Chirality Transfer in Gold(I)-Catalysed Direct Allylic Etherifications of Unactivated Alcohols: Experimental and Computational Study

Abstract

Gold(I)-catalysed direct allylic etherifications have been successfully carried out with chirality transfer to yield enantioenriched, γ-substituted secondary allylic ethers. Our investigations include a full substrate-scope screen to ascertain substituent effects on the regioselectivity, stereoselectivity and efficiency of chirality transfer, as well as control experiments to elucidate the mechanistic subtleties of the chirality-transfer process. Crucially, addition of molecular sieves was found to be necessary to ensure efficient and general chirality transfer. Computational studies suggest that the efficiency of chirality transfer is linked to the aggregation of the alcohol nucleophile around the reactive π-bound Au-allylic ether complex. With a single alcohol nucleophile, a high degree of chirality transfer is predicted. However, if three alcohols are present, alternative proton transfer chain mechanisms that erode the efficiency of chirality transfer become competitive.

Keywords: alcohols; allylations; asymmetric reactions; chirality transfer; gold.

Scheme 1

Previous work (racemic studies) and current chirality-transfer target.

Scheme 2

Proposed mechanism for successful chirality transfer and stereospecificity.

Scheme 3

Resubjection of products 5 db, 5 eb and 5 mb to the reaction conditions.

Scheme 4

Allylic etherification of 4 d without molecular sieves results in racemic product.

Scheme 5

Results by Widenhoefer et al.

Scheme 6

Control reactions to ascertain effects of conditions vs. substrate. (a) Standard substrate by using the conditions of Widenhoefer et al. (b) Substrate 4 j by using conditions that usually result in racemisation.

Scheme 7

Comparing results of reactions with no molecular sieves, activated sieves and unactivated sieves.

Scheme 8

Possible outcomes of the Au-mediated reaction of (R,E)-4 k with ethanol (2 o) to give either (S,E)- or (R,Z)-5 ko. Computed product free energies are indicated in kcal mol⁻¹, relative to the reactant set to 0.0 kcal mol⁻¹.

Figure 1

Computed structures of two forms of [(Ph₃P)Au{(R,E)-4 k}]⁺⋅EtOH, I, with computed free energies (kcal mol⁻¹, relative to I a set to zero) and selected distances in Å. Phosphine H atoms are omitted for clarity, with the exception of that interacting with the EtOH molecule in I a.

Figure 2

Key intermediates and energetics for the Au-catalysed reaction of (R,E)-4 k with ethanol (2 o) through anti attack to give either (S,E)-5 ko or (R,Z)-5 ko (L=PPh₃). Computed free energies are indicated in kcal mol⁻¹ and quoted relative to I a set to 0.0 kcal mol⁻¹.

Figure 3

Different forms of intermediate II: II b and II c are alternative species formed by anti attack of ethanol, whereas II a is formed by syn attack. Computed free energies (kcal mol⁻¹) are quoted relative to I a set to zero and selected distances are in Å. Phosphine phenyl substitutents are truncated at the ipso carbon for clarity.

Figure 4

Key intermediates and energetics for the Au-catalysed reaction of (R,E)-4 k with ethanol (2o) by syn attack to give either (S,E)-5 ko or (R,Z)-5 ko (L=PPh₃). Computed free energies are indicated in kcal mol⁻¹ and quoted relative to I a set to 0.0 kcal mol⁻¹.

Scheme 9

Possible mechanisms accounting for loss of chirality transfer in the Au-mediated reactions of (R,E)-4 k with three ethanol molecules to form both (S,E)-5 ko (pathway (i)) and (R,E)-5 ko (pathway (ii)).

Figure 5

Key intermediates and energetics for the Au-catalysed reaction of (R,E)-4 k in the presence of three ethanol molecules to give (i) (S,E)-5 ko and (ii) (R,E)-5 ko (L=PPh₃). Computed free energies are indicated in kcal mol⁻¹ and quoted relative to I a³⁽ⁱ⁾ set to 0.0 kcal mol⁻¹.

Figure 6

Computed structure of intermediate II a³⁽ⁱⁱ⁾ located along pathway (ii) on route to the formation of (R,E)-5 ko. The computed free energy is in kcal mol⁻¹ and is relative to I a³⁽ⁱ⁾ set to zero. Selected distances are in Å and phosphine phenyl substituents are truncated at the ipso carbon for clarity.

Scheme 10

Comparing results of reactions with no molecular sieves, unactivated sieves and large excess of alcohol nucleophile.

Scheme 11

Large excess of alcohol nucleophile results in racemisation with 4 j, overriding the effect of the ether moiety (CH₂OBn) and molecular sieves.

Scheme 12

Resubjecting 5 kb to reaction conditions: racemisation without molecular sieves and much slower erosion of e.r. with molecular sieves.