REGIOSELECTIVE SYNTHESIS OF (+)-GABACULINE HYDROCHLORIDE *G. Frater, U. Miller, U. Schopfer GIVAUDAN RESEARCH COMPANY LTD. Ueberlandstrasse 138 CH -8600 Diibendorf 3-CycZohexenecarboxyZicacid 121 has been functionaZiz5d to the preotected amino acid 5 in a novel reaction sequence, the crucial step being the acid cataZysed qcZizationof the y,6unsaturated isocyanate 3 to the bicyclic la&m 4. s was converted into gabaculine kydro---chloride I1 . HCZI. -Gabaculine (1) has been isolated by Mishima et al. _ l from Streptomyces toyocaensis. 1 a potent, irreversible inhibitor of y-aminobutyric acid-a-ketoglutaric acid transaminase iS (GABA-T)2. Three syntheses of 1 have been reported so far1~3~4 and iso-gabaculine has been _ prepared also5. Our strategy to synthesizel_ is based on our finding, that y,6 and S,E-unsaturated isocyanates undergo an acid catalyzed cyclization to 5 and 6-membered lactams, respectively.6 3-Cyclohexene-1-carboxylic acid (2) (Schemel)7 was converted to 1-isocyano-3-cyclohexene (3_) in 78,5% yield by the ethylchloroformate-NaNs-method*. Cyclization of 2 to 4 was carried out in PPA in 50% yieldg. Treatment of 4 first with thionylchloride in CHsOH and then with di-t. butyl-carbonate lo gave the protectedaminoacid E; (m.p. 55-560C; 85%). Bromination-dehydrobromination to 7 worked satisfactorily. -The stereochemistry of 5 (m.p. (pentane) 148-1490C) could be deduced from the NMR spectra: H(axial)-C(2) at 1,79 ppm, J(gem) s J(2,l) % J(2,3) s 12Hz; H-C(3) at 3,48 ppm, J(3,2 axial) Q 12, J(3,2 equa.) plr J(3,4) s 3Hz.