Reaction Design, Discovery, and Development as a Foundation to Function-Oriented Synthesis

Abstract

CONSPECTUS 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/or 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 twenty 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.

Concise Enantioselective Total Synthesis of Cardiotonic Steroids 19-Hydroxysarmentogenin and Trewianin Aglycone

“…Remarkably, it was discovered that the presence of OBz-containing γ-stereocenter results in excellent levels of stereocontrol, which allows a diastereoselective formation of the corresponding Michael adduct (>20:1 dr) even if Cu­(OTf) 2 (20 mol %) without chiral ligand is employed as the catalyst. While γ-alkoxide containing stereocenters are known to have a strong influence on the stereochemical outcome of intramolecular Michael reactions, , stereoselective intermolecular variants of such reactions (i.e., Michael addition in Scheme ) have not been described . Considering that the vinylogous polar Felkin-type model has been invoked to describe the selectivity of the cuprate addition to γ-alkoxy enones, we propose a similar model (i.e., 11 ) to explain the diastereoselectivity of the Michael reaction of 9 and 8 .…”

Synthesis of Highly Functionalized Decalins via Metallacycle-Mediated Cross-Coupling

“…7 This result is consistent with the conclusion that, while the alkyne–alkyne coupling remains effective for this substrate class, there exists a larger energetic barrier for intramolecular cycloaddition in comparison to that associated with the annulation processes previously achieved for the convergent synthesis of hydrindanes. 4–6 …”

“…4 This process was proposed to proceed by initial alkoxide-directed metallacycle-mediated alkyne–alkyne coupling, followed by intramolecular [4+2] cycloaddition to generate the presumed bridged bicyclic metallacyclopentene intermediate 3 . This species was then envisioned to undergo a formal cheletropic extrusion of Ti(O i- Pr) 2 and produce the angularly substituted diene-containing hydrindane product 4 .…”

From Dialkyltitanium Species to Titanacyclopropanes: An Ab Initio Study

“…This intermediate, not yet isolated to date, is assumed to be obtained from a transient diisopropoxydialkyltitanium, itself obtained by transmetalation between Ti­(OiPr) 4 and 2 equiv of Grignard reagents. The synthetic utility of A is amplified by its ability to undergo ligand exchange with various unsaturated moieties, including alkenes, alkynes, and imines, allowing efficient C–C coupling reactions with various unsaturated moieties. , A representative illustration in total synthesis is the coupling key step performed in the recent synthesis of (−)-Nahuoic C i (B ii ) acid …”