Total syntheses of (±)-lentiginosine and (±)-1-epi-lentiginosine from hexahydro-1H-indol-3-one

Article abstract of DOI:10.1016/S0040-4039(02)02607-2

Total syntheses of (±)-lentiginosine 1 and (±)-1-epi-lentiginosine 2 were achieved efficiently from hexahydro-1H-indol-3-one 7.

Full text of DOI:10.1016/S0040-4039(02)02607-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 499–501
Total syntheses of (±)-lentiginosine and (±)-1-epi-lentiginosine
from hexahydro-1H-indol-3-one
Chin-Kang Sha* and Chi-Min Chau
Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan, ROC
Received 8 October 2002; revised 7 November 2002; accepted 15 November 2002
Abstract—Total syntheses of (±)-lentiginosine 1 and (±)-1-epi-lentiginosine 2 were achieved efficiently from hexahydro-1H-indol-
3
-one 7. © 2002 Elsevier Science Ltd. All rights reserved.
A number of polyhydroxylated indolizidines, such as
lentiginosine 1, swainsonine 3, and castanospermine 4,
isolated from natural sources are powerful and specific
method for the construction of indolizidine alkaloids
starting from compound 7. We envisaged that reduc-
tion of the carbonyl group followed by cleavage of the
1
inhibitors of a- and b-glycosidases.
Lentiginosine 1, containing only two hydroxyl groups,
was isolated from the leaves of Astragalus lentiginosus
double bond in 7 would provide the intermediate 6
having the necessary functional groups for elaboration
of indolizidine alkaloids. The retro-synthetic analysis of
(±)-lentiginosine 1 is depicted in Scheme 1. The target
molecule 1 could be synthesized by cyclization of com-
pound 5. Functionalized intermediate 5 may be
obtained from aldehyde 6. Compound 6 should be
readily prepared from hexahydro-1H-indol-3-one 7 by
2
in 1990. Several successful total syntheses of 1 have
3
been achieved. In this communication, we report an
efficient total synthesis of (±)-lentiginosine 1 and (±)-
epi-lentiginosine 2 by an entirely different approach.
In our earlier work, we have developed a facile anionic
cyclization approach towards hexahydro-1H-indol-3-
one 7, and also applied that method to the total synthe-
NaBH reduction followed by ozonolysis.
4
4
5
sis of (−)-brunsvigine. As a continuation, we were
Luche reduction of compound 7 gave a single
interested in the development of a general synthetic
diastereomeric alcohol 8, Scheme 2. Treatment of com-
Scheme 1. P=protecting group.
*
Corresponding author. Tel.: +886-3-6722427; fax: +886-3-5725870; e-mail: cksha@mx.nthu.edu.tw
0
040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02607-2

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C.-K. Sha, C.-M. Chau / Tetrahedron Letters 44 (2003) 499–501
Scheme 2.
Scheme 3.
pound 8 with tert-butyldimethylchlorosilane (TBSCl) in
the presence of imidazole in N,N-dimethylformamide
Furthermore, starting with intermediate 11, the synthe-
sis of (±)-lentiginosine 1 was achieved in three steps
with good yield. Inversion of the configuration at C2 in
(
DMF) gave 9. Ozonolysis of the double bond in 9
6
afforded compound 10. Reduction of 10 with lithium
borohydride (LiBH ) furnished a single diastereomer
11 was achieved via a Mitsunobu reaction to furnish
14 (Scheme 3). Reaction of 14 with TsCl gave com-
pound 15 in 60% yield along with some recovered
4
1
1. The primary hydroxy group in 11 was tosylated
with p-toluenesulfonyl chloride (TsCl) to afford 12.
Removal of Boc group in 12 by trifluoroacetic acid
compound 14 (30%). Treatment of 15 with BF etherate
3
followed by reaction with KOH in methanol afforded
target molecule (±)-lentiginosine 1 (36%) and some TBS
group protected compound 16 (54%). Compound 16
was separated by flash column chromatography (SiO2,
(
TFA) in dichloromethane furnished 13. Treatment of
3 with KOH in methanol afforded (±)-1-epi-lentigi-
nosine 2.
1

C.-K. Sha, C.-M. Chau / Tetrahedron Letters 44 (2003) 499–501
501
CHCl :MeOH:NH3(aq.); 80:20:1) and then treated with
tetrabutylammonium fluoride (TBAF) in THF to give
Chem. 2002, 67, 4630; Yoda, H.; Katoh, H.; Ujihara, Y.;
Takabe, K. Tetrahedron Lett. 2001, 42, 2509; Klitzke, C. F.;
Pilli, R. A. Tetrahedron Lett. 2001, 42, 5605; Yoda, H.;
Kawauchi, M.; Takabe, K. Synlett 1998, 137; Paolucci, C.;
Musiani, L.; Venturelli, F.; Fava, A. Synthesis 1997, 1415;
Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1995, 60, 398.
3
(
±)-lentiginosine 1 in 88% yield. Overall, 1 was obtained
7
in 84% from 15. All spectral data of 1 and 2 were in
good agreement with those reported in the literature.
2
In summary, we have achieved total syntheses of (±)-
lentiginosine 1 and (±)-1-epi-lentiginosine 2 via a
straightforward approach from a simple starting mate-
rial, hexahydro-1H-indol-3-one 7. This methodology
might be applied to the total synthesis of other
indolizidine or pyrrolizidine alkaloids. Further work
along this line is in progress.
4. Sha, C.-K.; Hong, A.-W.; Huang, C.-M. Org. Lett. 2001,
3, 2177.
5. Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
6. Mitsunobu, O. Synthesis 1981, 1.
1
7. Our data of (±)-lentiginosine 1: H NMR (600 MHz, D O),
2
l 4.07 (ddd, J=7.6, 4.0, 1.6 Hz, 1H), 3.65 (dd, J=8.9, 4.0
Hz, 1H), 2.97 (br, J=11.2 Hz, 1H), 2.85 (dd, J=11.3, 1.6
Hz, 1H), 2.68 (dd, J=11.3, 7.6 Hz, 1H), 2.11 (ddd, J=11.3,
1
1.3, 3.0 Hz, 1H), 2.01 (m, 1H), 1.94–1.91 (m, 1H), 1.82–1.78
Acknowledgements
(
(
m, 1H), 1.66–1.63 (m, 1H), 1.50–1.41 (m, 1H), 1.30–1.21
m, 2H); C NMR (100 MHz, D O) l 85.5 (CH), 78.3 (CH),
13
2
7
2
1
1.3 (CH), 62.9 (CH ), 55.4 (CH ), 30.2 (CH ), 26.6 (CH ),
2 2 2 2
1
We thank the National Science Council of the Republic
of China for financial support.
−
5.7 (CH ); IR (neat) 3625, 1094, 1090 cm ; MS (EI) m/z
2
+
57 (M , 4), 140 (36), 123 (100); HRMS (EI) m/z calcd for
C H NO 157.1103, found 157.1101.
8
15
2
1
Our data of (±)-1-epi-lentiginosine 2: H NMR (600 MHz,
CDCl ), l 4.26–4.22 (m, 1H), 4.01 (dd, J=6.0, 4.1 Hz, 1H),
.42 (br s, 2H), 3.12–3.09 (m, 1H), 3.02 (dd, J=10.9, 1.8 Hz,
References
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3
1
. Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
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. For isolation and structure determination of lentiginosine,
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D. Biochemistry 1990, 29, 1886.
1H), 2.40 (dd, J=10.9, 7.2 Hz, 1H), 2.01–1.95 (m, 2H),
1.87–1.83 (m, 1H), 1.77–1.73 (m, 1H), 1.67–1.52 (m, 3H),
13
2
1.28–1.18(m, 1H); C NMR (100 MHz, CDCl
69.6 (CH), 67.9 (CH), 62.5 (CH ), 53.2 (CH
24.9 (CH ), 23.7 (CH ); IR (neat) 3626, 1095, 1089 cm ; MS
(EI) m/z 157 (M , 6), 140 (39), 123 (100); HRMS (EI) m/z
calcd for C 157.1103, found 157.1100.
) l 75.5(CH),
3
), 25.0 (CH ),
2
2
2
−
1
2
2
+
3
. For the synthesis of lentiginosine and analogues, see:
Chandra, K. L.; Chandrasekhar, M.; Singh, V. K. J. Org.
H15NO
2
8