A-Aminophosphinic acids

Campbell, M.M. and Carruthers, N., Synthesis of a-aminophosphonic and a-aminophosphinic acids and derived dipeptides from 4-acetoxyazetidin-2-ones, Chem. Commun., 730, 1980. 

Nucleophilic addition of methyl- or phenylphosphite n -butyl- esters to oxo-imine salts, generated by nitrone alkylation of triethyloxoniumtetrafluoro borate (Meerwein salt), leads to a-aminophosphinic acid esters (Scheme 2.201) (691). 

FIGURE 1.28 Chromatograms of the HPLC enantiomer separation of Z-protected a-aminophosphinic acids (a,b) and phosphinic acid-ilr-dipeptide (c) on (a and b) a 0-9-(tert-butylcarbamoyl)quinidine CSP and (c) corresponding 0-9-(fcrr-butylcarbamoyl)qninine-CSP, respectively. Experimental conditions Column dimensions, 150 mm x 4 mm ID mobile phase, methanol-50 mM sodium phosphate buffer (80 20 v/v) (pHa 5.6) temperature, 40°C flow rate, 1 mLmin detection, UV at 250 nm and optical rotation detection (ORD). (Reproduced from M. Lammerhofer et ah, Tetrahedron Asymmetry, 14 2557 (2003). With permission.)... 

Table 1 Selected Z-a-aminophosphinic acid derivatives and their corresponding mass spectral data. The equivalent E-a-analogs were also isolated. H-NMR for both E,Z-isomers supplied by author...

All types of surfactants promote the reaction but only the hydrogensulfate was successful in the case of cationic amphiphiles. Sometimes the enantioselectivity surpassed the values observed when methanol was used as a solvent. This method was even used successfully for the enantioselective hydrogenation of a-aminopho-sphonic [14] and a-aminophosphinic acid precursors [15]. The concentration of the surfactant leads to an efficient reaction only above the CMC. 

Janecki. T.. A novel route to substituted trienes and teti aenes. Synth. Commun., 23, 641, 1993. Campbell. M.M.. and Carrulhcrs. N.. Synthesis of a-aminophosphonic and a-aminophosphinic acids and derived dipeptides from 4-acetoxyazetidin-2-ones. J. Chem. Soc., Chem. Commun., 730, 1980. Campbell. M.M.. Carruthcrs. N.I.. and Mickel. S.J.. Aminophosphonic and aminophosphinic acid analogues of aspai tic acid. Tetrahedron, 38. 2513. 1982. 

Bis(trimethylsilyl) phosphonite. The reaction with ammonium phosphinate gives (MejSiO)2PH, which is reactive toward unactivated alkyl halides and imines. Accordingly, alkylphosphinic acids and a-aminophosphinic acids are more readily accessible. ... 

Kaboudin et al. have developed a simple and efficient method for the synthesis of a-aminophosphinic acids (577) in reaction of aromatic aldehydes (576) with ammonia solution and hypophosphorus acid in good yields (40-71%). Novel C2-symmetric phosphinic acid pseudodipeptides (578) have been also synthesized by the Michael addition of (577) to methyl acrylate (Scheme 141). 

Chen et al. have described a convenient and efficient synthetic protocol for preparation of a-aminophosphinic acid derivatives (583) in high yields and high enantiostereoselectivity, utilizing SnCU as the promoter and O-pivaloylated D-galactosylamine in (582) moiety as a chiral auxiliary by means of a Mannich-type reaction (Scheme 143). 

Scheme 4 Diastereoselective synthesis of a-aminophosphinic acids by Yamagishi et al. [39,40] (Ts 4-toluenesulfonyl)...

Scheme 6 NP-fC strategy associated with a-aminophosphinic acid preparation by (a) Borloo et al. [35] and (b) Cristau et al. [43, 44]...

Preparation of the acyclic phosphinic analogues 23 to Ciluprevir consisted of a peptide coupling between a-aminophosphinic acid 21 [32] and dipeptide 22 [36]. The a-aminophosphinic acid 20 was accessible from enantiopure precursor 19 (synthesis described by Pyun et al. [37] or Sheng et al. [38]), applying a synthetic sequence of five steps (Scheme 3). After coupling, a series of compotmds 23 harbouring various R groups (Ph, Me, Et, -Bu, i-Pr, Bn and mono- and disubsti-tuted benzyl derivatives) were obtained [32]. 

Continuing their rational design, Jiracek and al. described a-aminophosphinic acids 239, 240, structurally close to compounds 235 and 237 [161]. Each structure was obtained in 56-64% yield, by mixing ethyl 5-bromovalerate or ethyl 5-bromo-3,3-dimethylpentanoate with phosphinomethionine 238 in the presence of sodium and ammonia (Scheme 46). The //-phosphinic acid intermediate 238 was readily accessible by a sequence of three steps from acrolein [162-164]. 

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