Synthetic development towards benzodiazepine alkaloids : total synthesis of circumdatin F and C

Benzodiazepine alkaloids exhibit a multitude of interesting pharmacological activities. This thesis deals with the development of synthetic methods towards such alkaloids, of which the main efforts can be divided into three parts.

The first part describes the total synthesis of circumdatin F and C, which both possess a quinazolin-4(3H)-one as well as a 1,4-benzodiazepin-5 -one moiety and incorporated L-alanine. The difference between circumdatin F and C is a hydroxyl substituent in the aromatic ring of the benzodiazepinone moiety in circumdatin C. A tripeptide derivative was synthesised in two different ways to form a key intermediate, starting from methyl anthranilate and Cbz-L-Ala. The synthetic strategy was to induce cyclisation involving one six-membered and one seven-membered ring' accomplished by dehydration of the tripeptide to a benzoxazine, via rearrangement to an amidine intermediate, the natural products were obtained by cyclisation on silica gel. Additionally, new types of fused oxazepinones, which are analogues of the benzodiazepine alkaloids sclerotigenin and circumdatin F, were prepared in a 2 step synthesis from 2-(2-amino-benzoylamino) benzoic acid or its corresponding methyl ester.

In the second part of the thesis, a high-yielding synthesis of 2vinylquinazolin-4(3H)- one, 3-methyl-2-vinylquinazolin-4(3H)-one, 2-(1chlorovinyl)-quinazolin-4(3H)-one and 2-(1-bromovinyl)-quinazolin-4(3H)one have been prepared from anthranilamide and the appropriate acid chloride. These derivatives participated readily in nucleophilic addition reactions, with both carbon and nitrogen nucleophiles.

The third part describes synthetic approaches towards the synthesis of auranthine, which possesses a quinazolin-4(3H)-one, a 1,4-benzodiazepin-5one and a glutamine moiety. An auranthine precursor, 3-[2-(4-oxo-3,4dihydroquinazolin-2-yl)-ethyl]-3,4- dihydro-1H-benzo[e][1,4]diazepine-2,5 dione, was prepared. Several attempts have been made to cyclise the auranthine precursor with little success except for one type of reaction, which involved dehydration with 50% propylphosphonic acid anhydride solution in ethyl acetate and DMA. A solid of low solubility was collected and characterised as a C-acetyl derivative of auranthine.

List of scientific papers

I. Witt A, Bergman J (2001). "Total syntheses of the benzodiazepine alkaloids circumdatin F and circumdatin C. " J Org Chem 66(8): 2784-8
https://pubmed.ncbi.nlm.nih.gov/11304202

II. Witt A, Bergman J (2001). "Oxygen analogues of the benzodiazepine alkaloids sclerotigenin and circumdatin F." J Heterocycl Chem (In Print)

III. Witt A, Bergman J (2000). "Synthesis and reactions of some 2-Vinyl-3H-quinazolin-4-ones." J Tetrahedron 56: 7245-53

IV. Witt A, Gustavsson A, Bergman J (2001). "Synthetic studies towards the benzodiazepine alkaloid auranthine. Synthesis of an acetylated derivative." (Manuscript)

V. Witt A (2001). "Appendix: Supplementary Material" (Manuscript)