High-throughput screening of the asymmetric decarboxylative alkylation reaction of enolate-stabilized enol carbonates

Article abstract of DOI:10.1055/s-0030-1258094

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. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258094

1712
CLUSTER
High-Throughput Screening of the Asymmetric Decarboxylative Alkylation
Reaction of Enolate-Stabilized Enol Carbonates
Asymmetric
Deca
o
A
l
lkylati
a
on
R
eactio
n
T
ze
d
Enol Carbo
.
nates 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
Received 7 April 2010
tion of the Pd-catalyzed, asymmetric decarboxylative
Abstract: The use of high-throughput screening allowed for the op-
timization of reaction conditions for the palladium-catalyzed asym-
metric decarboxylative alkylation reaction of enolate-stabilized
enol carbonates. Changing to a nonpolar reaction solvent and to an
alkylation5 of enolate-stabilized enol carbonates for the
synthesis of all-carbon quaternary stereocenters through
automated high-throughput screening of reaction condi-
electron-deficient PHOX derivative as ligand from our standard tions.
reaction conditions improved the enantioselectivity for the alkyla-
Enol carbonate 1, derived from 2-methyl cyclohexa-1,3-
tion of a ketal-protected,1,3-diketone-derived enol carbonate from
28% ee to 84% ee. Similar improvements in enantioselectivity were
seen for a b-keto ester derived and an a-phenyl cyclohexanone-
derived enol carbonate.
dione, was selected as our substrate for the asymmetric
Pd-catalyzed decarboxylative alkylation reaction
(Scheme 1). Enol carbonate 1 was synthesized from
known monoketal 26 via deprotonation with NaH in THF
at 60 °C and trapping of the resulting thermodynamic eno-
late with allyl chloroformate in 69% yield. Interestingly,
ketal-opened product 3 was also formed in 12% yield,
suggesting that Pd-catalyzed enantioselective formation
of the quaternary stereocenter of 4 from 1 may be in com-
petition with ketal ring opening. Exposure of 1 to our stan-
dard decarboxylative alkylation conditions [Pd2dba3 and
(S)-t-BuPHOX in THF at 25 °C]7 resulted in formation of
48 in 62% yield. Allyl ketone 4 required derivatization to
ene-dione 5 via Ru-catalyzed metathesis9 with methyl
acrylate and Grubbs second-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.
Key words: 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 auto-
mation.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 optimiza-
O
Me
Me
O
NaH (2.7 equiv)
THF, 60 °C, 1 h;
O
O
Me
O
O
O
O
O
O
+
O
then allyl chloroformate
(2.0 equiv)
THF, 0–20 °C, 3 h
O
O
2
3
1
(12% yield)
(69% yield)
MesN
NMes
CO2Me
Cl2Ru
Ph
(Cy)3P
(S)-t-BuPHOX (15 mol%)
Pd2(dba)3 (6 mol%)
6 (5 mol%)
methyl acrylate (10 equiv)
O
O
O
O
THF, 25 °C, 60 h
(62% yield)
CH2Cl2, 40 °C, 3 h
(quant. yield)
O
O
4
5
28% ee
Scheme 1 Preparation of 5 from 2 via asymmetric decarboxylative alkylation
SYNLETT 2010, No. 11, pp 1712–1716
x
x
.x
x
.2
0
1
0
Advanced online publication: 14.06.2010
DOI: 10.1055/s-0030-1258094; Art ID: Y00510ST
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Asymmetric Decarboxylative Alkylation Reaction of Enolate-Stabilized Enol Carbonates
1713
In order to obtain ketone 4 with high levels of enantiose- only solvent resulted in no reaction, as the palladium cat-
lectivity, we conducted high-throughput, parallel screen- alyst precipitated from the reaction mixture. We believe
ing to determine the required catalyst and reaction that the use of a nonpolar solvent (mixture) produces a
conditions. Experiments were conducted in 1 mL vials higher affinity between the chiral Pd center and the inter-
within 96-well microtiter plates using a SymyxTM Tech- mediate enolate than when the reaction is conducted in
nologies (Santa Clara, CA) Core Module housed in a polar solvents.10
Braun N2-filled glovebox. A stock solution of substrate 1
in THF was added to each capped vial charged with
Pd2dba3 and (S)-t-BuPHOX in the appropriate solvent(s).
In order to improve enantioselectivity in the asymmetric
Pd-catalyzed decarboxylative alkylation of 1 to syntheti-
cally useful levels, we performed a screen of various
After 48 hours at 30 °C, the reactions were diluted with
ligands. Our ligand search was biased toward the PHOX
hexane and purified via parallel silica gel chromatography
ligand class, as these have proven especially effective in
using a Code Module housed in a fume hood. The result-
related reactions and are readily prepared and modified.11
ing purified alkylated products 4 were subjected to Ru-
The ligands employed in the screen are depicted in
Figure 1 and the reactions conducted in THF, diethyl
ether, toluene, and a 2:1 mixture of hexane and toluene
solvents are shown in Figure 2. The highest levels of
enantioselectivity were observed with the use of t-Bu-
PHOX ligands (L1–8) and with the use of a 2:1 hexane
and toluene solvent mixture. Ligand L9, which does not
possess a phosphine, did not yield product. Similarly,
catalyzed metathesis with excess methyl acrylate to afford
5,20 which was then analyzed by chiral SFC for enantio-
meric excess. As an initial screen, we investigated enanti-
oselectivity as a function of reaction solvent (Table 1).
Modification of our standard reaction conditions to lower
catalyst loadings and slightly higher reaction temperature
(30 °C) improved enantioselectivity to 40% ee (entry 1)
from 28% ee (Scheme 1). Reactions conducted in ethereal
PHOX ligands having a third, heteroatomic chelating
and polar solvents (entries 1–6) gave low levels of enantio-
group (L10–12) resulted in low yields and very low ee
(< 20% ee). Interestingly, ligand L13, the silyl-protected
derivative of L12, afforded product in 61% ee in the op-
posite enantiomer of that produced with (S)-t-BuPHOX
selectivity. Similarly, polar aromatic solvents gave the
poorest ee (entries 7 and 8). The best enantioselectivities
were observed with the use of nonpolar aromatic reaction
solvents (entries 9 and 10), with the use of hexane as a co-
solvent improving enantioselectivity up to 64% ee (entry
12). It is important to note that the use of hexane as the
(L1). Cyclohexyldiamine-derived ligands L23 and L24,
which have shown great synthetic use in other asymmetric
alkylation reactions,12 afforded 5 in enantiomeric excess-
es under 10%.13 Although the sterically encumbered
Table 1 Evaluation of Reaction Solvent
naphthyl- and mesityl-derived phosphines L5 and L6 de-
creased enantioselection, electron-deficient t-BuPHOX
CO2Me
derivatives L7 and L8 gave ee of 82% and 79%, respec-
1. (S)-t-BuPHOX (6.25 mol%)
Pd2(dba)3 (2.5 mol%)
solvent, 30 °C, 48 h
Me
tively, in 2:1 hexane and toluene as solvent. Interestingly,
the monomethoxylated t-BuPHOX derivative L2 afforded
product in only 46% ee in the nonpolar solvent mixture,
suggesting that ligand electronics greatly affect enantiose-
lection. It is hypothesized that, like the less polar sol-
vent(s) in Table 1, the highly electron-deficient phosphine
ligands (L7 and L8) create a more tightly associated
Pd-PHOX ligand complex, resulting in higher enantio-
selectivities.7d
O
O
O
O
O
O
2. Grubbs II 6 (3 mol %)
methyl acrylate (10 equiv)
CH2Cl2, 40 °C, 3 h
O
O
1
5
Entry
1
Solvent
THF
ee (%)a
40
2
Et2O
45
3
MeOt-Bu
DME
49
4
30
EtO
O
CO2Et
O
ligand (6.25 mol%)
Pd2(dba)3 (2.5 mol%)
O
O
5
p-dioxane
EtOAc
21
O
solvent, 30 °C, 48 h
6
27
7
9
24% ee
70% ee
(S)-t-BuPHOX in THF
L8 in hexane–toluene (2:1)
7
PhF
19
8
PhCl
19
Ph
9
benzene
55
Ph
O
ligand (6.25 mol%)
O
O
Pd2(dba)3 (2.5 mol%)
10
11
12
toluene
59
O
solvent, 30 °C, 48 h
hexane–toluene (1:1)
hexane–toluene (2:1)
61
8
10
11% ee
50% ee
(S)-t-BuPHOX in THF
L31 in hexane–toluene (2:1)
64
Scheme 2 Asymmetric Pd-catalyzed decarboxylative alkylation
reactions of enolate-stabilized enol carbonates 7 and 8
a Enantiomeric excesses determined via chiral SFC analysis of chro-
matographically-purified product 5.
Synlett 2010, No. 11, 1712–1716 © Thieme Stuttgart · New York

1714
N. T. McDougal et al.
CLUSTER
OMe
O
O
O
Ph
Ph
O
O
Ar2P
N
Me
Me
Ph2P
N
Ph2P
N
Ph2P
N
Ph2P
N
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
L1: (S)-t-BuPHOX
L2
L3
L4
L5: Ar = 2-naphthyl
OMe
O
Fe
Ph2P
N
O
O
O
O
Ar2P
N
Ar2P
N
Ar2P
N
HN
N
t-Bu
t-Bu
t-Bu
t-Bu
L6: Ar = 2,4,6-Me3C6H2
L7: Ar = 4-F3CC6H4
L8: Ar = 4-F3CC6H4
L9
L10
Ph
Fe
O
Ph
Ph
Ph
O
Ph
PPh2
Ph2P
N
O
N
O
Ph2P
Ph2P
N
O
Ph2P
N
S
Me
N
Me
Me
HO
Me
TBSO
t-Bu
L11
L12
L13
L14
L15
O
N
O
O
Ph2P
O
Ph2P
N
Ph2P
N
Ph2P
N
O
Me
Ph2P
N
Me
Ph
L16
L17
L18
L19
L20
O
O
O
O
Ph2P
N
HN
Ph2P
NH
N
N
Ph2P
N
Me
Me
PPh2
PPh2 Ph2P
Ph
Me
Ph
L22
L21
L23
L24
Figure 1 Ligands screened in the Pd-catalyzed decarboxylative alkylation reaction of 1
We screened other highly electron-deficient PHOX bonate 7 to the decarboylative alkylation catalyst derived
ligands (Figure 3), as well as re-screened the ligands from L8 in 2:1 hexane and toluene improved the enantio-
which gave the highest levels of enantioselectivity within selectivity for the formation of 918 to 71% ee from 24% ee
the first ligand screen, in order to test whether even more when using (S)-t-BuPHOX in THF.17 Similarly a-phenyl
highly electron-deficient PHOX derivatives could im- cyclohexanone derived enol cabonate 8 afforded allyl ke-
prove the enantioselectivity of the Pd-catalyzed decarbox- tone 1019 in 51% ee when exposed to the catalyst derived
ylative alkylation reaction of 1 (Table 2). The highest from L31 in the nonpolar solvent mixture, an improve-
levels of enantioselection were achieved with the trifluo- ment from 11% ee when (S)-t-BuPHOX is utilized in
romethylated t-BuPHOX derivative L2511,14 in the 2:1 THF.17
hexane and toluene mixture (entry 6). It is not too surpris-
ing that ligand L25 was found to be the best ligand with
respect to enantioselectivity, as it has been shown to give
In summary, we have used high-throughput screening for
the asymmetric, Pd-catalyzed decarboxylative alkylation
reaction of enolate-stabilized enol carbonates to afford
the highest levels of enantioselection for the asymmetric
quaternary-stereocenter-containing products with high
alkylation of ketones15 and for an asymmetric alkylation
levels of enantioselection. The high-throughput screening
of various solvents and ligands allowed us to improve the
within the our formal synthesis of hamigeran B.16
Simultaneous screening of the enantioselective alkylation enantioselectivities with the use of a nonpolar solvent
of enolate-stabilized enol carbonates 7 and 8 revealed im- mixture (hexanes–toluene, 2:1) and electron-deficient
proved enantioselectivities from our standard reaction t-BuPHOX derivatives.
conditions with the use of electron-deficient ligands in the
nonpolar hexane and toluene solvent mixture
(Scheme 2).17 Exposure of b-keto ester derived enol car-
Synlett 2010, No. 11, 1712–1716 © Thieme Stuttgart · New York

CLUSTER
Asymmetric Decarboxylative Alkylation Reaction of Enolate-Stabilized Enol Carbonates
1715
Table 2 Evaluation of Reaction Ligands
CO2Me
1. ligand (6.25 mol%)
Me
O
Pd2(dba)3 (2.5 mol%)
O
O
hexane–toluene (2:1), 30 °C, 48 h
O
O
O
2. Grubbs II 6 (3 mol%)
methyl acrylate (10 equiv)
CH2Cl2, 40 °C, 3 h
O
O
1
5
Entry
1
Ligand
L1
ee (%)a
64
2
L3
58
3
L4
55
4
L7
82
5
L8
79
6
L25
L26
L27
L28
L29
L30
L31
84
7
72
8
74
Figure 2 Dependence of enantiomeric excess of 5 on ligand struc-
ture and solvent in the decarboxylative alkylation reaction of 1
9
72
10
11
12
58
74
O
O
O
Me
Me
Ph
Ph
Ph2P
N
Ph2P
N
Ph2P
N
70
t-Bu
t-Bu
t-Bu
a Enantiomeric excesses determined via chiral SFC analysis of chro-
L1: (S)-t-BuPHOX
L3
L4
matographically-purified product 5.
OMe
CF3
NIH-NIGMS (R01 GM 080269-01), Abbott Laboratories, Amgen,
the Gordon and Betty Moore Foundation, and Caltech for financial
support.
O
O
O
Ar2P
N
Ar2P
N
Ar2P
N
t-Bu
t-Bu
t-Bu
References and Notes
L7: Ar = 4-F3CC6H4
L8: Ar = 4-F3CC6H4
L25: Ar = 4-F3CC6H4
(1) (a) Fuji, K. Chem. Rev. 1993, 93, 2037. (b) Corey, E. J.;
Guzman-Perez, A. Angew. Chem. Int. Ed. 1998, 37, 388.
(c) Christoffers, J.; Mann, A. Angew. Chem. Int. Ed. 2001,
40, 4591. (d) Douglas, C. J.; Overman, L. E. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5363.
O
O
O
Ph
Ph
t-Bu
Ph
Ar2P
N
Ar2P
N
Ar2P
N
Ph
t-Bu
t-Bu
(2) Chandler, W.; Carlson, E.; Rust, W.; Hajduk, D.; Han, H.;
L26: Ar = 2,5-F2C6H4
L27: Ar = 4-F3CC6H4
L28: Ar = 3,5-(F3C)2C6H4
Brown, J. J. Assoc. Lab. Autom. 2005, 10, 418.
(3) Murphy, V.; Bei, X.; Boussie, T. R.; Brummer, O.;
Diamond, G. M.; Goh, C.; Hall, K. A.; Lapointe, A. M.;
Leclerc, M.; Longmire, J. M.; Shoemaker, J. A. W.; Turner,
H.; Weinberg, W. H. Chem. Rec. 2002, 2, 278.
(4) For reviews, see: (a) Shimizu, K. D.; Snapper, M. L.;
Hoveyda, A. H. Chem. Eur. J. 1998, 4, 1885. (b) Traverse,
J. F.; Snapper, M. L. Drug Discovery Today 2002, 7, 1002.
(c) Stambuli, J. P.; Hartwig, J. F. Curr. Opin. Chem. Biol.
2003, 7, 420. (d) Jakel, C.; Paciello, R. Chem. Rev. 2006,
106, 2912.
(5) For reviews, see: (a) Tsuji, J.; Minami, I. Acc. Chem. Res.
1987, 20, 140. (b) Mohr, J. T.; Stoltz, B. M. Chem. Asian J.
2007, 1476.
(6) Subramanian, G.; Ramakrishnan, V. T.; Rajagopalan, K.
Synth. Commun. 1990, 20, 2019.
CF3
CF3
O
O
O
Ph
Ph
Ph
Ph
Ar2P
N
Ar2P
N
Ph
Ar2P
N
Ph
i-Pr
L29: Ar = 4-F3CC6H4
i-Pr
L30: Ar = 4-F3CC6H4
i-Pr
L31: Ar = 3,5-(F3C)2C6H4
Figure 3 Ligands screened in the Pd-catalyzed decarboxylative
alkylation reaction of 1
Acknowledgment
This publication is based on work supported by Award No. KUS-
11-006-02, made by King Abdullah University of Science and
Technology (KAUST). Additionally, the authors wish to thank
(7) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004,
126, 15044. (b) Mohr, J. T.; Behenna, D. C.; Harned, A. M.;
Synlett 2010, No. 11, 1712–1716 © Thieme Stuttgart · New York

1716
N. T. McDougal et al.
CLUSTER
Stoltz, B. M. Angew. Chem. Int. Ed. 2005, 44, 6924.
(c) Seto, M.; Roizen, J. L.; Stoltz, B. M. Angew. Chem. Int.
Ed. 2008, 47, 6873. (d) Sherden, N. H.; Behenna, D. C.;
Virgil, S. C.; Stoltz, B. M. Angew. Chem. Int. Ed. 2009, 48,
6840.
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 mL of the desired solvent to be screened and 18.8
mL 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 mL of an enol carbonate 1 solution (0.2 M
in THF) and 38 mL 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 mL of a methyl acrylate solution (0.9 M in CH2Cl2) and
50 mL 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 (%).
(8) Renouf, P.; Poirier, J.-M.; Duhamel, P. J. Org. Chem. 1999,
64, 2513.
(9) For a review, see: Grubbs, R. H. Tetrahedron 2004, 60,
7117.
(10) Reichardt, C. Solvents and Solvent Effects in Organic
Chemistry; VCH: New York, 1988.
(11) Tani, K.; Behenna, D. C.; McFadden, R. M.; Stoltz, B. M.
Org. Lett. 2007, 9, 2529.
(12) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(13) Trost, B. M.; Xu, J.; Schmidt, T. J Am. Chem. Soc. 2009,
131, 18343.
(14) McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.;
Stoltz, B. M. submitted for publication.
(15) Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nature
Chem. 2010, 2, 192.
(16) Mukherjee, H.; McDougal, N. T.; Virgil, S. C.; Stoltz, B. M.
manuscript in preparation.
(17) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu,
S. C.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. III. J. Am.
Chem. Soc. 2007, 129, 11876.
Selected Spectroscopic Data
(18) Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc.
1997, 119, 7879.
(19) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew Chem.
Int. Ed. 2002, 41, 3492.
Allyl {6-Methyl-1,4-dioxaspiro[4.5]dec-6-en-7-yl}-
carbonate (1)
1H NMR (300 MHz, CDCl3): d = 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):
d = 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)
(20) 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 (d = 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.
1H NMR (300 MHz, CDCl3): d = 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):
d = 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: tR(major) = 25.3 min; tR(minor):
34.6 min. Chiral SFC: tR(major) = 10.8 min; tR(minor) = 11.8
min.
Representative Screening Procedure
To 1 mL vials in a 96-well microtiter plate was added 59 mL
of a Pd2dba3 solution (0.0025 M in THF) using a Symyx
Core Module within a nitrogen-filled glove box. The
Synlett 2010, No. 11, 1712–1716 © Thieme Stuttgart · New York