Development of synthetic approaches to 3-acyl-5-hydroxytetramic acids and their application in the total synthesis of intergramycin
Final Report Abstract
In summary, we developed a useful preparative procedure for the synthesis of 5-hydroxy-3-acyltetramic acids. It was established that such compounds require some special handling and can only be purified by reverse phase HPLC. We also found that DMB protecting group should be preferentially used in the synthesis of 5-hydroxy-3-acyltetramic and can be cleaved by treatment with DDQ. The construction of the octalin core of the integramycin was studied using several model substrates. Unfortunately, a thermally activated Diels-Alder reaction produced the undesired cycloadduct. Therefore, an alternative approach based on alkyne-IMDA was pursued. The model substrates with different protecting group patterns was produced and treated with Rh-based Lewis acid catalyst. The best ratio was obtained for the substrate with two silicon ether protecting groups. As a result of these studies, a significant progress towards the total synthesis of complex natural product integramycin was achieved. Using advanced extended alkyne sulfone building block, the spiroketal intermediate was converted into the substrate for the intramolecular Diels-Alder reaction. The IMDA reaction itself was partially successful and produced the two expected adducts. After completion of the octalin core via conjugate reduction or some other methodology, the installation of the hydroxylated tetramic acid will be performed. Thus, we expect to complete the total synthesis of integramycin in the near future.
Publications
- (2013) Synthesis of the Spiroketal Core of Integramycin, Beilstein J. Org. Chem., 9, 2446–2450
Prusov EV
(See online at https://dx.doi.org/10.3762%2Fbjoc.9.282) - (2015) A Simple and Efficient Method for the Preparation of 5-Hydroxy-3-acyltetramic acids. Beilstein J. Org. Chem., 11, 323–327
Trenner J, Prusov EV
(See online at https://doi.org/10.3762/bjoc.11.37)
