The palladium-catalyzed aerobic kinetic resolution of secondary alcohols: Reaction development, scope, and applications

Article abstract of DOI:10.1002/chem.200902172

The first palladium-catalyzed enantioselective oxidation of secondary alcohols has been developed, utilizing the readily available diamine (-)-sparteine as a chiral ligand and molecular oxygen as the stoichiometric oxidant. Mechanistic insights regarding the role of the base and hydrogen-bond donors have resulted in several improvements to the original system. Namely, addition of cesium carbonate and tert-butyl alcohol greatly enhances reaction rates, promoting rapid resolutions. The use of chloroform as solvent allows the use of ambient air as the terminal oxidant at 23°C, resulting in enhanced catalyst selectivity. These improved reaction conditions have permitted the successful kinetic resolution of benzylic, allylic, and cyclopropyl secondary alcohols to high enantiomeric excess with good-toexcellent selectivity factors. This catalyst system has also been applied to the desymmetrization of meso-diols, providing high yields of enantioenriched hydroxyketones.

Full text of DOI:10.1002/chem.200902172

DOI: 10.1002/chem.200902172
The Palladium-Catalyzed Aerobic Kinetic Resolution of Secondary Alcohols:
Reaction Development, Scope, and Applications
David C. Ebner, Jeffrey T. Bagdanoff, Eric M. Ferreira, Ryan M. McFadden,
Daniel D. Caspi, Raissa M. Trend, and Brian M. Stoltz*[a]
12978
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Chem. Eur. J. 2009, 15, 12978 – 12992

FULL PAPER
Abstract: The first palladium-catalyzed
enantioselective oxidation of secondary
alcohols has been developed, utilizing
the readily available diamine (À)-spar-
teine as a chiral ligand and molecular
oxygen as the stoichiometric oxidant.
Mechanistic insights regarding the role
of the base and hydrogen-bond donors
have resulted in several improvements
to the original system. Namely, addi-
tion of cesium carbonate and tert-butyl
alcohol greatly enhances reaction rates,
promoting rapid resolutions. The use of
chloroform as solvent allows the use of
ambient air as the terminal oxidant at
238C, resulting in enhanced catalyst se-
lectivity. These improved reaction con-
ditions have permitted the successful
kinetic resolution of benzylic, allylic,
and cyclopropyl secondary alcohols to
high enantiomeric excess with good-to-
excellent selectivity factors. This cata-
lyst system has also been applied to the
desymmetrization of meso-diols, pro-
viding high yields of enantioenriched
hydroxyketones.
Keywords: alcohols
· asymmetric
catalysis · oxidation · palladium ·
synthetic methods
Introduction
(Scheme 1).[12] Employing molecular oxygen as the sole stoi-
chiometric oxidant, high yields of aldehydes and ketones
were obtained for a variety of alcohols. These conditions
The oxidation of alcohols to carbonyl compounds is one of
the most fundamental reactions in organic chemistry.[1]
Many different systems have been developed using a wide
variety of oxidants.[2] Until recently, however, catalytic enan-
tioselective variants have been largely unexplored.[3,4] The
limited number of these alcohol oxidations is somewhat un-
derstandable, since this process is inherently complexity-
minimizing.[5] While many enantioselective oxidative trans-
formations involve the selective creation of stereogenicity
from prochiral starting materials by transfer of a heteroatom
to the organic substrate (e.g., epoxidation, dihydroxylation,
sulfide oxidation),[6] enantioselective alcohol oxidation re-
quires the selective destruction of a stereocenter in a stereo-
ablative kinetic resolution process.[7,8] Kinetic resolutions
have the ability to provide compounds of high enantiomeric
excess for even modestly selective processes at higher levels
of conversion. Furthermore, the ready availability of a wide
range of racemic alcohols, the prevalence of chiral alcohols
in organic synthesis, and the potential for product recycling
by a simple reduction could make an oxidative kinetic reso-
lution of alcohols a synthetically useful process for the pro-
duction of enantioenriched materials.
Scheme 1. Uemuraꢁs oxidation of alcohols.
were attractive for a number of reasons. Molecular oxygen,
essential for cellular respiration in all aerobic organisms, is
an inexpensive, abundant, and environmentally benign oxi-
dant. The lack of additional co-oxidants simplified reaction
complexity, producing water as the sole byproduct. Also,
pyridine was found to be critical to the reaction both as
ligand and base. Uemura reported no catalytic activity in
the absence of pyridine, indicating a strong ligand accelera-
tion effect. We anticipated that the use of chiral ligands in
the place of pyridine could lead to significant enantiodiscri-
mination in the oxidation, while the ligand acceleration
could minimize racemic background oxidation by other pal-
ladium(II) species that could be present in the reaction. Fi-
nally, the non-coordinating nature of toluene could limit sol-
vent displacement of a chiral ligand from the palladium
center.
The proposed mechanism for the oxidation involves alco-
hol substitution and deprotonation of a palladium(II) com-
plex to generate intermediate palladium alkoxide
(Scheme 2). Subsequent b-hydride elimination from this
complex forms the product ketone and palladium hydride 2,
which then reacts with oxygen and another equivalent of al-
cohol to reform 1. Efforts by a number of researchers have
further clarified this mechanism.[13–15]
As part of a general program directed toward enantiose-
lective oxidation, we chose to pursue palladium(II) as a cat-
alytic metal for this process. Not only is palladium catalysis
prevalent in a variety of enantioselective transformations,[9]
but a number of systems involving palladium have been ap-
plied to the aerobic oxidation of alcohols.[10,11] Particularly
intriguing was a report by Uemura of racemic alcohol oxida-
tion utilizing a palladium(II) catalyst and pyridine in toluene
1
[a] Dr. D. C. Ebner, Dr. J. T. Bagdanoff, Dr. E. M. Ferreira,
Dr. R. M. McFadden, Dr. D. D. Caspi, Dr. R. M. Trend,
Prof. B. M. Stoltz
Based on this previous report of alcohol oxidation, we re-
cently developed a palladium-catalyzed oxidative kinetic
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis
Division of Chemistry and Chemical Engineering
California Institute of Technology
resolution of secondary alcohols.[16,17] Utilizing [Pd
ACHTUNGTRENNUNG
1200 E. California Blvd., MC 164-30, Pasadena, CA 91125 (USA)
Fax : (+1)626-564-9297
E-mail: stoltz@caltech.edu
amine (À)-sparteine, a variety of alcohols were resolved to
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902172.
Chem. Eur. J. 2009, 15, 12978 – 12992
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12979

B. M. Stoltz et al.
Scheme 2. Proposed mechanism for the palladium-catalyzed alcohol oxi-
dation.
modification of these conditions leading to dramatic im-
provements in reaction rate and selectivity, our extensive
substrate scope investigation, and applications, including the
desymmetrization of meso-diols.
Results and Discussion
Reaction development: Our initial exploration of the aero-
bic kinetic resolution of secondary alcohols with catalytic Pd
focused on substituting an appropriate chiral ligand for pyri-
dine in the oxidation.[16] While many of the compounds eval-
uated as ligands led to little or no alcohol oxidation, some
provided moderately reactive Pd complexes (Figure 1).
However, (À)-sparteine rapidly emerged as a uniquely effec-
tive ligand for this transformation, providing modest levels
of selectivity[18] in the oxidation of (Æ)-1-phenylethanol
((Æ)-3, Table 1).[19]
Figure 1. Ligands evaluated in Table 1.
Table 1. Initial ligand screen.
Reexamination of the general mechanism proposed by
Uemura was critical for optimization of the reaction. Nota-
bly, an acetate is coordinated to the palladium center
throughout the catalytic cycle, indicating the possible impor-
tance of the palladium(II) counterion in the resolution. In-
vestigation of a number of palladium sources permitted
counterion modification, resulting in greatly improved reac-
tivity and selectivity in the oxidation employing palladium
Ligand[a]
t
Conv
[%][b]
Alcohol
s[d]
[h]
ee [%][c]
1
2
3
4
5
6
7
8
9
A
72
24
72
24
24
24
24
24
24
24
2
3
2
0
3
–
–
–
–
–
–
0
0
8.7
13.7
–
–
–
–
–
–
1.0
1.0
1.6
8.8
(S)-tBu-BOX
cinchonidine
quinine
chloride complexes. [PdACTHNUTRGNE(NUG nbd)Cl2] proved to be the most ef-
fective precatalyst, providing good selectivity in the oxida-
tion of a number of benzylic alcohols (Scheme 3).
A
(À)-isopinocampheylamine
0
(R)-BINAP
29.0
77.0
31.6
15.1
Although useful in principle, a major limitation of this
resolution is the sluggish reaction rates. Usually, over four
days are required to provide alcohols in high enantiomeric
excess. The high operating temperature (808C) further dem-
onstrates the low activity of the system. During the course
of our studies to improve the reaction rate, we prepared the
discrete complex [Pd(sparteine)Cl2] (5). The reactivity of
this complex was substantially decreased relative to the
complex generated in situ with a 4:1 sparteine/Pd loading
(Table 2).[17a] Interestingly, reactivity could be restored by
adding three equivalents of sparteine relative to complex 5.
brucine
N
10
[a] See Figure 1. [b] Measured by GC. [c] Measured by chiral HPLC; see
Supporting Information for details. [d] Selectivity factor.[18]
We hypothesized that the excess sparteine acts as a general
base for the hydrogen chloride byproduct, generated as a
result of palladium alkoxide formation. Indeed, kinetic stud-
ies have confirmed the role of sparteine as base.[15a] Without
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Asymmetric Catalysis
FULL PAPER
was ultimately observed. Additional equivalents proved
more detrimental (entries 5 and 6). The more nucleophilic
base 1,4-diazobicycloACTHNUTRGNEU[GN 2.2.2]octane (DABCO) was even
poorer. The loss of reactivity with these bases is presumably
due to competition between the amine and sparteine for co-
ordination to the palladium center.[21] However, carbonate
bases were effective at accelerating the oxidations. Cesium
carbonate was found to be optimal, leading to the greatest
reactivity enhancement.[22] Surprisingly, excess sparteine rel-
ative to palladium was still required.
Scheme 3. Initial conditions for the Pd-catalyzed enantioselective oxida-
tion of alcohols.
Table 2. Effect of excess sparteine on the resolution for in situ and pre-
formed catalysts.
Several observations suggest cesium carbonate is acting as
a heterogeneous base. The solubility of cesium carbonate in
toluene is minimal, even at elevated temperatures. Also,
finely milled cesium carbonate performs much better than
the granular base of lower surface area.[23] Thus, sparteine,
which is much more soluble in toluene, may act as a better
kinetic base than the heterogeneous cesium carbonate for
neutralizing hydrogen chloride generated in the formation
of the palladium alkoxide. While the pKa values of sparte-
Catalyst[a]
[Pd(nbd)Cl2]
Conv
[%][b]
Alcohol
s[d]
ee [%][c]
1
G
59.9
98.7
23.1
(À)-sparteine (20 mol%)
AHCTUNGTRENNUNG
ine·HCl[24] and cesium bicarbonate[25] are similar, the excess
2
3
[Pd(sparteine)Cl2] (5)
4.6
3.4
6.0
carbonate base could minimize sparteine·HCl concentra-
tion,[26] inhibiting protonation of the palladium alkoxide and
accelerating the reaction (Scheme 4).[27]
[Pd(sparteine)Cl2] (5)
(À)-sparteine (15 mol%)
60.6
99.2
23.8
[a] 1 atm O2, 500 mg MS3ꢂ per mmol substrate, 0.1m substrate in
PhCH3. [b] Measured by GC. [c] Measured by chiral HPLC; see Support-
ing Information for details. [d] Selectivity factor.[18]
this added sparteine, palladium alkoxide formation is much
less favorable. Thus, it was anticipated that the addition of a
stoichiometric base would promote palladium alkoxide for-
mation, facilitating alcohol oxidation.
Scheme 4. Potential role of excess sparteine and base.
Early studies to supplant sparteine as a base centered on
the addition of amines (Table 3).[20] Initially, triethylamine
seemed promising (entry 3), but rapid catalyst deactivation
Another key development arose from our early investiga-
tions of the substrate scope. Generally, viable resolution
substrates featured a p system that has the capacity to over-
lap with a cation at the alcohol carbon atom (Scheme 5).[15b]
Because the transition state for b-hydride elimination in-
volves some cationic character at this carbon atom, we
speculated that methods of cation stabilization other than
Table 3. Added base in the kinetic resolution.
Additive
t
Conv
[%][b]
Alcohol
s[d]
[h]
ee [%][c]
1
2
3
4
5
6
7
8
9
(À)-sparteine (0.3 equiv)
none
13
13
13
26
13
13
13
13
13
13
29
2
34
<2
31
33
19
11
8
31
84
99
15
–
22
13
11
6
20
15
13
13
Et3N (0.4 equiv)
Et3N (0.4 equiv)
Et3N (2.0 equiv)
Et3N (4.0 equiv)
DABCO (0.4 equiv)
Na2CO3 (1.0 equiv)
K2CO3 (1.0 equiv)
Cs2CO3 (1.0 equiv)
26
29
19
14
7
27
56
68
10
[a] 10 mol% [Pd
G
MS3ꢂ per mmol substrate, 0.1m substrate in PhCH3. [b] Measured by
1H NMR spectroscopy. [c] Measured by chiral HPLC; see Supporting In-
formation for details. [d] Selectivity factor.[18]
Scheme 5. Stabilization of the b-hydride elimination transition state by
resonance and a b-silicon.
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B. M. Stoltz et al.
Table 5. Various non-oxidizing alcohols as additives.
adjacent aromatic rings could lower the energy barrier for
alcohol oxidation, increasing reaction rate. Based on this hy-
pothesis, b-silyl alcohol (Æ)-8 was prepared and exposed to
our palladium-catalyzed oxidation conditions. This alcohol
could potentially benefit from b-silicon stabilization by hy-
perconjugation in the transition state.[28] Indeed, (Æ)-8
proved to be a moderately active substrate for oxidative ki-
netic resolution, providing partially resolved alcohol in
16% ee (Table 4, entry 1). However, a problematic side re-
Additive
t
Conv
[%][b]
Alcohol
s[f]
[h]
ee [%][c]
1
2
3
4
5
none
5.5
5.5
5.5
19
5.5
5.5
31
66
67
48
60
42
19
57
57
57
35
98
95
56
89
48
16
90
94
90
12
12
10
7
11
8
nBuOH (1.0 equiv)
nBuOH (2.0 equiv)
nBuOH (8.0 equiv)
CF3CH2OH (1.0 equiv)
CF3CH2OH (2.0 equiv)
CF3CH2OH (8.0 equiv)
tBuOH (1.0 equiv)
tBuOH (4.0 equiv)
tBuOH (8.0 equiv)
Table 4. n-Butanol as additive in the kinetic resolution.
6
7
19
6
8[d]
9[d]
10[e]
22.5
11.5
19
16
20
16
[a] 10 mol% [Pd
G
1 atm O2, 500 mg MS3ꢂ per mmol substrate, 0.1m substrate in PhCH3.
[b] Measured by 1H NMR spectroscopy. [c] Measured by chiral HPLC;
see Supporting Information for details. [d] Conducted at 508C. [e] Con-
ducted at 458C. [f] Selectivity factor.[18]
nBuOH equiv
(S)-8 [%][b] (ee [%])[c]
9 [%][b]
10 [%][b]
1
2
3
4
0.0
0.7
2.1
4.2
75 (16)
60 (34)
35 (81)
45 (61)
15
10
5
10
30
60
50
<5
[a] 5 mol% [Pd
(nbd)Cl2], 20 mol% (À)-sparteine, 1 atm O2, 500 mg
est and most reliable levels of selectivity across a wide range
of concentrations (entries 8–10).[29] After optimizing exoge-
nous base and tert-butyl alcohol equivalents, the dramatic
effect of these additives on the resolution of (Æ)-1-phenyl-
1-propanol ((Æ)-11) was realized (Table 6). This resolution
provided highly enantioenriched (À)-11 in only 4.5 h instead
of 192 h without cesium carbonate and tert-butyl alcohol.
Importantly, selectivity is maintained in these dramatically
rate accelerated conditions. Further selectivity improve-
ments could be obtained by decreasing the temperature to
608C.[30]
MS3ꢂ per mmol substrate, 0.25m substrate in PhCH3. [b] Measured by
1H NMR spectroscopy. [c] Measured by chiral HPLC; see Supporting In-
formation for details.
action complicated analysis of this resolution. The partially
enantioenriched alcohol underwent silyl transfer from the a-
silyl ketone to provide oxidation-resistant silyl ether 9 and
desilylated ketone 10. To suppress formation of side product
9, a primary alcohol was added to the reaction. This unacti-
vated alcohol would not be readily oxidized under our reso-
lution conditions, but could act as a sacrificial alcohol to
react with the silyl ketone. As seen in entries 2–4, increasing
amounts of n-butanol led to decreased formation of silyl
ether 9. Fortuitously, reaction rates also increased with up to
2.1 equivalents of n-butanol. Rate enhancement was not lim-
ited to the oxidation of silyl alcohol (Æ)-8, as increased
rates were also observed in the resolution of other activated
alcohols.
Having observed a significant dependence on the rate of
oxidative kinetic resolution with the inclusion of n-butanol,
a variety of alcohol additives were evaluated for their ability
to enhance the reaction rate when coupled with cesium car-
bonate in the resolution of alcohol (Æ)-6 (Table 5). Addi-
tion of one equivalent of either n-butanol or trifluoroetha-
nol led to enhanced reactivity (entries 2 and 5). Increasing
equivalents led to decreased selectivity (entries 3 and 6).
Large excess of either alcohol impeded the reaction (en-
tries 4 and 7). This trend of initial rate acceleration followed
by rate inhibition and selectivity erosion at high concentra-
tions was observed across a wide variety of primary alcohol
additives.
Table 6. Direct comparison of original and rate accelerated oxidative ki-
netic resolution conditions.
Additives
none
t
Conv
[%][a]
Alcohol
s[c]
[h]
ee [%][b]
192
59
93
15
16
Cs2CO3 (1.2 equiv)
4.5
63
98
tBuOH (4.0 equiv)
[a] Measured by 1H NMR spectroscopy. [b] Measured by chiral HPLC;
see Supporting Information for details. [c] Selectivity factor.[18]
While the purpose of the carbonate base fit well with our
mechanistic model for the oxidative kinetic resolution, the
role of tert-butyl alcohol remained more subtle. One possi-
bility was that the modified reaction conditions were trans-
forming [Pd(sparteine)Cl2] into a more reactive complex.[31]
To verify this theory, 5 was exposed to one equivalent each
Interestingly, inclusion of tert-butyl alcohol proved to be
an excellent exogenous alcohol additive, providing the high-
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Asymmetric Catalysis
FULL PAPER
Table 7. Impact of solvent on reaction rate.
of tert-butyl alcohol and cesium carbonate. After four days
at 608C, carbonate 13 was isolated in nearly quantitative
yield (Scheme 6). Surprisingly, 13 displayed neither catalytic
nor even stoichiometric activity under kinetic resolution
conditions. This finding suggests carbonate 13 is a catalyst
deactivation product. While these additives provide dramat-
ic rate enhancement, they could also detrimentally affect
catalyst longevity.[32]
Solvent
Dielectric constant
Conv [%][a]
1
2
CH2Cl2
CHCl3
8.9
4.8
83
74
73
72
68
46
39
29
23
21
21
14
10
9
8
7
6
3
3
2
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
CH2Br2
CHCl3/1 equiv tBuOH
CHBr3
ClCH2CH2Cl
PhCH3/1 equiv tBuOH
PhCH3/tBuOH (1:1)
PhCH3
pinacolone
tert-amyl alcohol
THF
Cl2C=CHCl
Cl3CCH3
EtOAc
2-propanol
Cl2C=CCl2
H2O/2-propanol
CH3CN
7.8
4.8/12.5
4.4
10.4
2.4/12.5
2.4/12.5
2.4
12.7
5.8
7.5
3.4
7.2
6.1
20.2
2.3
80.1/20.2
37.3
37.3
2.2
Scheme 6. Formation of inactive Pd complex 13.
Alternatively, the observed rate enhancement could be
due to the hydrogen bonding potential of tert-butyl alcohol.
While hydrogen bonding plays an essential and well-docu-
mented role in the catalysis of a number of biological[33] and
synthetic processes,[34] less is known about its role in organo-
metallic transformations. A hydrogen-bond donor may en-
hance reactivity by stabilizing and solubilizing polar or
charged intermediates in the nonpolar solvent toluene. In
particular, cationic palladium complexes generated as the
immediate products of alcohol coordination and b-hydride
elimination result in the formation of chloride anions, which
could be solubilized by hydrogen-bond donors.[15b,d]
Based on this hypothesis, a more rigorous solvent screen
was performed with an emphasis on solvents capable of hy-
drogen-bond donation and solubilization of polar or charged
intermediates (Table 7).[35] Surprisingly, while common polar
solvents led to little oxidation (entries 12, 15, 16, 19, and
20), halogenated solvents that could act as weak hydrogen-
bond donors provided rapid reactions. Oxidations conducted
in the hydrogen-bond-donating solvent CH2Cl2 were the
fastest (entry 1), but catalyst selectivity in kinetic resolutions
suffered.[36] Chloroform, on the other hand, emerged as an
outstanding nonflammable solvent for rapid and selective
oxidation, even at 238C (entry 2). Strikingly, chlorinated sol-
vents lacking the ability to donate a hydrogen bond (en-
tries 13, 14, 17, and 21) were less effective. Some other fac-
tors do not appear to explain the observed trends. Oxygen
solubility is fairly similar in many of the solvents.[37] Also,
there is no clear trend between reaction rate and dielectric
constant, a measure of solvent polarity.[38]
CH3NO2
CCl4
[a] Measured by GC relative to internal standard (tridecane); see Sup-
porting Information for details.
À
Table 8. C D stretch of CDCl3 in the presence of potential hydrogen-
bond acceptors.
Concentration
Hydrogen
bond acceptor
n˜max
[cmÀ1
Predicted
D X bond
À
[m]
G
]
1
2
–
none
2258
–
0.25
2175
3
4
0.25
2230
2258
0.10[a]
–
[a] Near saturation concentration at 238C.
Spectroscopic evidence for hydrogen-bond formation be-
tween chloroform and catalytic species is found in IR spec-
tra of CDCl3 (Table 8).[39] A significant shift in the C D
species are present. Notably, no shift in the C D stretch was
observed with the catalytically inactive carbonate 13, sug-
gesting little or no hydrogen bonding occurs.
The change in solvent allows decreased amounts of (À)-
sparteine and cesium carbonate to be used with little effect
on rate. Performing the reactions at 238C also provides a
À
À
stretching frequency of CDCl3 occurred in the presence of
either (À)-sparteine (entry 2) or [Pd(sparteine)Cl2] (5)
(entry 3).[40,41] The observed decrease in lmax corresponds to
À
a lower energy C D stretching frequency due to a weaker
À
C D bond over free CDCl3 when hydrogen-bond-accepting
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B. M. Stoltz et al.
Table 9. Variety of conditions for the resolution of secondary alcohols.
dramatic increase in the catalyst selectivity. Furthermore, as
little as 5% O2 atmosphere is sufficient for oxidation, per-
mitting the use of ambient air as the terminal oxidant.
These developments greatly improve the safety of the oxida-
tive kinetic resolution, avoiding the use of flammable sol-
vents at elevated temperatures under an oxygen atmos-
phere.[42]
Concurrent with studies centered on the development of
improved conditions for oxidation, efforts were undertaken
to understand the mechanism of the reaction. We were espe-
cially interested in elucidating the steric and electronic influ-
ences of the sparteine ligand on the outcome of the kinetic
resolution. To this end, a number of palladium complexes
with sparteine were prepared.[15c,i] Subsequent X-ray analysis
of these crystalline complexes, coupled with theoretical cal-
culations,[15d] allowed us to develop a model for selectivity in
the oxidation (Scheme 7). Coordination of alcohol to com-
Conditions
[Pd(nbd)Cl2] (5 mol%),
(À)-sparteine (20 mol%), O2,
PhCH3 (0.1m), MS3ꢂ, 808C
t
Conv Alcohol s[c]
[h] [%][a] ee [%][b]
A
B
G
96 67
96
12
[PdACTHNUGTRENNG(U nbd)Cl2] (5 mol%),
9.5 67
99
15
(À)-sparteine (20 mol%), O2,
Cs2CO3 (1.2 equiv) tBuOH (4.0 equiv),
PhCH3 (0.25m), MS3ꢂ, 608C
C
[PdACHTNGUTRENNU(G nbd)Cl2] (5 mol%),
(À)-sparteine (12 mol%),
48 63
99
99
27
25
O2, Cs2CO3 (0.4 equiv),
CHCl3 (0.25m), MS3ꢂ, 238C
D
[PdACHTNGUTRENNU(G nbd)Cl2] (5 mol%),
(À)-sparteine (12 mol%),
24 62
air, Cs2CO3 (0.4 equiv),
CHCl3 (0.25m), MS3ꢂ, 238C
[a] Measured by GC relative to internal standard (tridecane). [b] Mea-
sured by chiral HPLC; see Supporting Information for details. [c] Selec-
tivity factor.[18]
alyst longevity. The rate-enhanced (B) conditions are the
fastest, often achieving highly enantioenriched alcohol in a
small fraction of the time required for the original (A) con-
ditions. Reactions performed in chloroform at 238C (C and
D) are the most selective, nearly doubling the selectivity
factor (s) for the resolution of some alcohols. Typically, both
molecular oxygen and ambient air can be used in oxidations
in chloroform with similar rates and selectivities. The devel-
opment of four distinct sets of conditions provides the op-
portunity to resolve the widest range of alcohol substrates in
order to maximize the selectivity of the process, while main-
taining reactivity and minimizing side reactions. The benefit
of this flexibility is evident in the broad scope of this
system.
Scheme 7. Model for kinetic resolution selectivity.
plex 5 leads to one of two diastereomeric alkoxides, 14 or
15. Alkoxide 14, formed from the fast reacting enantiomer
of alcohol, proceeds through a four-membered b-hydride
elimination transition state to afford product ketone. Com-
plex 15, on the other hand, has a higher energy barrier to b-
hydride elimination due to developing unfavorable steric in-
teractions with the departing chloride counterion. Confront-
ed with this high-energy transition state, protonation regen-
erates the observed enantiomer of alcohol.
As a result of our exploration of the oxidative kinetic res-
olution of secondary alcohols, four distinct sets of conditions
have been developed (Table 9): the original conditions (A)
in toluene with no exogenous base, the rate-enhanced condi-
tions (B) that take advantage of cesium carbonate and tert-
butyl alcohol additives, and the chloroform conditions at
238C under an atmosphere of either molecular oxygen (C)
or ambient air (D). In general, resolutions performed with-
out added carbonate base have slower rates but greater cat-
Substrate scope:[43] Our early studies focused on benzylic al-
cohols, as the racemates are commercially available or easily
prepared. The resolution is quite general for this class of
substrates, providing a wide range of 1-arylethanols in excel-
lent enantiomeric excess (Table 10). Substitution on the aryl
ring at the 3- and 4-positions (entries 1–8 and 12–14) is well
tolerated. Substitution at the ortho-position leads to much
slower rates of oxidation (entry 9), although reactivity im-
proves if the substituent is constrained in a ring (entries 10
and 11). Some heteroaromatic substrates (entries 18 and 19)
can also be resolved to high enantiomeric excesses.
Other structural variations are also tolerated by the cata-
lyst system (Table 11). Cyclic benzylic alcohols are able to
be resolved successfully. 1-Indanol (entries 1 and 2) is oxi-
dized rapidly, albeit with decreased selectivity, compared to
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Asymmetric Catalysis
FULL PAPER
Table 10. Resolution of 1-arylethanols.
Table 11. Resolution of other benzylic alcohols.
Alcohol
major enantiomer
Cond[a]
t
Conv
[%][b]
Alcohol
s[d]
Alcohol
major enantiomer
Cond[a]
t
Conv Alcohol s[d]
[%][b] ee [%][c]
[h]
ee [%][c]
[h]
1[e]
2[e]
3[f]
4[f]
5[f]
6[g]
7[g]
8[g]
B
C
B
C
D
A
C
D
12.5
48
9.5
45
24
54
48
24
64
60
67
63
62
63
59
57
99
99
99
99
99
97
98
93
20
31
15
27
25
14
23
20
1
2
B[e]
C
12
23
74
70
99
98
10
10
3
4
5
B[e]
C
D
12
24
16
62
58
60
99
98
99
21
28
28
6
7
8
B[f]
C
D
4.5
72
48
63
63
57
98
98
95
16
24
22
9
C
164
60
89
12
9[g]
A
A
14.5 70
97
93
9.0
18
10
11
B
15
12
57
55
99
95
47
29
10[h]
24
58
C[h]
11[i]
B
4.5
4.5
71
63
99
15
11
12
13
14
A
C
D
28
24
22
52
54
54
93
98
98
44
47
54
12[i]
13
B
C
93
75
15
16
17
A
C
D
112
48
24
55
60
56
99
99
98
47
31
37
122 55
9.0
AHCTUNGERTG[NNUN a–d] See footnotes [a–d] in Table 10. [e] Conducted at 408C. [f] Conduct-
ed at 808C. [g] R=Ac. [h] R=Boc. [i] Ar=3-bromophenyl.
18
19
A
A
120
120
67
67
94
94
8.3
next. Conditions in chloroform are particularly effective for
these substrates, providing enhanced selectivity over the
other methods (Table 12, cf. entries 11 and 12). While acy-
clic allylic alcohols are challenging, often leading to oxida-
tion with low selectivity, many cyclic allylic alcohols are re-
solved successfully. Of particular note are vinyl bromides
(entries 1, 2, and 5), which rapidly decompose with darken-
ing of the reaction mixture at elevated temperatures, indi-
cating the formation of aggregated palladium(0). While 2-
bromocyclopent-2-enol (entry 5) oxidizes fast enough to
allow moderate resolution at 608C with cesium carbonate
and tert-butyl alcohol, 2-bromocyclohex-2-enol (entries 1
and 2) is cleanly resolved with no decomposition only at
lower temperatures. Alkyl enol ethers are stable in the reac-
tions and are resolved to high enantiomeric excess (en-
tries 4, 7, and 8), providing access to enantioenriched a-hy-
droxyketone derivatives. The catalyst is also tolerant of a va-
riety of alkene substitution patterns. Cyclopentenols are usu-
ally oxidized more quickly, though less selectively, than cy-
clohexenols (cf. entries 4 and 7).
8.8
[a] Conditions A: [Pd
(1 atm), MS3ꢂ (500 mg per mmol substrate), PhCH3 (0.1m substrate),
808C; Conditions B: [Pd
O2 (1 atm), Cs2CO3 (0.5 equiv), tBuOH (1.5 equiv), MS3ꢂ (500 mg per
mmol substrate), PhCH3 (0.25m substrate), 608C; Conditions C: [Pd-
G
ACHTUNGTRENNUNG
A
(12 mol%), Cs2CO3 (0.4 equiv), MS3ꢂ (500 mg per mmolÀ1 substrate),
CHCl3 (0.25m substrate), 238C, open to ambient air under a short tube
of Drierite. [b] Conversion measured by GC or NMR spectroscopy.
[c] Measured by chiral HPLC or chiral GC; see Supporting Information
for details. [d] Selectivity factor.[18] [e] R=H. [f] R=OMe. [g] R=F.
[h] Conducted at 408C.
1-tetralol (entries 3–5). Other functional groups on the alco-
hol substrate, including protected amines (entries 9 and 10),
a tertiary alcohol (entry 11), and even aryl bromides (en-
tries 11 and 12), are tolerated under the reaction condi-
tions.[44]
Our success with benzylic alcohols led us to explore aryl
substituents on cyclic allylic alcohols. These substrates are
readily prepared through Suzuki coupling of arylboronate
The broad utility of chiral allylic alcohols in organic syn-
thesis led us to investigate this important class of molecules
Chem. Eur. J. 2009, 15, 12978 – 12992
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B. M. Stoltz et al.
Table 12. Resolution of allylic alcohols.
Table 13. Resolution of 2-aryl allylic alcohols.
Alcohol
major enantiomer
Cond[a]
t
Conv
[%][b]
Alcohol
s[d]
Alcohol
major enantiomer
Cond[a]
t
Conv
[%][b]
Alcohol
s[d]
35
[h]
ee [%][c]
[h]
ee [%][c]
1[e]
2[e]
3[f]
4[g]
C
D
C
C
33
25
31
74
64
55
51
52
96
86
74
86
12
16
13
23
1[e]
2[e]
A
B
D
B
C
D
A
B
C
A
B
C
A
C
D
7
57
53
56
58
58
56
58
54
55
57
60
58
59
57
59
99
99
99
99
99
99
99
97
92
99
99
99
99
94
99
1.5
10
3.5
11
10
31
89
47
31
28
39
30
46
23
33
24
30
26
21
26
3[e]
4[f]
5[f]
5[e]
6[f]
7[g]
8[g]
B
B
C
D
4
7
75
66
65
61
97
93
99
97
7.0
9.2
15
6[f]
7[g]
45
24
8[g]
1.5
17
9[g]
24
10
10[h]
11[h]
12[h]
13[i]
14[i]
15[i]
9
10
C
D
27
24
61
63
96
98
16
17
3.5
11
10
10
10
11
12
13
B
C
D
12
48
44
65
63
65
88
99
99
7.5
18
16
16
17
18
A
B
D
10
1.5
10
59
53
56
99
94
99
28
36
45
14
15
C
D
43
43
64
61
97
91
13
12
19
20
21
A
C
D
24
10
6
54
59
57
99
99
97
59
25
27
22
23
24
B
C
D
10
72
42.5
64
57
57
99
96
98
19
23
27
16
C
75
57
94
19
ACHTUNGTRENNUNG[a–d] See footnotes [a–d] in Table 10. [e] R=Br. [f] R=iPr. [g] R=OiBu.
25
26
27
A
B
C
17
3
24
52
57
55
99
97
97
122
27
33
esters and iodoenones[45] followed by ketone reduction.[46]
To our delight, subjection of these alcohols to any of our de-
veloped kinetic resolution conditions affords highly enan-
tioenriched allylic alcohols with short reaction times
(Table 13).[47] Both electron-rich (entries 7–9) and electron-
poor (entries 13–15) 2-aryl substituents lead to excellent se-
lectivity. The lack of an electronic influence on these resolu-
tions suggests selectivity is primarily due to steric factors, as
elucidated by our selectivity model (Scheme 7). Even het-
AHCTUNGERTG[NNUN a–d] See footnotes [a–d] in Table 10. [e] R=H. [f] R=Me. [g] R=OMe.
[h] R=F. [i] R =CF3.
especially effective in providing highly selective oxidation
(cf. entries 1 and 2, entries 4 and 6). Even 1-cyclopropyletha-
nol (entries 1–3), with relatively little steric differentiation
between alcohol substituents, is able to be resolved to high
enantiomeric excess. These resolutions also produce alcohols
with three contiguous stereocenters (entries 4–11), including
a quaternary stereocenter (entries 7 and 8). Furthermore,
for entries 4–11, the product ketones are also enantioen-
riched (Figure 2). Importantly, these molecules have the op-
posite configuration at C(3) and C(4) relative to the re-
solved alcohol, opening the door to enantiodivergent oppor-
tunities in synthesis.
Though a broad range of secondary alcohols is successful-
ly resolved with this system, limitations to the methodology
exist. A number of alcohols display limited rates of oxida-
tion, preventing their resolution (Figure 3). Benzylic alco-
hols with ortho-substituents (e.g. (Æ)-18 and (Æ)-19) and
sterically hindered alcohols such as (Æ)-20 and (Æ)-21 have
dramatically decreased oxidation rates. The presence of vici-
nal heteroatoms (e.g. (Æ)-22 and (Æ)-23) impedes the oxi-
ACHTUNGTRENNUNGeroaromatic substitution (entries 22–24) and a larger ring
size (entries 25–27) are tolerated, albeit with somewhat
longer reaction times.
Substitution at the 3-position of cyclic allylic alcohols was
also explored (Table 14). Again, allylic alcohols with 2-aryl
substituents are oxidized rapidly, and with exceptionally
high selectivity (entries 1–6). These resolutions have some
of the highest selectivities seen with this catalyst system. 3-
Substituted alcohols with 2-alkyl substituents are resolved to
high enantiomeric excess as well (entries 7–13). Interesting-
ly, analogous 2-alkyl allylic alcohols unsubstituted at the 3-
position oxidize with poor selectivity.[48]
Other forms of activation of the racemic alcohols were
also explored, such as a-cyclopropyl substituents. Several
substrates were exposed to our oxidative kinetic resolution
conditions (Table 15). Again, the chloroform conditions are
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Asymmetric Catalysis
FULL PAPER
Table 14. Resolution of 3-substituted cyclic allylic alcohols.
Alcohol
major enantiomer
Cond[a]
t
Conv
[%][b]
Alcohol
s[d]
[h]
ee [%][c]
1
2
3
A
B
D
4
1
6
53
53
55
99
98
94
83
63
26
Figure 2. Enantioenriched ketones obtained from the kinetic resolution.
4
5
6
A
B
C
4
1
9
56
56
51
99
99
95
50
51
83
7
8
9
A
B
C
8
1
10
73
61
78
98
85
99
8.6
9.0
7.5
10[e]
11[e]
12[e]
13[f]
B
C
D
C
8
27
43
72
65
58
64
61
99
94
97
91
15
19
13
11
Figure 3. Examples of alcohols displaying poor reactivity.
ACHTUNGTRENNUNG[a–d] See footnotes [a–d] in Table 10. [e] R=Me. [f] R=Bn.
Table 15. Resolution of cyclopropylcarbinyl alcohols.
Alcohol
major enantiomer
Cond[a]
t [h]
Conv
[%][b]
Alcohol
s[d]
ee [%][c]
1
2
3
B
C
D
22
72
68
76
67
66
96
99
96
6.1
13
10
Figure 4. Examples of alcohols oxidized with poor selectivity.
4
5
6
A
B
C
23
3
25
69
59
59
99
91
99
12
14
28
28). Substrates with electron-poor aromatic substituents are
much less selectively resolved than their electron-rich coun-
terparts (cf. (Æ)-29 and (Æ)-30 with Table 10 entries 4 and
12, respectively). At least in the case of benzylic alcohols,
steric effects alone do not fully account for these selectivity
differences. Saturated alcohols, such as (Æ)-31 also tend to
display lower selectivity factors in the resolution.
7
8
C
D
71
38
60
57
99
89
25
15
9
10
11
A
B
C
17
9
24
66
71
51
99
99
76
15
10
15
ACHTUNGTRENNUNG[a–d] See footnotes [a–d] in Table 10.
Applications: The wide use of alcohols in synthesis provides
numerous applications for our kinetic resolution.[51]
A
dation, presumably through catalyst coordination and deac-
tivation.[49] Finally, unactivated alcohols (e.g. (Æ)-24 and
(Æ)-25), particularly primary alcohols, are slow to oxidize
under any of our developed conditions.[50]
In addition to unreactive alcohols, certain classes of alco-
hols are resolved with poor selectivity (Figure 4). In some
cases, the steric difference between the two alcohol substitu-
ents seems too small for the catalyst to adequately distin-
guish between enantiomers (e.g. (Æ)-26, (Æ)-27, and (Æ)-
number of alcohols successfully resolved are intermediates
in the synthesis of variety of pharmaceuticals
a
(Scheme 8).[44,52] Boc-protected g-aminoalcohol (À)-32, re-
solved with good selectivity, is an intermediate in the syn-
thesis of a number of related antidepressants, including
fluoxetine·HCl (33). Tertiary alcohol (À)-34 and a related
ester were transformed to a known intermediate in the syn-
thesis of the leukotriene receptor antagonist montelukast
sodium (35). Finally, allylic alcohol (À)-36 is an intermediate
Chem. Eur. J. 2009, 15, 12978 – 12992
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B. M. Stoltz et al.
In addition to kinetic resolution, our catalyst system is
well suited for selective oxidation of meso-diols to hydroxy-
ketones.[17a,c,d] These reactions have the potential to provide
highly enantioenriched products in greater than 50% yield.
One example of this process was demonstrated with our ini-
tially developed resolution conditions (Scheme 10).[16] Selec-
tive oxidation of diol 41 provides ketoalcohol (+)-42 in
72% yield and 95% ee.
Scheme 10. Desymmetrization of diol 41.
Further efforts in the area of meso-diol desymmetrization
were inspired by the abundance of complex polyol- and
polyether-containing natural products, such as polymethoxy-
dienes 43a–e (Figure 5).[54] We envisioned access to these
molecules in enantioenriched form by late stage desymmet-
rization of a meso-diol stereochemical framework. This poly-
ether array could be prepared through diastereoselective bi-
Scheme 8. Secondary alcohols as drug intermediates.
in the enantioselective synthesis of human neurokinin-1
(hNK-1) receptor antagonist 37.
To further highlight the utility of the method, we have ex-
plored the Claisen rearrangement of resolved cyclic allylic
alcohols such as (À)-38 (Scheme 9).[47] Vinyl ether formation
Figure 5. Polyether natural products potentially accessible by meso-diol
desymmetrization.
directional chain synthesis from a simple symmetric precur-
sor.[55,56]
To demonstrate the utility of our palladium-catalyzed oxi-
dation system in this area, we developed a unified synthetic
approach to several meso-diol stereochemical arrays. Syn-
thesis of these meso-diols commenced from readily available
alcohol 44 (Scheme 11).[57] Alcohol protection as a benzyl
ether and palladium-catalyzed diene oxidation provides anti-
tris-benzyl ether 45.[58] Alkene dihydroxylation and oxidative
Scheme 9. Conversion of a resolved alcohol to a functionalized tetrahy-
drofuran.
and treatment with DIBAL-H at low temperature induces
Claisen rearrangement and subsequent reduction to form
primary alcohol (+)-39. Importantly, because our kinetic
resolution is able to produce alcohol (À)-38 in high enantio-
meric excess, the product alcohol is also highly enantioen-
riched. Furthermore, this alcohol can undergo a second pal-
ladium-catalyzed oxidative process developed in our labora-
tories[53] to form highly enantioenriched tetrahydrofuran
(À)-40 containing vicinal, fully substituted stereocenters.
cleavage with [PbACTHNGUTERN(NUG OAc)4] affords meso-dialdehyde 46. No
epimerization of the sensitive a-benzyloxy stereocenter is
observed with this two-step procedure. Diastereoselective
chelation-controlled addition of aryl Grignard reagents pro-
duces meso-diols 47a and 47b. The syn-ether array was gen-
erated by a similar sequence. Again starting from alcohol
44, TBS ether formation followed by [4+2] cycloaddition
with singlet oxygen, reductive opening, and benzylation of
the resulting diol affords syn-bis-benzylether 48.[59] Alkene
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Asymmetric Catalysis
FULL PAPER
Scheme 12. Oxidative desymmetrization of meso-diols.
ity of this oxidation in synthesis. Ongoing efforts to enhance
reactivity, to use other chiral ligands in place of sparteine,[60]
and to apply this kinetic resolution to natural product syn-
thesis will be reported in due course.
Experimental Section
Scheme 11. Preparation of meso-diols from a common starting material.
General oxidative kinetic resolution conditions
Kinetic resolution conditions A: Molecular sieves (3 ꢂ, 250 mg) were
added to an oven dried reaction tube with stir bar. After cooling, [Pd-
AHCTUNTGREG(NNUN nbd)Cl2] (6.7 mg, 0.025 mmol, 0.05 equiv) followed by toluene (2.5 mL)
cleavage and diastereoselective addition of aryl nucleophiles
produces diols 50a and 50b.
and then (À)-sparteine (23.0 mL, 23.4 mg, 0.10 mmol, 0.20 equiv) were
added. The reaction tube was then cooled to À788C, then vacuum evacu-
ated and purged with O2 (3ꢃ). Then, the tube was heated to 808C with
vigorous stirring under O2 atmosphere (1 atm, balloon) for 20 min. A so-
lution of (Æ)-6 (70.5 mL, 76.1 mg, 0.50 mmol, 1.0 equiv) and tridecane
(36.6 mL, 27.7 mg, 0.15 mmol, 0.30 equiv) in toluene (2.5 mL) was added,
and the reaction was allowed to proceed under O2 atmosphere at 808C.
Aliquots were filtered through a small plug of silica gel (Et2O eluent),
evaporated, and analyzed by GC for conversion and chiral HPLC for al-
cohol ee. Purification of 4-methoxyacetophenone (7) and (À)-6 was ac-
complished by direct chromatography of the crude reaction mixture.
Having generated the desired meso-diol substrates, we
looked to apply our enantioselective oxidation conditions.
Exposure of the meso-diols to catalytic quantities of
[Pd(sparteine)Cl2] (5) and excess (À)-sparteine under a bal-
loon of oxygen in chloroform provides highly enantioen-
riched hydroxyketones in excellent yields (Scheme 12).
These reactions establish the absolute configuration of four
stereocenters in a single catalytic asymmetric operation.
Based on these methods, we have begun to construct even
more complex polyether structural motifs toward the syn-
thesis of a variety of natural product frameworks.
Kinetic resolution conditions B: Molecular sieves (3 ꢂ, 500 mg) were
added to an oven dried reaction tube with stir bar. After cooling, [Pd-
AHCTUNTGREG(NNUN nbd)Cl2] (13.5 mg, 0.050 mmol, 0.05 equiv), followed by toluene (2 mL)
and then (À)-sparteine (46.0 mL, 46.9 mg, 0.20 mmol, 0.20 equiv) were
added. The reaction tube was cooled to À788C, then vacuum evacuated
and purged with O2 (3ꢃ). The tube was heated to 608C with vigorous
stirring under O2 atmosphere (1 atm, balloon) for 20 min. Finely pow-
dered Cs2CO3 (163 mg, 0.50 mmol, 0.50 equiv) was added, followed by a
solution of (Æ)-6 (141 mL, 152 mg, 1.0 mmol, 1.0 equiv), anhydrous
tBuOH (143 mL, 111 mg, 1.5 mmol, 1.5 equiv), and tridecane (73.2 mL,
55.3 mg, 0.30 mmol, 0.30 equiv) in toluene (2 mL). The reaction was al-
lowed to proceed under O2 atmosphere at 608C. Aliquots were filtered
through a small plug of silica gel (Et2O eluent), evaporated, and analyzed
by GC for conversion and chiral HPLC for alcohol ee. Purification of 7
and (À)-6 was accomplished by direct chromatography of the crude reac-
tion mixture.
Conclusions
Enantioselective oxidation with palladium(II) catalysts is a
powerful method for the preparation of enantioenriched
secondary alcohols. Research in this area has led to dramatic
improvements in reaction rate, selectivity, and operational
simplicity. The development of a number of distinct methods
has allowed the kinetic resolution of a wide range of sub-
strates. Benzylic, allylic, and a-cyclopropyl alcohols can be
resolved to high enantiomeric excesses, in many cases with
excellent selectivity. A variety of applications, including the
desymmetrization of meso-diols, have demonstrated the util-
Kinetic resolution conditions C: Molecular sieves (3 ꢂ, 500 mg) were
added to an oven dried reaction tube with stir bar. After cooling, [Pd-
AHCTUNGTERG(NNNU nbd)Cl2] (13.5 mg, 0.050 mmol, 0.05 equiv), followed by chloroform
Chem. Eur. J. 2009, 15, 12978 – 12992
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12989

B. M. Stoltz et al.
(2 mL, ACS reagent grade, stabilized with amylenes) and then (À)-spar-
teine (27.6 mL, 28.1 mg, 0.12 mmol, 0.12 equiv) were added. The reaction
tube was cooled to À788C, then vacuum evacuated and purged with O2
(3ꢃ). The reaction was allowed to warm to 238C and stirred vigorously
under O2 atmosphere (1 atm, balloon) for 15 min. Finely powdered
Cs2CO3 (130 mg, 0.40 mmol, 0.40 equiv) was added, followed by a solu-
tion of (Æ)-6 (141 mL, 152 mg, 1.0 mmol, 1.0 equiv) and tridecane
(73.2 mL, 55.3 mg, 0.30 mmol, 0.30 equiv) in chloroform (2 mL). The reac-
tion was allowed to proceed under O2 atmosphere at 238C. Aliquots
were filtered through a small plug of silica gel (Et2O eluent), evaporated,
and analyzed by GC for conversion and chiral HPLC for alcohol ee. Pu-
rification of 7 and (À)-6 was accomplished by direct chromatography of
the crude reaction mixture.
Hidai, Organometallics 1999, 18, 2291–2293; j) Z. Gross, S. Ini, Org.
Lett. 1999, 1, 2077–2080; k) Y. Kashiwagi, F. Kurashima, C. Kikuchi,
J.-i. Anzai, T. Osa, J. M. Bobbitt, Tetrahedron Lett. 1999, 40, 6469–
6472; l) K. Masutani, T. Uchida, R. Irie, T. Katsuki, Tetrahedron
Lett. 2000, 41, 5119–5123; m) M. Kuroboshi, H. Yoshihisa, M. N.
Cortona, Y. Kawakami, Z. Gao, H. Tanaka, Tetrahedron Lett. 2000,
41, 8131–8135.
[4] Subsequent to our initial report in this area, a number of further
studies were reported, see: a) H. Shimizu, K. Nakata, T. Katsuki,
Chem. Lett. 2002, 1080–1081; b) W. Sun, H. Wang, C. Xia, J. Li, P.
Zhao, Angew. Chem. 2003, 115, 1072–1074; Angew. Chem. Int. Ed.
2003, 42, 1042–1044; c) Y. Nishibayashi, A. Yamauchi, G. Onodera,
S. Uemura, J. Org. Chem. 2003, 68, 5875–5880; d) B. Graetz, S.
Rychnovsky, W.-H. Leu, P. Farmer, R. Lin, Tetrahedron: Asymmetry
2005, 16, 3584–3598; e) A. T. Radosevich, C. Musich, F. D. Toste, J.
Am. Chem. Soc. 2005, 127, 1090–1091; f) Z. Li, Z. H. Tang, X. X.
Hu, C. G. Xia, Chem. Eur. J. 2005, 11, 1210–1216; g) S.-S. Weng, M.-
W. Shen, J.-Q. Kao, Y. S. Munot, C.-T. Chen, Proc. Natl. Acad. Sci.
USA 2006, 103, 3522–3527; h) V. D. Pawar, S. Bettigeri, S.-S. Weng,
J.-Q. Kao, C.-T. Chen, J. Am. Chem. Soc. 2006, 128, 6308–6309;
i) Y.-Y. Li, X.-Q. Zhang, Z.-R. Dong, W.-Y. Shen, G. Chen, J.-X.
Gao, Org. Lett. 2006, 8, 5565–5567; j) W. Sun, X. Wu, C. Xia, Helv.
Chim. Acta 2007, 90, 623–626; k) T. Chen, J.-J. Jiang, Q. Xu, M. Shi,
Org. Lett. 2007, 9, 865–868; l) M. L. Kantam, T. Ramani, L. Chakra-
pani, B. M. Choudary, J. Mol. Catal. A 2007, 274, 11–15; m) R. I.
Kureshy, I. Ahmad, K. Pathak, N.-u. H. Khan, S. H. R. Abdi, J. K.
Prathap, R. V. Jasra, Chirality 2007, 19, 352–357; n) Y. Nakamura,
H. Egami, K. Matsumoto, T. Uchida, T. Katsuki, Tetrahedron 2007,
63, 6383–6387; o) K. Pathak, I. Ahmad, S. H. R. Abdi, R. I. Kure-
shy, N.-u. H. Khan, R. V. Jasra, J. Mol. Catal. A 2007, 274, 120–126;
p) O. Onomura, H. Arimoto, Y. Matsumura, Y. Demizu, Tetrahe-
dron Lett. 2007, 48, 8668–8672; q) S. Arita, T. Koike, Y. Kayaki, T.
Ikariya, Angew. Chem. 2008, 120, 2481–2483; Angew. Chem. Int.
Ed. 2008, 47, 2447–2449; r) M. Tomizawa, M. Shibuya, Y. Iwabuchi,
Org. Lett. 2009, 11, 1829–1831.
Kinetic resolution conditions D: Molecular sieves (3 ꢂ, 500 mg) were
added to an oven dried reaction tube with stir bar. After cooling, [Pd-
ACHTUNGTRENNUNG(nbd)Cl2] (13.5 mg, 0.050 mmol, 0.05 equiv), followed by chloroform
(2 mL, ACS reagent grade, stabilized with amylenes) and then (À)-spar-
teine (27.6 mL, 28.1 mg, 0.12 mmol, 0.12 equiv) were added. A short tube
containing Drierite was attached to the reaction tube. The reaction was
stirred vigorously at 238C for 15 min. Finely powdered Cs2CO3 (130 mg,
0.40 mmol, 0.40 equiv) was added, followed by
a
solution of (Æ)-6
(141 mL, 152 mg, 1.0 mmol, 1.0 equiv) and tridecane (73.2 mL, 55.3 mg,
0.30 mmol, 0.30 equiv) in chloroform (2 mL). The reaction was allowed
to proceed under an ambient air atmosphere at 238C. Aliquots were fil-
tered through a small plug of silica gel (Et2O eluent), evaporated, and
analyzed by GC for conversion and chiral HPLC for alcohol ee. Purifica-
tion of 7 and (À)-6 was accomplished by direct chromatography of the
crude reaction mixture.
Acknowledgements
The authors are grateful to the NDSEG (predoctoral fellowship to
D.C.E.), the NSF (predoctoral fellowships to D.C.E. and E.M.F.), the
University of California TRDRP (predoctoral fellowship to J.T.B.), Bris-
tol-Myers Squibb Company (predoctoral fellowship to E.M.F.), the
American Chemical Society Division of Organic Chemistry and Bristol-
Myers Squibb Foundation (predoctoral fellowship to R.M.T.), Eli Lilly
(predoctoral fellowships to D.D.C. and R.M.M.), the NIH-NIGMS (R01
GM65961-01), King Abdullah University of Science and Technology
(KAUST, Award No. KUS-I1-006–02), California Institute of Technology,
A. P. Sloan Foundation, the Dreyfus Foundation, Research Corporation,
Abbott, Amgen, AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline,
Johnson and Johnson, Eli Lilly, Merck, Novartis, Pfizer, and Roche for
generous funding.
[5] B. M. Stoltz, Chem. Lett. 2004, 33, 362–367.
[6] a) R. A. Johnson, K. B. Sharpless in Catalytic Asymmetric Synthesis,
2nd ed. (Ed.: I. Ojima), Wiley, New York, 2000, Chapter 6A,
pp. 231–280; b) X. Wen, I. Ojima in Catalytic Asymmetric Synthesis,
2nd ed. (Ed.: I. Ojima), Wiley, New York, 2000, Chapter 6A,
pp. 281–286; c) T. Katsuki in Catalytic Asymmetric Synthesis, 2nd
ed. (Ed.: I. Ojima), Wiley, New York, 2000, Chapter 6B, pp. 287–
326; d) H. B. Kagan in Catalytic Asymmetric Synthesis, 2nd ed. (Ed.:
I. Ojima), Wiley, New York, 2000, Chapter 6C, pp. 327–356;
e) R. A. Johnson, K. B. Sharpless in Catalytic Asymmetric Synthesis,
2nd ed. (Ed.: I. Ojima), Wiley, New York, 2000, Chapter 6D,
pp. 357–398; f) C. Bolm, J. P. Hildebrand, K. MuÇiz in Catalytic
Asymmetric Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley, New York,
2000, Chapter 6E, pp. 399–428; g) Asymmetric Oxidation Reactions
(Ed.: T. Katsuki), Oxford Press, New York, 2001.
[1] a) M. Hudlicky, Oxidations in Organic Chemistry, ACS Monograph
Series, ACS, Washington, 1990; b) T. T. Tidwell, Org. React. 1990,
39, 297–572; c) Comprehensive Organic Synthesis (Eds.: B. M. Trost,
I. Fleming), Pergamon, Oxford, 1991; d) F. A. Luzzio, Org. React.
1998, 53, 1–221.
[7] J. T. Mohr, D. C. Ebner, B. M. Stoltz, Org. Biomol. Chem. 2007, 5,
3571–3576.
[8] For discussions on kinetic resolution, see: a) H. B. Kagan, J. C.
Fiaud, in Topics in Stereochemistry, Vol. 18 (Ed.: E. L. Eliel), Wiley,
New York, 1988, pp. 249–330; b) J. M. Keith, J. F. Larrow, E. N. Ja-
cobsen, Adv. Synth. Catal. 2001, 343, 5–26; c) E. Vedejs, M. Jure,
Angew. Chem. 2005, 117, 4040–4069; Angew. Chem. Int. Ed. 2005,
44, 3974–4001.
[9] a) B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996, 96, 395–422;
b) M. Sodeoka, M. Shibasaki, Pure Appl. Chem. 1998, 70, 411–414;
c) T. Hayashi, J. Organomet. Chem. 1999, 576, 195–202; d) G. Helm-
chen, J. Organomet. Chem. 1999, 576, 203–214; e) B. M. Trost,
Chem. Pharm. Bull. 2002, 50, 1–14; f) T. V. RajanBabu, Chem. Rev.
2003, 103, 2845–2860; g) T. Graening, H.-G. Schmalz, Angew.
Chem. 2003, 115, 2684–2688; Angew. Chem. Int. Ed. 2003, 42, 2580–
2584; h) A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945–
2963; i) L. F. Tietze, H. Ila, H. P. Bell, Chem. Rev. 2004, 104, 3453–
3516; j) B. M. Trost, J. Org. Chem. 2004, 69, 5813–5837; k) M. So-
deoka, Y. Hamashima, Bull. Chem. Soc. Jpn. 2005, 78, 941–956;
[2] R. C. Larock, Comprehensive Organic Transformations, Wiley, New
York, 1999, pp. 1234–1248.
[3] a) K. Ohkubo, K. Hirata, K. Yoshinaga, M. Okada, Chem. Lett.
1976, 183–184; b) C. Berti, M. J. Perkins, Angew. Chem. 1979, 91,
923–924; Angew. Chem. Int. Ed. Engl. 1979, 18, 864–865; c) Y.
Ishii, K. Suzuki, T. Ikariya, M. Saburi, S. Yoshikawa, J. Org. Chem.
1986, 51, 2822–2824; d) Z. Ma, Q. Huang, J. M. Bobbitt, J. Org.
Chem. 1993, 58, 4837–4843; e) S. D. Rychnovsky, T. L. McLernon,
H. Rajapakse, J. Org. Chem. 1996, 61, 1194–1195; f) Y. Kashiwagi,
Y. Yanagisawa, F. Kurashima, J.-i. Anzai, T. Osa, J. M. Bobbitt,
Chem. Commun. 1996, 2745–2746; g) S. Hashiguchi, A. Fujii, K.-J.
Haack, K. Matsumura, T. Ikariya, R. Noyori, Angew. Chem. 1997,
109, 300–303; Angew. Chem. Int. Ed. Engl. 1997, 36, 288–290; h) T.
Hamada, R. Irie, J. Mihara, K. Hamachi, T. Katsuki, Tetrahedron
1998, 54, 10017–10028; i) Y. Nishibayashi, I. Takei, S. Uemura, M.
12990
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12978 – 12992

Asymmetric Catalysis
FULL PAPER
l) K. K. Hii, Pure Appl. Chem. 2006, 78, 341–349; m) M. Sodeoka,
Y. Hamashima, Pure Appl. Chem. 2006, 78, 477–494; n) Y. Hama-
shima, M. Sodeoka, Synlett 2006, 1467–1478.
[17] Concurrent with our publication, a related system was reported, see:
a) D. R. Jensen, J. S. Pugsley, M. S. Sigman, J. Am. Chem. Soc. 2001,
123, 7475–7476; b) D. R. Jensen, M. S. Sigman, Org. Lett. 2003, 5,
63–65; c) S. K. Mandal, D. R. Jensen, J. S. Pugsley, M. S. Sigman, J.
Org. Chem. 2003, 68, 4600–4603; d) S. K. Mandal, M. S. Sigman, J.
Org. Chem. 2003, 68, 7535–7537; e) M. S. Sigman, D. R. Jensen,
Acc. Chem. Res. 2006, 39, 221–229.
[10] a) W. G. Lloyd, J. Org. Chem. 1967, 32, 2816–2819; b) T. F. Black-
burn, J. Schwartz, J. Chem. Soc. Chem. Commun. 1977, 157–158;
c) E. Gꢄmez-Bengoa, P. Noheda, A. M. Echavarren, Tetrahedron
Lett. 1994, 35, 7097–7098; d) S. Aꢅt-Mohand, F. Hꢆnin, J. Muzart,
Tetrahedron Lett. 1995, 36, 2473–2476; e) K. P. Peterson, R. C.
Larock, J. Org. Chem. 1998, 63, 3185–3189; f) G.-J. ten Brink,
I. W. C. E. Arends, R. A. Sheldon, Science 2000, 287, 1636–1639;
g) K. Hallman, C. Moberg, Adv. Synth. Catal. 2001, 343, 260–263;
h) R. A. Sheldon, I. W. C. E. Arends, G.-J. ten Brink, A. Dijksman,
Acc. Chem. Res. 2002, 35, 774–781; i) M. J. Schultz, C. C. Park, M. S.
Sigman, Chem. Commun. 2002, 3034–3035; j) G.-J. ten Brink,
I. W. C. E. Arends, M. Hoogenraad, G. Verspui, R. A. Sheldon, Adv.
Synth. Catal. 2003, 345, 497–505; k) D. R. Jensen, M. J. Schultz, J. A.
Mueller, M. S. Sigman, Angew. Chem. 2003, 115, 3940–3943; Angew.
Chem. Int. Ed. 2003, 42, 3810–3813; l) G.-J. ten Brink, I. W. C. E.
Arends, M. Hoogenraad, G. Verspui, R. A. Sheldon, Adv. Synth.
Catal. 2003, 345, 1341–1352; m) S. Paavola, K. Zetterberg, T. Priva-
lov, I. Csçregh, C. Moberg, Adv. Synth. Catal. 2004, 346, 237–244;
n) T. Iwasawa, M. Tokunaga, Y. Obora, Y. Tsuji, J. Am. Chem. Soc.
2004, 126, 6554–6555.
[11] For reviews of palladium-catalyzed aerobic oxidations, see: a) J.
Muzart, Tetrahedron 2003, 59, 5789–5816; b) S. S. Stahl, Angew.
Chem. 2004, 116, 3480–3501; Angew. Chem. Int. Ed. 2004, 43, 3400–
3420; c) M. S. Sigman, M. J. Schultz, Org. Biomol. Chem. 2004, 2,
2551–2554; d) Reference [5].
[12] a) T. Nishimura, T. Onoue, K. Ohe, S. Uemura, Tetrahedron Lett.
1998, 39, 6011–6014; b) T. Nishimura, T. Onoue, K. Ohe, S.
Uemura, J. Org. Chem. 1999, 64, 6750–6755; c) T. Nishimura, Y.
Maeda, N. Kakiuchi, S. Uemura, J. Chem. Soc. Perkin Trans. 1 2000,
4301–4305; d) T. Nishimura, S. Uemura, Synlett 2004, 201–216.
[13] a) B. A. Steinhoff, S. S. Stahl, Org. Lett. 2002, 4, 4179–4181; b) B. A.
Steinhoff, I. A. Guzei, S. S. Stahl, J. Am. Chem. Soc. 2004, 126,
11268–11278; c) T. Privalov, C. Linde, K. Zetterberg, C. Moberg,
Organometallics 2005, 24, 885–893; d) M. J. Schultz, R. S. Adler, W.
Zierkiewicz, T. Privalov, M. S. Sigman, J. Am. Chem. Soc. 2005, 127,
8499–8507; e) B. A. Steinhoff, A. E. King, S. S. Stahl, J. Org. Chem.
2006, 71, 1861–1868.
[18] The selectivity factor (s) was determined using the equation s=kfast
slow =ln (1Àee)]/ln[(1ÀC)(1+ee)], where C is conversion and
[(1ÀC)
ee is enantiomeric excess of recovered alcohol, see reference [8a].
/
k
G
E
N
ACHTUNGTRENNUNG
[19] Recently, a similar palladium-catalyzed system utilizing a different
ligand for enantioselective alcohol oxidation has been developed,
see reference [4k].
[20] J. T. Bagdanoff, E. M. Ferreira, B. M. Stoltz, Org. Lett. 2003, 5, 835–
837.
[21] Complexes of [PdCl2] with a variety of monodentate amines do not
catalyze alcohol oxidation. For details, see reference [17b] and the
Supporting Information.
[22] The beneficial role of carbonates as exogenous bases in the kinetic
resolution was subsequently reported by Sigman as well, see refer-
ence [17d].
[23] A significant effect of cesium carbonate structure and particle size
has been found for palladium-catalyzed aryl halide aminations in
toluene, consistent with a heterogeneous process, see: C. Meyers,
B. U. W. Maes, K. T. J. Loones, G. Bal, G. L. F. Lemiere, R. A. Dom-
misse, J. Org. Chem. 2004, 69, 6010–6017.
[24] W. D. Crow, Aust. J. Chem. 1959, 12, 474–482.
[25] CRC Handbook of Chemistry and Physics, 76th ed. (Eds.: D. R.
Lide, H. P. R. Frederikse), Chemical Rubber Company, New York,
1995, Section 8, p. 43.
[26] Addition of sparteine·HCl inhibits alcohol oxidation, see referen-
ce [15a].
[27] Sigman has proposed that excess chloride ion in solution may inhibit
displacement of chloride by alcohol in [Pd(sparteine)Cl2]. Thus, for-
mation of insoluble CsCl may sequester excess chloride and pro-
mote alcohol coordination. For details, see reference [15f].
[28] J. B. Lambert, Y. Zhao, R. W. Emblidge, L. A. Salvador, X. Liu, J.-
H. So, E. C. Chelius, Acc. Chem. Res. 1999, 32, 183–190.
[29] tert-Butyl alcohol was found to be a competent solvent for this oxi-
dation, see reference [17c].
[14] For mechanistic studies of other non-enantioselective palladium-cat-
alyzed alcohol oxidations, see: a) S. S. Stahl, J. L. Thorman, R. C.
Nelson, M. A. Kozee, J. Am. Chem. Soc. 2001, 123, 7188–7189;
b) B. A. Steinhoff, S. R. Fix, S. S. Stahl, J. Am. Chem. Soc. 2002, 124,
766–767; c) G.-J. ten Brink, I. W. C. E. Arends, R. A. Sheldon, Adv.
Synth. Catal. 2002, 344, 355–369; d) J. A. Mueller, C. P. Goller, M. S.
Sigman, J. Am. Chem. Soc. 2004, 126, 9724–9734; e) M. M. Konnick,
I. A. Guzei, S. S. Stahl, J. Am. Chem. Soc. 2004, 126, 10212–10213;
f) C. R. Landis, C. M. Morales, S. S. Stahl, J. Am. Chem. Soc. 2004,
126, 16302–16303; g) W. Zierkiewicz, T. Privalov, Organometallics
2005, 24, 6019–6028; h) I. W. C. E. Arends, G.-J. ten Brink, R. A.
Sheldon, J. Mol. Catal. A 2006, 251, 246–254; i) B. A. Steinhoff, S. S.
Stahl, J. Am. Chem. Soc. 2006, 128, 4348–4355; j) R. J. Nielsen,
W. A. Goddard III, J. Am. Chem. Soc. 2006, 128, 9651–9660.
[15] For enantioselective palladium-catalyzed alcohol oxidation mecha-
nistic studies, see: a) J. A. Mueller, D. R. Jensen, M. S. Sigman, J.
Am. Chem. Soc. 2002, 124, 8202–8203; b) J. A. Mueller, M. S.
Sigman, J. Am. Chem. Soc. 2003, 125, 7005–7013; c) R. M. Trend,
B. M. Stoltz, J. Am. Chem. Soc. 2004, 126, 4482–4483; d) R. J. Niel-
sen, J. M. Keith, B. M. Stoltz, W. A. Goddard III, J. Am. Chem. Soc.
2004, 126, 7967–7974; e) J. M. Keith, R. J. Nielsen, J. Oxgaard,
W. A. Goddard III, J. Am. Chem. Soc. 2005, 127, 13172–13179;
f) J. A. Mueller, A. Cowell, B. D. Chandler, M. S. Sigman, J. Am.
Chem. Soc. 2005, 127, 14817–14824; g) B. V. Popp, S. S. Stahl, J. Am.
Chem. Soc. 2007, 129, 4410–4422; h) J. M. Keith, W. A. Goddard III,
J. Oxgaard, J. Am. Chem. Soc. 2007, 129, 10361–10369; i) R. M.
Trend, B. M. Stolz, J. Am. Chem. Soc. 2008, 130, 15957–15966.
[16] E. M. Ferreira, B. M. Stoltz, J. Am. Chem. Soc. 2001, 123, 7725–
7726.
[30] Resolutions conducted under an atmosphere of air instead of O2 dis-
played substantially lower reactivity and selectivity.
[31] An alternate explanation involves the formation of trace amounts of
CsOtBu in situ. However, reactions conducted with CsOtBu as base
led to oxidation but no kinetic resolution, see Supporting Informa-
tion for details.
[32] Palladium carbonate complex 13 was also observed on prolonged
exposure of 5 to cesium carbonate in chloroform at 238C.
[33] Comprehensive Biological Catalysis, Vol. 1–3 (Ed.: M. Sinnott), Aca-
demic Press, San Diego, 1998.
[34] For a recent review, see: M. S. Taylor, E. N. Jacobsen, Angew. Chem.
2006, 118, 1550–1573; Angew. Chem. Int. Ed. 2006, 45, 1520–1543.
[35] J. T. Bagdanoff, B. M. Stoltz, Angew. Chem. 2004, 116, 357–361;
Angew. Chem. Int. Ed. 2004, 43, 353–357.
[36] Goddard has proposed that the solubilization of charged intermedi-
ates by dichloromethane may be so great as to nearly completely
separate the chloride anion from the palladium complex in the b-hy-
dride elimination transition state, improving the oxidation rate but
limiting a key interaction for selectivity, see reference [15d].
[37] F. Fischer, G. Pfleiderer, Z. Anorg. Allg. Chem. 1922, 124, 61–69.
[38] For dielectric constant tables, see: CRC Handbook of Chemistry and
Physics, 76th ed. (Eds.: D. R. Lide, H. P. R. Frederikse), Chemical
Rubber Company, New York, 1995, Section 6, pp. 159–192.
À
[39] The IR spectrum of CHCl3 was also investigated. However, the C
H stretch was not well resolved. CDCl3 performs identically to
CHCl3 as reaction solvent.
[40] For a discussion of the hydrogen bonding of chloroform and its
effect on IR vibrational frequencies, see: R. D. Green, Hydrogen
À
Bonding by C H Groups, Wiley, New York, 1974.
Chem. Eur. J. 2009, 15, 12978 – 12992
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12991

B. M. Stoltz et al.
[41] A molecule of chloroform is also within hydrogen-bonding distance
in the solid-state structure of 5. CCDC 203513 for 5 contains the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[42] While we have never experienced an accident, reactions conducted
at elevated temperatures in flammable solvents should be conducted
with appropriate caution in a fume hood.
[52] Related oxidative kinetic resolutions en route to pharmaceutical
agents have been reported, see: a) I. S. Ali, A. Sudalai, Tetrahedron
Lett. 2002, 43, 5435–5436; b) V. V. Thakur, A. Sudalai, Indian J.
Chem. Sect. B 2005, 44, 557–562.
[53] a) R. M. Trend, Y. K. Ramtohul, E. M. Ferreira, B. M. Stoltz,
Angew. Chem. 2003, 115, 2998–3001; Angew. Chem. Int. Ed. 2003,
42, 2892–2895; b) R. M. Trend, Y. K. Ramtohul, B. M. Stoltz, J. Am.
Chem. Soc. 2005, 127, 17778–17788.
[43] For a brief discussion of the substrate scope of the oxidative kinetic
[54] M. R. Rao, J. D. Faulkner, J. Nat. Prod. 2002, 65, 1201–1203.
[55] For discussions on synthetic approaches based on bidirectional chain
synthesis, see: a) C. S. Poss, S. L. Schreiber, Acc. Chem. Res. 1994,
27, 9–17; b) S. L. Schreiber, M. T. Goulet, G. Schulte, J. Am. Chem.
Soc. 1987, 109, 4718–4720.
[56] For examples of bidirectional synthesis/terminus differentiation in
natural products synthesis, see: a) T. Harada, Y. Kagamihara, S.
Tanaka, K. Sakamoto, A. Oku, J. Org. Chem. 1992, 57, 1637–1639;
b) C. S. Poss, S. D. Rychnovsky, S. L. Schreiber, J. Am. Chem. Soc.
1993, 115, 3360–3361; c) S. L. Schreiber, T. Sammakia, D. E. Ueh-
ling, J. Org. Chem. 1989, 54, 15–16; d) N. Ikemoto, S. L. Schreiber,
J. Am. Chem. Soc. 1990, 112, 9657–9659.
[57] a) I. D. Reingold, L. J. DiNardo, J. Org. Chem. 1982, 47, 3544–3545;
b) I. D. Reingold, K. S. Kwong, B. E. Kahr, M. Menard, G. Cum-
mings, J. A. Kowalski, Synth. Commun. 1993, 23, 1463–1466.
[58] J.-E. Bꢈckvall, J.-O. Vꢉgberg, J. Org. Chem. 1988, 53, 5695–5699.
[59] C. R. Johnson, A. Golebiowski, T. K. McGill, D. H. Steensma, Tetra-
hedron Lett. 1991, 32, 2597–2600.
[60] D. C. Ebner, R. M. Trend, C. Genet, M. J. McGrath, P. OꢁBrien,
B. M. Stoltz, Angew. Chem. 2008, 120, 6467–6470; Angew. Chem.
Int. Ed. 2008, 47, 6367–6370.
À
resolution, see: B. M. Stoltz, D. C. Ebner in Handbook of C H
Transformation, Vol. 2 (Ed.: G. Dyker), Wiley-VCH, Weinheim,
2005, pp. 393–401.
[44] D. D. Caspi, D. C. Ebner, J. T. Bagdanoff, B. M. Stoltz, Adv. Synth.
Catal. 2004, 346, 185–189.
[45] F. S. Ruel, M. P. Braun, W. S. Johnson, Organic Syntheses, Collect.
Vol. X, Wiley, New York, 2004, pp. 467–471.
[46] J. L. Luche, A. L. Gemal, J. Chem. Soc. Chem. Commun. 1978, 601–
602.
[47] D. C. Ebner, Z. Novꢇk, B. M. Stoltz, Synlett 2006, 3533–3539.
[48] For example with conditions C, (Æ)-2-methylcyclopent-2-enol and
(Æ)-2-methylcyclohex-2-enol ((Æ)-26) are oxidized with selectivity
factors of 3.2 and 5.3, respectively.
[49] Low reactivity was also observed in a related system, see: I. A.
Sayyed, N. S. C. R. Kumar, A. Sudalai, Indian J. Chem. Sect. B 2005,
44, 1533–1535.
[50] For palladium-catalyzed alcohol oxidation conditions that allow the
resolution of some saturated alkyl alcohols, see reference [17c].
[51] For recent applications of our kinetic resolution to natural product
total synthesis, see: a) U. K. Tambar, D. C. Ebner, B. M. Stoltz, J.
Am. Chem. Soc. 2006, 128, 11752–11753; b) S. Krishnan, J. T. Bag-
danoff, D. C. Ebner, Y. K. Ramtohul, U. K. Tambar, B. M. Stoltz, J.
Am. Chem. Soc. 2008, 130, 13745–13754.
Received: August 5, 2009
Published online: November 10, 2009
12992
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Chem. Eur. J. 2009, 15, 12978 – 12992