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Full details of the direct and general method for the reductive alkylation of tertiary lactams and amides to give tertiary sec-alkylamines are presented. This one-pot method consists of in situ activation of a lactam or an amide with Tf2O/DTBMP, addition of a Grignard reagent, and reduction of the resulting iminium intermediates. Alkyl, benzyl, and aryl Grignard reagents and several reductants or reducing conditions (LiAlH4, NaBH4, Hantzsch ester, Bu3SnH, Pd(OH)2/C, H2) could be used effectively. Reductive alkylations of substituted lactams demonstrated good to excellent 1,3-asymmetric induction to provide the corresponding di- or trisubstituted pyrrolidine/piperidine in 6:1 (LiAlH4), 11:1 (Et 3SiH), and 20:1 (catalytic hydrogenation) cis/trans diastereoselectivity, respectively. The versatility of this methodology was demonstrated by its application in the concise stereoselective synthesis of piperidine alkaloid (-)-morusimic acid.

Direct entry: One-pot reductive alkylation of lactams/amides with Grignard reagents has been realized via lactam/amide activation with Tf2O. This method opens a direct entry to α-alkylated amines. The versatility of the method is illustrated by the concise syntheses of bioactive alkaloids (±)-bgugaine, (±)-coniine, (+)-preussin, and (?)-cassine.

(-)-Cassine has been synthesized by a new route, asymmetric aminohydroxylation followed by reductive amination.

l-Rhamnose is transformed to (-)-Cassine via a remarkable four step one pot reaction. The Horner-Wadsworth-Emmons [3 + 2]-1,3-dipolar cycloaddition reaction cascade is the pivotal step in this reaction sequence and makes the synthesis highly efficient. The Royal Society of Chemistry 2006.

The PdCl(2)-catalyzed cyclization of amino allylic alcohol 16 gave the cyclized product 17a with excellent diastereoselectivity. The versatility of compound 17a as the building block for synthesizing cis-2,6-disubstituted piperidine alkaloids has been dem

A highly efficient, flexible and diastereoselective route to all-cis-2,6-disubstituted 3-piperidinols has been accomplished. The key component of the synthesis is a chiral β-hydroxyester, which was obtained by lipase catalyzed kinetic resolution. Based on this starting material, diastereoselective alkylation of its dianion, Curtius rearrangement to a 2-oxazolidinone, Grignard reaction to introduce the side-chain and conversion of the aliphatic 2-oxazolidinone into a 3-piperidinol by imine cyclization lead to the exemplary total synthesis of naturally occurring (-)-(2R,3R,6S)-cassine.

Enantiodivergent synthesis of the enantio-pure cis,cis 3-protected 2,6-disubstituted piperidin-3-ol 1 has been achieved via a biochemical method, and the absolute stereochemistry of (+)-1 has been established by its conversion into the known piperidine (-

The asymmetric total synthesis of (-)-cassine (1) and (+)-spectaline (2) was achieved by starting with both enantiomers of the homochiral 3-oxygenated 2,6-cis-disubstituted piperidine 3.

11-Bromoundecan-2-one 6 was prepared in four steps from the commercially available undec-10-en-1-ol 3, and was used to alkylate ethyl 7-methyl-3-oxooct-6-enoate 9.The resulting intermediate was hydrolysed and decarboxylated to give the diketoolefin 11.Ozonolysis of the latter yielded the diketoaldehyde 16, wich was subjected next to condensation with nitroethane in alkaline conditions, followed by catalytic hydrogenation and cyclisation to give a ca. 50/50 mixture of 3-r-hydroxy-6-c (11-oxododecyl)-2-c-methylpiperidine and (+/-)3-epi-cassine. Another route to the key intemediate 11 was also studied, in wich 1,8-dibromooctane 13 was used to alkylate the enolates of ethyl acetoacetate and ethyl 7-methyl-3-oxooct-6-enoate, giving presumably of the olefinic diketodiester 15.Hydrolysis and decarboxylation of the crude reaction product, using aqueous baryum hydroxide, gave the desired compound 11 in an overall yield of 17 percent with respect to 1,8-dibromooctane 13.