Asymmetric Synthesis of Tetrasubstituted α-Aminophosphonic Acid Derivatives

Abstract

Due to their structural similarity with natural α-amino acids, α-aminophosphonic acid derivatives are known biologically active molecules. In view of the relevance of tetrasubstituted carbons in nature and medicine and the strong dependence of the biological activity of chiral molecules into their absolute configuration, the synthesis of α-aminophosphonates bearing tetrasubstituted carbons in an asymmetric fashion has grown in interest in the past few decades. In the following lines, the existing literatures for the synthesis of optically active tetrasubstituted α-aminophosphonates are summarized, comprising diastereoselective and enantioselective approaches.

Keywords: asymmetric synthesis; diastereoselective; enantioselective; tetrasubstituted carbons; α-aminophosphonates; α-aminophosphonic acid.

Figure 1

Structural analogy of α-amino acids and α-aminophosphonic acids.

Figure 2

Some examples of biologically active α-aminophosphonic acid derivatives.

Figure 3

Most active isomers of phospholeucine and alaphosphalin.

Figure 4

Asymmetric synthetic approaches to tetrasubstituted α-aminophosphonates: (a) addition of nucleophiles to phosphorylated imines; (b) addition of α aminophosphonates to electrophiles; (c) hydrophosphonylation of imines; (d) electrophilic amination.

Scheme 1

First stereoselective synthesis of tetrasubstituted α-aminophosphonic acids.

Scheme 2

Stereoselective synthesis of pyrrolidine-derived α-aminophosphonate 17.

Scheme 3

Synthesis of tetrasubstituted α-aminophosphonates 24 and 25.

Figure 5

Proposed transition state for the preparation of α-aminophosphonates 24 (* denotes antibonding molecular orbital).

Scheme 4

Synthesis of tetrasubstituted α-aminophosphonates from ketimines 29.

Figure 6

Proposed model of addition of carbon nucleophiles to ketimines 29.

Scheme 5

Synthesis of tetrasubstituted α-aminophosphonates from menthol-derived phosphonate imines 32.

Scheme 6

Synthesis of triazoline-derived α-aminophosphonate 43.

Scheme 7

Diastereoselective preparation of tetrasubstituted α-aminophosphonates 45.

Figure 7

Proposed transition states for the formation of tetrasubstituted α-aminophosphonates 45.

Scheme 8

Preparation of cyclic tetrasubstituted α-aminophosphonate 50.

Scheme 9

Sulfinimine-mediated synthesis of α-aminophosphonates 52.

Scheme 10

Sulfinimine-mediated synthesis of cyclic α-aminophosphonates 56.

Scheme 11

Synthesis of fluorine substituted α-aminophosphonates 58 derived from α,β-unsaturated sulfinyl imines 57.

Scheme 12

Synthesis of α-aminophosphonates 62.

Scheme 13

Synthesis of cyclopropane α-aminophosphonates 65.

Scheme 14

Synthesis of spirocyclic α-aminophosphonates 69.

Scheme 15

Synthesis of cyclic α-aminophosphonates 78 and 79.

Scheme 16

Synthesis of bicyclic tetrasubstituted α-aminophosphonates 84.

Figure 8

Proposed transition states for the formation of α-aminophosphonates 84.

Scheme 17

Synthesis of bicyclic α-aminophosphonates 90 and α-aminophosphonic acid derivatives 91.

Scheme 18

Multicomponent Kabachnik–Fields reaction for the synthesis of α-aminophosphonates 95.

Scheme 19

Synthesis of α-aminophosphonates 98 via phosphoramidate-α-aminophosphonate rearrangement.

Scheme 20

Aza-Darzens reaction for the synthesis of (R)- and (S)-107.

Scheme 21

Curtius rearrangement for the synthesis of α-aminophosphonate 116.

Scheme 22

Curtius rearrangement applied to the synthesis of α-aminophosphonate 123.

Scheme 23

Synthesis of α-aminophosphonic acid derivative (1R,2S)-130.

Scheme 24

Synthesis of α-aminophosphonic acid derivative (1S,2R)-130.

Scheme 25

First enantioselective synthesis of tetrasubstituted α-aminophosphonates.

Scheme 26

Stereoselective addition of α-nitrophosphonates to imines.

Scheme 27

Enantioselective conjugate addition of α-nitrophosphonates to enones.

Scheme 28

Synthetic applications of α-nitrophosphonates 148.

Scheme 29

Enantioselective addition of α-nitrophosphonates to conjugated esters.

Scheme 30

Enantioselective addition of α-nitrophosphonates to nitroalkenes.

Scheme 31

Enantioselective addition of α-nitrophosphonates to vinyl sulfones.

Scheme 32

Enantioselective nucleophilic addition of α-isocyanatophosphonates to aldehydes.

Scheme 33

Enantioselective nucleophilic addition of α-isocyanatophosphonates to aldehydes and imines.

Scheme 34

Enantioselective synthesis of spirocyclic α-aminophosphonates.

Scheme 35

First synthesis of tetrasubstituted α-aminophosphonic acids through a nucleophilic addition to α-iminophosphonates.

Scheme 36

Further catalytic asymmetric additions to α-iminophosphonates.

Scheme 37

Enantioselective preparation of α-aminophosphonate 187 and its synthetic applications.

Scheme 38

Rhodium-catalyzed enantioselective synthesis of α-alkynyl α-aminophosphonates 194.

Scheme 39

Rhodium-catalyzed enantioselective multicomponent reaction.

Scheme 40

Palladium-catalyzed enantioselective arylation of cyclic imines 204.

Scheme 41

Enantioselective addition of indoles to cyclic α-iminophosphonates.

Scheme 42

Enantioselective addition of Schiff base 213 to α-iminophosphonate 212.

Scheme 43

Enantioselective decarboxylative Mannich addition to imines 204.

Scheme 44

Enantioselective [3+2] cycloaddition with α-aminophosphonates 219.

Scheme 45

Enantioselective dipolar cycloaddition for the synthesis of chiral α-aminophosphonates.

Scheme 46

NHC-catalyzed formal [4+2] cycloaddition. XXV* represents the active carbene derived form of the catalyst XXV.

Scheme 47

First enantioselective hydrophosphorylation of ketimines.

Scheme 48

Catalytic asymmetric hydrophosphorylation of N-thiophosphinyl ketimines 239.

Scheme 49

Organocatalyzed asymmetric phospha–Mannich reaction.

Scheme 50

Enantioselective hydrophosphorylation of cyclic imines 243.

Scheme 51

Organocatalyzed nucleophilic addition of diphenyl phosphite to isatin ketimines 245.

Scheme 52

Enantioselective hydrophosphorylation of in situ generated N-acyl ketimines catalyzed by BINOL-derived phosphoric acid.

Scheme 53

Enantioselective synthesis of aziridines 250 and their applications.

Scheme 54

Proposed mechanism for the hydrophosphorylation of azirines 249.

Scheme 55

Enantioselective amination of β-ketophosphonates 257 catalyzed by zinc–oxazolidine complex.

Scheme 56

Chiral palladium complexes-catalyzed amination of phosphonates 260.

Scheme 57

Organocatalyzed asymmetric synthesis of tetrasubstituted aziridines 265.