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Review
. 2024 May;13(5):e202300306.
doi: 10.1002/open.202300306. Epub 2024 Apr 22.

Relevant Developments in the Use of Three-Component Reactions for the Total Synthesis of Natural Products. The last 15 Years

Enrique L Larghi  1 , Andrea B J Bracca  1 , Sebastian O Simonetti  1 , Teodoro S Kaufman  1
Affiliations
Review

Relevant Developments in the Use of Three-Component Reactions for the Total Synthesis of Natural Products. The last 15 Years

Enrique L Larghi et al. ChemistryOpen. 2024 May.

Abstract

Multicomponent reactions (MCRs) offer a highly useful and valuable strategy that can fulfill an important role in synthesizing complex polysubstituted compounds, by simplifying otherwise long sequences and increasing their efficiency. The total synthesis of selected natural products employing three-component reactions as their common strategic MCR approach, is reviewed on a case-by-case basis with selected targets conquered during the last 15 years. The revision includes detailed descriptions of the selected successful sequences; relevant information on the isolation, and bioactivity of the different natural targets is also briefly provided.

Keywords: Heterocycles; Multicomponent reactions; Natural products; Step-economy and efficiency; Total synthesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Selection of natural products recently targeted for partial or formal syntheses employing MCRs. In black and red, the final molecular fragments that included the MCR‐based efforts; in red the molecular fragments prepared with the aid of MCRs.
Scheme 1
Scheme 1
Total syntheses of sphinganine (8) and safingol (9).
Scheme 2
Scheme 2
Mechanism to the 3CR asymmetric synthesis of aziridines.
Scheme 3
Scheme 3
Total syntheses of some naturally occurring indolizidines.
Scheme 4
Scheme 4
Total synthesis of withasomnine (31).
Scheme 5
Scheme 5
Total syntheses of the rigidins A–D (38–41).
Scheme 6
Scheme 6
Proposed mechanism of the 3CR toward 56, the pyrrole core of the rigidins A–D.
Scheme 7
Scheme 7
Total synthesis of gelliusine E (47).
Scheme 8
Scheme 8
Bio‐MCR‐based proposed biosynthesis of manzamine A (53).
Scheme 9
Scheme 9
Synthesis of the key intermediate 68 toward the family of manzamine alkaloids.
Scheme 10
Scheme 10
Total syntheses of manzamine A (53), methyl ircinate (70), ircinol A (71), and ircinal A (72). The final steps.
Scheme 11
Scheme 11
Total synthesis of (±)‐exotine B (73).
Scheme 12
Scheme 12
Total synthesis of isourolithin A (82).
Scheme 13
Scheme 13
Synthesis of the vinyl iodide intermediate 98 toward rottnestol, featuring an enantioselective allylic substitution (EAS) methodology.
Scheme 14
Scheme 14
Concluding steps of the total synthesis of (+)‐rottnestol (89).
Scheme 15
Scheme 15
Three‐component EAS approach toward herboxidiene (104).
Scheme 16
Scheme 16
Total syntheses of psiguadial B (111) and a hetero‐Diels‐Alder based mechanistic proposal for its 3CR formation from 112, 113 and 114.
Scheme 17
Scheme 17
Catellani‐mediated total synthesis of (+)‐linoxepin (120).
Scheme 18
Scheme 18
Proposed mechanism of the Catellani reaction for accessing 130, a key intermediate for the total synthesis of linoxepin (120) and isolinoxepin (132).
Scheme 19
Scheme 19
Proposed mechanism for the elaboration of the 7‐membered oxygen ring within the synthesis of linoxepin (120) and isolinoxepin (132).
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