Total Synthesis
The complexity of natural products structures has challenged the creativity of synthetic organic chemists for decades. The goal to assemble such compounds artificially in the lab has led to the development of a plethora of innovative synthetic methods and elegant total synthetic approaches to even most complex natural products. In many cases, however, the efficiency of total synthetic routes is not sufficient for the preparation of larger amounts of compound or for broad structure-activity relationship (SAR) studies. Streamlining synthetic efforts by integrating enzymatic key steps has the potential to solve these issues in a sustainable way.
We are particularly interested in using natural product tailoring enzymes that are enabling the fast installation of molecular complexity. An example is our work towards the chemo-enzymatic preparation of sorbicillinoid natural products. Employing the FAD-dependent monooxygenase SorbC, the cognate oxidative enzyme catalyzing site- and enantioselective dearomatization in sorbicillinoid biosynthesis, we have developed streamlined total syntheses accessing a broad range of highly complex members of this exciting natural product family. This approach can also be utilized for the efficient generation of focused analog libraties for SAR studies. In addition, we employ substrate design that enables the expansion of the natural substrate scope of biosynthetic enzymes, in the case of sorbicillinoids by transient substrate structure mimicking.
Further reading:
A. Sib, T. A. M. Gulder; Stereoselective Total Synthesis of Bisorbicillinide Natural Products by Enzymatic Oxidative Dearomatization / Dimerization; Angew. Chem. Int. Ed. 2017, 56, 12888-12891.
A. Sib, T. A. M. Gulder; Chemo-Enzymatic Total Synthesis of Oxosorbicillinol, Sorrentanone, Rezishanones B and C, Sorbicatechol A, Bisvertinolone and (+) - Epoxysorbicillinol; Angew. Chem. Int. Ed. 2018, 57, 14650-14653.
T. M. Milzarek, M. Einsiedler, H. Aldemir, P. M. D'Agostino, J. K. Evers, G. Hertrampf, K. Lamm, M. Malay, A. Matura, J. I. Müller, T. A. M. Gulder; Bypassing Biocatalytic Substrates Limitations in Oxidative Dearomatization Reactions by Transient Substrate Mimicking; Org. Lett. 2019, 21, 4520-4524.
A. Sib, T. M. Milzarek, A. Herrmann, L. Oubraham, J. I. Muller, A. Pichlmair, R. Brack-Werner, T. A. M. Gulder; Chemo-Enzymatic Total Synthesis of Sorbicatechol Structural Analogs and Evaluation of Their Anti-Viral Potential; ChemBioChem 2020. 21, 492–495.