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

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.

Figure 1

Transition state of Simmons–Smith cyclopropanation.

Figure 2

Various modifications for Simmons–Smith cyclopropanation [9].

Figure 3

Some biologically active natural compounds.

Scheme 1

Synthesis of amino acid derivative of vindoline.

Scheme 2

Synthesis of 14,15-cyclopropanaovinblastine 15 and 14,15-cyclopropanovincristine 16.

Scheme 3

Synthesis of halogenated cyclopropanovindoline derivatives 14,15-bromocyclopropanovindoline 17 and 14,15-iodocyclopropanovindoline 18.

Scheme 4

Total synthesis of (−)-lundurine A.

Scheme 5

Synthesis of xylogranatopyridine B 35.

Scheme 6

Synthesis of tricyclic skeleton of daphnimacropodine B 43.

Scheme 7

Synthesis of (±)-terpendole E 51.

Scheme 8

Synthesis of asporyzin C 58 and JBIR-03 59.

Scheme 9

Total synthesis of (+)-omphadiol 62.

Scheme 10

Total synthesis of (+)-pyxidatol C 65.

Scheme 11

Synthesis of cycloheptadiene intermediate (69a and 69b) toward the total synthesis of pyxidatol C.

Scheme 12

Synthesis of hirsutene 77 and 1-desoxyhypnophilin 79.

Scheme 13

Synthesis of intermediate 85 toward the total synthesis of chlorahololide A 86.

Scheme 14

Synthesis of intermediate 88 toward the total synthesis of (+)-chloranthalactone F 89.

Scheme 15

Total synthesis of repraesentin F 96.

Scheme 16

Synthesis of peyssonnosol 103 and peyssonnoside A 106.

Scheme 17

Total synthesis of sordaricin 115 and sordarin 118.

Scheme 18

Synthesis of trachylobane (125a and 125b), kaurane 127, atisane 128 and beyerane framework 129.

Scheme 19

Synthesis of octanorcucurbitacin B 138.

Scheme 20

Synthesis of tricyclopropylamino acid derivative as an active pharmaceutical ingredient (API) 145.

Scheme 21

Synthesis of Boc-protected 5-azaspiro[2.4]heptane-6-carboxylic acid (S)-150.

Scheme 22

Synthesis of Boc-protected 4,5-methano-β-proline (157a and 157b).

Scheme 23

Synthesis of racemic 3,4-methanonipecotic acid 163.

Scheme 24

Synthesis of JP4-039 analogue 172.

Scheme 25

Synthesis of trans-methanoproline 177a.

Scheme 26

Synthesis of five 2-oxabicyclo[3.1.0]hexane-based nucleoside analogues.

Scheme 27

Synthesis of homologated (N)-methanocarba nucleoside 192.

Scheme 28

Synthesis of 1-(4R,5S,6R,7R)-5,6-dihydroxy-7-(hydroxymethyl)-.

Scheme 29

Synthesis of 3′-deoxy3′-C-hydroxymethyl-2′,3′-methylene-uridine 207.

Scheme 30

Synthesis of 4′/5′-spirocyclopropanated uridine and D-xylouridine derivatives (213–216).

Scheme 31

Synthesis of C-fluoro-branched cyclopropyl nucleosides (226–233).

Scheme 32

Synthesis of 4′,5′-BNA phosphoramidite 238.

Scheme 33

Synthesis of C1 to C12 fragment 245 of brevipolide H 246.

Scheme 34

Synthesis of clavosolide A 251.

Scheme 35

Total synthesis of (+/−)-cascarillic acid 255.

Scheme 36

Total synthesis of (+/−)-grenadamide 258.

Scheme 37

Synthesis of solandelactones A, B, E and F (268a–269b).

Scheme 38

Synthesis of compound 278 and compound 279.

Scheme 39

Synthesis of octahydropyrrolo[1,2-a]pyrazine A derivatives 286 and 287.

Scheme 40

Synthesis of carbamazepine analogue 291.

Scheme 41

Kilogram-scale synthesis of ciprofol 301.

Scheme 42

Synthesis of (+)-AMMP 309.

Scheme 43

Synthesis of oxaspiro[n,3,3]propellane 317.

Scheme 44

Synthesis of (+)-cibenzoline 321.

Scheme 45

Synthesis of (+)-tranylcypromine 326.

Scheme 46

Synthesis of (−)-milnacipran hydrochloride 331.