Catalytic enantioselective synthesis of 1,4-dihydropyridines via the addition of C(1)-ammonium enolates to pyridinium salts

Calum McLaughlin, Jacqueline Bitai, Lydia Barber, Alexandra Slawin, Andrew David Smith

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Abstract

The regio- and stereoselective addition of C(1)-ammonium enolates – generated in situ from aryl esters and the isothiourea catalyst (R)-BTM – to pyridinium salts bearing an electron withdrawing substituent in the 3-position allows the synthesis of a range of enantioenriched 1,4-dihydropyridines. This represents the first organocatalytic approach to pyridine dearomatisation using pronucleophiles at the carboxylic acid oxidation level. Optimisation studies revealed a significant solvent dependency upon product enantioselectivity, with only toluene providing significant asymmetric induction. Using DABCO as a base also proved beneficial for product enantioselectivity, while investigations into the nature of the counterion showed that co-ordinating bromide or chloride substrates led to higher product er than the corresponding tetrafluoroborate or hexafluorophosphate. The scope and limitations of this process are developed, with enantioselective addition to 3-cyano- or 3-sulfonylpyridinium salts giving the corresponding 1,4-dihydropyridines (15 examples, up to 95:5 dr and 98:2 er).
Original languageEnglish
Number of pages11
JournalChemical Science
VolumeAdvance Article
Early online date6 Aug 2021
DOIs
Publication statusE-pub ahead of print - 6 Aug 2021

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