New mono-quarternized bis-Cinchona alkaloid ligands for asymmetric dihydroxylation of olefins in aqueous medium: Unprecedented high enantioselectivity and recyclability

Article abstract of DOI:10.1002/adsc.200600253

New mono-quaternized allyl bromide salts of bis-Cinchona alkaloid ligands, [(QD)₂PHAL-Allyl]Br and [(QN)₂PHAL-Allyl]Br, have been synthesized which can be converted into their highly water-soluble multihydroxylated derivatives under asymmetric dihydroxylation (AD) conditions and, thus, easily recovered by a simple extraction method after reaction and reused. These mono-quaternized ligands exhibited superior catalytic efficiency to their neutral counterparts such as (DHQD)₂PHAL and (DHQ) ₂PHAL for the AD reactions of mono- and disubstituted styrenes under Upjohn conditions. Merely 0.1 mol% of osmium was enough to complete the reactions of mono- and disubstituted styrenes and, moreover, these ligands showed the highest enantioselectivities (e.g., for styrene, 97% ee with [(QD)₂PHAL-Allyl]Br) among those ever achieved under Upjohn conditions. Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/adsc.200600253

COMMUNICATIONS
DOI: 10.1002/adsc.200600253
New Mono-Quarternized Bis-Cinchona Alkaloid Ligands for
Asymmetric Dihydroxylation of Olefins in Aqueous Medium:
Unprecedented High Enantioselectivity and Recyclability
Doo Seung Choi,b Sang Seop Han,b Eun Kyung Kwueon,b Han Young Choi,a
Soon Ho Hwang,a Yil Sung Park,a,* and Choong Eui Songb,*
a
DongWoo Fine-Chem Co., Ltd, 1177, Wonjung-ri, Poseung-myun, Pyungtaek-si, Gyeonggi-do 451-820, Korea
Institute of Basic Science, Department of Chemistry, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu,
b
Suwon, Gyeonggi-do 440-746, Korea
Fax : (+82)-31-290-7075; e-mail: s1673@skku.edu
Received: May 31, 2006; Accepted: September 17, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: New mono-quaternized allyl bromide
salts of bis-Cinchona alkaloid ligands,
efficient methods of synthesizing chiral vicinal diols.[1]
Although this reaction offers a number of processes
that can be applied to the synthesis of chiral drugs,
natural products and fine chemicals, etc., the cost,
toxicity and contamination of products with osmium
strongly restricts its use in industry. To address this
issue, a great deal of effort has been directed at im-
mobilizing the catalyst system, for example, by cova-
lent attachment[2] of an alkaloid ligand to a soluble or
insoluble support, by immobilizing the osmium cata-
lyst itself, by the micro-encapsulation of OsO4 in a
dendrimer[3] or polymer matrix,[4] by use of various
ion-exchange supports[5] or by fixation of osmium
onto olefins covalently bound on silica[6] or on macro-
porous resins.[7] However, most examples of support-
ed catalysts exhibit inferior catalytic properties to
their homogeneous counterparts (1–5 mol% of
osmium is usually needed to complete the reaction,
whereas in homogeneous case 0.2 mol% of osmium is
enough to complete most of the reactions) and re-
quire additional synthetic steps for their preparation
that raises catalyst costs. Quite recently, an ionic
liquid,[8] poly(ethylene glycol)[9] or fluorous solvents[10]
have been used as reaction media as well as new im-
mobilizing agents for the catalyst in AD reactions.
The environmental impact of the use of ionic liquids,
polyethylene glycol and fluorous solvents is, however,
[(QD)2PHAL-Allyl]Br and [(QN)2PHAL-Allyl]Br,
have been synthesized which can be converted into
their highly water-soluble multihydroxylated deriva-
tives under asymmetric dihydroxylation (AD) con-
ditions and, thus, easily recovered by a simple ex-
traction method after reaction and reused. These
mono-quaternized ligands exhibited superior cata-
lytic efficiency to their neutral counterparts such as
(DHQD)2PHALand (DHQ) PHALfor the AD re-
2
actions of mono- and disubstituted styrenes under
Upjohn conditions. Merely 0.1 mol% of osmium
was enough to complete the reactions of mono- and
disubstituted styrenes and, moreover, these ligands
showed the highest enantioselectivities (e.g., for sty-
rene, 97% ee with [(QD)2PHAL-Allyl]Br) among
those ever achieved under Upjohn conditions.
Keywords: aqueous phase catalysis; asymmetric di-
hydroxylation; catalyst recycling; mono-quaternized
bis-Cinchona alkaloid ligands; unprecedented enan-
tioselectivity
The international chemistry community is under in- still unknown. Therefore, it would still be highly desir-
creasing pressure to change current working practices able to develop a more efficient and environmentally
and to find greener alternatives because of the in- benign immobilization method for catalyst recycling.
creasingly stringent environmental regulations. This
We report herein a new catalyst recycling protocol
means that chemical manufacturers need to develop for AD reactions using the new mono-quaternerized
more environmentally sustainable processes that pro- bis-Cinchona alkaloid ligands, [(QD)2PHAL-Allyl]Br
duce less waste and avoid, as much as possible, the and [(QN)2PHAL-Allyl]Br, which are converted into
use of toxic and/or hazardous reagents.
their highly water-soluble multihydroxylated deriva-
The Sharpless Os-catalyzed asymmetric dihydroxy- tives under AD conditions (Figure 1) and, thus, im-
lation (AD) of olefins is undoubtedly one of the most mobilized spontaneously in the aqueous phase after
2560
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2560 – 2564

Asymmetric Dihydroxylation of Olefins in Aqueous Medium
COMMUNICATIONS
Figure 1. In situ generation of the highly water-soluble mutihydroxylated ligands such as 1 from [(QD)2PHAL-Allyl]Br
during AD reactions.
reaction. These ligands exhibited superior catalytic ef- (QD)2PHAL[12] and (QN)2PHAL[12] with allyl bro-
ficiency to their neutral counterparts such as mide in THF, respectively. In order to compare the
(DHQD)2PHALand (DHQ) PHALfor the AD reac-
tions of mono- and disubstituted styrene derivatives known
catalytic efficiency of the new ligands with the well-
neutral ligands, (DHQD)2PHAL,
2
under Upjohn conditions.[11] Merely 0.1 mol% of (DHQ)2PHAL, (QD)2PHALand (QN) 2PHAL
osmium was enough to complete most reactions and, (Figure 2), the AD reactions of styrene were initially
moreover, highly interestingly, the mono-quarternized carried out using 0.1 mol% of OsO4 under Upjohn
ligands exhibited an unprecedented high enantioselec- conditions,[11] and the results are summarized in
tivity (e.g., for styrene, 97% ee with [(QD)2PHAL- Table 1. The catalytic activity of the mono-quater-
Allyl]Br.
nized ligands are comparable with the conventional
The mono-quaternized ligands, [(QD)2PHAL-Al- neutral ligands. However, highly interestingly, the
lyl]Br and [(QN)2PHAL-Allyl]Br, were simply pre- enantioselectivities of the mono-quaternized ligands,
pared in moderate yield by the reaction of [(QD)2PHAL-Allyl]Br and [(QN)2PHAL-Allyl]Br,
Figure 2. Chiral ligands used in this study.
Adv. Synth. Catal. 2006, 348, 2560 – 2564
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2561

Doo Seung Choi et al.
COMMUNICATIONS
Table 1. Asymmetric dihydroxylation of styrene.[a]
Entry
Ligand
Cooxidant
Time [h][b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
[(QD)2PHAL-Allyl]Br
[(QN)2PHAL-Allyl]Br
[(QD)2PHAL]
NMO·H2O
NMO·H2O
NMO·H2O
NMO·H2O
NMO·H2O
NMO·H2O
20
20
20
20
20
20
93
89
87
90
90
92
97
95
90
83
93
90
[(QN)2PHAL]
ACHTREUNG
ACHTREUNG
[a]
All the reactions were carried out on a 3 mmol reaction scale of styrene using 0.1 mol% of OsO4, 2.5 mol% of ligand
and 3.3 mmol of NMO·H2O in t-BuOH-H2O (v/v=1 : 1, 30 mL) at 208C. Styrene was added using a syringe pump for
18 h.
[b]
[c]
[d]
Reaction time includes the addition time (18 h) of olefin.
Isolated yield.
Determined by chiral HPLC.
were found to be higher (up to 97% ee) than those osmate ester 2 either can be hydrolyzed affording the
achieved with the conventional neutral ligands. To the free diol with high enantiomeric excess (enantioselec-
best of our knowledge, this ee value is the highest one tive catalytic cycle) or can react with a second olefin,
ever achieved with styrene under Upjohn conditions. forming an Os(VI) bis-glycolate 3 which liberates a
In order to verify the versatility of this result, other racemic diol by hydrolysis (non-enantioselective cata-
mono- and disubstituted olefins were subjected to lytic cycle).[13] However, the greatly enhanced hydro-
asymmetric dihydroxylation, and the results are sum- philic environment in the trioxo-Os(VIII) glycolate 2
G
marized in Table 2. In all cases, the reactions were not only may accelerate glycolate hydrolysis, but also
completed within 2 h after completion of adding may result in the minimal concentration of hydropho-
olefin, affording the desired diols with higher ees than bic olefins in the vicinity of the trioxo-Os(VIII) glyco-
G
those obtained with the corresponding neutral ligands. late 2 and consequently in prevention of formation of
One of the possible reasons for the improved enantio- Os(VI) bis-glycolate 3.
selectivity of the monoquaternized ligands might be
Encouraged by the above-described results, we next
attributed to highly polar hydroxy residues generated performed catalyst recycling experiment as follows.
in situ during reaction which would greatly enhance When the reaction was complete, the product was ex-
the hydrophilic environment in the trioxo-Os(VIII) tracted with hexane. The relative amounts of the
A
glycolate complex 2. Under NMO condition, the chiral ligands [hexaol (1), tetraols and diols] dissolved
Table 2. Asymmetric dihydroxylation of olefins using [(QD)2PHAL-Allyl]Br.[a]
Entry
Substrate
Time [h][b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
9
styrene
20 h
20 h
20 h
20 h
20 h
20 h
20 h
20 h
20 h
88
92
95
90
91
90
92
90
93
97
97
97
97
97
97
96
96
93
trans-b-methylstyrene
4-bromostyrene
4-chlorostyrene
4-fluorostyrene
3-chlorostyrene
3-fluorostyrene
2-chlorostyrene
2-vinylnaphthalene
[a]
All the reactions were carried out on a 3 mmol reaction scale of olefin using 0.1 mol% of OsO4, 2.5 mol% of
[(QD)2PHAL-Allyl]Br and 3.3 mmol of NMO·H2O in t-BuOH-H2O (v/v=1:1, 30 mL) at 208C. Olefins were added by a
syringe pump for 18 h.
Reaction time includes the addition time (18 h) of olefin.
Isolated yield.
[b]
[c]
[d]
Determined by chiral HPLC.
2562
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2560 – 2564

Asymmetric Dihydroxylation of Olefins in Aqueous Medium
COMMUNICATIONS
Table 3. Recycling experiments for AD reactions of styrene
using (QD)2PHAL-allyl bromide salt.[a]
Run 1
Run 2
Run 3
Run 4
Run 5
93%
92%
94%
90%
92%
97% ee
95% ee
95% ee
95% ee
95% ee
[a]
The recycle experiments were carried out on a 3 mmol
reaction scale of olefin using 0.1 mol% of OsO4, 2.5
mol% of [(QD)2PHAL-Allyl]Br and 3.3 mmol of NMO
in t-BuOH-H2O (v/v=1:1, 30 mL) at 208C for 24 h. Sty-
rene was added using a syringe pump for 18 h. From the
second run, the reaction was carried out with aqueous
phase recovered from the first run without further addi-
tion of [(QD)2PHAL-Allyl]Br. However, 0.05 mol% of
OsO4 was added in each run to regenerate reaction con-
dition.
in the two layers were determined by LC-MS. As ex-
pected, >95% of the ligand was immobilized in the
aqueous phase and, thus, the aqueous layer was then
recycled with a fresh batch of styrene and NMO with-
out any addition of ligand (Figure 3). For example,
when half the initial amount (0.05 mol%) of OsO4
was added in each run to regenerate the reaction con-
dition completely,[14] the recovered aqueous phase was
reused for at least 5 times without any significant loss
of activity and enantioselectivity (Table 3).
In summary, we have synthesized the new mono- conditions, especially to minimize Os leaching into
quaternized bis-Cinchona alkaloid ligands, the organic layer, is currently underway by our group.
[(QD)2PHAL-Allyl]Br and [(QN)2PHAL-Allyl]Br,
which are converted to the highly water-soluble hy-
droxylated derivatives such as 1 during reaction and,
thus, easily recovered by a simple extraction method
after reaction and reused. This new type of ligands ex-
hibited superior catalytic efficiency to the convention-
al neutral ligands for the AD reactions of mono- and
disubstituted styrene derivatives under Upjohn condi-
tions. Merely 0.1 mol% of osmium was enough to
complete most of reactions and, surprisingly, the
mono-quarternized ligands showed an unprecedented
high enantioselectivity (e.g., for styrene, 97% ee with
[(QD)2PHAL-Allyl]Br). Optimization of reaction
ExperimentalSection
Synthesis of [(QD)2PHAL-Allyl]Br
Allyl bromide (11.25 mL, 130 mmol) was added dropwise
into a solution of (QD)2PHAL(20 g, 26 mmol) in EtOAc
(800 mL) at 408C. The reaction mixture was stirred for 72 h.
After completion of the reaction, the precipitate was fil-
tered. The filtered solid was purified by flash column chro-
matography (CH2Cl2/MeOH 9:1) to give [(QD)2PHAL-Al-
lyl]Br as a light yellow solid; yield: 11.2 g (48%).
Figure 3.
Adv. Synth. Catal. 2006, 348, 2560 – 2564
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2563

Doo Seung Choi et al.
COMMUNICATIONS
A. A. Thomas, V. V. Fokin, K. B. Sharpless, Adv. Synth.
Catal. 2002, 344, 412–433.
[2] For reviews: a) C. E. Song, S.-g. Lee, Chem. Rev. 2002,
102, 3495–3524; b) Q.-H. Fan, Y.-M. Li, A. S. C. Chan,
Chem. Rev. 2002, 102, 3385–3466.
[3] W.-J. Tang, N.-F. Yang, B. Yi, G.-J. Deng, Y.-Y. Huang,
Q.-H. Fan, Chem. Commun. 2004, 1378–1379.
[4] a) S. Nagayama, M. Endo, S. Kobayashi, J. Org. Chem.
1998, 63, 6094–6905; b) S. Kobayashi, M. Endo, S. Na-
gayama, J. Am. Chem. Soc. 1999, 121, 11229–11230;
c) S. Kobayashi, T. Ishida, R. Akiyama, Org. Lett. 2001,
3, 2649–2652.
[5] a) B. M. Choudary, N. S. Chowdari, M. L. Kantam,
K. V. Raghavan, J. Am. Chem. Soc. 2001, 123, 9220–
9221; b) B. M. Choudary, N. S. Chowdari, K. Jyothi,
M. L. Kantam, J. Am. Chem. Soc. 2002, 124, 5341–
5349.
[6] a) A. Severeyns, D. E. De Vos, L. Fiermans, F. Ver-
poort, P. J. Grobet, P. A. Jacobs, Angew. Chem. Int. Ed.
2001, 40, 586–589; b) A. Severeyns, D. E. De Vos, P. A.
Jacobs, Green Chem. 2002, 4, 380–384.
[7] a) J. W. Yang, H. Han, E. J. Roh, S.-g. Lee, C. E. Song,
Org. Lett. 2002, 4, 4685–4688; b) K. J. Kim, H. Y. Choi,
S. H. Hwang, I. S. Park, E. K. Kwueon, D. S. Choi,
C. E. Song, Chem. Commun. 2005, 3337–3339; c) Y. S.
Park, C. H. Jo, H. Y. Choi, E. K. Kwon, C. E. Song,
Bull. Korean Chem. Soc. 2004, 25, 1671–1675; d) C. H.
Jo, S.-H. Han, J. W. Yang, E. J. Roh, U.-S. Shin, C. E.
Song, Chem. Commun. 2003, 1312–1313.
[8] a) C. E. Song, D.-u. Jung, E. J. Roh, S.-g. Lee, D. Y.
Chi, Chem. Commum. 2002, 3038–3039; b) L. C.
Branco, C. A. M. Afonso, Chem. Commun. 2002, 3036–
3037; c) L. C. Branco, C. A. M. Afonso, J. Org. Chem.
2004, 69, 4381–4389; d) L. C. Branco, A. Servanovic,
M. N. da Ponte, C. A. M. Afonso, Chem. Commun.
2005, 107–109; e) Q. Yao, Org. Lett. 2002, 4, 2197–
2199; f) R. Yanada, Y. Takemoto, Tetrahedron Lett.
2002, 43, 6849–6851.
Synthesis of [(QN)2PHAL-Allyl]Br
Allyl bromide (11.25 mL, 130 mmol) was added dropwise
into a solution of (QN)2PHAL(20 g, 26 mmol) in dry THF
(700 mL) at 408C. The reaction mixture was further stirred
for 72 h at the same temperature, and the solvent was re-
moved under vacuum. The resulting residue was treated
with 150 mLof CH Cl2 and washed with H2O twice. The or-
2
ganic layer was dried over anhydrous MgSO4 and filtered.
After concentration of the filtrate under vacuum, the result-
ing residue was purified by flash column chromatography
(CHCl3/MeOH 9:1) to give[(QN)2PHAL-Allyl]Br as a light
yellow solid; yield: 12.1 g (52%).
TypicalProcedure for Asymmetric Dihydroxyal tion
A 100-mLflask was charged with t-BuOH-H2O (1:1, v/v,
30 mL), [(QD)2PHAL-Allyl]Br (67 mg, 0.075 mmol) and
OsO4 (72 mL, of 1.0 wt% of aqueous solution, 0.003 mmol,
0.1 mol%). After stirring for 15 min, NMO·H2O (N-methyl-
morpholine N-oxide monohydrate) (446 mg, 3.3 mmol,
1.1 equivs.) was added. Subsequently, styrene (344 mL,
3 mmol) was added by a syringe pump for 18 h and the reac-
tion mixture was stirred at 208C. After completion of the re-
action, the chiral diol and N-methylmorpholine produced
during the reaction were successively extracted with hexane
(1ꢁ20 mL) and hexane/THF (3ꢁ30 mL) from the reaction
mixture. The recovered aqueous phase was recycled to the
next run. The combined organic layer was evaporated and
the crude product was purified by flash column chromatog-
raphy on silica (EtOAc/hexane 1:2) to give pure 1-phenyl-
1,2-ethanediol as a white solid.
In the recycling experiment, OsO4 (36 mL, of 1.0 wt% of
aqueous solution, 0.0015 mmol, 0.05 mol%), 446 mg
(3.3 mmol) of NMO·H2O and 15 mLof t-BuOH were added
to the aqueous phase recovered from the above experiment.
After stirring for 5 min, styrene (344 mL, 3 mmol) was added
by a syringe pump for 18 h. After completion of the reac-
tion, the reaction mixture was worked up as described
above.
[9] S. Chandrasekhar, Ch. Narsihmulu, S. S. Sultana, N. R.
Reddy, Chem. Commun. 2003, 1716–1717.
[10] Y. Huang, W.-D. Meng, F.-L. Qing, Tetrahedron Lett.
2004, 45, 1965–1968.
[11] V. VanRheenen, R. C. Kelly, D. Y. Cha, Tetrahedron
Acknowledgements
Lett. 1976, 23, 1973–1976.
This work was supported by the Korea Research Foundation
Grant (KRF-2005–005 J11901) funded by MOEHRD, and by
the grant of R01–2006–000–10426–0 (KOSEF) and R11–
2005–008–00000–0 (SRC program of MOST/KOSEF).
[12] C. E. Song, J. W. Yang, H. J. Ha, S.-g. Lee, Tetrahedron:
Asymmetry 1996, 7, 645–648.
[13] J. S. M. Wai, I. Marko, J. S. Svendsen, M. G. Finn, E. N.
Jacobsen, K. B. Sharpless, J. Am. Chem. Soc. 1989, 111,
1123–1125.
[14] According to ICP analysis, ca. half the amount of Os
used initially was leached into the product phase after
the first run. Thus, to regenerate the reaction condi-
tions completely, half the initial amount (0.05 mol%)
of OsO4 was added in each run.
References
[1] H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless,
Chem. Rev. 1994, 94, 2483–2547; P. Dupau, R. Epple,
2564
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2560 – 2564