Palladium-catalyzed aerobic oxidative kinetic resolution of alcohols with an achiral exogenous base

Article abstract of DOI:10.1021/jo034717r

Substitution of exogenous (-)-sparteine for a more practical achiral base in the aerobic oxidative kinetic resolution of secondary alcohols is described. Carbonate bases are the most effective of those screened and allow for effective kinetic resolution of benzylic, allylic, and aliphatic substrates. The procedure was also successfully extended to the oxidative desymmetrization of meso diols.

Full text of DOI:10.1021/jo034717r

P a lla d iu m -Ca ta lyzed Aer obic Oxid a tive
Kin etic Resolu tion of Alcoh ols w ith a n
Ach ir a l Exogen ou s Ba se
Sunil K. Mandal and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South
1400 East, Salt Lake City, Utah 84112-8500
sigman@chem.utah.edu
Received May 27, 2003
F IGURE 1. Origin of asymmetric induction.
Abstr a ct: Substitution of exogenous (-)-sparteine for a
more practical achiral base in the aerobic oxidative kinetic
resolution of secondary alcohols is described. Carbonate
bases are the most effective of those screened and allow for
effective kinetic resolution of benzylic, allylic, and aliphatic
substrates. The procedure was also successfully extended
to the oxidative desymmetrization of meso diols.
alkoxides (Figure 1). In this scenario, exogenous (-)-
sparteine is acting purely as a Brønsted base and not
directly influencing the asymmetric induction of the
process.6 Therefore, identification of an achiral base that
allows for equilibration of the alkoxides and rate-limiting
â-hydride elimination should give similar krel values as
above and the need for exogenous (-)-sparteine should
be avoided. Herein, we describe a new system for the
aerobic oxidative kinetic resolution of secondary alcohols,
utilizing a simple, achiral carbonate base as a replace-
ment for exogenous (-)-sparteine.
An obvious choice of an achiral base would be a tertiary
amine whose conjugate acid has a similar pKa to proto-
nated (-)-sparteine. However, tertiary amines have been
observed to slow oxidations via competitive binding of the
Pd.7 Additionally, two other key pieces of information
influenced the selection of bases: (1) chloride is an
incompetent base for alcohol oxidation, and (2) acetate
has been shown to be a viable base for this oxidation
without any added (-)-sparteine.8 Therefore, we choose
to evaluate weakly coordinating bases in a bascity range
similar to that of acetate and tertiary amines (pKa of
conjugate acids from 3 to 11 in H2O). Screening was
accomplished by using 5 mol % of isolated 1, the base of
interest, a balloon of O2, and activated 3 Å molecular
sieves in tert-butyl alcohol solvent for the aerobic oxida-
tive kinetic resolution of sec-phenethyl alcohol (Table 1).
At 20 mol % loading, a variety of bases permit aerobic
oxidation, albeit with low conversions.9 The nature of the
counterion does play a role in the oxidation with bicar-
bonate and acetate derived bases giving lower krel values
to that obtained with (-)-sparteine. In contrast, several
carbonate and fluoride sources produce comparable krel
values (krel: 17-25). The carbonate bases are especially
interesting due to their convenience and low cost. There-
fore, higher loadings of carbonate bases (50 mol %) were
We have recently reported the development of Pd
catalysts for the aerobic oxidative kinetic resolution of
alcohols.1-3 The most successful of these catalysts utilizes
(-)-sparteine as the chiral agent. In the optimal system,
5 mol % of Pd[(-)-sparteine]Cl2, 1, is used along with a
20 mol % excess of (-)-sparteine in tert-butyl alcohol.4 A
wide range of alcohols are effectively resolved with use
of these conditions. While (-)-sparteine is a relatively
inexpensive chiral agent, the need for 25 mol % loading
overall is impractical and certainly would become pro-
hibitive if a less abundant chiral agent was utilized.
Therefore, we sought to identify more practical conditions
that limit the usage of exogenous (-)-sparteine.
Mechanistic work from our laboratory provides a
framework for the elimination of exogenous sparteine.5
In these studies, exogenous (-)-sparteine was observed
to act as a Brønsted base to deprotonate Pd-bound
alcohol. High concentrations of (-)-sparteine provided
faster rates and higher krel values. Under these condi-
tions, kinetic experiments are consistent with rate-
limiting â-hydride elimination. Asymmetric induction is
proposed to arise from a combination of two factors: a
thermodynamic difference in diastereomeric alkoxides
formed, and a kinetic difference in the reaction of these
(1) (a) J ensen, D. R.; Pugsley, J . S.; Sigman, M. S. J . Am. Chem.
Soc. 2001, 123, 7475. (b) J ensen, D. R.; Sigman, M. S. Org. Lett. 2003,
5, 63.
(2) For a closely related system, see: (a) Ferreira, E. M.; Stoltz, B.
M. J . Am. Chem. Soc. 2001, 123, 7725. (b) Bagdanoff, J . T.; Ferreira,
E. M.; Stoltz, B. M. Org. Lett, 2003, 5, 835.
(3) For examples of other oxidative kinetic resolutions, see: (a) Sun,
W.; Wang, H.; Xia, C.; Li, J .; Zhao, P. Angew. Chem., Int. Ed. 2003,
42, 1042. (b) Masutani, K.; Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron
Lett. 2000, 41, 5119. (c) Nishibayashi, I.; Takei, I.; Uemura, S.; Hidai,
M. Organometallics 1999, 18, 2291. (d) Gross, Z.; Ini, S. Org. Lett. 1999,
1, 2077. (e) Hashiguchi, S.; Fujii, A.; Haack, K.-J .; Matsumura, K.;
Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 288. (f)
Rychnovsky, S. D.; McLernon, T. L.; Rajapakse, H. J . Org. Chem. 1996,
61, 1194.
(4) Mandal, S. K.; J ensen, D. R.; Pugsley, J . S.; Sigman, M. S. J .
Org. Chem. 2003, 68, 4600.
(5) (a) Mueller, J . A.; J ensen, D. R.; Sigman, M. S. J . Am. Chem.
Soc. 2002, 124, 8202. (b) Mueller, J . A.; Sigman, M. S. J . Am. Chem.
Soc. 2003, 125, 7005.
(6) At low (-)-sparteine concentrations where deprotonation is both
rate determining and enantiodetermining, exogenous (-)-sparteine acts
as a chiral Brønsted base. See ref 5b for details.
(7) (a) Schultz, M. J .; Park, C.; Sigman, M. S. Chem. Commun. 2002,
3034. (b) Steinhoff, B. A.; Fix, S. R.; Stahl, S. S. Org Lett. 2002, 4,
4179.
(8) Acetate was introduced into the reaction as the counterion on
Pd and the resulting kinetic resolution proved to be poor. See ref 5b
for details.
(9) krel is calculated by using the following equation: krel ) ln[(1 -
C)(1 - ee)]/ln[(1 - C)(1 + ee)], where C ) conversion and ee )
enantiomeric excess. See: Kagan, H. B.; Fiaud, J . C. Kinetic Resolu-
tion. Top. Stereochem. 1988, 18, 249.
10.1021/jo034717r CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/22/2003
J . Org. Chem. 2003, 68, 7535-7537
7535

TABLE 1. Scr een of Ach ir a l Ba ses
TABLE 2. Scop e of th e Aer obic Oxid a tive Kin etic
Resolu tion
loading,
mol %
b
entry
base
% conv (% ee)a
krel
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
(-)-sparteine
KF
CsF
Cs2CO3
K2CO3
Na2CO3
CaCO3
KHCO3
NaHCO3
NH4HCO3
NaOAc
KOAc
20
20
20
20
20
20
20
20
20
20
20
20
20
50
50
50
100
66.1 (94.2)
35.0 (46.3)
38.3 (54.2)
38.1 (51.3)
26.7 (31.2)
34.6 (44.0)
34.3 (45.8)
30.7 (38.8)
20.9 (21.7)
17.0 (15.3)
29.0 (31.4)
17.8 (15.7)
<15
16
21
25
18
18
17
24
22
13
7.9
10
7.3
NA
19
20
19
19
AgOAc
c
K2CO3
58.3 (95.3)
59.0 (96.6)
59.0 (96.0)
60.0 (97.0)
c
Na2CO3
c
CaCO3
KFd
a
b
Conversion determined by using the internal standard. Data
represent a single experiment. c Substrate concentration increased
d
from 0.25 to 0.375 M. 30 h.
evaluated and provided for an effective oxidative kinetic
resolution (entries 14-16). While it is difficult to directly
correlate the pKa of the bases and the effectiveness of
the kinetic resolution, it is interesting to note HCO3- has
a very similar pKa value (10.33) in H2O to the protonated
tertiary amine, Et3N+H (10.75).
a
The scope of the aerobic oxidative kinetic resolution of
secondary alcohols was explored by using 50 mol % of
Na2CO3 as exogenous base with 5 mol % of 1 (Table 2).10
Aryl-substituted acyclic (entries 1-8 and 13-15) and
cyclic (entries 9-12) alcohols are generally good sub-
strates under the new conditions. Several aliphatic
(entries 16-19) and allylic (entries 20-22) substrates are
also resolved effectively. In almost all cases, the kinetic
resolutions perform similarly to the previously reported
(-)-sparteine system with the notable exceptions of one
aromatic (entry 14) and one aliphatic (entry 16) alcohol.
To verify the feasibility of the reaction on a common
laboratory scale, an oxidative kinetic resolution was
performed on a 10-mmol (1.22 g) scale for sec-phenethyl
alcohol (entry 2). Good overall mass recovery was ob-
served for both the optically enriched alcohol (% yield,
31.4; % ee, 99.3) and the prochiral ketone byproduct (62%
isolated yield, 64% conversion by GC). This larger scale
reaction did require a slightly longer reaction time of
32 h, compared to 24 h for the smaller scale reaction,
and showed a slight decrease in krel values (18 as
compared to 20).
Conversion determined by GC, using tetradecane as the
internal standard. See the Supporting Information for chiral
b
separations. Data represent a single experiment. c 20 mol % of
d
(-)-sparteine or 50 mol % of Na2CO3. Conversion and ee data
correspond to the system with Na2CO3. See ref 4 for values with
(-)-sparteine. e Reaction performed on a 10-mmol scale (1.22 g).
f Conversion determined by 1H NMR.
The methodology was further extended to the oxidative
desymmetrization of meso 1,3-diols which yield enantio-
merically enriched â-hydroxycarbonyl compounds.11 Gen-
erally good yields (71-77%) and ee values (76-93.4%)
of â-keto alcohols are obtained from various meso 1,3-
diols (Table 3). These values are again very similar to
that reported for the (-)-sparteine system.
While the new system performs similarly to the previ-
ously reported system with exogenous (-)-sparteine and
does provide a more practical kinetic resolution strategy,
it is unclear if carbonate is solely acting as a Brønsted
base in this chemistry and not modifying the catalyst.
To investigate this issue, Pd[(-)-sparteine]Cl2 was treated
with 1.2 equiv of Na2CO3 in tert-butyl alcohol at 65 °C in
the absence of alcohol. The excess Na2CO3 and the
solvents were removed to yield a new complex, which was
identified as Pd[(-)-sparteine](CO3) via X-ray crystal-
(10) General procedure for the oxidative kinetic resolution of second-
ary alcohols and desymmetrization of meso diols: In a 5-mL round-
bottom flask equipped with a sidearm and stirbar, 0.7 mL of tert-butyl
alcohol, 5.6 mg (0.013 mmol, 0.05 equiv) of [(-)-sparteine]PdCl2, 14
mg (0.13 mmol, 0.50 equiv) of Na2CO3, 0.25 mmol (1.0 equiv) of the
alcohol or meso diol, and 25 mg of freshly activated crushed molecular
sieves (3 Å) were combined. The flask was then attached to the bottom
of a reflux condenser. A balloon filled with oxygen gas was then
(11) For examples of nonenzymatic desymmetrization of meso diols,
see: (a) Trost, B. M.; Mino, T. J . Am. Chem. Soc. 2003, 125, 2410. (b)
Hodgson, R.; Majid, T.; Nelson, A. J . Chem. Soc., Perkin Trans. 1 2002,
14, 1631. (c) J iang, L.; Burke, S. D. Org. Lett. 2002, 4, 3411-3414. (d)
Harada, T.; Sekiguchi, K.; Nakamura, T.; Suzuki, J .; Oku, A. Org. Lett.
2001, 3, 3309. (e) Harada, T.; Yamanaka, H.; Oku, A. Synlett 2001, 1,
61. (f) Yamada, S.; Katsumata, H. J . Org. Chem. 1999, 64, 9365. (g)
Oriyama, T.; Imai, K.; Hosoya, T.; Sano, T. Tetrahedron Lett. 1998,
39, 397. (h) Via acetal cleavage, see: Fujioka, H.; Nagatomi, Y.; Kotoku,
N.; Kitagawa, H. Tetrahedron 2000, 56, 10141. (i) Kinugasa, M.;
Harada, T.; Oku, A. J . Am. Chem. Soc. 1997, 119, 9067.
attached to the top of the condenser via
a three-way joint. The
apparatus was then evacuated (water aspirator) and refilled with
oxygen from the balloon three times and heated in an oil bath at 65
°C. Aliquots (0.1 mL) of the reaction were then periodically taken via
syringe. The aliquot was quenched with 2% TFA/methanol. The sample
was analyzed with use of a GC or HPLC equipped with a chiral column.
7536 J . Org. Chem., Vol. 68, No. 19, 2003

TABLE 3. Oxid a tive Desym m etr iza tion of Meso
1,3-Diols
complex is catalytically relevant, crystals of Pd[(-)-
sparteine](CO3) were submitted to the standard reaction
conditions without exogenous Na2CO3. Very little cataly-
sis is observed (12% conversion at 24 h). After adding
exogenous Na2CO3 to the new complex, the oxidation was
again very slow. Therefore, carbonate is presumably
acting primarily as a Brønsted base and not involved in
any ground state modifications to the catalyst structure.
While the precise details of this new system are not
defined, the mechanistic analysis outlined in the Intro-
duction seems to provide a reasonable explanation for the
observed outcome of this kinetic resolution in which an
achiral Brønsted base at high concentration can ef-
fectively equilibrate diastereomeric alkoxides followed by
rate-limiting â-hydride elimination.
In summary, we have disclosed a simple and effective
method for the oxidative kinetic resolution of secondary
alcohols using catalytic Pd[(-)-sparteine]Cl2 and an
achiral carbonate as an exogenous base. These conditions
offer a more practical method for oxidative kinetic
resolution by replacing a valuable chiral agent with an
inexpensive achiral base. Future work will focus on
identifying a new ligand for aerobic oxidative kinetic
resolution with antipodal selectivity and allowing modu-
lar structural modifications for improved asymmetric
catalysis.
a
b
Data represent a single experiment. See the Supporting
Information for chiral separations.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (NIGMS No. GM63540).
We thank the University of Utah Research Foundation,
Merck Research, and Rohm and Haas Research for
support of this research. We thank J ohnson-Matthey for
supplies of palladium salts. S.K.M. would like to thank
the University of Utah for sponsorship of a Faculty
Intern position.
F IGURE 2. ORTEP diagram of Pd[(-)-sparteine](CO3).
lography (Figure 2).12 The structure clearly shows car-
bonate incorporated as a bidentate dianionic ligand on
the square plane of palladium. To test whether the new
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, characterization data, chiral chromatographic separa-
tion details, and NMR spectra and X-ray analysis of Pd[(-)-
sparteine](CO3). This material is available free of charge via
the Internet at http://pubs.acs.org.
(12) See Supporting Information for the isolation, characterization,
and X-ray structural data.
J O034717R
J . Org. Chem, Vol. 68, No. 19, 2003 7537