Syntheses of the potent angiotensin converting enzyme inhibitor (3S)-1-(carboxymethyl)-3-[[(1S)-1-carboxy-3-phenylpropyl]amino]- 2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (4b; CGS 14831) and the related monoester prodrug (17a; CGS 14824A) are described together with preparative details for six- and eight-membered ring analogues. Inhibitory potencies and in vivo biological activity of the compounds are discussed. The data indicate that 17a has a biological profile comparable to that of enalapril.

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Syntheses of the potent angiotensin converting enzyme inhibitor 1-(carboxymethyl)-3-(mercaptomethyl)-2,3,4,5-tetrahydro-1H-1- benzazep in -2-one (4a) and the corresponding eight-membered ring analogue (4b) are described. The influence of ring size on the inhibitory potencies of these substances is discussed.

Treatment of 3-(p-tolyloxy)thiophene (3) with phenyllithium followed by carbonation with C02 was found to be a convenient procedure for the preparation of the thiophene-2-carboxylic acid 4, which was cyclized to 5 with PPE. Treatment of 3 with butyllithium followed by carbonation gave the thiophene-2,5-dicar boxylic acid 8 which was cyclized to 9. Alkaline permanganate oxidation of 4 gave the diacid 10, which was cyclized to the tricyclic acid 11. Similar lithiation reactions were observed with additional 3-(aryloxy)thiophenes and with 3-(arylthio)thiophenes, and xanthone analogues were prepared from the resulting intermediates.A number of antiallergy agents possess xanthone-like structures, and with this in mind we decided to explore new synthetic routes to thiophene-containing structures.The only reported synthesis of 9 1) is that of Morel et al.,1 who con-Scheme I densed 3-methoxythiophene2 3with o-anisoyl chloride and cyclized the resulting dimethoxy ketone 2 with pyridinium chloride. We envisioned that compounds such as 1 could be prepared from 3-(aryloxy)thiophenes via regioselective lithiation/carbonation2,3 and cyclization to the tricyclic system.This concept was realized in the following manner. 3-Bromothiophene was condensed4 with p-cresol (Scheme I) to give 3. Treatment of this substance with 1 equiv of phenyllithium was followed by carbonation with solid C02 in ether at -78 °C. Only one product was isolated, and this was shown to be 4, on the basis of its NMR spectrum and its cyclization to 5 with PPE in refluxing chloroform.5The lithiation/ carbonation of 3-phenoxythiophene was examined in detail, and the results are summarized in Scheme . By use of conditions similar to those described above, 3-phenoxythiophene-2-carboxylic acid (6) was obtained in good yield and was cyclized to the unsubstituted xanthone analogue l.1 However, when the entire acidic product from the lithiation/ carbonation was subjected to the cyclization conditions, a small amount of acidic material remained. This was identified (NMR) as 4-phenoxythiophene-2-carboxylic acid (7) and comprised 1.7% of the original carboxylic acid mixture. Thus, the regioselectivity of the lithiation/ carbonation of 3-phenoxythiophene was 98.3%. When the lithiation was conducted with 2 equiv of n-butyllithium at 0 °C, again two acids were formed. In this case, the second product was the thiophene-2,5-dicar boxylic acid (8), which amounted to 40% of the product. This substance was cyclized to the xanthone analogue with the carboxy function on the thiophene ring (9).