Chiral phosphoric acid (CPA) catalysis enables an enantioselective and diastereodivergent synthesis of trisubstituted allenes by conjugate addition of oxazolones to α-alkynyl-α,β-enones, in which switching the catalyst scaffold — flexible H8-BINOL (B2) versus rigid SPINOL (C1) — inverts the allene's axial chirality. The method is not fully diastereodivergent: alkyl ketone-side substituents (R3^3, e.g. n-propyl) give excellent outcomes under B2 but fail under the rigid C1 catalyst (very low yields, depressed diastereoselectivity, and very low reactivity for n-propyl), so the second diastereomeric allene series is inaccessible for that substrate class. The accompanying DFT model — reversible Michael addition of a Münchnone-form oxazolone followed by a stacking- versus stagger-form proton-transfer transition state, with the stagger form favored under B2 through CH–π dispersion and the stacking form selected in C1's small rigid cavity through steric fit — was developed for these two catalysts and is reported by the authors as reproducing the measured ee and dr for the substrates they studied; the paper gives no computed account of the alkyl-R3^3 failure under C1. The open problem is to make the stereodivergence general over the substrate range the reaction has been shown to cover, including alkyl R3^3 enones, so that both diastereomeric allene series are accessible on demand for the same substrate.

Background

Allenes are cumulated dienes (C=C=C) whose two terminal substituent planes are orthogonal; when each terminus bears two different groups the allene carries axial chirality, a stereogenic element present in natural products and useful in ligands and drug candidates. Trisubstituted allenes bearing an additional central stereocenter pose a stereochemical control problem: a fully stereodivergent method should deliver either diastereomeric product — both axial configurations at the allene for the same central configuration — on demand, typically by changing the catalyst. Chiral phosphoric acids (CPAs) are BINOL- or SPINOL-derived Brønsted acid organocatalysts whose 3,3'-aryl substituents form a chiral pocket that binds substrates through dual hydrogen bonding (the phosphate conjugate base and the proton act as a chiral ion pair); TRIP is a benchmark 3,3'-aryl BINOL CPA, H8-BINOL is its partially hydrogenated (more flexible, larger-pocket) variant, and SPINOL is a rigid spirobiindanol-based scaffold with a smaller, less deformable cavity. Oxazolones (azlactones) are five-membered azlactone rings used as C-nucleophile precursors for α-amino-acid-derived products; under Brønsted acid they can adopt a Münchnone-type (mesoionic, charge-separated) activation form. Wang, Zheng, Rajkumar, Xie, Yu, Peng and Yang (Nat. Commun. 11, 5527; 2020) reported that oxazolones add to α-alkynyl-α,β-enones (activated 1,3-enynes, i.e. aryl- or alkyl-substituted conjugated enynones; throughout, R1R^1 denotes the substituent at the alkyne terminus, R2R^2 the substituent at the β-carbon of the enone, and R3R^3 the ketone-side substituent) under CPA catalysis: a reversible Michael addition followed by a CPA-mediated proton transfer forms the C=C=C unit, and switching from the flexible (S)-H8-BINOL catalyst B2 (1-(4-methyl-naphthyl) substituents) to the rigid (R)-SPINOL catalyst C1 (1-naphthyl substituents) reverses the axial diastereoselectivity (dr 20:1 versus 1:12, both with high ee). Their DFT calculations attribute this to a stacking- versus stagger-form proton-transfer transition state (the oxazolone plane stacked over, or rotated out of, the catalyst pocket): under B2, CH–π dispersion interactions dominate and favor the stagger form; under C1, the stacking form is selected to fit the small rigid cavity where steric repulsion penalizes the alternative. The calculations also disclosed the Münchnone-type activation mode of oxazolones under Brønsted acid catalysis. Two features of the source study frame the open problem. First, scope: varying the ketone-side substituent R3^3 of the enone to alkyl groups (Et, nPr, nBu, iBu) works excellently under B2 (dr >9.4:1, ee >98%, products 3r–3u), but the same variations under C1 are 'not well tolerated' — very low yields, eroded diastereoselectivity, and very low reactivity for n-propyl — so the C1-selected diastereomeric allene series cannot be made for alkyl R3^3 substrates and the method is only conditionally diastereodivergent. Second, the reach of the mechanistic account: the stacking/stagger analysis was developed for the catalysts and substrates actually studied, where the calculations reproduce the measured selectivities (95% ee, 17:1 dr computed versus 91% ee, 20:1 dr observed under B2; 98% ee, 15:1 dr computed versus 97% ee, 12:1 dr observed under C1), and the paper explicitly declines to model the failing case — for R3^3 = n-propyl under C1 it records only the very low experimental reactivity, 'and thus further discussions on the diastereoselectivity is trivial'. Its remark that the diastereoselectivity is 'highly model dependent' concerns the choice of activation model (the favored Münchnone-type syn-addition transition state lies 4.2 kcal/mol below the favored enol-type anti-addition one), not transferability of the stacking/stagger picture across catalyst classes. The scope gap is therefore the open item the source leaves: the complementary, C1-selected allene diastereomer is inaccessible for alkyl R3^3 enones.

Problem Statement

The problem is to complete the diastereodivergent CPA-catalyzed addition of oxazolones to α-alkynyl-α,β-enones as a general method for trisubstituted allenes. For α-alkynyl-α,β-enones bearing alkyl ketone-side substituents R3^3 (ethyl, n-propyl, n-butyl, isobutyl and related), which currently give excellent yield, dr and ee only under the flexible H8-BINOL CPA B2 and fail under the rigid SPINOL CPA C1 (very low yields, eroded dr, and very low reactivity for n-propyl), identify catalyst and/or condition space — within or beyond the SPINOL-CPA class — that delivers the complementary allene diastereomer, that is, the axial configuration C1 selects for the substrates it does tolerate (the S-axial, stacking-form series in the source model), with yield, dr and ee comparable to what these same alkyl R3^3 substrates already give under B2 (dr >9.4:1, ee >98%), whereas under C1 they give very low yields and eroded dr. The target is that both diastereomers of the allene be accessible for the same substrate throughout the substrate range the reaction has been shown to cover — the R1^1, R2^2 and oxazolone R4^4 variations that both catalysts already tolerate and, in addition, the alkyl R3^3 enones, which are the documented failure of the catalyst-switch strategy — rather than only for aryl/heteroaryl/alkenyl/alkyl variations at R1^1 and R2^2. Because the R1^1, R2^2 and oxazolone R4^4 variations are already diastereodivergent under the existing B2/C1 pair, the outstanding target is the complementary (C1-selected) allene series for the alkyl R3^3 enones, whether delivered by a single catalyst/condition set or by a combination, and the already-covered R1^1/R2^2/R4^4 variations need not be re-established. Whether the complementary selectivity is obtained through a stacking-form proton transfer or by some other mechanism is not itself part of the target: the target is the observable diastereomeric outcome, with the source's mechanistic picture (Münchnone-type activation of the oxazolone, reversible Michael addition, stacking- versus stagger-form proton transfer whose balance is set by dispersion in the flexible backbone versus steric fit in the rigid small cavity) available as background and as a basis for rationalizing whatever solution is found.

References

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