Rhodium‐Catalyzed Enantioselective Intramolecular Hydroacylation of Trisubstituted Alkenes

Abstract

We report the first examples of transition metal-catalyzed enantioselective alkene hydroacylations with 1,1,2-trisubstituted alkenes. DFT and mechanistic studies are consistent with a reaction pathway for these rhodium-catalyzed processes including intramolecular alkene hydroacylation and α-epimerization to generate highly enantioenriched, polycyclic architectures. This reaction sequence enables the hydroacylation of 2-(cyclohex-1-en-1-yl)benzaldehydes to form hexahydro-9H-fluoren-9-ones in moderate to high yields (68-91 %) with high enantioselectivities (up to 99 % ee) and diastereoselectivities (typically >20:1).

Unique cyclolignan’s architecture obtained via acid catalyzed cyclization/intramolecular Friedel-Crafts tandem reaction

“…Johnson et al obtained a similar polycyclic architecture using Rh catalyzed intramolecular hydroacylation of an appropriate trisubstituted alkene. 17 However, compared to our results the previous method requires a heavy metal catalyst, leads to the racemic product and has low yield (43%).…”

Catalytic Enantioselective Transformations Involving C–H Bond Cleavage by Transition-Metal Complexes

“…224 In 2016, Scanlon, Stanley, and their co-workers reported a Rh-catalyzed asymmetric intramolecular hydroacylation of 1,1,2-trisubstituted cycloalkenes 307 to construct cis-tetracyclic hexahydro-9H-fluoren-9-one scaffolds 309. 225 The reaction is believed to proceed through intermediate 308 via an intramolecular hydroacylation/αepimerization sequence, and on the basis of control experiments and DFT calculations, the authors proposed that a cationic Rh 226 In all cases, only six-membered ring formation was observed, providing 3,4-dihydronaphthalen-1(2H)-ones 311 in excellent enantiopurity (see Scheme 79 for a related mechanistic evaluation concerning the effects of alkene substitution on the regioselectivity of migratory insertion). The Stanley group have also disclosed the synthesis of several pyrrole-and indole-fused cyclic ketones (Scheme 78).…”

“…Currently, this remains the only cobalt-catalyzed enantioselective hydroacylation study, although related reactions in racemic and achiral settings are known. − Notably, in late 2016, the Coltart research group published a complementary approach to chiral indanones, via the same retrosynthetic disconnection, however, in this case via C­(sp 2 )–H functionalization of the corresponding aldiminium (see Scheme ). In 2016, Scanlon, Stanley, and their co-workers reported a Rh-catalyzed asymmetric intramolecular hydroacylation of 1,1,2-trisubstituted cycloalkenes 307 to construct cis -tetracyclic hexahydro-9 H -fluoren-9-one scaffolds 309 . The reaction is believed to proceed through intermediate 308 via an intramolecular hydroacylation/α-epimerization sequence, and on the basis of control experiments and DFT calculations, the authors proposed that a cationic Rh species catalyzes both processes.…”

“…224 In 2016, Scanlon, Stanley, and their co-workers reported a Rh-catalyzed asymmetric intramolecular hydroacylation of 1,1,2-trisubstituted cycloalkenes 307 to construct cis-tetracyclic hexahydro-9H-fluoren-9-one scaffolds 309. 225 The reaction is believed to proceed through intermediate 308 via an intramolecular hydroacylation/αepimerization sequence, and on the basis of control experiments and DFT calculations, the authors proposed that a cationic Rh species catalyzes both processes. A Rh(I)-catalyzed hydroacylation of o-allylbenzaldehydes 310 with (R)-DTBM-SEG-PHOS was also reported by Stanley and co-workers.…”

Cobalt‐Catalyzed Enantio‐ and Diastereoselective Intramolecular Hydroacylation of Trisubstituted Alkenes

“…[13][14][15] These successful examples,however, are limited to substrates bearing either mono-or disubstituted (particularly 1,1disubstituted) alkenyl groups.I ntramolecular hydroacylation of trisubstituted alkenes,e nantioselective as well as racemic variants,remains largely unexplored. [16] Herein, we report on the development of an intramolecular enantio-and diastereoselective hydroacylation of 2-alkenylbenzaldehydes bearing trisubstituted alkenyl groups,areaction which is promoted by ac obalt/chiral diphosphine catalyst (Scheme 1b). Notably,g ood to high enantioselectivity is achieved regard-less of the E/Z ratio of the alkenyl group.The reaction allows facile preparation of av ariety of enantiomerically enriched trans-2,3-disubstituted indanones,for which existing synthetic methods have been limited in number and scope.…”