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

Abstract

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.

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

“…11 Conversion of the resulting homoallylic alcohol to enyne 6 was then accomplished by a sequence of desilylation (TBAF, THF), epoxide formation (TsCl, Et 3 N, DMAP, then NaH, THF), and nucleophilic addition of propynyl lithium. In accord with our earlier observations regarding the regio- and stereosleective coupling of 4-hydroxy-1,6-enynes with TMS-alkynes, 9, 12 exposure of stannyl-substituted TMS-acetylene 7 to the combination of Ti(O i- Pr) 4 and n -BuLi (−78 to 50 °C), followed by addition of the Lialkoxide of enyne 6 (−78 °C to rt) generated hydrindane 5 in 73% yield (rs ≥ 20:1), where the C9 quaternary center was established with high levels of stereoselectivity (ds ≥ 20:1).…”

The Development of Alkoxide‐Directed Metallacycle‐Mediated Annulative Cross‐Coupling Chemistry

“…While success in these endeavors required enyne substrates that were conformationally biased to support the transition state for intramolecular [4+2] cycloaddition ( 47 + 48 → 49 ; Figure 10), [24] our pursuits led to an interesting discovery regarding the reactivity of bridged bicyclic metallacyclopentenes (i.e. 49 ).…”

Synthesis of Angularly Substituted trans‐Fused Decalins through a Metallacycle‐Mediated Annulative Cross‐Coupling Cascade

“…[4] A subset of these were found to be useful for the establishment of cis -fused systems, yet none of the variants explored were capable of delivering trans -fused products. In an effort to overcome this limitation, we pursued development of the coupling process depicted in Figure 2.…”

“…These observations are consistent with our earlier investigations targeting the synthesis of angularly substituted hydrindanes and decalins. [4,5,7,9] Unfortunately, the regioselectivity seen in the protonation of the terminal organometallic species in the reaction cascade was both unexpected and undesired, showing a preference for the production of isomer 8 . We speculated that this result may derive from either a mechanistic ambiguity in the protonation of D (Figure 3B; competition between protonation with allylic transposition and direct protonation without allylic transposition) or interaction of the pendant metal alkoxide with the allylic organometallic in C (highlighted in blue), potentially stabilizing this isomeric allylic metal species and establishing a pathway to the undesired regioisomer (i.e.…”