On the Mechanism and Stereochemistry of Chiral Lithium‐Carbenoid‐Promoted Cyclopropanation Reactions

Abstract

An investigation into the mechanism and stereochemistry of chiral lithium-carbenoid-promoted cyclopropanation reactions by using density functional theory (DFT) methods is reported. Previous work suggested that this type of cyclopropanation reaction may proceed by competition between a methylene-transfer mechanism and a carbometalation mechanism. In this paper, it is demonstrated that the intramolecular cyclopropanation reactions promoted by chiral carbenoids 1 and 2 proceed by the methylene-transfer mechanism. The carbometalation mechanism was found to have a much higher reaction barrier and does not appear to compete with the methylene-transfer mechanism. The Lewis base group does not enhance the carbometalation pathway enough to compete with the methylene-transfer pathway. The present computational results are consistent with experimental observations for these cyclopropanation reactions. The factors governing the stereochemistry of the intramolecular cyclopropanation reaction by the methylene-transfer mechanism were examined to help elucidate the origin of the stereoselectivity observed in experiments. Both the directing group and the configuration at the C(1) centre were found to play a key role in the stereochemistry. Carbenoid 1 has a chiral C(1) centre of R configuration. The Lewis base group directs the cyclization of carbenoid 1 to form a single product. In contrast, the Lewis base group cannot direct the cyclization of carbenoid 2 to furnish a stereoselective product due to the S configuration of the chiral C(1) centre in carbenoid 2. This relationship of the stereochemistry to the chiral character of the carbenoid has implications for the design of new efficient carbenoid reagents for stereoselective cyclopropanation.

Homologation chemistry with nucleophilic α-substituted organometallic reagents: chemocontrol, new concepts and (solved) challenges

“…is significant considering that similar carbenoids could add in a 1,4-fashion as documented by Phillips 38 and Hernández-Galán. 39 It is conceivable that LiBr may not only exert a stabilizing effect on the carbenoid, but also display a mild Lewis acid activity enhancing the electrophilicity of the carbonyl-carbon.…”

Chemoselective and stereoselective lithium carbenoid mediated cyclopropanation of acyclic allylic alcohols

“…[54][55][56] Coordination with Lewis bases, either attached to the olefin, such as with allylic alcohols, or not, as is the case in coordination with polar solvents such as Et 2 O or THF is another factor needed to be taken into account to understand these reactions. This situation has been examined for lithium carbenoids on the internal cyclopropanation of a chiral carbenoid, 46 where theoretical studies support a methylene transfer mechanism, 54 as seems to be the case when coordination by polar solvents such as THF are taken into account in addition to the aggregation state of the halomethyl lithium carbenoid. 56 All these studies suggest a parallel behaviour of halomethyl lithium carbenoids to the one described by the Simmons-Smith reaction; although no experimental data are available for the chemoselectivity and stereoselectivity of the reaction of substituted halomethyl lithium carbenoids, thus justifying the study presented here.…”

Carbenes and Nitrenes

“…ee DFT calculations revealed that methylene transfer is the favoured mechanism in the lithium carbenoid cyclopropanation of (31). 62 The activation barrier of the carbometallation was shown to be very high; this mechanism can therefore not compete.…”