Piperidinol synthesis

A synthesis of an extended l,2,3,4-tetrahydro-j8-carbohne system (73) is somewhat similar. The 4-o-aminophenyl-3-piperidinol derivative 72, obtained in several steps from cinchonine, undergoes... 

The reactions depicted in Scheme 39 were already conducted in view of a potential use in the synthesis of pyrrolidinols and piperidinols. The structural feature of a 2-arylmethyl-3-hydroxysubstitution is not only found in preussin but also in anisomycin (152) [87] or in the piperidine alkaloid FR 901483 (153) [88] (Fig. 5). 

G. Rosse, F. Ouertani and H. Schroeder, Efficient solid-phase synthesis of fi-amino-substituted piperidinols, J. Comb. Chem., 1999, 1, 397-401. 

Synthesis (Kleemann et al. 1999, Janssen (Janssen), 1973 Janssen et al. (Janssen), 1973, Stokbroekx et al., 1973, Niemegeers et al., 1974) ) Treatment of 2-oxo-3,3-diphenyl-tetrahydrofuran, synthesized by treatment of diphenyl-acetic acid ethyl ester with ethylene oxide, with HBr(gas) yields bromo derivative i, which is then converted into butyryl chloride derivative ii by means of thionyl chloride in refluxing chloroform. Reaction of derivative ii with dimethylamine in toluene affords dimethyl (tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide, which is then condensed with 4-(4-chlorophenyl)-4-piperidinol by means of Na2C03 and Kl in refluxing 4-methyl-2-pentanone to provide loperamide. 

Cyclialkylation has been applied in the synthesis of iV-heterotri- and tetracycles. Reimann et al.332 have performed the stereoselective ring closing of the diastereo-meric mixture of piperidinols 101 and isolated the product ergoline with a C/D cis configuration in low yield [Eq. (5.130)]. It was also observed, however, that one of the isomers afforded the product quantitatively under identical conditions, whereas the other slowly decomposed. 

With the enantiomeric pair of 1 in hand, we examined the stereodivergent synthesis of a,a -disubstitued 3-piperidinol alkaloids. The basic strategy we used to prepare the building blocks (I-IV) from (-)-1 is presented in Figure 3. 

Fig. (3). Basic strategy for the stereodivergent synthesis of 3-piperidinol alkaloids...

Finally, the type IV chiral building block 15 was synthesized via the iminium reduction of the corresponding iminiun salt derived from the vinylogous urethane 14 as shown in Scheme 5. With all four stereoisomers of the chiral building blocks (I IV) for synthesis of 3-piperidinol alkaloid in hand, we examined the synthesis of prosafrinine,... 

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. 

A pentazocine (109) synthesis has been reported by Kametani and co-workers(45) from the methyl ester of tyrosine methylether (107) via the piperidinol intermediate 108, according to Scheme 4.16. Other piperidinol syntheses have been published by Kametani(46 49), Janssen,(50) and Henecka and Schubert.(51)... 

Synthesis of new 3-piperidinol-type chiral building blocks and their application to the alkaloids syntheses 99YGK1075. 

A mixture of 23 parts of the ethyl ester of 4-phenylisonipecotic acid and 15 parts of 2,2-diphenyl-4-bromobutyronitrile in 19 parts of xylene Is heated for 24 hours at 100°-120°C and then cooled and filtered to remove the precipitate of the hydrobromide of the ethyl ester of 4-phenylisonipecotic acid. The filtrate is then extracted with dilute hydrochloric acid and the extract is rendered alkaline by addition of concentrated aqueous potassium hydroxide and extracted with ether. This ether extract is treated with gaseous hydrogen chloride. The resulting precipitate is collected on a filter. The hydrochloride of the ethyl ester of 2,2-diphenyl-4-(4 -carboxy-4 -phenyl-1 -piperidinol butyronitrile thus obtained melts at about 220.5-222°C. See Meperidine hydrochloride for synthesis of 4-phenyl-isonipecotic acid ethyl ester. 

Various other reductive methods have been applied to amino-alcohol synthesis. (S)-(-)-3-Piperidinol was synthesised from both L-glutamic acid and (S)-malic acld. The routes involved cycli-sations of amino-alcohols in which the amino moiety was established by azide and nitrile reductions with H /Pd-C and LiAlH j respectively. Acyl cyanides were reduced to optically active amino-... 

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