Osmium-catalyzed asymmetric dihydroxylation of olefins by H2O2; dual role of the cinchona alkaloid ligand

Article abstract of DOI:10.1021/ol016450t

(matrix presented) A novel application of the cinchona alkaloid derivative (DHQD)₂PHAL in the osmium-catalyzed asymmetric dihydroxylation of olefins is presented. In a triple catalytic system using H₂O₂ as the terminal oxidant, the alkaloid ligand has a dual function in providing stereocontrol in the addition step and, via its N-oxidized form, acting as reoxidant for the in situ generated osmium(VI). The formation of the N-oxide is catalyzed by a biomimetic flavin.

Full text of DOI:10.1021/ol016450t

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3463-3466
Osmium-Catalyzed Asymmetric
Dihydroxylation of Olefins by H O ; Dual
2 2
Role of the Cinchona Alkaloid Ligand
Sandra Y. Jonsson, Hans Adolfsson,* and Jan-E. Ba1ckvall*
Department of Organic Chemistry, Stockholm UniVersity,
SE-106 91 Stockholm, Sweden
jeb@organ.su.se
Received July 18, 2001 (Revised Manuscript Received September 25, 2001)
ABSTRACT
A novel application of the cinchona alkaloid derivative (DHQD)2PHAL in the osmium-catalyzed asymmetric dihydroxylation of olefins is presented.
In a triple catalytic system using H O as the terminal oxidant, the alkaloid ligand has a dual function in providing stereocontrol in the addition
2
2
step and, via its N-oxidized form, acting as reoxidant for the in situ generated osmium(VI). The formation of the N-oxide is catalyzed by a
biomimetic flavin.
Herein we report on the first example of an enantioselective
catalytic redox process where the chiral ligand has two
fundamentally different modes of operation: (1) to provide
stereocontrol in the addition to the substrate, and (2) through
an oxidized form, to be responsible for the reoxidation of
the metal. The use of environmentally benign oxidants, like
molecular oxygen, air, or aqueous hydrogen peroxide, has
become increasingly important in the field of synthetic
organic chemistry.1 The direct oxidation of organic material
by these oxidants is, however, often slow and also very
unselective. Nature efficiently circumvents this problem in
biological redox processes, by introducing one or several
relaying electron-transfer mediators (ETMs) to reduce the
energy barrier between the terminal oxidant and the substrate
in question, leading to selectivity in the oxidation step.2 The
same principle is also applied in several synthetically useful
transition metal catalyzed oxidation reactions, where the
substrate-selective catalyst gets reoxidized by a suitable
ETM, which in turn is recycled by molecular oxygen or
hydrogen peroxide as the terminal oxidant.3,4
The osmium-catalyzed asymmetric dihydroxylation of
olefins undoubtedly qualifies as one of the most recognized
asymmetric processes known by the scientific community.5
Osmium tetroxide is an example of a highly substrate-
selective oxidant, reacting only with olefins to form the
parent syn-diols. With the introduction of the cinchona
alkaloid-based ligands a highly enantioselective process was
developed.6 In the reaction with an olefin, the catalytically
active Os(VIII) is reduced to Os(VI), and in order to run the
process with a catalytic amount of osmium tetroxide, a
number of different systems have been introduced for the
(3) (a) Tsuji, J. Palladium Reagents and Catalysts. InnoVations in
Organic Synthesis; Wiley: Chichester, U.K., 1995. (b) Ba¨ckvall, J. E.;
Hopkins, R. B.; Grennberg, H.; Mader, M.; Awasthi, A. K. J. Am. Chem.
Soc. 1990, 112, 5160. (c) Wo¨ltinger, J.; Ba¨ckvall, J. E.; Zsigmond, A. Chem.
Eur. J. 1999, 5, 1460.
(1) (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.
(2) (a) Moser, C. C.; Keske, J. M.; Warncke, K.; Faird, R. S.; Dutton, P.
L. Nature 1992, 355, 796. (b) Nugent, J. H. A. Eur. J. Biochem. 1996,
237, 519. (c) Hughes, M. N. The Inorganic Chemistry of Biological
Processes; Wiley: Chichester, U.K., 1981.
(4) (a) Bergstad, K.; Jonsson, S. Y.; Ba¨ckvall, J. E. J. Am. Chem. Soc.
1999, 121, 10424. (b) Jonsson, S. Y.; Fa¨rnegårdh, K.; Ba¨ckvall, J. E. J.
Am. Chem. Soc. 2001, 123, 1365. (c) EÄ ll, A. H.; Jonsson, S. Y.; Bo¨rje, A.;
Adolfsson, H.; Ba¨ckvall, J. E. Tetrahedron Lett. 2001, 42, 2569.
(5) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483. (b) Kolb, H. C.; Sharpless, K. B. In Transition Metals for
Organic Synthesis; Beller, M., Bolm, C., Eds.; VCH Wiley: Weinheim,
1998.
10.1021/ol016450t CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/09/2001

reoxidation of the metal into its active form. The most
common oxidants are potassium ferricyanide (present in the
AD-mixes)7 or N-methylmorpholine N-oxide (NMO, the
Upjohn process).8 Recently, molecular oxygen or air were
introduced as oxidants for the direct reoxidation of Os(VI)
in the catalytic reaction, thus providing a more environmen-
tally friendly system.9
with various tertiary mono- and diamines in the presence of
TEAA (tetraethylammonium acetate) (Table 1).
Table 1. cis-Selective Dihydroxylation of trans-5-Decene
Using Different Tertiary Amines in the Triple Catalytic Systema
We have previously reported on the use of aqueous
hydrogen peroxide as the terminal oxidant in the dihydroxy-
lation of olefins (Scheme 1).4
Scheme 1. Triple Catalytic System for Osmium-Catalyzed
Dihydroxylation of Olefins Using H2O2 as the Terminal Oxidant
a trans-5-Decene (0.5 mmol), tertiary amine (27 mol %), TEAA (2 equiv),
flavin 1 (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 yield of the diol. c Reference
4b.
In this triple-catalytic system the introduction of a catalytic
amount of a biomimetic flavin (1) as an electron-transfer
Thus, it was found that it is possible to use different tertiary
monoamines with essentially the same outcome (entries
1-6). We further investigated if our system was compatible
with the use of tertiary diamines (Table 1, entries 7 and 8).
When using TMEDA as the amine source a yield of 43% of
the corresponding diol was obtained (entry 7). The use of
catalytic OsO4 with chelating diamines is currently unknown,
since the bidentate ligands form very stable chelated osmate
esters, which are difficult to hydrolyze and/or reoxidize.5a,11-13
Next, we examined the use of Sharpless’ cinchona-based
ligand hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2-
PHAL, 3)6b as a tertiary amine source in the catalytic system.
When employing (DHQD)2PHAL as the tertiary amine in
the dihydroxylation of trans-5-decene (entry 8) a yield of
93% of the diol was obtained in 63% ee.
mediator allowed for the selective oxidation of N-methyl-
morpholine (NMM) to NMO,10 which in turn oxidizes the
reduced form of the osmium catalyst. The flavin reacts
rapidly with hydrogen peroxide, forming a flavin hydrop-
eroxide (2), the active catalyst for the oxidation of the tertiary
amine. Here we report on a highly enantioselective dihy-
droxylation of olefins using a chiral, amine-containing, ligand
as the source of chirality and as reoxidant for the in situ-
formed osmium(VI) intermediate (Scheme 2).
(6) (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. (c) Wang, Z. M.; Sharpless, K. B. J. Org.
Chem. 1994, 59, 8302.
Scheme 2
(7) Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55, 766.
(8) VanRheenen, V.; Kelly, R. C.; Cha, D. F. Tetrahedron Lett. 1976,
1973.
(9) Do¨bler, C.; Mehltretter, G.; Sundermeier, U.; Beller, M. J. Am. Chem.
Soc. 2000, 122, 10289.
(10) Bergstad, K.; Ba¨ckvall, J. E. J. Org. Chem. 1998, 63, 6650.
(11) Blades, K.; Donohoe, T. J.; Winter, J. J. G.; Stemp, G. Tetrahedron
Lett. 2000, 41, 4701.
(12) (a) Donohoe, T. J.; Moore, P. R.; Waring, M. J.; Newcombe, N. J.
Tetrahedron Lett. 1997, 38, 5027. (b) Blades, K.; Donohoe, T. J.; Winter,
J. J. G.; Stemp, G. Tetrahedron Lett. 2000, 41, 4701.
(13) Donohoe, T. J.; Blades, K.; Moore, P. R.; Winter, J. J. G.; Helliwell,
M.; Stemp, G. J. Org. Chem. 1999, 64, 2980.
Because the flavin/H2O2 system works very well for
oxidation of various tertiary amines to their corresponding
N-oxides,10 it was of interest to investigate if NMM could
be replaced by other tertiary amines in the triple catalytic
system. Dihydroxylation of trans-5-decene was carried out
3464
Org. Lett., Vol. 3, No. 22, 2001

Scheme 3. Proposed Catalytic Cycle for the Enantioselective Dihydroxylation of Olefins Using (DHQD)2PHAL for Oxygen Transfer
to Os(VI) and as Source of Chirality
Encouraged by the promising results obtained with the
triple catalytic system using (DHQD)2PHAL as the tertiary
amine source (cf. Scheme 1) we turned to the asymmetric
version of the reaction and set out to investigate the
possibility of using the ligand both as reoxidant and source
of chirality. For the asymmetric dihydroxylations, the solvent
was changed to t-BuOH because performing the oxidation
in acetone gave substantially lower enantioselectivity.14 The
most important factor for obtaining high enantioselectivity,
however, is the use of slow addition of the olefin to the
reaction mixture. As discovered in the original studies of
the catalytic asymmetric dihydroxylation, a low olefin
concentration efficiently prevents the reaction from entering
the enantio-detrimental second catalytic cycle.6a We have
further found that an improvement of the ee was obtained
when one-fifth of the hydrogen peroxide was added to the
reaction mixture 20 min prior to the introduction of the
olefin.4b Presumably, this builds up a low buffer concentra-
tion of amine oxide by oxidizing some of the tertiary amine.
After this initial preactivation, the remaining H2O2 as well
as the olefin were added over 9 h via separate syringe pumps.
When performing the asymmetric dihydroxylation on
styrene using (DHQD)2PHAL (6 mol %) both as ETM and
chiral source, an ee of 95%, was obtained (Scheme 2, Table
2, entry 1). Dihydroxylation of trans-stilbene (entry 2) and
R-methylstyrene (entry 3) gave the corresponding diols in
90% ee, respectively. Interestingly, with trans-â-methyl-
styrene (entry 4) an ee of 99% was obtained, which is higher
than with the method based on NMM. However, the
trisubstituted olefin 1-phenyl-1-cyclohexene (entry 5) gave
a substantially lower ee, even though the addition time of
both olefin and hydrogen peroxide was increased from 9 to
20 h.4b,6a
The results obtained with (DHQD)2PHAL both as the
ETM and chiral ligand are comparable to those obtained
employing NMM together with (DHQD)2PHAL. In two
cases, for R-methylstyrene and 1-phenyl-1-cyclohexene, ee’s
lower than those of the NMM-based procedure were
obtained.
The proposed catalytic cycle for the reaction is depicted
in Scheme 3. We envisage a rapid flavin-catalyzed formation
of the mono-N-oxide 4 of the ligand, which via its non-
oxidized tertiary amine coordinates to osmium tetroxide to
give 5. Previously, we have demonstrated that it is possible
to oxidize the tertiary amine functionality on DHQD by
employing the flavin/H2O2 system.15 Control experiments
show that oxidation of (DHQD)2PHAL using the flavin/H2O2
system selectively gives the mono-N-oxide 4.16 The olefin
enters the binding pocket, resulting in the enantioselective
formation of an osmium-glycolate (6). Reoxidation of
Os(VI) can now occur, having the active oxidant within the
ligand. The observed efficiency using only 6 mol % of 3 as
compared to 50 mol % of NMM indicates a fast intra-
(15) Utas, J. E.; Adolfsson, H. Unpublished results.
(16) Only the mono-N-oxide was observed according to spectral data
(m/z 794.9474). Performing the oxidation using MCPBA resulted in the
formation of a mixture of the mono-N-oxide and the di-N-oxide (m/z
810.9302).
(14) Argren, L.; Sutin, L. Org. Process Res. DeV. 1997, 1, 425.
Org. Lett., Vol. 3, No. 22, 2001
3465

the isolated (DHQD)2PHAL-mono-N-oxide (4) as the sto-
ichiometric reoxidant and chirality transfer agent in the
dihydroxylation of styrene afforded the corresponding diol
in 71% isolated yield and 98% ee (Scheme 4). Thus, it is
likely that the major pathway involves N-oxide 4.
Table 2. Asymmetric Dihydroxylation of Different Olefins
Using H2O2 as the Terminal Oxidanta,b
Scheme 4
Hydrolysis of the osmium-glycolate liberates the diol,
osmium tetroxide, and the free ligand, which can re-enter
the catalytic cycle. Thus, the ligand has a dual role in the
reaction, participating in both enantiodifferentiation and in
oxygen transfer.
In conclusion, we have developed an osmium-catalyzed
asymmetric dihydroxylation protocol using H2O2 as the
terminal oxidant and the alkaloid ligand (DHQD)2PHAL as
both electron transfer mediator and source of chirality. A
number of olefins were efficiently converted to the corre-
sponding syn-diols with excellent enantioselectivity via the
biomimetic triple catalytic system.
a Reference 4b. b TEAA (2 equiv), (DHQD)2PHAL (0.06 equiv), and
flavin 1 (0.05 equiv) were dissolved in t-BuOH (1.88 mL) and H2O (0.62
mL). The mixture was cooled to 0 °C, and OsO4 (0.02 equiv) was added
followed by one-fifth of the H2O2 (0.3 equiv, 30% aqueous). The mixture
was stirred for 20 min, and then the olefin (0.5 mmol, 1 equiv) 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.
c Isolated yields. d Enantiomeric excesses were determined by HPLC. The
absolute configuration of the diols were determined by comparison of optical
rotations with literature values. e Acetone/H2O (4.4:1) was employed. f The
enantiomeric excess was determined from optical rotational data (see ref
6c). g The olefin and H2O2 were introduced over 20 h.
Acknowledgment. Financial support from the Swedish
Natural Science Research Council, the Swedish Research
Council for Engineering Sciences, and the Swedish Founda-
tion for Strategic Research is gratefully acknowledged.
molecular oxygen transfer process (6 f 7). Although direct
oxidation of Os(VI) by flavin hydroperoxide cannot be
excluded, this potential background process seems unlikely
as a major pathway. When the tertiary amine was omitted
in the triple catalytic racemic version of the dihydroxylation,
the yield dropped dramatically.4b Furthermore, employing
Supporting Information Available: Experimental pro-
cedures, characterizations, and chiral-phase HPLC data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL016450T
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Org. Lett., Vol. 3, No. 22, 2001