An improved version of the Sharpless asymmetric dihydroxylation

Article abstract of DOI:10.1016/S0040-4039(00)01396-4

The osmium catalyzed asymmetric dihydroxylation of olefins (Sharpless AD) was studied under controlled pH conditions. It was found that providing a constant pH value of 12.0 leads to improved reaction rates for internal olefins. Hydrolysis aids such as methanesulfonamide can be omitted. For terminal olefins, working at a constant pH of 10.0 at room temperature leads to higher enantioselectivities compared to AD reactions without pH control. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01396-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8083–8087
An improved version of the Sharpless asymmetric
dihydroxylation
Gerald M. Mehltretter, Christian D o¨ bler, Uta Sundermeier and Matthias Beller*
Institut f u¨ r Organische Katalyseforschung (IfOK) an der Universit a¨ t Rostock e.V., Buchbinderstraße 5-6,
D-18055 Rostock, Germany
Received 9 August 2000; accepted 16 August 2000
Abstract
The osmium catalyzed asymmetric dihydroxylation of olefins (Sharpless AD) was studied under
controlled pH conditions. It was found that providing a constant pH value of 12.0 leads to improved
reaction rates for internal olefins. Hydrolysis aids such as methanesulfonamide can be omitted. For
terminal olefins, working at a constant pH of 10.0 at room temperature leads to higher enantioselectivities
compared to AD reactions without pH control. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric dihydroxylations; olefins; osmium.
1
The osmium catalyzed asymmetric dihydroxylation (Sharpless AD) has developed into one of
the most important tools for the enantioselective functionalization of olefins (Eq. (1)).
(1)
AD reactions are usually performed with commercially available AD-mixes, consisting of 0.4
mol% K [OsO (OH) ], 1 mol% (DHQD) PHAL (AD-mix i) or (DHQ) PHAL (AD-mix h), 3
2
2
4
2
2
equiv. of K [Fe(CN) ] and 3 equiv. of K CO . In the case of internal olefins the addition of at
3
6
2
3
2
3
2
least a stoichiometric amount of a hydrolysis aid such as Et NOAc or MeSO NH is required
4
2
to obtain reasonable reaction rates, due to hydrolysis problems of sterically hindered intermedi-
ate osmate esters.
During our work on the osmium catalyzed dihydroxylation of olefins with molecular oxygen
4
as the terminal oxidant, we recognized that internal olefins react best at pH values between 11.2
and 12.0, due to an enhanced hydrolysis of the intermediate osmate esters under strong basic
conditions. Surprisingly, no detailed investigations on the exact influence of the pH value on the
*
Corresponding author. Tel: +49-381/466930; fax: +49-381/4669324; e-mail: matthias.beller@ifok.uni-rostock.de
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01396-4

8084
5
rate and the selectivity of AD reactions with other reoxidants exist. In this paper we report our
studies on the influence of pH on the rate and selectivity for dihydroxylations of different olefins
using K [Fe(CN) ] as the reoxidant.
3
6
Initially, we examined the asymmetric dihydroxylation of trans-5-decene. Applying original
t
AD conditions (5 mmol trans-5-decene, 50 ml H O/ BuOH (1:1), 3 equiv. K [Fe(CN) ], 3 equiv.
2
3
6
K CO , 0.4 mol% K [OsO (OH) ], and 1 mol% (DHQD) PHAL), a pH value of 12.2 is
2
3
2
2
4
2
6
measured in the biphasic mixture at the start of the reaction. Consistent with the overall
stoichiometry (Eq. (2)), the pH of the mixture decreases continuously during the reaction to a
final value of 9.9, since two hydroxide ions are consumed for the dihydroxylation of each
molecule of trans-5-decene. As shown in Fig. 1a, product formation correlates well with the
decrease in pH. At room temperature full conversion of the olefin (94% isolated yield of
5
,6-decanediol, 93% ee) is not achieved before 34 hours reaction time. The dihydroxylation
proceeds rapidly at the start, but becomes significantly slower after the pH has reached a value
of ca. 11. This may be explained by the fact that the hydrolysis of the intermediate glycolate
ester is slower when the reaction mixture becomes less basic. We presumed therefore that an
increase in the overall rate would occur if the pH is maintained at a constant value above 11
during the entire reaction period.
Figure 1. Dihydroxylation of trans-5-decene with AD-mix without pH control (a) and with automatic titration (b)
In fact, when the dihydroxylation of trans-5-decene is performed at a constant pH value of
1
2
2.0 by using an automatic titration unit (2N NaOH), full conversion is obtained after less than
hours (95% isolated yield, 90% ee, see Table 1). Thus, the dihydroxylation of trans-5-decene is
7
significantly faster when run under a constant pH value of 12.0 rather than without pH control.
1a
Even if 1 equiv. of MeSO NH is added as advised in the original protocol (Table 1, entry 2),
2
2
the reaction is slower than the pH-controlled variant without MeSO NH . In addition, the
2
2
procedure presented here allows the reaction to be conveniently followed by simply observing
the titration curve (see Fig. 1b). Total conversion is indicated by titration of 5 ml of the NaOH
−
8
solution (10 mmol of OH per 5 mmol of olefin). The obtained ee of 90% is somewhat lower
compared to 93% ee without titration, which is probably due to competition of hydroxide ions
with the chiral ligand under the strong basic conditions. Consistent with this assumption, the
decrease in ee can be overcome by applying a higher ligand concentration (Table 1, entry 4).
(2)

8085
Table 1
a
Sharpless AD under controlled pH conditions
a
General conditions: 5 mmol olefin, 3 equiv. K [Fe(CN) ], 3 equiv. K CO , 0.4 mol% K [OsO (OH) ], 1 mol%
3
6
2
3
2
2
4
t
b
ligand, 50 ml H O/ BuOH (1:1). The given value is the pH value to which the automatic titration unit was set.
Titration with 2N NaOH. Isolated yields. The ee of 5,6-decanediol was determined by HPLC analysis of the
bisbenzoate derivative, all others by HPLC analysis of the purified diols (see Ref. 5b for details). 1 equiv.
MeSO NH is added. 4 mol% ligand. No remaining olefin was detected after the given reaction time. Benzaldehyde
and acetophenone are formed as the only byproducts. Incomplete reaction. The only other product detected was
recovered starting material. 1 mol% K [OsO (OH) ], 5 mol% ligand. Instead of K CO , a buffer solution (0.5 M
KH PO /2N NaOH, pH 10.0) was used.
2
c
d
e
f
g
2
2
h
i
k
2
2
4
2
3
9
2
4
Next we applied the presented method to tri- and tetrasubstituted olefins. With a-methylstil-
bene as the substrate, total turnover of the olefin is observed within 1.5 hours at a constant pH
of 12.0, compared to 21 hours without pH control (entries 5 and 6). However, the chemoselec-
tivity of the reaction is lower in the case of a constantly high pH throughout the reaction.

8086
The enhancement in rate is most striking for tetrasubstituted olefins. Without titration,
dihydroxylation of 2,3-dimethyl-2-butene yields 50% of pinacol after 20 hours, whereas under a
constant pH of 12.0 full conversion (98% isolated yield) of the substrate is obtained within only
5
hours (entries 7 and 8). In the case of 2-methyl-3-phenyl-2-butene, with 0.4 mol% catalyst, 95%
diol yield is obtained after 24 hours at constant pH compared to only 28% without titration
(
entries 9 and 10).
This considerable increase in the reaction rate opens the possibility to run the dihydroxylation
of 2-methyl-3-phenyl-2-butene even at 0°C (entry 11). This leads to a remarkable gain in
enantioselectivity of 52% ee compared to 38% ee reported by Sharpless et al. for the same
1
0
substrate at 25°C. Using (DQHD) PYR as the chiral ligand, an ee of even 61% is obtained
2
10
under these conditions (entry 12), compared to 44% at 25°C without pH control. Additionally,
no MeSO NH is required under the presented conditions, whereas 3 equiv. of this additive are
2
2
advised in the original protocol for tetrasubstituted olefins.
In agreement with the faster hydrolysis of osmium glycolates of terminal olefins a-methyl-
styrene shows no rate enhancement when the AD is performed at a constant pH of 12.0 (entries
1
3 and 14). However, when the AD of a-methylstyrene and of allyl phenyl ether is run at a
constant pH of 10.0 at room temperature, a slight increase in ee is observed compared to the
reactions without pH control due to the less basic conditions during the whole reaction period
(
entries 15 and 17).
In conclusion, we have shown that the pH value of the reaction medium in AD reactions is
a critical reaction parameter which effects rate, chemo- and enantioselectivity. By applying a
constant pH value of 12.0 during the reaction, significant improvements in rate and space-time
yield have been realized for 1,2-di-, tri- and tetrasubstituted olefins. In addition, the enantio-
selectivity in AD reactions of terminal olefins at room temperature is slightly enhanced by
applying a constant pH of 10.0. It is likely that the presented methodology is also applicable to
dihydroxylations with other reoxidants like NMO, H O etc.
2
2
Acknowledgements
This research was supported by the Ministry of Education, Science and Cultural Affairs of
Mecklenburg-Vorpommern and the Bayer AG. We thank Dr. M. Eckert and Dr. C. Militzer
(
Bayer AG) for helpful discussions. We also thank Dr. C. Fischer for performing HPLC studies
and Dr. M. Hateley for helpful comments on this manuscript.
References
1
. For reviews see: (a) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547; (b)
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; (c) Marko, I. E.; Svendsen, J. S. In Comprehensive Asymmetric Catalysis
II; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999; pp. 713–787.
2
3
. Akashi, K.; Palermo, R. E.; Sharpless, K. B. J. Org. Chem. 1978, 43, 2063–2066.
. 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, 2768–2771.
4. (a) D o¨ bler, C.; Mehltretter, G.; Beller, M. Angew. Chem. Int. Ed. 1999, 38, 3026–3028. (b) D o¨ bler, C.;
Mehltretter, G. M.; Sundermeier, U.; Beller, M. J. Am. Chem. Soc., in press.

8087
5
. The use of buffered reaction conditions (3 equiv. NaHCO , pH 10.3, aqueous layer) was reported to have
3
beneficial effects on the yield in AD reactions when base sensitive substrates are used or base sensitive products
are formed: (a) Kolb, H. C.; Bennani, Y. L.; Sharpless, K. B. Tetrahedron: Asymmetry 1993, 4, 133–141. (b)
Vanhessche, K. P. M.; Wang, Z.-M.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 3469–3472.
6
. The pH was measured in the vigourously stirred biphasic mixture with a pH sensitive electrode (Mettler Toledo
InPro 4200). The values were stable and only slightly different compared to the pH of the pure aqueous phase.
. Typical procedure: in a 250 ml two necked flask, equipped with a pH sensitive electrode and an automatic
titration unit (Schott TitroLine alpha), 4.95 g (3 equiv.) K [Fe(CN) ], 2.1 g (3 equiv.) K CO , 7.4 mg (0.4 mol%)
7
3
6
2
3
K [OsO (OH) ] and 39.0 mg (1 mol%) (DHQD) PHAL are dissolved in 50 ml of a 1:1 mixture of H O and
2
2
4
2
2
t
BuOH. After addition of 980 ml (5 mmol) of trans-5-decene, the biphasic mixture is stirred at room temperature
and kept at a constant pH of 12.0 by automatic titration with a 2N NaOH solution. After titration of 5 ml of
NaOH (1.8 h), the reaction is quenched by addition of 7.5 g Na SO . The mixture is stirred for another hour,
2
3
then 100 ml of ethyl acetate are added. After separation, the organic layer is dried over MgSO and concentrated.
4
Purification of the residue by column chromatography (hexane/EtOAc 2:1) gives 826 mg (95%) of 5,6-decanediol
as a colorless solid.
8
. Titration continues at a lower rate after full conversion due to overoxidation of the 5,6-decanediol product. This
is also the case for a-methylstilbene, allyl phenyl ether, but not for a-methylstyrene and the tetrasubstituted
olefins.
9. It is advisable to buffer the reaction solutions to avoid strong fluctuations in the pH during titration.
10. Morikawa, K.; Park, J.; Andersson, P. G.; Hashiyama, T.; Sharpless, K. B. J. Am. Chem. Soc. 1993, 115,
8
463–8464.
.