Asymmetric synthesis from terminal alkenes by cascades of diboration and cross-coupling

Abstract

Terminal, monosubstituted alkenes are ideal prospective starting materials for organic synthesis because they are manufactured on very large scales and can be functionalized via a broad range of chemical transformations. Alkenes also have the attractive feature of being stable in the presence of many acids, bases, oxidants and reductants. In spite of these attributes, relatively few catalytic enantioselective transformations have been developed that transform aliphatic α-olefins into chiral products with an enantiomeric excess greater then 90 per cent. With the exception of site-controlled isotactic polymerization of α-olefins, none of these catalytic enantioselective processes results in chain-extending carbon-carbon bond formation to the terminal carbon. Here we describe a strategy that directly addresses this gap in synthetic methodology, and present a single-flask, catalytic enantioselective conversion of terminal alkenes into a number of chiral products. These reactions are facilitated by a neighbouring functional group that accelerates palladium-catalysed cross-coupling of 1,2-bis(boronates) relative to non-functionalized alkyl boronate analogues. In tandem with enantioselective diboration, this reactivity feature transforms alkene starting materials into a diverse array of chiral products. We note that the tandem diboration/cross-coupling reaction generally provides products in high yield and high selectivity (>95:5 enantiomer ratio), uses low loadings (1-2 mol per cent) of commercially available catalysts and reagents, offers an expansive substrate scope, and can address a broad range of alcohol and amine synthesis targets, many of which cannot be easily addressed with current technology.

Figure 1. The diboration/cross coupling (DCC) strategy and potential applications

a, An efficient cross-coupling reaction that applies to alkyl pinacol boronates would enable conversion of terminal alkenes to a broad array of useful building blocks. b, The DCC reaction followed by oxidation provides an alternative to carbonyl allylation for the construction of homoallylic alcohols as in epothilone C. Amination or homologation of the DCC product can provide access to chiral amines and simple chiral hydrocarbon building blocks. Ar=3,5-diisopropylphenyl.

Figure 2. Observations on the Pd-catalyzed cross-coupling of 1,2-bis(boronates) with bromobenzene

a, Generalized mechanism for the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. b, Cross-coupling of bromobenzene with alkyl pinacol boronates shows a pronounced rate enhancement due to the presence of a vicinal boronate. c, A direct competition experiment suggests that the rate enhancement occurs at the first irreversible step or any step that precedes it.

Figure 3. Mechanistic considerations for the cross-coupling rate enhancement observed with 1,2-bis(boronates)

a, While rate enhancements in Suzuki-Miyaura couplings might result from internal Lewis base donation to the reacting boronate (as in A) internal Lewis acid activation as in B may allow the boronate to better bind a reactive Pd(OH) species. b, the stereochemical outcome of cross-coupling (retention of configuration at carbon) is consistent with an inner-sphere transmetallation suggesting internal Lewis acid activation is the more likely pathway.

Figure 4. Tandem single-pot diboration/cross coupling provides a new route to enantiomerically-enriched benzylic alcohols from terminal alkenes

Yield refers to isolated yield of purified product and is an average of two experiments (individual experimental values are within 10%). Enantiomeric ratio (er) was determined by chiral chromatography with an error < ±2%. Note ligand (S,S)-L1 employed for compound 17 and cross-coupling for 23 and 24 employed 1 equiv. LiCl. (R,R)-3,5-diethylphenyl-derived ligand used in place of L1 for 12. NaBO₃ used for oxidation of 12, 14, and 15.

Figure 5. The diboration/cross-coupling tandem sequence provide access to synthetically useful chiral homoallylic alcohols that aren't readily prepared by carbonyl allylation reactions

a, Construction of substituted homoallylic alcohols by DCC reaction/oxidation. b, Use of dichloroethane allows for in situ formation of vinyl chloride and provides an effective route to unsubstituted homoallylic alcohols and amines. Note: Yield refers to isolated yield of purified product and is an average of two experiments (individual experimental values are within 10%). Enantiomeric ratio (er) was determined by chiral chromatography with an error < ±2%.

Figure 6. Diboration/cross-coupling tandem reactions provide short new synthesis routes to important medicinal agents. That these routes employ new feedstocks relative to existing routes and can facilitate new SAR studies

a, Preparation of Boc protected (S)-amphetamine. b, Preparation of (S)-fenpropimorph. c, Construction of a key lignan building block. d, Synthesis of non-racemic Lyrica.