Rapid stereoselective access to key pumiliotoxin precursors from a common intermediate

Article abstract of DOI:10.1021/jo0497205

Epoxidation and dihydroxylation of 8-methyl-2,3,6,8a-tetrahydro-1H-indolizin-5-one proceeded from the concave face with good selectivity and gave advanced precursors for pumiliotoxin and allopumiliotoxin synthesis, respectively. The origin of the selectivity is believed to be stereoelectronic in nature and allows rapid entry to three different pumiliotoxin classes from a common intermediate.

Full text of DOI:10.1021/jo0497205

Ra p id Ster eoselective Access to Key
P u m iliotoxin P r ecu r sor s fr om a Com m on
In ter m ed ia te
Gavin O’Mahony, Mark Nieuwenhuyzen,
Paul Armstrong,† and Paul J . Stevenson*
School of Chemistry, Queen’s University,
Belfast, N. Ireland BT9 5AG
p.stevenson@qub.ac.uk
Received February 17, 2004
F IGURE 1. Retrosynthetic analysis showing key intermedi-
ates 1 and 2 in previous pumiliotoxin and allopumiliotoxin
synthesis.
Abstr a ct: Epoxidation and dihydroxylation of 8-methyl-
2,3,6,8a-tetrahydro-1H-indolizin-5-one proceeded from the
concave face with good selectivity and gave advanced
precursors for pumiliotoxin and allopumiliotoxin synthesis,
respectively. The origin of the selectivity is believed to be
stereoelectronic in nature and allows rapid entry to three
different pumiliotoxin classes from a common intermediate.
Gramain first reported the synthesis of compound 1
in racemic form,7a while Gallagher reported the first
asymmetric synthesis of this compound7b and demon-
strated that the 6-alkylidene unit of the target alkaloid
could be attached by aldol methodology. Six additional
routes to this key intermediate have been published to
date.8 Overman first reported ketone 2 as an entry to the
allopumiliotoxins,9 again with the 6-alkylidene entity
being introduced by aldol methodology, and to date, three
additional routes to this key indolizidine have been
reported.10
A literature survey revealed that electrophilic additions
to unsaturated indolizidin-5-ones and indolizidines usu-
ally proceed at the concave face.11 This selectivity is
opposite to what one would intuitively predict and has
been independently attributed by different groups to both
steric effects12 and to the Cieplak stereoelectronic effect,13
Pumiliotoxin alkaloids, isolated from the defensive skin
secretions of Dendrobates frogs1 have attracted the at-
tention of the synthetic organic chemistry community for
a number of years.2 The interesting structures and
biological properties of these alkaloids, coupled with the
fact that for all practical purposes these compounds are
essentially unavailable from the natural source, make
them ideal targets for synthesis and for developing new
synthetic methodologies. Allopumiliotoxins are related to
pumiliotoxins in that they contain an additional hydroxyl
group at C7. A number of ingenious solutions to the
synthesis of these molecules have been published which
include iminium ion chemistry,3 organonickel chemistry,4
organopalladium chemistry,5 and organochromium chem-
istry.6 In other approaches, two key indolizidines 1 and
2 (Figure 1) have emerged as key intermediates in the
synthesis of pumiliotoxin and allopumiliotoxin alkaloids,
respectively, using aldol methodology to attach the
6-alkylidene group.
(7) (a) Azzouzi, A.; Dufour, M.; Gramain, J . C.; Remuson, R.
Heterocycles 1988, 27, 133-148. (b) Fox, D. N. A.; Lathbury, D.; Mahon,
M. F.; Molloy, K. C.; Gallagher, T. J . Am. Chem. Soc. 1991, 113, 2652-
2656.
(8) Cossy, J .; Cases, M.; Gomez Pardo, D. Synlett 1996, 909-911.
Cossy, J .; Cases, M.; Gomez Pardo, D. Bull. Soc. Chim. Fr. 1997, 134,
141-144. Barrett, A. G. M.; Damiani, F. J . Org. Chem. 1999, 64, 1410-
1411. Martin, S. F.; Bur, S. K. Tetrahedron 1999, 55, 8905-8914. Ni,
Y.; Zhao, G.; Ding, Y. J . Chem. Soc., Perkin Trans. 1 2000, 3264-
3266. Sudau, A.; Munch, W.; Bats, J . W.; Nubbemeyer, U. Eur. J . Org.
Chem. 2002, 3315-3325. Wang, B., Fang, F., Lin, G., Tetrahedron Lett.
2003, 44, 7981-7984.
(9) Overman, L. E.; Goldstein, S. W. J . Am. Chem. Soc. 1984, 106,
5360-5361. Goldstein, S. W.; Overman, L. E.; Rabinowitz, M. H. J .
Org. Chem. 1992, 57, 1179-1190.
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Lett. 1999, 40, 1397-1400. Tan, C. H.; Holmes, A. B. Chem. Eur. J .
2001, 7, 1845-1854. Comins, D. L.; Huang, S. L.; McArdle, C. L.;
Ingalls, C. L. Org. Lett. 2001, 3, 469-471. Wang, B., Fang, F., Lin, G.
Tetrahedron Lett. 2003, 44, 7981-7984.
(11) Leeper, F. J .; Howard, S. Tetrahedron Lett. 1995, 36, 2335-
2338. Hussain, N.; Leonard, J . Tetrahedron Lett. 1987, 28, 4871-4874.
McKittrick, B. A.; Ganem, B. Tetrahedron Lett. 1985, 6, 4895-4898.
Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki. J . Org. Chem. 1995, 60,
398-404.
(12) (a) Mukai, C.; Yamaguchi, S.; Sugimoto, Y.; Miyakoshi, N.;
Kasamatsu, E.; Hanaoka, M. J . Org. Chem. 2000, 65, 6761-6765. (b)
de Vicente, J .; Arrayas, R. G.; Canada, J .; Carretero, J . C. Synlett 2000,
53-56. (c) K. B. Lindsay, K. B.; Pyne, G. J . Org. Chem. 2002, 67, 7774-
7780. (d) Mukai, C.; Sugimoto, Y.; Miyazawa, K.; Yamaguchi, S.;
Hanaoka, M. J . Org. Chem. 1998, 63, 6281-6287. (e) Davis, A. S.;
Gates, N. J .; Lindsay, K. B.; Tang, M.; Pyne, S. G. Synlett 2004, 49-
52.
† Chemical Synthesis Services (CSS), Almac House, 20 Seagoe
Industrial Estate, Craigavon, N. Ireland BT63 5PW.
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Alkaloids; Academic Press: New York, 1993; Vol. 43, p 185. Daly, J .
W. J . Med. Chem. 2003, 46, 445-452.
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1996, 96, 505-522.
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A.; Sharp, M. J .; Zablocki, J . J . Am. Chem. Soc. 1996, 118, 9062-9072.
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L. A.; Sharp, M. J .; Zablocki, J . J . Am. Chem. Soc. 1996, 118, 9073-
9082. (c) Overman, L. E.; Robinson, L. A.; Zablocki, J . J . Am. Chem.
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10.1021/jo0497205 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/27/2004
3968
J . Org. Chem. 2004, 69, 3968-3971

SCHEME 1. P r ep a r a tion of Sta r tin g Ma ter ia ls
SCHEME 2. Ep oxid a tion Stu d ies
F IGUR E 2. X-ray structure of alcohol 7 depicting relative
stereochemistry.
methodology. On further experimentation the best method
was found to be subjecting a toluene solution of diene 4
and 0.1 mol % of second generation Grubbs’ catalyst to
microwave irradiation for 15 min. The use of microwave
heating for facilitating ring closing metathesis is well
documented.20
Compound 5 was remarkably stable and conditions
could not be found to isomerize the double bond into
conjugation with the amide carbonyl group, making this
a robust intermediate. With substrate 5 at hand, func-
tionalization of the alkene was carried out. First, epoxi-
dation with m-CPBA proved to be reasonably selective,
affording a 10:1 mixture of diastereoisomeric epoxides
(Scheme 2). Treatment of epoxide 6 with potassium
carbonate resulted in a regioselective eliminative epoxide
ring opening reaction to give the tertiary allylic alcohol
7 in 54% yield. Epoxide 6 proved difficult to isolate and
purify in reasonable yield due to its water solubility and
coelution with m-CPBA and derived products on silica
gel column chromatography. Fortunately, conversion of
alkene 5 to alcohol 7 could be performed in 85% overall
yield for the two steps without isolating epoxide 6, using
strongly basic ion-exchange resin Amberlite IRA-400-
(OH). The resin acted as the base for the epoxide ring-
opening reaction and as a scavenger for unreacted
m-CPBA and its byproducts. Alcohol 7 was crystallized
to isomeric purity and the configuration at the tertiary
alcohol center was determined by single crystal X-ray
crystallography Figure 2. Gratifyingly the stereochem-
istry of the tertiary alcohol was correct, as anticipated,
for pumiliotoxin synthesis. Hydrogenation of alkene 7
over a palladium catalyst afforded saturated compound
1, a key intermediate in previous pumiliotoxin synthe-
ses.7
as recently elegantly articulated by Hanessian.14 How-
ever, it should be noted that Cieplak’s arguments have
recently come under scrutiny and appear to lack a solid
theoretical foundation.15 Regardless of origin, if this
remarkable face selectivity was retained in reactions of
8-methyl-2,3,6,8a-tetrahydro-1H-indolizin-5-one 5, then
it raised the exciting possibility that pumiliotoxin, al-
lopumiliotoxin, 8-epi-pumilioxtoxin, and 8-deoxypumil-
iotoxin16 alkaloids could all be prepared from a common
alkene precursor.
Scheme 1 outlines the approach that was followed for
synthesis of the starting material 5. Known carbamate
33g was deprotected and coupled in situ with 3-butenoic
acid using a modification of the method of Paolucci,17
affording rotameric tertiary amide 4. Olefin metathesis,
a now well-established route for preparing indolizidino-
nes,18 was used to effect the key cyclization. Second-
generation Grubbs’ catalyst is known to be superior to
first generation Grubbs’ catalyst for the formation of more
highly substituted cyclic alkenes.19 Therefore, using 1.5
mol % second-generation Grubbs’ catalyst, the reaction
proceeded to completion after 32 h in boiling dichlo-
romethane and the product could be isolated in 88% yield.
This is the first example of the synthesis of a trisubsti-
tuted alkene-containing indolizidinone using methathesis
(14) Hanessian, S.; Sailes, H.; Munro, A.; Therrien, E. J . Org. Chem.
2003, 68, 7219-7233.
(15) Dannnenberg, J . J . Chem. Rev. 1999, 99, 1225-1241.
(16) J ain, P.; Garraffo, H. M.; Spande, T. F.; Yeh, H. J . C.; Pannell,
L.; Daly, J . W. J . Nat. Prod. Lloydia 1995, 58, 100-104.
(17) Paolucci, C.; Mattioli, L. J . Org. Chem. 2001, 66, 4787-4794.
(18) Arisawa, M.; Takezawa, E.; Nishida, A.; Mori, M.; Nakagawa,
M. Synlett 1997, 1179-1180. Arisawa, M.; Takahashi, M.; Takezawa,
E.; Yamaguchi, T.; Torisawa, Y.; Nishida, A.; Nakagawa, M. Chem.
Pharm. Bull. 2000, 48, 1593-1596. Lim, S. H.; Ma, S.; Beak, P. J .
Org. Chem. 2001, 66, 9056-9062. Tarling, C. A.; Holmes, A. B.;
Markwell, R. E.; Pearson, N. D. J . Chem. Soc., Perkin Trans. 1 1999,
1695-1701. Barrett, A. G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles,
M. R.; Marshall, E. L.; Procopiou, P. A. Chem. Commun. 1996, 2231-
2232. Park, S. H.; Kang, H. J .; Ko, S.; Park, S.; Chang, S. Tetrahe-
dron: Asymmetry 2001, 12, 2621-2624. Felpin, F.; Lebreton, J . Eur.
J . Org. Chem. 2003, 3693-3712. Buschmann, N.; Ruckert, A.; Blechert,
S. J . Org. Chem. 2003, 67, 4325-4329.
Alkene 5 was next subjected to osmium tetraoxide
catalyzed dihydroxylation (Scheme 3). Although this
proceeded smoothly, an acetylation was necessary in
order to isolate the polar, water-soluble product 8. Only
monoacetylated product 8 was detected as a single
diastereoisomer (by proton NMR spectroscopy) in 84%
crude yield, which dropped to 54% on chromatographic
purification. It is not clear if the reaction was completely
diastereoselective or if the major diastereoisomer of the
diol was preferentially acylating, but in any case, iso-
(20) Grigg, R.; Martin, W.; Morris, J .; Sridharan, V. Tetrahedron
Lett. 2003, 44, 4899-4901. Mayo, K. G.; Nearhoof, E. H.; Kiddle, J . J .
Org. Lett. 2002, 4, 1567-1570.
(19) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956.
J . Org. Chem, Vol. 69, No. 11, 2004 3969

19.4, 19.8, 21.9, 23.8, 29.7, 31.4, 39.4, 40.3, 46.4, 47.2, 61.6, 62.7,
109.1, 111.2, 117.4, 117.8, 131.6, 132.1, 144.4, 145.0, 169.1, 170.4;
m/z 179 (M+, 27), 138 (73), 110 (43), 96 (26), 78 (24), 70 (100),
55 (29), 41 (68). Anal. Calcd for C11H17NO: C, 73.8; H, 9.5; N,
7.8. Found: C, 73.4; H, 9.5, N, 7.8.
5. Second-generation Grubbs’ catalyst (76 mg, 0.09 mmol) was
added to a solution of 1-((S)-2-isopropenyl-pyrrolidin-1-yl)but-
3-en-1-one (1.62 g, 9.0 mmol) in dry dichloromethane (150 mL)
and the resulting solution heated at reflux under argon for 26
h. A further portion of catalyst (38 mg) was added and the
mixture refluxed for a further 6 h. Removal of the solvent under
reduced pressure and purification by column chromatography
(9:1 dichloromethane/methanol) afforded the title compound
(1.21 g, 88%) as a brown oil: Rf 0.56; [R]25 ) -128.9 (c 1.8,
D
CHCl3); νmax (KBr)/cm-1 1647, 1456, 1413, 1278, 805; δH (500
MHz, CDCl3) 1.56 (1H, dq, J ) 11.9, 7.5 Hz), 1.76 (3H, s), 1.89-
1.94 (1H, m), 2.08-2.12 (1H, m), 2.25 (1H, quintet, J ) 5.9 Hz),
2.93-2.99 (1H, m), 3.01-3.08 (1H, m), 3.51 (1H, dt, J ) 12.0,
2.0 Hz), 3.82 (1H, dt, J ) 12.0, 9.1 Hz), 3.99-4.02 (1H, br m),
5.42 (1H, m); δC (125 MHz, CDCl3) 19.5, 22.5, 31.8, 33.8, 44.6,
62.3, 117.9, 132.3, 167.4; m/z 151 (M+, 98), 150 (29), 149 (28),
136 (100), 120 (18), 108 (23), 94 (45), 80 (22); C9H13NO requires
M+, 151.0997, found M+, 151.0999
F IGURE 3. X-ray structure of diol 9 confirming stereochem-
ical assignments.
SCHEME 3. Dih yd r oxyla tion Stu d ies
6. m-Chloroperoxybenzoic acid (50-55%, 736 mg, ∼2.24 mmol)
was added to a solution of (S)-8-methyl-2,3,6,8a-tetrahydro-1H-
indolizin-5-one (200 mg, 1.32 mmol) in dichloromethane (20 mL)
and the mixture stirred at rt for 16 h. The reaction mixture was
washed with saturated aqueous sodium bisulfite (3 × 10 mL),
saturated aqueous potassium carbonate (10 mL, causes emulsion
to form), water (10 mL), and brine (10 mL) and dried over
magnesium sulfate. Concentration under reduced pressure and
purification by column chromatography (9:1 dichloromethane/
methanol) afforded the title compound (99 mg, 45%) as a yellow
oil that solidified on standing: Rf 0.54; [R]25 ) -47.5 (c 0.6,
D
merically pure product was obtained. Proton NMR data
suggested that the dihydroxylation had proceeded from
the concave face, i.e., with the (R)-configuration at C-8
as expected. Reduction of amide 8 gave the known
crystalline amine 9.10c Single-crystal X-ray crystallogra-
phy, Figure 3 confirmed that the relative configuration
at the three chiral centers had indeed been correctly
assigned by proton NMR analysis. Finally, Swern oxida-
tion as reported by Comins10c gave the key allopumil-
iotoxin intermediate 2.
CHCl3); νmax (KBr)/cm-1 1646, 1489, 1449, 1027, 951, 844, 695;
δH (500 MHz, CDCl3) 1.44 (3H, s), 1.76-1.81 (2H, m), 1.97-
1.99 (1H, m), 2.15-2.18 (1H, m), 2.74 (1H, dd(AB), J ) 18.0,
1.2 Hz), 2.91 (1H, dd(AB), J ) 18.0, 2.5 Hz), 3.21 (1H, dd, J )
2.5, 1.2 Hz), 3.47-3.57 (2H, m), 3.71 (1H, dd, J ) 10.8, 5.3 Hz);
δC (125 MHz, CDCl3) 18.8, 21.7, 28.9, 33.4, 45.8, 57.1, 58.3, 59.6,
165.7; m/z 168 (M + 1+, 6), 167 (M+, 59), 98 (9), 96 (18), 70 (100),
55 (19), 43 (30), 41 (31); C9H13NO2 requires M+, 167.0946, found
M+, 167.0946.
7. Potassium carbonate (4.1 mg, 0.03 mmol) was added to a
stirred solution of (1aS,6aS,6bR)-6b-methylhexahydro-1-oxa-3a-
azacyclopropa[e]inden-3-one (50 mg, 0.30 mmol) in dry methanol
(5 mL) and the mixture stirred at rt for 6 h. The solvent was
removed under reduced pressure, the residue dissolved in
dichloromethane (10 mL) and washed with water (3 mL), and
the aqueous washing back-extracted with chloroform (10 mL).
The combined organic extracts were washed with brine (5 mL)
and dried over magnesium sulfate. Concentration under reduced
pressure and purification by column chromatography afforded
the title compound (27 mg, 54%) as an off-white waxy solid: Rf
In conclusion, we have demonstrated that two classes
of pumiliotoxin alkaloid can be readily stereoselectively
obtained from a common cyclic alkene.
Exp er im en ta l Section
4. Trifluoroacetic acid (7.64 g, 67.0 mmol) was added to a
stirred solution of (S)-2-isopropenylpyrrolidine-1-carboxylic acid
tert-butyl ester (1.41 g, 6.70 mmol) in dry dichloromethane (95
mL) and the solution stirred at rt for 2.5 h. The volatiles were
removed under reduced pressure and the residue taken up in
DMF (95 mL). Triethylamine (4.07 g, 40.2 mmol), diethyl
cyanophosphonate (3.28 g, 20.1 mmol), and vinylacetic acid (1.73
g, 20.1 mmol) were added, and the mixture was stirred at rt for
16 h. The solvent was removed under reduced pressure and the
residue dissolved in dichloromethane (50 mL) and washed with
saturated aqueous sodium bicarbonate (2 × 30 mL) and water
(30 mL). The combined aqueous washings were extracted with
dichloromethane (20 mL) and the combined organic extracts
washed with brine (30 mL) and dried over magnesium sulfate.
Concentration under reduced pressure and purification by
column chromatography (ether) afforded a rotameric mixture
0.51; [R]25 ) 294.9 (c 0.7, CHCl3); νmax (KBr)/cm-1 3422, 1662,
D
1599, 1473, 1457, 1143, 1128, 810; δH (500 MHz, CDCl3) 1.34
(3H, s), 1.76-1.86 (1H, m), 2.00-2.09 (2H, m), 2.12-2.19 (1H,
m), 3.44 (1H, ddd, J ) 11.7, 9.2, 7.2 Hz), 3.55 (1H, dd, J ) 10.3,
6.2 Hz), 3.70 (1H, ddd, J ) 11.7, 9.2, 2.4 Hz), 5.92 (1H, d, J )
9.7 Hz), 6.46 (1H, d, J ) 9.7 Hz); δC (125 MHz, CDCl3) 22.7,
24.4, 25.5, 45.0, 65.0, 66.8, 126.0, 145.1, 162.6; m/z 167 (M+, 25),
149 (10), 148 (11), 120 (7), 98 (59), 70 (100), 55 (51), 43 (58);
C9H13NO2 requires M+, 167.0946, found M+, 167.0948
7. Procedure without isolation of intermediate epoxide, using
Amberlite IRA-400(OH). m-Chloroperoxybenzoic acid (50-60%,
1.032 g, ∼2.99 mmol) was added to a solution of (S)-8-methyl-
2,3,6,8a-tetrahydro-1H-indolizin-5-one (300 mg, 1.99 mmol) in
dichloromethane (15 mL) and the mixture stirred at rt for 15 h.
The dichloromethane was removed under reduced pressure, the
residue dissolved in ethanol (9 mL), and Amberlite IRA-400-
(OH) (3.00 g) added [freshly prepared by stirring Amberlite IRA-
400(Cl) with 5% aqueous sodium hydroxide (∼5-6 times the
volume of the resin) for 10 min and filtering off, washing the
resin with distilled water until the washings were pH 7, and
of the title compound (0.90 g, 75%) as a brown oil: Rf 0.53; [R]25
D
) 26.2 (c 1.3 CHCl3); νmax (KBr)/cm-1 1647, 1416, 1193, 994, 910;
δH (500 MHz, CDCl3) 1.74 (3H, br s), 1.80-2.12 (4H, 2 × m),
3.01 (d, J ) 6.7 Hz), 3.14 (d, J ) 6.7 Hz), 3.45-3.59 (2H, m),
4.22-4.25 (m), 4.48-4.52 (m), 4.63 (s), 4.76 (s), 4.79 (s), 4.90
(s), 5.05-5.18 (2H, m), 5.93-6.04 (1H, m); δC (125 MHz, CDCl3)
3970 J . Org. Chem., Vol. 69, No. 11, 2004

drying under high vacuum]. The mixture was stirred at rt for
72 h. The resin was filtered off and the filtrate concentrated
under reduced pressure affording the title compound (282 mg,
85%) as a brown oil that was pure enough to use without further
purification.
ter (244 mg, 1.1 mmol) in dry THF (10 mL) was added dropwise
at rt (with some effervescence) and the resulting mixture stirred
at rt for 45 min. The reaction mixture was cooled to 0 °C,
saturated aqueous sodium hydroxide (4 mL) and water (4 mL)
were carefully added, and the biphasic mixture was stirred for
1 h. The aqueous layer was separated, diluted with brine (4 mL),
and extracted with chloroform (4 × 10 mL). The combined
organics were dried over magnesium sulfate and concentrated
under reduced pressure affording the title compound (143 mg,
78%) as an off-white solid that was used without further
purification. Analytical data were in agreement with reported
1. A solution of (8S,8aS)-8-hydroxy-8-methyl-2,3,8,8a-tetrahy-
dro-1H-indolizin-5-one (179 mg, 1.07 mmol) and 10% palladium
on carbon (57 mg) was stirred under 1 atm of H2 for 18 h at rt.
The catalyst was filtered off through a plug of Celite and the
filtrate concentrated under reduced pressure. Purification by
column chromatography (9:1 dichloromethane/methanol) af-
forded the title compound (181 mg, 100%) as a colorless waxy
solid. Analytical data were in agreement with published values:7
Rf 0.39; [R]25D ) -32.1 (c 1.0, CHCl3); νmax (KBr)/cm-1 3400, 1616,
1483, 1413, 1313, 1250, 1224, 1129; δH (500 MHz, CDCl3) 1.31
(3H, s), 1.74-1.97 (6H, m), 2.41 (1H, dd, J ) 18.5, 7.5 Hz), 2.53
(1H, ddd, J ) 18.5, 11.8, 7.5 Hz), 3.38 (1H, dd, J ) 10.5, 5.5
Hz), 3.51-3.55 (2H, m); δC (125 MHz, CDCl3) 22.0, 26.3, 26.4,
28.1, 35.1, 45.7, 66.1, 67.7, 168.9; m/z 169 (M+, 71), 154 (6), 126
(22), 112 (27), 111 (35), 99 (22), 83 (95), 70 (100), 55 (34), 43
(68), 41 (38); C9H15NO2 requires M+, 169.1103, found M+,
169.1110.
values:10c [R]25 ) -2.8 (c 0.6, CHCl3); νmax (KBr)/cm-1 3481,
D
3424, 1635, 1264, 1078; δH (500 MHz, CDCl3) 1.18 (3H, s), 1.54-
1.62 (2H, 2 × m), 1.71-1.82 (3H, 2 × m), 1.86-1.90 (3H, 3 ×
m), 2.03 (1H, ddd, J ) 12.6, 11.3, 3.1 Hz), 2.14-2.20 (1H, m),
2.69 (1H, br s), 2.97 (1H, ddd, J ) 11.3, 5.1, 2.1 Hz), 3.00-3.06
(1H, m), 3.22 (1H, dt, J ) 10.5, 5.3 Hz); δC (125 MHz, CDCl3)
20.4, 22.3, 23.8, 31.3, 50.1, 54.7, 70.7, 71.2, 74.5; m/z 171 (M+,
65), 154 (100), 128 (45), 126 (22), 112 (22), 97 (35), 84 (71), 70
(73), 43 (34); C9H17NO2 requires M+, 171.1259, found M+,
171.1253. Anal. Calcd for C9H17NO2: C, 63.2; H, 9.9; N, 8.2.
Found: C, 63.2; H, 10.1; N, 8.0.
8. Osmium tetraoxide (51 mg, 0.20 mmol) was added to a
solution of (S)-8-methyl-2,3,6,8a-tetrahydro-1H-indolizin-5-one
(300 mg, 2.0 mmol) and N-methylmorpholine (323 mg, 2.4 mmol)
in acetone (7.5 mL) and water (1.5 mL) and the resulting mixture
stirred at rt for 20 h. The solvents were removed under reduced
pressure and the residue dried under high vacuum. The black
residue was dissolved in pyridine (5 mL) and treated at 0 °C
with acetic anhydride (1 mL) and the mixture stirred at rt for
16 h. The solvents were removed under reduced pressure, and
the residue was redissolved in toluene (10 mL) and concentrated
under reduced pressure. This was repeated three times. The
residue was partitioned between brine (8 mL) and ethyl acetate
(6 × 10 mL). The combined organic extracts were dried over
magnesium sulfate and concentrated under reduced pressure.
Purification by column chromatography (9:1 dichloromethane/
methanol) afforded the title compound (244 mg, 54%) as a beige
solid: Rf 0.43; [R]25D ) -8.7 (c 0.6, CHCl3); νmax (KBr)/cm-1 3391,
1737, 1613, 1471, 1241, 1038, 979; δH (500 MHz, CDCl3) 1.26
(3H, s), 1.81 (1H, m), 1.89 (1H, s), 1.95-2.04 (3H, m), 2.14 (3H,
s), 2.49 (1H, dd, J ) 17.5, 10.1 Hz), 2.84 (1H, dd, J ) 17.5, 7.4
Hz), 3.41 (1H, dd, J ) 9.8, 6.4 Hz), 3.47-3.56 (2H, m), 5.01 (1H,
dd, J ) 10.1, 7.4 Hz); δC (125 MHz, CDCl3) 21.3, 22.55, 22.61,
25.9, 34.6, 46.0, 64.0, 70.0, 73.6, 166.8, 170.4; m/z 227 (M+, 69),
209 (8), 185 (42), 184 (31), 168 (17), 112 (70), 83 (40), 70 (100);
C11H17O4N requires M+, 227.1158, found M+, 227.1160. Anal.
Calcd for C11H17O4N: C, 58.2; H, 7.5; N, 6.2. Found: C, 57.8; H,
7.2; N, 6.2.
2. DMSO (136 mg, 1.74 mmol) was added dropwise to a
solution of oxalyl chloride (147 mg, 1.16 mmol) in dry dichlo-
romethane (1.9 mL) at -60 °C and the resulting solution stirred
for 20 min at -60 °C. A solution of (7S,8R,8aS)-8-ethyloctahy-
droindolizine-7,8-diol (100 mg, 0.58 mmol) in dry dichlo-
romethane (0.6 mL) was added dropwise and the reaction stirred
at -60 °C for 20 min. Triethylamine (587 mg, 5.8 mmol) was
added at -50 °C and the mixture stirred at rt for 45 min. Ethyl
acetate (5 mL) was added and the dichloromethane removed
under reduced pressure. A further portion of ethyl acetate (10
mL) was added and the mixture filtered. Concentration of the
filtrate and purification by column chromatography (98:2 ethyl
acetate/concentrated NH3) afforded the title compound (43 mg,
44%) as a yellow oil. Spectroscopic data were in agreement with
reported values:10c Rf 0.43; νmax (KBr)/cm-1 3433, 1723, 1373,
1307, 1229, 1124; δH (500 MHz, CDCl3) 1.18 (3H, s), 1.75-1.96
(4H, 2 × m), 2.16 (1H, t, J ) 7.7 Hz), 2.24 (1H, ddd, J ) 14.7,
3.8, 1.4 Hz), 2.29-2.38 (2H, 2 × m), 3.06 (1H, ddd, J ) 14.7,
12.4, 7.7 Hz), 3.16 (1H, m), 3.26 (1H, ddd, J ) 10.8, 7.6, 1.4 Hz),
3.78 (1H, br s, OH); δC (125 MHz, CDCl3) 16.82, 22.83, 23.52,
36.38, 50.18, 54.01, 72.39, 75.40, 209.24.
Ack n ow led gm en t. We thank DEL N. Ireland and
CSS Ltd. for providing funding for this work through
the CAST award scheme.
Su p p or tin g In for m a tion Ava ila ble: Spectra for com-
pounds 1, 2, and 4-9 and CIF files for compounds 7 and 9.
This material is available free of charge via the Internet at
http://pubs.acs.org.
9. Aluminum chloride (357 mg, 2.67 mmol) in dry ether (5
mL) was added to a stirred suspension of lithium aluminum
hydride (102 mg, 2.7 mmol) in dry ether (5 mL) under argon at
rt and the mixture stirred for 25 min. A solution of acetic acid
(7S,8R,8aS)-8-hydroxy-8-methyl-5-oxooctahydroindolizin-7-yl es-
J O0497205
J . Org. Chem, Vol. 69, No. 11, 2004 3971