BINOL-salen metal catalysts incorporating a bifunctional design.

Article abstract of DOI:10.1021/ol0158213

Salen metal complexes incorporating two chiral BINOL moieties have been synthesized and characterized crystallographically. The corresponding bisnaphthoxide complexes have been found to catalyze the asymmetric addition of benzyl malonate to cyclohexenone

Full text of DOI:10.1021/ol0158213

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1641-1644
BINOL−Salen Metal Catalysts
Incorporating a Bifunctional Design
Erin F. DiMauro and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
marisa@sas.upenn.edu
Received March 9, 2001
ABSTRACT
Salen metal complexes incorporating two chiral BINOL moieties have been synthesized and characterized crystallographically. The corresponding
bisnaphthoxide complexes have been found to catalyze the asymmetric addition of benzyl malonate to cyclohexenone in up to 90% ee. With
these modular catalysts, the Lewis acid and Bronsted base portions can be independently altered.
A number of recent studies have shown that multifunctional
ligands possess useful characteristics for catalysis and
asymmetric synthesis.1 For example, ligands have been
reported in which one portion engages a Lewis acid moiety
that coordinates an electrophilic substrate while another
portion of the ligand coordinates to the nucleophilic substrate
partner. The positioning by such a catalyst assembly of the
two reactant partners in close proximity and with the correct
relative geometry facilitates a reaction in a manner similar
to that of some enzyme catalysts (i.e., ligases). Dual
coordination by such catalyst assemblies further enables the
reaction by simultaneously enhancing the electrophilic
character of one partner and the nucleophilic character of
the other partner.2
and co-workers.1c,d In these complexes, the central lanthanide
metal is proposed to coordinate the electrophile while the
hemilable BINOLate oxygens deprotonate the nucleophile.
While several bifunctional ligands that operate along these
lines have been discovered,1,3 relatively few examples exist
in which separate and distinct sites are present for individual
activation of the electrophilic and nucleophilic portions.4 One
of the earliest examples of this latter motif can be found in
An example of this motif can be found in the hetero-
bimetallic complexes (1, Figure 1) developed by Shibasaki
(1) (a) Corey, E. J.; R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109,
5551-5553. (b) Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R. J. Am. Chem.
Soc. 1995, 117, 4832-4842. (c) Shibasaki, M.; Sasai, H.; Arai, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1236-1256. (d) Kim, Y. S.; Matsunaga,
S.; Das, J.; Sekine, A.; Oshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000,
122, 6506-6507 and references therein. (e) Gample, M. P.; Smith, A. R.
C.; Wills, M. J. Org. Chem. 1998, 63, 6068-6071. (f) Yamakawa, M.; Ito,
H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466-1478 and references
therein. (g) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003-
12004. (h) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573-575
and references cited herein.
Figure 1.
10.1021/ol0158213 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/03/2001

complex 2 developed by Hayashi and Ito,4a which catalyzes
the aldol reaction of isocyanoacetates and aldehydes.
The goal of the present work is to construct scaffolds in
which the Lewis acid and base elements can be independently
manipulated. In particular, new compounds can be envisioned
with functional groups specifically tailored to the nucleophile
and electrophile of a given reaction and with the optimal
spacing and orientation between groups. The structurally
well-defined and rigid salen scaffold was chosen as a starting
point, leading to general structure 3 (Figure 2). An apical
Scheme 1
Figure 2.
coordination sight at the salen metal center could act as the
docking site for a Lewis basic substrate. In addition, the ease
of preparation and derivatization of the salen backbone is
ideal for the rapid construction of many ligands.
to determine whether the diamine or BINOL portion of the
catalyst is the key feature controlling the transfer of asym-
metry.
The M1-BINOL-salen complexes (15-25) incorporating
Ni(II), Cu(II), Zn(II), or Pd(II) were prepared from the
corresponding metal salts as shown in Table 1. Nickel,
copper, zinc, and palladium were chosen on the basis of their
affinity for nitrogen, to promote the salen binding mode over
The tether connecting the salen to the basic functional
group must be short and/or rigid enough to prevent internal
complexation to the metal. In this Letter, the synthesis and
utility of salen 4 incorporating a BINOL structure is
presented. For 4, the biaryl bond provides the requisite tether
which prevents complexation of the free naphthols to the
metal center but positions them close to substrates bound to
the salen metal.
Table 1. Formation of M1-BINOL-Salen Complexes (eq 1)
BINOL-salen ligands 9-14 were prepared in four steps
as shown in Scheme 1. Aldehyde 75 was readily generated
from (S)-BINOL by lithiation and acylation of the bispro-
tected derivative 6. Cleavage of the MOM ethers then
provided the requisite aldehyde 8 which underwent ready
condensation with various diamines to provide salens 9-14.
The three diastereomeric salen compounds 11, 12, and 13,6
derived from diaminocyclohexane, were prepared in order
(2) For reviews on bifunctional catalysis, see: Sawamura, M.; Ito, Y.
Chem. ReV. 1992, 92, 857-871. van den Beuken, E. K.; Feringa, B. L.
Tetrahedron 1998, 54, 12985-13011. Rowlands, G. J. Tetrahedron 2001,
57, 1865-1882.
(3) For other heterobimetallic catalysts, see the following. Al‚Li: (a)
Keller, E.; Veldman, N.; Spek, A. L.; Feringa, B. L. Tetrahedron:
Asymmetry 1997, 8, 3403-3413. (b) Arai, T.; Hu, Q.; Zheng, X.; Pu, L.;
Sasai, H. Org. Lett. 2000, 2, 4261-4263. (c) Manickam, G.; Sundarajan,
G. Tetrahedron 1999, 55, 2721-2736. (d) Sundararajan, G.; Prabagaran,
N. Org. Lett. 2001, 3, 389-392. Zn‚Li: (e) Nina, S.; Soai, K. J. Chem.
Soc., Perkin Trans. 1 1991, 2717-2720.
(4) (a) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108,
6405-6406. (b) Kitajima, H.; Ito, K.; Aoki, Y.; Katsuki, T. Bull. Chem.
Soc. Jpn. 1997, 70, 207-217. (c) Sibi, M. P.; Cook, G. R.; Liu, P.
Tetrahedron Lett. 1999, 40, 2477-2480. (d) Hamashima, Y.; Sawada, D.;
Nogami, H.; Kanai, M.; Shibasaki, M. Tetrahedron 2001, 57, 805-814
and references therein. (e) Ooi, T.; Kondo, Y.; Maruoka, K. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1183-1185.
salen
conditions
M1
M1-salen complex
% yield
9
9
9
a
b
c
d
a
a
b
a
b
a
a
Ni
Cu
Zn
Pd
Ni
Ni
Cu
Ni
Cu
Ni
Ni
15
16
17
18
19
20
21
22
23
24
25
65
92
in situ
87
88
83
86
85
85
9
10
11
11
12
12
13
14
74
84
1642
Org. Lett., Vol. 3, No. 11, 2001

an undesired mode involving coordination to only the BINOL
components. Consistent with formation of the desired
complexes, a lower CdN stretch in the IR spectra of the
complexes relative to that of the free salen was observed.
Also, a C2-symmetry element is indicated from the 13C NMR
spectrum of the Ni- and Pd-BINOL-salen complexes.
An X-ray crystal structure of the nickel complex 22
provided further evidence for the structure of the salen metal
complex. Two conformational forms of the salen were
observed in the unit cell, one of which is illustrated in Figure
3. In this structure, the ancilliary naphthols adopt a parallel
between the naphthoate anion and the salen oxygens are
likely to be weak.7 As a result, it should be possible to
modulate the reactivity of the salen Lewis acid and the
naphthoate base independently.
The BINOL-salen-metal complexes were examined in
the Michael reaction8 of cyclohexenone with benzyl malonate
(Table 2). The active catalysts, 26a-26l were generated from
Table 2. Salen Naphthoxide Complexes (eq 2) in the Michael
Addition Reaction (eq 3)
entry
catalyst
M1
M2
base
% yielda
% eeb
1
2
3
4
5
6
7
8
9
10
11
12
13
15
Ni
Ni
Ni
Ni
Ni
Cu
Zn
Pd
Ni
Ni
Ni
Ni
Ni
H
Li
Na
K
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
0
20
55
75
80
73
57
70
49
84
79
88
83
26a
26b
26c
26d
26e
26f
26g
26h
26i
26j
26k
26l
NaOtBu
LiOtBu
KOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
2 (S)
7 (R)
15 (R)
31 (R)
31 (R)
8 (R)
10 (R)
31 (R)
54 (R)
71 (R)
42 (R)
21 (R)
a Isolated yields. b Enantiomeric excess determined by HPLC. Absolute
configuration based on optical rotation values.
Figure 3. X-ray crystal structure of 22. Non-heteroatom hydrogens
and solvent molecules omitted for clarity. Selected distances and
angles: O20-O31 2.65 Å, O43-O54 2.60 Å, C45-O54-O43
92.1°, C22-O31-O20 89.6°, C42-C41-C44-C45 56.3(1)°,
C19-C18-C21-C22 53.0(1)°.
the preformed M1-BINOL-salen complexes 15-25 via
treatment with the indicated base in THF9 prior to addition
of the reaction substrates. Beginning with Ni(II)-salen
complex 15, the effects of M2 were examined (entries 1-5,
Table 2).10 Replacement of both phenolic protons with a
arrangement with one naphthoate oxygen above and one
below the plane of the salen. The hydrogens on these
naphthols hydrogen bond with the metal-bound oxygen of
each BINOL fragment.
Formation of the Li, Na, K, or Cs naphthoxides of M1-
BINOL-salen complexes 15-25 would provide hetero-
bimetallic metal complexes 26. From the trends observed in
the crystal structure of the protonated form, interactions
(7) In the second structure in the unit cell, the ancilliary naphthols adopt
a nonparallel arrangement while most of the other features are the same as
the first structure. Once again, one naphthoate oxygen is above the plane
and one below the plane of the salen; however, only one of the naphthols
forms an intramolecular hydrogen bond with the salen nucleus. The second
naphthol participates in an intermolecular hydrogen bond with a naphthoate
oxygen from the other complex in the unit cell. See Supporting Information
for full details.
(8) For recent reviews, see: (a) ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999; Chapter 31. (b) Leonard, J.; Ciez-Barra, E.; Merino, S. Eur. J. Org.
Chem. 1998, 2051-2061.
(5) Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.; Yamamoto, N.; Iida,
T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2000 122, 2252-
2260.
(6) The BINOL portion of salen 13 is anticipated to create a chiral
conformation in the achiral diamine portion. See: Balsells, J.; Walsh, P. J.
J. Am. Chem. Soc. 2000, 122, 1802-1803.
(9) Of the solvents examined with the Ni‚Cs-BINOL-salen catalyst
26d (toluene, THF, CH2Cl2, CH3CN, DMF), THF gave the best results.
(10) The role of anion of the base used to provide M2 in the catalyst is
not clear (KOtBu vs Cs2CO3).
Org. Lett., Vol. 3, No. 11, 2001
1643

divalent metal (M1:M2 ) 1:1) such as Zn, Mg, and Ca was
ineffective. Presumably, a stable tetrahedral complex forms
between the four BINOL oxygens, rendering the naphthoates
ineffective as bases.
Scheme 2. Possible Catalytic Cycle for the Catalyzed Michael
Reaction
Next, the effects of M1 were examined with M2 ) Cs held
constant (entries 5-8). Among the various metal combina-
tions examined, the Ni‚Cs-BINOL-salen catalyst 26d gave
the best result (entry 5).
Exchanging the ethylenediamine linker in the Ni‚Cs-
BINOL-salen catalyst with a diaminobenzene or a diphenyl
ethylene linker resulted in a less effective catalyst (entries 9
and 13 vs entry 5). Switching to a cis-diaminocyclohexane
linker resulted in a more effective catalyst (entry 12 vs entry
5). Finally, the trans-diaminocyclohexane derivatives 26i and
26j (Figure 4) were examined (entries 10 and 11, Table 2).
transfer from the naphthol to the enolate intermediate would
then allow product release and catalyst regeneration.
Several control reactions were conducted in order to
determine whether the mechanism outlined in Scheme 2 is
reasonable for these reactions. First, the Lewis acid center
alone is not sufficient to ensure reactivity, since Ni-
BINOL-salen 15 is completely ineffective as a catalyst
(Table 2, entry 1). While a rapid reaction was obtained with
BINOL-derived Cs-naphthoxide 28, the lack of selectivity
with 28 suggests that a Cs-naphthoxide base alone is not a
sufficient determinant for good enantioselectivity. Rather,
the entire Ni‚Cs-BINOL-salen assembly is required for
selectivity. Finally, a decrease in yield and enantioselectivity
is observed upon switching from the Ni‚Cs-BINOL-salen
catalyst 26d to the Pd‚Cs-BINOL-salen catalyst 26g (Table
2, entry 8 vs entry 5). This result is consistent with the
proposed catalytic cycle since Pd(II) is less Lewis acidic than
Ni(II).
In conclusion, several novel salen complexes have been
synthesized and characterized. These complexes were ef-
fective catalysts for the Michael reaction. Significant
enantioselective cooperative effects between different com-
ponents of these modular ligands have been observed. The
Ni‚Cs-BINOL-salen complexes show promise as chiral
catalysts for asymmetric synthesis.
Figure 4.
The latter proved to be the matched catalyst system,
providing the Michael adduct in 71% ee (entry 11). Upon
cooling the reaction to -40 °C, the Michael adduct is
obtained in up to 90% ee with 10 mol % of 26j (Figure 4).11
Contrary to expectations, catalysts differing in the con-
figuration of the bisimine backbone afforded the same
prevailing enantiomer in the product (Figure 4). Furthermore,
all of the Ni‚Cs-BINOL-salen catalysts containing a
diaminocyclohexane backbone catalyzed the reaction with
improved selectivity over that of Ni‚Cs-BINOL-salen
catalyst 26d containing an ethylenediamine backbone. As
such, the chirality in the biaryl axis appears to be the
dominant control element responsible for facial selectivity.
A possible catalytic cycle for the Michael reaction is
depicted in Scheme 2. Deprotonation of the dibenzyl
malonate by the naphthoate anion would yield a malonate
anion held in proximity to the salen via coordination through
the naphthoate counterion (i.e., Cs). Coordination of the
cyclohexenone to an apical site of the Ni-salen complex
would activate the electrophile in close proximity to this
nucleophile, allowing the Michael addition to occur. Proton
Acknowledgment. Financial support was provided by
the National Institutes of Health (GM-59945) and Merck
Research Laboratories. The invaluable assistance of Dr.
Patrick Carroll in obtaining the X-ray structure is gratefully
acknowledged.
Supporting Information Available: Experimental details
and characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) Reaction time was 48 h at 20 and 0 °C and 5 d at -20 and -40 °C.
OL0158213
1644
Org. Lett., Vol. 3, No. 11, 2001