The peptide hormone ghrelin plays a key role in regulating hunger and energy balance within the body. Ghrelin signaling presents a promising and unexploited target for development of small-molecule therapeutics to treat obesity, diabetes, and other health conditions. Inhibition of ghrelin O-acyltransferase (GOAT), which catalyzes an essential octanoylation step in ghrelin maturation, offers a potential avenue for controlling ghrelin signaling. Through screening a small molecule library, we have identified a class of synthetic triterpenoids that efficiently inhibit ghrelin acylation by the human isoform of GOAT (hGOAT). These compounds function as covalent reversible inhibitors of hGOAT, providing the first evidence for involvement of a nucleophilic cysteine residue in substrate acylation by a MBOAT family acyltransferase. Surprisingly, the mouse form of GOAT does not exhibit susceptibility to cysteine modifying electrophiles revealing an important distinction in the activity and behavior between these closely related GOAT isoforms. This study establishes these compounds as potent small molecule inhibitors of ghrelin acylation and provides a foundation for the development of novel hGOAT inhibitors as therapeutics targeting diabetes and obesity.

Trichloroacetimidates are useful reagents for the synthesis of esters under mild conditions that do not require an exogenous promoter. These conditions avoid the undesired decomposition of substrates with sensitive functional groups that are often observed with the use of strong Lewis or Brønsted acids. With heating, these reactions have been extended to benzyl esters without electron donating groups. These inexpensive and convenient methods should find application in the formation of esters in complex substrates.

1,1'-Diarylbutyl groups are a common pharmacophore found in many biologically active small molecules. To access these systems under mild conditions, the reaction of diarylmethyl trichloroacetimidates with allyltributylstannanes was explored. Simply heating allyltributylstannane with the trichloroacetimidate resulted in substitution of the imidate with an allyl group. Unlike other methods used to access these systems, no strong base, transition metal catalyst, Brønsted acid or Lewis acid promoter was required to affect the transformation. Conversions are best with electron rich benzylic trichloroacetimidate systems, where excellent yields are achieved just by refluxing the reactants together in nitromethane.

Benzylic trichloroacetimidates are readily displaced by trimethylaluminum under Lewis acid promoted conditions to provide the corresponding methyl substitution product. This method is a convenient way to access 1,1'-diarylethanes and related systems, which play a significant role in medicinal chemistry, with a number of systems owing their biological activity to this functionality. Most benzylic substrates undergo ready displacement, with electron deficient systems being the exception. The use of an enantiopure imidate showed significant racemization, implicating the formation of a cationic intermediate.

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