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Synlett 2010(11): 1712-1716  
DOI: 10.1055/s-0030-1258094
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© Georg Thieme Verlag Stuttgart ˙ New York

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

Nolan T. McDougal, Scott C. Virgil, Brian M. Stoltz*
The Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Fax: +1(626)5649297; e-Mail: stoltz@caltech.edu;
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Publication History

Received 7 April 2010
Publication Date:
14 June 2010 (online)

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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 nonpolar 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.

Key words

asymmetric catalysis - high-throughput screening - ­palladium - ligands - solvent effect

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McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. submitted for publication.

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Mukherjee, H.; McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. manuscript in preparation.

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Experimental Data ¹H NMR and ¹³C NMR spectra were recorded on a Varian Mercury 300 (at 300 MHz and 75 MHz, respectively) and are reported relative to residual CHCl3 (δ = 7.26 and 77.0 ppm). IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm-¹). High-resolution mass spectra were recorded on a Agilent 6200 Series Time-of-Flight LC/MS/TOF system with a Agilent G1978A Multimode source in electrospray ionization (ESI) mode. Analytical chiral HPLC for 5 was performed with an Agilent 1100 Series HPLC utilizing a Chiralcel OD-H column with visualization at 254 nm and a 1 mL/min flow rate of 10% i-PrOH-90% hexane. Analytical chiral SFC for 5 was performed with a Mettler supercritical CO2 analytical chromatography system utilizing a Chiralcel AD-H column with visualization at 254 nm and a 3 mL/min flow rate of 2% i-PrOH-2% MeCN-96% CO2.
Representative Screening Procedure To 1 mL vials in a 96-well microtiter plate was added 59 µL of a Pd2dba3 solution (0.0025 M in THF) using a Symyx Core Module within a nitrogen-filled glove box. The Pd2dba3 solutions were evaporated to dryness under reduced pressure using a Genevac centrifugal evaporator within the glove box. To the dried vials charged with Pd2dba3 was added 113 µL of the desired solvent to be screened and 18.8 µL of the desired ligand solution (0.02 M in THF). To the catalyst solutions, which had been stirred at 30 ˚C for 30 min, was added 30 µL of an enol carbonate 1 solution (0.2 M in THF) and 38 µL of the same solvent to be screened. The reactions were stirred at 30 ˚C for 48 h. The crude reactions were purified via parallel silica gel chromatography, eluted with hexane-EtOAc = 5:1, using a Symyx Core Module within a fume hood. The fractions containing purified 4 were evaporated to dryness using using a Genevac centrifugal evaporator.
To each of the 1 mL vials containing purified 4 was added 50 µL of a methyl acrylate solution (0.9 M in CH2Cl2) and 50 µL of a Grubbs second-generation Ru catalyst 6 solution (0.0055 M in CH2Cl2) using a Symyx Core Module within a nitrogen-filled glove box. After stirring at 40 ˚C for 3 h, the crude reactions were again purified via parallel silica gel chromatography, eluted with hexane-EtOAc = 3:1, using a Symyx Core Module within a fume hood. The solutions of purified product 5 were directly subjected to chiral SFC analysis to determine ee (%).
Selected Spectroscopic DataAllyl {6-Methyl-1,4-dioxaspiro[4.5]dec-6-en-7-yl}- carbonate (1) ¹H NMR (300 MHz, CDCl3): δ = 5.95 (dddd, J = 18.6, 10.5, 5.7, 5.7 Hz, 1 H), 5.38 (ddd, J = 18.6, 2.7, 1.5 Hz, 1 H), 5.29 (ddd, J = 10.5, 2.7, 1.5 Hz, 1 H), 4.65 (ap dt, J = 5.7, 1.2 Hz, 2 H), 3.97-4.03 (m, 4 H), 2.20-2.27 (m, 2 H), 1.70-1.84 (m, 4 H), 1.58 (t, J = 1.9 Hz, 3 H). ¹³C NMR (75.0 MHz, CDCl3): δ = 152.1, 147.9, 131.2, 122.7, 118.9, 108.4, 68.6, 65.2, 33.0, 26.7, 19.4, 8.4. IR (thin film): 2952, 2884, 1756, 1700, 1442, 1366, 1346, 1235, 1114, 1036, 993 cm-¹. ESI-HRMS: m/z calcd for C14H19O5 [M + H]+: 255.1227; found: 255.1240.
( E )-Methyl 4-{6-Methyl-7-oxo-1,4-dioxaspiro[4.5]decan-6-yl}but-2-enoate (5) ¹H NMR (300 MHz, CDCl3): δ = 6.92 (ddd, J = 15.3, 6.9, 6.9 Hz, 1 H), 5.80 (d, J = 15.3 Hz, 1 H), 3.91-3.98 (m, 4 H), 3.70 (s, 3 H), 2.66 (dd, J = 14.7, 6.9 Hz, 1 H), 2.39-2.53 (m, 2 H), 2.36 (dd, J = 14.7, 6.9 Hz, 1 H), 1.89-1.94 (m, 2 H), 1.73-1.84 (m 2 H), 1.16 (s, 3 H). ¹³C NMR (75.0 MHz, CDCl3):
δ = 210.8, 166.5, 145.9, 113.1, 65.1, 64.9, 58.1, 51.3, 36.9, 35.8, 29.5, 19.1, 17.1. IR (thin film): 2954, 2890, 1714, 1654, 1436, 1335, 1273, 1177, 1072, 1030 cm-¹. ESI-HRMS: m/z calcd for C14H21O5 [M + H]+: 269.1384; found: 269.1382. Chiral HPLC: t R(major) = 25.3 min; t R(minor): 34.6 min. Chiral SFC: t R(major) = 10.8 min; t R(minor) = 11.8 min.