Synthetic studies towards 7- and 8-membered N-heterocycles, particularly 1,4-pyrrolobenzodiazepines : total synthesis of fuligocandin A and B

This dissertation is concerned with the synthesis of 7- and 8-membered N-heterocycles, particularly 1,4-pyrrolobenzodiazepines. A non-chromatographic method for conversion of carbonyl-functionalities to the corresponding thiocarbonyls is described.

A formal total synthesis of the pyrrolobenzodiazepine natural product DC-81 was developed starting from vanillin. The tricyclic core structure was successfully obtained in 6 steps and several approaches for transformation of this key diamide to obtain the target molecule DC-81 was investigated.

A convergent and concise synthesis of the pyrrolobenzodiazepine natural products fuligocandin A and B was developed employing Eschenmoser sulfide contraction as a key step. Fuligocandin B could be obtained in optically active form and the method was applied to obtain a number of vinologous amides.

The thionating power of a reagent obtained from P4S10 and pyridine was investigated and the actual structure of the crystalline reagent could for the first time be conclusively determined and confirmed by X-ray crystallography. A range of carbonyl compounds have been converted to the corresponding thiocarbonyl derivatives without the need for chromatographic purification.

The final part of this thesis features synthetic studies towards 7- and 8-membered heterocycles starting from anthranilnitrile. Accordingly, addition of Grignard reagents to N-acylderivatives of anthranilonitrile resulted in the formation of 1,4-benzodiazepin-3-ones and the method was also applied to obtain the higher homologue 1,5-benzodiazocin-4-one. Furthermore, the imino-intermediates initially formed by reaction of anthranilonitrile and Grignard reagents could be transformed to dibenzo-1,5-diazocines. Thus, an unusual briged N-heterocycle was isolated and its structure was confirmed by X-ray crystallography.

List of scientific papers

I. Practical, high-yielding formal synthesis of the DNA-binding antitumor agent pyrrolo(2,1-c][1,4]benzodiazepine-5-one, DC-81, starting from vanillin. Birgitta Pettersson, Vedran Hasimbegovic, Jan Bergman. [Manuscript]

II. Total synthesis of fuligocandines A and B. Birgitta Pettersson, Vedran Hasimbegovic, Jan Bergman. Tetrahedron Letters. 2010, 51, 238-239.
https://doi.org/10.1016/j.tetlet.2009.10.134

III. One-pot Eschenmoser episulfide contractions in DMSO: Applications to the synthesis of fuligocandins A and B and a number of vinylogous amides. Birgitta Pettersson, Vedran Hasimbegovic, Jan Bergman. Journal of Organic Chemistry. 2011, 76, 1554-1561.
https://doi.org/10.1021/jo101864n

IV. Thionations using a P4S10-pyridine complex in solvents such as acetonitrile and dimethyl sulfone. Jan Bergman, Birgitta Pettersson, Vedran Hasimbegovic, Per H. Svensson. Journal of Organic Chemistry. 2011, 76, 1546-1553.
https://doi.org/10.1021/jo101865y

V. Synthetic studies towards 1,5 benzodiazocines. Birgitta Pettersson, Jan Bergman, Per H. Svensson. [Manuscript]

VI. Synthesis of 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones by addition of Grignard reagents to derivatives of o-aminobenzonitrile. Birgitta Pettersson, Anna Rydbeck, Jan Bergman. Organic & Biomolecular Chemistry. 2009, 7, 1184-1191.
https://doi.org/10.1039/b819260j