Cyclopropylmethyl S-adenosyl-l-methionine: an enzymatic cyclopropylmethyl donor

The cyclopropylmethyl group has been valued in medicinal chemistry for its stereoelectronic properties in optimizing drug stability and target affinity. Selectively introducing a cyclopropylmethyl group is a challenge in organic synthesis. Here, we developed an enzymatic approach using a cyclopropylmethyl-S-adenosylmethionine analogue (CPM-SAM) and methyltransferases. CPM-SAM was prepared using an engineered AclHMT from iodomethyl-cyclopropane and S-adenosylhomocysteine. Enzyme cascades with engineered N-, S-, C-, and O-methyltransferases selectively cyclopropylmethylate diverse substrates under mild conditions. This strategy demonstrates the potential of SAM analogues and engineered methyltransferases in the late-stage incorporation of cyclopropylmethyl groups into bioactive molecules.