), 238(6.58), 200(2.30), 188(6.43), 159(6.75),
131(29.6), 99(33.8), 81 (base), 65(27.0), 53(46.7)

13c NMR (6L95 MHz):(C6D6): 8 : 147.95, 142.96, 139.32, 130.61, 124.76, 111.26,
69.66, 45.48, 40.58, 35.73, 30.72, 30.98, 29.90

lH-NMR (250MHz): 5: 7.35(brs, 1),7.21(brs,1),6.25(brs, 1), 5.70(brs, 1), 4.2511,
1:13 Hz, 1), 3.32(s, 4), 2.501111, 7), 1.82(t, 1:15 Hz, 2)

IR (neat): 3650-3050, 3000-2800, 1500, 1450, 1420, 1380, 1280, 1100-900 cm-l.

High Res. EIZMS: calculated for C14H180252: 282.0748; observed: 282.0755

cuuzmmmuxmmmmmmam - To a solution of the
allylic alcohol (0.700 g, 2.482 mmol) in CHzClz (50 ml) is added Et3N (1.52 ml,

10.92 mmol) dropwise. After stirring for five minutes, Msc133 (0.580 ml, 7.45
mmol) is added dropwise. The mixture is stirred for 0.5 hours, and quenched
with NH4Cl. The aqueous phase was separated, and extracted with CHzClz (4
x 25 ml). The combined organic phases were dried (MgSO4) and concentrated
in vacuo. The crude product was purified by chromatography on a column
of silica gel (40 mm o.d., 50 g, 230-400 mesh, packed in hexane/ ether (12:1),
run in hexane/ ether (5:1), 25 m1 fractions) using the flash technique.
Fractions 2-8 provided 0.5386g, (82%) of the cyclized product 30. Rf=0.72 in
hexane/ ether (1:1).

EIZMS (25eV): 264(M+, 62.7), 236(26.9), 208(base), 183(6.29), 14703.4), 11505.3),
91(24.7), 77(20.2), 6907.7), 55(29.3)

12C NMR (62.95 MHZ):(C6D6): 5 : 153.13, 141.30, 123.15, 119.02, 110.38, 53.63,
35.56, 35.49, 35.01, 27.20, 26.57, 22.63, 22.01

lH-NMR (250MHz): 5 : 7.27(d, I=2 HZ, 1), 6.18(d, I=2 Hz, 1), 3.15(m, 1), 2.45-
1.60(m, 10)

IR (neat): 3000-2800, 1590, 1500, 1440, 1410, 1305, 1285, 1230, 1195-1100, 1040,
1020 cm-1.

High Res. EIZMS: calculated for C14H16052: 264.0643; observed: 264.0629

,3... ' -.. 1.. : 1 11 . 11111-11. ' -Toa
solution of the allylic alcohol 28 (0.114 g., 0.404 mmol) in cyclohexane (5 ml)
was added 98% formic acid (20 ul) dropwise. After five minutes, the reaction
was quenched with NaHCO3 (10 ml) and extracted with CH2C12 (3 x 20 ml).
The combined organic phases were dried (MgSO4), and concentrated m
mg. The crude product was purified by chromatography on a column of
silica gel (10 mm o.d., 5 g, 230-400 mesh, hexane/ ether (1:1), 2 m1 fractions)
using the flash technique, to provide 98.0 mgs, (85.5%) of Spirocyclic 29.

45

EIZMS (25eV): 282(M+, 68.9), 238(21.4), 189(34.6), 17805.6), 150(54.2), 14508.7),
13504.1), 131 (base), 118(49.2), 115(31.6), 107(25.3)

13g; NMR (75.45 MHz): 5 : 154.36, 141.47, 114.31, 109.97, 74.33, 70.48, 53.91,
48.37, 45.12, 39.60, 39.51, 33.50, 28.07, 18.08

lH-NMR (300MHz): 5 : 7.27(d, I=2 Hz, 1), 6.14(d, I=2 Hz, 1), 3.94(dd, I=6.6, 3.3
Hz, 1), 3.36( m, 4), 2.63(d, I=15 Hz, 1), 2.31(d, I=15 HZ, 1), 2.61-2.18(m, 6), 2.08(m,
4)

IR (neat): 3430, 2930, 2860, 1600, 1508, 1440, 1268, 1210, 1168, 1129, 1066, 1030,
960, 893, 880, 742 cm-1.

financial) - To a solution of the allylic alcohol 28 (1.486 g., 5.2695 mmol) in
CHzClz (750 ml) was added celite (30 g), followed by PCC (2.04 g., 9.46 mmol)
in one portion. After stirring three hours, ice cold hexane (300 ml) was added
and the mixture was filtered through a pad of celite/ silica. After washing the
pad with CH2C12 (300 ml), the combined filtrates were dried (MgSO4), and
concentrated in vacug. The crude product was filtered through a four inch
pad of silica using hexane/ ether (1:1) as elutant to provide 0.900 g (61 %) of the
enone 31. Rf=0.41 in hexane/ ether (1:1).

E1 M5 25eV : 280(M+, 14.4), 252(4.50), 219(8.14), 18701.3), 15701.7), 13102.2),
10502.5), 95(45.9), 81 (base), 65(27.0)

EC NMR (62.95 MHz):(C6D6): 5 : 196.46, 144.39, 143.08, 142.90, 141.96, 139.40,
124.38, 111.32, 73.71, 43.13, 40.75, 39.66, 30.48, 19.22

lH-NMR @OMHZ): 5 : 7.33(t, I=4.2 Hz, 1), 7.22(brs, 1), 6.55(t, I=4.2 Hz, 1),
6.25(brs, 1), 3.35(s, 4), 2.91 (m, 2), 2.73(t, I=14 Hz, 2) 2.59(m, 4)

IR (neat): 3000-2800, 1665, 1605, 1505, 1450-1350, 1340, 1310-1120, 1105, 1070,
1025, 970, 950, 875, 860, 790, 740 cm-1.

flgh Res. EI/ MS: calculated for C14H160252: 280.0592; observed: 280.0580

WWW - To a solution of
enone 31 (1.70 g., 6.071 mmol) in CH2C12 (100 ml) was added BF3-OEt2 (75 111,

0.61 mmol) over 1 minute. After stirring for four hours,an additional portion

46

of BF3-OEt2 (35 ul) was added, and the reaction stirred another 1.5 hours. The
mixture was quenched with sat'd. NH4C1 (40 ml), and the aqueous phase was
separated and extracted with CH2C12 (4 x 75 ml). The combined organic
phases were dried (MgSO4), and concentrated in vacuo. The crude product
was purified by chromatography on a column of silica gel (50 mm o.d., 200 g,
230-400 mesh, packed in hexane/ ether (7:1), run in hexane/ ether (4:1), 500 ml
forerun, 50 ml fractions) using the flash technique. Fractions 3-7 provided
0.222 g (13%) of Spirocyclic adduct (29, C10=carbonyl), fractions 8-20 provided
0.939 g (55%) of the desired trans product 32, and fractions 21-32 provided a 2%
mixture of cis isomers, an unidentified product, and a small amount of trans
isomer. Rf=0.52 (spiro), Rf=0.46 (trans), Rf=0.29 (cis) in hexane/ ether (1:1).

EI/ MS (25eV): (Spiro isomer): 280(M+, 60.7), 25202.8), 22406.8), 19209.5),
15907.7), 148(base), 131 (51.4), 119(35.7), 105(29.0), 91(64.8), 81 (35.9)

lI-I-NMR (250MHz): (Spiro isomer): 5 : 7.35(d, I=2 HZ, 1), 6.20(d, I=2 HZ, 1),
3.35(m, 4), 2.90, 2.58(d of (1, ]=15, 9.5 Hz, 1) 2.80-2.08(m, 10)

EU MS (25e1fl: (Trans isomer): 280(M+, base), 219(3.12), 18701.2), 149(33.3),
131(53.6), 119(31.3), 105(20.5), 91(49.2), 7701.5)

fig NMR (62.95 MHz):(C5D6): 8: (Trans isomer): 209.10, 140.03, 123.19, 113.15,
110.02, 75.36, 56.22, 54.31, 42.57, 42.40, 40.57, 39.25, 24.37, 23.06

1_H-NMR QSOMHZ): 5 : (Trans isomer): 7.30(d, ]=2 Hz, 1), 6.25(d, I=2 Hz, 1),
3.86(d, I=8.8 HZ, 1), 3.25-2.10(m, 12)

IR (neat): (Trans isomer): 3000-2800, 1700, 1510, 1440, 1340, 1315, 1275, 1210,
1175, 1170, 1090, 1070, 1055, 1020 cm-1.

I-l_igh Res. EI/MS: (Trans isomer): calculated for C14H160252: 280.0592;
observed: 280.0589

W32)

A - Reduction of Ketone 32 - To the trans cyclized product 32 (100.0 mgs,
0.3570 mmol) in ether (6.0 ml) was added Lithium borohydride (2M, 1.3x, 0.23
ml, 0.4623 mmol) dropwise over five minutes. After stirring ten minutes,

47

N aOH (20%, 4.0 ml) was added and the mixture stirred for twenty minutes.
The mixture was separated, and the aqueous phase was extracted with CH2C12
(3 x 10 ml). The combined organic phases were dried (MgSO4) and
concentrated in vacuo to provide 92.0 mgs, (91 %), of the resulting alcohol
used without further purification. Rf=0.15 in (1:1) hexane/ ether.

EIZMS (25eV): 282(M+, 28.5), 264(5.97), 188(base), 17108.5), 149(33.8), 131(94.4),
119(39.8), 105(76.0), 91 (52.9), 77(28.3)

lH-NMR (250MHz): 5 : 7.24(m, 1.63), 6.17(d, ]=2 Hz, .63), 6.15(d, I=2 Hz, 1),
3.85(d, I=11 Hz, 1),.3.65(d, I=6.6 Hz, .63), 4.0-1.65(m, 15)

IR (neat): 3620-3100, 3010-2700, 1510, 1480-1200, 1180-1000, 980, 925, 900, 850,
745, 680 cm-1.

High Res. EIZMS: calculated for C14H130252: 282.0748; observed: 282.0751

B - Xanthate Ester Preparation - To the alcohol (0.0415 g, 0.1472 mmol,
prepared from ketone 32) in THF (2.0 ml) was added 2 crystals of imidazole
and 80% NaH (10.0 mgs, 2x, 0.2944 mmol) in one portion. After stirring at
reflux for 3.5 hours, carbon disulfide, C52, (0.44 ml, 7.36 mmol, 50x) was added
and the mixture stirred .5 hours at reflux. Methyl iodide (0.46 ml, 7.36 mmol,
50x) was added, and the mixture stirred .5 hours further at reflux. The
mixture was then cooled, and acetic acid (0.5 ml) was added. After two
minutes, the mixture was diluted with water (10 ml). The aqueous phase was
separated, and extracted with CH2C12 (3 x 25 ml). The combined organic
phases were rinsed with 0.1 N HCl (20 ml), followed by sat'd aq. NaHCO3 (40
ml), dried (MgSO4) and concentrated in vacuo. The crude product was
purified by chromatography on a pipette column of silica gel (5 mm o.d., 2 g,
230-400 mesh, eluted in hexane/ether (3:1), 1 ml fractions) using the flash
technique. Fractions 3-5 provided 0.0470 g (86%) of the xanthate ester
intermediate. Rf=0.5 in (5:1) hexane/ ether.

EI/ MS (25eV): 372(M+, 7.79), 339(4.59), 325(2.30), 265(22.4), 2360.43), 22300.4),
171 (41.5), 147(84.6), 131 (base), 118(26.936.9), 105(35.2), 91 (23.8), 75(33.7)

 

48

1fl-NMR (250MHz): 5 : 7.26(d, ]=2.2 HZ, 1), 7.25(d, ]=2.2 Hz, .55) 6.20(d, I=2.2
Hz, .55), 6.18(d, 1:2.2 Hz, 1) 3.92(d, I=11 Hz, 1),.3.75(d, I=6.6 Hz, .55) 3.3-1.9(m,
10), 2.55(s, 1.65), 2.50(s, 3)

IR (neat): 3000-2800, 1640, 1510, 1450-1400, 1220, 1050, 965, 915, 900, 865, 820, 740
cm-1.

C- Cleavage of Xanthate Ester to Dithiolane 33 - To the xanthate ester (0.0215
g., 0.578 mmol) in benzene (1.5 ml) was added HSnBu3 (23.3 ul, 0.0867 mmol,
1.5 x) and the mixture was refluxed for six hours. After cooling, the mixture
was concentrated in vacuo. The crude product was purified by
chromatography on a pipette column of silica gel (5 mm o.d., 2 g, 230-400
mesh, eluted in hexane/ ether (25:1), 1 ml fractions) using the flash technique.
Fractions 3 - 6 provided 0.0120g., 78% of the deoxygenated adduct 33. Rf=0.62
in (5:1) hexane/ ether.

EI/MS (25eV): 266(M+, 61.4), 238(2.29), 205(4.81), 172(98.4), 147(45.0), 131(base),
119(26.9), 105(69.2), 91 (45.9), 77(23.9)

IH-N MR (EOMHZ): 5 : 7.22(d, I=2.2 Hz, 1), 6.15(d, I=2.2 HZ, 1), 3.69(d, I=6.6 Hz,
1),.3.21(m, 4), 2.65-1.22(m, 11)

IR (neat): 3000-2800, 1510, 1450, 1275, 1180, 1070, 900, 840, 740 cm-1.

I_1I_igh Res. EI/ MS: calculated for C14H13052: 266.0799; observed: 266.0794

WWW - To a solution of trans
ketone 32 (0.098 g., 0.350 mmol) in THF (25 ml) was added TMS-

methyllithium (0.46 ml, 0.455 mmol, 1M, 1.3x) dropwise over ten minutes.
After six hours the reaction appeared to procede no further (TLC), and was
quenched with sat'd. NH4C1 (5 ml). The aqueous phase was separated, and
extracted with CH2C12 (4 x 15 ml). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. The crude product was purified by
chromatography on a column of silica gel (50 mm o.d., 200 g, 230-400 mesh,
hexane/ ether (15:1), 2.0L forerun, 100 ml fractions) using the flash technique.
Fractions 3-10 provided 0.0579 g (45%) of the desired alcohol 35 as a white

49

waxy solid, and fractions 12-19 provided 0.0476 g (49%) recovered trans
cyclized ketone. M.P. 66.5-68.5°C. Rf=0.58 in hexane/ ether (1:1).

EI/ MS L25e\fl: 368(M+, 2.83), 350(8.62), 256(3.55), 232(4.38), 219(9.60), 185(6.26),
14905.1), 131 (62.2), 11505.2), 91 (13.7), 73(base)

lH-NMR (250MHz): 5 : 7.24(d, I=1.8 Hz, 1), 6.16(d, I=1.8 HZ, 1), 3.75(d, I=9.8 Hz,
1), 3.31-3.05(m, 4), 3.85-1.40(m, 10), 1.01 (d, I=4.4 Hz, 2), 0.02(s, 9)

IR (neat): 3500, 3150-3100, 3000-2800, 1550, 1510, 1450-1420, 1350, 1320, 1250,
1210, 1160, 1050, 1020, 980, 935, 905, 850, 750, 700 cm-1.

_H_igh R_es. EI/MS: calculated for C13H2502525i: 368.1321; observed: 368.1311

WW - To a solution of I<H (0.0088 g, 0.2196 mmol, oil free)
in THF (5 ml) was added tertiary alcohol 35 (0.0404 g., 0.1098 mmol) in THF (2

ml). After stirring for two hours, the reaction was quenched with sat'd.
N H4Cl (5 m1), and diluted with CH2C12 (25 ml). The aqueous phase was
separated and extracted with CH2C12 (3 x 15 ml). The combined organic
phases were dried (MgSO4), and concentrated in vacuo. The crude product
was purified by chromatography on a column of silica gel (15 mm o.d., 5 g,
230-400 mesh, packed in hexane/ ether (10:1), eluted in hexane/ ether (3:1), 5
ml fractions) using the flash technique. Fractions 3-7 provided 0.0302 g (99%)
of the exocyclic olefin 36

E1/ MS (25eV): 278(M+, 24.22), 25009.1), 217(8.87), 185(26.8), 16006.5), 145(8.51),
131 (base), 11805.0), 10403.4), 91(22.4), 81 (27.2), 71 (38.9)

1%; NMR (62.95 MHz):(C6D6): 8 : 150.34, 140.16, 121.52, 113.19, 112.61, 110.32,
77.23, 56.10, 49.07, 44.69, 39.99, 39.16, 32.07, 31.87, 27.75

LH-NMR (250MHz): 5 : 7.27(d, I=1.8 Hz, 1), 6.15(d, I=1.8 Hz, 1), 4.8(5, 2), 3.90(d,
I=10 Hz, 1), 3.35-3.0(m, 4), 2.86-1.80(m, 9)

IR (neat): 3060, 3000-2800, 1635, 1510, 1450, 1270, 1145, 1070, 975, 845, 740, 700
cm-1.

Lligh Res. EI/ MS: calculated for C15H1gOS2: 278.0799; observed: 278.0789

WW - To a solution of NCS (0.2260 g., 1.608 mmol)
in CH3CN/ H20 020 ml, 4:1) was added AgNO3 (0.3080 g., 1.810 mmol) in one

portion. After stirring for three minutes, tertiary alcohol 36 (0.1480 g., 0.4022
mmol) in CH3CN (3 ml) was added in one portion. The yellow colored
reaction mixture turned snow white after stirring 25 minutes and was
quenched by treating the mixture at one minute intervals with sat'd aq.
N a2503, Na2CO3, and brine (1 ml each), successively. The mixture was then
diluted with hexane/CH2C12 (20 m1, 1:1), filtered through celite, rinsed, dried
(MgSO4), and concentrated in vacuo. The crude product was purified by
chromatography on a pipette column of silica gel (5 mm o.d., 2 g, 230-400
mesh, packed in hexane/ ether (10:1), eluted in hexane/ ether (5:1), 1 ml
fractions) using the flash technique. Fractions 4 - 8 provided 0.0763 g (94%) of
the keto-olefin 37. Rf=0.45 in hexane/ ether (1:1).

EI/ MS (25eV): 202(M+, 56.7), 187(2.85), 173(5.72), 15902.9), 146(base), 131 (44.6),
117(48.1), 10704.2), 99(53.4), 91(43.5), 77(33.7), 65(24.3), 56(61.4)

.1_3C NMR (76.702 MHZ):(C6D6): 5 : 214.1 (C10), 150.34 (C2), 141.26 (C11), 140.2
(C6), 120.5 (C3), 112.64 (C12), 112.48 (C13 methylene), 53.39 (C1), 45.48 (C4), 35.32
(C9), 34.39 (C7), 27.51 (C8), 26.94 (C5)

lH-NMR (250MHz): 5 : 7.28(d, ]=1.8 Hz, 1), 6.15(d, ]=1.8 Hz, 1), 4.93(d, I=20 Hz,
2), 3.75(d, I=8.7 HZ, 1), 3.21 (m, 1), 2.55(t, ]=11.2 Hz, 2), 2.30-2.10(m, 6)

IR (neat): 3000-2800, 1740, 1630, 1500, 1440, 1400, 1020, 1070-1000, 890, 730 cm-1.

High Res. EI/ MS: calculated for C13H1402: 202.1004; observed: 202.0997

W940) - To a solution of keto-olefin 37 (0.0600g., 0.2970
mmol) in CH2C12 (6 ml) was added Lombardo's reagent38 - ZnCH2Br2TiCl4

(7.70 ml, 1.78 mmol, 0.23M, 6x) rapidly in one portion. After stirring five
minutes, an additional equivalent of Lombardo's reagent (1.30 ml, 0.297
mmol, 1x) was added. After stirring forty minutes further, the reaction was
diluted with CH2C12 (50 ml), and quenched with cold N aHCO3 (10 ml). The
aqueous phase was separated and extracted with CH2C12 (3 x 20 ml). The
combined organic phases were dried (MgSO4), and concentrated in vacuo.
The crude product was purified by chromatography on a column of silica gel

51

(5 mm o.d., 3 g, 230-400 mesh, packed in hexane/ether (10:1), eluted in
hexane/ ether (6:1), 1 ml fractions) using the flash technique. Fractions 3-14
provided 0.0564 g (95%) of the bis-olefin 40 as a 6/1 mixture of isomers (1H
NMR). Rf=0.43 in hexane/ ether (1:1).

EIZMS (fieV): 200(M+, 42.1), 185(24.2), 171(24.9), 157(22.4), 143(20.1), 131 (24.0),
115(26.9), 10501.7), 91(46.1), 77(38.4), 65(29.5), 51(42.9), 39(base)

III-NMR (250MHz):(C6D6): 5 : 7.24(d, ]=1.8 Hz, 1), 7.20(brs, .16), 6.18(brs, .16),
6.16(d, I=1.8 Hz, 1), 5.44(brs, .16), 5.14(brs, .16), 4.85(m, 2.33), 4.76(brs, 1), 4.57(brs,
1), 3.87(d, I=4.9 Hz, 1), 3.04(q, J=6.6 Hz, 1), 2.8-1.75(m of m, 8)

IR (neat): 3080, 3000-2850, 1655, 1635, 1505, 1435, 1250, 1130, 1065, 885, 835, 800,
725 cm-1.

High Res. EI/MS: calculated for C14H160: 200.1201; observed: 200.1139

WM - To a solution of keto-olefin 37 (0.0200
g., 0.09901 mmol) in THF (3 ml) was added KH (0.0113 g., 0.09901 mmol, 1x,

35%KH) in one portion. After stirring for twenty minutes, Mel (7.4 ul, 0.1188
mmol, 1.1 x, filtered through P205 /si1ica) was added dropwise over 0.5
minute. After stirring for two hours, the mixture was diluted with THF (20
ml) and quenched with sat'd. NH4C1 (5 ml). The aqueous phase was
separated and extracted with CH2C12 (3 x 15 ml). The combined organic
phases were dried (MgSO4), and concentrated in vacuo. The crude product
was purified by chromatography on a column of silica gel (5 mm o.d., 5 g, 230-
400 mesh, packed in hexane/ ether (99:1), 30 ml forerun in hexane/ ether (40:1),
1 ml fractions) using the flash technique. Fractions 5-25 (20:1 hexane/ ether)
provided 7.5 mgs (Ca. 35%) of a mixture of bis methylated and isomeric
product. Rf=0.50 in hexane/ether (1:1). Fractions 26-36 (1:1 hexane/ ether)
provided 11.1 mgs (52%) of the desired alpha methyl ketone 41 as a
microcrystalline solid, M.P. = 71-74°C. Rf=0.43 in hexane/ ether (1:1).

EIZMS (25eV): 216(M+, 32.3), 201 (7.45), 187(2.34), 173(8.77), 160(base), 145(46.6),
131 (22.2), 115(25.1), 105(9.92), 91 (43.0), 77(36.0), 65(27.1), 55(34.3)

52

13c NMR 176.702MHz):1c6136): 5:215.3(C10),146.6(C2), 140.4 (C11), 120.8
(C3), 112.30 (C12), 111.39 1c13 methylene), 51.0 (C1), 48.88 (C4), 36.99 (C9), 36.14
(C7), 23.17 (C8), 22.38 (C5), 18.43 (C14 methyl)

lfl-NMR (250MHz): 5 : 7.28(d, I=1.8 Hz, 1), 6.12(d, I=1.8 Hz, 1), 5.05(brs, 1),
4.85(brs, 1), 3.17(d 0d d, I=13.4, 5.5 HZ, 1), 2.75-1.75(m, 8), 1.11(s, 3)

IR (neat): 3000-2800, 1738, 1700-1600, 1450, 1375, 1230-1020, 885 crn-l.

High Res. EI/MS: calculated for C14H1502: 216.1150; observed: 216.1154

WW - To Pseudo-
guaianolide 41 (0.0250 g., 0.1157 mmol) in EtOAc (3.0 ml) was added activated
charcoal (10 mgs) and PtO2 (0.0031g., 0.137 mmol) in one portion. The
mixture was stirred for one hour under a balloon atmosphere of H2 at room
temperature. The mixture was then filtered through a plug of celite, rinsed
with EtOAc, dried (MgSO4), and concentrated in vacuo to provide 0.0235 g.,

(93%) of a single pure product 43. Rf=0.43 in (1:1) hexane/ ether.

EIZMS (25eV): 218(M+, 69.4), 17509.5), 1162(base), 147(92.5), 133(344.9),
11905.0), 105
(21.8), 91(34.5), 77(40.0), 65(27.0), 54(30.5), 41 (46.2)

L3.C NMR (76.702 MHZ):(C6D6): 5 : 217.0 (C10), 152.0 (C2), 140.5 (C11), 121.8
(C3), 112.25 (C12), 52.0 (C1), 46.41 (C4), 38.0 (C6), 35.95 (C9), 34.95 (C7), 23.56 (C8),
23.10 (C5), 20.9 (C13 methyl), 22.95 (C14 methyl)

lfl-N MR (250MHz): 5 : 7.26(d, I=2 Hz, 1), 6.10(d, I=2 Hz, 1), 2.68 (d of t, I=6.8,
11.3 Hz, 1), 2.52(t, I=4.5 Hz, 2), 2.50-2.40(m, 1), 2.38-1.8(m, 6), 1.31(s, 3), 1.08(d,
I=6.8, 3)

High Res. EIZMS: calculated for C14H1302: 218.1307; observed: 218.1311

53

BIBLI RAP

1) a) Tanis, S. P., Tetrahedron Lett. 1982, _2_3_, 3115;
b) Tanis, S. P., Head, D. B. Tetrahedron Lett. 1982, 23, 5509;
c) Tanis, S. P., Herrinton, P. M. J. Org. Chem. 1983, g, 4572;
d) Tanis, S. P., Herrinton, P. M. 1912-. 1985, Q, 3988;
e) Tanis, S. P., Head, D. B. Tetrahedron Lett. 1984, _25, 4551;
f) Tanis, S. P., Head, D. B., Raggon, J. W. unpublished results;
g) Tanis, S. P., Herrinton, P. M., Dixon, L. Tetrahedron Lett. 1985, g, 5347;
h) Tanis, S. P., Herrinton, P. M., McMills, M. L Org. Chem. 1985, _50, 5887;
i) Tanis, S. P., Chang, Y., Head, D. B. Tetrahedron Lett. 1985, _2_6, 6147;
j) Tanis, S. P., Dixon, L. D. Tetrahedron Lett. 1987, 2_8J 2495;
k) Tanis, S. P., Johnson G. M., McMills, M. Tetrahedron Lett. 1988, 22,
4521;

1) Tanis, S. P., Chuang, Y. C., Head, D. B., I. Org. Chem. 1988 5;, 4929.

2) a) Marshall, J. A., Ellison, R. H., I. Am. Chem. Soc. 1976, 28, 4312;

b) DeClercq, P., Vandewalle, M., I. Org. Chem. 1977, 42, 3447, Kok, P.,
DeClercq, P. and Vandewalle, M., Bull. Soc. Chem. Belg.1978, _8_Z, 615,
Kok, P., DeClercq, P. and Vandewalle, M., L%Chem., 1979, 4_4_, 4553,
Demuynck, P., DeClercq, P., and Vandewallw, M., M., 1979, g, 4863;

c) Grieco, P. A., Ohfune, Y., Majetich, G., I. Am. Chem Soc. 1977, _9_9, 7393,
Grieco, P. A., gt._a1.., I. Org. Chem. 1978, 4;, 4552, Grieco, P. A.,;talv
I. Am. Chem. Soc. 1978, mg, 5946, Grieco, P. A., Ohfune, Y., Majetich,
G., L Org. Chem. 1979, g 3092, Grieco, P. A., Ohfune, Y., Majetich, G.,
Tetrahedron Lett. 1979, 3265;

d) Landsbury, P. T., Serelis, A. K., Tetrahedron Lett. 1978, 1909, Landsbury,
P. T., Hangauer, D., _i_bi_c_l_., 1979, 3263, Landsbury, P. T., Hangauer, D., and
Vacca,1. Am. Chem. Soc. 1980, 102, 3964;

e) Semmelhack M. F., et._al_., I. Am. Chem. SQ. 1978, 100, 5565;

f) Wender, P. A., Eissenstadt, M. A., and Filosa, M. P., I. Am. Chem. Soc.
1979, 101, 2196

g) Roberts, M. R, Schlessinger R. H., i_bid, 1979, 101, 7626, Quallich, G. J.,
and Schlessinger, R. H., M., 1979, Q, 7627;

h) Zeigler, F. E., and Faug, J. M., J. Org. Chem. 1981, 46, 825.

3) a) Marshall, J. A., Snyder, W. R, J. Org. Chem. 1975, 4_0, 1656;

b) Kretchmer, R. A., and Thompson, W. S., I. Am. Chem. Soc. 1976, Q,
3379.

4) a) Heathcock, C. H., in "The Total Synthesis of Natural Products", Vol.
2, J. W. ApSimon ed., Wiley, New York, 1973, pp. 402-519.

5) Heathcock, C. H., Tice C. M., and Germoth, T. C., I. Am. Chem. Soc. 1982,
1_Q_4, 6081.

6) a) See, for example Johnson, W. S., Acc. Chem. Res. 1968, 1, 1, Johnson, W.
5., Biggrg. Chem. 1976, 8, 51, Johnson, W. 5., Dawson, M. I., Ratcliffe, B.
E. I. Org. Chem. 1977, 42, 153, Johnson, W. 5., McCarry, B. E., Markezich,
R., Boots, S. G., I. Am. Chem. Soc. 1980, 102., 352, Gravestock, M. B.,
Morton, D. R., Boots, 5. G., Johnson, W. 8., ibid, 1980, m2, 800, Johnson,
W. S., McCarry, B. E. Okorie, D. A., Parry, R. J., ibid., 1981, E8, 88, and

references cited therein;

b) Van Tamelen, E. E., Acc. Chem. Res. 1978, 8, 152, Van Tamelen, E. E.,
Marson, S. A., I. Am. Chem. Soc. 1975, 9_7, 5614, Van Tamelen, E. E.,
Laughead, D. G., L Am. Chem. Soc. 1980, .1_(_)__2_, 869;

c) Goldsmith, D. J., I. Am. Chem. $0 1962, 83, 3913, Goldsmith, D. J.,
Phillips, C. F., ma, 1969, 2L 5862;

d) Boeckman, R. K., Jr., Bruza, K. J., Heinrich, G. R., LAm. Chem. Soc.
1978, m0, 7101, Morgans, D. J., Jr., Sharpless, K. B., i_bi_d, 1981, 188, 462.

7) Roberts, J. D., et. al. I. Am. Chem. $9. 1972, _9_4_, 6026.

8) See Devon, T. K., Scott, A. I. "Handbook of Naturally Occurring
Compounds", Academic Press, New York, 1972, Vol. II.

 

 

9) a) Fischer, H. S., Olivier, E. J., Fischer, H. D. in "Forschritte der
Chemie Organischer N aturstoffe", Springer Verlag, New York, 1979,
Vol. 38, pp. 47-388.
b) Romo, J., Romo de Vivas, A., "Forschritte der Chemie Organischer
N aturstoffe", Springer Verlag, New York, 1963, Vol. 25, pp. 90-130.

c) Yoshioka, H., Mabry, T. J. , Timmerman, B. N. "Sesquiterpene Lactones",
Univ. of Tokyo Press, Tokyo, 1973.

10) a) For an excellent review see Evans, F. J., Soper, C. J. ngygia 1978,
51, 193;

b) Blumberg, P. M. Crit. Rec. Toxicol 1980, 153; _i_12i_d_., idem. 1981, 199;

c) Hecker, E., Schmidt, R. Progr. Chem. Org. Nat. Prod. 1974, 81_, 377;
d) Evans, F. J., Taylor, S. E. idem. 1983, £1.47 1.

e) Wender, P. A., Hilleman, C. L., Szymonitka Tetrahedron Lett. 1980, 2_1,
2205.

 

11) a) Mitchell, J. C. in "Recent Advances in Phytochemistry" Runeckles,
V. C. Ed., Plenum Press: New York, 1975, Vol. 9, pp. 119-139;
b) Blenmink, E., Mitchell, J. C., Geissman, T. A., Towers, G. H. N.
Qantact Dermatitjg 1976, 2, 81;
c) Arny, H. V. |. Pharm. 1890, 121; 1897, 169;
d) Herz, W., Watanabe, H. I. Am. Chem. $9 1959, 81_, 6088;
e) Herz, W., Watanabe, H., Miyazaki, M., Kishida,Y., ibid., 1962, 84, 2605;
f) Emerson, M. T., Caughlan, C. N., Herz, W. Tetrahedron Lett. 1966, 6151;

g) Rodriguez, E., Towers, G. H. N ., Mitchell, J. C. Phytoghemistgy 1976, 15,
1573.

h) Meisels, A., Weizmann, A. I. Am. Chem. Soc. 1953, E, 3865.

55

i) Stuart, K. L., Barret, M. Tetrahedron Lett. 1969 2399.

j) Kupchan, S. M., Eakin, M. A., Thomas, A. M. I. Med. Chem. 1971, 14,
1147.

k) Pettit, G. R., Herald, C. L., Gust, D., Herald, D.L., Vanell, L. D., |. Org.
Chem. 1978, 4_3, 1092.

l) Sanchez-Viesca, F., Romo, J. Tetrahedron 1963, Q, 1285.

m) Cook, C. E., Wichard, L. R, Turner, B., Wall, M. E., Egley, G. H., Science
1966, 1814, 1189.

n) Herz, W., Kumar, N ., Blount, J. F. I. Org. Chem. 1981, Q, 1356.
12) see reference 9a, pp. 190, and 236.

 

13) a) Romo, J. Pure Appl. Chem. 1970, 21, 123;
b) Bohlmann, F., Borbowski, H., Arndt, C. Chem. Ber. 1966, 99, 2828;
c) Edgar, M. T., Greene, A. E., Crabbe, P. J. Org. Chem. 1979, 44, 159;
d) Rigby, J. H., Wilson, J. A. L Am. Chem. Soc. 1984, 186, 847.
e) Sanchez-Viesca, F., Romo, J. Tetrahedron 1963, Q, 1285.

14) a) Ogura, M., Cordell, G., Fainsworth, N. R. Phytochem. 1978, 12, 957;

b) Devreese, A. A., DeClerq, P. J., Vandewalle, M. Tetrahedron Lett. 1980,
21, 4767.

15) a) Suchy, M., Herout, V., Sorm, F. Coll. Czech. Commun. 1963, 28, 2257;

b) Doskotch, R. W., Hufford, C. D. |. Pharm. 8ci. 1969, g, 186;
c) Lee, K. H., et.al., Cancer Res. 1971, 81_, 1649;

d) For syntheses of 8, see Kretchmer, R. A., Thompson, W. J. I. Am. Chem.
fl. 1976, 98, 3379;

e) DeClercq, P., Vandewalle, M., J. Org. Chem. 1977, 4_2, 3447;
f) Grieco, P. A., Ohfune, Y., Majetich, G. I. Am. Chem. Soc. 1979, _9_9, 7393;
g) Quallich, G. J., Schlessinger, R. H. I. Am. Chem. $9 1979, 181, 7627.

16) a) Abu-Shady, H., Soine, .T. D. L Am. Pharm. Assoc. 1953, 4_2, 387, 1m,
idem, 1954, 4_3, 365;
b) Arny, H. V. |. Pharm. 1890, 121, 1897, 169;

c) Emerson, M. T., Caughlan, C. N ., Herz, W. Tetrahedron Lett. 1966, 6151;
d) For a synthesis of 9, see reference 15f.

17) a) Arny, H. V. | Pharm. 1890, 121, 1897, 169;
b) Herz, W. Watanabe, H. I. Am. Chem. Soc 1959, 81, 6088;
c) Herz, W. Watanabe, H., Miyazaki, M., Kishida, Y. M 1962, 84;, 2605;
d) Emerson, M. T., Caughlan, C. N ., Herz, W. Tetrahedron Lett. 1966, 6151 ;

e) Rodriguez, E., Towers, G. H. N ., Mitchell, J. C. Phytochemistry 1976, 1_5,
1573.

18) Johnson G. M. M. Science Thesis, Michigan State University, 1987.;
and presented in part at a) the 192nd National Meeting of the A.C.S.,
Anaheim, C.A., September 1986, ORGN 247, b) JUC Pharm. Sci. 1987,
Honolulu, Hawaii, December 1987,.M-U3-Y-13, c) 196th National A.C.S.
Symposium, Los Angles, CA,.September 1988,.ORGN-137; and also

 

 

56

reference 1k.

19) a) see reference 18 for in depth discussions and procedures, and also
b) Anderson, A. G., Kao L. G. |. Org. Chem. 1982, 17, 3590;
c) Keck, G. E., Webb, R. Tetrahedron Lett. 1979, 1185;
d) Keck, G. B, Webb, R., Yars, J. B. Tetrahedron 1981, a, 4007.
e) Lespieau, R., Bourguel M., "Organic Synthesis", Wiley and Sons, New
York, 1946, Vol. 1., 209.

20) a) Piers, E., Karunaratne V. Can. I. Chem. 1984, 6_2_, 629.
b) Ashley, E. C., Arnott, R. C. I. Org. Chem. 1968, L4, 1.

21) Brown, H. C. , Heim P., Yoon, N. M., I. Am. Chem. Soc. 1970, 92, 1637.

22) For an in depth discussion and experimental procedures for compounds
18b, 19b, 20a, and 20b, see Johnson G. M. M. Science Thesis, Michigan
State University, 1987.; and presented in part at the 192nd National

Meeting of the ACS, Anaheim, C.A., September 1986, ORGN 247; and also
reference 1k.

23) a) Sharpless, K. B., Palermo, R. E., Akashi K. I. Org. Chem. 1978, 4_3,
2063.

b) Schroeder, M. Chem Rev. 1980, w, 187

c) Van Rheenen, V., Kelley, R. C., Cha, D. Y., Tetrahedron Lett. 1976, _28,
1973.

d) Piers, E., Abeysekera B. F., Herbert, D. J., Suckling, I. D. Can. I. Chem.
1985, Q, 3418.

e) Pappo, R., Allen Jr., D. S., Lemieux, R U., Johnson, W. S. |. Org. Chem.
1956, 21, 478.

f) Danishefsky, S., Hirama, M., Gombatz, K., Harayama, T., Berman, E.,
Schuda, P. F. L Am. Chem. Soc. 1979, 1Q, 7020.

24) a) Fatiadi, A. J., Smthesis 1974, 229.
b) Bunton ,C. A., Shiner V. J., I. Chem. Soc.1960, 1953.
c) Dyhurst, G. "Periodate Oxidation of Diols and other Functional
Groups", Pergamon Press, New York, 1970.

25) a) Kishi ,Y., Smith-Palmer, T., Schmidt, G., N akata, T., Okigawa, M.,
Vranesic, B. LAm. Chem. Soc. 1978, 190, 2933.

b) Lemieux, R. U., Rudloff, E. V., Can. I. Chem. 1955, 88, 1701; ibid., idem.
1955, 1710., ibid., idem. 1955, 1714.

26) a) Sharpless, K. B., Carlson, H. J., Martin, V. S., Tsutomu, K. J. Org. Chem.
1981, 18, 3936.

b) Torii, 5., Tsutomu I. I. Org. Chem. 1985, E, 1822.
c) Danishefsky, S., DeNinno, M. J. Org Chem. 1986, 81, 2617.
d) Mosher, H. S., Williams, T. M., Halaska, R. C., Tian-Pa, Y.,

N achman, R. J., Talhouk, J. W., Weber, J. F. |. Org. Chem. 1986, 51, 2702.

 

27)

28)

29)
30)

57

a) Baily, P. S., "Ozonation in Organic Chemistry", Academia Press,
New York 1978.

b) Bauld, N. L., Thompson, J. A., Hudson, C. E., Baily, B. S. |. Am. Chem.
8_oc_. 1968, _9_0, 1822.

c) Lattimer, R. P., Gillies, C. W., Kuczkowski R. L. I. Am. Chem. Soc. 1974,
96, 348.

d) Pappas, J. J., Keaveney, E. O., Berger, M., Rush, R V. Tetrahedron Lett.

1966, 4273.

a) Hassall, C. H. Org. React. 1957, 9, 3;

b) Emmons, W. D., Lucas, G. B. I. Am. Chem. Sog. 1955, 22, 2287;

c) Suzuki, M., Takada, H., Noyori, R. J. Org. Chem. 1982, 4], 902;

d) McClure, J. D., Williams, P. H. I. Org. Chem. 1962, 22, 24;

e) Corey, E. J., Arnold, Z., Hutton, J. Tetrahedron Lett. 1970, 307;

f) Emmons, W. D., White, R. W. TetraLhedron, 1962, 12, 31;

g) Grieco, P. A., Yoloyama, Y., Gilman, S., Ohfune, Y. |. Chem. Soc.

Chem. Comm. 1977, 870;

h) Rastetter, W. H., Richard, T. J., Lewis, M. D. LOrg. Chem. 1978, 48, 3163;
i) Chambers, R. P., Clark, M. Tetrahedron Lett. 1970, 2741.

Rasmussen, J. K. Synthesis, 1977, 91; and references therein (104 - 107).
Vedej, E., Engler, D. A., Telchow, J. C. |. Qg. Chem. 1978, Q 188.

31) 3~(3-furyl) propanal is readily prepared as follows: Homer-Wadsworth

32)

33)
34)

35)

reaction between 3-furaldehyde and sodio-triethylphosphono acetate
provides ethyl-3-(3-furyl)acrylate (90%). Reduction with H2 and P-2 nickel
boride; Brown, C. A., Akuja, V. K. I. Org. Chem. 1973, 88, 2226; Bartok, M.,
Lakos-Lang, K., Bogatskaya, L. G., Kamalov, G. C., Bogot-skii, A. V. Dokl.

Akad. N auk. SSSR 1977, 2% 509; gave the 3'(3-furyl)acrylate (84%) which

was reduced (LAH) and oxidized (PCC) to give 3-(3-fury1)pr0panal (65 -
75%).

a) Piers, E., Grierson, G. R., Law, C. K., N agakura, I. Can. J. Chem. 1982
_6_(_), 210;
b) Shih, C., Swenton, J. S. |. Org. Chem. 1982, 4], 2825.

Chamberlin, A. R. Chung, J. Y. L. I. Am. Chem. Soc. 1983, 1_0§, 3653.

MMZ calculations were conducted on an IBM PC-XT using the MMPMI
program of Serena Software, Bloomington, Indiana.

a) Corey, E. J., Shulrnan, J. I. I. Org. Chem. 1970, 88, 777;

b) Meyers, A. 1., et. al., L Am. Chem. Soc. 1979, 1_01_, 7104;

c) Ho, T. L. 8mthesis Comm. 1972, 560;

d) Cristau, H. J., et. al., Syn. Comm. 1981, Q, 423;

e) Huurdeman, W. F. J., Wynberg, H. Tetrahedron Lett. 1971, 81, 3449;

58

f) Degani, I., Fochi, R., Regondi, V. Sm. Comm. 1981, 51;
g) Yonemitsu, O., et. a1., Tetrahedron Lett. 1987, 28, 4569;

h) Fetzion, M., Jurion, M. |. Chem. Soc. Chem. Comm. 1972, 382;

i) Oishi, T., Kamemoto, Ban, Y. Tetrahedron Lett. 1972, 11, 1085;

j) Stahl, I. Syn. Comm. 1981, 135;

k) Janout, V. and Regen, S. L. J. Org. Chem. 1982, 4], 2212;

l) Fujita, E. N agao, Y. Kaneko, K. Chem. Pharm. Bull. 1978, 28, 3743;
m) Oishi, T., et. a1., Tetrahedron Lett. 1974, 1, 11 ;

n) Morgans, D. J. Feigelson, G. B. I. Am. Chem. Soc. 1983, 1(15_, 1505;
0) Chang, H. L. W. Tgtrahedron Lett. 1972, 19, 1989;

p) Olah, G. A. Narang, S. C., Salem, G. F. 8yn. Comm. 1981, 657;

q) Cussans, N. J. Ley, S. V. 1. Chem. Soc. Perkin Trans. 1 1980, 1654.

 

 

36) Barton, D. H. R., McCombie, S. W. I. Chem. Soc. Perkin Trans. 1 1975, 1574.

37) a) McMurray, J. E., Isser, S. J. I. Am. Chem. Soc.1972, 21, 7132;
b) Wittig, G., Schoellkopf, U. Org. 83m. 1960, 419, 66;
c) Maerker, A. Qg. React. 1965, 14, 270;
(1) Ni, Z. J., and Luh, T. Y. L Org. Chem. 1988, _5_3, 2129;
e) Tabor, D. F., Amedio, J. C., Krishna, R. |. Org. Chem. 1988, Q, 2984
f) Becker, K. B. Tetrahedron 1980, E, 1717.

38) a) Lombardo, L., Tetrahedron Lett. 1978, 22, 2417.
b) Rigby, J. H., Senanayanke, C. I. Am. Chem. Soc. 1987, 199, 3147;

39) a) Peterson, D. J. I.Org. Chem. 1968, 88, 780;
b) Ager, D. J. Smthesis, 1984, 384;
c) Magnus, P., Cook, F. Chem. Comm. 1977, 513;
d) Magnus, P. AldrichimicaActa 1980, 1_3, 1980.

40) Grubbs, R. H. Cannizzo, L. F. J. Org. Chem. 1985, 2386.
41) Corey, E. J., Erickson, B. W. I. Org. Chem. 1971, 88, 3553.

42) a) Gonzalez A. G., et. a1. Tetrahedron 1988, g 4585;
b) Rigby, J. H. Wilson, J. Z. I. Am. Chem. Soc. 1984, mg, 8218.

43) Shultz, A. G., Motyka, L. A., Plummer, M. I. AM. Chem. Soc. 1986, 10_8,
1056, and references cited therein (21, 22); see also reference 1e.

 

44) Devreese, A. A., DeClercq, P. J., Vandewalle, M. Tetrahedron Lett. 1980,
_2_1, 4767.

45) a) Edgar, M. T., Greene, A. E., Crabbe, P. J. I. Org. Chem. 1978, 44;, 159;
b) Ando, M., Akahane, A., Yamoaka, H., Takase, K I. Org. Chem. 1982,
Q, 3909; .
c) reference 44.

46) a) Marx, J. N ., McGaughey, S. M. Tetrahedron 1972, 28, 3583;

59

b) Kaszonyi, A., Vojtko, J., Hrusovsky, M Coll Czech. Chem. Comm.

 

 

 

1982, 4_7, 2128;

c) Andrieux, J., Barton, D. H. R, Patin, H. L Chem. Soc. Perkin Trans. 1
1977, 359;

d) Hallman, P. S., McGarvey, B. R., Wilkinson, G. J. LChem. Soc. A 1968,
3143;

e) For prior examples see Kretchmer, R. A., Thompson, W. J. I. Am.
Chem. Soc. 1976, 98, 3379, Marshall, J. S., Ellison, R. H. I. Am. Chem.
EC.- 1978, 188, 4312, Wender, P. A., Eissenstadt, M. A., Filosa, M. P.,
I. Am. Chem. Soc. 1979, 101, 2196.

 

 

47) a) Schore, N ., et. a1., I. Org. Chem. 1987,82, 3595;
b) Kok, P., DeClercq, P., Vandewalle, Bull. Soc. Belg. 1978, 8_7, 615;
c) Heathcock, C. H., Del Mar, E. G., Graham, S. L. I. Am. Chem. Soc. 1982,
194, 1907;

d) DeClercq, P. Vandewalle, M. I. Org. Chem. 1977, _4_2, 3477.

48) Instrumentational considerations in conjunction with Steven P. Tanis
and Terry Scahill, The Upjohn Company.

49) DeClercq, P., Vandewalle, M. I. Org. Chem. 1977, 42, 3447.

50) Noyori R., Suzuki, M., Tsunoda, T. Tetrahedron Lett. 1980, 21, 1357.
51) Watson, 5. L., Eastham, J. F. I. Organomet. Chem. 1967, 9, 165.

52) Still, W. C., Mitra, A., Khan, M. I. Org. Chem. 1978, Q, 2923.

   

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