Boc
N
Boc
N
intermediates 16, 18 proved moderately active towards
b-galactosidases [16: bovine liver, IC50/mm 460, Ki/mm 228;
Aspergillus orizae, IC50 540, Ki 705; 18: bovine liver, 31%
inhibition at 1 mm].
In summary, short and efficient syntheses of 1,4-imino-
d-mannitol and -d-gulitol as well as of new amino analogues of
DIM and of deoxy-manno-nojirimycin are presented, demon-
strating the potential of the Henry reaction for the dia-
stereoselective assembly of iminopolyols.
HO
OH
MsO
OH
i, ii
iii
O
O
10
OH NHZ
OH NHZ
13
14
iv
v
NH2•HCl
Boc
N
HO
HO
HO
O
HO
HO
Financial support by the Landesgraduiertenfo¨rderung Baden-
Wu¨rttemberg (doctoral fellowship to F.-M. K.) and by the
Fonds der Chemischen Industrie is gratefully acknowledged.
NH OH
HO
•
NH
HCl
15
3•2HCl
vi, vii
Footnotes and References
NHAc
NH2•HCl
HO
* E-mail: jager.ioc@po.uni-stuttgart.de
† Nitro compounds, Part 6. Part 5: V. Ja¨ger and P. Poggendorf, Org. Synth.,
1996, 74, 130.
viii, ix
HO
NH OH
N
OH
Z
•
1 F.-M. Kieß, S. Picasso and V. Ja¨ger, presented in part at the 15th
International Symposium, Synthesis in Organic Chemistry, Oxford, July
22–24, 1997, A21.
HCl
17•HCl
16•HCl
Scheme 4 Reagents and conditions: i, H2 (4 bar), Pd–C, MeOH, 25 °C, 22
h; ii, ZCl, NaHCO3, dioxane, H2O, 0 to 25 °C, 24 h, then crystallization
(hexanes–EtOAc), 61% (10?13); iii, MsCl, NEt3, CH2Cl2, 210 to 25 °C,
22 h, 84%; iv, H2 (4 bar), Pd–C, MeOH, 25 °C, 18 h, 96%; v, 5 m HCl, 0 °C,
2 h, 90%; vi, ZCl, NaHCO3, dioxane, H2O, 0 to 25 °C, 20 h, 91%; vii, 3 m
HCl, MeOH, 0 to 25 °C, 3 h, 98%; viii, Ac2O, KHCO3, dioxane, H2O, 0 to
25 °C, 3 h, 87%; ix, H2, Pd–C, 0.1 m HCl, MeOH, 18 h, 96%
2 E.g. see (a) H. Paulsen and K. Todt, Adv. Carbohydr. Chem., 1968, 23,
115; (b) G. Legler, Adv. Carbohydr. Chem. Biochem., 1990, 48, 319; (c)
B. Winchester and G. W. J. Fleet, Glycobiology, 1992, 2, 199; (d)
M. L. Sinnott, Chem. Rev., 1990, 90, 1171.
3 G. W. J. Fleet, P. W. Smith, S. V. Evans and L. E. Fellows, J. Chem.
Soc., Chem. Commun., 1984, 1240.
4 L. E. Fellows, E. A. Bell, D. G. Lynn, F. Pilkiewicz, I. Miura and
K. Nakanishi, J. Chem. Soc., Chem. Commun., 1979, 977.
5 For reviews see e.g. G. Casiraghi, F. Zanardi, G. Rassu and P. Spanu,
Chem. Rev., 1995, 95, 1677; T. Hudlicky, D. A. Entwistle, K. K. Pitzer
and A. J. Thorpe, Chem. Rev., 1996, 96, 1195; V. Ja¨ger, R. Mu¨ller,
T. Leibold, M. Hein, M. Schwarz, M. Fengler, L. Jaroskova, M. Pa¨tzel
and P.-Y. LeRoy, Bull. Soc. Chim. Belg., 1994, 103, 491.
6 L. Henry, C. R. Hebd. Seances Acad. Sci., 1895, 120, 1265; G. Rosini,
in Comprehensive Organic Synthesis, ed. B. M. Trost, Pergamon, New
York, 1991, vol. 2, p. 321; M. Shibasaki, H. Sasai and T. Arai, Angew.
Chem., Int. Ed. Engl., 1997, 36, 1236.
by hydrogenation, followed by N-protection with benzyl
chloroformate (ZCl) (Scheme 4). The major diastereomer 13
(d-manno) was separated by crystallization. Regioselective
mesylation of the primary hydroxy group then led to the
methanesulfonate 14. Hydrogenolysis of the Z group was
accompanied by N-cyclization7 to afford the pyrrolidine 15. On
treatment of 15 with hydrochloric acid, the amino analogue of
DIM 3 was obtained as the bis(hydrochloride). The configura-
tion of 3 was again secured by X-ray crystallography.7c Due to
orthogonal protection, the two amino groups of 14 could be
functionalized individually, as is shown by the syntheses of the
5-acetylaminopyrrolidine 17 and the 4-aminopiperidine 4. After
Z protection of the ring nitrogen in 15, the 5-amino function was
liberated with aqueous acid to yield 16. N-Acetylation and
finally removal of Z furnished the 5-acetamido target compound
17 in the form of its hydrochloride (Scheme 4).
Next, the isomeric structure of the piperidine 4 was sought
from the methanesulfonate 14, by changing the order of steps.
After removal of both the Boc and the acetonide protecting
groups with acid, cyclization to the piperidine 18 took place on
treatment with base. Catalytic hydrogenation under acidic
conditions, followed by ion exchange chromatography, and
subsequent reaction with hydrobromic acid led to the piperidine
4 in form of the bis(hydrobromide) (Scheme 5). The l-manno
enantiomers of 3 and 4 were prepared according to the same
protocol, starting with d-6, readily accessible from l-serine.
7 (a) V. Ja¨ger and V. Wehner, Angew. Chem., Int. Ed. Engl., 1990, 29,
¨
1169; (b) J. Raczko, V. Ja¨ger, K. Peters, V. Wehner, R. Ohrlein,
B. Steuer and P. Poggendorf, Abstr. Pap. XVIth Int. Carbohydr. Symp.,
Paris, July 5–10, 1992, A 227; (c) F.-M. Kieß, Dissertation, Universita¨t
¨
Stuttgart, planned; (d) A. Menzel, H. Griesser, R. Ohrlein, V. Wehner
and V. Ja¨ger, unpublished work.
¨
8 R. Ohrlein and V. Ja¨ger, Tetrahedron Lett., 1988, 29, 6083; B.
Aebischer, J. H. Bieri, R. Prewo and A. Vasella, Helv. Chim. Acta, 1982,
65, 2251; cf. use of ‘anhydrous’ Bu4NF for silyl nitronate additions:
D. Seebach, A. K. Beck, T. Mukhopadhyay and E. Thomas, Helv. Chim.
Acta, 1982, 65, 1101.
9 (a) G. J. F. Chittenden, Carbohydr. Res., 1980, 84, 350; (b) B. Ha¨fele
and V. Ja¨ger, Liebigs Ann. Chem., 1987, 85; (c) J. Jurzak, S. Pikul and
T. Bauer, Tetrahedron, 1986, 42, 447; (d) R. W. Hoffmann, G. Eichler
and A. Endesfelder, Liebigs Ann. Chem., 1983, 2000.
10 (a) S. Guttmann and R. A. Boissonnas, Helv. Chim. Acta, 1958, 41,
1852; (b) P. Garner, Tetrahedron Lett., 1984, 25, 5855; (c) A. J. Blake,
E. C. Boyd, R. O. Gould and R. M. Paton, J. Chem. Soc., Perkin Trans
1, 1994, 2841.
11 W. D. Emmons and A. S. Pagano, J. Am. Chem. Soc., 1955, 77, 4557;
T. M. Williams and H. S. Mosher, Tetrahedron Lett., 1985, 26, 6269.
12 V. Ja¨ger and V. Wehner, Angew. Chem., Int. Ed. Engl., 1989, 28, 469;
B. Steuer, V. Wehner, A. Lieberknecht and V. Ja¨ger, Org. Synth., 1996,
74, 1.
OH
OH
HO
NH2•HBr
HO
NHZ
OH
i, ii
iii
14
OH
N
H
N
H
13 F. W. Lichtenthaler and H. P. Albrecht, Chem. Ber., 1969, 102, 964.
14 R. Appel and R. Kleinstu¨ck, Chem. Ber., 1974, 107, 5; for application to
cyclizations see, e.g. Y. Chen and P. Vogel, Tetrahedron Lett., 1992, 33,
4917; U. Veith, O. Schwardt and V. Ja¨ger, Synlett, 1996, 1181; see also
ref. 5.
•HBr
18
4•2HBr
Scheme 5 Reagents and conditions: i, 3 m HCl, MeOH, 0 to 25 °C, 6 h,
quant.; ii, KHCO3, H2O, 25 °C, 18 h, 92%; iii, H2, Pd–C, 1 m HCl, MeOH,
25 °C; 2.5 h; Dowex 50 W (H+ form); 1 N HBr; 94%
15 J. G. Buchanan, K. W. Lumbard, R. J. Sturgeon and D. K. Thompson,
J. Chem. Soc., Perkin Trans. 1, 1990, 699.
The iminopolyols were tested concerning their inhibitory
activity on 24 glycosidases.17 While DIM 1, in accord with the
literature,3 showed strong and very selective inhibition of
a-mannosidases [jack bean, IC50/mm 3, Ki /mm 1.6; almond, IC50
6, Ki 1.6], the 5-amino analogues 3 and 17 were inactive; this
emphasizes the crucial role of the 5-hydroxy function in 1.18
The piperidines 4 and 18 showed no activity either, nor did the
l-enantiomers of 3, 4 and 18. In contrast, the N-protected
16 1: S. Henkel, F.-M. Kieß and V. Ja¨ger, Z. Kristallogr., 1997, 212, 213;
d-gulo isomer: S. Henkel, F.-M. Kieß and V. Ja¨ger, ibid., 217.
17 A. Brandi, S. Cicchi, F. M. Cordero, R. Frignoli, A. Goti, S. Picasso and
P. Vogel, J. Org. Chem., 1995, 60, 6806.
18 D. A. Winkler and G. Holan, J. Med. Chem., 1989, 32, 2084;
B. Winchester, S. Al Daher, N. Carpenter, I. Cenci di Bello, S. S. Choi,
A. J. Fairbanks and G. W. J. Fleet, Biochem. J., 1993, 290, 743.
Received in Liverpool, UK, 23rd September 1997; 7/06915D
120
Chem. Commun., 1998