A new synthesis of N-acetylneuraminic acid (NeuSAc; 28) via the aldehyde 10 is described. The aldehyde 10 was obtained from N-acetyl-o-glucosamine (11; 5 steps, overall yield ca. 6 %) or from o-glucono-1,s-lactone (17; 6 steps, overall yield ra. 57%). Thus, on the one hand, N-acetyl-D-mannosamine (12), obtained from 11, was transformed into the known dithioacetal 14 and hence into the (ethy1thio)dihydrooxazole 16 which was cleaved under weakly acidic conditions to the aldehyde 10. On the other hand, the known ester 18, obtained from 17, was sulfonylated and further transformed via the azide 20 into the N-acetyl-o-rnannonate 22. Reduction of 22 to 23 and oxidation of 23 with 'periodinane' again gave 10. The aldehyde 10 was treated with the organozinc reagent 8 obtained from tert-butyl 2-(bromomethy1)acrylate (2) to yield predominantly 24 which was transformed (two steps) into the 2-methylidene-o-glycero-o-galacto-nononic acid 27 and hence into NeuSAc (28).
Introduction. -The well recognized biological importance of sialic acids and their conjugates has been taken as a motive for a number of syntheses of N-acetylneuraminic acid (NeuSAc; 28), the only sialic acid occurring in the human species (see [I-61 and ref. cit. therein). We have recently presented two syntheses [7] [S] of NeuSAc which are complementary to each other in that each one may be adopted to the preparation of different analogues, the first one for analogues modified at C( 1) to C(6), the second one for analogues modified at C(6) to C(9) (Scheme l a and l b , respectively). Both syntheses Scheme 1 0 CO,( t-Bu) a) NO2 1 3 R" + NHAc 4 6 R" ') In most partial syntheses [9%18] of NeuSAc, suitably protected o-mannosamine derivatives were chainelongated by reaction with either oxaloacetic acid, potassium di(tert-butyl) oxaloacetate, bromopyruvate, nitromethane, or phosphoranes. S c h m r 2 GIcNAc 11 AcHN MonNAc -12 13 14 61 1 c -16 ' d 0 % 10 COOME COOMe 17 i a 19 R=CF, 21 R=CH, alternative approach to 10, 18 was obtained on a large scale from D-glUCOnO-1,5-iactone (17; one step, 84%) according to Chittenden and coworkers [29], and was transformed via the crystalline triflate 19 into the manno-azide (20; 86% from 18; Scheme 2)2). The azide 20 was also prepared in a somewhat lower yield (75 %) by treatment of the mesylate 21 with LiN, in DMF. Hydrogenation of 20 in AcOEt/Ac,O 1:l ( v / v ) at atmospheric pressure in the presence of 10% Pd/C afforded 22 in almost quantitative yield. The ester 22 was reduced with LiBH, in THF/MeOH at 0" to give 23 (92%).
Oxidation of 23 with DMSO in the presence of the pyridine-SO, [30] or the Et,N-SO, complex led to the aldehyde 10 in modest yields. Oxidation with the 'periodinane' of Dess and Martin [31] gave the delicate aldehyde 10 in a yield of ca. 85%, containing ca. 5-7% impurities ('H-NMR). 2, It is important to use well dried Bu,NN, for this transformation of 19 into 20. Commercial Bu4NN3 (TCI, Japan) was dried by azeotropic removal of H,O with toluene, and finally in uucuo.