One-Pot Tandem Aldol-Cycloetherification Protocol in the Enantioselective Synthesis of Davanoids

Total synthesis of cis and trans diastereomers of prenylated davanoids like davanone, nordavanone, and davana acid ethyl ester was achieved in an enantioselective strategy. Various other davanoids could also be synthesized using standard procedures from the Weinreb amides derived from davana acids. Enantioselectivity in our synthesis was achieved employing a Crimmins' non-Evans syn aldol reaction that fixed the stereo -chemistry of the C3-hydroxyl group, while the C2-methyl group was epimerized in a late stage of the synthesis. A Lewis acid -mediated cycloetherification reaction was used to establish the tetrahydrofuran core of these molecules. Interestingly, a slight alteration of the Crimmins' non-Evans syn aldol protocol led to the complete conversion of the aldol adduct to the core tetrahydrofuran ring of davanoids, thus essentially dovetailing two important steps in the synthesis. The resulting one-pot tandem aldol-cycloetherification strategy enabled the enantioselective synthesis of trans davana acid ethyl esters and 2-epi-davanone/ nordavanone in just three steps in excellent overall yields. The modularity of the approach will enable the synthesis of various other isomers in stereochemically pure forms for further biological profiling of this important class of molecules.

Automated summary

The total synthesis of both cis and trans diastereomers of prenylated davanoids, such as davanone, nordavanone, and davana acid ethyl ester, was accomplished using an enantioselective strategy. By employing a Crimmins' non-Evans syn aldol reaction and a Lewis acid-mediated cycloetherification reaction, the tetrahydrofuran core of these molecules was established. Furthermore, a modification of the Crimmins' non-Evans protocol allowed for the conversion of the aldol adduct to the core tetrahydrofuran ring, facilitating a one-pot tandem aldol-cycloetherification strategy to achieve the enantioselective synthesis of davana acid ethyl esters and 2-epi-davanone/nordavanone in just three steps.