Synthesis of optically active 1,5-benzothiazepines

Optically active 1,5-benzothiazepines belong to the well known benzothiazepine type substances. Some of them possess important bioactivities. In this review article, optically active 2,3-dihydro-1,5-benzothiazepin-4(5 H )-ones, their 3-amino and 3-hydroxy derivatives, comprising the most important groups of these benzothiazepines, will be discussed in detail. Less known optically active 1,5-benzothiazepines will also be included


Introduction
The 1,5-benzothiazepine is one of the three possible benzocondensed derivatives, viz.1,4-, 4,1and 1,5-benzothiazepines of the 1,4-thiazepine. 1The parent 1,5-benzothiazepine has not yet been published in the chemical literature, but its derivatives are the most frequently investigated benzothiazepine type compounds.2,3-Dihydro-1,5-benzothiazepin-4(5H)-ones are especially popular substances since they possess wide range of bioactivities.Therefore, the 1,5benzothiazepines are useful compounds in the drug research which has stimulated the invention of a wide range of synthetic methods for their preparation and chemical transformations.This is due for the synthesis of optically active 1,5-benzothiazepines as well.
The major aim of this review is to provide examples for the synthesis of the known groups of the optically active 1,5-benzothiazepines.In some cases, the stereochemical studies of the synthesized new compounds are included.Their most important bioactivities will also be discussed together with the synthesis of special groups of substances.
For the synthesis of optically active 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones substituted at position 2 a retrosynthetic approach was invented by Lévai et al. 4 This retrosynthetic approach enabled the first synthesis of optically active 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones without functional groups capable of salt formation.Racemic nitrocarboxylic acids 4 and 5 5 were used as starting materials.Brucine salts of compounds 4 and 5 were crystallized from ethanol until each salt showed constant optical rotation, then the diastereomeric salts were decomposed with dilute hydrochloric acid to afford optically active nitrocarboxylic acid enantiomers.Optically active nitrocarboxylic acids were reduced to the appropriate aminocarboxylic acids 6 and 7 on treatment with Zn powder in acetic acid.Optically active 2,3-dihydro-1,5-benzothiazepin-4(5H)ones 8 and 9 were obtained by the ring closure of the optically active aminocarboxylic acids 6 and 7 in boiling xylene 4 (Scheme 2).

Synthesis and Bioactivities of Optically Active 3-Amino-2,3-dihydro-1,5benzothiazepin-4(5H)-ones
Optically active 3-amino-2,3-dihydro-1,5-benzothiazepin-4-(5H)-ones are especially useful substances in the drug research.One of their important effects is the angiotensin converting enzyme (ACE) inhibitory activity.The angiotensin converting enzyme (ACE) is a dipeptidyl carboxypeptidase catalyzing the hydrolysis of the decapeptide angiotensin I to the octapeptide angiotensin II.This octapeptide is a known vasoconstrictor promoting the release of the aldosterone.As a result, the ACE raises the blood pressure and, therefore, several ACE inhibitors are used to treat the hypertension and congestive heart failure. 18For this reason, a wide variety of ACE inhibitors have been synthesized and tested.In this review, we discuss only the optically active 3-amino-2,3-dihydro-1,5-benzothiazepine type ACE inhibitors.

Conclusions
Chemistry of well known groups of optically active 1,5-benzothiazepines are summarized in this review article.The most important procedures used for their synthesis are discussed with the help of adequate examples.Their most valuable bioactivities are mentioned in brief.Selected original papers included in the References will help the reader to find the original information concerning a special 1,5-benzothiazepine derivative.