Synthesis of epibatidine

Sestanj, K.; Melenski, Edward; Jirkovsky, Ivo

doi:10.1016/s0040-4039(00)73514-3

Cited by 38 publications

(15 citation statements)

References 8 publications

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“…Catalytic hydrogenation of 7-azabicyclo[2.2.1]-heptadienes has been reported to be a straightforward method for the preparation of 7-azabicyclo- The cis,endo compound 103 was converted into the 7-methyl-7-azabicyclo[2.2.1]heptene (105). 110 In addition, 103 was converted into the pseudo-norcocaine analogue 106.…”

Section: B Reduction Of 7-azabicyclo[221]hepta-25-dienes and 7-azmentioning

confidence: 99%

Chemistry of 7-Azabicyclo[2.2.1]hepta-2,5-dienes, 7-Azabicyclo[2.2.1]hept-2-enes, and 7-Azabicyclo[2.2.1]heptanes

1996

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ContentsI. Introduction 1179 II. Preparation of 7-Azabicyclo[2.2.1]hepta-2,5-dienes and 7-Azabicyclo[2.2.1]hept-2-enes by the [4+2] Cycloaddition Reaction 1179 A. Lewis Acid Catalyzed Reactions 1181 B. High-Pressure and Ultrasound Reactions 1182 C. Reactions with Acetylene Equivalents 1183 D. Miscellaneous Reactions 1183 III. Chemistry of the 7-Azabicyclo[2.2.1]hepta-2,5-dienes and 7-Azabicyclo[2.2.1]hept-2-enes 1184 A. Synthesis of Substituted Pyrroles 1184 B. Synthesis of Substituted Arene Derivatives 1185 C. Synthesis of the Organometallic Complexes 1187 IV. Synthetic Approaches to the 7-Azabicyclo[2.2.1]heptanes 1187 A. Intramolecular Cyclization of Cyclohexylamine Derivatives 1187 B. Reduction of 7-Azabicyclo[2.2.1]hepta-2,5-dienes and 7-Azabicyclo[2.2.1]hept-2-enes 1188 C. [3+2] Cycloaddition Reactions 1189 D. Intramolecular Cyclization of Substituted Proline Derivatives 1189 E. Miscellaneous Reactions 1190 V. Properties of 7-Azabicyclo[2.2.1]heptane Derivatives 1190 A. 7-Azabicyclo[2.2.1]heptane and 7-Azabicyclo-[2.2.1]heptene Derivatives as Potential Chemotherapeutic Drugs 1190

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Section: B Reduction Of 7-azabicyclo[221]hepta-25-dienes and 7-azmentioning

confidence: 99%

Chemistry of 7-Azabicyclo[2.2.1]hepta-2,5-dienes, 7-Azabicyclo[2.2.1]hept-2-enes, and 7-Azabicyclo[2.2.1]heptanes

1996

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“…[13][14][15][16][17][18] Similarly, another well exploited methodology for the synthesis of 1 has employed intramolecular nucleophilic ring closure of 1,4-aminocyclohexane derivatives 7, originally developed for the construction of 7-azanorbornane system, 19 and employs multiple steps even to reach the crucial trans-1,4-aminocyclohexanol derivatives. [20][21][22][23][24][25][26][27] More recently, 28 the elaboration of tropinone skeleton (6) into 1 via Favorskii rearrangement by Bai et al, although elegant, suffers from the poor yield. Moreover, these strategies lack easy adaptability for the synthesis of epibatidine analogues.…”

Section: Introductionmentioning

confidence: 99%

[3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides. 7. Stereoselective Synthesis of Epibatidine and Analogues^,

1998

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Epibatidine (1) is synthesized by employing a [3 + 2] cycloaddition strategy as a key step via nonstabilized azomethine ylide 10, generated by one-electron oxidative double desilylation of N-benzyl-2,5-bis(trimethylsilyl)pyrrolidine (12). Cycloaddition of 10 with trans-ethyl-3-(6-chloro-3-pyridyl)-2-propenoate (22a) gives 26 in which the 6-chloro-3-pyridyl moiety is endo-oriented. Decarboxylation followed by debenzylation gives unnatural epimer 30 of 1. The required cycloadduct 33, in which 6-chloro-3-pyridyl moiety is exo-oriented, is obtained stereoselectively utilizing cis-ethyl-(6-chloro-3-pyridyl)-2-propenoate (22b) as dipolarophile. 30 is also converted to 1 by epimerization reaction using KO(t)()Bu. An alternative route involving conjugate addition of 6-chloro-3-iodo pyridine (37) to 36, obtained by cycloaddition of 10 with ethyl propiolate, is also suggested for the stereoselective synthesis of 1. A number of substituted epibatidines (38, 39, 40, 41, and 42) are synthesized through this strategy using appropriate dipolarophiles. Formal synthesis of the N-methyl homoepibatidine 48 and its epimer 46 is suggested from the cycloaddition of homologous azomethine ylide 44, derived from 43, with 22a and 22b, respectively.

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“…ketone). δ H (300 MHz; CDCl 3 ; Me 4 Si) 8.34 (1H, d, J = 3.0 Hz, pyr H-6),7.66 (1H, dd, J = 9.0, 3.0 Hz, pyr H-4), 7.32 (1H, d, J = 9.0 Hz, pyr H-3), 7.00 (1H, s, H-3), 4.65 (1H, dd, J = 9.0, 3.0 Hz, H-4), 4.16 (1H, m, H-5), 3.36 (3H, s, OCH 3 ), 3.30 (3H, s, OCH 3 ), 2.93 (1H, dd, J = 15.0, 3.0 Hz, H-6), 2.66 (1H, dd, J = 15.0, 12.0 Hz, H-6), 1.40 (3H, s, CH 3 ), 1.36 (3H, s, CH 3 ).…”

mentioning

confidence: 99%

Approaches to the synthesis of (+)- and (−)-epibatidine †

Barros

Maycock

Ventura

2001

J. Chem. Soc., Perkin Trans. 1

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Synthetic approaches to the powerful analgesic alkaloids (ϩ)-and (Ϫ)-epibatidine are described. The starting material employed was natural (Ϫ)-quinic acid from which chiral enones and α-iodoenones were prepared. Stille coupling afforded suitable substrates for completion of the syntheses. A key step in this process was the diastereoselective reduction of a cyclohexanone with sodium borohydride and DMSO which sets up the stereochemistry necessary for the formation of the bicycloheptane system. The synthesis of a previously reported enone intermediate has also been improved.Scheme 6 Reagents and conditions: (a) DEAD, HN 3 , PPh 3 , THF, 0 ЊC/rt, 74%.

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Synthesis of epibatidine

Cited by 38 publications

References 8 publications

Chemistry of 7-Azabicyclo[2.2.1]hepta-2,5-dienes, 7-Azabicyclo[2.2.1]hept-2-enes, and 7-Azabicyclo[2.2.1]heptanes

Chemistry of 7-Azabicyclo[2.2.1]hepta-2,5-dienes, 7-Azabicyclo[2.2.1]hept-2-enes, and 7-Azabicyclo[2.2.1]heptanes

[3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides. 7. Stereoselective Synthesis of Epibatidine and Analogues^,

Approaches to the synthesis of (+)- and (−)-epibatidine †

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Synthesis of epibatidine

Cited by 38 publications

References 8 publications

Chemistry of 7-Azabicyclo[2.2.1]hepta-2,5-dienes, 7-Azabicyclo[2.2.1]hept-2-enes, and 7-Azabicyclo[2.2.1]heptanes

Chemistry of 7-Azabicyclo[2.2.1]hepta-2,5-dienes, 7-Azabicyclo[2.2.1]hept-2-enes, and 7-Azabicyclo[2.2.1]heptanes

[3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides. 7. Stereoselective Synthesis of Epibatidine and Analogues,

Approaches to the synthesis of (+)- and (−)-epibatidine †

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[3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides. 7. Stereoselective Synthesis of Epibatidine and Analogues^,