O OH HO 2 C NHAc OH OH OH H HO H O HO 2 C R N OH OH H HO H O MeO 2 C NHAc OAc OAc 1 OH OH O O HO HO O NBn 2 OAc OAc 5 3 OAc OMe N S 2 R = NHAc 4 NH 2 HN H 4 1 1 4 9 8 EtO 2 C O O OR EtO 2 C O O N 3 O O NR 2 O O NBn 2 EtO 2 C OH O ix 9 R = H 10 R = Bn xi xii 17 R = TMS xiii 4 18 Br O O NBn 2 EtO 2 C R R′ O O NBn 2 EtO 2 C O O O NBn 2 EtO 2 C O O 3 O MeO 2 C NBn 2 OAc OAc iii i OAc 6 R = H 7 R = Tf ii 8 iv viii vi v 11 16 R = TMS 12 R = OH, R′ = H 13 RR′ = O 14 R = H, R′ = OH 15 R = H, R′ = OTMS vi vii x OH HO R R 4 Diastereoselective routes to side-chain truncated analogues of N-acetylneuraminic acid† Martin Banwell,* a ‡ Chris De Savi, a David Hockless a and Keith Watson b a Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia b Biota Chemistry Laboratory, Chemistry Department, Monash University, Clayton, Victoria 3168, Australia Vitamin C 3 has been converted, in a completely stereo- controlled manner, into the side-chain truncated analogues 4 and 5 of N-acetylneuraminic acid 1. N-Acetylneuraminic acid 1 (Neu5Ac) and other members of the sialic acid class of carbohydrates play fundamental roles in many important biological processes, including cell adhesion and differentiation, immune responses, tumour metastasis and the development of neural cells. 1 In addition, they constitute a ligand commonly recognised by many infectious pathogens such as viruses, bacteria and parasites. 1 Consequently, sialic acids and various derivatives including the potent anti-influenza drug GG167 2 2 are assuming increasing importance as pharmacological tools and/or therapeutic agents. 3 In this regard there is now considerable interest 4 in side-chain truncated analogues of Neu5Ac which are currently only accessible via degradation of the natural product 1. 3,4 Therefore, we report herein on the stereocontrolled conversion of abundant vitamin C 3 into compounds 4 and 5, each of which embodies the sialic acid core but lacks the C-8/C-9 (side-chain) assemblage associated with the parent system 1. The reaction sequences used for these conversions offer possibilities for the synthesis 5 of a range of novel sialic acid analogues which can vary in both the nature and stereochemistry of the substituents attached to the pyranose ring. The reaction sequence (Scheme 1) leading to compound 4 starts with a literature procedure 6 for the oxidative degradation of vitamin C 3 to the a-hydroxy ester 6. The triflate derivative 7 of the latter compound was then prepared in quantitative yield by standard methods 7 and underwent a smooth S N 2 reaction with lithium azide 8 in DMF at room temperature to give the azide 8 {80%, [a] D 214.7 (c 2.6)§}. Reduction of this a-azido ester with LAH afforded the amino alcohol 9 {100%, [a] D 210.5 (c 1.5)} which was immediately protected as its N,N- dibenzyl derivative 10 {90%, [a] D +1.2 (c 2.1)}. Oxidation of compound 10 using the Swern reagent gave aldehyde 11 9 {95%, [a] D +3.9 (c 3.8)} which upon reaction with ethyl (2-bromo- methyl)acrylate, zinc dust and saturated aq. NH 4 Cl 10 in THF afforded the homoallylic alcohol 12 {87%, [a] D 214.8 (c 2.1)} in a completely diastereoselective fashion. 11 Oxidation of the latter compound with the Swern reagent afforded ketone 13 {90%, [a] D 272.9 (c 2.5)} and this was immediately reduced with NaBH 4 in EtOH to alcohol 14 {82%, [a] D 25.9 (c 2.3)} which proved to be the only isolable product of the reaction. Attempts to cleave the CNC double bond 12 within this last compound using ozone failed because of competing reaction at the aromatic rings associated with the N,N-dibenzylamino moiety. Consequently, a somewhat more circuitous method was devised for achieving this end. Thus, compound 14 was Scheme 1 Reagents and conditions: i, see ref. 6; ii, Tf 2 O (1.3 equiv.), 2,6-lutidine (1.3 equiv.), CH 2 Cl 2 , 250 to 210 °C, 0.75 h; iii, LiN 3 (2.5 equiv.), DMF, 18 °C, 3 h; iv, LAH (3.5 equiv.), THF, 18 to 65 °C, 3 h; v, BnBr (2.2 equiv.), K 2 CO 3 (2 equiv.), MeCN, 60 °C, 14 h; vi, (COCl) 2 (1.2 equiv.), DMSO, CH 2 Cl 2 , 278 to 0 °C, 1 h, then Et 3 N (2.6 equiv.); vii, Zn dust (1.2 equiv.), sat. aq. NH 4 Cl, THF, 60 °C, 0.75 h; viii, NaBH 4 (6 equiv.), EtOH, 210 °C, 1.5 h; ix, TMSCl (4.0 equiv.), hexamethyldisilazane (4.0 equiv.), pyridine, 0 to 18 °C, 19 h; x, AD-mix-a (2.2 equiv.), Bu t OH, H 2 O, 18 °C, 22 h; xi, Pb(OAc) 4 (0.9 equiv.), CaCO 3 (11 equiv.), CH 2 Cl 2 , 18 °C, 0.33 h; xii, 6% w/v HCl in MeOH, 18 °C, 18 h then Ac 2 O (10 equiv.), DMAP (trace), pyridine, 18 °C, 20 h; xiii, Pd black, 5% w/v HCO 2 H in MeOH, 18 °C, 0.5 h, then Ac 2 O (10 equiv.), DMAP (trace), pyridine, 18 °C, 20 h Chem. Commun., 1998 645 Published on 01 January 1998. Downloaded on 30/10/2014 05:35:34. View Article Online / Journal Homepage / Table of Contents for this issue