2-methylpiperidine, resolution

Discussion The starting point of the total synthesis of himbacine is the tartrate salt of (,S>2-mcthyI piperidine (3). This can be obtained from ( )-2-methylpiperidine using L-tartaric acid for resolution.5 3 is converted to (S)-/V-fert-butyloxycarbonyl-2-methylpiperidine (4) by treatment with... 

A. Vincze, L. Gefen, A. Fisher and P. Bel, Low resolution electron impact mass spectra of some quinuclidine and /V-methylpiperidine glycolates, J. Forens. Sci., 25(3), 655-665 (1980). 

Atkinson et al. used diastereomeric, enantiopure 3-diacylaminoquinazoline-4(3H)-ones (DAQs) for resolution of 2-methylpiperidine [49]. The N-N bond is an... 

The relative rates of faster reacting slower reacting amine enantiomers was shown to be 27 1, by a quantitative measure of each rate on pure enantiomers of 2-methylpiperidine. Interestingly, resolution with diastereomeric quinazoline 32b gave as the benzoylamide product the enantiomer of the above experiment, suggesting that the axis of chirality controls the enantiomer selectivity. For the use of similar quinazolines in enantiodivergent reactions, see Scheme 6.28. 

Another type of chiral quinazoline has been investigated by Atkinson in the resolution of racemic 2-methylpiperidine. Here, the chiral substituent is not present in the 2-quinazoline position but in the N-acyl groups [49]. Crystal structures of these compounds reveal their exo/endo conformation, and NMR experiments indicate that no conformational interconversion exo/endo-endo/exo takes place at room temperature, indicating a N-N axis of chirality. DAQ 33... 

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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