High-Throughput Screening of the Asymmetric Decarboxylative Alkylation Reaction of Enolate-Stabilized Enol Carbonates

Abstract

The use of high-throughput screening allowed for the optimization of reaction conditions for the palladium-catalyzed asymmetric decarboxylative alkylation reaction of enolate-stabilized enol carbonates. Changing to a non-polar reaction solvent and to an electron-deficient PHOX derivative as ligand from our standard reaction conditions improved the enantioselectivity for the alkylation of a ketal-protected,1,3-diketone-derived enol carbonate from 28% ee to 84% ee. Similar improvements in enantioselectivity were seen for a β-keto-ester derived-and an α-phenyl cyclohexanone-derived enol carbonate.Keywords asymmetric catalysis; high-throughput screening; palladium; ligands; solvent effect New methods for the construction of highly substituted carbocycles with defined stereochemistry are important for the synthesis of natural products and pharmaceutical agents. 1 Although automation is well-established within the pharmaceutical industry for the rapid synthesis of new chemical entities, identification of biological activity via screening, and process optimization, 2 less work has been performed within the academic community utilizing automation. 3 Similarly, the identification of efficient catalysts and their associated optimized reaction conditions, which cannot usually be predicted, often necessitates high-throughput methods to perform the required time-and labor-intensive screening. 4 Herein we report the optimization of the Pd-catalyzed, asymmetric decarboxylative alkylation 5 of enolate-stabilized enol carbonates for the synthesis of all-carbon quaternary stereocenters through automated high-throughput screening of reaction conditions. Enol carbonate 1, derived from 2-methyl cyclohexa-1,3-dione, was selected as our substrate for the asymmetric Pd-catalyzed decarboxylative alkylation reaction (Scheme 1). Enol carbonate 1 was synthesized from known mono-ketal 2 6 via deprotonation with NaH in THF at 60 °C and trapping of the resulting thermodynamic enolate with allyl chloroformate in 69% yield. Interestingly, ketal-opened product 3 was also formed in 12% yield, suggesting that Pdcatalyzed enantioselective formation of the quaternary stereocenter of 4 from 1 may be in competition with ketal-ring opening. Exposure of 1 to our standard decarboxylative alkylation conditions (Pd 2 dba 3 and (S)-t-BuPHOX in THF at 25 °C) 7 resulted in formation of 4 8 in 62% yield. Allyl ketone 4 required derivatization to ene-dione 5 via Ru-catalyzed metathesis 9 with methyl acrylate and Grubbs' 2 nd generation catalyst 6 in order to determine the enantiomeric excess of the product from the asymmetric alkylation reaction. Chiral HPLC analysis of 5 showed that the desired quaternary stereocenter-containing product was formed in a poor 28% ee under our standard reaction conditions.In order to obtain ketone 4 with high levels of enantioselectivity, we conducted highthroughput, parallel screening to determine the required catalyst and reaction conditions. Experiments were conducted in 1 mL vials within 96-well microtiter plates usin...

Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations

“…Since their development of an enantioselective allylic alkylation, the Stoltz group has increased the scope of this transformation substantially to include, 1,3-dioxan-5-one- ( 9 ), 21 β-thiocyclohexenone-( 10 ), 22,23 3-ketal- ( 11 ), 24 β-alkoxy-cycloheptenone- ( 12 ), 25,26 5-alkyl- and 5-alkoxy- ( 13 ), β-aminocyclohexenone- ( 14 ), 1-alkoxypiperidine-2,6-dione- ( 15 ), dihydropyridin-4(1 H )-one- ( 16 ), 27 cyclobutanone- ( 17 ), 28 valerolactam and 2-piperazinone- ( 18 ), 29 2-aminomethylcyclohexanone- ( 19 ), 30 4-oxazolidinone- ( 20 ), morpholin-3-one- ( 21 ), 1,2-oxazepan-3-one- ( 22 ), 31 and cyclopentanone-based ( 23 ) 32 allyl β-ketoesters (Figure 2). Notably, the use of oxygen- and nitrogen-based heterocycles allows for the facile synthesis of quaternary stereocenter-bearing polyketide and pharmaceutical-type fragments in a straightforward manner.…”

Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones

“…Employing identical reaction conditions from our ligand screen, using toluene as the solvent, we isolated α-Cq cyclopentanone ( S )-14b in 91% ee, achieving complete consumption of starting material 13b in 8.0 h (entry 1). Switching to the less polar solvent mixture 2:1 hexanes/toluene, which has previously provided increased ee’s for other α-Cq cyclic ketones constructed through palladium-catalyzed enantioselective decarboxylative allylic alkylation, 15 did not affect the reaction time but furnished ketone ( S )-14b in a diminished 88% ee (entry 2). Changing to ethereal solvents (entries 3 and 4) drastically decreased the reaction time, facilitating the full consumption of β-ketoester 13b in 1.0 h. While the use of MTBE (entry 3) afforded cyclopentanone ( S )-14b in nearly identical ee to the mixed nonpolar solvent system (entry 2), switching to THF (entry 4) proved deleterious.…”

Enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams

“…In the course of our investigations of the ketone enolate allylic alkylation and other alkylation processes, we have often encountered interesting ligand electronic effects and, in certain cases, pronounced solvent effects. xxxvii In keeping with our ultimate goal of N -heterocycle alkylation, we set out to further probe these subtle effects by examining enolate reactivity in a lactam series that would be amenable to both steric and electronic fine-tuning.…”