Piperidine derivs.: synthesis

Reduced pyrido[4,3-c]pyridazines are obtained from piperidine derivatives such as (371) with hydra2dne e.g. 79AF1835), whilst another related synthesis coupled the enamine (372) with phenacyl bromide semicarbazone to give (373) (74JAP(K)7488897). 

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. 

Certain esters have often been employed in attempts to confer organ selectivity to molecules possessing carboxyl functions. Thus, for example, treatment of piperidinecarboxylic acid 76 with N-hydroxysuccinimide and DCC affords the ester 77. In a convergent synthesis, the anion from diphenylacetonitrile (78) is alkylated with dibromoethane to afford the bromide 79. Alkylation of the piperidine derivative 77 with that halide 79 gives the anti-diarrheal agent difenoximide (80). The same sequence starting with the phenoxyethyl ester 81 gives fetoxylate (82). 

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>. 

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>. 

Khazanov, E. Barenholz, Y., Gibson, D., Najraeh, Y. Novel apoptosis-including trans-platinum piperidine and piperazine derivatives Synthesis and biological characterization. J. Med. Chem. 2002, 45, 5189-5195. ... 

Scheme 11.4 Synthesis of the Siegel bicyclic piperidine derivative...

The synthesis of the alkaloid (—)-dendroprimine is obtained via a piperidine derivative obtained through a one-pot azaelectrocyclization protocol <20060L3813>. A new synthesis of ( )-tashiromine is also reported <2006JOC704>. 

DFT Based Analysis for The Regio- and Stereoselective Synthesis of Tetrasubstituted Isoxazolidines From Cinnamoyl Piperidine Derivatives... 

A -bromo derivative (37.1.1.45), which is reacted with sodium ethoxide realizing the key moment of the synthesis—the transformation of the piperidine derivative to a quinuclidine derivative (37.1.1.46). Reducing the keto group in this molecule with lithium aluminum hydride gives the desired quinine (37.1.1.47) [17-22]. 

The synthesis and aqueous chemistry of a-acetoxy-A-nitrosomorpholine (22) has been described.58 It decomposes cleanly, with first-order kinetics, via an A-nitroso-iminium ion intermediate (23), with the pH-rate profile showing acid- and base-catalysed regions, and an extensive pH-independent region between 3 and 9, the latter being ca 100 times slower than its C-analogue, the corresponding piperidine derivative. Implications for the interaction of A-nitrosomorpholine with DNA are discussed. 

Extension of the approach described resulted in a short synthesis of (+)-mero-quinene (Fig. 13). Formation of this alkaloid also synthetically connects the indole with the quinoline alkaloids, a link which has been suggested from the biosynthetic point of view for multiple decades quinine alkaloids are expected to be enzymatically formed from the indole framework. Meroquinene is a simple piperidine derivative which can be obtained by degradation of cinchonine and other Cinchona alkaloids under acidic conditions. It also plays a key role in the chemical synthesis... 

Synthesis of 3-alkylated piperidine derivatives could of course be performed most directly by alkylation of 2-deoxyaldono- 1,5-lactams, as outlined in Scheme 8. After unsucessfull experiments due to solubility problems, we turned our interest to the alkylation at C-2 of unprotected 2-deoxy- -bromodeoxyaldonolactons. This strategy requires set-up of a dianion in the presence of a primary bromine, followed by stereoselective alkylation at C-2, two possible doubtful reactions (Scheme 9). Gratifyingly, both reactions could be performed satisfactory. 

The chiral piperidinones 46 formed by the reaction between Danishefsky s diene and the glycosyl imines are valuable synthons for the synthesis of higher substituted piperidine derivatives. 2,6-Disubstituted piperidinones 49 are obtained by addition of organocuprates complexes with boron trifluoride [53]. The reaction pathway is illustrated in Scheme 30. 

The anti-tumour properties of cryptopleurine (33) continue to stimulate synthetic work in this area, and two new syntheses have been reported this year. Snieckus and co-workers25 have described a short, efficient synthesis of the alkaloid, utilizing a benzamide-directed metallation reaction (Scheme 6). In the other synthesis,26 the piperidine derivative (35), prepared by a nitrone cycloaddition reaction, is cyclized... 

With adiponitrile, an open-chain dinitrile, however, such cyclization leading to a seven-membered cyclic imine occurs to a much lesser extent (see, e.g., eq. 7.25). The hydrogenative cyclizations have been utilized for the synthesis of pyrrolidine and piperidine derivatives from 1,2- and 1,3-dicyano compounds.118,119... 

Lithiated cyclic enamines 691 " 5 996 and amidines 692989,997 have been prepared by deprotonation of the corresponding heterocycles with f-BuLi in THF at — 78 °C, being allowed to react with several electrophiles. This methodology has been applied to the synthesis of pyrrolidine and piperidine derived compounds, intermediates 691 and 692 acting in these cases not as acyllithium equivalents. 

The often potent biological properties of piperidine derivatives underlie their vast use in pharmaceuticals, agrochemicals, and natural products. It is for this reason that there exists a myriad of synthetic routes to variously functionalized and substituted piperidine derivatives, which will be highlighted in the subsequent section. In the past year there have been two reviews highlighting two approaches to the synthesis of piperidines. One review focused on the use of aziridines in parallel and solid-phase synthesis of substituted piperidine derivatives as well as other scaffolds <07EJO1717>. The other review covered the synthesis of 3-arylpiperidines by radical 1,4- and 1,2-aryl migration <07T7187>. 

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