A novel concise total synthesis of (+)-lentiginosine

Article abstract of DOI:10.1016/S0040-4039(02)02606-0

A total synthesis of (+)-lentiginosine was achieved by using ethyl 3-(pyridin-2-yl)acrylate N-oxide as the starting material and an improved Sharpless asymmetric dihydroxylation as the key step.

Full text of DOI:10.1016/S0040-4039(02)02606-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 497–498
A novel concise total synthesis of (+)-lentiginosine
Zhi-Xiang Feng and Wei-Shan Zhou*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 7 October 2002; revised 7 November 2002; accepted 15 November 2002
Abstract—A total synthesis of (+)-lentiginosine was achieved by using ethyl 3-(pyridin-2-yl)acrylate N-oxide as the starting
material and an improved Sharpless asymmetric dihydroxylation as the key step. © 2002 Elsevier Science Ltd. All rights reserved.
Lentiginosine 1, was isolated from the leaves of Astra-
galus lentiginosus, whose absolute configuration created
an ambiguity.1 It was reported to be a selective and
powerful inhibitor of amyloglucosidases1a,2 and to be
twice as powerful as another natural polyhydroxyin-
dolizidine, castanospermine 2, which has potent glycosi-
dase inhibitory and anti-HIV activity.3 Consequently,
much attention has been devoted to the synthesis of
(+)-lentiginosine during the past decade. Most of the
previous methodologies utilized tartaric acid as starting
material.4 Others used a furanose derivative,5 1,2,7-tri-
hydroxyindolizidine derivatives,6 enol ether7 or pipecol-
inic acid8 as the chiral precursors. However, to the best
of our knowledge, only one approach to the target
compound 1 has been reported,9 starting from a non-
chiral pyridine derivative instead of the above-men-
tioned chiral pool.
our previous work10 for asymmetric dihydroxylation of
heteroaromatic acrylates, herein we describe an easy
route to (+)-lentiginosine starting from ethyl 3-(pyridin-
2-yl)acrylate N-oxide 3, which was derived from picoli-
naldehyde by Wittig reaction followed by oxidation11
(Scheme 1).
Asymmetric dihydroxylation (AD) of ethyl 3-(pyridyl-
2-yl)acrylate was not successful, so the nitrogen atom
on the pyridine ring was blocked with oxygen in order
not to interfere with the catalytic cycle of AD. AD of 3
using 3 mol% (DHQ)2PHAL and 5 equiv. of K2CO3
gave the diol 4 in 62% yield with 20% recovery of the
starting material and >99.9% ee.12 This new reaction
system has an advantage over the usual system (1 mol%
(DHQ)2PHAL and 3 equiv. of K2CO3) in the AD
reaction in that it reduces the reaction time and
increases the yield and the enantioselectivity, most
likely due to greater proportion of ligand13 and higher
pH14 used. In the next step, reduction of 4 using
ammonium formate15 as hydrogen source failed to pro-
duce 5 or 6. However, removal of oxygen atom from
N-oxide, reduction of pyridine ring and intramolecular
cyclization of the diol 4 were achieved in one step by
hydrogenation under 10 atm with 10% Pd–C in MeOH/
1
Et3N, affording a 3.2:1 (determined by H NMR) mix-
ture of the lactam 5 and 6 in 95% yield. The minor
isomer 6 could be readily removed by recrystallization
from ethyl acetate and pure 5 {[h]D +77.3 (c 1.4,
MeOH)} was obtained in 43% yield from 4. The stereo-
chemistry of 5 was assigned by a 2D-NOESY spectrum
Despite this plethora of methods, interest in the synthe-
sis of (+)-lentiginosine and its analogues remains undi-
minished. Development of general methods which
could have flexibility for the construction of these com-
pounds continues to be important for investigating
their structure–activity relationships. In continuation of
1
recorded with 600 MHz H NMR, in which no NOE
correlation was found between 6-H and 7-H. Mean-
while, the characteristic doublet at l 4.29 (H-8) and a
triplet at l 3.91 (H-7) with coupling constants J6,7
=
Keywords: (+)-lentiginosine; total synthesis; asymmetric dihydroxyla-
tion.
* Corresponding author. Tel.: +86-21-64163300; fax: +86-21-
64166128; e-mail: zhws@pub.sioc.ac.cn
J7,8=6.9 Hz established the trans–trans relationship.
Reduction of 5 with BH3:Me2S in THF8 furnished 1 in
75% yield {[h]D +1.7 (c 0.37, MeOH) (lit. [h]D +0.19 (c
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02606-0

498
Z.-X. Feng, W.-S. Zhou / Tetrahedron Letters 44 (2003) 497–498
Scheme 1. Reagents and conditions: (a) 0.4 mol% K2[OsO2(OH)4], 3 mol% (DHQ)2PHAL, 3 equiv. of K3[Fe(CN)6], 5 equiv. of
K2CO3 and 1 equiv. of MeSO2NH2 in H2O/tBuOH (1:1), 24 h, 62% with 20% recovery of the starting material; (b) 10% Pd–C,
10 atm H2, MeOH, 24 h, 43% of 5; (c) BH3:SMe2, THF, 0°C–rt, 10 h, 75%.
6 MeOH),4a [h]D +3.2 (c 0.27, MeOH);4d mp 104–106°C
Tetrahedron: Asymmetry 1994, 5, 1455–1456; (b) Brandi,
A.; Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti, A.;
Picasso, S.; Vogel, P. J. Org. Chem. 1995, 60, 6806; (c)
Giovannini, R.; Marcantoni, E.; Petrini, M. J. Org.
Chem. 1995, 60, 5706–5707; (d) Cordero, F. M.; Cicchi,
S.; Goti, A.; Brandi, A. Tetrahedron Lett. 1994, 35,
949–952; (e) Ha, D. C.; Yun, C. S.; Lee, Y. J. Org. Chem.
2000, 65, 621–623; (f) Yoda, H.; Katoh, H.; Ujihara, Y.;
Takabe, K. Tetrahedron Lett. 2001, 42, 2509–2512.
5. Yoda, H.; Kawauchi, M.; Takabe, K. Synlett 1998, 137–
138.
6. (a) Mccaig, A. E.; Meldrum, K. P.; Wightman, R. H.
Tetrahedron 1998, 54, 9429–9446; (b) Mccaig, A. E.;
Wightman, R. H. Tetrahedron Lett. 1993, 34, 3939; (c)
Goti, A.; Cordona, F.; Brandi, A. Synlett 1996, 761–763.
7. Rasmussen, O.; Delair, P.; Greene, A. E. J. Org. Chem.
2001, 66, 5438–5443.
1
(lit. 106–107°C)4d) whose H NMR spectrum was con-
sistent with the previous report.1b,4d
In conclusion, a very concise total synthesis gave (+)-
lentiginosine 1 in 20% overall yield in only three steps
from a readily available material 3 based on an
improved Sharpless asymmetric dihydroxylation and a
highly efficient protocol of cyclization. So far as we
know, this is the shortest route among those for using
non-chiral starting materials. Extension of this method-
ology to the synthesis of other polyhydroxy indolizidine
alkaloids is in progress.
Acknowledgements
8. Gurjar, M. K.; Ghosh, L.; Syamala, M.; Jayasree, V.
Tetrahedron Lett. 1994, 35, 8871–8872.
9. Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1995, 60, 398–404.
10. Feng, Z.-X.; Zhou, W.-S. Tetrahedron Lett. 2003, 44,
493–495.
We thank the National Natural Science Foundation of
China for the financial support of this work (29732061).
We also thank Professor Li-Jun Xia and Zuo-Ding
Ding for performing the HPLC analysis.
11. (a) Raatz, D.; Innertsberger, C.; Reiser, O. Synlett 1999,
1907–1909; (b) Agarwal, K. C.; Knaus, E. E. J. Hetero-
cyclic Chem. 1985, 22, 65–69.
12. Enantiomeric excess was determined by HPLC on Chiral-
cel OB-H column with n-hexane–i-PrOH as the eluent.
13. Bonini, C.; D’Auria, M.; Fedeli, P. Tetrahedron Lett.
2002, 43, 3813–3815.
14. Mehltretter, G. M.; Do¨bler, C.; Sundermeier, U.; Beller,
M. Tetrahedron Lett. 2000, 41, 8083–8087.
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