Asymmetric Synthesis Of Bioactive Piperidines

Piperidine alkaloids are widespread in nature and many piperidine-ring containing compounds exhibit significant biological activities. Consequently, the asymmetric synthese of these compounds have attracted much attention.Selectivity and flexibility are among the major concern in organic synthesis. Development of multifunctional chiral non-racemic building blocks or synthons has been proven to be a powerful strategy to suite the need of both versatility and flexibility. The aim of this thesis was to develop 3-hydroxyglutarimide 1 as a multifunctional synthon and the use of this synthon to the asymmetric synthese of (25, 3S)-L-733,060, (25, 3S)-CP-99,994 and deoxocassine. The main results and observations from these studies are listed as follows.1. A three-steps procedure (diazodation, amidation and ring expansion) was established to convert cheap and easily available (S)-glutamic acid into the desired (5)-N-(4-methoxybenzyl)-3-hydroxyglutarimide 1. The method is simple, high-yielding (with 70% overall yield from (S)-glutamic acid ) and the ee of 1 is higher than 98%.2. Detailed studies on the regio- and diastereo-selective reductive alkylation of (S)-N- (4-methoxybenzyl)-3-benzyloxyglutarimide 2 were undertaken. The results showed that the addition of RMgX to (S)-N- (4-methoxybenzyl)-3-benzyloxy glutarimide 2 occurred regioselectively at C-2 carbonyl to yield 7N,O-acetals 4 with good diastereoselectivity (C2/C6=86/14-100/0) and good yield (72-88%). It is important to note that substantial amounts of tautomeric ring-opening products (keto amides) 5 (10-81%) were obtained when the addition performed at -20 癈. The diastereomeric mixture of 4 and 5 were reduced with triethylsilane in the presence of boron trifluoride etherate to give trans-6 with good diastereoselectivityAbstract(trans/cis=92/8-98/2) and good yield (77-95%). The regio- and diastereo-selective reductive alkylation opens a versatile entrance to chiral non-racemic (55,6R)-6-alkyl-5-hydroxy-2- piperidinones 6.3. Based on the multifunctional chiral non-racemic synthon 1, enantioselective total synthesis of non-peptidic neurokinin NK1 receptor antagonist (2S, 3S)-L-733,060 (overall yield 15% from (S)-glutamic acid) was achieved using Lewis acid-promoted Si to C2 phenyl group migration of 8 as the key step. The Lewis acid-promoted Si to C2 phenyl group migration of 8 or 9 was in high diastereoselectivity (>95% c/s). This phenyl group migration reaction provides an achieved efficient entry to cis-6-pheny-5-hydroxy-2-piperidinone.4. Based on the multifunctional chiral non-racemic synthon 1, anenantioselective total synthesis of non-peptidic neurokinin NK1 receptor antagonist (2S, 3S)-CP-99,994 was accomplished in 12% overall yield from (S)glutamic acid by using 10. The key steps were diastereoselective borane reduction of a cyclic oxime ester to afford (2S, 3S)-disubstituted piperidine derivative 11 as a major diastereomer (cis/trans=9l:9) and the reduction of 12 with NaBH4.5. Based on the multifunctional chiral non-racemic synthon 1, anVIenantioselective total synthesis of antagonist (2R, 3R)-L-733061 was achieved in 13% overall yield from (S)-glutamic acid via the key intermediate (2R, 3R)-13. The reductive phenylation of (S)-2 provided (55, 6R)-6j. Other key steps included Swern oxidation to (2R, 3S)-75, followed L-selectride reduction to yield key intermediate(2R, 3R)-13.PhPh6. It was observed that sulphonate 79 or 80 failed to react with amine to yield (2R, 3R)-3-aminopiperidine. In order to install amino group at C3, sulphonate 14 was designed and synthesized. Thus, sulphonate 14 reacted with sulphonamide 85 to afford compound 15 with (2R, 3S)-configuration retension instead of the expected inversed (2R, 3R)- configuration. 15 was then converted to3S)-CP-99,994.7. Based on the multifunctional chiral non-racemic synthon 16, an enantioselective total synthesis of 2,6-disubstituted 3-hydroxypiperidine (-)-deoxocassine was achieved in 8% overall yield f...