NHC-catalyzed enantioselective synthesis of β-trifluoromethyl-β-hydroxyamides

Abstract

The N-heterocyclic carbene (NHC)-catalyzed formal [2 + 2] cycloaddition between α-aroyloxyaldehydes and trifluoroacetophenones, followed by ring opening with an amine or a reducing agent is described. The resulting β-trifluoromethyl-β-hydroxyamide and alcohol products are produced with reasonable diastereocontrol (typically ≈70:30 dr) and excellent enantioselectivity, and they can be isolated in moderate to good yield as a single diastereoisomer.

NHC-Catalyzed Reaction of Aldehydes for C(sp2)–O Bond Formation

“…The NHC-linked enolate was used as a C2 synthon for oxidant-free redox [2 + 2] annulation (Scheme 31) [205]. The chiral NHC-catalyzed formal [2 + 2] cycloaddition between α-aroyloxyaldehyde 107 and ketone 45 afforded the unstable β-lactone product 108.…”

De-epimerizing DyKAT of β-lactones generated by isothiourea-catalysed enantioselective [2 + 2] cycloaddition

“…1A). [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] In such processes, catalyst turnover is typically reliant upon an intramolecular cyclisation event from a pendant heteroatom nucleophile (oen either O or N) to generate a heterocyclic lactone or lactam product. While this catalytic strategy is powerful, in many circumstances the resultant heterocyclic lactone products can be difficult to isolate in high yields due to facile ring-opening and decomposition on attempted chromatographic purication.…”

De-epimerizing DyKAT of β-Lactones Generated by Isothiourea-Catalysed Enantioselective [2+2] Cycloaddition

“…20,21 In parRcular, the ability to generate C(1)-ammonium enolate intermediates from carboxylic acid derivaRves (via an in situ formed mixed anhydride), followed by stereoselecRve [n+2]-cycloaddiRons (n = 2, 3, 4) has been exploited by ourselves and others (Figure 1A). [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] In such processes, catalyst turnover is typically reliant upon an intramolecular cyclisaRon event from a pendant heteroatom nucleophile (omen either O or N) to generate a heterocyclic lactone or lactam product. While this catalyRc strategy is powerful, in many circumstances the resultant heterocyclic lactone products can be difficult to isolate in high yields due to facile ring-opening and decomposiRon on aoempted chromatographic purificaRon.…”