The Ziegler Laboratory (1965-2005)

New Synthetic Methodology and Natural Products Synthesis

The practice of synthesizing natural products has many benefits. The development of laboratory methods for the synthesis of important, physiologically-active substances that are available in nature in minute quantities provides a means to permit ample quantities of these materials to be available for pharmaceutical studies. In addition, total synthesis provides methods for the preparation of analogues that may not otherwise be available by manipulation of the structure of the natural product. The organic chemist may design a strategy for the synthesis of a natural product that employs well-tested methods to achieve a goal. A more challenging approach from the chemical perspective is the opportunity to discover new chemical reactions and to explore the subtleties of stereochemistry.

In the late 1990's our interest had focused upon the use of radical reactions to develop new strategies for synthesis. One of our targets was the oxygenated sesquiterpene FS-2 via radical fragmentation as shown in Fig. 1. We [J. Org. Chem. 1990, 55, 1416] had previously uncovered subtle strain factors that induce cyclic thionocarbonates to afford primary over secondary radicals during homolytic fragmentation induced by tri-n-butylstannyl radical (Fig.2; Tetrahedron Lett. 2000, 41, 5155).

Fig. 1

Fig. 2

Oxiranyl carbinyl radicals undergo rapid fragmentation to form allyloxyl radicals. We have been studying this process in tandem with the fragmentation of cyclopropylcarbinyl radicals. Besides leading to a new approach to prostanoids, kinetic studies have shown that the oxiranyl carbinyl radical is formed reversibly [J. Org. Chem. 1995, 60, 2666] in the presence of hydrogen atom donors (Fig. 3; Tetrahedron Lett. 1996, 37, 809).

Fig. 3

Physical organic chemists have studied the rate of inversion and rearrangement of oxiranyl radicals. We had been able to demonstrate that these radicals cyclize faster than they rearrange. This behavior is also exemplified by carbon-centered aziridinyl radicals. These new findings are being extended in the area of the mitomycin antibiotics (Figures 4 and 5) to the synthesis of natural products, and candidates whose chemistry may mimic the mode of action of these antibiotics. (Fig. 4; J. Org. Chem. 1997, 62, 1083) (Fig 5; Tetrahedron Lett. 1998, 39, 2455).

Fig. 4

Fig. 5

The facile rearrangement of allyl S-methyl xanthate to allyl S-methyl dithiocarbonate has been known for more than a century. We coupled the latter functionality as a leaving group with a xanthate as an initiator in a free radical process that led to carbocycles having dual functionality (Fig. 6; Tetrahedron Letters, 1987, 48, 5973.)

Fig. 6