Base‐Mediated Cyclization of 3‐[2‐(2‐Oxo‐2‐phenylethyl)‐1‐pyrrolidinyl]propanenitrile to 7‐Phenyl‐1,2,3,7,8,8a‐hexahydroindolizine‐6‐carbonitrile: What Lies Between?

Abstract

Three intermediates along the reaction path by which 3‐[2‐(2‐oxo‐2‐phenylethyl)‐1‐pyrrolidinyl]propanenitrile is converted into the rel‐(7R,8aR)‐ and (7R,8aS)‐diastereoisomers of 7‐phenyl‐1,2,3,7,8,8a‐hexahydroindolizine‐6‐carbonitrile upon treatment with potassium tert‐butoxide were isolated and characterized. They include the rel‐(6R,7R,8aR)‐ and (6R,7S,8aS)‐diastereoisomers of 7‐hydroxy‐7‐phenyloctahydroindolizine‐6‐carbonitrile (the former obtained as a monohydrate), and 7‐phenyl‐1,2,3,5,8,8a‐hexahydroindolizine‐6‐carbonitrile. The alcohol intermediates and the final products were also characterized by X‐ray crystallography.

Demethylative Lactonization Provides a Shortcut to High-Yielding Syntheses of Lamellarins

“…In our previous route to lamellarin G trimethyl ether (6), we constructed the pivotal enaminone 8 (R = Bn) by acylation of dihydropapaverine (9) with the benzyl-protected ester 10 9 (Scheme 1, top). However, in view of our extensive experience in the synthesis and use of enaminones as intermediates en route to alkaloids and other nitrogen heterocycles, 12,13 we felt that the route to 6 and related lamellarins could benefit from a more versatile synthesis of 8 and analogues by using an Eschenmoser sulfide contraction 14,15 between α-bromoketones such as 11 and the dihydroisoquinolinethione 12 (Scheme 1, bottom). Furthermore, because microwave heating of 8 with ethyl bromoacetate and potassium phosphate, although very successful in our previous route, suffered from competing alkylation of the phosphate anion and the consequent contamination of the resulting 5,6-dihydropyrrolo[2,1-a]isoquinoline intermediate 13 (R = Bn), 9 we believed that there was room for improvement in this step.…”

“…1 H and 13 C{ 1 H} NMR spectra were recorded on Bruker Avance I 300 MHz, Avance III 400 MHz, and Avance III 500 MHz spectrometers at frequencies of 300, 400, and 500 MHz, respectively, for 1 H spectra and at frequencies of 75, 101, and 126 MHz, respectively, for 13 C spectra. Chemical shifts (δ) of 1 H and 13 C signals recorded in CDCl 3 solution are reported as parts per million (ppm) downfield from Me 4 Si as the internal reference, while spectra recorded in DMSO-d 6 are referenced to the central peak of the solvent. Highresolution mass spectra were obtained on a Bruker Compact Q-TOF mass spectrometer.…”

“…1 H NMR (300 MHz, CDCl 3 , δ): 7.41 (s, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.80−6.71 (m, 2H), 6.50 (s, 1H), 4.25 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.86 and 3.85 (overlapping s, 9H). 13 (18) (5.00 g, 14.4 mmol) was dissolved in CHCl 3 (100 mL), and the solution was cooled in an ice bath. An accurately prepared solution of Br 2 (2.30 g, 14.4 mmol, 1 equiv) in CHCl 3 (50 mL) was transferred to a dropping funnel, and one drop was added to the ketone solution.…”

“…1 H NMR (500 MHz, CDCl 3 , δ): 7.44 (s, 1H), 7.11 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 6.45 (s, 1H), 3.94 (s, 3H), 3.91 (s, 6H), 3.87 (s, 6H). 13 (20). 6,7-Dimethoxy-3,4-dihydroisoquinoline-1(2H)-thione (12) (5.98 g, 26.8 mmol) was added to a solution of the bromoketone 19 (12.0 g, 28.2 mmol, 1.05 equiv) in dry MeCN (150 mL), and the resulting solution was stirred at room temperature for 18 h to ensure complete salt formation, after which time Ph 3 P (7.03 g, 26.8 mmol, 1 equiv) was added.…”

“…1 H NMR (300 MHz, CDCl 3 , δ): 6.76 (s, 2H), 6.74−6.68 (m, 3H), 6.60 (s, 1H), 6.45 (s, 1H), 4.62 (br t, J = 5.5 Hz, 2H), 4.07 (q, J = 7.1 Hz, 2H), 3.87 (s, 6H), 3.83 (s, 3H), 3.66 (s, 3H), 3.64 (s, 3H), 3.56 (s, 3H), 3.35 (s, 3H), 3.06 (br t, J = 6.3 Hz, 2H), 0.98 (t, J = 7.1 Hz, 3H). 13 mL) was added to the ethyl ester 21 (1.30 g, 2.15 mmol), followed by EtOH (100 mL) to ensure complete dissolution of the ester. The pale yellow solution was heated to reflux for 2 h, after which most of the EtOH was removed by rotary evaporation until the potassium carboxylate began to precipitate.…”