Although there are many synthetic methods to produce fluorinated and trifluoromethylated organic structures, the construction of difluoromethylated compounds remains a synthetic challenge. We have discovered that unactivated imines will react with difluoroenolates under exceedingly mild conditions when using magnesium salts and organic bases. We have applied this approach to the iminoaldol reaction to produce difluoromethylene groups as α,α-difluoro-β-amino-carbonyl groups. This method provides synthetically useful quantities of difficult to access α,α-difluoro-β-aminoketones without the need of protecting groups or the use of activated imines. Moreover, we have applied this strategy to create analogues of the dual orexin receptor antagonist, almorexant, in only two synthetic steps.
4-Deoxypentenosides
(4-DPs) are versatile synthons for rare or
higher-order pyranosides, and they provide an entry for structural
diversification at the C5 position. Previous studies have shown that
4-DPs undergo stereocontrolled DMDO oxidation; subsequent epoxide
ring-openings with various nucleophiles can proceed with both anti or syn selectivity. Here, we report
the synthesis of α- and β-linked 4′-deoxypentenosyl
(4′-DP) disaccharides, and we investigate their post-glycosylational
C5′ additions using the DMDO oxidation/ring-opening sequence.
The α-linked 4′-DP disaccharides were synthesized by
coupling thiophenyl 4-DP donors with glycosyl acceptors using BSP/Tf2O activation, whereas β-linked 4′-DP disaccharides
were generated by the decarboxylative elimination of glucuronyl disaccharides
under microwave conditions. Both α- and β-linked 4′-DP
disaccharides could be epoxidized with high stereoselectivity using
DMDO. In some cases, the α-epoxypentenosides could be successfully
converted into terminal l-iduronic acids via the syn addition of 2-furylzinc bromide. These studies support
a novel approach to oligosaccharide synthesis, in which the stereochemical
configuration of the terminal 4′-DP unit is established at
a post-glycosylative stage.
Controlling the cleavage of carbon−carbon bonds during a chemical reaction is a substantial challenge; however, synthetic methods that accomplish this objective produce valuable and often unexplored reactivity. We have designed a mild process to generate α,α-difluorobenzyl carbanions in the presence of potassium carbonate by exploiting the cleavage of C−C bonds during the release of trifluoroacetate. The initiating reagent is potassium carbonate, which represents an improvement over existing protocols that require a strong base. Fragmentation studies across substituted arenes and heteroarenes were conducted along with computational analyses to elucidate reactivity trends. Furthermore, the mildly generated α,α-difluorobenzyl carbanions from electron-deficient aromatics and heteroaromatic rings can react with aldehydes to create derivatives of difluoromethylbenzenes, which are valuable synthetic targets.
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