The Last Decade of Optically Active α-Aminophosphonates

α-Aminophosphonates and related compounds are important due to their real and potential biological activity. α-Aminophosphonates may be prepared by the Kabachnik–Fields condensation of oxo compounds, amines and dialkyl phosphites, or by the aza-Pudovik addition of the same P-reagents to imines. In this review, the methods that allow for the synthesis of α-aminophosphonates with optical activity are surveyed. On the one hand, optically active catalysts or ligands may induce enantioselectivity during the Kabachnik–Fields reaction. On the other hand, asymmetric catalysis during the aza-Pudovik reaction, or hydrogenations of iminophosphonates, may prove to be a useful tool. Lastly yet importantly, it is possible to start from optically active reagents that may be associated with diastereoselectivity. The “green” aspects of the different syntheses are also considered.


Introduction
α-Aminophosphonates form a representative group within phosphonates due to their potential biological activity, enabling them to be used in the pharmaceutical industry [1]. The biological activity is related to the enzyme inhibitory properties of the compounds under discussion. The biological activity includes anticancer and anti-HIV effects, among others. The basic methods for the synthesis of α-aminophosphonates are the Kabachnik-Fields condensation and the aza-Pudovik reaction [2]. The phospha-Mannich condensation involves the reaction of an oxo compound, such as an aldehyde or ketone, a primary and secondary amine, and dialkyl phosphite, while the Pudovik approach utilizes the addition of diakyl phosphites to the double bond of imines. As a matter of fact, the imines formed from the oxo compound and the primary amine may be the intermediate of the Kabachnik-Fields reaction.
It is a challenge to run the syntheses of α-aminophosphonates in an enantioselective manner. The stereoselective syntheses of α-aminophosphonic derivatives were summarized by Ordóñez and colleagues [3], and Palacios et al. [4]. The phospha-Mannich condensation of an oxo compound, amine and >P(O)H reagent may be carried out in the presence of an optically active catalyst or additive to obtain the corresponding product as a predominant enantiomer. The most relevant method for the preparation of optically active α-aminophosphonates is the enantioselective addition of dialkyl phosphites to the C=N unit of imines [5][6][7][8][9][10]. This is promoted by chiral catalysts or additives. The asymmetric hydrogenation of iminophosphonates is also an attractive method of choice. Lastly yet importantly, the Kabachnik-Fields reactions were performed using optically active amines, aldehydes or phosphites as the starting materials [8][9][10][11]. The condensation of benzaldehydes, para-aminoanizole and diisopropyl phosphite gave the corresponding aminophosphonates (4) under mild conditions, and when using an optically active phosphinic acid derivative (5) as the catalyst (Scheme 2) [13]. Scheme 1. Enantioselective synthesis of α-aminophosphonates (1) using zinc bis(trifluoromethylsulfonyl) imide (2, 3) as the catalyst.
A series of optically active α-aminophosphonate derivatives (6) was synthesized under mild conditions by applying substituted benzaldehydes, aniline derivatives and, in this case, triethyl phosphite and a chiral pyrrolidine-based organocatalyst (7). The yields fell in the range of 71-90%, and the enantiomeric purity was 73-92% (Scheme 3) [14]. The use of triethyl phosphite instead of diethyl phosphite is not advantageous due to the smell and atom efficiency of the condensation reaction.
The three-component reaction of 2-alkynylbenzaldehydes (8), an aniline derivative, and diethyl phosphite produced cyclic α-aminophosphonates (9) in the presence of silver carbonate, and an optically active spirocyclic phosphoric acid (10) as the catalyst. The yields and enantiomeric purities were variable (Scheme 4) [15]. Molecules 2023, 28,  A series of optically active α-aminophosphonate derivatives (6) was synthesized under mild conditions by applying substituted benzaldehydes, aniline derivatives and, in this case, triethyl phosphite and a chiral pyrrolidine-based organocatalyst (7). The yields fell in the range of 71-90%, and the enantiomeric purity was 73-92% (Scheme 3) [14]. The use of triethyl phosphite instead of diethyl phosphite is not advantageous due to the smell and atom efficiency of the condensation reaction.  A series of optically active α-aminophosphonate derivatives (6) was synthesized under mild conditions by applying substituted benzaldehydes, aniline derivatives and, in this case, triethyl phosphite and a chiral pyrrolidine-based organocatalyst (7). The yields fell in the range of 71-90%, and the enantiomeric purity was 73-92% (Scheme 3) [14]. The use of triethyl phosphite instead of diethyl phosphite is not advantageous due to the smell and atom efficiency of the condensation reaction. In the above sub-chapter, enantioselective Kabachnik-Fields reactions as described in the literature were summarized. The methods applied different optically active catalysts under a wide variety of reaction conditions. The efficiency of the catalysts depended on the nature of the reaction models. The products were obtained in good yields and in variable, 31-94% enantioselectivities. These catalysts are not simple, and in most cases, their cost is considerable, which constitutes a shortcoming.

Optically Active α-Aminophosphonate Derivatives Provided by the Aza-Pudovik Reaction
A highly enantioselective nucleophilic addition of dialkyl phosphites to imines, which was (11) catalyzed by a chiral cinchona-based phase transfer catalyst (12), was developed. Phase transfer catalysis is an up-to-date and "green" approach. The hydrophosphonylation took place in good to high yields and enantioselectivities (Scheme 5) [16]. In the above sub-chapter, enantioselective Kabachnik-Fields reactions as described in the literature were summarized. The methods applied different optically active catalysts under a wide variety of reaction conditions. The efficiency of the catalysts depended on the nature of the reaction models. The products were obtained in good yields and in variable, 31-94% enantioselectivities. These catalysts are not simple, and in most cases, their cost is considerable, which constitutes a shortcoming.

Optically Active α-Aminophosphonate Derivatives Provided by the Aza-Pudovik Reaction
A highly enantioselective nucleophilic addition of dialkyl phosphites to imines, which was (11) catalyzed by a chiral cinchona-based phase transfer catalyst (12), was developed. Phase transfer catalysis is an up-to-date and "green" approach. The hydrophosphonylation took place in good to high yields and enantioselectivities (Scheme 5) [16].
In this sub-chapter, enantioselective aza-Pudovik addition reactions were summarized. The presented chiral catalyst-promoted methods gave the corresponding products in variable yields and enantiomeric purities. The typical catalysts are the cinchona alkaloids, or their modified versions. There were no data released on the re-circulation of the organocatalysts. The aza-Pudovik addition is an attractive approach due to the mild conditions required, and the 100% atomic efficiency.

Synthesis of Enantiopure α-Aminophosphonates by the Asymmetric Hydrogenation of Iminophosphonates
The palladium-catalyzed asymmetric hydrogenation of α-iminophosphonates (32) performed at 40 °C for 24 h in a solvent mixture afforded the corresponding α-aminophosphonates (33) in 91-98% yields and 85-97% enantiomeric purities. (R)-Difluorophos or its analogue (34a or 34b) served as the ligand for Pd (Scheme 12) [24,25]. In this sub-chapter, enantioselective aza-Pudovik addition reactions were summarized. The presented chiral catalyst-promoted methods gave the corresponding products in variable yields and enantiomeric purities. The typical catalysts are the cinchona alkaloids, or their modified versions. There were no data released on the re-circulation of the organocatalysts. The aza-Pudovik addition is an attractive approach due to the mild conditions required, and the 100% atomic efficiency.

Scheme 11. Asymmetric hydrophosphonylation of iminophosphonates (30).
In this sub-chapter, enantioselective aza-Pudovik addition reactions were summarized. The presented chiral catalyst-promoted methods gave the corresponding products in variable yields and enantiomeric purities. The typical catalysts are the cinchona alkaloids, or their modified versions. There were no data released on the re-circulation of the organocatalysts. The aza-Pudovik addition is an attractive approach due to the mild conditions required, and the 100% atomic efficiency. Scheme 12. Synthesis of (S)-α-phenyl-α-amino-methylphosphonates (33).
In this sub-chapter, in most cases, enantiopure α-aminophosphonates were synthesized by asymmetric hydrogenation of iminophosphonates and enaminophosphonates. The methods discussed apply chiral catalysts, thereby allowing for the preparation of the corresponding products in good yields and 72-99% enantiomeric purities. The application of transition metal catalysts and the complexity and high cost of P-ligands constitutes a disadvantage. In this sub-chapter, in most cases, enantiopure α-aminophosphonates were synthesized by asymmetric hydrogenation of iminophosphonates and enaminophosphonates. The methods discussed apply chiral catalysts, thereby allowing for the preparation of the corresponding products in good yields and 72-99% enantiomeric purities. The application of transition metal catalysts and the complexity and high cost of P-ligands constitutes a disadvantage.

Optically Active α-Aminophosphonates by Miscellenious Methods
The asymmetric synthesis of α-iminophosphonates (49) was performed in two steps. First, the imin (48) was prepared, followed by a desymmetrized isomerization in the presence of a chiral cinchona catalyst (50). Following a deprotonation on the methylene unit of the benzyl group, an enantioselective protonation constituted the main enantiodifferentiating step. The deprotonated species was complexed by the phenolic OH function of the cinchona catalyst, establishing a =N. . .H. . .O=P network. The yields of this elegant method were variable, and fell in the range of 20-63%. The enantiomeric purities were between 72 and 96% (Scheme 18) [30].

Optically Active α-Aminophosphonates by Miscellenious Methods
The asymmetric synthesis of α-iminophosphonates (49) was performed in two steps. First, the imin (48) was prepared, followed by a desymmetrized isomerization in the presence of a chiral cinchona catalyst (50). Following a deprotonation on the methylene unit of the benzyl group, an enantioselective protonation constituted the main enantio-differentiating step. The deprotonated species was complexed by the phenolic OH function of the cinchona catalyst, establishing a =N…H…O=P network. The yields of this elegant method were variable, and fell in the range of 20-63%. The enantiomeric purities were between 72 and 96% (Scheme 18) [30]. A thiourea-coupled cinchona alkaloid-catalyzed (51) aza-Henry reaction of iminophosphonates (52) and nitromethane provided the corresponding α-aminophosphonates (53) under mild conditions in good yields, and with enantiomeric excesses (Scheme 19) [31]. This addition method has the advantage of 100% atomic efficiency. A thiourea-coupled cinchona alkaloid-catalyzed (51) aza-Henry reaction of iminophosphonates (52) and nitromethane provided the corresponding α-aminophosphonates (53) under mild conditions in good yields, and with enantiomeric excesses (Scheme 19) [31]. This addition method has the advantage of 100% atomic efficiency. Scheme 18. Asymmetric synthesis of α-iminophosphonates (49) by desymmetrization.
A thiourea-coupled cinchona alkaloid-catalyzed (51) aza-Henry reaction of iminophosphonates (52) and nitromethane provided the corresponding α-aminophosphonates (53) under mild conditions in good yields, and with enantiomeric excesses (Scheme 19) [31]. This addition method has the advantage of 100% atomic efficiency. The Reformatsky synthesis is a valuable process that is widely used for the formation of C−C bonds. An enantioselective aza-Reformatsky reaction starting from iminophosphonates (58) was developed. The reaction of α-iminophosphonates (58) and iodoacetate (59) in the presence of a Zn catalyst with a BINOL-ligand (60) afforded the corresponding amino acid esters (61) in excellent yields and enantioselectivities (Scheme 21) [33]. The amino acid esters (61) were converted to amino acids, and then they were used in the synthesis of P-containing β-lactams. The products (61) were of high enantiopurity. The Reformatsky synthesis is a valuable process that is widely used for the formation of C−C bonds. An enantioselective aza-Reformatsky reaction starting from iminophosphonates (58) was developed. The reaction of α-iminophosphonates (58) and iodoacetate (59) in the presence of a Zn catalyst with a BINOL-ligand (60) afforded the corresponding amino acid esters (61) in excellent yields and enantioselectivities (Scheme 21) [33]. The amino acid esters (61) were converted to amino acids, and then they were used in the synthesis of P-containing β-lactams. The products (61) were of high enantiopurity.
of C−C bonds. An enantioselective aza-Reformatsky reaction starting from iminophosphonates (58) was developed. The reaction of α-iminophosphonates (58) and iodoacetate (59) in the presence of a Zn catalyst with a BINOL-ligand (60) afforded the corresponding amino acid esters (61) in excellent yields and enantioselectivities (Scheme 21) [33]. The amino acid esters (61) were converted to amino acids, and then they were used in the synthesis of P-containing β-lactams. The products (61) were of high enantiopurity. α-Iminophosphonates (52) were converted to amino-cianophosphonates (65) in reaction with acetyl cyanid using a cinchona alkaloid (66) as the catalyst at −45-0°C. The yields fell in the range of 75-80%. The enantiomeric purity was 73-92% (Scheme 23) [35]. This transformation may be regarded as a special, rarely applied method. The low temperature needed is not robust.
An asymmetric Mannich reaction was developed by reacting α-iminophosphonates (73) with keto acids (74) in the presence of a saccharide-derived bifunctional amine-thiourea organocatalyst (75). The yields were up to 93%, and the enantiomeric purities covered the range of 90-99% (Scheme 26) [38]. The reaction of α,β-unsaturated aldehydes (78) and cyclic sulfonyl-iminophosphonate (77) in the presence of dibenzoquinone (79) as an oxidant afforded the corresponding products (81). The efficient carbene-catalyzed enantioselective cyclization reaction took place with 97-99% enantiomeric selectivity (Scheme 27) [39]. The precursor of the carbene is heterocycle 80. The mechanism of the reaction was substantiated. The key steps involve the formation of a vinyl enolate intermediate (82) from enal and the catalyst, and the sub- The reaction of α,β-unsaturated aldehydes (78) and cyclic sulfonyl-iminophosphonate (77) in the presence of dibenzoquinone (79) as an oxidant afforded the corresponding products (81). The efficient carbene-catalyzed enantioselective cyclization reaction took place with 97-99% enantiomeric selectivity (Scheme 27) [39]. The precursor of the carbene is heterocycle 80. The mechanism of the reaction was substantiated. The key steps involve the formation of a vinyl enolate intermediate (82) from enal and the catalyst, and the subsequent addition of vinyl enolate (82) to ketiminophosphonates to form the complex (83). The overall process is an asymmetric formal aza [4+2]-cycloaddition reaction. Ordónez applied different N-acyliminium salts for the synthesis of racemic α-aminophosphonates [40].
In this chapter, we collected methods for the synthesis of optically active αaminophosphonates that can be obtained by different types of reactions. Each process results in the formation of the desired optically active product using a chiral catalyst. The methods presented, in some cases, may differ from each other. For example, they may differ in the reaction conditions used. A few protocols gave the corresponding optically active products either in good yields, or else only in good enantiomeric purity, but in lower yields. The selection of the best method for the synthesis the corresponding products depends on the substrates. The enantioselective methods demonstrated may be useful in special cases. In this chapter, we collected methods for the synthesis of optically active α-aminophosphonates that can be obtained by different types of reactions. Each process results in the formation of the desired optically active product using a chiral catalyst. The methods presented, in some cases, may differ from each other. For example, they may differ in the reaction conditions used. A few protocols gave the corresponding optically active products either in good yields, or else only in good enantiomeric purity, but in lower yields. The selection of the best method for the synthesis the corresponding products depends on the substrates. The enantioselective methods demonstrated may be useful in special cases.
In this chapter, we collected methods for the synthesis of optically active α-aminophosphonates that can be obtained by different types of reactions. Each process results in the formation of the desired optically active product using a chiral catalyst. The methods presented, in some cases, may differ from each other. For example, they may differ in the reaction conditions used. A few protocols gave the corresponding optically active products either in good yields, or else only in good enantiomeric purity, but in lower yields. The selection of the best method for the synthesis the corresponding products depends on the substrates. The enantioselective methods demonstrated may be useful in special cases.
1,2-cyclohexylenediamine-related bis(phenylmethylphosphonates) (111) were synthetized from the corresponding optically active bis-imine (110) and dialkyl phosphites in a diastereoselective manner without the use of any catalyst. The method afforded the corresponding bis(α-aminophosphonate) derivatives (111) under MW-assisted conditions in variable yields of 19-68% (Scheme 38) [54]. However, this procedure is not reproduceable due to the use of a kitchen MW oven. The elegant methods shown above involve different optically active starting materials. The optical activity was preserved during the reactions. This kind of approach hides further future challenges.

Conclusions
To summarize the contents of this review, the most useful methods for the synthesis of optically active α-aminophosphonates and related derivatives as described in the last decade were surveyed. The target compounds are important due to their potential and real biological activity. The most important approach is the asymmetric Kabachnik-Fields reaction of an oxo compound, an amine and a dialkyl phosphite performed in the presence of an optically active catalyst or additive. Another frequently used protocol is the enantioselective aza-Pudovik addition of >P(O)H regents to the C=N unit of imines in the presence of chiral catalysts. There were no data released on the possible re-circulation of the catalysts. Asymmetric catalytic hydrogenation of iminophosphonates is also an attractive synthetic method. It is an elegant approach if one of the components (e.g., the amine or the phosphite) of the Kabachnik-Fields condensation is optically active. Of course, there are special methods as well. Throughout the discussion, we tried to point out the "green" aspects, but also described the disadvantages. Funding:. This project was supported by the National Research, Development and Innovation Office (K134318).

Conflicts of Interest:
The authors declare no conflicts of interest. The elegant methods shown above involve different optically active starting materials. The optical activity was preserved during the reactions. This kind of approach hides further future challenges.

Conclusions
To summarize the contents of this review, the most useful methods for the synthesis of optically active α-aminophosphonates and related derivatives as described in the last decade were surveyed. The target compounds are important due to their potential and real biological activity. The most important approach is the asymmetric Kabachnik-Fields reaction of an oxo compound, an amine and a dialkyl phosphite performed in the presence of an optically active catalyst or additive. Another frequently used protocol is the enantioselective aza-Pudovik addition of >P(O)H regents to the C=N unit of imines in the presence of chiral catalysts. There were no data released on the possible re-circulation of the catalysts. Asymmetric catalytic hydrogenation of iminophosphonates is also an attractive synthetic method. It is an elegant approach if one of the components (e.g., the amine or the phosphite) of the Kabachnik-Fields condensation is optically active. Of course, there are special methods as well. Throughout the discussion, we tried to point out the "green" aspects, but also described the disadvantages.