Stereoselective Synthesis of α-Amino-C-phosphinic Acids and Derivatives

α-Amino-C-phosphinic acids and derivatives are an important group of compounds of synthetic and medicinal interest and particular attention has been dedicated to their stereoselective synthesis in recent years. Among these, phosphinic pseudopeptides have acquired pharmacological importance in influencing physiologic and pathologic processes, primarily acting as inhibitors for proteolytic enzymes where molecular stereochemistry has proven to be critical. This review summarizes the latest developments in the asymmetric synthesis of acyclic and phosphacyclic α-amino-C-phosphinic acids and derivatives, following in the first case an order according to the strategy used, whereas for cyclic compounds the nitrogen embedding in the heterocyclic core is considered. In addition selected examples of pharmacological implications of title compounds are also disclosed.


Introduction
Optically active α-aminoalkylphosphonic acids 1 are probably the most important analogues of the α-amino acids 2, obtained by isosteric substitution of the planar and less bulky carboxylic acid (CO 2 H) by a tetrahedral phosphonic acid functionality (PO 3 H 2 ). These classes of compounds are currently attracting great interest in organic and medicinal chemistry, as well as in agriculture, due to their important biological and pharmacological properties [1][2][3][4][5]. The great importance of this type of compounds has prompted organic chemists to report numerous procedures for their racemic or stereoselective synthesis [6][7][8][9][10][11]. On the other hand, the optically active α-amino-C-phosphinic acids 3 are also considered as analogues of α-amino acids 2 where now the carboxylic group (CO 2 H) is replaced by a tetrahedral and sterically more demanding phosphinic acid functionality (PO 2 HR ). As part of peptides, α-amino-C-phosphinic acids 3 are much closer analogues to natural α-amino acids 2 than their α-aminophosphonic counterparts 1, due to their mono acidic character, and the higher stability of the P-C bond of 3 compared to the P-O bond of 1 (Figure 1) [12]. stability of the phosphorus center at room temperature, and their tautomeric equilibria with trivalent species that occurs without epimerization at the phosphorus center. This is the basis for synthetic applications of these compounds as chiral precursors in several stereospecific transformations [15]. Although, different structures of phosphonic and phosphinic groups compared with the carboxylic function could a priori disrupt enzyme-ligand interactions, they frequently are recognized by enzymes or receptors as inhibitors or false substrates [16,17]. Phosphinopeptides containing C-terminal α-aminophosphinic acids have been prepared by similar methods to those used with their phosphonic analogues, for example the coupling of N-protected amino acids or their active esters with α-aminophosphinates [18], or with free α-aminophosphinic acids in organic or aqueous-organic media has been reported [19]. Additionally, the synthesis of phosphinopeptides via the Mannich-type condensation of N-Cbz protected alkanamides/peptide amides, aldehydes and aryldichlorophosphines, followed by hydrolysis, has also been reported [20]. Therefore, the α-amino-C-phosphinic acids are currently attracting interest in medicinal chemistry due to their relevance mainly as pseudopeptides, which have acquired pharmacological importance in influencing physiologic and pathologic processes, primarily acting as inhibitors for proteolytic enzymes. The success of these compounds is based on the resemblance of phosphinic acids to the sp 3 transition state of the hydrolysis of peptide bonds. Considering that lengths of O-P and C-P bonds are significantly longer than the corresponding O-C and C-C bonds, the phosphinic fragment might be considered as an extended tetrahedral intermediate and thus can be treated similar to the transition state of the hydrolysis (Figure 2) [21]. Moreover, they can act as simple analogues of amino acids replacing the carboxylic group by the phosphinic moiety, as nonhydrolysable phosphate analogues or as chelating agents of metal ions present in the active site of the enzymes [22]. A number of excellent reviews on various aspects of their activity in natural systems have been published [16,17].
Simple pseudopeptides containing α-amino-C-phosphinate moieties replacing the scissile peptide bonds, rank among most potent inhibitors of metalloproteinases, where their tumorigenesis and invasion-related functions makes these enzymes molecular targets for the development of potential anticancer drugs [23]. The role of neutral aminopeptidase in the pathogenesis of hypertension provides an opportunity for regulating arterial blood pressure through its inhibition with this class of compounds [24]. Furthermore, these pseudopeptides appear to be excellent inhibitors to Plasmodium falciparum aminopeptidases, promising targets for a novel treatment of malaria [25,26]. α-Amino-C-phosphinic pseudopeptides have also revealed their potential activity in the regulation of matrix metalloproteinases (MMPs), whose overexpression or inadequate levels leads to pathological states such as osteoarthritis, rheumatoid arthritis and inflammation, but also it is associated with tumor growth, invasion and metastasis [27,28]. Additionally, is noteworthy that in these derivatives the stereochemistry affects their biological activity, hence the importance of the synthesis of these compounds in enantiomerically pure form [29,30]. Phosphinic, phosphonic and carboxylic acids differ in several characteristics. The carboxylic group is planar at carbon while their phosphorus analogues are tetrahedral and considerably larger in size (the phosphorus atom has a much larger atomic radius than carbon). Phosphinic and phosphonic acids exist mainly in their tetracoordinate form, and they are considered as mono-and diacids, respectively. The phosphinic acids (pK a~1 .0) are slightly stronger than the corresponding phosphonic acids (pK a~0 .5-1.5) and both more acidic than the carboxylic acid equivalent (pK a~2 .0-3.0); the former are mono acids and no evidence for the second acidity due to the P-H bond is reported, while for phosphonic acids, it is well-known that the second acidity is about 5 pK units higher than the first P-OH acidity. Similar to α-amino acids, the aminophosphonic and aminophosphinic acids have a zwitterionic form due to the internal hydrogen transfer between the P-OH and amino groups [13,14]. In addition, a characteristic feature of tetracoordinated phosphorus (III) compounds such as H-phosphonate and H-phosphinate derivatives, is the configurational stability of the phosphorus center at room temperature, and their tautomeric equilibria with trivalent species that occurs without epimerization at the phosphorus center. This is the basis for synthetic applications of these compounds as chiral precursors in several stereospecific transformations [15]. Although, different structures of phosphonic and phosphinic groups compared with the carboxylic function could a priori disrupt enzyme-ligand interactions, they frequently are recognized by enzymes or receptors as inhibitors or false substrates [16,17].
Phosphinopeptides containing C-terminal α-aminophosphinic acids have been prepared by similar methods to those used with their phosphonic analogues, for example the coupling of N-protected amino acids or their active esters with α-aminophosphinates [18], or with free α-aminophosphinic acids in organic or aqueous-organic media has been reported [19]. Additionally, the synthesis of phosphinopeptides via the Mannich-type condensation of N-Cbz protected alkanamides/peptide amides, aldehydes and aryldichlorophosphines, followed by hydrolysis, has also been reported [20]. Therefore, the α-amino-C-phosphinic acids are currently attracting interest in medicinal chemistry due to their relevance mainly as pseudopeptides, which have acquired pharmacological importance in influencing physiologic and pathologic processes, primarily acting as inhibitors for proteolytic enzymes. The success of these compounds is based on the resemblance of phosphinic acids to the sp 3 transition state of the hydrolysis of peptide bonds. Considering that lengths of O-P and C-P bonds are significantly longer than the corresponding O-C and C-C bonds, the phosphinic fragment might be considered as an extended tetrahedral intermediate and thus can be treated similar to the transition state of the hydrolysis (Figure 2) [21]. Moreover, they can act as simple analogues of amino acids replacing the carboxylic group by the phosphinic moiety, as non-hydrolysable phosphate analogues or as chelating agents of metal ions present in the active site of the enzymes [22]. A number of excellent reviews on various aspects of their activity in natural systems have been published [16,17]. In view of the broad biological applications of the optically active α-amino-C-phosphinic acids and their peptidic derivatives, in the last years the development of suitable synthetic methodologies for their preparation in optically pure form has been a topic of great interest in several research groups [31,32]. In this context, now we would like to report herein a summary of the stereoselective synthesis of α-amino-C-phosphinic acids and their derivatives covering the last 20 years. In this review article, the compounds have been classified in acyclic and phosphacyclic α-amino-Cphosphinic derivatives. In the first case an order is established according to the strategy used, in this way all procedures can be classified into C-P bond formation using a Pudovik or Kabachnik-Fields like reaction, C-H bond formation derived from catalytic asymmetric hydrogenation of α,β-dehydroaminophosphinates, resolution methodologies, preparation from chiral α-aminophosphonates and also P-C bond formation from chiral α-amino-H-phosphinic derivatives is included (Scheme 1). Otherwise, in the second case involving the phosphacyclic derivatives, the classification will be based in the presence or lack of the nitrogen atom in the heterocycle. Scheme 1. General overview of the synthetic strategies leading to α-amino-C-phosphinic acids.

Stereoselective C-P Bond Formation (Addition of Phosphorus Compounds to Imines)
A strategy widely used for the stereoselective synthesis of α-amino-C-phosphinic acids is the addition of a nucleophile HX (X = CN, PO2R, PO2RR′) to a preformed N-substituted chiral imine in the presence or absence of a chiral catalyst [33], leading to optically active α-amino carboxylic, α-aminophosphonic and α-aminophosphinic acids precursors, respectively. The extent of asymmetric induction at the Cα depends on the nature of the substituents (steric or hydrophobic interactions) and nucleophile-substrate interactions, which are favored in organocatalytic processes [34].
Indeed, the nucleophilic addition of phosphorus compounds (alkyl or aryl phosphinates) to imines, a Pudovik-like reaction [35], is an appropriate procedure for the preparation of α-amino-Cphosphinates. Generally, the high diastereoselective ratio can be explained on the basis of the most stable conformation of the Schiff bases, in which the C-H bond of the imine is eclipsed with the N-C-H fragment, as would be expected from the 1,3-allylic strain model [36,37], and the nucleophilic Simple pseudopeptides containing α-amino-C-phosphinate moieties replacing the scissile peptide bonds, rank among most potent inhibitors of metalloproteinases, where their tumorigenesis and invasion-related functions makes these enzymes molecular targets for the development of potential anticancer drugs [23]. The role of neutral aminopeptidase in the pathogenesis of hypertension provides an opportunity for regulating arterial blood pressure through its inhibition with this class of compounds [24]. Furthermore, these pseudopeptides appear to be excellent inhibitors to Plasmodium falciparum aminopeptidases, promising targets for a novel treatment of malaria [25,26]. α-Amino-C-phosphinic pseudopeptides have also revealed their potential activity in the regulation of matrix metalloproteinases (MMPs), whose overexpression or inadequate levels leads to pathological states such as osteoarthritis, rheumatoid arthritis and inflammation, but also it is associated with tumor growth, invasion and metastasis [27,28]. Additionally, is noteworthy that in these derivatives the stereochemistry affects their biological activity, hence the importance of the synthesis of these compounds in enantiomerically pure form [29,30].
In view of the broad biological applications of the optically active α-amino-C-phosphinic acids and their peptidic derivatives, in the last years the development of suitable synthetic methodologies for their preparation in optically pure form has been a topic of great interest in several research groups [31,32]. In this context, now we would like to report herein a summary of the stereoselective synthesis of α-amino-C-phosphinic acids and their derivatives covering the last 20 years. In this review article, the compounds have been classified in acyclic and phosphacyclic α-amino-C-phosphinic derivatives. In the first case an order is established according to the strategy used, in this way all procedures can be classified into C-P bond formation using a Pudovik or Kabachnik-Fields like reaction, C-H bond formation derived from catalytic asymmetric hydrogenation of α,β-dehydroaminophosphinates, resolution methodologies, preparation from chiral α-amino-phosphonates and also P-C bond formation from chiral α-amino-H-phosphinic derivatives is included (Scheme 1). Otherwise, in the second case involving the phosphacyclic derivatives, the classification will be based in the presence or lack of the nitrogen atom in the heterocycle. In view of the broad biological applications of the optically active α-amino-C-phosphinic acids and their peptidic derivatives, in the last years the development of suitable synthetic methodologies for their preparation in optically pure form has been a topic of great interest in several research groups [31,32]. In this context, now we would like to report herein a summary of the stereoselective synthesis of α-amino-C-phosphinic acids and their derivatives covering the last 20 years. In this review article, the compounds have been classified in acyclic and phosphacyclic α-amino-Cphosphinic derivatives. In the first case an order is established according to the strategy used, in this way all procedures can be classified into C-P bond formation using a Pudovik or Kabachnik-Fields like reaction, C-H bond formation derived from catalytic asymmetric hydrogenation of α,β-dehydroaminophosphinates, resolution methodologies, preparation from chiral α-aminophosphonates and also P-C bond formation from chiral α-amino-H-phosphinic derivatives is included (Scheme 1). Otherwise, in the second case involving the phosphacyclic derivatives, the classification will be based in the presence or lack of the nitrogen atom in the heterocycle. Scheme 1. General overview of the synthetic strategies leading to α-amino-C-phosphinic acids.

Stereoselective C-P Bond Formation (Addition of Phosphorus Compounds to Imines)
A strategy widely used for the stereoselective synthesis of α-amino-C-phosphinic acids is the Scheme 1. General overview of the synthetic strategies leading to α-amino-C-phosphinic acids.
Recently, Zhao et al. [40] described the synthesis of a P-chiral compound, whose RP chirality, was fully confirmed by X-ray analysis. In this context, the hydrophosphinylation of the N-(R)-αmethylbenzyl Schiff base (R)-4g with the (RP)-O-(−)-menthyl phenylphosphinate at 80 °C, gave after crystallization the optically pure O-menthyl phosphinate (R,S,R)-7 (Scheme 5). Rossi et al. [41] carried out the nucleophilic addition of the racemic ethyl phenylphosphinate onto the chiral imines 8a,b in chloroform at 60-70 °C, to obtain the α-amino-C-phosphinates 9a,b in 96% and 80% yield, respectively, and good diastereoselectivities (Scheme 6). The (S)-configuration at Cα of the major diastereoisomers 9a resulted from the preferred addition of ethyl phenylphosphinate onto the si face of the imine 8a, which adopts the most stable conformation according to the 1,3-allylic strain model [37], as shown in the Scheme 7 [41]. The (S)-configuration at C α of the major diastereoisomers 9a resulted from the preferred addition of ethyl phenylphosphinate onto the si face of the imine 8a, which adopts the most stable conformation according to the 1,3-allylic strain model [37], as shown in the Scheme 7 [41]. The (S)-configuration at Cα of the major diastereoisomers 9a resulted from the preferred addition of ethyl phenylphosphinate onto the si face of the imine 8a, which adopts the most stable conformation according to the 1,3-allylic strain model [37], as shown in the Scheme 7 [41]. The reaction of (R,S)-9a with aqueous AgNO3/HNO3 in methanol at 50 °C, produced the α-amino-C-phosphinate 10a in 63% yield and with 78:22 diastereoisomeric ratio, which by treatment with HBr/AcOH, afforded the enantiomerically pure (S)-α-aminobenzyl phenylphosphinic acid 6d (Scheme 8) [41]. The reaction of (R,S)-9a with aqueous AgNO 3 /HNO 3 in methanol at 50 • C, produced the α-amino-C-phosphinate 10a in 63% yield and with 78:22 diastereoisomeric ratio, which by treatment with HBr/AcOH, afforded the enantiomerically pure (S)-α-aminobenzyl phenylphosphinic acid 6d (Scheme 8) [41]. The (S)-configuration at Cα of the major diastereoisomers 9a resulted from the preferred addition of ethyl phenylphosphinate onto the si face of the imine 8a, which adopts the most stable conformation according to the 1,3-allylic strain model [37], as shown in the Scheme 7 [41]. The reaction of (R,S)-9a with aqueous AgNO3/HNO3 in methanol at 50 °C, produced the α-amino-C-phosphinate 10a in 63% yield and with 78:22 diastereoisomeric ratio, which by treatment with HBr/AcOH, afforded the enantiomerically pure (S)-α-aminobenzyl phenylphosphinic acid 6d (Scheme 8) [41]. Carbohydrate derivatives are efficient auxiliaries in many stereoselective chiral syntheses [42][43][44]. For example, Chen et al. [45] achieved the nucleophilic addition of ethyl phenylphosphinate to N-galactosylaldimines 11a-g in the presence of catalytic amounts of SnCl 4 in THF at room temperature to obtain the N-galactosyl α-aminoalkyl-C-phosphinates 12a-g in good yield and moderate diastereoselectivity (Scheme 9). Diastereoisomerically pure compounds 12a-c,e,g were obtained by recrystallization. Carbohydrate derivatives are efficient auxiliaries in many stereoselective chiral syntheses [42][43][44]. For example, Chen et al. [45] achieved the nucleophilic addition of ethyl phenylphosphinate to N-galactosylaldimines 11a-g in the presence of catalytic amounts of SnCl4 in THF at room temperature to obtain the N-galactosyl α-aminoalkyl-C-phosphinates 12a-g in good yield and moderate diastereoselectivity (Scheme 9). Diastereoisomerically pure compounds 12a-c,e,g were obtained by recrystallization. The (S)-configuration at the α-carbon of the major diastereoisomers 12a-g can be explained by the attack of ethyl phenylphosphinate from si face of (E)-imines 11a-g. The imine-SnCl4 complex and simultaneous chelation with the auxiliary's pivaloyl group inhibits free rotation along the N-anomeric carbon bond. According to this rationalization, the attack of the phosphinate in its P III phosphonous tautomeric form proceeds from the back face of the imine 11a-g, as shown in Scheme 10 [45]. The (S)-configuration at the α-carbon of the major diastereoisomers 12a-g can be explained by the attack of ethyl phenylphosphinate from si face of (E)-imines 11a-g. The imine-SnCl 4 complex and simultaneous chelation with the auxiliary's pivaloyl group inhibits free rotation along the N-anomeric carbon bond. According to this rationalization, the attack of the phosphinate in its P III phosphonous tautomeric form proceeds from the back face of the imine 11a-g, as shown in Scheme 10 [45].
The (S)-configuration at the α-carbon of the major diastereoisomers 12a-g can be explained by the attack of ethyl phenylphosphinate from si face of (E)-imines 11a-g. The imine-SnCl4 complex and simultaneous chelation with the auxiliary's pivaloyl group inhibits free rotation along the N-anomeric carbon bond. According to this rationalization, the attack of the phosphinate in its P III phosphonous tautomeric form proceeds from the back face of the imine 11a-g, as shown in Scheme 10 [45]. With the aim to assign the configuration, the reaction of N-galactosyl α-aminoalkyl-Cphosphinates 12a-g with 1 M HCl/MeOH at room temperature produced the α-amino-C-phosphinate hydrochlorides 13a-g in 78%-95% yield, which by hydrolysis with 1.5 M HCl under reflux followed by treatment with propylene oxide in ethanol at reflux, afforded the α-amino-C-phosphinic acids 6d and 14a-f in 82%-93% yield and with 73%-97% enantiomeric excess (Scheme 11) [45].

Chiral Catalyst
The stereoselective hydrophosphinylation of aldimines under organocatalytic conditions is emerging as a suitable method for the synthesis of optically active α-amino-C-phosphinates, in this regard the guanidines and guanidinium salts have shown to be highly efficient catalysts for enantioselective reactions [48]. For example, following the principle of activation of imines through hydrogen bonding, Tan et al. [49] carried out the hydrophosphinylation reaction of the N-tosyl imines 18a-g with arylphosphinates and alkylphosphinates in the presence of catalytic amounts of the guanidinium salt 19·HBArF4 in a CH2Cl2:toluene mixture and K2CO3 as a base at −40 °C, obtaining the α-amino-C-phosphinates 20a-k in 71%-93% yield and 3:1-16:1 diastereoisomeric ratio, with preference for the diastereoisomers (RC,SP)-20a-k with 82%-94% enantiomeric excess (Scheme 13). Scheme 11. Synthesis of the α-amino-C-phosphinic acids 6d and 14a-f.

Chiral Catalyst
The stereoselective hydrophosphinylation of aldimines under organocatalytic conditions is emerging as a suitable method for the synthesis of optically active α-amino-C-phosphinates, in this regard the guanidines and guanidinium salts have shown to be highly efficient catalysts for enantioselective reactions [48]. For example, following the principle of activation of imines through

Chiral Catalyst
The stereoselective hydrophosphinylation of aldimines under organocatalytic conditions is emerging as a suitable method for the synthesis of optically active α-amino-C-phosphinates, in this regard the guanidines and guanidinium salts have shown to be highly efficient catalysts for enantioselective reactions [48]. For example, following the principle of activation of imines through hydrogen bonding, Tan et al. [49] carried out the hydrophosphinylation reaction of the N-tosyl imines 18a-g with arylphosphinates and alkylphosphinates in the presence of catalytic amounts of the guanidinium salt 19·HBArF 4 in a CH 2 Cl 2 :toluene mixture and K 2 CO 3 as a base at −40 • C, obtaining the α-amino-C-phosphinates 20a-k in 71%-93% yield and 3:1-16:1 diastereoisomeric ratio, with preference for the diastereoisomers (R C ,S P )-20a-k with 82%-94% enantiomeric excess (Scheme 13).

Chiral Catalyst
The stereoselective hydrophosphinylation of aldimines under organocatalytic conditions is emerging as a suitable method for the synthesis of optically active α-amino-C-phosphinates, in this regard the guanidines and guanidinium salts have shown to be highly efficient catalysts for enantioselective reactions [48]. For example, following the principle of activation of imines through hydrogen bonding, Tan et al. [49] carried out the hydrophosphinylation reaction of the N-tosyl imines 18a-g with arylphosphinates and alkylphosphinates in the presence of catalytic amounts of the guanidinium salt 19·HBArF4 in a CH2Cl2:toluene mixture and K2CO3 as a base at −40 °C, obtaining the α-amino-C-phosphinates 20a-k in 71%-93% yield and 3:1-16:1 diastereoisomeric ratio, with preference for the diastereoisomers (RC,SP)-20a-k with 82%-94% enantiomeric excess (Scheme 13). Scheme 13. Hydrophosphinylation of aldimines 18a-g under organocatalytic conditions. Scheme 13. Hydrophosphinylation of aldimines 18a-g under organocatalytic conditions.

Chiral Amino Compounds
Possibly the simplest experimental proposal to prepare optically active α-amino-C-phosphinates is the "one-pot" three-component reaction, where the reactants are placed all together with or without solvent and catalyst, which is identical to the Kabachnik-Fields reaction widely studied in the synthesis of α-aminophosphonates [50][51][52].
Meng and Xu [19] reported a direct synthetic route for the preparation of phosphinopeptides containing C-terminal α-aminoalkyl-C-phosphinic acids, valuable peptide mimics. Thus, the "one-pot" three-component reaction of N-Cbz-aminoalkanamides (S)-21a-c obtained from N-protected amino acids, with benzaldehyde and phenyldichlorophosphine in dry acetonitrile at 80 • C followed by hydrolysis, produced the phosphinopeptides 22a-c in 65%-75% yield and low degree of asymmetric induction, obtaining the (S,S)-22a-c diastereoisomers as major products (Scheme 14).
According to the authors, the reaction of the N-Cbz-aminoalkanamide, benzaldehyde and phenyldichlorophosphine produce the N-acylimine 23b and phenylchlorophosphonous acid, which attacks to the imine favorably from the si face because the amino acid substituent blocks the opposite re face. Finally, a proton transfer affords the intermediate aminoalkylphosphinic chloride, which undergoes hydrolysis gave the (S,S)-phosphinopeptide 22b as major product (Scheme 15) [19]. [19] reported a direct synthetic route for the preparation of phosphinopeptides containing C-terminal α-aminoalkyl-C-phosphinic acids, valuable peptide mimics. Thus, the "onepot" three-component reaction of N-Cbz-aminoalkanamides (S)-21a-c obtained from N-protected amino acids, with benzaldehyde and phenyldichlorophosphine in dry acetonitrile at 80 °C followed by hydrolysis, produced the phosphinopeptides 22a-c in 65%-75% yield and low degree of asymmetric induction, obtaining the (S,S)-22a-c diastereoisomers as major products (Scheme 14). According to the authors, the reaction of the N-Cbz-aminoalkanamide, benzaldehyde and phenyldichlorophosphine produce the N-acylimine 23b and phenylchlorophosphonous acid, which attacks to the imine favorably from the si face because the amino acid substituent blocks the opposite re face. Finally, a proton transfer affords the intermediate aminoalkylphosphinic chloride, which undergoes hydrolysis gave the (S,S)-phosphinopeptide 22b as major product (Scheme 15) [19]. Similarly, a series of phosphinodepsipeptides were synthesized via a pseudo-four-component condensation reaction, in a convergent and atom economic synthetic strategy [53]. In this context, the "one-pot" reaction of N-Cbz-amino amides derived from amino acids with different aldehydes and aryldichlorophosphines in dry acetonitrile at 80 °C followed by alcoholysis with α-hydroxy esters or ethanol, produced the phosphinodepsipeptides 24a-k in 50%-66% yield and low diastereo selectivities, where the (RC*,RP*)-products were assumed as major diastereoisomers (Scheme 16). asymmetric induction, obtaining the (S,S)-22a-c diastereoisomers as major products (Scheme 14).

Scheme 14. Preparation of phosphinopeptides (S,S)-22a-c.
According to the authors, the reaction of the N-Cbz-aminoalkanamide, benzaldehyde and phenyldichlorophosphine produce the N-acylimine 23b and phenylchlorophosphonous acid, which attacks to the imine favorably from the si face because the amino acid substituent blocks the opposite re face. Finally, a proton transfer affords the intermediate aminoalkylphosphinic chloride, which undergoes hydrolysis gave the (S,S)-phosphinopeptide 22b as major product (Scheme 15) [19]. Similarly, a series of phosphinodepsipeptides were synthesized via a pseudo-four-component condensation reaction, in a convergent and atom economic synthetic strategy [53]. In this context, the "one-pot" reaction of N-Cbz-amino amides derived from amino acids with different aldehydes and aryldichlorophosphines in dry acetonitrile at 80 °C followed by alcoholysis with α-hydroxy esters or ethanol, produced the phosphinodepsipeptides 24a-k in 50%-66% yield and low diastereo selectivities, where the (RC*,RP*)-products were assumed as major diastereoisomers (Scheme 16). Similarly, a series of phosphinodepsipeptides were synthesized via a pseudo-four-component condensation reaction, in a convergent and atom economic synthetic strategy [53]. In this context, the "one-pot" reaction of N-Cbz-amino amides derived from amino acids with different aldehydes and aryldichlorophosphines in dry acetonitrile at 80 • C followed by alcoholysis with α-hydroxy esters or ethanol, produced the phosphinodepsipeptides 24a-k in 50%-66% yield and low diastereo selectivities, where the (R C *,R P *)-products were assumed as major diastereoisomers (Scheme 16). In a similar way, Meng et al. [54] reported the preparation of hybrid sulfonophosphinopeptides incorporating α-aminoalkyl-C-phosphinic acids. The compounds of interest were synthesized by reaction of the N-Cbz protected aminoalkanesulfonamides, benzaldehyde and phenyldichloro phosphine in dry acetonitrile at 45 °C and subsequent hydrolysis at room temperature, obtaining the sulfonophosphinodipeptides 26a-d in good yield, but low diastereoselectivity. The diastereo isomers (S,S)-26a-d were assumed as the major products (Scheme 17). Scheme 16. Synthesis of phosphinodepsipeptides (R C *,R P *)-24a-k.
In a similar way, Meng et al. [54] reported the preparation of hybrid sulfonophosphinopeptides incorporating α-aminoalkyl-C-phosphinic acids. The compounds of interest were synthesized by reaction of the N-Cbz protected aminoalkanesulfonamides, benzaldehyde and phenyldichloro phosphine in dry acetonitrile at 45 • C and subsequent hydrolysis at room temperature, obtaining the sulfonophosphinodipeptides 26a-d in good yield, but low diastereoselectivity. The diastereo isomers (S,S)-26a-d were assumed as the major products (Scheme 17). Scheme 16. Synthesis of phosphinodepsipeptides (RC*,RP*)-24a-k.
In a similar way, Meng et al. [54] reported the preparation of hybrid sulfonophosphinopeptides incorporating α-aminoalkyl-C-phosphinic acids. The compounds of interest were synthesized by reaction of the N-Cbz protected aminoalkanesulfonamides, benzaldehyde and phenyldichloro phosphine in dry acetonitrile at 45 °C and subsequent hydrolysis at room temperature, obtaining the sulfonophosphinodipeptides 26a-d in good yield, but low diastereoselectivity. The diastereo isomers (S,S)-26a-d were assumed as the major products (Scheme 17). Scheme 17. Synthesis of the sulfonophosphinodipeptides 26a-d.
In a similar way, Meng et al. [54] reported the preparation of hybrid sulfonophosphinopeptides incorporating α-aminoalkyl-C-phosphinic acids. The compounds of interest were synthesized by reaction of the N-Cbz protected aminoalkanesulfonamides, benzaldehyde and phenyldichloro phosphine in dry acetonitrile at 45 °C and subsequent hydrolysis at room temperature, obtaining the sulfonophosphinodipeptides 26a-d in good yield, but low diastereoselectivity. The diastereo isomers (S,S)-26a-d were assumed as the major products (Scheme 17). Scheme 17. Synthesis of the sulfonophosphinodipeptides 26a-d.

Resolution Methodologies
The resolution strategies of racemic compounds have also demonstrated its usefulness for the preparation of optically enriched α-amino-C-phosphinic acids. For example, Lämmerhofer et al. [60] carried out the chiral HPLC separation of N-Cbz phosphinic pseudopeptide esters 34a-d as well as their free C-terminal carboxylic derivatives 34e-h using a set of cinchona alkaloid-derived chiral anion-exchangers 35,36 (Scheme 21). Semi-preparative scale chromatography supplied single enantiomers in 100 mg quantities allowing the biological activity assays.
In a related work, Lämmerhofer et al. [61] developed a capillary electrochromatography (CEC) method for the separation of the stereoisomers of N-Cbz phosphinic pseudodipeptide methyl ester 37a and 38a and its N-DNP derivative with free C-terminal carboxylic group 37b and 38b, using a monolithic silica capillary column modified with a cinchona alkaloid-derived anion-exchange-type chiral selector 39 (Scheme 22). This method proved superiority compared to the HPLC separation, which was attributed to significantly enhanced plate numbers. Furthermore, Darses et al. [58] reported an alternative approach for the synthesis of α-amino-Cphosphinates through the asymmetric rhodium-catalyzed addition of organoboron derivatives to α,β-dehydroaminophosphinates. Indeed, the addition of potassium phenyltrifluoroborate to the α,β-dehydroaminophosphinate 30 [59] in the presence of NaHCO3, [RhCl(CH2CH2)2]2 as catalyst precursor and (S)-DifluorPhos 31 as chiral ligand in isopropyl alcohol at 90 °C, afforded the diastereoisomeric α-amino-C-phosphinates 32 and 33 in moderate yield and with 94% and 92% enantiomeric excesses, respectively (Scheme 20). Scheme 20. Asymmetric rhodium-catalyzed addition of phenyltrifluoroborate to 30.

Resolution Methodologies
The resolution strategies of racemic compounds have also demonstrated its usefulness for the preparation of optically enriched α-amino-C-phosphinic acids. For example, Lämmerhofer et al. [60] carried out the chiral HPLC separation of N-Cbz phosphinic pseudopeptide esters 34a-d as well as their free C-terminal carboxylic derivatives 34e-h using a set of cinchona alkaloid-derived chiral anion-exchangers 35,36 (Scheme 21). Semi-preparative scale chromatography supplied single enantiomers in 100 mg quantities allowing the biological activity assays.
In a related work, Lämmerhofer et al. [61] developed a capillary electrochromatography (CEC) method for the separation of the stereoisomers of N-Cbz phosphinic pseudodipeptide methyl ester 37a and 38a and its N-DNP derivative with free C-terminal carboxylic group 37b and 38b, using a monolithic silica capillary column modified with a cinchona alkaloid-derived anion-exchange-type chiral selector 39 (Scheme 22). This method proved superiority compared to the HPLC separation, which was attributed to significantly enhanced plate numbers. Scheme 20. Asymmetric rhodium-catalyzed addition of phenyltrifluoroborate to 30.

Resolution Methodologies
The resolution strategies of racemic compounds have also demonstrated its usefulness for the preparation of optically enriched α-amino-C-phosphinic acids. For example, Lämmerhofer et al. [60] carried out the chiral HPLC separation of N-Cbz phosphinic pseudopeptide esters 34a-d as well as their free C-terminal carboxylic derivatives 34e-h using a set of cinchona alkaloid-derived chiral anion-exchangers 35,36 (Scheme 21). Semi-preparative scale chromatography supplied single enantiomers in 100 mg quantities allowing the biological activity assays. In a related work, Lämmerhofer et al. [61] developed a capillary electrochromatography (CEC) method for the separation of the stereoisomers of N-Cbz phosphinic pseudodipeptide methyl ester 37a and 38a and its N-DNP derivative with free C-terminal carboxylic group 37b and 38b, using a monolithic silica capillary column modified with a cinchona alkaloid-derived anion-exchange-type chiral selector 39 (Scheme 22). This method proved superiority compared to the HPLC separation, which was attributed to significantly enhanced plate numbers. Taking into account that phosphinic dipeptides, although tested as stereoisomeric mixtures, are considered amongst the most potent inhibitors of bizinc cytosolic leucine aminopeptidase (LAP) [62], Mucha, et al. [63] carried out the chiral HPLC separation of all stereoisomers of phosphinic dipeptide homophenylalanyl-phenylalanine derivative 40 and 41 on a quinidine carbamate modified silica stationary phase 42 (Scheme 23). Significant differences in inhibition of the unprotected derivatives 43 and 44 show the importance of the molecular stereochemistry in spatial interaction with the enzyme active site.

P-C Bond Formation from Chiral α-Amino-H-phosphinic Derivatives
There is a continuously growing interest in phosphorus-carbon bond formation due to the great applications of organophosphorus compounds in synthetic organic and bioorganic chemistry [5,70]. In this context, the chiral α-amino-H-phosphinates have also proved efficiency as P-nucleophiles in Michael additions. In this regard, Yiotakis et al. [27,71] reported the synthesis of dehydroalaninyl phosphinic dipeptide analogues, which were tested as zinc-metalloproteases MMP-8 inhibitors. For this purpose, the optically pure α-amino-H-phosphinic acid (R)-66a [72] was reacted with TMSCl/DIPEA in CH2Cl2 followed by addition of tert-butyl 2-(bromomethyl)acrylate, obtaining the dehydroalanine derivative (R)-67 in 94% yield, presumably via an allylic rearrangement. Cleavage of the O-tert-butyl bond in (R)-67 with trifluoroacetic acid (TFA) and coupling with L-tryptophanylamide, gave the pseudotripeptide (R,S)-68 in 69% yield. Finally, the Michael-type addition of benzyl thiols to (R,S)-68, produced the cysteine analogues 69a-c in good yield (Scheme 29).

P-C Bond Formation from Chiral α-Amino-H-phosphinic Derivatives
There is a continuously growing interest in phosphorus-carbon bond formation due to the great applications of organophosphorus compounds in synthetic organic and bioorganic chemistry [5,70]. In this context, the chiral α-amino-H-phosphinates have also proved efficiency as P-nucleophiles in Michael additions. In this regard, Yiotakis et al. [27,71] reported the synthesis of dehydroalaninyl phosphinic dipeptide analogues, which were tested as zinc-metalloproteases MMP-8 inhibitors. For this purpose, the optically pure α-amino-H-phosphinic acid (R)-66a [72] was reacted with TMSCl/DIPEA in CH 2 Cl 2 followed by addition of tert-butyl 2-(bromomethyl)acrylate, obtaining the dehydroalanine derivative (R)-67 in 94% yield, presumably via an allylic rearrangement. Cleavage of the O-tert-butyl bond in (R)-67 with trifluoroacetic acid (TFA) and coupling with L-tryptophanyl-amide, gave the pseudotripeptide (R,S)-68 in 69% yield. Finally, the Michael-type addition of benzyl thiols to (R,S)-68, produced the cysteine analogues 69a-c in good yield (Scheme 29). On the other hand, McKittrick et al. [73] reported the synthesis of the phosphinic pseudotripeptide (R,S)-71, which not only inhibits the metalloprotease endothelin converting enzyme (ECE), but also the angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) with IC50 values <100 nM. Thus, the hydroxyphosphinyl group in enantiopure Cbz-protected phenylalanine phosphinic analogue (R)-66a [72] was reacted with diazomethane, followed by treatment with LDA in THF at −78 °C and subsequent addition of the triflate, to afford the P-alkylated α-amino-C-phosphinate (R)-70 in 43% yield, which was further transformed into pseudotripeptide (R,S)-71 (Scheme 30). Hamilton et al. [74] reported the synthesis of phenyl phosphinate derivatives 73a,b from Cbz-protected phenylalanine and valine phosphinic analogues [72] and their inhibitory properties against human neutrophile elastase (HNE) (valine analogue) and chymotrypsin (phenylalanine analogue) were evaluated, determining specific inhibitory activity for analogues having (R) configuration at α-carbon. Thus, the reaction of the α-amino-H-phosphinic acids (R)-66a,b with TMSCl and Et3N in CH2Cl2 at 0 °C followed by the addition of ethyl acrylate, produced the Michael adducts (R)-72a,b, which by reaction with thionyl chloride (SOCl2) in CH2Cl2 followed by addition of phenol, provided the phenyl C-phosphinates (R)-73a,b with 91:9 and 89:11 diastereoisomeric ratio, respectively (Scheme 31). On the other hand, McKittrick et al. [73] reported the synthesis of the phosphinic pseudotripeptide (R,S)-71, which not only inhibits the metalloprotease endothelin converting enzyme (ECE), but also the angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) with IC 50 values <100 nM. Thus, the hydroxyphosphinyl group in enantiopure Cbz-protected phenylalanine phosphinic analogue (R)-66a [72] was reacted with diazomethane, followed by treatment with LDA in THF at −78 • C and subsequent addition of the triflate, to afford the P-alkylated α-amino-C-phosphinate (R)-70 in 43% yield, which was further transformed into pseudotripeptide (R,S)-71 (Scheme 30). On the other hand, McKittrick et al. [73] reported the synthesis of the phosphinic pseudotripeptide (R,S)-71, which not only inhibits the metalloprotease endothelin converting enzyme (ECE), but also the angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) with IC50 values <100 nM. Thus, the hydroxyphosphinyl group in enantiopure Cbz-protected phenylalanine phosphinic analogue (R)-66a [72] was reacted with diazomethane, followed by treatment with LDA in THF at −78 °C and subsequent addition of the triflate, to afford the P-alkylated α-amino-C-phosphinate (R)-70 in 43% yield, which was further transformed into pseudotripeptide (R,S)-71 (Scheme 30). Hamilton et al. [74] reported the synthesis of phenyl phosphinate derivatives 73a,b from Cbz-protected phenylalanine and valine phosphinic analogues [72] and their inhibitory properties against human neutrophile elastase (HNE) (valine analogue) and chymotrypsin (phenylalanine analogue) were evaluated, determining specific inhibitory activity for analogues having (R) configuration at α-carbon. Thus, the reaction of the α-amino-H-phosphinic acids (R)-66a,b with TMSCl and Et3N in CH2Cl2 at 0 °C followed by the addition of ethyl acrylate, produced the Michael adducts (R)-72a,b, which by reaction with thionyl chloride (SOCl2) in CH2Cl2 followed by addition of phenol, provided the phenyl C-phosphinates (R)-73a,b with 91:9 and 89:11 diastereoisomeric ratio, respectively (Scheme 31). Hamilton et al. [74] reported the synthesis of phenyl phosphinate derivatives 73a,b from Cbz-protected phenylalanine and valine phosphinic analogues [72] and their inhibitory properties against human neutrophile elastase (HNE) (valine analogue) and chymotrypsin (phenylalanine analogue) were evaluated, determining specific inhibitory activity for analogues having (R) configuration at α-carbon. Thus, the reaction of the α-amino-H-phosphinic acids (R)-66a,b with TMSCl and Et 3 N in CH 2 Cl 2 at 0 • C followed by the addition of ethyl acrylate, produced the Michael adducts (R)-72a,b, which by reaction with thionyl chloride (SOCl 2 ) in CH 2 Cl 2 followed by addition of phenol, provided the phenyl C-phosphinates (R)-73a,b with 91:9 and 89:11 diastereoisomeric ratio, respectively (Scheme 31). Additionally, Lloyd et al. [75] synthesized the C-phosphinic acid 75 and tested its effect on ECE inhibition. In this context, the reaction of α-amino-H-phosphinic acid (R)-66a obtained by resolution [72], with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) followed by the Michael addition to ethyl 2-benzylacrylate and subsequent basic hydrolysis of the ethoxycarbonyl group, produced the C-phosphinic acid 74. Finally, the reaction of 74 with oxalyl chloride, followed by coupling with (S)-Trp-OMe and subsequent saponification with LiOH, afforded the phosphinic pseudopeptide 75 as a 4:1 diastereoisomeric mixture (Scheme 32). Roques et al. [76] reported the synthesis of the iodinated tripeptide (R,S,S)-78 analogue of a highly efficient aminopeptidase N inhibitor, as a tool for complete characterization of the biochemical and pharmacological properties of this enzyme. The Michael addition of N-Cbz alanine H-phosphinic analogue (R)-66c obtained by resolution [72], to the methyl benzylacrylate in the presence of N,O-bistrimethylsilylacetamide (BSA), followed by alkaline hydrolysis and subsequent coupling with the L-tyrosine benzyl ester, produced the tripeptide 76 in 57% yield as a diastereoisomeric mixture, which by saponification of benzyl ester and Cbz removal under acidic conditions, gave the (R,S,S)-77 diastereoisomer in 47% yield after HPLC separation. Finally, the radioiodination of (R,S,S)-77 was performed by using Na 125 I in sodium hydroxide solution and chloramine-T, providing the radiolabeled compound (R,S,S)-78 (Scheme 33).
In a similar way, Roques et al. [77] reported the synthesis of the phosphinic pseudopeptide (R,S,S)-81, which proved to be a potent dual inhibitor of the zinc metallopeptidases neprilysin and aminopeptidase N. For this purpose, the Michael addition of N-Cbz alanine H-phosphinic acid (R)-66c obtained by resolution [72], to ethyl p-bromobenzylacrylate followed by a Suzuki coupling using phenylboronic acid and subsequent alkaline hydrolysis of the ethyl ester, gave the C-phosphinic acid derivative 79 in 75% yield, which by the coupling with (S)-alanine methyl ester afforded the tripeptide 80 in 59% yield. Finally, the saponification of the methyl ester followed by the cleavage of the N-Cbz bond with BBr3 and the semipreparative HPLC purification, provided the enantiomerically pure phosphinic pseudopeptide (R,S,S)-81 in 92% yield (Scheme 34). Additionally, Lloyd et al. [75] synthesized the C-phosphinic acid 75 and tested its effect on ECE inhibition. In this context, the reaction of α-amino-H-phosphinic acid (R)-66a obtained by resolution [72], with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) followed by the Michael addition to ethyl 2-benzylacrylate and subsequent basic hydrolysis of the ethoxycarbonyl group, produced the C-phosphinic acid 74. Finally, the reaction of 74 with oxalyl chloride, followed by coupling with (S)-Trp-OMe and subsequent saponification with LiOH, afforded the phosphinic pseudopeptide 75 as a 4:1 diastereoisomeric mixture (Scheme 32). Additionally, Lloyd et al. [75] synthesized the C-phosphinic acid 75 and tested its effect on ECE inhibition. In this context, the reaction of α-amino-H-phosphinic acid (R)-66a obtained by resolution [72], with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) followed by the Michael addition to ethyl 2-benzylacrylate and subsequent basic hydrolysis of the ethoxycarbonyl group, produced the C-phosphinic acid 74. Finally, the reaction of 74 with oxalyl chloride, followed by coupling with (S)-Trp-OMe and subsequent saponification with LiOH, afforded the phosphinic pseudopeptide 75 as a 4:1 diastereoisomeric mixture (Scheme 32). Roques et al. [76] reported the synthesis of the iodinated tripeptide (R,S,S)-78 analogue of a highly efficient aminopeptidase N inhibitor, as a tool for complete characterization of the biochemical and pharmacological properties of this enzyme. The Michael addition of N-Cbz alanine H-phosphinic analogue (R)-66c obtained by resolution [72], to the methyl benzylacrylate in the presence of N,O-bistrimethylsilylacetamide (BSA), followed by alkaline hydrolysis and subsequent coupling with the L-tyrosine benzyl ester, produced the tripeptide 76 in 57% yield as a diastereoisomeric mixture, which by saponification of benzyl ester and Cbz removal under acidic conditions, gave the (R,S,S)-77 diastereoisomer in 47% yield after HPLC separation. Finally, the radioiodination of (R,S,S)-77 was performed by using Na 125 I in sodium hydroxide solution and chloramine-T, providing the radiolabeled compound (R,S,S)-78 (Scheme 33).
In a similar way, Roques et al. [77] reported the synthesis of the phosphinic pseudopeptide (R,S,S)-81, which proved to be a potent dual inhibitor of the zinc metallopeptidases neprilysin and aminopeptidase N. For this purpose, the Michael addition of N-Cbz alanine H-phosphinic acid (R)-66c obtained by resolution [72], to ethyl p-bromobenzylacrylate followed by a Suzuki coupling using phenylboronic acid and subsequent alkaline hydrolysis of the ethyl ester, gave the C-phosphinic acid derivative 79 in 75% yield, which by the coupling with (S)-alanine methyl ester afforded the tripeptide 80 in 59% yield. Finally, the saponification of the methyl ester followed by the cleavage of the N-Cbz bond with BBr3 and the semipreparative HPLC purification, provided the enantiomerically pure phosphinic pseudopeptide (R,S,S)-81 in 92% yield (Scheme 34). Roques et al. [76] reported the synthesis of the iodinated tripeptide (R,S,S)-78 analogue of a highly efficient aminopeptidase N inhibitor, as a tool for complete characterization of the biochemical and pharmacological properties of this enzyme. The Michael addition of N-Cbz alanine H-phosphinic analogue (R)-66c obtained by resolution [72], to the methyl benzylacrylate in the presence of N,O-bistrimethylsilylacetamide (BSA), followed by alkaline hydrolysis and subsequent coupling with the L-tyrosine benzyl ester, produced the tripeptide 76 in 57% yield as a diastereoisomeric mixture, which by saponification of benzyl ester and Cbz removal under acidic conditions, gave the (R,S,S)-77 diastereoisomer in 47% yield after HPLC separation. Finally, the radioiodination of (R,S,S)-77 was performed by using Na 125 I in sodium hydroxide solution and chloramine-T, providing the radiolabeled compound (R,S,S)-78 (Scheme 33).
In a similar way, Roques et al. [77] reported the synthesis of the phosphinic pseudopeptide (R,S,S)-81, which proved to be a potent dual inhibitor of the zinc metallopeptidases neprilysin and aminopeptidase N. For this purpose, the Michael addition of N-Cbz alanine H-phosphinic acid (R)-66c obtained by resolution [72], to ethyl p-bromobenzylacrylate followed by a Suzuki coupling using phenylboronic acid and subsequent alkaline hydrolysis of the ethyl ester, gave the C-phosphinic acid derivative 79 in 75% yield, which by the coupling with (S)-alanine methyl ester afforded the tripeptide 80 in 59% yield. Finally, the saponification of the methyl ester followed by the cleavage of the N-Cbz bond with BBr 3 and the semipreparative HPLC purification, provided the enantiomerically pure phosphinic pseudopeptide (R,S,S)-81 in 92% yield (Scheme 34). In a related work, Samios et al. [78] developed an efficient synthetic methodology for the preparation of the phosphinic pseudotripeptide known as RXP03, which has been widely studied as MMPs inhibitor [79,80]. Initially, reaction of the N-Cbz H-phosphinic acid analogue of phenylalanine (R)-66a [72] with bis(trimethylsilyl)amine (HMDS) followed by the addition of ethyl phenylpropylacrylate and subsequent hydrolysis of the ethyl ester group, gave C-phosphinate 82 in 90% yield, which by coupling with (S)-TrpNH2, afforded the phosphinic pseudotripeptides (R,S,S)-83 and (R,R,S)-84 in 77% yield, which were separated in 99% purity by preferential precipitation in EtOH (Scheme 35). This methodology allows the separation of the diastereoisomers based in their solubility differences, which was explained by conformational and solvation theoretical studies in terms of their intra-and intermolecular structure.
Similarly, the phosphinic pseudotripeptides (S,S,S)-85 and (S,R,S)-86 were obtained from the enantiomeric pure N-Cbz H-phosphinic acid analogue of phenylalanine (S)-66a in 64% yield. As in the previous example, each diastereoisomer showed different solubility properties in ethyl ether allowing their complete separation (Scheme 36) [78]. In a related work, Samios et al. [78] developed an efficient synthetic methodology for the preparation of the phosphinic pseudotripeptide known as RXP03, which has been widely studied as MMPs inhibitor [79,80]. Initially, reaction of the N-Cbz H-phosphinic acid analogue of phenylalanine (R)-66a [72] with bis(trimethylsilyl)amine (HMDS) followed by the addition of ethyl phenylpropylacrylate and subsequent hydrolysis of the ethyl ester group, gave C-phosphinate 82 in 90% yield, which by coupling with (S)-TrpNH2, afforded the phosphinic pseudotripeptides (R,S,S)-83 and (R,R,S)-84 in 77% yield, which were separated in 99% purity by preferential precipitation in EtOH (Scheme 35). This methodology allows the separation of the diastereoisomers based in their solubility differences, which was explained by conformational and solvation theoretical studies in terms of their intra-and intermolecular structure.
Similarly, the phosphinic pseudotripeptides (S,S,S)-85 and (S,R,S)-86 were obtained from the enantiomeric pure N-Cbz H-phosphinic acid analogue of phenylalanine (S)-66a in 64% yield. As in the previous example, each diastereoisomer showed different solubility properties in ethyl ether allowing their complete separation (Scheme 36) [78]. In a related work, Samios et al. [78] developed an efficient synthetic methodology for the preparation of the phosphinic pseudotripeptide known as RXP03, which has been widely studied as MMPs inhibitor [79,80]. Initially, reaction of the N-Cbz H-phosphinic acid analogue of phenylalanine (R)-66a [72] with bis(trimethylsilyl)amine (HMDS) followed by the addition of ethyl phenylpropyl-acrylate and subsequent hydrolysis of the ethyl ester group, gave C-phosphinate 82 in 90% yield, which by coupling with (S)-TrpNH 2 , afforded the phosphinic pseudotripeptides (R,S,S)-83 and (R,R,S)-84 in 77% yield, which were separated in 99% purity by preferential precipitation in EtOH (Scheme 35). This methodology allows the separation of the diastereoisomers based in their solubility differences, which was explained by conformational and solvation theoretical studies in terms of their intra-and intermolecular structure. Considering that phosphinic peptides are well recognized as peptide isosters and powerful inhibitors of many classes of enzymes, mainly zinc proteases, Yiotakis et al. [81,82] reported the synthesis of phosphinopeptidic building blocks incorporating a triple bond, which through 1,3-dipolar cycloaddition process, gives access to novel class of isoxazole-containing phosphinic peptides. Thus, the reaction of N-Cbz H-phosphinic acid analogue of phenylalanine (R)-66a [72] with TMSCl/DIPEA followed by the addition of ethyl α-propargylic acrylate and saponification of the ethyl ester, gave the C-phosphinates 87 in 96% yield and 3.5:1 diastereoisomeric ratio. Coupling of 87 with (S)-TrpNH2 afforded the tripeptide 88 as a diastereoisomeric mixture, from which the diastereoisomer (R,S,S)-88 was isolated by means of simple crystallization. Finally, the 1,3-dipolar cycloaddition reaction of (R,S,S)-88 with different nitrile oxides generated in situ from the chlorination of the corresponding oxime, furnished the isoxazoles (R,S,S)-89a-d in good yields (Scheme 37).
In a similar way, Stratikos et al. [84] reported the synthesis of the phosphinic tripeptide (R,S,S)-94, which was tested in the inhibition of the endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), involved in regulation of cytotoxic cellular responses. Thus, the reaction of N-Boc H-phosphinic acid analogue of homophenylalanine (R)-92 [72] with HMDS followed by the addition of ethyl isobutylacrylate and saponification of the ethyl ester, gave the C-phosphinate 93 in 72% yield, which by coupling with (S)-TrpNH2, deprotection and HPLC separation, afforded the phosphinic tripeptide (R,S,S)-94 in 87% (Scheme 39) [78]. Considering that phosphinic peptides are well recognized as peptide isosters and powerful inhibitors of many classes of enzymes, mainly zinc proteases, Yiotakis et al. [81,82] reported the synthesis of phosphinopeptidic building blocks incorporating a triple bond, which through 1,3-dipolar cycloaddition process, gives access to novel class of isoxazole-containing phosphinic peptides. Thus, the reaction of N-Cbz H-phosphinic acid analogue of phenylalanine (R)-66a [72] with TMSCl/DIPEA followed by the addition of ethyl α-propargylic acrylate and saponification of the ethyl ester, gave the C-phosphinates 87 in 96% yield and 3.5:1 diastereoisomeric ratio. Coupling of 87 with (S)-TrpNH2 afforded the tripeptide 88 as a diastereoisomeric mixture, from which the diastereoisomer (R,S,S)-88 was isolated by means of simple crystallization. Finally, the 1,3-dipolar cycloaddition reaction of (R,S,S)-88 with different nitrile oxides generated in situ from the chlorination of the corresponding oxime, furnished the isoxazoles (R,S,S)-89a-d in good yields (Scheme 37).
In a similar way, Stratikos et al. [84] reported the synthesis of the phosphinic tripeptide (R,S,S)-94, which was tested in the inhibition of the endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), involved in regulation of cytotoxic cellular responses. Thus, the reaction of N-Boc H-phosphinic acid analogue of homophenylalanine (R)-92 [72] with HMDS followed by the addition of ethyl isobutylacrylate and saponification of the ethyl ester, gave the C-phosphinate 93 in 72% yield, which by coupling with (S)-TrpNH2, deprotection and HPLC separation, afforded the Considering that phosphinic peptides are well recognized as peptide isosters and powerful inhibitors of many classes of enzymes, mainly zinc proteases, Yiotakis et al. [81,82] reported the synthesis of phosphinopeptidic building blocks incorporating a triple bond, which through 1,3-dipolar cycloaddition process, gives access to novel class of isoxazole-containing phosphinic peptides. Thus, the reaction of N-Cbz H-phosphinic acid analogue of phenylalanine (R)-66a [72] with TMSCl/DIPEA followed by the addition of ethyl α-propargylic acrylate and saponification of the ethyl ester, gave the C-phosphinates 87 in 96% yield and 3.5:1 diastereoisomeric ratio. Coupling of 87 with (S)-TrpNH 2 afforded the tripeptide 88 as a diastereoisomeric mixture, from which the diastereoisomer (R,S,S)-88 was isolated by means of simple crystallization. Finally, the 1,3-dipolar cycloaddition reaction of (R,S,S)-88 with different nitrile oxides generated in situ from the chlorination of the corresponding oxime, furnished the isoxazoles (R,S,S)-89a-d in good yields (Scheme 37).
On the other hand, the 1,3-dipolar cycloaddition reaction of propargylic C-phosphinic acid 87 (1:1 diastereoisomeric mixture) [81] with benzonitrile oxide, gave the isoxazole-phosphinate 90 in 83% yield, which by coupling with di-tert-butyl protected (S)-tyrosine followed by the cleavage of the tert-butyl group and semipreparative RP-HPLC isolation, provided the pure diastereoisomeric phosphinic tripeptide (R,R,S)-91 in 90% yield (Scheme 38) [83]. These compounds were administered intravenously and lowered mean arterial blood pressure in spontaneously hypertensive rats. In order to functionalize the phosphinic pseudopeptide framework, Yiotakis et al. [85] developed a simple and efficient method for P1′ diversification obtaining a variety of dehydrophosphinic peptides. According to this strategy, the treatment of N-Cbz phenylalanine H-phosphinic analogue (S)-66a [72] with TMSCl/DIPEA followed by addition of diethyl 2-methylenemalonate and subsequent alkaline hydrolysis, afforded the phosphinic pseudodipeptide (S)-95 in 67% yield, which was subjected to a Knoevenagel-type condensation with several aldehydes, to give the dehydrophosphinic peptides 96a-i in good yields (Scheme 40). In order to functionalize the phosphinic pseudopeptide framework, Yiotakis et al. [85] developed a simple and efficient method for P1′ diversification obtaining a variety of dehydrophosphinic peptides. According to this strategy, the treatment of N-Cbz phenylalanine H-phosphinic analogue (S)-66a [72] with TMSCl/DIPEA followed by addition of diethyl 2-methylenemalonate and subsequent alkaline hydrolysis, afforded the phosphinic pseudodipeptide (S)-95 in 67% yield, which was subjected to a Knoevenagel-type condensation with several aldehydes, to give the dehydrophosphinic peptides 96a-i in good yields (Scheme 40). In a similar way, Stratikos et al. [84] reported the synthesis of the phosphinic tripeptide (R,S,S)-94, which was tested in the inhibition of the endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), involved in regulation of cytotoxic cellular responses. Thus, the reaction of N-Boc H-phosphinic acid analogue of homophenylalanine (R)-92 [72] with HMDS followed by the addition of ethyl isobutylacrylate and saponification of the ethyl ester, gave the C-phosphinate 93 in 72% yield, which by coupling with (S)-TrpNH 2 , deprotection and HPLC separation, afforded the phosphinic tripeptide (R,S,S)-94 in 87% (Scheme 39) [78]. In order to functionalize the phosphinic pseudopeptide framework, Yiotakis et al. [85] developed a simple and efficient method for P1′ diversification obtaining a variety of dehydrophosphinic peptides. According to this strategy, the treatment of N-Cbz phenylalanine H-phosphinic analogue (S)-66a [72] with TMSCl/DIPEA followed by addition of diethyl 2-methylenemalonate and subsequent alkaline hydrolysis, afforded the phosphinic pseudodipeptide In order to functionalize the phosphinic pseudopeptide framework, Yiotakis et al. [85] developed a simple and efficient method for P 1 diversification obtaining a variety of dehydrophosphinic peptides. According to this strategy, the treatment of N-Cbz phenylalanine H-phosphinic analogue (S)-66a [72] with TMSCl/DIPEA followed by addition of diethyl 2-methylenemalonate and subsequent alkaline hydrolysis, afforded the phosphinic pseudodipeptide (S)-95 in 67% yield, which was subjected to a Knoevenagel-type condensation with several aldehydes, to give the dehydrophosphinic peptides 96a-i in good yields (Scheme 40). Gegnas et al. [86] described the synthesis of the phosphinic pseudopeptide 99, which proved to be an inhibitor of the D-glutamic acid-adding enzyme (MurD) of bacterial peptidoglycan biosynthesis. The nucleophilic addition of compound (R)-97 [72] to 2-methylene pentanedioate in the presence of sodium methoxide provided the dipeptide isostere as a mixture of four diastereoisomers, which under hydrogenolysis over Pd/C catalyst in methanol provided the derivative 98 with the free amino group in 56% yield. Compound 98 was further transformed into the target pseudopeptide 99 in 2% overall yield through a six steps sequence, whose biological activity lied below the sensitivity of the enzyme assay used (<1 nM) (Scheme 41). Additionally, Yiotakis et al. [87] developed an Ireland-Claisen rearrangement triggered by the phospha-Michael addition of silyl phosphonites to allyl acrylates, as a new strategy to access pharmacologically relevant C-phosphinic derivatives. In this context, the reaction of Cbz-protected phenylalanine H-phosphinic analogue (R)-66a [72] with the acrylate in the presence of DIPEA in CH2Cl2 followed by addition of TMSCl at −78 °C, provided the P-alkylated α-amino-C-phosphinic acid (R)-100 in 52% yield with retention of configuration at phosphorus atom (Scheme 42). Gegnas et al. [86] described the synthesis of the phosphinic pseudopeptide 99, which proved to be an inhibitor of the D-glutamic acid-adding enzyme (MurD) of bacterial peptidoglycan biosynthesis. The nucleophilic addition of compound (R)-97 [72] to 2-methylene pentanedioate in the presence of sodium methoxide provided the dipeptide isostere as a mixture of four diastereoisomers, which under hydrogenolysis over Pd/C catalyst in methanol provided the derivative 98 with the free amino group in 56% yield. Compound 98 was further transformed into the target pseudopeptide 99 in 2% overall yield through a six steps sequence, whose biological activity lied below the sensitivity of the enzyme assay used (<1 nM) (Scheme 41). Gegnas et al. [86] described the synthesis of the phosphinic pseudopeptide 99, which proved to be an inhibitor of the D-glutamic acid-adding enzyme (MurD) of bacterial peptidoglycan biosynthesis. The nucleophilic addition of compound (R)-97 [72] to 2-methylene pentanedioate in the presence of sodium methoxide provided the dipeptide isostere as a mixture of four diastereoisomers, which under hydrogenolysis over Pd/C catalyst in methanol provided the derivative 98 with the free amino group in 56% yield. Compound 98 was further transformed into the target pseudopeptide 99 in 2% overall yield through a six steps sequence, whose biological activity lied below the sensitivity of the enzyme assay used (<1 nM) (Scheme 41). Additionally, Yiotakis et al. [87] developed an Ireland-Claisen rearrangement triggered by the phospha-Michael addition of silyl phosphonites to allyl acrylates, as a new strategy to access pharmacologically relevant C-phosphinic derivatives. In this context, the reaction of Cbz-protected phenylalanine H-phosphinic analogue (R)-66a [72] with the acrylate in the presence of DIPEA in CH2Cl2 followed by addition of TMSCl at −78 °C, provided the P-alkylated α-amino-C-phosphinic acid (R)-100 in 52% yield with retention of configuration at phosphorus atom (Scheme 42). Additionally, Yiotakis et al. [87] developed an Ireland-Claisen rearrangement triggered by the phospha-Michael addition of silyl phosphonites to allyl acrylates, as a new strategy to access pharmacologically relevant C-phosphinic derivatives. In this context, the reaction of Cbz-protected phenylalanine H-phosphinic analogue (R)-66a [72] with the acrylate in the presence of DIPEA in CH 2 Cl 2 followed by addition of TMSCl at −78 • C, provided the P-alkylated α-amino-C-phosphinic acid (R)-100 in 52% yield with retention of configuration at phosphorus atom (Scheme 42). Scheme 41. Synthesis of the phosphinic pseudopeptide 99 and its activity as inhibitor of the D-glutamic acid-adding enzyme (MurD) isolated from E. coli.
Additionally, Yiotakis et al. [87] developed an Ireland-Claisen rearrangement triggered by the phospha-Michael addition of silyl phosphonites to allyl acrylates, as a new strategy to access pharmacologically relevant C-phosphinic derivatives. In this context, the reaction of Cbz-protected phenylalanine H-phosphinic analogue (R)-66a [72] with the acrylate in the presence of DIPEA in CH2Cl2 followed by addition of TMSCl at −78 °C, provided the P-alkylated α-amino-C-phosphinic acid (R)-100 in 52% yield with retention of configuration at phosphorus atom (Scheme 42). On the other hand, the diastereoselective synthesis of Pro-Phe phosphinyl dipeptide isosteres was accomplished from optically active prolinephosphinate derivative (R,R P )-101 [88], which was obtained in 13 steps from 1,1-diethoxyethyl(hydroxymethyl)phosphinate via a lipase-catalyzed acylation [89]. Thus, the Michael addition of the H-phosphinate (R,R P )-101 to t-butyl acrylate in the presence of t-BuOMgBr in THF at 0 • C, provided the C-phosphinate (R,R P )-102 in 95% yield, which by treatment with LiHMDS followed by the addition of benzyl bromide in THF at −78 • C, produced the Pro-Phe phosphinyl dipeptide (R,R P ,R)-103 in 81% yield and 4.8:1 diastereoisomeric ratio (Scheme 43). On the other hand, the diastereoselective synthesis of Pro-Phe phosphinyl dipeptide isosteres was accomplished from optically active prolinephosphinate derivative (R,RP)-101 [88], which was obtained in 13 steps from 1,1-diethoxyethyl(hydroxymethyl)phosphinate via a lipase-catalyzed acylation [89]. Thus, the Michael addition of the H-phosphinate (R,RP)-101 to t-butyl acrylate in the presence of t-BuOMgBr in THF at 0 °C, provided the C-phosphinate (R,RP)-102 in 95% yield, which by treatment with LiHMDS followed by the addition of benzyl bromide in THF at −78 °C, produced the Pro-Phe phosphinyl dipeptide (R,RP,R)-103 in 81% yield and 4.8:1 diastereoisomeric ratio (Scheme 43).

Synthesis of Phosphacyclic α-Amino-C-phosphinates
Several strategies for the preparation of P-heterocycles have been described over the last years, and excellent reviews have been published [90][91][92][93]. In the past 20 years, significant effort has been devoted to synthetic and reactivity studies of this particular class of compounds, here we only report the stereoselective methods recently reported in the literature where the α-amino-C-phosphinate motif is incorporated.

Synthesis of Phosphacyclic α-Amino-C-phosphinates
Several strategies for the preparation of P-heterocycles have been described over the last years, and excellent reviews have been published [90][91][92][93]. In the past 20 years, significant effort has been devoted to synthetic and reactivity studies of this particular class of compounds, here we only report the stereoselective methods recently reported in the literature where the α-amino-C-phosphinate motif is incorporated.

Synthesis of Phosphacyclic α-Amino-C-phosphinates
Several strategies for the preparation of P-heterocycles have been described over the last years, and excellent reviews have been published [90][91][92][93]. In the past 20 years, significant effort has been devoted to synthetic and reactivity studies of this particular class of compounds, here we only report the stereoselective methods recently reported in the literature where the α-amino-C-phosphinate motif is incorporated.
Additionally, the reaction of tris(benzyloxy)-D-arabinofuranose 113 with allylamine or benzylamine in the presence of MgSO4 in EtOH at reflux, provided the cyclic hemiaminal ethers 117a,b in 70% yield, which by nucleophilic addition of ethyl phenylphosphinate and cyclization in the presence of catalytic amounts of potassium tert-butoxide, afforded the 3-alkylamino-1,2oxaphosphinanes 118a,b in 12% and 7% yield, respectively (Scheme 51) [98]. Scheme 51. Synthesis of 118a,b and its antiproliferative activities against glioblastoma cell line C6.

Conclusions
In this review, we have covered recent progress in the development of stereoselective methodologies for the synthesis of both acyclic and cyclic α-amino-C-phosphinic acids and derivatives. As we have shown, a number of optically active α-amino-C-phosphinic derivatives are now accessible through different strategies; however, there is still a long way to be covered, considering the poor availability of stereoselective methods for the preparation of pure stereoisomers of phosphinic peptides, taking into account that diastereoisomers with a particular three dimensional structure are able to interact efficiently with the receptor binding site, while other configurations are discriminated. Authors believe that much effort must be made in this direction and further advances in the search and improvement of synthetic procedures, new chemical applications and biological activities of these interesting compounds will be a very rewarding task in coming years.

Conclusions
In this review, we have covered recent progress in the development of stereoselective methodologies for the synthesis of both acyclic and cyclic α-amino-C-phosphinic acids and derivatives. As we have shown, a number of optically active α-amino-C-phosphinic derivatives are now accessible through different strategies; however, there is still a long way to be covered, considering the poor availability of stereoselective methods for the preparation of pure stereoisomers of phosphinic peptides, taking into account that diastereoisomers with a particular three dimensional structure are able to interact efficiently with the receptor binding site, while other configurations are discriminated. Authors believe that much effort must be made in this direction and further advances in the search and improvement of synthetic procedures, new chemical applications and biological activities of these interesting compounds will be a very rewarding task in coming years.