Atropo-enantioselective synthesis of a C3-symmetric tripodal ligand with three axially chiral biaryl subunits

Article abstract of DOI:10.1016/S0957-4166(03)00406-3

In contrast to the numerous successful applications of C₂-symmetric biaryls as powerful tools for asymmetric synthesis, there have so far been only few reports on combinations of C₃-symmetry with axial chirality. We present here the

Full text of DOI:10.1016/S0957-4166(03)00406-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2225–2228
Atropo-enantioselective synthesis of a C3-symmetric tripodal
ligand with three axially chiral biaryl subunitsꢀ
Gerhard Bringmann,* Matthias Breuning, Robert-Michael Pfeifer and Petra Schreiber
Institut fu¨r Organische Chemie, Universita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
Received 7 May 2003; accepted 21 May 2003
Dedicated to Professor Dr. W. Malisch on the occasion of his 60th birthday
Abstract—In contrast to the numerous successful applications of C2-symmetric biaryls as powerful tools for asymmetric synthesis,
there have so far been only few reports on combinations of C3-symmetry with axial chirality. We present here the first
enantioselective synthesis of a novel family of tripodal ligands containing three axially chiral biaryl subunits in an (M,M,M)- or,
optionally, (P,P,P)-configured form. The incorporation of a PCl2- and a TiCl-fragment into the central cavity was achieved.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
and 5th sub-groups, in particular centrochiral trialka-
nolamines such as 14–6 are well suited for this purpose
(Fig. 1), because they form stable, mostly discrete so-
called metallatranes.6–8 As an example, Zr-complexes of
1 have been successfully used as chiral catalysts in the
stereoselective ring opening of meso-epoxides with azi-
dosilanes.9,10 In contrast, practically nothing is known
about the potentially promising combination of C3-
symmetry with axial chirality.11 Herein we report on
the atropo-enantioselective synthesis of the axially chi-
ral tripodal ligand 2, belonging to a novel type of
In view of the great success achieved with C2-symmetric
ligands in asymmetric synthesis,1 interest has focused
more recently on the preparation of homochiral auxil-
iaries possessing three rotationally hindered axes.2
Their application as chiral ligands in octahedral com-
plexes permits a reduction in the number of possible
diastereomorphous transition states, as for C2-symmet-
ric systems in tetrahedral or square-planar environ-
ments.2,3 For the oxophilic transition metals of the 4th
Figure 1. Known C3-symmetric trialkanolamines of type 1 and the novel threefold axially chiral tripodal ligand (M,M,M)-2.
ꢀ Part 106 in the series ‘Novel Concepts in Directed Biaryl Synthesis’. For Part 105, see: Bringmann, G.; Hamm, A; Schraut, M. Org. Lett.,
submitted.
* Corresponding author. Tel.: +49-931-8885323; fax: +49-931-8884755; e-mail: bringmann@chemie.uni-wuerzburg.de
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00406-3

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G. Bringmann et al. / Tetrahedron: Asymmetry 14 (2003) 2225–2228
tris(oxybiarylmethylene)amines, equipped with three
homochiral biaryl subunits, optionally in an (M,M,M)-
or (P,P,P)-configured form. Furthermore, we describe
the transformation of 2 into C3-symmetric complexes
containing a PCl2- or a TiCl-unit in the central cavity.
introduced by triple deprotonation of (M,M,M)-2 with
NaH and subsequent treatment with PCl5. According
1
to 31P, H, and 13C NMR spectra, the desired C3-sym-
metric product (M,M,M)-6 was formed quantitatively
(Scheme 2). By-products possessing either reduced or
no symmetry, e.g. structures involving intermolecular
bridges, were not detected in significant quantities. The
central nitrogen atom of 6 does not act as a donor
ligand for the phosphorus atom, which is evident from
the shift in the 31P NMR spectrum (l=−22.06 ppm).17
The isolation or further purification of (M,M,M)-6, e.g.
by column chromatography, proved to be difficult due
to its moisture sensitivity and low stability.18
2. Results and discussion
2.1. Synthesis of the tripodal ligand (M,M,M)-2
The synthesis of the tris(oxybiarylmethylene)amine
(M,M,M)-2 started from the homochiral phenylnaph-
thalene (M)-412,13 (Scheme 1), which is easily accessible
from the configurationally labile, since lactone-bridged
biaryl 3 (Scheme 1), with the efficient atropo-enantiose-
lective ring opening of 3 (e.g. by CBS15-reduction) as
the stereochemically deciding step.14
Scheme 2. Synthesis of the compounds (M,M,M)-6 and
(M,M,M)-7.
As an example of a transition metal, TiIV was incorpo-
rated by treatment of (M,M,M)-2 with NaH and then
with TiCl4, providing the C3-symmetric complex
(M,M,M)-7. Despite its high moisture sensitivity, it was
possible to characterize (M,M,M)-7 by NMR-, MS-,
and IR-investigations. All attempts to replace the
remaining chlorine ligand in (M,M,M)-7 by other
nucleophiles, failed. As an example, reaction of
(M,M,M)-7 with 1 equiv. of MeOH delivered, besides
unchanged (M,M,M)-7, only the free ligand (M,M,M)-
1
2 and Ti(OMe)4 according to H NMR. The ease of
this Ti-extrusion, the low stability and the high mois-
ture sensitivity of (M,M,M)-6 and (M,M,M)-7 indicate
that the internal cavity of (M,M,M)-2 is very narrow
and, even though an incorporation of PCl2- and TiCl-
fragments is possible, it does not provide an optimal
environment for delivering stable complexes.
Scheme 1. Enantioselective synthesis of the C3-symmetric
axially chiral tris(oxybiarylmethylene)amine (M,M,M)-2.
Treatment of (M)-4 with liquid ammonia in toluene led
to the corresponding primary amine as the initial
product. This was further alkylated in situ with an
additional 2 equiv. of (M)-4 to give the tertiary amine
(M,M,M)-5 in 79% yield. Deprotection of the oxygen
functional groups furnished the desired axially chiral
tripodal ligand (M,M,M)-2 in nearly quantitative yield.
By the same reaction sequence, lactone 3 can also be
converted into the enantiomeric tripodal ligand,
(P,P,P)-2, just by the use of the other enantiomer of
the ring-opening reagent.16
3. Conclusion
In summary, we have developed an easy and short
route for the enantioselective construction of threefold
axially chiral tripodal ligands, starting from a configu-
rationally labile lactone-bridged biaryl precursor. Using
the options provided by the ‘lactone method’,14 it
should be also possible to adapt this synthetic pathway
to the synthesis of electronically (e.g. OMe instead of
Me in the phenolic part) or sterically (e.g. tBu instead
of Me) modified analogs of (M,M,M)-2. Of particular
interest is the preparation of related systems possessing
a larger cavity. The synthesis of such spatially extended
C3-symmetric, axially chiral tripodal ligands and their
application in enantioselective catalysis is currently in
progress.
2.2. Incorporation of heteroatoms
The rigid biaryl portions of (M,M,M)-2 potentially
form a cage that might be capable of incorporating
heteroatoms or metals in its interior. As an example of
a main-group element, a phosphorus fragment was

G. Bringmann et al. / Tetrahedron: Asymmetry 14 (2003) 2225–2228
2227
4. Experimental
4.1. General remarks
3.7 mL, 3.7 mmol) was added at 0°C. The resulting
solution was stirred for 1 h and quenched with
aqueous K2CO3 (1N, 15 mL). The reaction mixture
was extracted three times with diethyl ether and the
combined organic layers were dried over MgSO4.
Purification by column chromatography afforded
crude (M,M,M)-2 as a yellow oil, which was precipi-
tated from dichloromethane/petroleum ether to give a
white powder (710 mg, 891 mmol, 97%): mp 161°C;
[h]2D0=−12.7 (c 1.2, CHCl3); 1H NMR (CDCl3, 200
MHz): l 7.88 (s, 6H), 7.85 (d, J=8.1 Hz, 3H), 7.44
(tm, J=7.2 Hz, 3H), 7.23–7.37 (m, 6H), 6.56, 6.64 (s,
s, 3H each), 3.08, 3.57 (d, d, J=13.6 Hz each, 3H
each), 2.32 (s, 9H), 1.60 (s, 9H) ppm. 13C NMR
(CDCl3, 50 MHz): l 153.2, 138.7, 137.7, 136.2, 133.1,
132.6, 131.7, 128.7, 128.1, 127.1, 126.6, 125.9, 125.6,
123.1, 121.1, 113.9, 56.2, 21.3, 19.6 ppm. IR (film): w
3550–2500, 3040, 1610, 1555, 1440, 1290, 1250, 1170,
1150, 1040, 820, 745 cm−1. MS: m/z 797 (M+, 10),
536 (42), 262 (29), 261 (66), 260 (46), 259 (100), 246
(39), 231 (34), 202 (36). Anal. calcd for C57H51NO3:
C, 85.79; H, 6.44; N, 1.76; found C, 85.50; H, 6.59;
N, 1.71.
Melting points were determined with a Kofler melting
point apparatus and are uncorrected. The optical
rotations were measured with a Perkin–Elmer polar-
imeter. The IR spectra were scanned from KBr pellets
or neat using
a Perkin–Elmer spectrophotometer
model 1420. The 1H and 13C NMR spectra were
recorded with a Bruker AC 250 (250 MHz) or a
Bruker Avance 400 (400 MHz) instrument using the
deuterated solvent as an internal reference; J values
are given in hertz. The 31P NMR spectrum of
(M,M,M)-6 was recorded at 163 MHz. The chemical
shift l refers to the signal of 85% H3PO4 (l=0).
Elemental analyses were performed in the Institute of
Inorganic Chemistry of the University of Wu¨rzburg.
Mass spectra were measured on a Finnigan MAT
2000 mass spectrometer at 70 eV. All reactions with
moisture and/or air sensitive materials were carried
out with flame-dried glassware using the Schlenk tube
technique under inert argon atmosphere.
4.2. Tris-{(M)-2-[1-(2%-benzyloxy-4%,6%-dimethylphenyl)]-
naphthylmethyl}amine (M,M,M)-5
4.4. General procedure for the synthesis of (M,M,M)-6
and (M,M,M)-7
In a three-necked flask equipped with a dry ice con-
denser, (M)-4 (500 mg, 1.16 mmol) and NH4Cl (120
mg, 2.24 mmol) were added to a mixture of toluene
(22 mL) and liquid ammonia (250 mL). The resulting
suspension was stirred for 12 h without further cool-
ing of the reaction flask. After evaporation of the
solvents, the residue was suspended in toluene (40
mL) and (M)-4 (1.00 g, 2.32 mmol) was added. The
mixture was refluxed for 2 d. After removal of the
solvent, the crude product was purified by column
chromatography (deactivated silica gel, petroleum
ether/diethyl ether 50:1“10:1) to yield (M,M,M)-5 as
To a suspension of NaH (12.4 mmol, 2.97 mg) in
diethyl ether (1 mL) was added (M,M,M)-2 (30 mg,
3.76 mmol) at 0°C and the reaction mixture was
stirred for 30 min. PCl5 (7.75 mg, 3.76 mmol) or
TiCl4 (1.0 mM in n-pentane, 3.76 mL, 3.76 mmol)
was added at 0°C and the reaction mixture was
allowed to warm to room temperature. After 6 h of
stirring, the solvent was removed in vacuo and the
residue was dried carefully. Due to the high moisture
sensitivity of (M,M,M)-6 and (M,M,M)-7 and their
low solubility, all spectroscopic investigations were
performed without further purification. According to
the NMR spectra, both compounds were analytically
pure, with yields >95%.
a
pale yellow oil, which was precipitated from
dichloromethane/petroleum ether to afford a white
solid (980 mg, 918 mmol, 79%): mp 183°C; [h]2D0=69.1
1
(c 1.1, CHCl3). H NMR (CDCl3, 200 MHz): l 8.24
(d, J=8.4 Hz, 3H), 7.85 (d, J=8.4 Hz, 6H), 7.40 (tm,
J=7.1 Hz, 3H), 7.19–7.32 (mc, 6H), 6.88–7.02 (m,
9H), 6.66 (mc, 9H), 6.54 (s, 3H), 4.50, 4.62 (d, d,
J=13.0 Hz each, 3H each), 3.21, 3.58 (d, d, J=14.7
Hz each, 3H each, CH2N), 2.37 (s, 9H), 1.54 (s, 9H)
ppm. 13C NMR (CDCl3, 50 MHz): l 156.3, 138.0,
137.8, 137.4, 136.4, 133.5, 132.7, 132.5, 127.9, 127.3,
126.8, 126.3, 126.0, 125.5, 125.4, 124.7, 124.5, 123.4,
123.3. 110.9, 69.3, 56.2, 21.7, 19.5 ppm. IR (KBr): w
3010, 1590, 1565, 1495, 1485, 1310, 1230 cm−1. MS:
m/z 1067 (M+, 22), 976 (6), 716 (73), 608 (24), 366
(14), 352 (25), 259 (100), 91 (48). Anal calcd for
C78H69NO3: C, 87.69; H, 6.51; N, 1.31; found C,
87.63; H, 6.37; N, 1.47.
(M,M,M)-6: 1H NMR (CDCl3, 200 MHz): l 7.62–
7.76 (m, 6H), 7.34–7.40 (m, 6H), 7.19–7.21 (m, 6H),
6.30, 6.6.0 (s, s, 3H each), 4.43 (d, br., J=10.9 Hz,
3H), 3.78, (s, br., 3H), 1.77 (s, 9H), 1.30 (s, 9H) ppm.
13C NMR (CDCl3, 50 MHz): l 153.4, 139.2, 138.2,
137.0, 133.9, 132.4, 128.6, 127.8, 127.0, 126.8, 126.7,
124.3, 122.5, 119.3, 114.8, 57.7, 20.7, 19.4 ppm. 31P
NMR (CDCl3, 162 MHz) l −22.06. IR (film): w 3052,
2967, 1618, 1578, 1448, 1044, 804 cm−1.
1
(M,M,M)-7: H NMR (CDCl3, 200 MHz): l 7.88 (s,
6H), 7.63–7.70 (m, 3H), 7.51 (s, br., 3H), 7.40–7.43
(mc, 3H), 7.19–7.25 (m, 6H), 6.29, 6.67 (s, s, 3H
each), 3.81, 4.50 (s, s, br., 3H each), 1.74 (s, 9H),
1.32 (s, 9 H, 6%-CH3). 13C NMR (CDCl3, 50 MHz): l
171.5, 154.7, 153.5, 139.2, 134.0, 132.6, 132.4, 128.1,
128.0, 127.1, 126.8, 126.7, 122.5, 121.3, 114.8, 57.9,
20.7, 19.3 ppm. IR (KBr): w 3052, 2921, 1648, 1618,
1448, 1069, 820 cm−1. MS: m/z 842 (M+, 9), 262
(100), 260 (46), 259 (43), 247 (45).
4.3. Tris-{(M)-2-[1-(2%-hydroxy-4%,6%-dimethylphenyl)]-
naphthylmethyl}amine (M,M,M)-2
To a solution of (M,M,M)-5 (980 mg, 918 mmol) in
dichloromethane (10 mL), BCl3 (1.0 M in n-hexane,

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G. Bringmann et al. / Tetrahedron: Asymmetry 14 (2003) 2225–2228
Acknowledgements
10. For the use of the trisalkanolamines 1 as ligands in
TiIV-catalyzed asymmetric sulfide oxidations, see: Di
Furia, F.; Licini, G.; Modena, G.; Motterle, R.; Nugent,
W. A. J. Org. Chem. 1996, 61, 5175–5177.
This work was supported by the Deutsche Forschungs-
gemeinschaft (SFB 347 ‘Selektive Reaktionen Metall-
aktivierter Moleku¨le’), by the ‘Fonds der Chemischen
Industrie’ (fellowship for M.B. and supplies) and by the
Freistaat Bayern (fellowship for R.-M.P.). We thank
Dr. C. Vedder for technical assistance, and Professor
Dr. L. Gade for helpful advice.
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