Raymond L. Funk

Synthesis of Molecules with Useful Biological Properties

Synthetic organic chemistry has undergone significant growth over the past two decades as a result of the rational development of new methods for controlling stereochemistry and/or constructing ring systems. It is our goal to contribute to the further advancement of this field and then apply our new methods in the synthesis of complex natural products or other compounds which might also possess useful biological properties.

Four mechanistically distinct methods developed in our laboratories that are representative of this endeavor are illustrated below. Thus, the Claisen-rearrangement-mediated ring contraction of macrocyclic lactones provides a stereocontrolled route to both carbocycles and heterocycles (eq. 1). In separate work, Lewis-acid-promoted cyclization of b-ketoesters with acetals allows rapid access to 2-carbalkoxycyclo-alkenones (eq. 2). Third, stabilized carbanions participate in intramolecular carbometalation reactions with alkoxyacetylenes to furnish functionalized cyclic enol ethers (eq. 3). Finally, retrocycloaddition reactions of substituted dioxins constitutes a mild and versatile preparation of new types of substituted acroleins (eq. 4).

These novel methods are currently in various stages of refinement and application. For example, the projected synthesis of the cytotoxic marine natural product acalycixeniolide A employs the ring contraction strategy for carbocycle construction (eq. 5). Cycloaddition reactions of 2-(acyloxy)acroleins (G=OCOR, eq. 4) have facilitated the rapid construction of taxol A-ring synthons. More recently, the preparation and cycloaddition reactions of 2-amidoacroleins have been investigated and have culminated in the total syntheses of the novel tricyclic alkaloids FR901483 (eq. 6) and fasicularin. The further exploitation of amidoacrolein cyclizations in other syntheses of other cytotoxic natural products such as FR901464 are under way.

Finally, the retrocycloaddition reactions of 5-acyl-1,3-dioxins proceed with excellent stereoselectivity to provide (Z)-2-acylalkenals. These reactive heterodienes undergo facile cycloaddition reactions as illustrated in the recently completed synthesis of the intriguing and strained marine natural product euplotin A (eq. 7). Numerous natural products embody the 5-acyl-3,4-dihydropyran substructure present in euplotin A and it is anticipated that they also can be constructed by application of this methodology.