Hindered Diphenyl Ethers Related to the Bisbenzylisoquinoline Alkaloids

Abstract

Sixteen steps from vanillin led to syntheses of ( a ) dimethyl 3-(4'-carbornethoxyphenoxy)-4,5-dimethoxyphthalate ( I c ) , a known degradation product of isochondrodendrine, and (b) the more hindered dimethyl 3-(4'-carbomethoxy-2'-methoxyphenoxp)-4,5-dimethoxyphthalate ( I a ) , which has not been derived from any alkaloid, though the usual concepts of biosynthesis do not rule out the occurrence of alkaloids which could lead to it. Diphenyl ethers related to l a would be expected to show the effects of steric hindrance, but even with the most hindered member of the group, 7-(41-carboxy-21-iodophenoxy)metameconine ( V A e ) , no evidence for a n appreciable half-life of rotational isomers could be obtained. Attempts to make diphenyl ethers through the condensation of phenols with dicyclohexylcarbodiimide led to other products.Diphenyl ethers of type I are of interest both because of their relationship to the bisbeilzylisoquii~oline alkaloids, and because of their place in the study of steric effects in diphenyl ethers. For example, the ester Ia would be expected to arise froin the hypothetical alkaloid IIa in the same reactions that actually gave Ic as the degradation product of the dimethyl ether of isochondrode~ldrine (IIb) (I). Indeed, our whole study of diphenyl -ethers arose from the efforts of Dr. J . A. McRae and his students to forin the ester Ia, the same biosynthetic argument3 that had succeeded for the structure of isochondrodendrine leading them to suppose IIa to be a probable structure for the alkaloid cularine (2, 3). The synthesis of Ia proved unexpectedly difficult, and the challenge presented by the difficulty maintained our interest even when it became apparent many years ago that Ia was not in fact closely related to cularine (111) (3).The early efforts of Dr. RllcRae and his students t o synthesize Ia had several practical results. Prolonged attempts to use the Ullmann reaction directly led t o the independent discovery of the transinethylation side reaction (5-7). Attempts to use the phthalide group as a guarded source of carboxyl groups led to two lines of attack continued in the present work: a study of the place of steric hindrance in the synthesis of diphenyl ethers (5, 9, 10, 13), and an extensive development of the chemistry of metameconine (IVa) (5,(8)(9)(10)(11)(12). Oxidation of the metameconines yielded phthalic acids. One of these (9) was related to pellotine (14) and to capaurine (15, 16), and another (11), an essential link in determining the structure of the bisbenzylisoquinoline alkaloids bebeerine and tubocurarine (17, 18), was synthesized by methods which added greatly to the security of its proof of structure.

The Principal Conformations of Some Ortho-Substituted Diphenyl Ethers

“…The 1l.m.r. spectrum of the present sample was identical with that of the sample made in the previous worl; (18).…”

“…A few substances, ~nentioned in the introductio~l but not in the sections below, were available as analytical samples from previous work (16)(17)(18)24).…”

“…ZThe asymmetry of ethers of low steric hindrance has been shown by ultraviolet spectroscopy (1-3), dipole moments (4-7), electron and X-ray diffraction (8-lo), microwave absorption, and relaxation times (11)(12)(13)(14), and from theoretical calculations of ultraviolet spectra (15). For highly hindered diphenyl ethers, the fact has been assumed from a sttrdy of models (3, [16][17][18]. …”

A Study of the Barriers to Rotation in Some Highly Substituted Diphenyl Ethers

“…1) are dissymmetric (without reflection symmetry) in this conformation and could, in principle, be resolved into optical isomers. Several attempts to carry out resolution have, however, failed (3)(4)(5)(6)(7). Since rotation of either or both rings about the ether linkage would convert 1 to either an enantiomer or a diastereomer (see Discussion), it is of interest to determine the magnitude of the energy barriers for these rotational processes.…”

A Series of Model Compounds for the Study of Aromatic Reactions

“…159..5161.5°. When the cold solution of diazotized 4-amino-7-nitrometan~econine from 3 g of the amine was poured into a mixture of water, chloroform, urea, potassiunl iodide, and iodine in the more elaborate procedure used in previous examples (8,15), the total yield of once-crystallized product was only 76y0. Three more recrystallizations of the first fraction of this material from ethanol gave the analytical sample, m.p.…”