2- piperidines diastereoselective synthesis

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. 

M. Ruiz, T. M. Ruanova, O. Blanco, F. Nunez, C. Pato, and V. Ojea, Diastereoselective synthesis of piperidine imino sugars using aldol additions of metalated bislactim ethers to threose and erythrose acetonides, J. Org. Chem., 73 (2008) 2240-2255. 

Kunz and coworkers reported the application of an immobilized chiral galacto-sylamine in diastereoselective synthesis of piperidine and amino acid derivates [14]. Preparation of the galactosylamine auxiliary from 1,6-hexandiol and P-D-galactopyranosyl azide (1) required a six-step synthesis protocol. The precursor 2 was loaded onto a polymer bound silane. Reduction of the azide function gave the corresponding immobilized amine 3 (Scheme 12.2). 

The diastereoselective synthesis of 2,6-disubstituted piperidines was realized by reduction of an imino functional group14. Depending on the reaction conditions and the hydride reagent used in the reduction, a cisjtrans ratio of 99 1 (DIBAL-H) or 5 95 [LiAlH4/Al(CH,)3] of 2,6-disubstituted piperidines was obtained in 94-97% yield15. 

Remuson and coworkers reported that highly diastereoselective synthesis of 2,6-cis-disubstituted-4-methylenepiperidines based on a Mannich type intramolecular cyclization of allylsilane [37]. Reaction of p-aminohydroxysilane 116 with carbonyl derivative in the presence of TFA in a mixture of H2O-THF (1 1) led to 4-methylenepiperidine 117. Oxidation with osmium tetraox-ide in the presence of Na3H3lOe in AcOH led to piperidin-4-one followed by the stereoselective reduction with NaBH4 afforded (- -)-241D (13) and its C-4 epimer 118 in a ratio of 83 17 (Scheme 20). 

Following the aldol reaction, the intermediate 246 was proposed to react from the si face as shown to eventually produce the piperidine diastereoselectively. This publication also details how enantiopure piperidines can be synthesized from chiral sulfinyl imines. The second and recent domino synthesis of piperidines 248 utilizes organocatalytic techniques to ensure enantiomeric excesses in the range 93-99%... 

Watson PS, Jiang B, Scott B. A diastereoselective synthesis of 2,4-disubstituted piperidines scaffolds for drug discovery. Org. Lett. 2000 2(23) 3679-3681. 

Ring-closing reactions promoted by mercuric salts are valuable transformations which find an increasing use in the total synthesis of various natural products.130-140 Several examples of solvomercurations demonstrating the applicability of these transformations to the synthesis of natural product precursors are presented in Table 2. Piperidines (entry a), 141 pyrans (entries b-d), 142-144 and furans (entries e, f)14S>146 have been obtained in good yields and diastereoselectivity. These derivatives serve as starting materials for various natural products and can be demercu-rated under reducing conditions.147... 

Williams JT, Bahia PS, Snaith JS (2002) Synthesis of 3,4-disubstituted piperidines by carbonyl ene and prins cyclizations a switch in diastereoselectivity between Lewis and Bronsted acid catalysts. Org Lett 4 3727-3730... 

The reaction of methyl phenyldiazoacetate with N-Boc-piperidine (36) is a good illustration of the potential of this chemistry because it leads to the direct synthesis of f/ireo-methylphenidate (37) [27]. The most efficient rhodium car-boxylate catalyst for carrying out this transformation is Rh2(S-biDOSP)2 (2), which results in the formation of a 71 29 mixture of the readily separable threo and erythro diastereomers. The threo diastereomer 37 is produced in 52% isolated yield and 86% ee [Eq. (19)]. Other catalysts have also been explored for this reaction. Rh2(R-DOSP)4 gives only moderate stereoselectivity while Rh2(R-MEPY)4 gave the best diastereoselectivity in this reaction (94% de) [29]. 

The chiral boron complex prepared in situ from chiral binaphthol and B(OPh)3 is utilized for the asymmetric aza-Diels-Alder reaction of Danishefsky s diene and imines [67] (Eq. 8A.43). Although the asymmetric reaction of prochiral imine affords products with up to 90% ee, the double asymmetric induction with chiral imine by using oc-benzylamine as a chiral auxiliary has achieved almost complete diastereoselectivity for both aliphatic and aromatic aldimines. This method has been successfully applied to the efficient asymmetric synthesis of anabasine and coniine of piperidine alkaloides. 

Application of the halogenation of y-aminoolefins preceding intramolecular cyclization has been applied to the synthesis of fused piperidines (Equation 33) <2003CC1918>. The presence of chiral substituents (e.g., via the nitrogen protecting group) generates a diastereoselective reaction (Equation 34). 

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. 

---