Enantiopure pseudo-C3-symmetric titanium alkoxide with propeller-like chirality

Article abstract of DOI:10.1021/ol062655w

(Chemical Equation Presented) An enantiopure amine tris(phenolate) ligand containing a single stereogenic center has been used to control the propeller-like chirality of a derived pseudo-C₃-symmetric titanium isopropoxide complex with excellent

Full text of DOI:10.1021/ol062655w

ORGANIC
LETTERS
2007
Vol. 9, No. 2
223-226
Enantiopure Pseudo-C3-Symmetric
Titanium Alkoxide with Propeller-Like
Chirality
Philip Axe,† Steven D. Bull,*,† Matthew G. Davidson,*,† Carly J. Gilfillan,†
Matthew D. Jones,† Diane E. J. E. Robinson,† Luke E. Turner,† and
William L. Mitchell‡
Department of Chemistry, UniVersity of Bath, ClaVerton Down, Bath, BA2 7AY, U.K.,
and Neurology Medicinal Chemistry 3, GSK PLC, Harlow, Essex, CM19 5AW, U.K.
s.d.bull@bath.ac.uk; m.g.daVidson@bath.ac.uk
Received October 30, 2006
ABSTRACT
An enantiopure amine tris(phenolate) ligand containing a single stereogenic center has been used to control the propeller-like chirality of a
derived pseudo-C3-symmetric titanium isopropoxide complex with excellent levels of diastereocontrol.
Tripodal trianionic ligands such as triamido amines1 and
trialkoxy amines2,3 have been used extensively for stabilizing
unusual metal coordination geometries and as scaffolds for
catalytically active metal complexes. Recently, amine tris-
(phenolate) ligands 1a,b have been introduced as a new class
of tripodal ligand for fundamental coordination studies and
as supports for metal-based catalysts (Figure 1).4 These
ligands are particularly well-suited to catalytic applications
because they generally afford well-defined monomeric metal
complexes that are stable to hydrolysis,5 while retaining
useful catalytic activity.6,7 Significantly, for the purposes of
this study, a number of these metal complexes display helical
chirality, with C3-symmetric Ti(IV) alkoxide complexes
demonstrating unusually high barriers to racemization.8 All
reports to date have employed achiral amine tris(phenolate)
(4) (a) Redshaw, C.; Rowan, M. A.; Homden, D. M.; Dale, S. H.;
Elsegood, M. R. J.; Matsui, S.; Matsuura, S. Chem. Commun. 2006, 3329.
(b) Groysman, S.; Goldberg, I.; Kol, M.; Genizi, E.; Goldschmidt, Z. AdV.
Synth. Catal. 2005, 347, 409. (c) Groysman, S.; Goldberg, I.; Kol, M.;
Goldschmidt, Z. Organometallics 2003, 22, 3793. (d) Davidson, M. G.;
Doherty, C. L.; Johnson, A. L.; Mahon, M. F. Chem. Commun. 2003, 1832.
(5) Ugrinova, V.; Ellis, G. A.; Brown, S. N. Chem. Commun. 2004, 468.
(6) Bull, S. D.; Davidson, M. G.; Johnson, A. L.; Robinson, D. E. J. E.;
Mahon, M. F. Chem. Commun. 2003, 1750.
† University of Bath.
‡ GSK PLC.
(1) Schrock, R. R. Acc. Chem. Res. 1997, 30, 9.
(2) Verkade, J. G. Coord. Chem. ReV. 1994, 137, 233.
(3) Verkade, J. G. Acc. Chem. Res. 1993, 26, 483.
(7) Kim, Y.; Verkade, J. G. Organometallics 2002, 21, 2395.
10.1021/ol062655w CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/23/2006

Figure 1. Ligands 1a,b, (R,R,R)-2, and (R)-3.
ligands for the synthesis of racemic metal complexes, with
potential applications of enantiopure metal complexes re-
maining unexplored. We reasoned that a pseudo-C3-sym-
metric ligand such as (R)-3 might be useful for the
preparation of chiral metal complexes with potential ap-
plications for chiral recognition or asymmetric catalysis.9
Consequently, we now report herein on the synthesis and
structural characterization of a chiral pseudo-C3-symmetric
titanium alkoxide (R,M)-12 that employs a chiral relay
strategy10 to control the propeller-like chirality of its amine
tris(phenolate) ligand.
Figure 2. (R,M)-4 and (R,P)-5 diastereoisomers of a five-coordinate
metal complex of tetradentate ligand (R)-3.
available.9,11,12 Although a chiral C3-symmetric version of
amine tris(phenolate) ligand (R,R,R)-2 may be envisaged,
the presence of three benzylic stereocenters means that it is
difficult to prepare in enantiopure form without recourse to
multistep synthesis as has been found previously for other
C3-symmetric ligand systems.13 Consequently, we considered
an alternative ligand design for controlling the propeller-
like chirality of metal complexes derived from a chiral,
tetradentate ligand (R)-3 that contains a single stereogenic
center.
Although the potential of using C3-symmetric ligands for
the preparation of chiral metal complexes for asymmetric
catalysis has been recognized, there are only a limited
number of chiral C3-symmetric metal complexes currently
(8) Kol, M.; Shamis, M.; Goldberg, I.; Goldschmidt, Z.; Alfi, S.; Hayut-
Salant, E. Inorg. Chem. Commun. 2001, 4, 177.
(9) Moberg, C. Angew. Chem., Int. Ed. 1998, 37, 248.
(10) Bull, S. D.; Davies, S. G.; Fox, D. J.; Garner, A. C.; Sellers, T. G.
R. Pure Appl. Chem. 1998, 70, 1501.
(11) Dro, C.; Bellemin-Laponnaz, S.; Welter, R.; Gade, L. H. Angew.
Chem., Int. Ed. 2004, 43, 4479.
(12) Gibson, S. E.; Castaldi, M. P. Chem. Commun. 2006, 3045.
(13) Wyatt, P.; Butts, C. P.; Patel, V.; Voysey, B. J. Chem. Soc., Perkin
Trans. 1 2000, 4222.
(14) In the most closely related example, Canary et al. employed a related
chiral relay approach for controlling the helical symmetry of metal
complexes derived from neutral tripodal tripyridyl ligands: Canary, J. W.;
Allen, C. S.; Castagnetto, J. M.; Wang, Y. J. Am. Chem. Soc. 1995, 117,
8484.
(15) For other, less closely related examples, see: (a) Alajar´ın, M.; Lo´pez-
Leonardo, C.; Vidal, A.; Berna´, J.; Steed, J. W. Angew. Chem., Int. Ed.
2002, 41, 1205. (b) Yao, Y.; Daley, C. J. A.; McDonald, R.; Bergens, S.
H. Organometallics 1997, 16, 1890.
(16) The configuration of the newly formed stereocenter of amine (R,R)-8
was assigned as (R) from an established literature precedent for addition of
methyllithium to this class of chiral imine and subsequently confirmed from
analysis of the X-ray crystal structure of (R,M)-12. See: Bernardinelli, G.;
Fernandez, D.; Gosmini, R.; Meier, P.; Ripa, A.; Schupfer, P.; Treptow,
B.; Kundig, E. P. Chirality 2000, 12, 529.
(17) A similarly poor yield was obtained for addition of methyllithium
to the structurally related imine (R)-13 under these conditions. See: Kundig,
E. P.; Botuha, C.; Lemercier, G.; Romanens, P.; Saudan, L.; Thibault, S.
HelV. Chim. Acta 2004, 87, 561.
It was proposed that complexation of the amine tris-
(phenolate) to a five-coordinate metal center would result
in a chiral metal complex (R,M)-4 whose helical chirality
would be controlled by its stereogenic R-methyl group
adopting a pseudoaxial conformation. This diastereoisomer
would occur preferentially because formation of the corre-
sponding diastereoisomer (R,P)-5 would be disfavored by
syn-pentane-like interactions between the pseudoequa-
torial R-methyl group and its proximal aryl ring (Figure 2).
Although examples of this type of conformational
control are rare, precedent does exist for control of helical
chirality using point chirality within metal-ligand com-
plexes.14,15
The enantiomerically pure ligand (R)-3 was prepared in
six steps using the synthetic protocol described in Scheme
1. 2-(Benzyloxy)-3,5-di-tert-butyl-benzaldehyde 6 was re-
(18) The configuration and enantiomeric purity of amine (R)-9 was
confirmed as >95% ee using our recently published NMR chiral deriva-
tization protocol involving treatment with 2-formyl-phenylboronic acid and
enantiopure BINOL. See: Pe´rez-Fuertes, Y.; Kelly, A. M.; Johnson, A. L.;
Arimori, S.; Bull, S. D.; James, T. D. Org. Lett. 2006, 8, 609.
(19) Prins, L. J.; Bla´squez, M.; Kolarovi, A.; Licini, G. Tetrahedron Lett.
2006, 47, 2735.
224
Org. Lett., Vol. 9, No. 2, 2007

bisbenzylated with 2-(benzyloxy)-1-(bromo-methyl)-3,5-di-
tert-butyl-benzene 10 in the presence of KI under basic
conditions to afford tertiary amine (R)-11. Subsequent
hydrogenolytic deprotection of the benzylic groups of (R)-
11 gave the desired ligand (R)-3 in 63% yield over the two
steps.19
Reaction of ligand (R)-3 with titanium tetra(isopropoxide)
gave an analytically pure yellow solid (R,M)-12 in 65% yield.
1H NMR spectroscopic analysis of (R,M)-12 indicated that
the proposed chiral relay strategy was successful in control-
1
ling the propeller-like conformation of the ligand. The H
NMR spectrum of (R,M)-12 revealed a quartet and four AB
doublets (two partially overlapped) between δ 4.05 and δ
3.10, corresponding to the two pseudoaxial and three
pseudoequatorial benzylic protons (Jgem g 13.0 Hz) of the
ligand fragment (Figure 3). A NOE experiment established
close proximity between the R-methyl protons and the two
inequivalent pseudoaxial benzylic protons. This observation
is consistent only with the predicted pseudoaxial orientation
of the R-methyl group implying that the complex exists in
solution as (R,M)-12 (Figure 3).
An X-ray crystal structure of (R,M)-12 was obtained
(Figure 4a) which is consistent with the structure inferred
in solution by NMR spectroscopy.20 Key structural param-
eters within (R,M)-12 are similar to those observed previously
for racemic titanium complexes derived from ligand 1a.6 The
approximately trigonal bipyramidal titanium center lies
slightly above the plane of the three equatorial phenolate
oxygen atoms, and the axial sites are occupied by the neutral
nitrogen atom of the ligand and the monodentate isopro-
poxide anion.
1
Figure 3. Selected NOEs and benzylic region of the H NMR
spectrum of (R,M)-12.
acted with (R)-phenylglycinol to afford chiral imine (R)-7
in 95% yield. Nucleophilic addition of methyllithium to imine
(R)-7 in THF at -85 °C gave chiral amine (R,R)-8 in 44%
yield and 96% de.16,17 Deprotection of this secondary amine
(R,R)-8 was achieved via a two-step protocol involving
oxidative cleavage with Pb(OAc)4, followed by acidic
hydrolysis using 3 M HCl(aq), to afford primary amine (R)-9
in 66% yield and >95% ee.18 Primary amine (R)-9 was then
The absolute (R)-configuration of the pseudoaxial R-meth-
yl stereocenter locks the helical chirality of the aryl substit-
uents of the chiral ligand into a (M)-propeller conformer.
The average tilt of the aryl groups (as defined by the average
angle between the aryloxide planes and the Ti-N bond
Scheme 1. Asymmetric Synthesis of Chiral Amine (R)-3
Org. Lett., Vol. 9, No. 2, 2007
225

atom (Figure 4b). This strongly suggests that monomeric
transition-metal complexes derived from (R)-3 that are used
for stereocontrol should behave in a manner identical to
thecorresponding metal complexes derived from “true” C3-
symmetric ligands such as (R,R,R)-2.
In conclusion, incorporation of a single stereogenic center
into an amine (trisphenolate) ligand (R)-3 controls the
propeller-like conformation of the ligand on coordination to
a five-coordinate metal center. We have shown that the
titanium alkoxide complex (R,M)-12 possesses pseudo-C3-
symmetry both in solution and in the solid state. Unlike
racemic complexes derived from achiral ligands, inversion
does not occur in solution, even at elevated temperatures,
suggesting that the R-methyl group imparts a high degree
of control over helical chirality. Therefore, to the best of
our knowledge, this represents the first example of an
enantiomerically pure and conformationally stable metal
phenolate complex. We are currently investigating whether
the helical chirality of metal complexes derived from pseudo-
C3-symmetric ligand (R)-3 can be exploited for chiral
recognition21 or asymmetric catalysis.22
Acknowledgment. We are grateful to the Royal Society,
EPSRC, and GlaxoSmithKline for funding and the Mass
Spectrometry Service at Swansea, University of Wales, for
their assistance.
Supporting Information Available: Experimental details
and spectroscopic characterization for these compounds
together with the crystal data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL062655W
(20) Crystal data: C55H89NO4Ti, M ) 876.17, yellow prism, 0.40 ×
0.30 × 0.25 mm3, tetragonal, space group P43, a ) b ) 14.584(2), c )
25.374(4) Å, V ) 5396.87(13) Å3, Z ) 4, Dc ) 1.078 g/cm3, F000 ) 1920,
Mo KR radiation, λ ) 0.71073 Å, T ) 150(2) K, 2θmax ) 55.0°, 21 199
reflections collected, 11 331 unique (Rint ) 0.0279). Final GOF ) 1.024,
R1 ) 0.0560, wR2 ) 0.1464, R indices based on 9438 reflections with I >
Figure 4. Molecular structure of (R,M)-12. (a) View highlighting
the pseudoaxial R-methyl stereocenter (carbon framework shown
in outline only, and hydrogen atoms except H19 omitted for clarity).
(b) View highlighting the propeller-like conformation of the com-
plex (isopropoxide ligand omitted for clarity). Selected bond lengths
(Å) and angles (deg): 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).
2σ(I) (refinement on F2), 573 parameters, 1 restraint, µ ) 0.200 mm-1
.
Absolute structure parameter ) 0.02(3). All non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were calculated at idealized
positions and refined using the riding model. The largest peak and hole in
the final difference Fourier map were 0.53 and -0.37 Å-3. Crystallographic
data have been deposited at the Cambridge Crystallographic Data Centre
with reference number CCDC 623640. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif.
(21) Moberg, C. Angew. Chem., Int. Ed. 2006, 45, 4721.
(22) Bringmann, G.; Pfeifer, R. M.; Rummey, C.; Hartner, K.; Breuning,
M. J. Org. Chem. 2003, 68, 6859.
vector) is 11°. Viewing the structure of (R,M)-12 along the
Ti-N bond vector from the top face reveals that the three
proximal t-butyl groups serve to create a C3-symmetric
environment within the coordination sphere of the titanium
226
Org. Lett., Vol. 9, No. 2, 2007