Stereoselective Synthesis of α‐Aminophosphonic Acids through Pudovik and Kabachnik‐Fields Reaction

Representative examples concerning the Pudovik and Kabachnik‐Fields reactions as the main strategies for the stereoselective synthesis of α‐aminophosphonic acids are dis ‐ cussed, classifying these reactions according to the chiral auxiliary and chiral catalyst. by treatment with N ‐bromosuccinimide (NBS), obtaining the ( S )‐α‐aminophosphonate 104 in 55% yield without racemization, which by hydrolysis of the phosphonate with HBr/AcOH followed by treatment with propylene oxide, led to the optically enriched ( S )‐phosphophenyl glycine 4 in 91% yield and 92% enantiomeric excess ( Scheme 36 ).


Introduction
Optically active α-aminophosphonic acids are the most important analogs of α-amino acids, which are obtained by isosteric substitution of the planar and less bulky carboxylic acid (CO 2 H) by a sterically more demanding tetrahedral phosphonic acid functionality (PO 3 H 2 ). Several αaminophosphonic acids have been isolated from natural sources, either as free amino acids or as constituents of more complex molecules [1], such as the phosphonotripeptide K-26 (Figure 1) [2].
The α-aminophosphonic acids, α-aminophosphonates, and phosphonopeptides are currently receiving significant attention in organic synthesis and medicinal chemistry as well as in agriculture, due to their biological and pharmacological properties. Additionally, the α-aminophosphonic acids are used as key synthetic intermediates in the synthesis of phosphonic acids, phosphonamides, and phosphinates, which not only play an important role as protease inhibitors but also in the wide range of biochemical pathways (Scheme 1) [3].
The inhibitory activity of the α-aminophosphonic acids and their derivatives has been attributed to the tetrahedral geometry of the substituents around the phosphonic moiety mimicking the tetrahedral high-energy transition state of the peptide bond hydrolysis, favoring the inhibition of a broad spectrum of proteases and ligases (Scheme 2) [4].
Furthermore, it is well known that the biological activity of the α-aminophosphonic acids and derivatives depends on the absolute configuration of the stereogenic α-carbon to phosphorous [5]. For example, (R)-phospholeucine is a more potent inhibitor of leucine aminopeptidase than the (S)-phospholeucine [6], and (S,R)-alaphosphalin shows higher antibacterial activity against both Gram-positive and Gram-negative microorganisms than the other three diastereoisomers [7]. Additionally, the L-Pro-L-Leu-L-Trp P tripeptide acts as an MMP-8 enzyme inhibitor, wherein the peptide responsible for the biological activity is that in which the three amino acids have L configuration (Figure 2) [8].  In view of the different biological and chemical applications of the α-aminophosphonic acids, nowadays the development of suitable synthetic methodologies for their preparation in optically pure form is a topic of great interest and many reviews have been recently published concerning their stereoselective synthesis [9]. In this context, Pudovik and Kabachnik-Fields reactions the main synthetic strategies for the stereoselective synthesis of α-aminophosphonic acids will be described in this chapter.

Stereoselective C-P bond formation (Pudovik methodology)
The diastereoselective and enantioselective hydrophosphonylation of aldimines and ketimines, called as the Pudovik reaction, involves the addition of a phosphorus nucleophile agent over the corresponding imine, in such a way that one or both of the reactants can incorporate a chiral auxiliary or nonchiral reagents may be reacted in the presence of a chiral catalyst (Scheme 3).

Chiral phosphorus compounds
One of the general methods for the synthesis of α-aminophosphonic acids involves the diastereoselective hydrophosphonylation of achiral imines with chiral phosphites to introduce the phosphonate function, which by hydrolysis afforded the optically enriched α-aminophosphonic acids. For example, the nucleophilic addition of chiral C 3 -symmetric trialkyl phosphite 2, obtained from the naturally occurring (1R,2S,5R)-(-)-menthol to the aldimine 1 in the presence of trimethylsilyl chloride (TMSCl) as an activator, provided the α-aminophosphonate 3 in 60% yield and moderate induction at the α-carbon atom (50% diastereoisomeric excess), which by hydrolysis with HCl in dioxane, followed by catalytic hydrogenolysis using Pd/C, produced the (R)-phosphophenyl glycine 4 in 70% yield and with 95% enantiomeric excess (Scheme 4) [10].
Additionally, the (R,R)-TADDOL framework has also proved its usefulness as a chiral auxiliary in the diastereoselective addition of Grignard reagents to chiral α-aminophosphonates.
The Pudovik reaction has also been reported incorporating the chiral auxiliary attached not only to the phosphite residue, but also to the imine fragment. As a proof of concept, Olszewski and Majewski [13] reported the hydrophosphonylation reaction of (S)-N-tert-butylsulfinylaldimines 14a-d with readily available chiral (R,R)-TADDOL phosphite 5 in the presence of potassium carbonate in CH 2 Cl 2 at room temperature, obtaining the α-aminophosphonates 15a-d in 80-87% yield and diastereoisomeric ratio (>95:5 d.r.). Simultaneous removal of both chiral auxiliaries in 15a-d by hydrolysis with 4 M HCl at 100°C, produced the (R)-α-aminophosphonic acids 4, 16a-c in 78-92% yield (Scheme 7).

Imines from chiral carbonyl compounds
The hydrophosphonylation of chiral Schiff bases is another general method for the synthesis of optically enriched α-aminophosphonates, which can be performed by addition of alkyl phosphites to chiral imines readily obtained by condensation of chiral aldehydes with nonchiral

Imines from chiral amino compounds
On the other hand, the stereoselective hydrophosphonylation of chiral Schiff bases can also be conducted by addition of alkyl phosphites to chiral imines readily obtained by condensation of nonchiral aldehydes with chiral amines. Additionally, the (R)-α-aminophosphonic acid 4 was obtained also starting from the aldimine (R)-26c.
The readily available chiral sulfinimides [19] containing an aryl-or tert-butylsulfinyl moiety represent valuable chiral auxiliaries in stereoselective synthesis [20]. In this regard [21], the nucleophilic addition of the lithium salt of the diethyl phosphite to the enantiopure imine (S)-32a [22,23], readily obtained by condensation of (S)-p-toluenesulfinamide with benzaldehyde gave the α-aminophosphonate (S S ,R C )-33a in 85% yield and 92:08 diastereoisomeric ratio. When the lithium salt of bis(diethylamido) phosphite was reacted with (S)-32a, the α-aminophosphonate (S S ,S C )-33b was obtained in good yield and diastereoselectivity [24]. Cleavage of the chiral auxiliary and hydrolysis of the diethyl phosphonate and diamidophosphite in (S S ,R C )-33a and (S S ,S C )-33b with hydrochloric acid in acetic acid at 100°C led to the enantiomerically pure (R)-and (S)-phosphophenyl glycine 4 (Scheme 13).
Mikolajczyk et al. [25] reported The N-tert-butylsulfinyl group activates the imines for the nucleophilic addition, serves as a powerful chiral directing group and after the addition reaction is readily cleaved upon treatment of the product with acid. Competitive nucleophilic attack at the sulfur atom is minimized in the addition to N-tert-butylsulfinyl imines versus N-p-tolylsulfinyl imines, due to the greater steric hindrance and reduced electronegativity of the tert-butyl group relative to the p-tolyl moiety [28]. Under this context, reaction of the chiral N-tert-butylsulfinyl imines (S)-43a-e with dimethyl phosphite in the presence of K 2 CO 3 in Et 2 O at room temperature gave the α-aminophosphonates (S S ,R C )-44a-e in 80-85% yield and with >95% diastereoisomeric excess, which by simultaneous cleavage of the sulfinyl group and hydrolysis of the diethyl phosphonate with 10 N HCl at reflux, followed by treatment with propylene oxide, produced the (R)-α-aminophosphonic acids 13, 38a, 45a-c in 83-88% yield (Scheme 17) [29].
On the other hand, the sugar-derived nitrones have also emerged as valuable synthetic intermediates in the stereoselective synthesis of α-aminophosphonic acids. For example, the hydrophosphonylation reaction of the nitrones 53a-c with the lithium salt of diethyl or dibenzyl phosphite, provided the N-glycosyl-α-aminophosphonates 54a-c in 41-63% yield and 90-98.7% diastereoisomeric excess, which by hydrolysis of the sugar fragment and the phosphonate with concentrated HCl and subsequent cleavage of the N-OH bond by hydrogenation using Pd/C, afforded the optically enriched α-aminophosphonic acids (S)-16a, 55a,b in 36-80% yield. Additionally, the nucleophilic addition of tris(trimethylsilyl) phosphite to the enantiomerically pure nitrone 53c in the presence of HClO 4 followed by hydrolysis of the sugar fragment and the phosphonate, led to the N-hydroxyphosphovaline (R)-56 in 78% yield, which by hydrogenation of the N-OH bond and treatment with 1 N HCl, gave the (R)-Val P 16a in 71% yield and 95.4% enantiomeric excess (Scheme 20) [32].
Huber and Vasella [33] reported the synthesis of optically enriched (S)-Val P 16a and (S)-Ser P 55b from the enantiopure nitrones 53a,b with a slight modification of the reaction conditions. Thus, the nucleophilic addition of tris(trimethylsilyl) phosphite to the sugar-derived nitrones 53a,b catalyzed by ZnCl 2 /HCl afforded directly the corresponding α-aminophosphonic acids (S)-16a, 55b in good yield and with 43.8 and 87.7% enantiomeric excess, respectively (Scheme 21).
Similarly, the addition of tris(trimethylsilyl) phosphite to the enantiopure nitrone 57 in the presence of Zn(OTf) 2 at −40°C and subsequent treatment with 1 N HCl in MeOH, led to the N-hydroxy-α-aminophosphonic acid (R)-58 in 71% yield, which by cleavage of the N-OH bond by hydrogenation using Pd(OH) 2 /C, provided the (R)-Met P 31c in 88% yield and 76.8% enantiomeric excess (Scheme 22) [33]. Scheme 20.

Chiral catalyst
Catalytic asymmetric synthesis is one of the most important topics in modern synthetic chemistry and is considered the most efficient methodology to bring about the synthesis of enantiomerically pure compounds [34]. For example, the hydrophosphonylation reaction of N-sulfonylaldimine 59 with diphenyl phosphite in the presence of catalytic amounts of hydroquinine gave the (S)-α-aminophosphonate 60 in quantitative yield and excellent enantiomeric excess (>99%). Cleavage of the N-sulfonyl group in (S)-60 by treatment with Mg in AcOH/AcONa and N,N-dimethylformamide (DMF) afforded the (S)-α-aminophosphonate 61 in 86% yield, which by hydrolysis of the diphenyl phosphonate with HBr in acetic acid followed by treatment with propylene oxide, produced the (S)-phosphophenyl glycine 4 in 83% yield and 98% enantiomeric excess (Scheme 23) [35].
In order to obtain the optically enriched (R)-phosphophenyl glycine 4, Wang et al. [36] carried out the nucleophilic addition of diethyl phosphite to the N-benzoylimine 62 in the presence of catalytic amounts of (S,S)-63 and ZnMe 2 , obtaining the (R)-α-aminophosphonate 64 in 91% yield and >99% enantiomeric excess. Simultaneous hydrolysis of the diethyl phosphonate and N-benzoyl group in (R)-64 with concentrated HCl at reflux, produced the optically enriched (R)-phosphophenyl glycine 4 in 96% yield (Scheme 24).
On the other hand, Joly and Jacobsen [37] reported that the addition of di(o-nitrobenzyl) phosphite to the achiral N-benzyl aldimines 1, 65a,b in the presence of catalytic amounts of the chiral urea 66, produced the (R)-α-aminophosphonates 67a-c in 87-93% yield and 90-98% enantiomeric excess. Finally, the simultaneous cleavage of the di(o-nitrobenzyl) phosphonate

Stereoselective C-P bond formation (Kabachnik-Fields methodology)
Another important method for the stereoselective synthesis of α-aminophosphonic acids is the "one-pot" three-component reaction, known as the Kabachnik-Fields reaction. In this process, the reactants (carbonyl compound, amine and the phosphorus nucleophile agent) are placed all together to give the diastereo or enantiomerically pure α-aminophosphonates, which are easily transformed into the corresponding α-aminophosphonic acids. To induce the stereochemistry in the α-aminophosphonates, the chirality inducer may be at the source of phosphorus, in the amine, in the aldehyde or ketone, or in a chiral catalyst. Additionally, the reactions are carried out in solvent or under solvent free conditions (Scheme 27).
On the other hand, Xu and Gao [40] carried out the stereoselective synthesis of the depsiphosphonopeptides 76 and 77, as key intermediates in the synthesis of α-aminophosphonic acids.

Chiral catalyst
The development of methodologies under chiral catalysis protocols has become one of the most relevant issues in the field of modern synthetic chemistry [46]. In this respect, List et al. [47] described the Kabachnik-Fields reaction of 2-cyclopentyl-2-phenylacetaldehyde, p-anisidine and di-(pent-3-yl) phosphite in the presence of catalytic amounts of the chiral phosphoric acid (S)-99 in cyclohexane at 50°C, obtaining the (R,R)-α-aminophosphonate 100 in 86% yield with both high diastereoisomeric and enantiomeric ratio. Removal of p-methoxyphenyl fragment with cerium ammonium nitrate (CAN) followed by the hydrolysis of the diethyl phosphonate in (R,R)-100 with TMSBr, produced the optically enriched (R,R)-α-aminophosphonic acid 101 in 54% yield (Scheme 35).