Acylphosphonates reduction

A useful approach for the preparation of chiral (3-aminophospho-nic acids from the naturally occurring a-amino acids has been reported.139 The overall scheme (Equation 3.4) involves formation of the phthalimide-acid halide from the starting a-amino acid followed by a Michaelis-Arbuzov reaction with triethyl phosphite to give the acylphosphonate. Complete reduction of the carbonyl group in three steps followed by hydrolysis of the ester and amide linkages provides the target material in very high yield without racemization (>99% ee). 

An obvious synthetic application of amine addition to the a-keto group in acylphosphonates would be reductive amination. This has been demonstrated [42], and shown to be a useful route to 1-aminoalkylphosphonic acids. Thus, selected acylphosphonates were reacted with benzhydrylamine, giving after reduction of the resulting imine intermediate with triacetoxyborohydride and acid hydrolysis, satisfactory yields of the corresponding aminoalkylphosphonic acids. However, a limitation of this approach is unwanted cleavage of the phos-phonate P-C bond, which was observed with other amines such as benzylamine and a-benzylmethylamine [42]. 

LTBA can also cleave selectively the P—C bond of acyl phosphonates 2.58, while preserving other functional groups [DSl] (Figure 2.28). Nevertheless, the reduction of similar compounds such as 2.59 by NaBH4 in EtOH buffered by boric acid does preserve the P—C bond and leads to diastereomeric a-phosphorylated alcohols [BS5, DSl] (Figure 2.28). After enolization by NaH, the P—C bond cleavage of acylphosphonates (Et0)2P(0)CH2C0R can be realized with LAH [HS7]. 

One example of reductive amination of acylphosphonates has been reported. Thus, reaction of dimethyl 1-oxoalkylphosphonates with benzhydrylamine results in the formation of an imine reduced in situ with NalllKOAc),. The reaction is independent of the solvent, and THF, CIFCh and CHCI3 give similar results - After selective removal of the benzhydrylic group by catalytic hydrogenation and hydrolysis with concentrated HCl, the 1 -aminoalkylphosphonic acids are isolated in satisfactory yields (30-60%, Scheme 7.66) ... 

NaBH3CN,5" BH3 MciS,-" calecholhorane," Al(O/ -Pr)3, ° or activated Zn in AcOH.5°5 Reduction of acylphosphonates using NaBH4 needs careful control of the reaction conditions (H2O or MeOH, KH2PO4, 0-5°C, pH = 6-7) to avoid hydrolysis of both starting acylphosphonates and reaction... 

Acylphosphonic acids react with pyridoxamine, which is a coenzyme of transaminases, with the formation of a-aminophosphonic acids (see also reductive amination. Section II. C. 4. c) The first step of the reaction is addition of the pyridoxamine to the carbonyl of the acylphosphonate, followed by prototropic rearrangement and hydrolysis to pyridoxal and an aminophosphonic acid (equation 59). This reaction is in contrast with the reverse... 

Reduction of the benzoylphosphonate anion and its monomethyl ester by sodium borohydride gave the corresponding a-hydroxyphosphonates Reduction of an a,j5-unsat-urated acylphosphonate by sodium borohydride under carefully controlled conditions (0-5 °C, pH 6-7) was one of the possible synthetic routes to the corresponding a-hydroxy a,y-unsaturated phosphonates, which served as starting materials towards 3-aminoalk-l-enylphosphonic acids (equation 77). ... 

As already mentioned, the selective reduction of the add stage down to the aldehyde can be accomplished by reduction of an acylphosphonic ester 189. Based on this fact a synthesis of permethric acid is proposed, which comprises several typical synthetic advantages of Homer-Hoflfmann phosphonic acid reagents of ready accessibility (Reaction scheme 118). In fact, the trans-caronaldehyde adduct of diethylphosphite... 

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