Catalytic asymmetric Henry reactions - A simple approach to optically active β-nitro α-hydroxy esters

Article abstract of DOI:10.1039/b105929g

The development and potential of a catalytic enantioselective Henry reaction of nitromethane with various α-keto esters catalyzed by chiral bisoxazoline-copper(II) complexes are presented.

Full text of DOI:10.1039/b105929g

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Catalytic asymmetric Henry reactions—a simple approach to optically
active b-nitro a-hydroxy esters†
Christina Christensen, Karsten Juhl and Karl Anker Jørgensen*
Center for Metal Catalysed Reactions, Department of Chemistry, Aarhus University, DK-8000 Aarhus C,
Denmark. E-mail: kaj@chem.au.dk
Received (in Cambridge, UK) 4th July 2001, Accepted 19th September 2001
First published as an Advance Article on the web 18th October 2001
The development and potential of a catalytic enantio-
selective Henry reaction of nitromethane with various a-
keto esters catalyzed by chiral bisoxazoline–copper(II) com-
plexes are presented.
2
ligand and Cu(OTf) as the Lewis acid gave the most promising
results with > 95% conversion and 92% ee of the Henry adduct
3a (entry 1) at rt, compared to > 95% conversion and 14% ee for
(R)-Ph-BOX–Cu(OTf) and 11% conversion and 18% ee for
2
(
2
4R,5S)-DiPh-BOX–Cu(OTf) (entries 2, 3). Reduction of the
The reaction between a carbonyl and a nitro compound, known
catalyst loading from 20 mol% to 10 mol% does not change the
conversion and enantioselectivity of the reaction significantly
1
as the Henry or nitroaldol reaction, constitutes a fundamental
carbon–carbon bond forming reaction in organic chemistry
which has been applied for the construction of numerous natural
products and other useful compounds.2
2
when using (S)-t-Bu-BOX–Cu(OTf) as the catalyst (entry 4).
The conversion and enantioselectivity of the reaction of 1a with
2 is also dependent on the amount of base relative to the catalyst.
The catalytic asymmetric version of the Henry reaction has
been successfully carried out in only a very few cases; Shibasaki
et al. have in a series of papers shown that rare-earth–lithium–
BINOL complexes can be applied as catalysts for the enantiose-
lective reaction of aldehydes with nitroalkanes.3
3
A reduction of the amount of Et N to 10 mol%, or an increase
to 40 mol%, relative to the catalyst (20 mol%) gave a significant
reduction in conversion and enantioselectivity for the first
combination, and a high conversion and a racemic product 3a
,4
for the latter combination (entries 5, 6). In the presence of NEt
3
This paper presents a new catalytic asymmetric Henry
reaction of a-keto esters 1 with nitromethane 2 in the presence
of easy-available chiral catalysts [eqn. (1)]. The present reaction
is an important new development of the Henry reaction as it
demonstrates (i) for the first time that ketones react in a catalytic
highly enantioselective fashion, (ii) the products formed contain
a chiral quaternary carbon center, the formation of which is a
particularly demanding task in organic synthesis,5 and (iii)
highly attractive functionalized optically active b-nitro a-
hydroxy esters 3 are formed.
and no chiral Lewis acid the reaction proceeds with full
conversion (entry 7). The reaction also proceeds well in the
6 2
presence of (S)-t-Bu-BOX–Cu(SbF ) as the catalyst: > 95%
conversion is found and 3a is obtained with 81% ee (entry 8).
Changing the Lewis acid from copper(II) to zinc(II) [(S)-t-Bu-
2
BOX–Zn(OTf) ] leads to a reaction with only 16% ee of the
other enantiomer (entry 9).
Table 1 Some representative results from the screening of reaction
conditions for the catalytic enantioselective Henry reaction of ethyl
pyruvate 1a with nitromethane 2 in the presence of Et
3
N as the base at room
temperature
Catalyst
Conver- Ee
loading Base sion
of 3a
a
b
Entry Catalyst
(%)
(%)
(%)
(%)
(
1)
1
2
3
4
5
6
7
8
9
a
(S)-t-Bu-BOX–Cu(OTf)
(R)-Ph-BOX–Cu(OTf)
(4R,5S)-DiPh-BOX–Cu(OTf)
2
20
20
20
10
20
20
—
20
20
20
20
20
10
10
40
20
20
20
> 95
> 95
11
84
11
> 95
> 95
> 95
87
92
14
18
81
49
< 5
—
81
2
2
(S)-t-Bu-BOX–Cu(OTf)
(S)-t-Bu-BOX–Cu(OTf)
(S)-t-Bu-BOX–Cu(OTf)
—
2
2
2
Different chiral ligands, Lewis acids and bases have been tested
as catalyst for the enantioselective Henry reaction of ethyl
pyruvate 1a with nitromethane 2. The most promising results
(S)-t-Bu-BOX–Cu(SbF6)
2
(S)-t-Bu-BOX–Zn(OTf)
2
216
6
were found when the chiral bisoxazoline ligands (S)-t-Bu-
Determined by 1H-NMR spectroscopy. b Determined by chiral GC using
BOX 4a, (R)-Ph-BOX 4b and (4R,5S)-DiPh-BOX 4c, were
a Chromopack CP-Chiracil (b-PM) column.
7
used in combination with copper(II) as the Lewis acid. Table 1
presents some representative results from the screening.
The reaction of 1a with 2 catalyzed by (S)-t-Bu-BOX–
2
Cu(OTf) is base dependent. The results for some representative
bases are: Hünigs base 31% conversion, 69% ee; dimethylani-
line 14% conversion, 9% ee; N-methylmorpholine 65% conver-
3
sion, 83% ee; Bn N 10% conversion, 14% ee, compared to
>
3
95% conversion and 92% ee applying Et N. It should also be
noted that lowering the reaction temperature did not improve
the enantioselectivity (at 0 °C: full conversion, 89% ee).
The potential of the reaction is demonstrated for the reaction
of the a-keto esters 1a–f with 2 catalyzed by (S)-t-Bu–BOX–
Of the three chiral bisoxazoline–copper(II) catalysts pre-
2
Cu(OTf) as shown in Table 2.‡
sented for the reaction, the combination of (S)-t-Bu-BOX 4a as
Ethyl pyruvate 1a reacts with nitromethane 2 to give
2
-hydroxy-2-methyl-3-nitropropanoic acid ethyl ester 3a in
†
Electronic supplementary information (ESI) available: spectroscopic and
analytical data. See http://www.rsc.org/suppdata/cc/b1/b105929g/
95% yield and with 92% ee (Table 2, entry 1). The correspond-
ing ethyl analogue 1b reacts in a similar way to give the Henry
2222
Chem. Commun., 2001, 2222–2223
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b105929g

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Table 2 Catalytic enantioselective addition of nitromethane to various a-
Notes and references
2 3
keto esters catalyzed by (S)-t-Bu-BOX–Cu(OTf) in the presence of Et N as
the base
‡ Representative experimental procedure. To a flame dried Schlenk tube
Cu(OTf) (36.2 mg, 0.100 mmol) and 2,2A-isopropylidenebis[(4S)-4-tert-
butyl-2-oxazoline] (30.9 mg, 0.105 mmol) were added. The mixture was
stirred under vacuum for 2 h and filled with N . Dry freshly distilled MeNO
(2 ml) was added and the solution was stirred for 1 h. Ethyl pyruvate 1a (56
ml, 0.50 mmol) was added followed by the addition of Et N (14 ml, 0.1
mmol) and reacted for 16 h under N at rt. The reaction mixture was filtered
through a plug of silica with Et O. The solvent was removed in vacuo and
the residue was purified by FC (silica: 10% Et O in CH Cl ) to yield
2
Entry
a-Keto ester
Yield (%)a
Ee (%)b
2
2
c
1
1a
1b
1b
1c
1d
1e
1f
95
46
73
69
47
81
99
92
90
87
87
77
86
93
c
2
3
d
3
2
d
4
2
d
5
2
2
2
c
2-hydroxy-2-methyl-3-nitropropanoic acid ethyl ester 3a as a pale yellow
oil (84 mg, 0.475 mmol, 95%) with 92% ee detected by chiral GC using a
6
c
7
Chromopack CP-Chiracil (b-PM) column, t(minor) = 23.4 min, t(major)
=
a
Isolated yield. b Determined by chiral GC or HPLC. c Reaction performed
2
3
1
2
2 2
4.1 min, [a] = +10.2° (c = 1.19 g per 100 ml in CH Cl ). H NMR (400
at rt. d Reaction performed at 50 °C.
D
3
MHz, CDCl ) d 4.83 (d, J = 14 Hz, 1H), 4.55 (d, J = 14 Hz, 1H), 4.34 (m,
2
H), 3.71 (s, 1H), 1.45 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (100
+
MHz, CDCl
3
) d 173.4, 80.9, 72.3, 62.9, 23.7, 13.8; HRMS [M + Na] calcd:
C
6
H
11NO , 200.0535; found: 200.0282.
5
adduct 3b in 46% yield and 90% ee at rt (entry 2). The yield of
the Henry adduct is increased to 73% without significant loss in
enantioselectivity by heating the reaction mixture to 50 °C
1 L. C. Henry, R. Hebd. Seances Acad. Sci., 1895, 120, 1265.
2 See e.g.: D. Seebach, E. W. Lehr and T. Weller, Chemia, 1973, 33, 1; G.
Rosini, Comprehensive Organic Synthesis, ed. B. M. Trost and C. H.
Heathcook, Pergamon Press, Oxford, 1991, Vol. 2, p. 321; M. Shibasaki
and H. Gröger in Comprehensive Asymmetric Catalysis I-III, ed. E. N.
Jacobsen, A. Pfaltz and H. Yamamoto, Springer-Verlag, Berlin–
Heidelberg, 1999, Chapter 29.3; F. A. Luzzio, Tetrahedron, 2001, 57,
(
entry 3). In the same manner, the corresponding benzyl ester 1c
gives 69% yield of 3c with 87% ee (entry 4). The a-keto ester
d reacts with 2 giving a moderate yield and enantioselectivty
entry 5) compared to the other reactions presented. The
aromatic a-keto esters 1e,f react with 2 in the presence of (S)-t-
Bu-BOX–Cu(OTf) as the catalyst to give the optically active
1
(
9
15.
3
See e.g.: H. Sasai, T. Suzuki, S. Arai, T. Arai and M. Shibasaki, J. Am.
Chem. Soc., 1992, 114, 4418; H. Sasai, T. Suzuki, N. Itoh and M.
Shibasaki, Tetrahedron Lett., 1993, 34, 851; H. Sasai, T. Tokunaga, S.
Watanabe, T. Suzuki, N. Itoh and M. Shibasaki, J. Org. Chem., 1995, 60,
2
Henry adducts in excellent yield and enantioselectivity as 81%
and 86% ee of 3e, and 99% yield and 93% ee of 3f, respectively,
are obtained (entries 6,7).
7
388; K. Iseki, S. Oishi, H. Sasai and M. Shibasaki, Tetrahedron Lett.,
996, 37, 9081; T. Arai, Y. M. A. Yamada, N. Yamamoto, H. Sasai and
1
This new catalytic enantioselective Henry reaction leads to a
simple synthetic approach to attractive functionalized optically
M. Shibasaki, Chem. Eur. J., 1996, 2, 1368.
4
5
See also: R. Chinchialla, C. Nájera and P. Sánches-Agulló, Tetrahedron:
Asymmetry, 1994, 5, 1393; A. P. Davis and K. J. Dempsey, Tetrahedron:
Asymmetry, 1995, 6, 2829.
For a review about the catalytic formation of molecules with quaternary
carbon centers: E. J. Corey and A. Guzman-Perez, Angew. Chem., Int.
Ed., 1998, 37, 388.
2
active b-nitro a-hydroxy esters, while reduction of the nitro
functionality gives the corresponding optically active b-amino
a-hydroxy esters which are highly attractive compounds in
8
organic chemistry, e.g. the side chain in taxol.
In summary, the first catalytic enantioselective addition
reaction of a-keto esters with nitromethane has been developed.
This approach shows for the first time that ketones undergo
catalytic highly enantioselective Henry reactions giving attrac-
tive optically active b-nitro a-hydroxy esters having a chiral
quaternary carbon center. Further work is in progress to
develop, understand and apply this new type of catalytic
enantioselective Henry reaction.
6 For recent reviews see: J. S. Johnson and D. A. Evans, Acc. Chem. Res.,
000, 33, 325; K. A. Jørgensen, M. Johannsen, S. Yao, H. Audrain and J.
2
Thorhauge, Acc. Chem. Res., 1999, 32, 605; A. K. Ghosh, P. Mathivanan
and L. Cappiello, Tetrahedron: Asymmetry, 1998, 9, 1.
7
The chiral bisoxazoline–copper(II) complexes can also catalyze the
highly enantioselective addition of nitro compounds to imines: N.
Nishiwaki, K. R. Knudsen, K. V. Gothelf and K. A. Jørgensen, Angew.
Chem., Int. Ed., 2001, 40, 2992.
We are indebted to The Danish National Research Founda-
tion for financial support.
8 C. Cativiela, M. D. Diez-de-Villegas and J. A. Gálvez, Tetrahedron:
Asymmetry, 1996, 7, 529 and references therein.
Chem. Commun., 2001, 2222–2223
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