Multicomponent catalytic enantioselective transformations that entail the combination of butadiene or isoprene (common feedstock), an enoate (prepared in one step) and B2(pin)2 (commercially available) are presented. These processes constitute an uncommon instance of conjugate addition of an allyl moiety and afford the desired products in up to 83% yield and 98:2 enantiomeric ratio. Based on DFT calculations stereochemical models and rationale for the observed profiles in selectivity are provided.

Conjugate (or 1,4-) additions of carbanionic species to α,β-unsaturated carbonyl compounds are vital to research in organic and medicinal chemistry, and there are several known chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates1. However, catalytic enantioselective 1,6-conjugate additions are uncommon, and ones that are able to incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic α,β,γ,δ-doubly unsaturated acceptors are unknown2. Chemical transformations that could generate a new bond at the C6 position of a dienoate are particularly desirable, as the resulting products would be subjected to further modifications; such reactions, especially when dienoates contain two equally substituted olefins, are scarce3 and are confined to reactions promoted by a phosphine–copper (with alkyl Grignard4,5, dialkylzinc or trialkylaluminum compounds6,7), a diene–iridium (with arylboroxines)8,9, and a bisphosphine–cobalt catalyst (with monosilyl-acetylenes)10. 1,6-conjugate additions are otherwise limited to substrates where there is full substitution at C411. It is not clear why certain catalysts favor bond formation at C6, and – while there are a small number of catalytic enantioselective conjugate allyl additions12,13,14,15 – related 1,6-additions and processes involving a propargyl unit are non-existent. In this manuscript, we show that an easily accessible organocopper catalyst can promote 1,6-conjugate additions of propargyl and 2-boryl-substituted allyl groups to acyclic dienoates with high selectivity. A commercially available allenylboron compound or a monosubstituted allene may be used. Products can be obtained in up to 83 percent yield, >98 percent diastereo- (for allyl additions) and 99:1 enantiomeric ratio. Mechanistic details, including the origins of high site- (1,6- versus 1,4-) and enantioselectivity as a function of the catalyst structure and reaction type, have been elucidated by means of density functional theory (DFT) calculations.

Multicomponent catalytic enantioselective transformations that entail the combination of butadiene or isoprene (common feedstock), an enoate (prepared in one step) and B 2 (pin) 2 (commercially available) are presented. These processes constitute an uncommon instance of conjugate addition of an allyl moiety and afford the desired products in up to 83% yield and 98:2 enantiomeric ratio. Based on DFT calculations stereochemical models and rationale for the observed profiles in selectivity are provided. Keywordsboron; conjugate additions; copper; enantioselective catalysis; synthesis Multicomponent catalytic transformations can convert readily accessible starting materials to substantially more complex molecules. [1] One desirable scenario would involve 1,3-dienes and especially butadiene, a common feedstock produced in more than 10 million tons per year worldwide. However, catalytic enantioselective reactions with these unsaturated hydrocarbons, the majority of which are cycloadditions, are limited in number. [2] There are only the seminal contributions of Krische [3] regarding coupling of butadiene with alcohols or aldehydes, and the disclosures on reactions of 1-substituted butadienes with aldehydes [4a] and combination of aryl-based reagents and sodium dimethylmalonate. [4b-c] Enantioselective processes have been recently developed that begin with the addition of a chiral Cu-B(pin) complex (pin = pinacolato) to an alkene, [5] affording organocopper species that may then react with another electrophile. Cu-based catalysts have accordingly been utilized to merge an allene and an aldehyde or ketone, [6] an allene and an allylic phosphate, [7] or an enyne and an aldehyde enantioselectively. [8] Related strategies, some with a Pd-based co-catalyst, entail the use of an aryl olefin and an aryl or benzyl halide (nonenantioselective) [9] or an allylic carbonate (enantioselective). [10] A catalytic process with butadiene, B 2 (pin) 2 and an enoate (Scheme 1) might be envisioned that constitutes enantioselective conjugate addition (ECA) of an allyl group, a class of Correspondence to: Amir H. Hoveyda. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript valuable reactions that remains severely underdeveloped. [11] Further, the only reported multicomponent enantioselective conjugate additions [12] begin with initial addition to an alkynyl or alkenyl group followed by an intramolecular conjugate addition. [13] The envisioned sequence would commence with the conversion of a 1,3-diene to allylcopper species ii and iii [14] and then iv or v (α-vs. γ-addition). One possible complication would be competitive boryl conjugate addition (i → vi, Scheme 1). [15 ] This is a more formidable chemoselectivity challenge compared to when an allenyl, [6,7,13b] an alkynyl [13a] or a styrenyl [13] substrate is used because these latter species are either less hindered and/or more electrophilic (vs. a butadiene).Preliminary experiments with butadiene and phosphine or N-heterocyclic carbe...

Multicomponent catalytic enantioselective transformations that entail the combination of butadiene or isoprene (common feedstock), an enoate (prepared in one step) and B2(pin)2 (commercially available) are presented.