Mixed La-Li heterobimetallic complexes for tertiary nitroaldol resolution

Article abstract of DOI:10.1021/ja064858l

A kinetic resolution of tertiary nitroaldols derived from simple ketones is described. Mixed BINOL/biphenol La-Li heterobimetallic complexes gave the best selectivity in retro-nitroaldol reactions of racemic tertiary nitroaldols. By using a mixture of La-Li₃-(1a)₃ complex (LLB 2a) and La-Li₃-(1b)₃ (LLB* 2b) complex in a ratio of 2/1, chiral tertiary nitroaldols were obtained in 80-97% ee and 30-47% recovery yield. Copyright

Full text of DOI:10.1021/ja064858l

Published on Web 08/19/2006
Mixed La-Li Heterobimetallic Complexes for Tertiary Nitroaldol Resolution
Shin-ya Tosaki, Keiichi Hara, Vijay Gnanadesikan, Hiroyuki Morimoto, Shinji Harada, Mari Sugita,
Noriyuki Yamagiwa, Shigeki Matsunaga,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received July 8, 2006; E-mail: mshibasa@mol.f.u-tokyo.ac.jp; smatsuna@mol.f.u-tokyo.ac.jp
Catalytic asymmetric nitroaldol (Henry) reactions1 of ketones
lead to synthetically versatile chiral tertiary nitroaldols. Enantiose-
lective nitroaldol reactions of R-keto esters have been achieved
using chiral Cu2a-d and Mg complexes2e and cinchona alkaloids;2f
however, there are no reports on the asymmetric synthesis of tertiary
nitroaldols derived from simple ketones.3 Even for a racemic
version, only a few methodologies with limited substrate scope are
available.4 The difficulty arises from the attenuated reactivity of
ketones and the strong tendency toward a retro-nitroaldol reaction
Figure 1. Structures of (R)-BINOL 1a-H2, biphenol (R)-1b-H2, and La-
under basic conditions. Therefore, the synthesis of tertiary nitroal-
dols with chirality control is in high demand. Herein, we describe
a kinetic resolution approach using BINOL 1a-H2/biphenol 1b-
H2 mixed La-Li heterobimetallic complexes (Figure 1). Tertiary
nitroaldols were obtained in 80-97% ee.
Li heterobimetallic complexes LLB 2a and LLB* 2b.
Table 1. Effects of LLB 2a/LLB* 2b Ratio on Kinetic Resolution of
Tertiary Nitroaldol (()-4a
Initial trials revealed that (R)-LLB 2a (Figure 1)5 promoted a
reaction of 3a with 10 equiv of nitromethane at -40 °C to afford
(S)-4a in 95% ee, albeit in poor yield (2%), after 5 days (eq 1).
Excess nitromethane was essential to obtain product 4a. Further
trials to improve the yield failed, however, possibly because the
nitroaldol reaction of 3a is thermodynamically unfavorable.6,7 Good
conversion is difficult to achieve in the absence of stoichiometric
amounts of trapping reagents, such as silylating reagent, to make
the reaction irreversible or stoichiometric amounts of chelating
metals to stabilize the product.
a Determined by 1H NMR analysis using mesitylene as an internal
standard. b Determined by chiral HPLC analysis.
selectivity (entries 3 and 4). Other chiral ligands gave less
satisfactory results.
The substrate scopes and limitations of the present kinetic
resolution are summarized in Table 2.14 Retro-nitroaldol reactions
of methyl ketone-derived substrates 4a-e with aliphatic substituents
proceeded smoothly to afford chiral 4a-e with good enantiose-
lectivity (entries 1-6). For each substrate, the reaction time was
optimized to achieve both a good recovery yield of 4 and high
enantiomeric excess. With 4b, catalyst loading was successfully
reduced to 2.5 mol % (2a: 1.67 mol %, 2b: 0.83 mol %), still
affording good selectivity (entry 3, 90% ee and 40% yield). In the
case of acetophenone-derived substrate 4f and ethyl ketone-derived
substrate 4g, higher conversion (entry 7, 69% conversion, 30%
recovery yield of 4f; entry 8, 65% conversion, 33% recovery yield
of 4g) was required to achieve good enantioselectivity (4f, 88%
ee; 4g, 88% ee).
In the present reaction, a combination of (R)-LLB 2a and (R)-
LLB* 2b in a ratio of 2:1 gave the best results (Table 1). We
speculate that ligand exchange between 2a and 2b would occur to
generate a mixed-ligand La-Li3-(1a)2/(1b) complex in equilibri-
um,15 which would be the most enantioselective and reactive
catalyst. ESI-MS supported the ligand exchange in situ. Analysis
of the 2a/2b ) 2:1 mixture revealed major peaks corresponding to
La-Li3-(1a)2/(1b) and La-Li3-(1a)/(1b)2 complexes and minor
peaks corresponding to 2a and 2b (Figure 2).16 Further investigation
to unequivocally determine the structure of the active species is
ongoing.
The nitroaldol reaction is reversible under basic conditions;
therefore, we planned to use (R)-LLB 2a for a kinetic resolution
of racemic tertiary nitroaldols via a retro-nitroaldol reaction.8,9 On
the basis of the high enantioselectivity achieved (eq 1), we
hypothesized that (R)-LLB 2a would preferentially convert the
matched enantiomer (S)-4a into 3a and nitromethane, while the
mismatched enantiomer (R)-4a would remain unchanged and be
recovered in an enantiomerically enriched form. Kinetic resolution
of (()-4a using 5 mol % of (R)-LLB 2a proceeded at -40 °C. As
expected, 4a was recovered in 76% yield and 30% ee [(R)-4a
major]10 after 24 h, together with ketone 3a and nitromethane. To
enhance the reaction rate, the reaction was performed at -20 °C,
giving good enantioselectivity (86% ee) in 48% recovery yield of
(R)-4a (Table 1, entry 1, 24 h, selectivity factor: s ) 23.8).11 To
further improve selectivity, we investigated various chiral ligands,
such as BINOL derivatives and biphenol derivatives. Inspired by
recent reports of a mixed-ligand chiral catalyst screening strategy,12
we also examined the mixture of two chiral ligands. The best
selectivity was obtained when using (R)-LLB 2a and (R)-LLB*
2b (Figure 1)13 in a ratio of 2:1 (entry 2, 90% ee, 50% yield, s )
58.4). Neither 2a/2b ) 1:2 ratio nor 2b alone had satisfactory
9
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J. AM. CHEM. SOC. 2006, 128, 11776-11777
10.1021/ja064858l CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Kinetic Resolution of tert-Nitroaldols 4a-ga
ments for Young Scientists (B) (for S.M.) from JSPS and MEXT.
H.M. and S.H. thank JSPS predoctoral fellowships.
Supporting Information Available: Experimental procedures,
spectral data of the new compounds, and ESI-MS data. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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(3) One example using 2,2,2-trifluoroacetophenone to give the product with
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(6) In the nitroaldol reaction in eq 1, excess nitromethane was required to
suppress undesired retro-nitroaldol reaction and to obtain kinetically
controlled product. We speculate that excess nitromethane was also
important due to a low equilibrium constant. Generally, equilibrium
constants for aldol(-type) reactions of ketone electrophiles are much lower
than those of aldehydes. For example, an equilibrium constant for aldol
reaction of benzaldehyde and acetone is 11.7 M-1, while that of
acetophenone and acetone is 1.89 × 10-3 M-1. (a) Guthrie, J. P. J. Am.
Chem. Soc. 1991, 113, 7249. (b) Guthrie, J. P. Wang, X.-P. Can. J. Chem.
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a Reaction was performed in THF (0.4 M) at -20 °C using 3.33 mol %
of (R)-LLB 2a and 1.67 mol % of (R)-LLB* 2b unless otherwise noted.
b Determined by 1H NMR analysis using mesitylene as an internal standard.
c Isolated yields after column chromatography. The theoretical maximum
is (100% - conversion)%. d Determined by chiral HPLC analysis. e (R)-
LLB 2a (1.67 mol %) and (R)-LLB* 2b (0.83 mol %) were used. f (R)-
LLB 2a (6.67 mol %) and (R)-LLB* 2b (3.33 mol %) were used. g Reaction
was run at -40 °C.
(7) (R)-LLB 2a also promoted nitroaldol reactions of other simple ketones in
high enantioselectivity, albeit in poor yields. Ketone 3d (90% ee, 5%
yield); 3e (89% ee, 20% yield).
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J. M.; Li, A.; Bui, T.; Anderson, J.; Lerner, R. A.; Barbas, C. F., III. J.
Am. Chem. Soc. 1999, 121, 7283 and references therein. For a retro-
nitroaldol reaction with a catalytic antibody, see: (b) Flanagan, M. E.;
Jacobsen, J. R.; Sweet, E.; Schultz, P. G. J. Am. Chem. Soc. 1996, 118,
6078.
Figure 2. ESI-MS chart of LLB 2a/LLB* 2b ) 2:1 mixture [m/z 840-
1060].15
Scheme 1. Transformations of tert-Nitroaldolsa
(9) Recent general review for nonenzymatic kinetic resolution: (a) Vedejs,
E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974. For examples of
nonenzymatic kinetic resolution of tert-alcohols, see: (b) Angione, M.
C.; Miller, S. J. Tetrahedron 2006, 62, 5254 and references therein.
(10) The absolute configurations of 4a, 4e, and 4f were determined to be R
after conversion into known compounds. See Supporting Information.
(11) The s values in this paper were calculated based on conversion and ee of
recovered 4 assuming first-order kinetic dependence on 4. Kinetic studies
are required to determine accurate s values. For discussion on the validity
of calculated s values, see: Keith, J. M.; Larrow, J. F.; Jacobsen, E. N.
AdV. Synth. Catal. 2001, 343, 5. See also ref 9a.
(12) Reviews: (a) Ding, K.; Du, H.; Yuan, Y.; Long, J. Chem.sEur. J. 2004,
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For selected examples, see: (c) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding,
K. J. Am. Chem. Soc. 2002, 124, 10. (d) Reetz, M. T.; Shell, T.;
Meiswinkel, A.; Mehler, G. Angew. Chem., Int. Ed. 2003, 42, 790. (e)
Pen˜a, D.; Minnaard, A. J.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries,
J. G.; Feringa, B. L. Org. Biomol. Chem. 2003, 1, 1087.
(13) Biphenol 1b-H2: Meyers, A. I.; Nelson, T. D.; Moorlag, H.; Rawson,
D. J.; Meier, A. Tetrahedron 2004, 60, 4459 and references therein.
(14) Because the known synthetic methods of racemic tertiary nitroaldols did
not afford satisfactory yield for 4f, we developed a new synthetic method.
See Supporting Information for details.
(15) Ligand liability of related rare earth-alkali metal heterobimetallic
complexes was reported. (a) Bari, L. D.; Lelli, M.; Salvadori, P. Chem.s
Eur. J. 2004, 10, 4594. See also: (b) Horiuchi, Y.; Gnanadesikan, V.;
Ohshima, T.; Masu, H.; Katagiri, K.; Sei, Y.; Yamaguchi, K.; Shibasaki,
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a Reagents and conditions: (a) cat. Pd-C, H2 (1 atm), MeOH, rt; Ac2O,
Et3N, CH2Cl2, 86% (2 steps); (b) cat. B(C6F5)3, Et3SiH, CH2Cl2, rt, 90%;
(c) Ph-acetylene, PhNCO, cat. Et3N, benzene, reflux, 84%; (d) NaNO2,
AcOH, DMSO, rt to 40 °C, 99%.
Scheme 1 illustrates the synthetic utility of tertiary nitroaldols
as chiral building blocks. Hydrogenation of 4a, followed by
acetylation, gave N-Ac amine 5a in 86% yield. Silylated adduct 6e
was successfully converted into isoxazole 7e (84%) and R-hydroxy
carboxylic acid 8e (99%).17
In summary, we achieved a kinetic resolution of tertiary
nitroaldols (()-4 derived from simple ketones. Mixed La-Li
heterobimetallic complexes had the best selectivity (80-97% ee
with 30-47% recovery yield). Further investigation of the structure
of the active species and application of the present mixed hetero-
bimetallic catalyst system to other asymmetric reactions are in
progress.
(16) For full details of ESI-MS data [m/z 200-1300] of LLB 2a, LLB* 2b,
2a/2b ) 2:1, and 2a/2b ) 1:2, see Supporting Information. Although it
is impossible to discuss quantitatively using MS, we believe the ESI-MS
data at least suggested the presence of mixed-ligand La-Li complexes in
the mixture of LLB 2a and LLB* 2b. NMR analysis only resulted in a
complex mixture spectrum.
(17) Matt, C.; Wagner, A.; Mioskowski, C. J. Org. Chem. 1997, 62, 234.
Acknowledgment. This work was supported by Grant-in-Aid
for Specially Promoted Research and Grant-in-Aid for Encourage-
JA064858L
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