Tools for the differential alkylation of natural products

Properties of small molecules are dramatically influenced by altering their structural and functional diversity; a feature that has inspired the development of chemoenzymatic strategies to manipulate small molecule pharmacology via differential attachment of groups. Methyltransferases (MTs) use S-adenosyl-L-methionine (SAM) as methyl donor and capable of utilizing SAM-analogues to differentially alkylate DNA, proteins, and natural products (NPs). Hence a platform to co-opt natural product MTs for natural product differential alkylation (alkylrandomization) will dramatically expand the potential scope of NP chemical diversity. The full potential of this technology is stifled by several impediments, including the instability, poor synthetic yield and diastereomeric mixtures associated with SAM or corresponding analogues. Within this context, a general platform to enable the generation and direct utilization of SAM analogues, beginning from stable precursors, would be considered advantageous. We propose novel chemoenzymatic strategies that rely upon methionine adenosyltransferases (MATs) and stable methionine analogues to synthesize SAM analogues and thereby opens the door to the further interrogation of MTs which operate upon macromolecular (protein/nucleic acid) and small molecule (NPs) substrates. Finally, the strategy presented can be utilized in a single vessel reaction for the differential alkylation of natural products.