LETTER
Synthesis of (+)-Azafagomine from D-xylose
703
3, 13C NMR (D2O): d 175.6 (COMe), 167.8 (COPh), 133.3,
131.7, 129.3, 128.2 (Ph), 73.3, 71.9, 70.1 (C-2, C-3, C-4), 63.9
(C-5), 52.1 (C-1), 21.0 . 1H-NMR (D2O): d 10.37 (bs, 1H,
BzNH), 7.82 (dd, 2H, PhH), 7.30-7.50 (m, 3H, PhH), 3.3-4.2
(m, 7H), 2.05 (s, 3H, CH3). MS (FAB): m/z 313.13; calc. for
C14H20N2O6 + H: 313.14.
Table 1 Inhibition of glucosidases by stereoisomers of 1
4, 13C-NMR (CDCl3): d 173.3 (COMe), 166.3 (COPh), 132.6,
131.7, 128.6, 127.2 (Ph), 109.6 (C(CH3)2), 76.8, 74.7, 69.5 (C-
2, C-3, C-4), 65.5 (C-5), 53.9 (C-1), 29.2, 27.1, 26.0, 25.3
(C(CH3)2), 20.3 ppm (CH3). 1H-NMR (CDCl3): d 9.1 (s, 1H,
BzNH), 7.8 (dd, 2H, PhH), 7.40-7.60 (m, 3H, PhH), 3.3-5.5
(m, 7H), 2.0 (s, 3H, Ac), 1.3 (2s, 12H, CH3’s). MS (FAB): m/
z 393.20; calc. for C12H18N2O5 + H: 393.20.
Compound (+)-1 was tested for inhibition of almond
b-glucosidase and yeast a-glucosidase, two enzymes that
(±)-1 was known to inhibit strongly (Table 1).11 Com-
pound (+)-1 was found to be an extremely weak inhibitor
of both enzymes. Based on this, the inhibition constant of
the active stereoisomer (-)-1 could also be calculated. The
difference in inhibition strength of the two antipodes is re-
markably large: for b-glucosidase it is more than 33.000
and for a-glucosidase it is about 1500. Therefore in this
case, the enzymes very definitely recognise the (-)-enan-
tiomer as a D-glucose analogue, while the (+)-enantiomer
apparently does not fit into the active site.
5, 1H NMR (CDCl3): d 9.3 (bs, 1H, BzNH), 7.85 (dd, 2H,
PhH), 7.40-7.60 (m, 3H, PhH), 4.25 (dt, 1H), 3.9 (m, 3H), 3.7
(m, 3H), 2.1 (s, 3H, Ac), 1.3 (s, 6H, CH3’s). MS (FAB): m/z
353.17; calc. for C12H18N2O5 + H: 353.17.
6, 1H NMR (CDCl3): d 9.1 (bs, 1H, BzNH), 7.85 (dd, 2H,
PhH), 7.40-7.60 (m, 3H, PhH), 4.65 (m, 1H), 3.7-4.3 (m, 6H),
3.2 (s, 3H, CH3SO2), 2.1 (s, 3H, Ac), 1.4 (s, 6H, CH3’s), 0.9
(s, 9H, t-Bu), 0.05 (s, 6H, SiCH3). MS (EI): m/z 467 (M+).
7, 1H-NMR (CDCl3): d 7.9 (dd, 2H, PhH), 7.40-7.60 (m, 3H,
PhH), 4.3-4.7 (m, 5H), 3.1 (q, 1H), 2.1 (s, 3H, Ac), 1.4 (d, 6H,
CH3’s), 0.9 (s, 9H, t-Bu), 0.1 (s, 6H, SiCH3).
In this paper we have reported an efficient synthesis of
(+)-azafagomine and also predicted the biological activity
of (-)-azafagomine. The difference in biological activity
of the antipodes is remarkably large. The synthesis can
also readily be used to synthesise (-)-azafagomine from
commercially available L-xylose, which may be required
for certain studies.
8, 13C-NMR (CDCl3): d 143.6, 140.0, 132.8, 131.8, 128.9,
127.3 (Ph’s), 78.7, 75.0, 70.4, 67.2 (C-2, C-3, C-4, C-5), 49.0
(C-1), 27.2, 26.7 ((CH3)2C), 22.6 (ArCH3), 21.0 (Ac). 1H-
NMR (CDCl3): d 9.0 (bs, 1H, BzNH), 7.8 (d, 2H, PhH, Jo,m 8.1
Hz), 7.5 (t, 1H, PhH), 7.4 (t, 2H, PhH), 6.2 (dd, 1H, NH, JNH,NH
5.5, JNH,1 3.0 Hz), 5.24 (d, 1H, OH, J 4.3 Hz) 5.04 (d, 1H, OH,
J 4.3 Hz), 4.99 (d, 1H, OH, J 4.8 Hz), 3.86 (dd, 1H, H-1, J1,2
8.4, JNH,1 3.0 Hz,), 3.69-3.75 (dd, 1H, H-5a, J5a,5b 11.0, J4,5a 6.2
Hz), 2.97-3.37 (m, 4H, H-2, H-3, H-4, H-5b).
Acknowledgement
We thank the Danish Natural Science Research Council for financi-
al support through the THOR program.
9, (3-4 amide rotamers can be observed) 13C-NMR (CDCl3)
the 2 major rotamers: d 171.6, 171.5 (C=O), 131.7-133.2,
126.4-129.1 (Ph), 111.0, 110.8 (C(CH3)2), 84.8, 83.7 (C-5),
73.0, 72.5 (C-4), 70.8, 67.8 (C-6), 55.3, 52.6 (C-3), 48.2, 46.7
(C-7), 27.0, 26.7 (C(CH3)2), 20.3, 20.2 (AcN). 1H-NMR
(CDCl3): d 7.3-7.6 (m, 5H, Ph), 4.5-4.9 (2d and 2dd, 1H), 3.6-
4.2 (m, 4H), 3.4 (m, 1H), 3.1 (m, 1H), 2.8 (m, 1H), 2.0 (3s,
3H), 1.4 (m, 6H). MS (FAB): m/z 335.17; calc. for
C17H22N2O5 + H: 335.16.
References and Notes
(1) Legler, G. Advan. Carbohydr. Chem. Biochem. 1990, 48, 319.
(2) Fleet, G. W.; Winchester, B. Glycobiology 1992, 2, 199.
(3) Lehmann, J.; Rob, B. Tetrahedron: Asymmetry 1994, 5, 2255.
(4) Cottaz, S.; Brimacombe, J. S.; Ferguson, M. A. J. Carbohydr.
Res. 1993, 247, 341.
(5) Sears, P.; Wong, C. -H. Chem. Commun. 1998, 1161.
(6) Ermert, P.; Vasella, A.; Weber, A.; Rupitz, K.; Withers, S. G.
Carbohydr. Res. 1993, 250, 113.
(7) Martin, O. R.; Saavedra, O. M. Tetrahedron Lett. 1995, 36,
799.
(8) Siriwardena, A. H.; Chiaroni, A.; Riche, C.; El-Daher, S.;
Winchester, B.; Grierson, D. S. J. Chem. Soc. Chem.
Commun. 1992, 1531.
10, 13C-NMR (D2O): d 75.7 (C-5), 68.5 (C-4, C-6), 46.5 (C-3,
C-7). 1H-NMR (D2O): d 3.82 (dt, 2H, J3b,4 = J6,7b 6.3, J4,5 = J5,6
6.3, J3a,4 = J6,7a 4.0 Hz, H-4, H-6), 3.61 (t, 1H, J4,5 = J5,6 6.3 Hz,
H-5), 3.24 (d, 2H, J3a,4 = J6,7a 4.0 Hz, H-3a, H-7a) 3.23 (d, 2H,
J3b,4 = J6,7b 6.3 Hz, H-3b, H-7b).
13, 13C-NMR (CDCl3): d 138.2, 137.9, 127.6-128.4 (Ph), 84.9,
80.3 (C-2, C-3), 74.1, 73.4, 71.6, 71.1, 70.7 (C-4, C-5, 3 Bn),
62.9 (C-1). 1H-NMR (CDCl3): d 7.2 (m, 15H, Ph), 4.4 (m, 6H,
Bn’s), 2.8-4.1 (m, 7H).
14, 13C-NMR (CDCl3): d 138.1, 127.6-128.4 (Ph), 74.2, 73.2,
72.1, 71.1, 68.2 (C-4, C-5, 3 Bn), 28.3 ((CH3)3C). 1H-NMR
(CDCl3): d 7.3 (m, 15H, PhH), 6.2 (bs, 1H, BocNH), 4.4-4.7
(m, 6H, Bn’s), 4.3 (bs, 2H, OH, NH), 4.0 (t, 1H, J 6 Hz, H-3),
3.7 (m, 2H), 3.55 (dd, 1H, J 8.3 Hz, J 6 Hz, H-5a), 3.45 (dd,
1H, J 8.3 Hz, J 7 Hz, H-5b), 3.2 (dd, 1H, J 12 Hz, J 4.3 Hz, H-
1a), 3.1 (dd, 1H, J 12 Hz, J 3.2 Hz, H-1b), 1.4 (s, 9H, CH3’s).
15, 1H NMR (CDCl3): d 7.2 (bs, 15H, PhH), 6.85 (bs, 1H,
NH), 4.4-4.7 (m, 7H), 3.9 (m, 3H), 3.4-3.8 (m, 3H), 1.95 (s,
3H, Ac), 1.4 (s, 9H, ((CH3)3C).
(9) Schmidt, R. R.; Dietrich, H. Angew. Chem. Int. Ed. Engl.
1991, 30, 1328.
(10) Ganem, B. Acc. Chem. Res. 1996, 29, 340.
(11) Bols, M.; Hazell, R. G.; Thomsen, I. Chem. Eur. J. 1997, 3,
940.
(12) 2, 13C NMR (DMSO-d6): d 166.2 (COPh), 132.8, 131.8,
128.6, 127.6 (Ph), 92.2 (C-1) 76.8, 71.6, 70.1 (C-2, C-3, C-4),
67.2 (C-5). 1H-NMR (DMSO-d6): d 10.19 (d, 1H, BzNH,
J
NH,NH 5.5 Hz), 7.8 (dd, 2H, PhH, Jo,m 8.1, Jo,p 1.5 Hz), 7.43-
7.55 (m, 3H, PhH), 5.94 (dd, 1H, NH, JNH,NH 5.5, JNH,1 3.0 Hz),
5.24 (d, 1H, OH, J 4.3 Hz) 5.04 (d, 1H, OH, J 4.3 Hz), 4.99 (d,
1H, OH, J 4.8 Hz), 3.86 (dd, 1H, H-1, J1,2 8.4, JNH,1 3.0 Hz,),
3.69-3.75 (dd, 1H, H-5a, J5a,5b 11.0, J4,5a 6.2 Hz), 2.97-3.37
(m, 4H, H-2, H-3, H-4, H-5b). MS (EI): m/z 269 (M+1). MS
(FAB): m/z 269.11; calc. for C12H16N2O5 + H: 269.11.
16, 1H NMR (CDCl3): d 7.3 (bs, 15H, PhH), 6.85 (bs, 1H,
NH), 5.0 (m, 1H), 4.4-4.7 (m, 7H), 3.9 (m, 1H), 3.5-3.8 (m,
3H), 3.25 (m, 1H), 2.95 (s, 3H, Ms), 1.95 (s, 3H, Ac), 1.45 (s,
9H, ((CH3)3C).
17, 13C-NMR (CDCl3): d 172.8, 138.3, 138.0, 137.7, 127.8-
128.5 (Ph), 77.8, 74.7, 73.4 (2C), 72.0, 67.0 (3 Bn, C-3, C.4,
Synlett 1999, No. 6, 701–704 ISSN 0936-5214 © Thieme Stuttgart · New York