Catalytic asymmetric carbon–carbon bond formation via allylic alkylations with organolithium compounds

Abstract

Carbon-carbon bond formation is the basis for the biogenesis of nature's essential molecules. Consequently, it lies at the heart of the chemical sciences. Chiral catalysts have been developed for asymmetric C-C bond formation to yield single enantiomers from several organometallic reagents. Remarkably, for extremely reactive organolithium compounds, which are among the most broadly used reagents in chemical synthesis, a general catalytic methodology for enantioselective C-C formation has proven elusive, until now. Here, we report a copper-based chiral catalytic system that allows carbon-carbon bond formation via allylic alkylation with alkyllithium reagents, with extremely high enantioselectivities and able to tolerate several functional groups. We have found that both the solvent used and the structure of the active chiral catalyst are the most critical factors in achieving successful asymmetric catalysis with alkyllithium reagents. The active form of the chiral catalyst has been identified through spectroscopic studies as a diphosphine copper monoalkyl species.

Enantioselective Synthesis of Tertiary and Quaternary Stereogenic Centers: Copper/Phosphoramidite‐Catalyzed Allylic Alkylation with Organolithium Reagents

“…[10] The addition of nBuLi to cinnamyl bromide (4 a) afforded the product 2 a with comparable regio-and enantioselectivity as observed for 1 a ( Table 2, entry 2). Different primary alkyl lithium reagents gave also very good enantioselectivities both with the chloride 1 a and bromide 4 a (entries [3][4][5][6].…”

“…A limitation found for the CuBr·SMe 2 /TaniaPhos system was that the use of simple allyl chlorides or secondary organolithium reagents in combination with this catalyst led to disappointing selectivities. [11] However, we showed in preliminary studies [10] that easily accessible phosphoramidites [12] might be suitable ligands for this transformation.…”

“…but with low regioselectivity (S N 2'/S N 2 40:60). [10] This protocol could also be extended to the first enantioselective synthesis of all-carbon quaternary stereogenic centers employing organolithium reagents. After extensive screening of different phosphoramidite ligands (see the Supporting Information for details), ligand L4 (Figure 1) turned out to be the best ligand for the addition of nBuLi to E-trisubstituted allyl bromide 9 a (Table 5).…”

“…[10] By using a catalyst comprising CuBr·SMe 2 and TaniaPhos as a chiral ligand, and by selecting a proper combination of dichloromethane and nhexane as solvent and co-solvent, we could tame the highly reactive alkyllithium reagents and apply these in a catalytic, highly regio-and enantioselective allylic alkylation of a large variety of allyl bromides (Scheme 1). A limitation found for the CuBr·SMe 2 /TaniaPhos system was that the use of simple allyl chlorides or secondary organolithium reagents in combination with this catalyst led to disappointing selectivities.…”

Inter- and intramolecular enantioselective carbolithiation reactions

“…However, recently a general catalytic methodology for the enantioselective intermolecular addition of alkyllithiums has been reported, though it implies transmetalation to copper complexes. In this case, the use of a copper-base chiral catalytic system allows carbon–carbon bond formation by allylic alkylation with alkyllithiums, with high enantioselectivities and high functional-group tolerance [28–29]. This process may open new interesting applications in organolithium chemistry, though it is beyond the scope of this review.…”