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

Herman O. Sintim, Hamad H. Al Mamari, Hasanain A.A. Almohseni, Younes Fegheh-Hassanpour, David M. Hodgson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1194-1202
Number of pages9
JournalBeilstein Journal of Organic Chemistry
Volume15
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Alkylation
  • Cycloaddition
  • Diazoester
  • Epimerisation
  • Tartaric acid

ASJC Scopus subject areas

  • Organic Chemistry

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this