Chromium(0)-promoted multicomponent cycloaddition of tethered diynes with cyclic trienes: Application to the total synthesis of 9-epi-pentalenic acid

Article abstract of DOI:10.1021/jo040204o

An efficient protecting group controlled regioselective chromium(0)-mediated three-component higher order cycloaddition of tethered diynes with cyclic trienes that generates five rings and six stereogenic centers in one step is described. Following a sequence of reactions featuring a chemoselective Baeyer-Villiger rearrangement and a regioselective cyclopropane hydrogenolysis, the total synthesis of 9-epi-pentalenic acid was achieved.

Full text of DOI:10.1021/jo040204o

Ch r om iu m (0)-P r om oted Mu lticom p on en t Cycloa d d ition of
Teth er ed Diyn es w ith Cyclic Tr ien es: Ap p lica tion to th e Tota l
Syn th esis of 9-epi-P en ta len ic Acid
J ames H. Rigby,* Mundruppady S. Laxmisha, Andrew R. Hudson, Charles H. Heap, and
Mary J ane Heeg
Department of Chemistry, Wayne State University, Detroit, Michigan 48202-3489
jhr@chem.wayne.edu
Received May 27, 2004
An efficient protecting group controlled regioselective chromium(0)-mediated three-component higher
order cycloaddition of tethered diynes with cyclic trienes that generates five rings and six stereogenic
centers in one step is described. Following a sequence of reactions featuring a chemoselective
Baeyer-Villiger rearrangement and a regioselective cyclopropane hydrogenolysis, the total synthesis
of 9-epi-pentalenic acid was achieved.
SCHEME 1. Ch r om iu m (0)-Med ia ted
Mu lticom p on en t Cycloa d d ition
In tr od u ction
In recent years, higher order cycloaddition has emerged
as a powerful tool for the rapid assembly of stereochemi-
cally rich and structurally elaborate polycyclic systems.1
Metal mediation of the cycloaddition process has resulted
in advances in which ring constructions not normally
accessible via conventional metal-free conditions have
become almost routine. These metal-mediated cycload-
ditions have made possible efficient construction of a
range of medium-sized-ring systems.2
Chromium(0)-promoted higher order cycloadditions,
such as [6π+2π] and [6π+4π] combinations, have also
received considerable attention in recent years due to
their stereocomplementarity and periselectivity advan-
tages over the corresponding metal-free cycloaddition
processes.3 An intriguing and potentially significant
extension of this chromium(0)-mediated ring assembly
has been realized with the recent discovery of a novel
and efficient three-component, one-pot cycloaddition
process, characterized by the Cr(0)-mediated combination
of 2 equiv of an alkyne with a cyclic triene4 to afford an
unusual tetracyclic ring system (Scheme 1). An intramo-
lecular variant of this reaction was also brought to
practice in which the two reacting alkyne partners are
tethered by spacers of various lengths and compositions.5
Noteworthy features of this protocol include simultaneous
formation of five rings and six stereogenic centers with
excellent stereo- and regiocontrol.
situations if this methodology is to become synthetically
useful. Among the most important of these is establishing
a regioselectivity profile of the cycloaddition step when
unsymmetrical diynes are employed. We now wish to
report that this issue has been addressed in some detail
in the context of the total synthesis of 9-epi-pentalenic
acid, in which a chromium(0)-mediated three-component
cycloaddition serves as the key strategy level transforma-
tion.
Pentalenic acid (1) was first isolated in 1978 from the
fermentation broth of Streptomyces griseochromogens6
and is believed to be the biogenetic precursor of the
antibiotic pentalenolactone. There has been a sustained
interest in the synthesis of pentalenic acid and several
new approaches have been reported.7 Initial inspection
of our target molecule revealed, however, that while the
current methodology would set all of the necessary
stereocenters for the molecule in the cycloaddition event,
one of the centers, at C-9, would be set in the opposite
fashion to that present in the natural product. Conse-
quently, we embarked on the synthesis of 9-epi-pentalenic
acid (2). While 9-epi-pentalenic acid is not a natural
product, and it has been synthesized previously,7i it would
While these sequences are quite attractive and show
much promise in relatively simple applications, several
important issues must be addressed in more complex
(1) For general reviews on metal-catalyzed cycloadditions, see: (a)
Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49-92. (b)
Hegedus, L. S. Coord. Chem. Rev. 1997, 161, 129-255. (c) Fru¨hauf,
H.-W. Chem. Rev. 1997, 97, 523-596. (d) Filippini, M.-H.; Rodriguez,
J . Chem. Rev. 1999, 99, 27-76. (e) Ojima, I.; Tzamarioudaki, M.; Li,
Z.; Donovan, R. J . Chem. Rev. 1996, 96, 635-662. (f) Hartley, R. C.;
Caldwell, S. T. J . Chem. Soc., Perkin Trans. 1 2000, 477-501. (g)
Wender, P. A. Pure Appl. Chem. 2002, 74, 25-31.
10.1021/jo040204o CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/03/2004
J . Org. Chem. 2004, 69, 6751-6760
6751

Rigby et al.
SCHEME 2. Retr osyn th esis of 9-epi-P en ta len ic
still represent an appropriate demonstration of our
methodology. The salient features of our synthetic strat-
egy are shown in Scheme 2. In terms of the synthesis
end game, it was envisioned that the carboxylic acid 7,
derived from the cyclopropane carboxylic acid 6 by a
regioselective cleavage of the sterically less encumbered
cyclopropane bond, could be processed to deliver the
target compound 2 by simple functional group transfor-
mations. The carboxylic acid 6 was seen to be available
from the cycloadduct 5 by a regioselective oxidative
cleavage of the less substituted double bond. At the outset
of our investigation, crucial questions remained regarding
the regiocontrol in the cycloaddition of unsymmetrical
tethered diyne 4 and cycloheptatriene complex 3, and a
viable method to oxidatively cleave the less substituted
Acid
(2) For general reviews on metal-promoted medium-size-ring syn-
thesis, see: (a) Yet, L. Chem. Rev. 2000, 100, 2963-3008. (b) Mehta,
G.; Singh, V. Chem. Rev. 1999, 99, 881-930. (c) Sieburth, S. McN.;
Cunard, N. T. Tetrahedron 1996, 52, 6251-6282. Seven-membered-
ring synthesis: (d) Trost, B. M.; Shen, H. C.; Schulz, T.; Koradin, C.;
Schirok, H. Org. Lett. 2003, 5, 4149-4151. (e) Wender, P. A.; Taka-
hashi, H.; Witulski, B. J . Am. Chem. Soc. 1995, 117, 4720-4721. (f)
Wender, P. A.; Pedersen, T. M.; Scanio, M. J . C. J . Am. Chem. Soc.
2002, 124, 15154-15155. (g) Trost, B. M.; MacPherson, D. T. J . Am.
Chem. Soc, 1987, 109, 3483-3484. (h) Noyori, R. Acc. Chem. Res. 1979,
12, 61-66. (i) Hoffmann, H. M. R. Angew Chem., Int. Ed. Engl. 1984,
23, 1-19. (j) Schwiebert, K. E.; Stryker, J . M. J . Am. Chem. Soc. 1995,
117, 8275-8276. Eight-membered-ring synthesis: (k) Evans, P. A.;
Robinson, J . E.; Baum, E. W.; Fazal, A. N. J . Am. Chem. Soc. 2002,
124, 8782-8783. (l) Wender, P. A.; Nuss, J . M.; Smith, D. B.; Sua´rez-
Sobrino, A.; Vågberg, J .; Decosta, D.; Bordner, J . J . Org. Chem, 1997,
62, 4908-4909. (m) Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J .
Am. Chem. Soc. 2000, 122, 7815-7816. (n) Wender, P. A.; Gamber, G.
G.; Hubbard, R. D.; Zhang, L. J . Am. Chem. Soc. 2002, 124, 2876-
2877. (o) Gilbertson, S. R.; DeBoef, B. J . Am. Chem. Soc. 2002, 124,
8784-8785. (p) Brenner, W.; Heimbach, P.; Hey, H.; Mu¨ller, E. W.;
Wilke, G. J ustus Liebigs Ann. Chem. 1969, 727, 161. (q) Diercks, R.;
Stamp, L.; tom Dieck, H. Chem. Ber. 1984, 117, 1913-1919. (r) Davis,
R. E.; Dodds, T. A.; Hseu, T.-H.; Wagnon, J . C.; Devon, T.; Tancrede,
J .; McKennis, J . S.; Pettit, R. J . Am. Chem. Soc. 1974, 96, 7562-7564.
(s) Lautens, M.; Tam, W.; Sood, C. J . Org. Chem. 1993, 58, 4513-
4515. (t) Rigby, J . H.; Ateeq, H. S.; Charles, N. R.; Henshilwood, J . A.;
Short, K. M.; Sugathapala, P. M. Tetrahedron 1993, 49, 5495-5506.
Nine-membered ring: (u) Kreiter, C. G.; Lehr, K.; Leyendecker, M.;
Scheldrick, W. S.; Exner, R. Chem. Ber. 1991, 124, 3-12. (v) Kreiter,
C. G.; Lehr, K. J . Organomet. Chem. 1993, 454, 199-204. Ten-
membered ring: (w) Rigby, J . H.; Ateeq, H. S.; Charles, N. R.; Cuisiat,
S. V.; Ferguson, M. D.; Henshilwood, J . A.; Krueger, A. C.; Ogbu, C.
O.; Short, K. M.; Heeg, M. J . J . Am. Chem. Soc. 1993, 115, 1382-
1396.
SCHEME 3. Mu lticom p on en t Cycloa d d ition of 9
w ith 3a
a
Reagents and conditions: (a) LDA/propargyl bromide, THF,
94%; (b) LAH, ether, 90%; (c) DMSO, oxalyl chloride, Et3N, CH2Cl2,
92%; (d) TMS-acetylene, n-BuLi, THF, 92%; (e) hν (Pyrex), 1,2-
dichloroethane, 65 °C, 16%; (f) PTSA, CH3CN/THF/H2O or Bu4NCl,
AcOH, CH3CN.
double bond in 5, to give two chemically distinguishable
carbonyl functionalities as required in 6 for further
chemical transformations. The notable features of this
synthetic plan are the following: (a) it is fundamentally
different from existing approaches to angular triquinane
natural products, (b) all stereocenters present in the
target are set in the initial cycloaddition reaction, leaving
only functional group manipulations, and (c) only one
carbon must be excised from the cycloadduct 5 to provide
the target compound, thus making the synthesis very
atom economical.8
(3) (a) Rigby, J . H. Tetrahedron 1999, 55, 4521-4538. (b) Rigby, J .
H. Acc. Chem. Res. 1993, 26, 579-585. (c) Chaffee, K.; Huo, P.;
Sheridan, J . B.; Barbieri, A.; Aistars, A.; Lalancette, R. A.; Ostrander,
R. L.; Rheingold, A. L. J . Am. Chem. Soc. 1995, 117, 1900-1907. (d)
Chaffee, K.; Sheridan, J . B.; Aistars, A. Organometallics 1992, 11, 18-
19. (e) O¨ zkar, S.; Kurz, H.; Neugebauer, D.; Kreiter, C. G. J .
Organomet. Chem. 1978, 160, 115-124.
(4) (a) Rigby, J . H.; Warshakoon, N. C.; Heeg, M. J . J . Am. Chem.
Soc. 1996, 118, 6094-6095. (b) Chen, W.; Chaffee, K.; Chung, H.-J .;
Sheridan, J . B. J . Am. Chem. Soc. 1996, 118, 9980-9981.
(5) Rigby, J . H.; Heap, C. R.; Warshakoon, N. C. Tetrahedron 2000,
56, 2305-2311.
Resu lts a n d Discu ssion
(6) Seto, H.; Sasaki, T.; Uzawa, J .; Takeuchi, S.; Yonehara, H.
Tetrahedron Lett. 1978, 19, 4411-4412.
As our synthetic plan required the use of an unsym-
metrical diyne in the cycloaddition event, we first sought
to investigate methods for controlling the regiochemistry
of the diyne cycloaddition. The first approach was to block
one end of the diyne with a trimethylsilyl group. The
diyne 9, which was prepared in four steps from ethyl
isobutyrate (Scheme 3), was chosen initially to study this
three-component cycloaddition.9 Thus, alkylation of ethyl
isobutyrate with LDA/propargyl bromide followed by
lithium aluminum hydride reduction of the resulting
ester gave alcohol 8. Swern oxidation and subsequent
(7) For excellent reviews of approaches to triquinane ring systems
and related natural products, see: (a) Mehta, G.; Srikrishna, A. Chem.
Rev. 1997, 97, 671-720. (b) Paquette, L. A. Top. Curr. Chem. 1979,
79, 41-165. (c) Paquette, L. A. Top. Curr. Chem. 1984, 119, 1-158.
For previous syntheses of pentalenic acid, see: (d) Crimmins, M. T.;
DeLoach, J . A. J . Am. Chem. Soc. 1986, 108, 800-806. (e) Crimmins,
M. T.; DeLoach, J . A. J . Org. Chem. 1984, 49, 2076-2077. (f) Sakai,
K.; Ohtsuka, T.; Misumi, S. Chem. Lett. 1981, 355-358. (g) Agnel, G.;
Negishi, E. J . Am. Chem. Soc. 1991, 113, 7424-7426. (h) Ihara, M.;
Katogi, M.; Fukumoto, K. J . Chem. Soc., Perkin Trans. 1 1988, 2963-
2970. (i) Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G.; Ranu, B. C.;
Papadopolous, P. Tetrahedron 1987, 43, 5685-5721. For previous
approaches to pentalenic acid, see: (j) Bintz-Giudicelli, C.; Weymann,
O.; Uguen, D. Tetrahedron Lett. 1997, 38, 2841-2844. (k) Rowley, E.
G.; Schore, N. E. J . Org. Chem. 1992, 57, 6853-6861. (l) Seo, J .; Fain,
H.; Blanc, J .-B.; Montgomery, J . J . Org. Chem. 1999, 64, 6060-6065.
(8) Trost, B. M. Science 1991, 254, 1471-1484.
6752 J . Org. Chem., Vol. 69, No. 20, 2004

Multicomponent Cycloaddition of Tethered Diynes
TABLE 1. Eva lu a tion of Regioselectivity in th e
Ch r om iu m (0)-Med ia ted Th r ee-Com p on en t Cycloa d d ition
SCHEME 4. Regiocon tr ol in th e High er Or d er
Cycloa d d ition of O-Silyla ted Diyn es
entry
R
products
ratio (a :b)
yield, %
1
2
3
H
TBS
TIPS
14a and 14b
15a and 15b
16a
1.8:1
14:1
100:0
36
65
70
SCHEME 5. Deter m in a tion of th e Ra tio of
Regioisom er sa
TMS-acetylide addition afforded 9, required for the
cycloaddition. The cycloaddition of 9 with complex 3
worked well in terms of dictating the regiochemistry of
the cycloaddition to give the cycloadduct 10 as a single
regioisomer, but the yield of the reaction was very poor,
most likely due to a very slow rate of the second
intramolecular homo[6+2] reaction, which allows more
time for other side reactions such as decomplexation to
occur. Another problem with employing the TMS blocking
approach in a synthetic effort is the eventual removal of
the vinylic silyl group at some point. This is not always
a trivial proposition as evidenced by two unsuccessful
attempts to cleave the TMS group in 10 with PTSA in
CH3CN/THF/H2O at 65 °C10 or Bu4NCl and AcOH in CH3-
CN,11 both of which resulted in virtually complete
recovery of starting material.
The second approach to control the regiochemistry of
the cycloaddition was to increase the steric bulk in the
vicinity of one of the alkynes. Toward this end, cycload-
ditions were performed with a series of diynes having
protecting groups of different steric bulk on the propar-
gylic hydroxyl group (Scheme 4). While the cycloaddition
of the diyne 11 having a free hydroxyl group with
complex 3 gave a mixture of regioisomeric cycloadducts
in poor yield, better results were obtained when TBS
protected diyne 12 was employed. This reaction gave the
corresponding cycloadducts in 65% overall yield and 14:1
regioselectivity in favor of the required regioisomer 15a .
The best result in terms of regioselectivity and reaction
yield was obtained when the sterically more demanding
TIPS group was used as the protecting group. Thus,
photolysis of complex 3 in 1,2-dichloroethane with slow
addition of diyne 13 gave the desired cycloadduct 16a in
70% yield as the sole observable regioisomer.12 The
cycloadducts in these examples were obtained as a 1:1
mixture of diastereoisomers at the oxygen-substituted
position.The ratio of regioisomers was determined by
a
Reagents and conditions: (a) TBAF, THF; (b) TPAP,
NMO, CH2Cl2; (c) NaBH4, CeCl3‚7H2O, MeOH, -78 °C, 87%; (d)
TIPSOTf, 2,6-lutidine, CH2Cl2, 93%.
conversion of the alcohols into the corresponding ketones
by cleavage of the protecting groups (if necessary) and
oxidation with TPAP/NMO (Scheme 5).13 The oxidation
removed the problem of dealing with four stereoisomers
in the mixture of cycloadducts and formation of R,â-
unsaturated ketone 17 with an olefinic proton at δ 6.56
allowed for facile differentiation of the two regioisomers.
Enone 17 was reduced under Luche conditions14 at -78
°C to give the allylic alcohol 19 as a single diastereoiso-
mer. Although this avoided the problem of dealing with
a mixture of diastereoisomers for the rest of the synthetic
sequence, X-ray analysis of the product showed that the
hydroxyl group stereochemistry was opposite to that
present in the target. Attempts to reduce the enone 17
with DIBAL and LAH afforded predominantly the 1,4-
reduced products, while efforts to invert the alcohol
stereochemistry in 19 by Mitsunobu and modified Mit-
sunobu conditions15 led to the recovery of starting mate-
rial. It was assumed that the hydroxyl group stereochem-
istry could be set by an oxidation-reduction protocol at
a later stage and the synthesis was advanced from alcohol
19. This decision was predicated on the fact that in some
of the previous syntheses of pentalenic acid, the hydroxyl
group stereochemistry at C-1 was set by a dissolving
metal reduction of the corresponding ketone late in the
synthesis.7d,h The alcohol 19 was protected as its TIPS
ether by treatment with TIPSOTf and 2,6-lutidine in
dichloromethane to give 20 as a single diastereoisomer.
(9) (a) Magnus, P.; Principe, L. M.; Slater, M. J . J . Org. Chem. 1987,
52, 1483-1486. (b) Ojima, I.; Kass, D. F.; Zhu, J . Organometallics 1996,
15, 5191-5195. (c) Pearson, A. J .; Shively, J r, R. J . Organometallics
1994, 13, 578-584. (d) Yamamoto, Y.; Kitahara, H.; Ogawa, R.;
Kawaguchi, H.; Tatsumi, K.; Itoh, K. J . Am. Chem. Soc. 2000, 122,
4310-4319.
(10) Wender, P. A.; Smith, T. E. J . Org. Chem. 1996, 61, 824-825.
(11) Kojima, A.; Takemoto, T.; Sodeoka, M.; Shibasaki, M. Synthesis
1998, 581-589.
(12) Although electronic factors cannot be ruled out in dictating the
regioselectivity of the cycloaddition, marked improvement in the
regioselectivity observed when an electronically similar TBS group was
replaced by a TIPS group indicates that steric effects are predominant.
(13) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(14) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981, 103, 5454-
5459.
(15) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. J pn. 1967, 40,
2380-2382. (b) Mukaiyama, T.; Shintou, T.; Fukumoto, K. J . Am.
Chem. Soc. 2003, 125, 10538-10539.
J . Org. Chem, Vol. 69, No. 20, 2004 6753

Rigby et al.
of hydrolysis aid (MeSO2NH2), and pyridine (1 equiv).19
Under these conditions the desired diol 24 was obtained
as the major product in 51% yield along with regioiso-
meric diol 25 and tetraol 26. The reaction was amenable
to scale-up giving sufficient quantities of 24 for further
use. Efforts were made to improve the regioselectivity of
the dihydroxylation by using a bulky ligand20 on osmium,
which gave the undesired diol 25 as the major pro-
duct.With diol 24 in hand, we began to explore the most
effective means of cleavage to gain access into the angular
triquinane skeleton. Due to the problems encountered in
simpler systems with the oxidative cleavage of the diol
and being cognizant of the need to differentiate the
resultant carbonyl groups, alternative routes to achieve
these objectives were pursued. Among the more attractive
options was a sequence involving a Baeyer-Villiger
rearrangement of the vicinal diketone 27.21 It was
believed that the differentiation of the two carbonyl
groups could be achieved by careful opening of the
anhydride 28 with an alkoxide or alcohol nucleophile to
yield the corresponding ester 29. Although examination
of molecular models did not give a clear indication as to
which of the two carbonyl groups in 28 would be more
accessible, it was assumed that the presence of a cyclo-
propyl group adjacent to one of them would assist in the
proper regiochemical outcome.
The diol 24 was oxidized with DMSO/trifluoroacetic
anhydride to give the vicinal dione 27 in good yield.22
Treatment of 27 with m-CPBA (1.3 equiv) at 0 °C,
buffered with an excess of NaHCO3, gave the cyclic
anhydride 28 in excellent yield23 and no trace of epoxide
formation was observed. Although Baeyer-Villiger rear-
rangement of cyclic vicinal diones to corresponding
anhydrides has been reported,23e-f,24 to the best of our
knowledge, the formation of eight-membered anhydrides
by the Baeyer-Villiger reaction of cyclic seven-membered
vicinal diones is without precedent in the literature. This
outcome is all the more significant because it left a
potentially reactive olefin untouched during the reac-
tion.24 With cyclic anhydride 28 in hand, the ring opening
proved straightforward. As anticipated on electronic
grounds, treatment of 28 with methanol and triethyl-
amine in CH2Cl2 gave ester 29 as a single regioisomer.
R egioselect ive Clea va ge of t h e Cyclop r op a n e
Rin g. With a viable strategy for the synthesis of the
tricyclic core at our disposal, the next task in the
SCHEME 6. High er Or d er Cycloa d d ition of 22a
a
Reagents and conditions: (a) CrO3, H2SO4, H2O, 86%; (b) 2,2-
dimethylpropane-1,3-diol, PTSA, benzene, 48%; (c) hν, DCE, 45%;
(d) PTS, acetone, 29%.
One limitation of this cycloaddition methodology is the
lack of control at the newly formed alcohol stereocenter
in the cycloadduct 16a . However, since the cycloaddition
affords such a large increase in molecular complexity in
a single chemical operation, it was considered acceptable.
A potential solution to this problem would be to use a
diyne that possesses a hydroxyl group surrogate, which
does not generate a new stereocenter during the cycload-
dition step. The diyne 22 was viewed as an ideal choice
for this purpose. The requisite diyne 22 was prepared
from 11 by an oxidation and protection protocol through
the intermediate ynone 21 as shown in Scheme 6.
Cycloaddition of 22 with 3 gave the adduct 23 as a single
regioisomer, albeit in moderate yield. It was known from
earlier work that the enone 17 could be selectively
reduced to give alcohol 19 in good yields. Therefore the
deprotection of the acetal moiety in 23 was attempted
under acidic conditions. This seemingly simple transfor-
mation, however, proved difficult and the best yield (29%)
for the deprotection was obtained when PTSA in acetone
was used. At this point, it was deemed prudent to proceed
with the projected synthesis with use of pentacycle 20.
R egioselect ive Clea va ge of t h e Disu b st it u t ed
Alk en e. With diene 20 in hand, work was initiated
toward the regioselective oxidative cleavage of the di-
substituted alkene moiety in the presence of the osten-
sibly more reactive trisubstituted olefin. As mentioned
before, the completion of the synthesis relies not only on
successful regioselective oxidative cleavage of the disub-
stituted olefin, but also on a viable method for success-
fully differentiating the two resulting carbonyl groups.
After many unsuccessful attempts to regioselectively
epoxidize the disubstituted double bond,16 osmium tetrox-
ide catalyzed dihydroxylation was investigated. This
reaction, however, proved to be troublesome and required
a detailed investigation. The UpJ ohn dihydroxylation
conditions17 resulted in mostly recovered starting mate-
rial, as did dihydroxylation under stoichiometric condi-
tions in conjunction with TMEDA.18 After some experi-
mentation, the dihydroxylation was achieved with
moderate regioselectivity with use of OsO4 (20 mol %),
potassium ferricyanide as the co-oxidant, a large excess
(19) J ohnson, R. A,; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: New York, 1993.
(20) Andrus, M. B.; Lepore, S. D.; Sclafani, J . A. Tetrahedron Lett.
1997, 38, 4043-4046.
(21) Mechanistically, this rearrangement is slightly different from
the normal Baeyer-Villiger rearrangement of ketones when m-CPBA
is used. For details, see: Cullis, P. M.; Arnold, J . R. P.; Clarke, M.;
Howell, R.; DeMira, M.; Naylor, M.; Nicholls, D. J . Chem. Soc., Chem.
Commun. 1987, 1088-1089.
(22) Amon, C. M.; Banwell, M. G.; Gravatt, G. L. J . Org. Chem. 1987,
52, 4851-4855.
(23) For some examples of Baeyer-Villiger rearrangement of vicinal
diones to anhydrides, see: (a) Kwart, H.; Wegemer, N. J . J . Am. Chem.
Soc. 1961, 83, 2746-2755. (b) Sawaki, Y.; Foote, C. S. J . Am. Chem.
Soc. 1979, 101, 6292-6296. (c) Leffler, J . E. J . Org. Chem. 1951, 16,
1785-1787. (d) Hassall, C. H. Org. React. 1957, 9, 73. (e) J acobs, R.
T.; Feutrill, G. I.; Meinwald, J . J . Org. Chem. 1990, 55, 4051-4062.
(f) Komarov, I. V.; Monsees, A.; Kadyrov, R.; Fischer, C.; Schmidt, U.;
Bo¨rner, A. Tetrahedron: Asymmetry 2002, 13, 1615-1620.
(24) A Baeyer-Villiger rearrangement of medium-size cyclic 1,2-
diones in the presence of an olefin has been reported but the
chemoselectivity was very poor, see: Mayer, W.; Meier, H. Chem. Ber.
1989, 122, 509-517.
(16) Epoxidation attempts with m-CPBA gave a complex mixture
of products.
(17) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973-1976.
(18) Tomioka, K. Synthesis 1990, 541-549.
6754 J . Org. Chem., Vol. 69, No. 20, 2004

Multicomponent Cycloaddition of Tethered Diynes
SCHEME 7. Regioselective Dih yd r oxyla tion a n d An h yd r id e Op en in ga
a
Reagents and conditions: (a) OsO4, K3Fe(CN)6, K2CO3, py, MeSO2NH2, t-BuOH/H2O (1:1); (b) DMSO, (CF3CO)2O, Et3N, CH2Cl2,
93%; (c) m-CPBA, NaHCO3, CH2Cl2, 0 °C, 96%; (d) MeOH, Et3N, CH2Cl2, 89%.
SCHEME 8. On e-P ot La cton iza tion a n d
synthetic sequence was the regioselective cleavage of the
cyclopropane moiety in acid 29. Unfortunately, this
Cyclop r op a n e Clea va gea
projected cleavage was found to be particularly difficult
under a variety of conditions. For example, catalytic
hydrogenation-based methods led to recovery of starting
material while dissolving metal reduction attacked the
ester group to give the corresponding alcohol, while
leaving the cyclopropane unit intact. We next investi-
gated trimethylsilyl iodide-mediated cyclopropyl ring
cleavage. Although there have been a number of reports
on TMSI-mediated cleavage of cyclopropyl ketones25 and
cyclopropyl carboxylic esters,26 we could identify only one
report of cyclopropyl carboxylic acid cleavage with
TMSI.27 Attempted opening of the cyclopropane ring in
29 under the reported conditions appeared to result in
no reaction after several hours at ambient temperature.
a
Reagents and conditions: (a) HI (1.1 equiv), CH2Cl2, 2 h; (b)
However, much to our surprise, lactone 30 was isolated
as the major product along with recovered acid after
92%.
aqueous workup of the reaction. The likely mechanism
HI (3 equiv), CH2Cl2, 24 h; (c) n-Bu3SnH, AIBN, toluene, reflux,
for this process involves a cationic cyclization of the acid
mediated by the putative acid generated upon addition
yields, respectively. Reductive removal of the iodide in
31 with tributyltin hydride in refluxing toluene was
of water. Indeed, treatment of acid 29 with hydriodic acid
straightforward, furnishing lactone 32 in 92% yield
(1.1 equiv) in CH2Cl2 for less than 2 h gave lactone 30 in
(Scheme 8).
a respectable 82% yield. This reaction also gave a minor
It was anticipated that this lactonization protocol
product, the structure of which was established by X-ray
would facilitate the synthesis of the target molecule.
analysis as the iodolactone 31. It was assumed that
However, compound 30 could also present a selectivity
iodolactone 31 presumably arises by a tandem acid-
issue between the two similar carbonyl groups. The need
catalyzed lactonization and regioselective iodide-medi-
to invert the stereochemistry of the hydroxyl group at
ated cyclopropane cleavage.28 Initial experiments to drive
C-1 and to decarboxylate the acid derived from the
this process toward 31 revealed that the cyclopropane
lactone at some stage provided an ideal situation to deal
cleavage was extremely sluggish and required longer
with the lactone moiety at a later stage in the synthesis.
reaction times. However, the reaction rate can be in-
Consequently, the immediate focus in the synthetic
creased by using excess HI at the expense of the overall
sequence was to find methods to improve the efficacy of
reaction yield. The optimum result was obtained by
the cyclopropane cleavage process. Although the regiose-
stirring 29 for 24 h with HI (3 equiv) in CH2Cl2, which
lective cyclopropane cleavage was accomplished during
gave the iodide 31 and the lactone 30 in 40% and 19%
the unanticipated acid-catalyzed lactonization of acid 29,
the yields were disappointing and an alternative method
was sought.
(25) Miller, R. D.; McKean, D. R. J . Org. Chem. 1981, 46, 2412-
2414.
(26) Brown, S. P.; Bal, B. S.; Pinnick, H. W. Tetrahedron Lett. 1981,
22, 4891-4894.
Catalytic hydrogenation, which was unsuccessful with
acid 29, was now attempted on lactone 30. After some
experimentation, it was found that hydrogenolysis of 30
with Pearlman’s catalyst29 under a hydrogen atmosphere
(27) Buttinelli, P.; Gargaro, G.; Loreto, M. A.; Pellacani, L.; Tardella,
P. A. Gazz. Chim. Ital. 1985, 115 (3), 155.
(28) Treatment of the lactone 30 with HI indeed gave iodolactone
31 along with recovered starting material, which confirmed that 30 is
an intermediate in this tandem lactonization and cyclopropane cleav-
age.
(29) Pearlman, W. M. Tetrahedron Lett. 1967, 8, 1663-1664.
J . Org. Chem, Vol. 69, No. 20, 2004 6755

Rigby et al.
SCHEME 9. Com p lem en ta r y Regioselectivity in
Cyclop r op a n e Hyd r ogen olysisa
SCHEME 10. Im p r oved Con d ition s for
Cyclop r op a n e Clea va gea
a
Reagents and conditions: (a) H2, Pd(OH)2, EtOH, 5-7 days;
(b) H2, PtO2, EtOAc, 56 h.
at atmospheric pressure gave the desired regioisomer 32
in 80% yield along with the undesired product 33 (14%)
(Scheme 9). Due to poor solubility of the substrate in
ethanol, which necessitated the use of high dilution
conditions, the reaction was very sluggish requiring 5 to
7 days to reach completion.30 In an effort to accelerate
the reaction, hydrogenolysis of 30 was also carried out
with Adam’s catalyst. Although the reaction was much
faster in this case, it led to a reversal in cleavage
regioselectivity to give 32 and 33 in 12% and 72% yields,
respectively. The structure of 33 was unambiguously
established by X-ray analysis of the deprotected alcohol.
Although we do not know the origin of this unusual
selectivity, to the best of our knowledge the observed
regioselectivity preference in the catalytic hydrogenation
of bicyclo[3.1.0]hexanes is without precedent.31 While the
discovery of this unusual hydrogenation is of no signifi-
cance to the current synthesis, potential synthetic ap-
plications of this reaction, in other contexts, are currently
being examined in our group.
The successful regioselective cleavage of lactone 30
with Pearlman’s catalyst prompted a more detailed
investigation of this hydrogenation process in an effort
to shorten the reaction time. As mentioned above, the
real problem encountered in this reaction was the poor
solubility of 30 in ethanol. It was reasoned that the
cleavage of the TIPS protecting group in 30 before the
cyclopropane hydrogenolysis would make the material
more soluble and would thus accelerate this process.
Toward this end, the deprotection of the TIPS group in
30 was attempted. Under standard deprotection condi-
tions (TBAF/THF), the TIPS group in 30 was indeed
cleaved to give the corresponding alcohol, but the reaction
was accompanied by a competing epimerization of the
ester group. The mixture of epimers proved difficult to
separate and a better method to deprotect the TIPS group
without any epimerization or with complete epimeriza-
tion was sought. After a detailed investigation, it was
found that the addition of 4 Å molecular sieves to the
reaction mixture containing TBAF deprotected the TIPS
ether in 30 to give 34 with complete epimerization at the
a
Reagents and conditions: (a) TBAF, THF, 4 Å MS; (b) TBAF,
THF/H2O (3:1); (c) H2, Pd(OH)2 (30 mol %), EtOH, 48 h.
ester center, while addition of water served to deprotect
the TIPS group to give 35 without any concomitant
epimerization. The epimeric alcohols 34 and 35 were now
very soluble in ethanol and the cyclopropane hydro-
genolysis with Pd(OH)2 was complete in 2 days, giving
36 and 37, respectively, as single regioisomers in high
yields. These conditions for cyclopropane cleavage are a
significant improvement over the previous conditions for
the hydrogenation of lactone 30, which not only was
sluggish, but also gave a mixture of regioisomers 32 and
33. The alcohols 36 and 37 were found to be identical
with those obtained by the deprotection of TIPS ether
32 under conditions identical with those described for the
deprotection of 30 (Scheme 10).
With a viable method for the regioselective cleavage
of the cyclopropane in hand, the synthesis continued. The
next focus became the opening of the lactone and decar-
boxylation of the resulting acid to reveal the methyl group
present at C-9 in the target molecule. Significantly, this
represents the only carbon atom present in the initial
cycloadduct 16a that does not appear in the final target
molecule. It was presumed that a carbonyl group situated
adjacent to the lactone would provide an appropriate
handle to open this function by a ketyl radical-mediated
process. The ketone was also necessary for the projected
dissolving metal reduction to install the hydroxyl group
with the requisite stereochemistry at C-1 of the target
molecule. To implement this objective, alcohol 36 was
oxidized with TPAP/NMO13 to give the ketone 38 in good
yield (Scheme 11). With 38 in hand, the critical ketyl
radical-mediated opening of the lactone moiety was next
investigated. The reagent of choice for this transforma-
tion was SmI2. However, all attempts to open the lactone
with SmI2 led to recovery of starting material.32 In
contrast, treatment of lactone 38 with tributyltin hydride
and catalytic AIBN in refluxing toluene furnished the
desired acid 39. Although tributyltin hydride has been
used for the cleavage of acetates and benzoates situated
adjacent to ketones,33 to the best of our knowledge this
represents the first example of tin hydride-mediated
(30) Use of other solvents such as ethyl acetate for the hydrogenation
completely suppressed the reaction.
(31) A detailed study of hydrogenation of bicyclo[n.1.0]alkanes with
Pt and Pd/C has been reported, see: Stahl, K.-J .; Hertzsch, W.; Musso,
H. Liebigs Ann. Chem. 1985, 1474. A similar regioselectivity preference
in the opening of fused cyclopropanes has been observed with Zeise’s
dimer-catalyst, see: Ma, B.; Snyder, J . K. Org. Lett. 2002, 4, 2731-
2734.
(32) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 1135-1138.
6756 J . Org. Chem., Vol. 69, No. 20, 2004

Multicomponent Cycloaddition of Tethered Diynes
SCHEME 11. Dissolvin g Meta l Red u ction of 41a
SCHEME 12. Dissolvin g Meta l Red u ction of 46a
a
Reagents and conditions: (a) TPAP, NMO, CH2Cl2, 93%; (b)
a
Reagents and conditions: (a) TPAP, NMO, CH2Cl2, 84%; (b)
n-Bu3SnH, AIBN, toluene, reflux; (c) 2,2′-dithiopyridine-1,1′-di-
N-oxide, PPh3, then t-BuSH, irradiation with a 150-W tungsten
lamp, 77% (two steps); (d) KOH, MeOH, 83%; (e) NaH/THF, NH3,
MeOH, Li; (f) TMSCHN2, MeOH, 75% (two steps).
n-Bu3SnH, AIBN, toluene reflux; (c) 2,2′-di-thiopyridine-1,1′-di-
N-oxide, PPh3, then t-BuSH, irradiation with a 150-W tungsten
lamp, 86%; (two steps); (d) KOH, MeOH, 90%; (e) NaH/THF, NH3,
MeOH, Li; (f) TMSCHN2, MeOH (50% of 42 and 16% of 43; over
two steps).
changes at remote positions in the substrate structure
can have a significant effect on the diastereoselectivity
of the process. This prompted us to investigate the
dissolving metal reduction of the epimeric keto-acid 46.
The stereochemistry of the carboxylic group is inconse-
quential for the synthesis since a double bond is intro-
duced in the next step. Efforts to epimerize ester 40 with
NaOMe/MeOH led to an inseparable mixture of 40 and
45. This result prompted an effort to prepare acid 46
having the epimeric carboxylic group from alcohol 37.
Following the same sequence of reactions as described
for the conversion of 36 into 41, carboxylic acid 46 was
efficiently obtained from 37 in four steps (Scheme 12).
Dissolving metal reduction of 46 followed by esterification
with TMSCHN2 furnished ester 47 in 75% yield as a
single diastereoisomer, whose structure was unambigu-
ously established by single-crystal X-ray analysis. This
revealed that the stereochemistry of all relevant stereo-
centers in 47 was correct as required in the target
molecule.
With 42 and 47 in hand, the final stage in the synthesis
of the target molecule required the installation of a
double bond adjacent to the ester group. This transfor-
mation was expected to be straightforward with use of
selenium chemistry. However, as pointed out previously,
both compounds 42 and 47 are epimeric to the natural
series at C-9, and as it turned out, this minor difference
contributed significantly to the difficulties faced in trying
to introduce the requisite double bond. Thus, reaction of
42 and 47 with LDA/PhSeCl followed by selenoxide
elimination with H2O2/AcOH gave 49 in 24% and 30%
yield, respectively (Scheme 13). Similar results were
obtained when this transformation was carried out with
Trost’s sulfenylation chemistry, which gave 49 in 28%
yield.35 A number of other conditions, such as R-haloge-
nation, were attempted but to no avail. Owing to the
difficulties faced in this transformation presumably due
opening of sterically hindered lactones. Due to the
polarity of 39, several attempts to separate the acid from
the tin residues met with limited success and, conse-
quently, purification was delayed until after the decar-
boxylation. Thus, after evaporation of the solvent and
volatiles, a CH2Cl2 solution of the crude acid 39 was
treated with 2,2′-dithiopyridine-1,1′-di-N-oxide and tri-
phenylphosphine, followed by irradiation in the presence
of t-BuSH to provide the decarboxylated product 40 in
86% yield over two steps.34 The spectral data of the ester
40 were similar to the analogous compound reported in
the natural series.7h
All that remained was to finish the synthesis of 9-epi-
pentalenic acid by using the steps as reported previously
for the C-9 epimer of 40 in the natural series.7h Thus,
hydrolysis of the ester 40 with KOH/MeOH afforded acid
41. Dissolving metal reduction of 41 with Li/NH3 in the
presence of MeOH as the proton source followed by
esterification with TMSCHN2 gave alcohol 42 in 50%
yield along with lactone 43 in 16% yield, which arose from
lactonization of the wrong diastereoisomer. This result
was particularly surprising since dissolving metal reduc-
tion of the analogous ketone having the natural C-9
configuration reportedly gave a single diastereoisomer.
Analysis of molecular models revealed no obvious inter-
action between the methyl group at C-9 and the carbonyl
group.
Although dissolving metal reduction of 41 gave disap-
pointing results compared to those of the related ketone
in the natural series, this strongly suggested that subtle
(33) Redlich, H.; Neumann, H.-J .; Paulsen, H. Chem. Ber. 1977, 110,
2911-2921. For the tributyltin hydride-mediated cleavage of tertiary
R-acetoxy carbonyl compounds, see: Grewal, R. S.; Hayes, P. C.;
Sawyer, J . F.; Yates, P. J . Chem. Soc., Chem. Commun. 1987, 1290-
1292. For the cleavage of benzoates, see: Chen, S.-H.; Wei, J .-M.; Vyas,
D. M.; Doyle, T. W.; Farina, V. Tetrahedron Lett. 1993, 34, 6845-6848.
(34) (a) Barton, D. H. R.; Samadi, M. Tetrahedron 1992, 48, 7083-
7090. (b) Anaya, J .; Barton, D. H. R.; Caballero, M. C.; Gero, S. D.;
Grande, M.; Laso, N. M.; Hernando, J . I. M. Tetrahedron: Asymmetry
1994, 5, 2137-2140.
(35) (a) Trost, B. M. Chem. Rev. 1978, 78, 363-382. (b) Trost, B.
M.; Salzmann, T. N.; Hiroi, K. J . Am. Chem. Soc. 1976, 98, 4887-
4902.
J . Org. Chem, Vol. 69, No. 20, 2004 6757

Rigby et al.
SCHEME 13. Syn th esis of 9-epi-P en ta len ic Acid a
(10 mL) [placed outside the photochemical box] was added
dropwise to the photochemical reactor via syringe pump over
a 2-h period. After the addition was complete the lamp was
switched off and the green solution was concentrated under
reduced pressure. The residue was taken up in 1:1 hexanes:
dichloromethane (500 mL), filtered through a pad of Celite,
and washed with dichloromethane (100 mL) and the filtrate
was concentrated under reduced pressure. Purification by flash
chromatography (hexanes) yielded diene 16a as a 1:1 mixture
of diastereomers (2.5 g, 70%), which were separated after
intensive purification. Data for the more polar diastereoiso-
mer: Rf 0.7 (hexanes); 1H NMR (400 MHz, CDCl3) δ 5.70 (dd,
J ) 12.0, 6.8 Hz, 1H), 5.56 (ddd, J ) 11.2, 7.6, 1.6 Hz, 1H),
5.52 (t, J ) 2.8 Hz, 1H), 4.42 (d, J ) 2.4 Hz, 1H), 2.77 (td, J
) 7.2, 3.2 Hz, 1H), 2.59 (t, J ) 8.8 Hz, 1H), 1.91 (ddd, J )
13.6, 8.8, 4.8 Hz, 1H), 1.72 (td, J ) 7.6 Hz, 4.8, 1H), 1.61 (d, J
) 13.8 Hz, 1H), 1.57 (d, J ) 13.8 Hz, 1H), 1.47 (d, J ) 12.8
Hz, 1H), 1.25-1.20 (m, 2H), 1.13-1.03 (m, 24H), and 0.80 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 154.3, 131.6, 125.3, 124.6,
80.3, 60.6, 59.7, 49.5, 48.7, 43.2, 33.0, 29.0, 28.9, 26.5, 23.0,
22.5, 18.5, 18.4, 12.9; IR (neat) 3020, 2946, 2927, 2867, 1466,
1362, 1179, 1123, 1050 cm-1; HRMS calcd for [C25H40OSiNa]+
407.2741, found 407.2739. Data for the less polar diastere-
a
Reagents and conditions: (a) (i) LDA, THF, PhSeCl, (ii) H2O2,
AcOH, THF, 0 °C; (b) (i) LDA, THF, PhSSO2Ph, (ii) m-CPBA (1
equiv), CH2Cl2, 0 °C; (iii) toluene reflux; (c) TBSOTf, 2,6-lutidine,
CH2Cl2, 0 °C; (d) TBAF, THF; (e) 10% aq KOH, MeOH, 55 °C.
1
omer: Rf 0.8 (hexanes); H NMR (300 MHz, CDCl3) δ 5.65-
5.54 (m, 2H), 5.51 (d, J ) 3.3 Hz, 1H), 3.86 (s, 1H), 2.78-2.72
(m, 1H), 2.59 (t, J ) 8.7 Hz, 1H), 1.91 (septet, J ) 5.1 Hz,
1H), 1.76 (d, J ) 12.9 Hz, 1H), 1.72-1.68 (m, 1H), 1.49 (dd, J
) 13.5, 11.7 Hz, 2H), 1.46-1.42 (m, 1H), 1.24-1.18 (m, 1H),
1.12 (s, 3H), 1.08-1.05 (m, 21H), 0.82 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 153.6, 129.6, 128.2, 125.5, 78.4, 64.8, 60.7, 49.6,
48.9, 45.7, 34.1, 29.1, 28.7, 26.6, 24.5, 22.9, 18.2, 18.1, 12.3;
IR (neat) 3021, 2923, 2866, 1467, 1090, 1057, 1050 cm-1. Anal.
Calcd for C25H40: C 78.07, H 10.49. Found: C 78.04, H 10.45.
to the free hydroxyl group in 47, this hydroxyl group was
protected by treatment with TBSOTf and 2,6-lutidine to
give TBS ether 48. Treatment of 48 with LDA/PhSeCl
followed by selenoxide elimination and deprotection gave
the unsaturated ester 49 in a respectable 53% yield.
Finally, hydrolysis of 49, following literature conditions,7h
gave 9-epi-pentalenic acid (2).
Alcoh ol 19. Cerium trichloride heptahydrate (15.4 g, 41.2
mmol) was added to a solution of enone 17 (7.1 g, 31.7 mmol)
in methanol (200 mL) and stirred for 0.5 h. The reaction was
cooled to -78 °C, sodium borohydride (1.52 g, 41.2 mmol) was
added in five equal portions over 0.25 h and the suspension
was stirred for an additional 2 h at -78 °C. A saturated
solution of ammonium chloride (50 mL) was added and the
reaction mixture slowly warmed to room temperature. Water
(100 mL) was added and the mixture extracted with dichlo-
romethane (3 × 100 mL). The combined organic extracts were
concentrated under reduced pressure. Purification by flash
chromatography (9:1 hexanes:ethyl acetate) yielded alcohol 19
as a white powder (6.2 g, 87%): Rf 0.3 (9:1 hexanes:ethyl
acetate); mp 101-103 °C (hexanes); 1H NMR (500 MHz,
CDCl3) δ 5.72 (dd, J ) 10.5, 6.5 Hz, 1H), 5.62 (dd, J ) 11.0,
7.0 Hz, 1H), 5.56 (t, J ) 2.5 Hz, 1H), 4.29 (br d, J ) 4.5 Hz,
1H), 2.82 (td, J ) 7.2, 3.2 Hz, 1H), 2.62 (t, J ) 8.0 Hz, 1H),
1.92 (ddd, J ) 12.8, 9.2, 5.2 Hz, 1H), 1.77 (ddd, J ) 7.2, 5.6,
2.0 Hz, 1H), 1.64 (s, 2H), 1.51 (br d, J ) 4.5 Hz, 1H), 1.49 (d,
J ) 13.0 Hz, 1H), 1.31-1.23 (m, 2H), 1.14 (s, 3H), 0.80 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 155.2, 131.3, 125.2, 124.6, 79.5,
60.7, 60.5, 49.7, 48.8, 43.0, 33.2, 29.3, 28.7, 26.6, 22.7, 22.6;
IR (CHCl3) 3604, 3022, 2958, 2927, 2865, 1443, 1365, 1266,
1068 cm-1; HRMS calcd for [C16H20O]+ 228.1514, found
228.1514. The structure was further confirmed by X-ray
analysis.
Compounds 49 and 2 exhibited spectral data fully
consistent with the assigned structures. In view of the
lack of conclusive literature data for comparison,36 further
support for the structure of 49 came from the reduction
of 49 with Mg/MeOH,37 which gave an epimeric mixture
of 42 and 47.
Con clu sion s
Through the total synthesis of 9-epi-pentalenic acid,
we have illustrated the utility and demonstrated several
critical aspects of the Cr(0)-mediated higher order cy-
cloaddition. Several novel and interesting regio- and
chemoselective processes were developed during the
course of the study. In addition, an unanticipated one-
pot lactonization and cyclopropane cleavage has been
observed during the synthesis. One lesson learned from
this study is that minor structural variations at remote
centers, particularly in the angular triquinane skeleton,
can unexpectedly alter the efficiency and diastereoselec-
tivity of otherwise routine chemical transformations.
Exp er im en ta l Section
Dion e 27. A solution of diol 24 (2.00 g, 4.8 mmol) in
dichloromethane (10 mL) was added dropwise to a stirred
solution of trifluoroacetic anhydride (2.8 mL, 19.7 mmol) and
dimethyl sulfoxide (2.1 mL, 29.2 mmol) in 1:1 dichloromethane:
THF (60 mL) at -78 °C. The reaction was stirred for 2 h at
-78 °C and triethylamine (8.3 mL, 59 mmol) was added. The
reaction was stirred for a further 1 h at -78 °C before being
allowed to slowly warm to room temperature. The reaction
mixture was quenched with water (100 mL) and diluted with
dichloromethane (100 mL). The layers were separated and the
organic layer was washed with water and brine, dried over
anhydrous MgSO4, and concentrated under reduced pressure.
Purification by flash chromatography (5:1 hexanes:ethyl ac-
Dien e 16a . A vigorous stream of argon was bubbled through
1,2-dichloroethane (1.5 L) in a photochemical reactor (outfitted
with a water-cooled Pyrex filter) for 0.5 h. Tricarbonylcyclo-
heptatriene chromium(0) complex (2.0 g, 8.8 mmol) was added
and a vigorous stream of argon was bubbled through the red
solution for a further 0.5 h. The solution was irradiated with
a medium-pressure mercury light under a steady flow of argon
as a solution of diyne 13 (2.32 g, 8.79 mol) in 1,2-dichloroethane
(36) In the only available limited 1H NMR data of 9-epi-pentalenic
acid, the olefinic proton appeared at δ 6.87, see ref 7i.
(37) Youn, I. K.; Yon, G. H.; Pak, C. S. Tetrahedron Lett. 1986, 27,
2409-2410.
6758 J . Org. Chem., Vol. 69, No. 20, 2004

Multicomponent Cycloaddition of Tethered Diynes
etate) yielded dione 27 as a yellow solid (1.85 g, 93%): Rf 0.55
(5:1 hexanes:ethyl acetate); mp 107-108 °C (CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 5.18 (t, J ) 2.4 Hz, 1H), 4.55 (d, J ) 1.6
Hz, 1H), 3.66 (dd, J ) 8.0, 3.2 Hz, 1H), 3.10 (t, J ) 8.4 Hz,
1H), 2.34-2.27 (m, 2H), 2.05 (br d, J ) 7.2 Hz, 2H), 1.97 (d, J
) 14.8 Hz, 1H), 1.75 (d, J ) 13.6 Hz, 1H), 1.70 (d, J ) 14.4
Hz, 1H), 1.18 (s, 3H), 1.06-1.03 (m, 21H), 0.87 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 203.6, 201.1, 164.6, 113.3, 79.9, 62.4,
60.1, 57.3, 49.3, 43.6, 42.0, 34.4, 34.2, 29.1, 28.4, 22.9, 18.5,
for [C26H43IO5SiNa]+ 613.1817, found 613.1825. The structure
was further confirmed by X-ray analysis.
Meth od II: To a stirred solution of acid 29 (19 mg, 43.0
µmol) in dichloromethane (3 mL) was added a solution of 57%
hydriodic in water (55.0 µL, 0.13 mmol) and the mixture was
stirred for 24 h at room temperature. A saturated solution of
sodium sulfite was added and the product was extracted with
ethyl acetate. The organic layer was washed with water and
brine and dried over anhydrous MgSO4. Solvent evaporation
followed by purification by flash chromatography (hexanes:
ethyl acetate 3:1 to 1:1) afforded lactone 30 (3.7 mg, 19%) and
iodide 31 (10.2 mg, 40%).
18.4, 13.0; IR (CHCl3) 2946, 2868, 1716, 1680, 1182, 1123 cm-1
;
HRMS calcd for [C25H38O3SiNa]+ 437.2482, found 437.2490.
Anal. Calcd for C25H38: C 72.41, H 9.24. Found: C 72.15, H
9.15.
1,7,7-Tr im et h yl-6-oxo-d eca h yd r ocyclop en t a [c]p en t a -
len e-4-ca r boxylic Acid Meth yl Ester (40). Tributyltin
hydride (0.46 mL, 1.68 mmol) and AIBN (22.8 mg, 0.14 mmol)
were added to a solution of ketone 38 (0.26 g, 0.85 mmol) in
toluene (55 mL). A vigorous stream of argon was bubbled
through the solution for 0.5 h and the solution was purged
and back-filled two times. The solution was refluxed for 2 h
and allowed to cool to room temperature. Concentration under
reduced pressure yielded crude acid 39, which was used
directly for the next step without further purification.
2,2′ Dithiopyridine-1,1-dioxide34 (0.25 g, 1.0 mmol) and
triphenylphosphine (0.27 g, 1.03 mmol) were added to a
solution of crude acid 39 [assumed quantitative yield from
previous step] in dichloromethane (81 mL) and the solution
was stirred for 0.5 h at room temperature in the dark. tert-
Butyl thiol (0.28 mL, 2.56 mmol) was added, and the solution
was irradiated for 15 min with a 150 W tungsten lamp and
concentrated under reduced pressure. Purification by thick
layer chromatography (1:1 hexanes:CH2Cl2 to CH2Cl2) fur-
nished keto-ester 40 (0.19 g, 86% over two steps) as a colorless
oil: Rf 0.3 (CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 3.63 (s, 3H),
2.67-2.63 (m, 2H), 2.53-2.48 (m, 1H), 2.32-2.26 (m, 1H), 2.14
(d, J ) 14.4 Hz, 1H), 2.16-2.09 (m, 1H), 1.88-1.74 (m, 3H),
1.85 (d, J ) 13.6 Hz, 1H), 1.52-1.47 (m, 1H), 1.24-1.18 (m,
1H), 1.15 (s, 3H), 1.07 (s, 3H), 0.97 (d, J ) 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 224.6, 175.6, 59.0, 58.1, 54.1, 52.8,
52.2, 51.6, 46.4, 45.8, 35.0, 34.9, 32.0, 27.7, 27.0, 15.8; IR
(CHCl3) 2928, 2852, 1729, 1198, 1170, 1075 cm-1; HRMS calcd
for [C16H24O3Na]+ 287.1618, found 287.1614.
Ca r boxylic Acid 29. To a stirred solution of anhydride 28
(1.65 g, 3.86 mmol) in dichloromethane (80 mL) was added
methanol (0.96 mL, 23.7 mmol) and triethylamine (1.35 mL,
9.70 mmol). The reaction was stirred at room temperature for
48 h and concentrated under reduced pressure. The residue
was dissolved in ethyl acetate, acidified with dilute HCl,
washed with water and brine, and dried over anhydrous
MgSO4. Solvent evaporation followed by purification by flash
chromatography (1:1 hexanes:ethyl acetate) yielded acid 29 as
a white solid (1.58 g, 89%): Rf 0.5 (1:1 hexanes:ethyl acetate);
1
mp 185-187 °C (CH2Cl2); H NMR (500 MHz, CDCl3) δ 5.41
(dd, J ) 2.5, 1.5 Hz, 1H), 4.50 (t, J ) 2.0 Hz, 1H), 3.65 (s, 3H),
3.62 (t, J ) 2.5 Hz, 1H), 3.29 (dt, J ) 11.2, 6.4 Hz, 1H), 2.44
(ddd, J ) 15.0, 6.5, 1.5 Hz, 1H), 2.20 (ddd, J ) 12.0, 10.0, 7.2
Hz, 1H), 2.01 (dd, J ) 13.2, 7.6 Hz, 1H), 1.83 (d, J ) 13.0 Hz,
1H), 1.69 (dd, J ) 9.0, 7.0 Hz, 1H), 1.63 (dd, J ) 9.0, 7.5 Hz,
1H), 1.40 (d, J ) 12.5 Hz, 1H), 1.22 (s, 3H), 1.12-1.06 (m,
21H), 0.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.7, 173.4,
151.8, 118.3, 78.8, 61.9, 55.4, 54.7, 54.1, 51.5, 42.4, 36.6, 30.3,
30.1, 27.3, 26.4, 25.8, 18.5, 12.8; IR (CHCl3) 2947, 1728, 1707,
1463, 1220, 1132 cm-1; HRMS calcd for [C26H42O5SiNa]+
485.2694, found 485.2686. Anal. Calcd for C26H42: C 67.49, H
9.15. Found: C 67.56, H 8.99.
La cton es 30 a n d 31. Meth od I: To a stirred solution of
acid 29 (2 g, 4.3 mmol) in dichloromethane (300 mL) was added
a solution of 57% hydriodic acid in water (1.8 mL, 4.4 mmol)
and the resultant solution was stirred for 2 h at room
temperature. A saturated solution of sodium sulfite (100 mL)
was added, the layers were separated, and the aqueous layer
was extracted with ethyl acetate (3 × 50 mL). The combined
organic extracts were dried over anhydrous MgSO4 and
concentrated under reduced pressure. Purification by flash
chromatography (hexanes:ethyl acetate 3:1 to 1:1) yielded
lactone 30 as a white powder (1.64 g, 82%): Rf 0.3 (2:1 hexanes:
6-Hydr oxy-1,7,7-tr im eth yld eca h ydr ocyclopen ta [c]p en -
ta len e-4-ca r boxylic a cId Meth yl Ester (47). To a solution
of 46 (40 mg, 0.16 mmol) in THF (5 mL) was added NaH (11.5
mg, 0.48 mmol) at 0 °C and the solution was stirred for 30
min. After the mixture was cooled to -78 °C, anhydrous liquid
ammonia (40 mL), anhydrous methanol (2 mL), and lithium
foil (34 mg, 4.9 mmol) were added and the reaction was stirred
at the same temperature for 0.5 h. A saturated solution of
ammonium chloride (10 mL) was added, and ammonia was
allowed to evaporate. The residue was carefully acidified with
1 M hydrochloric acid at 0 °C and the product was extracted
with ethyl acetate. The combined organic extracts were washed
with brine, dried over anhydrous MgSO4, and concentrated
under reduced pressure.
1
ethyl acetate); mp 170-171 °C (CH2Cl2); H NMR (400 MHz,
CDCl3) δ 4.06 (s, 1H), 3.65 (s, 3H), 3.17 (td, J ) 9.6, 7.2 Hz,
1H), 3.03 (dt, J ) 11.6, 7.6 Hz, 1H), 2.62 (dd, J ) 16.4, 10.8
Hz, 1H), 2.58 (dd, J ) 16.4, 10.8 Hz, 1H), 2.12 (ddd, J ) 14.8,
9.6, 6.4 Hz, 1H), 2.03-1.94 (m, 1H), 1.95 (d, J ) 8.4 Hz, 1H),
1.91 (d, J ) 5.6 Hz, 1H), 1.86 (d, J ) 8.6 Hz, 1H), 1.69 (d, J )
13.6 Hz, 1H), 1.31 (ddd, J ) 14.4, 10.4, 1.6 Hz, 1H), 1.21 (s,
3H), 1.20-1.08 (m, 21H), 1.00 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 173.8, 169.4, 103.4, 87.5, 62.1, 52.7, 52.1, 47.4, 41.7,
39.5, 37.0, 32.2, 31.2, 29.7, 27.9, 26.3, 23.7, 18.6, 18.5, 13.0;
IR (neat) 2947, 2862, 1728, 1707, 1246, 1132 cm-1; HRMS calcd
for [C26H42O5SiNa]+ 485.2694, found 485.2686. Iodide 31 (0.3
g, 15%): Rf 0.7 (2:1 hexanes:ethyl acetate); mp 156-158 °C
(ethyl acetate); 1H NMR (500 MHz, CDCl3) δ 3.97 (dd, J )
11.5, 6.0 Hz, 1H), 3.95 (s, 1H), 3.68 (s, 3H), 3.34 (ddd, J )
18.0, 9.0, 1.5 Hz, 1H), 3.01 (dd, J ) 15.0, 7.0 Hz, 1H), 2.83
(dd, J ) 14.5, 8.5 Hz, 1H), 2.56 (dd, J ) 16.0, 5.5 Hz, 1H),
2.50 (dd, J ) 12.0, 5.5 Hz, 1H), 2.40 (dd, J ) 16.0, 5.0 Hz,
1H), 2.26-2.19 (m, 2H), 2.12 (d, J ) 14.0 Hz, 1H), 2.09-2.02
(m, 1H), 1.87 (d, J ) 14.0 Hz, 1H), 1.16-1.10 (m, 3H), 1.07 (s,
3H), 1.06 (s, 15H), 1.05 (s, 3H), 0.99 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 173.5, 168.9, 102.9, 89.4, 57.1, 56.9, 55.3, 52.2,
52.1, 44.4, 42.0, 40.5, 37.4, 31.2, 30.2, 26.6, 22.5, 18.5, 13.1;
IR (neat) 2945, 1738, 1463, 1258, 1120, 883 cm-1; HRMS calcd
The crude residue was dissolved in methanol (5.0 mL) and
stirred with TMSCHN2 (0.16 mL of 2 M solution in hexane,
0.32 mmol) for 0.5 h. Acetic acid (0.2 mL) was added and the
solution concentrated under reduced pressure. Purification by
thick layer chromatography (2:1 cyclohexane:ethyl acetate)
yielded ester 47 (32 mg, 75%) as a white solid: Rf 0.65 (1:1
cyclohexane:ethyl acetate); mp (hexane) 107-109 °C; 1H NMR
(500 MHz, CDCl3) δ 3.67 (s, 3H), 3.26 (d, J ) 9.5 Hz, 1H),
3.02-2.96 (m, 1H), 2.27 (dd, J ) 16.5, 8.0 Hz, 1H), 2.15 (t, J
) 6.5 Hz, 1H), 1.93-1.85 (m, 3H), 1.71 (d, J ) 13.5 Hz, 1H),
1.69-1.63 (m, 1H), 1.56 (d, J ) 13.5 Hz, 1H), 1.53-1.48 (m,
1H), 1.46 (br s, 1H), 1.30-1.19 (m, 2H), 0.98 (s, 3H), 0.97 (d,
J ) 7.0 Hz, 3H), 0.88 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
175.0, 85.5, 58.7, 58.1, 55.1, 51.7, 50.4, 45.9, 45.7, 41.8, 35.9,
31.8, 27.6, 27.0, 20.7, 17.0; IR (neat) 3443, 2950, 1736, 1595,
1460, 1172 cm-1; HRMS calcd for [C16H26O3Na]+ 289.1774,
J . Org. Chem, Vol. 69, No. 20, 2004 6759

Rigby et al.
found 289.1770. The assigned structure was further confirmed
by X-ray analysis.
) 6.5 Hz, 3H), 0.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
165.7, 146.1, 138.7, 84.5, 61.9, 60.4, 59.4, 52.1, 51.6, 44.9, 43.8,
33.1, 30.4, 27.1, 23.9, 14.8; IR (neat) 3436, 2952, 1717, 1629,
1238 cm-1; HRMS cacld for [C16H24O3Na]+ 287.1618, found
287.1619.
Meth yl-9-epi-p en ta len a te (49). To a solution of ester 48
(28 mg, 0.07 mmol) in dry THF (3 mL) was added LDA
[prepared from diisopropylamine (52 µL, 0.37 mmol) and 1.6
M BuLi (0.22 mL, 0.37 mmol) in THF (2 mL)] at -78 °C and
the mixture was stirred for 30 min at the same temperature
and at 0 °C for 15 min. After the mixture was cooled to -78
°C, a solution of PhSeCl (70 mg, 0.37 mmol in 1 mL of THF)
was added and the reaction mixture was stirred for another 3
h at -78 °C. The reaction was quenched with water and the
aqueous layer was extracted with ethyl acetate. The organic
layer was washed with 10% HCl, water, and brine and dried
over anhydrous MgSO4. Solvent evaporation followed by
purification by thick layer chromatography (20:1 cyclohexane:
ethyl acetate) furnished the crude seleno-ester, which was used
directly for the next step.
To this crude seleno-ester in THF (3 mL) at 0 °C were added
glacial acetic acid (44 µL, 0.73 mmol) and 30% H2O2 (83 µL,
0.73 mmol) and the resulting solution was stirred at the same
temperature for 1 h. The product was extracted with ethyl
acetate and the organic layer was washed with saturated
NaHCO3 solution, water, and brine and dried over anhydrous
MgSO4. Solvent evaporation furnished the crude product,
which was directly used for the desilylation reaction.
To a solution of this crude ester in dry THF (2 mL) was
added a 1 M solution of TBAF in THF (0.21 mL, 0.21 mmol)
and the mixture was stirred for 24 h. THF was evaporated
and the residue was dissolved in ethyl acetate, washed with
water and brine, and dried over anhydrous MgSO4. Solvent
evaporation followed by purification by thick layer chroma-
tography (2:1 hexanes:ethyl acetate) furnished ester 49 (10.2
mg, 53%) as a colorless oil: Rf 0.3 (3:1 hexanes:ethyl acetate);
1H NMR (500 MHz, CDCl3) δ 6.76 (t, J ) 2.0 Hz, 1H), 3.72 (s,
3H), 3.54 (d, J ) 2.0 Hz, 1H), 3.13 (dd, J ) 7.5, 1.5 Hz, 1H),
3.0 (dd, J ) 5.5, 2.5 Hz, 1H), 1.86 (d, J ) 13.0 Hz, 1H), 1.83-
1.71 (m, 2H), 1.61 (d, J ) 13.5 Hz, 1H), 1.67-1.57 (m, 2H),
1.51 (br s, 1H, OH), 1.10-0.91 (m, 1H), 0.99 (s, 3H), 0.97 (d, J
9-epi-P en ta len ic Acid . To a solution of ester 49 (8 mg, 30
µmol) in MeOH (3 mL) was added 10% aq KOH (0.5 mL) and
the resulting solution was heated at 55 °C for 3 h. MeOH was
evaporated and the residue acidified with 10% HCl at 0 °C.
The product was extracted with ethyl acetate. The organic
layer was washed with water and brine and dried over
anhydrous MgSO4. Solvent evaporation followed by purifica-
tion by thick layer chromatography (ethyl acetate) furnished
acid 2 (7.2 mg, 95%) as a colorless oil: Rf 0.4 (ethyl acetate);
1H NMR (500 MHz, CDCl3) δ 6.91 (d, J ) 2.0 Hz, 1H), 3.57 (d,
J ) 2.0 Hz, 1H), 3.13 (d, J ) 8.5 Hz, 1H), 3.03 (d, J ) 2.5 Hz,
1H), 1.87 (d, J ) 13.5 Hz, 1H), 1.83-1.67 (m, 3H), 1.63 (d, J
) 13.0 Hz, 1H), 1.64-1.58 (m, 1H), 1.04-0.97 (m, 1H), 1.0 (s,
3H), 0.98 (d, J ) 7.0 Hz, 3H), 0.92 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 169.5, 148.9, 138.2, 84.4, 62.0, 60.5, 59.1, 52.1, 44.9,
43.9, 33.1, 30.3, 27.0, 23.8, 14.8; IR (neat) 3379, 2926, 1687,
1630, 1461 cm-1; HRMS calcd for [C15H22O3Na]+ 273.1461,
found 273.1458.
Ack n ow led gm en t. The authors wish to thank Na-
tional Institute of Health for their generous support of
this research through grant GM-30771.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization data for all relevant compounds, 1H
spectra for compounds 2, 17-20, 24, 27-32, 34-38, 40, and
43-49 and 13C NMR spectra for compounds 2, 17-19, 24, 28-
32, 34, 36, 44, 45, 47-49, as well as a CIF file containing X-ray
crystallographic data for compounds 19, 31, deprotected 33,
and 47. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O040204O
6760 J . Org. Chem., Vol. 69, No. 20, 2004