The synthesis of the 2,3-difluorobutan-1,4-diol diastereomers

Abstract

The diastereoselective synthesis of fluorinated building blocks that contain chiral fluorine substituents is of interest. Here we describe optimisation efforts in the synthesis of anti-2,3-difluorobutane-1,4-diol, as well as the synthesis of the corresponding syn-diastereomer. Both targets were synthesised using an epoxide opening strategy.

Synthesis of Fluorine‐Containing Molecular Entities Through Fluoride Ring Opening of Oxiranes and Aziridines

“…Szpera et al had similar findings for ring opening of epoxy acetal 107 . Notably, product (±)‐108 is quite acid‐sensitive and treatment of substrate 107 with Et 3 N/3HF not only opens the oxirane ring but then causes the rearrangement of the acetal moiety as well (Scheme ) …”

Hydrodifluoromethylation of Alkenes with Difluoroacetic Acid

“…[4] Furthermore,t he exothermic decomposition of these reagents at elevated temperature or in contact with water presents safety concerns,e specially for large-scale synthesis. [5] In response to these challenges,l atestage difluoromethylation reactions of (hetero)arenes [6] and new transformations,such as the hydrodifluoromethylation of alkene starting materials,h ave been developed. In 2015, Dolbier and co-workers disclosed an elegant photocatalytic hydrodifluoromethylation of electron-deficient alkenes.…”

Skipped Fluorination Motifs: Synthesis of Building Blocks and Comparison of Lipophilicity Trends with Vicinal and Isolated Fluorination Motifs

“…The 1,4-butanediol targets (C5, C6, C7). Alcohol oxidation of known racemic syn-56 51 (Scheme 10a) using Dess-Martin periodinane gave ketone 57, and subsequent treatment with excess DAST efficiently led to the vicinal trifluoro motif in 58. Simultaneous TMSI-mediated 67 deprotection of the two benzyl alcohols afforded the diol C5.…”

“…In their synthesis of fluorinated palmitic acid derivatives, the O'Hagan group employed sequential deoxyfluorinations in neat DAST to obtain the skipped-tetrafluoro motif in the centre of the long aliphatic chain: 49 following the first deoxofluorination of ketone In this contribution, we report on a systematic investigation to compare internal vicinal fluorination motifs with their (internal) skipped counterparts, using the 1,4-butanediol and 1,5pentanediol scaffolds C and H (Figure 3). For this investigation, we opted to have a constant The synthesis 51 and lipophilicities 27 of C2-C4 have been reported and are included for discussion purposes, which also will involve comparison with monofluorinated and geminal difluorinated analogues C6,C7 and H6-H9, as well as with the hexafluorinated H10. The synthesis of H2-H5 employs different strategies compared to the literature precedence, and is, where relevant, fully stereoselective.…”