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

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 formed by formal cheletropic extrusion of Ti­(O<i>i</i>-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 such 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

Progress Toward the Asymmetric De Novo Synthesis of Limonoids

Asymmetric de novo construction of limonoids remains a challenging problem in stereoselective synthesis due to the diverse and complex structures associated with this class of natural products. Here, a unique synthetic pathway to an “intact” limonoid system is described. The synthetic route is based on exploiting an oxidative rearrangement reaction of a densely functionalized late-stage intermediate to simultaneously establish the stereodefined C10 quaternary center and an allylic acetate at C12. This is a unique example of a complex rearrangement reaction that proceeds on a system whose presumed intermediate allyl cation is highly hindered and lacks neighboring protons that are otherwise required for cation termination

Synthesis of Neurotrophic <i>Seco</i>-prezizaane Sesquiterpenes (1<i>R,</i>10<i>S</i>)‑2-Oxo-3,4-dehydro­neomajucin, (2<i>S</i>)‑Hydroxy-3,4-dehydroneo­majucin, and (−)-Jiadifenin

An asymmetric approach to the synthesis of neurotrophic <i>seco</i>-prezizaane sesquiterpenes is described that is based on the strategic application of a hydroxyl-directed metallacycle-mediated [2 + 2 + 2] annulation and an intramolecular radical cyclization cascade. Targets prepared are among the most potent members of the natural product class and include (1<i>R,</i>10<i>S</i>)-2-oxo-3,4-dehydro­neomajucin, (2<i>S</i>)-hydroxy-3,4-dehydro­neomajucin, and (−)-jiadifenin. In addition to representing the first application of the alkoxide-directed metallacycle-mediated hydrindane-forming annulation reaction in natural product synthesis and the first total synthesis of (2<i>S</i>)-hydroxy-3,4-dehydro­neomajucin, these pursuits have resulted in the elucidation of a complex radical cascade process for installation of the C5 quaternary center common to the natural product class

Synthesis of Alkaloid (−)-205B via Stereoselective Reductive Cross-Coupling and Intramolecular [3+2] Cycloaddition

An asymmetric synthesis of alkaloid (−)-205B, a tricyclic member of the architecturally diverse family of natural products isolated from the skin of neotropical poison frogs, is described that proceeds through two recently developed stereoselective synthetic methods: (1) Ti-mediated allylic alcohol–imine reductive cross-coupling and (2) intramolecular [3+2] cycloaddition of a glyoxylate-based homoallylic nitrone. The utility of this latter cycloaddition process for the assembly of the stereochemically dense piperidine core of 205B is noteworthy, as this method enables direct [3+2] cycloaddition of an intermediate homoallylic (<i>E</i>)-nitrone via a pathway that is stereochemically unscathed by competitive [3,3]-sigmatropic rearrangement processes. Overall, the synthesis is asymmetric, concise, and highly stereoselectivefeatures which point to the potential future utility of these chemical methods in natural product synthesis and medicinal chemistry

Cyclopropenes in Metallacycle-Mediated Cross-Coupling with Alkynes: Convergent Synthesis of Highly Substituted Vinylcyclopropanes

Stereodivergent metallacycle-mediated cross-coupling reactions are described for the synthesis of densely functionalized vinylcyclopropanes from the union of alkynes with cyclopropenes. Strategies explored include hydroxyl-directed and nondirected processes, with the latter of these delivering vinylcyclopropanes with exquisite levels of regio- and stereoselectivity. Challenges inherent to these coupling reactions include diastereoselectivity (with respect to the cyclopropene) and regioselectivity (with respect to both coupling partners)

Three-Component Coupling Sequence for the Regiospecific Synthesis of Substituted Pyridines

A de novo synthesis of substituted pyridines is described that proceeds through nucleophilic addition of a dithiane anion to an α,β-unsaturated carbonyl followed by metallacycle-mediated union of the resulting allylic alcohol with preformed trimethylsilane-imines (generated in situ by the low-temperature reaction of lithium hexamethyldisilazide with an aldehyde) and Ag­(I)- or Hg­(II)-mediated ring closure. The process is useful for the convergent assembly of di- through penta-substituted pyridines with complete regiochemical control