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Page 1: Branched-chain sugars. Reaction of 1,2:5,6-di- O -isopropylidene-α- D - ribo -hexofuranos-3-ulose with sodium cyanide and methyl nitroacetate

Branched-chain sugars. Reaction of 1,2:5,6-di-0-isopropylidene- a-D- vibo-hexofuranos-3-ulose with sodium cyanide and methyl nitroacetate

ALEX ROSENTHAL A N D B. L. CLIFF L)el)ar/~na~t o/'Clre~,~is/ry, The U~~iversi/y of Brilish Col~rmbio, Vrr~rcorrver, Bl.itis11 Colrrrlibin V61' 11,1/.5

Received July 14, 1975

ALEX ROSENTHAL and B. L. CLIFF. Can. J. Chem. 54, 543 (1976). Treatment of 1,2:5,6-di-O-isopropylidene-~-~-r.ibo-hexofuranos-3-uose (1) with sodiulii

cyanide in anhydrous ethanol followed by addition of an equimolar amount of methyl nitro- acetate gave 3-C-cyano-1,2:5,6-di-O-isopropylidene-~-~-glucofuranose (2) in 57% yield. When methyl nitroacetate was first added to sodium cyanide in alcohol followed by the addition of ketose 1 then the clllo-cyanohydrin epimer 4 was produced in 855; yield. 3-C-(Carbomethoxy- R,S-nitromethyl)-l,2:5,6-di-O-isopropylidene-~-~-allofuranose (6) was produced in low yield in the latter reaction and was isolated and characterized as its 3-0-acetate derivative 7. Selective acetolysis of the 5,6-0-isopropylidene group of the branched-chain sugars was achieved using acetic anhydride andp-toluenesulfonic acid monohydrate. The proof of structure of the cyano- hydrins is described.

ALEX ROSENTHAL et B. L. CLIFF. Can. J. Chem. 54, 543 (1976). Le traitement du di-0-isopropylidene-1,2:5,6 U-D-ribo-hexofuranne ulose-3 (1) avec le

cyanure de sodium dans I'Cthanol anhydre, suivi par l'addition d'une quantiti equimolCculaire de nitroacktate de rnethyle, conduit au cyano-3-C di-0-isopropylidene-1,2:5,6 U-D-gluco- furannose (2) avec un rendement de 57%. Lorsque l'on additionne en premier lieu le nitro- acCtate de mithyle au cyanure de sodium dans I'alcool puis le cCtose 1 , il y a alors formation de 1'0110-cyanohydrine Cpimkre, 4, avec un rendement de 8576. On obtient le (carbomCthoxy- R,S-nitromCthy1)-3-C di-0-isopropylidkne-1,2:5,6 U-D-allofurannose (6) avec un faible rende- ment dans cette dernikre reaction; on l'a isolC et caractCrisC sous forme de son dirivi 3-0-acetate 7. On a effectuC une acitolyse sClective du groupe 0-isopropylidene-5,6 des s cres i chaine ramifiie en utilisant l'anhydride acCtique et le monohydrate de l'acide p-toluknesulfonique. On dicrit la preuve de structure des cyanohydrines.

[Traduit par le journal]

Although the Kiliani and Fischer cyanohydrin synthesis (1) has been widely applied to aldoses the procedure has been very little used to prepare branched-chain sugars from ketoses. Bourgeois (2) has recently reported in a preliminary com- munication application of the cyanohydriil syn- thesis to 1,2:5,6-di-0-isopropylidene-a-D-ribo- hexofiiranos-3-ulose, 1, (3) to yield an epimeric mixture of cyanohydrins. The structures of the cyanohydrins were not proven but were assunled on mechanistic grounds.

During the past decade our laboratory has been involved in a study of glycosyl a-amino acids (4-7) related to the polyoxins (8). Because our first reported routes (4-7) involved inany steps we have investigated the application of the cyanohydrin and methyl nitroacetate addition synthesis to ketoses as novel facile routes for the synthesis of branched-chain glycosyl a-amino acids. In this communication we wish to present proof of structure of the cyanohydrins froin ketose 1, the effect of p H on controlling propor-

tions of products, and in addition, present soine of the preliminary work dealing with the branched-chain methyl nitroacetate adduct of the same ketose.

As depicted in i'able 1, treatment of ketose 1 with one molar equivaleilt of sodiunl cyanide in anhydrous ethanol, followed by chrolnatographic purification of the cyanohydrin on silica using 1 : 1 benzene - ethyl acetate as developer, af- forded crystalline 3-C-cyano-1,2:5,6-di-0-isopro- pylidene-a-D-glucofuranose, 2, in 357, yield. The yield of 2 was increased to 577, by adding, after the addition of sodium cyanide to the ketose, one molar equivalent of inethyl nitroacetate. Less than a 57 , yield of allo-cyanohydrin 4 accom- panied the gluco-epin~er. After column chroma- tography there was no evidence (in the pmr spectrum) of any methyl nitroacetate-ketose addition compound 6.

Very surprisingly, when the order of addition of methyl nitroacetate to the ketose was changed then the allo-cyanohydrin 4 was formed pre-

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544 CAN. J . CHEM. VOL. 53, 1976

TABLE 1. Application of'the cyanohydrin synthesis to ketose 1 in the presence of methyl nitroacetate (MNA)

Cyanohydrin Reaction

Ketose NaCN MNA Solvent time 7' gIrrco(2) rrllo(4) MNA(6) I'rocedure (g) (8) (8) (dl 0) ("'7 (76) (7;) ( r,; , C) f~

A 1.06 0.195 None EtOH(2) 18 20 3 5 3 A 1.43 0.290 0.706 EtOH(2) 18 20 57 4 B 1.14 0.219 0.525 EtOH(5) IS -- 7 7 6 85 7

B 1.10 0.21 None EtOH(5) 1 8 22 5 7 1 AcOH(O.25)

"Per ccnt yield of 6 calculated from a n analysis of the pmr spectrum o r thc product rnisturc.

= N H A c

1 &H, A'

ponderantly. Thus, addition of the ketose 1 t o a previously formed equimolar mixture of sodium cyanide and methyl nitroacetate in ethanol gave. after chron~atographic separation on silica gel using 4:6 benzene- ethyl acetate as developer, the 0110-epirner 4 in 8.57, yield. This product also could be directly crystallized out of the product mixture. The rnp of 4 was substantially higher than that reported by Bourgeois (2). A11 analysis of the pmr spectrum of the residue obtained froill

the mother liquor, after removal of the aNo- epimer, showed the presence of about 6% of gluco-cyanohydrin 2, and a low yield (approxi- mately 7y0) of the methyl nitroacetate-ketose addition compound 6. Attempts to obtain pure 6 by repeated chromatography were unsuccessful because 6 was quite unstable. Approximately the same ratio of a1lo:gluco-epinlers was obtained when glacial acetic acid was used instead of nlethyl nitroacetate.

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ROSENTHAL A N D CLlFF 545

The proof of structure of the epinieric cyano- hydrins 2 and 4 was provided in the following way. Lithium aluminuni liydride reduction of the gl~rco-cyanohydrin 2 followed by acetylation afforded the corresponding 3-C-acetaniinoniethyl gluco-derivative 8, which had a pnir spectrum identical to that of a substance which was obtain- ed (9) by application of the nitromethane syn- thesis (10, 11) to ketose 1 followed by reduction and acetylation. Unequivocal proof of structure of a substance identical with conipound 8 has been provided (9). Similar treatment of the epimeric 0110-cyanohydrin 4 afforded the known 3 - C-acetaniidoiiiethyl- 1,2:5,6-di-0-isopropyli- dene-a-D-allofuranose 9 (9).

When a niolar equivalent of ketose 1 was added to a mixture of one equivaleilt of sodium cyanide and one equivalent of methyl nitro- acetate in ethanol, and the resulting inixture allowed to react for 18 h at room teiiiperature followed by an immediate acetylation of the partially purified product inixture with acetic anhydride in the presence of p-toluenesulfonic acid nionohydrate as catalyst, four products were obtained. The niixture of products was chronia- tographed on silica usiiig 9 : 1 benzene - ethyl acetate as developer to afford the 0-acetyl derivatives of each product, namely. the glirco- cyanoliydriii 3, the 0110-cyanohydrin 5, the ~nethyl nitroacetate adduct 7, and the tri-0- acetyl allo-cyanohydrin 10 in the ratio of 1 :23:4: 72, respectively. Proof of the structure of com- pound 10 was provided by the fact that selective Iiydrolysis of the 5,6-0-isopropylidene group of the 0110-cyanohydrin 5 followed by acetylation afforded a substaiice identical (111p and piiir) with conlpound 10. This selective acetolysis of the 5,6-0-isopropylidene group of di-0-isopropyli- dene sugar derivatives using p-toluenesulfonic acid monohydrate is a catalyst is noteworthy as it can provide a means of markedly reducing the number of steps required in sonic nucleosidc syntheses.

Experimental Nuclear magnetic resonance spectra were determined

in deuteriochloroform solution with TMS as tlie internal standard using a Varian HA-100 spectrometer. Optical rotations were measured at room temperature with a Perkin-Elmer automatic polarimeter Model 141. Chemi- cal analyses were performed by Mr. P. Borda of the

Microanalytical Laboratory, University of British Co- lumbia.

Trerrtr,lerlt of 1,2:5,6-rli-O-Iso~11~011~ lirle~le-a-D-riba- /1e.~ofirrntros-3-1rlose, I, 1vir11 Soclir1tiz C!'crtiirle (old Metllyl Nitr,orrcetcrte

I'rocerlrrr~e A to Yielrl glrico-Cj~ertrolryrlrit~ 2 To a solution of ketose 1 (1.43 g) in a I iydro~~s e t h a ~ ~ o l

(2 ml) was added sod~uni cyanide (0.290 g). A solution of methyl nitroacetate (0.706 g) in anhydrous ethanol (2 nil) was added dropwise and the reaction ni ix t~~re stirred for 18 11 at room temperature. Tlie ethanol was removed by evaporation under reduced pressure. After the addition of 10 ml of chloroforni, a precipitate of non-carbohydrate material was renioved by filtration. Water (10 nil) was added and the niixture extracted w~tli chloroforn~ (5 X 20 nil). Tlie combined chloroforni extracts were dried over magnesiuni sulfate, filtered, and evaporated to yield a syrup (1.13 g). This syrup was chromatographecl on silica (50 g, 24 X 2.8 cm) using 1 :I benzene - ethyl acetate as developer to yield ketose 1 (0.44 g) and 0.739 g (61 (,; ) of a syrup which crystallized on standing.

3-C-Cyano-1 ,2:5,6-di-0-isopropylidene-a-D-glucofuran- ose, 2, was recrystallized from benzene-hexane, mp 99-100 "C; [aIDz4 +51.6' (C 1.4, chloroform); T (CDCI3). 4.08 (d, IH, H-1, J1,? = 4), 5.45 (d, l H , H-2), 5.6-6.0 (m, 5H, one proton exchanges in DzO), 8.45, 8.49, 8.64. and 8.66 (12H, CH3). Atrcrl. calcd. for CI3Hl9N06: C 54.73, H 6.71, N 4.91; found: C 54.87, H 6.77, N 4.92. The ratio of gluco- to allo-epimers was 13: 1.

Procecllrre B to Yialcl cil lo-Cycir~ol~)~cl~~i~~ 4 To a mixture of sodium cyanide (0.219 g) in anhydrous

ethanol (2 ml) was added methyl nitroacetate (0.525 g)? followed immediately by a solution of ketose 1 ( I .14 g) in 5 ml ethanol. After the reaction niixture was stirred over- night, the precipitate of non-carbohydrate material was renioved by filtration. Evaporation of the filtrate afforded a syrup which was triturated with 20 nil of water and extracted with chloroform (5 X 20 ml). The conibined chloroforni extracts were dried (MgS04), filtered, and evaporated to yield a clear syrup. This syrup was chro- matographed on a column of silica (130 g, 5 X 16 cni) using 4:6 benzene - ethyl acetate as developer to yield ketose 1 (0.247 g) and a syrup (0.986 g). The syrup was crystallized from benzene-hexane to afford 3-C-cyano- 1 ,2:5,6-di-0-isopropylidene-a-D-allofuranose, 4, (0.75 g, 85';;; on reacted ketose), nip 61-64 "C; [a],?4 + 8 . 6 (C 1.4, cliloroform); r (CDCI3), 4.18 (d, lH, H-1, JI,? =

4), 5.31 (d, l H , H-2, J1,l = 4), 5.10-6.29 (overlapping signals, 4H), 6.35 (s, lH , OH, exchanges in DzO), 8.51$ 8.64, and 8.72 (s, 4 methyl groups). Atlcrl. calcd. for C13H,,N06: C 54.73, H 6.71, N4.91; found: C 54.89, H 6.81, N 4.98.

The nmr spectrunl of the syrup obtained from the mother liquors after crystallization of 4 showed the presence of 4, the gllrco-cyanohydrin 2, and the methyl nitroacetate addition compound 6. Tlie ratio of products 4, 2, and 6 was 87:6:7, respectively. Attempts to obtain pure 6 by repeated slow chromatography led to tlie de- composition of compound 6.

Procerl~rre C The reaction was carried out in the same way as

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