Direct access to bicyclic precursors of octulosonic acids is achieved by treatment of differentially (or not) protected γ,δ‐bis(silyloxy) cis‐α,β‐epoxy aldehydes with ethyl 2‐(trimethylsilyloxy)‐2‐propenoate in the presence of boron trifluoride−diethyl ether. An X‐ray crystallographic structure of a bicycle (compound 33a) was obtained and used to determine the absolute configurations of the different stereogenic centers and thus the diastereoselective preference of the aldol reaction (syn) and the regioselectivity of the epoxide ring‐opening (C‐6 atom). Functionalization and opening of the bicyclic compound to afford octulosonic analogues in their furanoside forms was studied. An octulosonic 8‐phosphate analogue has been synthesized. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

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A direct synthesis of bicyclic precursors of ulosonic acids is achieved by reaction of cis-a,b-epoxyaldehydes with ethyl 2-(trimethylsilyloxy)-2-propenoate in the presence of boron trifluoride diethyl etherate.Higher 3-deoxy-2-ulosonic acids are natural carbohydrates possessing between 7 and 9 carbon atoms along with a ketone functionality at the a-position of a carboxylic acid. Ulosonic acids act in many important biological processes. An example is 3-deoxy-D-arabino-2-heptulosonic acid (DAH; 1) which, in its 7-phosphate form, is an important intermediate in the shikimic acid pathway. 1 3-Deoxy-D-manno-octulosonic acid (KDO; 2), which, in its 8-phosphate form, is a component of the outer membrane lipopolysaccharide of Gram-negative bacteria 2 and it is an important target for the design of inhibitors for enzymatic cell wall assembly. 5-N-Acetyl neuraminic acid (Neu5Ac; 3) has emerged as a key biomolecule in cellular recognition, adhesion phenomena and in cell infection by certain viruses (Figure). 3 FigureWork towards the elaboration of ulosonic acids and analogues has accelerated and several such endeavors, including enzymatic and chemoenzymatic syntheses, starting from carbohydrates and de novo ones have already appeared in the literature. [4][5][6][7][8][9] Some years ago, we reported 10 a versatile synthesis of a protected DAH, starting from a non-carbohydrate precursor. The methodology was based on [4+2+1] carbon atom incorporation, starting from an a,b-epoxyaldehyde. The target compound was obtained in 7 steps and 19% yield. Recently, exploring a more direct access to heptulosonic analogues, we have developed a new methodology based on [4+3] carbon atom incorporation. 11 The Mukaiyama reaction of trans-a,b-epoxyaldehydes with ethyl 2-(trimethylsilyloxy)-2-propenoate 4, in the presence of the Lewis acid BF 3 -etherate, led to the direct synthesis of a separable mixture of 5-and 6-fluoroheptulosonic analogues in their pyranosidic or furanosidic form (Scheme 1). Scheme 1These promising results led us to investigate this reaction further. We would like to report in this work a completely distinct reaction pathway observed when cis-, instead of trans-a,b-epoxyaldehydes, are employed.Three cis-a,b-epoxyaldehydes were synthesized, possessing n = 4 carbon atoms 17 and n = 5 with identical or distinct hydroxyl protecting groups 15, 16. These two last epoxyaldehydes 15 and 16 were prepared as potential precursors to octulosonic analogues via [5+3] carbon atom incorporation. Racemic cis-a,b-epoxyaldehyde 17 was synthesized in 3 steps, starting from commercially available cis-1,4-butene-2-diol, in 48% total yield. 12 Cis-a,bepoxyaldehydes 15 and 16 were synthesized from commercially available compound 9. Reduction of the ester group, acetate protection of the primary hydroxyl group and deprotection of the acetonide were easily realized in good yield. The desired differentiation of hydroxyls can be achieved in the next step: firstly, the primary hydroxyl group was protected by using 1.2 equivalents of TBDMSCl, in the p...

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