Piperidine derivatives resolution

As in the case of the piperidine derivatives, azepine drugs in complex with protein were searched for in the PDB using the MSD server. Since the number of hits was very low no resolution criteria was used for this search that yielded one each in azepin and benzothiazepine and five in fused-diazepine (Table 6). 

Earlier in this chapter we described the resolution of the piperidine 8 by classical resolution. The Bristol-Meyers Squibb company also investigated an enzymatic resolution.3 Various esterases and lipases had been used before on various derivatives of 8 but none was efficient. Two methods were successful. Accurel PP, a lipase immobilised on polypropylene, resolved the N-Cbz derivative 10 to give 46% yield of (/ )-(-)-10 with 99.4% ee. Unfortunately this is not the wanted enantiomer and the ester (5)-(+)-144 could be isolated only by chromatography. 

The piperidine precursor 56 to 1-deoxymannojirimycin is obtained by the kinetic resolution of the a-furfuryl amine derivative using Sharpless epoxidation conditions <97JCS(P1)741>. 

Conversion of piperidin-2-one to the cjco-cyclic enaminone by the Tebbe reaction allows the synthesis of the pipecolic acid derivative <97TA1115>. Enzymatic resolution of 3-hydroxy-... 

We found that the kinetic resolution of racemic piperidines alkylated at the 2- or 3-p>osition was performed using the provisional enantiomeric conformation of naphthamide 3a derived from chiral crystals. ) Chiral crystals of naphthamide 3a were added to a THF solution of racemic lithium amides prep>ared by the reaction of substituted piperidines with w-BuLi at -80°C the reaction mixture was stirred for 5 hours at -20°C because the substitution reaction did not proceed below -20°C. 

Various chiral imidazoles and triazoles were therefore tested in the KR of 2-methylpiperidine however, Uttle or no enantioselectivity was observed. Fortunately, after screening various co-catalysts, chiral hydroxamic acids [134], in particular the as-(lR,2S)-aminoindanol-derived hydroxamic acid 145, were found to give excellent results at room temperature. Finally, further optimization of the catalytic resolution conditions, including the use of mesityl-substituted a-hydroxyenone 144 to deter N-heterocychc carbene (NHC)-catalyzed side reactions [135], led to the effective KR of various 2-substituted piperidines with selectivity factors ranging from s = 12 to 23 (Scheme 41.59). 

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