First total synthesis of N-4909 and its diastereomer; a stimulant of apolipoprotein E secretion in human hepatoma Hep G2 cells.

Both (R)- and (S)-3-hydroxy-13-methyltetradecanoic acids were prepared via a lipase-catalyzed enantioselective acylation. The total synthesis of N-4909 and its diastereomer were achieved by a coupling of either (R)- or (S)-3-hydroxy-13-methyltetradecanoic acid moiety with a hexapeptide moiety and by a cyclization with HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) and HOAt (1-hydroxy-7-azabenzotriazole) in a high dilution condition. The R configuration of 3-hydroxy-13-methyltetradecanoic acid was found to be important for stimulating the activity of apolipoprotein E secretion in human hepatoma Hep G2 cells.