Lessons Learned During Spiroketalization Experiments: Progress and Setbacks in the Preparation of Oxygenated Rubromycins and Synthesis of 3′-Deoxyheliquinomycinone

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.