Piperidines chiral—

Reaction of the chiral piperidine derivative 602 with the activated alkyne 603 afforded the corresponding oxazoloquinoline derivative 604 (98H747) (Scheme 102). 

The first asymmetric synthesis of (-l-)-abresoline was achieved from the chiral piperidine derivative 153, which upon treatment of its hydroxy side-chain substituent with carbon tetrabromide, triphenylphosphine, and triethyl-amine cyclized to the frarcr-quinazolidine 154. Deketalization and silyl protection of the phenolic group, followed by stereoselective reduction with lithium tri-t -butylborohydride (L-Selectride ), gave an alcohol, which after acylation and deprotection furnished (-l-)-abresoline 155 (Scheme 25) <2005TL2669>. 

The polarized carbon-nitrogen double bond can also be reduced enantiospecifically using chiral hydrides (7lJCS(C)2560). Although only modest asymmetric inductions were observed, this method holds promise for the synthesis of chiral piperidines (equation 54). 

The intramolecular [2 + 2] photocycloaddition of cyclohexadienone derivative 51, which is substituted with chiral piperidine ring in the solid state, proceeds enantioselectively and optically active products 52 and 53 were obtained [28], Two crystal modifications of 51, the a-form (mp 102-104°C) and (3-form (mp 127-128°C), gave optically active 52 and 53, respectively, upon irradiation in the solid state. 

Stereoselective Syntheses of Chiral Piperidines via Addition Reactions to 4-Pyridones... 

The asymmetric hydrogenation of pyridine derivatives is a practical and direct method to chiral piperidine derivatives that are important synthetic intermediates and the structural unit of many biologically active compounds. Recently, some attempts to develop enantioselective hydrogenation of pyridine derivatives have been made. 

The use of chiral chloroformates, such as that derived from tranx-2-(a-cumyl)cyclohexanol, allows diastereoselective additions to 4-methoxypyridine. The introduction of a tri-ixo-propylsilyl group at C-3 greatly enhances the diastereoselectivity. The products of these reactions are multifunctional chiral piperidines which have found use in the asymmetric synthesis of natural products. ... 

Metal-mediated cyclizations have been applied to piperidine synthesis (Scheme 16). Ring closing metathesis catalyzed by Ru catalysts is used to prepare chiral piperidines <97TL677, 97AG(E)3036>. Similarly to the cyclization to 37 is Ti-(II)-mediated intramolecular cyclization of optically active enyne precursors for preparing chiral piperidines <97TL8351>. 

Palladium catalyzed cyclization of optically active amine (49) gave chiral piperidine (50) in excellent yield (Scheme 21) <94CL21>. 

A new class of tricyclic models such as 401 was also based on a Friedlander reaction between chiral piperidine-2,4-diones 400 and azo-methine 399 (Scheme 88) with yields of about 70%. Alkylation of the lactam allows the introduction of various pendant arms on the chiral cyclic inducer. Compound 401 is used for the preparation of various enantiose-lective NADH mimics (03T4911). 

Lewis acid-catalyzed (EtAlCla, ZnClz) aza Diels-Alder reaction of imines derived from amino acid esters or carbohydrates with Danishefsky s diene provide precursors of chiral piperidine alkaloids. When using imines derived from 0-pivaloylated glycosylamines and ZnCl2 as Lewis acid, highly diastereoselective tandem-Mannich-Michael reactions are observed. The carbohydrate moiety is easily removed by treatment with HCl/MeOH. By employing galactopyranosylamine or arabinosylamine derivatives both enantiomeric series are readily available. 

Prolinol silyl ether catalysts were also able to control the Mannich reaction of acetaldehyde. Xu and coworkers utilised Michael adducts of aldehydes with nitroalkenes in the subsequent Mannich-type reaction with imines followed by cyclisation. Highly substituted chiral piperidines were formed. Suitable imines for organocatalytic Mannich reactions can also be generated in situ from amido sulfones (Scheme 8.34). ... 

A highly enantioselective inverse-electron-demand aza-Diels-Alder reaction of A-sulfonyl-l-aza-1,3-butadienes 88 and aldehydes 71 was reported by Chen and his co-workers. Scheme 3.31 [46]. Few chiral piperidine derivatives 89 were prepared via this methodology. The addition of water in the reaction media led to a dramatic acceleration of the reaction. Presumably, water is helpful for the hydrolysis of the catalyst-incorporated intermediate to release the catalyst and thus enable the catalytic turnover. Noteworthy, replacement of acetic acid to stronger acid, e.g. p-tolue-nesulfonic acid, resulted in no reaction. 

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