Investigation into Factors Influencing Stereoselectivity in the Reactions of Heterocycles with Donor−Acceptor-Substituted Rhodium Carbenoids

Abstract

Rhodium-catalyzed decomposition of aryldiazoacetates in the presence of pyrroles or furans results in mono- or biscyclopropanation of the heterocycle, but with opposite enantioinduction. In the absence of sterically encumbering groups, the cyclopropanation of furan occurs with initial bond formation at the 2-position. If this pathway is sterically blocked, cyclopropanation can occur with initial bond formation at the 3-position of the furan ring; in this case, the cyclopropanation reaction takes place on the opposite face of the heterocycle, and the opposite enantioinduction is observed. Upon extension of this methodology to benzofurans, a highly enantioselective monocyclopropanation reaction occurs to furnish a product derived from initial bond formation at the 2-position of the benzofuran. When this reaction pathway is inhibited by sterically encumbering substituents on the benzofuran, no cyclopropanation of the furan ring is observed, and instead, double cyclopropanation of the benzene ring occurs. Double cyclopropanation of the benzene ring was also observed in reactions with indoles.

Rhodium Carbenoid Approach for Introduction of 4-Substituted (Z)-Pent-2-enoates into Sterically Encumbered Pyrroles and Indoles

“…When N -methylpyrroles are used as substrates, alkylation occurs rather than cyclopropanation 5a. The reaction of aryldiazoacetates with N -Boc-pyrrole results in double cyclopropanation of the pyrrole rings 6. Similarly, reaction of N -Boc-indole with aryldiazoacetates causes double cyclopropanation of the benzene ring to occur 6.…”

“…The reaction of aryldiazoacetates with N -Boc-pyrrole results in double cyclopropanation of the pyrrole rings 6. Similarly, reaction of N -Boc-indole with aryldiazoacetates causes double cyclopropanation of the benzene ring to occur 6. However, if the indole is 6-substituted, C–H functionalization of a side-chain becomes the preferred reaction 6.…”

Late-stage C–H functionalization of complex alkaloids and drug molecules via intermolecular rhodium-carbenoid insertion

“…Further application of this method to apovincamine (14a) led to bis-cyclopropanation of the electron-rich indole ring 16, with only minimal formation of the C-H insertion product (Fig. 3b) 44 . Attempts with other dirhodium catalysts provided similar reaction outcomes.…”

Synthesis of Complex Hexacyclic Compounds via a Tandem Rh(II)-Catalyzed Double-Cyclopropanation/Cope Rearrangement/Diels–Alder Reaction

“…The stereoselective double cyclopropanation of aromatic rings by donor/acceptor carbenoids has been observed previously. 11 A subsequent divinylcyclopropane rearrangement 3 of 13 would form tetracycle 14 . The bis-cyclopropane 13 contains two divinylcyclopropanes.…”

“…14 The rhodium carbenes of donor/acceptor carbenes are sterically demanding and preferentially initiate the cyclopropanation at the least substituted carbon of the alkene. 14 As it is well-established that cyclopropanation of a 1,4-disubstituted benzene ring does not occur, 7,11 we assume the site for greater initial bond formation during the cyclopropanation would not be adjacent to a ring substituent. Four possible orientations ( II – V ) would fit this criterion, although only transition state II would avoid steric interference with the “wall” of the catalyst and is electronically favored for delocalization of the positive charge build up into the methoxy group.…”