In the preceding communication, 1 we described the synthesis of a potentially general precursor (2, Scheme 1) of the highly promising chemotherapeutic agent Taxol 2 (1, Scheme 2) and its analogues. Our strategy for the elaboration of this ABbicyclic precursor into the ABC-tricyclic core of the taxanes was predicated on the view 1b that epimerization of the C7 center of Taxol 3 proceeds through the intermediacy of the AB-bicyclic enolaldehyde or its ketone isomer, leading to the intriguing possibility that the C-ring of Taxol could self-assemble under exceptionally mild conditions from a considerably less complex AB-bicyclic ketoaldehyde precursor (e.g., 9). In this communication, the viability of this aldol cyclization strategy is demonstrated in a synthesis of Taxol (1), representing the shortest sequence yet reported for the preparation of this important natural product. 4,5 The elaboration of our general taxane precursor (2, Scheme 1) into Taxol started with its homologation with Ph 3 PC(H)-OMe (91%) 6 followed by a one-step hydrolysis of the enol ether and acetonide groups (HCl, NaI) to provide aldehyde 3 (94%). 7 Selective protection of the C9 hydroxyl was then accomplished in 92% yield with TESCl and pyridine. Dess-Martin periodinane oxidation 8 of the C10 alcohol and introduction of C20 with [Me 2 NCH 2 ]I (g0.1 M) 9 and Et 3 N (excess) was conducted in one operation to produce enal 4 in 97% yield. The remaining carbons of the taxane skeleton were then introduced through the addition of 4 to a solution of allylmagnesium bromide and ZnCl 2 (89%) 10 which after BOM (benzyloxymethyl) protection (N,N-diisopropylethylamine solvent) provided the ether 5 as a single diastereomer. 10c The presence of ZnCl 2 in the former reaction completely suppressed addition of the Grignard reagent to the cyclic carbonate. Removal of the C9 silyl group (NH 4 F, MeOH) 11 provided an unstable hydroxyketone (93% over two steps) which was reacted immediately with PhLi 12 to form the C2 benzoate providing, after in situ acetylation, the acetate 6 in 79% yield. Transposition of the acetoxyketone under kinetic 5a or equilibrating conditions (Et 2 NH, KOAc, DMF) 13 resulted in limited success. However, when the guanidinium base 7 14 was employed for this transposition, the desired acetoxyketone 8 and recyclable 6 were obtained in 80% as a 4:3 equilibrium mixture. The monosubstituted alkene in 8 was then cleaved through addition of an ozone solution to form aldehyde 9 in 86% yield.The viability of the key aldol cyclization was addressed at this point. Previous studies in our laboratory 1b,15 showed that ketoaldehydes similar to 9 but incorporating a C1-C2 cyclic carbonate did not undergo aldol cyclization, preferring instead

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A convenient two-step homologation of both aliphatic and aromatic ketones to the corresponding carboxylic acid has been developed. First ketones were converted to epoxynitriles with the Darzens reaction. Second, a Lewis acid mediated rearrangement of these epoxynitriles with lithium bromide was achieved to give homologated secondary alkanoic acids (as well as aryl-alkanoic) in good yields. The mechanism and the scope of the rearrangement reaction were investigated. This strategy constitutes a two-step homologation of ketones to secondary carboxylic acids.

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