1650 J . Org. Chem., Vol. 42, No. 9, 1977
Notes
Synthesis and Absolute Configuration of the Optically Active Forms of 2-[ Bis(2-chloroethyl)amino]-4-methyltetrahydro2H- 1,3,2-oxazaphosphorine 2-Oxide (4-Methylcyclophosphamide)
crotonate (3) with (-)-l(S)-phenylethylamine [4(S)]gave the separable diastereoisomers of ethyl 3-N-[1(S)-methylbenzyllaminobutyrate ( 5 ) having readily determinable absolute configurations a t the newly introduced asymmetric carbon atom (C-3).5 These were reduced in two stages to give the requisite enantiomers of 3-aminobutan-l-01(7).Condensation Ryszard Kinas, Krzysztof Pankiewicz, and Wojciech J. Stec* bis(2-chloroethyl) of each of these enantiomers with N,Nphosphoramidic dichloride gave in each case a mixture of two Polish Academg of Sciences, Centre of Molecular and Macromolecular Si udies, 90-362-E6di,Boczna 5, Poland separable isomers of 4-methylcyclophosphamide, designated “fast” and “slow” according to their relative mobilities on Peter B Farmer, Alan B Foster, and Michael Jarman TLC. Since the absolute configuration of the starting mateChester Reattg Research Institute, Institute of Cancer Research, rials 7 is known, the four enantiomeric 4-methylcyclophosRoyal C a w e r Hospital, Fulham Road, phamides have predetermined configurations a t C-4. London S W 3 6 J B ,England Determination of the absolute configurations a t phosphorus for the pairs of diastereoisomers 2 for which the absolute Received September 9,1976 configuration at C-4 is known is equivalent to the assignment of cis and trans geometry to the “fast” and the “slow” isomers The cytochrome 1’450 mediated oxidation of the antitumor agent 2-[bis(2-chloroethyl)amino]tetrahydro-2H-l,3,2-oxa- 2. Contrary to the assignments made by Struck et al.4 for the faster migrating racemic 2 (mp 72-74 OC) and the slower mizaphosphorine 2-oxide (cyclophosphamide 1) to give the 4grating racemic 2 (mp 102 “C) we assign, taking the example hydroxy derivative is well documented1 and has prompted of the fast and the slow products derived from 3-(R)-aminomany detailed investigations.2 4-Methylcyclophosphamide butan-1-01, the spatial arrangement 4-Meeq-2NR2eq(trans) (2) is of interest since the methyl group prevents further oxito the slower migrating 2 (and hence the configuration 2S,4R) dative metabolism of the 4-hydroxy d e r i ~ a t i v eThe . ~ isolation and 4-Meeq-2NR2,, e 4-Meax-2NR2eq(cis) to the faster miand configurational assignment of the cis and trans forms of grating 2 (2R,4R) on the basis of the following arguments: (1) 4-methylcyclophosphamide (2) has been described recently NMR spectrum ( h p 2 (2S,4R) absorbs at lower field in its by Struck et al.4 We now report evidence which indicates that -13.5 ppm, external H3P04) than 2 (2R,4R) ( h p -11.0 these configurational assignments are erroneous and also pprn)$, (2) 2(2S,4R) exhibits a lower up0 value (1218 cm-’ in describe the synthesis of the optically active forms of cis- and trans- 4-methylcyclop hosphamide. Scheme I1 The synthesis of the four optically active forms of 4-methH ylcyclophosphamide (2) was based on (+)- and (-)-3-amiI nobutan-1-01 (7)as depicted in Scheme I. Treatment of ethyl Scheme I CH,CH=CHCOOC,H,
3
+
,H CH,
