Synthesis of N‐(3‐Phenylpropyl)‐Substituted Tricyclic ABE Ring Analogues of the Alkaloid Methyllycaconitine

Abstract

The synthesis of several ABE tricyclic analogues 5, 31 and 32 of the alkaloid methyllycaconitine (1) is reported. The analogues contain two key pharmacophores: a tertiary N-(3-phenylpropyl) substituent attached to a 3-azabicyclo-[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)benzoate ester. Double Mannich reaction of the cyclic β-keto esters 6 and 17 with the bis(aminol) ether 7 using methyltrichlorosilane as an activating agent provided an efficient method for the construction of the 3-azabicyclo[3.3.1]nonanes 8 and 18. Ring-closing metathesis of the derived dienes 11, 19, and 20 afforded the tricyclic ethers 12, 21, and 22, respectively, the C-8 ester of which was reduced

Synthesis of AE and BE Ring Analogues of the Alkaloid Methyllycaconitine

“…with neopentyl‐type alcohols in dry acetonitrile using 10 mol‐% of DMAP and 2 equiv. of DCC for 6 h has been reported 32. In the present work however, these conditions failed to effect conversion of alcohol 16a to anthranilate ester 17a .…”

Synthesis of Bridgehead-Substituted Azabicyclo[2.2.1]heptane and -[3.3.1]nonane Derivatives for the Elaboration of α7 Nicotinic Ligands

“…The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated under reduced pressure. A 35.88 g (95% yield) amount of desired compound 4 was thus isolated as a pale yellow oil and was engaged in the following step without purification: 1 5-Chloromethyl-2-methoxypyridine (5). At 0 °C, to a solution of (6-methoxy-pyridin-3-yl)methanol (4; 58 g, 416.8 mmol) in toluene (480 mL) was added 39.5 mL (64.46 g, 541.8 mmol) of thionyl chloride dropwise, the temperature being maintained around 0 °C.…”

“…The title compound was obtained in 97% yield (8.5 g) as a pale yellow oil from 13 according to general procedure D. 1 H NMR (200 MHz, CDCl 3 ) δ 8.07 (d, J = 2.5 Hz, 1 H), 7.50 (dd, J = 8.7, 2.6 Hz, 1 H), 6.70 (d, J = 8.7 Hz, 1 H), 3.89 (s, 3 H), 3.45 (t, J = 6. 5 3 0 -(3-Bromopropyl)-1 0 ,2 0 ,3 0 ,4 0 ,5 0 ,6 0 -hexahydro[3,3 0 ]bipyridinyl-6-ol Hydrobromide (15). The title compound was obtained in quantitative yield (12.9 g) as a brown powder from 14 according to general procedure E: 1 H NMR (400 MHz, D 2 O) δ 7.93 (d, J = 9.3 Hz, 1 H), 7.66 (s, 1 H), 6.85 (d, J = 9.5 Hz, 1 H), 3.68 (d, J = 13.2 Hz, 1 H), 3.44 (s, 2 H), 3.33 (d, J = 13.9 Hz, 1 H), 3.23 (m, 2 H), 2.35 (m, 1 H), 1.88 (m, 6 H), 1.54 (m, 1 H); J-MOD 13 3-Cyano-3-pyridin-3-ylpentanedioic Acid Diethyl Ester (18).…”

“…The title compound was obtained in 84% yield (17 g) as a brown oil from 17 according to general procedure A: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.76 (dd, J = 2.5, 0.6 Hz, 1 H), 8.52 (dd, J = 4.7, 1. 5 (5-Oxo-3-pyridin-3-ylpyrrolidin-3-yl)acetic Acid Ethyl Ester (19). The title compound was obtained in 65% yield (9.5 g) as an orange oil from 18 according to general procedure C: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (dd, J = 2.4, 0.5 Hz, 1 H), 8.44 (dd, J = 4.7, 1.5 Hz, 1 H), 7.75 (br s, 1 H), 7.70 (ddd, J = 8.0, 2.4, 1.6 Hz, 1 H), 7.35 (ddd, J = 8.0, 4.7, 0.7 Hz, 1 H), 3.85 (q, J = 7.1 Hz, 2 H), 3.68 (d, J = 10.1, 0.7 Hz, 1 H), 3.54 (d, J = 10.1 Hz, 1 H), 2.88 (d, J = 14.9 Hz, 1 H), 2.83 (d, J = 14.9 Hz, 1 H), 2.69 (d, J = 16.…”

“…For over 10 years, the identification of new potent and selective α7 nicotinic ligands has attracted both pharmaceutical companies and academic groups. − These molecules open the opportunity of new promising treatments for cognitive dysfunction related pathologies (e.g., schizophrenia, Alzheimer’s disease). − Among the wide panel of chemical series developed for this purpose, some of them carry an azabicyclic moiety where the nitrogen atom is positioned at the bridgehead. − In most cases, aromatic or heteroaromatic functional groups are carried by the carbon atoms located on the bridges but not on the opposing bridgehead position of the azabicyclic moiety (Figure ).…”