Stereoselective synthesis of α-aminonitriles at non-anomeric positions of monosaccharides

Article abstract of DOI:10.1016/S0040-4039(00)01090-X

α-Aminonitriles have been stereoselectively introduced at non-anomeric positions of monosaccharides, in which the carbon C-α is one of the atoms of the sugar ring. Target compounds were prepared from various ulose derivatives and amines using titanium(IV) isopropoxide as a mild and effective Lewis acid. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01090-X

Tetrahedron Letters 41 (2000) 6403±6406
Stereoselective synthesis of a-aminonitriles at non-anomeric
positions of monosaccharides
Denis Postel,* Albert Nguyen Van Nhien, Michelle Pillon, Pierre Villa
and Gino Ronco
Â
Â
Laboratoire de Chimie Organique et Cinetique, Universite de Picardie-Jules Verne, 33 rue Saint Leu,
80039 Amiens, France
Received 6 April 2000; accepted 27 June 2000
Abstract
a-Aminonitriles have been stereoselectively introduced at non-anomeric positions of monosaccharides, in
which the carbon C-a is one of the atoms of the sugar ring. Target compounds were prepared from various
ulose derivatives and amines using titanium(IV) isopropoxide as a mild and e€ective Lewis acid. # 2000
Elsevier Science Ltd. All rights reserved.
a-Aminonitriles are important starting materials for the synthesis of many aminoacids and
heterocycles with biological activities.1 Moreover, they are readily hydrolyzed to give a-amino-
carboxamides or reduced to give 1,2-diamines, which are of interest as ligands for platinum(II)
complexes with potential antitumor properties.2,3 It is envisaged that a-aminonitriles might serve
as precursor of new azaspironucleoside analogues of TSAO.4,5 Also, aminonitriles have been used
to synthesize various 4-amino-2,3-dihydroisothiazole-1,1-dioxides via carbanion mediated
sulfonamide intramolecular cyclizations (CSIC).6,7 In contrast, attempts to synthesise 4-amino-
2,3-dihydroisothiazole-1,1-dioxides from uloses have not been successful due to diculties
encountered in the preparation of the required aminonitrile precursors.7
Optically active a-aminonitriles have been obtained by asymmetric Strecker syntheses.1,8
Optical induction is e€ected by chiral and hindered amines such as l-1-phenylethylamine or tetra-
O-pivaloyl-b-d-galactosamine. In such a reaction enantiomeric excess is solvent dependant.9
Chiral aminonitriles have been obtained by resolution of racemates corresponding optically
active organic acid.1 More recently, a-aminonitriles have been obtained by the hydrogenation of
^
a-azidonitriles derived from a SN2 reaction of N3 with optically a-methanesulfonyloxynitrile
derivatives.10,11
We now report the stereoselective synthesis of new a-aminonitriles at non-anomeric positions
of monosaccharides, where the C-a is also one of the carbon atoms of the sugar ring.
Treatment of the ulose derivative 1 with KCN, NH4Cl and either octylamine or benzylamine
(Strecker synthesis) (Scheme 1) at room temperature gave the cyanohydrine 2 but no a-aminonitrile
* Corresponding author. Tel: 03 22 82 75 70; fax 03 22 82 75 68; e-mail: denis.postel@sc.u-picardie.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01090-X

6404
was detected. The same cyanohydrine was also observed, in a similar reaction in which crushed
molecular sieve was added. The lack of reactivity could be explained by the following: (i) ketoses
are generally more sterically hindered than aldehydes; and (ii) ketose carbonyl carbons are
generally less electrophilic than those of aldehydes or a-ketoesters.
Scheme 1. (i) Octylamine or benzylamine, KCN, NH4Cl, MeOH; (ii) benzylamine, molecular sieves (4 A), iPrOH; (iii)
RNH2, Ti(OiPr)4, MeOH then TMSiCN
In order to increase the electrophilic character of the ulose carbonyl in 1, the aminocyanation
was performed in the presence of titanium(IV) isopropoxide as the Lewis acid catalyst. This
reagent is known to be mild, e€ective and compatible with a variety of acid-sensitive functional
groups such as lactams, tert-butyldimethylsilyl ethers or acetonides.12
The aminocyanation of the d-glucose derivative 1 was performed by a reaction with NH3,
methylamine, octylamine and benzylamine, respectively. The (Z/E) imine intermediates 3/30 were
not isolated and the cyanating agent TMSiCN was added after 12 h. Under these conditions, the
a-aminonitrile derivatives 4a±d were obtained in 50±98% yield.13
The con®guration at the quaternary carbon was determined by both X-ray crystallography and
1H NMR spectroscopy. In the latter, NOE e€ects were studied by selective irradiation of the
amino proton and inspection of the behaviour of the H-4 signal. These indicated that the
diastereoisomer with the (R)-con®guration at the a-carbon (C-3) was exclusively formed by
stereoselective attack of CN^ at the b-face of the sugar ring.
Similarly, uloses of the d-xylose derivatives 5, 7, 9, and the d-fructose derivative 11
stereoselectivally led to the a-aminonitriles 6a±d, 8, 10 and 12a,c in, respectively, 60±98% yield.14
It would appear that the titanium(IV) isopropoxide acts as both a dehydrating agent and Lewis
acid to give the imine intermediate. Moreover, this catalyst would seem to be inducing
stereoselectivity by chelating with the N-atom of the imine group and the O-atom at C-2; such a
complex would hinder the a-face of the sugar ring and give preference for the addition of CN^ at
the b-face.

6405
The treatment of the d-galactofuranose derivative 13 using the same conditions resulted in
inversion at C-4 (Scheme 2) to give the d-glucose a-aminonitrile 4a in poor yield (12%).
Scheme 2.
With the exception of ammonia, aminocyanations were also achieved using an alternative
procedure. The solvent and cyanating agent were added to a stirred mixture of titanium(IV)
isopropoxide and amine after complete disappearance of the ketone band in the IR spectrum was
observed. This method gave the a-aminonitriles 4c and 4d in 53% yield (Scheme 3). A low yield
was obtained when 1 was reacted with methylamine to give the a-aminonitriles 4b and 40b (16%).
However, the epimeric mixture showed a large excess of the CN b-face form (4b:40b, 7:1).
Scheme 3. (iv) Ti(OiPr)4, RNH2 then TMSiCN
Reduction of the cyano group of the a-aminonitriles 4a and 6a with LiAlH4 gave the
corresponding 1,2-diamine derivatives 14 (52%) and 15 (66%). The byproducts 16 (12%) and 17
(26%) were also isolated, resulting from base-catalyzed elimination of HCN and subsequent
reduction of the corresponding imine.
Work is now underway to explore reaction conditions which might best preserve the nitrile
group during the total deacetalation of the a-aminonitrile derivatives.

6406
In conclusion, we have reported a simple and short stereoselective synthesis of a-aminonitriles
and 1,2-diamines from monosaccharides, based on the use of titanium(IV) isopropoxide as a mild
Lewis acid catalyst. These compounds represent a new class of disubstituted sugar derivatives
which are good precursors of various glyco-a-aminoacids, glycopeptides and spiroheterocycles.
Such modi®cation leaves the anomeric position free for further derivatization. Such studies are
being continued in our laboratory.
Acknowledgements
We thank the Conseil Regional de Picardie and the Ministere Francais de la Recherche for
®nancial support and G. Mackenzie for helpful discussions.
References
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4. Velazquez, S.; Chamorro, C.; Perez-Perez, M. J.; Alvarez, R.; Jimeno, M. L.; Domenech, A. M.; Perez, C.;
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5. Balzarini, J.; Camarasa, M. J.; Karisson, A. Drugs of the Future 1993, 18, 1043±1055.
6. Marco, J. L.; Ingate, S. T.; Manzano, P. Tetrahedron Lett. 1998, 39, 4123±4124.
7. Marco, J. L.; Ingate, S. T. Tetrahedron Lett. 1997, 38, 4835±4836.
8. Stout, D. M.; Black, L. A.; Matier, W. L. J. Org. Chem. 1983, 48, 5369±5373.
9. Kunz, H.; Sager, W.; Pfrengle, W.; Schanzenbach, D. Tetrahedron Lett. 1988, 29, 4397±4400.
10. E€enberger, F.; Kremser, A.; Stelzer, U. Tetrahedron: Asymmetry 1996, 7, 607±618.
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3332.
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13. Procedure for the preparation of 3-amino-3- C-cyano-3-deoxy-1,2:5,6-di-O-isopropylidene-ꢀ-d-allofuranose 4a: A
mixture of 1 (1 g), MeOH±NH3 (7N, 5.4 mL), Ti(OiPr)4 (1.2 equiv.) and dry MeOH (2.4 mL) was stirred at room
temperature. After 5 h, TMSiCN (1 equiv., 0.5 mL) was added and the solution was stirred for 5 h. Water (0.5
mL) and EtOAc were added and the solution was evaporated under reduced pressure. Silica gel column
chromatography (eluent hexane:ethyl acetate, 4:1) gave 4a (0.88 g, 80%) as a solid; m.p. 79±82ꢀC; [ꢀ]D +5 (c 1.2,
1
CHCl3). H NMR (CDCl3) ꢁ 5.84 (d, 1H, H-1, J1,2=3.5 Hz), 4.68 (d, 1H, H-2), 4.29 (m, 1H, H-5, J5,6b=4.5 Hz),
4.10 (dd, 1H, H-6a, J5,6a=6.0 Hz), 3.92 (dd, 1H, H-6b, J6a,6b=9.0 Hz), 3.59 (d, 1H, H-4, J4,5=9.0 Hz), 2.02 (s, 2H,
NH2), 1.49 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.29 (s, 6H, CH3); 13C NMR (CDCl3) ꢁ 118.6 (CN), 113.7
(CH3CCH3), 110.1 (CH3CCH3), 103.9 (C-1), 83.3 (C-2), 81.6 (C-4), 75.0 (C-5), 67.6 (C-6), 62.7 (C-3), 27.1
(CH3), 26.8 (CH3), 26.7 (CH3), 25.2 (CH3).
14. Selected spectroscopic values: compound 6a: 13C NMR (CDCl3) ꢁ 143.3 (3C, C ipso), 128.6, 128.1, 127.4 (15C, Ph),
118.5 (CN), 113.4 (CH3CCH3), 103.9 (C-1), 87.9 (Ph3C), 83.3 (C-2), 79.9 (C-4), 63.3 (C-5), 62.3 (C-3), 26.5, 26.4
(2C, CH3); compound 8: 13C NMR (CDCl3) ꢁ 137.2, 128.5, 127.9 (6C, Ph), 118.5 (CN), 113.5 (CH3CCH3), 104.1
(C-1), 83.0 (C-2), 79.7 (C-4), 74.0 (PhCH2O), 69.1 (C-5), 62.4 (C-3), 26.5, 26.3 (2C, CH3); compound 10: 13C NMR
(CDCl3) ꢁ 166.0 (CˆO), 133.3, 129.8, 129.3, 128.4 (6C, Ph), 118.0 (CN), 113.5 (CH3CCH3), 104.0 (C-1), 82.9 (C-2),
79.4 (C-4), 62.8 (C-5), 61.1 (C-3), 26.4, 26.2 (2C, CH3).