Lessons Learned During Spiroketalization Experiments: Progress and Setbacks in the Preparation of Oxygenated Rubromycins and Synthesis of 3′‐Deoxyheliquinomycinone. Issue 34 (15th November 2016)

• Record Type: Journal Article
• Authors: Wilsdorf, Michael; Sörgel, Sebastian; Reissig, Hans‐Ulrich
• Is Part Of: European journal of organic chemistry. Issue 34(2016)
• Page Start: 5757
• Page End: 5769
• Publication Date: 2016-11-15
• Subjects: 3‐Hydroxyrubromycins -- Spiro compounds -- Solvent effects -- Natural products -- Friedel–Crafts alkylation; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201601225
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract : In this account we disclose our results on the synthesis of 3‐hydroxy‐substituted rubromycin derivatives. We reevaluate our methoxyallene‐based first‐generation approach to this class of natural products, that so far suffered from a notoriously inefficient late‐stage spiroketalization step. While resuming model studies we recognized that the success of this acid‐mediated key transformation is highly solvent‐dependent. Methanol turned out to be the solvent of choice. With one substrate an unexpected intramolecular Friedel–Crafts‐type alkylation provided an interesting hexacyclic side‐product. Based on these observations and with several adjustments to the synthetic route, but still maintaining the original retrosynthetic strategy, here we present a second‐generation approach that eventually allowed the preparation of several rubromycin derivatives (on an up to >100 mg scale) for the first time. Abstract : Methanol pops in, pops out. The inconspicuous action of methanol changes the game for the delicate, acid‐mediated spiroketalization of the synthesis of C‐3 hydroxy‐substituted rubromycin spiroketals.