The first catalytic asymmetric Aza-Henry reaction of nitronates with imines: A novel approach to optically active β-nitro-α-amino acid- and α,β-diamino acid derivatives [1]

Full text of DOI:10.1021/ja010588p

J. Am. Chem. Soc. 2001, 123, 5843-5844
5843
Table 1. Enantioselective Aza-Henry Reactions of Nitronates
1a-d with N-(p-Methoxyphenyl)-R-Imino Ester 2c Catalyzed by a
Series of Chiral Copper Complexes 4-7
The First Catalytic Asymmetric Aza-Henry Reaction
of Nitronates with Imines: A Novel Approach to
Optically Active â-Nitro-r-Amino Acid- and
r,â-Diamino Acid Derivatives
Kristian Rahbek Knudsen, Tine Risgaard,
Nagatoshi Nishiwaki, Kurt V. Gothelf, and
Karl Anker Jørgensen*
yieldb erythro: ee erythrod config.
entrya nitronate
catalyst
(R)-4
(R)-5a
(R)-5b
(S)-6a
(S)-6b
(S)-6c
(S)-6de
(4R,5S)-7a
(4R,5S)-7b
(4R,5S)-7c
(4R,5S)-7de
(S)-6a
(4R,5S)-7de
(4R,5S)-7a
product (%)
threo
(%)
(C2,C3)
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
99
99
58
90
63
67
92
52
68
54
94
67
87
93
1:3
11:1
7:1
3:1
5:1
18:1
6:1
6:1
10:1
9:1
25:1
5:1
16
12
56
90
56
89
70
96
97
26
95
>98
83
88
(R,R)
(S,S)
(R,R)
(S,S)
(S,S)
(S,S)
(S,S)
(R,R)
(R,R)
(R,R)
(R,R)
(S,S)f
(R,R)f
(R,R)f
3
4
5
6
Center for Metal Catalyzed Reactions
Department of Chemistry, Aarhus UniVersity
DK-8000 Aarhus C, Denmark
ReceiVed March 5, 2001
7
8
9
The Henry (nitro aldol) reaction,1 and its aza analogue,2 are
fundamental C-C bond-forming reactions in organic chemistry.
Compared with the development of catalytic enantioselective aldol
reactions, there are astonishingly few examples on asymmetric
catalytic nitro aldol reactions. Only the chiral heterobimetallic
catalysts reported by Shibasaki et al. have proven to be effective
for asymmetric Henry reactions.3 In extension of this work, they
have developed a catalytic asymmetric aza-Henry reaction (nitro-
Mannich reaction).3c When nitromethane was used as the substrate,
high enantioselectivities were obtained for this reaction using
N-phosphinoylimines. However, 60 mol % of the chiral ligand
in the chiral ytterbium catalyst was required, and successful
reactions were reported for only nitromethane.
10
11
12
13
14
39:1
32:1
a The reactions were performed in THF by adding 1.5 equiv of 1
during a period of 1 h, to a mixture of the catalyst (20 mol %) and 2c
at -100 °C. b Isolated yield of a mixture of the diastereomers of 3.
c The diastereomeric ratio was determined using 1H NMR. d The
enantiomeric excess was determined by chiral HPLC analysis. e CH2Cl2
was used as the solvent. f Proposed absolute configuration obtained by
comparing the absolute configuration induced by the respective catalysts
for 3a.
This communication presents the first catalytic highly diastereo-
and enantioselective aza-Henry reaction that proceeds in the
absence of a base and with lower catalyst loading. In this reaction,
the presence of a base is avoided by the application of silyl
nitronates 1a-d instead of nitro compounds for the reaction with
R-imino esters 2a-c in the presence of a chiral Lewis acid. It
should be noted that a racemic fluoride-induced reaction of silyl
nitronates with aldehydes has been described by Seebach et al.,4
and very recently another racemic version of this reaction using
Sc(OTf)3 was reported.5
ratio of the erythro:threo-isomers; however, only 16% ee of
erythro-3a (entry 1) (threo-3a, 55% ee) was obtained. The use
of (S)-tBu-BOX-copper complexes10 5a,b as the catalyst also
gave low to medium enantiomeric excess; however, these catalysts
improved and reversed the diastereoselectivity to 11:1 and 7:1,
The reaction of the trimethylsilyl nitronate 1a6 with N-protected
R-imino esters 2a-c in the presence of various Lewis acids was
investigated first (eq 1). Application of N-(p-tosyl)-R-imino ester
2a gave unstable products that underwent retro aza-Henry reaction,
or elimination of the nitro group, in the reaction with 1a catalyzed
by a Lewis acid. However, when the more electron-rich N-phenyl-
R-imino-ester 2b and N-(p-methoxyphenyl)-R-imino ester 2c were
applied in the reaction catalyzed by various copper Lewis acids,
the aza-Henry products were obtained as stable compounds in
satisfactory yields. Application of the N-(p-methoxyphenyl) (PMP)
group for protection of the imine functionality also has the impor-
tant advantage that it can be easily removed from the product,2,7
and we have therefore used 2c for the present development.
The reaction of 1a with 2c proceeds to some extent in the
absence of a catalyst even at -78 °C. Thus, the catalytic reactions
(eq 1) were performed at -100 °C to avoid the racemic reaction.
Various chiral Lewis acid complexes such as BINOL-AlMe,
TADDOLate-TiCl2, DBFOX-Ni(ClO4)2,8 DBFOX-Mg(ClO4)2,
and DBFOX-Zn(OTf)2 were initially tested as catalysts, but very
low enantioselectivities were obtained. Much more promising
results were obtained when the chiral copper catalysts 4-7 were
used (Table 1). Application of catalyst (R)-Tol-BINAP-CuClO4
49 for the reaction of 1a with 2c led to a high yield of 3a in a 1:3
(1) (a) Rosini, G.; Ballini, R. Synthesis 1988, 833. (b) Torssell, K. B. G.;
Gothelf, K. V. Nitroethane. In Encyclopaediea of Reagents for Organic
Synthesis; Paquette, L., Ed.; Wiley: New York, 1995; Vol. 6, p 3735. (c)
Kisanga, P. B.; Verkade, J. G. J. Org. Chem. 1999, 64, 4298. (d) Luzzio, F.
A. Tetrahedron 2001, 57, 915.
(2) (a) Baer, H. H.; Urbas, L. In the Chemistry of the Nitro and Nitroso
Groups, Part 2; Patai, S., Ed.; Interscience: New York, 1970; p 117. (b)
Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J. Org. Chem. 1998,
63, 9932.
(3) (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem.
Soc. 1992, 114, 4418. (b) Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai,
H.; Shibasaki, M. Chem. Eur. J. 1996, 2, 1368. (c) Yamada, K.; Harwood:
S. J.; Gro¨ger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 3504.
(4) (a) Colvin, E. W.; Seebach, D. Chem. Commun. 1978, 689. (b) Seebach,
D.; Beck, A. K.; Mukhopadhyay, T.; Thomas, E. HelV. Chim. Acta 1982, 65,
1101.
(5) Anderson, J. C.; Paece, S. Synlett 2000, 850.
(6) (a) Torssell, K. B. G.; Zeuthen, O. Acta Chem. Scand. 1978, B32, 118.
(b) Colvin, E. W.; Beck, A. K.; Bastani, B.; Seebach, D.; Kai, Y.; Dunitz; J.
D. HelV. Chim. Acta 1980, 63, 697.
(7) Fukuyama, T.; Frank, R. K.; Jewell, C. F. J. Am. Chem. Soc. 1980,
102, 2, 2122.
(8) Kanemasa, S.; Oderaotoshi, Y.; Sakaguchi, S.; Yamamoto, H.; Tanaka,
H.; Wada, E.; Curran, D. P. J. Am. Chem. Soc. 1998, 120, 3074.
10.1021/ja010588p CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/23/2001

5844 J. Am. Chem. Soc., Vol. 123, No. 24, 2001
Communications to the Editor
respectively (entry 2,3). Much better results were obtained when
turning to the (S)-Ph-BOX-copper catalysts 6a-d. The reaction
between 1a and 2c catalyzed by 6a gave the N-protected â-nitro-
R-amino ester 3a in an excellent yield and with 90% ee of the
threo-isomer (entry 4). It is notable that similar high enantio-
selectivity of the major diastereomer was obtained when using
the chiral copper(II) catalyst 6c, and, additionally the diastereo-
selectivity was significantly improved (entry 6). For the reaction
between 1a and 2c, the cis-DiPh-BOX-copper catalysts 7a-d
turned out to be superior.11 The chiral copper(I) catalysts 7a,b
induced good diastereoselectivities and remarkably high enantio-
selectivities of up to 97% ee (entry 8,9). Very high yield and
diastereoselectivity of 25:1 were also obtained using the chiral
copper(II) catalyst 7d, and furthermore, erythro-3a was obtained
with 95% ee (entry 11).
Scheme 1
Scheme 2
To show the potential of this new reaction, it is demonstrated
that the catalytic approach can be applied to other trimethylsilyl
nitronates. The choice of catalyst was optimized for the reactions
of silyl nitronates 1b-d with imine 2c to give 3b-d, and the
best results of these reactions are presented in Table 1 as entries
12-14. For the reaction of the nitroethane-derived nitronate 1b
with 2c catalyzed by 6a, an excellent enantioselectivity >98%
ee was obtained (entry 12), and furthermore, this reaction also
proceeds with a satisfactory diastereoselectivity. The analogous
reactions of nitronates 1c,d catalyzed by 7d and 7a, respectively,
gave also satisfactory enantioselectivities as 83 and 88% ee of
3c and 3d, respectively, were obtained. Furthermore, very high
diastereoselectivities of 39:1 and 32:1 were obtained in favor of
erythro-3c and erythro-3d, respectively (entries 13,14). Thus, the
reactions of the silyl nitronates 1a-d with 2c all proceed in high
yield, diastereo- and enantioselectivity giving â-nitro-R-amino
esters which are a new class of optically active R-amino acid
derivatives. Furthermore, it is notable that the reaction is very
flexible with respect to both chiral ligands and copper salts.
The high synthetic potential of the aza-Henry reaction (eq 1)
is also due to the easy conversion of the â-nitro-R-amino acid
derivatives into a variety of important functionalities, for example,
1,2-diamines. This has previously been demonstrated for alkyl-
and aryl-substituted 2-nitro amines;2b,5,12 however, the conversion
of â-nitro-R-amino esters into R,â-diamino acid derivatives has
not been described previously. As a matter of fact, only few
syntheses of optically active R,â-diamino acid derivatives have
been reported.13 For compound erythro-3a (catalyst (R)-6a used:
90% ee) the reduction of the nitro group was performed using
Raney-Ni to give the protected diamino ester 8 in 80% yield
(Scheme 1). Compound 8 was converted into the corresponding
2-thioimidazolidine derivative 9 by cyclization with Cl2CS. Both
the reduction and cyclization reactions proceeded without loss
of enantioselectivity. Product 9 was obtained as a crystalline
compound which was characterized by X-ray crystallography (see
Supporting Information). From the knowledge of the absolute
configuration of 9, the absolute configuration of erythro-3a was
assigned to be (2R,3R).
The absolute configuration of erythro-3a, led us to propose
the mechanism outlined in Scheme 2 to account for the stereo-
chemical induction of the reaction. It is proposed that both the
R-imino ester 2c, in a bidentate fashion, and the silyl nitronate
coordinate to the copper center. It is well-known that silyl
nitronates decompose in the presence of acids, and therefore, it
is assumed that when the silyl nitronate interacts with the Lewis
acid, as described for 10, the TMS-group dissociates from the
nitronate to give 11. As it has been described for silyl nitronates,6b
it should also be expected that there is a rapid equilibrium between
the E- and Z-forms of the copper nitronate 11. This enables a
six-membered cyclic transition state for 11, with a pentacoordi-
nated copper center. This model can account for both the catalytic
activity, diastereo- and enantioselectivity of the reaction. By
coordination to the copper center, the R-imino ester is activated
for addition of the nucleophilic nitronate. In the chair-conforma-
tion of the cyclohexane-like transition state the nitronate sub-
stituent obtains the less sterically crowded and more stable
equatorial position. This explains the predominant formation of
the erythro-product. The chiral (R)-Ph-BOX ligand shown in 11
favors the formation of the (2R,3R) enantiomer of the product,
since the intermediate leading to the opposite enantiomer of the
product would have unfavorable steric interaction between the
bulky PMP-substituent of the R-imino ester and of the phenyl
substituent of the ligand.
In summary, the development of a new highly enantio- and
diastereoselective copper-bisoxazoline-catalyzed aza-Henry reac-
tion between silyl nitronates and an R-imino ester giving highly
valuable optically active â-nitro-R-amino esters has been de-
scribed. It was demonstrated that high selectivities could be
obtained for various trimethylsilyl nitronates in the presence of
various copper-bisoxazoline catalysts. Furthermore, it was shown
that the optically active â-nitro-R-amino esters can be converted
to a synthetically valuable R,â-diamino acid derivatives. The
absolute configuration of one of the products was determined,
and a model for the catalytic intermediate was proposed.
(9) For the use of Tol-BINAP-Cu(I) as catalyst for addition reaction to
related imines, see e.g.: (a) Drury, W. J., III; Ferraris, D.; Cox, C..; Young,
B.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 11006; (b) Yao, S.; Fang, X.;
Jørgensen, K. A. Chem. Commun. 1998, 2547. (c) Ferraris, D.; Young, B.;
Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548. (d) Ferraris, D.;
Dudding, T.; Young, B.; Drury, W. J., III; Lectka, T. J. Org. Chem. 1999,
64, 2168. (e) Yao, S.; Saaby, S.; Hazell, R. G.; Jørgensen, K. A. Chem. Eur.
J. 2000, 6, 2435. (f) Saaby, S.; Fang, X.; Gathergood, N.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2000, 39, 4114; see also: Fujii, A.; Hagiwara, E.;
Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450; Hagiwara, E.; Fujii, A.;
Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474.
(10) For recent reviews dealing with the use of chiral bisoxazoline-Lewis
acids as catalysts see: (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J.
Tetrahedron: Asymmetry 1998, 9, 1. (b) Jørgensen, K. A.; Johannsen, M.;
Yao, S.; Audrain, H.; Thorhauge, J. Acc. Chem. Res. 1999, 32, 605. (c)
Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
Acknowledgment. We are grateful to Dr. Rita G. Hazell for
performing the X-ray crystallographic analysis of compound 9. This work
was made possible by a grant from the Danish National Research
Foundation.
Note Added in Proof: See also Shibasaki et al., Synlett, 2001,
June 1 issue for nitro-Mannich reactions of nitro compounds with
imines.
(11) (a) Lowental, R. E.; Masamune, S. Tetrahedron 1991, 32, 7373. (b)
Reichel, F.; Fang, X.; Yao, S.; Ricci, M.; Jørgensen, K. A. Chem. Commun.
1999, 1505.
(12) (a) Barrett, A.; G. M.; Spilling, C. D. Tetrahedron Lett. 1988, 29,
5733. (b) Sturgess, M. A.; Yarberry, D. J. Tetrahedron Lett. 1993, 34, 4743.
(13) (a) Nakamura, Y.; Hirai, M.; Tamotsu, K.; Yonezawa, Y.; Shin, C.
Bull. Chem. Soc. Jpn. 1995, 68, 1369. (b) Burke, S. G.; Davies, S. G.;
Hedgecock, C. J. R. Synlett 1996, 621. (c) Merino, P.; Lanaspa, A.; Merchan,
F. L.; Tejero, T. Tetrahedron Lett. 1997, 38, 1813. (d) Baumgartner, H.;
O’Sullivan, A. C. Tetrahedron 1997, 53, 2775.
Supporting Information Available: Complete experimental proce-
dure, characterization and 1H and 13C NMR spectra (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA010588P