Stereodivergent catalytic doubly diastereoselective nitroaldol reactions using heterobimetallic complexes

Article abstract of DOI:10.1021/ol800653d

(Chemicall Equation Presented) Stereodivergent construction of three contiguous stereocenters in catalytic doubly diastereoselective nitroaldol reactions of α-chiral aldehydes with nitroacetaldehyde dimethyl acetal using two types of heterobimetallic catalysts is described. A La-Li-BINOL (LLB) catalyst afforded anti,syn-nitroaldol products in >20:1-14:1 selectivity, and a Pd/La/Schiff base catalyst afforded complimentary syn,syn-nitroaldol products in 10:1-5:1 selectivity.

Full text of DOI:10.1021/ol800653d

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2231-2234
Stereodivergent Catalytic Doubly
Diastereoselective Nitroaldol Reactions
Using Heterobimetallic Complexes
Yoshihiro Sohtome, Yuko Kato, Shinya Handa, Naohiro Aoyama, Keita Nagawa,
Shigeki Matsunaga, and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
mshibasa@mol.f.u-tokyo.ac.jp
Received March 21, 2008
ABSTRACT
Stereodivergent construction of three contiguous stereocenters in catalytic doubly diastereoselective nitroaldol reactions of r-chiral aldehydes with
nitroacetaldehyde dimethyl acetal using two types of heterobimetallic catalysts is described. A La-Li-BINOL (LLB) catalyst afforded anti,syn-
nitroaldol products in >20:1-14:1 selectivity, and a Pd/La/Schiff base catalyst afforded complimentary syn,syn-nitroaldol products in 10:1-5:1 selectivity.
The construction of multiple stereocenters in one-pot via
carbon-carbon bond-formation reaction enables rapid access
to densely functionalized molecules from readily available
substrates. Among several of the efficient strategies reported,1
chiral catalyst-based methodologies are attractive in terms
of the diversity in stereocontrol.2 Depending on the chiral
catalysts used, the stereochemical outcome of the reaction
can, in principle, be flexibly modified. Here, we describe
our studies on this issue with catalytic doubly diastereose-
lective nitroaldol (Henry) reactions.
selective nitroaldol reactions have been reported.6 Nitroaldol
reactions of R-chiral aldehydes with nitromethane as a donor
under catalyst-control conditions have been intensively
studied to give nitroaldols with two contiguous stereo-
centers;3,6 however, doubly diastereoselective nitroaldol
reactions of R-chiral aldehydes with nitroalkanes other than
nitromethane, wherein products with three contiguous ste-
reocenters can be obtained, are quite limited.7 Substrate-
controlled reactions using a stoichiometric7a,b and/or
substoichiometric7c amount of an achiral base have been
developed, affording thermodynamically stable anti,anti-
Catalytic asymmetric nitroaldol reactions provide nitrogen-
containing chiral building blocks useful for the synthesis of
natural products and pharmaceuticals.3 Since our report in
1992,4,5 various chiral catalysts for enantio- and diastereo-
(3) Reviews: (a) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem.
2007, 2561. (b) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C.
Tetrahedron: Asymmetry 2006, 17, 3315. (c) Palomo, C.; Oiarbide, M.;
Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442. (d) Ono, N. The Nitro
Group in Organic Synthesis; Wiley-VCH: New York, 2001.
(1) Recent reviews: (a) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew.
Chem., Int. Ed. 2007, 46, 1570. (b) Chapman, C. J.; Frost, C. G. Synthesis
2007, 1. (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134. (d) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A.
Chem. Commun. 2003, 551. (e) Kolodiazhnyi, O. I. Tetrahedron 2003, 59,
5953.
(4) Selected early works on catalytic asymmetric nitroaldol reactions:
(a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem.
Soc. 1992, 114, 4418. (b) Sasai, H.; Kim, W.-S.; Suzuki, T.; Shibasaki,
M.; Mitsuda, M.; Hasegawa, J.; Ohashi, T. Tetrahderon Lett. 1994, 35,
6123. (c) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.;
Shibasaki, M. J. Org. Chem. 1995, 60, 7388. For other works see a review:
(d) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. 1997, 36,
1236.
(2) A review: Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed.
2004, 43, 46.
10.1021/ol800653d CCC: $40.75
Published on Web 05/09/2008
2008 American Chemical Society

Table 1. Optimizations on Nitroaldol Reaction with (R)-LLB 1
entry
nitroalkane (x equiv)
T (°C)
time (h)
product
yielda (%)
drb (5:6:others)
1
2
3
4
5
6
4a(3.0)
4b(3.0)
4c(3.0)
4a(3.0)
4a(3.0)
4a(1.1)
b
-20
-20
-20
-40
-50
-50
24
24
24
48
48
48
5aa
5ab
5ac
5aa
5aa
5aa
92
82
32
97
96
97
1.8:1:-
0.8:1:0.8
1:1:0.6
11:1:-
>20:1:-
>20:1:-
a Isolated yield of 5+6+others. Determined by H NMR.
1
nitroaldols in good to excellent diastereoselectivity. Stereo-
selective synthesis of other diastereomers, however, remains
a formidable task.8 There are no efficient methods using
chiral catalysts for kinetically controlling stereochemistry
adjacent to a nitro group in the doubly diastereoselective
nitroaldol reactions. Therefore, there is much room for
improvement. Herein, we discuss the usefulness of hetero-
bimetallic Lewis acid/Brønsted base bifunctional catalysts9
to address this issue. In reactions of R-chiral aldehydes with
a functionalized nitroalkane, LaLi3tris(binaphthoxide) com-
plex (LLB 1, Figure 1) gave anti-syn-nitroaldols in up to
Scheme 1
.
Doubly Diastereoselective Nitroaldol Reaction of
R-Chiral Aldehyde 3 with Nitroalkane 4
adducts often decrease the chiral-catalyst-induced kinetic
stereoselectivity. We hypothesized that the heterobimetallic
bifunctional catalysts developed in our group would over-
come these problems.
From the viewpoint of synthetic accessibility, N-Boc-
protected aldehyde (S)-3a derived from L-phenylalanine was
selected as a model substrate. Because aldehyde 3a is
(5) For related recent works in our group, see: (a) Tosaki, S.; Hara, K.;
Gnanadesikan, V.; Morimoto, H.; Harada, S.; Sugita, M.; Yamagiwa, N.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 11776. (b)
Mihara, H.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. Chem. Asian J.
2008, 3, 359. (c) Nitabaru, T.; Kumagai, N.; Shibasaki, M. Tetrahedron
Lett. 2008, 49, 272.
Figure 1. Structure of (R)-LaLi3tris(binaphthoxide) (1: LLB) and
(6) For selected works by other groups, see: (a) Corey, E. J.; Zhang,
F.-Y. Angew. Chem., Int. Ed. 1999, 38, 1931. (b) Christensen, C.; Juhl, K;
Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 4875. and references
therein. (c) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41,
861. (d) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125,
2054. (e) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692. (f) Palomo, C.;
Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005, 44, 3881. (g) Sohtome,
Y.; Takemura, N.; Takada, K.; Takagi, R.; Iguchi, T.; Nagasawa, K. Chem.
Asian J. 2007, 2, 1150. and references therein. (h) Li, H.; Wang, B.; Deng,
L. J. Am. Chem. Soc. 2006, 128, 732. (i) Marcelli, T.; van der Haas, R. N. S.;
van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 929.
(j) Arai, T.; Watanabe, M.; Yanagisawa, A. Org. Lett. 2007, 9, 3595. and
references therein. (k) Uraguchi, D.; Sakaki, S.; Ooi, T. J. Am. Chem. Soc.
2007, 129, 12392. (l) Xiong, Y.; Wang, F.; Huang, X.; Wen, Y.; Feng, X.
Chem. Eur. J. 2007, 13, 829. (m) Bandini, M.; Benaglia, M.; Sinisi, R.;
Tommasi, S.; Umani-Ronchi, A. Org. Lett. 2007, 9, 2151. (n) Tur, F.; Saa´,
J. M. Org. Lett. 2007, 9, 5079. For other examples, see reviews in ref 3.
proposed structure of a Pd:La:(S,S)-Schiff base:OAr ) 1:1:1:1
complex 2.
>20:1 (desired anti,syn-isomer:other isomers) diastereose-
lectivity, while a Pd-La-Schiff base complex10 (2, Figure
1) gave syn,syn-nitroaldols in up to 10:1 diastereoselectivity.
A possible reaction profile of the doubly diastereoselective
nitroaldol reaction is illustrated in Scheme 1. The difficulties
in selectively synthesizing one of eight possible stereoisomers
arises from two intrinsic factors: (1) R-chiral aldehydes are
easily racemized under basic conditions, and (2) competitive
retro-nitroaldol reaction and epimerization of the nitroaldol
2232
Org. Lett., Vol. 10, No. 11, 2008

notoriously prone to racemize under basic conditions, suitable
selection of the chiral catalyst and reaction conditions was
important. Optimization studies with (R)-LLB 1 for the
reaction of (S)-3a11 and nitroalkanes 4 are summarized in
Table 1. Among the nitroalkanes investigated (entries 1-3),
nitroacetaldehyde dimethyl acetal (4a)12 gave promising
results. With nitroalkane 4a at -20 °C, (R)-LLB 1 gave
anti,syn-5aa as the major reaction product together with
syn,syn-adduct 6aa in 92% yield.13,14 Although the ratio of
5:6 was unsatisfactory (entry 1, 5:6 ) 1.8:1), the result was
promising as an initial trial because anti-nitroaldol products
7 and 8 were not observed in entry 1. In contrast, complex
mixtures of diastereomers were produced when using nitro-
ethanol (4b) (entry 2: 5:6:7+8 ) 0.8:1:0.8) and nitroethane
(4c) (entry 3, 5:6:7+8 ) 1:1:0.6). Because the acetal moiety
in nitroalkane 4a is potentially useful for further function-
alization of the products, we selected 4a for further optimiza-
tions. The reaction temperature was key to improving
diastereoselectivity (entries 4 and 5), and anti,syn-5aa was
obtained in 96% yield with >20:1 diastereoselectivity at -50
°C. The optical purity of 5aa was confirmed to be >99% ee
by chiral stationary phase HPLC analysis. These results
suggested that racemization of the aldehyde, retro-reaction,
and epimerization of the product were effectively suppressed
under the optimized reaction conditions. It is also noteworthy
that the reaction proceeded smoothly with as little as 1.1
equiv of 4a, affording anti,syn-5aa in 97% yield with >20:1
diastereoselectivity (entry 6).
Table 2. Nitroaldol Reaction of Various R-Chiral Aldehydes
3a-3i with Nitroalkane 4a Using (R)-LLB 1 for anti,syn-5
b
a Isolated yield. Determined by H NMR. c (S)-LLB (1) was used.
1
Scheme 2. Unsuccessful Nitroaldol Reaction of (S)-3a with
Nitroalkane 4a by Using Mismatched (S)-LLB 1
The optimized reaction conditions were applied to several
R-chiral aldehydes (Table 2). (R)-LLB 1 promoted the
reaction of (S)-R-amino aldehydes with 1.1 equiv of nitroal-
(7) (a) Hanessian, S.; Kloss, J. Tetrahedron Lett. 1985, 26, 1261. (b)
Hanessian, S.; Devasthale, P. V. Tetrahedron Lett. 1996, 37, 987. (c)
Wehner, V.; Ja¨ger, V. Angew. Chem., Int. Ed. 1990, 29, 1169. (d) Ferna´ndez,
R.; Gasch, C.; Go´mez-Sa´nchez, A.; V´ılchez, J. E.; Castro, A. L.; Dia´nez,
M. J.; Estrada, M. D.; Pe´rez-Garrido, S. Carbohydr. Res. 1993, 247, 239.
(e) Soengas, R. G.; Este´vez, J. C.; Este´vez, R. J. Tetrahedron: Asymmetry
2003, 14, 3955. (f) Bernardi, L.; Bonini, B. F.; Dessole, G.; Fochi, M.;
Comes-Franchini, M.; Gavioli, S.; Ricci, A.; Varchi, G. J. Org. Chem. 2003,
68, 1418.
(8) Hanessian et al. reported an exceptional example using (R)-LLB 1
as a chiral catalyst. Although there remained a room for improvement in
diastereoselectivity (anti-syn-5:syn-syn-6:others ) 20:5.5:2.5), anti-syn-5
was obtained as a major product. See Hanessian, S.; Brassard, M.
Tetrahedron 2004, 60, 7621.
kane 4a, giving anti,syn-nitroaldols 5 with >20:1 (5:other
isomers) diastereoselectivity. Ester and acetal functional
groups in aldehydes were compatible under the present
reaction conditions, affording products in 98-86% yield and
>20:1 diastereoselectivity (entries 4-6). The present system
was also applicable to R-oxy aldehydes (entries 8 and 9).
O-Benzyl-protected-aldehyde 3h was less reactive than
R-amino aldehydes, and the reaction was performed at -20
°C to give 5ha in 80% yield with 14:1 diastereoselectivity
(entry 8). With aldehyde (R)-3i, (S)-LLB 1 was suitable, and
ent-5ia was obtained in >20:1 (ent-5:other isomers) diaste-
reoselectivity (entry 9).
Preliminary trials to synthesize syn,syn-product 6aa from
(S)-3a using (S)-LLB failed, in which the stereochemical
course of the reaction should be controlled by (S)-LLB to
override the mismatched steric bias of R-chiral (S)-3a
(Scheme 2). Nitroaldol adducts were obtained in 24% yield
with poor diastereoselectivity (5aa:6aa:others ) 2.8:1:2.6).
Thus, we screened other chiral catalysts for switching the
diastereoselectivity, and a Pd:La:(S,S)-Schiff base:OAr ) 1:1:
(9) (a) Reviews on Lewis acid-Brønsted base bifunctional catalysis
Matsunaga, S.; Shibasaki, M. Bull. Chem. Soc. Jpn. 2008, 81, 60. (b)
Shibasaki, M.; Matsunaga, S. Chem. Soc. ReV. 2006, 35, 269. (c) Shibasaki,
M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187.
(10) (a) Handa, S.; Nagawa, K.; Sohtome, Y.; Matsunaga, S.; Shibasaki,
M. Angew. Chem., Int. Ed. 2008, 47, 3230. For related bimetallic Schiff
base catalysts, see: (b) Handa, S.; Gnanadesikan, V.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 4900. (c) Chen, Z.; Morimoto,
H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170.
(11) For the synthesis of aldehyde 3 without racemization: Tokuyama,
H.; Yokoshima, S.; Lin, S.-C.; Li, L.; Fukuyama, T. Synthesis 2002, 1121,
and references therein.
(12) Synthesis of nitroalkane 4a: Ja¨ger, V.; Poggendorf, P. Org. Synth.
1997, 74, 130. For the use of nitroacetaldehyde diethyl acetal for anti-anti-
selective nitroaldol reaction, see ref 7c.
(13) The stereochemistry of 5aa was determined by O-methyl mandelate
method: (a) Trost, B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem. 1994,
59, 4202. (b) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga,
S. L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370. See the Supporting
Information
.
(14) The stereochemistry of 6aa was unequivocally determined by X-ray
crystallographic analysis. See the Supporting Information
.
Org. Lett., Vol. 10, No. 11, 2008
2233

Table 3. Nitroaldol Reaction of R-Chiral Aldehydes 3 with
Nitroalkane 4a Using (S,S)-Pd-La complex 2 for syn,syn-6
entry
aldehyde (R)
product yielda (%) drb (6:5:others)
1
2
3
3a: PhCH2-
3b: CH3-
3d: EtO2C(CH2)2-
b
6aa
6ba
6da
1
87
70
78
10:1:trace
5:1:trace
8:1:trace
Figure 2. Two hypothetical transition-state models: (a) Felkin-Anh
model for anti,syn-5 using LLB 1 and (b) hydrogen-bond chelation
model for syn,syn-6 using Pd-La complex 2.
a Isolated yield. Determined by H NMR.
1:1 complex 2 (Ar ) 4-Br-C6H4-, Figure 1)10a gave
promising results (Table 3). With the heterobimetallic (S,S)-
Pd-La complex 2, nitroaldol reactions of 3a, 3b, and 3d
proceeded at -30 °C, giving syn,syn-nitroaldol 6 with 10:
1-5:1 (6:5) diastereoselectivity.15 No racemization of R-chiral
aldehyde occurred during the nitroaldol reaction, as con-
firmed by chiral stationary-phase HPLC analysis.
Scheme 3. Transformations of Nitroaldol Adduct 5ha and 6aa
In the present reactions, (R)-LLB 1 gave anti,syn-product 5
(Table 2) and the Pd:La:(S,S)-Schiff base:OAr ) 1:1:1:1
complex 2 gave syn,syn-product 6 (Table 3). Stereochemisty
adjacent to a nitro group is speculated to be kinetically controlled
by chiral catalysts.16 Interestingly, facial selectivity of aldehydes
changed depending on the chiral catalysts used. Because the
results in both Tables 2 and 3 were obtained with matched pairs
of chiral catalysts and aldehydes, the results implied that the
conformation of aldehydes 3 in the transition state in Table 2
is different from that in Table 3. The stereochemical course of
the reaction with (R)-LLB 1 can be explained by Felkin-Anh
model from the opened conformation of (S)-3 (Figure 2a), while
that with (S,S)-Pd-La complex 2 is speculated to be obtained
from the chelated conformation of (S)-3 through intramolecular
hydrogen bonding (Figure 2a).17,18 We believe that the
favorable conformation of aldehyde 3 in the transition-state
changes depending on the property of chiral catalysts.
Mechanistic studies to clarify the origin of selectivity are
ongoing.
5ha and 6aa followed by treatment with Cbz-Cl gave N-
Cbz-protected amine 9 and 11 in 80% and 94% yield,
respectively. Hydrolysis of the acetal moiety in 9 under acidic
conditions afforded 10 in 78% yield.
In summary, we achieved stereodivergent doubly diaste-
reoselective nitroaldol reactions of R-chiral aldehydes with
a functionalized nitroalkane using two types of heterobime-
tallic catalysts, LLB 1 for anti,syn-products 5 and a
Pd-La-Schiff base complex 2 for syn,syn-products 6. The
facial selectivity of R-chiral aldehydes in nitroaldol reactions
changed depending on the chiral catalysts. Further investiga-
tions to develop a catalyst to selectively synthesize other
isomers, especially syn,anti-8 are ongoing.
Transformations of 5ha and 6aa were successfully per-
formed without epimerization, demonstrating its potent
synthetic utility (Scheme 3). Reduction of the nitro group in
Acknowledgment. We thank Mr. H. Morimoto at the
University of Tokyo for X-ray crystallography work. This
work was supported by Grant-in-Aid for Specially Promoted
Research, a Grant-in-Aid for Encouragements for Young
Scientists (B) (for Y.S.), and Mitsubishi Chemical Corpora-
tion Fund (for S.M.).
(15) Trials to synthesize anti,syn-5 by mismatched (R,R)-Pd-La complex
2 failed. (R,R)-Pd-La complex 2 afforded products 6aa as a major adduct
in lower dr and yield (6aa:others ) 8:1, 61% yield) than (S,S)-Pd-La
complex 2.
(16) LLB 1 is known as a suitable catalyst for syn-selective nitroaldol
reaction of prochiral aldehydes with nitroehthane and nitroethanol (ref 4c).
The Pd-La-Schiff base complex 2 gave anti-nitroaldol adducts in the reaction
of prochiral aldehydes with nitroehthane (ref 10a). Although the precise
reason why the Pd-La complex 2 gave syn,syn-6 with nitroalkane 4a has
not been clarified yet, we speculate that coordinating dimethylacetal moiety
in nitroalkane 4a may be important for changing the geometry of nitronate
generated from 4a. Further mechanistic studies are required for more detailed
discussion.
Supporting Information Available: Experimental pro-
cedures, spectral data of new compounds, and X-ray crystal-
lography data of 6aa (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(17) For related reports utilizing intramolecular hydrogen bonding for
anti-Felkin-Anh stereocontrol of N-Boc-protected R-amino aldehydes, see:
(a) Jung, C.-K.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 17051. (b)
Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P. J. Org. Chem. 1990,
55, 1439. (c) Dondoni, A.; Perrone, D.; Merino, P. J. Org. Chem. 1995,
60, 8074.
OL800653D
(18) Aldehyde 3g lacking an N-H group gave much less satisfactory
results with the Pd-La Schiff base complex 2.
2234
Org. Lett., Vol. 10, No. 11, 2008