Enantioselective construction of remote quaternary stereocentres

Abstract

Small molecules that contain all-carbon quaternary stereocentres-carbon atoms bonded to four distinct carbon substituents-are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for synthesizing quaternary stereocentres that are remote from other functional groups are underdeveloped. Here we report a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids. This method provides direct access to quaternary all-carbon-substituted β-, γ-, δ-, ε- or ζ-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group. The scope of the process also includes incorporation of pre-existing stereocentres along the alkyl chain, which links the alkene and the alcohol, in which the stereocentre is preserved. The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre.

Figure 1. Approaches to constructing acyclic all-carbon quaternary stereocenters

a, Conventional enantioselective, catalytic approaches. α-functionalization of carbonyls (I). β-functionalization of carbonyls (II). α-quaternary centers adjacent to alkene (III). b, Proposed modular strategy using a redox relay enantioselective Heck reaction of trisubstituted alkenes and resulting mechanistic analysis.

Figure 2. Enantioselective construction of remote quaternary stereocenters

Conditions for 2a, 2i–2n, 3c, 3f, 3i–3j: 10 mol% Pd(CH₃CN)₂(OTs)_2, 4 mol% Cu(OTf)₂, 14 mol% ligand, 3 equiv ArB(OH)₂ (two batch addition, 12 h between additions). a, Exploration of scope using various arylboronic acids. b, Evaluation of various chain-lengths between the alkene and alcohol on the substrate. c, Exploration of the alkene substituents. d, Proposed origin of enantioselectivity as a function of alkene geometry. TBS is tert-butyldimethylsilyl.

Figure 3. Evaluation of alkene substrates containing a branch point

Conditions: 10 mol% Pd(CH₃CN)₂(OTs)_2, 4 mol% Cu(OTf)₂, 14 mol% ligand, 3 equiv PhB(OH)₂. a, Independence of catalyst enantiomer on the conservation of the chiral center during the proposed chain-walking process. b, Accessing distinct diasteromers using a combination of catalyst and substrate controlled asymmetric synthesis. c, Proposed mechanistic origin for the observed formation of 5 from 4. d, Isotopic labeling experiment and analysis.