A Regioselective One Pot Synthesis and Synthetic Applications of Cyanodeoxy Sugars by Cyanotrimethylsilane [1] Syed Najam-ul-Hussain Kazmia, Zaheer Ahmed3, Abdul Malik3 *, Nighat Afzab, Wolfgang Voelterc a H. E. J. Research Institute of Chemistry, University of Karachi, Karachi 75270, Pakistan b Pharmaceutical and Fine Chemical Division, P.C.S.I.R. Laboratories, Karachi 75280, Pakistan c Abteilung für Physikalische Biochemie, Physiologisch-chemisches Institut der Universität Tübingen. Hoppe-Seyler-Straße 4, 72076 Tübingen. Germany Z. Naturforsch. 50b, 294-302 (1994); received June 28, 1994 Anhydro Sugars, Cyanodeoxy Sugars, Epoxy Ring Opening, Branched Chain Pyranoses, Cyanotrimethylsilane The regioselective epoxide opening of different 2,3-anhydropyranoses by cyanotrimethyl­ silane is investigated. The isolated cyanodeoxy pyranoses allow easy access to the correspond­ ing branched-chains aminomethyl sugars by lithium aluminium hydride reduction or sugar amides by controlled acid hydrolysis. Introduction described by them and involves initial formation Cyanodeoxy sugars assume a key role in the of C12A1CN species by the reaction of cyanotri­ syntheses of C-glycosyl compounds and branched- methylsilane and aluminium chloride. The reac­ chain sugars [2-5] besides serving as precursors tion of the C12A1CN species with oxiranes gives for most of the naturally occurring C-nucleoside a cyano-aluminated product [12] that undergoes antibiotics and their analogs [2-6], One method fra«s-metallation with cyanotrimethylsilane to give employed, amongst others, for the synthesis of trimethylsilyloxy nitrile with the regeneration of cyanodeoxy sugars involves cleavage of the oxir- the A1C13 species. An alternate mechanism is also ane ring in 2,3-anhydropyranosides by a variety of proposed [13] in which a complex is formed be­ nitrile containing reagents [7], The epoxides of tween the Lewis acid and the oxygen of the monocyclic sugars have a flexible half-chair con­ strained ether. Ring opening then occurs via a six- formation [8-10] and exist in two forms 5H0 and membered transition state in which the nucleo- °H5; trans -diaxial epoxide cleavage in these leads philic attack by the carbon of the isocyanide form in general to a binary mixture of isomeric com­ of trimethylsilyl cyanide occurs simultaneously pounds. Moreover, if a trans-hydroxy group is ad­ with chloride attack on silicon. Exchange of oxy­ jacent to the epoxide group, epoxide migration gen and chloride between silicon and aluminium may occur, giving several undesirable side prod­ then gives the product and regenerates the cata­ ucts [11]. A reaction which overcomes these limit­ lyst. In the present work we found that epoxide ing factors in the trans -diaxial opening of the ring opening in a group of 2,3-anhydro sugars with oxirane rings in 2,3-anhydro sugars with cyanotri­ cyanotrimethylsilane and aluminium chloride re­ methylsilane in presence of 1 equivalent of an­ sults in partial transformation to cyanodeoxy su­ hydrous aluminium chloride as catalyst. The role gars which did not consume periodate, and did not of aluminium chloride in controlling the ambident react with lead tetraacetate, thus indicating the reactivity of cyanotrimethylsilane and the prefer­ absence of a 1,2-glycol moiety. The product in ential formation of nitriles over isonitriles has al­ each case arises from the more stable predominant conformation of the epoxy sugar. The isomeric ready been reported in literature by Imi et al. [12]. The reaction path way of the reactants was also products were formed in trace amounts and could be eliminated easily through column chromatogra­ phy. Apart from the cyanodeoxy sugars the un­ changed anhydro sugars could also be recovered * Reprint requests to Prof. Dr. A. Malik. and recycled. The absence of trimethylsilyl ether 0932-0776/95/0200-0294 $06.00 © 1994 Verlag der Zeitschrift für Naturforschung. All rights reserved. S. N. Kazmi et al. • A Regioselective One Pot Synthesis 295 moiety in the products is probably due to the hy­ Epoxide migration was not observed in the case drolysis by the hydrogen chloride present as im­ of anhydro sugar (1) which has an adjacent purity in the catalyst. hydroxy group trans to the epoxide ring. The ap­ proach of the Lewis catalyst for co-ordination with Results and Discussion the oxirane oxygen is sterically hindered in 5 by As model compounds we synthesized benzyl- the a-oriented bulky substituent at C-l as well as 2, 3-anhydro-a-D-lyxopyranoside (1) [14], benzyl- hydrogen bonding [21], and should have resulted 2.3-anhydro-/3-L-ribopyranoside (2) [14], methyl- in exceptionally low yield of the cyanodeoxy sugar 2.3-anhydro-4,6-0-benzylidene-a-D-allopyranoside (10) if the second mechanism is operative. How­ (3) [15], methyl-2,3-anhydro-4,6-0-benzylidene- ever, the yield of 10 was comparable to those of a-D-mannopyranoside (4) [16], and benzyl-2,3-an- other sugars (Table I) which reflects that the oxir­ hydro-a-D-ribopyranoside (5) [17], respectively. ane ring is cleaved by C12A1CN species (mechan­ The anhydro sugars (1) and (2) have been shown ism 1). The time of reaction was, however, signifi­ by 'H NMR to exist almost entirely in the favored cantly decreased to 4h rather than 8-18 h half-chair conformation 5H0. 7rans-diaxial open­ required for other epoxy sugars apparently be­ ing leads to benzyl-3-cyano-3-deoxy-a-D-arabino- cause of the approach of C12A1CN species from pyranoside (6) and benzyl-3-cyano-3-deoxy-/3-L- the sterically less hindered direction. xylopyranoside (7), respectively. The attack by The structures of compounds 6-10 were fully cyanide at position 3 is also favoured by steric con­ supported by the analytical data (Table I) as well siderations as position 2 is comparatively blocked as 400 MHz *H NMR spectra. The chemical shift by the bulky substituent at C-l. The anhydro assignments were facilitated by a series of 'H ^ H sugars (3) and (4) are locked in the :’H0 confor­ homodecoupling experiments, 'H-'H-correlated mation by the trans -fused 4,6-O-benzylidene ring spectroscopy (COSY-45°), and 2 D-7-resolved and the cleavage gives diaxial products (8) and (9) spectra. The conformations adopted by pyranoside according to the Fürst-Plattner rule [19]. The rings in compounds (6 - 10) were determined by anhydro sugar (5) undergoes trans -diaxial cleav­ vicinal coupling constants and chemical shift cor­ age to give benzyl-3-cyano-3-deoxy-a-D-xylopyr- relations. The chemical shifts for 1-H appeared to anoside (10). In this epoxy sugar the conformation be the most helpful of all parameters in assigning during the reaction is evidently 5H0, which is stabi­ conformations to all five compounds. It remained lized in the transition state by hydrogen bonding fairly constant for compounds (8 - 10) and showed between the 4-hydroxy group and the ring oxygen close agreement to the a-glycosidic sugars of 4Q atom. The participation of the 5H0 conformation conformation in which this proton resonates com­ has already been described in the literature [20] to paratively downfield due to the equatorial orien­ explain the persistent formation of xylopyranoside tation. On the other hand, in sugars 6 and 7 the derivatives from this epoxy sugar. signals of 1-H appeared at comparatively upfield Table I. Physical data and analy­ Com­ Reaction Yieldb M d c Formula Found/Calcd (%) ses3 of compounds 6-10. pound time (h) (%) C H N 6 9 59 66.60 c 13h 15n o 4 62.42 6.01 5.60 (62.46 6.07 5.62) 7 8 62 -13.04 c 13h 15n o 4 62.39 5.99 5.68 (62.46 6.07 5.62) 8 18 47 20.13 Ci5H17N 0 5 61.79 5.92 4.83 a Elemental analyses were car­ (61.83 5.88 4.81) ried out with a Carlo Erba Ele­ mental Analyzer, MOD-1106; 9 16 53 100.29 c 15h 17n o 5 61.81 5.80 4.75 b the isolated yield; c the optical (61.83 5.88 4.81) rotations were measured on a 10 4 55 25.10 c 13h 15n o 4 62.43 6.03 5.64 Schmidt and Haensch Polar- (62.46 6.07 5.62) tronic-D Polarimeter using chloro­ form as solvent. 296 S. N. Kazmi et al. • A Regioselective One Pot Synthesis (H 3C)3SiCN + A1C1, (H 3Q 3S1CI + C12 A1CN C1->A1-C=N RI / V Y C = N-A1C1; w ork-up (2 ) R 1 = H, R 2 = OH (7) R = H, R = OH work-up o a ^ P h Scheme 1 (8 ) r' = cn, r : = oh (9) r' = oh ,r 2 = c n S. N. Kazmi et al. ■ A Regioselective One Pot Synthesis 297 Tab. II. !H NMR data 3 of compounds 6- 10. Compound Conformation Pyranoside ring ArH 6 1C 4.67 (1 H, d, 1-H), 4.19 (1 H, dd, 5-Ha), 7.34-7.28 (5H, m) 4.69 (2H, dd, C H .-Ph), 3.90 (1 H, dd, 5-Hb), 3.69 (1 H, m, 4-H), 3.66 (1 H, dd, 2-H), 2.89 (1 H, dd, 3-H) 7 1C 4.64 (1 H, d, 1-H), 4.21 (1 H, dd, 5-Ha), 7.35-7.28 (5H, m) 4.59 (2H, dd, C H ,-Ph), 3.98 (1 H, dd, 5-Hb), 3.87 (1 H, m, 4-H), 3.60 (1 H, dd, 2-H), 2.98 (1 H, dd, 3-H) 8 C l 5.01 (1H, d, 1-H), 4.23 (1H, dd, 6-Ha), 7.53-7.39 (5H, m) 9.38 (1H, s, HC-Ph), 4.05 (1 H, dd, 6-Hb), 3.91 (1 H, m, 5-H), 3.46 (3 H, s, OCH,) 3.72 (1 H, dd, 4-H), 3.51 (1 H, dd, 3-H), 3.10 (1H, dd, 2-H) 9 C l 5.12 (1H, d, 1-H), 4.05 (1H, dd, 6-Ha), 7.53-7.34 (5H, m) 10.02 (1H, s, HC-Ph), 3.92 (1 H, dd, 6-Hb), 3.86 (1 H, m, 5-H), 3.37 (3 H, s, OCH3) 3.71 (1 H, dd, 4-H), 3.61 (1 H.