Regio- and Diastereoselective Carbometalation Reaction of Cyclopropenes.

Content Provider	Europe PMC
Author	Cohen, Yair Marek, Ilan
Copyright Year	2022
Abstract	ConspectusThe various facets of the chemistryof cyclopropane derivatives,the smallest carbocycle, are amazingly diverse and continue to fascinatetheoreticians, synthetic or structural chemists having interest infundamental physical, medicinal chemistry, and natural product synthesis.The challenges generated by this intriguing cyclic arrangement ofonly three tetravalent carbons represent a wide area of the chemicalspectrum. From fundamental aspects of bonding through the synthesisof highly strained molecules, the understanding of the mode of actionin biological systems to the selective cleavage into acyclic substratesmakes the chemistry of these small rings fascinating. Therefore, efficientroutes to prepare differently polysubstituted cyclopropanes have alwaysbeen of a primordial importance. In the past decade, we and othershave expanded the scope of the carbometalation reaction of cyclopropenesas a broad and general method to the formation of stereodefined cyclopropanederivatives. Although cyclopropenes, with their even higher strainenergy, easily undergo addition reactions of organometallic reagents,their carbometalation reactions generate new regio-, diastereo-, andenantioselectivity issues that needed to be addressed. These variousstereochemical aspects accompanied our research from its origins totoday, and we are proposing in this Account, a didactic overview ofthe different ways by which cyclopropenes can lead to the formationof polysubstituted cyclopropanes or open-products possessing severalstereogenic centers as a single regio- and diastereomer.Weinitially launched our research campaign on the chemistry ofthese strained three-membered rings by the regio- and diastereoselectivecopper-catalyzed carbomagnesiation of enantiomerically enriched cyclopropenylcarbinols. The directing alcohol governed both the regio- and diastereoselectivityof the addition and also served as a good leaving group as it undergoesa selective 1,2-elimination reaction to provide enantioenriched alkylidenecyclopropanesin excellent yields and enantiomeric excesses. Then, we turned ourattention to the regio- and stereoselective synthesis of stereodefinedtri- and tetrasubstituted cyclopropanes through the diastereoselectiveaddition to sp2- monosubstituted cyclopropenyl ester derivatives.With the aim to further expand this concept to the formation of penta-and hexa-substituted cyclopropanes as single isomer, we had firstto design the preparation of the required 1,2-disubstituted cyclopropenesthat would control the regioselective addition of the organometallicderivatives. The synthesis of penta- and hexa-substituted cyclopropaneswas then reported for the first time as a single regio- and diastereomer.It should be noted that the in situ formed cyclopropyl-metalintermediate is configurationally stable and can be subsequently functionalizedwith pure retention of the configuration by addition of electrophiles.Then, the enantioselective-catalyzed carbometalation reaction of achiralcyclopropenes allowed the synthesis of several new classes of cyclopropanederivatives in high enantiomeric ratios. Finally, by combining theregio- and diastereoselective carbometalation reaction of a cyclopropenewith a subsequent reaction of the resulting cyclopropylmetal species,a selective carbon–carbon bond cleavage was observed to leadto the preparation of acyclic substrates possessing several stereocentersincluding a quaternary carbon stereogenic center. Our original visionof using strain within an embedded double bond in a three-memberedring has provided new routes to the stereoselective synthesis of polysubstitutedcyclopropanes and has been extremely successful, as it representsa current new tool for the synthesis of persubstituted cyclopropanesas a single diastereomer.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC9535813&blobtype=pdf
ISSN	00014842
Journal	Accounts of Chemical Research [Acc Chem Res]
Volume Number	55
DOI	10.1021/acs.accounts.2c00424
PubMed Central reference number	PMC9535813
Issue Number	19
PubMed reference number	36102664
e-ISSN	15204898
Language	English
Publisher	American Chemical Society
Publisher Date	2022-09-14
Access Restriction	Open
Rights License	Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). © 2022 The Authors. Published by American Chemical Society
Content Type	Text
Resource Type	Article
Subject	Chemistry Medicine