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Review
. 2024 Dec 4;29(23):5726.
doi: 10.3390/molecules29235726.

Glycine-Based [3+2] Cycloaddition for the Synthesis of Pyrrolidine-Containing Polycyclic Compounds

Tieli Zhou  1 , Xiaofeng Zhang  2   3 , Desheng Zhan  4 , Wei Zhang  3
Affiliations
Review

Glycine-Based [3+2] Cycloaddition for the Synthesis of Pyrrolidine-Containing Polycyclic Compounds

Tieli Zhou et al. Molecules. .

Abstract

The synthesis of pyrrolidine compounds with biological interest is an active research topic. Glycine could be a versatile starting material for making pyrrolidine derivatives. This review covers recent works on glycine-based [3+2] cycloaddition and combines other annulation reactions in the one-pot synthesis of pyrrolidine-containing heterocyclic compounds. Synthetic method development, substrate scope, and reaction mechanisms are discussed. Applications of the compounds in drug discovery are briefly mentioned. This paper is helpful for chemists in the development of efficient and sustainable methods for the preparation of bioactive pyrrolidine compounds.

Keywords: Glycine; annulation; azomethine ylides; cycloaddition; dipolarophile; pyrrolidine.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Representative pyrrolidine-containing natural products.
Figure 2
Figure 2
Representative FDA-approved pyrrolidine-containing drugs.
Scheme 1
Scheme 1
The formation of semi- and non-stabilized AMYs from glycines.
Figure 3
Figure 3
Pyrrolizidine- and indolizidine-bearing natural products.
Scheme 2
Scheme 2
Synthesis of pyrrolizidines 30.
Scheme 3
Scheme 3
Synthesis of indolizidines 31.
Scheme 4
Scheme 4
Preparation of aldehyde 35.
Scheme 5
Scheme 5
Intermolecular cycloaddition for indolizidine 36.
Figure 4
Figure 4
Bioactive compounds containing pyrrolidine.
Scheme 6
Scheme 6
Preparation of intermediates 44, 47, and 49.
Scheme 7
Scheme 7
Synthesis of octahydro-1H-pyrrolo[3,2-c]pyridines and octahydropyrano[4,3-b]pyrroles.
Figure 5
Figure 5
Examples of HCV NS5B inhibitors.
Scheme 8
Scheme 8
The synthesis of cis-pentacyclic compounds 41.
Figure 6
Figure 6
Pyrrolidine-containing fused and spiro natural products.
Scheme 9
Scheme 9
Synthesis of trans-pentacyclic compounds 42 and their bioactivities.
Scheme 10
Scheme 10
Two enantiomers of compound 42j and their bioactivities.
Scheme 11
Scheme 11
Pseudo five-component synthesis of tetracyclic pyrrolizidines 73.
Scheme 12
Scheme 12
Synthesis of tetracyclic pyrrolizidines 74.
Scheme 13
Scheme 13
One-pot and two-step synthesis of tetracyclic pyrrolizidines 75.
Scheme 14
Scheme 14
Double cycloaddition involving glycine and olefinic oxindoles.
Scheme 15
Scheme 15
Comparison of maleimides and olefinic oxindoles in double cycloadditions.
Figure 7
Figure 7
Pyrrolidine-containing congregated polycyclic natural products.
Scheme 16
Scheme 16
Cyclization and cycloaddition cascade for constructing tricyclic amines.
Scheme 17
Scheme 17
Preparation of multi-functional aldehydes 99–101.
Scheme 18
Scheme 18
The synthesis of tricyclic amines 102 and 103.
Scheme 19
Scheme 19
Synthesis of tricyclic amines 104 and 105.
Scheme 20
Scheme 20
Preparation of multi-functional compound 115.
Scheme 21
Scheme 21
Synthesis of aspidosperma alkaloids 82, 83, and 118.
Scheme 22
Scheme 22
Preparation of multi-functional aldehydes 122 (A) and 126 (B).
Scheme 23
Scheme 23
The synthesis of tricyclic amine 129.
Scheme 24
Scheme 24
The synthesis of tricyclic amine 132.
Scheme 25
Scheme 25
Preparation of multi-functional aldehydes 133 and 135.
Scheme 26
Scheme 26
Synthesis of tricyclic amines 136, 138, and 139.
Scheme 27
Scheme 27
Synthesis of tricyclic amines 140 and 141.
Scheme 28
Scheme 28
Preparation of multi-functional aldehyde 147.
Scheme 29
Scheme 29
The synthesis of bridged tricyclic amines 148 and 149.
Scheme 30
Scheme 30
The synthesis of bridged tricyclic amines 152.
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