The principle objectives of this research project are the synthesis, in enantiomerically pure form, of diazonamide A (revised structure, 1) and N-methylwelwitindolinone C isothiocyanate (2).
The specific aims will focus on six challenges: 1.
The first aim i s an efficient synthesis of the desired stereochemistry at the C10/C11 centers as an advanced fragment leading to diazonamide A. Aryllead(IV) compounds are highly selective and mild reagents for the production of quaternary centers. Our studies in this area have been especially fruitful. 2.
The second aim i s the execution of an effective aryl-aryl coupling reaction to set the C16/C18 bond. Organometallic technology can be employed to perform this aryl-aryl coupling reaction. Many such examples exist in the literature, and our own studies concur with this assessment. 3.
The third aim i s the efficient synthesis of the bis-oxazole system in conjunction with generation of the macrobicyclic structure of diazonamide A. Cyclodehydration of a N-acyI-D-aminoketone will effectively generate the C29 through C31 oxazole, whereas the C26 through C28 chlorooxazole can be effectively prepared via a [3+2] cycloaddition strategy. 4.
The fourth aim i s the efficient synthesis of the entire ring system of N-methylwelwitindolinone C isothiocyanate. An intramolecular conjugate addition reaction between C3 and C16, coupled with an efficient intermolecular coupling of the indole C4 position with C11, will efficiently generate the central sevenmembered ring of 2. 5. The fifth aim is the successful synthesis of the C11/C12 array of stereocenters in Nmethylwelwitindolinone C isothiocyanate. Directed introduction of functionality at C12 from C11 will allow both centers to be developed simultaneously. 6. The sixth specific aim is the synthesis of selected derivatives of both these targets for biological testing and evaluation. Collaborations for testing have been established. Diazonamide A is a cytotoxic agent and Nmethylwelwitindolinone C isothiocyanate is a multidrug resistance (MDR) reversal agent. Only a vigorous synthetic program toward these natural products and selected derivatives will allow for their full examination both as biological agents for cell cycle study and as possible therapeutics.
