A heterobimetallic Pd/La/Schiff base complex for anti-selective catalytic asymmetric nitroaldol reactions and applications to short syntheses of β-adrenoceptor agonists

Article abstract of DOI:10.1002/anie.200705617

(Chemical Equation Presented) Two metals in a pod: The combination of Pd and La with a dinucleating Schiff base was developed for anti selectivity in the catalytic asymmetric nitroaldol reaction (see scheme). Short syntheses of β-adrenoceptor agonists by using the heterobimetallic catalyst are presented.

Full text of DOI:10.1002/anie.200705617

Communications
DOI: 10.1002/anie.200705617
Nitroaldol Reaction
A Heterobimetallic Pd/La/Schiff Base Complex for anti-Selective
Catalytic Asymmetric Nitroaldol Reactions and Applications to Short
Syntheses of b-Adrenoceptor Agonists**
Shinya Handa, Keita Nagawa, Yoshihiro Sohtome, Shigeki Matsunaga,* and
Masakatsu Shibasaki*
Chiral b-amino alcohols are useful building blocks found in
various biologically active natural products, pharmaceuticals,
chiral auxiliaries, and chiral ligands.[1] Various methods for
catalytic enantioselective synthesis of b-amino alcohols have
been developed over the past decade,[2] and the catalytic
asymmetric nitroaldol (Henry) reaction is an efficient method
for providing b-amino alcohols by reduction of the nitro
moiety in nitroaldol adducts.[3] Since our first report of the
catalytic asymmetric nitroaldol reaction,[4] various chiral
catalysts, which are effective with nitromethane as a donor,
have been developed.[5] However, diastereo- and enantiose-
lective nitroaldol reactions that use nitroethane and other
nitroalkanes as donors are limited. To realize direct nitroaldol
reactions, chiral Brønsted base catalysts could deprotonate
the a proton of the nitroalkane to generate a metal nitronate,
but epimerization of the products must be prevented to
achieve high diastereoselectivity under kinetic control. Syn-
selective asymmetric reactions have been established by our
group and others;[6] but anti-selective asymmetric reactions
required pre-activation of nitroalkanes to silylnitronates[7] to
avoid basic conditions. Therefore, a new catalyst for anti-
selective asymmetric nitroaldol reactions for direct use with
nitroalkanes is needed in terms of atom economy.[8] Quite
recently, Ooi and co-workers[9] reported an elegant chiral P-
spiro triaminoiminophosphorane catalyst for the first direct
nitroaldol reaction with excellent anti selectivity, enantiose-
lectivity, and broad substrate generality.[10–11] Considering the
importance of anti amino alcohols as precursors for various
important pharmaceuticals such as b-adrenoceptor agonists,
additional studies of the anti-selective reactions are desirable.
Herein, we report a new heterobimetallic Pd/La/1 complex
(Scheme 1) for anti-selective nitroaldol reactions, and its
Scheme 1. Dinucleating (R,R)-Schiff base ligand 1-H4 and the proposed
structures of heterobimetallic Cu/Sm/(R,R)-1 and Pd/La/(R,R)-1 com-
plexes with an ArOHadditive.
application to short syntheses of b-adrenoceptor agonists
2a·HCl (ritodrine·HCl) and 2b·HCl.
2a·HCl is a selective b2-adrenoceptor agonist, clinically
used for the prevention of pre-term birth (Scheme 2),[12] and
related compound 2b·HCl is a selective b3-adrenoceptor
Scheme 2. Structures and retrosynthesis of (À)-ritodrine 2a·HCl and
b3-adrenoceptor agonist 2b·HCl. PG=protecting group.
[*] S. Handa, K. Nagawa, Dr. Y. Sohtome, Dr. S. Matsunaga,
Prof. Dr. M. Shibasaki
agonist that provides a new therapeutic for urinary dysfunc-
tion.[13] The common chiral anti b-amino alcohol unit (4’-
hydroxynorephedrine) in both drugs is key for high biological
activity, and we anticipated the anti-nitroaldol reaction to be
one of the most straightforward methods for constructing two
contiguous stereocenters in the common unit (Scheme 2). 2a
and 2b could be synthesized by reduction of the nitro group of
the anti-nitroaldol adduct with subsequent reductive alkyla-
tion of the amine moiety. Initially, we planned to utilize anti-
selective nitroaldol reactions catalyzed by a Nd/Na/chiral
amide complex recently developed by our group,[11] but when
used with aldehyde precursors suitable for 2a and 2b the
reactions resulted in low enantioselectivities of the prod-
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: mshibasa@mol.f.u-tokyo.ac.jp
smatsuna@mol.f.u-tokyo.ac.jp
Homepage: http://www.f.u-tokyo.ac.jp/~kanai/e_index.html
[**] This work was partially supported by a Grant-in-Aid for Specially
Promoted Research from MEXT, and a Grant-in-Aid for Encourage-
ments for Young Scientists (B) (Y.S.), from JSPS, and Mitsubishi
Chemical Corporation Fund (S.M.), and Toray Co Ltd.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
ucts.[14] Therefore, we turned our attention to developing a
new catalyst suitable for b-adrenoceptor agonists syntheses.
We recently reported the utility of dinucleating Schiff base
1-H4 (Scheme 1) in nitro-Mannich reactions of N-Boc imines
(Boc = tert-butylcarboxy) with nitroethane and nitropro-
pane.[15] Schiff base 1-H4 selectively incorporated Cu into
the inner N2O2 cavity and an oxophilic rare earth metal,
having a large ionic radius, into the outer O4 cavity. The
cooperative functions of the two metals[16,17] in the hetero-
bimetallic Cu/Sm/1 complex (Scheme 1; M = Cu, RE = Sm)
were key to achieving high diastereo- and enantioselectivity
in the nitro-Mannich reactions. An achiral 4-tert-butylphenol
additive improved the enantioselectivity by performing as an
achiral ligand. We hypothesized that suitable selection of a
dinucleating Schiff base, a transition metal (M)/rare earth
metal (RE) combination, and a phenolic additive would
afford an optimal chiral environment for the anti-selective
nitroaldol reaction. Thus, we initiated optimization reactions
by using Schiff base 1-H4, a phenolic additive, aldehyde 3a,
and nitroethane 4a (Table 1). The Cu/Sm/1 and 4-tert-
butylphenol system, which was optimal for the nitro-Mannich
reactions, gave poor reactivity and selectivity (Table 1,
entry 1). Screening of other rare earth metals (Table 1,
entries 1-4) indicated that La(O-iPr)3 had the best reactivity
(Table 1, entry 4), and additional optimization with regard to
the inner metal (Table 1, entries 4–7) revealed that the best
combination was Pd(OAc)2 and La(O-iPr)3. These conditions
gave 5aa in 82% yield, anti/syn = 5.3:1, and 58% ee (Table 1,
entry 7). Other metals such as Ni(OAc)2 and Zn(OAc)2 gave
less satisfactory results (Table 1, entries 5–6). The phenolic
additive also affected both the diastereo- and enantioselec-
tivity (Table 1, entries 7-9), and 4-bromophenol was found to
be optimal (Table 1, entry 9). Finally, minor modifications of
the solvent and the reaction time
Table 1: Optimization of the reaction conditions.
Entry M[a] RE[b] ArOHSolvent
Yield
d.r.
[%] anti/
syn[c]
ee
[%][f]
[d]
[d]
1
2
3
4
5
6
7
8
Cu Sm 4-tBuC6H4OHTFH
Cu Gd 4-tBuC6H4OHTFH
Cu Dy 4-tBuC6H4OHTFH
33
26
25
73
61
30
82
2.3:1
2.3:1
2.8:1
2:1
2:1
1:2
1
4
3
28
12
2
Cu La
Ni La
Zn La
Pd La
Pd La
4-tBuC6H4OHTFH
4-tBuC6H4OHTFH
4-tBuC6H4OHTFH
4-tBuC6H4OHTFH
4-MeO-
5.3:1
58
THF
65
3.3:1
49
84
C6H4OH
9
Pd La
4-BrC6H4OHFTH
4-BrC6H4OHFT/H
77
xylenes
12:1
92
77
19:1
10[e] Pd La
[a] M(OAc)2 was used. [b] RE(O-iPr)3 was used. [c] Determined by
1HNMR analysis. [d] ent-5aa was the major product. [e] Reaction time
was 69 h. [f] Values determined for the anti product.
92–77% ee, albeit with modest anti selectivity (Table 2,
entries 10–12). The reaction with nitropropane (4b) as a
donor proceeded smoothly to give product 5ab in anti/syn =
19:1 and 85% ee (Table 2, entry 13). By using a 5 mol%
catalyst loading, good anti selectivity and enantioselectivity
were maintained, but a long reaction time was required
(Table 2, entry 14).
4-benzyloxybenzaldehyde 3k was selected for the syn-
thesis of 2a and 2b. A catalytic asymmetric nitroaldol
gave the optimum results in THF/
Table 2: anti-Selective nitroaldol reactions with various aldehydes and nitroalkanes.[a]
xylenes, producing 5aa in 92%
yield, anti/syn = 19:1, and 84% ee
(Table 1, entry 10).
The substrate scope and limita-
tions are shown in Table 2. Aro-
matic aldehydes with electron-
donating substituents at the para-,
meta-, or ortho-position gave prod-
ucts with high anti selectivity and
good enantioselectivity (Table 2,
entries 2–7). For the less reactive
aldehyde 3e, the reaction at À308C
was required for good conversion
(Table 2, entry 6 versus entry 7),
and aldehyde 3 f having an elec-
Entry
R
3
R’
4
Product
t
[h]
Yield[b]
[%]
d.r.
ee
anti/syn[c]
[%][f]
1
2
C6H5
3a
3b
3b
3c
3d
3e
3e
3 f
3g
3h
3i
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3CH2
CH3
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4a
5aa
5ba
5ba
5ca
5da
5ea
5ea
5 fa
5ga
5ha
5ia
69
72
72
72
72
72
72
72
72
85
85
72
85
120
92
80
97
81
83
47
78
87
80
70
75
65
67
82
19:1
19:1
15:1
13:1
21:1
22:1
15:1
8:1
12:1
5:1
3:1
4:1
19:1
16:1
84
87
83
83
81
88
83
72
80
80
77
92
85
85
4-CH3C6H4
4-CH3C6H4
3-CH3C6H4
2-CH3C6H4
4-CH3OC6H4
4-CH3OC6H4
4-ClC6H4
2-furyl
E-cinnamyl
Ph(CH2)2
Cy
C6H5
C6H5
3[d]
4
5
6
7[d]
8
9
10
11
12[d]
13
14[e]
tron-withdrawing
substituent
resulted in a slightly lower stereo-
selectivity (Table 2, entry 8). Heter-
oaromatic aldehyde 3g gave prod-
uct 5ga with good d.r. and ee values
(Table 2, entry 9). The present
system is also applicable to both
a,b-unsaturated and aliphatic alde-
hydes, which delivered products in
3j
3a
3a
5ja
5ab
5aa
[a] The reaction was run with 10 mol% of Pd/La/1 complex and 4-bromophenol at À408C unless
otherwise noted. Cy=cyclohexyl. [b] Yield of product isolated after column chromatography.
[c] Determined by 1HNMR analysis of the crude reaction mixture. [d] Reaction was run at À308C.
[e] Reaction was performed with 5 mol% of Pd/La/1 complex and 4-bromophenol. [f] Determined for
anti-5.
Angew. Chem. Int. Ed. 2008, 47, 3230 –3233
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Communications
reaction run with the Pd/La/(S,S)-1 complex and 4-bromo-
reaction, and mechanistic studies to elucidate the precise
roles of the two metals[20,21] are ongoing.
phenol afforded anti-adduct 5ka in 85% yield, anti/syn =
14:1, and 83% ee on a 1.0-mmol scale.[18] Salt-free ritodrine
(2a) was obtained in a one-flask operation from 5ka
(Scheme 3). Treatment of 5ka in ethyl acetate with Pd/C
under H2 (1 atm) at room temperature for 12 h gave
Received: December 8, 2007
Revised: February 4, 2008
Published online: March 17, 2008
Keywords: agonists · amino alcohols · asymmetric catalysis ·
.
nitroaldol reaction
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Scheme 3. Syntheses of b2-adrenoceptor agonist (À)-ritodrine 2a·HCl
and b3-adrenoceptor agonist 2b·HCl; Reagents and conditions: a) Pd/
La/(S,S)-1 (10 mol%), 4-bromophenol (10 mol%), THF/xylenes,
À308C, 85 h, 85%, anti/syn=14:1, 83% ee; b) 1. Pd/C, H2, EtOAc, RT,
12 h; 2. 7a, 608C, 24 h; then HCl in CH3OH, 93%; c) 1. Pd/C, H2,
EtOAc, RT, 12 h; 2. 7b, 608C, 24 h; then HCl in CH3OH, 73%.
intermediate 6 without epimerization. Completion of the
conversion of 5ka into 6 was verified by TLC analysis, and
then aldehyde 7a[19] was added to the reaction mixture. The
reaction mixture was heated at 608C under H2 (1 atm) for
24 hours to facilitate the reductive alkylation to afford salt-
free ritodrine (2a). After treating 2a with HCl in methanol
2a·HCl was obtained in 93% yield. Both the use of ethyl
acetate as the solvent, instead of methanol, and the addition
of aldehyde 7a after the formation of intermediate 6 were
important in achieving the one-pot process to transform 5ka
into 2a. Under similar conditions 2b·HCl was obtained from
5ka and aldehyde 7b[13c] in 73% yield by the one-pot process
to convert 5ka into 2b.
In summary, we developed an anti-selective catalytic
asymmetric nitroaldol reaction utilizing a newly tuned Pd/La/
1 complex with 4-bromophenol as an additive. anti-Nitroaldol
adducts were obtained in up to 97% yield, anti/syn = 22:1–
3:1, and 92–72% ee. We also demonstrated the utility of the
reaction in the short syntheses of clinically important b-
adrenoceptor agonists 2a·HCl and 2b·HCl. Investigations
into improving the stereoselectivity and reactivity of the
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[17] For related attempts to develop bifunctional asymmetric cata-
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therein.
[18] On a 0.2-mmol scale, 5ka was isolated in 78% yield, anti/syn =
16:1, and 85% ee by using 10 mol% catalyst.
[19] Aldehyde synthesis: 7a, N. Aberle, J. Catimel, E. C. Nice, K. G.
Watson, Bioorg. Med. Chem. Lett. 2007, 17, 3741. For aldehyde
7b, see reference [13c].
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49, 272.
[20] The control experiments suggested that both Pd(OAc)2 and
La(O-iPr)3 were essential in the present reaction. We assume
that cooperative functions of Pd and La metal centers are
important for good anti-selectivity and enantioselectivity. For
results and discussion, see the Supporting Information.
[21] One of the possible reaction mechanisms is as follows; the La–
OAr moiety could function as a Brønsted base to deprotonate a
proton of the nitroalkane. The La–nitronate would then react
with the aldehyde, which is coordinated to the Pd metal center,
from TS-A rather than TS-B (see scheme below) to avoid steric
repulsion between the R’ group and the Pd/La catalyst, prefer-
entially giving anti-adducts. However, other reaction mecha-
nisms cannot be ruled out at this stage. Detailed mechanistic
studies will be reported in due course as a full article. For a
recent example utilizing the Brønsted basic property of La–OAr
moiety in asymmetric catalysis, see: H. Morimoto, G. Lu, N.
Aoyama, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2007,
129, 9588, and references therein.
[12] Ritodrine (2a) is clinically utilized as a racemate, but (À)-
Ritodrine is 40 to 90-fold more active than (+)-Ritodrine in
several biological assays, and is supposed to be the actual active
species. See, N. Yamazaki, Y. Fukuda, Y. Shibazaki, T. Niizato, I.
Kosugi, S. Yoshioka, US Patent 5,449,694, 1995, and references
therein.
[13] a) N. Tanaka, T. Tamai, H. Mukaiyama, A. Hirabayashi, H.
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Hirabayashi, H. Muranaka, T. Ishikawa, J. Kobayashi, S.
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JP2002-64840.
[14] p-Alkoxybenzaldehydes, such as p-anisaldehyde, are much less
reactive than other aldehydes in anti-selective nitroaldol reac-
tion. p-Anisaldehyde was previously utilized by Jørgensen and
co-workers, see reference [7b], resulting in less satisfactory yield
and anti-selectivity than with other aldehydes.
[15] S. Handa, V. Gnanadesikan, S. Matsunaga, M. Shibasaki, J. Am.
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