Cycloaddition of the (fluoroalkyl)imines 7a-c with the ketene formed in situ from (benzyloxy)acetyl chloride and triethylamine provided stereoselectively cis-(fluoroalkyl)azetidinones 5a-c in moderate yields. The corresponding N-Boc-isoserinates 11a-c and protected synthons 12a-c have been prepared from these azetidinones 5a-c. Cycloaddition of the chiral imine 18 (R F ) CF 3 ) with the same ketene led to the diastereoisomeric azetidinones 19 and 20 with a poor diastereoisomeric excess (10-20%). However, the two diastereoisomers could be easily separated by crystallization and provided enantiomerically pure N-Boc-isoserinates 23 (R,R) and 23 (S,S) after ring opening and debenzylation.

Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.

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anti-(Trifluoromethyl) β-amino alcohols 2 have been prepared in good yields and with 90% diastereoisomeric excess through a reaction of 1-(trifluoromethyl) epoxy ethers 3 with dimethylaluminum amide, followed by the in situ chelation-controlled stereoselective reduction of the intermediate amino ketone. The salen-mediated chiral epoxidation of 1-(trifluoromethyl) enol ether 4a led to the homochiral epoxy ethers 11a and 12a in a good enantiomeric excess. Reaction with dimethylaluminum amide followed by a reduction step provided the chiral amino alcohols 15a and 16a, respectively.

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