Electrophilic Trapping of Zirconium Enolates Obtained by Copper-Catalyzed Addition of In Situ Generated Organozirconium Reagents

Abstract

Building complex structures from simple starting materials is important for effective organic synthesis. In this context, domino reactions comprising hydrozirconation of alkenes, their subsequent utilization in a copper-catalyzed conjugate addition to enones, followed by electrophilic trapping of the formed zirconium enolates with activated alkene and carbocations are described. Reactivity of metal enolates was studied by DFT calculations.

β-Chloroaldehydes from Trapping Zirconium Enolates Produced in Asymmetric 1,4-Additions

“…14 However, Nemethova et al recently demonstrated that a few specialized electrophiles can be used to trap zirconium enolates (Scheme 1, B). 15 In that work, highly electrophilic carbenium ions gave trapped products in <20% yield.…”

“…The development of tandem ACA/trapping reactions initiated by organozirconium reagents has been difficult to realize, and a variety of approaches examined in our laboratory did not lead to useful results, possibly because of the strength of the Zr–O bond in the intermediate enolate . However, Nemethova et al recently demonstrated that a few specialized electrophiles can be used to trap zirconium enolates (Scheme , B ) . In that work, highly electrophilic carbenium ions gave trapped products in <20% yield.…”

“…The trapping procedure shows tolerance (Scheme 2) to aromatic rings (examples 9, 10, 14, and 16), an alkyl silane (example 11), an alkyl bromide (15), and a benzyl-protected alcohol (example 16). When tert-butyldimethylsilyl-protected alcohols were used (examples 13 and 14), free alcohols were obtained as the major product.…”

Synthesis of the Taxol Core via Catalytic Asymmetric 1,4-Addition of an Alkylzirconium Nucleophile

“…Having demonstrated that 9 could reliably be added to 6 , we next turned our attention to the preparation of a suitable intermediate for the synthesis of the desired product. The trapping of zirconium enolates is a challenging problem, and we recently reported trapping reactions using the Vilsmeier–Haack reagent to give β-chloroaldehydes from our ACA zirconium enolates . It was found that this trapping protocol also worked for our substrate; using 16.5 mmol of 6 , 3.6 g of 11 (corresponding to 69% yield) could be obtained with 92% ee, requiring minimal modification (Scheme , steps a and b).…”

Are Organozirconium Reagents Applicable in Current Organic Synthesis?

“…The first example of Zr-enolate trapping initiated by the Cu-catalyzed conjugate addition (CA) of alkylzirconium species 4 was published by our team in 2017. 64 In this case, the generated Zr-enolates 17 were successfully trapped by organic carbocations and an activated alkene. The reaction proceeded well under simplified racemic reaction conditions.…”