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

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.

Figure 1

Representative pyrrolidine-containing natural products.

Figure 2

Representative FDA-approved pyrrolidine-containing drugs.

Scheme 1

The formation of semi- and non-stabilized AMYs from glycines.

Figure 3

Pyrrolizidine- and indolizidine-bearing natural products.

Scheme 2

Synthesis of pyrrolizidines 30.

Scheme 3

Synthesis of indolizidines 31.

Scheme 4

Preparation of aldehyde 35.

Scheme 5

Intermolecular cycloaddition for indolizidine 36.

Figure 4

Bioactive compounds containing pyrrolidine.

Scheme 6

Preparation of intermediates 44, 47, and 49.

Scheme 7

Synthesis of octahydro-1H-pyrrolo[3,2-c]pyridines and octahydropyrano[4,3-b]pyrroles.

Figure 5

Examples of HCV NS5B inhibitors.

Scheme 8

The synthesis of cis-pentacyclic compounds 41.

Figure 6

Pyrrolidine-containing fused and spiro natural products.

Scheme 9

Synthesis of trans-pentacyclic compounds 42 and their bioactivities.

Scheme 10

Two enantiomers of compound 42j and their bioactivities.

Scheme 11

Pseudo five-component synthesis of tetracyclic pyrrolizidines 73.

Scheme 12

Synthesis of tetracyclic pyrrolizidines 74.

Scheme 13

One-pot and two-step synthesis of tetracyclic pyrrolizidines 75.

Scheme 14

Double cycloaddition involving glycine and olefinic oxindoles.

Scheme 15

Comparison of maleimides and olefinic oxindoles in double cycloadditions.

Figure 7

Pyrrolidine-containing congregated polycyclic natural products.

Scheme 16

Cyclization and cycloaddition cascade for constructing tricyclic amines.

Scheme 17

Preparation of multi-functional aldehydes 99–101.

Scheme 18

The synthesis of tricyclic amines 102 and 103.

Scheme 19

Synthesis of tricyclic amines 104 and 105.

Scheme 20

Preparation of multi-functional compound 115.

Scheme 21

Synthesis of aspidosperma alkaloids 82, 83, and 118.

Scheme 22

Preparation of multi-functional aldehydes 122 (A) and 126 (B).

Scheme 23

The synthesis of tricyclic amine 129.

Scheme 24

The synthesis of tricyclic amine 132.

Scheme 25

Preparation of multi-functional aldehydes 133 and 135.

Scheme 26

Synthesis of tricyclic amines 136, 138, and 139.

Scheme 27

Synthesis of tricyclic amines 140 and 141.

Scheme 28

Preparation of multi-functional aldehyde 147.

Scheme 29

The synthesis of bridged tricyclic amines 148 and 149.

Scheme 30

The synthesis of bridged tricyclic amines 152.