Total synthesis of (+)-lentiginosine from d-glucose

Article abstract of DOI:10.1016/j.tetlet.2008.07.057

A total synthesis of (+)-lentiginosine, a potent and selective amyloglucosidase inhibitor, is reported from a d-glucose-derived epoxide in 38% overall yield. In this synthesis, ambient conditions and readily available starting materials and reagents are used.

Full text of DOI:10.1016/j.tetlet.2008.07.057

Tetrahedron Letters 49 (2008) 5534–5536
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of (+)-lentiginosine from D-glucose
*
Mohammad Abrar Alam, Yashwant D. Vankar
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A total synthesis of (+)-lentiginosine, a potent and selective amyloglucosidase inhibitor, is reported from
Received 9 June 2008
Revised 4 July 2008
Accepted 9 July 2008
Available online 12 July 2008
a
D
-glucose-derived epoxide in 38% overall yield. In this synthesis, ambient conditions and readily avail-
able starting materials and reagents are used.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
(+)-Lentiginosine
D-Glucose
Epoxide
Barton deoxygenation
The synthesis and biological evaluation of naturally occurring
and rationally designed glycosidase inhibitors has gained impor-
tance1 through the introduction of drugs for the treatment of
various diseases such as diabetes type II,2 Gaucher’s disease3 and
influenza infections.4 In addition, the design and synthesis of
new glycosidase inhibitors against diseases such as AIDS5 and can-
cer6 are also being developed. The majority of glycosidase inhibi-
tors are either derivatives of azasugars or carbasugars, and most
of them are either mono or bicyclic. (+)-Lentiginosine 1 (Scheme
1), a bicylic azasugar and the least hydroxylated naturally occur-
ring indolizidine derivative, was isolated in 1990 from the leaves
of Astragalus lentiginosus.7 It shows amyloglucosidase inhibition
can be obtained from the dimesylate B. The dimesylate could read-
ily be derived from the olefin C which can be obtained from the
corresponding glucose-derived epoxide D, via epoxide opening
and deoxygenation of the resulting alcohol.
Thus, epoxide 2, obtained from D
-glucose in four steps,19 upon
treatment with allylmagnesium chloride20 gave the hydroxy deriv-
ative 3 in 95% yield, which was characterized by the presence of its
internal olefinic proton at d 5.74 as a multiplet in its 1H NMR spec-
trum in addition to other spectral data.21 The hydroxy group was
removed using the Barton deoxygenation22 to give the olefin 4.
Derivative 4 was treated with 10% HCl in methanol to give the ace-
tonide-deprotected acetal23 5 in 98% yield, which typically showed
the absence of the two geminal methyl groups at d 1.0 and the
appearance of one methoxy resonance at d 3.39 in its 1H NMR spec-
trum. The free hydroxy group of 5 was protected as its benzyl ether
to give 6 in 97% yield. The acetal moiety of 6 was hydrolyzed24 by
treatment with 3 M HCl in refluxing dioxane, followed by reduc-
tion with NaBH4 to give diol 7 in 88% yield. This diol was treated
with MsCl/Et3N to give the corresponding dimesylate 8 in 96%
yield, which showed the presence of two methyl singlets at d 2.9
in its 1H NMR spectrum. The double bond of 8 was cleaved using
OsO4/NaIO4 followed by reduction with NaBH4 to give the hydroxy
derivative 9 in good yield.25,26 Treatment of 9 with neat benzyl-
amine27 at 90 °C gave the pyrrolidine derivative 10. The 1H NMR
spectrum showed the complete disappearance of the mesylate
singlets and an increase in the number of phenyl protons, which
confirmed the formation of the pyrrolidine system. Hydroxypyrrol-
idine 10 on treatment with MsCl/Et3N formed a very polar com-
pound, most likely a quaternary ammonium salt,28 which upon
treatment with Pd/C in methanol under 5 atm H2 gave (+)-lentigi-
nosine 1 in 81% yield. All the spectral and analytical data for 1 were
activity at submicromolar concentration (IC50 = 0.43 lg/L) and is
the most potent and selective amyloglucosidase inhibitor known
so far. Due to its interesting activity, many groups have reported
its synthesis. Syntheses of optically active (+)-lentiginosine use
starting materials such as ribonolactone,8 tartaric acid,9 -xylose,10
D
pipecolic acid,11 -homoproline,12 chiral sulfoxide,13 lactam deriv-
D
atives14 and pyridine N-oxide derivatives.15 Some racemic synthe-
ses are also reported in the literature.16 Although the synthesis of
(ꢀ)-lentiginosine is known from
D
-glucose,17 to the best of our
knowledge, no synthesis of (+)-lentiginosine from
been reported.
D-glucose has
In continuation of our efforts to synthesize glycosidase inhibi-
tors,18 we herein report a new synthesis of (+)-lentiginosine from
D-glucose. Retrosynthetically (Fig. 1) the target molecule 1 can be
obtained from the hydroxy pyrrolidine derivative A which, in turn,
* Corresponding author. Tel.: +91 512 259 7169; fax: +91 512 259 0007.
E-mail address: vankar@iitk.ac.in (Y. D. Vankar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.057

M. A. Alam, Y. D. Vankar / Tetrahedron Letters 49 (2008) 5534–5536
5535
O
OH
O
O
ref. 19
AllylMgCl,THF,1 h
-20 oC to rt, 95%
O
O
( )2
D-Glucose
O
O
BnO
BnO
O
2
3
1. PhOCSCl, Py
0 oC to rt, 96%
O
( )
( )
3
3
O
OMe
OH
10% HCl in MeOH
3 h, rt, 98%
2. TBTH, AIBN
toluene, reflux, 75%
O
BnO
O
BnO
5
4
1. 3N HCl, Dioxane
reflux, 8 h
( )3
OH
( )3
OH
OMe
NaH, BnBr, DMF,
0 oC to rt, 4 h, 97%
2. NaBH4 in MeOH,
1 h, 0 oC to rt, 88%
(two steps)
OBn
OBn
OMs
BnO
BnO
6
7
1. OsO4, NMO, 20 h, rt
OMs
( )3
OMs
( )3
OMs
2. NaIO4, MeOH:H2O (6:1)
MsCl, Et3N,DCM
0 oC to rt, 3 h, 97%
0 oC to rt, 30 min
3. NaBH4 in MeOH, 1 h,
90% (three steps)
OH
BnO
OBn
BnO
OBn
8
9
Bn
N
1.MsCl, Et3N, DCM
0 oC to rt, 3 h,
OH
( )3
H
N
BnNH2, 80 oC
OH
OH
20 h, 91%
2. 10% Pd/C, H2,
MeOH, 24 h, 5 atm
81% (two seps)
OBn
BnO
10
1
(+)-Lentiginosine
OAc
H
Ac2O, Et3N, DCM
overnight, 99%
OAc
N
11
Scheme 1.
OBn
H
OH
Supplementary data
Supplementary data associated with this article can be found, in
H
N
OMs
( 3)
OMs
OBn
OH
BnN
BnO
OBn
the online version, at doi:10.1016/j.tetlet.2008.07.057.
1
B
A
OH
References and notes
O
O
( )
3
O
O
O
1. (a) Pearson, S. R.; Mathe0-Allainmat, M.; Fargeas, V.; Lebreton, J. Eur. J. Org.
Chem. 2005, 2159; (b) Stutz, A. E. Iminosugars as Glycosidase Inhibitors:
Nojirimycin and Beyond; Wiley-VCH, 1999; (c) Lillielund, V. H.; Jensen, H. H.;
Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515; (d) Dwek, R. A.; Butters, T. D.;
Platt, F. M.; Zitzmann, N. Nat. Rev. 2002, 1, 65; (e) Asano, N. Glycobiology 2003,
13, 93R; (f) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J.
Phytochemistry 2001, 56, 265; (g) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G.
W. J. Tetrahedron: Asymmetry 2000, 11, 1645; (h) Mehta, G.; Ramesh, S. Can. J.
Chem. 2005, 83, 581; (i) Laventine, D. M.; Jenkins, P. R.; Cullis, P. M. Tetrahedron
Lett. 2005, 46, 2295.
2. (a) Aoki, K.; Nakamura, A.; Ito, S.; Nezu, S.; Iwasaki, T.; Takhashi, M.; Kimura,
M.; Terauchi, Y. Diabetes Res. Clin. Pract. 2007, 78, 30; (b) Treadway, J. L.;
Mendys, P.; Hoover, D. J. Expert Opin. Struct. Biol. 1995, 5, 605.
3. Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000, 100, 4683 and references
cited therein.
D-glucose
O
BnO
O
BnO
C
D
Figure 1. Retrosynthesis of (+)-lentiginosine.
in agreement with the data reported in the literature.29 Moreover,
1 was further characterized as its acetate derivative 11.30
In conclusion, we have synthesized (+)-lentiginosine from the D-
glucose-derived epoxide 2 in an efficient manner in 38% overall
yield. This synthetic scheme can be utilized for the preparation
of analogues of lentiginosine, and work towards this direction is
being pursued in our laboratory.
4. Moscona, A. Eng. J. Med. 2005, 353, 1363.
5. (a) Chery, F.; Cronin, L.; O’Brein, J. L.; Murphy, P. V. Tetrahedron 2004, 60, 6597;
(b) Robina, I.; Moreno-Vargas, A. J.; Carmona, A. T.; Vogel, P. Curr. Drug Metab.
2004, 5, 329; (c) Rudd, P. M.; Elliott, T.; Cresswell, P.; Wilson, I. A.; Dwek, R. A.
Science 2001, 291, 2370; (d) Gruters, R. A.; Neefjes, J. J.; Tersmette, M.; de
Goede, R. E. Y.; Tulp, A.; Huisman, H. G.; Miedema, F.; Ploegh, H. L. Nature 1987,
330, 74.
Acknowledgements
6. (a) Lagana, A.; Goetz, J. G.; Cheung, P.; Raz, A.; Dennis, J. W.; Nabi, J. R. Mol. Cell
Biol. 2006, 26, 3181; (b) Platt, F. M.; Butters, T. D. Exp. Rev. Mol. Med. 2000, 1; (c)
Klein, J. L. D.; Roberts, J. D.; George, M. D.; Kurtzberg, J.; Breton, P.; Chermann, J.
C.; Olden, K. Br. J. Cancer 1999, 80, 87; (d) Goss, P. E.; Reid, C. L.; Bailey, D.;
Dennis, J. W. Clin. Cancer Res. 1997, 3, 1077; (e) Ratner, L.; Heyden, N. V.;
Dedera, D. Virology 1991, 181, 180; (f) Balfour, J. A.; McTavish, D. Drugs 1993,
46, 1025.
Y.D.V. thanks the Department of Science and Technology, New
Delhi, for financial support in the form of a Ramanna Fellowship
(Grant No. SR/S1/RFOC-04/2006). M.A.A. thanks IIT, Kanpur for a
senior research fellowship.

5536
M. A. Alam, Y. D. Vankar / Tetrahedron Letters 49 (2008) 5534–5536
7. Pastuszak, I.; Molyneux, R. J.; James, L. F.; Elbein, A. D. Biochemistry 1990, 29,
1886–1891.
29.7, 26.7, 26.2; HRMS (ESI): calcd for C19H26O5 [M+Na]+ 357.1677, found
357.1441.
8. Chen, M. J.; Tsai, Y. M. Tetrahedron Lett. 2007, 48, 6271.
9. Cardona, F.; Moreno, G.; Guarna, F.; Vogel, P.; Schuetz, C.; Merino, P.; Goti, A. J.
Org. Chem. 2005, 70, 6552.
10. Yoda, H.; Kawauchi, M.; Takabe, K. Synlett 1998, 137.
11. Gurjar, M. K.; Ghosh, L.; Syamala, M.; Jayasree, V. Tetrahedron Lett. 1994, 35,
8871.
12. Rabiczko, J.; Urban, L. Z.; Chmielewski, M. Tetrahedron 2002, 58, 1433.
13. Raghavan, S.; Sreekanth, T. Tetrahedron: Asymmetry 2004, 15, 565.
14. Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1995, 60, 398.
15. Feng, Z. H.; Zhou, W. S. Tetrahedron Lett. 2003, 44, 497.
16. Cardona, F.; Goti, A.; Brandi, A. Eur. J. Org. Chem. 2007, 1551.
17. Chaudhari, V. D.; Kumar, K. S. A.; Dhavale, D. D. Tetrahedron 2006, 62, 4349.
18. (a) Kumar, A.; Rawal, G. K.; Vankar, Y. D. Tetrahedron 2008, 64, 2379; (b) Doddi,
R. V.; Vankar, Y. D. Eur. J. Org. Chem. 2007, 33, 5583; (c) Jayakanthan, K.; Vankar,
Y. D. Tetrahedron Lett. 2006, 47, 8667; (d) Jayakanthan, K.; Vankar, Y. D. Org.
Lett. 2005, 7, 5441; (e) Reddy, G. B.; Vankar, Y. D. Angew. Chem., Int. Ed. 2005,
44, 2001; (f) Rani, S.; Agarwal, A.; Vankar, Y. D. Tetrahedron Lett. 2003, 44, 5001.
19. Morillo, M.; Lequart, V.; Grand, E.; Goethals, G.; Usubillaga, A.; Villa, P.; Martin,
P. Carbohydr. Res. 2001, 334, 281.
22. Gadikota, R. R.; Keller, A. I.; Callam, C. S.; Lowary, T. L. Tetrahedron: Asymmetry
2003, 14, 737.
23. Shi, Z. D.; Yang, B. H.; Wu, Y. L. Tetrahedron 2002, 58, 3287.
24. Wong, A.; Munos, J. W.; Devasthali, V.; Johnson, K. A.; Liu, H. Org. Lett. 2004, 6,
3625.
25. Chen, G.; Sasaki, M.; Li, X.; Yudin, A. K. J. Org. Chem. 2006, 71, 6067.
26. (2S,3R,4R)-2,3-Bis(benzyloxy)-8-hydroxyoctane-1,4-diyl dimethanesulfonate (9):
½ ꢁ
a 2D5 +1.98 (c 0.50, CH2Cl2). IR (thin film, cmꢀ1): 3561, 3030, 2937, 2872, 1496,
1353, 1173, 1072. 1H NMR (500 MHz, CDCl3): d 7.36–7.25 (10H, m), 4.81–44.78
(1H, m), 4.72 (1H, d, J = 9.2 Hz), 4.67 (1H, d, J = 9.2 Hz) 4.64 (1H, d, J = 9.2 Hz),
4.57 (1H, d J = 9.2 Hz), 4.38 (2H, d, J = 3.6 Hz), 3.88 (1H, q, J = 3.6, 7.6 Hz), 3.68
(1H, t, J = 4.0 Hz), 3.56 (2H, t, J = 5.2 Hz), 2.96 (3H, s), 2.96 (3H, s), 1.77–1.73
(1H, m), 1.60 (1H, m), 1.49–1.39 (3H, m), 1.37–1.27 (1H, m). 13C NMR
(125 MHz, CDCl3): d 137.0, 128.6, 128.3, 128.2, 81.1, 75.9, 74.6, 73.4, 68.3, 62.2,
38.7, 37.4, 32.0, 30.6, 21.0. HRMS (ESI): calcd for C24H34O9S2 [M+H]+ 531.1722,
found 531.1720.
27. Fleet, G. W. J.; Son, J. C.; Green, D. S. C.; Bello, I. C. D.; Winchester, B. Tetrahedron
1988, 44, 2649.
28. Adams, C. E.; Walker, F. J.; Sharpless, K. B. J. Org. Chem. 1988, 50, 420.
29. Cardona, F.; Moreno, G.; Guarna, F.; Vogel, P.; Schuetz, C.; Merino, P.; Goti, A. J.
Org. Chem. 2005, 70, 6552.
20. Bravo, P.; Mele, A.; Salania G, Viant F. Bioorg. Med. Chem. Lett. 1994, 4, 1577.
21. (1R)-1-((3aR,6S,6aR)-6-(Benzyloxy)-2,2-dimethyl tetrahydrofuro[2,3-d][1,3]diox-
ol-5-yl)pent-4-en-1-ol (3): IR (thin film, cmꢀ1): 3410, 3066, 3031, 2984, 2931,
30. (+)-1,2-Diacetoxyindolizidine (11): ½a D25
ꢁ
+2.10 (c 1.00, CH2Cl2). IR (thin film,
1497, 1454, 1382, 1311, 1217, 1092, 1023. ½a D25
ꢁ
+1.5 (c 0.5, CH2Cl2). 1H NMR
cmꢀ1): 2937, 2854, 2794, 1741, 1372, 1243, 1046. 1H NMR (500 MHz, CDCl3): d
4.99–4.97 (1H, m), 4.92 (1H, dd, J = 2.0, 6.4 Hz), 3.01–2.96 (2H, m), 2.59 (1H, dd,
J = 5.2, 8.8 Hz), 2.06 (3H, s), 2.05 (3H, s), 2.04–2.02 (1H, m), 1.99–1.85 (2H, m),
1.83–1.65 (2H, m), 1.40–1.33 (2H, m), 1.24–1.85 (1H, m). 3C NMR (125 MHz,
CDCl3): d 170.8, 170.2, 82.1, 67.6, 59.8, 53.0, 28.7, 24.5, 23.6, 21.0, 20.9; HRMS
(ESI): calcd for C12H19NO4 [M+H]+ 242.1392, found 242.1392.
(400 MHz, CDCl3), d 7.29 (5H, m), 5.99 (1H, d, J = 3.9 Hz), 5.74 (1H, m), 4.93 (2H,
m), 4.66 (1H, d, J = 11.7 Hz), 4.56 (1H, d, J = 3.6 Hz), 4.25 (1H, d, J = 11.7 Hz),
4.41 (1H, d, J = 3.1 Hz), 4.00 (1H, d, J = 3.1 Hz), 3.88 (2H, m), 2.20 (1H, m), 2.07
(1H, m) 1.66 (2H, m) 1.41 (3H, s), 1.25 (3H, s); 13C NMR (100 MHz, CDCl3): d
138.3 136.8, 128.7, 128.4, 128.0, 114.7, 111.6, 105.0, 82.0, 81.8, 71.8, 69.0, 33.4,