Stereodivergent 1,3-difunctionalization of alkenes by charge relocation

Abstract

Alkenes are indispensable feedstocks in chemistry. Functionalization at both carbons of the alkene-1,2-difunctionalization-is part of chemistry curricula worldwide¹. Although difunctionalization at distal positions has been reported^2-4, it typically relies on designer substrates featuring directing groups and/or stabilizing features, all of which determine the ultimate site of bond formation^5-7. Here we introduce a method for the direct 1,3-difunctionalization of alkenes, based on a concept termed 'charge relocation', which enables stereodivergent access to 1,3-difunctionalized products of either syn- or anti-configuration from unactivated alkenes, without the need for directing groups or stabilizing features. The usefulness of the approach is demonstrated in the synthesis of the pulmonary toxin 4-ipomeanol and its derivatives.

Fig. 1. Examples of state-of-the-art remote functionalization reactions of alkenes.

a, Current paradigm for the distal functionalization of alkenes, relying on directing-group-mediated metal catalysis. b, Friedel–Crafts-type reactions of alkenes generally provide mixtures of products—which depend on the substrate, reagent and solvent—with selectivity observed only with specialized substrates. c, This work: stereodivergent, reagent-controlled 1,3-difunctionalization of alkenes through charge relocation. DG, directing group; Bpin, pinacol boronate.

Fig. 2. General reaction scheme, optimization and the scope of syn-selective 1,3-hydroxyacylation.

a, 1,3-Hydroacylation of cyclohexene. b, Scope of syn-alcohols. c, Comparison with transition-metal catalysis. All yields in the table of optimization correspond to nuclear magnetic resonance yields using 1,3,5-trimethoxybenzene as an internal standard. All products were obtained at greater than 20:1 d.r. and regioisomeric ratio (r.r.), unless otherwise mentioned. All yields correspond to isolated material. See Supplementary Information for further details and additional scope entries. *The reported yields correspond to averages over three runs. In cases in which competing pathways led to the observation of enone byproducts in the crude mixtures, the following percentages were observed: ^a37, ^b24, ^c30. Additional substrate scope is presented in Extended Data Fig. 1 and Supplementary Information.

Fig. 3. Stereodivergence of the 1,3-difunctionalization of alkenes and extension to other product classes.

a, Selected example of syn-selective hydroxyacylation in contrast to anti-configured product 29. b, Scope of anti-selective 1,3-hydroxyacylation, achieved by the addition of DMSO at 35 °C and quenching with tetrabutylammonium bromide at room temperature. c, Additional 1,3-difunctionalization reactions using other nucleophiles—tetrabutylammonium halides, dimethylacetamide, dimethylformamide or TEMPO—at 35 °C. d, 1,4-Dicarbonyl synthesis through Kornblum-type oxidation, employing DMSO at 35 °C, followed by NEt₃ at room temperature. All products were obtained at greater than 20:1 d.r. and 20:1 r.r., unless otherwise mentioned (Supplementary Information). *The reported yields correspond to averages over three runs. In cases in which competing pathways led to observation of enone byproducts in the crude mixtures, the following percentages were observed: ^a5, ^b10, ^c11.

Fig. 4. Application and mechanistic investigation of the 1,3-difunctionalization of alkenes.

a, Synthesis of 4-ipomeanol and other biologically active molecules. b, Proposed mechanism of 1,3-alkene difunctionalization, involving charge relocation. c, Mechanistic investigations support the hypothesis that nascency of the charge does not affect the constitution of the obtained product (Supplementary Information). d, Complete stereocontrol for the formation of a 1,2,3-trisubstituted cyclohexane.

Extended Data Fig. 1. Additional products of syn-selective 1,3-hydroxyacylation.

^*Percentages of observed enone by-products in the crude mixtures (see the Supplementary Information for additional details).