Enantioselective organocatalytic activation of vinylidene–quinone methides (VQMs)

Jean Rodriguez (1) , Damien Bonne (1)

1 ISM2 - Institut des Sciences Moléculaires de Marseille

Vinylidene-quinone methides (VQMs) are highly electrophilic chiral reagents that can be generated in situ from 2-(phenylethynyl)phenols. They were characterized for the first time in 2012 but their enantioselective organocatalytic activation was addressed only very recently. Their specific reactivity has revealed innovative strategies notably for the control of axial chirality. Vinylidene-quinone methides (VQMs) were synthesized and identified for the first time in 2012 by Freccero via excited-state intramolecular proton transfer (ESIPT) by irradiation of ortho-alkynylphenols. 1,2 These intriguing highly electrophilic intermediates are variants of well-known ortho-quinone methides (o-QMs) widely used in enantioselective transformations. 3 A critical feature of VQMs 2 is their intrinsic axial chirality that can be controlled during their generation from 2-alkynylnaphthols 1 with a chiral non-racemic organocatalyst (Scheme 1). 4 Once generated, VQMs can be involved in stereoselective cycloadditions or nucleo-philic additions with transfer of chirality. This allows access to original centrally chiral enantioenriched polycyclic pyrans 3 or to axially chiral naphthols 4. The first example of enantioselective activation of a VQM was described by the group of Irie in 2013 (Scheme 2). 5 The use of cinchonidine as the organocatalyst directly transformed symmetric bis-2-alkynylnaphthol 5a to axially chiral pyran 6a in good yield and moderate enantioselectivity through an intramolecular inverse-electron demand hetero-Diels-Alder reaction. This original strategy has been exemplified and developed last year by the group of Yan using a quinine-derived thiourea I for the organocatalytic activation. 6 Under these optimized conditions, this unique transformation proceeds highly chemo-and enantioselectively even with challenging non-symmetric bis-alkynylnaphthols 5b. Recently, DFT calculations showed that the axial chirality of the VQM intermediate is generated during the protonation step (Scheme 3). 7 First, the thiourea moiety of the catalyst acts as a Brønsted acid to activate the functionalized naphthol 5, which is deprotonated by the tertiary amine moiety of the catalyst I to form the intermediate 7. Afterward, the alkyne is enantioselectively protonated by the ammonium salt of the catalyst to give the chiral VQM intermediate 8, via the transition state 9. Then, a transfer of chirality operates during the key intramolecular [4+2]-hetero-Diels-Alder cycloaddition leading to 6. Scheme 1 Exploiting the reactivity of chiral VQMs. Scheme 2 Enantioselective synthesis of 2-aryl naphthopyran atropisomers.

Mots clés: Axial chirality; Vinylidene–quinone methides; Enantioselective organocatalysis

Domaines: Chimie organique

Jean Rodriguez, Damien Bonne. Enantioselective organocatalytic activation of vinylidene–quinone methides (VQMs). Chemical Communications, 2019, 55 (75), pp.11168-11170. ⟨10.1039/c9cc05097c⟩. ⟨hal-02354840⟩