Enzyme‐Catalyzed Meinwald Rearrangement with an Unusual Regioselective and Stereospecific 1,2‐Methyl Shift

Abstract

The Meinwald rearrangement is a synthetically useful reaction but often lacks regioselectivity and stereocontrol. A significant challenge in the Meinwald rearrangement of internal epoxides is the non-regioselective migration of different substituents to give a mixture of products. Herein, an enzyme-catalyzed regioselective and stereospecific 1,2-methyl shift in the Meinwald rearrangement of internal epoxides is reported. Styrene oxide isomerase (SOI) catalyzed the unique isomerization of internal epoxides through 1,2methyl shift without 1,2-hydride shift to give the corresponding aldehydes and a cyclic ketone as the sole product. SOI-catalyzed isomerization showed high stereospecificity, fully retaining the stereoconfiguration. The synthetic utility of this enzymatic Meinwald rearrangement was demonstrated by its incorporation into three new types of enantioselective cascades, to convert transβ-methyl styrenes into the corresponding R-configured alcohols, acids, or amines in high ee and yield.

Efficient Chemoenzymatic Synthesis of α-Aryl Aldehydes as Intermediates in C–C Bond Forming Biocatalytic Cascades

“…Concurrently, work from the Li lab also demonstrated that SOI is stereospecific for the trans migration by observing the transfer of a trans-methyl group over the cishydrogen. 25 Consistent with this observation, reactions with the (±)-trans-2a-3-d 1 showed no deuterium at C β and 25% deuterium at C γ . The theoretical maximum labeling at C γ would be 50%, indicating efficient transfer by SOI followed by hydrogen exchange due to enolization in protic solvent.…”

“…In the case with the deuterium cis to the phenyl ring ( (±)- cis -2a-3- d 1 ), the amino acid product contained deuterium only at C β , indicative of migration of the trans hydrogen (Figure b). Concurrently, work from the Li lab also demonstrated that SOI is stereospecific for the trans migration by observing the transfer of a trans -methyl group over the cis -hydrogen . Consistent with this observation, reactions with the (±)- trans -2a-3- d 1 showed no deuterium at C β and 25% deuterium at C γ .…”

“…22 It was hypothesized that SOI forms a carbocation intermediate after C−O cleavage and that the active site environment directs a stereospecific hydride shift to produce a single enantiomer of α-methylphenylacetaldehyde (Figure S5). 22,23,25 However, reactions with rac-18a produced both enantiomers of the corresponding aldehyde. If the mechanism were to proceed through a sp 2hybridized, carbocation intermediate, a stereospecific hydride shift would only produce a single enantiomer of the chiral aldehyde.…”

“…We were drawn to recent reports from the lab of Li, who produced α-aryl aldehydes using a two-enzyme cascade from Pseudomonas sp. VLB120 . − In this system, a flavin-dependent styrene monooxygenase (SMO) catalyzes epoxidation of styrene to produce styrene oxide. This molecule is the substrate for styrene oxide isomerase (SOI), an integral membrane enzyme.…”

Cascade Biotransformations for Enantioconvergent Conversion of Racemic Styrene Oxides to (R)-Mandelic Acids

“…Enzymatic cascades involving multiple enzymes in one pot allow for direct syntheses of valuable enantiopure chemicals from cheap starting materials. − In addition to the use of nonchiral substrates, the use of easily available racemic substrates for enantioconvergent cascade conversion to enantiopure chemicals , has been receiving increasing attention. We are interested in developing a new enantioconvergent cascade to convert racemic epoxides into the corresponding enantiopure hydroxy acids.…”