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General Overview

Cyclopropane rings are found as important structural features in many natural products, pharmaceuticals and agrochemicals. The high ring strain in cyclopropanes means that they can be introduced and further functionalized, but in most cases, they remain as an integral structural motif in the final active agent. Classic example are the pyrethroid insecticides/insect repellents such as (+)-trans-chrysanthemic acid.

Cyclopropane rings are often introduced to lock a molecule in a particular active conformation thus enhancing potency.

The efficient synthesis of multifaceted cyclopropane rings can be very demanding since a great deal of structural complexity can be contained in this ring system.  Methodology is needed to cope with, and deliver regio-, diastereo-, and enantio-selective synthesis.

The synthesis of cyclopropanes can be divided into two major synthetic strategies.

  1. The addition/transfer of carbenes/carbenoids from metals to alkenes
  2. The use of nucleophilic reagents to add to electrophilic centers, then SN2-like ring closure using carbanions and phosphorus and sulfur ylides.


The enantioselective synthesis of chiral cyclopropanes has been an area of intense research
focus over the past several decades and a range of ligand/metal catalysts have been developed for the transfer of carbenes from metal complexes inducing chirality in the cyclopropane product.

Of course, there are several synthetic strategies to build molecules containing cyclopropane rings including synthesis of the cyclopropane or introduction of a preformed cyclopropane synthon.  This guide only covers reactions in which the cyclopropane ring is constructed.

Green Criteria for Cyclopropanation

  1. Solvents should be chosen to minimize any potential safety and environmental impact.
  2. If possible, H340/341/H360/H361 labelled dipolar aprotic/halogenated or ethereal solvents should be avoided/substituted.
  3. Catalytic rather than stoichiometric metal processes are preferred.
  4. Base are metals preferred to Pt group metals for catalytic reactions.
  5. TON/TOF optimised for catalytic reactions.
  6. Inventory of hazardous (diazoalkanes) and higher mol. wt. reagents like ylides optimized.
  7. Can reactions using hazardous/high-reactivity reagents be more efficiently/safely run in flow rather than batch reactors?


General Literature Reviews on Cyclopropanation

Wu, W.; Lin, Z.; Jiang, H. Recent advances in the synthesis of cyclopropanes. Org. Biomol. Chem. 2018, 16, 7315–7329.

Ebner, C.; Carreira, E. M. Cyclopropanation Strategies in Recent Total Syntheses. Chem. Rev. 2017, 117, 11651–11679.  

Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Stereoselective Cyclopropanation Reactions. Chem. Rev. 2003, 103, 977–1050.   

Chen, D. Y.-K.; Pouwer, R. H.; Richard, J.-A. Recent advances in the total synthesis of cyclopropane-containing natural products. Chem. Soc. Rev. 2012, 41, 4631–4642.

Archambeau, A.; Miege, F.; Meyer, C.; Cossy, J. Intramolecular Cyclopropanation and C–H Insertion Reactions with Metal Carbenoids Generated from Cyclopropenes. Acc. Chem Res. 2015, 48, 1021–1031.   

Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Asymmetric Cyclopropanation Reactions Synthesis. 2014; 46 (08), 979–1029.
Zhang, D.; Song, H.; Qin, Y. Total Synthesis of Indoline Alkaloids: A Cyclopropanation Strategy. Acc. Chem. Res. 2011, 44, 447–457.

Kulinkovich, O. G. Cyclopropanes in Organic Synthesis;  John Wiley & Sons, 2015.

Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C.; Tanko, J.; Hudlicky, T. Use of cyclopropanes and their derivatives in organic synthesis. Chem. Rev. 1989, 89, 165–198.

De Meijere, A. Introduction: Cyclopropanes and Related Rings. Chem. Rev. 2003, 103, 931–932.