General strategy for the asymmetric synthesis of the picrotoxanes

Full text of DOI:10.1021/ja953060r

J. Am. Chem. Soc. 1996, 118, 233-234
233
Scheme 1. Synthesis and Cyclization of Enyne 7a
General Strategy for the Asymmetric Synthesis of
the Picrotoxanes
Barry M. Trost* and Michael J. Krische
Department of Chemistry, Stanford UniVersity
Stanford, California 94305-5080
ReceiVed September 5, 1995
The important role of picrotoxinin (1) as a GABA antagonist
has made it an invaluable tool for neurophysiology.1 It is
representative of a growing family of compounds represented
by corianin (2), asteromurin A (3), coriamyrtin (4), tutin (5),
and the novel structurally related picrodendrins, some of which
show very similar biological functions.2 The high potency of
a
(a) LDA, THF, -78 °C, CH2O, 64%. (b) TBDMSCl, C3H4N2,
DMF, 60 °C, 95%. (c) LiCH2CN, THF, -78 °C, 73%. (d) C5H5N+H
Br3-, C5H5N, 0 °C, 96%. (e) (i) DIBAL-H, PhCH3, -78 °C, workup
with NaHSO4, H2O; (ii) HCtCMgCl, THF, 0 °C. (f) TBDMSCl,
C3H4N2, DMF, 60 °C, 61% for steps e and f. (g) See text. (h) TBAF,
THF, room temperature, 89%. (i) SOCl2, C5H5N, ether, 0 °C, 66%;
CsOAc, DMF, 60 °C, 79%; K2CO3, CH3OH, room temperature, 97%.
these compounds, the unusual pentacyclic structure, and the high
density of functionality have made them challenging targets for
synthesis.3 In this communication, we develop a general
strategy that provides flexibility to approach a number of
members of this family. This strategy evolved from develop-
ments in metal-catalyzed Alder ene type reactions.4
Tricycle 6a was envisioned to be a key intermediate since it
possesses all of the carbons required and has appropriate
functionality to adjust the oxidation level where needed to access
each of the picrotoxanes illustrated. Its accessibility in enan-
the [6.5] ring junction, presumably derives from torsional strain
rather than steric strain.5 The addition of ethynylmagnesium
chloride to the aldehyde generated from 10 gave a 2:1
diastereomeric mixture at the secondary alcohol 11, a stereo-
chemistry that is irrelevant with respect to the ultimate targets.
Nonetheless, the minor epimer was converted to the major one
using a Mitsunobu protocol so that 7 could be obtained
diastereomerically pure.
Surprisingly, the protocol that effected smooth cycloisomer-
ization of a related monocyclic enyne failed.6 However, one
of the advantages of transition metal catalyzed reactions stems
from the prospect of tailoring the active site to overcome such
failures. Using a variety of monodentate (i.e., Ph3P or Ph3As)
or bidentate [i.e., dppe or 2-(diphenylphosphino)benzoic acid
(12)] ligands gave 20-37% yields of 6a. A promising yield
of 43% was obtained when the bidentate ligand dppe and a
ligand that could internally deliver a proton, 12, was employed.
Assessing the difficulty as steric in nature because of the creation
of a 1,3-diaxial interaction between the silyloxymethyl sub-
stituent and one of the cyclopentyl ring bonds, we designed the
bis-phosphole ligand 13 that ties back the diphenylphosphino
moiety, thereby opening up the catalytic active site. Indeed,
the combination of 13 and an internal proton delivery system,
12, with catalytic palladium acetate (DCE, 60 °C) gave a 70%
yield of 6. The latter was converted straightforwardly to the
diol 14 as in Scheme 1.7 Both alcohols were simultaneously
oxidized8 [(COCl)2, DMSO, (C2H5)3N, CH2Cl2, -78 °C;
NaClO2, (CH3)2CdCHCH3, NaH2PO4, t-C4H9OH, 0 °C; CH2N2,
ether, 0 °C, 79% overall] to the diester 15.
tiopure form Via an intramolecular Alder ene reaction from
enyne 7 would provide a facile entry since the latter was readily
available from carvone in seven steps as delineated in Scheme
1. The axial selectivity in the addition of the metalated
acetonitrile to convert 8 to 9, which sets the stereochemistry of
(1) Narabashi, T. Physiol. ReV. 1974, 54, 813. Olsen, R. N.; Ticku, M.
K.; Miller, T. Mol. Pharmacol. 1978, 14, 381. Nistri, A.; Constantini, A.
Progress in Neurobiology; Permagon: New York, 1979; Vol. 13, pp 117-
235. Dicken, C. C.; Diesz, R. A.; Lux, H. D. Amino Acid Neurotransmitters;
Raven Press: New York, 1981; pp 301-307. Shirai, Y.; Hosie, A. M.;
Buckingham, S. D.; Holyoke, C. W., Jr.; Baylis, A. H.; Satelle, D. B.
Neurosci. Lett. 1995, 189 (1), 1. Lynch, J. W.; Rajendra, S.; Barry, P. H.;
Schofield, P. R. J. Biol. Chem. 1995, 270 (23), 13799. Feigenspan, A.;
Waessle, H.; Bormann, J. Nature (London) 1993, 361 (6408), 159. Ffrench-
Constant, R. H.; Morllock, D. P.; Shaffer, C. D.; MacIntyre, R. J.; Roush,
R. T. Proc. Natl. Acad. Sci. U.S.A. 1991, 88 (16), 7209.
(2) Nagahisa, M.; Koike, K.; Narita, M.; Ohmoto, T. Tetrahedron 1994,
50 (37), 10859. Ozoe, Y.; Hasegawa, H.; Mochida, K.; Koike, K.; Suzuki,
Y.; Nagahisa, M.; Ohmoto, T. Biosci., Biotechnol., Biochem. 1994, 58 (8),
1506. Koike, K.; Suzuki, Y.; Ohmoto, T. Phytochemistry 1994, 35 (3), 701.
Costaneda, P.; Bahena, A.; Garcia, E.; Chavez, D.; Mata, R.; Guitierrez,
A. J. Nat. Prod. 1993, 56 (9), 1575. Susuki, Y.; Koike, K.; Ohmoto, T.
Phytochemistry 1992, 31 (6), 2059. Koike, K.; Ohmoto, T.; Kawai, T.; Sato,
T. Phytochemistry 1991, 30 (10), 3353. Koike, K.; Fukuda, H.; Mitsunaga,
K.; Ohmoto, T. Chem. Pharm. Bull. 1991, 39 (4), 934. Ohmoto, T.; Koike,
K.; Fukuda, H.; Mitsunaga, K.; Ogata, K.; Kagei, K. Chem. Pharm. Bull.
1989, 37 (11), 2988. Sarma, N. S.; Rambabu, M.; Anjaneyulu, A. S. R.;
Rao, C. B. S. Indian J. Chem., Sect B 1987, 26B (2), 189. Dahmen, J.;
Leander, K. Phytochemistry 1987, 17 (11), 1949. Porter, L. A. Chem. ReV.
1967, 67, 411. Fischer, N. H.; Olivier, E. J.; Fischer, H. D. Fortschr. Chem.
Org. Naturst. 1979, 38, 268.
(3) Wakamatsu, K.; Kigoshi, H.; Niiyama, K.; Niwa, H.; Yamada, K.
Tetrahedron 1986, 42, 5551. Niwa, H.; Wakamatsu, K.; Hida, T.; Niiyama,
K.; Kigoshi, H.; Yamada, M.; Nagase, H.; Suzuki, M.; Yamada, K. J. Am.
Chem. Soc. 1984, 106, 4547. Tanaka, K.; Uchiyama, F.; Sakamoto, K.;
Inubishi, Y. Chem. Pharm. Bull. 1983, 31, 1943, 1948, 1972. Tanaka, K.;
Uchiyama, F.; Sakamoto, K.; Inubishi, Y. J. Am. Chem. Soc. 1982, 104,
4965. Corey, E. J.; Pearce, H. L. J. Am. Chem. Soc. 1979, 101, 5841.
Tetrahedron Lett. 1980, 21, 1823. Miyashita, M.; Suzuki, T.; Yoshikoshi,
A. J. Am. Chem. Soc. 1989, 111, 3728.
(4) Trost, B. M.; Tanoury, G. J.; Lautens, M.; Chan, C.; MacPherson,
D. T. J. Am. Chem. Soc. 1994, 116, 4255. Trost, B. M.; Romero, D. L.;
Rise, F. J. Am. Chem. Soc. 1994, 116, 4268.
(5) Trost, B. M.; Florez, J.; Jebaratnam, D. J. J. Am. Chem. Soc. 1987,
109, 613.
(6) Trost, B. M.; Jebaratnam, D. J. Tetrahedron Lett. 1987, 28, 1611.
(7) Pegolotti, J. A.; Young, W. G. J. Am. Chem. Soc. 1961, 83, 3251.
Kruinga, W. H.; Strijtueen, B.; Kellogg, R. M. J. Org. Chem. 1981, 46,
4321. Torisawa, Y.; Okake, H.; Ikegami, S. Chem. Lett. 1984, 9, 1555.
0002-7863/96/1518-0233$12.00/0 © 1996 American Chemical Society

234 J. Am. Chem. Soc., Vol. 118, No. 1, 1996
Scheme 2 Synthesis of a Pivotal Intermediatea
Communications to the Editor
Scheme 3. Bifurcation of Common Intermediate to
Picrotoxinin and Corianina
a
(a) (CH3)2NCH(OCH3)2, Ac2O, 100 °C, 68%. (b) LHMDS +
t-C4H9OOH, THF, 0 °C, 77%. (c) (CF3SO2)2O, N-methylimidazole, 100
°C, 85%. (d) LiBH4, HOAc, THF, 0 °C, 71%. (e) PhSH, CH3CN, TMS-
Cl (catalytic), room temperature, 98%. (f) Ph3SnH, AIBN, PhCH3,
reflux, 84%. (g) MCPBA, CH2Cl2, 0 °C, 87%.
a
(a) CF3CO3H, CSA, CH2Cl2, reflux, 63%. (b) OsO4, C5H5N, room
identical in all respects to an authentic sample. The previous
conversion of picrotoxinin to picrotin makes this route a formal
synthesis of the latter as well.3
temperature, 75%. (c) Zn, HOAc, CH3OH, 60 °C, 96%. (d)
(CH3)2C(OCH3)2, CH3COCH3, TsOH, 70%. (e) KOH, CH3OH, H2O,
room temperature then CH2N2, ether, 0 °C, 91%. (f) CH3COCl,
(C2H5)3N, DMAP, CH2Cl2, 86%. (g) HCl, H2O, THF, room temperature,
67%. (h) TMSOSO2CF3, lutidine, DCE, room temperature, 85%. (i)
NaCN, CH3OH, THF, room temperature, 90%. (j) t-C4H9OLi, t-C4H9OH,
PhCH3, 100 °C, 68%. (k) HF, H2O, CH3CN, 100 °C, 92%.
Adjustment of the oxidation pattern to form corianin began
with a chemoselective dehydration of diol 20 to alkene 22. Acid-
promoted borohydride treatment chemoselectively reduced the
R-hydroxy fused butyrolactone to lactol 23a. Deoxygenation
Via radical desulfurization of the corresponding sulfide14 23b
followed by hydroxyl-directed epoxidation of diene15 23c
completed a synthesis of corianin, identical to an authentic
sample.
The stage was set for creation of the bis-lactone of picro-
toxinin. All attempts to effect direct oxidative cyclizations using
lead tetraacetate failed.9 The sequence ultimately employed (see
Scheme 2) revealed several interesting features of this unusual
ring system. The transiently generated epoxide (which may be
isolated) underwent facile ring opening with retention of
configuration to lactone 16, for which an X-ray structure
confirmed its connectivity and stereochemistry. Formation of
the six-membered-ring lactone (as in 16-18) appears to be
thermodynamically favored over either five-membered-ring
lactone as long as the conformation is restricted in the form of
the bromo ether. On the other hand, cleavage of the bromo
ether allowed facile equilibration to the fused five-membered-
ring lactone 19. Surprisingly, closure of the bridged lactone
proved to be extremely sensitive to the nature of the protecting
groups on the five-membered-ring diol. A cyclic derivative like
the acetonide failed to cyclize. Replacing the acetonide with
acyclic TMS ethers permitted smooth cyclization under basic
conditions to give our pivotal intermediate 20.
The advent of a metal-catalyzed Alder ene reaction not only
realized a more efficient strategy to the bicyclic core of the
picrotoxanes than previously practiced but also highlights one
of the strengths of catalytic versus thermal methods, that is,
the ability to modify the catalytic system to achieve success if
one protocol fails, an opportunity that is lacking in thermal
processes. The result herein is the construction of intermediates
possessing sufficiently differentially substituted carbons that
each carbon of the core structure can be modified to permit
entry to many members of the picrotoxane family, not just
picrotoxinin itself. While syntheses of picrotoxinin and corianin
illustrate this point, syntheses of asteromurin A, coriamyrtin,
and tutin can all be envisioned to derive readily from intermedi-
ates reported herein. Efforts in this regard are the subject of
future work.
To demonstrate the generality of this strategy, syntheses of
both picrotoxinin10 and corianin11 were completed as outlined
in Scheme 3. Dehydroxylation12 occurred readily to form the
strained alkene 21, which was chemo- and diastereoselectively
epoxidized under nucleophilic conditions13 to give picrotoxinin,
Acknowledgment. We thank the National Institutes of Health,
General Medical Sciences Institute, for their generous support of our
programs. Mass spectra were recorded by the Mass Spectrometry
Facility of the University of CaliforniasSan Francisco. We are
especially grateful for the pioneering studies of David Jebaratnam,
Andrew Thomas, and Curt Haffner, who set the stage for this work.
(8) Omura, K.; Swern, D. Tetrahedron 1978, 1651. Manusco, A. J.;
Brownfain, D. S.; Swern, D. J. Org. Chem. 1979, 44, 4148. Bal, B. S.;
Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091. Delcanale,
E.; Montanari, F. J. Org. Chem. 1986, 51, 567.
(9) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1980, 21, 1819.
(10) Boullay, P. F. G. Bull. Pharm. 1812, 4, 367. Barth, L.; Kretschy,
M. Monatsh. Chem. 1881, 1, 99; 1881, 2, 796; 1884, 5, 65. Paterno, E.;
Ogliatoro, A. Gazz. Chim. Ital. 1876, 6, 531; 1877, 7, 193; 1881, 11, 36.
Conroy, H. J. Am. Chem. Soc. 1951, 73, 1889; 1957, 79, 5550. Craven, B.
M. Tetrahedron Lett. 1960. Acta Crystallogr. 1962, 15, 387. Mackay, M.
F.; Sadek, M. Aust. J. Chem. 1983, 36, 2111. Andrews, P. R.; Brownlee,
R. T. C.; Mackay, M. F.; Poulton, D. B.; Sadek, M.; Winkler, D. A. Aust.
J. Chem. 1983, 36, 2219; Synform 1985, 3 (3), 177.
Supporting Information Available: Characterization data for 1,
6a, 7-10, 15-18, 19a, 20b, 21, 22, 23c, and corianin and experimental
procedure for conversion of 7 to 6 (8 pages). This material is contained
in libraries on microfiche, immediately follows this article in the
microfilm version of the journal, can be ordered from the ACS, and
can be downloaded from the Internet; see any current masthead page
for ordering information and Internet access instructions.
(11) Okuda, T.; Yoshida, T. Tetrahedron Lett. 1971, 4499. Okuda, T.;
Yoshida, T.; Chen, X. M.; Jing, X.; Fukushima, M. Chem. Pharm. Bull
1987, 35, 182.
JA953060R
(12) Crank, G.; Eastwood, F. W. Aust. J. Chem. 1964, 17, 1392. Josan,
J. S.; Eastwood, F. W. Aust. J. Chem. 1968, 21, 2013. Eastwood, F. W.;
Harrington, K. J.; Josan, J. S.; Pura, J. L. Tetrahedron Lett. 1970, 5223.
(13) Clark, C.; Hermans, P.; Meth-Cohen, O.; Moore, C.; Taljaard, H.
C.; Van Vuuren, G. J. Chem. Soc., Chem. Commun. 1986, 1378.
(14) Nicolaou, K. C.; McGarry, D. G.; Somers, P. K.; Veale, C. A.; Furst,
G. T. J. Am. Chem. Soc. 1987, 109, 2504.
(15) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307.