ENDOGENOUS NATRIURETIC FACTORS .6. THE STEREOCHEMISTRY OF A NATRIURETIC GAMMA-TOCOPHEROL METABOLITE LLU-ALPHA

2,7,8-Trimethyl-(S)-2-(beta-carboxyethyl)-6 chroman (S-LLU-alpha) isol ated from human uremic urine is apparently an oxidative side-chain deg radation product of gamma-tocopherol. This compound exhibits natriuret ic activity in vivo and it appears to mediate the inhibition of the 70 pS K+ channel in the apical membrane of the thick ascending limb of t he nephron. The stereochemistry at the C-2 of LLU-alpha has been unequ ivocally established to be S(+) by X-ray crystallographic analysis of a diastereomeric amide derivative. It was also established that the ch roman ring oxidation of S-LLU-alpha proceeded without racemization at C-2. This finding can be extended to nonepimerization at C-2 of alpha- 6 tocopherols (Vitamin E) during side-chain oxidation and stereospecif icity (retention or inversion) of oxidative opening of the chroman rin g. The resolution of the enantiomers of the parent compound and deriva tives was accomplished by chiral high-performance liquid chromatograph y. The stereospecific enzymatic hydrolysis by an array of commercially available enzymes of the racemic methyl ester of LLU-alpha was invest igated. The lipase from Humicola languinosa appears to be the best enz yme for resolution by selective hydrolysis of the racemic methyl ester .