Representative examples concerning the Pudovik and Kabachnik‐Fields reactions as the main strategies for the stereoselective synthesis of α‐aminophosphonic acids are discussed, classifying these reactions according to the chiral auxiliary and chiral catalyst.
- α‐aminophosphonic acids
- stereoselective synthesis
- Pudovik and Kabachnik‐Fields
Optically active α‐aminophosphonic acids are the most important analogs of α‐amino acids, which are obtained by isosteric substitution of the planar and less bulky carboxylic acid (CO2H) by a sterically more demanding tetrahedral phosphonic acid functionality (PO3H2). Several α‐aminophosphonic acids have been isolated from natural sources, either as free amino acids or as constituents of more complex molecules , such as the phosphonotripeptide K‐26 (Figure 1) .
The α‐aminophosphonic acids, α‐aminophosphonates, and phosphonopeptides are currently receiving significant attention in organic synthesis and medicinal chemistry as well as in agriculture, due to their biological and pharmacological properties. Additionally, the α‐aminophosphonic acids are used as key synthetic intermediates in the synthesis of phosphonic acids, phosphonamides, and phosphinates, which not only play an important role as protease inhibitors but also in the wide range of biochemical pathways (Scheme 1) .
The inhibitory activity of the α‐aminophosphonic acids and their derivatives has been attributed to the tetrahedral geometry of the substituents around the phosphonic moiety mimicking the tetrahedral high‐energy transition state of the peptide bond hydrolysis, favoring the inhibition of a broad spectrum of proteases and ligases (Scheme 2) .
Furthermore, it is well known that the biological activity of the α‐aminophosphonic acids and derivatives depends on the absolute configuration of the stereogenic α‐carbon to phosphorous . For example, (
In view of the different biological and chemical applications of the α‐aminophosphonic acids, nowadays the development of suitable synthetic methodologies for their preparation in optically pure form is a topic of great interest and many reviews have been recently published concerning their stereoselective synthesis . In this context, Pudovik and Kabachnik‐Fields reactions the main synthetic strategies for the stereoselective synthesis of α‐aminophosphonic acids will be described in this chapter.
2. Stereoselective C‐P bond formation (Pudovik methodology)
The diastereoselective and enantioselective hydrophosphonylation of aldimines and ketimines, called as the Pudovik reaction, involves the addition of a phosphorus nucleophile agent over the corresponding imine, in such a way that one or both of the reactants can incorporate a chiral auxiliary or nonchiral reagents may be reacted in the presence of a chiral catalyst (Scheme 3).
2.1. Chiral phosphorus compounds
One of the general methods for the synthesis of α‐aminophosphonic acids involves the diastereoselective hydrophosphonylation of achiral imines with chiral phosphites to introduce the phosphonate function, which by hydrolysis afforded the optically enriched α‐aminophosphonic acids. For example, the nucleophilic addition of chiral C3‐symmetric trialkyl phosphite
Palacios et al.  proposed also the chiral cyclic (R,R)‐ α,α,α’,α’-tetraphenyl-2,2-disubstituted 1,3-dioxolane-4,5-dimethanol (TADDOL) phosphite
Additionally, the (
The Pudovik reaction has also been reported incorporating the chiral auxiliary attached not only to the phosphite residue, but also to the imine fragment. As a proof of concept, Olszewski and Majewski  reported the hydrophosphonylation reaction of (
2.2. Imines from chiral carbonyl compounds
The hydrophosphonylation of chiral Schiff bases is another general method for the synthesis of optically enriched α‐aminophosphonates, which can be performed by addition of alkyl phosphites to chiral imines readily obtained by condensation of chiral aldehydes with nonchiral amines. In this context, Bongini et al.  carried out the synthesis of (
2.3. Imines from chiral amino compounds
On the other hand, the stereoselective hydrophosphonylation of chiral Schiff bases can also be conducted by addition of alkyl phosphites to chiral imines readily obtained by condensation of nonchiral aldehydes with chiral amines. For example, the nucleophilic addition of dimethyl phosphite to the imine (
On the other hand, Vovk et al.  carried out the addition of sodium diethyl phosphite to the imine (
Nucleophilic addition of triethyl phosphite to the chiral base imines (
Smith et al. explored the generality of the diastereoselective addition of the lithium salt of diethyl phosphite to a variety of imines. Thus, addition of LiPO3Et2 to aldimines (
The readily available chiral sulfinimides  containing an aryl‐ or
Mikolajczyk et al.  reported the addition of the lithium salt of the bis(diethylamido)phosphine borane complex to the
On the other hand, the addition of the lithium salt of diethyl phosphite to the enantiopure
With the aim of obtaining the phosphonic analog of aspartic acid (
On the other hand, the addition of diethyl trimethylsilyl phosphite to chiral
Lu et al.  reported the addition of diethyl phosphite to the enantiopure sulfinylketimines (
On the other hand, the sugar‐derived nitrones have also emerged as valuable synthetic intermediates in the stereoselective synthesis of α‐aminophosphonic acids. For example, the hydrophosphonylation reaction of the nitrones
Huber and Vasella  reported the synthesis of optically enriched (
Similarly, the addition of
2.4. Chiral catalyst
Catalytic asymmetric synthesis is one of the most important topics in modern synthetic chemistry and is considered the most efficient methodology to bring about the synthesis of enantiomerically pure compounds . For example, the hydrophosphonylation reaction of
In order to obtain the optically enriched (
On the other hand, Joly and Jacobsen  reported that the addition of di(
Another exceptional example of the chiral catalyst approach is reported by Shibasaki et al.  who found that the catalytic hydrophosphonylation of the aldimine
3. Stereoselective C‐P bond formation (Kabachnik‐Fields methodology)
Another important method for the stereoselective synthesis of α‐aminophosphonic acids is the “one‐pot” three‐component reaction, known as the Kabachnik‐Fields reaction. In this process, the reactants (carbonyl compound, amine and the phosphorus nucleophile agent) are placed all together to give the diastereo or enantiomerically pure α‐aminophosphonates, which are easily transformed into the corresponding α‐aminophosphonic acids. To induce the stereochemistry in the α‐aminophosphonates, the chirality inducer may be at the source of phosphorus, in the amine, in the aldehyde or ketone, or in a chiral catalyst. Additionally, the reactions are carried out in solvent or under solvent free conditions (Scheme 27).
3.1. Chiral phosphorus compounds
The “one‐pot” three‐component reaction of benzyl carbamate, benzaldehyde, and diethyl (
On the other hand, Xu and Gao  carried out the stereoselective synthesis of the depsiphosphonopeptides
3.2. Chiral carbonyl compounds
In order to prepare conformationally restricted α‐aminophosphonic acids, Fadel et al.  carried out the TMSCl promoted three‐component reaction of the chiral ketal (2
Similarly, the one‐pot reaction of chiral ketal (2S)‐
3.3. Chiral amino compounds
The “one‐pot” three‐component reaction of (
On the other hand, Fadel et al.  carried out the “one‐pot” reaction of
Enantiomerically pure carbamates and urea have also shown a potential as chiral auxiliaries in the stereoselective synthesis of α‐aminophosphonic acids. For example, the “one‐pot” reaction of carbamate
3.4. Chiral catalyst
The development of methodologies under chiral catalysis protocols has become one of the most relevant issues in the field of modern synthetic chemistry . In this respect, List et al.  described the Kabachnik‐Fields reaction of 2‐cyclopentyl‐2‐phenylacetaldehyde,
In another example, Shibata et al.  reported that the reaction of benzaldehyde,