Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jul 26;28(15):5651.
doi: 10.3390/molecules28155651.

Simmons-Smith Cyclopropanation: A Multifaceted Synthetic Protocol toward the Synthesis of Natural Products and Drugs: A Review

Ramsha Munir  1 , Ameer Fawad Zahoor  1 , Sadia Javed  2 , Bushra Parveen  1 , Asim Mansha  1 , Ahmad Irfan  3 , Samreen Gul Khan  1 , Ali Irfan  1 , Katarzyna Kotwica-Mojzych  4 , Mariusz Mojzych  5
Affiliations
Review

Simmons-Smith Cyclopropanation: A Multifaceted Synthetic Protocol toward the Synthesis of Natural Products and Drugs: A Review

Ramsha Munir et al. Molecules. .

Abstract

Simmons-Smith cyclopropanation is a widely used reaction in organic synthesis for stereospecific conversion of alkenes into cyclopropane. The utility of this reaction can be realized by the fact that the cyclopropane motif is a privileged synthetic intermediate and a core structural unit of many biologically active natural compounds such as terpenoids, alkaloids, nucleosides, amino acids, fatty acids, polyketides and drugs. The modified form of Simmons-Smith cyclopropanation involves the employment of Et2Zn and CH2I2 (Furukawa reagent) toward the total synthesis of a variety of structurally complex natural products that possess broad range of biological activities including anticancer, antimicrobial and antiviral activities. This review aims to provide an intriguing glimpse of the Furukawa-modified Simmons-Smith cyclopropanation, within the year range of 2005 to 2022.

Keywords: Furukawa reagent; Simmons–Smith cyclopropanation; drugs; natural products.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Transition state of Simmons–Smith cyclopropanation.
Figure 2
Figure 2
Various modifications for Simmons–Smith cyclopropanation [9].
Figure 3
Figure 3
Some biologically active natural compounds.
Scheme 1
Scheme 1
Synthesis of amino acid derivative of vindoline.
Scheme 2
Scheme 2
Synthesis of 14,15-cyclopropanaovinblastine 15 and 14,15-cyclopropanovincristine 16.
Scheme 3
Scheme 3
Synthesis of halogenated cyclopropanovindoline derivatives 14,15-bromocyclopropanovindoline 17 and 14,15-iodocyclopropanovindoline 18.
Scheme 4
Scheme 4
Total synthesis of (−)-lundurine A.
Scheme 5
Scheme 5
Synthesis of xylogranatopyridine B 35.
Scheme 6
Scheme 6
Synthesis of tricyclic skeleton of daphnimacropodine B 43.
Scheme 7
Scheme 7
Synthesis of (±)-terpendole E 51.
Scheme 8
Scheme 8
Synthesis of asporyzin C 58 and JBIR-03 59.
Scheme 9
Scheme 9
Total synthesis of (+)-omphadiol 62.
Scheme 10
Scheme 10
Total synthesis of (+)-pyxidatol C 65.
Scheme 11
Scheme 11
Synthesis of cycloheptadiene intermediate (69a and 69b) toward the total synthesis of pyxidatol C.
Scheme 12
Scheme 12
Synthesis of hirsutene 77 and 1-desoxyhypnophilin 79.
Scheme 13
Scheme 13
Synthesis of intermediate 85 toward the total synthesis of chlorahololide A 86.
Scheme 14
Scheme 14
Synthesis of intermediate 88 toward the total synthesis of (+)-chloranthalactone F 89.
Scheme 15
Scheme 15
Total synthesis of repraesentin F 96.
Scheme 16
Scheme 16
Synthesis of peyssonnosol 103 and peyssonnoside A 106.
Scheme 17
Scheme 17
Total synthesis of sordaricin 115 and sordarin 118.
Scheme 18
Scheme 18
Synthesis of trachylobane (125a and 125b), kaurane 127, atisane 128 and beyerane framework 129.
Scheme 19
Scheme 19
Synthesis of octanorcucurbitacin B 138.
Scheme 20
Scheme 20
Synthesis of tricyclopropylamino acid derivative as an active pharmaceutical ingredient (API) 145.
Scheme 21
Scheme 21
Synthesis of Boc-protected 5-azaspiro[2.4]heptane-6-carboxylic acid (S)-150.
Scheme 22
Scheme 22
Synthesis of Boc-protected 4,5-methano-β-proline (157a and 157b).
Scheme 23
Scheme 23
Synthesis of racemic 3,4-methanonipecotic acid 163.
Scheme 24
Scheme 24
Synthesis of JP4-039 analogue 172.
Scheme 25
Scheme 25
Synthesis of trans-methanoproline 177a.
Scheme 26
Scheme 26
Synthesis of five 2-oxabicyclo[3.1.0]hexane-based nucleoside analogues.
Scheme 27
Scheme 27
Synthesis of homologated (N)-methanocarba nucleoside 192.
Scheme 28
Scheme 28
Synthesis of 1-(4R,5S,6R,7R)-5,6-dihydroxy-7-(hydroxymethyl)-.
Scheme 29
Scheme 29
Synthesis of 3′-deoxy3′-C-hydroxymethyl-2′,3′-methylene-uridine 207.
Scheme 30
Scheme 30
Synthesis of 4′/5′-spirocyclopropanated uridine and D-xylouridine derivatives (213–216).
Scheme 31
Scheme 31
Synthesis of C-fluoro-branched cyclopropyl nucleosides (226–233).
Scheme 32
Scheme 32
Synthesis of 4′,5′-BNA phosphoramidite 238.
Scheme 33
Scheme 33
Synthesis of C1 to C12 fragment 245 of brevipolide H 246.
Scheme 34
Scheme 34
Synthesis of clavosolide A 251.
Scheme 35
Scheme 35
Total synthesis of (+/−)-cascarillic acid 255.
Scheme 36
Scheme 36
Total synthesis of (+/−)-grenadamide 258.
Scheme 37
Scheme 37
Synthesis of solandelactones A, B, E and F (268a–269b).
Scheme 38
Scheme 38
Synthesis of compound 278 and compound 279.
Scheme 39
Scheme 39
Synthesis of octahydropyrrolo[1,2-a]pyrazine A derivatives 286 and 287.
Scheme 40
Scheme 40
Synthesis of carbamazepine analogue 291.
Scheme 41
Scheme 41
Kilogram-scale synthesis of ciprofol 301.
Scheme 42
Scheme 42
Synthesis of (+)-AMMP 309.
Scheme 43
Scheme 43
Synthesis of oxaspiro[n,3,3]propellane 317.
Scheme 44
Scheme 44
Synthesis of (+)-cibenzoline 321.
Scheme 45
Scheme 45
Synthesis of (+)-tranylcypromine 326.
Scheme 46
Scheme 46
Synthesis of (−)-milnacipran hydrochloride 331.
See this image and copyright information in PMC

References

    1. Nakamura M., Hirai A., Nakamura E. Reaction pathways of the Simmons−Smith reaction. J. Am. Chem. Soc. 2003;125:2341–2350. doi: 10.1021/ja026709i. - DOI - PubMed
    1. Denmark S.E., Edwards J.P., Wilson S.R. Solution and solid-state structure of the “Wittig-Furukawa” cyclopropanation reagent. J. Am. Chem. Soc. 1991;113:723–725. doi: 10.1021/ja00002a078. - DOI
    1. Charette A.B., Juteau H. Design of amphoteric bifunctional ligands: Application to the enantioselective Simmons-Smith cyclopropanation of allylic alcohols. J. Am. Chem. Soc. 1994;116:2651–2652. doi: 10.1021/ja00085a068. - DOI
    1. Ukaji Y., Sada K., Inomata K. Synthesis of silicon substituted cyclopropylmethyl alcohols in optically active form via asymmetric Simmons-Smith reaction of γ-silicon substituted allylic alcohols. Chem. Lett. 1993;22:1227–1230. doi: 10.1246/cl.1993.1227. - DOI
    1. Gonzalez J., Gonzalez J., Perez-Calleja C., Lopez L.A., Vicente R. Zinc-Catalyzed Synthesis of Functionalized Furans and Triarylmethanes from Enynones and Alcohols or Azoles: Dual X–H Bond Activation by Zinc. Angew. Chem. Int. Ed. 2013;52:5853–5857. doi: 10.1002/anie.201301625. - DOI - PubMed

LinkOut - more resources