Total Synthesis
Over the past 7 years at the University of Colorado, we have invested a substantial amount of effort into the total synthesis of complex natural products, some of which are shown to the right.
In choosing our targets we have attached a premium to molecules that have potent and interesting biological activity and at the same time offer opportunities to advance the field of synthesis. In this light we have focussed on chemistries such as tandem ring-opening-ring-closing metathesis, the conversion of furans to pyrans, and Ti(II)-mediated subunit couplings.
In efforts to enhance the value of furans as starting materials for polyether synthesis, we have developed a concise approach to the synthesis of pyran building blocks that can be employed in the context of polyether syntheses. A key discovery by Jim Henderson in 2005 underpins our ability to convert furans in two steps (Achmatowicz oxidation and then ionic reduction) to 2,6-syn substituted pyranones. This discovery has since been employed in a relatively concise total synthesis of norhalichondrin B by Kate Jackson and in the synthesis of pyranicin.
Within the theme of tandem metathesis, we have completed total syntheses of cyanthiwigin U, cyanthiwigin W, cyanthiwigin Z, cylindramide A, aburatubolactam A, and trans-kumausyne. The cyanthiwigin U synthesis provided an initial indicator of the potential power of two-directional metathesis for the conversion of simple and readily accessible starting materials to complex ring systems in a single step. Subsequent work in the context of cylindramide A demonstrated the ability of this chemistry to be engage a second reactant in a tandem ring-opening-ring-closing-cross metathesis sequence. This powerful tandem process allowed the assembly of close to half of cylindramide in very short order from simple materials. Further elaboration of these strategies led to the syntheses of aburatubolactam A and trans-kumausyne, and also formed the basis of our initial venture into the halichondrin arena.
Stimulated by the question of how to devise new ways to couple together subunits, we have invested in Ti(II)-mediated chemistry. Our initial forays in this area defined a new approach to the assembly of complex polyketide-derived domains by the coupling of olefins with alkynes. By taking advantage of silicon tethers, it is possible to rapidly prepare compounds such as 7-demethylpiericidin A1. .We also evaluated this chemistry in the context of our synthesis of dictyostatin. One of the questions raised by this synthesis was whether we could develop a convenient method for the coupling of olefins with esters and derivatives to produce ketones. A solution to this question that we believe should prove general in complex molecule synthesis was obtained by sequencing a Kulinkovich cyclopropanation with a highly selective cyclopropanol opening mediated by Fe(III). The first example of this advance was published in the context of a synthesis of spirolaxine methyl ether and more recently we employed this in the context of work directed toward spirastrellolide.
