Asymmetric nitroaldol reaction catalyzed by a C2-symmetric bisoxazolidine ligand

Article abstract of DOI:10.1021/ol800442s

A C₂-symmetric bisoxazolidine was found to effectively catalyze the asymmetric Henry reaction of aliphatic and aromatic aldehydes.ss- Hydroxy nitroalkanes were produced in up to 99% yield and 95% ee. The bisoxazolidine-catalyzed nitroaldol form

Full text of DOI:10.1021/ol800442s

ORGANIC
LETTERS
2
008
Vol. 10, No. 9
831-1834
Asymmetric Nitroaldol Reaction
Catalyzed by a C -Symmetric
Bisoxazolidine Ligand
1
2
Shuanglong Liu and Christian Wolf*
Department of Chemistry, Georgetown UniVersity, Washington, D.C. 20057
cw27@georgetown.edu
Received February 27, 2008
ABSTRACT
A C -symmetric bisoxazolidine was found to effectively catalyze the asymmetric Henry reaction of aliphatic and aromatic aldehydes. ꢀ-Hydroxy
2
nitroalkanes were produced in up to 99% yield and 95% ee. The bisoxazolidine-catalyzed nitroaldol formation requires relatively short reaction
times, proceeds under mild conditions and is applicable to a wide range of substrates including sterically hindered aldehydes.
The ever-increasing industrial and academic demand for
enantiopure chemicals continues to nurture the development
of powerful synthetic methods that utilize highly efficient
widespread use as chiral ligands in asymmetric catalysis and
as important building blocks of natural products or pharma-
ceuticals.
3
1
chiral catalysts and auxiliaries. The nitroaldol (Henry)
It is therefore surprising that few efficient asymmetric
variants of the Henry reaction have been developed to date.
While some of these methods require the use of activated
silyl nitronates and tetrabutylammonium triphenylsilyldi-
reaction provides an atom-economical entry to ꢀ-hydroxy
nitroalkanes which are invaluable precursors for a wide range
of synthetic targets including (R)-denopamine and (R)-
2
4
arbutamine. The nitro group can be conveniently converted
fluorosilicate (TBAT), others provide excellent results with
into several other functionalities by reduction, Nef reaction,
nucleophilic displacement, or other means, thus generating
R-hydroxy ketones, aldehydes, carboxylic acids, azides,
sulfides, and other important bifunctional compounds. In
particular, reduction of ꢀ-hydroxy nitroalkanes gives con-
venient access to ꢀ-amino alcohols which have found
aromatic aldehydes; however, yields and ee values typically
decrease when aliphatic or sterically hindered aldehydes are
used. Despite significant advances in this field, critical
5
(
3) (a) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem.
Soc. 1989, 111, 4028–4036. (b) Noyori, R.; Kitamura, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 49–69. (c) Soai, K.; Niwa, S. Chem. ReV. 1992,
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2, 833–856. (d) Liu, G.; Ellman, J. A. J. Org. Chem. 1995, 60, 7712–
713. (e) Prasad, K. R. K.; Joshi, N. N. J. Org. Chem. 1997, 62, 3770–
(
1) (a) Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E.,
3771. (f) Sol a` , L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.; Peric a` s,
M. A.; Riera, A.; Alvarez-Larena, A.; Piniella, J.-F. J. Org. Chem. 1998,
63, 7078–7082. (g) Wolf, C.; Hawes, P. A. J. Org. Chem. 2002, 67, 2727–
2729. (h) Wolf, C.; Francis, C. J.; Hawes, P. A.; Shah, M. Tetrahedron:
Asymmetry 2002, 13, 1733–1741. (i) Merino, P.; Tejero, T. Angew. Chem.,
Int. Ed. 2004, 43, 2995–2997. (j) Vicario, J. L.; Badia, D.; Carrillo, L.;
Reyes, E.; Etxebarria, J. Curr. Org. Chem. 2005, 9, 219–235.
(4) (a) Risgaard, K. V.; Gothelf, K. A.; Jorgensen, K. A. Org. Biomol.
Chem. 2003, 1, 153–156. (b) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 2054–2055.
Eds. StereoselectiVe Synthesis in Methods of Organic Chemistry, Houben-
Weyl, 4th ed.; Thieme: Stuttgart, Germany, 1995; Vol. 21. (b) Ojima, I.,
Ed. Catalytic Asymmetric Synthesis, 2nd ed.; Wiley-VCH: New York, 2000.
(
c) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022. (d) Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2024–2032. (e) Wolf, C., Ed.
Dynamic Stereochemistry of Chiral Compounds; RSC Publishing: London,
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008.
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2) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett. 2002,
4
, 2621–2623.
10.1021/ol800442s CCC: $40.75
Published on Web 04/03/2008
 2008 American Chemical Society

shortcomings of many catalytic nitroaldol reactions reported
to date include long reaction times that often exceed 48 h,
the use of expensive catalysts, and the need for additives
such as molecular sieves.
We recently reported the synthesis of the first diketone-
2
derived C -symmetric bisoxazolidine from readily available,
inexpensive starting materials and demonstrated the useful-
ness of this new class of chiral ligands in asymmetric
catalysis. Bisoxazolidine 1 exhibits a catalytically useful
parameters including solvent, temperature, and catalyst
loading revealed that ꢀ-hydroxy nitroalkanes can be obtained
in excellent yields and ee’s. Employing 8 mol % of 1,
nitromethane, and dimethylzinc to generate a zinc nitronate
species in situ, and benzaldehyde in apolar solvents at -15
°C, we obtained 2-nitro-1-phenylethanol, 2, in 92% yield
and 92% ee within 9 h (Scheme 2).
(
S,S)-N,O-diketal unit and is easily prepared in 90% yield
Scheme 2. Bisoxazolidine-Catalyzed Nitroaldol Reaction
and 99% de by formic acid-promoted condensation of
(
(
1R,2S)-cis-1-amino-2-indanol and 1,2-cyclohexanedione
Scheme 1).
Scheme 1. Formation of Bisoxazolidine Catalyst 1
The optimized procedure was then applied to a variety of
benzaldehyde derivatives and the corresponding ꢀ-nitro
alcohols 3-11 were generally isolated in high yield and
enantiomeric excess (Table 1). Aromatic aldehydes bearing
electron-withdrawing groups proved more reactive and
furnished nitroaldol products 5 to 8 in up to 96% yield and
9
5% ee within 10 h (entries 4-7). Less reactive aldehydes
such as 4-methoxybenzaldehyde required longer reaction
times but gave excellent results (entries 2, 3 and 8).
Importantly, the bisoxazolidine-catalyzed Henry reaction is
also suitable to sterically hindered and heteroaromatic
aldehydes. 2-Nitro-1-(2,6-dimethylphenyl)ethanol, 10, and
2
Ligand 1 possesses a rigid C -symmetric structure and
average separation between the nitrogen and oxygen atoms
of 2.35 Å which facilitates bidentate coordination to metal
ions and organometallic compounds. We found that this
aminoindanol-derived N,O-diketal catalyzes the enantiose-
lective alkynylation of a range of aromatic and aliphatic
aldehydes, generating chiral propargylic alcohols in high
2-nitro-1-(3-thienyl)ethanol, 11, were formed in 84% to 96%
yield and 88% to 91% ee, respectively (entries 9 and 10).
Several aliphatic aldehydes were then employed in the same
procedure. We were pleased to find that the corresponding
Henry reaction products 12 to 18 were formed in 84-96%
yields with ee values ranging from 75% to 86% (Table 2).
It is noteworthy that both linear and branched aliphatic
aldehydes gave excellent results within 12 h. For example,
heptanal was converted to 1-nitro-2-heptanol, 14, in 90%
yield and 84% ee, and sterically hindered pivalaldehyde gave
6
yield and ee. Excellent results and positive nonlinear effects
due to enantioselective dual phase distribution behavior of
scalemic 1 were obtained when this catalyst was applied in
the alkylation of aldehydes with dimethyl- and diethylzinc
7
reagents.
Encouraged by the success with bisoxazolidine-catalyzed
asymmetric additions of alkyl- and alkynylzinc reagents to
aldehydes, we decided to explore the use of 1 in the
asymmetric Henry reaction. Screening of typical reaction
3
,3-dimethyl-1-nitro-2-butanol, 16, in 92% yield and 86%
ee (entries 3 and 5). The Henry reaction is also applicable
to R,ꢀ-unsaturated substrates, and cinnamaldehyde was
converted to nitroaldol product 15 in almost quantitative
yields and 82% ee (entry 4).
(
5) (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1992, 114, 4418–4420. (b) Trost, B. M.; Yeh, V. S. C. Angew.
Chem., Int. Ed. 2002, 41, 861–863. (c) Trost, B. M.; Yeh, V. S. C.; Ito, S.;
Bremeyer, N. Angew. Chem., Int. Ed. 2002, 41, 861. (d) Evans, D. A.;
Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2003, 42, 12692–12693. (e) Palomo, C.; Oiarbide, M.; Mielgo,
A. Angew. Chem., Int. Ed. 2004, 43, 5442–5444. (f) Marcelli, T.; van der
Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int.
Ed. 2006, 45, 929–931. (g) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua,
N. C. Tetrahedron: Asymmetry 2006, 17, 3315–3326. (h) Bandini, M.;
Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici, C. Chem. Commun.
Shibasaki was first to demonstrate the potential of nitro
aldol reactions for the formation of multifunctional products
bearing several stereocenters. For example, a sequence of
two nitrolaldol reactions and subsequent diastereomerization
in the presence of an (R)-binaphthoxide-derived lanthanoid
catalyst gave bicyclic 20 from aldehyde 19 in 41% yield
1
0
and 65% ee (Scheme 3). To date, several groups have
2
9
2
007, 616–618. (i) Arai, T.; Watanabe, M.; Yanagisawa, A. Org. Lett. 2007,
, 3595–3597. (j) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem.
007, 2561–2574.
(10) Sasai, H.; Hiroi, M.; Yamada, Y. M. A.; Shibasaki, M. Tetrahedron
Lett. 1997, 38, 6031–6034.
(
(
(
6) Wolf, C.; Liu, S. J. Am. Chem. Soc. 2006, 128, 10996–10997.
7) Liu, S.; Wolf, C. Org. Lett. 2007, 9, 2965–2968.
(11) (a) For syn-selective reactions, see : Sasai, H.; Tokunaga, T.;
Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org. Chem. 1995, 60,
7388–7389. (b) Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Eur. J. Org.
Chem. 2006, 2894–2897. (c) For anti selective reactions, see : Ooi, T.; Doda,
K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054–2055. (d) Sohtome,
Y.; Takemura, N.; Iguchi, T.; Hashimoto, Y.; Nagasawa, K. Synlett 2006,
144–146.
8) (a) Choudary, B. M.; Ranganath, K. V. S.; Pal, U.; Kantam, M. L.;
Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 13167–13171. (b) Ginotra, S. K.;
Singh, V. K. Org. Biomol. Chem. 2007, 5, 3932–3937. (c) Saa, J. M.; Tur,
F.; Gonzalez, J.; Vega, M. Tetrahedron: Asymmetry 2006, 17, 99–106.
(
9) (a) Kogami, Y.; Nakajima, T.; Ikeno, T.; Yamada, T. Synthesis 2004,
1
947–1950. (b) Ma, K.; You, J. Chem. Eur. J. 2007, 13, 1863–1871.
1832
Org. Lett., Vol. 10, No. 9, 2008

Table 1. Enantioselective Nitroaldol Reaction of Aromatic
Aldehydes
Table 2. Bisoxazolidine-Catalyzed Henry Reaction of Aliphatic
Aldehydes
a
a
a
All reactions were performed on a 1 mmol scale using 8 mol % of 1
b
as catalyst, 10 equiv of nitromethane, and 3 equiv of dimethyl zinc. Isolated
yields. c Determined by HPLC on Chiralcel OD and Chiralpak AD or by
d
GC on octakis(6-O-methyl-2,3-di-O-pentyl)-γ-cyclodextrin. The absolute
configuration of the major enantiomer was determined by chiral HPLC
analysis using Chiralcel OD and Chiralpak AD as described in the
5
h,9
literature.
Scheme 3. Shibasaki’s Synthesis of Bicyclic Nitroaldol Product
2
0
a
All reactions were performed on a 1 mmol scale using 8 mol % of 1
b
as catalyst, 10 equiv of nitromethane, and 3 equiv of dimethyl zinc. Isolated
yields. Determined by HPLC on Chiralcel OD and Chiralpak AD or by
GC on octakis(6-O-methyl-2,3-di-O-pentyl)-γ-cyclodextrin. The absolute
configuration of the major enantiomer was determined by chiral HPLC
c
d
5
d,8
analysis using Chiralcel OD and OJ as described in the literature.
reported enantio- and diastereoselective procedures using
chiral aldehydes or nitromethane homologues such as nitro-
ethane. In most cases, however, expensive catalysts or silyl
nitronates are required to achieve high yields and stereose-
lectivity. We therefore decided to test the potential of 1 to
overcome some of these drawbacks.
We observed that bisoxazolidine 1 catalyzes the Henry
reaction between benzaldehyde and nitroethane with remark-
able stereocontrol and apparently favors formation of the syn
diastereomer. 2-Nitro-1-phenylpropanol, 21, was obtained in
determined as 87:13. Both diastereoisomers were produced
in excellent enantiomeric excess (Scheme 4).
11
The reaction probably involves zinc-mediated dual activa-
tion of the nitronate and the aldehyde substrate (Scheme 5).
Deprotonation of nitromethane by dimethylzinc in the
presence of bisoxazolidine 1 is expected to generate zinc
complex 22. Coordination of the aldehyde then sets the stage
for enantioselective carbon-carbon bond formation via
transition state 23. Replacement of the formed alkoxide from
8
8% yield and the ratio of the syn to the anti isomer was
Org. Lett., Vol. 10, No. 9, 2008
1833

Scheme 4
.
Formation of 2-Nitro-1-phenylpropanol
Scheme 5
.
Dual Activation in the Zn-Catalyzed Henry Reaction
Using 1 as Ligand
complex 24 by another prenucleophilic reagent finally
produces the nitroaldol product 25 and regenerates the loaded
catalyst 22.
Our results show that bisoxazolidine 1 is an effective
catalyst of the asymmetric nitroaldol reaction and produces
simplicity of the preparation of enantiopure 1 make this an
attractive new chiral ligand that may find multiple use in
asymmetric catalysis. Further studies of catalytic applications
of bisoxazolidines are currently underway in our laboratory.
ꢀ
-hydroxy nitroalkanes in high yield and enantiomeric
excess. We believe that this procedure has several merits
including simplicity of operation, relatively short reaction
times, and high stereocontrol with a wide range of substrates.
In particular, the excellent results obtained with sterically
hindered aliphatic and aromatic aldehydes extend the scope
Supporting Information Available: Synthetic procedure
and full characterization of nitroaldol products. This material
is available free of charge via the Internet at http://pubs.acs.org.
of this reaction. The rigid, C
2
-symmetric structure and the
OL800442S
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Org. Lett., Vol. 10, No. 9, 2008