An enantiopure pseudo-C3-symmetric titanium triflate with propeller-like chirality as a catalyst for asymmetric sulfoxidation reactions

Article abstract of DOI:10.1039/b918141p

A chiral pseudo-C₃-symmetric titanium triflate that employs the point chirality of a single stereogenic centre to control the propeller chirality of its aryl rings has been used to catalyse an asymmetric sulfoxidation reaction. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b918141p

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An enantiopure pseudo-C3-symmetric titanium triflate with propeller-like
chirality as a catalyst for asymmetric sulfoxidation reactions†
Philip Axe,a Steven D. Bull,*a Matthew G. Davidson,*a Matthew D. Jones,a Diane E. J. E. Robinson,a
William L. Mitchellb and John E. Warrenc
Received 26th June 2009, Accepted 16th September 2009
First published as an Advance Article on the web 5th October 2009
DOI: 10.1039/b918141p
A chiral pseudo-C3-symmetric titanium triflate that employs
the point chirality of a single stereogenic centre to control the
propeller chirality of its aryl rings has been used to catalyse
an asymmetric sulfoxidation reaction.
Amine tris-(phenolate) ligands have recently been introduced as
a versatile class of tripodal ligand for preparing a wide range
of transition metal complexes.1 Many of these complexes are
monomeric five-coordinate trigonal bipyramidal structures that
arise from simultaneous coordination of their three aryloxide
and tertiary amino groups to a metal centre.2 Tripodal metal
Fig. 2 (R,M)- and (R,P)-diastereoisomers of pseudo-C3-symmetric tita-
nium complexes.
complexes such as titanium triflate 1 and titanium isopropoxide
2 are racemic,3,4 because complexation of the achiral amine
tris-(phenol) ligand results in the formation of (M)- and (P)-
enantiomers arising from the propeller-like chirality of their aryl
rings (Fig. 1). A number of these tripodal metal complexes
have been used as catalysts in stereoselective polymerization
reactions and other types of synthetic transformations.5 However,
all reports to date have employed racemic metal complexes, with
catalytic applications of enantiopure metal complexes remaining
unexplored.
diastereoisomer (R,M)-3 occurs preferentially because the corre-
sponding diastereoisomer (R,P)-4 is disfavoured by syn-pentane-
like interactions between the pseudoequatorial methyl group and
its proximal aryl ring.7 This chiral relay strategy8 results in the
ortho-tert-butyl substituents of its aryl propeller fragment creating
a C3-symmetric environment within the coordination sphere of the
titanium centre.9 We were interested in determining whether these
types of pseudo-C3-symmetric titanium complex could be used for
asymmetric catalysis, and now report herein that they may be used
as catalysts for asymmetric sulfoxidation reactions.
Titanium isopropoxide (R,M)-3 was reacted with Me3SiOTf
in toluene at reflux to afford a chiral titanium triflate as a
red crystalline solid in 99% yield. An X-ray crystal structure†
was obtained, which was found to be a 3 : 1 mixture of
the diastereoisomeric titanium triflates (R,M)-5 (Fig. 3a) and
(R,P)-6 (Fig. 3b). The major diastereoisomer (R,M)-5 contains
an approximately trigonal bipyramidal titanium centre that lies
slightly above the plane of the three equatorial phenolate oxygen
atoms, with the axial sites occupied by the neutral nitrogen atom
of the ligand and a monodentate triflate anion. The absolute (R)-
configuration of its pseudoaxial methyl stereocentre locks the
helical chirality of the aryl substituents of its ligand framework
into a (M)-propeller conformer. The average tilt of the aryl
groups of (R,M)-5 (as defined by the average angle between the
aryloxide planes and the Ti–N bond vector) is 12◦. Viewing the
structure of (R,M)-5 along its Ti–N bond vector from the top face
reveals that the three proximal tert-butyl groups serve to create
a C3-symmetric environment within the coordination sphere of
its titanium atom (Fig. 3c). The minor diastereoisomer (R,P)-
6 contains a pseudoequatorial methyl group that results in its
aryl rings adopting a (P)-propeller conformation, resulting in its
proximal tert-butyl groups creating a stereochemical environment
around its titanium centre that is pseudo-enantiomeric to that
observed for (R,M)-5.
Fig. 1 Titanium triflate (rac)-1 and titanium isopropoxide (rac)-2.
We have recently described the synthesis of a diastereomeri-
cally pure pseudo-C3-symmetric titanium isopropoxide (R,M)-
3 whose helical chirality is controlled by its stereogenic methyl
substituent adopting a pseudoaxial conformation (Fig. 2).6 This
aDepartment of Chemistry, University of Bath, UK BA2 7AY.
E-mail: s.d.bull@bath. ac.uk; Fax: +44 1225 386231; Tel: +44 1225 383551
bNeurology Medicinal Chemistry 3, GSK PLC, Harlow, Essex, UK CM19
5AW
cSTFC Daresbury Laboratory, Daresbury, Warrington, UK WA4 4AD
† Electronic supplementary information (ESI) available: Preparation, spec-
troscopic and X-ray data for titanium triflate (R,M)-5 and representative
asymmetric sulfoxidation protocol. CCDC reference number 737968. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/b918141p
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Table 1 Asymmetric sulfoxidation reactions of sulfide 7 catalysed by pseudo-C3-symmetric titanium complexes (R,M)-3 or (R,M)-5
Entry
Catalyst
Solvent/additive
Oxidant
Ratio (8 : 9)a
(R)-8 (% ee)
1
(R,M)-3
(R,M)-3
(R,M)-3
(R,M)-5
(R,M)-5
(R,M)-5
(R,M)-5
(R,M)-5
(R,M)-5
(R,M)-5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2 + 4 A sieves
ClCH2CH2Cl
Acetone
CHP (2 equiv.)
CHP (2 equiv.)
CHP (2 equiv.)
CHP (1 equiv.)
TBHP (2 equiv.)
CHP (2 equiv.)
CHP (2 equiv.)
CHP (2 equiv.)
CHP (2 equiv.)
CHP (3 equiv.)
9 : 1 (63%)
85 : 15
91 : 9
97 : 3 (54%)
99 : 1 (25%)
78 : 22
86 : 14
94 : 6 (70%)
89 : 11
18
23
23
8
2
3b
4
5
6
7
8
3
˚
32
23
9
37
47
9
Toluene
Toluene
10c
33 : 67
a Reactions which resulted in incomplete consumption of sulfide 7 have % conversion values reported in brackets. b Reaction carried out at -78 ◦C.
c Reaction carried out for 36 h.
The 1H NMR spectrum of the titanium triflate (R,M)-5 at
room temperature was similar to that previously observed for
titanium isopropoxide (R,M)-3, displaying a quartet and four
AB doublets (two partially overlapped between d = 4.15 ppm
and d = 3.40 ppm) that were assigned to the two pseudoaxial
and three pseudoequatorial benzylic protons (Jgem ≥ 13.0 Hz)
of its ligand framework. This observation is consistent with the
complex existing in solution as a single conformer (R,M)-5, with
no resonances observed for the corresponding diastereoisomer
(R,P)-6 that had been observed in the solid state (Fig. 3).
the solvent to dichloroethane (23% ee, entry 7) or acetone (9%
ee, entry 8) did not result in improved enantiocontrol. However,
use of the non-coordinating solvent toluene did afford improved
enantioselectivity to afford sulfoxide (R)-8 in 78% yield and 37% ee
(entry 9).
We then investigated whether the ee of chiral sulfoxide (R)-8
was being enhanced by a competing kinetic resolution pathway
involving ‘matched’ stereoselective oxidation of the minor (S)-
enantiomer of sulfoxide 8 to its corresponding sulfone9. Therefore,
sulfide 7 was treated with three equivalents of CHP in toluene at
-30 ◦C with aliquots of the reaction mixture being analysed after
24 and 36 h. After 24 h, all of the starting sulfide 7 had been
consumed, affording a 83 : 17 ratio of sulfoxide 7 : sulfone 8, with
(R)-8 being present in 35% ee. After 36 h, the ratio of sulfoxide to
sulfone was found to be 33 : 67, with recovered sulfoxide (R)-8 now
being present in an improved 47% ee (entry 10), clearly implying
that a ‘matched’ kinetic resolution pathway was operating to
enhance the enantiomeric excess of (R)-8. In order to confirm
that kinetic resolution was occurring, (rac)-sulfoxide 8 was treated
with two equivalents of cumene hydroperoxide in the presence
of 10 mol% of (R,M)-5 in toluene at -30 ◦C for 8 h, which
gave 55% conversion to its corresponding sulfone 9, resulting in
sulfoxide (R)-8 being recovered in 16% ee. This indicates that the
(S)-enantiomer of sulfoxide 8 is preferentially oxidised under these
conditions, albeit with a relatively small selectivity factor (S) of
1.57.11
Analysis of the crude reaction product arising from treatment of
one equivalent of titanium triflate (R,M)-5 with two equivalents
of sulfide 7 and four equivalents of CHP revealed that a new
titanium sulfoxide complex was present. This was revealed by the
presence of a new series of characteristic diastereotopic benzylic
proton resonances between d = 4.70 and 3.05 ppm in its 1H NMR
spectrum and a molecular ion at 946.5 (C59H80NO4STi) in its
mass spectrum.12 This suggests that the structural integrity of the
amine-tris-(phenolate) ligand framework of the titanium complex
is retained throughout the course of the asymmetric sulfoxidation
reaction.13 This, in turn, implies that a chiral relay network
operates throughout the catalytic cycle,14 with the point chirality of
the stereogenic methyl group controlling the propeller chirality of
We have previously shown that titanium triflate (rac)-1 could
be used as an air- and moisture-resistant Lewis acid for aza-
Diels–Alder reactions.3 Therefore, titanium isopropoxide (R,M)-
3 and titanium triflate (R,M)-5 were screened as catalysts for
the aza-Diels–Alder reaction of N-benzylidene-benzylamine with
Danishefsky’s diene, however the resultant N-benzyl-2-phenyl-
2,3-dihydropyridin-4-one proved to be racemic in both cases.
Alternatively, Licini and co-workers have reported that a related
titanium isopropoxide (rac)-2 could be used as a catalyst for
sulfoxidation reactions using aqueous hydrogen peroxide as a
stoichiometric oxidant.4 In a modification of their conditions, we
found that reaction of benzyl(phenyl)sulfide 7 and two equivalents
of cumene hydroperoxide (CHP) with 10 mol% of titanium
isopropoxide complex (R,M)-3 in CH2Cl2 at -30 ◦C for 24 h
resulted in 63% conversion to afford sulfoxide 8 and sulfone 9 in
a 9 : 1 ratio. Chiral HPLC analysis of the crude reaction mixture
revealed that sulfoxide 8 had been formed in 18% enantiomeric
excess (ee) in favour of its (R)-enantiomer (Table 1, entry 1).10
Using 10 mol% of titanium triflate complex (R,M)-5 as catalyst
under the same conditions gave sulfoxide 8 and sulfone 9 in an
85 : 15 ratio, with (R)-8 having been formed in 23% ee (entry 2).
Attempts to improve the enantioselectivity of the sulfoxidation
reaction by carrying out the reaction using 10 mol% of (R,M)-
5 at -78 ◦C (23% ee, entry 3), using one equivalent of cumene
hydroperoxide (8% ee, entry 4), or changing the oxidant to tert-
butyl hydroperoxide (TBHP) (3% ee, entry 5) proved unsuccessful.
˚
Addition of 4 A molecular sieves to the reaction mixture resulted
in a 78 : 22 ratio of sulfoxide 8 to sulfone 9, with (R)-8 being
isolated in an improved 32% ee (Table 1, entry 6). Changing
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In conclusion, we have shown that a pseudo-C3-symmetric tita-
nium triflate (R,M)-5 that displays propeller chirality may be used
to catalyse the asymmetric sulfoxidation of benzyl(phenyl)sulfide
7 with moderate enantioselectivity. To the best of our knowledge,
this represents the first example where the point chirality of a single
stereogenic centre has been used to control propeller chirality
within the same ligand framework of a tripodal metal complex
for asymmetric catalysis.15
Acknowledgements
We thank the EPSRC and GlaxoSmithKline for funding.
Notes and references
1 H. Kawaguchi and T. Matsuo, J. Organomet. Chem., 2004, 689, 4228.
2 G. Licini, M. Mba and C. Zonta, Dalton Trans., 2009, 5265.
3 (a) S. D. Bull, M. G. Davidson, A. L. Johnson, D. E. J. E. Robinson
and M. F. Mahon, Chem. Commun., 2003, 1750; (b) S. D. Bull, M. G.
Davidson, A. L. Johnson, M. F. Mahon and D. E. J. E. Robinson,
Chem.–Asian J., 2010, DOI: 10.1002/asia.200900305.
4 (a) M. Mba, L. J. Prins and G. Licini, Org. Lett., 2007, 9, 21; (b) C.
Zonta, E. Cazzola, M. Mba and G. Licini, Adv. Synth. Catal., 2008,
350, 2503.
5 (a) W. Wang, M. Fujiki and K. Nomura, Macromol. Rapid Commun.,
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M. D. Jones and M. D. Lunn, Chem. Commun., 2008, 1293; (e) T.
Nagataki and S. Itoh, Chem. Lett., 2007, 36, 748; (f) A. J. Chmura, C. J.
Chuck, M. G. Davidson, M. D. Jones, M. D. Lunn, S. D. Bull and M. F.
Mahon, Angew. Chem., Int. Ed., 2007, 46, 2280; (g) W. Su, Y. Kim, A.
Ellern, I. A. Guzei and J. G. Verkade, J. Am. Chem. Soc., 2006, 128,
13727.
6 P. Axe, S. D. Bull, M. G. Davidson, C. J. Gilfillan, M. D. Jones, D. E. J. E.
Robinson, L. E. Turner and W. L. Mitchell, Org. Lett., 2007, 9, 223.
7 A similar chiral relay approach has been used to control the helical
symmetry of metal complexes derived from neutral tripodal tripyridyl
ligands that have been used as chiral solvating agents for sulfides and
sulfoxides, see: J. W. Canary, C. S. Allen, J. M. Castagnetto and Y.
Wang, J. Am. Chem. Soc., 1995, 117, 8484.
8 S. D. Bull, S. G. Davies, D. J. Fox, A. C. Garner and T. G. R. Sellers,
Pure Appl. Chem., 1998, 70, 1501.
9 Also see: G. Bernardinelli, T. M. Seidel, E. P. Kundig, L. J. Prins, A.
Kolarovic, M. Mba, M. Pontinic and G. Licini, Dalton Trans., 2007,
1573.
10 The configuration of the newly formed stereocentre of the major
enantiomer of sulfoxide (R)-8 was confirmed from the positive sign
of its specific rotation and the order of its elution from a Chiralcel OD-
H column HPLC column. See: J. Legros and C. Bolm, Chem.–Eur. J.,
2005, 11, 1086.
11 J. M. Goodman, A. K. Kohler and S. C. M. Alderton, Tetrahedron
Lett., 1999, 40, 8715.
12 Treatment of titanium triflate (R,M)-5 with two equivalents of racemic
sulfoxide 8 gave 1H NMR and mass spectra that were identical to those
observed for the crude product formed in the ‘stoichiometric’ chiral
sulfoxidation reaction of sulfide 7.
13 Licini and co-workers have shown that the structural integrity of the
amine-tris-(phenolate) ligand framework of titanium complex (rac)-2
was maintained in their sulfoxidation reactions, see ref. 4a.
14 (a) For previous examples of metal complexes where the point chirality
of a chiral ligand has been used to control the atropisomerism of a
second achiral ligand for asymmetric catalysis, see: K. Mikami, K.
Wakabayashi and K. Aikawa, Org. Lett., 2006, 8, 1517; (b) K. Ding,
Chem. Commun., 2008, 909.
Fig. 3 Molecular structure of titanium triflate. (a) View highlighting
the pseudoaxial methyl stereocentre of (R,M)-5 (carbon framework
shown in outline only, and hydrogen atoms except H19 omitted for
◦
˚
clarity). Selected bond lengths (A) and angles ( ): Ti(1)–O(1) 1.786(2),
Ti(1)–O(2) 1.848(2), Ti(1)–O(3) 1.836(2), Ti(1)–O(4) 1.848(2), Ti(1)–N(1)
2.351(2), N(1)–Ti(1)–O(1) 179.51(9), O(3)–Ti(1)–O(2) 116.35(1). (b) View
highlighting the pseudoequatorial methyl stereocentre of (R,P)-6. (c) View
highlighting the propeller-like conformation of (R,M)-5 (triflate ligand
omitted for clarity).
the aryl rings to induce asymmetry into the ‘remote’ coordination
sphere of the titanium centre where the stereoselective oxidation
reactions are occurring.
The diastereoisomeric X-ray crystal structures obtained for the
titanium triflate (Fig. 3) suggest that the moderate enantioselec-
tivities observed in this sulfoxidation reaction may be due to com-
peting formation of interconverting diastereoisomeric (R,M)- and
(R,P)-transition states that could potentially catalyse formation of
the opposing enantiomers of chiral sulfoxide 8. Consequently, we
are currently exploring whether the enantioselectivities of this type
of sulfoxidation reaction can be improved using a chiral titanium
complex derived from a pseudo-C3-symmetric ligand that contains
a more sterically demanding stereogenic (R)-tert-butyl group. We
anticipate that this type of ligand will be more likely to result in
exclusive formation of an (R,M)-transition state that should lead
to formation of (R)-sulfoxide 8 in much higher ee.
15 For a previous example where the point chirality of a chiral auxiliary
fragment was used to control the propeller chirality of a separate
aluminium tris-(phenolate) complex for asymmetric conjugate addition
reactions, see: H. Ito, T. Nagahara, K. Ishihara, S. Saito and H.
Yamamoto, Angew. Chem., Int. Ed., 2004, 43, 994.
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The Royal Society of Chemistry 2009
Dalton Trans., 2009, 10169–10171 | 10171
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