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

Abstract

A practical method for enantioselective synthesis of fluoroalkyl-substituted Z-homoallylic tertiary alcohols has been developed. Reactions may be performed with ketones containing a polylfluoro-, trifluoro-, difluoro- and monofluoroalkyl group along with an aryl, a heteroaryl, an alkenyl, an alkynyl, or an alkyl substituent. Readily accessible unsaturated organoboron compounds serve as reagents. Transformations were performed with 0.5–2.5 mol % of a boron-based catalyst, generated in situ from a readily accessible valine-derived aminophenol and a Z- or an E-γ-substituted boronic acid pinacol ester. With a Z organoboron reagent, additions to trifluoromethyl and polyfluoroalkyl ketones proceeded in 80–98% yield, 97:3 to >98:2 α:γ selectivity, >95:5 Z:E selectivity and 81:19 to >99:1 enantiomeric ratio. In notable contrast to reactions with unsubstituted allylboronic acid pinacol ester, additions to ketones with a mono- or a difluoromethyl group were highly enantioselective as well. Transformations were similarly efficient, α- and Z-selective when an E-allylboronate compound was used, but enantioselectivities were lower and, in certain cases, the opposite enantiomer was favored (up to 4:96 er). With a racemic allylboronate reagent that contains an allylic stereogenic center, additions were exceptionally α-selective, affording products, expected from γ-addition of a crotylboron compound, in up to 97% yield, 88:12 diastereomeric ratio and 94:6 enantiomeric ratio. Utility is highlighted by gram scale preparation of representative products through transformations that were performed without exclusion of air or moisture, and through applications in stereoselective olefin metathesis where Z-alkene substrates are required. Mechanistic investigations aided by computational (DFT) studies were carried out and offer insight into different selectivity profiles.

Zinc Hydroxide‐Catalyzed Asymmetric Allylation of Acetophenones with Amido‐Functionalized Allylboronate in Water

“…For this purpose, Zn (OH) 2 was chosen as a metal additive due to its easy availability and high cost efficiency. Initially, the reaction was performed by employing a catalytic amount of L-valine derived aminophenol L1, which has an efficient chiral motif for zinc-mediated asymmetric allylboration [27][28][29] and has been recently applied to amido-functionalized allylboration of isatins by our group in organic solvents, [21] to provide low but significant enantiomeric enrichment of the product (Entry 1, 56% yield, 13% ee). On the other hand, chiral reagents bearing 1,2-aminoalcohol, diamine, or diol structure (L2-6) showed almost no or poor effects on both yields and enantioselectivities (Entries 2-6).…”

γ‐, Diastereo‐, and Enantioselective Addition of MEMO‐Substituted Allylboron Compounds to Aldimines Catalyzed by Organoboron–Ammonium Complexes

“…4 m vs. 4 n ) has been provided (electrostatic attraction between the heterocycle O atom and the ammonium group of the catalyst). However, why, unlike previous cases,, the reaction with thienyl‐substituted imine are similarly enantioselective (cf. 4 o vs. 4 p ), and what might be the cause of the lower d.r.…”

Access to enantioenriched compounds bearing challenging tetrasubstituted stereocenters via kinetic resolution of auxiliary adjacent alcohols

“…Inspired by the success of accessing diaryl tertiary alcohols using KRA* method, we further surveyed tertiary alcohols with all aliphatic substituents (three sp 3 carbons), which represents one of the most challenging topics in the field of asymmetric catalysis. Very limited methods have been developed to address the issue, and to date the most effective methods were reported by Hoveyda and co-workers, using asymmetric allylation and propargylation of methyl and mono, di, or trifluoromethyl ketones 31 , 32 , 56 – 58 and the kinetic resolution of methyl tertiary alcohols 39 . Asymmetric desymmetrization has also been developed, but with specific types of substrates 59 – 62 .…”