Asymmetric Synthesis of Dihydroindanes by Convergent Alkoxide-Directed Metallacycle-Mediated Bond Formation

Abstract

A convergent synthesis of highly substituted and stereodefined dihydroindanes is described from alkoxide-directed Ti-mediated cross-coupling of internal alkynes with substituted 4-hydroxy-1,6-enynes (substrates that derive from 2-directional functionalization of readily available epoxy alcohol derivatives). In addition to describing a new and highly stereoselective approach to bimolecular [2+2+2] annulation that delivers products not available with other methods in this area of chemical reactivity, evidence is provided to support annulation by way of regioselective alkyne–alkyne coupling, followed by metal-centered [4+2] rather than stepwise alkene insertion and reductive elimination. Overall, the reaction proceeds with exquisite stereochemical control and defines a convenient, convergent, and enantiospecific entry to fused carbocycles of great potential value in target-oriented synthesis and medicinal chemistry.

5.34 Early Transition Metal Mediated Reductive Coupling Reactions

“…Scheme 66A depicts two coupling reactions that demonstrate the ability to selectively functionalize the enyne at the alkene or alkyne motif. 147 To date, only enyne substrates bearing both an internal alkyne and a terminal alkene are capable of selective hydroxyl-directed reaction at the terminal alkene -this selectivity is different than that previously reported for intermolecular coupling of a preformed Ti-alkyne complex to an enyne containing both a terminal alkyne and a terminal monosubstituted alkene (i.e., Scheme 64C).…”

“…147 This result has proven unique to enyne substrates bearing 1,1-disubstituted alkenes and furnishes a useful stereoselective entry to densely functionalized hydroindane motifs. As illustrated in Scheme 66C, a diyne-alkene [2 þ 2 þ 2] annulation process has also been described that secures an alternative entry to substituted carbocycles.…”

Acceleration of metallacycle-mediated alkyne–alkyne cross-coupling with TMSCl

“…This early success marked the beginning of a program to explore what we later termed “Class II” 1 alkoxide-directed metallacycle-mediated cross-coupling, led to a process for alkene–alkyne coupling (Figure 1B), 8 and ultimately to a Ti-centered annulative cross-coupling (alkyne + alkyne + alkene) for the stereoselective synthesis of angularly substituted hydrindanes (Figure 1C). 9 While successful, we have on occasion had difficulties optimizing reaction conditions for coupling, being limited by the concentration and quality of the commercial Grignard reagents employed in initial alkyne activation, physical properties associated with the ethereal solvent that the Grignard is in, and the relatively low concentrations that are required when employing this reagent combination (initial Ti-alkyne complex formation is typically carried out at ~ 0.1M – higher concentrations often result in heterogeneous solutions). 10 In recent studies, we have turned to the reagent combination of Ti(O i -Pr) 4 /2 n -BuLi in toluene as a suitable alternative to Ti(O i -Pr) 4 /2RMgX, and have observed success in annulative coupling processes 11 and imine–allylic alcohol coupling reactions.…”

“…[2+2+2] annulation en route to hydrindanes), the instability of the metallacyclopentadiene intermediate does not surface as an issue that impacts reaction efficiency. 9 …”

LiOO t -Bu as a terminal oxidant in a titanium alkoxide-mediated [2+2+2] reaction cascade

“…1,3 In studies associated with our desire to develop this latter area of coupling technology, we recently discovered a metallacycle-mediated annulation reaction between TMS-alkynes ( 1 ) and 1,6-enynes ( 2 ) that produces angularly substituted hydroindanes ( 3 ) with outstanding levels of diastereoselectivity (> 20:1; Figure 1A). 4 Experiments aimed at understanding the mechanism for this process led to the proposal that this [2+2+2] annulation process proceeded by initial alkoxide-directed alkyne–alkyne coupling (→ I ), 5 followed by intramolecular [4+2] cycloaddition (→ II ), and finally cheletropic extrusion of the metal center. When the enyne coupling partner possesses a distal propargylic ether ( 4 ), we found that the annulation sequence is interrupted by an elimination that traps the otherwise fleeting organometallic intermediate III (Figure 1B).…”