Synthesis of (±)-bakkenolide-A and its C-7, C-10, and C-7,10 epimers by means of an intramolecular Diels-Alder reaction

Article abstract of DOI:10.1021/jo015624h

(±)-Bakkenolide-A (1) was prepared in five steps from ethyl 4-benzyloxyacetoacetate by sequential alkylations with tiglyl bromide and (Z)-5-bromo-1,3-pentadiene, followed by an intramolecular Diels-Alder reaction of (E,Z)-triene 25b as the key step. The hydrindane cycloadduct 28 was subjected to hydrogenation and spontaneous or acid-catalyzed lactonization, followed by a Witttig reaction to introduce the exocyclic methylene group of 1. The known 7-epibakkenolide-A (2) and novel 10-epi- and 7,10-diepibakkenolide-A (3 and 4, respectively) stereoisomers were obtained as minor byproducts. When (E)-5-bromo-1,3-pentadiene was used instead of the Z-isomer, the 10-epi-and 7,10-diepibakkenolides were the major products. In both cases exo cyclization was preferred over endo. An alternative approach was based on a similar intramolecular Diels-Alder cycloaddition, using dimethyl malonaate instead of ethyl 4-benzyloxyacetoacetate as the starting material for the double alkylation preceding the cycloaddition step. The cycloadduct was then converted into the corresponding α-phenylseleno propargyl esters 16 or 22. However, attempted formation of the spiro center by a radical cyclization resulted chiefly in reductive deselenization.

Full text of DOI:10.1021/jo015624h

J . Org. Chem. 2001, 66, 4361-4368
4361
Syn th esis of (()-Ba k k en olid e-A a n d Its C-7, C-10, a n d C-7,10
Ep im er s by Mea n s of a n In tr a m olecu la r Diels-Ald er Rea ction
Thomas G. Back,* Victor O. Nava-Salgado, and J oseph E. Payne
Department of Chemistry, University of Calgary, Calgary, Alberta, Canada T2N 1N4
tgback@ucalgary.ca
Received March 7, 2001
(()-Bakkenolide-A (1) was prepared in five steps from ethyl 4-benzyloxyacetoacetate by sequential
alkylations with tiglyl bromide and (Z)-5-bromo-1,3-pentadiene, followed by an intramolecular
Diels-Alder reaction of (E,Z)-triene 25b as the key step. The hydrindane cycloadduct 28 was
subjected to hydrogenation and spontaneous or acid-catalyzed lactonization, followed by a Witttig
reaction to introduce the exocyclic methylene group of 1. The known 7-epibakkenolide-A (2) and
novel 10-epi- and 7,10-diepibakkenolide-A (3 and 4, respectively) stereoisomers were obtained as
minor byproducts. When (E)-5-bromo-1,3-pentadiene was used instead of the Z-isomer, the 10-epi-
and 7,10-diepibakkenolides were the major products. In both cases exo cyclization was preferred
over endo. An alternative approach was based on a similar intramolecular Diels-Alder cycloaddition,
using dimethyl malonate instead of ethyl 4-benzyloxyacetoacetate as the starting material for the
double alkylation preceding the cycloaddition step. The cycloadduct was then converted into the
corresponding R-phenylseleno propargyl esters 16 or 22. However, attempted formation of the spiro
center by a radical cyclization resulted chiefly in reductive deselenization.
Bakkenolide-A (1) is the simplest member of a family
of sesquiterpene â-methylene spiro lactones that are
formally related to the eremophilanes.1 It was first
isolated in 1968 from the wild butterbur Petasites japoni-
cus by Woods and Kitahara et al.,2 and independently
by Naya et al.3 Bakkenolide-A displays cytotoxicity
against several carcinoma cell lines,4 as well as insect
antifeedant activity.5 Several syntheses of 16 and its
congeners7 have been reported. We recently prepared the
6-keto derivative of bakkenolide-A via a radical cycliza-
tion to establish the spiro lactone moiety, followed by an
intermolecular high-pressure Diels-Alder reaction to
construct the six-membered ring.8 Unfortunately, poor
stereoselectivity in the Diels-Alder step and difficulty
in reducing the 6-keto group thwarted our attempts to
prepare 1 by this method. We now report9 a stereoselec-
tive new approach based on an intramolecular Diels-
Alder reaction10 that provided (()-1 as the principal
product, along with smaller amounts of the known7k (()-
7-epibakkenolide-A (2) and novel (()-10-epibakkeno-
lide-A (3) and (()-7,10-diepibakkenolide-A (4) analogues.
Resu lts a n d Discu ssion
We first investigated the method indicated retrosyn-
thetically in Scheme 1, where an intramolecular Diels-
(7) For syntheses of some related products, see: homogynolide-A:
(a) Hartmann, B.; Kanazawa, A. M.; Depre´s, J .-P.; Greene, A. E.
Tetrahedron Lett. 1991, 32, 767. (b) Hartmann, B.; Kanazawa, A. M.;
Depre´s, J .-P.; Greene, A. E. Tetrahedron Lett. 1993, 34, 3875. (c) Mori,
K.; Matsushima, Y. Synthesis 1995, 845. (d) Srikrishna, A.; Reddy, T.
J . Indian J . Chem. 1995, 34B, 844; homogynolide-B: (e) Coelho, F.;
Depre´s, J .-P.; Brocksom, T. J .; Greene, A. E. Tetrahedron Lett. 1989,
30, 565. (f) Srikrishna, A.; Nagaraju, S.; Venkateswarlu, S. Tetrahedron
Lett. 1994, 35, 429. (g) Srikrishna, A.; Nagaraju, S.; Venkateswarlu,
S.; Hiremath, U. S.; Reddy, T. J .; Venugopalan, P. J . Chem. Soc., Perkin
Trans. 1 1999, 2069; palmosalide C: (h) Hartmann, B.; Depre´s, J .-P.;
Greene, A. E.; Freire de Lima, M. E. Tetrahedron Lett. 1993, 34, 1487;
norbakkenolide-A: (i) Srikrishna, A.; Nagaraju, S.; Sharma, G. V. R.
J . Chem. Soc., Chem. Commun. 1993, 285; 4-epibakkenolide: (j)
Srikrishna, A.; Viswajanani, R.; Sattigeri, J . A. J . Chem. Soc., Chem.
Commun. 1995, 469; 7-epibakkenolide-A: (k) Srikrishna, A.; Reddy,
T. J . Tetrahedron 1998, 54, 11517; 9-acetoxyfukinanolide: (l) Hamelin,
O.; Depre´s, J .-P.; Greene, A. E.; Tinant, B.; Declercq, J .-P. J . Am. Chem.
Soc. 1996, 118, 9992.
* Address correspondence to: T. G. Back, Tel.: (403) 220-6256,
Fax: (403) 289-9488.
(1) For a review of bakkenolide-A and other sesquiterpene lactones,
see: Fischer, N. H.; Olivier, E. J .; Fischer, H. D. In Progress in the
Chemistry of Organic Natural Products; Herz, W., Grisebach, H., Kirby,
G. W., Eds.; Springer-Verlag: New York, 1979; Vol. 38, Chapter 2.
(2) Abe, N.; Onoda, R.; Shirahata, K.; Kato, T.; Woods, M. C.;
Kitahara, Y. Tetrahedron Lett. 1968, 369.
(3) Naya, K.; Takagi, I.; Hayashi, M.; Nakamura, S.; Kobayashi, M.;
Katsumura, S. Chem. Ind. (London) 1968, 318. These authors referred
to 1 as fukinanolide, an alternative name to bakkenolide A.
(4) (a) J amieson, G. R.; Reid, E. H.; Turner, B. P.; J amieson, A. T.
Phytochemistry 1976, 15, 1713. (b) Kano, K.; Hayashi, K.; Mitsuhashi,
H. Chem. Pharm. Bull. 1982, 30, 1198.
(5) For example, see: (a) Harmatha, J .; Nawrot, J . Biochem. Syst.
Ecol. 1984, 12, 95. (b) Nawrot, J .; Harmatha, J .; Novotny´, L. Biochem.
Syst. Ecol. 1984, 12, 99. (c) Nawrot, J .; Bloszyk, E.; Harmatha, J .;
Novotny´, L.; Drozdz, B. Acta Entomol. Bohemoslov. 1986, 83, 327. (d)
Isman, M. B.; Brard, N. L.; Nawrot, J .; Harmatha, J . J . Appl. Entomol.
1989, 107, 524. (e) Nawrot, J .; Koul, O.; Isman, M. B.; Harmatha, J .
J . Appl. Entomol. 1991, 112, 194.
(6) (a) Hayashi, K.; Nakamura, H.; Mitsuhashi, H. Chem. Pharm.
Bull. 1973, 21, 2806. (b) Evans, D. A.; Sims, C. L.; Andrews, G. C. J .
Am. Chem. Soc. 1977, 99, 5453. (c) Greene, A. E.; Depre´s, J .-P.; Coelho,
F.; Brocksom, T. J . J . Org. Chem. 1985, 50, 3943. (d) Greene, A. E.;
Coelho, F.; Depre´s, J .-P.; Brocksom, T. J . Tetrahedron Lett. 1988, 29,
5661. (e) Srikrishna, A.; Reddy, T. J .; Nagaraju, S.; Sattigeri, J . A.
Tetrahedron Lett. 1994, 35, 7841.
(8) Back, T. G.; Gladstone, P. L.; Parvez, M. J . Org. Chem. 1996,
61, 3806.
(9) Preliminary communication: Back, T. G.; Payne, J . E. Org. Lett.
1999, 1, 663.
(10) For reviews of the intramolecular Diels-Alder reaction, see:
(a) Ciganek, E. Org. React. (N.Y.), 1984, 32, 1. (b) Fallis, A. G. Can. J .
Chem. 1984, 62, 183. (c) Taber, D. F. Intramolecular Diels-Alder and
Alder Ene Reactions; Springer-Verlag, Berlin, 1984. (d) Craig, D. Chem.
Soc. Rev. 1987, 16, 187. (e) Roush, W. R. In Advances in Cycloaddition;
Curran, D. P., Ed.; J AI Press: Greenwich, CT, 1990; Volume 2, p 91.
(f) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1990, Chapter 3. (g) Roush, W. R. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette,
L. A., Eds.; Pergamon Press: Oxford, 1991; Volume 5, Chapter 4.4.
(h) Fallis, A. G. Acc. Chem. Res. 1999, 32, 464.
10.1021/jo015624h CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/16/2001

4362 J . Org. Chem., Vol. 66, No. 12, 2001
Back et al.
Sch em e 2
Sch em e 1
obtained when a small amount of the radical inhibitor
2,6-di-tert-butyl-4-methylphenol (butylated hydroxytolu-
ene, BHT) was included in the reaction mixture to
suppress polymerization, which was probably initiated
by traces of peroxides in the absence of BHT. The E,E-
triene 6a thus produced a high yield of the unseparated
mixture of cis- and trans-fused cycloadducts 11a and 11b,
respectively, in the ratio of 40:60, as determined by NMR
integration. As expected, a much improved ratio of 80:
20 in favor of the desired cis-fused product 11a was
produced similarly from the E,Z-isomer 6b, albeit in
considerably lower yield (Scheme 2).
The product 11a ,b was hydrogenated to afford 12a ,b
quantitatively. The mixture of cis- and trans-fused hy-
drindanes (series a and b, respectively, in Scheme 3) was
then carried through subsequent steps because of dif-
ficulties in separating the two isomers. Identification of
the cis and trans isomers in the mixtures of products was
possible by comparison of their NMR spectra with those
of the final products 1-4 (vide infra). The mixture of
diesters 12a ,b was subjected to saponification and de-
carboxylation, followed by esterification with propargyl
or allyl alcohol to furnish esters 14a ,b and 15a ,b, and
selenenylation to give 16a ,b and 17a ,b, respectively
(Scheme 3). Finally, homolytic cleavage of the selenide14
moiety of propargyl ester 16a ,b with tri-n-butyltin hy-
dride was studied under a variety of conditions, including
the slow addition of the tin hydride/AIBN mixture to
16a ,b. However, instead of the desired 5-exo-dig cycliza-
tion,15 only reductive deselenization was observed, thereby
regenerating 14a ,b. Similar results were obtained with
triphenyltin hydride, while attempts to induce photolytic
Alder reaction is followed by a radical cyclization ensuing
from the homolytic cleavage of the phenylseleno group
in 5. Our intention was to control the stereochemistry of
the hydrindane ring system (i.e. cis- vs trans-fused) by
appropriate choice of E or Z geometry of the diene moiety
(vide infra) of 6. Previous studies11 of intramolecular
Diels-Alder reactions of other 1,3,8-nonatrienes have
revealed that compounds containing a (3Z)-diene moiety
favor the formation of cis-hydrindanes, whereas the
corresponding (3E)-dienes afford poorer stereoselectivity
favoring the trans-fused cycloadducts. Moreover, a pre-
cedent for obtaining the desired configuration at the spiro
center in the subsequent radical cyclization of 5 was
found in the related endo-selective radical cyclization of
acetal 7 during an earlier synthesis of 1 by Srikrishna
et al.6e
Thus, dimethyl malonate was alkylated sequentially
with tiglyl bromide 812 to afford 9, followed by either (E)-
or (Z)-5-bromo-1,3-pentadiene (10a and 10b, respectively;
Scheme 2).13 The products 6a and 6b were then subjected
to the intramolecular Diels-Alder reaction in toluene in
a sealed Parr apparatus at 190 °C. Improved yields were
(11) (a) House, H. O.; Cronin, T. H. J . Org. Chem. 1965, 30, 1061.
(b) Pyne, S. G.; Hensel, M. J .; Byrn, S. R.; McKenzie, A. T.; Fuchs, P.
L. J . Am. Chem. Soc. 1980, 102, 5960. (c) Boeckman, J r., R. K.; Alessi,
T. R. J . Am. Chem. Soc. 1982, 104, 3216.
(12) Katzenellenbogen, J . A.; Crumrine, A. L. J . Am. Chem. Soc.
1976, 98, 4925.
(14) (a) For homolytic cleavage of selenides with tin hydrides, see:
Clive, D. L. J .; Chittattu, G. J .; Farina, V.; Kiel, W. A.; Menchen, S.
M.; Russell, C. G.; Singh, A.; Wong, C. K.; Curtis, N. J . J . Am. Chem.
(13) The preparation of (E)-10a was achieved by
a literature
procedure: (a) Pre´vost, C.; Miginiac, P.; Miginiac-Groizeleau, L. Bull.
Soc. Chim. Fr. 1964, 2485. (Z)-10b was prepared by bromination of
(Z)-2,4-pentadiene-1-ol with phosphorus tribromide. The (Z)-dienol was
in turn obtained via the method of (b) Margot, C.; Rizzolio, M.;
Schlosser, M. Tetrahedron 1990, 46, 2411.
Soc. 1980, 102, 4438. (b) For
a review of radical reactions and
deselenizations of selenium compounds, see: Back, T. G. In Organose-
lenium Chemistry - A Practical Approach; Back, T. G., Ed.; Oxford
University Press: Oxford, 1999; Chapter 9.

Synthesis of (()-Bakkenolide-A
J . Org. Chem., Vol. 66, No. 12, 2001 4363
Sch em e 3
Sch em e 4
Sch em e 5
selenide cleavage and cyclization of 16a ,b also failed. The
allyl ester 17a ,b was subjected to similar treatment, but
again afforded only the products of reductive deseleni-
zation 15a ,b. The failure of radicals derived from 16a ,b
or 17a ,b to cyclize, in contrast to the facile cyclization of
7, is attributed to a more strained transition state when
the acetylenic or allenic moiety is attached via an ester
linkage instead of the acetal in 7.6e,16 This in turn permits
hydrogen atom transfer from the tin hydride to the
radical center to compete effectively with cyclization.
However, it is also interesting to note that we,8,17a and
later Byers et al.,17b observed that the radicals generated
in the R-position of allyl and propargyl esters of â-keto
cyclopentanecarboxylic acids cyclize smoothly to produce
the corresponding spiro lactones (e.g., Scheme 4). Thus,
the failure of radicals derived from 16a ,b and 17a ,b to
cyclize in an analogous manner was unexpected and
remains somewhat puzzling.
The analogous radical cyclization step using a pendant
acetylenic sulfone moiety was also investigated.18 Sele-
nenylation of the corresponding 3-(p-toluenesulfonyl)-
propargyl ester analogue of 14a ,b was unsuccessful.
Therefore, the selenenylation step was carried out first,
using the benzyl ester 18a ,b, followed by saponification
and reesterification with alcohol 21. The latter compound
was in turn prepared from the selenosulfonation, sele-
noxide elimination, and deprotection of propargyl tert-
butyldimethylsilyl ether19 (Scheme 5). Again, treatment
of ester 22a ,b with tri-n-butyltin hydride and AIBN
afforded only the product of reductive deselenization
23a ,b. Attempts were also made to effect an intramo-
lecular conjugate addition of the ester enolate of 23a ,b
(15) For reviews of radical cyclization, see: (a) Giese, B. Radicals
in Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon
Press: Oxford, 1986; Chapter 4. (b) Curran, D. P. Synthesis 1988, 417.
(c) Curran, D. P. Synthesis 1988, 489. (d) J asperse, C. P.; Curran, D.
P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237. (e) Curran, D. P. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 4, Chapter 4.2. (f) Motherwell, W. B.; Crich, D. Free
Radical Chain Reactions in Organic Synthesis; Academic Press:
London, 1992, Chapter 7. (g) Malacria, M. Chem. Rev. 1996, 96, 289.
(h) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J .; Thoma, G.; Kulicke,
K. J .; Trach, F. Org. React. (N.Y.) 1996, 48, 301. (i) Curran, D. P.;
Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; VCH:
New York, 1996. (j) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53,
17543.
(16) Nevertheless, other types of spiro-γ-lactones have been prepared
by 5-exo-dig cyclizations of radicals derived from propargyl R-bromoac-
etates; see: Kolt, R. J .; Griller, D.; Wayner, D. D. M. Tetrahedron Lett.
1990, 31, 7539.
(17) (a) Back, T. G.; Gladstone, P. L. Synlett 1993, 699. (b) Byers,
J . H.; Shaughnessy, E. A.; Mackie, T. N. Heterocycles 1998, 48, 2071.
(18) (a) For another example of a 5-exo-dig radical cyclization of an
acetylenic sulfone, see: Bogen, S.; Gulea, M.; Fensterbank, L.; Mal-
acria, M. J . Org. Chem. 1999, 64, 4920. (b) For a review of acetylenic
and allenic sulfones, see: Back, T. G. Tetrahedron 2001, in press.
(19) The selenosulfonation of the tert-butyldimethylsilyl ether of
propargyl alcohol and oxidation to the corresponding selenoxide was
carried out as reported previously: Back, T. G.; Krishna, M. V. J . Org.
Chem. 1987, 52, 4265.

4364 J . Org. Chem., Vol. 66, No. 12, 2001
Back et al.
Sch em e 6
The stereochemistry of the intramolecular Diels-Alder
reaction requires further comment. Four transition states
A-D (Scheme 8) are possible (neglecting stereochemistry
associated with the spiro center), depending on whether
the geometry of the pre-Diels-Alder triene moiety is E,E
or E,Z, and on whether an exo or endo approach is taken
between the diene and dienophile components. Extensive
earlier investigations of intramolecular Diels-Alder
reactions10 have shown that the partitioning between exo
and endo transition states depends on the length and
nature of the tether, the E,Z configurations of the triene,
and the nature and location of substituents and activat-
ing groups. In (3E)-1,3,8-nonatrienes, the corresponding
exo and endo transition states are often comparable,
resulting in poor stereoselectivity, generally favoring the
trans-hydrindane.11 On the other hand, the endo transi-
tion state of (3Z)-nonatrienes is significantly more strained
than the exo, thus leading to higher stereoselectivity in
favor of the corresponding cis-hydrindane.11 In the present
case, as expected, cis-fused cycloadducts were formed
preferentially (cis:trans ) 80:20 and 73:27) from E,Z-6b
and E,Z-25b, respectively, indicating that transition state
A (exo) is favored over C (endo). Similarly, exo transition
state D was slightly preferred over endo-B when the
isomeric E,E-6a and E,E-25a were employed, resulting
in the selective formation of the corresponding trans-
fused cycloadducts, but with relatively poor stereoselec-
tivity (cis:trans ) 40:60 and 34:66, respectively). How-
ever, the reason for the preferential formation of the
bakkenolide-A spiro-configuration (i.e., in 1 and 3), as
opposed to the 7-epi configuration (in 2 and 4), is less
clear.
The method in Scheme 7 therefore provides a simple
five-step synthetic approach from keto ester 26 to (()-
bakkenolide-A (1), which was formed stereoselectively
when the E,Z-triene 25b was employed in the key
intramolecular Diels-Alder step. Minor amounts of the
7-epi- 10-epi-, and 7,10-diepibakkenolide-A stereoisomers
2-4 were also isolated. Thus, the E,Z-isomer 25b un-
derwent preferential exo cycloaddition, leading to cis-
fused hydrindane products 1 and 2. On the other hand,
exo cycloaddition of the corresponding E,E-triene 25a
resulted in the stereoselective formation of trans-fused
hydrindane cycloadducts, thus favoring the novel 10-epi-
and 7,10-diepibakkenolide-A stereoisomers 3 and 4. Since
the opportunity exists to introduce further modifications
to the diene and dienophile components before their
incorporation into the â-keto ester 26, this approach may
also provide general access to other, more highly substi-
tuted members of the bakkenolide family.
to the acetylenic sulfone moiety.20 However, in all cases,
only complex mixtures were produced.
To circumvent the unsuccessful radical cyclization step,
we next attempted to produce the spiro lactone moiety
by lactonization of 24, in turn obtained by the intramo-
lecular Diels-Alder reaction of 25, followed by a Wittig
reaction to install the exocyclic double bond, as shown
retrosynthetically in Scheme 6. The known21 â-keto ester
26 was thus alkylated with tiglyl bromide (8) and,
separately, with dienyl bromides 10a or 10b to produce
the pre-Diels-Alder trienes 25a and 25b, respectively.
The intramolecular Diels-Alder reaction of each triene
was carried out separately, as in the case of 6a and 6b,
to afford the cycloadduct 28 as a mixture of four possible
diastereomers (Scheme 7), which again could not be
separated at this stage. The unseparated mixture derived
from each of 25a and 25b (series a and b, respectively,
in subsequent steps in Scheme 7) was therefore subjected
to simultaneous hydrogenation and hydrogenolysis of the
benzyl group, followed by spontaneous or acid-catalyzed
lactonization, and a Wittig reaction. When the E,E-
isomer 25a was used, a high yield of 95% of cycloadduct
28a was obtained, which afforded 90% of lactone 29a and,
following the Wittig step, 62% of a mixture of (()-
bakkenolide-A (1) and its 7-epi-, 10-epi-, and 7,10-diepi
analogues (2-4, respectively) in the ratio of 24:10:34:32,
in which the trans-fused (10-epi) isomers 3 and 4
dominated. A lower yield of 54% was produced in the
cycloaddition of the E,Z-isomer 25b, but the remaining
steps were comparable in yield to those from 25a .
However, the final product mixture contained 1-4 in the
very different ratio of 54:19:16:11, thus strongly favoring
the cis-fused isomers 1 and 2.
Products 1-4 were separated by preparative reverse
phase HPLC. Bakkenolide-A (1) was identified by com-
parison to an authentic sample (GC-MS, 1H and 13C
NMR), while its epi-spiro stereoisomer 2 had spectro-
scopic properties consistent with those reported in the
literature.7k Stereoisomers 3 and 4, which both contain
trans-fused hydrindanes and differ from each other in
the relative configurations of their spiro centers, are new
compounds that were fully characterized. It was possible
to distinguish them on the basis of an NOE that was
observed between the angular methyl group and one of
the exocyclic methylene protons in one epimer (assigned
structure 4), while the other epimer (assigned structure
3) showed no such effect. Moreover, a small long-range
coupling of ca. 0.8 Hz was observed between the angular
methyl group and the proton at C-10 in the trans-fused
diastereomers 3 and 4, as well as in several of their
synthetic precursors. No such coupling was discerned in
the cis-fused series.
Exp er im en ta l Section
NMR spectra were recorded in deuteriochloroform and are
reported relative to residual chloroform or TMS as the internal
standard. Mass spectra were obtained by EI at 70 eV. Chro-
matography refers to flash chromatography on silica gel (230-
400 mesh), unless otherwise noted.
Dim eth yl 2-[2-Meth yl-2(E)-bu ten yl]m a lon a te (9). Dim-
ethyl malonate (3.5 g, 27 mmol) in 10 mL of THF was added
dropwise to NaH (700 mg, 29 mmol) in 250 mL of dry THF,
and the mixture was stirred for 30 min at room temperature.
A solution of tiglyl bromide12 (4.0 g, 27 mmol) in 10 mL of THF
was then added dropwise. After 18 h, the reaction was
quenched with 100 mL of saturated aqueous NH4Cl solution.
The aqueous phase was separated and extracted with ether
(3 × 100 mL), and the combined organic phases were dried
over MgSO4 and concentrated in vacuo. The residue was
(20) For a review of conjugate additions to acetylenic sulfones, see:
ref 18b and Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993; Chapter 4.
(21) Meul, T.; Miller, R.; Tenud, L. Chimia 1987, 41, 73.

Synthesis of (()-Bakkenolide-A
J . Org. Chem., Vol. 66, No. 12, 2001 4365
Sch em e 7
(Z)-5-Br om o-1,3-p en ta d ien e (10b). A mixture of (Z)-2,4-
Sch em e 8
pentadien-1-ol (0.900 g, 10.7 mmol) and PBr3 (0.42 mL, 4.4
mmol) in 10 mL of ether was stirred for 2 h at 0 °C in a flask
wrapped in aluminum foil. Ice-water (10 mL) was added to
quench the reaction, and the mixture was extracted with ether
(5 × 10 mL). The combined organic layers were dried over
MgSO4, and the solvent was carefully removed under reduced
pressure at room temperature. The product, which is a strong
lachrymator, was distilled, bp 42-43 °C (25 mmHg), to afford
1
1.15 g (72%) of 10b as a colorless liquid; H NMR δ 6.69 (dt,
J ) 16.8, 10.7 Hz, 1 H), 6.14 (t, J ) 10.8 Hz, 1 H), 5.73 (m, 1
H), 5.43-5.26 (m, 2 H), 4.13 (d, J ) 8.5 Hz, 2 H). The NMR
spectrum compares favorably with the signals attributed to
the Z-component of an E,Z-mixture of 10 reported in the
literature.22
Dim eth yl 2-[2-Meth yl-2(E)-bu ten yl]-2-[2(E)-4-p en ta d i-
en yl]m a lon a te (6a ). Diester 9 (2.86 g, 14.3 mmol) in 5 mL of
THF was added dropwise to NaH (377 mg, 15.7 mmol) in 75
mL of dry THF, and the mixture was stirred for 30 min at
room temperature. A solution of (E)-5-bromo-1,3-pentadiene
10a 13a (2.10 g, 14.3 mmol) in 3 mL of THF was then added
dropwise. After 18 h, the reaction was quenched with 50 mL
of saturated aqueous NH4Cl solution. The aqueous phase was
separated and extracted with ether (3 × 50 mL), and the
combined organic phases were dried over MgSO4 and concen-
trated in vacuo. The residue was chromatographed (hexane:
ethyl acetate, 10:1) to afford 3.2 g (84%) of (E,E)-6a as a
1
colorless oil; IR (neat): 1736, 1203, 1007 cm-1; H NMR (400
MHz) δ 6.28 (dt, J ) 10.3, 16.9 Hz, 1 H), 6.06 (dd, J ) 10.4,
15.1 Hz, 1 H), 5.55 (dt, J ) 7.6, 15.1 Hz, 1 H), 5.29 (q, J ) 6.7
Hz, 1 H), 5.11 (d, J ) 16.9 Hz, 1 H), 5.01 (d, J ) 10.1 Hz, 1 H),
3.70 (s, 6 H), 2.67 (s, 2 H), 2.64 (d, J ) 7.7 Hz, 2 H), 1.57 (d,
J ) 6.7 Hz, 3 H), 1.52 (s, 3 H); 13C NMR (100 MHz) δ 172.1,
137.1, 135.1, 130.8, 128.8, 125.1, 116.6, 58.3, 52.6, 43.0, 36.3,
16.8, 14.0; MS (m/z, %) 266 (0.18, M+), 165 (82), 41 (100). Anal.
Calcd for C15H22O4: C, 67.65; H, 8.33. Found: C, 67.47; H,
8.50.
Dim eth yl 2-[2-Meth yl-2(E)-bu ten yl]-2-[2(Z)-4-p en ta d i-
en yl]m a lon a te (6b). The procedure for preparing 6a was
repeated with NaH (142 mg, 5.9 mmol), diester 9 (984 mg, 4.9
mmol), and (Z)-5-bromo-1,3-pentadiene (723 mg, 4.9 mmol) to
chromatographed (hexanes:ethyl acetate, 5:1) to afford 4.8 g
(90%) of 9 as a colorless oil; IR (neat): 1738, 1337, 1236, 1152
cm-1; 1H NMR (400 MHz): δ 5.28 (q, J ) 6.6 Hz, 1H), 3.72 (s,
6 H), 3.58 (t, J ) 7.8 Hz, 1 H), 2.59 (d, J ) 7.8 Hz, 2 H), 1.62
(s, 3 H), 1.56 (d, J ) 6.6 Hz, 3 H); 13C NMR (100 MHz) δ 170.0,
131.8, 122.0, 52.8, 51.0, 39.0, 15.7, 13.8; MS (m/z, %) 200 (41,
M+), 81 (100).
(22) Dienyl bromide10 has also been prepared as an E,Z-mixture:
Davies, A. G.; Griller, D.; Ingold, K. U.; Lindsay, D. A.; Walton, J . C.
J . Chem. Soc., Perkin Trans. 2 1981, 633.

4366 J . Org. Chem., Vol. 66, No. 12, 2001
Back et al.
afford 1.17 g (90%) of 6b as a colorless oil; IR 1736, 1286, 1201,
1101 cm-1; 1H NMR (400 MHz) δ 6.60 (ddt, J ) 16.8, 10.6, 1.0
Hz, 1 H), 6.09 (t, J ) 11.0 Hz, 1 H), 5.36-5.24 (m, 2 H), 5.20
(dd, J ) 16.8, 1.7 Hz, 1 H), 5.13 (d, J ) 10.1 Hz, 1 H), 3.69 (s,
6 H), 2.77 (dd, J ) 7.8, 1.5 Hz, 2 H), 2.68 (s, 2 H), 1.56 (dd, J
) 6.7, 0.8 Hz, 3 H), 1.51 (s, 3 H); 13C NMR (100 MHz) δ 171.7,
132.4, 131.8, 130.2, 125.5, 124.8, 118.2, 57.5, 52.3, 42.4, 30.5,
16.3, 13.6; MS (m/z, %) 266 (0.2, M+), 165 (85), 41(100). Anal.
Calcd for C15H22O4: C, 67.65; H, 8.33. Found: C, 67.46; H,
8.22.
In tr a m olecu la r Diels-Ald er Cycloa d d ition of (E,E)-
Tr ien e 6a a n d (E,Z)-Tr ien e 6b. Triene 6a (2.00 g, 7.52
mmol), BHT (200 mg), and 400 mL of toluene were heated at
190 °C for 24 h in a sealed Parr apparatus. The toluene was
removed under reduced pressure, and the residue was chro-
matographed (hexanes:ethyl acetate, 10:1) to afford 1.58 g
(79%) of an unseparated mixture of cis- and trans-hydrindanes
11a and 11b, respectively, as a pale yellow oil in the ratio of
40:60, as determined by NMR integration; IR (neat) 1734,
1250, 1194, 1165 cm-1; 1H NMR (400 MHz) δ 5.65-5.50 (m, 2
H, both isomers), 3.73 (s, 3 H, both isomers); 3.70 (s, 3 H, 11b),
3.69 (s, 3 H, 11a ), 2.69-1.45 (m, 8 H, both isomers), 0.90 (d,
J ) 6.7 Hz, 3 H, 11a ), 0.88 (d, J ) 6.6 Hz, 3 H, 11b), 0.87 (s,
3 H, 11a ), 0.59 (d, J ) 0.8 Hz, 3 H, 11b); MS (m/z, %) 266 (3,
M+), 147 (100). Anal. Calcd for C15H22O4: C, 67.65; H, 8.33.
Found: C, 67.27; H, 8.59.
of a 40:60 mixture of cis and trans isomers 14a and 14b, each
obtained as a pair of stereoisomers, as a colorless oil; IR
(neat): 3303, 2126, 1736, 1163 cm-1 1H NMR (400 MHz) δ
;
4.66-4.65 (four s, 3 H, all isomers), 2.90 (m, 1 H, all isomers),
2.45-2.43 (four s, 1 H, all isomers), 2.20-0.90 (m, 12 H, all
isomers), 0.89 (s, 3 H, 14a , minor isomer), 0.87 (s, 3 H, 14a ,
major isomer), 0.83, 0.82, 0.78, 0.77 (four overlapping d, each
with J ) 6.7 Hz, 3 H, all isomers), 0.62 (d, J ) 0.9 Hz, 3 H,
14b, major isomer), 0.60 (d, J ) 0.9 Hz, 3 H, 14b, minor
isomer); MS (m/z, %) 234 (13, M+), 179 (38), 124 (100). Anal.
Calcd for C15H22O2: C, 76.88; H, 9.46. Found: C, 76.93; H,
9.36.
Allyl Ester s 15a ,b. The preparation of 15a ,b from 252 mg
(1.28 mmol) of 13a ,b and 373 mg (6.43 mmol) of allyl alcohol
was carried out in 89% yield by the same procedure as used
in the preparation of 14a ,b. The product was obtained as a
40:60 mixture of cis and trans isomers 15a and 15b, each
formed as a pair of stereoisomers, in the form of a colorless
1
oil; IR (neat) 1731, 1163, 983, 922 cm-1; H NMR (400 MHz)
δ 5.91 (m, 1 H, all isomers), 5.29 (crude d, J ) 17.2 Hz, 1 H,
all isomers), 5.20 (crude d, J ) 10.4 Hz, 1 H, all isomers), 4.55
(m, 2 H, all isomers), 2.85 (m, 1 H, all isomers), 2.10-1.00 (m,
12 H, all isomers), 0.89 (s, 3 H, 14a , minor isomer), 0.87 (s, 3
H, 14a , major isomer), 0.83, 0.82, 0.78, 0.77 (four overlapping
d, each with J ) 6.7 Hz, 3 H, all isomers), 0.62 (d, J ) 0.7 Hz,
3 H, 14b, major isomer), 0.60 (d, J ) 0.7 Hz, 3 H, 14b, minor
isomer); MS (m/z, %) 236 (42, M+), 179 (83), 149 (100). Anal.
Calcd for C15H24O2: C, 76.23; H, 10.24. Found: C, 76.25; H,
9.93.
The reaction was repeated with the (E,Z)-triene 6b as in
the case of 6a to afford 40% of an 80:20 mixture of hydrindanes
11a and 11b.
R-P h en ylselen o P r op a r gyl Ester s 16a ,b. A solution of
LDA (0.32 mmol) in 5 mL of dry THF was cooled to -78 °C,
and the mixture of isomers 14a ,b (50 mg, 0.21 mmol) in 1 mL
of THF was added dropwise via syringe. After 15 min, this
was followed by the similar addition of benzeneselenenyl
chloride (40 mg, 0.21 mmol) in 1 mL of THF. The solution was
stirred at -78 °C for 1 h and then warmed slowly to room
temperature and quenched with 10 mL of saturated aqueous
NH4Cl solution. The aqueous phase was extracted with ether
(3 × 20 mL), and the combined organic layers were dried over
MgSO4 and concentrated in vacuo. The residue was chromato-
graphed (hexanes:ethyl acetate, 10:1) to afford 77 mg (93%)
of 16a ,b as a mixture of stereoisomers in the form of a yellow
oil; IR (neat) 2182, 1726, 1243, 1173, 737 cm-1; 1H NMR (400
MHz) δ (signals from individual stereoisomers could not be
identified) 7.65-7.20 (m, 5 H), 5.00-4.50 (m, 2 H), 2.70-1.00
(m, 13 H), 1.00-0.50 (m, 6 H). Anal. Calcd for C21H26O2Se: C,
64.78; H, 6.73. Found: C, 64.41; H, 6.91.
Diester s 12a ,b. The 40:60 mixture of 11a ,b (1.58 g, 5.94
mmol) in 80 mL of ethyl acetate containing 50 mg of 10% Pd/C
was stirred under hydrogen at 1 atm of pressure and room
temperature for 24 h. The reaction mixture was filtered
through Celite and concentrated under reduced pressure. The
residue was chromatographed (hexanes:ethyl acetate, 10:1) to
yield 1.57 g (99%) of an unseparated mixture of cis- and trans-
hydrindane isomers 12a and 12b, obtained in the same 40:60
ratio (NMR integration) as a colorless oil; IR (neat) 1734, 1255,
1192, 1096 cm-1; 1H NMR (400 MHz) δ 3.73 (s, 6 H, 12b); 3.72
(s, 3 H, 12a ), 3.71 (s, 3 H, 12a ), 2.60-1.00 (m, 12 H, both
isomers), 0.91 (s, 3 H, 12a ), 0.84 (d, J ) 6.6 Hz, 3 H, 12b),
0.80 (d, J ) 6.6 Hz, 3 H, 12a ), 0.62 (d, J ) 0.7 Hz, 3 H, 12b);
MS (m/z, %) 268 (<0.1, M+), 145 (100). Anal. Calcd for
C
15H24O4: C, 67.14; H, 9.01. Found: C, 66.76; H, 8.86.
Ca r boxylic Acid s 13a ,b. The 40:60 mixture of diesters
12a ,b (1.57 g, 5.86 mmol) was refluxed in 150 mL of 15%
aqueous H2SO4 for 4 days. The reaction mixture was then
basified with NaOH to pH 14 and extracted with ether (3 ×
20 mL). The combined organic layers were dried over MgSO4
and evaporated to afford 161 mg (10%) of recovered 12a ,b. The
aqueous phase was acidified to pH 2 and placed in a continuous
extraction apparatus with ether for 24 h. The organic extract
was dried over MgSO4 and evaporated to provide 981 mg (85%)
of a 40:60 mixture of cis and trans isomers 13a and 13b, each
obtained as a pair of stereoisomers,23 in the form of a colorless
oil; IR (neat) 3200-2500, 1702, 1231, 942 cm-1; 1H NMR (400
MHz) δ 13.0 (broad s, 1 H, all isomers), 2.90 (m, 1 H, all
isomers), 2.20-1.10 (m, 12 H, all isomers), 0.91 (s, 3 H, 13a ,
minor isomer), 0.89 (s, 3 H, 13a , major isomer), 0.84, 0.83, 0.80
and 0.79 (four overlapping d, each with J ) 6.6 Hz, 3 H, all
isomers), 0.64 (d, J ) 0.9 Hz, 3 H, 13b, major isomer), 0.62 (d,
J ) 0.9 Hz, 3 H, 13b, minor isomer); MS (m/z, %) 196 (22,
M+), 109 (82), 40 (100). Anal. Calcd for C12H20O2: C, 73.43; H,
10.27. Found: C, 73.16; H, 10.42.
R-P h en ylselen o Allyl Ester s 17a ,b. The preparation of
17a ,b from 200 mg (0.85 mmol) of 15a ,b was carried out in
63% yield by the same procedure used in the preparation of
16a ,b. The product 17a ,b was obtained as a mixture of
stereoisomers in the form of a yellow oil; IR (neat) 1716, 1239,
1168 cm-1 1H NMR (400 MHz) (signals from individual
;
stereoisomers could not be identified) δ 7.65-7.15 (m, 5 H),
6.00-5.73 (m, 1 H), 5.35-4.90 (m, 2 H), 4.65-4.40 (m, 2 H),
2.70-1.00 (m, 12 H), 1.00-0.50 (m, 6 H).
Rea ction of Selen id es 16a ,b w ith Tr i-n -bu tyltin Hy-
d r id e. The mixture of stereoisomers of 16a ,b (30 mg, 0.08
mmol) was refluxed in 5 mL of dry, degassed benzene under
an argon atmosphere. A solution of tri-n-butyltin hydride (33
mg, 0.11 mmol) and AIBN (5 mg, 0.03 mmol) in 5 mL of
benzene was added over 3 h via a syringe pump. The solution
was refluxed for another 3 h and then concentrated under
reduced pressure. The residue was chromatographed (hexanes:
ethyl acetate, 10:1) to afford 14.5 mg (80%) of 14a ,b as colorless
oil, identical to an authentic sample.
Rea ction of Selen id es 17a ,b w ith Tr i-n -bu tyltin Hy-
d r id e. The mixture of stereoisomers of 17a ,b (30 mg, 0.08
mmol) was treated with tri-n-butyltin hydride as in the
preceding procedure to afford 14 mg (78%) of 15a ,b as colorless
oil, identical to an authentic sample.
P r op a r gyl ester s 14a ,b. The mixture of isomers of 13a ,b
(300 mg, 1.53 mmol) and propargyl alcohol (428 mg, 7.65
mmol) was refluxed in 30 mL of chloroform containing several
drops of concentrated H2SO4 for 5 h. The mixture was washed
with water and saturated aqueous Na2CO3 solution, dried over
MgSO4, and concentrated in vacuo. The residue was chromato-
graphed (hexane:ethyl acetate, 10:1) to afford 355 mg (99%)
Ben zyl Ester 18a ,b. Carboxylic acid 13a ,b (70 mg, 0.36
mmol) and NaH (35 mg, 1.4 mmol) were stirred in 6 mL of
dry DMF for 30 min. Benzyl bromide (244 mg, 1.43 mmol) in
1 mL of DMF was added dropwise, and the resulting solution
(23) The (2R,3aâ,4â,7aR)-steroisomer of 13b has been reported:
Ferraz, H. M. C.; Silva, L. F., J r. J . Org. Chem. 1998, 63, 1716.

Synthesis of (()-Bakkenolide-A
J . Org. Chem., Vol. 66, No. 12, 2001 4367
was stirred for 12 h at room temperature. The solvent was
evaporated under vacuum, and 10 mL of water and 20 mL of
ether were added. The aqueous phase was extracted repeatedly
with ether, and the combined organic layers were dried over
MgSO4 and concentrated in vacuo. The product was chromato-
graphed (hexanes:ethyl acetate, 10:1) to afford 95 mg (93%)
of a 40:60 mixture of cis and trans isomers 18a and 18b, each
formed as a pair of stereoisomers, in the form of a colorless
Rea ction of Selen id es 22a ,b w ith Tr i-n -bu tyltin Hy-
d r id e. The mixture of stereoisomers of 22a ,b (30 mg, 0.055
mmol) was treated with tri-n-butyltin hydride as in the case
of 16a ,b to afford 14 mg (66%) of a 40:60 mixture of cis- and
trans-hydrindanes 23a and 23b, each consisting of nearly
equal amounts of two stereoisomers (NMR integration), in the
form of a light yellow oil; IR (neat) 2207, 1731, 1337, 1163,
1
1086 cm-1; H NMR (400 MHz) δ 7.87 (d, J ) 8.3 Hz, 2 H),
oil; IR (neat) 1731, 1156 cm-1
;
1H NMR (400 MHz) δ 7.37-
7.37 (d, J ) 7.9 Hz, 2 H), 4.76 (m, 2 H), 2.85 (m, 1 H), 2.46 (s,
3 H), 2.10-1.05 (m, 12 H), 0.88 (s, 3 H, one isomer of 23a ),
0.87 (s, 3 H, other isomer of 23a ), 0.83, 0.82, 0.78, 0.75 (four
overlapping d, each with J ) 6.6 Hz, 3 H, all isomers), 0.60
(d, J ) 0.8 Hz, 3 H, one isomer of 23b), 0.55 (d, J ) 0.9 Hz, 3
H, other isomer of 23b). Anal. Calcd for C22H28O4S: C, 68.00;
H, 7.26. Found: C, 67.75; H, 7.34.
Eth yl 4-Ben zyloxy-2-[2-m eth yl-2(E)-bu ten yl]a cetoa c-
eta te (27). A solution of â-keto ester 26 (10.3 g, 43.5 mmol)
in 75 mL of THF was added dropwise over 10 min to NaH
(60% suspension, 1.74 g, 43.5 mmol) in 100 mL of THF. After
30 min, tiglyl bromide (8) (6.48 g, 43.5 mmol) in 100 mL of
THF was added dropwise over 15 min, and the reaction
mixture was stirred for 18 h. It was then filtered and the THF
was removed under reduced pressure. Water (150 mL) was
added, and the mixture was extracted with ether (3 × 100 mL).
The extracts were combined, dried over MgSO4, and concen-
trated under reduced pressure. Chromatography (hexanes:
ethyl acetate, 1:5) afforded 11.2 g (85%) of 27 as a colorless
oil; IR (neat) 1750, 1733 cm-1; 1H NMR (200 MHz) δ 7.35 (m,
5 H), 5.24 (m, 1 H), 4.58 (s, 2 H), 4.18-4.05 (m, 4 H), 3.82 (t,
J ) 7.6 Hz, 1 H), 2.55 (m, 2 H), 1.60 (t, J ) 1.1 Hz, 3 H), 1.53
(crude d, J ) 6.7 Hz, 3 H), 1.20 (t, J ) 7.1 Hz, 3 H); MS (m/z,
%) 258 (4), 207 (16), 167 (38), 91 (100). Anal. Calcd for
7.34 (m, 5 H, all isomers), 5.13-5.10 (m, 2 H, all isomers),
2.92 (m, 1 H, all isomers), 2.30-1.00 (m, 12 H, all isomers),
0.89 (s, 3 H, 18a , major isomer), 0.87 (s, 3 H, 18a , minor
isomer), 0.83, 0.82, 0.79, 0.75 (four overlapping d, each with J
) 6.6 Hz, 3 H, all isomers), 0.62 (d, J ) 0.7 Hz, 3 H, 18b,
minor isomer), 0.61 (d, J ) 0.7 Hz, 3 H, 18b, major isomer);
MS (m/z, %) 286 (18, M+), 179 (14), 149 (62), 91 (100). HRMS
calcd for C19H26O2: 286.1933; Found: 286.1944.
R-P h en ylselen o Ben zyl Ester s 19a ,b. The mixture of
stereoisomers of 18a ,b (95 mg, 0.33 mmol) was selenenylated
by the same procedure used in the preparation of 16a ,b to
afford 120 mg (82%) of 19a ,b as a mixture of stereoisoimers
in the form of a yellow oil; IR (neat) 1721, 1250, 1178 cm-1
;
1H NMR (400 MHz) (signals from individual stereoisomers
could not be identified) δ 7.55-7.20 (m, 5 H), 5.21-4.90 (m, 2
H), 2.70-1.00 (m, 12 H), 1.00-0.50 (m, 6 H); MS (m/z, %) 442
(2, M+), 193 (55), 149 (78, 91 (100). HRMS calcd for C25H30O2-
Se: 442.1411; Found: 442.1426.
3-(p-Tolu en esu lfon yl)-2-p r op yn -1-ol (21) a n d its ter t-
Bu tyld im eth ylsilyl Eth er 20. (E)-1-(tert-Butyldimethylsily-
loxy)-2-(phenylseleno)-3-(p-toluenesulfonyl)-2-propen-1-ol and
the corresponding selenoxide were prepared as described
previously.19 The selenoxide (5.99 g, 12.0 mmol) and 10 g of
anhydrous MgSO4 were refluxed for 4 h in 300 mL of benzene.
The mixture was then filtered, concentrated under reduced
pressure, and chromatographed (hexanes:ethyl acetate, 9:1)
to afford the corresponding acetylenic sulfone as an oil that
crystallized from pentane to afford 2.61 g (67%) of the
acetylenic sulfone 20 as white needles, mp 44-45 °C; IR (KBr)
2202, 1596, 1335, 1161 cm-1; 1H NMR (200 MHz) δ 7.89 (d, J
) 8.6 Hz, 2 H), 7.38 (d, J ) 8.6 Hz, 2 H), 4.42 (s, 2 H), 2.48 (s,
3 H), 0.85 (s, 9 H), 0.06 (s, 6 H); MS (m/z, %) 324 (1, M+), 237
(75), 173 (79), 128 (100). Anal. Calcd. for C16H24O3SSi: C,
59.22; H, 7.45. Found: C, 59.09; H, 7.30.
The above acetylenic sulfone 20 (1.00 g, 3.09 mmol) was
stirred for 1 h in 20 mL of 50% aqueous trifluoroaceetic acid.
The mixture was diluted with 30 mL of ethyl acetate, washed
rapidly with 5% NaOH solution, dried over MgSO4, and
concentrated in vacuo. The residue was chromatographed
(hexanes:ethyl acetate, 3:1) to afford 0.507 g (78%) of 21 as a
pale yellow oil that was best used without delay; 1H NMR (200
MHz) δ 7.90 (d, J ) 8.6 Hz, 2 H), 7.40 (d, J ) 8.6 Hz, 2 H),
4.41 (s, 2 H), 2.48 (s, 3 H), 1.72 (br s, 1 H).
Acetylen ic Su lfon e 22a ,b. The mixture of stereoisomers
of R-phenylseleno benzyl ester 19a ,b (300 mg, 0.68 mmol) was
refluxed in a mixture of 10 mL of 15% aqueous H2SO4 and 10
mL of 1,4-dioxane for 3 days. The reaction was basified with
NaOH to pH 14 and washed with ether (3 × 20 mL). The
combined organic layers afforded 126 mg of recovered 19a ,b.
The aqueous phase was acidified to pH 2 and extracted with
ether (3 × 20 mL). The organic extracts were dried over MgSO4
and concentrated in vacuo to afford 103 mg (43%) of the desired
free R-phenylseleno carboxylic acid, contaminated with a small
amount of the deselenized acid 13a ,b.
The partially purified R-phenylseleno carboxylic acid (60 mg,
0.17 mmol), acetylenic sulfone 21 (85 mg, 0.40 mmol) and DCC
(140 mg, 0.68 mmol) were stirred in 10 mL of dry dichlo-
romethane for 12 h at room temperature. The solvent was
evaporated, and the residue was chromatographed (hexanes:
ethyl acetate, 10:1) to afford 60 mg (64%) of 22a ,b, in the form
C
18H24O4: C, 71.03; H, 7.95. Found: C, 70.60; H, 8.20.
Eth yl 4-Ben zyloxy-2-[2-m eth yl-2(E)-bu ten yl]-2-[2(E),4-
p en ta d ien yl]a cetoa ceta te (25a ). A solution of keto ester 27
(3.38 g, 11.1 mmol) in 10 mL of THF was added to NaH (60%
suspension, 0.445 g, 11.1 mmol) in 25 mL of THF. The reaction
mixture was stirred for 30 min, and a solution of bromide 10a
(1.65 g, 11.1 mmol) in 10 mL of THF was added. The reaction
mixture was refluxed for 2 h and allowed to cool to room
temperature. The mixture was filtered, and the THF was
removed under reduced pressure. Water (75 mL) was added,
and the mixture was extracted with ether (3 × 50 mL). The
extracts were combined, dried over MgSO4, and concentrated
under reduced pressure. Chromatography (hexanes:ethyl ac-
etate, 7:1) afforded 3.69 g (90%) of 25a as a colorless oil; IR
(neat) 1745, 1718, 1609 cm-1;1H NMR (200 MHz) δ 7.34 (m, 5
H), 6.25 (dt, J ) 16.8, 10.2 Hz, 1 H), 6.10-5.93 (m, 1 H), 5.50
(dt, J ) 14.7, 7.2 Hz, 1 H), 5.25 (m, 1 H), 5.14-4.97 (m, 2 H),
4.54 (s, 2 H), 4.19 (s, 2 H), 4.08 (q, J ) 7.2 Hz, 2 H), 2.75-2.60
(m, 4 H), 1.63-1.47 (m, 6 H), 1.19 (t, J ) 7.2 Hz, 3 H); 13C
NMR δ (50 MHz) 204.8, 171.4, 137.0, 136.6, 134.7, 130.6, 128.4,
128.3, 127.9, 127.7, 124.6, 116.3, 74.2, 73.3, 61.4, 61.0, 42.1,
35.5, 16.9, 14.0, 13.5; MS (m/z, %) 281 (27), 207 (100), 91 (93).
Eth yl 4-Ben zyloxy-2-[2-m eth yl-2(E)-bu ten yl]-2-[2(Z)-4-
p en ta d ien yl]a cetoa ceta te (25b). Product 25b was prepared
from 1.30 g (4.27 mmol) of keto ester 27, 0.636 g (4.27 mmol)
of Z-bromide 10b, and NaH (60% suspension, 0.171 g, 4.28
mmol) via the same procedure as used for the preparation of
1
25a . This afforded 1.45 g (92%) of 25b as a colorless oil; H
NMR (200 MHz) δ 7.34 (m, 5 H), 6.58 (dt, J ) 16.8, 10.6 Hz,
1 H), 6.08 (t, J ) 11.1 Hz, 1 H), 5.35-5.06 (m, 4 H), 4.54 (s, 2
H), 4.18 (s, 2 H), 4.12 (q, J ) 7.2 Hz, 2 H), 3.00-2.60 (m, 2 H),
2.69 (br s, 2 H), 1.57 (d, J ) 4.4 Hz, 3 H), 1.50 (t, J ) 1.2 Hz),
1.18 (t, J ) 7.2 Hz, 3 H); MS (m/z, %) 281 (23), 207 (100), 91
(88). Anal. Calcd for C23H30O4: C, 74.56; H, 8.16. Found: C,
74.52; H, 8.50.
In tr a m olecu la r Diels-Ald er Cycloa d d ition of (E,E)-
Tr ien e 25a a n d (E,Z)-Tr ien e 25b. Compound 25a (1.05 g,
2.84 mmol) in 400 mL of toluene containing BHT (200 mg)
was heated at 190 °C for 24 h in a sealed Parr apparatus. The
toluene was removed under reduced pressure, and chroma-
tography of the residue (hexanes:ethyl acetate, 8:1) afforded
1.00 g (95%) of 28 as a mixture of stereoisomers in the form of
of a yellow oil; IR (neat) 2212, 1700, 1342, 1229, 1163 cm-1
;
1H NMR (400 MHz) (signals from individual stereoisomers
could not be identified) δ 7.95-7.30 (m, 9 H), 4.90-4.55 (m,
2H), 2.43 (s, 3 H) superimposed on 2.70-1.10 (m, 12 H), 1.10-
0.70 (m, 6 H). The product was used directly without further
purification.
a light yellow oil; IR (neat) 1746, 1715 cm-1 1H NMR (400
;

4368 J . Org. Chem., Vol. 66, No. 12, 2001
Back et al.
MHz) (signals from individual stereoisomers could not be
identified) δ 7.40-7.25 (m, 5 H), 5.70-5.55 (m, 2 H), 4.55 (m,
2 H), 4.25-4.00 (m, 4 H), 2.70-1.40 (m, 8 H), 1.21-1.14 (m, 3
H), 0.95-0.50 (m, 6 H); MS (m/z, %) 370 (M+, 1), 279 (21), 233
(20), 147 (33), 91 (100). HRMS calcd for C23H30O4: 370.2144.
Found 370.2148.
Hz, 1 H), 1.98 (m, 2 H), 1.70-1.40 (m, 7 H), 1.20 (m, 1 H),
1.00 (s, 3 H), 0.86 (d, J ) 6.8 Hz, 3 H); 13C NMR (100 MHz) δ
150.7, 106.0, 70.6, 50.1, 48.8, 46.4, 44.3, 42.6, 34.1, 31.1, 23.6,
21.2, 19.4, 16.6; MS (m/z, %) 234 (M+, 10%), 219 (8), 124 (100),
123 (45), 111 (71). These spectra were identical to those
obtained from an authentic sample provided by Dr. J . Har-
matha of the Czech Academy of Sciences.
The mixture of isomers of 28 was similarly prepared in 54%
yield from compound 25b.
(()-7-Epibakkenolide-A (2): 1H NMR (200 MHz) δ 5.07 (m,
1 H), 4.99 (m, 1 H), 4.75 (m, 2 H), 2.47 (dd, J ) 13.6, 12.3 Hz,
1 H), 2.41 (d, J ) 14.2 Hz, 1 H), 2.10-1.40 (m, 10 H), 0.97 (s,
3 H), 0.82 (d, J ) 6.6 Hz, 3 H); these signals were superim-
posed on those corresponding to 1; the ratio of integrated
intensities of signals of 2 to 1 was ca. 4:1; the NMR spectrum
of 2 closely matches that reported in the literature;7k MS (m/
z, %) 234 (M+, 72%), 219 (30), 124 (78), 123 (82), 111 (100).
(()-10-Epibakkenolide-A (3): 1H NMR (400 MHz) δ 5.08 (m,
1 H), 4.97 (m, 1 H), 4.79 (m, 2 H), 2.17 (d, J ) 13.2 Hz, 1 H),
2.06 (dd, J ) 13.3, 12.2 Hz, 1 H), 1.80 (m, 2 H), 1.60-1.20 (m,
8 H), 0.91 (d, J ) 0.8 Hz, 3 H), 0.86 (d, J ) 6.5 Hz, 3 H); 13C
NMR (100 MHz) δ 151.9, 104.9, 70.1, 51.8, 50.2, 49.1, 45.4,
43.8, 42.3, 30.0, 26.4, 24.5, 17.2, 11.9; MS (m/z, %) 234 (M+,
10%), 219 (7), 124 (67), 123 (100), 111 (80). HRMS calcd for
C15H22O2: 234.1620. Found: 234.1630.
Sp ir o La cton e 29. A mixture of isomers of 28 (57 mg, 0.15
mmol) obtained from 25a and 20 mg of 10% Pd-C was stirred
in 5 mL of ethyl acetate under 1 atm of hydrogen for 3 days.
The mixture was then filtered through Celite, the filtrate was
concentrated under reduced pressure, and the residue was
chromatographed (hexanes:ethyl acetate, 5:1) to afford 39 mg
(90%) of the corresponding hydroxy ester as a colorless oil that
lactonized slowly and spontaneously upon standing. Alterna-
tively, to accelerate lactonization, the hydroxy ester (81 mg,
0.30 mmol) was stirred for 7 h in 1.5 mL of dioxane and 0.5
mL of 6 M HCl. The mixture was then diluted with water and
extracted with ether (3 × 10 mL). The combined organic layers
were dried over MgSO4, the solvent was removed under
reduced pressure, and chromatography of the residue (hex-
anes:ethyl acetate, 3:1) afforded 72 mg (quantitative) of a
mixture of stereoisomers of 29 as a colorless oil; IR (neat) 1756,
(()-7,10-Diepibakkenolide-A (4): 1H NMR (400 MHz) δ 5.17
(m, 1 H), 5.03 (m, 1 H), 4.77 (m, 2 H), 2.09 (dd, J ) 12.2, 5.8
Hz, 1 H), 1.99 (d, J ) 12.8 Hz, 1 H), 1.90-1.13 (m, 10 H), 0.85
(d, J ) 6.7 Hz, 3 H), 0.80 (d, J ) 0.8 Hz, 3 H); double
irradiation of the signal at δ 0.80 ppm resulted in an enhance-
ment of 2% of the signal at δ 5.17 ppm; 13C NMR (100 MHz)
δ 149.9, 106.1, 70.5, 50.3, 49.3, 45.0, 43.1, 42.4, 30.0, 26.2, 24.5,
17.1, 13.1; MS (m/z, %) 234 (M+, 5%), 219 (4), 124 (100), 123
(56), 111 (81). HRMS calcd for C15H22O2, 234.1620: Found:
234.1627.
1740 cm-1 1H NMR (400 MHz) (signals from individual
;
stereoisomers could not be identified) δ 4.72-4.56 (m, 2 H),
2.45-1.05 (m, 12 H), 1.00-0.80 (m, 6 H); MS (m/z, %) 236 (M+,
5), 221 (6), 123 (100), 109 (77).
The mixture of isomers of 29 was similarly prepared in 93%
yield from 28 that had been obtained from 25b. The products
were used directly without further purification.
Ba k k en olid e-A (1) a n d Its Ster eoisom er s 2-4. n-Bu-
tyllithum (2.17 M, 0.27 mL, 0.59 mmol) was added to meth-
yltriphenylphosphonium iodide (0.24 g, 0.59 mmol) in 4 mL
of dry ether. A solution of the mixture of stereoisomers of 29
(47.0 mg, 0.199 mmol; derived from E,E-triene 25a ) in 1 mL
of ether was added, and the reaction mixture was stirred for
an additional 2 h. The reaction was quenched with water, and
the mixture was extracted with ether (5 × 10 mL). The
combined extracts were dried over MgSO4, the solvent was
removed under reduced pressure, and chromatography of the
residue (hexanes:ethyl acetate, 5:1) afforded 28.9 mg (62%) of
the mixture of isomers 1-4 in the ratio of 24:10:34:32 (GC
analysis). They were separated by preparative reversed phase
HPLC (elution with methanol-water, 7:3) and eluted in the
order: 1, 2, 4, and 3. Products 1, 3, and 4 were >95% pure,
while 2 was obtained as a 4:1 mixture with 1. The same
products 1-4 were obtained in 61% yield in the ratio of 54:
19:16:11 when the starting material 29 was obtained from E,Z-
triene 25b. The properties of the products are as follows.
(()-Bakkenolide-A (1): 1H NMR (400 MHz) δ 5.12 (m, 1 H),
5.04 (m, 1 H), 4.78 (m, 2 H), 2.26 (m, 1 H), 2.10 (t, J ) 13.1
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada (NSERC)
for financial support. We thank Dr. J . Harmatha of the
Czech Academy of Sciences for a generous gift of
authentic bakkenolide-A (1) and for providing us with
useful information about its biological properties. We
also thank Mr. M. Hamilton (University of Calgary) for
assistance in the preparation of 3-(p-toluenesulfonyl)-
2-propyn-1-ol (20).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of both authentic and synthetic samples of 1,
1H NMR spectra of products 2-4, and 13C NMR spectra of new
compounds 3 and 4. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O015624H