The 13C spectra of a series of thyroid hormones and derivatives including thyroxine (T4) sodium salt, T,-N-acetyl methyl ester, triiodothyronine (T3), T,-sodium salt, T3-methyl ester hydrochloride, sodium triiodothyroacetate apd ethyl triiodothyropropionate were assigned using chemical shift trends from model compounds, coupling constants and relaxation times. The 13C spectra of a series of diphenyl ethers were assigned and the chemical shift trends observed were analyzed on the basis of conformational changes engendered by mesomeric or steric effects.The importance of the thyroid hormones thyroxine (T4, 1) and 3,5,3'-triiodothyronine (T,, 2) in regulating metabolic processes has resulted in numerous studies being conducted on these materials.' A wide variety of R'I' 1, T4, R = I 2, T , , R = H derivatives of T, and T3 have been found to possess hormonal activity, including molecules in which the diphen 1 ether oxygen is replaced by a methyleneThe possible importance of conformational factors was pointed out by Zenker and Jorgensen3 who studied the 3,5-diiodo-2',5'-dimethyl-(3) and 33-diiodo-2',3'-dimethyI-thyronines (4) and found that the latter compound had 100 times the activity of the former. These authors reasoned that the steric interaction of the 2-methyl group with the A ring iodines would be sufficient to lock the molecules in a pair of conformations in which the methyl group ortho to the hydroxyl group is syn to the A ring (3) and anti to the A ring (4). In a molecule such as T3 the corresponding conformations are termed the proximal and distal conformers. It was suggested that the distal conformer was the biologically active species and this is in accord with later experiments which showed that thyroxine binding globulin binds preferentially to d i~t a l -T ,~ and that T4 undergoes deiodination to T3 in peripheral tissue. ' Crystallographic studies have shown that a number of T3 derivatives exist in the distal conformation 6-8group. z * Authors to whom correspondence should be addressed.(T3; T,-methyl ester; 3,5,3'-triiodothyroacetic acid diethanolamine salt), while an equal number of derivatives exist as the proximal (T, * HC1; 3,5,3'-triiodothyropropionic acid ethyl ester; 3'-isopropyl-3,5-diiodothyronine hydrochloride).Recent NMR studies on a series of T, and T4 model compounds12 and on T,-N-acetyl methyl ester', have determined barriers to rotation around the 0-C-1' bond in the range of 7.9-8.6 kcal m-'. These values, which are reasonably close to theoretical calculat i o n~, '~ indicate that both conformers are easily accessible in solution and that rotational barriers do not determine the activity of these compounds.One important point still to be determined is the solution conformations of the thyroid hormones. As part of our program to study the solution conformations of the thyroid hormones using lanthanide shift reagents (LSR's), it was necessary to carry out the I3C assignments of a number of hormone derivatives and model compounds.It was hoped that the conformational mobility of these sys...

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The barrier to rotation in the N-acetyl methyl ester of the thyroxine was found to be 8.6 kcal mol-1. Previous experiments determining the barrier to rotation in triiodothyropropionic acid in HCl-ethanol were shown to be in error.

A series of diphenyl ethers linked to 2-azabicyclo[2.2.2]octan-3-ones and 2-azabicyclo[2.2.1]heptan-3-ones were synthesized as substrates for conformational analysis using the lanthanide shift reagent NMR technique. The materials were prepared by displacement of the exo-6-tosyloxy bicyclic lactam with the corresponding phenoxide which results in formation of the phenyl ether with retention of stereochemistry. This double-inversion process presumably involves anchimeric assistance by the lactam nitrogen. The synthesis and properties of a number of these systems are described. Complete 13C assignments for the series are presented.

Aus den überbrückten Hydroxylactame (Ia)‐(IIIa) werden über die Tosylate (b‐Reihe) mit entsprechenden Alkoholaten und Phenolaten zahlreiche Ether hergestellt.