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FURANS IN SYNTHESIS; STUDIES DIRECTED TOWARD THE
SYNTHESIS OF GUAIANOLIDE, PSEUDOGUAIANOLIDE,
AND TIGLANE DITERPENE NATURAL PRODUCTS

presented by

MARK CHAD McMILLS

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Master of Science Chemistry

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FURAN S IN SYNTHESIS;
STUDIES DIRECTED TOWARD THE SYNTHESIS OF GUAIANOLIDE,
PSEUDOGUAIANOLIDE, AND TIGLANE DITERPENE
NATURAL PRODUCTS

By

Mark Chad McMills

A THESIS

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

MASTER OF SCIENCE

Department of Chemistry

1987

ABSTRACT

FURANS IN SYNTHESIS;
STUDIES DIRECTED TOWARD THE SYNTHESIS OF GUAIANOLIDE
PSEUDOGUAIANOLIDE, AND TIGLANE DITERPENE
NATURAL PRODUCTS

By

Mark Chad McMills

The construction of the bicyclo[5.3.0]decane skeleton is important as the
precursor to projected syntheses of the guaiane, pseudoguaiane, and tiglane
classes of natural products. These compounds are of interest because of their
broad spectrum of biological properties including cytotoxic, antineoplastic,
and antileukemic activity. Other important biological properties include
allergenic, antihelmenthic, contraceptive, molluscicidal, and
antiinflammatory activity. This thesis describes entries into the
bicyclo[5.3.0]decane system and approaches toward guaiane, and
pseudoguaiane sesquiterpenes as well as the tiglane diterpenes. Central to the
construction of these ring systems are the use of a suitably substituted furan
acting as a cationic cyclization terminator in an annulative process. Use of
the furyl moiety in cationic cyclizations will impart stereochemical and
regiochemical control in the synthesis of guaianolide, pseudoguaianolide,
and tiglane diterpene natural products. In addition, furan manipulation will
then readily afford the requisite butyrolactone residue or 1,4 dicarbonyl
system needed to complete this synthetic endeavor.

FOR CHAD WILLIAM AND MICHAEL MAN DERSON
YOU LEFT FAR TOO SOON

ACKNOWLEDGMENTS

The author would like to express his appreciation to Steven P. Tanis for his
creativity and hard work, but also for being more than a preceptor. Both his
tutelage and friendship made Michigan State more than just an education.
To Michigan State for support in the form of a teaching assistantship and
especially the National Institutes of Health for financial support of our
program(GM 33947). Thanks to Lisa, Bryon, and Paul, not only for their
chemical intuition, but especially for their friendship during the good and bad
times. To Tonya and Melinda for being good secretaries, and better friends.
To Michele and Greg for being home away from home. The author also
wishes to thank many of the faculty and staff, especially Dr. Reusch who
helped during a difficult situation(and had some great parties). A special note
for two who have left; to Jeff and Rick, MSU became much less weird without
you, unfortunatelyl! Finally to Lauren for making life complete in eVery'way
(and saying yes).

iii

TABLE OF CONTENTS

gig
LIST OF TABLES .................................................. v
LIST OF FIGURES ................................................. vi
LIST OF EQUATIONS ............................................. vii
LIST OF SCHEMES ................................................ ix
INTRODUCTION ................................................. 1
RESULTS AND DISCUSSION ...................................... 10
CONCLUSION .................................................... 27 -
EXPERIMENTAL .................................................. 30
LIST OF REFERENCES ............................................. 49

iv

Table 1

LIST OF TABLES

Effect of Silyl Ligands on Enolate Claisen ..........

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

Figure 8.
Figure 9.

Figure 10.
Figure 11.
Figure 12.

Figure 13.

LIST OF FIGURES

Guaianolides ....................................
Generalized Pseudoguaianolides ..................
Ambrosanolides .................................
Helenanolides ....................................
Tiglane Diterpenes ................................
Furan Oxidation States ............................
Generalized Cyclization Modes .....................
Retrosynthetic View ...............................
Tiglane Disconnection .............................
Retrosynthetic Disconnection .......................
Enolate Claisen Disconnection .....................
Enolate Claisen Stereochemistry ....................

Furan Enolate Claisen ..............................

vi

~ 5’
\ImOJOJNNNm

11

20

23

24

(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)

(11)

(12)
(13)
(14)
(15)

(16)

(17)

LIST OF EQUATIONS

Biosynthetic Formation .................
Biosynthetic Tiglane Diterpene Formation .....
Allylic Alcohol Cyclization ...............
Tertiary Carbocation Cyclization ............
Spiro Enone Cyclization .................
Bridged Enone Cyclization ................

Type A Cyclization ....................

Type C Cyclization .....................
Furan To Cyclohexenone .................
Initial Synthetic Effort ...................

Previous Synthesis of Bicyclo[5.3.0]Decane Ring
System ............................

Preparation of Cyclization Substrate 45 .........
Preparation of 3-(3-furyl)propanal 49 ..........
Preparation of Cyclization Precursors 41 and 42. . . .
Preparation of Cyclized Products 50 and 51 .......

Pseudoguaianolide 58 From N on-Methylated
Precursor ...........................

Preparation of Exo-Methylenated 38 ...........

vii

10

11

12

13

13

14

15

16

(18)
(19)
(20)
(21)
(22)
(23)
(24)
(25)
(26)

(27)

Preparation of Cyclization Precursor 65 .........
Preparation of Bromomethyl Furylacrylate 73 .....
Preparation of Tiglane Precursor 79.‘ ...........
Preparation of Methyl Furan Tiglane Precursor 81. . .
Proposed Tiglane Synthesis .................
Anticipated Type B Synthesis 88 ..............
Ester Enolate Claisen Precursor 90 .............
Preparation of Claisen Product 92 .............
Preparation of Furan Claisen Product 95 .........

Proposed Pseudoguaianolide Synthesis 99 ........

viii

17

19

21

21

23

24

26

Scheme 1.

Scheme 11.

Scheme Ill
Scheme IV.
Scheme V.

Scheme VI.

LIST OF SCHEMES

Type B Pseudoguaiane Differentiation ........

Retrosynthetic Routes Toward Type A
Compounds ...............................

Possible Enolization Routes .................
Synthetic Routes Toward 61 and 62 ..........
Synthetic Routes Toward 67 and 68. .........

Retrosynthetic Route To Tiglane Diterpenes. .

ix

12
15
17
18

19_

Introduction

The synthesis of the bicyclo[5.3.0]decane skeleton1 is a crucial aspect in the
construction of guaianolide2 , pseudoguaianolide3 , and tiglane diterpene4
classes of natural products. The broad spectrum of biological activities
exhibited by these materials and their scarcity in natural sources make facile
entry into these classes important for both testing and clinical application.
Potent biological properties include antitumor5 , cytotoxic6 , antineoplastic7 , ~
antileukemic8 , as well as allergenic9 , antihelmenthiclo, antifeedant11 ,
contraceptive12 , cocarcinogenic13 , molluscicidal14 and antiinflammatory
activity”. These guaianolide and pseudoguaianolide sesquiterpene lactones
are thought to be derived biosynthetically from farnesyl pyrophosphate l by a-
series of oxidations, cyclizations and rearrangements16 (eqn. 1), a possibility
which has previously been exploited for the preparation of severely
underfunctionalized bicyclo[5.3.0]decanes.

 

1 Guaiane‘ Pseudoguaiane

The guaianolides are represented by estafiatin17 2, gallardin133,
compressanolide19 4, and zaluzanin C20 5 (figure 1).These compounds
usually possess a cis ring fusion at C1-C5 and a butyrolactone moiety
appended at C6-C7 or C7-C8. The pseudoguaianolides are a large family of
sesquiterpene lactones produced by a rearrangement of the C14 methyl group
from C4 to C5 as in Equation 1. These have the generalized structure of A and
B(Figure2).

   

Figure 1. Guaianolides

Figure 2. Generalized Pseudoguaianolides

The ambrosanolides (structure A) exhibit the C15 methyl group in the B
orientation ; less abundant are the helenanolides (as in B) with an a oriented
C15 methyl group. The ambrosanolides are represented by damsin21 6,
parthenin22 7, confertin23 8, and rudmollin24 9 (Figure 3).

 

Figure 3. Ambrosanolides

The helenanolides (Figure 4) are highly oxidized and usually possess
intense biological activity. These are represented by aromatin25 10,
helenalin26 11, mexicanin-127 12 and fastigilin-C28 13. Potent cytotoxic and
antineoplastic

 

Figure 4. Helenanolides

activity have been associated with fastigilin C 13, one of the few compounds
in this class with functionality at each carbon of the cycloheptane - B ring.
Thus far, fastigilin C 13 has not yielded to total synthesis.

 

Figure 5. Tiglane Diterpenes

The tiglane diterpenes (Figure 5) represented by phorbol29 14, and its
derivative resiniferonol30 15, are thought to arise biosynthetically from a
geranyl geraniol derivative 16 to form Casbene 17 which further rearranges to
the tiglane skeleton31 (eqn. 2). Interest in this class of compounds is the
result of their potent co-carcinogenic properties exhibited by a number of
phorbol esters”. Wender33 has published the first elegant synthesis of the
[5.3.2.1] system, but a total synthesis of phorbol or its derivatives has not yet
been accomplished.

(2)

 

Tiglane

The majority of previous syntheses of guaiane and pseudoguaianes have
focused on the stereocontrolled construction of the 5,7 ring system, followed
by the addition of a butyrolactone moiety34 . In the case of the tiglanes,
Wender has reported the synthesis of a rigid 6,7 system, with a cyclopentyl
ring being appended in the final stages. An alternative strategy utilizing the
bicyclo[5.3.0]decane ring followed by a cyclohexyl annulation has not been
examined. Given the common structural elements possessed by these
systems, we will endeavor to develop the 5,7,6 system from a suitable
bicyclo[5.3.0]decane system possessing a 1,4 dicarbonyl moiety for eventual -
cyclohexane annulation. A protocol which might allow the preparation of
highly functionalized polycyclic systems, such as those mentioned above,
with complete control of stereochemistry might result from the cationic
cyclization of suitably functionalized furan derivatives. Our strategy is based
on the use of furans in various capacities during a synthesis.

The furyl moiety can be thought of as a precursor to a wide variety of
functional groups as is illustrated in Figure 6. Taken with the known and
demonstrated ability of the furan ring system to function as a cationic
cyclization terminator35 this oxidation cascade could allow the ready
construction of compounds 2-14.

 

 

(lo 0
O 0

Figure 6. Furan Oxidation States

Tanis and Herrinton36 have shown that furans can function as
terminators in a variety of reaction conditions with several different.
functionalities used as initiators (eqn. 3,4,5,6). These cyclizations have also
been studied using an epoxide initiator function. Furan terminated cationic
cyclizations have now resulted in the synthesis of fused-, spirocyclic-, and
bridged systems. Included among the relevant examples are the formal total
synthesis of (+)- and (-)- aphidicolin37 and (+/-)-nakafuran-933 .

 

HO 0 \ ° \
\
\ HCOOH (3)
Allylic Alcohol

 

 

 

61 - 68 %
0 o
I OH /
/ HCOOH /
: (4)
3° Carbocation
n n
56 %
/ O
HCOOH O
3 / . <5)
Enone
72 %
HCOOH
; ( 6)
Enone

   

Retrosynthetically, three different types of closures are necessary for the
synthesis of guaianolides, pseudoguaianolides and tiglane diterpenes (Figure
7). We designate these as Type A,B, and C. The Type A, B, and C closures will
terminate with a furyl anion equivalent; however the cyclopentane
introduction might be accomplished with either sense of polarity .

TYPE A

R a H I: Estaiiatin
R s H 3 Compressanolide =
R = CH3 3 Damsin

 

o /
TYPE B
R R R
n a 9 CH3 . Contertin +
R = A CH3 = Fastigiilin / 0 = w = db
+/.
TYPE c

o o O
Tiglane Diterpenes = fl :3 fl
R' R R' R +/ R'

Figure 7. Generalized Cyclization Modes

The Type A closure could require a vicinal cyclopentane dication
equivalent. We had previously investigated the use of a cyclopentenone
derived vinyl spiroepoxide as such dication equivalents. The potential
advantages of such an approach are regiochemical integrity and generality.
That is, the first C-C bond construction via an SN2' process (eqn. 7) generates
the second potential electron deficient center , thus guaranteeing
regiochemical integrity. The generality can be found in the use of this
chemistry for either guaianolide, or pseudoguaianolide construction by
simply using cyclopentenone, or 2-methylcyclopentenone for the spiro
epoxide synthesis”.

 

Type B closures require an addition to a cyclopentenone with either sense
of polarity, then closure occurring distal to the cyclopentanone. One possible
Type B closure is outlined in Scheme 1.

o o 9'
a
+ I on _ o
21 22 21

Scheme 1.

 

 

The Type C closure (eqn. 8) could afford a precursor to the tiglane
diterpenes. In this case, we will examine an alkylative addition of an intact
furyl acrylate 27 to give 28 followed by cationic closure to form the tiglane
skeleton. Herein, we view the furan as a six member ring surrogate;
providing the C ring after furan manipulation, one carbon homologation,
and closure to the corresponding cyclohexenone (eqn. 9).

 

002Et
6025! 0
0° 0 CO
’ O
o / o
0&3

Results and Discussion

Our analysis M igflg) has suggested that the guaianolides and
pseudoguaianolides which fall into the Type A closure can be constructed via
a furan terminated cationic cyclization in which the cyclopentane unit is
introduced as a dication equivalent. Of critical importance in such a system is
the regiochemical integrity of the carbon-carbon bond forming sequence.
Therefore, we anticipate generating the second electron deficient center as a
result of the chemistry employed in the initial carbon-carbon bond formation.
As illustrated in equation 10, SNZ' addition of 3-(3-furyl)propylmagnesium
bromide to 31 gave 32 (88%). Based on prior experience40 , we oxidized 32 to
aldehyde 32A (69%) which furnished cyclization substrate 33 after addition of -
methyllithium(91%). The 2° alcohol smoothly cyclizes in a two phase, formic
acid/ cyclohexane mixture, to give the prototype bicyclo[5.3.0]decane system 34
in 50-70% yield. A slight modification41 of the original procedure, adding
catalytic B-toluene sulfonic acid to the formic acid/cyclohexane mixture
increases the yields to 90%. We speculate that the initially formed formate
ester is rapidly protonated and ionized in the presence of a stronger Bronsted
acid, resulting in cyclization in shorter reaction times and less destruction of
the product tricycle. ‘

° 1) mc (89. 2%) ”°
32A B- one
CuBrS(Cng 2) emu (so 6%)

3.1. n met-1,004

 

Unfortunately nearly all attempts to cleave the exocyclic olefin resulted in
either no reaction or total destruction of starting material. We realized
success only in a rather lengthy sequence (eqn. 11 ) involving ketone enolate
hydroxylation, reduction to the corresponding vicinal diol and periodate

10

11

cleavage42 . The low yields obtained caused considerable concern and
prompted us to seek a shorter and higher yield alternative.

 

 

 

H O OH O 1) W57%
° RMgBr R 2) Thexyl some 50%
3) P00 sees
71% a (11)
a . rm 4) LDA. wow 72%
5) unease
R "Go“ "' 6) mac, 35%
3.5. 2!. 31

As an alternative, we sought a method that would not require a potentially
troublesome carbon-carbon single or double bond cleavage. Given the
requirement that we must carry the C-4 carbonyl into the sequence either
intact (protected) or in a reduced oxidation state (OH); we considered the
sequence outlined in Figure 8.

O o
O O
ot=>Ct3
/

Figure 8. Retrosynthetic View

 

Although "enolonium" ion43 equivalents are indeed known we did not
consider this sequence further because the mildness of the furyl nucleophile
is incompatible with the relatively unreactive enolonium ion equivalent of
Wender and Marino. An alternative which would afford a similar molecule,
without the necessity of employing a highly energetic a-keto cation is
presented in Scheme 2. The crucial bond construction, then cyclization, is
now to proceed via a cyclization initiator which is held entirely within the
forming seven member ring.

12

 

O
x \
O
42.
O O
X X
X = Ethylene Ketal = O— H
X a DIIthketal
OH O
3.9. 4.1. 4.1

Scheme 2.

In the forward direction, this was accomplished using 1,3-cyclopentanedione
as the cyclopentyl moiety and 3-(3-furyl)pr0panal as the remaining carbon
skeleton for the cycloheptyl portion of the bicyclo[5.3.0]decane system.
Bromination of 1,3 cyclopentanedione according to either Swenton44 or -
Piers44 (eqn. 11) gave 3-bromo-2-cyclopentenone 44 (56%), which was
protected as the corresponding ethylene dithioketal 45 (60.3 %)45 .

O
S t PBr3
wen on CH 0'3 o s/—\s
HS SH ( 12)
BF3 - ELZO
Br Br
Piers OaPBrz 5.5. 4'5-
Benzene
0

Vinyl bromide 45 will serve as the cyclopentenyl anion 43 depicted in Scheme
2. The requisite 3-(3-furyl)propanal is also readily prepared as described in
equation 13. The Homer-Emmons reaction between
sodio(triethyl)phosphonoacetate and 3-furaldehyde gives the ethyl-3-(3-
furyl)acrylate 46 (90%) which is smoothly reduced to the corresponding

13

propionate ester with Hz/NizB‘i6 to give 47 (84%). Reduction (LAH)
followed by oxidation (PCC) of the 1° alcohol furnishes 3-(3-furyl)propanal 49
(67%)

 

 

 

O
H Et020/\PO(OEI)2 \ coast 0025'
/ \ / \ __.[f\/
o (90%) o (84%) o
51 51 (13)

.. CFC” ("f/K
Zetep
(67%)

With these pieces in hand we turned our attention to the synthesis of the
cyclization substrate. Metal halogen exchange (nBuLi,-78°C) and reaction
with 3-(3-furyl)propana1 afforded the allylic alcohol 41 in an excellent 90%

 

 

purified yield (eqn. 14). then -
s, \1H[/\s O \ (\8
S 1)n-BuLi-78° P00 (14)
79.2%
)90.2%
HO
3.1.

exposed 41 to "standard cyclization" conditions (HCOOH,cyclohexane, RT, 1-5
min.)47 (eqn. 15). Using these standard conditions we obtained a less polar
material in excellent yield (85.5%). The 1H NMR spectrum of this material
contains two doublets at high field (6.14 and 7.27 ppm), typical for a 2,3
disubstituted furan. We had anticipated observing the olefinic proton
resonance of the trisubstituted double bond at ca. 5.00-6.00 ppm; instead we
saw a doublet of doublets centered at 4.08 ppm which we assigned as a
carbinol methine resonance. This led us to believe that we had not cyclized to
the linearly fused [5.3.0] system 39 but instead to a spiro fused [4.5.0] system 51
(eqn.15).

14

(15)

 

 

Support for this supposition was provided by the presence of an isolated AB
system (a to the dithioketal) at 2.73 and 2.31 ppm. Further confirmation for
the outcome was given by 13C N MR with multiplicity analysis. This
contained four singlets, three doublets and seven triplets, which corresponds .
to our proposed structure; also a hydroxyl band was found in the IR at 3650
cm'1 ‘

The facility with which the spiro closure occurs suggests that the C-0 bond
is likely to be poorly disposed with respect to the olefin-pi system for
protonation and ionization, and that instead the dithioketal is ruptured to
afford a sulfur stabilized allyl cation leading ultimately to 51. An alternative
which should exclusively activate the C-0 bond to cleavage was next
examined. Exposure of 41 to mesyl chloride and triethylamine according to
Chamberlin48 furnished the desired bicyclo[5.3.0]decane ring system 50 (92%)
with the double bond isomerized to the 1,5 position as confirmed by 1H- and
13C -NMR (eqn. 15). This was not the anticipated product; however, it may
serve the same purpose as the desired deconjugated olefin should we be able
to form the thermodynamic dienolate 54 and selectively alkylate at C-5
(Scheme 3) 56. The alternative dienolate 55 would strand the CC double
bond in a useless C-1;C-2 position.

15

   

Preliminary MM2“9 calculations performed upon the dienes
corresponding to the dienolates suggests that desired path to 56 is favored.
Despite the "favorable" outcome of the MM2 study we were concerned that
double bond placement in the actual system would be difficult to control.
This caused us to question our control of C-10 stereochemistry. Given those
doubts we elected to examine an enone initiated closure for the construction
of the seven membered ring. In such a system we envisioned C-10-
functionalization, followed by introduction of the C-5 methyl group via
alkylation of the thermodynamic enolate (eqn. 16).

(16)

 

We had previously examined enone initiated furan terminated
cyclizationsso and found this route to be a productive technique for the
construction of cyclic systems. Such a closure (equation 16) was believed to be
more promising than those previously attempted as it held the enone
initiator entirely within the forming cycle, thus reducing the degrees of
freedom. In the event, oxidation of alcohol 41 with PCC gave enone 42

16

(79.2%, eqn 14) which was exposed to 10 equivalents of BF3-OEt2 in CHZCIZ to

afford ketone 40 in 64% chromatographed yield. The ring fusion in equation
15, 40 is depicted as trans based upon the observation of a doublet at 3.66 ppm
with a coupling constant I= 8.5 Hz, in good accord with the literature51 range
of 8.5 to 10.5 Hz for trans fused ketones related to 40. The minor isomer shows
a doublet at 3.12 ppm with a coupling constant of approximately 13 Hz. This
assignment is also supported by MM2 calculations in which product 40 is
found to be more stable than its cis congener by ca. 2 kcal / mole. Conversion
of 40 to a methyl precursor 38 has been accomplished using Peterson
olefination52 technology (equation 17). Conversion of 38 to guaianolides and
pseudoguaianolides is currently being pursued; the results will be reported in
due course.

 

 

   

Having successfully constructed our first generation 10-des methyl
compounds, we next studied the cyclization of substrates bearing the requisite
10-methyl. Toward that end, addition of methyllithium to enone 42 gave the
tertiary alcohol 60(93%). This compound upon addition of formic acid
afforded not the expected bicyclo[5.3.0]decane, but gave instead the spirocyclic
3° alcohol 62 (Scheme 4). Again we attribute the isolation of the spirocyclic
material to the same factors described previously MSW. Application of
direct hydroxyl activation via exposure of 60 to mesyl chloride-triethylamine
led to the derivative bicyclo[5.3.0]decane system (Scheme 4) 61 (75 %), again
with the double bond isomerized to the 1,5 position.

17

I/\S o \
:fl MeCl EtaN 3‘.

(75%)

 

     

Scheme 4.

We have also examined the possibility of introduction of the
pseudoguaiane C-S methyl group prior to cyclization. In this case 2-
methylcyclopentanedione serves as the source of the 5-membered ring.
Careful bromination (eqn. 18) of 2-methylcyclopentanedione 63 affords the 3-
bromo enone 64 (80.6%) which gives thioketal 65 after exposure to.
ethanedithiol and BF3-OEt2 (72%)53 . Treatment with n-BuLi and reaction of
the resulting anion with 3-(3-fury1)propanal leads to the desired allylic

alcohol 66 (79.1%; Scheme 4).
BF: EgoH

Unfortunately our preliminary studies have indicated that neither acid
induced cyclization or mesyl chloride-triethylamine provided a
bicyclo[5.3.0]decane system (Scheme 5). These reaction conditions afforded a
spirocyclic analog 68 (77.3%) and an allylic chloride equivalent 67 (60.8%) of
the starting material respectively. Again allylic strain is the likely cause of the
lack of desired reactivity of this allylic alcohol.

 

 

l8

HCOOH (:8

«m» .0.
r-x r\.° ..
S S S
1) n- BuLl -78° 19.
air g M
MsCl EgN
5.5.

(61%)

 

Cl
Scheme 5. 51

In this section we have shown the ease of forming the bicyclo[5.3.0]decane
system, if a judicious choice of cyclization substrate is made. Provided the
deprotection of the enone initiated cyclization product 40 can be
accomplished, we can routinely synthesize gram quantities of advanced
intermediates. We anticipate converting this material to a number of the
simpler guaianolide and pseudoguaianolides such as damsin 6, zaluzanin 5,
estafiatin 2, and parthenin 8.

An Approach To the Synthesis of Tiglane Diterpenes
The tiglane diterpenes provide attractive targets for total chemical
synthesis and thus have attracted considerable interest“. We have
considered the possibility (Scheme 6) of constructing this basic tiglane
skeleton via furan terminated cationic cyclization followed by elaboration of
the trisubstituted furan containing product to the requisite six-membered D
ring. This approach is presented retrosynthetically in Scheme 6.

19

PHORBOL

 

In order to prepare the desired cyclization substrate we must synthesize the
operational equivalent of the depicted cyclopentenone anion and couple this
with a relatively complex furan containing bromomethacrylate 73. A model
bromomethacrylate was prepared in straightforward fashion as described in »
equation 19.

c E ‘ E:
j: 1)NAH ‘ m02t1m83 / \ C02 (19)
Etozc mica): 2) 3-iuraldehydefi o CH: 2) h?

o a:
(98%) (95%)
7.4. 7.3.

 

Horner-Emmons reaction of triethylphosphonopropionate with 3-
furaldehyde furnished 74 (98 %). Bromination was realized upon exposure of
74 to NBS, CC14, hv to give the unstable allylic bromide 73 (94.8 %). With 73
in hand, we examined its coupling with anion 76. Many attempts to alkylate
the ethylene ketal of 2-lithio-2-cyclopentenone5s were made to no avail.
After a number of attempts had failed, we examined the bromofuryl
methacrylate and found that it had reacted in the dark at -20° C. Tentatively
this product has been assigned as the cyclopentanoid 75 listed below.
Conversion of the bromide 73 to 75 was likely accomplished via a radical like
cyclization56 .

20

meagre:

15.

The difficulties encountered in this least motion approach caused us to
consider preparing 72 in two discreet steps. First, the addition of a propionate
equivalent; and second, an aldol type addition-dehydration. Our initial
question was the design of a propionate equivalent which could function
both as an electrophile and then as a nucleophile (Figure 9).

o \Ncoza 0 . +
Oi“ => O-*»°7’E‘*(‘f

’- O

0/

Figure 9. Tiglane Disconnection

A solution was suggested by the work of Semmelhack57 and Heathcock53 .
We considered employing triethyl-2-phosphonoacrylate 77 as the
electrophile/nucleophile in a one pot conjugate addition Homer-Emmons
sequence. Treatment of Smith's59 cyclopentenyl bromide 76 with n-BuLi
followed by CuI afforded the corresponding cuprate to which triethyl-Z-
phosphonoacrylate was added. After 2 hours at -78°C and 1 hour at 0°C, 3-

furaldehyde was added to give 78 (35%). Ketal hydrolysis and cyclization with
BF3-OEt2 in CH2C12 gave 79 in an excellent 64% yield for the two step process

(eqn. 20).

21

 

 

 

 

O o 1) n‘BUl-i "78° 0 o
B, 2) Cul «10° _ COzEt
3) COZEI PO(OEI)2
90(0151)2
7.6. 71 (2°)
1) H30* 94%
13.

2) BF, 0 ago 64%

 

Having demonstrated the utility of this protocol, we have extended the
methodology to include a methyl group on the furan prior to cyclization. A
similar process was followed with the exception of the exchange of 5-methyl-
3-furaldehyde for 3-furaldehyde and trimethyl-Z-phosphonoacrylate instead .
of the triethyl ester (eqn. 21).

o]
0
O
0
re
0
I
a
E
O
‘
O
I
0‘)
O

  

 

 

cozcn,
o 1) 14,0; 35.7%
90mm); 52 3% 2’ 3‘: ' 32° 65”"

 

After construction of the bicyclo[5.3.0]decane system we anticipate
concluding our efforts in the synthesis of resiniferonol 15 as outlined in
equation 22.

22

o H COZCHa
1)NaBH,
C ——
2) Protect
o /
CH3
(22)
11.

1) Kinetic Ketalization
3.3. 2
2) CH3OATMS

3) Deprotect

 

 

 

TYPE B Cyclization Toward Guaianolides
The final mode of cyclization to be investigated has been termed "Type B".
The Type B closure illustrated in Figure 10 should prove useful for the »
synthesis of confertin and fastigilin like pseudoguaianolides.

 

Figure 10. Retrosynthetic Disconnecb‘on

Our initial plan (eq 23) consisted of a Michael addition of the cuprate
prepared from 2-bromoacrolein to cyclopentenone 86 or 2-
methylcyclopentenone and subsequent aldol addition of 3-furaldehyde.
Marine60 has shown the utility of the anion of protected 2-bromoacrolein 87,
however, under no circumstance could we detect any Michael products. After
many attempts, this route was abandoned.

23

0 OH

O OH O
LiCu
+ on + H yawn
O 71* I)” _ .. m
0 firm

£5. 51 n

We then examined possible alternatives for the introduction of a
propionate or propionaldehyde equivalent. The placement of a double bond
at the 5,6 position, and the reduction of the Clo-15 olefin of 88 would render
this the product of an Ireland ester enolate Claisen reaction61 minus the C-6
hydoxyl moiety (Figure 11). Our first efforts were directed toward the
synthesis of a simple model system without the furan present.

0 \ o
o \ (\0 o’_\o o
5 ° ° 0 9' /\ H
0 => :5 +
10 (Lo 0
g on
156).),

Figure 11. Enolate Gideon Disconnection

The synthesis begins with the protected 2-Bromocyclopentenone 76 as
outlined in equation 24. Treatment of 76 with n-BuLi followed by
formaldehyde afforded alcohol 89 (70%) which led to propionate ester 90
(96%). With the Claisen precursor 90 in hand we studied the sigmatropic
rearrangement sequence leading to the a—methylene-cyclopentenone depicted
in equation 25. We found that the reaction proceeded to afford a 10:1
diastereomeric ratio with the stereochemistry anticipated to be as shown.

F‘\ m

e 1 -9 war
fi’ ' L. GAO). _°'_’K_/_. U‘o (24)
2) (CH0). Pyridine
70% 96% | o
11 19. 9.9.

24

O 0 0 O
O 1) LDA -78° 1430’
-——.
O 2) TBDMS Cl 0 74% O ( 25)
3) -78° - RT . OTBDMS OH
~90%
9.9. 9.1. n

This outcome can be accounted for by assuming the formation of the E-
enolateé2 (LDA no HMPA) and rearrangement of the ketene acetal via the
six membered Zimmerman-Traxler63 chair like transition state as

previously described by Ireland64 (Figure 12).
l/\o o
.._.. Q;
on
Ha
22

O I"

 

 

 

93' Figure 12. Enolate Claisen Stereochemistry

In a similar fashion we synthesized a compound with the furyl residue
present (eqn.26). The substitution of 3-furaldehyde for formaldehyde in the
initial organometallic capture gave alcohol 93 (89%) This alcohol was then
converted to the corresponding propionate ester and then subjected to the
Ireland conditions. This sequence provided not only the expected acid 95
(70%), but also a small amount of a second rearrangement product 96 which
results from an enolate Claisen rearrangement through the furyl residue55

(Figure 13).

25

 

   

 

 

 

 

 

 

 

o o o
1 n-BuU -78°
3' ) : OH 3k.
2) 3-Furaldehye Pyridine
89% 89%
IE 11 (26)
1) LDA -78° 0
2) TBDMS c1 / HMPA
; +
2.1 3) ~78° - Reflux H C \ O
4) H30* 3
70% 95/ 5 00211
2.6.
o
\ \
OTBDMS mo 0
cozii
Figure 13. Furan Enolate Claisen 25.

We then studied the effect of the Silyl function in the ketene acetal upon the

course of the rearrangement. Table 1 shows our results. It appears, from this
limited number of examples explored, that the use of t-BuMeZSiCl offers an

optimum ratio of desired to undesired rearrangement products.

26

Table 1. E1166! d Slyl Sibetiiuent

   

o
O
1) LDA -78°
————. o +
2) R,Sic1
3) 1130' 5 0H
CH,
22
B,Sic1 Yield 95196
t-Bulle, 69% 95:5
(Ila), 79% 75:25
(HM, 7395 20:80

Presently we are studying the synthesis of several complex compounds such

as fastigilin C from 95. A possible conversion of 95 to fastigilin is outlined in
equation 27.

 

  
 

   

1) "2 I "'28 1) NIBH‘
2) Base 2) Protect \
o” 3) CH9' 3) socr,/ LewisAcid °
2! (27)
1) Ketaiize
2) Deprotect 1) Deprotect
3) Oxidize 2) Hydride
4) 001.“. M
"BMW

 

Conclusions

We have shown through examples in this thesis, that furan is a versatile
synthon for varied reaction sequences ultimately leading to the
bicyclo[5.3.0]decane ring system. Various placements of furan, and differing
cyclization modes can lead ultimately to most members of the guaiane, ‘
pseudoguaiane, or tiglane classes of natural products. Work is continuing to
cleave the thioketal protecting group to reveal a nearly complete
pseudoguaiane like skeleton. Alkylation of the probable thermodynamic
enolate and subsequent unmasking of the of the furan should give us easy
access to compounds such as damsin and parthenin.

In the tiglane series we are now close to a phorbol like system. To
complete the construction of the 5,7,6 system, we must open the furan, _
homologate one carbon, and ring close to a six member ring. With the
cyclohexenone in place, we are set for addition of oxygen at C4, C9, and C14.
Conjugate addition 1,4 to the enone will provide the necessary methyl group
at C . Finally, addition of an isopropenyl anion to the remaining ketone of
the initial enone will give the final hydroxyl group.

Type C cyclization is the least well established mode of the three. We are
very close to a cyclized substrate, but have not closed to the cyclic compound
as yet. Of paramount importance will be finding conditions that will cyclize ,
but not destroy the furan terminator. The ester enolate Claisen will be used
for the synthesis of the unsubstituted compound deoxyfastigilin.
Unfortunately this method may not be practical for the synthesis of fastigilin
C. A new Michael variant by Mukaiyama may provide easy access to a
compound using a thioester as the initiator function. This compound would
also have the correct stereochemistry set at the ring fusion relative to the
pendant methyl function. This will leave us with an alcohol that can be
oxidized and reduced for the final stereocenter in fastigilin C. If these
possibilities fail we can modify the product of the ester enolate reaction for
the introduction of a hydroxyl group. These advances have made our

27

28

program in furan chemistry applicable to a great variety of synthetic targets
which complement current methodology.

EXPERIMENTAL SECTION

29

EXPERIMENTAL SECTION

General. Tetrahydrofuran (THF) and benzene were dried by distillation

under argon from sodium benzophenone ketyl; methylene chloride
(CHzClz), triethylamine, methanesulfonyl chloride (mesyl chloride),

pyridine, boron trifluoride etherate (BF3-OEt2), hexamethylphosphorus

triamide (HMPA), chlorotrimethylsilane (TMSCl), and diisopropylamine
were dried under argon by distillation from calcium hydride. Formic acid
(98%) was purchased from Fluka and used as received. All lithium reagents
were purchased from Aldrich Chemical used as a known molarity. Petroleum
ether refers to 35-60°C boiling point fraction of petroleum benzin. Diethyl
ether was purchased from Columbia Chemical and used as received. All .
other reagents were used as received unless otherwise stated; all reactions
were performed under argon with the rigid exclusion of moisture from all
reagents and glassware unless otherwise mentioned.

Melting points were determined on a Thomas-Hoover capillary melting
point apparatus and are uncorrected. Infrared spectra were recorded on a
Perkin-Elmer Model 167 spectrometer with polystyrene as standard. Proton
magnetic resonance spectra (1H NMR) were recorded on a Varian T-60 at 60
MHz, a Varian FT-80 at so MHz, a Bruker WM-250 spectrometer at 250 MHz,
or a Bruker WM-300 at 300 MHz as mentioned in deuteriochloroform or
deuteriobenzene. Chemical shifts are reported in parts per million (5 scale)
from residual proton resonance. Data are reported as follows: chemical shifts
(multiplicity: s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, a = apparent), coupling constant (Hz), integration. Electron
impact (El-MS, 70 ev) mass spectra were recorded on a Finnigan 4000 with an
INCOS 4021 data system. Gas chromatography was conducted on a Hewlett-
Packard 5880 system using a methyl silicone 30 meter column.

Flash column chromatography was performed according to the method of
Still et. al. 55 using Merck silica gel and eluted with solvents mentioned. The
column outer diameter (OD) is listed in millimeters.

3O

31

3-brommclopentenone 44.
To 1,3-cyclopentanedione (10.0g, 102.0 mmol) in CHC13 (150 mL) is added

phosphorus tribromide (19.38 mL, 204.1 mmol, 2.0 eq) in one portion. The

resulting suspension was refluxed for 19hr., cooled, cast into ice/ water (500
mL), extracted with CHC13 (100 mL), the organic phases combined, dried

(MgSO4), and concentrated. Chromatography of the residue on a column of

silica gel (150g, 230-400 mesh, 40mm OD, ether-hexane, 1:1, 25 mL fractions)
using the flash technique gave 44 (10.88g, 66.3%) as a low melting solid.
1H NMR (80 MHz, CDC13) 5= 6.42 (t, I=1.93 Hz, 1H), 3.10-2.90 (m, 2H), 2.65-

2.48 (m, 2H)

1-dithianyl-B-bromo-Z-cyclopentene 45.
To a round bottom flask is added bromoenone 44 (5.43g, 33.75 mmol),

ethanedithiol (3.68 mL, 43.87 mmol, 1.3eq), and 4A molecular sieves (10g). To .
this solution was added BF3~OEt2 (0.581 mL, 4.72 mmol) over 5 min., stirred

12 hr., quenched with sat'd. NH4C1 (30 mL), extracted with CHC13 (50 mL), the
organic phases combined, dried (MgSO4), and evaporated in vacuo. The

product was chromatographed on a column of silica (90g, 230-400 mesh,
30mm OD, ether-hexane, 1:1, 20 mL fractions) using the flash technique gave
45 (4.83g, 60.3%) as a fluffy white solid.

1H NMR (80 MHz, CDC13) 5- 5.95 (t, I= 1.96 Hz, 1H), 3.40 (s, 4H), 2.78-2.65 (m,
4H)

3- 3- l 2-eth la late .

To oil free N aH (11.52g, 0.48 mole,washed 3x with hexane) covered with
dry ether (1L) was added triethyl phosphonoacetate (87.4g, 0.48 mole) in
250mL ether was added dropwise over a 2 hr. period. Stirring was continued
for an additional 4 hrs.; then 3-(3-furyl)propanal (34.56 mL, 0.4 mole) in 100
mL ether was added dropwise over 1 hr. The reaction was stirred overnight,
quenched with brine(400 mL), the mixture was separated,the aqueous phase
extracted with hexane(500 mL), the combined phases were dried (N a2504),

32

for an additional 4 hrs.; then 3-(3-furyl)propanal (34.56 mL, 0.4 mole) in 100
mL ether was added dropwise over 1 hr. The reaction was stirred overnight,
quenched with brine(400 mL), the mixture was separated,the aqueous phase
extracted with hexane(500 mL), the combined phases were dried (N a2504),
and concentrated. Distillation of the residual liquid(88-90°C, 6mm) gave 70.86
(88.9%) of 46 as a water white liquid.

1H NMR (80 MHz, CDC13) 5- 7.63 (bs, 1H), 7.58 (d, I=15.8 Hz, 1H), 7.40 (m, 1H),
6.55 (bs, 1H) ,6.13 (d, I=15.8 Hz, 1H), 4.20 (q, I=7.2 Hz, 2H), 1.30 (t, #72 Hz, 3H)

3-(3-furyl)-3-ethylpropionate 47.
A Parr Hydrogenation bottle (500 mL) was charged with Ni(OAC)2.4H2O

(4.98g. 0.02 mole) and 95% ethanol(100 mL). To the mixture was added
N aBH4 in ethanol (20mL, 1.0M 4.0g N aBH4, 95 mL EtOH, 5 mL 2.0 M NaOH).
Evolution of Hz was complete within 1 hr., then 3-(3-furyl)ethylacrylate 46
(33.20g, 0.20 mole) in EtOH(50mL) was added in one portion. The mixture
was hydrogenated under 30 psi of H2, until uptake was complete (5 hr.). The .
catalyst was removed by filtration through a pad of celite, the filter cake
washed with EtOH(IOO mL), the filtrate diluted with brine(500 mL), extracted
with ether/hexane(500 mL,1:4), dried (NaZSO4), and concentrated to give 47 as
a colorless oil (31.56g, 93.9%) which was used without further purification.

1H NMR (80 MHz, CDC13) 6- 7.30 (t, #186 Hz, 1H), 7.20 (m, 1H), 6.23 (m,
1H), 4.10 (q, I=7.25 Hz, 1H), 3.00-2.15 (m, 4H), 1.,21 (t, I=7.25 Hz, 1H)

EI-MS (70eV) m/e= 169 (M++1, 30.02) 168 (M+, 59.84) 127 (12.17) 123 (23.69) 96
(10.38) 95 (100) 94 (32.29) 83 (17.38) 82 ( 12.02) 81 ( 55) 67 ( 27.84) 65 ( 19.31) 53 (
12.71)

Thioketal allylic alcohol 41.
To a solution of thioketal 45 ( 1.0g, 4.22 mole) in dry THF(15 mL) cooled

in a dry ice-acetone bath was added n-BuLi (2.81 mL, 6.75 mmol, 2.4 M)
dropwise over 15 min. The solution was stirred at -78°C for 1.5 hrs., then 3-(3-
furyl)propanal 49 (0.68g, 5.48 mmol) in THF(S mL) was cooled to -78°C and

added via cannula over 10 min. After 2 hrs. at -78°C the reaction was
quenched with sat'd. NaHCO3 (20 mL) , extracted with ether (3x15 mL), the

combined organics were dried (MgSO4), and evaporated in vacuo to yield a

33

yellow oil. The oil was purified by chromatography on a column of silica gel
(50g, 230-400' mesh, 30mm OD, 1:1, ether-hexane, 20 mL fractions) using the
flash technique to yield 1.07g (90.8%) 41 of a slightly yellow oil.

1H NMR (250 MHz, C6D6) 6- 7.12 (t, ]=1.66 Hz, 1H), 7.05 (m, 1H), 6.05 (m,
1H), 5.76 (d, I=1.77 Hz, 1H), 5.75 (d, I=1.77 Hz, 1H), 3.89 (bt, I=6.5 Hz, 1H), 2.85
(m, 2H), 2.55 (t, ]=6.6 Hz, 2H), 2.45-2.10 (m, 6H), 1.6-1.4 (m, 2H), 1.35 (bs, 1H)
13C NMR (62.95 MHz, C6D6) 6' 147.95, 142.96, 139.32, 130.61, 124.76, 111.26,
69.66, 45.48, 40.58, 35.72, 30.72 30.98, 29.90

EI-MS (70 eV) m/e= 283 (M++1,0.46),282 (M+, 7.81) 254 (1.01), 238 (19.62), 188
(13.31), 131 (44.73), 99 (32.39), 98 (14.93), 97 (12.85), 95 (21.49), 82 (21.16), 81 (100),
65 (16.76), 53 (33.46)

IR (neat) 3410, 2930, 2860, 1710, 1485, 1420, 1250, 1135, 1035, 995, 899, 720, 600
cm'1

Thioketal enone 42.
To a solution of FCC (0.57g, 2.66 mmol) and celite (10g) covered with .
CI-IzC12(70 mL) was added 41 (0.50g, 1.77 mmol) in CH2C12(10 mL) over 5 min.
After 2 hrs. an additional 1.5 eq. PCC (0.57g) was added in one portion. The
reaction was stirred for an additional 2 hrs.; then was filtered through a fritted
filter covered with a plug of celite and silica gel. The resulting water white
solution was concentrated and the residue chromatographed on a column of
silica gel(30g 230-400 mesh, 1:1 ether-hexane) using the flash technique to
yield 0.39g (79.2%) of the thioketal 42.
1H NMR (250 MHz, C6D6) 5- 7.09 (t, 1:1.7 Hz, 1H), 7.01 (m, 1H), 6.35 (at,
I=1.87 Hz, 1H), 6.02 (m, 1H), 2.78 (s, 4H), 2.7-2.3 (m, 8H)
13C NMR (62.9MHz, C6D5) 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
EI-MS (70eV) m/e= 281 (M++1), 1.79) 280 (M+, 21.87) 252(5.25) 221 (2.37) 220
(2.32) 219 (10.23) 187 (13.53) 186 (10.40) 185( 20.59) 157 (11.25) 130 (11.63) 125
(12.76) 97 (21.12) 95 (50.89) 81 (100, base) 67 (10.65) 65 (17.49) 61 (15.64) 53 (45.83)
IR (neat) 2920, 2850, 1720, 1665, 1600, 1500, 1370, 1275, 1185, 1022, 872, 785 cm"1

Cydgj’ allylic alcohol 3).

34

To allylic alcohol 41 (0.64g, 2.27 mmol) in CH2C12(40 mL) was added Et3N

(1.39 mL, 9.98 mol, 3 eq); followed by mesyl chloride (0.527 mL. 6.81 mmol, 4

eq) over 10 min. After 0.5 hr. the reaction was quenched with saturated
N H4Cl (10 ml). extracted with CH2C12 (4x20 mL), the organic phases were

combined, washed with brine (20 mL), dried (MgSO4) and concentrated to
yield an oil. The crude product was purified by chromatography on a column
of silica gel (15g , 230-400 mesh,20 mm OD 1:1 ether-hexane, 5 mL fractions)
using the flash technique gave 0.553g (92.2%) of 50 as a water white oil.

1H NMR (250 MHz, C6D6) 5- 7.09 (d, I=1.89 Hz, 1H), 5.99 (d, I=1.89 Hz, 1H),
2.65-1.98 (m, 10H), 1.73-1.35 (m, 4H)

13C NMR (62.9 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

EI-MS (70 eV) m/e= 266 (M++2, 15.44) 264 (M13100) 236 (19.05) 235 (13.30) 208
(61.08) 207 (69.95)

IR (neat) 2940, 2870, 1600, 1505, 1440, 1429, 1315, 1295, 1230, 1200, 1160, 1120,
1045, 920, 890, 860, 750 cm-1

Spiro_cyclized allylic alcohol 51.
To allylic alcohol 41 (0.114g, 0.404 mmol) in cyclohexane (5 mL) was added

formic acid (0.018g, 0.404 mmol, 98%) over 2 min. After 5 min. the reaction
was quenched with sat'd. NaHCOg, extracted with CH2C12 (10 mL), the

organic phases combined, dried (MgSO4), and concentrated. Chromatography

of the product on a column of silica gel (5g, 230-400 mesh, 10mm OD, ether-
hexane, 1:1, 2 mL fractions) gave 51 (0.098g, 85.5%) as an oil.

1H NMR (300 MHz, CDC13) 5-7.27 (d, I=1.87 Hz, 1H), 6.14 (d, I=1.87 Hz, 1H),
3.94 (dd, ]=6.60, 3.28 Hz, 1H), 3.36 (m, 4H), 2.63 (d, 1:14.68 Hz, 1H) 2.31 (d,
1:14.68 Hz, 1H), 2.61-2.18 (m, 6H) 2.08 (m, 4H)

13C NMR (75.47 MHz, CDC13) 5-154.36 (s), 141.47 (d), 114.31 (5), 109.97 (d),
74.33 (d), 70.48 (s), 53.91 (t), 48.37 (s), 4512 (t), 39.60 (t), 3951 (t), 3350 (t), 2807
(t), 18.08 (t)

EI-MS (70 ev) m/e= 282 (M+,68.89) 238 (21.41) 189 (34.60) 178 (15.63) 150 (54.17)
145 (18.66) 135 (14.11) 132 (54.02) 131 (100) 118 (49.17) 115 (31.56) 107 (25.34)

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

35

Cyclized eno'ne 40
To solution of enone 42 (0.212g, 0.714 mmol) in CH2C12(20 mL) was added

BF3-OEt2 (0.0439 mL, 0.357 mmol) over 2 min. After 2 hrs. the reaction was
complete by thin layer chromatography. The reaction was quenched with
sat'd. NH4C1(10 mL), extracted with CHzClz (3x10 mL), the organic phases
were combined, washed with brine(30 mL), dried (MgSO4) and concentrated.

Chromatography on a column of silica gel(12g, 230-400 mesh, 1:1 ether -
hexane 20mm OD, 2 mL fractions) using the flash technique gave 0.132g
(62.2%) of 40 as a clear oil.
1H NMR (250 MHz, C6D6) 5- 7.02 (d, I=1.8 Hz, 1H), 5.93 (d, I=1.8 Hz, 1H), 3.66
(bd, ]=8.5 Hz, 1H), 2.96-1.9 (m, 10H), 1.45-1.19 (m, 3H)
40 Cis isomer 1H NMR (250 MHz, C606) 5- 7.00 (d, J=1.94 Hz, 1H), 5.81 (d,
I=1.94 Hz, 1H), 3.12 (d, I=13.1 Hz, 1H)
13C NMR (62.9 MHz, C6D5) 5- 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
EI-MS (70 eV) m/e= 282 (M++2, 3.89( 281 (M++1, 6.17) 280(M+, 41.21) 252 (2.68) .
219 (3.22) 187 (10.47) 186 (9.93) 149 (49.26) 134 (12.48) 133 (16.91) 132 (26.04) 131
(100) 119 (48.72) 118 (33.29) 104 (35.97) 91 (51.28) 77 (3691)
IR (neat) 2920, 2849, 1695, 1498, 1430, 1330, 1260, 1190, 1150, 1055, 720, 600 cm'1
GC 42 retention time= 28.76 min.

40 trans retention time= 27.26 min.

40 cis retention time= 27.65 min.

Tertigy allylic alcohol 69,
To thioketal enone 42 (0.070g, 0.25 mmol) in THF (5 mL) cooled to -78°C

with a dry ice acetone bath, was added methyllithium (0.25 mL, 0.35 mmol,

1.4M, 1.4 eq) over 2 min., the solution stirred for 45 min., warmed to 0°C,
quenched with sat'd. N aHC03 (5 mL), extracted with CH2C12 (20 mL), the

organic phases combined, dried(MgSO4), and concentrated. The resulting oil
was chromatographed on a column of silica gel (7g, 230-400 mesh, 10mm OD,
ether-hexane, 1:1, 5 mL fractions) using the flash technique to give 60 (0.069g,
93.2%) as an oil.

36

1H NMR (80 MHz, CDCl3) 5-735 (t, I= 1.91 Hz, 1H), 7.25 (m, 1H), 6.30 (bs,1H),

5.72 (t, I=1.36 Hz, 1H), 3.35 (s, 4H), 2.95-2.25 (m, 6H), 1.95-1.60 (m, 2H), 1.40 (s,
3H)

Cyclized tertig_ry alcohol 41.
To tertiary alcohol 60 (0.069g, 0.233 mmol) in CH2C12 (10 mL) was added

triethylamine (0.13 mL, 0.0932 mmol, 4 eq) and mesyl chloride (0.054 mL,

0.699 mmol, 3 eq). The reaction was stirred 2 hr., quenched with sat'd.
N aHCOg (10 mL), extracted with CH2C12 (20 mL), the organic phases

combined, dried (MgSO4), and concentrated. The residue was

chromatographed on a column of silica gel (6g, 230-400 mesh, 10mm OD,

ether-hexane, 1:1, 2 mL fractions) using the flash technique gave 61 (0.064g,

75%) as a water white oil.

1H NMR (250 MHz, CDC13) 5- 7.30 (d, I=1.91 Hz, 1H), 6.18 (d, I=1.91 Hz, 1H),

3.29-3.03 (m, 4H), 2.66-2.35 (m, 4H), 2.24-1.87 (m, 2H), 1.83-1.68 (m, 2H), 0.96 ((1,
=7.63 Hz, 3H)

Petersen intermediate 52.
To a flame dried round bottom flask was added ketone 40 (0.064g, 0.230

mmol) and THF(15 mL). Trimethylsilylmethyllithium (0.299 mL, 1.0 M, 1.3
eq.) was added over 10 min. at RT, the reaction was stirred for 2 hrs; then
quenched with sat. NH4C1. The aqueous portion was extracted with CH2C12

(10 mL) and ether (10 mL), the organic phases were combined, washed with
brine(15 mL) and dried (MgSO4). Concentration in vacuo furnished the
crude product as an oil, which was purified by chromatography on a column
of silica gel (5g, 230-400 mesh, 10 mm OD, ether-hexane, 1:1, 2 mL fractions)
using the flash technique to provide 0.085g (91.7%) of 59 as a colorless oil.

1H NMR (250 MHz, C6D6) 6- 7.00 (d, I=1.83 Hz, 1H), 5.93 (d, I=1.83 Hz, 1H),
3.75 (d, I=10.23 Hz, 1H), 2.90-2.56 (m, 7H), 2.49-1.92 (m, 4H), 1.82-1.67 (m, 1H),
1.58-1.42 (m, 1H), 0.13 (m, 9H)

50 cis compound 1H NMR (250MHz, C6D6) 5- 6.96 (d, I=1.94 Hz, 1H), 5.76 (d,
I=1.94 Hz, 1H), 3.16 (d, I=14.5 Hz, 1H)

IR (neat) 3460, 2958, 2930, 2885, 1508, 1443, 1425, 1250, 1160, 1060, 950, 900, 865,
845, 743, 695 cm-1

37

Olefination of gclized enone 38.
To a flame dried round bottom flask was added oil free KH (0.0236g, 0.206

mmol, washed 3x with hexane) covered with THF(S mL) and a solution of 59

(0.0379g, 0.103 mmol) in THF(2 mL) was added over 5 min. The reaction was
stirred at RT for 3hr, then carefully quenched with sat'd. NH4C1(5 mL). The

mixture was cast into CH2C12(10 mL), the organic phase was washed with
brine(5 mL), dried (MgSO4), and evaporated in vacuo. The residue was

chromatographed on a column of silica gel (3g, 230-400 mesh, 5mm OD, ether-
hexane, 1:1, 1 mL fractions) using the flash technique to provide 38 (19.4 mg.,
67.8%) as a colorless oil.

1H NMR (250 MHz, C6D6) 5- 7.06 (d, I=1.82 Hz, 1H), 7.00 (d, I=1.82 Hz, 1H),
4.75 (m, 1H), 4.72 (m, 1H), 3.91 ((1, 1:10.45 Hz ,IH), 3.05-2.0 (m, 9H), 1.89-1.68
(m, 4H)

38 cis compound 1H NMR (250 MHz, C6D5) 7.00 (d, I=1.88 Hz, 1H), 5.90 (d,
I=1.88 Hz, 1H), 3.12 (d, 1:15.04 Hz, 1H) .
13C NMR (62.9 MHz, C6D5) 6- 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

EI-MS (70 eV) m/e= 280 (M++2, 2.26) 279 (M++1, 3.77) 278 (M+, 20.59) 252
(1.98) 251 (3.04) 250 (19.27) 185 (11.70) 160 (15.31) 133 (10.81) 132 (12.88) 131 (100)
118 (15.40) 115 ( 10.78) 104 (11.79) 91(16.16)

38 cis compound EI-MS(70 eV) m/e= 280 (M++2, 0.95) 279 (M++1, 1.49) 278
(M+, 8.42) 186 (7.66) 185 (53.67) 147 (12.68) 146 (100) 145 (10.75) 128 (4.21) 129
(288) 117 (11.6) 116 (3.06) 115 (9.77) 103 (4.78) 91 (9.09)

IR (neat) 2918, 2840, 1635, 1495, 1430, 1330, 1210, 1180, 1143, 1050, 720, 680 cm"1
GC 38 trans retention time = 17.90 min.

GC 38 cis retention time = 18.63 min.

Methyl gyclomntenyl allylic alcohol fi.
n-BuLi (0.324 mL, 2.4 M, 0.876 mmol, 1.1 eq) was added to bromoeneone 65

(0.200g, 0.797 mmol) in dry THF (10 mL) cooled to -78°C using a dry ice
acetone bath. After 1 hr. 3-(3-furyl)propanal (0.118g, 0.956 mmol) in THF (5

mL) cooled to -78°C was added over 5 min., stirred 2 hr., quenched with sat'd.
N aHCO3, extracted with ether (10 mL), the organic phases combined, dried

38

(MgSO4), and concentrated. Chromatography of the resultant oil on a

column of silica gel (15g, 230-400 mesh, 20mm OD, ether-hexane, 1:1, 5 mL
fractions) using the flash technique gave 66 (0.186g, 79.1%) as a water white
oil.

1H NMR (250 MHz, CDC13) 8- 7.38 (1, I=1.78 Hz, 1H), 7.25 (m, 1H), 6.29 (m,
1H), 4.46 (t, I=5.3 Hz, 1H), 3.32 (m, 4H), 2.84-2.68 (m, 3H), 2.58-2.26 (m, 3H), 2.04-
1.47 (m, 2H), 1.79 (t, I=0.87 Hz, 3H)

Chloride displacement of allylic alcohol 52.
To a round bottom flask was added methyl cyclopentene 66 (0.0195g, 0.0658
mmol) in CHzClz (2.5 mL), triethylamine (0.036 mL.0.263 mol, 4 eq), and

mesyl chloride (0.0153 mL, 0.197 mol, 3 eq) over 10 min. The reaction was
stirred for 36 hr., quenched with sat'd. NaHCO3, extracted with CH2C12 (10
mL), the organic phases combined, dried (MgSO4), and concentrated. The

residual oil was chromatographed on a column of silica gel (2.5g, 230-400
mesh, 5mm OD, ether-hexane, 1:1, 1mL fractions) using the flash technique to -
give 67 (0.0126g, 60.8%) as an oil.

1H NMR (250 MHz, CDC13) 5- 7.39 (t, I=1.8 Hz, 1H), 7.26 (bs, 1H), 6.29 (bs, 1H),
4.70 (t, 5.8 Hz, 1H), 3.32 (m, 4H), 2.48 (dt, #83, 1.05 Hz, 2H), 2.65-1.86 (m, 6H),
1.78 (t, I=0.96 Hz, 3H)

Methyl 2-dimethylphosphonoac_rylate 71.
To a round bottom flask is added trimethylphosphonoacetate (34.67g, 0.19

mol), paraformaldehyde (12.0g, 0.40 mol), pyrrolidine (20 draps, catalytic) with
methanol (600 mL). The solution was refluxed for 20 hr., cooled, evaporated
in vacuo, taken up in benzene (500 mL), p-toluenesulfonic acid added (0.10g,
catalytic), and refluxed with a Dean-Stark condenser. After 16 hr., the
solution was cooled, evaporated in vacuo, and the residue distilled (94-100°C,
1m) to give 77 (25.52g, 67.8%)as a slightly yellow liquid

1H NMR (250 MHz, C6D6) 5- 6.61 (dd, I=26.5, 1.23 Hz, 1H), 6.56 (m, 1H), 3.46
(s, 3H), 3.42 (s, 3H), 3.29 (s, 3H)

EI-MS (70 ev) m/e= 195 (M+,30.05) 163 (82.21) 162 (35.10) 136 (13.90) 135 (22.08)
134 (17.87) 133 (34.05) 109 (100) 105 (16.03) 93 (32.77) 79 (23.28) 54 (21.83) 47
(29.65)

39

IR (neat) 3005, 2958, 2855, 1727, 1442, 1399, 1303, 1260, 1190, 1167, 1140, 1038, 840
-1 -
cm

1-gyclopentenyl-2—3-(3-fugl) ethylaglate 78
To cyclopentenylbromide 76 (0.20g, 0.976 mmol) covered with THF(15 mL)

cooled to -78°C with a dry ice acetone bath was added n-BuLi (0.468mL, 2.5M,
1.3eq.) over a 5 min. period. After stirring 45 min. , Cul (0.009g, 5 mol %) was
added in one portion stirred for an additional 30 min., warmed to -40°C for 15
min., then recooled to -78°C with a dry ice acetone bath. Phosphonoacrylate
77 (0.23g, 0.976 mmol) in TI-IF(5 mL) was added, stirred 30 min. at -78°C,
warmed to 0°C and 3-(3-furyl)propanal (0.093g, 0.976 mmol) in THF(I mL)

was added over 10 min. After stirring for 1 hr. the reaction was quenched
with sat'd. NH4C1 (50 mL), extracted with ether (30 mL) the organic phases

combined, washed with brine(10 mL), dried (MgSO4), and concentrated.

Chromatography of the residue through a column of silica gel (15g, 230-400
mesh, 10mm OD, ether-hexane, 1:1, 2 mL fractions) using the flash technique
gave 78 (0.094g, 31.7%) as a clear oil.

1H NMR (250 MHz, CDC13) 5- 7.73 (bs, 1H), 7.61 (s, 1H), 7.41 (m,1H), 6.64 (m,
1H), 5.51 (at, I=2.20 Hz, 1H), 4.24 (q, i=7.2 Hz, 2H), 4.04-3.82 (m,4H),'3.26 (aq,
J=1.4 HZ, 2H), 2.65-1.95 (m, 4H), 1.31 (t, I=7.2 Hz, 3H)

EI-MS (20 eV) m/e=- 304(M+, 100) 275 (31.94) 260 (20.83) 259 (23.61) 231 (95.83)
223 (28.47) 215 (22.92) 214 (40.97) 213 (45.83) 203 (27.08) 186 (72.22) 185 (48.61) 149
(37.50) 125 (61.81) 115 (65.28) 91 (45.83) 81 (66.67) 55 (7014)

IR (neat) 3120, 2950, 1715, 1650, 1600, 1520, 1430, 1335, 1298, 1200, 1150, 1043,
1020, 935, 918, 803, 758 cm-1

2-gyclopgntenone—2-3—(3-fug lgthylagylate 28A
To furylacrylate 78 (0.085g, 0.279 mmol) in THF(S mL) was added 5% HCl
(10 drops), stirred 0.5 hr., quenched with sat‘d. NaHC03(5 drops), extracted

with CHZCL2(20 mL), the organic phases combined, dried (MgSO4), and
evaporated in vacuo . The oil recovered was chromatographed on a column
of silica gel (5g, 230-400 mesh, 10mm OD, ether-hexane, 1:1, 2 mL fractions)
using the flash technique to give 78A (0.065g, 90.2%) as a light yellow oil.

40

1H NMR (250 MHz, CDC13) 5- 7.64 (s,1H), 7.63 (s,1H), 7.41 (t, I=1.66 Hz, 1H),
7.20 (m,1H), 6.49 (m,1H), 4.24 (q, 1:7.1 Hz, 2H), 3.42 (d, I=2.40 Hz, 1H), 3.40 (d,
1:240 Hz, 1H), 2.68-2.36 (m,4H), 1.31 (t, J=7.1 Hz, 3H)

EI-MS (70 eV) m/e= 261 (M++1, 7.84) 260 (M+, 53.59) 215 (26.26) 214 (80.12) 187
(18.12) 186 (100) 185 (76.76) 155 (33.03) 148 (22.25) 127 (28.36) 115 (24.01) 109
(20.45) 99 (43.12) 91 (30.24) 81 (37.39) 77 (27.10) 57 (31.08) 55 (3796)

IR (neat) 3055, 2959, 2920, 1765, 1690, 1630, 1420, 1265, 1248, 1205,1122, 1020,
910, 735, 708, 616 cm-1

Cyclized enone ac_ry1ate 22.

To a flame dried round bottom flask was added cyclopentenone 78A
(0.0168g, 0.0646 mmol), covered with CH2C12(5 mL), and BF3-OEt2 (0.079 mL,

0.0646 mmol., 10 eq.) was added over 2 min. from a microliter syringe. The
reaction was stirred for 4 hr. , quenched with sat'd. NH4C1, extracted with
CH2C12(10 mL), the organic phases combined, washed with brine(20 mL),
dried (MgSO4), and concentrated. Chromatography of the residue on a _

column of silica gel (2g, 230-400 mesh, 5mm OD, ether-hexane, 1:1, 1mL
fractions) using the flash technique gave 79 (0.0108g, 64.3%) as a clear oil.

1H NMR (250 MHz, CDC13) 5- 7.44 (s, 1H), 7.38 (d, 1:192 Hz, 1H), 6.34 (d,
I=1.92 Hz, 1H), 4.28 (q) I=7.15 Hz, 1H), 3.57 (t, I=10.3 Hz, 1H), 2.95-2.45 (m,4H),
2.28-2.03 (m, 1H), 1.34 (t, I=7.15 Hz, 1H) ‘

EI-MS (70 eV) m/e= 261 (M++1,5.69) 260 (M+, 42.00) 231 (11.60) 215 (30.40) 214
(75.83) 203 (20.41) 187 (22.13) 186 (17.85) 185 (9.94) 175 (100) 159 (16.65) 158
(45.33) 131 (69.92) 130 (64.34) 115 (23.63) 102 (17.51) 91 (28.36) 81 (3.76) 77 (47.91)
55 (37.70)

IR (neat) 2930, 2920, 1740, 1703, 1635, 1610, 1570, 1422, 1258, 1203, 1178, 1125,
960, 803, 750 cm-1

1- do ten 1-2-3- 5-meth l-3-fu l 2-eth la late .

To a flame dried round bottom flask was added bromocyclopentene 76
(0.500g, 2.44 mmol), covered with THF(30 mL), cooled to -78°C with a dry ice
acetone bath, and n-BuLi (1.62 mL, 3.90 mmol, 2.4M) added over 10 min.
After 45 min. at -78°C, CuI (0.557g, 2.92 mmol, 1.2eq) was added in one
portion, stirred at -78°C for 30 min, warmed to -40°C for 15 min., and recooled

41

to -78°C. Phosphonoacrylate 77 (0.568g, 2.92 mmol, 1.2eq) in 5 mL TI-IF was
cooled in a dry ice acetone bath, added via cannula, stirred for an additional 2
hr., and warmed to 0°C. 5-Methyl-3-furfural (0.322g, 2.92 mmol, 1.2eq) in
THF(S mL) was cooled to -78°C added via cannula, stirred for 2 hr., quenched
with sat'd. N aHCO3, extracted with ether(30 mL), the organic phases
combined, washed with brine, and concentrated. Chromatography of the
residue on a column of silica gel (60g, 230-400 mesh, 30mm OD, ether-hexane,
1:1, 10 mL fractions) using the flash technique gave 80 (0.388g, 52.3%) as a light
yellow oil.

1H NMR (250 MHz, C6D6) 8- 7.86 (bs, 1H), 7.50 (bs, 1H), 6.28 (at, 1:103, 1H),
5.56 (m, 1H), 3.48 (s, 3H), 3.66-3.43 (m, 6H), 1.89 (d, I=1.03 Hz, 3H), 2.19-1.92 (m,
4H)

80 cis compound 1H NMR (250 MHz, C6D6) 5- 7.57 (bs, 1H), 6.39 (at, 1=1.05
Hz, 1H), 6.37 (bs, 1H), 5.75 (m, 1H), 3.40 (s, 3H), 1.92 (t, I=1.05 Hz, 3H)

13C NMR (62.95 MHZ, C6D6) 5= 157.57, 153.49, 144.02, 131.63, 131.47, 122.99,
107.26, 106.36, 65.30, 63.97, 51.67, 36.08, 34.39, 27.95, 26.39, 25.22, 24.14, 13.07
EI-MS (70 eV) m/e= 304 (M13058) 260 (5.35) 20002.12) 199 (8.95) 129 (9.75) 128 1
(8.67) 115 (12.35) 91 (14.59) 77 (15.91) 65 (15.94) 59 (12.19) 57 (11.31) 55 (23.71) 43
(100)

IR (neat) 3128, 2950, 2880, 1710, 1648, 1605, 1530, 1438, 1340, 1298, 1250, 1205,
1140, 1088, 1043, 1014, 950, 912, 810, 763 cm-1

80 CC retention time = 15.51 min.

Deprotection of oxoketal 80A.
To a solution of furyl cyc10pentene 80 (0.066g, 0.217 mmol) in THF(10 mL)

was added 5% HQ (10 drops). After 15 min. the reaction was quenched with
sat'd. NaHCO3 (2 mL), extracted with ether(10 mL), the organic phases

combined, dried (MgSO4), and concentrated. Chromatography of the residue
on a column of silica gel (5g, 230-400 mesh, 5mm OD, ether-hexane, 1:1, 1 mL
fractions) using the flash technique gave 80A (0.048g, 85.7%) as a mobile oil.
1H NMR ( 250 MHz, C6D6) 5- 7.70 (bs, 1H), 7.23 (bs, 1H), 6.81 (m, 1H), 6.08 (bs,
1H), 3.63 (d, I=2.44 Hz, 1H), 3.61 (d, 1:244 Hz, 1H), 3.47 (s, 3H), 1.84 (d, I=1.00
Hz, 3H), 2.05-1.68 (m, 4H)

80A cis compound 1H NMR (250 MHz, C5D6) 5- 7.59 (bs, 1H), 6.82 (m, 1H),
6.42 (bs, 1H), 6.35 (bs, 1H), 3.37 (s, 3H), 1.89 (d, I=1.66, 3H)

42

13C NMR ( 62.9 MHz, C606) 5- 207.62, 157.29, 154.08, 144.02, 131.46, 129.67,

127.32, 122.85, 107.76, 106.38, 51.63, 34.33, 26.32, 24.19, 13.05

EI-MS (70 eV) m/e= 261 (M++1, 2.11) 260 (M+, 15.41) 228 (7.42) 201 (5.75) 200
(25.72) 199 (19.44) 158 (9.23) 157 (10.46) 149 (23.51) 129 (13.49) 128 (12.95) 115 (
18.67) 91 (25.45) 77 ( 22.93 ) 65 (26.08) 55(23.15) 43 (100)

IR (neat) 3058, 2955, 2922, 1765, 1695, 1632, 1438, 1265, 1248, 1205, 1140, 1090,
918, 735, 700 cm-1

GC 80A cis retention time = 13.57 min.

GC 80A trans retention time = 13.75 min.

Cyclization of enone 81.
To a round bottom flask with furyl cyclopentenone 80A (0.048g, 0.1846
mmol) covered with CHzClz (10 mL) was added BF3-OEt2 (0.090 mL, 0.732

mmol, 3.96 eq.) via a microliter syringe. The reaction was stirred for 4 hrs.,
quenched with sat'd. NH4C1, extracted with CHzClz (20 mL), the organic
phases combined, washed with brine (20 mL), dried (MgSO4), and.

concentrated. The residual oil was chromatographed on a column of silica gel
(4g, 230-400 mesh, 5mm OD, ether-hexane, 1:1, 1 mL fractions) using the flash
technique to give 81 (0.032g, 66.7%) as a yellow oil.

1H NMR ( 250 MHz, C6D6) 8- 7.55 (bs, 1H) 5.55 (m, 1H), 3.91-3.62 (m, 1H), 3.49
(s, 3H), 3.48-3.20 (m, 1H), 3.10-2.68 (m, 2H), 2.24-1.53 (m, 4H), 1.90 (s, 3H)

81 cis compound 1H NMR (250 MHz, C6D6) 5- 7.58 (d, ]=2.98 Hz, 1H), 5.59
(m, 1H), 3.48 (s, 3H)

13C NMR (62.9 MHz, C6D6) 6'- 215.86, 167.43, 155.67, 151.43, 131.14, 129.31,
119.09, 108.18, 51.63, 49.45, 40.81, 34.63, 28.01, 25.75, 12.96

EI-MS (70 eV) m/e= 261 (M++1, 4.41) 260 (M+, 33.59), 229 (16.92) 228 (33.59) 217
(10.30) 203 (32.82) 201 (25.58) 200 (14.32) 190 (12.77) 189 (100) 175 (12.77) 173
(22.01) 172 (24.42) 159 (22.59) 158 (14.09) 157 (13.48) 145 (78.38) 144 (56.31) 143
(13.48) 131 (14.25) 129 (21.01) 128 (18.89) 127 (10.39) 115 (63.06) 102 (13.48) 91
(34.94) 77(21.36) 59 (21.20) 55 (22.94) 43 (95.75)

81 cis compound EI-MS (70 eV) m/e= 261 (M++1, 6.13) 260 (M+,47.37) 229
(17.74) 228 (26.77) 217 (11.99) 203 (36.94) 201 (36.13) 200 (15.00) 190 (12.85) 189
(100) 175 (11.88) 173 (23.87) 172 (23.55) 159 (27.85) 158 (15.59) 157 (13.33) 145
(76.45) 144 (52.10) 143 (13.28) 131 (16.02) 129 (23.17) 128 (20.43) 127 (9.89) 116
(15.16) 91 (37.85) 77 (27.10) 63 (20.59) 59 (23.44) 55 (20.57) 51 (51.72) 43 (99.89)

43

IR (neat) 2950, 2920, 1742, 1707, 1635, 1612, 1575, 1438, 1260, 1200, 1178, 1129,
953, 800, 758 “cm-1

Esterification of gyclomntene methanol 2]).
To a solution of cyclopentene methanol 89 (0.200g, 1.28 mmol) in CH2C12

(10 mL) was added pyridine (0.155 mL, 1.92 mmol, 1.5 eq.), cooled to 0°C, and
propionyl chloride (1.33 mL, 1.53 mmol, 1.2 eq.) added over 5 min. The
reaction was stirred 0.5 hr. at 0°C, quenched with sat'd. NaHCOg, extracted

with ether (25 mL), the organic phases combined, washed with brine (15 mL),
dried (MgSO4), and concentrated. Chromatography of the resulting oil on a
column of silica gel (25g, 230-400 mesh, 30mm OD, ether-petroleum ether, 1:1,
20 mL fractions) using the flash technique gave 90 (0.261 g,95.9%) as an oil.

1H NMR (80 MHz, CDC13) 5- 6.07 (m, 1H), 4.70 (d, I=1.8 Hz, 1H), 4.67 (d, I=1.8
Hz, 1H), 3.95 (s, 4H), 2.35 (q, ]=7.2 Hz, 2H), 2.55-1.95 (m, 4H), 1.17 (t, J=7.2 Hz,
3H) ,

EI-MS (70 eV) m/e= 212 (M+, 3.37) 169 (1.02) 156 (9.08) 155 (50.06) 139 (77.12) ~
138 (30.66) 125 (14.69) 11 (12.22) 95 (21.72) 94 (10.19) 86 (9.15) 79 (11.73) 67 (45.44)
66 (22.00) 65 (10.75) 57 (100)

IR (neat) 2930, 2900, 1735, 1615, 1250, 1190, 1030, 960, 840 cm-1

Ester enolate Claisen 21.
To a solution of LDA (n-BuLi, 2.5mL, 2.45 M, 1.3 eq., diisopropylamine,

0.859 mL, 6.13 mmol, 1.3 eq.) in THF (40 mL) cooled to -78°C with a dry ice
acetone bath was added cyclopentenyl ester 90 (1.0g, 4.72mmol) in THF (10
mL) over 5 min. After 1 hr., TBDMS chloride (0.924g, 6.13 mmol) and HMPA
(1.067 mL, 6.13 mmol) in THF (10 mL) were added over 10 min. stirred at -

78°C for 1 hr., warmed to RT for 2 hrs., refluxed for 15 min., quenched with
sat'd. NH4C1, extracted with CHzClz (60 mL), the organic phases combined,

washed with brine (50 mL), dried (MgSO4) and concentrated. The oil was
purified on a silica gel column (75g, 230-400 mesh, 30mm OD, ethyl acetate, 15
mL fractions) using the flash technique to give 91 (0.586g, 73.9%) as a water
white oil.

44

1H NMR (250 MHz, CDCl3) 6‘ 5.28 (d, I=2.2 Hz, 1H), 4.99 (d, I=2.2 Hz, 1H), 3.94
(m, 4H), 2.52'(m, 1H), 1.98-1.44 (m, 5H), 1.16 (d, ]=6.8 Hz, 3H), 0.91 (s, 9H), 0.26
(s, 6H) .

EI-MS (70 eV) m/e= 326 (M+, 0.55) 301 (0.63) 269 (1.98) 233 (4.90) 225 (7.87) 179
(9.58) 170 (7.93) 169 (57.22) 147 (25.47) 139 (59.20) 135 (26.72) 111 (11.36) 99 (13.43)
95 (12.54) 92 (10.48) 77 (11.74) 75 (94.53) 74 (10.01) 73 (10.01) 73 (100) 67 (23.84) 66
(10.86) 57 (43.36)

IR (neat) 2965, 2920, 1655, 1415, 1308, 1257, 1221, 1142, 1030, 920, 880, 656 crn-I

Hydrolysis of Claisen product 22,

To the aqueous phase retained from above was added 5% N aOH until
basic. The solution was extracted with CHzClz (50 mL) and ethyl acetate (30

mL), the organic phases combined, and 5% HCl was added until acidic. The
combined organic solution was stirred for 3.5 hr., extracted with CH2C12 (20

mL), ethyl acetate (20 mL), the organic phase washed with brine (20 mL), dried
(MgSO4), and concentrated. .
1H NMR (250 MHz, CDC13) 5- 6.17 (d, I=1.95 Hz, 1H), 5.39 (d, 1=1.95 Hz, 1H),
3.10 (m, 1H), 2.76 (m, 1H), 2.55-1.71 (m, 4H), 1.26 (d, I=6.5 Hz, 3H)

EI—MS (70 eV) m/e= 169 (M++1, 14.75) 168 (M+, 2.40) 140 (5.54) 119 (8.33) 111
(22.70) 96 (16.11) 95 (20.32) 83 (8.83) 77 (10.94) 75 (100) 73 (19.43) 67 (31.38) 57 (
44.98)

IR (neat) 3012, 2945, 1710, 1655, 1520, 1420, 1300, 1218, 1034, 961, 882,645 cm'1
GC 92 syn retention time = 7.03 min.

GC 92 anti retention time = 7.57 min.

3- 3- 1 do ntene methanol

To a flame dried round bottom flask with bromocyclopentene 70 (1.00g,
4.88 mmol) in dry THF (50 mL) cooled to -78°C with a dry ice acetone bath,
was added n-BuLi (2.78 mL, 6.83 mmol, 2.45 M, 1.4 eq.) over 10 min, stirred
for 2 hrs., TMEDA (1.03mL, 6.83 mmol, 1.4 eq.) added, stirred for 2 hrs., and 3-
furaldehyde (0.655g, 6.83 mmol) in THF (5 mL) was added over 10 min. The
solution was stirred 2 hrs., warmed to 0°C, quenched with sat'd. NH4C1,

extracted with ether (50 mL), the organic phases combined, washed with brine
(50 mL), dried (MgSO4), and evaporated in vacuo . Chromatography of the

45

resulting oil on a column of silica gel (75g, 230-400 mesh, 30mm OD, ether-
hexane, 1:1, 20 mL fractions) using the flash technique gave 93 (0.963g, 88.9%)
as an oil.

1H NMR (80 MHz, CDC13) 5- 7.45 (m, 1H), 7.40 (t, I=1.36 Hz, 1H), 6.40 (m, 1H),
5.40 (m, 1H), 4.62 (d, I=8.6 Hz, 1H), 4.05 (m, 4H), 2.50-1.95 (m, 4H)

EI-MS (70 eV) m/e= 222 (M+, 19.12) 194 (11.87) 193 (68.78) 1769 (17.74) 178
(76.38) 177 (26.73) 163 (21.08) 161 (31.34) 149 (25.35) 121 (28.92) 111 (41.82) 109
(47.23) 107 (31.80) 105 (24.88) 97 (29.15) 95 (95.16) 91 (39.40) 87 (22.12) 83 (80.88)
82 (32.83) 81 (100) 79 (38.36) 77 (39.17) 69 (43.89) 55 (76.73)

IR (neat) 3630, 2993, 2903, 1622, 1501, 1422, 1382, 1304, 1120, 1030, 940, 880,723,
660 cm-1

Esterification of gyclogntene methanol 24.

Pyridine (3.43 mL, 34.0 mmol) and DMAP (10 mg., catalytic) were added to
furylcyclopentenyl methanol 93 (6.29g, 28.33 mmol) in CH2C12 (100 mL),
cooled to 0°C, and propionyl chloride (2.95 mL, 34.00 mmol) was added over 5 .

min. The solution was stirred for 0.5 hr., cooling removed, stirred an
additional 0.5 hr., quenched with sat'd. NaHCO3, extracted with CHzClz (35

mL), washed with water (20 ml), brine (20 mL), dried (MgSO4), and

concentrated. Chromatography of the resulting oil on a column of silica gel
(200g, 230-400 mesh, 60mm OD, ether-petroleum ether, 1:1, 50 mL fractions)
using the flash technique gave 94 (7.03g, 89.2%) as a water white liquid.

1H NMR (80 MHz, CDC13) 5- 7.43 (m, 1H), 7.37 (t, 1:120 Hz, 1H), 6.49 (bs, 1H),
6.42 (m,, 1H), 6.12 (m, 1H), 3.90 (bs, 4H), 2.65-1.95 (m, 6H), 1.15 (t, I=6.5 Hz, 3H),
EI-MS (70 eV) m/e= 278 (M+, 3.59) 205 (16.16) 177 ( 10.00) 161 (9.16) 136 (27.21)
109 (31.55) 105 (14.43) 103 (10.51) 101 (37.29) 99 (13.16) 95 (14.65) 91 (15.95) 87
(11.71) 86 ( 14.75) 81 (13.96) 79 (14.33) 77 (22.5) 66 (12.29) 65 (19.67) 57 (100)

IR (neat) 2952, 1730, 1612, 1510, 1426, 1250, 1190, 1030, 933, 880, 773, 621 cm-1

Ester enolate Claisen 25.
To LDA (n-BuLi, 1.92 mL, 2.43 M, 4.67mmol, 1.3 eq., diisopropylamine,

0.655 mL, 4.67 mmol, 1.3 eq.) in THF (50 mL) cooled to - 8°C in a dry ice
acetone bath was added furylcyclopentenyl ester 94 (1.00g, 3.597 mmol) over 5
min. After stirring 45 min. at -78°C TBDMS Cl (0.704g, 4.67 mol, 1.3 eq.) and

46

HMPA (0.813mL, 4.67 mmol) in THF (5 mL) were added over 10 min., stirred

for 2 hrs., warmed to RT, then refluxed 4 hrs. The reaction was quenched
with sat'd. NH4Cl, 5% NaOH (until basic) was added to the aqueous phase,

extracted with CH2C12 (65 mL), the organic phases combined, stirred with 5%
HQ (until acidic) for 3 hrs., extracted with CHzClz (50 mL), ethyl acetate (30
mL), dried (Mg 504), and concentrated. Chromatography of the residue on a

column of silica gel (65g, 230-400 mesh, 20mm OD, ethyl acetate, 15 mL
fractions) using the flash technique gave 95 (0.588g, 69.8%) as a mobile oil.

1H NMR (250 MHz, CDC13) 5- 8.43 (bs, 1H), 7.41 (t, 1:1.2 Hz, 1H), 6.92 (m, 1H),
6.52 (m, 1H), 3.16 (m, 1H), 2.87-1.65 (m, 5H), 1.27 (d, I=6.8 Hz, 3H)

EI-MS (70 eV) m/e= 235 (M++1, 2.43) 234 (M+, 20.11) 205 (6.01) 189 ( 4.08) 162
(6.93) 161 ( 73.56) 160 (7.14) 150 (7.74) 149 (100) 119 (9.07) 115 (6.58) 112 (6.68) 111
(14.94) 105 (23.77) 104 (8.72) 103 (10.41) 97 (8.79) 91 (13.54) 83 (16.39) 81 (32.24) 79
(11.71) 77 (18.53) .

IR (neat) 3008, 2967, 1735, 1670, 1618, 1500, 1422, 1304, 1248, 1130, 1041, 920, 880,
730, 661 cm-1

Command 29. .
1H NMR (250 MHz, CDC13) 7.33 (d, I=1.6 Hz, 1H) 7.29 (m, 1H) 6.22 (d, I=1.6 Hz,

1H) 3.96 (d, 1:2.34, 1H) 3.94 (d, 1:234, 1H) 3.26 (m, 2H) 2.8-2.29 (m, 4H), 1.53 (d,
1:7.06, 3H)

MS (EI, 70 eV) m/e 234 (M+, 25.10) 233 (25.03) 188 (6.46) 162 (9.68) 161 (100) 159
(7.46) 149 (12.05) 147 (11.90) 145 (11.93) 133 (10.35) 131 (15.56) 119 (12.84) 115
(15.17) 105 (30.27) 103 (15.60) 95 (20.01) 91 (27.34) 79 (20.87) 78 (10.12) 77 (31.75)
75 (27.79) 73 (41.39) 55 (36.71)

2-3- 3- l-1-meth leth la late

NaH (5.00g, 50%, 104.2 mmol, washed 3X with hexane) was coated with 150
mL of dry benzene. Ethyl methyl phosphonoacetate (24.79g, 104.2 mmol) was
added over a 20 min. period. Copious foaming occurred with H2 evolution.
After stirring 1 hr., 3-furylaldehyde (10.0g, 104.17 mmol) was added, the

solution was warmed gently with a heat gun, and stirred 1.5 hr. more. The
reaction was carefully quenched with sat'd. NH4C1, extracted with ether (150

mL), the organic phases combined, washed with brine (50 mL), dried (MgSO4),
and evaporated in vacuo. Purification of the product on a column of silica gel

47

(120g, 230-400 mesh, 40mm OD, petroleum ether-ether, 5:1, 50 mL fractions)
using the flash technique gave 74 (18.00g, 96%) as a water white liquid.

1H NMR (250MHz, CDC13) 5- 7.58 (bs, 1H), 7.18 (bs, 1H), 7.00 (t, 1:1.86 Hz,
1H), 6.20 (m, 1H), 4.07 (q, I=6.86 Hz, 2H), 1.97 (d, I=1.3 Hz, 3H), 1.03 (t, J=6.86 Hz,
3H)

EI-MS (70 ev) m/e= 182(M++2, 44.69) 181 (M++1, 100) 180 (M+, 56.72) 149
(13.19) 135 (52.62) 124 (10.65) 95 (12.70) 84 (17.64) 79 (12.84) 76 (35.62) 75 (94.09)
74 (17.64) 73 (85.48) 59 (76.08)

2-3- 3- l -1-bromometh l eth la late

To a round bottom flask was added furyl ethyl acrylate 74 (18.00g, 100.0
mmol), NBS (17.99g, 100.0 mmol), benzoyl peroxide (0.09g, catalytic), and
carbon tetrachloride (400 mL). The solution was heated to reflux under argon,
and a GE lamp (250 watt) was shown on the reaction flask. The reaction was
stirred 4 hr., cooled, filtered through florisil, and concentrated.
Chromatography of the product on a column of silica gel (250g, 230-400 mesh,
60mm OD, petroleum ether-ether, 5:1, 30 mL fractions) using the flash
technique gave 73 (24.54g, 94.8%) as a light brown oil.
1H NMR (250MHz, CDC13) 5- 7.52 (bs, 1H), 7.28 (bs, 1H), 6.94 (bs, 1H), 6.39 (bs,
1H), 4.22 (s, 2H), 4.03 (q, I=6.90 Hz, 2H), 0.96 (t, I=6.90 Hz, 3H)
EI-MS (70 ev) m/e= 261 (M++2, 2.24) 260 (M++1, 7.27) 259 (M+, 6.68) 258 (7.18)
180 (12.72) 179 (100) 151 (10.65) 107 (10.93) 106 (13.15) 105 (17.78) 79 (39.01) 78
(30.83) 77 (35.70)

Cyclization of bromofu_ryl agylate 75.
Bromofuryl acrylate 73 (2.0g, 7.92 mmol) was placed in a -20°C freezer, after

two weeks the product was chromatographed on a column of silica gel (40g,
230-400 mesh, 20mm OD, petroleum ether-ether, 5:1, 25 mL fractions) to give
75 (1.1g, 80%) as a mobile oil.

1H NMR (80 MHz, CDC13) 5- 7.55 (d, 1:2.5 Hz, 1H), 7.50 (bs, 1H), 6.95 (d,1: 2.5
Hz, 1H), 4.40 (s, 2H), 4.30 (q, I= 6.1 Hz, 2H), 1.39 (t, I=6.1 Hz, 3H)

EI-MS (70 ev) m/e= 131 (2.05) 120 (2.86) 119 (4.77) 117 (9.70) 116 (5.50) 107 (4.89)
105 (3.55) 99 (3.23) 92 (12.71) 91 (45.72) 89 (8.83) 85 (41.78) 84 (34.76) 83 (13.08) 74

48

(95.03) 73 (61.99) 61 (55.22) 60 (13.96) 56 20.33) 55 (70.29) 53 (22.47) 45 (28.08) 44
(57.45) 43 (100)

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52

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See Ref. 29.
See Ref. 4 a,b,c.

32.

33.

35.

36.

37.

38.
39.

40.

41.

42.

43.

45.

53

See Ref. 29 a,b,c.
See Ref. 29 k.
See examples 21 e,f,g, 22c, 23 a,d, 25 b,c, 26c, 27b.

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g) Tanis, S.P., McMills, M.C., Iohnson, G.M. Tetrahedron Lett.
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See Ref. 35 d,c,a.

a) See Ref. 35b.
b) Tanis, S.P., Chuang, Y—W. I. Am. Chem. Soc. manuscript in
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See Ref. 35c.
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a) Unpublished observation. Tanis, SP. and McMills, M.C.
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Iohnson, G.M., Masters Thesis, Mchigan State University (1987).
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a) Shih, C., Swenton, IS. I. Org. Chem. 1982, 47, 2825.
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See Ref. 43a.

47.

48.

49.

50.

51.

52.

53.

' 54.

55.

57.

58.

59.

54

a) Brown, C.A., Akuja, V.K. I. Org. Chem. 1973, 38, 2226.
b) Bartok, M., Lakos-Lang, K., Bogatskaya, L.G., Kamalov, G.C., Bogot-skii,
A.V. Dokl. Akad. Nauk. SSSR 1977,234, 509.

See Ref 35.

a) Chamberlin, A.K., Chung, I.Y.L. Tetrahedron Lett. 1982, 23, 2619.
b) Chamberlin, A.R., Chung, I.Y.L. I. Am. Chem. Soc. 1983,105, 3653.

MMZ calculations conducted on IBM PC-XT using MMPMI Program of
Serena Software Bloomington Ind.

See Ref. 29i, 35a,c,d.

a) Devreese, A.A., Demuynck, M., DeClercq, P.I., Vandewalle, M.
Tetrahedron 1983,39, 3039.

b) Devreese, A.A., Demuynck, M., DeClercq, P.I., Vandewalle, M.
Tetrahedron 1983, 39, 3049.

c) Rigby, I,H., Wilson, I.Z. I. Am. Chem. Soc. 1984,106, 8217.

a) Petersen, D]. I. Org. Chem. 1968, 33, 780.

b) Ager, D.I. Synthesis 1984, 384.

c) Burford, C., Cooke, F., Ehlinger, E., Magnus, P. I. Am. Chem. Soc.
1977, 99, 4536.

d) Cooke, F., Magnus, P. Chem. Comm. 1977, 513.

e) Stork, G., Iung, ME. I. Am. Chem. Soc. 1974, 96, 3682.

f) Magnus, P. Aldrichimica Acta. 1980,13, 1980.

See Ref. 43a.
See Ref. 29.

Smith, A.B., Branca, S.I., Guaciaro, M.A., Wovkulich, P.M., Korn, A.
Org. Syn. 1983, 61, 65.

a)Baldwin, I.E. Chem. Comm. 1976, 734.
b) Spillmeyer, D.C., Houk, K.N. I. Org. Chem. 1987, 52, 959.

Semmelhack, M.E., Tomesch, I.C., Czarny, M., Boettger, S. I. Org. Chem.
1978, 42, 1259.

Kleschick, W.A., Heathcock, C.H. I. Org. Chem. 1978, 42, 1256.

SeeRef54.

60.

61.

62.

63.

65.

66.

55

a) Marino, I.P., Farina, I.S. Tetrahedron Lett. 1975, 45, 3901.

b) Marino, I.P., Farino, IS. I. Org. Chem. 1976, 41, 3213.

c) Marino, I.P., Floyd, D.M. I. Am. Chem. Soc. 1974, 96, 7138.

d) Grieco, P.A., Wang, C-L.I., Majetich, G. I. Org. Chem. 1976, 41, 726.

a) Ireland, R.E., Mueller, R.H., Willard, A.K. I. Am. Chem. Soc. 1976, 98,
2808.

b) Ireland, R.E., Wilcox, C.S. Tetrahedron Lett. 1977, 33, 2839.

c) for a similar system see Burke, S.D., Fobare, W.F., Pacofsky, G]. I. Org.
Chem. 1983,48, 5221.

d) Burke, S.D., Pacofsky, G.I. Tetrahedron Lett. 1986, 27, 1986.

a) Ireland, R.E., Willard, A.K. Tetrahedron Lett. 1975, 3975.

b) See Ref. 60a.

c) See Ref. 60b.

d) Ireland, R.E., Mueller, R.H. I. Am. Chem. Soc. 1972, 94, 5897.
Zimmerman, H.E., Traxler, MD. I. Am. Chem. Soc. 1957, 79, 1920.
See Ref. 60, 61.

a) Raucher, I., Lui, A.S-T., MacDonald, IE. I. Org. Chem. 1979, 44, 1885. -
b) Nemoto, H., Shitara, E., Fukumoto, K. Heterocycles 1985, 23, 549.
c) Ibid Idem, 1911.

Still, W. C., Kahn, M., Mitra, A. I. Org. Chem. 1978, 41, 2923.

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