A Mechanistically Guided Design Leads to the Synthesis of an Efficient and Practical New Reagent for the Highly Enantioselective, Catalytic Dihydroxylation of Olefins

Article abstract of DOI:10.1021/ol035192s

(Equation presented) The catalytic asymmetric dihydroxylation of olefins has been accomplished with high enantioselectivities using a proline-based catalyst. The pre-transition-state assembly for styrene is shown.

Full text of DOI:10.1021/ol035192s

ORGANIC
LETTERS
2003
Vol. 5, No. 19
3455-3458
A Mechanistically Guided Design Leads
to the Synthesis of an Efficient and
Practical New Reagent for the Highly
Enantioselective, Catalytic
Dihydroxylation of Olefins
Jinkun Huang and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received June 26, 2003
ABSTRACT
The catalytic asymmetric dihydroxylation of olefins has been accomplished with high enantioselectivities using a proline-based catalyst. The
pre-transition-state assembly for styrene is shown.
The high enantioselectivity and broad applicability of the
biscinchona alkaloid-catalyzed dihydroxylation of olefins by
osmium tetraoxide have made this reaction a synthetic tool
of extraordinary utility.1,2 Although initially the underlying
reasons for its effectiveness were obscure, a series of
mechanistic studies generated a transition-state model that
has turned out to be both rational and powerfully predictive.3-7
The model can be illustrated by the proposed pre-transition-
state assembly, 1, for the enantioselective dihydroxylation
of styrene by OsO4 using a pyridazine-linked bisdihydro-
quinidine catalyst. On the basis of this model, several new
and useful catalysts have been designed, including the Noe-
Lin (2)5d and Zhang (3)8 systems for the position-selective
and enantioselective terminal dihydroxylation of oligoprenols
(e.g., farnesyl acetate).
(5) (a) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc.
1995, 117, 10805. (b) Corey, E. J.; Guzman-Perez, A.; Noe, M. C.
Tetrahedron Lett. 1995, 36, 3481. (c) Corey, E. J.; Noe, M. C.; Ting, A.
Tetrahedron Lett. 1996, 37, 1735. (d) Corey, E. J.; Noe, M. C.; Lin, S.
Tetrahedron Lett. 1995, 36, 8741. (e) Corey, E. J.; Noe, M. C.; Guzman-
Perez, A. J. Am. Chem. Soc. 1995, 117, 10817.
(6) (a) Corey, E. J.; Noe, M. C.; Grogan, M. J. Tetrahedron Lett. 1996,
37, 4899. See also: (b) DelMonte, A. J.; Haller, J.; Houk, K. N.; Sharpless,
K. B.; Singleton, D. A.; Strassner, T.; Thomas, A. A. J. Am. Chem. Soc.
1997, 119, 9907.
(1) For a review of the catalytic asymmetric dihydroxylation of olefins,
see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(2) 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.
(3) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 11038.
(4) (a) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1993, 115, 12579.
(b) Corey, E. J.; Noe, M. C.; Sarshar, S. Tetrahedron Lett. 1994, 35, 2861.
(c) Corey, E. J.; Noe, M. C.; Grogan, M. J. Tetrahedron Lett. 1994, 35,
6427. (d) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319. (e)
Corey, E. J.; Noe, M. C.; Sarshar, S. J. Am. Chem. Soc. 1993, 115, 3828.
(7) Corey, E. J.; Sarshar, S.; Azimioara, M. D.; Newbold, R. C.; Noe,
M. C. J. Am. Chem. Soc. 1996, 118, 7851.
(8) Corey, E. J., Zhang, J. Org. Lett. 2001, 3, 3211.
10.1021/ol035192s CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/28/2003

droxylation of olefins that was based on guidance from the
mechanistic model. On the basis of the model, we expected
that the (R)-proline-derived catalyst 4 would be effective
whereas the (S)-proline diastereomer (5) would not be.
A simple two-step synthesis of the (R)-proline-based
catalyst 4 is summarized in Scheme 1. Conversion of
dihydroquinidine (6) to the sodium salt with NaH in
dimethylformamide followed by reaction with 1 equiv of 3,6-
dichloropyridazine afforded the cross-coupling product 8. A
second coupling of 8 with the (R)-proline amide 9 under
palladium catalysis produced catalyst 4 as a crystalline solid,
mp 131-132 °C, [R]22 +29.0 (c ) 1.2, CHCl3). The (R)-
D
proline amide 9 was prepared by coupling of the acid chloride
of N-carbobenzyloxy-(R)-proline with dihydroindole fol-
lowed by hydrogenolysis of the Cbz protecting group, as
shown in Scheme 1 (bottom). The (S)-proline-derived
diastereomer of 4 (5) was also prepared by the route shown
in Scheme 1 starting from (S)-proline.
Ligand 4 dramatically accelerated the dihydroxylation of
a series of olefins under the same conditions that have been
employed previously for catalytic reactions with the biscin-
chona alkaloid-OsO4-K3Fe(CN)6-t-BuOH-H2O system.
The results obtained for the catalytic dihydroxylation of 12
olefinic substrates under promotion by ligand 4 are sum-
marized in Table 1. Both the rates and enantioselectivities
observed using ligand 4 (0.7 mol %) with these substrates
are at least equal to the best that have been reported for any
other ligand, including the popular Sharpless biscinchona
ligand (DHQD)2PHAL. The synthetic accessibility of ligand
4, the requirement for only 0.7 mol % in the catalytic
dihydroxylation, the ease of recovery of 4 for reuse, and the
exceptional catalytic efficiencies and enantioselectivities that
are documented in Table 1 all combine to recommend the
use of this new reagent.
The use of ligand 5, the diastereomer of 4 derived from
(S)-proline, in the catalytic dihydroxylation of olefins led to
only poor enantioselectivity as expected from the mechanistic
model. The enantioselectivity was in fact no better than with
In this paper, we describe the synthesis and successful
application of a new ligand for the enantioselective dihy-
Scheme 1
3456
Org. Lett., Vol. 5, No. 19, 2003

mediated dihydroxylation produced styrenediol of 56 and
53% ees, respectively. Similarly, much lower ees were
observed with 5 as ligand and either trans-stilbene or
1-phenylcyclohexene as a substrate than those recorded in
Table 1 for ligand 4.
Table 1. Enantioselective Dihydroxylation of Olefins
Catalyzed by 4 (0.7 mol %)
The pre-transition-state assembly for the enantioselective
dihydroxylation of styrene by OsO4 and ligand 4 that was
anticipated from the mechanistic model3,4 is shown in 10.
This structure contains the following elements, in common
with other highly enantioselective chiral ligand-OsO4
complexes: (1) a U-shaped conformation that allows attack
by the axial oxygen and one equatorial oxygen of OsO4 on
the π-bond of the substrate, as it is bound within the pocket
that forms from the structural subunits of the U, and (2) a
minimum motion pathway from this arrangement for the [3
+ 2]-cycloaddition, which directly produces the pentacoor-
dinate osmate(VI) ester in the energetically most favorable
geometry.3,4 The rate acceleration for the observed enanti-
oselective pathway relative to other modes of reaction is due
to a lowering of ∆Gq that results from increased binding to
ligand 4 in the transition state and to initial precomplexation
of the reactants (these reactions follow saturation, i.e.,
Michaelis-Menten kinetics4d). [3 + 2]-Cycloaddition to the
opposite π-face of the olefin is unfavorable because there is
no comparably stable three-dimensional transition-state ar-
rangement. The pyridazine ring at the bottom of the U-shaped
binding pocket is oriented to allow coplanarity of the O-C
and N-C subunits attached at positions 3 and 6 (for
maximum conjugation of O and N into the electron-attracting
pyridazine ring). The prolyl amide linkage is coplanar in 10,
and the planes of the proline and dihydroindole rings are
1
approximately at a 90° angle. Two-dimensional NOE H
NMR studies of the monomethiodides of 4 and 5 confirm
that the proline R-C-H and indoline methylene protons at
C(2) are juxtaposed as indicated in the depictions 4, 5, and
10 shown herein. The mechanistic model predicts that 5, the
diastereomer of ligand 4, cannot form a similar favorable
U-shaped binding pocket and, thus, should not lead to the
level of enantioselectivity realized with ligand 4. We believe
that the experimental results disclosed herein for ligands 4
and 5 add additional weight to the already strong case4d for
the mechanistic model.
a Reaction performed at 0 °C following the general procedure in the ref
9; ees were determined by 1H NMR analysis of Mosher diesters. b Ees
determined in these two cases by HPLC analysis using a Chiracel OJ
column.
In conjunction with the development of 4 as a useful
reagent for the asymmetric dihydroxylation of olefins, we
undertook to find a more practical substitute for K3Fe(CN)6
as the stoichiometric oxidant in the Sharpless procedure. In
larger scale reactions, the huge amount of K3Fe(CN)6 that
is normally required (3 mol/mol of olefin) and the attendant
workup and disposal issues represent major drawbacks. Some
years ago, we observed that sodium chlorite (NaClO2), an
inexpensive oxidant, could replace K3Fe(CN)6 in catalytic
enantioselective oxidations with biscinchona catalysts.10
the simpler dihydroquinidine 8 (Scheme 1). Thus, with
styrene as a substrate and 5 and 8 as chiral ligands, the OsO4-
(9) General Procedure for Catalytic Asymmetric Dihydroxylation.
A mixture of ligand 4 (5 mg, 0.008 mmol), K2OsO4‚2H2O (1.0 mg, 0.0027
mmol), K3Fe(CN)6 (1.18 g, 3.57 mmol), K2CO3 (0.493 g, 3.57 mmol), and
MeSO2NH2 (113 mg, 1.19 mmol, only when 1,2-disubstituted or trisub-
stituted olefins were used as substrates) in 12 mL of 1:1 t-BuOH-H2O
was stirred at 0 °C for 0.5 h. The olefin (1.19 mmol) was added to the
suspension, and the resulting mixture was stirred vigorously at 0 °C for
Org. Lett., Vol. 5, No. 19, 2003
3457

However, a major disadvantage of the NaClO2 system was
the oxidation of the catalytic ligand (resulting in its loss)
and also overoxidation of the olefinic substrate. A recent
reinvestigation of NaClO2 as an oxidant has led to the
development of an excellent dihydroxylation system consist-
ing of 0.7 mol % OsO4, 10 mol % K3Fe(CN)6, 50 mol %
NaClO2, and 4 equiv of K2CO3 with 1:1 t-BuOH-H2O as
the solvent. The best results are obtained when the NaClO2
is added slowly to the reaction mixture. A representative
procedure appears below.11 In general, enantioselectivities
were very good and reaction rates were satisfactory, as shown
for the five examples in Table 2.
Table 2. Enantioselective Dihydroxylation of Olefins
Catalyzed by 4 (0.7 mol %) with NaClO2 as a Cooxidant
The yields of product diol were also good but somewhat
lower than those for the conventional Sharpless procedure.
In the case of stilbene as the substrate, the lower yield was
accounted for by the coproducts benzil (15%) and benzoic
acid (∼5%), both of which appear to be formed by further
oxidation of the intermediate Os(VI) ester. The chiral ligand
4 could be recovered efficiently from the NaClO2-promoted
dihydroxylations under the conditions employed.11 We
believe that the NaClO2 procedure described herein is at least
as practical as any currently available.12
designed and shown to be at least the equal of the best
biscinchona catalysts such as (DHQD)2PHAL. Though the
noncinchona elements in 11 and 4 are very different, these
catalysts are both excellent reagents for the asymmetric
dihydroxylation of a variety of olefins, and the enantio-
selectivity vs olefin structure profiles are essentially the same.
From a practical standpoint, however, 4 is superior to 11
Catalyst 4 is structurally quite distinct from the monoqui-
nidine dihydroxylation catalyst 114c that has previously been
8-24 h. The reaction was monitored by TLC (20-50% EtOAc/hexane).
After completion of the reaction as indicated by TLC, the reaction mixture
was quenched with Na2SO3 (1.5 g) at 0 °C and then allowed to warm to
room temperature and stirred for 45 min. The reaction mixture was extracted
three times with ethyl acetate (3 × 25 mL). The combined organic extract
was washed with 1 N KOH (to remove methanesulfonamide when
necessary) and 15 mL of brine, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by silica gel chromatography to give the
diol (10-70% EtOAc in hexane) as a colorless solid or colorless oil and
the ligand 4 (5% TEA/EtOAc for elution; quantitative recovery). The
enantiomeric excess (ee) of diols was determined either by chiral-column
HPLC analysis or 1H NMR analysis of the corresponding MTPA esters.
(10) Corey, E. J.; Noe, M. C. Unpublished work, 1994.
(11) Representative Procedure for Catalytic Asymmetric Dihydroxy-
lation Using K3Fe(CN)6 and NaClO2 as Cooxidants. A mixture of ligand
4 (8 mg, 0.013 mmol), K2OsO4‚2H2O (1.0 mg, 0.0027 mmol), K3Fe(CN)6
(17 mg, 0.05 mmol), and K2CO3 (0.276 g, 2.0 mmol) in 5.0 mL of 1:1
t-BuOH-H2O was stirred at 0 °C for 0.5 h. Styrene (0.057 mL, 0.5 mmol)
was added to the suspension. To the resulting stirred mixture was added a
solution of NaClO2 (31 mg in 0.2 mL of H2O) over 5 h by syringe pump.
Stirring was continued at 0 °C until the reaction was complete as indicated
by TLC. The reaction mixture was treated with Na2SO3 (0.7 g) and then
allowed to warm to room temperature and stirred for 45 min. The reaction
mixture was extracted three times with ethyl acetate (3 × 25 mL). The
organic extract was washed with 15 mL of brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel chromatography
to give styrenediol (50% EtOAc in hexane) as a colorless solid, yield )
134 mg (97%), and the ligand 4 (5% TEA-EtOAc, 100%). The enantio-
meric purity was determined to be 90% by 1H NMR integration analysis of
the corresponding bis-MTPA ester (CDCl3, 500 MHz): δ 6.28 ppm (dd, 1
H, (R, major)), 6.18 ppm (dd, 1 H, (S, minor)).
because of the greater ease of synthesis. The experimental
results obtained with 114c and 4, by themselves, provide
strong support for our three-dimensional transition-state
model,3,4 which is as aesthetically pleasing as it is powerfully
predictive.
Acknowledgment. We are grateful to Pfizer, Inc., for
generous support of this research.
Supporting Information Available: Experimental pro-
cedures and physical data are given for compounds 4, 8, and
9 and characterization data for chiral 1,2-diols. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) See: Wirth, T. Angew. Chem., Int. Ed. 2000, 39, 334.
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