Catalytic enantioselective 1,6-conjugate additions of propargyl and allyl groups

Abstract

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 chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates. Nonetheless, catalytic enantioselective 1,6-conjugate additions are uncommon, and ones that incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic α,β,γ,δ-doubly unsaturated acceptors are unknown. Chemical transformations that could generate a new bond at the C6 position of a dienoate are particularly desirable because the resulting products could then be subjected to further modifications. However, such reactions, especially when dienoates contain two equally substituted olefins, are scarce and are confined to reactions promoted by a phosphine-copper catalyst (with an alkyl Grignard reagent, dialkylzinc or trialkylaluminium compounds), a diene-iridium catalyst (with arylboroxines), or a bisphosphine-cobalt catalyst (with monosilyl-acetylenes). 1,6-Conjugate additions are otherwise limited to substrates where there is full substitution at the C4 position. It is unclear why certain catalysts favour bond formation at C6, and-although there are a small number of catalytic enantioselective conjugate allyl additions-related 1,6-additions and processes involving a propargyl unit are non-existent. Here 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 allenyl-boron compound or a monosubstituted allene may be used. Products can be obtained in up to 83 per cent yield, >98:2 diastereomeric ratio (for allyl additions) and 99:1 enantiomeric ratio. We elucidate the mechanistic details, including the origins of high site selectivity (1,6- versus 1,4-) and enantioselectivity as a function of the catalyst structure and reaction type, by means of density functional theory calculations. The utility of the approach is highlighted by an application towards enantioselective synthesis of the anti-HIV agent (-)-equisetin.

Figure 1. Possible conjugate addition pathways, the initial experiment and a plausible catalytic cycle

a, In a conjugate reaction, addition to the C4 site is kinetically favored (→ii or iii); subsequent 1,1′-reductive elimination (or α-addition) could afford product iv (Route A), or a 1,3—π-allyl shift (→v) may precede reductive elimination, affording 1,6-allenyl addition product vi (Route B). Alternatively, ii/iii may be directly converted to vii by a γ-addition (3,3′-reductive elimination type) process (Route C). b, Proof-of-principle experiment indicates that with an allenyl–copper intermediate, Route C predominates. c, Plausible catalytic cycle for the preferential formation of the 1,6-propargyl addition product. Abbreviations: R, or G, various organic functional groups; LUMO, lowest unoccupied molecular orbital; M, metal; pin, pinacolato; Mes, 2,4,6-trimethylphenyl.

Figure 2. Catalytic enantioselective 1,6-propargyl conjugate additions

a, Screening of a variety of chiral phosphine and NHC ligands indicated that the chiral copper catalysts derived from the latter series are significantly more effective, and that corresponding to imidazolinium salt 9b is optimal. b, The catalytic process is broadly applicable, affording products uniformly with >98% propargyl and 1,6-addition selectivity and in up to 80% yield and 98:2 e.r. Products containing a tertiary or an all-carbon quaternary carbon stereogenic center can be accessed. Abbreviations: pin, pinacolato; TBS, tert-butyldimethylsilyl, Mes, 2,4,6-trimethylphenyl; Mes, 2,4,6-trimethylphenyl. Reactions were performed under N₂ under the conditions shown in the box for 4a, except for 10a-c, where 10 mol % 9b and CuCl were used and mixture was allowed to stir for 24 h. Conversions, propargyl:allenyl and 1,6-:1,4-addition ratios were measured by analysis of ¹H NMR spectra of unpurified mixtures; the variance of values estimated to be <±2%. Yields correspond to isolated and purified products and represent an average of at least three runs (±5%). See the Supplementary Information for experimental details and spectroscopic analyses.

Figure 3. Catalytic diastereo- and enantioselective multicomponent 1,6-conjugate addition of 2-B(pin)-substituted allyl moieties

a, The pathway through which 1,6-addition products may be generated by a multicomponent process involving a dienoate, an allene and B₂(pin)₂. b, Preliminary experiment with an achiral NHC–Cu complex demonstrates that, although inefficient, reactions are exceptionally γ-, group- and 1,6-selective. Screening studies to identify an effective chiral catalyst indicates that a different NHC ligand is optimal for these transformations (vs. propargyl additions). c, The alternative approach entailing initial synthesis of a diboryl reagent leads to lower enantioselectivity. d, The catalytic protocol has considerable scope. Abbreviations: pin, pinacolato; TBS, tert-butyldimethylsilyl. Reactions were performed under N₂ under the conditions shown for synthesis of rac-12a (Fig. 3b). Conversions, propargyl:allenyl, 1,6-:1,4-addition and diastereomeric ratios (d.r.) were measured by analysis of ¹H NMR spectra of unpurified mixtures; the variance of values estimated to be <±2%. Yields correspond to isolated and purified products and represent an average of at least three runs (±5%). Ketone 12k was obtained after oxidative work-up. See the Supplementary Information for experimental details and spectroscopic analyses.

Figure 4. Mechanistic considerations

a, Based on DFT calculations [ωB97XD/Def2TZVPP//ωB97XD/Def2SVP level of theory (THF)] stereochemical models were developed for NHC–Cu-catalyzed 1,6-propargyl additions with catalysts bearing an N-mesityl moiety (from 9b). The issue is the larger energetic differentiation arising from steric repulsion between an o-methyl unit of the N-aryl group and the allenylcopper moiety (i.e., Me⋯^.H_a, 9b) versus one involving an aryl proton (i.e., H_N⋯^.H_a, 9d). b, Routes by which a phosphine–based and non-ligated Cu complex might generate products, respectively. c, Transition state energies for enantioselective allyl additions are consistent with the observation that the catalyst derived from 9d is optimal (vs. 9b). Steric repulsion involving a meta-methyl group of the NHC ligand with the carboxylic ester and the allylcopper substituents are the distinguishing elements. See the Supplementary Information for details of calculations. Abbreviations: NHC, N-heterocyclic carbene; E_rel, relative energy.

Figure 5. Functionalizations and demonstration of utility

a, The kinetically favored alkene can be readily isomerized to the thermodynamically preferred isomer under one set of basic conditions, while with water present, cleavage of the diester moiety leads to the formation of β-substituted aldehydes. b, Alkylation followed by enzymatic desymmetrization of the diester unit proceeds with excellent stereochemical control. c, Oxidation of the alkenyl–B(pin) moiety affords otherwise difficult-to-access γ,δ-unsaturated ketones with vicinal stereogenic centers at the α- and β-carbon sites. d, Application to synthesis of gram quantities of enantiomerically enriched triene 24, previously used in the total synthesis of anti-HIV agent (–)-equisetin showcases utility of the catalytic approach. Abbreviations: dabco, 1,4-diazabicyclo[2.2.2]octane; dbu, 1,8-diazabicyclo[5.4.0]undec-7-ene ; DMSO, dimethylsulfoxide; Ad, adamantyl; dppf, 1,1′-bis(diphenylphosphino)ferrocene; MOM, methoxymethyl; pin, pinacolato.