Enantiocontrolled preparation of indolizidines: Synthesis of (-)-2-epilentiginosine and (+)-lentiginosine

Article abstract of DOI:10.1021/jo010298r

A highly stereoselective approach to (-)-2-epilentiginosine and (+)-lentiginosine has been developed based on a diastereofacially selective cycloaddition of dichloroketene with a chiral dienol ether. The two naturally occurring indolizidines are each obtained enantioselectively (≥ 99:1) in ca. 8.5% overall yield.

Full text of DOI:10.1021/jo010298r

5438
J . Org. Chem. 2001, 66, 5438-5443
En a n tiocon tr olled P r ep a r a tion of In d olizid in es: Syn th esis of
(-)-2-Ep ilen tigin osin e a n d (+)-Len tigin osin e
Martin O. Rasmussen, Philippe Delair, and Andrew E. Greene*
Universite´ J oseph Fourier de Grenoble, LEDSS, Chimie Recherche (LEDSS),
38041 Grenoble Cedex, France
Andrew.Greene@ujf-grenoble.fr
Received March 21, 2001
A highly stereoselective approach to (-)-2-epilentiginosine and (+)-lentiginosine has been developed
based on a diastereofacially selective cycloaddition of dichloroketene with a chiral dienol ether.
The two naturally occurring indolizidines are each obtained enantioselectively (g99:1) in ca. 8.5%
overall yield.
Hydroxylated indolizidines, several of which are potent
inhibitors of glycosidases and of potential use in cancer
chemotherapy, are widespread in nature and popular
synthetic targets.1,2 Somewhat surprisingly, in view of
the present state of asymmetric synthesis, the vast
majority of the reported enantioselective syntheses of
these compounds rely on chiral pool material to secure
the natural products in their native form. We have
recently reported a dichloroketene-chiral enol ether
based approach to indolizidines and demonstrated its
effectiveness through the preparation of (-)-slaframine.3
We now report an extension of this approach to provide
ready access to the dihydroxylated indolizidines (-)-2-
epilentiginosine (1)4 and (+)-lentiginosine (2).5
(-)-2-Epilentiginosine, a metabolite of the fungus
Rhizoctonia leguminicola4b and the locoweeds Astragalus
oxyphysus4d and A. lentiginosus,5a has been postulated
to arise biosynthetically from (1R,8aS)-1-hydroxyindolizi-
dine (3),6 itself produced from L-lysine via L-pipecolic acid,
and engender swainsonine.4b-d (+)-Lentiginosine, a strong
inhibitor of the fungal R-glucosidase amyloglucosidase,
has as well been extracted from the leaves of A. lentigi-
nosus and most likely also issues biosynthetically from
(1R,8aS)-1-hydroxyindolizidine.5a While several synthe-
ses of both of these dihydroxylated indolizidines have
been reported,4,5 they almost invariably involve elabora-
tion of racemic or chiral pool starting material.
It appeared that an effective enantioselective route to
these natural products might be possible through regio-
and diastereoselective cycloaddition of dichloroketene
with an enantiopure enol ether I to provide cyclobutanone
II, which through Beckmann ring expansion, dechlori-
nation, and cyclization could be expected to produce
indolizidinone III, an attractive platform for accessing
(-)-2-epilentiginosine (1) and (+)-lentiginosine (2).
* To whom correspondence should be sent. Tel: (33) 4-76-51-46-86.
Fax: (33) 4-76-51-44-94.
(1) For reviews on the occurrence, biological properties, and syn-
theses of indolizidines, see: Elbein, A. D.; Molyneux, R. J . In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Pergamon: New York, 1996; Vol. 5, Chapter 1. Burgess, K.; Henderson,
I. Tetrahedron 1992, 48, 4045-4066. Takahata, H.; Momose, T. In The
Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1993; Vol. 44,
Chapter 3. Michael, J . P. Nat. Prod. Rep. 1995, 12, 535-552. Michael,
J . P. Nat. Prod. Rep. 1997, 14, 21-41. Michael, J . P. Nat. Prod. Rep.
1997, 14, 619-636. Michael, J . P. Nat. Prod. Rep. 1998, 15, 571-594.
Michael, J . P. Nat. Prod. Rep. 1999, 16, 675-696. Michael, J . P. Nat.
Prod. Rep. 2000, 17, 579-602. Broggini, G.; Zucchi, G. Synthesis 1999,
905-917. Mitchinson, A.; Nadin, A. J . Chem. Soc., Perkin Trans. 1
1999, 2553-2591.
The synthesis of these indolizidines began with the
conversion of the S-enantiomer of 1-(triisopropylphenyl)-
(5) (a) Pastuszak, I.; Molyneux, R. J .; J ames, L. F.; Elbein, A. D.
Biochemistry 1990, 29, 1886-1891. (b) Yoda, H.; Kitayama, H.;
Katagiri, T.; Takabe, K. Tetrahedron: Asymmetry 1993, 4, 1455-1456.
(c) Gurjar, M. K.; Ghosh, L.; Syamala, M.; J ayasree, V. Tetrahedron
Lett. 1994, 35, 8871-8872. (d) Nukui, S.; Sodeoka, M.; Sasai, H.;
Shibasaki, M. J . Org. Chem. 1995, 60, 398-404. (e) Giovannini, R.;
Marcantoni, E.; Petrini, M. J . Org. Chem. 1995, 60, 5706-5707. (f)
Brandi, A.; Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti, A.; Picasso,
S.; Vogel, P. J . Org. Chem. 1995, 60, 6806-6812. (g) Goti, A.; Cardona,
F.; Brandi, A. Synlett 1996, 761-763. (h) McCaig, A. E.; Meldrum, K.
P.; Wightman, R. H. Tetrahedron 1998, 54, 9429-9446. (i) Yoda, H.;
Kawauchi, M.; Takabe, K. Synlett 1998, 137-138. (j) Ha, D.-C.; Yun,
C.-S.; Lee, Y. J . Org. Chem. 2000, 65, 621-623.
(6) (a) Clevenstine, E. C.; Walter, P.; Harris, T. M.; Broquist, H. P.
Biochemistry 1979, 18, 3663-3667. (b) Harris, C. M.; Harris, T. M.
Tetrahedron Lett. 1987, 28, 2559-2592. (c) Shono, T.; Kise, N.; Tanabe,
T. J . Org. Chem. 1988, 53, 1364-1367. (d) Takahata, H.; Banba, Y.;
Momose, T. Tetrahedron: Asymmetry 1990, 1, 763-764. See also refs
4c,d.
(2) For a reviews on polyhydroxylated alkaloids that inhibit gly-
cosidases, see: Nash, R. J .; Watson, A. A.; Asano, N. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Perga-
mon: New York, 1996; Vol. 11, Chapter 5. Asano, N.; Nash, R. J .;
Molyneux, R. J .; Fleet, G. W. J . Tetrahedron: Asymmetry 2000, 11,
1645-1680.
(3) Pourashraf, M.; Delair, P.; Rasmussen, M.; Greene, A. E. J . Org.
Chem. 2000, 65, 6966-6972.
(4) (a) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J . Chem.
1984, 37, 1503-1509. (b) Harris, T. M.; Harris, C. M.; Hill, J . E.;
Ungemach, F. S.; Broquist, H. P.; Wickwire, B. M. J . Org. Chem. 1987,
52, 3094-3098. (c) Harris, C. M.; Schneider, M. J .; Ungemach, F. S.;
Hill, J . E.; Harris, T. M. J . Am. Chem. Soc. 1988, 110, 940-949. (d)
Harris, C. M.; Campbell, B. C.; Molyneux, R. J .; Harris, T. M.
Tetrahedron Lett. 1988, 29, 4815-4818. (e) Heitz, M.-P.; Overman, L.
E. J . Org. Chem. 1989, 54, 2591-2596. (f) Takahata, H.; Banba, Y.;
Momose, T. Tetrahedron: Asymmetry 1992, 3, 999-1000. See also ref
5a.
10.1021/jo010298r CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/07/2001

Enantiocontrolled Preparation of Indolizidines
J . Org. Chem., Vol. 66, No. 16, 2001 5439
Sch em e 1a
F igu r e 1. Lowest-energy conformation of enol ether 5b (b )
enol oxygen).
tion-oxidation (84% yield), mesylate formation, and base-
induced cyclization (88% yield). The resultant crystalline
indolizidinone 8a proved amenable to diastereomeric
upgrading (g99:1) through recrystallization from dichlo-
romethane-hexane, which also provided crystals suitable
for X-ray diffraction analysis.14 Pleasingly, the expected
formation of the required 1R,8aS stereoisomer was thus
confirmed. Cleavage of the chiral controller in indoliz-
idinone 8a with neat trifluoroacetic acid at ambient
temperature then gave the hydroxy indolizidinone 8b in
98% yield.
In the presence of lithium aluminum hydride in THF,
8b gave rise in 80% yield to (1R,8aS)-1-hydroxyindolizi-
dine (3) ([R]D27 -51.0; lit.6b,d - 49, - 49.7), whose identity
was verified through spectral comparison with an inde-
pendently prepared6b sample (eq 1).
a
Key: a(i) KH, Cl2CdCHCl. (ii) C4H9Li; 3-butenyl triflate.
bLiAlH4 (60%, 3 steps). Cl3CCOCl, Zn-Cu. d(i) MSH; Al2O3. (ii)
c
Zn-Cu, NH4Cl (82%, 3 steps). eSia2BH; H2O2, NaOH (84%). (i)
f
CH3SO2Cl, (C2H5)3N. (ii) NaH (88%, 70% after recryst., 2 steps).
gCF3COOH (98%).
ethanol (4), a highly effective chiral controller developed
for asymmetric dichloroketene-olefin cycloadditions,7 into
the E-enol ether 5b via the corresponding ynol ether 5a
(Scheme 1).8 This partial reduction of 5a was efficiently
accomplished with lithium aluminum hydride in ether,
but a careful study of the reaction conditions was
necessary in order to achieve the desired result.
On the basis of previous work from our laboratory3,9
and molecular modeling studies10 (Figure 1), it had
appeared that enol ether 5b would undergo cycloaddition
with dichloroketene11 largely on the CR-re face to generate
cyclobutanone 6. In the event, cycloaddition proceeded
smoothly and, indeed, with high face selectivity to provide
1
6 (dr 95:5, H NMR). The depicted sense of the cyclo-
addition was subsequently confirmed by X-ray diffraction
(see below). The cycloadduct was next transformed into
pyrrolidinone 7a through exposure to Tamura’s Beck-
mann conditions,12 followed by dechlorination13 (82%
yield from 5b).
While direct R-hydroxylation of 8b (or 8a ) proved
unsatisfactory, the same end could be achieved through
dehydration-dihydroxylation thanks to the C-8a stereo-
chemical anchor, which allowed reintroduction of the C-1
hydroxyl group with the same stereogenicity. Dehydra-
tion of alcohol 8b with the Martin sulfurane reagent15
proceeded readily and reproducibly to provide the desired
conjugated derivative; similar yields could occasionally
be obtained with DCC in the presence of cuprous chlo-
ride,16 but this method was less reliable and, thus, the
former procedure was favored. OsO4-catalyzed vicinal
dihydroxylation then gave diol 9 as the major product
The indolizidine skeleton could be readily constructed
from pyrrolidinone 7a through sequential hydrobora-
(7) Delair, P.; Kanazawa, A.; B. M. de Azevedo, M.; Greene, A. E.
Tetrahedron: Asymmetry 1996, 7, 2707-2710.
(8) See: Kann, N.; Bernardes, V.; Greene, A. E. Org. Synth. 1997,
74, 13-22.
(9) (a) B. M. de Azevedo, M.; Greene, A. E. J . Org. Chem. 1995, 60,
4940-4942. (b) Kanazawa, A.; Delair, P.; Pourashraf, M.; Greene, A.
E. J . Chem. Soc., Perkin Trans I 1997, 1911-1912. (c) Nebois, P.;
Greene, A. E. J . Org. Chem. 1996, 61, 5210-5211. (d) Kanazawa, A.;
Gillet, S.; Delair, P.; Greene, A. E. J . Org. Chem. 1998, 63, 4660-
4663. (e) Delair, P.; Brot, E.; Kanazawa, A.; Greene, A. E. J . Org. Chem.
1999, 64, 1383-1386.
(10) Molecular modeling was performed on an IBM RS 6000
workstation running Insight II Discover 98.0 (MSI, San Diego). The
structure was energy minimized with the force field cvff.frc. and the
minimization algorithm VA09A. The molecular dynamics was per-
formed at 500 K in a vacuum (dielectric constant fixed at 1; 200 000
steps of 1 fs) and consisted of generation of 400 structures.
(11) For reviews on ketene cycloadditions, see: Hyatt, J . A.;
Raynolds, P. W. Org. React. 1994, 45, 159-646. Tidwell, T. T. Ketenes;
Wiley: New York, 1995.
(14) Crystal data for C25H39N1O2, orthorhombic P212121 (N° 19), a
) 6.188(3), b ) 11.029(2), c ) 35.053(8) Å, V ) 2392(1) Å3, dcalc ) 1.071
g/cm3, F(000) ) 848, µ (Mo KR) ) 0.66 cm-1, 2θ range (Mo KR) 4.36-
59.94°, 4030 measured reflections. 1685 independent reflections, with
I > 2σ(I), R ) 0.069, Rw ) 0.069, GoF ) 1.99. Full lists of atomic
coordinates, bond lengths and angles, and anisotropic thermal param-
eters have been deposited as Supporting Material with the Cambridge
Crystallographic Data Centre
(15) Arhart, R. J .; Martin, J . C. J . Am. Chem. Soc. 1972, 94, 5003-
5010.
(16) Corey, E. J .; Andersen, N. H.; Carlson, R. M.; Paust, J .; Vedejs,
E.; Vlattas, I.; Winter, R. E. K. J . Am. Chem. Soc. 1968, 90, 3245-
3247. Alexandre, C.; Rouessac, F. Bull. Soc. Chim. Fr. (2), 1971, 1837-
1840.
(12) Tamura, Y.; Minamikawa, J .; Ikeda, M. Synthesis 1977, 1-17.
(13) J ohnston, B. D.; Slessor, K. N.; Oehlschlager, A. C. J . Org.
Chem. 1985, 50, 114-117.

5440 J . Org. Chem., Vol. 66, No. 16, 2001
Rasmussen et al.
(4:1 ratio),17 but this derivative could not be easily
purified or, once purified, readily reduced (eq 2).
to the preparation of pyrrolizidines, in addition to other
indolizidines.
Exp er im en ta l Section
The reaction mixture was generally poured into water and
the separated aqueous phase was then thoroughly extracted
with the specified solvent. After being washed with 10%
aqueous HCl and/or NaHCO3 (if required), water, and satu-
rated aqueous NaCl, the combined organic phases were dried
over anhyd Na2SO4 or MgSO4 and then filtered and concen-
trated under reduced pressure on a Bu¨chi Rotovapor to yield
the crude reaction product. Tetrahydrofuran and ether were
distilled from sodium-benzophenone and dichloromethane;
dimethylformamide and triethylamine were distilled from
calcium hydride.
Fortunately, however, the corresponding acetonide
10,4e formed efficiently by acid-catalyzed exchange with
acetone dimethyl acetal (ADA), could be easily purified
by column chromatography. This derivative, whose ster-
eochemistry was verified by X-ray crystallography,18
could now be reduced in high yield to give, following
hydrolysis, (-)-2-epilentiginosine (1) ([R]D25 -39.3; lit.4e,5a
-39.4, -32.5). The diacetate derivative of this material
was found to be spectrally indistinguishable from that
of the naturally derived substance.4b
Enantiopure (+)-lentiginosine (2) could also be secured
from diol 9. In the presence of a carefully controlled
amount of 2,4,6-triisopropylbenzenesulfonyl chloride (TPB-
SCl) and triethylamine in dichloromethane at 0 °C, the
cis diol underwent selective sulfonation of the R-hydroxyl
group to give sulfonate 11 in high yield (eq 3).17 Remark-
2-[(S)-1-((E)-Hexa -1,5-d ien yloxy)eth yl]-1,3,5-tr iisop r op -
ylben zen e (5b). An argon-flushed flask was charged with 8.17
g (71.3 mmol) of a 35% suspension of potassium hydride in
mineral oil. The mineral oil was removed by washing with
pentane and the flask was capped with a rubber septum and
connected to a Nujol-filled bubbler by means of a syringe
needle. The potassium hydride was suspended in 115 mL of
THF, and 8.00 g (32.2 mmol) of (S)-(+)-1-(2,4,6-triisopropyl-
phenyl)ethanol (4) was added portionwise. The mixture was
stirred until hydrogen evolution was complete (ca. 3 h), cooled
to -50 °C, and treated dropwise with trichloroethylene (3.20
mL, 4.68 g, 35.6 mmol), after which the reaction mixture was
allowed to warm to 15 °C over 4 h, whereupon a few drops of
methanol were added. The crude product was isolated with
pentane in the usual way and purified by filtration through
silica gel (pretreated with 2.5% triethylamine, v/v) with
pentane to afford 8.18 g (74%) of pure 2-((S)-1-((E)-1,2-
dichloroethenyloxy)ethyl)-1,3,5-triisopropylbenzene:3 mp 38-
25
41 °C (pentane); [R]D -15.5 (c 1.0, CHCl3); IR 3086, 1623,
1
1609 cm-1; H NMR (200 MHz): δ 1.23-1.30 (m, 18 H), 1.67
(d, J ) 6.9 Hz, 3 H), 2.85 (hept, J ) 6.9 Hz, 1 H), 3.32-3.75
(m, 2 H), 5.57 (s, 1 H), 5.96 (q, J ) 6.9 Hz, 1 H), 7.03 (s, 2 H);
13C NMR (50.3 MHz) δ 21.0 (CH3), 23.9 (CH3), 24.5 (CH3), 24.8
(CH3), 29.4 (CH), 34.1 (CH), 76.5 (CH), 98.3 (CH), 122.1 (C),
131.3 (C), 143.0 (C), 148.5 (C); mass spectrum (EI), m/z 343
and 341 (M+), 231 (100).
ably, no â-sulfonated or disulfonated material could be
detected in the crude reaction mixture.19 The pure trans
hydroxy acetate 12 was next efficiently obtained from the
sulfonate by treatment with tetrabutylammonium ac-
etate (TBAA) in toluene,20,21 followed by recrystallization.
In contrast to the cis diol 9, trans hydroxy acetate 12
underwent smooth reduction on treatment with lithium
To a solution of 7.95 g (23.2 mmol) of the dichloro enol ether
in 75 mL of THF at -78 °C was added dropwise 21.5 mL (51.6
mmol) of 2.4 M n-butyllithium in hexanes. The reaction
mixture was allowed to warm to -40 °C and then treated
dropwise over 10 min with 7.10 g (34.8 mmol) of 3-butenyl
trifluoromethanesulfonate. The solution was stirred at -30 °C
for 23 h, whereupon it was poured into cold saturated aqueous
ammonium chloride. The product was isolated with pentane
in the usual way to give 8.44 g of 2-[(S)-1-(hex-5-en-1-ynyloxy)-
ethyl]-1,3,5-triisopropylbenzene (5a ), which was used below
24
aluminum hydride to yield (+)-lentiginosine (2) ([R]D
+ 3.1, mp 108-109 °C; lit.5f +3.2, 106-107 °C), whose
identity was confirmed through spectral comparison with
independently synthesized material.5d
The nonchiral pool indolizidine approach presented in
this paper is enantioselective (g99:1), high-yielding (ca.
8.5% overall yields), and flexible and should be applicable
1
immediately: IR 3074, 2268, 1642, 1608 cm-1; H NMR (200
(17) For clarity, only the major cis diastereomer is shown.
(18) Crystal data for C11H17N1O3, orthorhombic P212121 (N° 19), a
MHz) δ 1.20-1.30 (m, 18 H), 1.69 (d, J ) 6.8 Hz, 3 H), 2.00-
2.15 (m, 4 H), 2.86 (hept, J ) 6.9 Hz, 1 H), 3.19-3.45 (m, 2
H), 4.85-4.96 (m, 2 H), 5.52-5.78 (m, 2 H), 7.01 (s, 2 H); 13C
NMR (50.3 MHz) δ 17.3 (CH2), 21.6 (CH3), 23.9 (CH3), 24.1
(CH3), 29.3 (CH), 34.0 (CH2), 34.1 (CH), 37.7 (C), 82.8 (CH),
89.8 (C), 115.0 (CH2), 120.3 (CH), 121.9 (C), 131.0 (C), 137.5
(CH), 148.4 (C).
) 6.787(2), b ) 8.281(2), c ) 19.914(6) Å, V ) 1119.2(5) Å3, dcalc
)
1.254 g/cm3, F(000) ) 456, µ (Mo KR) ) 0.91 cm-1, 2θ range (Mo KR)
4.10-59.96°, 1915 measured reflections. 1372 independent reflections,
with I > 1σ(I), R ) 0.060, Rw ) 0.063, GoF ) 1.97. Full lists of atomic
coordinates, bonds lengths and angles, and anisotropic thermal
parameters have been deposited as Supporting Material with the
Cambridge Crystallographic Data Centre
A mixture of the above acetylenic ether 5a and 4.40 g (115.9
mmol) of lithium aluminum hydride in 90 mL of ether was
refluxed for 0.5 h. After being cooled to 5 °C, the mixture was
carefully treated successively with 4.4 mL of water, 4.4 mL of
15% aqueous NaOH, and 13.2 mL of water and then stirred
for 0.5 h. After the addition of sodium sulfate, the mixture
was filtered and the filtrate was concentrated under reduced
pressure to yield the crude product, which was purified by
column chromatography on silica gel (pretreated with 2.5%
triethylamine, v/v) with pentane to give 6.13 g (81%, 2 steps)
(19) For other examples of this type of selectivity, see: Denis, J .-
N.; Correa, A.; Greene, A. E. J . Org. Chem. 1990, 55, 1957-1959. Lee,
Y. S.; Kang, D. W.; Lee, S. J .; Park, H. J . Org. Chem. 1995, 60, 7149-
7152. Chun, J .; He, L.; Byun, H.-S.; Bittman, R. J . Org. Chem. 2000,
65, 7634-7640.
(20) Cf. Hawryluk, N. A.; Snider, B. B. J . Org. Chem. 2000, 65,
8379-8380.
(21) From the sulfonate the corresponding trans diol could also be
obtained by using tetrabutylammonium nitrite, but the yield was lower.
See: Binkley, R. W. J . Org. Chem. 1991, 56, 3892-3896. The endo
sulfonate derived from the minor cis diol was considerably less reactive
than 11 with both of these reagents, which permitted in both cases,
through careful reaction monitoring, substantial diastereochemical
enrichment to be achieved prior to recrystallization. Separation of the
diastereomers by silica gel chromatography could not be readily
accomplished.
26
of diene ether 5b: [R]D -50.2 (c 2.0, CHCl3); IR 3075, 1670,
1
1655, 1609 cm-1; H NMR (200 MHz) δ 1.25-1.33 (m, 18 H),
1.64 (d, J ) 6.9 Hz, 3 H), 1.90-2.12 (m, 4 H), 2.91 (hept, J )
6.9 Hz, 1 H), 3.41-3.65 (br m, 2 H), 4.85-5.02 (m, 3 H), 5.39

Enantiocontrolled Preparation of Indolizidines
J . Org. Chem., Vol. 66, No. 16, 2001 5441
(q, J ) 6.9 Hz, 1 H), 5.76 (dddd, J ) 6.5, 6.5, 10.3, 16.8 Hz, 1
H), 6.11 (dt, J ) 1.0, 11.3 Hz, 1 H), 7.05 (s, 2 H); 13C NMR
(50.3 MHz) δ 22.5 (CH3), 23.9 (CH3), 24.6 (CH3), 27.3 (CH2),
29.0 (CH), 34.0 (CH), 34.9 (CH2), 74.3 (CH), 105.5 (CH), 114.6
(CH2), 121.9 (CH), 132.2 (C), 138.2 (CH), 145.4 (CH), 146.8
(C), 147.6 (C); mass spectrum (CI), m/z 346 (M + NH4+, 0.9),
328 (M+, 0.1), 231 (100). HRMS m/e calcd for C23H36O (M+):
328.2766. Found: 328.2763.
(CH2), 120.5 (CH), 123.2 (CH), 132.5 (C), 137.1 (CH), 145.4
(C), 147.6 (C), 148.8 (C), 175.8 (C); mass spectrum (CI), m/z
386 (MH+, 100), 230 (61), 138 (24). HRMS m/e calcd for C25H39
-
NO2 (M+): 385.2981. Found: 385.2986.
(4R,5S)-5-(4-Hyd r oxybu tyl)-4-[(S)-1-(2,4,6-tr iisop r op yl-
p h en yl)eth oxy]p yr r olid in -2-on e (7b). To a stirred solution
of 7.32 g (19.0 mmol) of pyrrolidinone 7a in 65 mL of THF at
0 °C was added 15.0 mL of a freshly prepared 2.6 M solution
of disiamylborane in THF. After being stirred at 20 °C for 5
h, the solution was cooled to 0 °C and carefully treated with
13.0 mL of water, 13.0 mL of 3 M aqueous sodium hydroxide,
and 13.0 mL of 35% aqueous hydrogen peroxide. The mixture
was then vigorously stirred for 17 h at 20 °C, whereupon it
was filtered through Celite with ethyl acetate. The crude
product was isolated from the filtrate with ethyl acetate in
the usual way and purified by silica gel chromatography with
0-10% methanol in ethyl acetate to give 6.42 g (84%) of alcohol
7b: mp 108-109 °C (hexane); [R]D25 -107.6 (c 2.0, CHCl3); IR
3410, 3222, 1693, 1608 cm-1; 1H NMR (300 MHz) δ 1.15-1.23
(m, 19 H), 1.29-1.47 (m, 4 H), 1.51 (d, J ) 6.8 Hz, 3 H), 2.48
(AB of ABX, δa ) 2.43, δb ) 2.52, J ab ) 17.4 Hz, J ax ) 3.2 Hz,
J bx ) 6.2 Hz, 2 H), 2.83 (hept J ) 6.9 Hz, 1 H), 3.03-3.20 (m,
1 H), 3.44-3.65 (m, 4 H), 3.65-3.70 (m, 1 H), 3.75-3.93 (br s,
1 H), 5.02 (q, J ) 6.8 Hz, 2 H), 6.88-7.06, (br s, 2 H), 7.27 (s,
1 H); 13C NMR (75.5 MHz) δ 22.0 (CH2), 23.1 (CH3), 23.9 (CH3),
24.7 (CH3), 31.8, (CH2), 33.9 (CH2), 34.0 (CH), 37.0 (CH2), 61.4
(CH), 62.1 (CH2), 71.2 (CH), 77.4 (CH), 120.5 (CH), 123.2 (CH),
132.6 (C), 147.7 (C), 176.2 (C); mass spectrum (CI), m/z 404
(3S,4S)-4-Bu t-3-en yl-2,2-d ich lor o-3-[(S)-1-(2,4,6-tr iiso-
p r op ylp h en yl)eth oxy]cyclobu ta n on e (6). To a stirred mix-
ture of 7.82 g (23.8 mmol) of enol ether 5b and 3.7 g (ca. 57
mmol) of Zn-Cu couple in 260 mL of ether at 0 °C under argon
was added over 1.75 h a solution of 3.20 mL (5.22 g, 28.7 mmol)
of freshly distilled trichloroacetyl chloride in 60 mL of ether.
The resulting mixture was stirred an additional 1 h at 0 °C
and 2 h at 20 °C, after which the ether solution was separated
from the excess couple and added to a large volume of pentane,
and the resulting mixture was partially concentrated under
reduced pressure in order to precipitate the zinc chloride. The
supernatant was decanted and washed successively with a cold
aqueous solution of sodium bicarbonate, water, and brine and
then dried over anhydrous sodium sulfate. Evaporation of the
solvent under reduced pressure left 10.60 g of cyclobutanone
6 (containing ca. 5% of its diastereomer (δ 4.49 ppm)), as an
oil: IR 3077, 1808, 1643, 1608, 1573 cm-1; 1H NMR (200 MHz)
δ 1.29-1.38 (m, 18 H), 1.83 (d, J ) 6.8 Hz, 3 H), 1.77-1.87
(m, 1 H), 2.01-2.38 (m, 3 H), 2.99 (hept, J ) 6.9 Hz, 1 H),
3.32-3.52 (br m, 1 H), 3.59-3.67 (m, 1 H), 3.91 (br s, 1 H),
4.17 (d, J ) 7.6 Hz, 1 H), 4.95-5.06 (m, 2 H), 5.47 (q, J ) 6.8
Hz, 1 H), 5.72 (dddd, J ) 6.6, 6.7, 10.3, 17.0 Hz, 1 H), 7.12-
7.19 (m, 2 H). HRMS m/e calcd for C25H36Cl2O2 (M+) + Li:
445.2252. Found: 445.2271.
(4R,5S)-5-Bu t-3-en yl-4-[(S)-1-(2,4,6-tr iisopr opylph en yl)-
eth oxy]p yr r olid in -2-on e (7a ). A solution of 10.60 g of
cyclobutanone 6 in 230 mL of dichloromethane was treated
with 7.7 g (35.8 mmol) of O-mesitylenesulfonylhydroxylamine
and a small amount of sodium sulfate and then stirred at 20
°C for 7 h, with additional 2.0-g (9.4 mmol) portions of
O-mesitylenesulfonylhydroxylamine added after 2 and 4 h.
After filtration of the mixture over Celite, the solvent was
removed under reduced pressure, and the resulting material
in 25 mL of toluene was placed on a column of basic alumina
(220 g, Merck activity 1) and eluted rapidly with methanol.
Evaporation of the solvents left a white solid, which was
triturated with dichloromethane, which was then filtered over
Celite and evaporated under reduced pressure to afford 11.62
g of (4S,5S)-5-but-3-enyl-3,3-dichloro-4-[(S)-1-(2,4,6-triisopro-
pylphenyl)ethoxy]pyrrolidin-2-one, used directly below: IR
3407, 3226, 3053, 1736, 1641, 1607 cm-1; 1H NMR (200 MHz)
δ 1.20-1.27 (m, 18 H), 1.75 (d, J ) 6.9 Hz, 3 H), 1.85-1.99
(m, 1 H), 2.28-2.33 (m, 1 H), 2.58-2.64 (m, 1 H), 2.78-2.92
(m, 2 H), 3.11-3.28 (br m, 1 H), 3.30-3.40 (m, 1 H), 3.72-
3.90 (m, 1 H), 3.93 (d, J ) 6.2 Hz, 1 H), 4.80-4.92 (m, 2 H),
5.38-5.65 (m, 2 H), 6.94-7.07 (br m, 3 H); mass spectrum (CI),
m/z 454 (MH+, 31), 231 (100).
(MH+, 100), 403 (2.9), 231 (32.8). Anal. Calcd for C25H41
-
NO3+0.5 H2O: C, 72.78; H, 10.26; N, 3.39. Found: C, 72.79;
H, 10.13; N, 3.42.
(1R,8a S)-1-[(S)-1-(2,4,6-Tr iisop r op ylp h en yl)et h oxy]-
h exa h yd r oin d olizin -3-on e (8a ). To a stirred solution of 6.30
g (15.6 mmol) of alcohol 7b in 65 mL of dichloromethane and
4.30 mL (3.12 g, 30.9 mmol) of triethylamine at 0 °C was added
2.40 mL (3.55 g, 31.0 mmol) of methanesulfonyl chloride. The
mixture was stirred at 20 °C for 1.5 h and then water was
added. The crude product was isolated with dichloromethane
in the usual way to give 7.67 g of crude methanesulfonic acid
4-{(2S,3R)-5-oxo-3-[(S)-1-(2,4,6-triisopropylphenyl)ethoxy]pyr-
rolidin-2-yl} butyl ester, which was used immediately below:
IR 3429, 1696, 1606 cm-1
(m, 22 H), 1.51 (d, J ) 6.9 Hz, 3 H), 1.63 (m, 2 H), 2.46 (AB of
ABX, δa ) 2.42, δb ) 2.50, J ab ) 17.3 Hz, J ax ) 3.2 Hz, J bx
;
1H NMR (300 MHz) δ 1.15-1.24
)
6.0 Hz, 2 H), 2.83 (hept, J ) 6.8 Hz, 1 H), 2.95 (s, 3 H), 3.12
(m, 1 H), 3.46 (m, 1 H), 3.69 (m, 1 H), 3.84 (m, 1 H), 4.12 (t, J
) 6.5 Hz, 2 H), 5.03 (q, J ) 6.7 Hz, 1H), 6.95-7.10 (m, 3 H);
13C NMR (75.5 MHz) δ 21.8 (CH2), 23.1 (CH3), 23.9 (CH3), 24.6
(CH3), 28.7 (CH2), 33.7 (CH2), 33.9 (CH), 36.8 (CH2), 37.3 (CH3),
61.4 (CH), 69.3 (CH2), 71.2 (CH), 77.3 (CH), 120.5 (CH), 123.2
(CH), 132.5 (C), 147.7 (C), 175.9 (C).
A solution of the above crude mesylate in 50 mL of THF
and 11 mL of DMF was added dropwise to a stirred mixture
of 3.11 g (77.8 mmol) of 60% sodium hydride (in mineral oil)
in 75 mL of THF and 11 mL of DMF at 0 °C. The resulting
mixture was stirred for 2 h at 20 °C, diluted with 50 mL of
ether, and then carefully treated with water. The crude
product was isolated with ether in the usual way and purified
by silica gel column chromatography with 40-60% ethyl
acetate in pentane to provide 5.32 g (88%, 2 steps) of indoliz-
idinone 8a as a white solid. Recrystallization of this material
from hexane-dichloromethane gave 4.20 g (79% recovery) of
stereochemically pure (de g 98%, by NMR) indolizidinone 8a :
mp 194-195 °C (hexane-dichloromethane); [R]D25 -105 (c 2.0,
CHCl3); IR 1690, 1607 cm-1; 1H NMR (300 MHz) δ 0.96 (m, 1
H), 1.16-1.34 (m, 20 H), 1.50 (d, J ) 7.0 Hz, 3 H), 1.57 (m, 1
H), 1.73-1.79 (m, 2 H), 2.47-2.56 (m, 2 H), 2.57-2.62 (m, 1
H), 2.82 (hept, J ) 7.0 Hz, 1 H), 3.12 (br s, 1 H), 3.30 (ddd, J
) 3.1, 3.1, 12.0 Hz, 1 H), 3.63 (m, 1 H), 3.85 (br s, 1 H), 4.09
(dd, J ) 4.8, 13.2 Hz, 1 H), 5.05 (q, J ) 6.7 Hz, 1 H), 6.92 (s,
1 H), 7.01 (s, 1 H); 13C NMR (75.5 MHz) δ 23.1 (CH3), 23.6
(CH2), 23.9 (CH3), 24.4 (CH2), 24.8 (CH3), 30.7 (CH), 34.0 (CH),
37.6 (CH2), 40.0 (CH2), 64.2 (CH), 71.0 (CH), 74.9 (CH), 120.6
(CH), 123.2 (CH), 132.2 (C), 147.7 (C), 170.7 (C); mass
spectrum (EI), m/z 385 (M+, 6.6), 342 (8.0), 230 (38). Anal.
The above dichloro pyrrolidinone in 150 mL of methanol
previously saturated with ammonium chloride was stirred with
6.0 g (ca. 92 mmol) of Zn-Cu couple at 20 °C for 11 h,
whereupon the mixture was filtered to remove the excess
couple. The filtrate was concentrated under reduced pressure
and the residue was then processed with ethyl acetate in the
usual way to give the crude product. Purification of this
material by silica gel column chromatography with ethyl
acetate in pentane (4:6) provided 7.52 g (82%, 3 steps) of
25
pyrrolidinone 7a as a foam: [R]D -95.9 (c 1.2, CHCl3); IR
3216, 1697, 1640, 1607 cm-1; 1H NMR (300 MHz) δ 1.13-1.40
(m, 20 H), 1.52 (d, J ) 6.9 Hz, 3 H), 1.87-2.07 (m, 2 H), 2.47
(AB of ABX, δa ) 2.43, δb ) 2.51, J ab ) 17.2 Hz, J ax ) 6.1 Hz,
J bx ) 3.0 Hz, 2 H), 2.83 (hept, J ) 6.9 Hz, 1 H), 2.99-3.24 (br
s, 1 H), 3.44-3.51 (m, 1 H), 3.71 (m, 1 H), 3.76-3.94 (br s, 1
H), 4.90-4.98 (m, 2 H), 5.03 (q, J ) 6.9 Hz, 1 H), 5.64 (dddd,
J ) 6.6, 6.7, 10.3, 17.0 Hz, 1 H), 6.66 (br s, N-H), 6.93 (br s,
1 H), 7.01 (br s, 1 H); 13C NMR (75.5 MHz) δ 23.1 (CH3), 23.9
(CH3), 24.6 (CH3), 28.2 (CH), 29.1 (CH), 30.1 (CH2), 33.5 (CH2),
33.9(CH), 36.8 (CH2), 61.1 (CH), 71.0 (CH), 77.3 (CH), 115.6

5442 J . Org. Chem., Vol. 66, No. 16, 2001
Rasmussen et al.
Calcd for C25H39NO2: C, 77.87; H, 10.19; N, 3.63. Found: C,
77.86; H, 10.25; N, 3.65.
°C, the reaction mixture was treated with sodium bisulfite (1.0
g, 9.6 mmol), and the resulting mixture was stirred for 30 min,
partially concentrated under reduced pressure, and then
filtered through Celite with ethyl acetate. The filtrate was
dried over sodium sulfate and concentrated under reduced
pressure to afford the crude product, which was purified by
silica gel column chromatography with 5% methanol in
chloroform to afford 0.357 g (70%) of a 4:1 mixture of cis diol
9 and its 1R,2R,8aS-isomer, respectively: IR 3326, 1681, 1265
(1R,8a S)-1-Hyd r oxyh exa h yd r oin d olizin -3-on e (8b). A
solution of the above indolizidinone 8a (4.20 g,10.9 mmol) and
7.10 mL (10.5 g, 92.2 mmol) of trifluoroacetic acid in 55 mL of
dichloromethane at 20 °C was stirred for 3 h, whereupon the
reaction mixture was concentrated to dryness under reduced
pressure. Purification of the resulting solid by silica gel column
chromatography with 2-10% methanol in ethyl acetate gave
1
1.66 g (98%) of alcohol 8b: mp 67-69 °C (dichloromethane-
cm-1; H NMR (300 MHz, acetone-d6, major isomer) δ 1.13-
hexane); [R]D +11 (c 1.0, acetone); IR 3381, 1666 cm-1
;
1H
1.33 (m, 2 H), 1.53 (ddddd, J ) 3.2, 3.2, 12.9, 12.9, 12.9 Hz, 1
H), 1.71 (m, 1 H), 1.90 (m, 1 H), 1.99 (m, 1 H), 2.71 (ddd, J )
3.6, 12.9, 12.9 Hz, 1 H), 2.90-3.09 (br s, 1 H), 3.31 (ddd, J )
3.1, 3.1, 12.2 Hz, 1 H), 3.94 (dd, J ) 2.9, 6.0 Hz, 1 H), 4.03 (m,
1 H), 4.17 (d, J ) 6.0 Hz, 1 H), 4.28-5.03 (br s, 1 H); 13C NMR
(75 MHz, acetone-d6, major isomer) δ 25.0 (CH2), 26.0 (CH2),
31.0 (CH2), 41.4 (CH2), 64.2 (CH), 71.5 (CH), 72.5 (CH), 172.1
(C); mass spectrum (EI) m/z 171 (M+, 92), 84 (100). Anal. Calcd
for C8H13NO3: C, 56.13; H, 7.65; N, 8.18; Mr, 171.0896.
Found: C, 55.74; H, 7.68; N, 8.12; Mr (mass spectrum, EI),
171.0897.
25
NMR (500 MHz, acetone-d6) δ 1.10 (dddd, J ) 3.5, 12.4, 12.4,
12.8, 1 H), 1.20 (ddddd, J ) 3.7, 4.9, 13.0, 13.0, 13.0 Hz, 1 H),
1.44 (ddddd, J ) 3.4, 3.4, 13.2, 13.2, 13.2 Hz, 1 H), 1.62 (m, 1
H), 1.83 (m, 1 H), 1.96 (m, 1 H), 2.16 (ddd, J ) 1.6, 5.1, 17.1
Hz, 1 H), 2.56 (dd, J ) 7.7, 17.1 Hz, 1 H), 2.60 (dddd, J ) 1.5,
3.4, 12.9, 12.9 Hz, 1 H), 3.22 (ddd, J ) 3.6, 3.6, 7.8 Hz, 1 H),
3.99-4.02 (m, 2 H), 3.9-4.2 (br s, 1 H); 13C NMR (125 MHz)
δ 24.0 (CH2), 25.0 (CH2), 30.8 (CH2), 40.0 (CH2), 40.3 (CH2),
65.9 (CH), 70.7 (CH), 171.1 (C); mass spectrum (EI) m/z 155
(M+, 25), 126 (42), 83 (100). Anal. Calcd for C8H13NO2: C,
61.91; H, 8.44; N, 9.03. Found: C, 61.82; H, 8.49; N, 8.95.
(1R,8a S)-Octa h yd r oin d olizin -1-ol (3). A solution of al-
cohol 8b (0.096 g, 0.62 mmol) in 1.7 mL of THF was added to
a mixture of lithium aluminum hydride (0.073 g, 1.92 mmol)
in 9 mL of THF at 20 °C, and the resulting mixture was stirred
for 21 h. After being cooled to 0 °C, the mixture was carefully
treated successively with 0.073 mL of water, 0.073 mL of 10%
aqueous sodium hydroxide and 0.220 mL of water. The mixture
was then stirred for 2 h, treated with anhydrous sodium
sulfate, and filtered. The filtrate was concentrated under
reduced pressure to give the crude product, which was purified
by silica gel column chromatography with 0-10% methanol
saturated with ammonia in ethyl acetate and evaporative
(1S ,2S ,8a S )-1,2-(I s o p r o p y lid e n e d io x y )h e x a h y d r o -
in d olizin -3-on e (10). A mixture of 0.341 g (1.99 mmol) of the
above cis diols and 1.0 g of Dowex 50W × 8 (H+ form) in 50
mL of 2,2-dimethoxypropane (ADA) was stirred at 40 °C for
3.5 h, after which it was partially concentrated, filtered
through Celite, and evaporated to dryness. Purification of the
resulting crude product by silica gel column chromatography
with 0-60% ethyl acetate in dichloromethane gave 0.039 g of
the 1R,2R,8aS-acetonide and 0.291 g (69%) of acetonide 10:
mp 110-111 °C (hexane-dichloromethane); [R]D25 +31.3 (c 1.0,
1
CHCl3); IR 1694 cm-1; H NMR (500 MHz) δ 1.06 (dddd, J )
3.5, 12.8, 12.8, 12.8 Hz, 1 H), 1.22-1.33 (m, 1 H), 1.35 (s, 3
H), 1.42 (s, 3 H), 1.50 (ddddd, J ) 3.5, 13.5, 13.5, 13.5, 13.5
Hz, 1 H), 1.64-1.67 (m, 1 H), 1.89-1.97 (m, 2 H), 2.69 (ddd, J
) 3.5, 13.0, 13.0 Hz, 1 H), 3.44 (dd, J ) 3.0, 12.5 Hz, 1 H),
4.16 (dd, J ) 4.8, 13.3 Hz, 1 H), 4.32 (d, J ) 6.5 Hz, 1 H), 4.61
(d, J ) 6.7 Hz, 1 H); 13C NMR (75.5 MHz) δ 23.8 (CH2), 24.6
(CH2), 25.4 (CH3), 26.8 (CH3), 30.8 (CH2), 40.5 (CH2), 62.2 (CH),
77.4 (2 × CH), 112.6 (C), 168.5 (C); mass spectrum (CI) m/z
212 (MH+, 100), 211 (42), 171 (12), 124 (16). Anal. Calcd for
27
distillation to afford 0.070 g (80%) of alcohol 3: [R]D -51.0
(c 0.7, ethanol) (lit.6b,d -49, -49.7); IR 3356, 2800 cm-1 1H
;
NMR (300 MHz) δ 1.16 (m, 2 H), 1.44 (m, 2 H), 1.56 (m, 1 H),
1.68 (ddd, J ) 2.8, 7.6, 10.5 Hz, 1 H), 1.77 (m, 1 H), 1.95 (m,
2 H), 2.14 (m, 1 H), 2.28 (m, 1 H), 2.90 (ddd, J ) 2.4, 8.7, 8.7
Hz, 1 H), 2.94 (m, 1 H), 3.33 (br s, 1 H), 3.82 (ddd, J ) 4.7,
7.6, 10.0 Hz, 1 H); 13C NMR (75.5 MHz) δ 24.0 (CH2), 24.9
(CH2), 28.6 (CH2), 31.7 (CH2), 52.5 (CH2), 53.3 (CH2), 70.8 (CH),
75.7 (CH); mass spectrum (EI) m/z 141 (M+, 6), 97 (100). The
1H NMR spectrum was in excellent agreement with that of
an independently prepared6b sample (spectrum kindly provided
by Professor C. Harris). HRMS m/e calcd for C8H15NO (M+):
141.1154. Found: 141.1149.
C
11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.38; H,
8.04; N, 6.44.
(1S,2R,8a S)-Octa h yd r oin d olizin -1,2-d iol ((-)-2-Ep ilen -
tigin osin e 1). A stirred solution of 0.040 g (0.19 mmol) of
acetonide 10 in 3 mL of THF was treated with 1.4 mL (1.4
mmol) of a 1 M solution of borane in THF. After being stirred
at 55 °C for 12.5 h, the reaction mixture was allowed to cool
to 20 °C, treated with ethanol, and evaporated to dryness. A
solution of the resulting residue in 5 mL of ethanol was stirred
at 60 °C for 2 h and then evaporated to dryness. The residue
that resulted was stirred in 6 mL of 1 N HCl at reflux for 30
min, whereupon the reaction mixture was concentrated under
reduced pressure, and the resulting residue was passed
through a column of 6 g of Dowex 1 × 8-200 resin (OH- form)
with water. The clear oil that was obtained on evaporation
was purified by silica gel chromatography with 5-15% metha-
nol saturated with ammonia in chloroform to give 0.025 g (84%,
2 steps) of pure 1: [R]D25 -39.3 (c 0.44, CHCl3), (lit.4e,5a -39.4,
-32.5); IR 3378, 2854, 2803 cm-1; 1H NMR (300 MHz) δ 1.18-
1.31 (m, 2 H), 1.40-1.55 (m, 1 H), 1.58-1.67 (m, 1 H), 1.78-
1.89 (m, 2 H), 1.96-2.08 (m, 2 H), 2.15 (dd, J ) 5.3, 10.1 Hz,
1 H), 2.19-2.41 (br s, 2 H), 2.97 (dddd, J ) 1.4, 2.5, 4.7, 10.9
Hz, 1 H), 3.48 (ddd, J ) 0.4, 6.8, 10.1 Hz, 1 H), 3.63 (dd, J )
7.7, 7.7 Hz, 1 H), 4.19 (ddd, J ) 5.3, 7.0, 7.0 Hz, 1 H); 13C
NMR (75.5 MHz) δ 23.7 (CH2), 24.9 (CH2), 28.5 (CH2), 52.7
(CH2), 61.7 (CH2), 67.3 (CH), 67.9 (CH), 75.0 (CH); mass
spectrum (CI) m/z 158 (MH+, 100), 157 (32). HRMS m/e calcd
for C8H15NO2 (M+) + H: 158.1181. Found:158.1171.
(1S,2S,8aS)-1,2-Dih ydr oxyh exah ydr oin dolizin -3-on e (9)
a n d 1R,2R,8a S-Isom er . To a solution of 1.66 g (10.7 mmol)
of alcohol 8b in 60 mL of dichloromethane at 0 °C was added
a solution of Martin sulfurane15 (10.19 g, 15.15 mmol) in 45
mL of dichloromethane. The reaction mixture was stirred at
25 °C for 2 h and then concentrated under reduced pressure.
Purification of the crude product by silica gel chromatography
with 20-50% ethyl acetate in dichloromethane provided 1.21
g (82%) of (S)-6,7,8,8a-tetrahydro-5H-indolizin-3-one (ee g
98%. HPLC: Chiralcel OD-H column, 5 mm, 2-propanol/
hexane ) 1:9, 0.5 mL/min, tR ) 24.8 min (versus 31.4 min for
the (R)-enantiomer)). [R]D23 +23.9 (c 1.6, CHCl3); IR 1674, 1581
1
cm-1; H NMR (300 MHz) δ 0.96 (dddd, J ) 3.6, 12.5, 12.5,
12.6 Hz, 1 H), 1.23 (ddddd, J ) 3.5, 5.1, 12.9, 12.9, 12.9 Hz, 1
H), 1.46 (dddd, J ) 3.2, 3.2, 13.1, 13.1 Hz, 1 H), 1.69 (m, 1 H),
1.87 (m, 1 H), 2.05 (m, 1 H), 2.78 (ddd, J ) 3.6, 12.9, 12.9 Hz,
1 H), 3.81 (m, 1 H), 4.22 (dd, J ) 5.1, 13.2 Hz, 1 H), 6.09 (dd,
J ) 1.5, 5.9 Hz, 1 H), 6.97 (dd, J ) 1.5, 5.9 Hz, 1 H); 13C NMR
(75.5 MHz) δ 23.3 (CH2), 25.2 (CH2), 30.6 (CH2), 39.1 (CH2),
61.3 (CH), 127.3 (CH), 146.8 (CH), 168.7 (C); mass spectrum
(EI) m/z 137 (M+, 46), 108 (100), 81 (49). HRMS m/e calcd for
C8H11NO (M+): 137.0841. Found:137.0839.
A 2.5% solution of osmium tetraoxide in tert-butyl alcohol
(1.90 mL, 0.040 g, 0.15 mmol) was added to a solution of 0.407
g (2.97 mmol) of the above indolizidinone and 0.534 g (4.80
mmol) of trimethylamine N-oxide (TMAO) dihydrate in 12 mL
of tert-butyl alcohol-water (3:1), and the resulting solution was
stirred at 35-40 °C for 3.5 h. After being allowed to cool to 25
The diacetate derivative of 1 ((1S,2R,8aS)-octahydro-1,2-
diacetoxyindolizine)4b,e was prepared as previously described:
4b [R]D25 -67.4 (c 0.3, CHCl3) (lit.4e -71.9); IR 2802, 1747 cm-1
;
1H NMR (300 MHz) δ 1.16-1.29 (m, 2 H), 1.41-1.65 (m, 2 H),
1.76-1.88 (m, 2 H), 2.02 (s, 3 H), 2.04 (s, 3 H), 2.05-2.15 (m,
2 H), 2.20 (dd, J ) 5.6, 10.1 Hz, 1 H), 2.98 (m, 1 H), 3.54 (dd,

Enantiocontrolled Preparation of Indolizidines
J . Org. Chem., Vol. 66, No. 16, 2001 5443
J ) 7.0, 10.0 Hz, 1 H), 4.71 (dd, J ) 7.3, 8.7 Hz, 1 H), 5.19
(ddd, J ) 5.6, 7.1, 7.1 Hz, 1 H); 13C NMR (75.5 MHz) δ 20.5
(CH3), 20.7 (CH3), 23.6 (CH2), 25.1 (CH2), 28.7 (CH2), 52.7
(CH2), 59.4 (CH2), 65.0 (CH), 68.4 (CH), 75.1 (CH), 170.0 (C);
mass spectrum (CI) m/z 242 (MH+, 100), 180 (23). The 1H NMR
spectrum was in excellent agreement with that of a sample
prepared4b from the natural product (spectrum kindly provided
by Professor C. Harris). HRMS m/e calcd for C12H19NO4 (M+)
+ H: 242.1392. Found: 242.1404.
23.8 (CH2), 30.8 (CH2), 39.9 (CH2), 59.5 (CH), 78.4 (CH), 80.0
(CH), 165.9 (C), 172.5 (C); mass spectrum (FAB) m/z 214 (MH+,
48), 73 (100). HRMS m/e calcd for C10H15NO4 (M+) + H:
214.1081. Found: 214.1079.
(1S,2S,8a S)-Oct a h yd r oin d olizin -1,2-d iol ((+)-Len t ig-
in osin e (2)). To a stirred solution of 0.0227 g (0.106 mmol) of
acetate 12 in 1.0 mL of THF at 0 °C was added 0.024 g (0.63
mmol) of lithium aluminum hydride. The mixture was stirred
at 20 °C for 5 h, cooled to 5 °C, diluted with 1 mL of THF, and
then carefully treated successively with 0.048 mL of water and
0.038 mL of 10% aqueous NaOH. The resulting mixture was
stirred for 1 h, dried with sodium sulfate, and then processed
with ethyl acetate to give, after recrystallization from dichlo-
romethane-pentane, 0.0114 g of pure lentiginosine as a white
solid. The residue obtained from the mother liquor on evapora-
tion was reduced as above to provide an additional 0.0011 g
(75% combined yield) of lentiginosine (2): mp 108-109 °C (lit.5f
106-107 °C); [R]D24 +3.1 (c 0.31, CH3OH) (litt.5f +3.2); IR 3361
2,4,6-Tr iisop r op ylben zen esu lfon ic Acid (1S,2S,8a S)-1-
H yd r oxy-3-oxo-oct a h yd r oin d olizin -2-yl E st er (11) a n d
1R,2R,8a S-isom er . To a stirred solution of 0.161 g (0.94
mmol) of the above cis diols and 0.230 mL of triethylamine
(0.167 g, 1.65 mmol) in 9.1 mL of dichloromethane at 0 °C was
added 0.438 g (1.45 mmol) of 2,4,6-triisopropylbenzenesulfonyl
chloride. The mixture was stirred at 20 °C for 20 h and then
concentrated under reduced pressure. The resulting material
was purified by silica gel chromatography with 10-40% ethyl
acetate in cyclohexane to provide 0.373 g (91%) of sulfonate
11 and its 1R,2R,8aS-isomer as a white solid: IR 3384, 3054,
1
cm-1; H NMR (300 MHz, D2O) δ 1.18-1.35 (m, 2 H), 1.39-
1.55 (m, 1 H), 1.61-1.70 (m, 1 H), 1.77-1.88 (m, 1 H), 1.93-
2.00 (m, 2 H), 2.07 (ddd, J ) 2.9, 11.6, 11.7 Hz, 1 H), 2.74 (AB
of ABX, δa ) 2.64, δb ) 2.84, J ab ) 11.2 Hz, J ax ) 7.3 Hz, J bx
) 1.6 Hz, 2 H), 2.96 (br d, J ) 11.0 Hz, 1 H), 3.67 (dd, J ) 4.0,
8.7 Hz, 1 H), 4.08 (ddd, J ) 1.8, 3.9, 7.5 Hz, 1 H); 13C NMR
(75.5 MHz, D2O) δ 25.6 (CH2), 26.5 (CH2), 30.1 (CH2), 55.5
(CH2), 62.8 (CH2), 71.1 (CH), 78.2 (CH), 85.5 (CH); mass
spectrum (FAB) m/z 158 (MH+, 100%). The 1H NMR spectrum
was in perfect agreement with that of an independently
prepared5d sample (spectrum kindly provided by Professor M.
Shibasaki). Anal. Calcd for C8H15NO2: C, 61.12; H, 9.62; N,
8.91; Mr + H 158.1180. Found: C, 60.75; H, 9.68; N, 8.75; Mr
(mass spectrum), 158.1181.
1710, 1599 cm-1 1H NMR (300 MHz, major isomer) δ 1.09
;
(dddd, J ) 3.6, 12.6, 12.6, 12.6 Hz, 1 H), 1.21-1.33 (m, 19 H),
1.38-1.53 (m, 1 H), 1.62-1.67 (m, 1 H), 1.86-1.92 (m, 1 H),
1.99-2.07 (m, 1 H), 2.70 (ddd, J ) 3.6, 12.9, 12.9 Hz, 1 H),
2.89 (hept, J ) 6.9 Hz, 1 H), 3.41 (ddd, J ) 2.9, 2.9, 12.3 Hz,
1 H), 4.03-4.16 (m, 3 H), 4.21 (dd, J ) 2.3, 5.8 Hz, 1 H), 4.92
(d, J ) 5.8 Hz, 1 H), 7.18 (s, 2 H); 13C NMR (75.5 MHz, major
isomer) δ 23.8 (CH2), 23.9 (CH3), 24.7 (CH2), 25.0 (CH3), 25.1
(CH3), 30.2 (CH2), 30.4 (CH), 34.7 (CH), 41.1 (CH2), 62.7 (CH),
70.6 (CH), 76.2 (CH), 124.4 (C), 128.9 (C), 151.7 (C), 154.9 (C),
164.3 (C); mass spectrum (FAB) m/z 438 (MH+, 100), 203 (11).
Anal. Calcd for C23H35NO5S: C, 63.13; H, 8.06; N, 3.20; S, 7.33;
Mr + H 438.2284. Found: C, 63.09; H, 8.04; N, 3.23; S, 7.38;
Mr (mass spectrum, FAB), 438.2314.
Ack n ow led gm en t. We are most thankful to Dr. A.
Durif, Dr. M.-T. Averbuch, and Dr. C. Philouze for the
X-ray structure determinations, Ms. M.-L. Dheu-An-
dries for the molecular modeling study, and Professors
C. Harris and M. Shibasaki for spectra. A fellowship
from the Danish Research Academy to M. O. R. and
financial support from the Universite´ J oseph Fourier
and the CNRS (UMR 5616) are gratefully acknowl-
edged.
Acetic Acid (1S,2R,8a S)-1-Hyd r oxy-3-oxo-octa h yd r oin -
d olizin -2-yl Ester (12). To a stirred solution of 0.149 g (0.34
mmol) of the above sulfonates in 3.2 mL of toluene was added
0.244 g (0.81 mmol) of tetrabutylammonium acetate. The
solution was stirred at 20 °C for 10 h and then concentrated
under reduced pressure. The resulting material was purified
by silica gel chromatography with 40-60% ethyl acetate in
cyclohexane to provide 0.058 g of a mixture of acetates.
Recrystallization of this material from dichloromethane-pen-
tane gave 0.051 g (70%) of pure acetate 12: mp 188-189 °C;
[R]D25 -51.9 (c 1.0, CHCl3); IR 3280, 1743, 1689 cm-1; 1H NMR
(300 MHz) δ 1.07-1.24 (m, 1 H), 1.25-1.33 (m, 2 H), 1.67-
1.74 (m, 1 H), 1.86-1.92 (m, 1 H), 2.15 (s, 3 H), 2.11-2.19 (m,
1 H), 2.59-2.70 (m, 1 H), 3.22 (ddd, J ) 3.8, 6.0, 11.3 Hz, 1
H), 3.85-3.89 (m, 2 H), 4.07-4.14 (m, 1 H), 5.02 (dd, J ) 1.5,
6.4 Hz, 1 H); 13C NMR (75.5 MHz) δ 20.8 (CH3), 22.9 (CH2),
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 1, 2, 3, 5b, 6, 7a , 12, the olefin from 8b, and the
diacetate from 1 and ORTEP drawings for 8a and 10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O010298R