Reaction design, discovery, and development as a foundation to function-oriented synthesis

Abstract

Convergent C-C bond-forming reactions define the fabric of organic synthesis and, when applied in complex molecule synthesis, can have a profound impact on efficiency by decreasing the longest linear sequence of transformations required to convert simple starting materials to complex targets. Despite their well-appreciated strategic significance, campaigns in natural product synthesis typically embrace only a small suite of reactivity to achieve such bond construction (i.e., nucleophilic addition to polarized π-bonds, nucleophilic substitution, cycloaddition, and metal-catalyzed "cross-coupling"), therefore limiting the sites at which convergent coupling chemistry can be strategically employed. In our opinion, it is far too often that triumphs in the field are defined by chemical sequences that do not address the challenges associated with discovery, development, and production of natural product-inspired agents. We speculated that advancing an area of chemical reactivity not represented in the few well-established strategies for convergent C-C bond formation may lead to powerful new retrosynthetic relationships that could simplify approaches to the syntheses of a variety of different classes of natural products. Our studies ultimately embraced the pursuit of strategies to control the course of metallacycle-mediated "cross-coupling" between substrates containing sites of simple π-unsaturation (ubiquitous functionality in organic chemistry including alkenes, alkynes, allenes, aldehydes, and imines, among others). In just eight years since our initial publication in this area, we have defined over 20 stereoselective intermolecular C-C bond-forming reactions that provide access to structural motifs of relevance for the synthesis of polyketides, fatty acids, alkaloids, and terpenes, while doing so in a direct and stereoselective fashion. These achievements continue to serve as the foundation of my group's activity in natural product and function-oriented synthesis, where our achievements in reaction development are challenged in the context of complex targets. Among our early efforts, we achieved the most concise synthesis of a benzoquinone ansamycin ever described (macbecin I), and moved beyond this achievement to explore the role of our chemistry in function-oriented synthesis targeting the discovery of natural product-inspired Hsp90 inhibitors. These later efforts have led to the discovery of a uniquely selective benzoquinone ansamycin-inspired Hsp90 inhibitor that lacks the problematic quinone present in the natural series. This achievement was made possible by a concise chemical synthesis pathway that had at its core the application of metallacycle-mediated cross-coupling chemistry.

Figure 1

Selected history of metallacycle-mediated cross-coupling.

Figure 2

Ever-present challenges associated with metallacycle-mediated cross-coupling reactions.

Figure 3

Design of alkoxide-directed metallacycle-mediated cross-coupling reactions.

Figure 4

Class I alkoxide-directed metallacycle-mediated cross-coupling.

Figure 5

Examples of stereoselective convergent coupling reactions that proceed by Class II alkoxide-directed metallacycle-mediated coupling.

Figure 6

Representative benzoquinone ansamycins, geldanamycin analogs and benzenoid ansamycins.

Figure 7

Summary and challenges encountered in our macbecin synthesis.

Figure 8

First–generation chemical approach for the synthesis of natural product-inspired Hsp90 inhibitors.

Figure 9

Hsp90-relevant conformation of macbecin.

Figure 10

Plan for heteroatom variants of benzoquinone ansamycins.

Figure 11

Synthesis of coupling partner 57.

Figure 12

Preparation of macrocyclic ether, non-benzoquinone analogs of geldanamycin by metallacycle-mediated alkyne–alkyne coupling.

Figure 13

Binding affinity of analogs to Hsp90α, Hsp90β and Grp94 and their cytotoxicity in different cancer cell lines. IC₅₀ values are from an average of four fluorescence polarization and three cytotoxicity experiments, each of which were read in triplicate. NT; not tested. Evaluation of synthetic macrolactams in vitro was accomplished via a cell titer glo assay.