Recent advances in the application of [2 + 2] cycloaddition in the chemical synthesis of cyclobutane-containing natural products

doi:10.1007/s13659-024-00457-9

Review

. 2024 Jun 11;14(1):37.

doi: 10.1007/s13659-024-00457-9.

Recent advances in the application of [2 + 2] cycloaddition in the chemical synthesis of cyclobutane-containing natural products

Song-Yu Hou¹, Bing-Chao Yan¹, Han-Dong Sun¹, Pema-Tenzin Puno²

Affiliations

¹ Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, Yunnan, People's Republic of China.
² Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, Yunnan, People's Republic of China. punopematenzin@mail.kib.ac.cn.

PMID: 38861197
PMCID: PMC11166626
DOI: 10.1007/s13659-024-00457-9

Review

Recent advances in the application of [2 + 2] cycloaddition in the chemical synthesis of cyclobutane-containing natural products

Song-Yu Hou et al. Nat Prod Bioprospect. 2024.

. 2024 Jun 11;14(1):37.

doi: 10.1007/s13659-024-00457-9.

Authors

Song-Yu Hou¹, Bing-Chao Yan¹, Han-Dong Sun¹, Pema-Tenzin Puno²

Affiliations

¹ Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, Yunnan, People's Republic of China.
² Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, Yunnan, People's Republic of China. punopematenzin@mail.kib.ac.cn.

PMID: 38861197
PMCID: PMC11166626
DOI: 10.1007/s13659-024-00457-9

Abstract

Cyclobutanes are distributed widely in a large class of natural products featuring diverse pharmaceutical activities and intricate structural frameworks. The [2 + 2] cycloaddition is unequivocally the primary and most commonly used method for synthesizing cyclobutanes. In this review, we have summarized the application of the [2 + 2] cycloaddition with different reaction mechanisms in the chemical synthesis of selected cyclobutane-containing natural products over the past decade.

Keywords: Cyclobutane; Natural products; Total synthesis; [2 + 2] Cycloaddition.

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Conflict of interest statement

All the authors declare that there is no competitive interest related to this work.

Figures

**Scheme 1**
Representative drugs and natural products containing cyclobutane motifs

**Scheme 2**
[2 + 2] cycloaddition between alkene and ketene in the synthesis of ( −)-isoscopariusin A

**Scheme 3**
[2 + 2] cycloaddition between alkene and keteniminium ions in the synthesis of ( −)-isoscopariusin A

**Scheme 4**
Intramolecular [2 + 2] cycloaddition between alkene and allene in the synthesis of ( −)-cajanusine

**Scheme 5**
Total synthesis of ( −)-hebelophyllene E

**Scheme 6**
Total synthesis of ( +)-hippolide J

**Scheme 7**
Total synthesis of hippolachnin A

**Scheme 8**
Scopariusicides A, B and its proposed biosynthesis

**Scheme 9**
Total synthesis of scopariusicide A

**Scheme 10**
Total synthesis of aquatolide by Takao

**Scheme 11**
Total synthesis of aplydactone by Zhang

**Scheme 12**
Mechanism of the direct photocatalytic [2 + 2] cycloaddition and EnT pathway

**Scheme 13**
EnT mediated [2 + 2] cycloaddition by T.P.Yoon

**Scheme 14**
EnT mediated [2 + 2] cycloaddition in the total synthesis of ( +)-isoscopariusins B and C

**Scheme 15**
Photocatalytic [2 + 2] cycloaddition in the total synthesis of artochamin J

**Scheme 16**
Total synthesis of piperarborenine B

**Scheme 17**
Total synthesis of isatiscycloneolignan A

**Scheme 18**
Total synthesis of barbarumamide C

**Scheme 19**
EnT mediated [2 + 2] cycloaddition in the total synthesis of sceptrin

**Scheme 20**
Mechanism of the [2 + 2] cycloaddition mediated by SET

**Scheme 21**
SET mediated intramolecular [2 + 2] cycloaddition by T.P. Yoon

**Scheme 22**
SET mediated intramolecular [2 + 2] cycloaddition in the total synthesis of ( ±)-nyingchinoid D by George

**Scheme 23**
Total Synthesis of endiandrin A and di-O-methylendiandrin A

**Scheme 24**
Cu(ClO₄)₂·6H₂O mediated intramolecular [2 + 2] cycloaddition in the total synthesis of ( +)-piperarborenine B

**Scheme 25**
Total Synthesis of six meroterpenoids by Fe-catalyzed [2 + 2] cycloaddition

**Scheme 26**
Non-classic intermolecular [2 + 2] cycloaddition between coumarin analogs and high-tensile bicyclo[1.1.0]butane derivatives

**Scheme 27**
Non-classic intermolecular [2 + 2] cycloaddition in the total synthesis of hippolachnin A

See this image and copyright information in PMC

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Hai QX, Hu K, Chen SP, Fu YY, Li XN, Sun HD, He HP, Puno PT. Hai QX, et al. Nat Prod Bioprospect. 2024 Aug 15;14(1):45. doi: 10.1007/s13659-024-00465-9. Nat Prod Bioprospect. 2024. PMID: 39143298 Free PMC article.

References

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[1] Rotella DP. The discovery and development of boceprevir. Expert Opin Drug Discov. 2013;8:1439–1447. doi: 10.1517/17460441.2013.843525. - DOI - PubMed

[2] Rotella DP. The discovery and development of boceprevir. Expert Opin Drug Discov. 2013;8:1439–1447. doi: 10.1517/17460441.2013.843525. - DOI - PubMed

[3] Rizza SA, Talwani R, Nehra V, Temesgen Z. Boceprevir. Drugs Today Barc Spain. 2011;47:743–751. doi: 10.1358/dot.2011.47.10.1656503. - DOI - PubMed

[4] Rizza SA, Talwani R, Nehra V, Temesgen Z. Boceprevir. Drugs Today Barc Spain. 2011;47:743–751. doi: 10.1358/dot.2011.47.10.1656503. - DOI - PubMed

[5] Wolleb H, Carreira EM. Total Synthesis of (+)-Dendrowardol C. Angew Chem Int Ed. 2017;56:10890–10893. doi: 10.1002/anie.201705809. - DOI - PubMed

[6] Wolleb H, Carreira EM. Total Synthesis of (+)-Dendrowardol C. Angew Chem Int Ed. 2017;56:10890–10893. doi: 10.1002/anie.201705809. - DOI - PubMed

[7] Zhao N, Xie S, Tian P, Tong R, Ning C, Xu J. Asymmetric total synthesis of (+)-astellatol and (−)-astellatene. Org Chem Front. 2019;6:2014–2022. doi: 10.1039/C9QO00384C. - DOI

[8] Zhao N, Xie S, Tian P, Tong R, Ning C, Xu J. Asymmetric total synthesis of (+)-astellatol and (−)-astellatene. Org Chem Front. 2019;6:2014–2022. doi: 10.1039/C9QO00384C. - DOI

[9] Chuang H-Y, Isobe M. Novel synthesis of right segment of solanoeclepin A org. Lett. 2014;16:4166–4169. - PubMed

[10] Chuang H-Y, Isobe M. Novel synthesis of right segment of solanoeclepin A org. Lett. 2014;16:4166–4169. - PubMed

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Recent advances in the application of [2 + 2] cycloaddition in the chemical synthesis of cyclobutane-containing natural products

Affiliations

Recent advances in the application of [2 + 2] cycloaddition in the chemical synthesis of cyclobutane-containing natural products

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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