“…The highly regioselective formation of chloro acetate 20 is noteworthy . This result is consistent with literature observations ,, on the nucleophilic opening of related 3,4-disubstituted heterocycles under conditions where the intermediate bears a significant positive charge (Scheme ). 5 Effect of Charge on Regioselectivity…”
Section: Resultssupporting
confidence: 93%
“…As shown in Scheme , opening of 5 with HBr affords a single β-bromohydrin while opening the same epoxide with dialkylamines gives a 1:1 mixture of regioisomers . The latter reaction also contrasts with the opening of dialkylaziridinium ions with dialkylamines, which again is completely regiospecific. , These results suggest that the directing effect of the ring heteroatom in 3,4-disubstituted heterocycles is more pronounced when nucleophilic addition proceeds by way of a cationic intermediate.…”
Section: Resultsmentioning
confidence: 91%
“…In addition to these acyclic derivatives, 2-deoxyribose based syntheses were also developed for piperidines 4 and 5 . The racemate of epoxide 5 is a precursor to the gastrointestinal stimulant cisapride, while racemic 4 has been shown to be an invaluable carbohydrate scaffold for drug discovery in the area of extracellular signaling . Enantiopure (3 R ,4 S )- 4 and (3 R ,4 S )- 5 were readily synthesized from 2-deoxyribose.…”
We have developed concise routes to a number of useful chiral 5-carbon synthetic building blocks using readily available O-1-methyl-2-deoxyribose as starting material. Novel transformations include the use of indium triflate to catalyze the oxidation of a methyl furanoside to the corresponding lactone with MCPBA and the Vasella-type fragmentation of a 5-iodo furanoside using chromium(II) chloride when zinc proved ineffective. In addition, 3,4-disubstituted piperidine derivatives were prepared without hydroxyl group protection via a simple reductive amination reaction.
“…The highly regioselective formation of chloro acetate 20 is noteworthy . This result is consistent with literature observations ,, on the nucleophilic opening of related 3,4-disubstituted heterocycles under conditions where the intermediate bears a significant positive charge (Scheme ). 5 Effect of Charge on Regioselectivity…”
Section: Resultssupporting
confidence: 93%
“…As shown in Scheme , opening of 5 with HBr affords a single β-bromohydrin while opening the same epoxide with dialkylamines gives a 1:1 mixture of regioisomers . The latter reaction also contrasts with the opening of dialkylaziridinium ions with dialkylamines, which again is completely regiospecific. , These results suggest that the directing effect of the ring heteroatom in 3,4-disubstituted heterocycles is more pronounced when nucleophilic addition proceeds by way of a cationic intermediate.…”
Section: Resultsmentioning
confidence: 91%
“…In addition to these acyclic derivatives, 2-deoxyribose based syntheses were also developed for piperidines 4 and 5 . The racemate of epoxide 5 is a precursor to the gastrointestinal stimulant cisapride, while racemic 4 has been shown to be an invaluable carbohydrate scaffold for drug discovery in the area of extracellular signaling . Enantiopure (3 R ,4 S )- 4 and (3 R ,4 S )- 5 were readily synthesized from 2-deoxyribose.…”
We have developed concise routes to a number of useful chiral 5-carbon synthetic building blocks using readily available O-1-methyl-2-deoxyribose as starting material. Novel transformations include the use of indium triflate to catalyze the oxidation of a methyl furanoside to the corresponding lactone with MCPBA and the Vasella-type fragmentation of a 5-iodo furanoside using chromium(II) chloride when zinc proved ineffective. In addition, 3,4-disubstituted piperidine derivatives were prepared without hydroxyl group protection via a simple reductive amination reaction.
“…Following the highly regioselective ring opening of racemic 3,4-epoxypiperidine with HBr, (−)- 2a could be transformed into enantiopure trans -4-bromo-3-hydroxy-piperidine, which can be further transformed into other enantiopure compounds such as cis -4-amino-3-hydroxy- and cis -3,4-dihydroxy-piperidine. Moreover, (−)- 2a is a useful intermediate for the preparation of single enantiomer of antidepressant Ifoxetine sulfate and prokinetic agent Cisapride hydrate. , 3 Hydrolysis of (±)- 2a (15 mM) to 3a with frozen/thawed cells (10 g cdw/L) of Sphingomonas sp. HXN-200.…”
The bacterial strain Sphingomonas sp. HXN-200 was used to catalyze the trans dihydroxylation ofN-substituted 1,2,5,6-tetrahydropyridines 1 and 3-pyrrolines 4 giving the corresponding 3,4-dihydroxypiperidines 3 and 3,4-dihydroxypyrrolidines 6, respectively, with high enantioselectivity and high activity. The trans dihydroxylation was sequentially catalyzed by a monooxygenase and an epoxide hydrolase in the strain with epoxide as intermediate. While both epoxidation and hydrolysis steps contributed to the overall enantioselectivity in trans dihydroxylation of 1, the enantioselectivity in trans dihydroxylation of the symmetric substrate 4 was generated only in the hydrolysis of meso-epoxide 5. The absolute configuration for the bioproducts (+)-3 and (+)-6 was established as (3R,4R) by chemical correlations. Preparative trans dihydroxylation of 1a and 4b with frozen/thawed cells of Sphingomonas sp. HXN-200 afforded the corresponding (+)-(3R,4R)-3,4-dihydroxypiperidine 3a and (+)-(3R,4R)-3,4-dihydroxy pyrrolidine 6b in 96% ee both and in 60% and 80% yield, respectively. These results represent first examples of enantioselective trans dihydroxylation with nonterpene substrates and with bacterial catalyst, thus significantly extending this methodology in practical synthesis of valuable and useful trans diols. Enantioselective hydrolysis of racemic epoxide 2a with Sphingomonas sp. HXN-200 gave 34% of (-)-2a in >99% ee, which is a versatile chiral building block. Further hydrolysis of (-)-2a with the same strain afforded (-)-(3S,4S)-3a in 96% ee and 92% yield. Thus, both enantiomers of 3a can be prepared by biotransformation with Sphingomonas sp. HXN-200.
Practical Synthesis of Ethyl cis-4-Amino-3-methoxy-1-piperidine Carboxylate, a Key Intermediate of Cisapride. -The title compound (X) is prepared from the tetrahydropyridine (I) via an efficient stereoselective formation of cis-fused oxazolidinopiperidine (VIII) from the trans-bromohydrin (V) and a regioselective oxazolidinone ring opening of (VIII) as key steps. -(KIM, BONG J.; PYUN, DO K.; JUNG, HEE J.; KWAK, HYUN J.; KIM, JAE H.; KIM, EUN J.; JEONG, WON J.; LEE, CHEOL H.; Synth. Commun.
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