A trifunctional catalyst for one-pot synthesis of chiral diols via heck coupling-N-oxidation-asymmetric dihydroxylation: Application for the synthesis of diltiazem and taxol side chain

Article abstract of DOI:10.1021/jo026687i

A heterogeneous bifunctional catalyst composed of OsO₄^2--WO₄^2- and a trifunctional catalyst comprising PdCl₄^2--OsO₄^2-- WO₄^2-, designed and prepared by an ion-exchange technique using layered double hydroxides (LDH) as an ion-exchanger and their homogeneous bifunctional analogue, K₂OsO₄-Na₂WO₄ and trifunctional analogue, Na₂PdCl⁴-K2OsO₄-K₂ OSO₄-NNa₂WO₄, devised for the first time are evaluated for the synthesis of chiral vicinal diols. These bifunctional and trifunctional catalysts perform asymmetric dihydroxylation-N-oxidation and Heck-asymmetric dihydroxylation-N-oxidation, respectively, in the presence of Sharpless chiral ligand, (DHQD)2PHAL in a single pot using H₂O₂ as a terminal oxidant to provide N-methylmorpholine oxide (NMO) in situ by the oxidation of N-methylmorpholine (NMM). The heterogeneous bifunctional catalyst supported on LDH (LDH-OsW) displays superior activity to afford diols with higher yields over the other heterogeneous catalysts developed by the ion exchange on quaternary ammonium salts covalently bound to resin (resin-OsW) and silica (silica-OsW) or homogeneous catalysts in the achiral dihydroxylation reactions. The LDH-OsW and its homogeneous analogue are found to be very efficient in performing a simultaneous asymmetric dihydroxylation (AD)-N-oxidation of a wide and varied range of aromatic, cyclic, and mono, di-, and trisubstituted olefins to obtain chiral vicinal diols with higher yields and ee's using H₂O₂. Further, the use of OsO₄^2--WO₄^2-- WO₄^2- catalysts as such or in the supported form offers a simplified procedure for catalyst recycling, which shows consistent activity for a number of cycles. In this process, Os^VI is recycled to Os^VIII by a coupled electron transfer-mediator (ETM) system based on NMO-WO₄^2- using H₂O₂, leading to a mild and selective electron transfer. The one-pot biomimic synthesis of chiral diols is mediated by a recyclable trifunctional heterogeneous catalyst (LDH-PdOsW) consisting of active palladium, tungsten, and osmium species embedded in a single matrix. This protocol, which provides prochiral olefins and NMO in situ by Heck coupling and N-oxidation of NMM, respectively, required for the AD, unfolds a low cost process. We extended the present method to the one-pot synthesis of trisubstituted chiral vicinal diols with moderate to excellent ee's by AD of trisubstituted olefins that are obtained by in situ Heck arylation of disubstituted olefins. The heterogeneous trifunctional catalysts offers chiral diols with unprecedented ee's and excellent yields in the AD of prochiral cinnamates, which are obtained in situ from acrylates and halobenzenes for the first time. The new variants such as LDH support and Et₃N·HX inherently composed in the heterogeneous multicomponent system and slow addition of H202 facilitates the hydrolysis of osmium monogylcolate ester to subdue the formation of bisglycolate ester to achieve higher ee's. Without resorting to recrystallization, the chiral diols of cinnamates thus synthesized with 99% ee's and devoid of osmium contamination are directly put to use in the synthesis of diltiazem and Taxol side chain with an overall improved yield to demonstrate the synthetic utility of the trifunctional heterogeneous catalyst. The high binding ability of the heterogeneous osmium catalyst enables the use of equimolar ratio of ligand to osmium to give excellent ee's in AD in contrast to the homogeneous osmium system in which the excess molar quantities of the expensive chiral ligand to osmium are invariably used. Further, the XRD, FT-IR, UV-vis DRS, and XPS studies indicate the retention of the coordination geometries of the specific divalent anions anchored to LDH matrix in their monomeric form during the ion exchange and after the reaction.

Full text of DOI:10.1021/jo026687i

A Tr ifu n ction a l Ca ta lyst for On e-P ot Syn th esis of Ch ir a l Diols via
Heck Cou p lin g-N-Oxid a tion -Asym m etr ic Dih yd r oxyla tion :
Ap p lica tion for th e Syn th esis of Diltia zem a n d Ta xol Sid e Ch a in
Boyapati M. Choudary,* Naidu S. Chowdari, Sateesh Madhi, and Mannepalli L. Kantam
Inorganic & Physical Chemistry Divisions, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
choudary@iict.ap.nic.in
Received November 11, 2002
2-
A heterogeneous bifunctional catalyst composed of OsO42--WO4 and a trifunctional catalyst
comprising PdCl42--OsO42--WO42-, designed and prepared by an ion-exchange technique using
layered double hydroxides (LDH) as an ion-exchanger and their homogeneous bifunctional analogue,
K2OsO4-Na2WO4 and trifunctional analogue, Na2PdCl4-K2OsO4-Na2WO4, devised for the first
time are evaluated for the synthesis of chiral vicinal diols. These bifunctional and trifunctional
catalysts perform asymmetric dihydroxylation-N-oxidation and Heck-asymmetric dihydroxylation-
N-oxidation, respectively, in the presence of Sharpless chiral ligand, (DHQD)2PHAL in a single
pot using H2O2 as a terminal oxidant to provide N-methylmorpholine oxide (NMO) in situ by the
oxidation of N-methylmorpholine (NMM). The heterogeneous bifunctional catalyst supported on
LDH (LDH-OsW) displays superior activity to afford diols with higher yields over the other
heterogeneous catalysts developed by the ion exchange on quaternary ammonium salts covalently
bound to resin (resin-OsW) and silica (silica-OsW) or homogeneous catalysts in the achiral
dihydroxylation reactions. The LDH-OsW and its homogeneous analogue are found to be very
efficient in performing a simultaneous asymmetric dihydroxylation (AD)-N-oxidation of a wide
and varied range of aromatic, cyclic, and mono, di-, and trisubstituted olefins to obtain chiral vicinal
2-
diols with higher yields and ee’s using H2O2. Further, the use of OsO42--WO4 catalysts as such
or in the supported form offers a simplified procedure for catalyst recycling, which shows consistent
activity for a number of cycles. In this process, OsVI is recycled to OsVIII by a coupled electron transfer-
mediator (ETM) system based on NMO-WO42- using H2O2, leading to a mild and selective electron
transfer. The one-pot biomimic synthesis of chiral diols is mediated by a recyclable trifunctional
heterogeneous catalyst (LDH-PdOsW) consisting of active palladium, tungsten, and osmium species
embedded in a single matrix. This protocol, which provides prochiral olefins and NMO in situ by
Heck coupling and N-oxidation of NMM, respectively, required for the AD, unfolds a low cost process.
We extended the present method to the one-pot synthesis of trisubstituted chiral vicinal diols with
moderate to excellent ee’s by AD of trisubstituted olefins that are obtained by in situ Heck arylation
of disubstituted olefins. The heterogeneous trifunctional catalysts offers chiral diols with unprec-
edented ee’s and excellent yields in the AD of prochiral cinnamates, which are obtained in situ
from acrylates and halobenzenes for the first time. The new variants such as LDH support and
Et3N‚HX inherently composed in the heterogeneous multicomponent system and slow addition of
H2O2 facilitates the hydrolysis of osmium monogylcolate ester to subdue the formation of bisglycolate
ester to achieve higher ee’s. Without resorting to recrystallization, the chiral diols of cinnamates
thus synthesized with 99% ee’s and devoid of osmium contamination are directly put to use in the
synthesis of diltiazem and Taxol side chain with an overall improved yield to demonstrate the
synthetic utility of the trifunctional heterogeneous catalyst. The high binding ability of the
heterogeneous osmium catalyst enables the use of equimolar ratio of ligand to osmium to give
excellent ee’s in AD in contrast to the homogeneous osmium system in which the excess molar
quantities of the expensive chiral ligand to osmium are invariably used. Further, the XRD, FT-IR,
UV-vis DRS, and XPS studies indicate the retention of the coordination geometries of the specific
divalent anions anchored to LDH matrix in their monomeric form during the ion exchange and
after the reaction.
In tr od u ction
utilization of manpower, consumption of energy and
chemicals, and generation of waste is a major goal in
synthetic chemistry. Performing the multistep synthesis
in one pot is an attractive strategy to achieve this goal.1
The cocktail approach has been realized in the in vitro
Improving the efficiency of organic processes in terms
of lowering the process time, inventory of equipment,
* To whom correspondence should be addressed. Fax: 0091-40-
27160921.
10.1021/jo026687i CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/07/2003
1736
J . Org. Chem. 2003, 68, 1736-1746

Synthesis of Diltiazem and Taxol Side Chain
synthesis of corrin from R-aminolevulinic acid using 12
enzymes with an overall yield of 20% in a single flask.2
The elegant uncatalyzed multicomponent reaction (MCR),
comprising the condensation of the five components, viz.
primary amines, aldehydes, carbon dioxide, alcohols, and
isocyanides, to R-acylaminocarbonamides based on a
Zipper principle was developed by Ugi.2a The single
molecule catalyst, which performs multifunctionality in
C-C bond-forming reactions with high enantioface dis-
crimination,3 was developed by Shibasaki. Significant
progress using homogeneous and heterogeneous bifunc-
tional catalysts for one-pot reactions was achieved.4 The
recent design of the BINOL-BINAP copolymer catalyst
for the tandem asymmetric diethylzinc addition and
hydrogenation of acetyl benzaldehydes marks a new era
in bifunctional catalysis.4a
Sharpless AD of olefins offers one of the most efficient
methods for the preparation of chiral diols, the key
intermediates for many biological compounds.5,6 An ef-
fective reoxidation system that facilitates the Os(VI)/Os-
(VIII) cycle in the AD reactions naturally improves high
throughput. Several reoxidation systems using N-meth-
ylmorpholine N-oxide (NMO),7 potassium ferricyanide,8
or molecular oxygen9 have been developed. The use of
the ferricyanide in AD reaction, which encounters the
problem of effluent disposal due to handling of large
amounts of salts (1.4 g per mmol of olefin), is not feasible
practically or economically on a large scale. On the other
hand, the use of NMO7 has definite advantages such as
facilitation of the reaction in higher concentrations, easy
recyclability of the reduced N-methylmorpholine (NMM),
and economical by a factor of 5 over the potassium
ferricyanide. Besides, the ee’s of the resultant chiral diols
could be achieved as high as those obtained with K3Fe-
(CN)6 in case of aromatic olefins, by adopting the slow
addition of olefin to the reaction mixture with the aid of
an automated pump. Conversely, the lower ee’s and over-
oxidation in the case of aromatic olefins containing
R-hydrogen are the major concerns in the use of O2 as
the reoxidant for osmium(VI) in AD reaction. H2O2 as
direct reoxidant leads to the nonselective reaction with
a low yield of diol due to over-oxidations.10 Recently,
Ba¨ckvall developed the electron-transfer mediator (ETM)
based on NMO/flavin for osmium-catalyzed AD of olefins
using H2O2 as a terminal oxidant with high efficiency.11
Although the AD reactions catalyzed by OsO4 could be
applied to the synthesis of pharmaceuticals, fine chemi-
cals, etc., the high cost, and possible contamination of
toxic osmium in the product, restricts its use in industry.
Heterogenization of OsO4 via microencapsulation,12 ion-
exchange techniques,13 and covalent anchoring14 are
employed to address the issue of complete recovery of
osmium from the reaction media. We recently designed
the unique single-pot biomimic synthesis of chiral diols
mediated by a trifunctional heterogeneous catalyst,
consisting of active palladium, tungsten, and osmium
species embedded in a single matrix. This method
provides prochiral olefins and NMO in situ by Heck
coupling and N-oxidation of NMM, respectively, required
for the AD.13a The ETM based on the NMO/WO42- system
is indeed found to be excellent in AD reactions catalyzed
in the heterogeneous phase.15 We report herein (i) the
one-pot synthesis of chiral diols using both bifunctional
2-
(OsO42--WO42-) and trifunctional (PdCl42--OsO4
-
(1) (a) Tietze, L. F.; Haunert, F. In Stimulating Concepts in
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WO42-) catalysts developed for the first time in homoge-
neous phase and compared with the heterogeneous
analogues obtained via ion-exchange methods using LDH
as an ion exchanger and H2O2 as a terminal oxidant in
terms of activity and enantioselectivity, (ii) in situ
synthesis and dihydroxylation of various functionalized
and trisubstituted olefins using H2O2 as the terminal
oxidant in which NMM is recycled to NMO in trifunc-
tional heterogeneous catalysis, and (iii) without resorting
to recrystallization, the chiral diols synthesized with
unprecedented higher ee’s can be directly put to use in
the synthesis of diltiazem and taxol side chain to dem-
onstrate the synthetic utility of the trifunctional hetero-
geneous catalyst.
(10) Milas, N. A.; Sussman, S. J . Am. Chem. Soc. 1936, 58, 1302.
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J .-E. J . Am. Chem. Soc. 2001, 123, 1365. (c) J onsson, S. Y.; Adolfsson,
H.; Ba¨ckvall, J .-E. Org. Lett. 2001, 3, 3465. (d) Ell, A. H.; J onsson, S.
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63, 6094. (b) Kobayashi, S.; Endo, M.; Nagayama, S. J . Am. Chem.
Soc. 1999, 121, 11229. (c) Kobayashi, S.; Ishida, T.; Akiyama, R. Org.
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(13) (a) Choudary, B. M.; Chowdari, N. S.; Madhi, S.; Kantam, M.
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P. J .; J acobs, P. A. Angew. Chem., Int. Ed. 2001, 40, 586.
(15) We have also tested Ti(IV) as an ETM, and the results are
inferior; see: Choudary, B. M.; Chowdari, N. S.; J yothi, K.; Madhi, S.;
Kantam, M. L. Adv. Synth. Catal. 2002, 344, 503.
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J . Org. Chem, Vol. 68, No. 5, 2003 1737

Choudary et al.
TABLE 1. Mea su r ed Bin d in g En er gies for P a lla d iu m ,
Osm iu m , a n d Tu n gsten of Bifu n ction a l a n d Tr ifu n ction a l
Ca ta lysts
Resu lts a n d Discu ssion
P r ep a r a tion a n d Ch a r a cter iza tion of Ca ta lysts.
Homogeneous bifunctional catalytic systems composed of
admixtures of K2OsO4-Na2WO4 and trifunctional cata-
lytic system comprising Na2PdCl4-K2OsO4-Na2WO4 and
their heterogeneous analogues exchanged on a single
matrix, LDH, and quaternary ammonium resin and
silica16-18 were prepared and examined in dihydroxyla-
tion reactions in a single pot using H2O2 as a terminal
oxidant under identical conditions. LDH is a class of
layered material, consisting of alternating cationic
M(II)1-xM(III)x(OH)2x+ and anionic An-‚zH2O layers.19 The
cationic layers are separated from each other by the
anions and water molecules. The positively charged
layers in LDH contain edge-shared metal M(II) and
M(III) hydroxide octahedra, with charges neutralized by
the An- anions located in the interlayer spacing or at the
edges of the lamellae. A wide variety of LDHs containing
various divalent and trivalent cations [M(II) ) Mg, Zn,
Ni, Cu; M(III) ) Al, Ga, In, Cr, Fe] in combination with
different anions can be prepared. LDHs have been
investigated extensively in a wide range of applications
such as catalysts,13,16 materials,19,20 and bioactive nano-
Pd
Os
W
catalyst
3d5/2
3d3/2
4p
4f7/2 4f5/2 4f7/2 4f5/2
LDH-OsWa
LDH-OsWb
54.2 56.8 34.9 36.9
54.3 56.8 34.9 37.0
LDH-PdOsWa 337.2 342.8 50.5 54.5 57.0 35.0 37.0
LDH-PdOsWb 337.1 342.6 50.2 54.3 56.6 34.7 36.9
a
b
Fresh catalyst. Used catalyst.
ternary ammonium form of resin and silica to obtain
bifunctional resin-OsW and silica-OsW.
X-ray powder diffraction patterns of the initial LDH
and the exchanged catalysts LDH-OsW and LDH-
PdOsW hardly differ in the range 2θ ) 3-65°. The
observed basal spacings remain unchanged after the
anion exchange, which indicates the location of divalent
anions OsO42- and WO42- in the bifunctional catalyst and
2-
PdCl42-, OsO42-, and WO4 in trifunctional catalyst on
the edge positions of LDH. In the FTIR spectra of these
exchanged catalysts, broad absorption bands appear near
830-860 cm-1, which are assigned to the vibrational
asymmetric OdMdO (M ) Os and/or W) stretching in
contrast to the sharp bands observed at 819 cm-1 for
potassium osmate and 831, 857 cm-1 for sodium tung-
state. The observation of broad bands in the same region
for the catalysts indicates that the OsO42- and WO42- are
unaffected upon exchange onto the support both in
bifunctional and trifunctional catalysts while experienc-
ing very weak interactions with the support. The Pd-Cl
composites.21 Small hexagonal LDH crystals with Mg1-x
-
Alx(OH)2(A)x‚zH2O [A ) Cl, NO3, CO3] composition were
synthesized following the existing procedures.19b Resins
are another class of polymeric supports originating from
organic precursors, which are widely employed as cata-
lyst carriers and in solid phase organic synthesis. Silica
gel, an inorganic support, a commonly employed support
in heterogeneous catalysis, is also considered for the
2-
2-
immobilization of osmium. OsO4 and WO4 were co-
exchanged concomitantly onto a chloride saturated LDH
to obtain the bifunctional catalyst, LDH-[OsO4,WO4]
(abbreviated as LDH-OsW). Further, three bivalent
anions, PdCl42-, OsO42- and WO42- were simultaneously
coexchanged onto a single LDH matrix to yield LDH-
[PdCl4,OsO4,WO4] (abbreviated as LDH-PdOsW). Simi-
stretching of PdCl4 is also observed at 335 cm-1 for
2-
LDH-PdOsW. The UV-vis diffuse reflectance spectra
of the catalysts show broad bands with the absorption
maxima at 253 (WO42-), 280 (PdCl42-), and 293 nm
(OsO42-). No shift in the absorption maxima for these
multifunctional heterogeneous catalysts was observed
compared to the spectra of their pure precursors. These
results indicate the presence of related divalent anions
in trifunctional and bifunctional catalysts as assigned.
All these studies indicate the retention of the coordina-
tion geometries of the specific divalent anions anchored
to LDH matrix in their monomeric form. The BET surface
areas of LDH-OsW and LDH-PdOsW are found to be
60 and 68 m2 g-1, respectively.
X-r a y P h otoelectr on Sp ectr oscop y (XP S). The
X-ray Photoelectron spectroscopic (XPS) results of the
fresh and used bifunctional LDH-OsW and trifunctional
LDH-PdOsW catalysts show almost identical binding
energies for Os,22 W,23 and Pd24 (Table 1). It confirms that
the oxidation states of the respective metals remain static
2-
larly, OsO42--WO4 were co-exchanged onto the qua-
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Kantam, M. L.; Choudary, B. M.; Reddy, C. V.; Rao, K. K.; Figueras,
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1998, 14, 2890.
(23) ESCA of W: (a) Sohn, J . R.; Park, M. Y. Langmuir 1998, 14,
6140. (b) Dong, L.; Hu, Y.; Xu, F.; Lu, D.; Xu, B.; Hu, Z.; Chen, Y. J .
Phys. Chem. B 2000, 104, 78. (c) Peng, Y.; Meng, Z.; Zhong, C.; Lu, J .;
Yang, Z.; Qian, Y. Chem. Lett. 2001, 64.
(24) ESCA of Pd: (a) Kumar, G.; Blackburn, J . R.; Albridge, R. G.;
Moddeman, W. E.; J ones, M. M. Inorg. Chem. 1972, 11, 296. (b) Kili,
K.; Hilaire, L.; Normand, F. L. Phys. Chem. Chem. Phys. 1999, 1, 1623.
(c) Verduraz, F. B.; Omar, A.; Escard, J .; Pontvianne, B. J . Catal. 1978,
53, 126.
(21) Choy, J . H.; Kwak, S. Y.; Park, S. J .; J eong, Y. J .; Porier, J . J .
Am. Chem. Soc. 1999, 121, 1399.
1738 J . Org. Chem., Vol. 68, No. 5, 2003

Synthesis of Diltiazem and Taxol Side Chain
TABLE 2. Ach ir a l Dih yd r oxyla tion of tr a n s-Stilben e
TABLE 3. Ach ir a l Dih yd r oxyla tion of tr a n s-Stilben e
Usin g H2O2 a s th e Ter m in a l Oxid a n ta
Usin g Va r iou s Bifu n ction a l Ca ta lytic System sa
entry
NMM (equiv)
Na2WO4 (equiv)
yield (%)
entry
catalyst
yield (%)
1
2
3
15
52
95
1
2
3
4
K2OsO4‚2H2O-Na2WO4‚2H2O
LDH-OsW
50
95
87
79
0.27
0.27
0.01
resin-OsW
silica-OsW
a
The trans-stilbene (1 mmol), K2OsO4‚2H2O (1 mol %), H2O2
(1.5 mmol), and H2O-acetone (1:5) were stirred at room temper-
ature for 20 h.
a
The trans-stilbene (1 mmol), catalyst (0.01 mmol), and NMM
(0.5 mmol) were taken in a round-bottomed flask containing H2O-
acetone (1:5, 5 mL), and H2O2 (1.5 mmol) was slowly added over
12 h under stirring.
during ion-exchange process and at the end of the
reaction. These results also ruled out the formation of
bimetallic species.
SCHEME 1. Asym m etr ic Dih yd r oxyla tion of
tr a n s-Stilben e Usin g Bifu n ction a l Ca ta lysts
Mu ltifu n ction a l Ca ta lysis. Osmium-catalyzed AD of
olefins using NMO oxidant provides NMM as a byproduct
and requires additional unit operations for recycling of
NMM in the process. Similarly, an additional unit
operation necessitates for the production of substituted
prochiral olefins used in the usual AD reactions. Hence,
the need to develop a multifunctional catalyst for the
synthesis of prochiral substrates, oxidant, and finally
chiral diols in one pot is highly desirable.
and the heterogenized catalysts in general have distinctly
faster reactivity than K2OsO4‚2H2O-Na2WO4‚2H2O.
B. On e-P ot Syn th esis of Ch ir a l Diols. 1. Osm iu m -
Tu n gsten Ca ta lytic System . Buoyed with the results
obtained in the achiral dihydroxylation, we employed the
heterogeneous bifunctional catalyst LDH-OsW for si-
multaneous AD of trans-stilbene and N-oxidation of
NMM in the presence of H2O2 using the Sharpless chiral
ligands. To a mixture of 1 mol % of LDH-OsW or K2-
OsO4‚2H2O-Na2WO4‚2H2O, 1,4-bis(9-O-dihydroquinidi-
nyl)phthalazine ((DHQD)2PHAL), trans-stilbene and NMM
in tBuOH-H2O (5:1), H2O2 was slowly added over a
period of 12 h (for heterogeneous system) and 20 h (for
homogeneous system) to afford the desired diol in 93%
yield with 99% ee (Scheme 1).
Effect of Solven t. We have also examined the effect
of solvent on activity and enantioselectivity in the LDH-
OsW-catalyzed AD of trans-stilbene using H2O2 as the
terminal oxidant. The H2O-acetone proved to be a good
solvent for obtaining high yields. However, H2O-tBuOH
was found to be the best solvent to obtain high ee’s
similar to that obtained in the case of homogeneous
catalysis,5 and the order was found to be: H2O-CH3CN
< H2O-CH3CN-acetone < H2O-acetone < H2O-
tBuOH.
Va r ia tion of Ter tia r y Am in e. Although NMO is
employed extensively in dihydroxylations, trimethyl-
amine N-oxide is also used as an efficient oxidant in the
dihydroxylation of sterically hindered olefins and allylic
alcohols.25 As LDH-WO4 catalyzes the oxidation of
various tertiary amines to their corresponding N-oxides,16c
it is of interest to investigate the dihydroxylations using
various tertiary amines. Under optimized conditions, as
described above, dihydroxylation of trans-stilbene gave
the diol in good to excellent yields, although the activity
varies with the nature of amine (Table 4).
The bifunctional heterogeneous catalyst LDH-OsW
and its homogeneous counterpart K2OsO4‚2H2O-Na2-
WO4‚2H2O were further subjected to AD of various olefins
ranging from mono- to trisubstituted and activated to
simple to give vicinal chiral diols with excellent yields
and ee’s, and the results are summarized in Table 5. Slow
A. On e-P ot Syn th esis of Diols via Ach ir a l Dih y-
d r oxyla tion s. We first investigated the dihydroxylation
of trans-stilbene using H2O2 as the terminal oxidant. In
a general experimental procedure, to a mixture compris-
ing the olefin and 1 mol % of the K2OsO4‚2H2O in H2O-
acetone (1:5), H2O2 was charged slowly over a period of
12 h and stirred at room temperature for a further period
of 8 h. Direct reoxidation of Os(VI) by H2O2 led to a
nonselective reaction, wherein diol was obtained in 15%
yield (Table 2). In another experiment, wherein NMM
was introduced in the system, which was oxidized to
generate NMO by a slow addition of H2O2, gave diol in
52% yield. Recently, we reported the oxidation of tertiary
amines using tungstate catalyst.16c Indeed, the use of
catalytic amount of the Na2WO4 in the osmium catalyzed
dihydroxylation of olefins accelerated the generation of
NMO in situ from NMM, as is evident from an enhanced
yield (95%) of the corresponding diol under identical
conditions (Table 2). The rate of reaction is compar-
able to the osmium catalyzed dihydroxylation using
NMO cooxidant. More interestingly, both the catalysts
(K2OsO4‚2H2O and Na2WO4‚2H2O) could be recovered
from the reaction by an aqueous workup.
Recently, we developed the heterogeneous osmium
2-
catalyst by an ion-exchange of OsO4 on various ion
exchangers for AD of olefins.13b At the same time, we also
developed the heterogeneous tungsten catalyst via an ion-
2-
exchange of WO4 on LDH for oxidation of various
tertiary amines to the corresponding N-oxides in water
with high atom economy.16c These two discoveries
prompted us to design a new heterogeneous bifunctional
catalyst consisting of osmium and tungsten oxides on a
single matrix to perform AD and N-oxidation reactions
simultaneously in a single pot.
The heterogeneous bifunctional catalyst, consisting of
osmium and tungsten oxides and their homogeneous
counterparts were first screened for achiral dihydroxy-
lation of trans-stilbene. An activity profile of the dihy-
droxylation of trans-stilbene with various catalysts con-
ducted under similar conditions (12 h) described in Table
3 reveals that LDH-OsW displays the highest activity
(25) Donohoe, T. J .; Waring, M. J .; Newcombe, N. J . Synlett 2000,
1, 149.
J . Org. Chem, Vol. 68, No. 5, 2003 1739

Choudary et al.
TABLE 4. Asym m etr ic Dih yd r oxyla tion of
tr a n s-Stilben e Usin g Va r iou s Ter tia r y Am in es Med ia ted
by Heter ogen eou s Bifu n ction a l Ca ta lysta
SCHEME 2. Ca ta lytic Cycle in th e
LDH-P d OsW-Ca ta lyzed Syn th esis of Ch ir a l Diols
Usin g H2O2 a s th e Ter m in a l Oxid a n t
entry
amine
yield of diol (%)
ee (%)
1
2
3
NMM
NEt3
NMe3
95
91
70
99
97
88
a
The trans-stilbene (1 mmol), LDH-OsW (0.01 mmol), (DHQD)2-
PHAL (0.01 mmol), and amine (50 mol %) were taken in a round-
bottomed flask containing H2O-tBuOH (1:5, 5 mL), and H2O2 (1.5
mmol) was slowly added over 12 h under stirring.
TABLE 5. Asym m etr ic Dih yd r oxyla tion of Olefin s Usin g
K2OsO4‚2H2O/NMM/Na 2WO4‚2H2O/H2O2 a n d LDH-OsW/
NMM/H2O2 System s
attractive candidate as such. Further, being water-
soluble, the homogeneous composite catalyst could be
easily separated from the organic product upon usual
workup, but a higher molar ratio of ligand to osmium
(L/Os ) 3) is employed to obtain optimum ee’s. In
contrast, the use of equimolar ratio of ligand to osmium
is sufficient to give the diols with excellent ee’s in the
heterogeneous catalytic system. This is attributed to the
high binding ability of the heterogeneous osmium with
the chiral ligand. The use of heterogeneous bifunctional
catalyst makes the process more efficient in terms of
higher activity and easier catalyst recovery by simple
filtration over the homogeneous analogue.
This novel protocol described here realized chiral diols
using the heterogeneous catalyst, NMM in substoichio-
metric amounts and a cheaper oxidant, H2O2 instead of
NMO in stoichiometric amounts in currently practiced
dihydroxylations. This methodology offers the diols with
higher yields and ee’s than the Kobayashi MC OsO4/NMO
system.12 This process rivals the one employed by Ba¨ck-
vall et al. using flavine, a biomolecule-induced homoge-
neous catalytic oxidation of NMM to NMO in dihydrox-
ylation.11 The flavine-based process encounters the
problem of catalyst recovery and the use of OsO4, flavine,
and chiral ligand, as high as 2-6 mol %, whereas the
basic advantage of our heterogeneous process is the easy
recyclability of the bifunctional catalytic system, compris-
ing 1 mol % of each component: osmium, tungsten, and
chiral ligand. Even so, the homogeneous bifunctional
system composed of 1 mol % of each component, osmium,
tungsten, and 3 mol % chiral ligand, did give chiral diols
with excellent yields and ee’s. Further, these bifunctional
catalysts offer 99% ee, as opposed to the 91% ee observed
using flavine in the AD of trans-stilbene (Table 5, entry
6). It is very significant to note that our bifunctional
systems, both homogeneous and heterogeneous, offer
higher yields and excellent ee’s in AD of cinnamate esters
over the Sharpless methodology (Table 5, entries 7 and
8), which could be ascribed to the slow addition of both
olefins and oxidant.
a
K2OsO4‚2H2O (3.68 mg, 0.01 mmol), Na2WO4‚2H2O (3.29 mg,
0.01 mmol), NMM (0.5 mmol), TEAA (2 mmol), and (DHQD)2PHAL
(0.03 mmol, 23 mg) in H2O-tBuOH (1:3, 5 mL) were stirred at
room temperature for 20 min. To this mixture were added an olefin
(1 mmol) and H2O2 (1.5 mmol) over a period of 20 h using separate
b
syringe pumps. 1 mol % of LDH-OsW and (DHQD)2PHAL,
NMM (0.5 mmol) were used. Olefin and H2O2 were added slowly
over a period of 12 h. c ee determined by HPLC analysis. Two
d
equivalents of TEAA was used. e In this case, the olefin was
charged in one portion. f The yields and ee’s described in paren-
theses are obtained at the end of the fifth cycle.
addition of olefin to the reaction mixture is warranted,
except in the case of trans-stilbene to keep the availability
of the olefin at a bare minimum level to achieve higher
ee.26 Trisubstituted olefins were also dihydroxylated to
the corresponding diol with higher ee’s in the presence
of tetraethylammonium acetate (TEAA) additive (Table
5, entries 4 and 5). This phenomenon substantiates that
the hydrolysis of osmate ester, a pronounced slow process
in the case of trisubstituted olefins, is accelerated with
the addition of the additive to afford higher yield and ee.
All these catalysts were reused for five cycles with almost
consistent activity and enantioselectivity (Table 5, entry
8). Although similar ee’s and yields were obtained using
both the homogeneous and heterogeneous systems, the
former system took a longer reaction time (20 h). Nev-
ertheless, the use of a less toxic and nonvolatile osmium
source, K2OsO4‚2H2O, in combination with Na2WO4‚2H2O
makes the catalytic system the most promising and
2. P a lla d iu m -Osm iu m -Tu n gsten Ca ta lytic Sys-
tem . To generate the prochiral olefins in situ for AD
reaction, the trifunctional catalyst LDH-PdOsW was
examined in a tandem Heck-N-oxidation-AD, composed
of a multicomponent system in a single-pot, while the
continuous supply of NMO was ensured through the
oxidative cycle of NMM in situ by H2O2 as described in
Scheme 2.
A mixture of iodobenzene, styrene, and Et3N in the
presence of 1 mol % of LDH-PdOsW was stirred without
(26) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless,
K. B. Adv. Synth. Catal. 2002, 344, 421.
1740 J . Org. Chem., Vol. 68, No. 5, 2003

Synthesis of Diltiazem and Taxol Side Chain
TABLE 6. Syn th esis of Ch ir a l Diols Usin g Heter ogen eou s Mu ltifu n ction a l Ca ta lyst (LDH-P d OsW)a
a
LDH-PdOsW (0.01 mmol), aryl halide (1 mmol), olefin (1 mmol), and Et3N (1.1 mmol) were stirred at 70 °C for 8-16 h. After completion
of the Heck coupling, as monitored by TLC, the heating was stopped, and a mixture of (DHQD)2PHAL (0.01 mmol) and NMM (0.5 mmol)
t
in BuOH-H2O (5:1, 5 mL) was added in one portion to the reaction flask. H2O2 (1.5 mmol) was then slowly added over a period of 15 h.
ee determined by chiral HPLC analysis. c The absolute configuration was determined by comparison of specific rotations with literature
b
values. After fifth cycle. e Na2PdCl4-K2OsO4‚2H2O-Na2WO4‚2H2O. f (DHQ)2PHAL is used as a ligand.
d
SCHEME 3. Syn th esis of Ch ir a l Diols Usin g
Heter ogen eou s Mu ltifu n ction a l Ca ta lyst
conditions described above with an addition of additive
to give chiral diol with excellent ee (Table 6, entry 7).9c,27
Similarly, trisubstituted stilbene and corresponding chiral
diol were prepared by Heck coupling and AD in a single
pot (Table 6, entry 8) in excellent yield, but ee is
moderate. The ee’s of these products are determined as
their ketal derivatives.27a This forms one of the few
examples making trisubstituted olefins directly by Heck
coupling.28
solvent at 70 °C for 8 h. The use of acetonitrile solvent is
recommended for the solid substrates. At this stage, the
heating was stopped, and to this was added a mixture of
(DHQD)2PHAL (1 mol %) and NMM in tBuOH-H2O
(5:1). Subsequently, H2O2 was slowly added over a period
of 12 h to afford the desired diol in 85% yield with 99%
ee (Scheme 3).
As shown in Table 6, various chiral diols were obtained
in good yields with higher ee’s using the trifunctional
heterogeneous catalyst. The methodology described here
uses bulk chemicals such as styrene and acrylates as
starting materials to prepare prochiral substrates, stil-
benes, and cinnamates in situ and those upon dihydroxy-
lation gives chiral diols in a single-pot. The reaction
mediated by Na2PdCl4-K2OsO4-Na2WO4 system in ho-
mogeneous medium is slow and time-consuming (Table
6, entry 3) similar to the one observed in the bifunctional
catalysis.
The LDH-PdOsW was recovered quantitatively by
simple filtration, while the chiral ligand was recovered
by simple acid/base extraction (>95% recovery). The
recovered catalyst was reused with the addition of the
replenished chiral ligand (to makeup 1 mol %) at the
appropriate stage and consistent activity was noticed
even after the fifth cycle (Table 6, entry 2). In AD of
methyl cinnamate, we obtained 99% ee with our hetero-
geneous multifunctional catalyst (entry 4, slow addition
of H2O2) as against 87-88% ee’s reported by Sharpless
and others. It is significant to note a higher ee for the
AD of methyl cinnamate was obtained, despite avail-
ability of all the olefin from the beginning of the reaction.
It is well documented in the literature that the bases
or less often acids are used in the dihydroxylation
reactions for hydrolysis of osmate esters.27 Introduction
of additives and/or slow addition of olefin or oxidant to
the reaction mixture indeed accelerates the hydrolysis
Next, we applied the present method for the synthesis
of chiral diols via trisubstituted olefins and subsequent
AD in a single pot. Using methyl methacrylate for Heck
coupling with iodobenzene, a complete conversion was
observed within 5 h, generating trisubstituted olefin,
which was in turn subjected to AD under identical
(27) AD of trisubstituted olefins: (a) Rosini, C.; Scamuzzi, S.; Focati,
M. P.; Salvadori, P. J . Org. Chem. 1995, 60, 8289. (b) Mehltretter, G.
M.; Dobler, C.; Sundermeier, U.; Beller, M. Tetrahedron Lett. 2000,
41, 8083. (c) Battaglia, A.; Barbaro, G.; Giorgianni, P.; Guerrinni, A.;
Bertucci, C.; Geremia, S. Chem. Eur. J . 2000, 6, 3551.
(28) Littke, A. F.; Fu, G. C. J . Am. Chem. Soc. 2001, 123, 6989.
J . Org. Chem, Vol. 68, No. 5, 2003 1741

Choudary et al.
TABLE 7. F a ctor s Affectin g ee in th e AD Rea ction of
Meth yl Cin n a m a te
SCHEME 4
entry
catalyst
additive
slow addition (h) ee (%)
1
2
3
4
5
6
K2OsO4‚2H2O
LDH-Os
88
94
95
95
98
99
LDH-Os
Et3N‚HI
Et3N‚HI
Et3N‚HI
Et3N‚HI
LDH-PdOs
LDH-PdOsW
LDH-PdOsW
12
15
of the formed osmium monoglycolate to obtain higher ee
in AD reactions.26 We conducted separate experiments
to study the effect of the support, Et3N.HI (a byproduct
in the Heck reaction) and slow addition of oxidant on the
ee in the AD of methyl cinnamate. As can be seen in the
Table 7, the ee is enhanced from 88 to 94%, when an
experiment was conducted with LDH-OsO4 in place of
K2OsO4‚2H2O using NMO as the oxidant in H2O-tBuOH
(entries 1 and 2). It is ascribed to the basicity of the
surface OH groups of LDH support, which accelerates
the hydrolysis of the osmium monoglycolate ester. Next,
we obtained 95% ee, when an experiment was conducted
with LDH-OsO4-Et3N‚HI or LDH-PdOs-Et3N‚HI and
methyl cinnamate using NMO as the oxidant in H2O-t-
BuOH (entries 3 and 4). The Et3N‚HI salt could acceler-
ate the hydrolysis of the osmium monoglycolate complex
to subdue the second cycle as was done by tetraethyl-
ammonium acetate (TEAA) additive, which is known for
faster rates and higher ee. When, H2O2 was slowly added
over a period of 12-15 h to a reaction mixture composed
of LDH-OsW, methyl cinnamate, Et3N‚HI, and NMM
in H2O-tBuOH, a chiral diol was obtained with 98-99%
ee.
Thus, these results unambiguously demonstrate that
the present system composed of new variants such as
LDH support, Et3N‚HX and slow addition of H2O2
facilitates the hydrolysis of osmium monogylcolate ester
to subdue the formation of bisglycolate ester5d to achieve
higher ee’s as described in Tables 6 and 7.
Syn th etic Ap p lica tion s of Tr ifu n ction a l Ca ta lyst.
The chiral diols of cinnamates thus obtained with higher
ee’s (99%) and free from osmium (even in the crude
product) as indicated by AAS and SEM-EDX in the AD
reactions mediated by the trifunctional heterogeneous
catalyst are directly used to make diltiazem and taxol
side chain without recrystallization.
iazem, is mainly manufactured by the enzymatic kinetic
resolution of the trans-methyl glycidate.30g However,
there is an inherent drawback in the kinetic resolution,
since the maximum yield of one enantiomer could not
exceed 50%.
The crude chiral diol [ethyl (2R,3S)-2,3-dihydroxy-3-
(4-methoxyphenyl)propionate] with 99% ee was obtained
by a similar protocol using (DHQ)2PHAL ligand. The
crude product, which does not show even traces of
osmium by SEM-EDX and AAS was purified by column
chromatography to remove other organic impurities. The
chiral diol was converted to the corresponding sulfite and
subsequently upon reaction with 2-aminothiophenol in
the presence of Fe3+-exchanged clay in xylene at 138 °C
yields a cyclic lactam. N-alkylation, followed by acylation
of lactam gave diltiazem [(+)-(2S,3S)-isomer] in 37%
overall yield (Scheme 4). It is significant to note that
Fe3+-exchanged clay was used for this purpose as a new
variant to the conventional acid catalysts to obtain
quantitative yields.
Ta xol Sid e Ch a in . The Taxol side chain was also
synthesized using the LDH-PdOsW-catalyzed multi-
component coupling reaction as the key step as described
in the Scheme 5. Taxol,31 isolated from the bark of yew
species, is considered to be the most promising cancer
chemotherapeutic agent and has been approved for the
treatment of metastatic carcinoma of the ovary. Attach-
ment of the C-13 side chain to the baccatin III32 nucleus
is the key synthetic strategy for Taxol. Since the presence
of this side chain has proved to be essential for the
biological activity of Taxol, the development of short and
practical synthetic routes for phenylisoserine derivatives,
which are adaptable for industrial-scale production, has
become very important.33
Diltia zem . Diltiazem, a typical calcium antagonist
that has been used throughout the world as a remedy
for angina and hypertension,29,30 was synthesized as
described in Scheme 4. Among the four possible stereo-
isomers of diltiazem, only the (+)-(2S,3S)-isomer exhibits
potent coronary vasodilating activity. Synthesis of a (-)-
trans-methyl glycidate, a key intermediate for the dilt-
(29) Nagao, T.; Sato, M.; Nakajima, H.; Kiyomoto, A. Chem. Pharm.
Bull. 1973, 21, 92.
(30) (a) Watson, K. G.; Fung, Y. M.; Gredley, M.; Bird, G. J .; J ackson,
W. R.; Gountzos, H.; Matthews, B. R. Chem. Commun. 1990, 1018. (b)
Yamamoto, M.; Hayashi, M.; Masaki, M.; Nohira, H. Tetrahedron:
Asymmetry 1991, 2, 403. (c) Schwartz, A.; Madan, P. B.; Mohacsi, E.;
O’Brien, J . P.; Todaro, L. J .; Coffen, D. L. J . Org. Chem. 1992, 57, 4320.
(d) Chang, S.; Galvin, J . M.; J acobsen, E. N. J . Am. Chem. Soc. 1994,
116, 6937. (e) Lohray, B. B.; J ayachandran, B.; Bhushan, V.; Nan-
danan, E.; Ravidranathan, T. J . Org. Chem. 1995, 60, 5983. (f)
Imashiro, R.; Kuroda, T. Tetrahedron Lett. 2001, 42, 1313. (g) Gentile,
A.; Giordano, C.; Fuganti, C.; Ghirotto, L.; Servi, S. J . Org. Chem. 1992,
57, 6635.
Sharpless et al. developed a process for the Taxol side
chain through AD of methyl cinnamate that led to 23%
overall yield, but the diol needs to be recrystallized to
(31) Taxol side chain: (a) Wani, M. C.; Taylor, H. L.; Wall, M. E.;
Coggon, P.; McPhail, A. T. J . Am. Chem. Soc. 1971, 93, 2325. (b)
Nicolaou K. C. et al. Nature 1994, 367, 630.
(32) Della Casa de Marcano, D. P.; Halsall, T. G. Chem. Commun.
1975, 365.
1742 J . Org. Chem., Vol. 68, No. 5, 2003

Synthesis of Diltiazem and Taxol Side Chain
SCHEME 5
of the exchanged catalysts over the homogeneous osmium
catalysts. This result is in consonance with LDH-WO4
catalyzed oxidative bromination16d and ionic polymer
supported osmium tetraoxide in achiral dihydroxyla-
tion.35
C. Heter ogen eity. Several experiments were con-
ducted to understand the stability and heterogeneity of
the trifunctional catalysts. It was found that the Heck
olefination occurs predominantly on the surface, al-
though, there is a leaching of palladium in minor quanti-
ties from the heterogeneous catalyst.36 However, the
osmium and W oxides on the LDH matrix remain bound
throughout the reaction. These results are in good
agreement with the earlier results.13b,14
The plausible mechanistic path for the Heck coupling,
AD, and N-oxidation mediated by trifunctional catalyst
composed of Pd, Os, and W is depicted in Scheme 2. The
Heck coupling and AD reaction likely follows an identical
path.5d,13a,36 The peroxo species generated from tungstate
and H2O2 rapidly recycle the NMM to NMO, which in
enrich the ee.8c As the trifunctional heterogeneous cata-
lyst in the present case afforded the diol with 99% ee and
without traces of osmium (Table 6, entry 5), it was
directly used after column chromatography in the syn-
thesis of Taxol side chain starting from bromobenzene
and methyl acrylate as shown in Scheme 5. The treat-
ment of methyl 2,3-dihydroxy-3-phenylpropionate with
HBr-AcOH yields bromo acetate, which in turn reacts
with NaN3 in DMF followed by deacetylation with NaOAc
in MeOH to afford azido alcohol.34 Benzoylation followed
by hydrogenation of azido alcohol gave the (2R,3S)-N-
benzoyl-3-phenylisoserine methyl ester in 67% overall
yield.
Both the homogeneous and heterogeneous bifunctional
and trifunctional catalysts comprising of Pd/Os and W,
performed Heck coupling, N-oxidation, and AD reactions
exhibiting their own characteristic features in the diver-
sified multifunctional activities without loosing their
identity. These results substantiate the retention of
coordination geometries of metal complexes in their
monomeric form as supported by IR, UV-DRS, and XPS
data of the heterogeneous catalysts and rule out the
formation of bi- or tri-heterometallic species during the
exchange process and dihydroxylation reaction. Further,
the higher ee’s obtained using a chiral ligand, (DHQD)2-
PHAL of the large dimension substantiate the location
of OsO42- on the surface of LDH only, as the diffusion of
the chiral ligand to interact with the OsO42- located in a
very small interlamellar space, 3 Å of LDH, is very
remote. The XRD data indeed confirms the location of
OsO42- on the edge position of layered double hydroxides.
The large positive electric potential of the exchanged
catalyst surface induces an enrichment of cooxidant close
to the surface. Similarly, the olefin and aryl halide also
build up their concentrations close to the surface as they
have a high adsorption coefficient on the support surface.
Apart from this, spatial organization and electrical
shielding16b are responsible for the superior performance
turn reoxidizes OsVI to OsVIII
.
Con clu sion
A single-pot biomimic synthesis of chiral diols mediated
by the recyclable bifunctional catalysts composed of
2-
OsO42--WO4 and trifunctional catalysts comprising
2-
2-
PdCl42--OsO4 -WO4 species both in the homoge-
neous phase and embedded on a matrix of the layered
double hydroxides to unfold a low cost process is de-
scribed. This protocol provides the desired prochiral
olefins and NMO in situ from cheaper precursors for the
synthesis of chiral vicinal diols to minimize the unit
operations as exemplified with the synthesis of diltiazem
and Taxol side chain. Dispensing the usual protocol of
isolation and purification of the intermediates, the mul-
tifunctional catalyst triggers the reaction to obtain the
chiral diols in one pot. The oxidant, H2O2, employed here
in place of NMO is environmentally acceptable as the
only byproduct is water. More interestingly, even the
water produced from H2O2 during the N-oxidation is
consumed in the dihydroxylation reaction to mark the
highest atom economy in the production of chiral diols.
The possible large-scale synthesis of diols employing this
catalytic system using H2O2 as an oxidant directed to
minimize the solid waste effluent is addressed. The
simple procedure, easy recovery, and reusable catalytic
systems are expected to contribute to the development
of benign chemical processes and products.
Exp er im en ta l Section
Gen er a l Meth od s. IR spectra for samples as KBr pellets
were recorded on an FTIR spectrometer. Diffuse reflectance
UV spectra for samples as KBr pellets were recorded on a UV-
1
Vis spectrometer. H and 13C NMR spectra were recorded on
a 200 MHz spectrometer. Chemical shifts (δ) are reported in
1
(33) (a) Denis, J . N.; Greene, A. E.; Serra, A. A.; Luche, M. J . J .
Org. Chem. 1986, 51, 46. (b) Denis, J . N.; Correa, A.; Greene, A. E. J .
Org. Chem. 1990, 55, 1957. (c) Ojima, I.; Habus, I.; Zhao, M.; Georg,
G. I.; J ayasinghe L. R. J . Org. Chem. 1991, 56, 1681. (d) Denis, J . N.;
Correa, A.; Greene, A. E. J . Org. Chem. 1990, 55, 6939. (e) Honig, H.;
Seufer-Wasserthal, P.; Weber, H. Tetrahedron 1990, 46, 3841. (f) Deng,
L.; J acobsen, E. N. J . Org. Chem. 1992, 57, 4320.
ppm, using TMS and CDCl3 as internal standards for H NMR
and 13C NMR, respectively. X-ray powder diffraction (XRD)
data were collected on a diffractometer using Cu KR radiation
(35) Cainelli, G.; Contento, M.; Manescalchi, F.; Plessi, L. Synthesis
1989, 45.
(34) (a) Fleming, P. R.; Sharpless, K. B. J . Org. Chem. 1994, 59,
8302. (b) Lee, D.; Kim, M.-J . Tetrahedron Lett. 1998, 39, 2163.
(36) Choudary, B. M.; Sateesh, M.; Chowdari, N. S.; Kantam, M.
L.; Sreedhar, B. J . Am. Chem. Soc. 2002, 124, 14127.
J . Org. Chem, Vol. 68, No. 5, 2003 1743

Choudary et al.
(λ ) 1.5405 Å). X-ray photoemission spectra were recorded
with a dual anode (Mg and Al) apparatus using the Mg KR
anode. The pressure in the spectrometer was about 10-9 Torr.
For energy calibration we have used the carbon 1s photoelec-
tron line. The carbon 1s binding energy was taken to be 285.0
eV. Spectra were deconvoluted using Sun Solaris based Vision
2 curve resolver. The location and the full width at half-
maximum (fwhm) for a species was first determined using the
spectrum of a pure sample. The location and fwhm of products,
which were not obtained as pure species, were adjusted until
the best fit was obtained. Symmetric Gaussian shapes were
used in all cases. Binding energies for identical samples were,
in general, reproducible to within (0.1 eV. Specific surface
areas are calculated from BET nitrogen isotherms determined
at -196 °C on samples degassed at 250 °C for 12 h before the
experiment. SEM-EDX (scanning electron microscopy-energy-
dispersive X-ray analysis) was performed. High performance
liquid chromatography (HPLC) was performed using the
following apparatus: SHIMADZU LC-10AT (liquid Chromato-
graph), SHIMADZU SPD-10A (UV detector), and SHIMADZU
C-R6A Chromatopac. ACME silica gel (100-200 mesh) was
used for column chromatography and thin-layer chromatog-
raphy was performed on Merck precoated silica gel 60-F254
plates. Optical rotations were obtained on a J ASCO P-1020
WO4‚2H2O (3.29 mg, 0.01 mmol), (DHQD)2PHAL (0.03 mmol,
23 mg), and NMM (0.5 mmol) were taken in a round-bottomed
flask containing tBuOH-water (5:1, 5 mL) and stirred at room
temperature for 20 min. To this mixture were added an olefin
(1 mmol) and H2O2 (1.5 mmol) over a period of 12 h for LDH-
OsW and 20 h for K2OsO4‚2H2O-Na2WO4‚2H2O using sepa-
rate syringe pumps. After the addition was complete, the
reaction mixture was stirred for another 2 h. Toluene was
added to the reaction mixture to get the phase separation, and
the aqueous phase was extracted with toluene (2 × 5 mL). The
organic phase was washed with 1 N HCl to recover the chiral
ligand. The organic solvent was removed, and the crude
material was chromatographed on silica gel to afford the
corresponding cis-diol.
Gen er a l P r oced u r e for th e Syn th esis of Ch ir a l Diols
Usin g LDH-P d OsW. LDH-PdOsW (40 mg, 0.01 mmol), aryl
halide (1 mmol), olefin (1 mmol), and Et3N (111 mg, 1.1 mmol)
were introduced into a round-bottomed flask and stirred at
70 °C for 8-16 h under nitrogen atmosphere. After completion
of the Heck coupling, as monitored by TLC, the heating was
stopped and the reaction was allowed to reach room temper-
ature. A mixture of (DHQD)2PHAL (7.8 mg, 0.01 mmol) and
t
NMM (50 mg, 0.5 mmol) in BuOH-H2O (5:1, 5 mL) was added
in one portion to the reaction flask under stirring. H2O2 (169
µL, 30% aqueous, 1.5 mmol) was then slowly added over 15 h
using a syringe pump. After the addition was complete, the
stirring was continued for an additional 1 h and the catalyst
was filtered and washed with ethyl acetate (10 mL). The
combined filtrates were extracted with 1 N HCl (2 × 5 mL) to
recover the chiral ligand from the aqueous layer. The resulting
organic phase was further washed with brine solution (5 mL)
and the solvent was removed. The crude material thus
obtained was chromatographed on silica gel using hexane/ethyl
acetate (2:1) as an eluant to afford the corresponding cis-diol.
P r ep a r a tion of cis-(+)-3-(Acetyloxy)-2,3-d ih yd o-5-[2-
(dim eth ylam in o)eth yl]-2-(4-m eth oxyph en yl)-1,5-ben zoth i-
a zep in -4(5H)-on e Hyd r och lor id e (Diltia zem Hyd r och lo-
r id e). LDH-PdOsW (0.4 g, 0.1 mmol), 4-iodoanisole (10
mmol), ethyl acrylate (10 mmol), and Et3N (11 mmol) were
stirred at 70 °C for 16 h under nitrogen atmosphere. After
completion of the Heck coupling, the heating was stopped and
the reaction was allowed to reach room temperature. A
mixture of (DHQ)2PHAL (78 mg, 0.1 mmol) and NMM (0.5 g,
polarimeter and reported as follows: [R]temperature
(con-
wavelength
centration (c ) g/100 mL), and solvent). Slow addition of olefins
was carried out using a syringe pump.
K2OsO4‚2H2O, MgCl2‚6H2O, AlCl3‚6H2O, TEAA, (DHQD)2-
PHAL, (DHQ)2PHAL, and NMO were purchased from
a
commercial supplier. Allyl 1-naphthyl ether and ethyl (4-
methoxyphenyl) cinnamate were prepared while the other
olefins were purchased from a commercial supplier. All the
other solvents and chemicals were obtained from commercial
sources and used with further purification.
P r ep a r a tion of Ca ta lysts. The preparation of LDH (Mg-
Al-Cl) was based on literature procedure.19b
LDH-OsW. LDH (1 g) was suspended in 100 mL of aqueous
solution containing K2OsO4‚2H2O and Na2WO4‚2H2O (0.4
mmol each) and stirred at 25 °C for 12 h under nitrogen
atmosphere. The solid catalyst was filtered, washed thoroughly
with 500 mL of water, and vacuum-dried to obtain 1.172 g of
LDH-OsW (0.34 mmol g-1 each of Os and W).
Resin -OsW. Resin was obtained by quaternization of
triethylamine (2.1 mL, 21 mmol) with 1 g of chloromethylated
styrene-divinylbenzene copolymer (Merrifield resin, capacity
∼2.1 mequiv/g) in chloroform (20 mL) under reflux for 24 h.
Quaternary ammonium resin (1 g) was suspended in 100 mL
of aqueous solution containing K2OsO4‚2H2O and Na2WO4‚
2H2O (0.4 mmol each) and stirred at 25 °C for 12 h under
nitrogen atmosphere. The solid catalyst was filtered, washed
thoroughly with 500 mL of water, and vacuum-dried to obtain
resin-OsW.
Silica -OsW. Modified silica was obtained by quaterniza-
tion of triethylamine (0.7 mL, 7 mmol) with bromopropylsilica
(capacity 0.7 mequiv/g) in chloroform (20 mL) under reflux for
24 h. Quaternary ammonium silica (1 g) was suspended in 100
mL of aqueous solution containing K2OsO4‚2H2O and Na2WO4‚
2H2O (0.4 mmol each) and stirred at 25 °C for 12 h under
nitrogen atmosphere. The solid catalyst was filtered, washed
thoroughly with 500 mL of water, and vacuum-dried to obtain
Silica-OsW.
LDH-P d OsW. LDH (1 g) was suspended in 100 mL of
aqueous solution containing Na2PdCl4, K2OsO4‚2H2O, and Na2-
WO4‚2H2O (0.3 mmol each) and stirred at 25 °C for 12 h under
nitrogen atmosphere. The solid catalyst was filtered, washed
thoroughly with 500 mL of water, and vacuum-dried to obtain
1.181 g of LDH-PdOsW (0.25 mmol g-1 each of Pd, Os, and
W).
t
5 mmol) in BuOH-H2O (5:1, 50 mL) was added in one portion
to the reaction flask under stirring. H2O2 (30% aqueous, 15
mmol) was then slowly added over 15 h using a syringe pump.
After the addition was complete, the stirring was continued
for an additional 1 h and the catalyst was filtered and washed
with ethyl acetate (100 mL). After removal of the solvent, the
thus obtained crude material was chromatographed on silica
gel using hexane/ethyl acetate (1:1) as an eluant to afford ethyl
(2R,3S)-2,3-dihydroxy-3-(4-methoxyphenyl)propionate (92%
yield): [R]25D 5.98 (c 1.0, CHCl3) [lit.37 [R]25D 6.0 (c 0.84, CHCl3)];
1H NMR δ 1.29 (t, J ) 7.3 Hz, 3H), 2.75 (brs, 2H), 3.80 (s,
3H), 4.23 (q, J ) 7.3 Hz, 2H), 4.34 (dd, J ) 3.3, 6.6 Hz, 1H),
4.89 (dd, J ) 3.3, 6.6 Hz, 1H), 6.90 (d, J ) 8.6 Hz, 2H), 7.36
i
(d, J ) 8.6 Hz, 2H); HPLC (Daicel Chiralcel OJ , 10% PrOH
in hexane, flow rate 1.0 mL/min) tR ) 23.2 (major), tR ) 26.0
(minor).
The diol (1.2 mmol) was dissolved in dry pyridine (2 mL)
under argon. The reaction mixture was cooled to 0 °C, and
freshly distilled thionyl chloride (1.3 mmol) was added drop-
wise. The reaction mixture was stirred at 0 °C for 2 h and
poured onto crushed ice containing dilute HCl. The reaction
mixture was extracted with ether, washed with dilute HCl,
aqueous NaHCO3, and brine, dried (Na2SO4), and evaporated
under reduced pressure to give a pale yellow oil that was
chromatographed over silica gel to furnish 4(S)-(p-methox-
yphenyl)-5(R)-(carboxyethyl)-1,3-dioxathiolane 2-oxide (98%
yield).
Asym m etr ic Dih yd r oxyla tion of Olefin s Usin g LDH -
OsW w ith Slow Ad d ition of Olefin a n d H2O2. Heteroge-
neous bifunctional LDH-OsW (0.01 mmol) or a homogeneous
composite mixture of K2OsO4‚2H2O (3.68 mg, 0.01 mmol), Na2-
(37) Matsuura, F.; Hamada, Y.; Shioiri, T. Tetrahedron 1994, 50,
9457.
1744 J . Org. Chem., Vol. 68, No. 5, 2003

Synthesis of Diltiazem and Taxol Side Chain
A flame-dried two-necked 25 mL round-bottomed flask was
charged with cyclic sulfite (1 mmol), Fe3+-clay (100 mg), and
dry xylene (5 mL) and stirred under nitrogen. Freshly distilled
2-aminothiophenol (0.9 mmol) was added dropwise, and the
reaction mixture was refluxed for 12 h. The crude compound
was chromatographed to get the cis-(+)-2,3-dihydro-3-hydroxy-
2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (50% yield).
The hydroxy lactam (0.54 mmol) was dissolved in ethyl acetate
(5 mL), and 2-(dimethylamino)ethyl chloride hydrochloride
(0.694 mmol) was added followed by the addition of finely
ground K2CO3 (2.16 mmol) and a drop of water. The hetero-
geneous mixture was stirred at reflux for 12 h. The solvent
was removed, and the crude product was chromatographed to
obtain N-alkylated product (88%). The N-alkylated lactam
(0.317 mmol), Ac2O (1 mmol), Et3N (2 mmol), and DMAP (0.03
mmol) taken in CH2Cl2 (5 mL) were heated at reflux under
N2 for 3 h. The mixture was poured into ice-water, and brine
was added. The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (10 mL). The combined
organic layers were washed with 5% NH4OH (5 mL) solution,
dried (Na2SO4), and evaporated. The residue was dissolved in
MeOH (2 mL) and treated with anhydrous HCl until the pH
was 2. Ether (3 mL) was added to the resulting solution. The
precipitated solids were collected by filtration and washed with
10% MeOH-ether to afford diltiazem hydrochloride (92%
yield): [R]25 102.0 (c 1.0, MeOH) [lit.30c [R]25 102.0 (c 1.0,
tion of the solvent, the crude product was purified by column
chromatography to give (2R,3S)-N-benzoyl-3-phenylisoserine
methyl ester (92% yield): [R]25 -48.7 (c 1.0 MeOH) [lit.33a
D
[R]25 -48.0 (c 1.0, MeOH)]; H NMR δ 2.98 (d, 1H), 3.75 (s,
1
D
3H), 4.67 (m, 1H) 5.58 (dd, 1H), 7.06 (d, 1H), 7.20-7.56 (m,
8H), 7.80 (d, 2H); 13C NMR δ 52.3, 55.6, 73.2, 127.3, 128.2,
129.0, 132.1, 134.6, 137.0, 167.1, 172.5; MS m/z 300 (M+ + 1),
281 (M+ - H2O).
Ch a r a ct er iza t ion of Diols. 1-P h en yl-1,2-et h a n ed iol
(Ta ble 5, en tr y 1):13b 1H NMR δ 2.04 (brs, 1H), 2.46 (brs,-
1H), 3.63 (dd, 1H, J ) 8.2, 11.4 Hz), 3.72 (dd, 1H, J ) 3.6,
11.4 Hz), 4.79 (dd, 1H, J ) 3.6, 8.2 Hz), 7.28-7.34 (m, 5H);
13C NMR δ 68.0, 74.7, 126.0, 128.0, 128.5, 140.4; HPLC (Daicel
i
Chiralcel OD-H, 5% PrOH in hexane, flow rate 0.5 mL/min)
tR ) 34.7 (major), tR )38.9 (minor).
2-P h en yl-1,2-p r op a n ed iol (Ta ble 5, en tr y 2):13b 1H NMR
δ 1.50 (s, 3H), 3.15 (brs, 2H), 3.60 (d, 1H, J ) 11.2 Hz), 3.75
(d, 1H, J ) 11.2 Hz), 7.24-7.44 (m, 5H); 13C NMR δ 26.0, 70.9,
74.8, 125.0, 127.1, 128.4, 145.0; HPLC (Daicel Chiralcel OJ ,
10% iPrOH in hexane, flow rate 1.0 mL/min) tR ) 9.2 (minor),
tR )12.5 (major).
1-P h en yl-1,2-p r op a n ed iol (Ta ble 5, en tr y 3):13b 1H NMR
δ 0.97 (d, 3H, J ) 6.3 Hz), 2.65 (brs, 2H), 3.79 (dq, 1H, J )
6.3, 7.6 Hz), 4.28 (dd, 1H, J ) 7.6 Hz), 7.25-7,3.4 (m, 5H); 13
C
NMR δ 18.6, 72.1, 79.4, 126.8, 127.9, 128.3, 141.0; HPLC
i
D
D
(Daicel Chiralcel OD, 5% PrOH in hexane, flow rate 1.0 mL/
1
MeOH)]; H NMR δ 1.90 (s, 3H, COCH3), 2.85-2.94 (dd, J )
4.9 Hz, 6H, NCH3), 3.20-3.58 (m, 2H, NCH2), 3.83 (s, 2H,
OCH3), 4.37-4.62 (m, 2H, NCH2), 5.02 (d, J ) 7.8 Hz, 1H,
CHOCOCH3), 5.13 (d, J ) 7.8 Hz, 1 H, SCHAr), 6.90-7.73
(m, 8H, ArH); MS m/z 415 (M+ + 1).
min) tR ) 15.0 (major), tR )16.28 (minor).
2-Met h yl-1-p h en yl-1,2-p r op a n ed iol (Ta b le 5, en t r y
4):13b 1H NMR δ 1.03 (s, 3H), 1.15 (s, 3H), 2.78 (brs, 2H), 4.43
(d, 1H), 7.23-7.35 (m, 5H); 13C NMR δ 23.4, 26.4, 73.4, 80.7,
127.4, 127.6, 127.8, 140.6; HPLC (Daicel Chiralcel OD, 2.5%
iPrOH in hexane, flow rate 1.0 mL/min) tR ) 22.8 (major), tR
) 27.1 (minor).
P r ep a r a tion of (2R,3S)-N-Ben zoyl-3-p h en ylisoser in e
Meth yl Ester (Ta xol Sid e Ch a in ). LDH-PdOsW (0.4 g, 0.1
mmol), bromobenzene (10 mmol), methyl acrylate (10 mmol),
and Et3N (11 mmol) were stirred at 70 °C for 16 h under
nitrogen atmosphere. After completion of the Heck coupling,
the heating was stopped and the reaction was allowed to reach
room temperature. A mixture of (DHQ)2PHAL (78 mg, 0.1
1-P h en yl-1,2-cycloh exa n ed iol (Ta ble 5, en tr y 5):13b 1H
NMR δ 1.35-1.89 (m, 9H), 2.51 (s, 1H), 3.96 (dd, 1H, J ) 4.7,
11.1 Hz), 7.21-7.53 (m, 5H); 13C NMR δ 21.1, 24.3, 30.9, 38.5,
74.5, 75.7, 125.1, 127.0, 128.5, 146.3; HPLC (Daicel Chiralcel
i
OJ , 5% PrOH in hexane, flow rate 1.0 mL/min) tR ) 17.6
t
mmol) and NMM (0.5 g, 5 mmol) in BuOH-H2O (5:1, 50 mL)
(minor), tR ) 21.9 (major).
1,2-Dip h en yl-1,2-eth a n ed iol (Ta ble 6, en tr y 1):13b 1H
NMR δ 2.73 (brs, 2H), 4.69 (s, 2H), 7.09-7.22 (m, 10H); 13C
NMR δ 79.1, 126.9, 127.9, 128.1, 139.8; HPLC (Daicel Chiralcel
was added in one portion to the reaction flask under stirring.
H2O2 (30% aqueous, 15 mmol) was then slowly added over 15
h using a syringe pump. After the addition was complete,
stirring was continued for an additional 1 h and the catalyst
was filtered and washed with ethyl acetate (100 mL). After
removal of the solvent, the thus obtained crude material was
chromatographed on silica gel using hexane/ethyl acetate
(1:1) as an eluant to afford methyl (2R,3S)-2,3-dihydroxy-3-
i
OJ , 10% PrOH in hexane, flow rate 1.0 mL/min) tR) 12.1
(minor), tR ) 13.3 (major).
Meth yl 2,3-d ih yd r oxy-3-p h eylp r op ion a te (Ta ble 6, en -
tr y 5): 1H NMR δ 3.32 (br, 2H), 3.81 (s, 3H), 4.36 (d, J ) 2.8
Hz, 1H) 5.01 (d, J ) 2.8 Hz, 1H), 7.36 (m, 5H); 13C NMR δ
52.8, 74.4, 74.7, 126.2, 128.1, 128.4, 139.9, 173.1; HPLC (Daicel
Chiralcel OJ , 10% iPrOH in hexane, flow rate 1.0 mL/min) tR
) 19.1 (minor), tR ) 26.7 (major).
phenylpropionate (90% yield): [R]25D 10.71 (c 1.0 CHCl3) [Lit.33b
1
[R]25 10.70 (c 1.0, CHCl3)]; H NMR δ 3.32 (br, 2H), 3.81 (s,
D
3H), 4.36 (d, J ) 2.8 Hz, 1H), 5.01 (d, J ) 2.8 Hz,1H), 7.36 (m,
5H); 13C NMR δ 52.8, 74.4, 74.7, 126.2, 128.1, 128.4, 139.9,
173.1; HPLC (Daicel Chiralcel OJ , 10% iPrOH in hexane, flow
rate 1.0 mL/min) tR ) 19.1 (major), tR ) 26.7 (minor).
Eth yl 2,3-d ih yd r oxy-3-(4-m eth oxyp h en yl)p r op ion a te
1
(Ta ble 6, en tr y 6): H NMR δ 1.29 (t, J ) 7.3 Hz, 3H), 2.75
(brs, 2H), 3.80 (s, 3H), 4.23 (q, J ) 7.3 Hz, 2H), 4.34 (dd, J )
3.3, 6.6 Hz, 1H), 4.89 (dd, J ) 3.3, 6.6 Hz, 1H), 6.90 (d, J )
8.6 Hz, 2H), 7.36 (d, J ) 8.6 Hz, 2H); HPLC (Daicel Chiralcel
The diol (2 mmol) was placed in a 25 mL single-necked
round-bottomed flask followed by adddition of 2.9 mL of 30
wt % HBr-AcOH (13.2 mmol). The reaction mixture was
heated at 45 °C for 30 min. Upon quenching with NaHCO3
solution and extraction with ether, the methyl (2R,3S)-2-
acetoxy-3-bromo-3-phenylpropionate was obtained with 96%
yield.
The acetoxy bromoester (1 mmol) and NaN3 (1.5 mmol) in
DMF (5 mL) were stirred at 50 °C for 12 h. After completion
of the reaction, the solvent was removed, suspended in
methanol, and filtered through a pad of silica gel. The filtrate
was stirred with AcONa (10 mol %) for 12 h to afford methyl
(2R,3S)-3-azido-2-hydroxy-3-phenylpropionate (85% yield).
A mixture of azido alcohol (0.5 mmol), benzoyl chloride, (1
mmol), Et3N (2 mmol), and DMAP (0.03 mmol) in 5 mL of ethyl
acetate was stirred at room temperature for 4 h, whereupon
1.4 mL of methanol was added. After being stirred for 3 h,
the reaction mixture was treated with 10 mg of 10% Pd/C and
stirred for 2 days under hydrogen atmosphere. Upon evapora-
i
OJ , 10% PrOH in hexane, flow rate 1.0 mL/min) tR ) 23.2
(major), tR ) 26.0 (minor).
Meth yl 2,3-d ih yd r oxy-2-m eth yl-3-p h en ylp r op a n oa te
(Ta ble 6, en tr y 7):27c 1H NMR δ 1.56 (s, 3H), 3.0 (d, 2H), 3.64
(s, 3H), 4.74 (d, 1H), 7.2-7.4 (m, 5H); 13C NMR δ 22.4, 52.5,
77.3, 78.0, 126.8, 128.1, 128.3, 139.1, 175.0; HPLC (Daicel
Chiralcel OJ , 10% iPrOH in hexane, flow rate 1.0 mL/min) tR
) 20.04 (minor), tR ) 20.96 (major).
1-Meth yl 1,2-Dip h en yl-1,2-eth a n ed iol (Ta ble 6, en tr y
8):27a 1H NMR δ 1.35 (s, 3H), 2.5 (d, 1H), 2.60 (s, 1H), 4.8 (d,
1H), 7.05-7.40 (m, 10H). A ketal derivative of the diol was
made as described: To 15 mL CHCl3, in a 100 mL round-
bottomed flask, was added 0.29 mmol of diol, 0.1 mL of 2,2′-
dimethoxypropane, and traces of 4-toluenesulfonic acid. After
3 h of reflux, the heat was removed and the reaction mixture
was transferred to a separating funnel and washed subse-
quently with 10% aqueous NaHCO3 and water. The organic
J . Org. Chem, Vol. 68, No. 5, 2003 1745

Choudary et al.
layer was dried over Na2SO4 and then concentrated to get
2,2′,4-trimethyl-4,5-diphenyl-1,3-dioxolane (95% yield): 1H
NMR δ 7.4-7.2 (m, 10H), 4.96 (s, 1H), 1.72 (s, 3H), 1.62 (s,
Ackn owledgm en t. N.S.C. and S.M. thank the Coun-
cil of Scientific and Industrial Research, India, for the
award of a senior research fellowship. We also thank
K. J yothi for technical support.
i
3H), 1.25 (s, 3H); HPLC (Daicel Chiralcel OD, 2% PrOH in
hexane, flow rate 0.5 mL/min) tR ) 8.66 (minor), tR ) 10.03
(major).
J O026687I
1746 J . Org. Chem., Vol. 68, No. 5, 2003