First comprehensive bakkane approach: Stereoselective and efficient dichloroketene-based total syntheses of (±)- and (-)-9-acetoxyfukinanolide, (±)- and (+)-bakkenolide a, (-)-bakkenolides III, B, C, H, L, V, and X, (±)- and (-)-homogynolide A, (±)-homogynolide B, and (±)-palmosalide C

Article abstract of DOI:10.1021/ja0208456

Cycloaddition of dichloroketene with dimethylcyclohexenes has been used as the key reaction in an efficient, general approach to the bakkanes. New methods and methodologies that have been developed in this work include spiro β-methylene-γ-butyrolactonizations, a vicinal dicarboxylation, an angelic ester preparation, a transesterification, an epoxy ketone double reduction, and a retro aldol-aldol approach to low-energy aldol isomers.

Full text of DOI:10.1021/ja0208456

Published on Web 11/27/2002
First Comprehensive Bakkane Approach: Stereoselective and
Efficient Dichloroketene-Based Total Syntheses of (()- and
(-)-9-Acetoxyfukinanolide, (()- and (+)-Bakkenolide A,
(-)-Bakkenolides III, B, C, H, L, V, and X, (()- and
(-)-Homogynolide A, (()-Homogynolide B, and
(()-Palmosalide C
Timothy J. Brocksom,† Fernando Coelho,‡ Jean-Pierre Depre´s,*
Andrew E. Greene,* Marco E. Freire de Lima,§ Olivier Hamelin,| Benoˆıt Hartmann,
Alice M. Kanazawa, and Yanyun Wang#
Contribution from the Chimie Recherche (LEDSS), UniVersite´ Joseph Fourier,
BP 53X, 38041 Grenoble, France
Received June 17, 2002
Abstract: Cycloaddition of dichloroketene with dimethylcyclohexenes has been used as the key reaction
in an efficient, general approach to the bakkanes. New methods and methodologies that have been
developed in this work include spiro â-methylene-γ-butyrolactonizations, a vicinal dicarboxylation, an angelic
ester preparation, a transesterification, an epoxy ketone double reduction, and a retro aldol-aldol approach
to low-energy aldol isomers.
gynolide B (2b*),4 (+)-palmosalide C (3),5 (-)-9-acetoxyfuki-
nanolide (4*),6 and (-)-bakkenolides III and B-E (5a-
Introduction
The bakkane family comprises sesquiterpenes that have in
common a hydrindane skeleton and a spiro-fused γ-butyrolac-
tone that generally bears an otherwise rare â-methylene func-
tion.1 The archetype of this family, bakkenolide A (fukinanolide)
(1*, Chart 1),2 was first isolated in 1968 from the flower stalks
of the wild butterbur Petasites japonicus by two Japanese groups
working independently.3
e*).3b-d,4,7 The number of known bakkanes, however, truly
mushroomed in 1999 with Wu and co-workers’ publications
on the root constituents of Petasites formosanus Kitamura.8
Thirty-five new bakkanes were disclosed, primarily additional
C-1 and/or C-9 oxygenated congeners of bakkenolide A (e.g.,
5f-i*), thus bringing the total number of known bakkanes to
approximately 50. While most of these have to date been isolated
from plants indigenous to Japan and Taiwan, plants native to
China, The Czech Republic, France, Iran, Norway, Scotland,
Spain, and Switzerland and an octocoral found in the Indian
Ocean have also yielded various bakkanes.1b
Over the next three decades, several more complex bakkanes
were isolated, including (-)-homogynolide A (2a*),4 (-)-homo-
* To whom correspondence should be addressed. E-mail: (J.-P.D.) Jean-
Pierre.Depres@ujf-grenoble.fr; (A.E.G.) Andrew.Greene@ujf-grenoble.fr.
† Current address: Universidade Federal de Sao Carlos, CP 676, 13565-
905 Sao Carlos, Brazil.
Through a combination of degradation, spectroscopic, and
X-ray diffraction studies, the structure and the relative and
absolute stereochemistry of bakkenolide A were determined;3
it would now appear that most, if not all, of the bakkanes belong
to this enantiomeric series. Furthermore, among the known
bakkanes, only two are not â-methylene-γ-butyrolactones, and
these are also the only ones to have inverted stereochemistry at
‡ Current address: Unicamp, CP 6154, 13081-970 Campinas, Brazil.
§ Current address: Universidade Federal de Rural Rio do Janeiro, 23890-
000 Serope´dica, Brazil.
| Current address: CEA, 17 rue des Martyrs, 38054 Grenoble, France.
Current address: Aventis CropScience, 14-20 rue P. Baizet, BP 9163,
69263 Lyon, France.
# Current address: University of Georgia, Athens, GA 30602-2556.
(1) See: (a) Fischer, N. H.; Oliver, 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. (b)
Silva, L. F., Jr. Synthesis 2001, 671-689.
(4) (a) Harmatha, J.; Samek, Z.; Syna´ckova, M.; Novotny, L.; Herout V.; Sorm,
F. Collect. CzechosloV. Chem. Commun. 1976, 41, 2047-2058. (b)
Jakupovic, J.; Grenz, M.; Bohlmann, F. Planta Med. 1989, 55, 571-572.
(5) Wiemer, D. F.; Wolfe, L. K.; Fenical, W.; Strobel, S. A.; Clardy, J.
Tetrahedron Lett. 1990, 31, 1973-1976.
(2) An asterisk with a compound number signifies that a single enantiomer is
depicted with the absolute stereochemistry as indicated. Bakkane numbering
is used in this paper.
(3) (a) Abe, N.; Onoda, R.; Shirahata, K.; Kato, T.; Woods, M. C.; Kitahara,
Y. Tetrahedron Lett. 1968, 9, 369-373. (b) Shirahata, K.; Kato, T.;
Kitahara, Y.; Abe, N. Tetrahedron 1969, 25, 3179-3191 and 4671-4680.
(c) Naya, K.; Takagi, I.; Hayashi, M.; Nakamura, S.; Kobayashi, M.;
Katsumura, S. Chem. Ind. (London) 1968, 318-320. (d) Naya, K.; Hayashi,
M.; Takagi, I.; Nakamura, S.; Kobayashi, M. Bull. Chem. Soc. Jpn. 1972,
45, 3673-3685. This plant is known vernacularly in the north-east of Japan
as “bakka”, but as “fuki” in Japanese, and thus an often confusing dual
nomenclature has arisen for several members of this family.
(6) Naya, K., Kawai, M.; Naito, M.; Kasai, T. Chem. Lett. 1972, 241-244.
(7) (a) Abe, N.; Onoda, R.; Shirahata, K.; Kato, T.; Woods, M. C.; Kitahara,
Y.; Ro, K.; Kurihara, T. Tetrahedron Lett. 1968, 9, 1993-1997. (b)
Shirahata, K.; Abe, N.; Kato, T.; Kitahara, Y. Bull. Chem. Soc. Jpn. 1968,
41, 1732-1733.
(8) (a) Wu, T.-S.; Kao, M.-S.; Wu, P.-L.; Lin, F.-W.; Shi, L.-S.; Teng, C.-M.
Phytochemistry 1999, 52, 901-905. (b) Wu, T.-S.; Kao, M.-S.; Wu, P.-L.;
Lin, F.-W.; Shi, L.-S.; Liou, M.-J.; Li, C.-Y. Chem. Pharm. Bull. 1999,
47, 375-382.
9
10.1021/ja0208456 CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 15313-15325
15313

A R T I C L E S
Brocksom et al.
sigmatropic rearrangement as the key transformation.13 Remark-
ably, our disclosures14a,b on the synthesis of racemic bakkenolide
A in 1985 and the first synthesis of (+)-bakkenolide A in 1988
were the next publications in this area. Since this period,
however, synthetic activity has increased considerably, with
publications from several laboratories15 in addition to our
own.14c-i
Chart 1
Our general interest in the bakkanes, initially in bakkenolide
A, originated from a desire to exploit further the synthetic
potential of dichloroketene and its cycloadducts.16,17 Because
of the propensity of this ketene to undergo for stereoelectronic
reasons axial carbonyl bonding and to prefer due to electronic
factors adjacency of the Cl2C group to the olefinic carbon that
is better able to stabilize an incipient positive charge,17,18 it
appeared that its cycloaddition with 1,6-dimethylcyclohexene,
as well as certain derivatives, might proceed highly stereo- (and
regio-) selectively to give adduct II, in which three or more of
the stereocenters of the bakkanes would be in place with the
correct relative configurations (eq 1).
1-Methylcyclohexene was known19 to undergo smooth cy-
cloaddition with dichloroketene to give the expected dichloro-
cyclobutanone adduct; it was anticipated that the additional C-6
(13) Evans, D. A.; Sims, C. L. Tetrahedron Lett. 1973, 4691-4694. Evans, D.
A.; Sims, C. L.; Andrews, G. C. J. Am. Chem. Soc. 1977, 99, 5453-5461.
See also ref 10.
(14) For our preliminary communications, see: (a) Greene, A. E.; Depre´s, J.-
P.; Coelho, F.; Brocksom, T. J. J. Org. Chem. 1985, 50, 3943-3945 ((()-
bakkenolide A). (b) Greene, A. E.; Coelho, F.; Depre´s, J.-P.; Brocksom,
T. J. Tetrahedron Lett. 1988, 29, 5661-5662 ((+)-bakkenolide A). (c)
Coelho, F.; Depre´s, J.-P.; Brocksom, T. J.; Greene, A. E. Tetrahedron Lett.
1989, 30, 565-566 ((()-homogynolide B). (d) Hartmann, B.; Kanazawa,
A. M.; Depre´s, J.-P.; Greene, A. E. Tetrahedron Lett. 1991, 32, 767-768
((()-homogynolide A). (e) Hartmann, B.; Kanazawa, A. M.; Depre´s, J.-
P.; Greene, A. E. Tetrahedron Lett. 1993, 34, 3875-3876 ((-)-homogy-
nolide A). (f) Hartmann, B.; Depre´s, J.-P.; Greene, A. E.; Freire de Lima,
M. E. Tetrahedron Lett. 1993, 34, 1487-1490 ((()-palmosalide C). (g)
Hamelin, O.; Depre´s, J.-P.; Greene, A. E.; Tinant, B.; Declercq, J.-P. J.
Am. Chem. Soc. 1996, 118, 9992-9993 ((()-9-acetoxyfukinanolide). (h)
Hamelin, O.; Depre´s, J.-P.; Heidenhain, S.; Greene, A. E. Nat. Prod. Lett.
1997, 10, 99-103 ((-)-9-acetoxyfukinanolide). (i) Hamelin, O.; Wang,
Y.; Depre´s, J.-P.; Greene, A. E. Angew. Chem., Int. Ed. 2000, 39, 4314-
4316 ((-)-bakkenolides III, B, C, and H).
the C-7 spiro center.5,9 While the biogenesis of the bakkanes
hasnot been firmly established, they are believed to issue from
the eremophilanes, compounds with which they frequently co-
exist.3,5-7,9,10 Diverse biological properties have been attributed
to members of the bakkane family, including selective cytotoxic
activity,8b,11 antifeedant effects,12 and inhibition of platelet
aggregation,8a traits generally associated with the conjugated
R-methylene-γ-butyrolactones.
(15) (a) Srikrishna, A.; Nagaraju, S.; Venkateswarlu, S. Tetrahedron Lett. 1994,
35, 429-432 ((()-homogynolide B). (b) Srikrishna, A.; Reddy, T. J.;
Nagaraju, S.; Sattigeri, J. A. Tetrahedron Lett. 1994, 35, 7841-7844 ((()-
bakkenolide A). (c) Srikrishna, A.; Viswajanani, R.; Sattigeri, J. A. J. Chem.
Soc., Chem. Commun. 1995, 469-470 ((()-4-epi-bakkenolide A). (d)
Srikrishna, A.; Reddy, T. J. Indian J. Chem. 1995, 34B, 844-846 ((-)-
homogynolide A). (e) Mori, K.; Matsushima, Y. Synthesis 1995, 845-850
((-)-homogynolide A). (f) Srikrishna, A.; Nagaraju, S.; Venkateswarlu,
S.; Hiremath, U. S.; Reddy, T. J.; Venugopalan, P. J. Chem. Soc., Perkin
Trans. 1 1999, 2069-2076 ((()-homogynolide B). (g) Back, T. G.;
Gladstone, P. L.; Parvez, M. J. Org. Chem. 1996, 61, 3806-3814. Back,
T. G.; Payne, J. E. Org. Lett. 1999, 1, 663-665. Back, T. G.; Nava-Salgado,
V. O.; Payne, J. E. J. Org. Chem. 2001, 66, 4361-4368 ((()-bakkenolide
A).
(16) For leading references to our work with dichloroketene, see: Pourashraf,
M.; Delair, P.; Rasmussen, M. O.; Greene, A. E. J. Org. Chem. 2000, 65,
6966-6972. Rasmussen, M. O.; Delair, P.; Greene, A. E. J. Org. Chem.
2001, 66, 5438-5443.
(17) For reviews on dichloroketene, see: Hyatt, J. A.; Raynolds, P. W. Org.
React. 1994, 45, 159-646. Tidwell, T. T. Ketenes; Wiley: New York,
1995.
Evans and Sims in 1973 published the first successful bakkane
total synthesis, a 13-step preparation of racemic bakkenolide A
that proceeded in ca. 1.5% overall yield, with a novel [2,3]-
(9) Torres, P.; Ayala, J.; Grande, C.; Mac´ıas, M. J.; Grande, M. Phytochemistry
1998, 47, 57-61.
(10) A successful “biomimetic” conversion of fukinone to bakkenolide A has
been realized: Hayashi, K.; Nakamura, H.; Mitsuhashi, H. Chem. Pharm.
Bull. 1973, 21, 2806-2807. See also: Marshall, J. A.; Cohen, G. M. J.
Org. Chem. 1971, 36, 877-882 and refs 2c,d.
(11) Jamieson, G. R.; Reid, E. H.; Turner, B. P.; Jamieson, A. T. Phytochemistry
1976, 15, 1713-1715. Antitumor Compounds of Natural Origin: Chemistry
and Biochemistry; Aszalos, A., Ed.; CRC Press: Boca Raton, FL, 1981.
See also: Kano, K.; Hayashi, K.; Mitsuhashi, H. Chem. Pharm. Bull. 1982,
30, 1198-1203.
(12) Nawrot, J.; Bloszyk, E.; Harmatha, J.; Novotny, L. Z. Angrew. Entomol.
1984, 98, 394-398. Hamatha, J.; Nawrot, J. Biochem. Syst. Ecol. 1984,
12, 95-98. Nawrot, J.; Harmatha, J.; Novotny, L. Biochem. Syst. Ecol.
1984, 12, 99-101. Nawrot, J.; Bloszyk, E.; Harmatha, J.; Novotny, L.;
Drozdz, B. Acta Entomol. BohemosloV. 1986, 83, 327-335. Nawrot, J.;
Harmatha, J.; Bloszyk, E. 4th International Conference on Stored-Product
Protection, Tel-Aviv, Sept. 1986. Kreckova, J.; Krecek, J.; Harmatha, J.
Pr. Nauk. Inst. Chem. Org. Fiz. Politech. Wroclaw. 1988, 33, 105-107.
Rosinski, G.; Bloszyk, E.; Harmatha, J.; Knapik, A. Pr. Nauk. Inst. Chem.
Org. Fiz. Politech. Wroclaw. 1988, 33, 91-94.
(18) (a) Hassner, A.; Fletcher, V. R.; Hamon, D. P. G. J. Am. Chem. Soc. 1971,
93, 264-265. (b) Hassner, A.; Krepski, L. R. J. Org. Chem. 1979, 44,
1376-1379. See also: Valenti, E.; Perica`s, M. A.; Moyano, A. J. Org.
Chem. 1990, 55, 3582-3593.
(19) (a) Krepski, L. R.; Hassner, A. J. Org. Chem. 1978, 43, 2879-2882. (b)
Greene, A. E.; Depre´s, J.-P. J. Am. Chem. Soc. 1979, 101, 4003-4005.
9
15314 J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002

Syntheses of Bakkanes
A R T I C L E S
Scheme 1 a
methyl group would prove innocuous and, furthermore, that the
cycloaddition would take place principally trans to this group
for stereoelectronic reasons. If this were, in fact, observed, it
was hoped that methods could then be developed for regio-
selectively converting the dichlorocyclobutanones II into five-
membered carbocycles that would possess appropriate func-
tionalization to allow facile construction of the spiro-fused
γ-butyrolactone unit and, ultimately, the natural products.
In this paper, we provide full details of a comprehensive
bakkane approach that we have been able to develop over the
past several years through the successful implementation of this
general strategy. Described below, in addition to the preparation
of (()- and (+)-bakkenolide A, are the first syntheses of
representatiVes of the more highly oxygenated bakkanes: (()-
and (-)-homogynolide A, (()-homogynolide B, (()-palmo-
salide C, (()- and (-)-9-acetoxyfukinanolide, and (-)-bakkeno-
lides III, B, C, H, L, V, and X (Chart 1).14 As will be noted,
the stereoselective nature of these syntheses results from our
being able to parlay through internal asymmetric induction the
stereoselectivity of the above-mentioned dichloroketene-olefin
[2 + 2] cycloaddition; the efficiency stems from several new
synthetic methods that were developed in the context of this
work.
Results and Discussion
a (a) CCl3COCl, Zn-Cu, POCl3, (C2H5)2O, 20 °C. (b) n-BuLi, THF,
-78 °C, then (CH3CO)2O, -78 f 20 °C; RuO2 (cat), NaIO4, CH3CN-
CCl4-H2O (1.5:1:1), 20 °C. (c) LiAlH4, THF, ∆. (d) TMSI, CHCl3, 20
°C. (e) 13, DME-HMPA, LHMDS (2×), -60 °C. (f) HF, CH3CN, 20 °C,
separation.
Bakkenolide A. The required 1,6-dimethyl-1-cyclohexene (8)
was best prepared by the route shown in eq 2. Cheap 2,3-
We envisioned at this point transformation of dichlorocy-
clobutanone 9 into a bis-electrophile for five-membered ring
formation and rapid access to the bakkane framework by
reaction with a â-methylene-γ-butyrolactone synthon. Working
with model systems, a simple and reliable one-pot protocol was
developed for the oxidative cleavage of a wide range of R,R-
dichlorocyclobutanones: sequential treatment with n-butyl-
lithium, acetic anhydride, and ruthenium dioxide-sodium peri-
odate cleanly provided the corresponding succinic acids V in
73-94% yields (eq 4).24 It is worth pointing out that this
dichloroketene cycloaddition-cleavage tandem (ΙΙΙ f V) is
tantamount to a stereospecific vicinal dicarboxylation procedure,
for which little else exists.
dimethylcyclohexanol (6) was oxidized20 on a large scale to
provide a diastereomeric mixture of ketones, which underwent
highly regioselective chlorination with sulfuryl chloride21 to give
7. Reduction22 of this material in two stages then provided the
desired olefin 8 in ca. 50% overall yield with an isomeric purity
in excess of 96% following distillation. Other preparations were
considerably less regioselective and, in addition, less conducive
to large-scale work and facile olefin isolation.
To our considerable satisfaction, this olefin indeed underwent
highly regio- and stereoselective cycloaddition (g90%) in the
presence of trichloroacetyl chloride, phosphorus oxychloride,
and zinc-copper couple19a to deliver the desired adduct 9 in
80% yield (Scheme 1). A minor amount of an inseparable isomer
(later determined to be the diastereomer) could be detected by
1H NMR, but over the course of the remainder of the synthesis,
conveniently, this material gradually filtered out. That the major
product was, in fact, the desired diastereomer was readily
demonstrated by conversion19b to the known23 bicyclo[4.3.0]-
nonanone 12 (eq 3).
Application of the cleavage method to the above adduct 9
delivered the expected diacid 10a, which could be readily
reduced to the corresponding diol 10b in excellent overall yield.
The bis-electrophile cyclization substrate, diiodide 10c, was next
prepared in 75% yield with trimethylsilyl iodide in chloroform.25
(20) Nwaukwa, S. O.; Keehn, P. M. Tetrahedron Lett. 1982, 23, 35-38.
(21) Warnhoff, E. W.; Johnson, W. S. J. Am. Chem. Soc. 1953, 75, 494-496.
(22) Kochi, J. K.; Singleton, D. M. J. Am. Chem. Soc. 1968, 90, 1582-1589.
(23) Naya, K.; Takagi, I.; Kawaguchi, Y.; Asada, Y.; Hirose, Y.; Shinoda, H.
Tetrahedron 1968, 24, 5871-5879.
(24) Depre´s, J.-P.; Coelho, F.; Greene, A. E. J. Org. Chem. 1985, 50, 1972-
1973. Depre´s, J.-P.; Greene, A. E. Org. Synth. 1990, 68, 41-48.
(25) Jung, M. E.; Ornstein, P. L. Tetrahedron Lett. 1977, 2659-2662.
9
J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002 15315

A R T I C L E S
Brocksom et al.
Scheme 2 a
cyclohexen-1-one28 was asymmetrically reduced with lithium
aluminum hydride that had been pretreated with (-)-N-
methylephedrine and 2-(ethylamino)pyridine, as described by
Terashima and co-workers,29 to give in 81% yield and g95%
ee (R)-2-methyl-2-cyclohexen-1-ol (15*), which was then
converted into N-phenylcarbamate 16* (82% yield). This
derivative was treated with lithium dimethylcuprate in ether to
afford, through a highly syn SN2′-selective intramolecular methyl
delivery,30 (S)-1,6-dimethyl-1-cyclohexene (8*) in 90% yield.31
Conversion of this olefin into (+)-bakkenolide A (1*) was
effected as in the racemic series to give material (mp 80-80.5
°C, [R]D +18) chromatographically and spectroscopically
indistinguishable from the naturally derived product (mp 80.5-
80.6 °C, [R]D +173d).
Homogynolide B. Encouraged by the bakkenolide A success,
we next targeted certain of the more highly oxygenated
bakkanes, starting with homogynolide B (2b*, Chart 1), a C-3
oxygenated derivative that had been isolated from Homogyne
alpina4 and found to possess significant antifeedant activity
against a number of grain and feed pests.12 It was initially hoped
that the synthesis of homogynolide B might be readily ac-
complished from a trans-2,3-dimethyl-3-cyclohexen-1-ol deriva-
tive by simply repeating the steps used in the bakkenolide A
approach. This proved optimistic, however. 2,3-Dimethyl-3-
cyclohexen-1-one could be easily prepared from 2,3-dimethyl-
anisole under Birch conditions,32 but clean, selective reduction
to the corresponding trans alcohol could not be realized; in
addition, several inversion attempts on derivatives of the cis
alcohol (secured selectively with L-Selectride) resulted mainly
in elimination.
It was reasoned that with an acetal protecting group, the
introduction of the C-3 asymmetric center could be postponed
to a later and perhaps more opportune stage in the synthesis
and, additionally, that concomitant hydrolysis of this group and
lactonization would probably be feasible. Thus, the dimethyl-
trimethylene acetal of 2,3-dimethyl-3-cyclohexen-1-one32 (17)
was exposed to in situ generated dichloroketene, which smoothly
delivered the expected cyclobutanone 18 as the sole product in
81% yield (Scheme 3). The oxidative cleavage of the four-
membered ring of this adduct under standard conditions was
attended by loss of the acetal protecting group. This problem
could be readily overcome, however, by effecting the cleavage
with ozone in lieu of ruthenium dioxide-sodium periodate, which
gave, following esterification, diester 19a in 75% yield. Reduc-
tion of this material with lithium aluminum hydride then
provided in 89% yield the desired diol 19b.
a (a) LiAlH4, 2-(ethylamino)pyridine, (-)-N-methylephedrine, (C2H5)2O,
-78 °C. (b) C6H5NCO, (C2H5)2O, 20 °C; recryst. (c) Li(CH3)2Cu, (C2H5)2O,
0 f 20 °C. (d) As in Scheme 1.
Several other procedures were also tested for this conversion,
but they produced substantial amounts of the corresponding
tetrahydrofuran.
The next challenge, finding a linchpin for forming the five-
membered carbocycle that would, in addition, provide for facile
construction of the â-methylene-γ-butyrolactone, was also
subjected to a separate study. Although neither â-methylene-
γ-butyrolactone itself nor â-methyl-R,â-butenolide proved use-
ful, due to instability toward conjugation and preferential
endocyclic proton loss, respectively, the easily prepared acrylate
derivative 13 was found to be a general â-methylene-γ-
butyrolactonization reagent (eq 5). A variety of these lactones
could be prepared in 44-81% overall yields.26
Pleasingly, when diiodide 10c was subjected to this new
lactonization approach, a 2:1 mixture of racemic bakkenolide
A (1) and its C-7 epimer was obtained in 54% yield. This
selectivity, while modest, can be explained by evoking a
U-shaped ester dienolate27 and a preferred reactive conformation
for ring closure that avoids bringing the silyloxymethyl and
angular methyl groups into proximity. By using DME-HMPA
at -58 °C in place of THF-HMPA at -78 °C, the epimeric
ratio could be slightly improved to 2.5:1 without modification
of the overall yield. Changes in the counterion and/or the
protecting group, like solvent modification, had surprisingly little
effect on the reaction outcome. Racemic bakkenolide A, readily
obtained from the mixture by crystallization from cold pentane,
was found to be in all respects (other than mp and optical
rotation) identical to an authentic sample of natural bakkenolide
A.
A consideration at this point was that in a number of
previously studied systems, neither the dimesylates nor the iodo
mesylates had performed well in cycloalkylations (poor yields,
unfavorable diastereoselectivity),33 which made the diiodide
(28) Warnhoff, E. W.; Martin, D. G.; Johnson, W. S. Org. Synth. 1963, Coll.
Vol. 4, 162-166.
(29) Kawasaki, M.; Suzuki, Y.; Terashima, S. Chem. Lett. 1984, 239-242. The
procedure of Corey and Bakshi was subsequently found to be superior:
Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611-614.
(30) Gallina, C.; Ciattini, P. G. J. Am. Chem. Soc. 1979, 101, 1035-1036. See
also: Goering, H. L.; Kantner, S. S.; Tseng, C. C. J. Org. Chem. 1983, 48,
715-721.
This short, efficient preparation of the racemic product (six
steps, 10% yield) could be easily translated into the first total
synthesis of (+)-bakkenolide A (Scheme 2). 2-Methyl-2-
(31) That little or no erosion of enantiopurity had taken place during this
transformation was later established by conversion of the cycloadduct into
1,2-dimethylcyclo[4.3.0]nonan-8-one (9* f 12*, eq 3), which was then
transformed into its [R,R]-1,2-dimethylethylene acetal. 13C NMR indicated
g95/5 diastereomeric purity. See: Hiemstra, H.; Wynberg, H. Tetrahedron
Lett. 1977, 2183-2186.
(26) Greene, A. E.; Coelho, F.; Depre´s, J.-P.; Brocksom, T. J. J. Org. Chem.
1985, 50, 1973-1975.
(27) See: Cainelli, G.; Cardillo, G.; Contento, M.; Trapani, G.; Ronchi, A. U.
J. Chem. Soc., Perkin Trans. 1 1973, 400-404 and references therein.
(32) Marshall, J. A.; Babler, J. H. Tetrahedron Lett. 1970, 11, 3861-3864.
9
15316 J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002

Syntheses of Bakkanes
A R T I C L E S
Scheme 3 a
borohydride in 2-propanol then gave in 76% yield a separable
3:2 mixture of â (δ 3.84) and R (δ 3.40 br) hydroxy lactones.36
The more polar R hydroxy derivative 21b4a was esterified with
tiglic acid in the presence of DCC and DMAP in warm toluene37
to afford in 75% yield racemic homogynolide B, spectroscopi-
cally and chromatographically identical to an authentic sample
of the natural product.
This first synthesis of a functionalized bakkenolide is
reasonably short and efficient, proceeding from olefin 17 in 11
steps and ca. 2% overall yield.
Homogynolide A. Homogynolide A (2a, Chart 1), a second
B-ring oxygenated bakkenolide isolated from Homogyne alpina4
with antifeedant activity against grain and feed pests,12 appeared
to lend itself to straightforward preparation along the lines
described for the synthesis of homogynolide B. The structural
similarity of these two molecules belied, however, the challenges
that lay ahead.
4,5-Dimethyl-3-cyclohexen-1-one (24a), which, surprisingly,
had not been previously prepared, was accessed from benzo-
quinone by using the excellent conjugate addition procedure
described by Liotta and co-workers,38 followed by reaction with
zinc powder in acetic acid (eq 6). Acetalization of 24a was then
performed with 2,2-dimethylpropane-1,3-diol (DMPD) and
p-toluenesulfonic acid in refluxing toluene to provide the
cyclization substrate, olefin acetal 24b, in high yield.39
a (a) CCl3COCl, Zn-Cu, POCl3, (C2H5)2O, 20 °C. (b) n-BuLi, THF,
-78 °C, then (CH3CO)2O, -78 f 20 °C; O3, CH2Cl2-CH3OH-C5H5N,
-78 °C, then CH3SCH3, -78 f 20 °C; aqueous NaOH, CH3I, HMPA, 20
°C. (c) LiAlH4, THF, 20 °C. (d) 1,2-Phenylene phosphorochloridite, C5H5N,
(C2H5)2O, 0 °C; I2, CH2Cl2, 20 °C; (CH3)2C(CH2OH)2, BF3‚O(C2H5)2,
CH2Cl2, 0 °C. (e) 13, THF-HMPA, LHMDS (2×), -78 f 20 °C;
separation. (f) HF, CH3CN, 20 °C. (g) NaBH4, (CH3)2CHOH, 0 °C;
separation (â recycled with PCC, 80%). (h) Tiglic acid, DCC, DMAP,
C6H5CH3, 65 °C.
analogous to 10c desirable.34 Considerable effort was expended
in this direction, but most attempts to prepare diiodide 19c were
thwarted by elimination to give the methylene derivative or
cyclization to afford the tetrahydrofuran, both stemming from
the slowness of the neopentyl displacement. Fortunately, Corey’s
phosphite method35 allowed conversion into the diiodide, albeit
in only moderate yield and with attendant loss of the protecting
group. Reprotection, however, provided the desired acetal in
good yield.
To our temporary delight, application of the chemistry
employed in the homogynolide B synthesis produced highly
stereoselectively and in good overall yield the diester acetal 25
(eq 7). The â configuration at C-4 (bakkane numbering) was
â-Methylene-γ-lactonization of this diiodide began by trans-
formation with acrylate 13 to an equimolar mixture of readily
separated epimeric hydrindanes (71% yield). Each was treated
with aqueous hydrofluoric acid in acetonitrile, which smoothly
effected both double deprotection and lactonization to afford
the corresponding keto lactones. The keto lactone (21a) from
the less polar ester acetal provided spectroscopic data that were
perfectly concordant with the literature values for the natural
product-derived substance,4a whereas the C-7 epimeric lactone
from the more polar ester acetal produced data that were clearly
different. Reduction of the desired keto lactone with sodium
not considered secure, however, because for this outcome
dichloroketene has to overcome the presence of an encumbering
axial substituent at C-2. Thus, the diester acetal was subjected
(36) The former could be recycled through PCC oxidation to keto lactone 21a
(80% yield).
(33) (a) Coelho, F. A. Ph.D. Thesis, University of Grenoble, 1987. (b) Hartmann,
B. Ph.D. Thesis, University of Grenoble, 1992.
(37) See: Denis, J.-N.; Greene, A. E.; Gue´nard, D.; Gue´ritte-Voegelein, F.;
Mangatal, L.; Potier, P. J. Am. Chem. Soc. 1988, 110, 5917-5919.
(38) Solomon, M.; Jamison, W. C. L.; McCormick, M.; Liotta, D.; Cherry, D.
A.; Mills, J. E.; Shah, R. D.; Rodgers, J. D.; Maryanoff, C. A. J. Am. Chem.
Soc. 1988, 110, 3702-3704.
(34) The acetal protecting group turned out to be a particularly fortunate choice
in that subsequent work showed the diiodide-acetal pairing to be optimal,
others providing without exception unfavorable diastereoselectivities (1:
3-5).33 These diastereomeric ratios, while reflecting rather small differences
in transition state energies, indicate nonetheless that subtle conformational
and perhaps steric effects operate in reactions of these nonrigid molecules.
(35) Corey, E. J.; Anderson, J. E. J. Org. Chem. 1967, 32, 4160-4161.
(39) This acetal could also be prepared from ethyl 5,6-dimethyl-2-oxo-3-
cyclohexenecarboxylate (Pietrusiewicz, K. M.; Monkiewicz, J.; Bodalski,
R. J. Org. Chem. 1983, 48, 788-790) by decarbethoxylation (DMSO-
H2O, ∆, 90%) followed by acetalization (90%).
9
J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002 15317

A R T I C L E S
Brocksom et al.
Scheme 4 a
to hydrolysis, thioacetalization, and Raney nickel desulfurization
to give diester 26c, which was, in fact, distinctly different from
the dimethyl ester of 10a (Scheme 1).40 Cycloaddition therefore
takes place cis to the C-4 methyl and, to respect both electronic
and stereoelectronic requirements,17,18 must involve a semi-boat
conformation. An analogous R-face cycloaddition, also thought
to involve a semi-boat conformation, has previously been
observed with dichloroketene and 3-methylcholest-2-ene.18b
Faced with this impasse, we elected to replace the acetal with
a protected â-hydroxyl group to eliminate the presence of an
encumbering C-2 axial substituent and thus allow, in all
probability, the cycloaddition to proceed with the desired
orientation. The reduction of ketone 24a was studied in some
detail, and the results obtained are shown in eq 8. Lithium
aluminum hydride in THF at -78 °C provided the most
favorable â/R ratio of alcohols, as can be seen, and in excellent
yield (98%).41 Conversion of the â alcohol 27a so obtained into
the corresponding benzyl ether 27c was next readily ac-
complished in nearly quantitative yield (Scheme 4).
Reaction of this new cycloaddition substrate with in situ
generated dichloroketene cleanly afforded a single product,
dichlorocyclobutanone 28, which after oxidative cleavage as
with homogynolide B (lithium dimethylcuprate24 was found to
be more effective than n-butyllithium) yielded diester 29a. That
this diester could be converted into the dimethyl ester of 10a
(Scheme 1) (H2, Pd/C; PCC; HS(CH2)2SH, BF3; Ra-Ni) served
to confirm the expected stereochemical outcome of the cyclo-
addition. The four chiral centers in diester 29a are thus
introduced with virtually complete stereochemical control;
however, that at C-2 must ultimately be adjusted.
a (a) LiAlH4, THF, -78 °C. (b) NaH, C6H5CH2Br, (n-C4H9)4N+I-, THF,
∆. (c) CCl3COCl, POCl3, Zn-Cu, (C2H5)2O, 20 °C. (d) Li(CH3)2Cu,
(C2H5)2O, -50 °C, then (CH3CO)2O, -50 f 20 °C; O3, CH2Cl2-CH3OH,
-78 °C, then CH3SCH3, -78 f 20 °C; aqueous NaOH, CH3I, HMPA, 20
°C. (e) LiAlH4, THF, 20 °C. (f) (CF3SO2)2O, 2,6-di-tert-butylpyridine,
CH2Cl2, -30 °C. (g) (n-C4H9)4N+I-, C6H5CH3, 20 °C. (h) (CH3)3SiI,
CH2Cl2, 20 °C. (i) PCC, CH2Cl2, 20 °C. (j) (CH3)2C(CH2OH)2, BF3‚O(C2H5)2,
CH2Cl2, 0 °C. (k) 13, LHMDS (2 equiv), DME-THF-HMPA, -58 °C;
aqueous HF, CH3CN, 20 °C, separation. (l) LiAl(Ot-C4H9)3H, THF, 0 °C.
(m) 32, C6H5CH3, 70 °C.
The next problem was to prepare a suitable diiodide for
reaction with acrylate 13. Although the previously successful
phosphite method35 and several other iodination procedures
failed entirely with diol 29b (obtained from diester 29a with
lithium aluminum hydride), fortunately the ditriflate of this diol
could be prepared and underwent clean double displacement
(as opposed to the dimesylate) in the presence of tetrabutyl-
ammonium iodide to yield diiodide 29d in 53% overall yield
from the diester.
Aware from our previous work that an acetal at C-2 would
probably furnish the best ratio of C-7 epimers, we nonetheless
first examined cycloalkylation with this benzyl ether and with
the corresponding dimethylthexylsilyl derivative (prepared
analogously). Concordant with the earlier findings, however,
the ratio of C-7 epimers turned out to be distinctly unfavorable
(ca. 1:3), regardless of the experimental conditions employed.
Therefore, the C-2 â benzyloxyl substituent, having served its
role in the cycloaddition, was now replaced by an acetal group
for the purpose of achieving a stereochemically satisfactory
cycloalkylation. This switch, which also anticipated the intro-
duction of the required C-2 R oxygen substituent, could be
accomplished through sequential debenzylation, oxidation, and
acetalization, which gave 30c in 72% overall yield.42
Cyclization of diiodide 30c under the usual conditions,
followed by brief treatment of the resulting esters with aqueous
hydrofluoric acid in acetonitrile to effect concomitant double
deprotection and lactonization, provided keto lactone 31a,
together with its C-7 epimer, in indeed a much improved ratio
and in good overall yield.43 After separation, keto lactone 31a
was effectively reduced with lithium tri-tert-butoxyaluminum
hydride with >95/5 stereoselectivity to give in high yield the
desired R hydroxy lactone 31b. In contrast, sodium borohydride
in isopropyl alcohol, with or without added cerium trichloride,
gave nearly equimolar amounts of the epimeric alcohols.41 Both
keto lactone 31a and hydroxy lactone 31b provided spectral
(40) That this was indeed the epimer at C-4 and not at C-10 was proven by
comparison with an authentic sample of trans diester, obtained by base
treatment of the dimethyl ester of 10a.
(41) For a discussion of diastereoselectivity in the reduction of cyclic ketones
with metal hydrides, see: No´gra´di, M. StereoselectiVe Synthesis; VCH:
Weinheim, 1995; pp 100-121.
(42) Attempted preparation of diiodide 30c from the C-2 acetal corresponding
to 29b failed due to competing reactions during ditriflate formation.
(43) While the overall yield remained relatively constant (ca. 75%), the ratio
varied experimentally from 3:1 to 1:1.
9
15318 J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002

Syntheses of Bakkanes
A R T I C L E S
Scheme 5 a
data in excellent agreement with the literature values4a for the
products derived from natural homogynolide A.
The remaining transformation, conversion of hydroxy lactone
31b into homogynolide A, required the development of a new
procedure for the preparation of angelate esters. Existing
procedures44 were unsatisfactory, often producing large amounts
of the thermodynamically more stable tiglate ester; attempted
formation of homogynolide A from hydroxy lactone 31b by
using angelic acid in the presence of DCC and DMAP, for
example, yielded only the tiglate ester. After some study, it was
discovered that by employing the mixed Yamaguchi anhydride45
derived from angelic acid and 2,4,6-trichlorobenzoyl chloride
in dry toluene at 70-80 °C in the absence of free base, a range
of alcohols could be converted into their angelate esters in
excellent yields and without even a trace amount of tiglate ester
contamination (eq 9).46 Application of this procedure to the
problem at hand was quite successful and provided in 97% yield
racemic homogynolide A, whose identity was established
through direct spectral comparison with the natural substance.
The respectable efficiency of this first synthesis of the
homogynolide A (15 steps, 2% overall yield) prompted us to
use it for the preparation of the natural substance. With the idea
of exploiting the chiral pool for securing olefin 27c*, (-)-
carvone47 was considered a possible starting material: stereo-
selective reduction to give (-)-cis-carveol, followed by appli-
cation of the previously used method of Gallina and Ciattini30
(see 16* f 8*, Scheme 2) and degradation of the isopropenyl
group of the resulting diene, it seemed, could yield the desired
olefin. Luche reduction48 of (-)-carvone ((-)-33*, eq 10) did
cleanly afforded the cis alcohol; however, the N-phenylcarbam-
ate derivative 34b* proved to be totally unreactive in the
presence of lithium dimethylcuprate (LDMC), probably due to
the high energy transition-state conformation (1,3-diaxial in-
teraction) required to form the product 35*. This result, together
a (a) Li(CH3)2Cu, (C2H5)2O, 0 f 20 °C, then ClPO(OC2H5)2, HMPA,
-50 f 20 °C. (b) O3, CH2Cl2-CH3OH-C5H5N, 20 °C, then p-NO2C6H4-
COCl, CH2Cl2-C5H5N, -30 °C f reflux. (c) Li, CH3NH2, THF-t-
C4H9OH-(C2H5)2O, -78 f -15 °C. (d) H2CrO4, (C2H5)2O, 0 °C. (e)
LiAlH4, THF, -78 °C. (f) NaH, C6H5CH2Br, (n-C4H9)4N+I-, THF, ∆. (g)
As in Scheme 4.51
double bond (using limonene as a model), led us to study an
alternative, conjugate-addition approach from (+)-carvone ((+)-
33*) (Scheme 5).
Conjugate addition of lithium dimethylcuprate to (+)-
carvone,47,49 followed by enolate trapping with diethyl chloro-
phosphate, gave stereoselectively and in high yield enol
phosphate 36*. Ozonolysis of this diene proceeded selectively
in the desired sense, due to a now deactivated endocyclic double
bond, to give in 85% yield the acetyl-substituted derivative. Even
better, however, was that when the intermediate hydroperoxide
was subjected to Criegee rearrangement,50 the acetoxy-
substituted derivative 37* was produced directly in 62% yield.
Birch reduction of this material in methylamine conveniently
provided trans alcohol 27b*, which was best converted into cis
alcohol 27a* through oxidation-reduction. This alcohol was
then transformed into the dichloroketene cycloaddition substrate
27c*, from which the first synthesis of (-)-homogynolide A
(45) See: Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993. The mixed anhydride formed with
trifluoroacetic anhydride has been reported to convert (E)-2-methyl-2-
butenol to its angelate ester in only 21% yield. See: Ru¨cker, G.; Mayer,
R.; Lee, K. R. Arch. Pharm. (Weinheim, Ger.) 1989, 322, 821-826.
(46) Hartmann, B.; Kanazawa, A.; Depre´s, J.-P.; Greene, A. E. Tetrahedron
Lett. 1991, 32, 5077-5080.
with the difficulty encountered in efficiently degrading the
isopropenyl group in the presence of the trisubstituted endocyclic
(44) See, for example: Bohlmann, F.; Tietze, B.-M. Chem. Ber. 1970, 103,
561-563. Hoskins, W. M.; Crout, D. H. G. J. Chem. Soc., Perkin Trans.
I 1977, 538-544. Beeby, P. J. Tetrahedron Lett. 1977, 3379-3382. Kubo,
A.; Nakahara, S.; Inaba, K.; Kitahara, Y. Chem. Pharm. Bull. 1985, 33,
2582-2584. Kubo, A.; Nakahara, S.; Inaba, K.; Kitahara, Y. Chem. Pharm.
Bull. 1986, 34, 4056-4068. Nakayama, J.; Nakamura, Y.; Tajiri, T.;
Hoshino, M. Heterocycles 1986, 24, 637-640. Bal-Tembe, S.; Bhedi, D.
N.; De Souza, N. J.; Rupp, R. H. Heterocycles 1987, 26, 1239-1249. Dev,
V.; Bottini, A. T. J. Nat. Prod. 1987, 50, 968-971. Joseph-Nathan, P.;
Cerda, C. M.; Roman, L. U.; Hernandez, J. D. J. Nat. Prod. 1989, 52,
481-496. For relevant studies of the problem of Z f E isomerization during
esterification, see: Roush, W. R.; Blizzard, T. A. J. Org. Chem. 1984, 49,
1772-1783 and 4332-4339.
(47) For the use of carvone in synthesis, see: Ho, T.-L. EnantioselectiVe
Synthesis; John Wiley-Interscience: New York, 1992; Chapter 6 and
references therein.
(48) Luche, J.-L.; Rodriguez-Hahn, L.; Crabbe´, P. J. Chem. Soc., Chem.
Commun. 1978, 601-602.
(49) Posner, G. H. Org. React. 1972, 19, 1-113.
(50) Criegee, R.; Kaspar, R. J. Liebigs Ann. Chem. 1948, 560, 127-135. Criegee,
R. Angew. Chem., Int. Ed. Engl. 1975, 14, 745-752. For some applications,
see: Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24, 2363-
2366. Okamura, W. H.; Aurrecoechea, J.-M.; Gibbs, R. A.; Norman, A.
W. J. Org. Chem. 1989, 54, 4072-4083.
9
J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002 15319

A R T I C L E S
Brocksom et al.
Scheme 6 a
(2a*) could be achieved by using the chemistry developed for
the racemic product.51 The synthetic (-)-homogynolide A (mp
62-64 °C, CD ∆ꢀ217 -2.50) provided a high-field proton NMR
spectrum identical to that of the naturally derived substance
(mp4a 62-65 °C, CD4a ∆ꢀ220 -2.51).
Palmosalide C. The sole reported bakkane of marine origin,
palmosalide C (3, Chart 1), differs from all of the known
terrestial members of this family, except senauricolide,9 by the
presence of the unusual spiro â,γ-epoxy-γ-butyrolactone func-
tion, which is found in only a few other sesquiterpenes, such
as dysetherin,52a ptychanolide,52b spirotubipolide,52c and spiroden-
sifolins A and B52d (none synthesized to date), and through its
relative configuration at the C-7 spiro center and unsaturation
at C-1,C-10. Palmosalide C was isolated by Fenical and co-
workers5 from the telestacean octocoral Coelogorgia palmosa,
a rare gorgonian-like soft coral found in the Indian Ocean.
The most difficult synthetic challenge in preparing palmo-
salide C obviously resides in accessing the epoxy lactone: not
only does a procedure that is compatible with the B-ring
unsaturation or equivalent have to be found simply for its
construction, but, in addition, the issue of stereochemistry at
both C-7 and C-11,C-12 needs to be addressed. The latter
concern is not necessarily trivial, as demonstrated by Dreiding
and co-workers in their failed approach to ptychanolide.52e
The ∆1(10) analogue of a bis-electrophile such as 10c (Scheme
1) was considered an attractive intermediate for the present
synthesis, due, in particular, to its expected accessibility and
the many synthetic options it might permit. Thus, diester 10d
(Scheme 6), available in quantitative yield from diacid 10a by
treatment with ethereal diazomethane, was phenylselenenylated53
at C-10 through reaction with LDA and phenylselenenyl chloride
to give the expected selenide, which on exposure to ozone
provided the unsaturated diester 38a in 60% overall yield.
Conversion of diester 38a into diol 38b, surprisingly, could not
be achieved satisfactorily with lithium aluminum hydride in THF
or ether or with Dibal-H in THF; Dibal-H in toluene, however,
was quite effective and delivered the desired diol in 91% yield.
The transformation of diol 38b into a useful bis-electrophile
was expected to be somewhat challenging because of the
increase in reactivity at C-9 (now allylic position) relative to
that at C-6 (neopentyl position). Treatment of the bis-trimeth-
ylsilyl derivative of diol 38b with trimethylsilyl iodide,25 in fact,
generated uniquely the tetrahydrofuran (cf. 10b f 10c, Scheme
1). Many other attempts were similarly unproductive. Fortu-
nately, however, it was found that the bis-mesylate could be
prepared with 5 equiv of methanesulfonyl chloride and 5 equiv
of collidine in dichloromethane at 20 °C and that it underwent
in situ clean allylic displacement, without rearrangement, with
a (a) CH2N2, (C2H5)2O, 20 °C. (b) LDA, THF, HMPA, -78 °C, then
C6H5SeCl; O3, CH2Cl2, -78 °C, then (i-C3H7)2NH, -78 f 20 °C. (c)
DIBAL-H, C6H5CH3, 0 °C. (d) C2H5SO2Cl, collidine, CH2Cl2, 20 °C. (e)
(CH3)3CO2CCH2CO2CH3, NaH, HMPA, 0 f 20 °C, then NaCN, 110 °C.
(f) LDA, NCCO2CH3, -78 f 20 °C. (g) CF3CO2H, CH2Cl2, 20 °C, then
evaporation, SOCl2, DMF, 60 °C, then evaporation, CH2N2, ether, 0 °C,
then evaporation, aqueous HCl-CH3OH, 0 °C. (h) CH3MgBr, (C2H5)2O, 0
°C. (i) SOCl2, C5H5N, C6H5CH3, 60 °C, separation. (j) 41b: SO2Cl2,
C6H5CH3, 20 °C. (k) m-ClC6H4CO3H, CH2Cl2, 20 °C, separation. (l) 42b:
Zn, CH3CO2H-(C2H5)2O.
the chloride generated during the reaction to give in 70% yield
the chloro mesylate (38c, SO2CH3 replaces SO2C2H5).54 Other
reaction conditions led to poorer results, often due to allylic
rearrangement. The corresponding bromide could also be
prepared by using methanesulfonyl bromide, but the yield was
considerably lower than that of the chloride.
With an appropriate bis-electrophile now available, ring
closure was first attempted with â-methyl-R,â-butenolide, which,
had it been successful, would have swiftly positioned us within
striking distance of palmosalide C. Unfortunately, however, none
of the desired hydrindane was ever observed. Pattenden and
Gedge55 had earlier observed that alkylation of this lactone with
prenyl bromide occurred predominantly at the endocyclic γ
(51) The diiodo alcohol 30a* was, however, subjected to the Noe acetal
technique (91% efficiency) to remove the ca. 8% of enantiomeric material
that originated from cis conjugate addition to (+)-carvone. Noe, C. R. Chem.
Ber. 1982, 115, 1591-1606.
(52) (a) Schram, T. J.; Cardellina, J. H., II. J. Org. Chem. 1985, 50, 4155-
4157. (b) Takeda, R.; Naoki, H.; Iwashita, T.; Mizukawa, K.; Hirose, Y.;
Isida, T.; Inoue, M. Bull. Chem. Soc. Jpn. 1983, 56, 1125-1132. (c) Iguchi,
K.; Mori, K.; Matsushima, M.; Yamada, Y. Chem. Pharm. Bull. 1987, 35,
3532-3533. (d) Tori, M.; Arbiyanti, H.; Taira, Z.; Asakawa, Y. Tetrahedron
Lett. 1992, 33, 4011-4012. (e) For the synthesis of a nonnatural spiro
â,γ-epoxy-γ-butyrolactone, see: Solaja, B.; Huguet, J.; Karpf, M.; Dreiding,
A. S. Tetrahedron 1987, 43, 4875-4886. For examples of diterpenes with
this lactone function, see: Cardenas, J.; Pavon, T.; Esquivel, B.; Toscano,
A.; Rodriguez-Hahn, L. Tetrahedron Lett. 1992, 33, 581-584.
(53) Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J. Am. Chem. Soc. 1973,
95, 6137-6139. Iodination, followed by treatment with DBU, also yielded
38a, but less efficiently.
(54) See: Collington, E. W.; Meyers, A. I. J. Org. Chem. 1971, 36, 3044-
3045. See also: Bishop, C. E.; Morrow, G. W. J. Org. Chem. 1983, 48,
657-660. Majetich, G.; Song, J. S.; Ringold, C.; Nemeth, G. A.; Newton,
M. G. J. Org. Chem. 1991, 56, 3973-3988.
(55) Pattenden, G.; Gedge, D. R. Tetrahedron Lett. 1977, 4443-4446. The
R-carbomethoxy derivative also failed to give satisfactory results.
9
15320 J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002

Syntheses of Bakkanes
A R T I C L E S
position. A less direct, but possibly more stereorational, stepwise
approach was therefore considered at this stage.
effected in an acceptable yield, and therefore the classical
Grignard methylation-dehydration procedure was adopted for
this transformation. On treatment with methylmagnesium bro-
mide, keto lactone 40a was smoothly converted into a diaster-
eomeric mixture of tertiary alcohols 40b (83%),62 which under
optimized dehydration conditions63 provided an easily separated
1.5:1 mixture of the exo and endo olefins 41a,b (80%). The
undesired exo isomer (41a) on treatment with osmium tetroxide-
sodium periodate readily returned keto lactone 40a (67% yield)
and could thus be recycled.
With the long-sought diene 41b in hand, all that remained
was to epoxidize selectively the molecule at C-11,C-12, but this
double bond was quickly determined to be the less reactive:
both m-chloroperbenzoic acid and dimethyldioxirane reacted
preferentially at C-1,C-10. Furthermore, the bis-epoxide, formed
with an excess of m-chloroperbenzoic acid, underwent selective
reduction with several reagents at the lactone site. After
considerable experimentation, however, a productive protocol
for effecting the desired epoxidation was found based on
selectiVe deactiVation of the C-1,C-10 double bond. Treatment
of diene 41b with sulfuryl chloride64 in the presence of sodium
carbonate delivered with total regio- and stereoselectivity allylic
chloride 42a (75% yield), which, precedent suggested,65 might
now undergo selectively butenolide epoxidation. Pleasingly, this,
in fact, occurred on exposure to m-chloroperbenzoic acid to give
a separable 1.2:1 mixture of diastereomeric epoxides 42b,c in
86% yield. The major isomer (42b) on treatment with zinc in
acetic acid suffered dechlorination with concomitant retrans-
position of the double bond to give in 92% yield racemic
palmosalide C, identified through direct chromatographic and
spectroscopic comparison with an authetic sample of the natural
product.66
While the lithium anion of tert-butyl acetate produced the
sultone from the chloro mesylate by abstraction of a sulfonate
hydrogen, and the corresponding copper reagent56 gave a 1:1
mixture of SN2 and SN2′ adducts, the sodium anion of tert-
butyl methyl malonate afforded in good yield the desired
hydrindane, contaminated however with a small amount of the
tetrahydrofuran derivative. The formation of this side product,
which stems most likely from malonate attack on sulfur, could
be completely suppressed by using the corresponding chloro
ethanesulfonate 38c. Addition of chloro ethanesulfonate 38c to
hexamethylphosphoric triamide containing the sodium anion of
tert-butyl methyl malonate and sodium hydride, followed by in
situ decarbomethoxylation of the resulting malonate (1:1 mixture
of C-7 epimers) with sodium cyanide,57 cleanly yielded ester
39a in 54% yield.
Although A-ring â-face (convex) approach in the case of
saturated bakkane derivatives can be readily predicted from
molecular models and has, in fact, been observed,13,15e with a
∆
1(10) derivative such as 39a, the face selectivity to be expected
on reaction at C-7 is less obvious because of a flattening of the
rings. In an initial approach to palmosalide C, however, ester
39a on exposure to LDA and then tert-butyldimethylsilyloxy-
acetone was found to yield a mixture of two diastereomeric
hydroxy esters that on lactonization, hydrogenation, and dehy-
dration afforded only bakkenolide A and its ∆11(12) isomer (eq
11).58 R-Face attack is thus clearly preferred in this ∆1(10)
This first and, to date, only synthesis of this novel marine
bakkane requires 17 steps from diacid 10a. It proceeds with
modest stereochemical control at C-11,C-12, but virtually
complete control at the C-4, C-5, and C-7 stereocenters.
9-Acetoxyfukinanolide. While the modified strategy used
for palmosalide C could have, in principle, been adapted to
provide 9-acetoxyfukinanolide (4, Chart 1), it seemed a more
expeditious route to this natural product might be available from
the same dichloroketene-dimethylcyclohexene cycloadduct 9
bakkane derivative, which can be attributed a posterori to
dominant steric hindrance now by the angular methyl group.
While the initial approach was obviously not viable, this clear
facial bias pointed to an alternative strategy for the stereo-
selective construction of the “inverted” lactone of palmosalide
C.
(61) (a) Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron Lett. 1983,
24, 1605-1608. Paquette, L. A.; Bellamy, F.; Wells, G. J.; Bo¨hm, M. C.;
Gleiter, R. J. Am. Chem. Soc. 1981, 103, 7122-7133. Stille, J. K. Angew.
Chem., Int. Ed. Engl. 1986, 25, 508-524. (b) Hayashi, T.; Katsuro, Y.;
Kumada, M. Tetrahedron Lett. 1980, 21, 3915-3918. Brownbridge, P.
Synthesis 1983, 1-28. (c) Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron
Lett. 1980, 21, 2531-2534. Takai, K.; Sato, K.; Oshima, K.; Nozaki, H.
Bull. Chem. Soc. Jpn. 1984, 57, 108-115. (d) Stang, P. J.; Hanack, M.;
Subramaniam, L. R. Synthesis 1982, 85-126. Scott, W. J.; McMurry, J.
E. Acc. Chem. Res. 1988, 21, 47-54. Farina, V.; Krishnamurthy, V.; Scott,
W. J. Org. React. 1997, 50, 1-652.
Ester 39a was treated with LDA and then methyl cyanofor-
mate (Mander’s reagent59) to give in 80% yield a single
malonate, presumed to have the stereochemistry indicated in
39b. In the presence of trifluoroacetic acid, this malonate was
converted into an acid ester, which on successive treatment with
thionyl chloride, ethereal diazomethane, and hydrochloric acid
generated keto lactone 40a.60 This one-pot sequence of four steps
proceeded in a highly satisfactory 75% overall yield.
The next objective was to convert keto lactone 40a into the
corresponding â-methyl-â,γ-butenolide in anticipation of ep-
oxidation. Unfortunately, the preparation from 40a of the vinyl
iodide,61a trimethylsilyl enol ether,61b enol phosphate,61c or enol
triflate61d derivative for subsequent methylation could not be
(62) On hydrogenation followed by dehydration, the tertiary alcohols afforded,
in addition to the endocyclic olefin, the previously prepared 7-epi-
bakkenolide A, thereby confirming the presumed C-7 configuration in
malonate 39b.
(63) With 4-hydroxy-4-methyl-2-oxaspiro[4.4]nonan-1-one as a model system,
numerous dehydration conditions were examined. With the exception of
p-TsOH in refluxing toluene (only endo, yield < 30%), SOCl2 in pyridine
at 60 °C gave the best endo/exo ratio (1/1.2).
(64) Poutsma, M. L. J. Am. Chem. Soc. 1965, 87, 4285-4293. Bulliard, M.;
Balme, G.; Gore´, J. Tetrahedron Lett. 1989, 30, 5767-5770. Chlorine or
iodobenzene dichloride could also be used for this purpose. For other
examples of ene-type chlorination, see: Rodriguez, J.; Dulce`re, J.-P. Synlett
1991, 477-478 and references therein.
(65) Williard, P. G.; de Laszlo, S. E. J. Org. Chem. 1985, 50, 3738-3749.
Selective formation of a dibromo (or similar) derivative for double bond
protection could not be achieved.
(66) The minor epoxide isomer (42c) on similar treatment produced material
distinctly different from the natural product.
(56) Kuwajima, I.; Doi, Y. Tetrahedron Lett. 1972, 1163-1166.
(57) Mu¨ller, P.; Siegfried, B. Tetrahedron Lett. 1973, 3565-3568.
(58) That the C-7 configuration of the ∆11(12) isomer that corresponded to that
of bakkenolide A was demonstrated by hydrogenation of each to a mixture
of the same dihydro derivatives.
(59) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425-5428.
(60) See: Smith, A. B., III; Dieter, R. K. Tetrahedron 1981, 37, 2407-2439.
Miller, R. D.; Theis, W. Tetrahedron Lett. 1987, 28, 1039-1042.
9
J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002 15321

A R T I C L E S
Brocksom et al.
Scheme 7 a
possible to use the â-hydroxy ester from 45a for lactone
construction in a way parallel to that shown in eq 11. This
approach had to be abandoned, however, because of the
difficulty encountered in stereoselectively reducing â-keto ester
45a and, additionally, in effecting the desired condensation in
a closely related model system.
In 1989, Cossy and Leblanc disclosed69 an effective spiro
â-methylene-γ-butyrolactam synthesis based on free-radical
cyclization of N-propargyl â-keto amides with manganese
triacetate70 in ethanol. This type of approach seemed worth
investigating because propargylic â-keto esters could reasonably
be expected to behave similarly. The report by Bertrand and
co-workers71 that an ethyl propargyl malonate also cyclized in
the presence of manganese triacetate allowed us to be optimistic.
A search of the literature, however, failed to reveal any
pertinent examples of transesterification of a â-keto ester with
a propargylic alcohol, and, in fact, attempts using conventional
procedures led, in our hands, to generally poor results.72 After
some study, though, it was discovered that by simply displacing
the equilibrium without catalysis, propargylic â-keto esters could
be readily prepared from methyl, ethyl, and tert-butyl â-keto
esters with primary and secondary propargylic alcohols.73 Most
likely proceeding through a ketene intermediate, this exceedingly
simple, yet effective, method could also be applied to a large
range of nonpropargylic alcohols with results generally far
superior to those in the literature (eq 13). Applied to the problem
at hand, the desired propargyl â-keto ester 45b was secured in
87% yield.74
a (a) Zn, CH3CO2H, 70 °C, 3 h. (b) N2CHCO2C2H5, SbCl5, CH2Cl2, -78
f -30 °C, 12 h. (c) HOCH2CtCH, C6H5CH3, ∆. (d) Mn(O2CCH3)3,
C2H5OH, 20 °C. (e) SmI2, THF-H2O, 20 °C. (f) TBAF, THF, 0 °C;
CH3COCl, (C2H5)3N, DMAP, THF, 20 °C.
(Scheme 7). 9-Acetoxyfukinanolide (9-acetoxybakkenolide A),
isolated by Naya and co-workers from the leaves of Petasites
japonicus Maxim in 1972,6 was targeted with the expectation
that the chemistry developed might later be extrapolated to allow
access to the most synthetically challenging and numerous
bakkenolides, those oxygenated at C-1 and at C-9 (e.g., 5a-i,
Chart 1).
The approach that was conceived called for a regioselective
cyclobutanone ring expansion of 9 to provide X, which would
be the platform for constructing the â-methylene-γ-butyrolactone
intermediate that would then be converted into 9-acetoxyfuki-
nanolide (4) (eq 12).67
With the requisite keto ester available, the crucial spiro
â-methylene-γ-lactonization was next attempted. Pleasingly, in
the presence of 2.5 equiv of manganese triacetate in deoxygen-
ated ethanol at 20 °C, 45b cleanly underwent 5-exo dig
cyclization to provide in 68% yield a single lactone (46).
It is noteworthy that recent work has revealed the generality
of the spiro â-methylene-γ-lactonization reaction leading to 46
(Table 1). As can be seen in the table, the free-radical cyclization
(69) Cossy, J.; Leblanc, C. Tetrahedron Lett. 1989, 30, 4531-4534. Cossy, J.;
Bouzide, A.; Leblanc, C. J. Org. Chem. 2000, 65, 7257-7265.
(70) Snider, B. B. Chem. ReV. 1996, 96, 339-363 and references therein.
(71) Oumar-Mahamat, H.; Moustrou, C.; Surzur, J. M.; Bertrand, M. P. J. Org.
Chem. 1989, 54, 5684-5688. For a catalytic approach, see: Hirase, K.;
Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2002, 67, 970-973.
For related protocols for effecting free-radical spiro lactonization, see: Back,
T. G.; Gladstone, P. L.; Parvez, M. J. Org. Chem. 1996, 61, 3806-3814
and ref 76. See also: Clive, D. L. J.; Tao, Y.; Khodabocus, A.; Wu, Y.-J.;
Angoh, A. G.; Bennett, S. M.; Boddy, C. N.; Bordeleau, L.; Keller, D.;
Kleiner, G.; Middleton, D. S.; Nichols, C. J.; Richardson, S. R.; Vernon,
P. G. J. Am. Chem. Soc. 1994, 116, 11275-11286. For a review of the
various methods for preparing â-methylene-γ-butyrolactones, see ref 1b.
(72) For a review on transesterification, see: Otera, J. Chem. ReV. 1993, 93,
1449-1470.
(73) Mottet, C.; Hamelin, O.; Garavel, G. D.; Depre´s, J.-P.; Greene, A. E. J.
Org. Chem. 1999, 64, 1380-1382. For the basis of this work, see: Bader,
A. R.; Cummings, L. O.; Vogel, H. A. J. Am. Chem. Soc. 1951, 73, 4195-
4197. Bader, A. R.; Vogel, H. A. J. Am. Chem. Soc. 1952, 74, 3992-
3994. For a mechanistic study, see: Campbell, D. S.; Lawrie, C. W. J.
Chem. Soc., Chem. Commun. 1971, 355-356.
(74) Initially, the â-keto ester was refluxed in toluene in the presence of a
catalytic amount of p-toluenesulfonic acid and with slow distillation;
however, the present method has been found much superior.
The cycloadduct was dechlorinated with zinc in warm acetic
acid to give cyclobutanone 44 (Scheme 7), which underwent
regioselective ring expansion (84:16) in the expected sense in
the presence of ethyl diazoacetate and antimony pentachloride68
to provide the â-keto ester 45a as a single isomer in 64% yield
after purification. It was hoped at this point that it might be
(67) In an earlier approach based on the cycloalkylation of acrylate 13 with
10c, in which a formyl or a chloroformyl group replaces the C-10 (bakkane
numbering) iodomethyl, only the formation of the undesired tetrahydrofuran
derivatives from internal alkylation on oxygen was observed regardless of
the experimental conditions.
(68) Liu, H. J.; Ogino, T. Tetrahedron Lett. 1973, 4937-4940. Sonawane, H.
R.; Nanjundiah, B. S.; Shah, V. G.; Kulkarni, D. G.; Ahuja, J. R.
Tetrahedron Lett. 1991, 32, 1107-1108. See also: Mock, W. L.; Hartman,
M. E. J. Org. Chem. 1977, 42, 459-465 and 466-472. Boron trifluoride
etherate has also been used in this reaction.14i
9
15322 J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002

Syntheses of Bakkanes
A R T I C L E S
Table 1. Synthesis of Spiro-fused â-Methylene-γ-lactones from
Propargylic â-Keto Estersa
this substance, however, failed to yield 9-acetoxyfukinanolide,
but did provide material with spectroscopic data closely similar
to those described for the natural product. To ascertain the
configuration at C-7, Barton deoxygenation (NaH, CS2, CH3I;
(C4H9)3SnH)79 was carried out on the hydroxy lactone (47) to
eliminate the stereocenter at C-9. This, pleasingly, indeed
afforded bakkenolide A (1), which seemed to indicate unequivo-
cally that the stereochemical problem lay simply at C-9.
At this crucial point in our work, an authentic sample of the
natural product was, fortunately, finally secured from Japan.
Acid hydrolysis of this material provided alcohol 48*, which
was, as expected, different from our synthetic intermediate (47)
(eq 14). What was initially puzzling, though, was that the
corresponding ketones (49* and 46) were also different! A
logical explanation was soon found, however: a C-7,C-9 retro
aldol-aldol epimerization must have taken place in the Barton
sequence during xanthate formation, effectively transforming
the unnatural C-7 configuration into the natural, hence the
conversion into bakkenolide A (eq 15). That this interpretation
a Mn(O2CCH3)3‚2H2O (ca. 2.4 equiv) in deoxygenated C2H5OH, 20 °C,
14 h. b Yields are for pure, homogeneous products (except for 58b).
c Relative configuration determined by X-ray crystallography. See ref 75.
d 2:1 mixture of diastereomers.
was, in fact, correct was established on treatment of alcohol 47
with sodium hydride, which quickly generated a unique product,
alcohol 48.80
of various acyclic as well as cyclic propargylic â-keto esters
results in synthetically useful yields of the corresponding
â-methylene-γ-lactones, even when a reactive benzylic site
(entries 1,2) is present in the substrate. An encumbering
propargylic substituent, however, has a detrimental effect on
the yield (entry 1 vs entry 5). This procedure offers a direct
route to these polyfunctional compounds1b and should find
additional application.
Molecular mechanics calculations performed on the four
possible C-7,C-9 diastereomers revealed, as now expected, this
alcohol, with the natural relative stereochemistry, to be of lowest
energy, followed by 47.81 It does not seem unreasonable to
assume that the formation of 9-acetoxyfukinanolide in nature
involves a similar retro aldol-aldol equilibration for adjusting
the stereochemistry at these two vicinal stereocenters.
This fortuitous discovery provided a straightforward de´noue-
ment for the synthesis. Exposure of alcohol 47 (Scheme 7) to
base, optimally tetrabutylammonium fluoride (TBAF), and in
situ acetylation of the resulting equilibrated material gave
directly and in good yield racemic 9-acetoxyfukinanolide,
Unfortunately, NMR and molecular modeling studies with
lactone 46 were ambiguous, and the results of Srikrishna and
co-workers76 in related cyclizations were not sufficiently
consistent to allow us to assign with confidence the C-7
configuration. Nevertheless, because this keto lactone repre-
sented, potentially, the penultimate intermediate in our synthesis,
the reduction and acetylation reactions were studied despite the
stereochemical uncertainty. While hydride reducting agents, such
as NaBH4, BH3‚NH3, and Dibal-H, reduced selectively the
lactone function, SmI277 in 2% aqueous THF at 20 °C afforded
a unique hydroxy lactone (47) in 92% yield.78 Acetylation of
(77) For reviews, see: Molander, G. A. Chem. ReV. 1992, 92, 29-68. Molander,
G. A. Org. React. 1994, 46, 211-367. Molander, G. A.; Harris, C. R. Chem.
ReV. 1996, 96, 307-338. Krief, A.; Laval, A.-M. Chem. ReV. 1999, 99,
745-777. For a similar reduction problem and an alternative solution,
see: Wang, T.-Z.; Pinard, E.; Paquette, L. A. J. Am. Chem. Soc. 1996,
118, 1309-1318.
(78) NMR experiments for the purpose of assigning stereochemistry again were
not unequivocable.
(79) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975,
1574-1585. Hartwig, W. Tetrahedron 1983, 39, 2609-2645.
(80) For a related example, see: White, J. D.; Cutshall, N. S.; Kim, T.-S.; Shin,
H. J. Am. Chem. Soc. 1995, 117, 9780-9781.
(81) Molecular modeling was performed on a Silicon Graphics MD25G
workstation running Insight II Discover, version 2.3.0 (Biosym Technolo-
gies, San Diego). The structures were energy minimized with the force
field cvff.frc. and the minimization algorithm VA09A. Diastereomer 48,
39.4 kcal/mol; 47, 40.5 kcal/mol; 9-epi-48, 41.7 kcal/mol; 7-epi,9-epi-48,
42.3 kcal/mol.
(75) Crystal data for (()-56b: C14O3H18, monoclinic, C2/c, a ) 8.314(3) Å, b
) 10.297(5) Å, c ) 29.384(8) Å, â ) 90.729(3)°, V ) 2515(1) Å3, Z )
8, dcalcd ) 1.237 mg/m3, F(000) ) 1008.0, Θmax range 2.08-29.96°, 5604
measured reflections, 3877 [R(int) ) 0.03610] independent reflections, R(1)
[1 > 2σ(I)] ) 0.0482, wR2 [all data] ) 0.592, GOF (all data) ) 1.967.
(76) Srikrishna, A.; Nagaraju, S.; Sharma, G. V. R. J. Chem. Soc., Chem.
Commun. 1993, 285-288 and refs 15a-d,f.
9
J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002 15323

A R T I C L E S
Brocksom et al.
Scheme 8 a
identical except for rotation and melting point with the natural
sample. Single-crystal X-ray analyses14g of hydroxy lactone 47
(dichloroacetate derivative) and the racemic natural product
subsequently confirmed the stereochemical evolution over the
course of this first total synthesis.
The preparation of 9-acetoxyfukanolide could thus be ac-
complished in seven steps and 15% overall yield from dimeth-
ylcyclohexene 8 and with virtually complete stereochemical
control. By substituting enantiopure (S)-1,6-dimethyl-1-cyclo-
hexene (8*) for 8, the natural product itself could be similarly
obtained (mp 93 °C, [R]25 -28.6; lit.6 96-97 °C, [R]25
D
D
-28.5).
Bakkenolides III, B, C, H, L, V, and X. No approach to
the bakkanes could be considered general without providing an
entry to the numerous C-1,C-9 dioxygenated bakkenolides.
These densely functionalized, synthetically challenging lactones,
isolated from Petasites japonicus Maxim and Petasites formo-
sanus Kitamura (Compositae),3b,c,7a,b,8 possess significant inhibi-
tory activity toward Hep G2, Hep G2,2,15, and P-388 tumor
cell lines8b and PAF, arachidonic acid, and collagen-induced
platelet aggregation.8a The keto lactone 46* from the previous
synthesis appeared to offer various possibilities toward this end,
but in all of them, dehydrogenation to the ∆1(10) derivative
seemed essential.
The trimethylsilyl enol ether of 46* could be formed cleanly
with trimethylsilyl chloride and triethylamine in warm DMF,
but in the presence of palladium acetate,82 it afforded only a
low yield of the desired enone, the remainder of the material
being the starting ketone 46*. Fortunately, the obvious alterna-
tive of phenylselenenylation-oxidative elimination83 proceeded
smoothly to deliver the dehydro derivative 51a* in 77% yield
(Scheme 8).
Because direct, base-catalyzed epoxidation led to total
destruction of the molecule, a three-step protocol for transform-
ing enone 51a* to the corresponding epoxy ketone was
examined, with the hope that the R isomer 52b* would be
produced. This epoxy ketone was viewed as a potentially useful
compound for accessing the C-1R,C-9â (or R) diol, which, once
in hand, could be subjected to C-7,C-9 stereochemical equilibra-
tion through the previously used retro aldol-aldol reaction to
obtain the lowest-energy isomer, (-)-bakkenolide III (5a*), the
envisaged pivotal synthetic intermediate.84
On the basis of a chelation model85 and literature precedent,13,15e
it appeared that Luche reduction48 of enone 51a* might
selectively generate the desired R-hydroxyl, which would be
well-positioned to direct the epoxidation to the same face of
the allylic system in the presence of the homoallylic system.
Oxidation of the resulting epoxy alcohol would then restore the
carbonyl function and give epoxy ketone 52b*. To our delight,
this scenario, in reality, played out as planned: Luche reduction
of enone 51a* in ethanol provided highly stereoselectively
(g98%) the retro aldol-prone86 allylic alcohol 51b*, which on
a (a) NaHMDS, THF, -65 °C; C6H5SeBr, -65 f 0 °C; H2O2,
CH3CO2H-H2O, 0 °C. (b) NaBH4, CeCl3, C2H5OH, -30 °C. (c) VO(acac)2,
TBHP, C6H5CH3, 50-60 °C. (d) (ClCO)2, DMSO, CH2Cl2, -60 °C;
(C2H5)3N, -60 f 20 °C. (e) SmI2, THF-H2O, 20 °C. (f) (C4H9)4NF, THF,
0 °C.
[VO(acac)2]-catalyzed epoxidation with tert-butyl hydroperox-
ide87 (57%, two steps) and Swern oxidation (83%) afforded
epoxy ketone 52b* via epoxy alcohol 52a*. While the stereo-
chemical assignments were at this point tentative, they were
soon confirmed.
Samarium(II) iodide was known to both effectively cleave R
heteroatom substituents in ketone derivatives and reduce
ketones,77 and thus it was surprising to find that these two
transformations had not previously been coupled for producing
1,3-diols from epoxy ketones. Because Birch conditions,
known88 to be capable of effecting this type of conversion,
lacked the necessary chemoselectivity, the possibility of using
samarium diiodide as an alternative was examined in some
detail. It was eventually found that in the presence of excess
reagent in 1% aqueous THF at 20 °C for 0.5 h, epoxy ketone
52b* suffered clean, chemoselective double reduction to gener-
ate a unique diol (53*) in 83% yield. This diol was initially
assigned the C-1R,C-9â configurations on the basis of the above
considerations and because samarium diiodide was known to
produce, generally, the more stable84 isomer (e.g., 46 f 47,81
Scheme 7); a single-crystal X-ray analysis14i offered, nonethe-
less, most welcome confirmation. Only the C-1 configuration
is relevant at this point, however.
The crucial retro aldol-aldol reaction for correcting the C-7
stereocenter was next investigated. To our utter delight, diol
53* on exposure to TBAF in THF at 0 °C for 0.5 h did indeed
smoothly isomerize as predicted to the lowest energy84 C-7,C-9
isomer, notwithstanding the complexity of the system and the
alternative pathways that might attend such a transformation.
That the crystalline product, formed in 82% yield, was, in fact,
(-)-bakkenolide III (5a*)8b was initially shown through direct
comparison with the hydrolysis product3c,d,7a of (-)-bakkenolide
B and then confirmed by single-crystal X-ray analysis.14i
(82) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011-1013.
(83) For a review, see: Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1-296.
(84) Calculations were performed on an IBM RS 6000 workstation running
Insight II Discover 98.0 (MSI, San Diego). The structures were energy
minimized with the force field cvff.frc. and the minimization algorithm
VA09A. Diastereomer 5a*, 39.2 kcal/mol; 53*, 40.0 kcal/mol; 7-epi,9-
epi-5a*, 42.0 kcal/mol; 9-epi-5a*, 44.3 kcal/mol.
(85) Cf.: Krief, A.; Surleraux, D.; Ropson, N. Tetrahedron: Asymmetry 1993,
4, 289-292.
(86) For a closely related (postulated) example in mass spectrometry, see ref
3b.
(87) Itoh, T.; Jitsukawa, K.; Kaneda, K.; Teranishi, S. J. Am. Chem. Soc. 1979,
101, 159-169. For reviews, see: Sharpless, K. B.; Verhoeven, T. R.
Aldrichimica Acta 1979, 12, 63-74. Jørgensen, K. A. Chem. ReV. 1989,
89, 431-458.
(88) Devreese, A. A.; Demuynck, M.; De Clercq, P. J.; Vandewalle, M.
Tetrahedron 1983, 39, 3039-3048. Swindell, C. S.; deSolms, S. J.
Tetrahedron Lett. 1984, 25, 3801-3804.
9
15324 J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002

Syntheses of Bakkanes
A R T I C L E S
Scheme 9 a
a (a) (Z)-2,4,6-Cl3C6H2CO2COC(CH3)dCHCH3, C6H5CH3, ∆. (b) (CH3)2CHCH2CO)2O, C5H5N, C6H5CH3, 20 °C. (c) (CH3CO)2O, C5H5N, C6H5CH3, 20
°C. (d) (CH3CO)2O, C5H5N, DMAP, 20 °C. (e) ((CH3)2CHCO)2O, C5H5N, DMAP, 20 °C.
(-)-Bakkenolide III, with its two hydroxyl groups in quite
different steric environments, is the ideal platform for accessing
the entire range of C-1,C-9-difunctionalized bakkenolides. To
illustrate this point, the representative bakkenolides B, C, and
H, and, quite recently, L, V, and X, have been prepared (Scheme
9). The angelic ester, (-)-bakkenolide C (5c*),3c,d,7a was readily
synthesized in 86% yield by using the Yamaguchi mixed
anhydride under our earlier developed conditions (see eq 9), to
the complete exclusion of tiglic ester and diacylated material.
The mono esters (-)-bakkenolide V (5h*)8b and (-)-bakkeno-
lide X (5i*)8b could also be secured highly selectively and in
good yield with isovaleryl anhydride and acetic anhydride,
respectively. The diesters (-)-bakkenolide B (5b*)3c,d,7a,8b and
(-)-bakkenolide L (5g*)8b were easily obtained from (-)-
bakkenolide C and (-)-bakkenolide III, however, with excess
acetic anhydride in the presence of DMAP. Similarly, the
diisobutyrate (-)-bakkenolide H (5f*),8 which shows significant
cytotoxic activity in several different systems, could be secured
directly from (-)-bakkenolide III in 94% yield through exposure
to excess isobutyric anhydride and DMAP.
A number of new and practical methods have resulted from
this work. These include (1) spiro â-methylene-γ-butyrolac-
tonization procedures, (2) a vicinal dicarboxylation, (3) an
angelic ester preparation, (4) a transesterification protocol, (5)
an epoxy ketone double reduction, and (6) a retro aldol-aldol
approach to low-energy aldol isomers. Natural product synthesis
has thus once again proven an excellent vehicle for the
development of new synthetic methodologies. Those above
should find additional application.
Acknowledgment. This paper is dedicated with appreciation
to Professor Jean Lhomme for his scientific and administrative
contributions to the chemistry in Grenoble. We thank Profs. J.
Lhomme, G. Mehta, and A. Rassat and Drs. A. Gadras and J.-
L. Luche for their interest in our work, Dr. I. Gautier-Luneau
and Prof. P. Sinay¨ for fruitful discussions, and Profs. F.
Bohlmann, W. Fenical, T. Kato, M. Kawai, and M. Noda, Dr.
J. Harmatha, Ms. N. Pujol, and Mr. K. Watanabe for invaluable
samples and spectra. In addition, we are indebted to Ms. M.-L.
Dheu-Andries and Dr. P. Vatton for their assistance with the
molecular modeling, Drs. M.-T. Averbuch, J.-P. Declercq, A.
Durif, C. Philouze, and B. Tinant for the X-ray structure
determinations, and Mr. F. Bargiggia, Mr. M. Cook, Ms. G.
Garavel, Ms. S. Heidenhain, and Mr. C. Mottet for helpful
experimental work. We also gratefully acknowledge financial
support from the Universite´ Joseph Fourier and the CNRS
(UMR 5616) and from Rhoˆne-Poulenc Agro and fellowship
awards from the MESR (to O.H.), the CNPq (to F.C., A.M.K,
and M.E.F.de L.), and Rhoˆne-Poulenc Agro (to B.H.).
The synthesis of the naturally occurring bakkanes (-)-
bakkenolides III, B, C, H, L, V, and X could thus be
accomplished in high yield and with virtually complete stereo-
selectivity from an efficiently prepared intermediate, keto lactone
46*. The key, thermodynamically driven adjustment of stereo-
chemistry integrated into the approach is especially noteworthy.
Conclusion
A simple, yet highly effective, [2 + 2] cycloaddition reaction
of dichloroketene with dimethylcyclohexenes has been exploited
for the development of the first comprehensive approach to the
bakkanes. The ability of the approach to reach the complex
members of the family is seen in the efficient syntheses of the
compact, densely functionalized bakkenolides III, B, C, H, L,
V, and X.
Supporting Information Available: Experimental details and
characterization data for the syntheses of 1, 1*, 2a, 2a*, 2b*,
3, 4, 4*, 5a-c*, 5f-i*, 54b-58b (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA0208456
9
J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002 15325