Conformational studies of 1,3-thiazolidines

Abstract

The nmr spectra of 1,3-thiazolidine, 2-fer/-butyl-l,3-thiazolidine, V,S-diacetylcysteamine, N,N,S-triacetylcysteamine, cysteamine hydrochloride, sodium 2-aminoethylmercaptide, and bisaminoethyl disulfide have been obtained and completely analyzed. On the basis of the coupling constants the thiazolidines are considered to exist in conformations close to envelopes with either C-4 or C-5 as the flap atom and with the 2 substituent anti to the flap (2 or 3a). Conformational analysis of five-membered rings by nmr methods is often made difficult by the profusion of nearly equienergy conformers which must be considered and by the inadequacy of the Karplus equation for determination of reliable rotational angles. In spite of these difficulties, considerable progress has been made with five-membered rings having an ethylene group isolated by heteroatoms in the 1 and 3 positions. These include 1,3-dioxolanes,2-8 1,3-dithiolanes,9 and 1,3-oxathiolanes.9-11 Research in these laboratories directed toward analyzing preferred conformations of coenzyme A necessitated study of the nmr spectra of acyclic cysteamine derivatives possessing an ethylene bridge separating sulfur and nitrogen atoms. A study of 1,3-thiazolidine and its 2-teri-butyl derivative was also needed as a means to define model coupling constants for gauche-and trans-related vicinal protons in the SCH2CHoN unit. The results of these investigations of model systems permit us to discuss the preferred conformation of the thiazolidines studied and to compare the rotational angles of thiazolidines to those of previously studied heterocycles. ResultsjV.S-Diacetylcysteamine (I) and N,N, S-triacetylcysteamine (II) together with N-acetylcysteamine (III) were all obtained by acetylation of cysteamine using an (1) Taken from the Ph.D. Thesis of T. J. B. submitted in partial fulfillment of the requirements for the Ph.D. degree in chemistry of the Polytechnic Institute of Brooklyn.(2) F. Alderweireldt and M. Anteunis, Bull Soc. Chim. Belg., 74, 488 (1965).

A multinuclear NMR study of derivatives of thiazolidine

“…All the compounds studied below 273 K have at least one coupling constant ( J 2 , 3 or J3,4) larger than 12 Hz; for 2-unsubstituted compounds, the value of coupling constant between H-3 and the second H-2 is included between 6.5 and 7. 5 Hz. So using the stereochemical dependence of vicinal coupling constants in the HCNH fragment, it is possible to determine in those compounds the orientation of the N-H bond and of the 2and 4-substituents: the values observed in thiazolidines are only consistent with an axial N-H bond.…”

Synthetic routes to nucleoside analogs of N-substituted 1,3-thiazolidines

“…To gain some understanding of the dependence of the stereochemical outcome of this reaction on the type of system involved, 4(R)-carboxythiazolidine hydrochloride (15), prepared from L-cysteine hydrochloride inonohydrate (9) by treatment with formaldehyde (S), was subjected to each of the benzoylation conditions (see Scheme 2). Thus, treatment of 15 with benzoyl chloride in pyridine and subsequent methylation of the product afforded optically active 3-benzoyl-4(R)-(iiiethoxycarbonyl)thiazolidine (16 when the benzoylation reaction was carried out in chloroform containing 2 equiv. of pyridine, the product 17 obtained after methylation showed a slight loss of optical activity.…”

“…Previous studies (14) of the conformations of five-membered rings containing hetero atoms have indicated that the ring may exist in a variety of interconverting pseudorotational forms, although the presence of potential energy barriers in certain systems owing to the nature, number, positions, and steric requirements of the substituents sometimes restricts such pseudorotation and gives rise to preferred conformations of the five-membered ring having definite energy minima (15)(16)(17). The diastereotopic methylene proton signals appear in the spectrum of 18b at 3.22 and 3.51 ppm: the higher field signal appears as a doublet of doublets with a vicinal coupling constant (J,,,) of 7.7 Hz, whereas the lower field signal appears as a broadened doublet with a vicinal coupling constant (J,,,,) of about 0 Hz.…”

“…A racemic mixture of 3-benzoyl-4-methoxycarbonyl-2,2-dimethylthiazolidine (14) (15) 4(R)-Carboxythiazolidine (1.34 g, 10 mmol), obtained from L-cysteine hydrochloride monohydrate (9) by the method of Ratner and Clarke (8) was dissolved into 2N hydrochloric acid (5 ml) and then water was immediately evaporated to give the hydrochloride 15 as white crystals (1.72 g, 100%). (16) To a solution of 4(R)-carboxythiazolidine hydrochloride (15) (500 mg, 3 mmol) in pyridine (50 ml, 620 mmol) at 0°C was added benzoyl chloride (424 mg, 3 mmol) and the mixture was stirred for 8 h at room temperature. Pyridine was evaporated and the residue was dissolved in dichloromethane (100 ml).…”

Structure of 2-(p-chlorophenyl)thiazolidine

“…As can be seen from the torsion angles, the thiazolidine ring of the 2PT and 2CPT molecules adopts an envelope conformation (Wilson & Bazzone, 1974;Baert, Muller, Barbry & Couturier, 1987). The best leastsquares plane through four of the five ring atoms of both molecules omits the N atom (Chacko, 1974;Goodman, Chen, Benedetti, Pedone & Corradini, 1972;Loscalzo, Kallen & Voet, 1973;Parthasarathy, Paul & Korytnyk, 1976).…”