Enantioselective Synthesis of (-)-Pumiliotoxin C from a Chiral Amino Ester and an Acetylenic Sulfone that Acts as an Alkene Dipole Equivalent

Article abstract of DOI:10.1021/jo980647q

A new synthesis of the naturally occurring (-)-enantiomer of the dendrobatid alkaloid pumiliotoxin C (1) was achieved by the conjugate addition of methyl (-)-cis-2-amino-trans-6-methylcyclohexanecarboxylate (3) to 1-(p-toluenesulfonyl)-1-pentyne (4), followed by intramolecular acylation to afford (4aS,5R,8aR)-4a,5,6,7,8,8a-hexahydro-5-methyl-2-propyl-3-(p-toluenesulfonyl)-4- quinolinone(2). The acetylenic sulfone thus acts as the synthetic equivalent of an alkene dipole species. The required enantiopure amino ester 3 was obtained by an approach based on pig liver esterase (PLE)-mediated hydrolysis. Thus, the (-)- and (+)-enantiomers of racemic dimethyl trans-3-methylcyclohexane-cis,cis-1,2-dicarboxylate (6) afforded the corresponding half-esters 7 and 8, respectively, when treated with PLE. The desired half-ester 7 was recovered intact after selective conversion of the free carboxylic acid group of the byproduct 8 into its benzyl ester. Half-ester 7 was converted into enantiopure (-)-6 with diazomethane, followed by regioselective saponification and Curtius rearrangement to afford the required enantiopure key intermediate 3. Finally, hydrogenation of the enol triflate of enaminone 2, followed by reductive desulfonylation, afforded the product (-)-1.

Full text of DOI:10.1021/jo980647q

6566
J . Org. Chem. 1998, 63, 6566-6571
En a n tioselective Syn th esis of (-)-P u m iliotoxin C fr om a Ch ir a l
Am in o Ester a n d a n Acetylen ic Su lfon e th a t Acts a s a n Alk en e
Dip ole Equ iva len t
Thomas G. Back* and Katsumasa Nakajima
Department of Chemistry, University of Calgary, Calgary, Alberta, Canada T2N 1N4
Received April 7, 1998
A new synthesis of the naturally occurring (-)-enantiomer of the dendrobatid alkaloid pumiliotoxin
C (1) was achieved by the conjugate addition of methyl (-)-cis-2-amino-trans-6-methylcyclohex-
anecarboxylate (3) to 1-(p-toluenesulfonyl)-1-pentyne (4), followed by intramolecular acylation to
afford (4aS,5R,8aR)-4a,5,6,7,8,8a-hexahydro-5-methyl-2-propyl-3-(p-toluenesulfonyl)-4-quinolinone
(2). The acetylenic sulfone thus acts as the synthetic equivalent of an alkene dipole species. The
required enantiopure amino ester 3 was obtained by an approach based on pig liver esterase (PLE)-
mediated hydrolysis. Thus, the (-)- and (+)-enantiomers of racemic dimethyl trans-3-methylcy-
clohexane-cis,cis-1,2-dicarboxylate (6) afforded the corresponding half-esters 7 and 8, respectively,
when treated with PLE. The desired half-ester 7 was recovered intact after selective conversion of
the free carboxylic acid group of the byproduct 8 into its benzyl ester. Half-ester 7 was converted
into enantiopure (-)-6 with diazomethane, followed by regioselective saponification and Curtius
rearrangement to afford the required enantiopure key intermediate 3. Finally, hydrogenation of
the enol triflate of enaminone 2, followed by reductive desulfonylation, afforded the product (-)-1.
The dendrobatid alkaloids are components of the toxic
C is one of the less toxic dendrobatid alkaloids and acts
as a reversible blocker of the nicotinic acetylcholine
receptor channel.4 It is therefore of interest in pharma-
cological studies of nerve and muscle systems. The poor
availability of 1 in nature, from relatively exotic sources,
and its interesting and potentially useful biological
activity have prompted a number of approaches to its
synthesis. These include syntheses of racemic 1,5 the
natural enantiomer (-)-1,6 and the unnatural antipode
(+)-1.7
skin secretions of certain neotropical frogs of the genera
Phyllobates and Dendrobates, as well as of several other
species of toads and frogs.1,2 These secretions act as a
chemical defense against predation and have also been
used as blowgun dart poisons by hunters of indigenous
tribes, such as the Embera´ Choco´ of Colombia.
Pumiliotoxin C (1) is a relatively abundant member of
the decahydroquinoline class of dendrobatid alkaloids.
Major sources are the species Dendrobates pumilio2g and
Dendrobates auratus.2e,f Nevertheless, it was reported
that 2540 frogs were required to afford 80 mg of the
alkaloid.2g The isolation and structure determination of
1 was reported in 1969 by Daly et al.,3 and the absolute
configuration of the naturally occurring (-)-enantiomer
was established to be (2S,4aS,5R,8aR).2h Pumiliotoxin
(4) (a) Warnick, J . E.; J essup, P. J .; Overman, L. E.; Eldefrawi, M.
E.; Nimit, Y.; Daly, J . W.; Albuquerque, E. X. Mol. Pharmacol. 1982,
22, 565. (b) Daly, J . W.; Nishizawa, Y.; Padgett, W. L.; Tokuyama, T.;
McCloskey, P. J .; Waykole, L.; Schultz, A. G.; Aronstam, R. S.
Neurochem. Res. 1991, 16, 1207.
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I.; Milot, G. J . Am. Chem. Soc. 1993, 115, 6652. (d) Polniaszek, R. P.;
Dillard, L. W. J . Org. Chem. 1992, 57, 4103. (e) Brandi, A.; Cordero,
F. M.; Goti, A.; Guarna, A. Tetrahedron Lett. 1992, 33, 6697. (f) Comins,
D. L.; Dehghani, A. Tetrahedron Lett. 1991, 32, 5697. (g) LeBel, N. A.;
Balasubramanian, N. J . Am. Chem. Soc. 1989, 111, 3363. (h) Abe, K.;
Tsugoshi, T.; Nakamura, N. Bull. Chem. Soc. J pn. 1984, 57, 3351. (i)
Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane, S.;
Hattori, K.; Yamamoto, H. J . Am. Chem. Soc. 1983, 105, 2831. (j)
Overman, L. E.; J essup, P. J . J . Am. Chem. Soc. 1978, 100, 5179. (k)
Ibuka, T.; Mori, Y.; Inubushi, Y. Chem. Pharm. Bull. 1978, 26, 2442.
(l) Oppolzer, W.; Fehr, C.; Warneke, J . Helv. Chim. Acta 1977, 60, 48.
(m) Habermehl, G.; Andres, H.; Miyahara, K.; Witkop, B.; Daly, J . W.
Liebigs Ann. Chem. 1976, 1577. (n) Oppolzer, W.; Fro¨stl, W.; Weber,
H. P. Helv. Chim. Acta 1975, 58, 593. (o) Ibuka, T.; Masaki, N.; Saji,
I.; Tanaka, K.; Inubushi, Y. Chem. Pharm. Bull. 1975, 23, 2779.
(6) (a) Naruse, M.; Aoyagi, S.; Kibayashi, C. J . Chem. Soc., Perkin
Trans. 1 1996, 1113. (b) Comins, D. L.; Dehghani, A. J . Chem. Soc.,
Chem. Commun. 1993, 1838. (c) Murahashi, S.; Sasao, S.-I.; Saito, E.;
Naota, T. Tetrahedron 1993, 49, 8805. (d) Bonin, M.; Royer, J .;
Grierson, D. S.; Husson, H.-P. Tetrahedron Lett. 1986, 27, 1569. (e)
Oppolzer, W.; Flaskamp, E. Helv. Chim. Acta 1977, 60, 204.
(1) For reviews, see: (a) Witkop, B.; Go¨ssinger, E. In The Alkaloids:
Chemistry and Pharmacology; Brossi, A., Ed.; Academic Science: New
York, 1983; Vol. 21, Chapter 5. (b) Daly, J . W.; Spande, T. F. Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley-
Interscience: New York, 1986; Vol. 4, pp 1-274.
(2) For lead references, see: (a) Daly, J . W.; Brown, G. B.; Mensah-
Dwumah, M.; Myers, C. W. Toxicon 1978, 16, 163. (b) Mensah-
Dwumah, M.; Daly, J . W. Toxicon 1978, 16, 189. (c) Daly, J . W.; Myers,
C. W.; Whittaker, N. Toxicon 1987, 25, 1023. (d) Daly, J . W.; Secunda,
S. I.; Garraffo, H. M.; Spande, T. F.; Wisnieski, A.; Cover, J . F., J r.
Toxicon 1994, 32, 657. (e) Tokuyama, T.; Tsujita, T.; Shimada, A.;
Garraffo, H. M.; Spande, T. F.; Daly, J . W. Tetrahedron 1991, 47, 5401.
(f) Daly, J . W.; Secunda, S. I.; Garraffo, H. M.; Spande, T. F.; Wisnieski,
A.; Nishihira, C.; Cover, J . F., J r. Toxicon 1992, 30, 887. (g) Tokuyama,
T.; Nishimori, N.; Shimada, A.; Edwards, M. W.; Daly, J . W. Tetrahe-
dron 1987, 43, 643. (h) Daly, J . W.; Witkop, B.; Tokuyama, T.;
Nishikawa, T.; Karle, I. L. Helv. Chim. Acta 1977, 60, 1128. (i)
Tokuyama, T.; Nishimori, N.; Karle, I. L.; Edwards, M. W.; Daly, J .
W. Tetrahedron 1986, 42, 3453. (j) Edwards, M. W.; Daly, J . W.; Myers,
C. W. J . Nat. Prod. 1988, 51, 1188. (k) Daly, J . W.; Highet, R. J .; Myers,
C. W. Toxicon 1984, 22, 905. (l) Garraffo, H. M.; Caceres, J .; Daly, J .
W.; Spande, T. F.; Andriamaharavo, N. R.; Andriantsiferana, M. J .
Nat. Prod. 1993, 56, 1016. (m) Daly, J . W.; Garraffo, H. M.; Pannell,
L. K.; Spande, T. F. J . Nat. Prod. 1990, 53, 407.
(7) (a) Toyota, M.; Asoh, T.; Matsuura, M.; Fukumoto, K. J . Org.
Chem. 1996, 61, 8687. (b) Toyota, M.; Asoh, T.; Fukumoto, K.
Tetrahedron Lett. 1996, 37, 4401. (c) Schultz, A. G.; McCloskey, P. J .;
Court, J . J . J . Am. Chem. Soc. 1987, 109, 6493. (d) Masamune, S.;
Reed, L. A., III. Davis, J . T.; Choy, W. J . Org. Chem. 1983, 48, 4441.
(3) Daly, J . W.; Tokuyama, T.; Habermehl, G.; Karle, I. L., Witkop,
B. Liebigs Ann. Chem. 1969, 729, 198.
S0022-3263(98)00647-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/25/1998

Enantioselective Synthesis of (-)-Pumiliotoxin C
J . Org. Chem., Vol. 63, No. 19, 1998 6567
Sch em e 1
Sch em e 3
Sch em e 2
We now report a relatively concise enantioselective
synthesis of (-)-1 based on the use of an acetylenic
sulfone as the synthetic equivalent of an alkene dipole
in a key cycloaddition sequence.8 Unsaturated sulfones
are valuable compounds in organic synthesis.9 The
electron-withdrawing sulfone group activates an adjacent
alkene or alkyne toward conjugate addition and renders
vinyl and acetylenic sulfones useful dienophiles in cy-
cloadditions. Moreover, the products of conjugate or
cycloadditions are saturated or vinyl sulfones that often
contain relatively acidic R-protons, providing a site for
incorporating electrophiles via the corresponding anions.
Finally, the sulfone moiety can be employed as a dispos-
able activating group in such processes, since it can be
reductively removed at the end of a synthetic protocol.
In this manner, acetylenic sulfones act as the synthetic
equivalents of dipole or “multipole” species,10 as in
Scheme 1.
Our approach to (-)-pumiliotoxin C is outlined retro-
synthetically in Scheme 2. The two key intermediates 3
and 4 afford enaminone 2 by conjugate addition of the
amino group of 3 to the acetylenic sulfone moiety of 4,11
followed by intramolecular acylation of the resulting
enamine sulfone by the ester group.12 The sulfone 4 thus
acts as the synthetic equivalent of the hypothetical
alkene dipole 4a . Preferential hydrogenation of the
enaminone from the exo side then regulates the stereo-
center at C-2 and reductive removal of functional groups
completes the synthesis of 1. We also report a new
stereoselective synthesis of the (-)-enantiomer of 3,
which was required in enantiopure form for the enantio-
selective synthesis of (-)-1.
Resu lts a n d Discu ssion
The preparation of the required (-)-3 was recently
reported in six steps from a chiral intermediate that was
itself derived from (R)-(+)-pulegone.13 The p-toluene-
sulfonamide of the antipode (+)-3 had been prepared
earlier by a relatively lengthy sequence and was eventu-
ally employed in the synthesis of (+)-1.7c Our approach
to (-)-3 is shown in Scheme 3. The known racemic
anhydride 5 is readily available from the Diels-Alder
reaction of piperylene with maleic anhydride,14 followed
by hydrogenation and equilibration in the presence of a
tertiary amine.15 The corresponding racemic diester 6
was then subjected to hydrolysis with pig liver esterase
(11) For examples of conjugate additions of amines to other acety-
lenic sulfones, see: (a) Truce, W. E.; Brady, D. G. J . Org. Chem. 1966,
31, 3543. (b) Truce, W. E.; Markley, L. D. J . Org. Chem. 1970, 35, 3275.
(c) Truce, W. E.; Onken, D. W. J . Org. Chem. 1975, 40, 3200. (d)
Stirling, C. J . M. J . Chem. Soc. 1964, 5863. (e) Pink, R. C.; Spratt, R.;
Stirling, C. J . M. J . Chem. Soc. 1965, 5714. (f) McMullen, C. H.;
Stirling, C. J . M. J . Chem. Soc. B 1966, 1217. (g) McDowell, S. T.;
Stirling, C. J . M. J . Chem. Soc. B 1967, 351. (h) Cossu, S.; De Lucchi,
O.; Durr, R. Synth. Commun. 1996, 26, 4597.
(8) Preliminary communication of the synthesis of racemic 1: Back,
T. G.; Nakajima, K. Tetrahedron Lett. 1997, 38, 989.
(9) For reviews, see: (a) Simpkins, N. S. Sulphones in Organic
Synthesis; Pergamon Press: Oxford, 1993. (b) Fuchs, P. L.; Braish, T.
F. Chem. Rev. 1986, 86, 903. (c) Trost, B. M. Bull. Chem. Soc. J pn.
1988, 61, 107. (d) Simpkins, N. S. Tetrahedron 1990, 46, 6951. (e)
Tanaka, K.; Kaji, A. In The Chemistry of Sulphones and Sulphoxides;
Patai, S., Rappoport, Z., Stirling, C. J . M., Eds.; Wiley: Chichester,
1988; Chapter 15.
(12) For examples of reactions of other enamine sulfones with
electrophiles, see: (a) Back, T. G.; Collins, S.; Law, K.-W. Can. J . Chem.
1985, 63, 2313. (b) Fatutta, S.; Pitacco, G.; Russo, C.; Valentin, E. J .
Chem. Soc., Perkin Trans. 1 1982, 2045.
(13) Davies, S. G.; Bhalay, G. Tetrahedron: Asymmetry 1996, 7, 1595.
(14) Frank, R. L.; Emmick, R. D.; J ohnson, R. S. J . Am. Chem. Soc.
1947, 69, 2313.
(10) Back, T. G.; Wehrli, D. Tetrahedron Lett. 1995, 36, 4737.
(15) Craig, D. J . Am. Chem. Soc. 1950, 72, 1678.

6568 J . Org. Chem., Vol. 63, No. 19, 1998
Back and Nakajima
(PLE),16 in the hope of achieving a kinetic resolution.
However, when the hydrolysis was stopped at 50%
completion, substantial amounts of both enantiomers had
been consumed, affording the corresponding half-esters
7 and 8 in the ratio of 3:1, which was too inefficient for
the purpose at hand. The hydrolysis was therefore
permitted to go to completion, whereupon the enantio-
mers (-)-6 and (+)-6 underwent hydrolysis to afford the
half-esters 7 and 8, respectively, as the principal prod-
ucts.17 The mixture of 7 and 8 proved difficult to separate
and was therefore treated with benzyl chloroformate and
DMAP,18 resulting in the selective conversion of the
undesired half-ester 8 into the mixed diester 10, and only
partial conversion of 7 into the corrresponding diester 9.
Thus, the unreacted isomer 7 was recovered in 56% yield
(based on the amount of 7 in the initial mixture of 7 and
8), while an additional 11% was obtained by recycling
the mixture of diesters 9 and 10 through hydrogenolysis
and reesterification.19 The recovered 7 was then con-
verted into the required enantiopure dimethyl ester (-)-
620 with diazomethane, followed by regioselective saponi-
fication to afford a 7:1 mixture of half-esters 11 and 7.
The unseparated products were subjected to a Curtius
rearrangement with diphenylphosphoryl azide (DPPA)21
and trapped with benzyl alcohol, at which stage the
desired product 12 was easily separated from the analo-
gous regioisomer derived from 7. Hydrogenolysis of the
Cbz group then provided the required key intermediate
(-)-3 in >95% purity, as determined by NMR integration
of the spectrum of the corresponding salt 13, formed with
(R)-mandelic acid. Enantio- and diastereomerically pure
(within the limits of NMR detection) 3 was easily
recovered by recrystallization of 13, followed by basifi-
cation.22,23 This procedure therefore provides a concise
approach to the enantiopure diester (-)-6 and amino
ester (-)-3
Sch em e 4
Sch em e 5
The remainder of the synthesis of (-)-1 proceeded as
planned. The required acetylenic sulfone 4 was obtained
(16) (a) Toone, E. J .; Werth, M. J .; J ones, J . B. J . Am. Chem. Soc.
1990, 112, 4946 and references therein. (b) Ohno, M.; Otsuka, M. Org.
React. 1989, 37, 1. (c) Zhu, L.-M.; Tedford, M. C. Tetrahedron 1990,
46, 6587.
(17) By analogy to the PLE-mediated hydrolysis of dimethyl cis-
1,2-cyclohexanedicarboxylate, and from the active site model described
by J ones et al. for the latter compound (ref 16a), we had hoped to obtain
11 directly from (-)-6. Unfortunately, the different behavior of the
methyl-substituted cyclohexane diester necessitated the more circui-
tous approach shown in Scheme 3. A similar switch in the stereose-
lectivity of hydrolysis of dimethyl cis-1,2-cyclopropanedicarboxylate by
PLE was reported when methyl groups were introduced at the
3-position. See: Schneider, M.; Engel, N.; Ho¨nicke, P.; Heinemann,
G.; Go¨tisch, H. Angew. Chem., Int. Ed Engl. 1984, 23, 67.
(18) Kim, S.; Lee, J . I.; Kim, Y. C. J . Org. Chem. 1985, 50, 560.
(19) Efforts to separate the mixture of 9 and 10 by chromatography
failed. Similarly, conversion of the free carboxylic acid groups of 7 and
8 to their respective esters with methyl mandelate produced insepa-
rable mixtures.
(20) GC analysis of (-)-6 obtained in this manner on a chiral column
indicated no detectable amount of the (+)-enantiomer under conditions
giving a clean separation of the enantiomers of racemic 6 (see the
Supporting Information).
(21) Shioiri, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc. 1972,
94, 6203.
(22) Since the precursor (-)-6 was enantiopure, a very small degree
of epimerization apparently occurred during the saponification or
Curtius rearrangement steps leading to (-)-3. Enantiopure (-)-3
obtained from recrystallized 13 was again treated with (R)-mandelic
acid and subjected to NMR analysis to confirm that further epimer-
ization had not taken place during the basification step.
(23) Resolution of racemic 3 via recrystallization of diastereomeric
salts produced with mandelic acid proved unsuccessful. For examples
of resolutions of other amines with mandelic acid and related com-
pounds, see: Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry
of Organic Compounds; Wiley-Interscience: New York, 1994; p 334.
by selenosulfonation of 1-pentyne, followed by selenoxide
elimination of the adduct 14 (Scheme 4).24 The conjugate
addition of (-)-3 to 4 afforded adduct 15, which cyclized
to the key intermediate enaminone 2 in high yield upon
treatment with LDA (Scheme 5). Hydrogenation of the
corresponding enol triflate 16 occurred stereoselectively
from the exo side and provided decahydroquinoline
stereoisomers 17 (mixture of C-3 epimers) and 18 (pure
C-3 epimer) in the ratio of 5:1. Reductive desulfonyla-
tion25 of the Cbz derivative of 17, followed by deprotec-
tion, then afforded (-)-pumiliotoxin C (1) in 42% overall
yield from enaminone 2, while the similar treatment of
18 provided 2-epipumiliotoxin C (19) in 9% yield from 2.
(24) (a) Back, T. G.; Collins, S.; Kerr, R. G. J . Org. Chem. 1983, 48,
3077. (b) Back, T. G.; Collins, S.; Gokhale, U.; Law, K.-W. J . Org. Chem.
1983, 48, 4776. (c) Miura, T.; Kobayashi, M. J . Chem. Soc., Chem.
Commun. 1982, 438.
(25) For examples of reductive desulfonylations with Na/Hg, see:
ref 9c and references therein.

Enantioselective Synthesis of (-)-Pumiliotoxin C
J . Org. Chem., Vol. 63, No. 19, 1998 6569
in 100 mL of ethanol at room temperature and 1 atm pressure
for 13 h to regenerate 5.209 g (66% recovery) of a mixture of
7 and 8 in the ratio of ca. 1:2.7. The mixture was resubjected
to the above esterification procedure with benzyl chloroformate
to provide an additional 426 mg (11%) of 7 (total recovery 67%).
This approach therefore provides a relatively concise
synthesis of the natural (-)-enantiomer of pumiliotoxin
C from readily available starting materials.
Exp er im en ta l Section
Dim eth yl (-)-tr a n s-3-Meth ylcycloh exa n e-cis,cis-1,2-d i-
ca r boxyla te (6). Excess ethereal diazomethane was added
to a solution of 7 (2.580 g, 12.90 mmol) in 50 mL of methanol
to give 2.715 g (98%) of (-)-6 as a colorless oil after evaporation
of the solvent: IR (film) 1739 cm-1 (lit.28 for racemic 6, 1740
All NMR spectra, including those shown in the Supporting
Information, were obtained in deuteriochloroform. The pH 8.0
phosphate buffer was prepared according to a literature
procedure.26 Pig liver esterase (PLE) was obtained from the
Sigma Chemical Company as a crude lyophilized powder from
porcine liver, containing less than 5% buffer salt, 19 units/mg
of solid. m-CPBA was purified by washing with a pH 7.5
phosphate buffer and was assumed to be 100% pure.27 Benzyl
chloroformate contained 7% benzyl chloride, as determined by
NMR spectroscopy, and was used without further purification.
The anhydride 515 was converted to the known28 racemic
dimethyl ester 6 by the general procedure of Bussert et al.29
GC analyses of 6 were performed on a 30 m Cyclodex-B column
from J & W Scientific. Se-Phenyl p-tolueneselenosulfonate
was prepared from p-toluenesulfonhydrazide and benzenese-
leninic acid.30 All other reagents were obtained from com-
mercial sources and were purified as required by standard
procedures.
P LE-Ca ta lyzed Hyd r olysis of Dim eth yl (()-tr a n s-3-
Meth ylcycloh exa n e-cis,cis-1,2-d ica r boxyla te (6). A mix-
ture of 6 (9.449 g, 44.15 mmol) and PLE (233 mg, 100 units/
mmol of 6) in 200 mL of pH 8.0 phosphate buffer was stirred
at room temperature for 5 days. During the hydrolysis, 0.5
M NaOH solution was periodically added to maintain the pH
of the solution at 7-8 (total 73 mL, 36.5 mmol of NaOH). The
aqueous layer was basified to pH 9.0 by the addition of more
0.5 M NaOH solution and washed with 3 × 100 mL of ether.
The aqueous layer was then acidified to pH < 2 with 10% HCl
solution, and the products were extracted with 3 × 100 mL of
ether, dried over MgSO4, and concentrated in vacuo to give
8.310 g (94%) of an inseparable mixture of 7 and 8 in the ratio
of ca. 1:1 (NMR integration) as a brown oil. This was used
directly in the next step without further purification.
1
cm-1); H NMR (200 MHz) δ 3.67 (s, 3 H), 3.66 (s, 3 H), 2.88
(dt, J ) 6.9, 4.4 Hz, 1 H), 2.53 (dd, J ) 7.2, 4.6 Hz, 1 H), 2.40-
2.20 (m, 1 H), 2.05-1.85 (m, 1 H), 1.80-1.45 (m, 4 H), 1.25-
1.08 (m, 1 H), 1.03 (d, J ) 6.8 Hz, 3 H); 13C NMR (50 MHz) δ
173.8, 173.4, 51.0, 49.3, 40.1, 31.1, 29.1, 25.9, 20.1, 19.5; MS,
m/z (rel intensity, %) 214 (0.9, M+), 182 (10), 154 (26), 95 (49),
40 (100); exact mass calcd for C11H18O4 214.1205, found
214.1213; [R]2D3 -43.8 (c 1.04, CHCl3).
t r a n s-3-Me t h ylcycloh e xa n e -cis,cis-1,2-d ica r b oxylic
Acid , 2-Mon om eth yl Ester (11). A mixture of (-)-6 (2.677
g, 12.51 mmol) and NaOH (591 mg, 14.8 mmol) in 35 mL of
water was refluxed for 2.5 h and acidified with 10% HCl
solution. The solution was extracted with 3 × 50 mL of ether,
dried over MgSO4, and concentrated in vacuo to afford 2.356
g (94%) of an inseparable mixture of 11 and 7 in a ratio of 7:1
(NMR integration) as an oil: IR (film) 3500-2600, 1736, 1705
1
cm-1; H NMR (200 MHz) (signals from 7 (vide supra) were
superimposed upon the following signals assigned to 11) δ
11.51 (br m, 1 H), 3.68 (s, 3 H), 2.88 (m, 1 H), 2.58 (dd, J )
6.4, 4.6 Hz, 1 H), 2.48-2.21 (m, 1 H), 2.08-1.83 (m, 1 H), 1.83-
1.30 (m, 4 H), 1.29-1.13 (m, 1 H), 1.06 (d, J ) 6.9 Hz, 3 H);
13C NMR (100 MHz) δ 180.5, 173.9, 51.5, 48.9, 40.0, 30.7, 29.4,
25.7, 20.2, 19.6; MS, m/z (rel intensity, %) 200 (0.72, M+), 182
(10), 168 (15), 154 (25), 122 (37), 96 (68), 95 (100), 81 (94), 67
(52), 55 (50), 41 (56); exact mass calcd for C10H16O4-H2O
182.0943, found 182.0954.
Meth yl (-)-cis-2-[N-(Ca r boben zyloxy)a m in o]-tr a n s-6-
m eth ylcycloh exa n eca r boxyla te (12). A solution of the 7:1
mixture of 11 and 7 (2.356 g, 11.78 mmol), triethylamine (1.70
mL, 12.2 mmol), and diphenylphosphoryl azide (2.55 mL, 11.9
mmol) in 50 mL of toluene was refluxed for 4.5 h, washed with
K2CO3 solution, dried over MgSO4, and concentrated in vacuo
to provide 2.476 g of the corresponding mixture of isocyanates
(-)-tr a n s-3-Met h ylcycloh exa n e-cis,cis-1,2-d ica r boxy-
lic Acid , 1-Mon om et h yl E st er (7). Benzyl chloroformate
(6.80 mL, ca. 44.9 mmol) and triethylamine (6.60 mL, 47.4
mmol) were added to a solution of the mixture of 7 and 8
obtained in the preceding procedure (7.905 g, 39.53 mmol) in
250 mL of dichloromethane, and the resulting mixture was
stirred at 0 °C for 5 min. DMAP (5.792 g, 47.78 mmol) was
added, and the mixture was stirred at 0 °C for another 30 min.
It was extracted with 3 × 100 mL of 1.0 M NaOH solution,
then with 10% HCl solution, brine, and dried over MgSO4. The
combined aqueous layers were acidified with concentrated HCl
and extracted with 3 × 100 mL of ether, dried over MgSO4
and evaporated under reduced pressure to afford 2.194 g (56%
based on the amount of 7 in the starting material) of recovered
as a yellow oil with IR (film): 2273, 1738 cm-1
. This was
refluxed with benzyl alcohol (2.00 mL, 19.4 mmol) in 3.0 mL
of pyridine for 20 min. The pyridine and excess benzyl alcohol
were removed under vacuum. The residue was chromato-
graphed over silica gel (elution with 5% ethyl acetate-
hexanes) to afford 1.563 g (50% based on the amount of 11 in
the mixture of starting materials) of 12 as a pale yellow oil:
1
IR (film) 3364, 3345, 1729 cm-1; H NMR (200 MHz) δ 7.37-
7.30 (br s, 5 H), 5.30 (m, 1 H), 5.08 (s, 2 H), 4.16 (m, 1 H), 3.63
(s, 3 H), 2.30 (dd, J ) 10.1, 3.6 Hz, 1 H), 2.08-1.83 (m, 2 H),
1.83-1.50 (m, 4 H), 1.15-1.00 (m, 1 H), 0.94 (d, J ) 6.5 Hz, 3
H); 13C NMR (100 MHz) δ 173.3, 155.4, 136.4, 128.0, 127.6,
66.1, 52.1, 51.1, 47.5, 32.0, 29.8, 28.6, 19.9, 19.5; MS, m/z (rel
intensity, %) 305 (4, M+), 170 (20), 108 (17), 91 (100); exact
mass calcd for C17H23NO4 305.1627, found 305.1623; [R]D23
-26.9 (c 1.02, CHCl3).
1
7 as an oil: IR (film) 3500-2500, 1738, 1726, 1699 cm-1; H
NMR (200 MHz) δ 11.51 (br m, 1 H), 3.64 (s, 3 H), 2.89 (m, 1
H), 2.55 (dd, J ) 6.8, 4.4 Hz, 1 H), 2.48-2.21 (m, 1 H), 2.08-
1.83 (m, 1 H), 1.83-1.30 (m, 4 H), 1.29-1.13 (m, 1 H), 1.08 (d,
J ) 6.8 Hz, 3 H); 13C NMR (100 MHz) δ 179.7, 174.1, 51.3,
49.2, 40.1, 31.0, 29.4, 26.0, 20.2, 19.6; MS, m/z (rel intensity,
%) 200 (7, M+), 182 (58), 169 (62), 154 (73), 122 (71), 113 (71),
95 (92), 83 (100), 68 (79), 55 (90); exact mass calcd for C10H16O4
200.1049, found 200.1056; [R]2D2 -41.3 (c 1.04, CHCl3).
Met h yl (-)-cis-2-Am in o-tr a n s-6-m et h ylcycloh exa n e-
ca r boxyla te (3). A solution of 12 (1.393 g, 4.567 mmol) and
formic acid (0.1 mL) in 20 mL of methanol was hydrogenated
for 19 h over 10% palladium on charcoal (143 mg) at room
temperature and at 1 atm. The catalyst was removed by
filtration through Celite, and the solvent was evaporated. The
residue was triturated with 50 mL of ether and washed with
3 × 25 mL of 1.0 N NaOH solution. The ether layer was
separated, dried over MgSO4, and evaporated carefully without
heating to afford 695 mg (89%) of 3 as a colorless oil: IR (film)
The dichloromethane layer was concentrated in vacuo, and
the crude mixture of 9 and 10 was obtained as an oil, which
was hydrogenated over 10% palladium on charcoal (170 mg)
(26) Kobayashi, S.; Kamiyama, K.; Ohno, M. Chem. Pharm. Bull.
1990, 38, 350.
(27) Schwartz, N. N.; Blumbergs, J . H. J . Org. Chem. 1964, 29, 1976.
(28) Kawasaki, K.; Matsumura, H. Chem. Pharm. Bull. 1969, 17,
1158.
(29) Bussert, J . F.; Greenlee, K. W.; Derfer, J . M.; Boord, C. E. J .
Am. Chem. Soc. 1956, 78, 6076.
(30) Back, T. G.; Collins, S.; Krishna, M. V. Can. J . Chem. 1987,
65, 38.
1
3439, 3386, 3312, 1729 cm-1; H NMR (200 MHz) δ 3.69 (s, 3
H), 3.32 (m, 1 H), 2.17 (dd, J ) 11.1, 3.1 Hz, 1 H), 2.05-1.80
(m, 1 H), 1.80-1.40 (m, 5 H), 1.37 (br s, 2 H), 1.07-0.91 (m, 1
H), 0.88 (d, J ) 6.3 Hz, 3 H); 13C NMR (50 MHz) δ 174.1, 54.4,
50.4, 47.4, 33.2, 32.3, 26.8, 19.9, 18.5; MS, m/z (rel intensity,

6570 J . Org. Chem., Vol. 63, No. 19, 1998
Back and Nakajima
%) 171 (4, M+), 97 (20), 70 (23), 56 (100); exact mass calcd for
C9H17NO2 171.1259, found: 171.1257; [R]2D3 -21.7 (c 1.06,
CHCl3).
H); MS, m/z (rel intensity, %) 393 (7, M+), 362 (5), 301 (7), 238
(93), 95 (69), 91 (65), 83 (100). Anal. Calcd for C21H31NO4S:
C, 64.12; H, 7.89; N, 3.56. Found: C, 63.84; H, 7.79; N, 3.44.
4a,5,6,7,8,8a-Hexah ydr o-5-m eth yl-2-pr opyl-3-(p-tolu en e-
su lfon yl)-4-qu in olin on e (2). n-Butyllithium (2.30 mmol)
was added to a solution of diisopropylamine (320 (µL, 2.29
mmol) in 3.0 mL of THF, and the resulting solution was stirred
for 15 min at -78 °C. A solution of compound 15 (758 mg,
1.93 mmol) in 5.0 mL of THF was added, and the resulting
mixture was stirred for another 20 min at -78 °C and then
for 40 min at room temperature. The THF was evaporated
and chromatography over activated neutral alumina (80-200
mesh) with 10% ethyl acetate-hexanes, followed by ethyl
acetate-methanol (2:1), afforded 339 mg (45%) of unreacted
15 as a light yellow oil and 346 mg (50%; 91% based on the
amount of consumed 15) of 2 as a pale yellow solid foam,
respectively. Recrystallization from methanol gave 2 as a
white powder: mp 163-164 °C; IR (KBr) 3283, 1657, 1281,
1148, 1132 cm-1; 1H NMR (400 MHz) δ 7.88 (d, J ) 8.1 Hz, 2
H), 7.23 (d, J ) 8.0 Hz, 2 H), 5.48 (m, 1 H), 3.81 (m, 1 H), 3.19
(dt, J ) 13.3, 7.7 Hz, 1 H), 2.79 (dt, J ) 13.3, 7.7 Hz, 1 H),
2.38 (s, 3 H), 1.98-1.78 (m, 3 H), 1.73 (dd, J ) 10.5, 3.8 Hz, 1
H), 1.78-1.50 (m, 5 H), 1.09 (t, J ) 7.3 Hz, 3 H), 1.02-0.76
(m, 1 H), 0.64 (d, J ) 6.5 Hz, 3 H); MS, m/z (rel intensity, %)
361 (2), 360 (3), 296 (100), 269 (71), 228 (49), 190 (54), 91 (66),
41 (44). Anal. Calcd for C20H27NO3S: C, 66.48; H, 7.48; N,
3.88. Found: C, 66.33; H, 7.44; N, 3.95. [R]2D3 +207.3 (c 1.01,
CHCl3).
The above product (662 mg, 3.87 mmol) was treated with
(R)-mandelic acid (590 mg, 3.88 mmol) to form diastereomeric
ammonium salts in the ratio of 97:3 (NMR integration).
Recrystallization from 20 mL of ethanol-ether (1:3) afforded
1
13: mp 104-105 °C; H NMR (200 MHz) δ 7.48-7.40 (m, 2
H), 7.33-7.20 (m, 3 H), 6.30-5.65 (br m, 4 H), 4.88 (s, 1 H),
3.70 (s, 3 H), 3.20 (m, 1 H), 2.25 (dd, J ) 8.8, 3.5 Hz, 1 H),
2.08 (m, 1 H), 1.80-1.30 (m, 5 H), 1.05 (m, 1 H), 0.87 (d, J )
6.5 Hz, 3 H); 13C NMR (100 MHz) δ 178.3, 174.1, 142.0, 127.8,
126.9, 126.5, 74.4, 52.0, 49.7, 47.0, 31.3, 28.8, 28.0, 19.2, 18.6.
Anal. Calcd for C17H25NO5: C, 63.16; H, 7.74; N, 4.33.
Found: C, 63.26; H, 8.14; N, 4.36. Basification of the above
salt with 1.0 N NaOH solution afforded homogeneous (NMR)
3: [R]D23 -24.2 (c 1.06, CHCl3); lit.13 [R]2D2 -31.0 (c 1.07,
CHCl3). The corresponding p-toluenesulfonamide was ob-
tained from 3 and p-toluenesulfonyl chloride: [R]2D3 -43.3 (c
1.19, CHCl3); lit.13 [R]D22 -34.3 (c 1.20, CHCl3); lit.7c for the
p-toluenesulfonamide of the antipode of 3: [R]2D2 +34.9 (c
1.17, CHCl3).
(E)-2-(P h en ylselen o)-1-(p -t olu en esu lfon yl)-1-p en t en e
(14). A solution of Se-phenyl p-tolueneselenosulfonate (3.02
g, 9.68 mmol) and 1-pentyne (1.60 mL, 16.3 mmol) in 8.0 mL
of chloroform was placed in a 10 mm diameter glass test tube
inside a water-cooled condenser, and the mixture was irradi-
ated in a Rayonet UV reactor with 254 nm lamps for 4 h. The
chloroform was evaporated and chromatography over silica gel
(elution with 10% ethyl acetate-hexanes) afforded 3.52 g (96%)
of 14 as a single regio- and stereoisomer (NMR) in the form of
a pale green oil that crystallized from hexanes: mp 50-52 °C;
5-Meth yl-2-pr opyl-3-(p-tolu en esu lfon yl)decah ydr oqu in -
olin e (17) a n d Its 2-Ep im er (18). A solution of 2 (115 mg,
0.319 mmol) and triflic anhydride (80 µL, 0.48 mmol) in 3.0
mL of dichloromethane was refluxed under argon for 18 h and
concentrated in vacuo to afford crude 16 as a gray solid (192
mg), which was used directly in the next step. A solution of
16 (192 mg) in 6.0 mL of methanol was hydrogenated over
PtO2 (99 mg, 0.44 mmol) at 100 atm for 6 days. The catalyst
was removed by filtration through Celite, and the filtrate was
concentrated in vacuo. The residue was triturated with
dichloromethane and washed with saturated K2CO3 solution.
The dichloromethane layer was separated and dried over
MgSO4. The solvent was evaporated, and the crude material
was chromatographed over silica gel (elution with 17% ethyl
acetate-hexanes) to give one of the C-3 epimers of 17 contain-
ing a minor impurity.32 Further elution with 25% ethyl
acetate-hexanes gave 18 as a single diastereomer (19 mg, 17%
overall from 2). Finally, elution with ethyl acetate provided
the other C-3 epimer of 17, along with a minor impurity.32 The
first and third fractions were combined (86 mg), and this crude
mixture was used directly in the next step. Compound 18 was
recrystallized from hexanes to provide colorless needles: mp
IR (KBr) 1564, 1304, 1272, 1139, 1079 cm-1 1H NMR (200
;
MHz) δ 7.68 (d, J ) 8.3 Hz, 2 H), 7.55-7.26 (complex, 7 H),
5.86 (s, 1 H), 2.84 (br t, J ) 7.8 Hz, 2 H), 2.42 (s, 3 H), 1.64
(sextet, J ) 7.5 Hz, 2 H), 0.96 (t, J ) 7.3 Hz, 3 H); 13C NMR
(50 MHz) δ 160.9, 143.7, 139.5, 136.6, 129.9, 129.7, 129.6,
126.8, 125.9, 123.9, 34.8, 23.3, 21.4, 13.6; MS, m/z (rel
intensity, %) 380 (14, M+), 248 (10), 223 (19), 183 (16), 157
(69), 155 (39), 139 (33), 91 (100). Anal. Calcd for C18H20O2-
SSe: C, 56.99; H, 5.30. Found: C, 56.99; H, 5.34.
1-(p-Tolu en esu lfon yl)-1-p en tyn e (4).31 A solution of m-
CPBA (3.204 g, 18.57 mmol) and 14 (3.49 g, 9.18 mmol) in
100 mL of chloroform was refluxed for 7 h, washed with
saturated K2CO3 solution, and dried over MgSO4. The chlo-
roform was evaporated, and chromatography over silica gel
(elution with 10% ethyl acetate-hexanes) afforded 1.917 g
(94%) of 4 as a light red oil: IR (film) 2199, 1327, 1156 cm-1
;
1H NMR (200 MHz) δ 7.88 (d, J ) 8.3 Hz, 2 H), 7.36 (d, J )
8.6 Hz, 2 H), 2.46 (s, 3 H), 2.33 (t, J ) 7.0 Hz, 2 H), 1.58 (sextet,
J ) 7.3 Hz, 2 H), 0.96 (t, J ) 7.3 Hz, 3 H); 13C NMR (50 MHz)
δ 144.8, 138.9, 129.5, 126.6, 96.8, 78.2, 21.2, 20.3, 20.2, 12.9;
MS, m/z (rel intensity, %) 222 (90, M+), 139 (100), 129 (49),
107 (64), 91 (62), 65 (50).
1
113-114 °C; IR (film) 1291, 1145, 1084 cm-1; H NMR (400
MHz) δ 7.75 (d, J ) 8.1 Hz, 2 H), 7.33 (d, J ) 8.1 Hz, 2 H),
3.52 (dt, J ) 11.4, 3.7 Hz, 1 H), 3.38 (dt, J ) 12.5, 4.0 Hz, 1
H), 3.03 (m, 1 H), 2.43 (s, 3 H), 2.08-1.85 (m, 3 H), 1.75-1.21
(m, 11 H), 0.96 (t, J ) 7.3 Hz, 3 H), 0.91-0.82 (m, 1 H), 0.47
(d, J ) 6.3 Hz, 3 H); 13C NMR (100 MHz) δ 144.2, 136.1, 129.6,
128.3, 60.9, 52.1, 46.3, 42.3, 35.2, 32.2, 27.4, 22.5, 21.6, 20.8,
19.2, 19.1, 13.9; MS, m/z (rel intensity, %) 349 (2.6, M+), 306
(100), 194 (55), 151 (70), 91 (69), 72 (65), 41 (51); exact mass
(E)- a n d (Z)-Meth yl cis-2-{N-[2-(1-p-Tolu en esu lfon yl)-
1-p en ten yl]}a m in o-tr a n s-6-m eth ylcycloh exa n eca r boxy-
la te (15). A solution of 3 (484 mg, 2.83 mmol) and 4 (611 mg,
2.75 mmol) in 10 mL of ethanol was stirred for 20 h at room
temperature. The ethanol was evaporated, and chromatog-
raphy over activated neutral alumina (80-200 mesh) with 10%
ethyl acetate-hexanes afforded 1.014 g (94%) of 15 as a
mixture of (E)- and (Z)- isomers in the ratio of 1:2.5 (NMR
integration; respective geometries determined by NOE experi-
ments), in the form of a light yellow oil that crystallized from
ether to give a white powder with the same E:Z ratio: mp 92-
101 °C; IR (KBr) 3321, 1735, 1599, 1274, 1127, 1078 cm-1; 1H
NMR (400 MHz) (signals assigned to the (Z)-isomer) δ 7.81
(d, J ) 8.2 Hz, 2 H), 4.54 (s, 1 H), 3.60 (s, 3 H), 0.98 (d, J )
6.3 Hz, 3 H); (signals assigned to the (E)-isomer) 7.76 (d, J )
8.2 Hz, 2 H), 4.99 (s, 1 H), 3.64 (s, 3 H), 0.93 (d, J ) 6.5 Hz, 3
calcd for C20H31NO2S 349.2075, found 349.2049; [R]22 +20.0
D
(c 0.40, in CHCl3).
(32) The impurity was tentatively identified as the 4-hydroxy
derivative of 17. No attempts were made to remove it, since it
underwent reductive elimination to the ∆3 olefin with sodium amalgam
and hydrogenation to the desired product 1 in subsequent steps. The
indicated configuration at C-3 of 18 was established by NOE experi-
ments conducted upon its N-Cbz derivative. When H-2 was irradiated
(δ 4.58), 10% enhancement of the signal of H-3 (δ 3.48) was observed,
while irradiation of H-3 gave 15% enhancement of the H-2 signal.
Decoupling experiments of the N-Cbz derivative indicated J ) 3.6
Hz between H-2 and H-3, and J ) 8.3 and 11.3 Hz between H-3 and
the two protons at H-4. These results are consistent with an axial
hydrogen atom at C-3 and a cis relationship between H-2 and H-3.
The indicated configurations at C-2 of 17 and 18 was confirmed by
(31) Compound
4 has been previously prepared by a different
route: Iwata, N.; Morioka, T.; Kobayashi, T.; Asada, T.; Kinoshita, H.;
Inomata, K. Bull. Chem. Soc. J pn. 1992, 65, 1379.
their respective conversions into the known products
respectively.
1 and 19,

Enantioselective Synthesis of (-)-Pumiliotoxin C
J . Org. Chem., Vol. 63, No. 19, 1998 6571
(-)-P u m iliotoxin C (1). The mixture of crude epimers of
17 (86 mg) and benzyl chloroformate (370 µL, ca. 2.44 mmol)
was refluxed for 3 h in 2.0 mL of chloroform and saturated
K2CO3 solution (4:1), and the organic layer was separated and
dried over MgSO4. The solvent was evaporated and the crude
material was chromatographed over silica gel with 5% ethyl
acetate-hexanes to remove excess benzyl chloroformate, and
then with ethyl acetate to afford the N-Cbz derivative of 17
(123 mg) as an oil.
The above product, Na2HPO4 (148 mg, 1.04 mmol), and 5%
sodium amalgam (10.0 g, 21.7 mg-atoms of Na) in 6.0 mL of
methanol-THF (1:1) was stirred at room temperature for 5 h
and filtered through Celite, and the filtrate was concentrated
in vacuo. The residue was triturated with dichloromethane
and washed with saturated K2CO3 solution. The dichlo-
romethane layer was separated and dried over MgSO4. The
solvent was evaporated and the crude material was chromato-
graphed over silica gel (elution with 10% ethyl acetate-
hexanes) to give the desulfonylated N-Cbz derivative of 17 (52
mg) as an oil.
289-291 °C (sealed capillary). For the (-)-enantiomer: lit.6a
284-288 °C; lit.6b 237-239 °C; lit.6c 286-288 °C, lit.6d 220-
225 °C, lit.6e 286-288 °C; 1H NMR (400 MHz) δ 9.60 (m, 1 H),
8.30 (m, 1 H), 3.33 (m, 1 H), 3.00 (m, 1 H), 2.55-2.30 (m, 2
H), 2.23-1.95 (m, 4 H), 1.92-1.84 (br d, 1 H), 1.83-1.75 (br
d, 1 H), 1.72-1.35 (m, 6 H), 1.32-1.20 (m, 1 H), 1.04-0.95
(m, 1 H), 0.92 (t, J ) 7.4 Hz, 3 H), 0.90 (d, J ) 6.2 Hz, 3 H);
13C NMR (100 MHz) δ 60.1, 58.0, 40.9, 34.8, 34.3, 29.1, 27.2,
25.2, 23.1, 20.6, 19.7, 19.1, 13.7 (these values are in excellent
23
agreement with the literature5b,6c
); [R]D -16.8 (c 0.45, Me-
OH); lit.6a [R]2D6 -15.2 (c 0.46, MeOH); lit.6b [R]2D2 -12.9 (c 0.35,
MeOH); lit.6c [R]D21 -16.2 (c 1.00, MeOH); lit.6d [R]2D0 -13.1 (c
1.0, MeOH); lit.6e [R]2D0 -14.5 (c 1.00, MeOH).
2-Ep ip u m iliotoxin C (19). Compound 18 (34 mg, 0.097
mmol) was similarly converted into 2-epipumiliotoxin C (19)
(6.6 mg, 9% overall from 2) as a yellow oil: IR (film) 3276 cm-1
;
1H NMR (400 MHz) δ 3.13 (dt, J ) 10.5, 4.1 Hz, 1 H), 2.84-
2.75 (m, 1 H), 1.90-1.01 (m, 17 H), 1.00 (d, J ) 7.2 Hz, 3 H),
0.91 (t, J ) 7.0 Hz, 3 H); 13C NMR (100 MHz) δ 50.0, 49.5,
42.0, 38.4, 32.5, 31.6, 29.7, 25.3, 20.5, 19.4, 19.3, 14.2 (these
values are in good agreement with the literature,5c although
some minor impurity signals were also evident); MS, m/z (rel
intensity, %) 195 (1.6, M+), 194 (3), 166 (5), 152 (100).
A mixture of the latter product and 10% palladium on
charcoal (20 mg) in 3 mL of ethanol was hydrogenated at room
temperature and 1 atm for 4.5 h. The catalyst was removed
by filtration through Celite, and the filtrate was concentrated
in vacuo. The residue was triturated with chloroform and
washed with saturated K2CO3 solution. The chloroform layer
was separated and dried over MgSO4. The solvent was
evaporated, and the crude material was chromatographed over
silica gel (elution with 5% triethylamine-hexanes) to afford
(-)-pumiliotoxin C (1) (26 mg, 42% overall yield from 2) as a
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada (NSERC)
for financial support.
Su p p or tin g In for m a tion Ava ila ble: The 1H and 13C
NMR spectra of compounds 7, 11, 12, 3, 13, 18, and 1, as well
as the GC (chiral column) of both (()-6 and (-)-6 (19 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
1
yellow oil: IR (film) 3300 cm-1; H NMR (400 MHz) δ 2.87-
2.83 (m, 1 H), 2.58-2.50 (m, 1 H), 2.00-1.80 (m, 2 H), 1.75-
0.88 (m, 15 H), 0.91 (t, J ) 6.9 Hz, 3 H), 0.85 (d, J ) 6.6 Hz,
3 H); 13C NMR (100 MHz) δ 57.8, 56.0, 42.6, 39.6, 35.9, 33.3,
27.4, 27.2, 27.0, 21.2, 19.9, 19.1, 14.3; MS, m/z (rel intensity,
%) 195 (4, M+), 194 (8), 166 (60), 152 (100). The free base was
converted to the corresponding hydrochloride salt, which was
recrystallized from 2-propanol to give colorless needles: mp
J O980647Q