Abstract
(R,R)-Dimethyl tartrate acetonide 7 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 17, 24, 33a–f, 38a,b, 41 of R,R-configuration, i.e., a stereoretentive process (13–78% yields). Separable trans-dialkylated tartrates 34a–f can be co-produced in small amounts (9–14%) under these conditions, and likely arise from the achiral dienolate 36 of tartrate 7. Enolate oxidation and acetonide removal from γ-silyloxyalkyl iodide-derived alkylated tartrates 17 and 24 give ketones 21 and 26 and then Bamford–Stevens-derived diazoesters 23 and 27, respectively. Only triethylsilyl-protected diazoester 27 proved viable to deliver a diazoketone 28. The latter underwent stereoselective carbonyl ylide formation–cycloaddition with methyl glyoxylate and acid-catalysed rearrangement of the resulting cycloadduct 29, to give the 3,4,5-tricarboxylate-2,8-dioxabicyclo[3.2.1]octane core 31 of squalestatins/zaragozic acids. Furthermore, monoalkylated tartrates 33a,d,f, and 38a on reaction with NaOMe in MeOH at reflux favour (≈75:25) the cis-diester epimers epi-33a,d,f and epi-38a (54–67% isolated yields), possessing the R,S-configuration found in several monoalkylated tartaric acid motif-containing natural products.
Highlights
Since their isolation was reported in the early 1990s [1,2], the squalestatins/zaragozic acids (e.g., squalestatin S1/zaragozic acid A (1), Figure 1) have been of enduring interest to synthetic chemists, due to a combination of a synthetically challenging densely functionalised 2,8-dioxabicyclo[3.2.1]octane core [3,4,5,6], combined with an increasing range of intriguing biological ac
We report in detail the evolution of chemistry that provides an asymmetric entry to the tricarboxylate core of these natural products, with particular focus on tartrate alkylation methodology to establish the fully-substituted C-5 stereocentre
The general viability of the α-ketoester to α-diazoester functional group interconversion envisaged in Scheme 2 (10 → 3) was readily established on a simpler but closely structurallyrelated system (Scheme 3)
Summary
Since their isolation was reported in the early 1990s [1,2], the squalestatins/zaragozic acids (e.g., squalestatin S1/zaragozic acid A (1), Figure 1) have been of enduring interest to synthetic chemists, due to a combination of a synthetically challenging densely functionalised 2,8-dioxabicyclo[3.2.1]octane core [3,4,5,6], combined with an increasing range of intriguing biological ac-Beilstein J. The study was notable in showing that the intermediate ester enolate 14 possessed sufficient stability not to undergo significant β-elimination under conditions of its generation and its alkylation: slow addition of pre-cooled LDA (−70 °C) to a mixture of the acetonide and electrophile in THF/HMPA at −78 °C, followed by slow warming to ≈−10 °C before work-up.
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