Electronically Activated Organoboron Catalysts for Enantioselective Propargyl Addition to Trifluoromethyl Ketones

Abstract

A broadly applicable, practical, scalable, efficient and highly α- and enantioselective method for addition of a silyl-protected propargyl moiety to trifluoromethyl ketones has been developed. Reactions, promoted by 2.0 mol % of a catalyst that is derived in situ from a readily accessible aminophenol compound at ambient temperature, were complete after only 15 minutes at room temperature. The desired tertiary alcohols were isolated in up to 97% yield and 98.5:1.5 enantiomeric ratio. Alkyl-, alkenyl-, alkynyl-, aryl- or heteroaryl-substituted trifluoromethyl ketones can be used. Utility is highlighted by application to a transformation that is relevant to enantioselective synthesis of BI 653048, a compound active against rheumatoid arthritis.

Practical, Broadly Applicable, α-Selective, Z-Selective, Diastereoselective, and Enantioselective Addition of Allylboron Compounds to Mono-, Di-, Tri-, and Polyfluoroalkyl Ketones

“…The transformation with ap-2 was similarly efficient and selective, which was unexpected since previous studies had indicated transformations with a carboxylic ester (vs dialkyl amide) are less efficient and less enantioselective. 8 With sterically more demanding triphenylsilyl-substituted ap-3 , 6k,10 efficiency (87–88% yield), α selectivity (>98:2) and er (≥98:2) remained high (Scheme 3), along with a boost in reaction rate (45 min) and Z selectivity, regardless of the reaction temperature (≥96:4 vs 74:26–83:17 Z : E with ap-1,2 ). The importance of this finding regarding utility in synthesis aside, the clear influence of catalyst structure on Z : E selectivity is notable (see below for analysis).…”

“…The lower er in the reactions with 2-furyl and 2-thienyl ketones compared to their 3-substituted analogues are consistent with formerly disclosed observations regarding allyl–B(pin), and allenyl–B(pin) additions. 10 Regarding pyridyl product 10 , 2.5 mol % ap-3 , 5.0 mol % Zn(OMe) 2 , 12 hours, and 60 °C were required for >98% conversion; this might be in part because the corresponding hydrate was the starting material. The X-ray structure secured for Z - 10 allowed us to establish the absolute stereochemical identity of the major product.…”

“…The highly enantioselective formation of difluoro- and monofluoro-substituted 16a–c and 17a–c , on the other hand, were unexpected (96:4–98.5:1.5 er, Scheme 7); this was because addition of allyl–B(pin) to these same ketones was minimally enantioselective (Scheme 1a). 10 The X-ray structure of p -bromobenzoate derivative 18 showed that there was no change in the sense of stereochemical induction (vs the trifluoromethyl analogs). Moreover, these data show that the number of fluorine atoms adjacent to the ketone unit has considerable influence on Z selectivity of the process: Z : E ratio descended in the order of 97:3 ( Z - 3a , Scheme 3) to 91:9 ( Z - 16a , Scheme 7) to 78:22 ( Z - 17a ) with three, two and one fluorine atom on the α-alkyl site, respectively.…”

“…10 A collection of experimental and computational data suggests that in the favored mode of addition i (Scheme 1) there is minimization of electron–electron repulsion caused by the non-bonding electrons of the ketone oxygen and the fluorine atoms through electrostatic interaction with the catalyst’s ammonium group. We later showed that with a phosphinoylimine and the more Lewis acidic Zn(OMe) 2 (vs NaO t -Bu) reaction of γ -substituted allyl–B(pin) compounds proceed more efficiently and with far higher γ selectivity (Scheme 1b).…”

“…Would additions to the less electrophilic difluoro- and monofluoromethyl ketone analogues occur with much lower enantioelectivity, as they did when symmetric allyl–B(pin) compounds were used or will the new method offer broader scope? 10 …”