The piperidine unit is an extremely important pharmacophore that can be found in many natural and synthetic bioactive compounds.
Our group is a major supplier for piperidines with over 60 different chiral and achiral piperidines manufactured from small scale to tons.
We have been recently interested in the synthesis of R and S 3-amino-piperidines which are valuable intermediates for the synthesis of launched as well as under development pharmaceuticals such as alogliptin or linagliptin.
Asymmetric hydrogenation is one of the most efficient methods for the preparation of chiral compounds. Furthermore, pyridines are either commercially available or readily prepared using various methods, making them the starting material of choice in the synthesis of chiral piperidines. Tremendous success has been achieved in the reduction of C=C, C=O and C=N fonctions. However enantioselective hydrogenation of aromatic compound is still a challenge. Some good enantioselectivities have been reported in the hydrogenation of furans, pyrroles, indoles and quinolines but up to now only few examples of enantioselective reduction of pyridines are described.
In 2000, Hegedus et al. reported the stereoselective reduction of chiral nicotinamides with Pd/C. Glorius et al. used a similar approach. Starting from a chiral oxazolidinone substituted pyridine they prepared chiral piperidines in one step by reduction with Pd(OH)2, the oxazolidine moiety being cleaved during the reaction. Later, Charette et al. described the iridium catalyzed asymmetric hydrogenation of N-iminopyridinium ylides. More recently, Zhang and Lei used a sequential of combination of heterogenous (Pd/C) and homogenous (Rh-Tangphos) hydrogenation for the synthesis of nipecotic acid derivatives. Rueping et al. described the organocatalytic enantioselective reduction of pyridines to tetrahydropyridines using a chiral BrØnsted acid as catalyst.
In order to synthesize R and S 3-amino-piperidines, we decided to develop a new approach. Our route is a combination of conventional and new chemistry. In the first part of the synthesis, we convert the 3-amino-pyridine 1 to the protected 1,2,5,6-tetrahydro-pyridine 2 which is subsequently reduced enantioselectively to give the piperidine 3.
Starting from 3-amino-pyridine we have been able to prepare the enamine 2 with an overall yield of more than 80% using conventional chemistry.
We have then developed a new high yielding (≥ 90%) and highly enantioselective (ee ≥ 95%) hydrogenation of 2. This method gives access to unprotected R or S 3-amino-piperidine (free base or salt), as well as protected on any of the two nitrogen atoms. It can be extended to the synthesis of other substituted piperidines from the parent pyridine.