ABSOLUTE-CONFIGURATION OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANOL FORMED METABOLICALLY FROM 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is an important m etabolite of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK). Using the chiral derivatizing agent, (R) -(+)-alpha-methylbenzyl isocyanate [(R)-(+)-MBIC], previous work has s hown that the enantiomeric ratio of metabolically formed NNAL and its glucuronide derivative may be species dependent. However, the absolute configuration of such NNAL has not been previously reported. Syntheti cally prepared racemic NNAL was converted to diastereomeric esters by reaction with (R)-(+)- and -alpha-methoxy-alpha-(trifluoromethyl)pheny lacetic acid (MTPA) chloride (Mosher's reagent) and the products were characterized by H-1-NMR. Based on chemical shift data, the absolute c onfiguration of NNAL in each diastereomeric ester was assigned. Hydrol ysis of (R)-NNAL-(R)-MTPA gave (R)-NNAL, This was converted to the cor responding carbamate by reaction with (R)-(+)-alpha-MBIC and the absol ute configurations of the diastereomeric carbamates formed by reaction of(R)- and (S)-NNAL with (R)-(+)-MBIC were thereby assigned. Conversi on of metabolically produced NNAL to the same carbamates allowed us to assign the NNAL formed from NNK by rat liver microsomes as (R)-NNAL. The major and minor NNAL-glucuronide diastereomers found in the urine of patas monkeys and humans exposed to NNK were similarly assigned; th ey were formed from (R)NNAL and (S)-NNAL, respectively.