We report the development of a divergent synthetic process entailing four-step access to the elaborate fused skeletons reminiscent of aspidophytines and transtaganolides. A variety of branched precursors were synthesized on the basis of Ugi condensations and installation of diazoimide and subjected to rhodium-catalyzed tandem reactions. Switching of cyclization modes was demonstrated by the choice of the amine building blocks installed at site C.
Angularly substituted
trans-fused hydroindanes are now accessible
by the direct and convergent union of trimethylsilyl (TMS)-alkynes
with 4-hydroxy-1,6-enynes by a process that forges three C–C
bonds, one C–H bond, and two new stereocenters. The annulation
is proposed to proceed by initial formation of a Ti–alkyne
complex (with a TMS-alkyne) followed by regioselective alkoxide-directed
coupling with the enyne, stereoselective intramolecular cycloaddition,
elimination of phenoxide, 1,3-metallotropic shift, and stereoselective
protonation of the penultimate allylic organometallic intermediate.
Several examples are given to demonstrate the compatibility of this
reaction with substrates bearing aromatic and aliphatic substituents,
and an empirical model is presented to accompany the stereochemical
observations.
Copper-catalyzed 6-endo cyclization of N-propargylic β-enaminocarbonyls was developed for the synthesis of oxidation-labile 1,6-dihydropyridines. This synthetic method allows flexible and regio-defined assembly of various substituents at the N1, C2, C3, C4, and C6 positions of 1,6-dihydropyridines under mild conditions.
Development of designer natural product variants, 6-aza-artemisinins, enabled us to achieve structural modification of the hitherto unexplored cyclohexane moiety of artemisinin and concise de novo synthesis of the tetracyclic scaffold in just four steps from the modular assembly of three simple building blocks. This expeditious catalytic asymmetric synthetic approach generated lead candidates exhibiting superior in vivo antimalarial activities to artemisinin.
Bridged bicyclic metallacyclopentenes generated from the [4+2] cycloaddition of metallacyclopentadienes with alkenes have been proposed as reactive intermediates in the course of [2+2+2] annulation reactions. Recently a collection of alkoxide-directed Ti-mediated [2+2+2] annulation reactions have been discovered for the synthesis of densely functionalized hydrindanes, where the bridged bicyclic metallacyclopentenes from intramolecular [4+2] were treated as fleeting intermediates en route to cyclohexadiene products by formal cheletropic extrusion of Ti(Oi-Pr)2. In studies aimed at understanding the course of these organometallic cascade reactions it was later discovered that these bridged bicyclic intermediates can be trapped by various elimination processes. Here, we have realized metallacycle-mediated annulation reactions for the assembly of angularly substituted decalins – structural motifs that are ubiquitous in natural products and molecules of pharmaceutical relevance. In addition to defining the basic annulation reaction we have discovered a surprising stability associated with the complex organometallic intermediates generated in the course of this coupling process and document here the ability to control the fate of this species. Ligand-induced cheletropic extrusion of the titanium center delivers cyclohexadiene-containing products, while several distinct protonation events have been identified to realize polycyclic products that contain three new stereocenters (one of which is the angular quaternary center that is a hallmark of alkoxide-directed titanium-mediated [2+2+2] annulation reactions). Examples of this metallacycle-mediated annulation reaction are provided to demonstrate that a range of stereodefined fused bicyclo[4.4.0]-decanes are accessible, including those that contain aromatic and aliphatic substituents, and an empirical model is presented to accompany the observations made.
Alkoxide-directed metallacycle-mediated cross-coupling is a rapidly growing area of reaction methodology in organic chemistry. Over the last decade, developments have resulted in > thirty new and highly selective intermolecular (or “convergent”) C–C bond-forming reactions that have established powerful retrosynthetic relationships in stereoselective synthesis. While early studies were focused on developing transformations that forge a single C–C bond by way of a functionalized and unsaturated metallacyclopentane intermediate, recent advances mark the ability to employ this organometallic intermediate in additional stereoselective transformations. Among these more advanced coupling processes, those that embrace the metallacycle in subsequent [4+2] chemistry have resulted in the realization of a number of highly selective annulative cross-coupling reactions that deliver densely functionalized and angularly substituted carbocycles. This review discusses the early development of this chemistry, recent advances in reaction methodology, and shares a glimpse of the power of these processes in natural product synthesis.
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