Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids.

(,)-Dimethyl tartrate acetonide in THF/HMPA undergoes deprotonation with LDA and reaction at -78 °C during 12-72 h with a range of alkyl halides, including non-activated substrates, to give single diastereomers (at the acetonide) of monoalkylated tartrates , , , , of -configuration, i.e., a stereoretentive process (13-78% yields). Separable dialkylated tartrates can be co-produced in small amounts (9-14%) under these conditions, and likely arise from the achiral dienolate of tartrate . Enolate oxidation and acetonide removal from γ-silyloxyalkyl iodide-derived alkylated tartrates and give ketones and and then Bamford-Stevens-derived diazoesters and , respectively. Only triethylsilyl-protected diazoester proved viable to deliver a diazoketone . The latter underwent stereoselective carbonyl ylide formation-cycloaddition with methyl glyoxylate and acid-catalysed rearrangement of the resulting cycloadduct , to give the 3,4,5-tricarboxylate-2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids. Furthermore, monoalkylated tartrates ,,, and on reaction with NaOMe in MeOH at reflux favour (≈75:25) the -diester epimers ,, and (54-67% isolated yields), possessing the configuration found in several monoalkylated tartaric acid motif-containing natural products.