Publication of the week, number 95, 18th September 2015

Palladium catalysed carboalkoxylation of alkenes is a useful method for the construction of substituted tetrahydrofurans. This week’s ASAP from Wolfe etal (University of Michigan, Ann Arbor) delivers an enantioselective method for this reaction-

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Reagents: Aryl halide, 2 mol% [Pd2(dba)3], 6 mol% ligand, NaOtBu, toluene, 90°C. Previously experiments with the related carboamination and chiral phosphoramidite ligands produced good yields and high ee’s of the corresponding pyrrolidines. However in the oxygen case the same success was not observed. But “During the course of a rather extensive screen of chiral ligands, we encountered a promising lead result.” “a chiral phosphite ligand L1 derived from (S,S)- TADDOL and (-)-menthol, afforded the desired product in 72 % yield with 81:19 e.r. We sought to further optimize this result through modification of this ligand, which can easily be prepared from a TADDOL and a chiral alcohol.

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The ligands are easily prepared from phosphorus trichloride. So the e.r’s are reasonable and changing the stereochemistry of the ligands produces an excess of the other enantiomer. Time to fiddle with the reaction conditions and the aryl halide and or the starting material! The aryl halide structure had no effect on the ee%. Changing the solvent to 1,4-dioxane increased the e.r to between 82:18 and 95:5 with the yields between 18 and 71%; the former being a bromo styrene and the latter a bromonaphthalene. The starting material in these cases was the benzyl alcohol.

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The other compound was a side product present in around 5 – 10% amounts.

An interesting extension of the reaction was to asymmetrically form quaternary centers:

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The authors conclude “… we have developed a new enantioselective synthesis of tetrahydrofurans via asymmetric Pd-catalyzed carboalkoxylation reactions of γ-hydroxyalkenes with aryl bromides. The development and optimization of ligand L7 was key to obtaining high levels of asymmetric induction. Our preliminary studies on the influence of TADDOL-based phosphite ligand structure on enantioselectivity indicate the structure of the phosphite alkoxy group (derived from a chiral alcohol) has the greatest influence on relative levels of asymmetric induction obtained with a structurally related series of ligands. Moreover (and perhaps not surprisingly), large changes in the alkoxy group have a larger impact on selectivity than fine-tuning of closely related structures. These results should help to guide future development of other chiral catalysts for heterocycle-forming alkene difunctionalization reactions.

So a nice reaction to give us tetrahydrofurans and chiral quaternary centers. A good addition to the toolbox.

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Prof. dangerdackel (199 Posts)

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