Efficient syntheses of ( +)-N-methylpseudoconhydrine (5) and (-)-hydroxysedamine (10) are described starting from the readily available (2RS,SS)-Methyl 5-(ferf-butyldimethylsilyloxy)-2-ethoxypiperidine-l-carboxylate (1) and proceeding via homochiral acyliminium ion as an intermediate. Compounds 5 and ?b were obtained in 32 and 34%, resp., overall yield from 1. After deprotection of the OH function of 3a, b the diastereomeric mixture of 6a, b was separated and converted to pseudoconhydrine ?b and epi-pseudoconhydrine ?a, respectively. Reduction of the urethane moiety of 3a, b followed by treatment with hydrochloric acid provided enantio-and diastereopure 5. Reaction of 1-phenyl-1-(trimethylsi1oxy)ethene with 1 afforded 8a and 8b in a ratio of 1:9. Deprotection of 8a, b and separation of the diastereomers give after diastereoselective reduction of the ketone function and conversion of the urethane moiety into the methyl group natural (-)-hydroxysedamine (10). Starting from Eb, deprotection and inversion of the OH function furnished 12 as a single homochiral diastereomer which was converted to ent-10.J3-Hydroxypiperidine alkaloids are found in nature, e.g. in Conium, Prosopis, Azima, Carica, and Cassia Many of these alkaloids display significant pharmacological activities, especially those from Prosopis africana[2a] and Microcus philipinensis[2b]. Therefore, they offer attractive targets for (asymmetric) synthesis[lb1.
(+)-N-Methylpseudoconhydrine 5 (-)-H ydroxysedam ine 10In this field we concentrated on enantiopure 5-hydroxypipecolic acids starting with lr3]. We anticipated that (+)-Nmethylpseudoconhydrine (5)r41 and (-)-hydroxysedamine[sl (10) should be available by addition of allyltrimethylsilane and 1 -phenyl-1 -(trimethylsilyloxy)ethene, respectively, to the homochiral acyliminium generated from 1 with Lewis acids to yield 2a, b and Sa, b. Subsequent transformations of the functional groups and separation of the diastereomers should be straightforward. This would be the first chiral pool synthesis of natural (-)-hydroxysedamine (10) by starting from 1.The a-ethoxy carbamate 1r7] was treated with allyltrimethyl~ilane[~~,~I and zinc chloride to give via N-acyliminium ion the P-hydroxypiperidine derivatives 2a, b in a ratio of 24:76 (determined by GC analysis) in 96% overall yield (Scheme 1). A preferred trans diastereoselectivity was also observed in the reaction of cyanotrimethylsilane/ZnCl~ with lr7]. 'H-NMR spectroscopy of 1 revealed an axial orientation of the tert-butyltrimethylsiloxy group, and therefore the less shielded a-side of the N-acyliminium ion is attacked. This axial orientation can be interpreted by an attractive gauche effect of the nitrogen substituent and the J3-oxygen Catalytic hydrogenation of 2a, b with Pd/C in methanol resulted in a diastereomeric mixture of 3a, b (3:7) which was separated after deprotection of the OH function with a 6 M methanolic hydrogen chloride solution by column chromatography. Interestingly, the 13C-NMR spectra of 3a, b display single resonances for each of the ca...
