Osmium-catalyzed asymmetric dihydroxylation of olefins by H2O2 using a biomimetic flavin-based coupled catalytic system

Article abstract of DOI:10.1021/ja0035809

Selective cis-dihydroxylation of olefins with the aid of a triple catalytic system using H₂O₂ as the terminal oxidant has been developed. In this process Os(VI) is recycled to Os(VIII) by a coupled electron-transfer-mediator system based on N-methylmorpholine and a biomimetic flavin, leading to a mild and selective electron transfer. Aliphatic, aromatic, and functionalized olefins were successfully cis-dihydroxylated, employing the triple catalytic system. The present biomimetic catalytic system works well in asymmetric dihydroxylation and gave optically active diols in good isolated yields and high enantiomeric excesses (up to 99% ee).

Full text of DOI:10.1021/ja0035809

J. Am. Chem. Soc. 2001, 123, 1365-1371
1365
Osmium-Catalyzed Asymmetric Dihydroxylation of Olefins by H2O2
Using a Biomimetic Flavin-Based Coupled Catalytic System
Sandra Y. Jonsson,† Katarina Fa1rnegårdh,‡,§ and Jan-E. Ba1ckvall*,†
Contribution from the Department of Organic Chemistry, Arrhenius Laboratory, Stockholm UniVersity,
SE-106 91 Stockholm, Sweden and Department of Organic Chemistry, UniVersity of Uppsala, Box 531,
SE-751 21 Uppsala, Sweden
ReceiVed October 3, 2000
Abstract: Selective cis-dihydroxylation of olefins with the aid of a triple catalytic system using H2O2 as the
terminal oxidant has been developed. In this process Os(VI) is recycled to Os(VIII) by a coupled electron-
transfer-mediator system based on N-methylmorpholine and a biomimetic flavin, leading to a mild and selective
electron transfer. Aliphatic, aromatic, and functionalized olefins were successfully cis-dihydroxylated, employing
the triple catalytic system. The present biomimetic catalytic system works well in asymmetric dihydroxylation
and gave optically active diols in good isolated yields and high enantiomeric excesses (up to 99% ee).
Selective oxidation reactions are of current interest in
synthetic organic chemistry both on the laboratory scale and
on large-scale industrial production.1,2 A good oxidation system
should be highly selective for oxidation of one specific
functionality without cross-oxidation of other functionalities.
Furthermore, the oxidation system should work with high
selectivity for as many variations as possible within the
functionality class.
transfer mediators (ETMs) between the substrate-selective redox
system and O2 or H2O2.3
The concept of an ETM has also been used in nonbiological
biomimetic oxidation reactions.4-8 For example, in the industrial
process for aerobic oxidation of ethene to acetaldehyde, pal-
ladium chloride is used as the substrate-selective catalyst, and
copper chloride is employed as the ETM for the reoxidation of
Pd(0) by O2.4 We have recently designed and developed
selective catalytic systems for aerobic 1,4-oxidation of 1,3-
dienes,5 aerobic allylic oxidation of olefins,5a and aerobic
oxidation of alcohols6 on the basis of the principle of selective
electron transfer involving ETMs.
Osmium tetroxide is one of the most selective oxidants
known: it dihydroxylates all olefins and it reacts only with
olefins.1c Thus, being an ideal substrate-selective catalyst but
at the same time toxic and expensive, it is highly desirable to
develop good reoxidation systems for osmium, rendering the
dihydroxylation catalytic on osmium. Several reoxidation
systems have been developed,8-12 of which the two most
commonly used today are based on N-methylmorpholine N-
In a selective oxidation a substrate-selective redox reagent
or oxidant interacts with the substrate, and this leads to a specific
oxidative transformation. Many oxidations are two-electron
oxidations where the redox couple (often Mn+2/Mn) will take
up two electrons from the substrate. Often these types of
oxidations are carried out with stoichiometric amounts of the
redox couple, which produces stoichiometric amounts of the
reduced form of the oxidant. In a catalytic reaction the reduced
form of the redox reagent is reoxidized to its oxidized state. It
is attractive if this reoxidation could be accomplished by the
use of O2 or H2O2, since these oxidants are inexpensive and
environmentally friendly.2 However, reoxidation of the reduced
form of the substrate-selective catalyst by O2 or H2O2 may not
always be trivial, since the energy barrier for electron transfer
can be high. In nature, where oxidations are common in various
biological systems, this has been solved by the use of electron-
(3) (a) Moser, C. C.; Keske, J. M.; Warncke, K.; Faird, R. S.; Dutton, P.
L. Nature 1992, 355, 796-802. (b) Nugent, J. H. A. Eur. J. Biochem. 1996,
237, 519-31. (c) Hughes, M. N. The Inorganic Chemistry of Biological
Processes; Wiley: Chichester, UK, 1981.
(4) Tsuji, J. Palladium Reagents and Catalysts. InnoVations in Organic
Synthesis; Wiley: Chichester, UK, 1995.
(5) (a) Ba¨ckvall, J. E.; Hopkins, R. B.; Grennberg, H.; Mader, M.
Awasthi, A. K. J. Am. Chem. Soc. 1990, 112, 5160. (b) Wo¨ltinger, J.;
Ba¨ckvall, J. E.; Zsigmond, A. Chem. Eur. J. 1999, 5, 1460.
(6) (a) Ba¨ckvall, J. E.; Chowdhury, R. L. Karlsson, U. J. Chem. Soc.,
Chem. Commun. 1991, 473. (b) Wang, G.-Z.; Andreasson, U.; Ba¨ckvall, J.
E. J. Chem. Soc.; Chem. Commun. 1994, 1037.
(7) (a) Bystro¨m, S. E.; Larsson, E. M.; Åkermark, B. J. Org. Chem. 1990,
55, 5674. (b) Yokota, T.; Sakurai, Y.; Sakaguchi, S.; Ishii, Y. Tetrahedron
Lett. 1997, 38, 3923-3926.
(8) Torii, S.; Liu, P.; Bhuvaneswari, N.; Amatore, C.; Jutand, A. J. Org.
Chem. 1996, 61, 3055.
(9) (a) Milas, N. A.; Sussman, S. J. Am. Chem. Soc. 1936, 58, 1302. (b)
Milas, N. A.; Sussman, S. J. Am. Chem. Soc. 1937, 59, 2345. (c) Milas, N.
A.; Sussman, S.; Mason, H. S. J. Am. Chem. Soc. 1939, 61, 1844. (d) Milas,
N. A.; Trepagnier, J. H.; Nolan, J. T.; Iliopulos, M. I. J. Am. Chem. Soc.
1959, 81, 4730.
(10) (a) Akashi, K.; Palermo, R. E.; Sharpless, K. B. J. Org. Chem. 1978,
43, 2063. (b) Sharpless, K. B.; Akashi, K. J. Am. Chem. Soc. 1976, 98,
1986.
†
Stockholm University.
‡ University of Uppsala.
§ Present adress: Dr. Katarina Fa¨rnegårdh, Pharmacia & Upjohn, 112
87 Stockholm, Sweden.
(1) (a) Schro¨der, M. Chem. ReV. 1980, 80, 187. (b) Singh, H. S. In
Organic Synthesis by Oxidation with Metal Compounds; Mijs, W. J., De
Jonge, C. R. H. I., Eds.; Plenum: New York, 1986; Chapter 12. (c) Kolb,
H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483.
(d) Marko´, I. E.; Svendsen, J. S. In ComprehensiVe Organometallic
Chemistry II; Hegedus, L. S., Ed.; Elsevier Science Ltd.: Oxford, UK, 1995;
Vol. 12; p 1137. (e) Kolb, H. C.; Sharpless, K. B. In Transition Metals for
Organic Synthesis; Beller, M., Bolm, C., Eds.; VCH-Wiley: Weinheim,
1998; Vol. 2, pp 219-242. (f) Beller, M.; Sharpless, K. B. In Applied
Homogeneous Catalysis; Cornils, B., Herrman, W. A., Eds.; VCH-
Weinheim, 1996; p 1009.
(2) (a) Sima´ndi, L. I. Catalytic ActiVation of Dioxygen by Metal
Complexes; Kluwer: Dordrecht, The Netherlands, 1992. (b) Strukul, G.
Catalytic Oxidations with Hydrogen Peroxide as Oxidant; Kluwer: Dor-
drecht, The Netherlands, 1992.
10.1021/ja0035809 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/26/2001

1366 J. Am. Chem. Soc., Vol. 123, No. 7, 2001
Jonsson et al.
Table 1. cis-Selective Dihydroxylation of trans-5-Decene
Scheme 1. Upjohn Procedure for the Osmium-Catalyzed
Dihydroxylation
Employing H2O2 as the Terminal Oxidanta
NMM
equivb
flavin (3)
yield
entry
equivb
additive
(%) of 2c
1d
2
3
4
5
10
16
58
69
72
47
83
95
0.27
0.27
0.27
2 equiv of TEAAe
0.05
0.05
0.05
0.05
6
2 equiv of TEAAe
2 equiv of TEAAe
2 equiv of TEAAe
7f
8
0.27
0.27
a The olefin (0.5 mmol), OsO4 (0.01 mmol, 0.02 equiv), and
additional catalysts (according to the Table) were dissolved in acetone
(1.88 mL) and H2O (0.62 mL). Then H2O2 (1.5 equiv, 30% aqueous)
was added over 9 h, unless otherwise noted. After complete addition
of the oxidant, the mixture was stirred for an additional 7-17 h.
b Equivalent to olefin. c Isolated yields of cis-addition product. d H2O2
was added in one portion. e Tetraethylammonium acetate. f H2O2 was
added over 2.5 h.
oxide (NMO)11 and K3[Fe(CN)6],12 the latter being mainly used
in asymmetric dihydroxylation. However, only very few pro-
cedures for reoxidation of osmium(VI) by H2O2 or O2 are
known.9,13-16 Milas9 found that H2O2 can be employed as a
direct reoxidant for Os(VI), but in many cases this leads to
nonselective reactions with low yields due to over-oxidations.
Krief has shown that O2 can reoxidize Os(VI) in the presence
of a selenoxide under irradiation by visible light.14 Recently,
Beller reported a procedure for aerobic osmium-catalyzed
dihydroxylation of olefins.15 At the same time we published a
preliminary communication on the biomimetic osmium-
catalyzed dihydroxylation by H2O2.16 In the latter process the
Os(VI) is recycled to Os(VIII) by a coupled catalytic ETM
system based on NMO/flavin, leading to a mild and selective
electron transfer. We now give a full account on this work,
report on the asymmetric dihydroxylation of the reaction, and
discuss the versatility and mechanistic aspects of this new
biomimetic process.
examined. A mixture of acetone and water was used as the
solvent system throughout the study. Stoichiometric amounts
of NMO were employed in a control experiment, which gave
9
95% yield of diol 2. Direct reoxidation of osmium(VI) by H2O2
led to a nonselective reaction where 2 was a minor product
obtained in 10% yield (Table 1, entry 1). Slow addition of the
H2O2 to the reaction mixture did not change the outcome of
the reaction much (entry 2). The next precaution undertaken to
avoid over-oxidation was to include NMM in the system, which
can trap the peroxide via in situ generation of NMO. Including
0.27 mol % NMM in the system led to less over-oxidation, and
the diol was isolated in 58% yield (entry 3). It has previously
been observed that addition of tetraethylammonium acetate
(TEAA) improves the outcome of osmium-catalyzed dihydroxy-
lations,10,18,19 probably due to the increased rate of hydrolysis
of the intermediate osmate ester. Addition of 2 equiv of TEAA
to the reaction mixture afforded an improved yield of 69% (entry
4).
Results and Discussion
In the Upjohn procedure,11 NMO is employed as the terminal
oxidant in the dihydroxylation of olefins. The reoxidation of
Os(VI) to Os(VIII) by NMO leads to formation of N-methyl-
morpholine (NMM) (Scheme 1).
One objective with the present project was to continuously
recycle NMM back to NMO by either O2 or H2O2 in a catalytic
process. It was known from previous work in our group that
tertiary amines undergo efficient flavin-catalyzed oxidations by
H2O2 to the corresponding N-oxides.17
We have recently shown that tertiary amines are efficiently
oxidized to their corresponding N-oxides by a biomimetic flavin
hydroperoxide 4 generated from the flavin analogue 3.17
A. Osmium-Catalyzed Dihydroxylation by H2O2. The
combined catalytic ETM system NMO-flavin for the reoxidation
of Os(VI) to Os(VIII) by H2O2 has been studied under different
reaction conditions.
1. Regeneration of NMO by H2O2. For our initial investiga-
tions we chose trans-5-decene 1 as a model substrate, and
several reaction conditions employing H2O2 as the terminal
oxidant and osmium tetroxide as catalyst (Table 1, eq 1) were
Furthermore, the catalytic intermediate flavin hydroperoxide
oxidizes NMM to NMO more than 6000 times faster than H2O2
does. It was therefore highly attractive to apply this biomimetic
N-oxidation to the recycling of NMM to NMO in the osmium-
catalyzed dihydroxylation, which would provide a favorable
reoxidation of Os(VI). Thus, in situ generation of NMO from
a catalytic amount of NMM by the use of catalytic amounts of
flavin 3 (5 mol %) in the dihydroxylation afforded a good
isolated yield (72%, entry 5). Excluding NMM, and thereby
using only the flavin as ETM, led to a dramatic decrease in
yield (47%, entry 6).
(11) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. F. Tetrahedron Lett.
1976, 1973. (b) VanRheenen, V.; Cha, D. Y.; Hartley, W. M. Organic
Syntheses; Wiley & Sons: New York, 1988; Collect. Vol. VI, pp 342-
348.
(12) Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55, 766.
(13) Austin, R. G.; Michaelson, R. G.; Myers; R. S. In Catalysis of
Organic Reactions; Augustine, R. L., Eds.; Marcel Dekker: New York,
1985; p 269.
(16) Bergstad, K.; Jonsson, S. Y.; Ba¨ckvall, J. E. J. Am. Chem. Soc.
1999, 121, 10424.
(17) Bergstad, K.; Ba¨ckvall, J. E. J. Org. Chem. 1998, 63, 6650.
(14) Krief, A.; Colaux-Castillo, C. Tetrahedron Lett. 1999, 40, 4189.
(15) (a) Do¨bler, C.; Mehltretter, G.; Beller, M. Angew. Chem., Int. Ed.
1999, 38, 3026. (b) Do¨bler, C.; Mehltretter, G. M.; Sundermeier, U.; Beller,
M. J. Am. Chem. Soc. 2000, 122, 10289.
(18) Lohray, B. B.; Bhushan, V.; Kumar, K. R. J. Org. Chem. 1994, 59,
1375.
(19) Bergstad, K.; Piet, J. J. N.; Ba¨ckvall, J. E. J. Org. Chem. 1999, 64,
2545.

Osmium-Catalyzed Dihydroxylation of Olefins
J. Am. Chem. Soc., Vol. 123, No. 7, 2001 1367
Table 2. Cis-Dihydroxylation of Different Olefins Employing
Table 3. Effect of Solvent on the cis-Dihydroxylation of
trans-5-Decene Employing the Triple Catalytic System
H2O2 as the Terminal Oxidanta
entry
solvent
yield (%)
1
2
3
H2O-acetone
H2O-t-BuOH
H2O-CH3CN
95
81
60
a Experimental conditions: The olefin (0.5 mmol), N-methylmor-
pholine (27 mol %), TEAA (2 equiv), OsO4 (2 mol %), and flavin 3 (5
mol %) were dissolved in acetone or CH3CN or t-BuOH (1.88 mL)
and H2O (0.62 mL). H2O2 (1.5 equiv, 30% aqueous) was added to this
mixture over 9 h. After complete addition of the oxidant, the mixture
was stirred for an additional 7 h. b Isolated yields.
With NMM and TEAA (method B) the yield was improved to
69 and 50%, respectively, whereas a 95% yield was obtained
in both cases for the corresponding optimized triple catalytic
H2O2 oxidation (method C). Also trans-2-octene (entry 3), trans-
4-octene (entry 4), 1-methyl-cyclohexene (entry 6), and 2,2-
dimethyl styrene (entry 11), which under Milas conditions
(method A) gave 24-35% yield, afforded 82-95% yield with
the triple catalytic system (method C). Substrates such as
R-methylstyrene (entry 9), styrene (entry 10), and 2-methyl-1-
heptene (entry 12) work well with the traditional Milas9 system
(A) and the system B, but also in these cases a significant
improvement was obtained employing the triple catalytic system.
The functionalized substrate, allyl phenyl ether (entry 13),
proceeded excellently, giving the diol in 95% yield. Dihydroxy-
lation of 1-phenyl-1-cyclohexene (entry 7) did also proceed
nicely with our triple catalytic system, and the diol was isolated
in 93% yield.
a Experimental conditions unless otherwise noted: (A) H2O2 (1.5
equiv, 30% aqueous) was added all at once to a mixture of the olefin
(1.0 mmol) and OsO4 (2 mol %) in acetone (3.8 mL) and H2O (1.2
mL). The reaction mixture was stirred 20-26 h at 20 °C. (B) The olefin
(0.5 mmol), N-methylmorpholine (27 mol %), TEAA (2 equiv), and
OsO4 (2 mol %) were dissolved in acetone (1.88 mL) and H2O (0.62
mL). H2O2 (1.5 equiv, 30% aqueous) was added to this mixture over
9 h. After complete addition of the oxidant, the mixture was stirred for
an additional 7-15 h. (C) As in B, also the flavin 3 was added before
addition of the H2O2 started. b Isolated yields. c 4.4:1 acetone-H2O was
employed. d Addition time 14 h. e No diol could be isolated.
2. Solvent Effects. It was found that the solvent has a
significant effect on the yield in the dihydroxylation with the
triple catalytic system. A few solvent systems were studied in
the dihydroxylation of trans-5-decene, and the results are given
in Table 3 (eq 2). The highest yield was obtained with H2O-
Next, we examined the effect of TEAA on the dihydroxy-
lation employing the triple catalytic system. Addition of TEAA
to the reaction mixture did indeed result in a significant
improvement, and 2 was obtained in an excellent yield (95%,
entry 8). Interestingly, a shorter addition time of H2O2 (2.5 h)
did not result in any considerable change in the reaction
outcome, and the diol 2 was isolated in 83% yield (entry 7).
The turnover rate of the triple catalytic system is comparable
to standard osmium-catalyzed dihydroxylation.11 When decreas-
ing the amount of OsO4 to 1 mol % in the triple catalytic alkaline
system, the yield of the diol dropped to 64%.
Several different olefins, were dihydroxylated to their cor-
responding diols, employing the optimal conditions from entry
8, Table 1. As can be seen from Table 2 (method C), most
olefins tested were efficiently cis-dihydroxylated to the corre-
sponding diols in good to excellent yields. Control experiments
were carried out in all cases in which H2O2 was applied as co-
oxidant without the electron-transfer mediators NMM and flavin
(method A), or with the electron-transfer mediator NMM in
combination with TEAA (method B). The use of hydrogen
peroxide as oxidant without the electron-transfer mediators
NMM and flavin in the osmium-catalyzed dihydroxylation
(method A) led to inefficient and nonselective reactions. For
example, the diols from trans-5-decene (entry 1) and trans-
stilbene (entry 2) were formed in only 10% yield in each case
in the H2O2 oxidation without NMM and flavin (method A).
acetone as solvent, which is employed in typical OsO4-catalyzed
dihydroxylations when N-methylmorpholine is used as the
oxidant.20 When the solvent was changed to H2O-tert-BuOH
the yield decreased slightly (to 81%). A moderate yield (60%)
was obtained when H2O-acetonitrile was used as solvent.
3. Variation of Tertiary Amine. Various N-oxides have been
employed in osmium-catalyzed dihydroxylation. For example
trimethylamine N-oxide was used as an efficient oxidant in the
hydroxylation of sterically hindered olefins21 and in the oxidation
of allylic alcohols.22 N-methylmorpholine N-oxide has recently
been successfully used in the dihydroxylation of olefins with a
polymer-supported osmium catalyst,23 and with homogeneous
conditions on an industrial scale.20 Since the flavin/H2O2 system
works very well for oxidation of various tertiary amines to their
corresponding N-oxides17 it was of interest to investigate if
NMM can be replaced by other tertiary amines in the triple
catalytic system. Under the optimized conditions from above,
dihydroxylation of trans-5-decene was carried out with five
(20) Ahlgren, L.; Sutin, L. Org. Process Res. DeV. 1997, 1, 425-427.
(21) Ray, R.; Matteson, D. S. Tetrahedron Lett. 1980, 21, 449.
(22) Donohoe, T. J.; Waring, M. J.; Newcombe, N. J. Synlett 2000, 1,
149.
(23) (a) Nagayama, S.; Endo, M.; Kobayashi, S. J. Org. Chem. 1998,
63, 6094. (b) Kobayashi, S.; Endo, M.; Nagayama, S. J. Am. Chem. Soc.
1999, 121, 11229.

1368 J. Am. Chem. Soc., Vol. 123, No. 7, 2001
Jonsson et al.
Table 4. cis-Selective Dihydroxylation of trans-5-Decene Using
Table 5. Asymmetric Dihydroxylation of Styrene under Different
Different Tertiary Amines in the Triple Catalytic Systema
Conditions Employing the Chiral Ligand (DHQD)2PHALa
mol %
entry chiral ligand
temperature method Ab or
°C
method Bc yield (%)d ee (%)a
1
2e
3
4
5
6
3
3
3
3
6
6
0
0
0
20
0
0
A
A
B
B
A
B
91
87
84
85
80
80
74
79
88
86
87
95
a Enantiomeric excesses were determined by HPLC. b (A) Styrene
(0.5 mmol), N-methylmorpholine (27 mol %), TEAA (2 equiv),
(DHQD)2PHAL as shown in the table, flavin 3 (5 mol %) and OsO4 (2
mol %) were dissolved in t-BuOH (1.88 mL) and H2O (0.62 mL). Then
H2O2 (1.5 equiv, 30% aqueous) was added over 9 h. After complete
addition of the oxidant, the mixture was stirred for an additional
3-6 h. c (B) N-methylmorpholine (0.50 equiv), TEAA (2 equiv),
(DHQD)2PHAL as shown in the table, and flavin 3 (0.05 equiv) were
dissolved in t-BuOH (1.88 mL) and H2O (0.62 mL). OsO4 (0.02 equiv)
was added followed by 1/5 of the H2O2 (0.3 equiv, 30% aqueous). The
mixture was stirred for 20 min, and then styrene (0.5 mmol) and the
remaining H2O2 (1.2 equiv) were added over 9 h. After complete
addition of the oxidant and olefin, the mixture was stirred for an
additional 2-7 h. d Isolated yields. e The olefin was introduced dropwise
over 9 h.
a The olefin (0.5 mmol), tertiary amine (27 mol %), TEAA (2 equiv),
flavin 3 (5 mol %), and OsO4 (2 mol %) were dissolved in acetone
(1.88 mL) and H2O (0.62 mL). H2O2 (1.5 equiv, 30% aqueous) was
added to this mixture over 9 h. After complete addition of the oxidant,
the mixture was stirred for an additional 5-10 h. b Isolated yields.
different tertiary amines (Table 4, eq 3).
to be important for the enantioselectivity in NMO-based
reactions.25a Therefore also, the olefin was added slowly (over
9 h) according to the optimized version of the asymmetric
Upjohn process reported by Sharpless,25a since excess olefin in
solution considerably reduces the ee of the product. This led to
an improvement from 74% ee when all olefin was added at
once (entry 1, Table 5) to 79% ee when the olefin was added
over 9 h (entry 2). When the olefin was introduced slowly, the
reaction mixture remained yellow, but when it was added in
one portion in the beginning of the reaction, the solution took
on a brown-blackish tint.25a
Triethylamine, N,N-dimethyl(cyclohexylmethyl)amine, and N,N-
dimethylbenzylamine gave around 90% of diol under these
conditions, whereas trimethylamine afforded 81% yield of diol.
Thus, it is possible to use different tertiary amines with
essentially the same outcome. This is of importance since a
particular amine oxide is known to have certain advantages in
a given dihydroxylation. For example Donohoe et al.22 dem-
onstrated that the anti/syn selectivity observed for dihydroxy-
lation of E-allylic alcohols under Upjohn conditions11 (NMO)
was improved significantly under the so-called Poli24 conditions
(Me3NO),22 in one case from 5:1 to 12:1. The advantage with
the present procedure is that any tertiary amine can be used
instead of the corresponding N-oxide.
4. Enantioselective Dihydroxylation. Encouraged by the
promising results obtained with the triple catalytic system (Table
2), we investigated if the system was compatible with the use
of Sharpless’ chiral ligands.1c,25 We chose styrene as a model
substrate and hydroquinidine 1,4-phthalazinediyl diether
((DHQD)2PHAL)25b as the ligand, and several reaction condi-
tions were examined to optimize the enantioselectivity (Table
5, eq 4). In the preliminary experiment we used 3 mol % chiral
It was also found that an improvement of the ee was obtained
1
when /5 of the hydrogen peroxide was added to the reaction
mixture 20 min prior to the introduction of the olefin (Method
B). Presumably, this builds up a low buffer concentration of
NMO by transforming some of the NMM to NMO. After this
initial preactivation, the remaining H2O2 as well as the olefin
were added over 9 h via separate syringe pumps. With this
procedure, a considerable improvement in the enantiomeric
excess was observed (entry 3). An attempt to run the oxidation
at room temperature (entry 4) gave a slight drop in ee.25a When
increasing the amount of chiral ligand from 3 mol % (entry 1)
to 6 mol % (entry 5) employing method A, an improvement of
the ee was obtained. Finally, with method B, in the presence of
6 mol % of ligand at 0 °C, an optimized ee of 95% was obtained.
Under the above-optimized conditions, asymmetric dihy-
droxylation of trans-stilbene, R-methylstyrene, trans-â-meth-
ylstyrene, and 1-phenyl-1-cyclohexene was carried out in the
presence of the (DHQD)2PHAL ligand (Table 6). It was found
that for the asymmetric dihydroxylation, employing the triple
catalytic system, the enantioselectivity is strongly influenced
by the ligand concentration. To obtain enantioselectivities over
90%, an excess of chiral ligand compared to osmium (Os/L )
1:3) is required.
ligand. In these asymmetric dihydroxylations the solvent was
changed to t-BuOH since the oxidation in acetone gave lower
ee.20 The rate of addition of olefin has previously been shown
In the case of trans-stilbene the highest ee was observed when
the solvent was replaced by acetone-H2O using 6 mol % ligand.
Table 6 shows the effect of solvent, for example 91% ee was
obtained in acetone-H2O (entry 5) versus 79% ee in t-BuOH-
H2O (entry 4). These results are in contrast to those previously
reported by Sharpless et al.,26 where the best yield for the
(24) Poli, G. Tetrahedron Lett. 1989, 30, 7385.
(25) (a) Wai, J. S. M.; Marko´, I.; Svendsen, J. S.; Finn, M. G.; Jacobsen,
E. N.; Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 1123. (b) Sharpless,
K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong,
K. S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J.
Org. Chem. 1992, 57, 2768.
(26) Wang, Z.-M.; Sharpless, K. B. J. Org. Chem. 1994, 59, 8302.

Osmium-Catalyzed Dihydroxylation of Olefins
J. Am. Chem. Soc., Vol. 123, No. 7, 2001 1369
Table 6. Asymmetric Dihydroxylation of Different Alkenes Using
OsO4-NMM-Flavin-H2O2
Scheme 3. The Flavin Cycle in the Osmium-Catalyzed
Dihydroxylation Employing H2O2 as the Terminal Oxidant
a
a N-methylmorpholine (0.14 mmol, 0.50 equiv), TEAA (2 equiv),
chiral ligand as shown in the table, and flavin 3 (0.05 equiv) were
dissolved in t-BuOH (1.88 mL) and H2O (0.62 mL). The mixture was
cooled down to 0 °C, and OsO4 (0.01 mmol, 0.02 equiv) was added
1
followed by /5 of the H2O2 (0.3 equiv, 30% aqueous). The mixture
was stirred for 20 min, and then the olefin (0.5 mmol) and the remaining
H2O2 (1.2 equiv) were added over 9 h. After complete addition of the
oxidant and olefin, the mixture was stirred for an additional 2-7 h.
b Isolated yields. c Enantiomeric excesses were determined by HPLC.
d 4.4:1 acetone/H2O was employed. e The absolute configurations of
the diols were determined by comparison of optical rotations with
literature values.22 f The olefin and H2O2 were introduced over 20 h.
OsO4 (Os(VIII)) dihydroxylates the olefin, and the Os(VI)
produced is efficiently reoxidized to Os(VIII) by NMO. The
flavin hydroperoxide is in turn rapidly recycling NMM to NMO,
and the reduced flavin is reoxidized by H2O2. This coupled
biomimetic system leads to a mild kinetically controlled5a,27
electron transfer from the substrate (olefin) to H2O2 at room
temperature and does not require the complex structure of
naturally occurring enzymes to distinguish between the electron-
transfer processes.27 The high kinetic control requires close
interaction (contact) between the redox couples involved in the
cascade through coordination or weak bonding. For example,
the olefin is coordinated to Os(VIII), and the N-oxide coordi-
nates to Os(VI). Furthermore, it is known that flavoenzymes
via their hydroperoxides are the active species in amine oxidases
and hepatic flavoenzymes.28 Presumably, intramolecular hy-
drogen bonding in the flavin hydroperoxide leads to an efficient
interaction between the peroxy oxygen and the amine (Scheme
3), resulting in the high rate-enhancement (6000-8000 com-
pared to H2O2).17 Finally, it is known that H2O2 selectively reacts
with the reduced form of the reactive flavin hydroperoxide.
The role of flavin 3 is most likely to act as a precursor for
the active catalyst. In the presence of molecular oxygen (air),
an intermediate flavin hydroperoxide 4 is easily generated from
3 (Scheme 3).17,29 The latter is thought to be the actual oxidizing
species, which can transfer one of its oxygen atoms to NMM
giving NMO in a mild and fast reaction (steps ii and iii). The
flavin hydroperoxide 4 is highly active for amine oxidation, and
similar hydroperoxides are known to be involved in hepatic
flavoenzymes.28 The reduced flavin 7 is recycled to the active
hydroperoxide 4 by loss of OH- to give the cationic alloxazine
8 (step iv), which subsequently reacts with H2O2.17,30
Scheme 2. Triple Catalytic System for Osmium-Catalyzed
Dihydroxylation of Olefins Using H2O2 as the Terminal
Oxidant
asymmetric dihydroxylation of trans-stilbene was obtained in
t-BuOH/H2O. The oxidation of R-methylstyrene proceeded
excellently in our triple catalytic system, and we were able to
obtain an enantiomeric excess of 99% (entry 7). The methyl
substituent on trans-â-methylstyrene (entry 9) seems to have
very little effect on the enantioselectivity, and the ee was the
same as that of styrene (entries 1 and 2). The trisubstituted olefin
1-phenyl-1-cyclohexene required a longer addition time of both
olefin and hydrogen peroxide.25a When increasing the addition
time from 9 to 20 h, the enantioseletivity was improved from
69% (entry 11) to 92% (entry 12). Thus, by employing slow
addition techniques, good enantiocontrol can be obtained for
substrates that are problematic.1d,25a Aliphatic alkenes gave
substantially lower enantioselectivities. For example trans-5-
decene gave the corresponding diol in 57% ee using 3 mol %
chiral ligand and 63% ee with 6 mol % ligand, respectively.
B. Mechanistic Aspects. The mechanism of the biomimetic
triple catalytic H2O2 oxidation is depicted in Scheme 2. The
oxidation involves a cascade of selective electron-transfer
reactions, which transport two electrons from the substrate
(olefin) to hydrogen peroxide. The substrate-selective catalyst
(27) This system contains four oxidants with falling redox potentials,
and four species that can be oxidized. Therefore, there are 10 redox reactions
that can occur but only four of these are involved due to the kinetic control.
(28) Murahashi, S.-I. Angew. Chem., Int. Ed. Engl. 1995, 34, 2443.
(29) For reaction of O2 with related flavins to give flavin hydroperoxides,
see: (a) Kemal, C.; Bruie, T. C. Proc. Natl. Acad. Sci. U.S.A. 1976, 73,
995. (b) Mager, H. I. X.; Berends, W. Tetrahedron 1976, 32, 2303.

1370 J. Am. Chem. Soc., Vol. 123, No. 7, 2001
Jonsson et al.
Ever since the Upjohn procedure was published in 197611
the NMO-based procedure has become one of the standard
methods for osmium-catalyzed dihydroxylation. However, in
the asymmetric dihydroxylation (AD) NMO has not been fully
appreciated since it was difficult to obtain high ee with this
oxidant. The preferred oxidant for AD, introduced by Sharp-
less as the AD-mix,1c is K3Fe(CN)6, which gives high ee with
various olefins when phthalazine ligands (DHQD)2PHAL and
(DHQ)2PHAL) are employed.
CP-3380 chromatograph using a DBWAX-5 column. Optical rotations
were obtained on a Perkin-Elmer 241 Polarimeter and are reported as
follows [R]temperaturewavelength, concentration (c ) g/100 mL), and solvent.
Slow additions of olefins were carried out using a Sage model 355
syringe pump. Plastic syringes and a syringe pump Sage model 365
were used for slow addition of H2O2.
All olefins and reagents were obtained from commercial suppliers
and used without further purification. N-methylmorpholine (NMO) was
obtained from Fluka, and H2O2 (30% aqueous) and OsO4 (as a 2.5 wt
% solution in t-BuOH) were purchased from Aldrich. Tetraethylam-
monium acetate (TEAA, 99%) and (DHQD)2PHAL (99%) were
acquired from Aldrich. The flavin 3 used was synthesized according
to a previously published procedure.17
threo-5,6-Decanediol (2). General Procedure A for Dihydroxy-
lation of trans-5-Decene with OsO4 and H2O2. trans-5-Decene (1
mmol) was dissolved in acetone (3.75 mL) and H2O (1.25 mL) at room
temperature. OsO4 (251 µL, 2.5 wt% 0.02 mmol) was added followed
by H2O2 (155 µL, 30% aqueous 1.5 mmol). The reaction mixture was
stirred for 26 h at room temperature and then quenched by addition of
Na2S2O4 (120 mg) and magnesium silicate (240 mg). After 2 h of
stirring the mixture was diluted with ethyl acetate and filtered through
a pad of Celite, and the Celite bed was washed thoroughly with ethyl
acetate. The solvent was removed to give a residue which was purified
by flash chromatography using a mixture of pentane/EtOAc (80:20) to
afford 2 (0.018 g, 10%).
threo-5,6-Decanediol (2). General Procedure B for Dihydroxy-
lation of trans-5-Decene Using OsO4-NMM with Slow Addition of
H2O2 in the Presence of TEAA. trans-5-Decene (0.5 mmol) was
dissolved in acetone (1.88 mL) and H2O (0.62 mL) at room temperature.
To this mixture was added NMM (15 µL, 0.14 mmol), tetraethylam-
monium acetate (261 mg, 1 mmol), and OsO4 (125 µL, 2.5 wt %, 0.01
mmol). H2O2 (77 µL, 30% aqueous, 0.75 mmol) was then introduced
over 9 h using a syringe pump. The yellow mixture was stirred for an
additional 14 h and then quenched by addition of Na2S2O4 (60 mg)
and magnesium silicate (120 mg). After 2 h of stirring the mixture
was diluted with ethyl acetate and filtered through a pad of Celite, and
the Celite bed was washed thoroughly with ethyl acetate. The solvent
was removed, and the residue was purified by flash chromatography
using a mixture of pentane/EtOAc (80:20) to give 2 (0.060 g, 69%)
threo-5,6-Decanediol (2). General Procedure C for Dihydroxy-
lation of trans-5-Decene Using OsO4-NMM-Flavin with Slow
Addition of H2O2 in the Presence of TEAA. trans-5-Decene (0.5
mmol) was dissolved in acetone (1.88 mL) and H2O (0.62 mL) at room
temperature. To this mixture was added NMM (15 µL, 0.14 mmol),
tetraethylammonium acetate (261 mg, 1 mmol), flavin 3 (6.7 mg, 0.025
mmol), and OsO4 (125 µL, 2.5 wt %, 0.01 mmol). H2O2 (77 µL, 30%
aqueous, 0.75 mmol) was then introduced over 9 h using a syringe
pump. The yellow mixture was stirred for an additional 7 h and then
quenched by addition of Na2S2O4 (60 mg) and magnesium silicate (120
mg). After 2 h of stirring the mixture was diluted with ethyl acetate
and filtered through a pad of Celite, and the Celite bed was washed
thoroughly with ethyl acetate. The solvent was removed to give the
crude diol. The crude diol was purified by flash chromatography using
a mixture of pentane/EtOAc (80:20) to afford 2 (0.084 g, 96%)
(1R)-1-Phenyl-1,2-ethandiol. General Procedure for Asymmetric
Dihydroxylation of Styrene Using OsO4-NMM-Flavin with Slow
Addition of Olefin and H2O2 in the Presence of TEAA. To a flask
charged with t-BuOH (1.88 mL) and H2O (0.62 mL) was added NMM
(27 µL, 0.25 mmol), tetraethylammonium acetate (261 mg, 1 mmol),
(DHQD)2PHAL (23 mg, 0.03 mmol), and flavin 3 (6.7 mg, 0.025
mmol). This stirred mixture was cooled to 0 °C, and OsO4 (125 µL,
2.5 wt% 0.01 mmol) was added, followed by 1/5 of the H2O2 (1/5 × 77
µL, 30% aqueous, 1/5 × 0.75 mmol). The yellow reaction mixture was
stirred for 20 min, and then the neat alkene (0.5 mmol) and the rest of
the H2O2 were added over a period of 9 h using separate syringe pumps.
After the addition was complete, the resulting clear yellow solution
was stirred at 0 °C for an additional 2 h and quenched by addition of
Na2S2O4 (60 mg) and magnesium silicate (120 mg). After 2 h of stirring
the mixture was diluted with ethyl acetate and filtered through a pad
of Celite, and the Celite bed was washed thoroughly with ethyl acetate.
The solvent was removed, and the residue was purified by flash
More recently, however, it was demonstrated that NMO can
be employed as oxidant in the AD reaction to give high ee (up
to 98%) in aqueous tert-BuOH with slow addition of the olefin.20
Also, recent work by Kobayashi23 and our present study show
that NMO is indeed a viable oxidant in AD under appropriate
reaction conditions. In light of this renaissance of NMO as a
useful oxidant in AD, the catalytic in situ generation of the
N-oxide from tertiary amine is of particular importance.
In the osmium-catalyzed AD, two catalytic cycles have been
inferred by Sharpless and co-workers,25a one cycle with a
monoglycolate ester giving high ee and a second cycle with a
bisglycolate ester giving poor ee. A problem with NMO is
apparently that it is difficult to avoid involvement of the second
cycle. By slow addition of the olefin, formation of the
bisglycolate ester is depressed, and hence the involvement of
the second cycle becomes less important. Also, slow addition
of the oxidant may have a similar effect as well as addition of
TEAA. A good example demonstrating the effect of slow
addition is the dihydroxylation of 1-phenylcyclohexene (Table
6). An increase of the addition time for olefin and H2O2 from
9 to 20 h increased the enantioselectivity from 69 to 92% ee
(entries 11 and 12). To the best of our knowledge this is the
highest ee reported for this olefin when NMO is used to recycle
Os(VI) to Os(VIII) (cf. Scheme 2).
Conclusions
We have developed a mild triple catalytic system consisting
of osmium tetroxide, N-methylmorpholine, and the biomimetic
flavin analogue 3, where hydrogen peroxide is used as the
terminal oxidant. With this multistep electron-transfer system
the oxidation potential of H2O2 has been lowered stepwise, and
thus it is possible to direct the selectivity toward the desired
transformation. This stepwise electron transfer with falling redox
potential is reminiscent of electron-transfer processes occurring
in biological systems. A number of olefins were selectively cis-
dihydroxylated to their corresponding diols in good to excellent
yields, and by the use of chiral ligands high enantiomeric
excesses (ee’s) were obtained. The process does not require
access to an amine oxide but rather a tertiary amine in catalytic
amounts, which generates the amine oxide in situ. Since a variety
of tertiary amines are readily available this allows a useful
variation of the in situ generated amine oxide.
Experimental Section
1
General Methods. H and 13C NMR spectra were recorded on a
Varian Unity 400 (400 MHz 1H, 100 MHz 13C) spectrometer. Chemical
shifts (δ) are reported in ppm, using residual solvent as internal standard.
Merck silica gel 60 (240-400 mesh) was used for flash chromatog-
raphy, and analytical thin-layer chromatography was performed on
Merck precoated silica gel 60-F254 plates. Analytical high-pressure liquid
chromatography (HPLC) was performed on a Waters liquid chromato-
graph using a Daicel Chiralcel OD-H column or a Daicel Chiracel
OK-H column. Gas chromatography (GC) was performed on a Varian
(30) For the use of isomeric flavins in catalytic oxidations, see: (a)
Murahashi, S.-I.; Oda, T.; Masui, Y. J. Am. Chem. Soc. 1989, 111, 5002.
(b) Mazzini, C.; Lebreton, J.; Furstoss, R. J. Org. Chem. 1996, 61, 8.

Osmium-Catalyzed Dihydroxylation of Olefins
J. Am. Chem. Soc., Vol. 123, No. 7, 2001 1371
chromatography using a mixture of pentane/EtOAc (80:20) to afford
(1R)-1-phenyl-1,2-ethanediol (0.055 g, 80%). Analysis by HPLC
showed that the product was of 95% ee.
tR(minor) ) 38.9 min25b), (1R)-1-phenyl-1,2-ethanediol40 (HPLC (Daicel
Chiralcel OK column, 98:2 hexane/2-propanol, flow rate 1.0 mL/
min): tR(major) ) 53.2 min25b), 2-methyl-1-phenyl-1,2-propanediol,41
2-methyl-1,2-heptanediol,42 3-phenoxy-1,2-propanediol,43 (1R,2R)-1-
phenylpropane-1,2-diol44 (HPLC (Daicel Chiralcel OD-H column, 95:5
hexane/2-propanol, flow rate 0.5 mL/min): tR(major) ) 28.1 min, tR-
(minor) ) 30.5 min44).
Characterization of Products. The following compounds are known
compounds, and their spectra were in accordance with those reported
in the literature: threo-5,6-decanediol (1b),31 (R,R)-5,6-decanediol
([R]25D +19.8 (c 1.00, CHCl3)),31 (R,R)-1,2-Diphenyl-1,2-ethanediol32
([R]25 +86.5 (c 1.00, EtOH)),26 octane-2,3-diol,33 octane-4,5-diol,34
D
cis-1,2-cyclohexanediol,35 cis-1-methyl-1,2-cyclohexanediol,36 (1R,2R)-
1-phenyl-1,2-cyclohexane-diol37 (Daicel Chiralcel OD-H column, 90:
10 hexane/2-propanol, flow rate 0.5 mL/min): tR(major) ) 31.4 min,
tR(minor) ) 33.9 min25b), 1,2-diphenyl-1,2-ethanediol (meso),38 (1R)-
1-phenyl-1,2-propanediol39 (HPLC (Daicel Chiralcel OD-H column,
95:5 hexane/2-propanol, flow rate 0.5 mL/min): tR(major) ) 34.7 min,
Acknowledgment. Financial support from the Swedish
Natural Science Research Council, the Swedish Research
Council for Engineering Sciences, and the Swedish Foundation
for Strategic Research is gratefully acknowledged.
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