Piperidines ring synthesis from

The reactions of dichlorocarbene with morpholine and piperidine enamines derived from cyclopentanone and cyclohexanone have been reported to lead to ring expanded and a-chloromethylene ketone products (355,356). Similarly a-chloro-a, -unsaturated aldehydes were obtained from aldehyde derived enamines (357). Synthesis of aminocyclopropanes (353,359) could be realized by the addition of diphenyldiazomethane (360) and the methylene iodide-zinc reagent to enamines (367). 

The resulting derivatives (269) can be considered as strategically important intermediates in the synthesis of glycosidase inhibitors and carbocyclic nucleosides (150). A new approach to the stereoselective synthesis of the piperidine ring with the use of [4+ 2] [3+ 2]-cycloaddition from specially prepared substrates is also very interesting (431)b, c. In the context of this problem, the conditions for the formation of systems containing quaternary vicinal stereocenters were found. 

The rare reports of quinolizidine formation by a nitrone cycloaddition strategy include the racemic total synthesis of lasubine II (58), one of a series of related alkaloid isolated from the leaves of Lagerstoemia subcostata Koehne (Scheme 1.14) (104). While these alkaloids were previously accessed by infennolecular nitrone cycloaddition reactions, this more recent report uses an intramolecular approach to form the desired piperidine ring. Thus, cycloaddition of nitrone 59 affords predominantly the desired bridged adduct 60 along with two related... 

A short total synthesis of (-l-)-prosopinine 36 from (R)-serine was achieved via cyclohydrocarbonylation catalyzed by Rh-BIPHEPHOS complex for the construction of the key piperidine ring (2R,33 )-33 (Scheme 6). Compound 33 was converted to (-l-)-prosopinine 36 via the nucleophilic displacement of the ethoxy group with organocopper reagent 34 forming 35, followed by deprotection. A similar procedure has been used for the total synthesis of (—)-deoxoprosophylline 37. 

Piperidine ring-expansion methodology and aziridinium ion intermediate formation has been demonstrated to provide good regio- and stereochemical control in the synthesis of substituted azepanes. Reaction of 298 with azide ion afforded 300 from preferential attack from behind by the azide ion at the methine carbon in the intermediate 299 (Scheme 38) <2002J(P1)2080>. 

A total synthesis for 3,14-dihydroxy isomorphinans from 4a-(2-aminoethyl)-l,2,3,4,4a,9-hexahydro-6-methoxyphenanthrene (34, Scheme 3.5) has been published/116) The urethane epoxide (116) was given upon treatment of 34 with ethyl chloroformate-triethylamine, followed by m-chloroperbenzoic acid oxidation. During base treatment, regioselective opening of the epoxide occurred with concomitant piperidine ring formation to 117. 

Other substituted piperidines, particularly piperidinols, have been exploited as benzomorphan precursors. The first 6,7-benzomorphan lacking a 6-alkyl substituent, the parent heterocycle, was reported by May et al. in 1968<43,44) in a synthesis from 2-cyano-4-phenylpyridine (102) (Scheme 4.15). The 2-carbomethoxypiperidine (103) was prepared readily, but it proved resistant to direct cyclization to 3-methylbenzomorphan-l-one (105) with polyphosphoric acid, presumably because the more stable 2,4-diequatorial isomer is not favorable for ring closure for geometric reasons. Hydrolysis to the corresponding acid (104), however, gives an intermediate that closes to 105 in 94% yield. The parent heterocycle 106 is produced by standard techniques. 

SS20846A (183) as well as 184 and 185 were isolated from Streptomyces luteogriseus and their structures determined by EIMS, and two-dimensional NMR [456]. SS20846A had been isolated previously from Streptomyces sp. S20846, and was found to inhibit intestinal motility in mice [457]. A recent synthesis of 183 has been reported in which a LiC104 catalyzed stereoselective cycloaddition of a 1-azatriene iron tricarbonyl complex with Danishefsky s diene was used to form the piperidine ring [458]. 

The piperidine ring is probably the most common heterocycle occurring in pharmaceuticals. Piperidine is often used as a secondary amine in the synthesis of drugs. The local anaesthetic bupivacaine 20 (used as the racemate or the ( S)-enantiomer levobupivacaine) is a pipecolinic acid derivative. The antihistamine bamipine 21 and the analgesic fentanyl 22 are derived from 4-aminopiperidines. The ... 

From the alkaloids, by more extensive degradation (60,147), or from meroquinene (64, 148), d-/3-cincholoiponic acid (CV) is obtainable. This acid is unstable with respect to a stereoisomer, d-a-cincholoiponic acid, into which it is transformed when it is heated with aqueous potash (65). This result suggests that the /3-acid, and thence, the alkaloids themselves, possess the cis orientation of the groups attached to the piperidine ring. The conclusion is strengthened by consideration of the synthesis of the a- and /3-cincholoiponic acids (c/. Section IV, 2). When malonic ester was added to the nitrile CVI, a reaction mixture was obtained from... 

As the absolute configuration of quinine was still unknown and stereochemical analysis did not exist, Rabe s ultimate objective was unfortunately far in advance of the realm of possibility. Even if he had successfully achieved the synthesis of the molecular structure of quinine, he would have conceivably produced sixteen different products, of which quinine would have required selective isolation from the other fifteen stereoisomers. Despite these overarching challenges, Rabe was able to effect a partial synthesis of quinine (1) from Pasteur s degradation product quinotoxine (3, cf. Scheme 2). This remarkable achievement is documented in Scheme 3 wherein, following bromination of the free amine in the piperidine ring of 3... 

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