Multicatalytic, asymmetric Michael/Stetter reaction of salicylaldehydes and activated alkynes

Abstract

We report the development of a multicatalytic, one-pot, asymmetric Michael/Stetter reaction between salicylaldehydes and electrondeficient alkynes. The cascade proceeds via amine-mediated Michael addition followed by an N-heterocyclic carbene-promoted intramolecular Stetter reaction. A variety of salicylaldehydes, doubly activated alkynes, and terminal, electrophilic allenes participate in a one-step or two-step protocol to give a variety of benzofuranone products in moderate to good yields and good to excellent enantioselectivities. The origin of enantioselectivity in the reaction is also explored; E∕Z geometry of the reaction intermediate as well as the presence of catalytic amounts of catechol additive are found to influence reaction enantioselectivity.catalysis | organic synthesis | tandem catalysis

Evolution of asymmetric organocatalysis: multi- and retrocatalysis

“…As the Stetter reaction is significantly influenced by olefin geometry (E-isomers react with higher yield and enantioselectivity) the authors performed the reaction sequence with allenoates 206 (Scheme 31). 89 These starting materials (as well as 201) formed the intermediate aldehydes with high E-selectivity, whereas ketoalkynoates gave mixtures of E and Z isomers. Thus, employing 73 and 206 in a sequential multicatalytic reaction afforded the desired products 207 in reasonable yields and with up to 98% ee (Scheme 31).…”

“…Interestingly, the tertiary amine (198 or 199) not the carbene 160 acts as nucleophilic catalyst for the Michael reaction although both are present from the outset of the reaction, which was confirmed by control experiments. 89 Further investigations indicated that the enantioselectivity of the reaction is possibly enhanced by traces of strong hydrogen bonding donors, such as catechols, 91 derived from Dakin-oxidation of salicylaldehydes. When the reaction was performed stepwisely the final products were isolated in good yields, however, in lower and more uniform enantioselectivities.…”

“…Employing a phosphonate ester as alkyne component afforded 204d in low yield and with better selectivity. 89 In order to achieve better yields and high regio-and enantioselectivities, Lathrop and Rovis examined the reaction of salicylaldehyde (73) with alkynes bearing a single electronwithdrawing group 89,92 (the thus-generated intermediate aldehydes have been used previously in the Stetter reaction affording the corresponding products in high enantioselectivity). However, an initial attempt resulted in the isolation of starting materials only.…”

Organocatalysis

“…This selectivity, governed by the identity of the catalytic base used, promotes highly enantioselective hetero-Diels-Alder reaction over homoenolate-mediated cyclopentene formation (9). Alternatively, Filloux et al (10) used an achiral N-heterocyclic carbene catalyst in combination with a chiral prolinol derivative to affect an asymmetric cascade involving a Michael addition and subsequent Stetter reaction sequence, promoted by their respective catalysts. Through this protocol, they showed that a family of asymmetric benzofuranones could be accessed by combining salicylaldehydes with alkynes or allenes.…”

“…This section highlights examples from the fields of iminium, enamine, dienamine, and singly occupied molecular orbital (SOMO) catalysis, in which mechanistic insight, reaction partner scope, or product accessibility has been expanded in significant ways. The next classification of articles is somewhat broader and includes those modes of activation that are catalyzed by nonamine-centered Lewis bases (7)(8)(9)(10). Although there are fewer established modes of generic activation that fall into this category, the potential for reaction discovery in this arena is evident from the highlighted examples, which represent quite disparate modes of activation arising from phosphorus, chalcogen, and N-heterocyclic carbene catalysts.…”