Studies towards the total synthesis of mumbaistatin: synthesis of highly substituted benzophenone and anthraquinone building blocks

Model compounds and building blocks for a planned total synthesis of the highly potent glucose-6-phosphate (G6P) translocase inhibitor mumbaistatin (1) and structural analogs were elaborated: compound 1 represents a lead structure in the development of potential new antidiabetic drugs. With the model substrate 20 it was demonstrated that highly functionalized, tetra-ortho-substituted benzophenones can be prepared by nucleophilic addition of an aryllithium-building block to a benzaldehyde followed by oxidation. For compound 37, a potential precursor of the anthraquinone part of mumbaistatin, various approaches via aryne/phthalide annulations were developed and evaluated. The required functionalized arenes were prepared exploiting, among others, regioselective bromination and ortho-lithiation reactions. Coupling reactions of the anthracene-carbaldehyde 44 derived from 37 with various metalated arenes proved to be unexpectedly difficult and failed so far. (C) 2003 Elsevier Science Ltd. All rights reserved.