1,3,2-Oxazaphosphinane analogs of phosphorylacetic acid derivatives: synthesis and properties

Abstract

Reactions of 2 AlkO 1,3,2 oxazaphosphinanes with alkyl N haloacetylamino or N chloro methyl N methoxycarbonylamino carboxylates mainly give products with retention (Alk = Me) and opening of the ring (Alk = Et). In aqueous solution, cyclic products with the N isopropyl group are only stable, while the rest undergo hydrolysis with cleavage of the P-N bond of the ring. Oxazaphosphinane analogs of phosphorylacetamide and phosphorylacetohydrazide were synthesized.Key words: 2 alkoxy 1,3,2 oxazaphosphinanes, 2 alkoxy 3 alkyl 1,3,2 oxazaphosphinanes, the Arbuzov rearrangement, alkyl haloacetylamino carboxylates, N chloromethyl N methoxy carbonylglycine methyl ester, N [(2 oxo 1,3,2λ 5 oxazaphosphinan 2 yl)acetyl]glycine methyl ester, hydrolysis, alkyl N [(3 alkyl 2 oxo 1,3,2λ 5 oxazaphosphinan 2 yl)acetyl]amino carboxy lates, N {[(3 bromopropylamino)ethoxyphosphoryl]acetyl}glycine methyl ester, N [(3 isopro pyl 2 oxo 1,3,2λ 5 oxazaphosphinan 2 yl)methyl] N methoxycarbonylglycine methyl ester,Earlier, 1 we have described synthesis of 1,3,2 oxaza phosphinane analogs of phosphorylacetates with poten tial biological activity, in which, by analogy with carcino lytic cyclophosphamide, the oxazaphosphinane ring plays the role of a "carrier" of a pharmacophoric group to a cell through cell membranes. 2 It is known that condensation products of phosphorylacetic acid and amino acids, e.g., with aspartic acid (PALA preparation), are strong carcino lytics 3 and the corresponding hydrazides exhibit anti amnestic, antihypoxic, and antidepressant activities. 4 In connection with this, it was of interest to synthesize a series of 1,3,2 oxazaphosphinane analogs of these and some structurally related compounds.1,3,2 Oxazaphosphinane analogs of phosphorylacetic acid containing fragments of amino acid esters were syn thesized by the Arbuzov reaction described in detail for the reactions of 2 alkoxy 3 alkyl 1,3,2 oxazaphosphin anes (1) with bromoacetates. 1 In the present work, com pounds 1 reacted with alkyl N haloacetylamino carboxy lates (2) (Scheme 1).Reactions with N bromoacetyl derivatives were car ried out in benzene at 20-50 °C, while those with N chloroacetyl derivatives, in toluene at 100-110 °C. As with bromoacetates, 1 the reactions gave cyclic (3) and acyclic products (4). According to 31 P NMR data, their ratio is virtually independent of the nature of the substitu ent R 1 at the N atom in oxazaphosphinanes 1 but is deter mined by the substituent R 2 in the alkoxy group (Table 1). For instance, for R 2 = Me, cyclic products are dominant (the ratio 3 : 4 varies from 93 : 7 to 86 : 14), while for R 2 = Et, the major product is an acyclic one (3 : 4 = 25 : 75)*. For pairs of compounds 3f, 4g and 3g, 4h, the 31 P NMR spectra in benzene show doubled signals due to diastereomeric anisochronism.The use of oxazaphosphinane 1d in the Arbuzov reac tion with N chloromethyl N methoxycarbonylglycine methyl ester (5) (Scheme 2) afforded cyclic (6) and acy clic products (7) in the 82 : 18 ratio ( 31 P NMR).In this case, the 31 P NMR spectrum...