Short syntheses of enantiopure calystegine B2, B3, and B4

Article abstract of DOI:10.1039/b102353p

Calystegine B₂, B₃, and B₄ have been prepared in 5 steps from the benzyl protected methyl 6-iodoglycopyranosides of glucose, galactose and mannose, respectively, by using a zinc-mediated domino reaction followed by ring-cl

Full text of DOI:10.1039/b102353p

Short syntheses of enantiopure calystegine B2, B3, and B4
Philip R. Skaanderup and Robert Madsen*
Department of Chemistry, Building 201, Technical University of Denmark, DK-2800 Lyngby, Denmark.
E-mail: rm@kemi.dtu.dk
Received (in Corvallis, OR, USA) 12th March 2001, Accepted 26th April 2001
First published as an Advance Article on the web 31st May 2001
Calystegine B2, B3, and B4 have been prepared in 5 steps
from the benzyl protected methyl 6-iodoglycopyranosides of
glucose, galactose and mannose, respectively, by using a
zinc-mediated domino reaction followed by ring-closing
olefin metathesis as the key steps.
B4 (3) starting from glucose, galactose and mannose, re-
spectively.6 Calystegine B2 and B4 are potent inhibitors of b-
glucosidase and trehalase.7
The starting material for all three syntheses is the correspond-
ing benzyl protected methyl 6-deoxy-6-iodo-a- -glycopyrano-
D
side (Scheme 1). Sonicating a mixture of glucopyranoside 4 and
excess zinc dust in dry THF caused a reductive fragmentation to
generate the 5,6-unsaturated aldehyde8 which was trapped in
situ as the corresponding benzyl imine. Slow addition of allyl
bromide to the mixture led to allylation of the imine to give a
5+1 mixture of amino dienes. The major diastereomer 53a was
isolated in 71% yield and the stereochemistry verified after
completing the synthesis of 1. Cbz-protection of the amino
group gave 6† which was metathesised into cycloheptene 7 with
the saturated N-heterocyclic carbene catalyst (PCy3)(C3H4-
N2mes2)Cl2RuNCHPh.4,9,10 The double bond in 7 is slightly
polarized and can be hydroborated11 followed by oxidation12 in
Many polyhydroxylated alkaloids are important glycosidase
inhibitors due to their structural resemblance to sugars.1 A
special class of these alkaloids is the calystegines which consist
of a polyhydroxy-nortropane ring system.2 Up to date, 14
different calystegines have been isolated from various plant
species. Their structures have been elucidated mainly by NMR
spectroscopy and they have been divided into four different
classes: A, B, C and N. The absolute configuration, however, is
known only for calystegine B2 (1) and the configuration of all
the remaining calystegines is presumed to be analogous to that
of 1 based on biosynthetic considerations.2 So far, only
calystegine A3 and B2 have been prepared by chemical
synthesis.3
We have recently introduced a zinc-mediated domino
reaction followed by ring-closing olefin metathesis for synthe-
sis of polyhydroxylated carbocycles from sugars.4,5 The domino
reaction allows for the stereocontrolled introduction of an
amino group and is then well suited for preparing the seven-
membered carbocycle in the calystegines. Herein, we exploit
these reactions for short syntheses of calystegine B2, B3 (2) and
Scheme 1 Reagents and conditions: (a) Zn, BnNH2, CH2NCHCH2Br, THF,
sonication, 40 °C; (b) CbzCl, KHCO3, EtOAc, H2O; (c) 2% (PCy3)(C3H4-
N2mes2)Cl2RuNCHPh, CH2Cl2, rt; (d) BH3·THF, THF, 250 ? 0 °C, then
NaOH, H2O2, 0 °C, then Dess-Martin periodinane, CH2Cl2, rt; (e) H2, Pd/
C.
Scheme 2 Reagents and conditions: (a) Zn, BnNH2, CH2NCHCH2Br, THF,
sonication, 40 °C; (b) CbzCl, KHCO3, EtOAc, H2O; (c) 2% (PCy3)(C3H4-
N2mes2)Cl2RuNCHPh, CH2Cl2, rt; (d) BH3·THF, THF, 250? 0 °C, then
NaOH, H2O2, 0 °C, then Dess-Martin periodinane, CH2Cl2, rt; (e) H2, Pd/
C.
1106
Chem. Commun., 2001, 1106–1107
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102353p

5.00 (m, 2H), 4.92 (d, 1H, J 11.1), 4.84 (d, 1H, J 11.1), 4.72 (d, 1H, J 11.1),
4.56 (d, 1H, J 12.8), 4.53 (d, 1H, J 12.4), 4.29 (d, 1H, J 11.9), 4.18 (bs, 1H),
3.90 (d, 1H, J 13.2), 3.83 (dd, 1H, J 7.8, 3.2), 3.67 (d, 1H, J 13.2), 3.56 (bs,
1H), 2.66 (bs, 1H), 2.45 (m, 1H), 2.29 (m, 1H); dC (CDCl3) 140.5, 139.1,
139.0, 138.7, 135.8, 135.1, 128.2–126.6 (20C), 118.9, 116.7, 82.6, 81.5,
80.1, 74.7, 74.5, 69.7, 56.7, 50.7, 34.5.
§ Spectral data for 15: dH (CDCl3) 7.43–7.25 (m, 20H), 6.00 (ddd, 1H, J
17.7, 10.4, 8.1), 5.79 (m, 1H), 5.39 (bd, 1H, J 17.5), 5.34 (bd, 1H, J 10.4),
5.10 (bd, 1H, J 17.9), 5.09 (bd, 1H, J 9.8), 4.83 (d, 1H, J 11.5), 4.75 (d, 2H,
J 11.5), 4.71 (d, 1H, J 11.9), 4.58 (d, 1H, J 11.1), 4.44 (d, 1H, J 11.9), 4.29
(m, 1H), 3.89 (m, 1H), 3.83 (d, 1H, J 12.8), 3.82 (m, 1H), 3.77 (d, 1H, J
12.8), 3.08 (dt, 1H, J 8.0, 3.9), 2.51 (m, 1H), 2.36 (m, 1H); dC (CDCl3)
140.6, 138.8, 138.6, 138.5, 136.4, 136.2, 128.8–125.9 (20C), 118.1, 117.0,
82.3, 81.1, 79.4, 74.4, 73.1, 70.4, 57.1, 51.7, 34.6.
a one pot procedure to give a 3+1 mixture of ketones. Major
ketone isomer 8 was isolated in 61% yield and hydrogenated to
give calystegine B2 ([a]20 +23.8 (c 0.31, H2O)). NMR data and
optical rotation were in Daccordance with those reported for the
natural product.13
The same sequence was then applied to the synthesis of
calystegine B3 and B4 (Scheme 2). Subjecting galactose-derived
iodoglycoside 9 to the domino reaction gave a 2+1 mixture of
amino dienes. Major diastereomer 10‡ was isolated in 59%
yield and then converted into cycloheptene 12. Hydroboration
and oxidation gave a 3+1 mixture of ketones and the major
isomer 13 was isolated in 64% yield. Hydrogenation then
furnished calystegine B3 ([a]20 +75.6 (c 0.55, H2O)) with NMR
data and optical rotation in Daccordance with the data for the
natural compound.13 Subjecting mannose-derived iodoglyco-
side 14 to the domino reaction gave a 8+1 mixture of amino
dienes and the major diastereomer 15§ was isolated in 71%
yield. The stereochemical outcome in these allylations is
noteworthy. In all three cases the major product is the (R)-
benzylamine which is the correct stereochemistry for the
calystegines. The major product 15 from mannose is consistent
with predictions from the Felkin-Anh model while the major
isomers from glucose and galactose are not. This, however, does
correspond with our previous experience on zinc-mediated
alkylations of glucose and mannose substrates.4a Finally, amine
15 was converted into cycloheptene 17 which was hydroborated
and oxidised to give a 3+1 ratio of ketones. The major isomer 18
was isolated in 63% yield and deprotected to give calystegine
B4 ([a]2D0 246.4 (c 0.18, H2O)). NMR data and optical rotation
were similar to those reported for the natural product.7
In conclusion, a general strategy for preparation of the
calystegines has been devised. Calystegine B3 and B4 have been
prepared for the first time and their absolute configuration
confirmed. These syntheses should hold great promise for
making the calystegines and their analogues more readily
available for biological investigations.
1 Iminosugars as Glycosidase Inhibitors, ed. A. E. Stütz, Wiley-VCH,
Weinheim, 1999.
2 N. Asano, R. J. Nash, R. J. Molyneux and G. W. J. Fleet, Tetrahedron:
Asymmetry, 2000, 11, 1645; A. A. Watson, D. R. Davies, N. Asano, B.
Winchester, A. Kato, R. J. Molyneux, B. L. Stegelmeier and R. J. Nash,
in ACS Symposium Series, vol. 745, ed. A. T. Tu and W. Gaffield, ACS,
Washington, DC, 2000, p. 129.
3 (a) F.-D. Boyer and I. Hanna, Tetrahedron Lett., 2001, 42, 1275; (b) T.
Faitg, J. Soulié, J.-Y. Lallemand and L. Ricard, Tetrahedron: Asym-
metry, 1999, 10, 2165; (c) C. R. Johnson and S. J. Bis, J. Org. Chem.,
1995, 60, 615; (d) F.-D. Boyer and J.-Y. Lallemand, Tetrahedron, 1994,
50, 10443; (e) O. Duclos, M. Mondange, A. Duréault and J. C. Depezay,
Tetrahedron Lett., 1992, 33, 8061.
4 (a) L. Hyldtoft and R. Madsen, J. Am. Chem. Soc., 2000, 122, 8444; (b)
L. Hyldtoft, C. S. Poulsen and R. Madsen, Chem. Commun., 1999,
2101.
5 For application to seven- and eight-membered rings, see: I. Hanna and
L. Ricard, Org. Lett., 2000, 2, 2651.
6 Recently, the method in ref. 4 was used for a very similar synthesis of
1 (see ref. 3a) which has prompted us to publish our results now.
7 N. Asano, A. Kato, H. Kiza, K. Matsui, A. A. Watson and R. J. Nash,
Carbohydr. Res., 1996, 293, 195.
8 B. Bernet and A. Vasella, Helv. Chim. Acta, 1979, 62, 1990.
9 M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1,
953.
We thank the Danish Natural Science Research Council for
financial support.
10 For a recent review on olefin metathesis in carbohydrate chemistry, see:
M. Jørgensen, P. Hadwiger, R. Madsen, A. E. Stütz and T. M.
Wrodnigg, Curr. Org. Chem., 2000, 4, 565.
11 W. Wang, Y. Zhang, M. Sollogoub and P. Sinaÿ, Angew. Chem., Int.
Ed., 2000, 39, 2466.
Notes and references
† All Cbz-protected compounds showed mixtures of rotamers by NMR.
‡ Spectral data for 10: dH (CDCl3) 7.35–7.22 (m, 20H), 5.98 (ddd, 1H, J
17.9, 10.0, 8.5), 5.65 (m, 1H), 5.31 (bd, 1H, J 10.0), 5.15 (bd, 1H, J 17.5),
12 D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277.
13 N. Asano, A. Kato, K. Oseki, H. Kizu and K. Matsui, Eur. J. Biochem.,
1995, 229, 369.
Chem. Commun., 2001, 1106–1107
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