Catalytic Enantioselective Benzilic Ester Rearrangement

Abstract

We report the first examples of catalytic enantioselective benzilic ester rearrangement reaction. In the presence of a catalytic amount of Cu(OTf)2 and a chiral box ligand under mild conditions, reaction of 2,3‐diketoesters with alcohols afforded structurally diverse α‐aryl(alkyl) substituted‐α‐hydroxy malonates (tartronic esters) in good to excellent yields with high enantioselectivities. Preliminary mechanistic studies indicated that hemiketalization, rather than the dynamic kinetic resolution of hemiketal, was the enantiodetermining step under our reaction conditions.

Transformation of a Chiral Glycolic Acid to an Isoaurone: Stereochemical Assignment of a Benzilic Acid Rearrangment Product

“…[3] Of outstanding significance was the recent demonstration by Zhu and coworkers of a catalytic asymmetric version with an acyclic system which used a well-known chiral Cu catalyst to control the enantiofacial selectivity. [4] However, this result does not mitigate the difficulty in obtaining high diastereoselectivities in these systems that has been both demonstrated by us [5] and by other workers. [6] In 1989, Brady et al [7] reported a highly stereoselective benzilic acid rearrangement on the α-diketone 5 [4,5,8] (an intermediate involved in a ring-chain tautomerism event that allows the equilibration of the two diastereomeric benzofurano-3-ones 4 a and 4 b) to give a single isomer of the αhydroxypropanoic acid product 6 which was originally assigned the (2R,3S)-configuration (Scheme 2).…”

“…[4] However, this result does not mitigate the difficulty in obtaining high diastereoselectivities in these systems that has been both demonstrated by us [5] and by other workers. [6] In 1989, Brady et al [7] reported a highly stereoselective benzilic acid rearrangement on the α-diketone 5 [4,5,8] (an intermediate involved in a ring-chain tautomerism event that allows the equilibration of the two diastereomeric benzofurano-3-ones 4 a and 4 b) to give a single isomer of the αhydroxypropanoic acid product 6 which was originally assigned the (2R,3S)-configuration (Scheme 2). The authors proposed that the hydroxide attacks the α-diketone 5 at carbonyl carbon-2 in accordance with Cram's rule to form preferentially the diastereomer adduct A (Scheme 2(a)) which was hypothesised to be stabilized by intramolecular hydrogen bonding (Scheme 2 (b)) forcing it into a conformation that would afford the product (2R,3S)-6 after the 1,2-rearrangment had occurred (the authors also proposed that the carbonyl unit would be coordinated with a sodium ion, obviously to enhance the reactivity).…”

“…[7] In fact, as mentioned above, the first highly enantioselective version was reported in 2020 in a acyclic system. [4] A plausible mechanistic pathway is shown in Scheme 8. It is suspected that 5 would be transformed into the phenoxide derivative 5' in the basic medium, this would then undergo the BAR, with the first step stereoselective nucleophile addition of hydroxide to give intermediate 9 that undergoes a stereoselective [1,2]-migration of the chiral migrating group.…”

Natural Product Synthesis Enabled by Domino Processes Incorporating a 1,2-Rearrangement Step

“…The benzilic acid rearrangement (BAR) and benzilic ester rearrangement (BER) convert 1,2-diketones to tertiary α-hydroxy acids and α-hydroxy esters, respectively. , Mechanistically, the reaction proceeds through nucleophilic addition of hydroxide or alkoxide to one of the carbonyl groups followed by 1,2-alkyl/aryl shift (Scheme a). It has been successfully employed in natural product synthesis and in the structure modification of complex natural products, such as FK-506, an important immunosuppressant .…”

Catalytic Enantioselective Benzilic Ester Rearrangement

“…Performing the reaction at 0 8C using bisoxazoline L12 as ligand, compounds 2 y-2 aa were isolated in good yields with good to high enantiopurities. The (S)-absolute configuration of 2 a was determined by X-ray crystallographic analysis [25] and the configuration of the other a-hydroxy malonates were assigned in analogy. Performing the gram scale reactions of 1 a (4.0 mmol) and 1 o (5.0 mmol) with tBuOH (2.0 equiv) in the presence of only 2.5 mol % of the L9-Cu catalyst afforded 2 a and 2 t, respectively, without erosion of yields and ees.…”