Concise syntheses of diflouroanalogues of cyclitols and sugars
thesisposted on 2014-12-15, 10:35 authored by Erwan Kérourédan
The synthesis of (1 fl*,2f*,3S*,4S',)-5,5-dif luorocyclohexane-1,2,3,4-tetrol was accomplished with an overall yield of 20 % from trifluoroethanol over 8 steps featuring a key dehydrofluorination/metallation followed by trapping of aldehyde (scheme). The route based on a fluorinated building block approach delivered rapidly a small library of difluoroanalogues of carbasugars using readily available and inexpensive starting materials where the use of protecting group chemistry was reduced to its minimum as well as purification. This chemistry is unique as a method for the rapid syntheses of difluorinated molecules of this level of complexity and relevance to saccharides. Upjohn r dehydrofluorination/ R3R4c Donohoe f RCM R'v f R", F retaliation, R1 X OH OH OH Claisen The synthesis in water of a range of trifluoroethanol ethers represents an atom efficient and sustainable solution to the multigram scale syntheses of some trifluoroethyl ethers 3-(2 2',2'-Trifluoroethoxy)prop-1-ene was obtained on a mole scale with 99 % yield. Dehydrofluorination/metallation at low temperature (-100 Â°C) followed by trapping of aldehyde occurred efficiently with a wide variety of substrates allowing a rapid synthesis of dienols on a comfortable scale (up to 75 mmol). After Claisen rearrangement of the dienols, sodium borohydride was found to be the most diastereoselective as well as practical reducing agents tested for the reduction of the hydroketones. Ring closing metathesis using second generation Grubbs' catalyst afforded rapidly key difluorinated cyclohexenes in high yield and low catalyst loading from free diols such as (1 S*,2S*)-6,6-Difluorocyclohex-3-ene-1,2-diol which was obtained with an overall yield of 44 % from trifluoroethanol over 5 steps. The scope and limitations of Upjohn and Donohoe dihydroxylation procedures were identified for our substrates presenting an extensive variety of substitutions. Dihydroxylation under Upjohn conditions exhibited from average to excellent diastereoselectivity depending of the position and level of substitutions. Donohoe-type dihydroxylations delivered the expected outcome for each substrate in very high diastereoselectivity. Indeed (1S*,2S*,3r*,4S*,6S,,)-5>5-difluoro-2,6-dimethylcyclo hexane-1,2,3,4-tetrol was obtained as a single diastereoisomer with an overall yield of 11 % from trifluoroethanol over 8 steps. Also, the use of these intermediates as candidate for analogues of NDP sugars was investigated for a limited number of our substrates such as (1 S*,4f*>5R*,6S'*)-6- (benzyloxy-difluoro.S-dihydroxycyclohexyl dibenzyl phosphate which was synthesised with an overall yield of 27 % from trifluoroethanol over 8 steps.
Date of award2006-01-01
Awarding institutionUniversity of Leicester