Chiral piperidines synthesis

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). 

Diastereoselectivity in functionalized piperidine synthesis has also been reported using chiral sulfinimines (Scheme 18) <2003OL3855>. It was postulated that the observed selectivity arose from an intermediate alkoxy aluminium species shielding one face of the imine during reduction. 

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>. 

Aliphatic amine derivatives such as amides, carbamates and sulfonamides also participate in Pd - catalyzed intramolecular C-N bond formation. The relative reactivity of these amino nucleophiles toward cyclization has been evaluated in the PdCL-catalyzed cyclization of iV-protected 4-pentenylamines and 5-hexenylamines, and it was found to be urea > carbamate > tosylamide > benzamide. The PdCl2(CH3CN)2-catalyzed dehydrative cyclization of alkenyl urethanes bearing an allylic hydroxyl group has been elegantly applied to the synthesis of chiral piperidine alkaloids. The cyclization reaction occurs with complete stereocontrol in good yields in the presence of 15-20 mol % of catalyst without any reoxidant (eq 16). 

The synthesis of chiral piperidines has been accomplished through an intramolecular cyclization reaction using chiral phosphoric acid catalysts (Scheme 3.31) [29], Treatment of protected amines bearing tethered unsaturated acetals with catalytic amounts of a chiral phosphoric acid catalyzed the formation of chiral piperidines with high selectivity. 

As chiral 1,2,3,4-tetrahydroquinoUnes and chiral piperidines are valuable building blocks for many natural compounds as well as starting materials for various biologically active compounds (Figure 32.10), " general approaches to the synthesis of these molecules are highly beneficial. 

Chiral piperidine derivatives have notable biological activities, " " and they are an important structural unit in many biologically important complexes, " alkaloidal natural products,and So, the synthesis... 

SCHEME 19 PT-catalyzed asymmetric synthesis of chiral piperidine derivatives. 

J. A. Klun et al. Synthesis and repellent efficacy of a new chiral piperidine analog Comparison with DEET and Bayiepel activity in human-volunteer laboratory assays against Ac fes aegypti and Anopheles stephensi. J Med Entomol, 40, 293, 2003. 

Chiral and nonracemic A-cyanomethyloxazolidines in diastereoselective synthesis, particularly of pyrrolidine and piperidine derivatives 99CSR383. 

Diastereoselective synthesis, particularly of piperidine derivatives using chiral and nonracemic A-cyanomethyloxazolidines 99CSR383. 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

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