A tetradentate ligand for the enantioselective Ti(IV)-promoted oxidation of sulfides to sulfoxides: Origin of enantioselectivity

Article abstract of DOI:10.1021/ja305991k

A detailed stereomechanistic analysis has led to the design of a new tetradentate ligand for the enantioselective Ti(IV)-catalyzed oxidation of unsymmetrical sulfides to sulfoxides with high selectivity. The pathway of this oxidation and the closely related and long-known Kagan-Modena oxidation have been clarified to identify the likely origin of the enantioselectivity.

Full text of DOI:10.1021/ja305991k

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Communication
A Tetradentate Ligand for the Enantioselective Ti(IV)-Promoted
Oxidation of Sulfides to Sulfoxides: Origin of Enantioselectivity
Timothy R Newhouse, Xin Li, Megan M. Blewett, Clare M. C. Whitehead, and E. J. Corey
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 09 Oct 2012
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A Tetradentate Ligand for the Enantioselective Ti(IV)-Promoted
Oxidation of Sulfides to Sulfoxides: Origin of Enantioselectivity
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Timothy R. Newhouse, Xin Li, Megan M. Blewett, Clare M. C. Whitehead, and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
Supporting Information Placeholder
system have been used for the large-scale synthesis of
ABSTRACT: A detailed stereo-mechanistic analysis has led
to the design of a new tetradentate ligand for the
various pharmaceuticals, most noteworthy of which is the
blockbuster product esomeprazole (Nexium®).1
enantioselective
Ti(IV)-catalyzed
oxidation
of
As is detailed in the Supporting Information, extensive
and repeated preparative experiments on the Kagan
system with purified reagents confirmed that two DET’s
per Ti(IV) are required for good enantioselectivity and that
approximately one equiv. of H2O per Ti(IV) is optimal for
enantioselectivity, although this can be replaced by
isopropyl alcohol (4 equiv. per Ti) as in the Modena
system.3
unsymmetrical sulfides to sulfoxides with high selectivity.
The pathway of this oxidation and the closely related and
long-known Kagan-Modena oxidation have been clarified
to identify the likely origin of enantioselectivity.
Almost three decades ago Kagan and co-workers
reported that a reagent formed from Ti(O-i-Pr)4, (R,R)-
diethyl tartrate (DET) and water in a ratio of 1:2:1 in
CH2Cl2 catalyzes the reaction of tert-butylhydroperoxide
with arylalkyl sulfides to form the sulfoxides with
enantiomeric excesses (ee) averaging ca. 80% at –22 °C for
prolonged reaction times (Eq. 1).1,2 In the absence of
water, considerably lower enantioselectivities were
observed. The conditions of catalyst formation and the
temperature of reaction are absolutely critical. The active
catalyst appears to be unstable at higher temperatures and
at lower temperatures both the rate of reaction and ee of
the product are markedly diminished.
We also found by a series of preparative experiments
that the ee of the sulfoxide 1 produced under the optimal
Kagan conditions increased as the time of the oxidation
was extended beyond the point at which all of the starting
sulfide was consumed. The increase in the ee of the
sulfoxide is due to its enantioselective oxidation to the
corresponding sulfone. At a reaction time of 16h, 14h
beyond the disappearance of the starting sulfide, the ee of
sulfoxide 1 rose from ca. 80% at 2h to 96% and it was
accompanied by 18% of methyl p-tolylsulfone. In addition,
exposure of sulfoxide 1 of 82% ee to Kagan oxidation at –
20 °C for 15h produced sulfoxide 1 of >98% ee, plus
considerable sulfone.5 From these results it is obvious that
part of the reason for the success of the reported high
enantioselectivity of some Kagan oxidations lies in the use
of extended reaction times and the intervention of kinetic
resolution of the product 1.2f Previous reports indicate a
divergence of views regarding the occurrence of further
oxidation to sulfone and whether this influences the ee of
the sulfoxide product.2a,2b
At about the same time, Modena’s group3 reported
similar results using a 4:1 ratio of DET to Ti(O-i-Pr)4 and 4
equiv. of isopropyl alcohol at –20 °C. Although no water
was deliberately added to Modena’s reactions, its
adventitious presence seems possible. The purpose of the
present work was elucidation of both the reaction pathway
and basis for enantioselection of Kagan type oxidations,
which continue to be enigmatic despite much research in
this area.1
Kagan has reported2a that there is
a nonlinear
relationship between the enantioselectivity of sulfoxide
formation and the optical purity of DET for the Kagan
process. Our own experiments5 have shown that there is a
linear relationship at short reaction times and that the
nonlinearity arises out of long reaction times most likely
because of the further oxidation of the sulfoxide. The
linearity shown by our data obviate the requirement to
consider an M2L4 pathway, as proposed previously.2d
One reason for the difficulty of understanding the basis
for enantioselection in the DET-Ti(O-i-Pr)4 system
emerged from the extensive 2D-NMR study of Potvin and
Fieldhouse4 which revealed the presence of a complex
mixture of species, possibly in rapid equilibrium on the
reaction time scale. Although the Kagan process is
complicated, even more complex modifications of the
We analyzed a number of possible structures for the
Kagan process starting from the evidence that two DET
ligands are attached via their hydroxyl groups to Ti and the
likelihood that the active oxidant also involved η2-
coordinated hydroperoxide. The η2-coordination mode for
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Figure 1. P and M helical diastereomers of Ti(dimethyl
tartrate)2(t-BuOOH)
Figure 2. The P and M helical isomers of Ti(2)(t-
BuOOH)
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cases. To ensure that the minimized structures were true
local minima
a
standard frequency analysis was
performed.13
Three dimensional modeling and stereochemical
analysis revealed that the P diastereomer of the active
oxidant shown in Figure 1 should favor the formation of
the R-sulfoxide 1 from methyl p-tolylsulfide using the
Kagan (R,R)-DET-Ti(O-i-Pr)4 (2:1) catalyst, whereas the
corresponding M diastereomer is unlikely to lead to
enantioselective oxidation. These analyses suggested that
DET might advantageously be replaced by a suitable
tetradentate chiral ligand, which might be superior to a
pair of DET subunits for entropic reasons while also
favoring the formation of the P form of the active oxidant.
Tetraol 2 emerged as a potentially superior ligand for the
enantioselective Ti(IV)- catalyzed oxidation of sulfides to
sulfoxides, not only because it provides the entropic
advantage over DET but also because it favors the
formation of the t-butylperoxy/COOMe analog of the P-
complex 3 over the M diastereomer by ca. 1.6 kcal/mol as
hydroperoxides to titanium (IV),6 vanadium (V),7 and even
lithium8 has been documented by X-ray crystallography.
In addition density functional studies have revealed the
favorable nature of η2-coordination to Ti(IV).5,9
There are two possible diastereomers for
a
hexacoordinate (octahedral or near octahedral) complex of
Ti(IV) with two DET’s and one η2-hydroperoxide ligand.10
The most stable arrangement of each of these helical
isomers was determined by density functional theory
(DFT) calculations which indicated the structures shown in
Figure 1.11 The P (or ꢀ) diastereomer shown in panel A is
more stable than the M (or Λ) form (panel B), the
calculated energy difference (ꢀE0) being 2.2 kcal/mol.5,12
To reduce computational cost, diethyl tartrate was
replaced by dimethyl tartrate (DMT) and cumene
hydroperoxide was replaced with t-butyl hydroperoxide.
Figure 3. Synthesis of Ligand 2 and proposed pre-
transition state assembly
To locate the lowest energy structures, several starting
geometries were generated by different methods and then
optimized by DFT.11 For all light atoms, this was
performed using the B3LYP density functional with the 6-
31G* basis set and for titanium the Los Alamos National
Lab electrostatic core potential was used with two double-
zeta basis sets (LANL2DZ).
Input structures were
generated with Spartan ’08 using molecular mechanics
(MMFF) and a semi-empirical method (PM3), as well as
without optimization.
The B3LYP energy surface of the resulting lowest energy
structure was then explored further by scanning the
dihedral angles corresponding to the orientation of the
carbomethoxy substituents of the dimethyl tartrate
ligands. A proton was then attached to each of the tartrate
oxygens on Ti with hydrogen bonding to any nearby
electron donor oxygen. These low energy structures were
finally optimized by moving the one oxygen-bound proton
to each of the four other possible locations, followed by re-
optimizing with the proton at each location. The electronic
energies reported include a zero-point energy correction
and are referenced to the lowest energy isomer in both
a
Reagents and conditions: a. 4.0 equiv. (COCl)2, 0.1 equiv.
DMF, CH2Cl2 (0.8 M), 0-23 °C, 12h; b. 0.50 equiv 1,4-bis(2-
hydroxyethyl)benzene, 1.0 equiv. pyridine, CH2Cl2 (0.5 M),
0-23 °C, 24h, 89% (2 steps); c. 20 equiv. HF-pyridine, 3.0
equiv. H2O, CH3CN (2.8 M), 0-23 °C, 3h, 77%.
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Figure 4. Variation of the Linker and Comparison to
the Kagan Process
°C with a mixture of ligand 2, Ti(O-i-Pr)4, H2O (ratio 1:1:1)
1
2
3
4
5
6
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and 2 equivalents of cumene hydroperoxide (CHP), the
starting sulfide was completely consumed in 1h with the
formation of the corresponding (R)-sulfoxide (1) (95%
conversion by 1H-NMR analysis, 90% isolated yield) having
92% enantiomeric purity (by chiral HPLC analysis) along
with 5% of the corresponding sulfone. The absolute
configuration of the sulfoxide corresponds to that expected
for 3 as the active oxidant assuming that a lone pair of the
sulfide attacks the coordinated peroxide backside to the
oxygen-oxygen bond with the other lone pair, methyl
group and p-tolyl groups positioned to minimize steric
repulsion (especially with the COOR group of 4, shown in
blue), as shown in the pre-transition state assembly 4
(Figure 3B).
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A comparison of the oxidation of sulfides with the
combination 2, Ti(O-i-Pr)4, CHP, H2O (ratio 1:1:2:1) with
the optimum Kagan reagent (R,R)-DET, Ti(O-i-Pr)4, CHP,
H2O (2:1:2:1) in CH2Cl2 at –20 °C is instructive. After a
reaction time of 1h with the Kagan reagent, the conversion
of methyl p-tolylsulfide to the sulfoxide is only 79% and
the ee is at best only 80-86%.
In all cases the
predominating enantiomer is the (R)-sulfoxide. One
equivalent of water is beneficial in both cases since the ee
values of the (R)-sulfoxide in the absence of water were
found to be only 59% with the ligand 2 system and 28%
with (R,R)-DET (2 equiv. per Ti) as ligand; the yields of
sulfoxide were reduced by a factor of about 1.5. The
enantioselective formation of 1 can also be effected using
only 20 mol % of ligand 2 and Ti(O-i-Pr)4 on larger scale.5
We have also examined the application of ligand 2,
Ti(O-i-Pr)4, CHP, H2O – system (ratio 1:1:2:1 in CH2Cl2 at
–20 °C) to a series of other unsymmetrical sulfides with
the results that are summarized in Figure 4B. In each case
the enantioselectivities that were observed are higher than
those obtained in the optimized Kagan system. It should
also be mentioned that the use of ligand 2-based reagent
has the advantage over DET that the efficient recovery of
the ligand for reuse is possible due to its ready extraction
from the aqueous citric acid2g used in workup of the
reaction. Oxidations using the ligand 2 system can also be
performed at –40 °C and are more enantioselective (e.g.
96% ee for 1). We are currently investigating other useful
applications of ligand 2 to enantioselective catalysis.
aConversion determined by 1H-NMR analysis after a 1h
A small series of ligands (5) based on two linked (R,R)-
monoethyl tartrate subunits, which are analogous to
tetraol 2, were synthesized and evaluated for the oxidation
of methyl p-tolylsulfide to the sulfoxide (Figure 4A). Of
these 5a was found to be almost as effective as 2 in
promoting reaction enantioselectivity and rate. The
effectiveness of the other ligands decreased in the order
5b > 5c >> 5d.5 With ligand 5d the ee of sulfoxide formed
under Kagan conditions was only ca. 15%, a finding which
is easily understandable since this ligand does not allow
formation of a structure analogous to 3.
reaction time; conditions under which methyl p-tolylsulfone is
b
not formed. Value in parentheses is that reported by Kagan
c
and co-workers2b for extended reaction times. Reaction time
was 12h. dThis experiment was performed by Dr. Rong-Jie
Chien – under Kagan conditions.
indicated by DFT calculations (Figure 2).5,12
Ligand
2 was conveniently synthesized from the
acetonide of (R,R)-tartaric acid monoethyl ester by the
sequence: (1) conversion to the corresponding acid
chloride using (COCl)2 and a catalytic amount of DMF in
CH2Cl2 (initially at 0 °C and then at 23 °C for 12h), (2)
reaction with 1,4-bis(2-hydroxyethyl)benzene and
pyridine at 0 – 23 °C for 24h, and (3) acetonide cleavage
using 20 equivalents of HF-pyridine and 3 equivalents of
H2O at 23 °C for 3h (Figure 3A).5
There are a number of reasonable possibilities for the
favorable effect of water (or 4 equiv. of i-PrOH)2,3 on the
enantioselectivity of the Kagan-Modena oxidation of
sulfides to sulfoxides: (1) water (or i-PrOH) improves the
ratio of the P helical isomer of Ti(DET)2CHP to the M
isomer; the former being on the enantioselective pathway
When methyl p-tolylsulfide is oxidized in CH2Cl2 at –20
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gratefully
acknowledged
for
a
sample
of
whereas the latter is not; (2) water inhibits oxidation via
other non-enantioselective paths; or (3) water increases
the rate of oxidation of sulfide via the P helical isomer of
1
2
3
dihydrobenzothiophene and for data on its oxidation.
Ti(DET)2CHP relative to that for the M helical isomer.14
A
REFERENCES
4
5
6
7
8
9
more precise clarification of the influence of water on
enantioselectivity is challenging because of the presence of
multiple species in the Kagan-Modena system.4
(1) Reviews: (a) O’Mahony, G. E.; Kelly, P.; Lawrence, S. E.;
Maguire, A. R. ARKIVOC 2011, 1 – 110. (b) Wojaczynska, E.;
Wojaczynski, E. Chem. Rev. 2010, 110, 4303 – 4356. (c) Kagan, H.
B. in Organosulfur Chemistry in Asymmetric Synthesis. Taru, T.
and Bolm, C. eds. Wiley-VCH Verlag, Weinheim, 2008.
(2) (a) Pitchen, P.; Kagan, H. B. Tetrahedron Lett. 1984, 25,
1049 – 1052. (b) Pitchen, P.; Duñach, E.; Deshmukh, M. N.; Kagan,
H. B. J. Am. Chem. Soc. 1984, 106, 8188 – 8193. (c) Kagan, H. B.;
Duñach, E.; Nemecek, C.; Pitchen, P.; Samuel, O.; Zhao, S.-H. Pure
Appl. Chem. 1985, 57, 1911 – 1916. (d) Puchot, C.; Samuel, O.;
Duñach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986,
108, 2353 – 2357. (e) Zhao, S. H.; Samuel, O.; Kagan, H. B.
Tetrahedron 1987, 43, 5135 – 5144. (f) Zhao, S. H.; Samuel, O.;
Kagan, H. B. Org. Synth. 1989, 68, 49 – 56. (g) Brunel, J.-M.; Diter,
P.; Duetsch, M.; Kagan, H. B. J. Org. Chem. 1995, 60, 8086 – 8088.
(h) Brunel, J. M.; Kagan, H. B. Synlett 1996, 404 – 406.
(3) Di Furia, F.; Modena, G.; Seraglia, R. Synthesis 1984, 325 –
326.
The rates of Kagan-Modena oxidations increase with
increasing hydroperoxide and sulfide concentrations with
DET as ligand.5 In the case of the sulfide reactant, the rate
dependence is almost, but not strictly first order, possibly
because the sulfide can complex to Ti and compete with
hydroperoxide for Ti coordination to form an η2–peroxy
complex. A similar inhibition has also been observed for
DET as the ratio of DET to Ti is increased from 2 to 4. The
oxidations with 2 as ligand also show positive order
kinetics for the sulfide and hydroperoxide.5
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It is of some interest in connection with the
enantioselective Kagan process15 and the oxidations
directed by ligand 2 that the ligand-free oxidation of
methyl p-tolylsulfide with Ti(O-i-Pr)4 and CHP alone in
CH2Cl2 at –20 °C is much faster and leads rapidly to
approximately 2:1 mixtures of racemic sulfoxide and
sulfone.2 Thus, the ligands (R,R)-DET and 2 actually
decelerate the ligand-free, Ti(IV)-catalyzed process. It is
possible that the beneficial effect of water is due to
reduction of amounts of Ti(O-i-Pr)4 or species having just
one DET attached to titanium.
(4) Potvin, P. G.; Fieldhouse, B. G. Tetrahedron: Asymmetry
1999, 10, 1661 – 1672.
(5) See the Supporting Information for details.
(6) Boche, G.; Moebus, K.; Harms, K.; Marsch, M. J. Am. Chem.
Soc. 1996, 118, 2770 – 2771.
(7) Mimoun, H.; Chaumette, P.; Mignard, M.; Saussine, L.;
Fischer, J.; Weiss, R. Nouv. J. Chim. 1983, 7, 467.
(8) Boche, G.; Moebus, K.; Harms, K.; Lohrenz, J. C. W.; Marsch,
M. Chem. Eur. J. 1996, 2, 604 – 607.
(9) Seenivasaperumal, M; Federsel, H.-J.; Szabó, K. J. Adv. Synth.
Catal. 2009, 351, 903 – 919.
(10) (a) For stereochemical nomenclature, see Moss, E. P. Pure
Appl. Chem. 1996, 68, 2193 – 2222. (b) For the original
nomenclature of helical handedness (lel, ob) see Corey, E. J.;
Bailar, J. C. J. Am. Chem. Soc. 1959, 81, 2620 – 2629.
(11) All DFT calculations were performed with Gaussian 09: (a)
Frisch, M. J. et al. Gaussian 09, Rev. A.02; Guassian, Inc.:
Wallingford, CT, 2009. Structures were rendered with CYLView:
(b) CYLview, 1.0b; Legault, C. Y., Université de Sherbrooke, 2009
(http://www.cylview.org).”
(12) The energy of the P diastereomer was also found to be
lower than that of the M diastereomer using the M06-2X/6-
31G*//LANL2DZ procedure, the difference being somewhat
greater than the values reported above.
(13) The procedures used in our work for DFT satisfactorily
reproduced the bond lengths and angles of the titanium-
hydroperoxide complex described in the X-ray analysis of Boche
et al. (Ref. 8). Additionally, the extent to which the tertiary alkyl
group of the peroxide is out of plane is closely reproduced (see
the Supporting Information for details). This deviation from
planarity has a through space steric effect on the conformation of
In conclusion, the present work has resulted in the
development of a new and highly effective chiral ligand (2)
for the enantioselective, Ti(IV)-promoted oxidation of
sulfides to sulfoxides and also a logical pathway for the
process. In addition these studies, together with a careful
examination of the Kagan process, have clarified this
important, but long-mysterious area. Finally, our work has
revealed a striking similarity between the enantioselective
oxidations with 2 and DET as ligands for Ti as a
consequence of parallel mechanistic paths.
ASSOCIATED CONTENT
Supporting Information. Optimized XYZ coordinates for the
P and M forms of Ti(DMT)(t-BuOOH), Ti(2)(t-BuOOH), XYZ
coordinates of other Ti complexes, full reference 11a, full
experimental details for oxidation reactions and the syntheses
of ligands 2 and 5, initial rates and reaction progress kinetic
data, nonlinear effects data. This material is available free of
charge via the Internet at http://pubs.acs.org.
the neighboring five-membered tartrate titanacycle.
This
secondary interaction helps to explain the increase in ee
associated with replacing the t-butyl hydroperoxide by cumene
hydroperoxide in the Kagan oxidation.
(14) A Swedish group9 has described evidence that H2O can
also favor the formation of monomeric Ti species from dimeric
oxygen-bridged structures.
(15) For related work on the pathway of the (Katsuki-
Sharpless) DET-Ti(O-i-Pr)4-ROOH-catalyzed epoxidation of allylic
alcohols, see: (a) Sharpless, K. B.; Woodward, S. S.; Finn, M. G. Pure
Appl. Chem. 1983, 55, 1823 – 1836. (b) Corey, E. J. J. Org. Chem.
1990, 55, 1693 – 1694. (c) Woodward, S. S.; Finn, M. G.; Sharpless,
K. B. J. Am. Chem. Soc. 1991, 113, 106 – 113. (d) Finn, M. G.;
Sharpless, K. B. J. Am. Chem. Soc. 1991, 113, 113 – 126. (e) Cui, M.;
Adam, W.; Shen, J. H.; Luo, X. M.; Tan, X. J.; Chen, K. X.; Ji, R. Y.;
Jiang, H. L. J. Org. Chem. 2002, 67, 1427 – 1435.
AUTHOR INFORMATION
Corresponding Author
corey@chemistry.harvard.edu
ACKNOWLEDGMENT
The authors dedicate this paper to Prof. Henri B. Kagan for his
pioneering contributions to asymmetric synthesis. This work
was supported by Bristol Myers-Squibb for a Postdoctoral
Fellowship to TRN, Zhejiang University for a Cooperating
Research Fellowship to XL, by the Hertz Foundation for a
Graduate Fellowship to MMB, and by the Harvard
Undergraduate Research Program (CMCW). Dr. R.-J. Chien is
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