Synthesis of an optically active C1-symmetric Al(salalen) complex and its application to the catalytic hydrophosphonylation of aldehydes

Article abstract of DOI:10.1002/anie.200501008

(Chemical Equation Presented) Quite universally: The chiral trigonal-bipyramidal Al(salalen) complex 1 was synthesized and found to be an efficient catalyst for enantioselective hydrophosphonylation of various aldehydes with dimethyl phosphite (see scheme

Full text of DOI:10.1002/anie.200501008

Communications
Asymmetric Catalysis
2,4-di(tert-butyl)phenol and chiral secondary amines derived
from cyclohexane-1,2-diamine and 1,2-diphenylethylenedi-
amine did not proceed. Thus, the salalen ligand 4 was
synthesized in a stepwise manner (Scheme 1). Reductive
Synthesis of an Optically Active C1-Symmetric
Al(salalen) Complex and Its Application to the
Catalytic Hydrophosphonylation of Aldehydes**
Bunnai Saito and Tsutomu Katsuki*
For the last few decades asymmetric catalysis of optically
active complexes has been a major topic in synthetic
chemistry, and various types of chiral ligands have been
introduced.[1] Among these, tetradentate ligands have been
widely used because of their good ability to form complexes.
In particular, chiral salen ligands have received a great deal of
attention owing to their high asymmetry-inducing ability and
ready availability. Chiral metallosalen complexes show potent
and diverse asymmetric catalytic activities and have been
used as catalysts for a wide range of enantioselective
reactions, including epoxidation, aziridination, sulfoxidation,
Michael reaction, epoxide opening, etc.[2] Salen complexes
adopt mostly an octahedral configuration in which two
ancillary ligands are trans-oriented. However, recent studies
have disclosed that cis-b isomers show unique catalytic
behavior.[2c] For example, a di-m-oxo Ti(salen) complex that
bears chiral cis-b-salen ligands catalyzes asymmetric cyana-
tion with high enantioselectivity.[3] Furthermore, a di-m-oxo
Ti(salen) complex has been found to be an excellent pre-
catalyst for asymmetric sulfoxidation, in which a monomeric
cis-b-peroxo complex has been proven to be the active
species.[4] Kol and co-workers reported quite recently that
treatment of an achiral hybrid salan/salen tetradentate
[ONN(Me)O]-type ligand (hereafter referred to as salalen)
with titanium and zirconium tetraethoxides yielded the
Scheme 1. Synthesis of the optically active salalen ligand 4: a) 1 and 2,
MeOH, room temperature, then NaBH4 (2.5 equiv), 08C ! RT;
b) (Boc)2O, EtOH, room temperature (67%, 2 steps); c) aq.CH 2O,
Pd/C, H2, MeOH, room temperature; d) 3m HCl, MeOH, room tem-
perature; e) 2, MeOH, room temperature (76%, 3 steps).Boc =tert-
butoxycarbonyl.
amination of aldehyde 2 with monoammonium salts of
diamine 1[6] in the presence of sodium borohydride, followed
by N-protection with the tert-butoxycarbonyl (Boc) group,
gave the corresponding amine 3 in 67% yield. The N-
methylation of amine 3, deprotection of the Boc group with
aqueous HCl, and condensation of the resulting primary
amine with aldehyde 2 afforded the desired ligand 4 in 76%
yield. The salalen ligand 4 was then treated with Et2AlCl to
give the corresponding Al(salalen) complex 5 in high yield
corresponding octahedral Ti-and Zr(salalen)(OEt) com-
(Scheme 2). Recrystallization of 5 from heptane and
2
plexes, in which the two diastereotopic ethoxy groups are cis-
oriented and the coordinated amino nitrogen atom that is
ꢀ
closer to the metal ion by one C C bond than the ethylene
carbon is chiral.[5] Thus, we expected that the chiral salalen
ligand would establish a unique asymmetric reaction site that
induces a high extent of asymmetry. Herein, we describe the
synthesis of a chiral aluminum salalen complex and its
application to the asymmetric hydrophosphonylation of
aldehydes to give optically active a-hydroxy phosphonates.
We initially attempted the synthesis of an optically active
salalen ligand according to Kolꢀs procedure, but the attempt
ended in failure because the key Mannich condensation of
Scheme 2. Synthesis of Al(salalen) complex 5.
dichloromethane gave single crystals, one of which was
submitted for X-ray diffraction analysis (Figure 1).[7] This
analysis demonstrated that complex 5 has a unique structure
that is different from that of Al(salen) complexes:[8] it adopts
a distorted trigonal-bipyramidal configuration, and the abso-
lute configuration of the coordinated tertiary amine is S. As
the chiral ligand adopts a unique cis-b-like structure and as
the methyl group on the nitrogen atom is located in the
middle of the chiral ligand and close to the chloro ligand that
should be replaceable by a substrate such as an aldehyde, we
expected that the orientation of the substrate ligated to the
[*] B.Saito, Prof.T.Katsuki
Department of Chemistry, Faculty of Science
Graduate School, Kyushu University
33, Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan)
Fax: (+81)92-642-2607
E-mail: katsuscc@mbox.nc.kyushu-u.ac.jp
[**] Financial support was provided by CREST of the Japan Science and
Technology Agency.B.S.is grateful for research fellowships from the
Japan Society for the Promotion of Science for Young Scientists.
Salalen refers to an achiral hybrid salan/salen tetradentate ligand.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
4600 ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200501008
Angew. Chem. Int. Ed. 2005, 44, 4600 –4602

Angewandte
Chemie
Table 1: Asymmetric hydrophosphonylation of benzaldehyde.
Entry
R
Solvent
T [8C]
Yield [%][a]
ee [%][b]
Config.[c]
1
2
3
4
5
6
7
Me
Et
Ph
Me
Me
Me
Me
Me
Me
THF
THF
THF
Et2O
iPr2O
THF
iPr2O
THF
iPr2O
RT
RT
RT
RT
RT
0
92
96
87
97
94
91
94
87
80
73
70
17
68
79
87
89
90
S
S
S
S
S
S
S
0
8[d]
9[d]
ꢀ15
Figure 1. X-ray crystal structure of 5.Hydrogen atoms have been omit-
ted for clarity.The tert-butyl group (C30–C33) attached to C26 is disor-
dered (disorder omitted for clarity).
ꢀ15
81–90
[a] Yield of isolated product.[b] Determined by HPLC analysis using a
chiral stationary phase column (Daicel Chiralpak AS-H; hexane/iPrOH
4:1).[c] Determined by chiroptical comparison (ref[.10d]).[d] The
reaction was carried out for 48 h.
aluminum ion should be efficiently regulated by the ligand.
Thus, we considered that 5 should be a highly efficient chiral
Lewis acid catalyst. To explore the catalytic behavior of 5, we
first examined the asymmetric hydrophosphonylation of
aldehydes.
in THF (Table 2). The electronic effect on enantioselectivity
was investigated with para-substituted benzaldehyde deriva-
tives, and we found that an electron-withdrawing group
Optically active a-hydroxy phosphonates and phosphonic
acids are biologically active compounds that are widely used
in pharmaceutical applications, and much effort has been
directed toward the development of asymmetric hydrophos-
phonylation of carbonyl compounds (the Pudovik reac-
tion).[9,10] To the best of our knowledge, LLB (LaLi3tris(bi-
naphthoxide)) and ALB (AlLibis(binaphthoxide)) reported
by Shibasaki and co-workers are the most efficient catalysts
for this reaction and have been complementarily used as
catalysts for the reaction of various aldehydes.[10d,f] Recently,
Kee and co-workers reported that chiral Al(salen) complexes
serve as catalysts for asymmetric hydrophosphonylation;
however, the enantioselectivities obtained were modest (up
to 49% ee).[11] The introduction of a novel catalyst that can
show wide applicability for various aldehydes, especially
aliphatic ones, is therefore still required to achieve a highly
efficient Pudovik reaction.
With the Al(salalen) complex 5 in hand, we first examined
the asymmetric hydrophosphonylation of benzaldehyde with
dimethyl phosphite at room temperature under various
conditions (Table 1, entries 1–5). All the reactions proceeded
smoothly to give the desired product in acceptable yields and
the best enantioselectivity was observed in the reaction with
diisopropyl ether as solvent. The reactions with dialkyl
phosphites, especially dimethyl phosphite, showed better
enantioselectivities than those with diphenyl phosphite (see
entries 1–3). Lowering the temperature of the reaction in
diisopropyl ether to 08C improved the enantioselectivity to
89% ee (entry 7), whereas a further reduction of the temper-
ature affected the reproducibility of the enantioselectivity
(entry 9).[12] The enantioselectivity of the reaction in THF was
inferior to that in diisopropyl ether at room temperature, but
the reaction at ꢀ158C showed the best and most reproducible
enantioselectivity of 90% ee, albeit with some reduction of
the chemical yield (entry 8).
Table 2: Asymmetric hydrophosphonylation of various aldehydes.
Entry
R
Yield [%][a]
ee [%]
Config.
1
2
3
4
5
6
7
8
p-O2NC6H4
p-ClC6H4
p-MeOC6H4
o-ClC6H4
95
88
87
96
77
94
89
61
94[b]
88[b]
81[b]
91[b]
83[b]
91[b]
89[d]
89[d]
S[c]
S[c
S[c]
S[c]
=
(E)-PhCH CH
PhCH2CH2
(CH3)2CH
CH3CH2
S[e]
[a] Yield of isolated product.[b] Determined by HPLC analysis using a
chiral stationary phase column (Daicel Chiralpak AS-H; hexane/iPrOH
7:3).[c] Determined by chiroptical comparison (ref[.10d]).[d] Deter-
mined by HPLC analysis using a chiral stationary phase column (Daicel
Chiralpak AS-H; hexane/iPrOH 9:1) after conversion of the product into
the corresponding benzoate.[e] Determined by chiroptical comparison
(ref.[13]).
increases the enantioselectivity (entries 1–3); the highest
enantioselectivity of 94% ee was observed in the reaction
with p-nitrobenzaldehyde (entry 1), although the reaction of
o-chlorobenzaldehyde also proceeded with high enantiose-
lectivity (entry 4). The reaction of an a,b-unsaturated alde-
hyde (cinnamaldehyde) was a little slow and showed a slightly
reduced enantioselectivity of 83% ee (entry 5). To our
delight, high enantioselectivity was also observed in the
reactions of aliphatic aldehydes. Both nonbranched (entries 6
and 8) and branched (entry 7) aliphatic aldehydes gave the
corresponding a-hydroxy phosphonates with high enantiose-
lectivities and in good yields. To the best of our knowledge,
this is the first example where a molecular catalyst can be
Thus, we examined the asymmetric hydrophosphonyla-
tion of various aldehydes with complex 5 as catalyst at ꢀ158C
Angew. Chem. Int. Ed. 2005, 44, 4600 –4602
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
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aldehydes with enantioselectivities greater than 80% ee.
In conclusion, we have synthesized a chiral, trigonal-
bipyramidal aluminum(salalen) complex 5 that provides a
unique asymmetric reaction site in which an asymmetric
nitrogen atom is bound to the metal ion and the N-methyl
group is cis to the chloro ligand. Moreover, complex 5 is an
efficient catalyst for the enantioselective hydrophosphonyla-
tion of various aldehydes with dimethyl phosphite. Further
application of this novel aluminum complex to other asym-
metric reactions is under investigation.
Experimental Section
Complex 5 (12.5 mg, 0.02 mol) and dimethyl phosphite (10.1 mL,
0.21 mmol) were dissolved in THF (1.0 mL) under nitrogen, and the
solution was stirred for 10 min at room temperature. After cooling to
ꢀ158C, aldehyde (0.20 mmol) was added to the solution and the
solution was stirred for 48 h. The reaction was quenched with 1m HCl
and extracted with AcOEt (3 ” ca. 1 mL), and the combined organic
phase was passed through a pad of Celite and Na2SO4. After removal
of the solvent under reduced pressure, the residue was chromato-
graphed on silica gel (hexane/acetone, 7:3–3:7) to give the corre-
sponding a-hydroxy phosphonate. The ee values were determined by
HPLC on a chiral stationary phase under the conditions described in
the footnotes to Table 1 and Table 2.
[12] Complex 5 and the product, dimethyl a-hydroxyphenylmethyl-
phosphonate, are weakly soluble in diisopropyl ether.
A
suspension of 5 in diisopropyl ether became homogeneous
upon addition of dimethyl phosphite, but the solution became
heterogeneous again as the reaction proceeded. This turbidity
might reduce the reproducibility of the enantioselectivity of the
reaction at ꢀ158C.
[13] Y. Zhang, C. Yuan, Z. Li, Tetrahedron 2002, 58, 2973 – 2978.
Received: March 19, 2005
Published online: June 27, 2005
Keywords: aldehydes · aluminum · asymmetric catalysis ·
.
hydrophosphonylation · N,O ligands
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4602
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