Chiral Substituted Poly-N-vinylpyrrolidinones and\nBimetallic Nanoclusters in Catalytic Asymmetric Oxidation\nReactions
A new class of poly-N-vinylpyrrolidinones containing an asymmetric center at C5 of the pyrrolidinone ring were synthesized from L-amino acids. The polymers, particularly 17, were used to stabilize nanoclusters such as Pd/Au for the catalytic asymmetric oxidations of 1,3- and 1,2-cycloalkanediols and alkenes, and Cu/Au for C-H oxidation of cycloalkanes. It was found that the bulkier the C5 substituent in the pyrrolidinone ring, the greater the optical yields produced. Both oxidative kinetic resolution of (\xc2\xb1)-1,3- and 1,2-trans-cycloalkanediols and desymmetrization of meso cis-diols took place with 0.15 mol% of Pd/Au (3:1)-17 under oxygen atmosphere in water to give excellent chemical and optical yields of (S)-hydroxy ketones. Various alkenes were oxidized with 0.5 mol% of Pd/Au (3:1)-17 under 30 psi. of oxygen in water to give the dihydroxylated products in >93% ee. Oxidation of (R)-limonene at 25oC occurred at the C-1,2-cyclic alkene function yielding (1S,2R,4R)-dihydroxylimonene 49 in 92% yield. Importantly, cycloalkanes were oxidized with 1 mol% of Cu/Au (3:1)-17 and 30% H2O2 in acetonitrile to afford chiral ketones in very good to excellent chemical and optical yields. Alkene function was not oxidized under the reaction conditions. Mechanisms were proposed for the oxidation reactions and observed stereo- and regio-chemistry were summarized.
INTRODUCTION<!>RESULTS AND DISCUSSION.<!>Synthesis of Chiral Substituted Poly-N-vinylpyrrolidinones\n(CSPVPs or substituted PVPs containing an asymmetric center).<!>Synthesis of Bimetallic Nanoclusters-CSPVP.<!>Catalytic asymmetric oxidation of cycloalkanediols.<!>Catalytic asymmetric oxidation of alkenes.<!>Catalytic asymmetric oxidation of alkanes.<!>CONCLUSION.
<p>Bimetallic nanoclusters which comprised of two metals have distinct
properties from those comprised of single metals and bulk molecules. For this
reason, they have attracted great interest in recent years.1,2
However, asymmetric oxidations of diols, alkenes, and cycloalkanes using bimetallic
nanoclusters have not yet been reported previously.</p><p>In Au-bimetallic nanoclusters, such as Pd/Au, it has been suggested that Au
pulls electron density from Pd leading to a greater interaction of
Pd(Î´+) with the substrates.3,4 Nanoclusters are
generally stabilized by inorganic oxides, glutathione,5 or organic polymers including
poly-N-vinylpyrrolidinone (PVP),3 poly(amidoamine) (PAMAM),6 chitosan,7 and others,8 which prevent the nanoparticles from aggregation and
oxidation.9 The use of
chiral polymers as chiral inducers with bimetallic nanoclusters in the catalytic
asymmetric oxidation reactions is unprecedented.</p><p>Organic transformation reactions of bimetallic nanoclusters1 in the oxidation of
alcohols,3,10,11
formic acid oxidation,12 aldehyde
oxidation,13 oxidation of
tetralin,14 Ullmann
coupling,15 Suzuki
coupling reaction,16 tandem
oxidation-Michael addition reaction,17 have been reported. However, these reports do not include
studies of enantio- or stereo-selectivity. Although desymmetrization of meso diols
and diol derivatives using various organic reagents and enzymes have
appeared,18–21 reports on the enantioselective
oxidation of a mixture of racemic diols via kinetic resolution are limited, with the
exception of oxidation of racemic benzylic vicinal diols.22 Hence, asymmetric oxidation of racemic or
meso diols using bimetallic nanoclusters and chiral stabilizer may shed light onto
the chemistry of the stabilizer and enhance the synthetic applicability of the
method.</p><p>Catalytic asymmetric syn-dihydroxylation reactions have been intensely
pursued, and the Sharpless asymmetric dihydroxylation process is a major
breakthrough in asymmetric catalysis.23 However, there are a few shortfalls in the methodology and they
include: a lower enantioselectivity in some Z-1,2-disubstituted
alkenes, alkenes containing stereogenic centers, and the toxicity and volatility of
osmium tetraoxide catalyst.23
Various improvements on the enantioselectivity of syn-dihydroxylation using osmium
as catalyst have been made.24,25 Other asymmetric dihydroxylation
reactions with osmium-free catalysts26 including palladium-catalyzed difunctionalization of
alkenes,27
RuO4,28
KMnO4,29 and iron
complexes30 have also been
investigated. Asymmetric syn- and anti-dihydroxylation of alkenes using bimetallic
nanoparticles and chiral polymers have not been disclosed previously. Avoidance of
the use of toxic osmium metal and improving the enantioselectivity in the oxidation
of alkenes would advance the asymmetric synthesis of diols from alkenes.</p><p>Regio- and enantioselective C-H oxidation of cycloalkanes is one of the most
challenging transformations in organic synthesis. The preferred C-H oxidative sites
often took place because of the weaker C-H bond dissociation energy, through-bond
electronic effect, steric effect, conjugation and hyperconjugation, and releasing
strain.31 The uses of
homogeneous catalysts such as iron complexes,32–34 gold
reagents,35 and
others31,36–38 in C-H oxidation have appeared. Due to various possible
reactive sites in even medium-size organic molecules, the regio- and
enantio-selective C-H oxidations inevitably require directing or activating groups
such as heteroatoms and allylic moiety.39–41 Although
simple C-H oxidation of cyclohexane with Au nanoclusters on hydroxyapatite
support42 or with
Pt/TiO243 has been
studied, no reports on the use of bimetallic nanoclusters and chiral supports in the
catalytic asymmetric C-H oxidation have surfaced. C-H oxidation is a highly
atom-economic process, and regioselective catalytic asymmetric C-H oxidation would
provide a powerful tool for organic synthesis.</p><p>We report herein the synthesis of a class of chiral substituted
poly-N-vinylpyrrolidinones (CSPVP) and their chiral induction
by chelating Pd/Au or Cu/Au nanoclusters in enantioselective oxidation reactions of
diols, alkenes, and cycloalkanes.</p><!><p>In the reported study of Pd/PVP nanoparticles using extended X-ray
absorption fine structure spectroscopy, it has been suggested that the amide
function of PVP chelated with Pd and stabilized the nanoparticles.14,44 We hypothesize that in the complex of substituted PVP and
nanoparticles, a substituent on the pyrrolidinone ring would affect the
stereochemical outcome of the reactions, resulting in asymmetric oxidations.</p><!><p>To investigate the effects of the polymers on the bimetallic
nanoparticles in oxidation reactions, we synthesized four CSPVPs 15
- 18 from optically pure amino acids (Scheme 1) and utilized them
as stabilizers in the asymmetric oxidation reactions. Our synthesis of CSPVPs
started from the polymerization of chiral 5-substituted
N-vinylpyrrolidinones 9 – 11,
which were prepared from the vinylation of the corresponding
5-substituted-2-pyrrolidinones, 6 – 8,
respectively. Chiral 6 - 8 were made from L-amino
acids by following a reported procedure.45–47 Hence,
N-Boc L-(S)-amino acids, 1
and 2, were separately coupled with Meldrum's acid followed
by reduction of the ketone function with sodium borohydride, cyclization under
heat,45 and removal of
the Boc group with trifluoroacetic acid (TFA) in CH2Cl2 to
give 5 and 7, respectively. The N-Boc
protecting group of 3 can be removed selectively in the presence of
O-tert-butyl group by
TFA/CH2Cl2 at 25oC providing
6. From our studies (vide infra), it appears that
a bulky substituent at C5 of the polymer would afford a higher
enantioselectivity. Consequently,
(R)-5-benzhydryloxymethyl-2-pyrrolidinone (8) was
synthesized from the alkylation of compound 5 with sodium hydride
and benzhydryl bromide. N-Vinylation of 6 –
8 with Na2PdCl4 and vinyl
acetate48 gave the
corresponding N-vinylpyrrolidinones 9 -
11, respectively.</p><p>To prepare uniform micron-size monodisperse particles,49 we utilized a dispersion
polymerization method50 to
prepare polymers 15 – 17 (Scheme 1). The
dispersants, poly(5-substituted N-vinylpyrrolidinone-co-vinyl
acetate) 12 – 14 were prepared from the
copolymerization reactions of respective monomers 9 –
11 and 1 equiv. of vinyl acetate in the presence of a catalytic
amount of azobisisobutyronitrile (AIBN) in refluxing acetone. Polymerization of
9 – 11 separately with a catalytic amount
of AIBN and in the presence of 1% of respective copolymer 12
– 14 in DMF at 120oC for 7 days gave polymers
15 – 17. Polymer 18 was
prepared through the removal of the tert-butyl group of polymer
15 with TFA. Polymers 15 - 18 are
soluble in water and their molecular weights were determined by gel permeation
chromatography [see Figure
S1 in Supporting
Information (SI)]. Average molecular weights of 15 -
18 are listed (Scheme 1). Both R- and
S-stereochemistry are likely presented in the stereogenic
center (marked with *) in the polymer alkane backbone, and they are not
identifiable. Presumably, this stereogenic center of the polymers can be
isotactic, atactic, and syndiotactic,51 and likely has lesser effect on the asymmetric
oxidation reactions. The average sizes, size distribution, and shapes of the
polymers were also studied by atomic force microscopy (AFM) and dynamic light
scattering (DLS). AFM images of the polymers such as 17 in aqueous
solution showed spheroid and ellipsoid shapes with diameter ~20 – 30 nm
(Figures S2A-S2B).
DLS graphs of 17 showed a major ensemble of 12 – 20 nm sizes
particles with an average size of 18.6 nm along with a few 152 nm-sized
particles, suggesting that different shapes and few large aggregates were
presented in the aqueous solution (Figures S3A - S3B). On the
contrary, nanoclusters Pd/Au-17 showed more discrete sizes in
solution by DLS (vide infra).</p><!><p>Nanoclusters can be prepared by a number of methods including molecular
beams, chemical reduction, thermal decomposition, ion implantation,
electrochemical synthesis, radiolysis, sonochemical synthesis, and biosynthesis,
and are characterized by various analytical techniques.52 We have synthesized various bimetallic
nanoclusters including Pd/Au and Cu/Au, using the chemical reduction
method3 in the presence
of chiral polymer 15, 16, 17, or
18. We used gold due to its high catalytic activity and
synergistic electronic effects.3–9 For
example, a solution of Na2PdCl4 (3 equiv.),
HAuCl4 (1 equiv.), and CSPVP 17 (0.11 equiv.; based
on the amount of Au) in water was treated with NaBH4 at
25oC for 30 min (Scheme 1) to give a light brown to dark grey
solution depending on the concentrations (Figure S4). The resulting solution
was used in the subsequent catalytic reactions without further manipulation.
Similarly, Cu/Au (3:1)-17 was also prepared using CuCl (3 equiv.),
HAuCl4 (1 equiv.), and CSPVP 17 (0.11 equiv.). The
aforementioned nanocluster solution was filtered through a Vivaspin 20
centrifugal filter device (3,000 MWCO), washed with deionized water twice, and
lyophilized to give a powder, which was used for various characterization
including inductively coupled plasma-mass spectrometry (ICP-MS; see SI),
transmission electron microscopy (TEM; Figure S5), X-ray photoelectron
spectroscopy (XPS; Figure
S6), AFM (Figures
S2C - S2D), DLS (Figures S3C - S3D), and IR. Results of the ICP-MS showed a ratio of
3.12 ± 0.58 of Pd and Au in the Pd/Au (3:1)-17 complex, and
a ratio of 3.0 ± 0.4 of Cu and Au in the Cu/Au (3:1)-17
sample. This is in agreement of the 3:1 ratio of the two metals used in
preparation of the nanoclusters. TEM images revealed average diameters of 3.44
± 1.63 nm and 3.66 ± 1.95 nm for Pd/Au (3:1)-17 and
Cu/Au (3:1)-17, respectively (Figure S5). The nano-sizes (2
– 4 nm) of the nanoclusters are similar to those reported for Pd/Au using
PVP as a stabilizer.3,14 XPS spectra of the Pd/Au
(3:1)-17 showed the binding energies of 84.1 eV and 335.1 eV
derived from 4f7/2 Au and 3d5/2 Pd, respectively (Figure S6).14 The spectra of Cu/Au
(3:1)-17 displayed binding energies of 84.1 eV and 932.7 eV for
respective 4f7/2 Au and 2p3/2 Cu (Figure S6). The binding energy
values are consistent with those reported in the XPS database. From the AFM
images of Pd/Au (3:1)-17, 50 – 200 nm in diameters and ~5.8
nm in heights of spherical particles were found, and in DLS, 100 – 140 nm
sized nanoparticles were revealed (Figure S2C, 2D), suggesting the
size of polymer 17 wrapped particles was ~5 times larger than
polymer 17 alone, and the measured sizes of the polymer-particles
from AFM and DLS were similar. As reported previously, AFM does not resolve
subtle shape differences from the diameters, but can provide relatively accurate
height of the nanoparticles.53
The ~5.8-nm height revealed by AFM is similar to that found by TEM. A small
amount of ~15.7 nm-sized particles found in DLS of Pd/Au-17 sample
may derive from free polymer 17 without complexing Pd/Au in the
aqueous solution. The approximate total numbers of metal atoms and molecules of
polymer in a spherical nanocluster can be calculated utilizing the magic-cluster
sizes Ntotal = 1/3 (10n3 - 15n2 + 11n –
3), where n is the number of layers of shell in the metallic nanoparticles with
face-centered cubic close-packed structure.54 Since the average sizes of Pd/Au (3:1)-17
and Cu/Au (3:1)-17 nanoclusters are 3.44 and 3.66 nm, respectively
(from TEM), there are respectively ~727 and 1,151 atoms of Pd/Au (3:1) and Cu/Au
(3:1) in a nanocluster calculating from the aforementioned equation and particle
sizes (see SI for calculation). Each Pd/Au and Cu/Au nanoclusters are stabilized
by approximately 20 and 32 molecules of polymers, respectively (see
SI).4 Because of the
numbers of molecules and extended structure of the chiral polymer, the sizes of
the bimetallic nanocluster/polymer found by AFM and DLS are much larger than
those in the nanoclusters found by TEM (the polymer cannot be observed by TEM).
The amide C=O absorption band of the pyrrolidinone ring at 1650
cm−1 of polymer 17 in IR spectrum shifted to
1641 cm−1 for Pd/Au (3:1)-17, implying a greater
character of δ−O-C=Nδ+ of the amide
group in the nanoclusters due to chelation with the metals.</p><!><p>After screening different ratios of Pd versus Au such as 1:1, 2:1, 3:1
of the bimetallic nanoclusters, Pd/Au (3:1)-CSPVP appears to provide the highest
catalytic activity and chemical yields3 in the aerobic catalytic asymmetric oxidation of
cycloalkanediols. Initially,
(±)-trans-1,3-cyclohexanediol (20) was used
to screen the enantioselectivity of various CSPVPs such as 15
– 18, and results are summarized in Table 1. For instance, treatment of
(±)-20 with 0.15 mol% of Pd/Au (3:1)-CSPVP
15, 16, 17, or 18 (the
amount of catalyst is based on the total moles of Pd and Au) and 0.3 equiv of
K2CO3 in water under 1 atmospheric oxygen at
60oC for 7 days gave 46 – 49% chemical yields [or 92
– 97.5% yields based on reacted
(S,S)-20] and 70 – 99%
ee optical yields of (S)-3-hydroxycyclohexanone
(23) along with the recovered
(R,R)-20 (Table 1, entries 1 – 4). Results suggest that
a bulkier C5-substituent on the pyrrolidinone ring of the polymer provided a
greater optical yield. Since polymer 17 provided the highest
chemical and optical yields, it was used for all other oxidation reactions
including oxidations of alkenes and cycloalkanes. Diol
(R,R)-20 was recovered in 50%
yield and 92% ee from the reaction with Pd/Au (3:1)-17, suggesting
that it reacted much slower than
(S,S)-20 under the reaction
conditions, i.e., a kinetic resolution is resulted. Hydroxyl ketone
(S)-23 did not undergo oxidation, revealing an
electron-withdrawing ketone group impeded further oxidation. The rate of the
oxidation reaction was enhanced in the presence of 0.3 equiv of
K2CO3. Using 0.15 mol% of Pd/Au (3:1)-17,
other five- and seven-membered cycloalkanes, such as 1,3-trans
diols (±)-19 and (±)-21 and
1,2-trans diols (±)-28 -
(±)-30, were similarly oxidized to give excellent
chemical and optical yields. Results are presented in Table 1 (entries 5 and 6, and entries 10 –
12). When the amounts of catalysts were increased to 0.30 mol% (double) or 0.60
mol% (quadruple) of Pd/Au (3:1)-17, the oxidations of
(±)-20 were respectively completed in 6 and 5 days, with
chemical yields of 47% (99% ee) and 49% (99% ee) of
(S)-23. Hence, an increase of the amounts of
catalyst shortens the reaction time. Oxidation of (±)-20
with 0.15 mol% of Pd-17 without Au under similar reaction
conditions (at 60oC for 7 days) gave only 29% yield of
(S)-23 in 95% ee, indicating bimetallic Pd/Au
provided higher chemical and optical yields in the catalytic oxidation
reactions. Catalyst Au-17 alone gave no oxidized product. When the
temperature of the reaction was increased from 60oC to
80oC, the rate of the reaction did not change (7 days and 47% yield
was found), whereas the optical yield of (S)-23
decreased to 94% ee. Further increasing the temperature to 100oC
resulted in completion of the reaction in 6 days with a 47% yield of
(S)-23 in 89% ee, indicating that higher
reaction temperature lowers the optical yield. The recyclability of the Pd/Au
(3:1)-17 catalyst was also examined. Hence, the catalyst,
recovered from the oxidation reaction of (±)-20, was reused
under similar reaction conditions for a second time, and 39% yield (99% ee) of
(S)-23 was isolated. The catalyst was further
recycled for a third time, but only 18% yield (98% ee) of
(S)-23 was obtained, showing the catalyst can
be reused albeit with lower catalytic activities. The turnover number (TON) of
the catalytic oxidation reaction after three cycles is 706 (SI). The absolute
configurations of (S)-22,
(S)-23 and
(S)-31 –
(S)-33 were determined by comparison of the
sign of the reported specific rotations (see SI).55–58 Optical purities were measured through HPLC/chiral
column of their benzoyl derivatives, which were synthesized by the treatment of
the hydroxyl ketones with benzoyl chloride and pyridine (SI). In all cases, PVP
was used in place of CSPVP under similar reaction conditions to provide the
racemic products for HPLC/chiral column analyses. The selectivity factor values
of the HPLC/chiral column separation are 1.10 – 1.28 (see Table S1 in
SI), indicating an acceptable separation. The specific rotation of
(S)-24 has not been reported previously and
its absolute configuration was assumed based on the retention time of its
benzoate derivative in HPLC/chiral column. The (R)-enantiomer
has a lower retention time than that of (S)-enantiomer, which
is in agreement with benzoate derivatives of
(S)-22 and
(S)-23 (see SI). The absolute configurations
and optical purities of the unreacted diols
(R,R)-19 –
(R,R)-21 and
(R,R)-28 –
(R,R)-30 were similarly
determined by comparison of the sign of the reported specific
rotations59,60 (SI) and through HPLC/chiral column of
their dibenzoate derivatives obtained from the reactions of the diols with
benzoyl chloride and pyridine (SI).</p><p>To our surprise, the meso 1,3-cis and
1,2-cis-cycloalkanediols did not undergo oxidation
reactions under similar reaction conditions as those of
trans-diols. It may due to the fact that
cis-diols form stable complexes with the
nanoparticles.61
However, under elevated pressure of oxygen (30 psi.) and temperature
(120oC), the reactions took place in 3 days to give 89 –
97% yields and 90 – 92% ee of the oxidized (S)-hydroxyl
ketones (Table 1, entries 7 – 9
and entries 13 – 15). The higher reaction temperature (120oC)
lowers the optical yields in the catalytic oxidation reactions. No changes in
reaction rate and chemical and optical yields in the oxidation reaction of
meso-35 were found when doubling the amount of 17
but maintaining the same amount of Pd/Au (3:1; 0.15 mol%). This oxidative
desymmetrization of meso-diols is synthetically useful, since it provides the
chiral hydroxyketones without the recovery of starting diols. Importantly, both
trans- and cis-diols gave only the
(S)-hydroxy ketones.</p><p>Scheme 2 outlined a proposed mechanism and oxidative sites for the
enantioselective oxidation reactions of diols. A η2-peroxido
PdII (peroxopalladium) species II62 may form similar to that
reported.63 A diol
such as (S,S)-20 attacks Pd of
II leading to complex III, which undergoes proton
transfer to give IV. Subsequent removal of C1-H by
K2CO3 leads to (S)-23
and I and hydrogen peroxide. Presumably, the
C5(R)-bulky substituent of pyrrolidinone ring directs the
stereo- and regio-chemistry of the oxidation reactions. The oxidative sites in
trans- and cis-diols are depicted in
VI and VII, respectively.</p><p>The pro-S-configurated carbon center of
trans-diols (1,3- and 1,2-diols) of five-, six-, and
seven-membered ring oxidizes much slower than the
pro-R-configurated carbon center. Notably, the transition
states are difficult to discern given the complexity of the polymer structures.
Oxidation of I with H2O2 gives
II.64
Nanocluster Pd/Au-17 provides excellent enantioselectivities (91
– 99% ee) in the oxidation of diols, and results of the
enantioselectivity from the oxidation of trans-diols are
comparable to those reported using enzymes.65,66</p><!><p>The success in catalytic asymmetric oxidation of diols led us to examine
the oxidation of alkenes. Although no oxidation of alkenes took place at 1
atmospheric of oxygen, various alkenes were readily oxidized at 30 psi. of
oxygen in excellent to good chemical yields and excellent optical yields.
Results of the oxidation are summarized in Table
2 (entries 1 – 7). For example, treatment of
1,2-dihydronaphthalene (37) with 0.5 mol% of Pd/Au
(3:1)-17 in water at 25oC under 30 psi. of oxygen
for 3 days gave (1S,2R)-38 in 86%
yield and 99% ee (Table 2, entry 1). Only
a single product was obtained in the reaction. The Sharpless dihydroxylation of
37 using DP-PHAL gave 56% ee of
(1R,2S) enantiomer of
38.67
Other disubstituted alkenes including trans- and
cis-β-methylstyrene (39 and
39A, respectively; Table 2, entries 2 and 3) also
underwent oxidation reactions at 25oC. In the oxidation of
trans-39, the syn-adduct
(1S,2S)-40 was isolated in
87% yield and 99% ee along with a small amount of anti-adduct
(1R,2S)- 41 in 6% yield and
97% ee. Similarly, in the oxidation of cis-39A,
the syn-adduct (1S,2R)-41A was
isolated in 90% yield and 98% ee as well as 8% yield of anti-adduct
(1R,2R)-40A in 98% ee.
Notably, the dihydroxylation takes place from the re face of
the alkenes (in regarding to C1 of 37 or 39).
Trisubstituted alkenes such as (R)-(+)-limonene
(48), containing a stereogenic center, also underwent
stereoselective oxidation at 25oC to give a single stereoisomer
(1S,2R,4R)-49.
No other stereoisomers were detected. The oxidation of alkenes containing an
electron-withdrawing group such as trans-cinnamic acid ester
42 and indene (45) only proceeded at
50oC giving the syn-adducts
(2R,3S)-43 (82% yield; 99%
ee) and (1S,2R)-46 (67% yield;
93% ee), respectively, as the major products. The respective anti-adducts,
(2R,3R)-44 (3% yield; 97% ee)
and (1R,2R)-47 (11% yield; 94%
ee) were also isolated as minor products. Since
(1R,2R)-47 was obtained in
11% yield, we questioned whether this anti-adduct could be produced as the major
product. As expected, in the presence of 0.3 equiv of
K2CO3 at 70oC for 5 h,
(1R,2R)-47 was isolated in
59% yield and 91% ee. However, only syn-addut
(1S,2R)-38 was isolated when
0.3 equiv of K2CO3 was added to the oxidation reaction of
37 at 25oC. The absolute configurations were
determined by comparing the sign and specific rotations of the respective
reported molecules (see SI).65,66,68,69 Optical
purities of all dihydroxylated molecules were measured using HPLC/chiral column
(SI). To determine the stereochemistry of 49 (which has not been
reported previously), we independently prepared
(1S,2R,4R)-49
and its
(1R,2S,4R)-diastereomer by
the reaction of (R)-48 with OsO4
(catalytic amount)-NMO followed by silica gel column chromatography (SI). The
cyclic trisubstituted alkene reacted preferentially compared to the acyclic
terminal disubstituted olefin group, suggesting electron-donating groups such as
alkyl and aryl enhance the reactivity towards the nanoclusters. The formation of
(1S,2R,4R)-49
from the dihydroxylation reaction of limonene is remarkable, since the
dihydroxyl functions were delivered from the same side of the bulky isopropenyl
group. The highest reported % ee's of the dihydroxylation products of
39, 39A, 42 (the ethyl ester analog),
and 45 from Sharpless asymmetric dihydroxylation reactions are
98,70 81,71 99,69 and 89,72 respectively. Hence, the
Pd/Au-17 provided higher or similar enantiomeric selectivities
in the catalytic asymmetric dihydroxylation reactions.</p><p>A proposed mechanism and stereo- and regio-chemistry for the
enantioselective oxidation of alkenes62,73 are depicted
in Scheme 3. Similar to that described in Scheme 2,
η2-peroxido PdII (peroxopalladium) species
II undergoes syn-addition reaction with alkenes via transition
state VIII under high oxygen pressure, where Pd adds to C1
containing larger aryl or alkyl group (RL) and oxygen adds to C2
containing smaller alkyl group (RS), resulting in
metallo-1,2-dioxolane IX.63 C1 containing either an aromatic ring (entries 1
– 6) or more substituted carbon (entry 7) is better able to accommodate
the partial positive charge in the transition state (vide
infra). Carbon-1 of IX undergoes a 1,2-alkyl shift from Pd
to oxygen (path a) leading to intermediate X, which hydrolyzes to
give the syn-adducts. In 37 and
(R)-48 (Table
2, entries 1 and 7), the 1,2-alkyl shift takes place rapidly and only
the syn-adducts were found. In other investigated alkenes (39
– 45), in addition to major path a, water attacks C1 of
intermediate IX from the backside, path b, providing anti-addition
diols as the minor products (Table 2,
entries 2 – 5). In supporting this hypothesis, an addition of 0.3 equiv.
of K2CO3, a stronger nucleophile than water, resulted in
the formation of anti-adduct
(1R,2R)-47 being the major
product (Table 2, entry 6). Structures of
the respective metallo-1,2-dioxolanes derived from the oxidation of
benzocycloalkenes, trans- and cis-alkenes are
depicted in XIIa, XIIb, XIIIa, and
XIIIb, which resulted from the addition reactions of
η2-peroxido PdII from the
Re-face of the alkenes. For trisubstituted alkene such as
(R)-limonene, the addition took place from the
Si-face (structure XIIc).</p><p>The asymmetric aerobic oxidation of alkenes by Pd/Au-17 at
ambient temperature or 50oC provided excellent chemical and optical
yields of the syn-dihydroxylated products and in certain cases where higher
temperature (such as 70oC) is required, an addition of a weak base
such as K2CO3 afforded anti-dihydroxylated molecules as
the major products.</p><!><p>To explore the scope of the oxidation reactions, a more challenging
catalytic asymmetric C-H oxidation was investigated. We found that Cu/Au
(3:1)-17 provided greater chemical and optical yields in C-H
oxidation than Pd/Au (3:1)-17. Results of the catalytic asymmetric
C-H oxidation reactions of various substituted achiral cycloalkanes using 1 mol%
Cu/Au (3:1)-17 and H2O2 at 50oC
are summarized in Table 2. Without
hydrogen peroxide, under oxygen atmosphere (30 psi.), no oxidation products were
detected. For example, oxidation of
meso-trans-1,4-diisopropylcyclohexane (50) gave an
87% yield of (2R,5S)-51 in 81% ee
(Table 2, entry 8). The specific
rotation and 1H and 13C NMR spectral data of
(2R,5S)-51 were in agreement
with those of the reported compound synthesized from
(S)-perillaldehyde.74 The four methine C-H's of 50,
possessing weaker bond dissociation energies,31 and four sterically less hindered
methyls were not oxidized under the reaction conditions, suggesting rigid or
less freely rotated methylene groups are oxidized faster than methine and methyl
groups. Higher ee's were obtained when a directing group such as hydroxyl
was presented. Hence, oxidation of alcohols 52 - 54,
and 1-isopropenylcyclohexanol (58) gave excellent chemical and
optical yields of (R)-55 -
(R)-57, and
(R)-59, respectively (Table 2, entries 9 – 12). Likely, under the
reaction conditions, the alcohols were initially formed and they subsequently
oxidized to the ketones. Importantly, in the absence of elevated pressure of
oxygen, the alkene function of 58 was not oxidized at
50oC, despite the presence of an activating allylic hydroxyl
group. This is significant since alkene functional group is more reactive than
the alkane moiety. The regiochemistry of (R)-55 -
(R)-57, and
(R)-59 were analyzed by 2D COSY spectroscopy.
In the COSY spectrum of (R)-55, the signal at
δ 2.41 – 2.30 ppm assigned for C2-hydrogens has no correlation
with other protons, while the signals at ~2.25 and 2.05 ppm assigned for C5
hydrogens show correlation with C4 hydrogens at 2.01 and 1.60 ppm. Similar
correlations were found in the 2D COSY spectra of
(R)-56, (R)-57,
and (R)-59 (SI). Moreover,
(R)-56 and
(R)-57 were independently synthesized from
(S)-23 and
(S)-24, respectively, by silylation of the
C3-hydroxyl group followed by addition reaction with isopropylmagnesium bromide,
removal of the silicon protecting group, and oxidation with IBX-DMSO (see SI).
Their NMR spectra and specific rotations were similar to those obtained from the
C-H oxidations. A medium-sized natural product, (+)-sclareolide
(60), also underwent regioselective oxidation to give
2S-2-hydroxysclareolide (61) in 38% yield and
3% yield of 1-oxosclareolide along with 46% recovery of 60 after
silica gel column chromatographic separation. No other regioisomers were found.
1H and 13C NMR spectral data of 61 and
1-oxosclareolide are identical to those reported.75,34 Notably, unlike the reported iron complex-catalyzed
oxidation,34 the
C2-equatorial hydroxyl function of 61 does not undergo further
oxidation, likely due to steric hindrance (C2-axial-H is shielded by
C15-β- and C16-methyls75).</p><p>Based on the previously suggested mechanism of copper complexes bearing
trispyrazolylborate ligands,76
a mechanism for the C-H oxidation reactions involving Cu/Au-17 was
proposed and the stereo- and regio-chemistry of the major C-H oxidative sites
were depicted in Scheme 4. Cuo/Au XIV reacts with
H2O2 to give copper(II) oxo complex XV,
which abstracts a hydrogen atom from cycloalkanes such as 50 to
generate hydroxyl copper(I) and cycloalkyl radical (likely not a free
radical76) in a
cage-like complex XVI. A rapid combination of the cycloalkyl
radical with hydroxyl radical in XVII takes place and subsequently
releases the alcohol and regenerates XIV. The alcohols oxidized
under the reaction conditions to give ketones.76 Oxidative sites for the C-H oxidation
reactions are summarized in XIX - XXI. The two
isopropyl substituents orient at the equatorial positions and copper(II) oxo
XV likely approaches the C3 equatorial hydrogen, resulting in
the observed 2R,5S configuration in
51. In the hydroxyl directed oxidation, C1 hydroxyl group
coordinates with copper(II) oxo XV and abstraction of the C3
equatorial or axial hydrogen will lead to the observed C3-R
configuration.</p><!><p>Various substituted poly-N-vinylpyrrolidinones containing a
stereogenic center were synthesized from L-amino acids and used in the catalytic
asymmetric oxidations of cyclic diols, dihydroxylation of alkenes, and C-H oxidation
of cycloalkanes. Polymer 17 afforded the highest enantiomeric
selectivities. Excellent chemical yields and enantioselectivity were found. Both
(±)-trans and meso-cis diols were
oxidized under oxygen atmosphere with Pd/Au-CSPVP to give
(S)-hydroxy ketones. Trans- and
cis-alkenes oxidized under 30 psi. of oxygen to afford
syn-diols as the major products. The resulting diols do not
undergo further oxidation. Various substituted cycloalkanes including
1,4-disubstituted cyclohexane and 1-substituted 1-cycloalkanols were oxidized by
Cu/Au-17 and H2O2 to furnish chiral
cycloalkanones. Remarkably, disubstituted terminal alkene function was not oxidized
under the C-H oxidation reaction conditions, which demonstrates a high potential for
the synthetic methodology.</p>