Synthesis of enantiopure axially chiral C3-symmetric tripodal ligands and their application as catalysts in the asymmetric addition of dialkylzinc to aldehydes

Article abstract of DOI:10.1021/jo034697t

The enantioselective synthesis of a novel-type C₃-symmetric tripodal ligand that is composed of a central mesitylene-derived core and three functionalized, axially chiral biaryl subunits is described. The triol (M,M,M) -3 is a suitable catalyst for the enantioselective addition of dialkylzinc to various aromatic aldehydes with asymmetric inductions of up to 98% ee.

Full text of DOI:10.1021/jo034697t

3
Syn th esis of En a n tiop u r e Axia lly Ch ir a l C -Sym m etr ic Tr ip od a l
Liga n d s a n d Th eir Ap p lica tion a s Ca ta lysts in th e Asym m etr ic
Ad d ition of Dia lk ylzin c to Ald eh yd es†
Gerhard Bringmann,* Robert-Michael Pfeifer, Christian Rummey, Kristina Hartner, and
Matthias Breuning
Institut f u¨ r Organische Chemie, Universit a¨ t W u¨ rzburg, Am Hubland, D-97074 W u¨ rzburg, Germany
bringman@chemie.uni-wuerzburg.de
Received May 22, 2003
3
The enantioselective synthesis of a novel-type C -symmetric tripodal ligand that is composed of a
central mesitylene-derived core and three functionalized, axially chiral biaryl subunits is described.
The triol (M,M,M)-3 is a suitable catalyst for the enantioselective addition of dialkylzinc to various
aromatic aldehydes with asymmetric inductions of up to 98% ee.
In tr od u ction
together by an amino function (Figure 1). The introduc-
tion of metal fragments into the central cage of (M,M,M)-1
to give, e.g., the titanium complex (M,M,M)-2, however,
proved to be difficult; the low stability of (M,M,M)-2 and
its high tendency to extrude the metal with destruction
of the chelate complex indicated that the cavity of
Symmetry elements are important structural features
in many chiral metal catalysts since they can reduce the
number of possible diastereomeric intermediates or
1
transition states. They prevent the transient formation
of an intermediate additional stereogenic center at the
active metal site, which would be created in a dissym-
metric complex upon coordination of the substrate(s) or
by ligand-substrate exchange processes, thus strongly
increasing the probability of an efficient chirality trans-
fer. C -Symmetric bidentate ligands are well-known to
2
fulfill this task in tetrahedral and square-planar com-
plexes, a concept frequently and highly successfully
applied in the field of asymmetric synthesis. Extension
of this strategy to octahedral complexes leads to the
requirement of C
a large number of tripodal systems assembled from three
(
M,M,M)-1 is very small and not sufficiently suited for
the incorporation of transition metals. In this paper, we
present the synthesis of two novel C -symmetric, 3-fold
3
axially chiral tripodal ligands of types 3 and 4 possessing
a more spacious cavity, and their highly successful
application as chiral catalysts in the enantioselective
addition of dialkylzinc to various aromatic aldehydes.
2
Resu lts a n d Discu ssion
1
3
-symmetric tridentate ligands. Whereas
3
Design of t h e C -Sym m et r ic Tr ip od a l Liga n d s.
One possibility to increase the size of the chiral cavity of
centrochiral subunits have been investigated during the
8
past years,1,3 there have as yet been only few reports
the ligand (M,M,M)-1 would be to change the topology
1
of the tripodal system from acyclic [sketch A, Figure 2,
already realized in (M,M,M)-1] to exocyclic (sketch B),
3
about the combination of C -symmetry and axial chiral-
1
4
ity, even though biaryls in general provide powerful tools
in asymmetric synthesis.5
where the three axially chiral biaryl subunits are con-
nected to a joint cyclic spacer whose trivalent structure
is in agreement with C -symmetry, for which a mesity-
3
lene-derived core was expected to be a simple and
suitable building block.9 The three homochiral biaryl
moieties can be attached in two principally different ways
Our initial efforts in this area resulted in the prepara-
tion of the tris(oxybiarylmethylene)amine (M,M,M)-1,
which possesses three axially chiral biaryl subunits tied
6
,7
*
Corresponding author. Phone: 49-931-8885323. Fax: 49-931-
8
884755.
(sketch C, options C
oxygen atoms or via their benzylic N- or O-functionalities.
As an example of the first option, C , the trisaryl ether
(M,M,M)-3 was chosen. In the desired C -symmetric
I
and CII), either via their phenolic
†
Part 107 in the series Novel Concepts in Directed Biaryl Synthesis.
For part 106, see ref 6.
1) (a) Moberg, C. Angew. Chem., Int. Ed. 1998, 37, 248-268. (b)
Keyes, M. C.; Tolman, W. B. Adv. Catal. Proc. 1997, 2, 189-219.
2) Burk, M. J .; Harlow, R. L. Angew. Chem., Int. Ed. Engl. 1990,
9, 1467-1469.
3) (a) Nugent, W. A.; Harlow, R. L. J . Am. Chem. Soc. 1994, 116,
142-6148. (b) Verkade, J . G. Acc. Chem. Res. 1993, 26, 283-486.
4) (a) Baret, P.; B e´ guin, C.; Gaude, D.; Gellon, G.; Mourral, C.;
I
(
3
(
2
(
(6) Bringmann, G.; Breuning, M.; Pfeifer, R.-M.; Schreiber, P.
Tetrahedron: Asymmetry 2003, 14, 2225-2228.
6
(
(7) For the now recommended M/ P-denotion for axial chirality,
see: Helmchen G. In Methods of Organic Chemistry (Houben Weyl),
4th ed.; Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann, E.,
Eds.; Thieme: Stuttgart, Germany, 1995; Vol. E21a, pp 11-13.
(8) Turro, N. J . Angew. Chem., Int. Ed. Engl. 1986, 25, 882-901.
Pierre, J .-L.; Serratrice, G.; Favier, A. Tetrahedron 1994, 50, 2077-
2
094. (b) Baker, M. J .; Pringle, P. J . J . Chem. Soc., Chem. Commun.
993, 314-316. (c) Kaufmann, D.; Boese, R. Angew. Chem., Int. Ed.
1
Engl. 1990, 29, 545-546.
(
5) (a) Rossini, C.; Frazini, L.; Raffaelli, A.; Salvadori, P. Synthesis
992, 503-517. (b) Pu, L. Chem. Rev. 1998, 98, 2405-2494. (c)
McCarthy, M.; Guiry, P. J . Tetrahedron 2001, 57, 3809-3844.
3
(9) For other C -symmetric compounds with a central mesitylene-
derived core, see: Armstrong, S. K.; Clunas, S.; Muir, K. W. Synthesis
1999, 993-998. See also refs 12 and 17.
1
1
0.1021/jo034697t CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/13/2003
J . Org. Chem. 2003, 68, 6859-6863
6859

Bringmann et al.
F IGURE 1. The axially chiral tripodal ligand (M,M,M)-1 and its titanium complex (M,M,M)-2, and the concrete target ligands
(M,M,M)-3 and (M,M,M)-4.
3
F IGURE 2. Schematic sketches of acyclic and exocyclic C -symmetric systems.
conformation, the three hydroxymethylene groups are
directed into the interior of the central cavity, which
should be distinctly larger as compared to that of
delivered the tripodal ligand (M,M,M)-3 in just a single
step and 89% yield. Etherification occurred at the phe-
nolic position as proven by HMBC correlation experi-
ments. Conversion of the diol (M)-5 into the O-protected
secondary amine (M)-7 was accomplished according to
literature protocols.13 Deprotonation of (M)-7 and reaction
with 0.3 equiv of 6 led to (M,M,M)-8, which was depro-
(
M,M,M)-1, thus providing an ideal “anchor site” for
metal fragments to be embedded. The second possibility,
II, would be realized in the tripodal ligand (M,M,M)-4,
C
in which the three biaryl subunits are tethered to the
central benzene ring by three flexible bismethylenamino
spacers, thus leading to a wide and open cage.
3
tected by treatment with BCl to give the desired tripodal
ligand (M,M,M)-4 in 68% yield over the two steps.
Con for m a tion a l Beh a vior of (M,M,M)-3 in Solu -
Syn th esis of th e C
3
-Sym m etr ic Tr ip od a l Liga n d s
1
(
M,M,M)-3 a n d (M,M,M)-4. The synthesis of (M,M,M)-3
tion . The H NMR spectra of (M,M,M)-3 permitted
1
0
and (M,M,M)-4 started with (M)-5 (Scheme 1). This
enantiomerically pure, axially chiral biaryl diol can be
prepared in a multigram scale from commercially avail-
able materials in just three steps, with the atropo-
enantioselective reductive ring cleavage of a configura-
tionally labile biaryl lactone precursor as the stereochem-
ically decisive step.11 The second building block, 1,3,5-
tris-bromomethylbenzene (6), was obtained in 78% yield
from the corresponding triacid by a modified literature
procedure.12 Treatment of 6 with 3.3 equiv of (M)-5
preliminary insight into its conformational behavior
(Figure 3): In solvents such as CD
3 8
OD or [D ]-THF,
which favor the formation of intermolecular H-bridges,
(
11) (a) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999,
5
25-558. (b) Bringmann, G.; Tasler, S. In Current Trends in Organic
Synthesis; Scolastico, C., Nicotra, F., Eds.; Kluwer Academic/Plenum
Publishers: New York 1999; pp 105-116. (c) Bringmann, G.; Menche,
D. Acc. Chem. Res. 2001, 34, 615-624. (d) Bringmann, G.; Breuning,
M.; Pfeifer, R.-M.; Schenk, W.; Kamikawa, K.; Uemura, M. J . Orga-
nomet. Chem. 2002, 661, 31-47. (e) Bringmann, G.; Tasler, S.; Pfeifer,
R.-M.; Breuning, M. J . Organomet. Chem. 2002, 661, 49-65.
(
12) (a) Bilger, C.; Royer, R.; Demerseman, P. Synthesis 1988, 902-
9
04. (b) Spino, C.; Clouston, L.; Berg, D. Can. J . Chem. 1996, 74, 1762-
1764. (c) Reppe, W.; Schweckendieck, W. J . Liebigs Ann. Chem. 1948,
(10) (a) Bringmann, G.; Breuning, M.; Henschel, P.; Hinrichs, J . Org.
Synth. 2001, 79, 72-83. (b) Bringmann, G.; Hartung, T. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 761-762. (c) Bringmann, G.; Hartung, T.
Tetrahedron 1993, 49, 7891-7902.
104-116.
(13) Bringmann, G.; Breuning, M. Tetrahedron: Asymmetry 1998,
9, 667-679.
6
860 J . Org. Chem., Vol. 68, No. 18, 2003

Axially Chiral C
3
-Symmetric Tripodal Catalysts
SCHEME 1. Syn th esis of th e Tr ip od a l Liga n d s (M,M,M)-3 a n d (M,M,M)-4
minor isomer, only two of the three biaryl subunits still
deliver isochronous signals, which hints at the existence
of a pseudo-C -symmetric conformer like (M,M,M)-3A
Figure 4). Since the formation of H-bridges with the
2
(
solvent is not possible, two biaryl substituents might now
be locked on the one side of the central core by an
intramolecular H-bridge between the phenolic hydroxy
groups, while the third biaryl unit should retain its
conformational freedom. Direct evidence of the C -sym-
3
metric conformer (M,M,M)-3B, in which all three biaryls
are tied together by intramolecular H-bridges, was not
1
found. H NMR measurements in CDCl
3
at lower tem-
peratures down to -60 °C indicated a “freezing out” of
at least one more conformer, the structure and symmetry
properties of which, however, could not be clarified due
to the increasing complexity of the spectra. The formation
of intramolecular H-bridges is also supported by semiem-
pirical calculations (AM1),14 which predict the C
-sym-
3
metric conformer (M,M,M)-3B (Figure 4, bottom) as an
energetically favored minimum structure in the gas
phase.15
Ap p lica tion of th e Tr ip od a l Liga n d s a s Ch ir a l
Ca ta lysts in th e En a n tioselective Ad d ition of Di-
a lk ylzin c to Ald eh yd es. The potential of the axially
chiral tripodal ligands as a novel type of catalysts for
asymmetric synthesis was investigated in the enantiose-
lective addition of diethylzinc to aldehydes, since this
well-established reaction should permit a convenient
comparison with other successful catalysts known in the
literature.16 To our knowledge, there has as yet been only
3
one other report on C -symmetric tripodal ligands applied
in this type of reaction, which, however, failed to produce
satisfying levels of asymmetric induction.17
The reaction conditions were optimized with benzal-
dehyde (9a ) as the model substrate (Table 1). Disappoint-
ingly, only the acyclic tripodal ligand (M,M,M)-1 cata-
F IGURE 3. Diagnostically decisive part of the 1H NMR
spectra of (M,M,M)-3 (a) in CDCl and (b) in CD OD.
3
3
only a single set of signals with three spectroscopically
identical biaryl subunits was observed, probably the
averaged set of signals over all conformers. In the aprotic
solvents C D , CD CN, and CDCl , by contrast, two sets
6 6 3 3
of signals in an 85:15 ratio were found, with the main
isomer again providing a single set of signals. In the
(
14) Dewar, M. J . S.; Zoebisch, E. G.; Healy, E.; Steward, J . J . P. J .
Am. Chem. Soc. 1985, 107, 3902-3909.
(15) Performed on a Pentium III (450 MHz) workstation with the
VAMP-6.5 program package.
(
16) (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833-856. (b) Pu,
L.; Yu, H.-B. Chem. Rev. 2001, 101, 757-824.
(17) Armstrong, S. K.; Clunas, S. Synthesis 2000, 2, 281-288.
J . Org. Chem, Vol. 68, No. 18, 2003 6861

Bringmann et al.
F IGURE 4. Conformers of (M,M,M)-3, (M,M,M)-3A, and (M,M,M)-3B, and the AM1-calculated minimum structure of (M,M,M)-
3
B.
TABLE 1. Op tim iza tion of th e Rea ction Con d ition s for
th e Ad d ition of Dieth ylzin c to Ben za ld eh yd e (9a )
a
Ca ta lyzed by (M,M,M)-1, (M,M,M)-3, or (M,M,M)-4
ligand
mol‚%)
Ti(OiPr)4
(equiv)
T
(°C)
ee (%)
b
b
conversionc
(config)d
F IGURE 5. Structure of the C
M,M,M)-11.
3
-symmetric titanium catalyst
(
(
e
(
(
(
(
(
(
(
(
(
(
(
M,M,M)-1 (20)
0
0
0
20
20
20
20
20
20
20
0
quant
0
0
56 (R)
M,M,M)-3 (20)f
M,M,M)-4 (20)f
M,M,M)-3 (20)
M,M,M)-3 (20)
M,M,M)-4 (20)
M,M,M)-3 (20)
M,M,M)-3 (20)
M,M,M)-3 (20)
M,M,M)-3 (10)
M,M,M)-3 (5)
cavities of (M,M,M)-3 and (M,M,M)-4. Under these condi-
tions, the tripodal ligand (M,M,M)-3, but not (M,M,M)-
0.4
1.4
1.4
3.0
1.4
1.4
1.4
1.4
trace
quant
0
quant
quant
quant
quant
quant
4
, catalyzed the ethylation of benzaldehyde (9a ) to give
78 (R)
the desired ethyl carbinol (R)-10a quantitatively and with
good to excellent asymmetric inductions of up to 98% ee.
The proposed in situ formation of the rigid, C -symmetric
3
titanium complex (M,M,M)-11 (Figure 5) was proven by
NMR spectroscopy of a 1:1 mixture of (M,M,M)-3 and Ti-
60 (R)
24 (R)
98 (R)
90 (R)
68 (R)
40
40
40
(
OiPr)
ylzinc were found to be 20 mol‚% of (M,M,M)-3 in
4
refluxing CH Cl in the presence of 1.4 equiv of Ti(OiPr) .
4
. Optimum conditions for the addition of dieth-
a
All reactions were carried out with 10 µmol of benzaldehyde
c
9
a . b Relative to benzaldehyde 9a . Estimated according to TLC.
d
2
2
Determined by HPLC on a Chiracel OD-H column; config )
configuration of the main enantiomer. Solvent: n-hexane. f In
e
At room temperature, the ee decreased to 78%, and at 0
°C, it dropped to merely 24%.19 Furthermore, the data
n-hexane or toluene as the solvent, no reaction occurred.
4
reveal that an excess of Ti(OiPr) is necessary to achieve
quantitative conversion of 9a ; only traces of 10a were
formed if the reaction was carried out with a substoichio-
lyzed the ethylation of 9a with a moderate ee of 56%. No
product formation was observed in the presence of
metric amount of Ti(OiPr)
or 5 mol‚%) or a larger excess of Ti(OiPr)
4
. Lower catalyst loading (10
(3 equiv) led
(M,M,M)-3 and (M,M,M)-4, even though the latter is built
4
up of three biarylic amino alcohol units, a substructure
that is known to catalyze this type of reaction.1
3,18
to significantly lower degrees of asymmetric induction.
Finally, the synthetic use of (M,M,M)-3 as a catalyst
was evaluated in the ethylation of a series of different
aromatic aldehydes (Table 2). All reactions were carried
out under optimized conditions affording the R-configured
ethylcarbinols 10 in >90% chemical yield and with high
For
further experiments, we tried C-ethylations in the pres-
ence of Ti(OiPr) , since we expectedsbesides an accelera-
4
tion of the reaction due to Lewis-activation of 9a san in
situ incorporation of a Ti(OiPr) fragment into the central
(
18) (a) Ko, D.-H.; Kim, K.-H.; Ha, D.-C. Org. Lett. 2002, 4, 3759-
3
762. (b) Superchi, S.; Mecca, T.; Giorgio, E.; Rossini, C. Tetrahedron:
(19) This is one of the rare cases where diethylzinc additions deliver
higher asymmetric inductions at higher temperatures. The same effect
was observed for a chiral titanium-sulfonamide complex, see: Ram o´ n,
D. J .; Yua, M Tetrahedron: Asymmetry 1997, 8, 2479-2496.
Asymmetry 2001, 12, 1235-1239. (c) Vysko cˇ il, Sˇ .; J aracz, S.; Smr cˇ ina,
M.; Sˇ t ´ı cha, M.; Hanu sˇ , V.; Pol a´ sˇ ek, M.; Ko cˇ ovsk y` , P. J . Org. Chem.
1
998, 63, 7727-7737.
6
862 J . Org. Chem., Vol. 68, No. 18, 2003

3
Axially Chiral C -Symmetric Tripodal Catalysts
TABLE 2. En a n tioselective Alk yla tion of Va r iou s
9e with its chlorine substituent in the para position
delivered high enantiomeric excesses. The dialkylzinc
reagent was varied exemplarily for benzaldehyde (9a ) as
Ar om a tic Ald eh yd es 9 Ca ta lyzed by 20 m ol‚% of
a
(
M,M,M)-3
2
the substrate. The addition of (nBu) Zn delivered (R)-1-
phenylpentan-2-ol (10i) in 84% yield and an excellent ee
of 97%. With the less reactive Me
reaction occurred.
2
Zn, however, no
Con clu sion
aldehyde
R
R′
Et
“2,3-benzo” Et
alcohol yield (%)b ee (config)c
In summary, we have developed an economical and
simple access to a novel type of enantiomerically pure,
C -symmetric tripodal ligands possessing three axially
3
chiral biaryl subunits. The ligand (M,M,M)-3 was suc-
cessfully utilized as the catalyst in the enantioselective
addition of dialkylzinc to various aromatic aldehydes,
delivering enantiomeric excesses of up to 98%.
9
9
9
9
9
9
9
9
9
9
a
b
c
d
e
f
g
h
a
a
10a
10b
10c
10d
10e
10f
10g
10h
10i
93
96
97
81
91
91
94
95
84
90 (R)
86 (R)
96 (R)
96 (R)
44 (R)
94 (R)
96 (R)
98 (R)
97 (R)
4-MeO
2-MeO
4-Cl
Et
Et
Et
2-Cl
Et
3,5-MeO
4-Me
Et
Et
nBu
Me
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft (SFB 347 Selective
Reactions of Metal-activated Molecules, and Graduierten-
kolleg 690 Electron Density: Theory and Experiment),
by the Fonds der Chemischen Industrie (fellowship for
M.B. and research funds), and by the Freistaat Bayern
10j
a
All reactions were carried out with 50 µmol of the aromatic
aldehyde 9; the amounts of the other reagents are given relative
b
c
to 9. Isolated yields after PLC. Determined by HPLC (Chiracel
OD-H); config ) configuration of the main enantiomer.
(
fellowship for R.-M.P.). Furthermore, we thank S.
to excellent enantioselectivities of up to 98% ee.20 Only
with 2-chlorobenzaldehyde (9f) as the substrate was a
moderate asymmetric induction (ee 44%) obtained. The
reasons for this are not evident, since both the likewise
Graupner for technical assistance.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all new compounds, and
1
13
H and C NMR spectra for (M,M,M)-3, (M,M,M)-4, and
2
-substituted derivative 9d (R ) OMe) and the aldehyde
(M,M,M)-8. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) n-Heptanal as a representative of an aliphatic aldehyde did not
react under these conditions.
J O034697T
J . Org. Chem, Vol. 68, No. 18, 2003 6863