Catalytic asymmetric direct α-amination reactions of 2-keto esters: A simple synthetic approach to optically active syn-β-amino-α-hydroxy esters

Article abstract of DOI:10.1021/ja0175486

The catalytic enantioselective direct α-amination reaction of 2-keto esters with easily available azo dicarboxylates as the nitrogen source and chiral bisoxazoline-copper(II) complexes as the catalyst is presented. The reations proceed with excellent enan

Full text of DOI:10.1021/ja0175486

Published on Web 02/21/2002
Catalytic Asymmetric Direct r-Amination Reactions of 2-Keto Esters: A
Simple Synthetic Approach to Optically Active syn-â-Amino-r-hydroxy Esters
Karsten Juhl and Karl Anker Jørgensen*
Center for Metal Catalyzed Reactions, Department of Chemistry, Aarhus UniVersity, DK-8000 Aarhus C, Denmark
Received November 15, 2001
Scheme 1 a
The direct catalytic enantioselective reaction of an electrophilic
nitrogen source constitutes a fundamental challenge in chemistry.
One of these reactions is the electrophilic amination of enols and
enolates, which has received considerable interest in recent years.1
Optically active R-amino acids have been obtained through this
reaction by amination of chiral ketene acetals with dialkyl azo
dicarboxylates.2 Asymmetric catalytic amination reactions of silyl
enol ethers have also been developed,3 and to our knowledge only
one example of a direct asymmetric catalytic R-amination reaction
is knownsthat is, a reaction without prior silyl enol ether or silyl
ketene acetal formation.4
In this Communication we present the first direct asymmetric
catalytic R-amination reaction of 2-keto esters with commercially
available azo dicarboxylates (eq 1). This new catalytic enantiose-
lective reaction provides an easy entry to optically active syn-â-
amino-R-hydroxy esters, known as the chiral fragments of many
important molecules.
a Key: (a) chiral copper complex 4-7; (b) L-Selectride, -78 °C to room
temperature; (c) 0.5 N NaOH, 2 h; (d) TMSCHN2 in MeOH/toluene.
Some representative results using this procedure from the screening
of the different chiral Lewis acids 4-7 for the reaction of 1a with
the azo dicarboxylates 2a-d are presented in Table 1.
The first four entries in Table 1 show the reaction of 1a with
the different azo dicarboxylates 2a-d in the presence of (S)-4 as
the catalyst in CH2Cl2. Only DEAD 2a and dibenzyl azodicar-
boxylate 2b reacted with 1a under these reaction conditions, and
for 2a and 2b, 55% yield and 68% ee, and 39% yield and 90% ee
of 9a and 9b, respectively, were obtained. Changing the solvent to
THF improved the yield of the R-aminated product and the use of
2b resulted in 60% yield of 9b with 82% ee (entry 6). Several
other chiral bisoxazoline-copper(II) complexes have also been
tested for the reaction of 1a with 2b and under these conditions
catalyst (4R,5S)-6 gave the highest enantioselectivity as 89% ee of
9b was obtained (entry 8).
The enantioselective direct R-amination turned out to be a general
reaction for 2-keto esters using especially dibenzyl azodicarboxylate
as the nitrogen source and chiral bisoxazoline-copper(II) complexes
4, 6, and 7 as the catalyst. Table 2 shows the results for the direct
R-amination of different 2-keto esters 1a-h.
Ethyl 2-keto-4-phenylbutyrate 1a reacted with dibenzyl azodi-
carboxylate 2b in both THF and CH2Cl2 as the solvents using the
chiral bisoxazoline-copper(II) complexes 4, 6, and 7 as the catalysts
to give after four reaction steps the R-aminated product 9b in good
yield and up to 90% ee (Table 2, entries 1-3). Reaction of ethyl
2-keto butyrate 1b with 2b led to a smooth reaction applying 4, 6,
and 7 as the catalysts and 9e was formed with up to 92% ee and
isolated in moderate yields (entries 4-6). Prolongation of the alkyl
chain of the 2-keto ester to pentyl (compound 1c) also gave a
smooth reaction and the R-aminated product 9f could be isolated
in up to 78% yield and 97% ee with use of the different chiral
catalysts (entry 7-9). The last five entries (entry 10-14) demon-
strate the potential of the direct R-amination reaction: the 2-keto
Recently, we reported a catalytic asymmetric direct homoaldol
reaction of pyruvate5 and a catalytic asymmetric direct Mannich
reaction of 2-keto esters with R-imino esters.6 In these reactions
we have proposed7 a new property of chiral bisoxazoline-copper-
(II) complexes:6,8 first to promote the keto to enol tautomerization,
and then to catalyze the enantioselective C-C bond formation. The
crucial step in these reactions is the formation of the nucleophilic
enol form and we anticipated that this methodology could be
extended to azo dicarboxylates.
The reaction of ethyl 2-keto-4-phenylbutyrate 1a with various
azo dicarboxylates was chosen as a test reaction for the chiral Lewis
acid-catalyzed direct R-amination reaction. In the presence of the
copper catalyst (R)-4, the 2-keto ester 1a reacted smoothly with
diethyl azodicarboxylate 2a (DEAD) in CH2Cl2 at room temperature
to give product 3a. The measured ee values were low to moderate
and decreased to racemic after normal flash chromatography
purification. Clearly the acidity of the R-proton next to the ketone
moiety9 did not allow purification of 3a at this stage without loss
of enantioselectivity. This problem could be circumvented by a
stereoselective reduction (>90% de) of the keto functionality by
L-Selectride3,10 prior to removal of the copper catalyst (Scheme 1).
By quenching the reaction with aqueous NaOH, alcohol 8 was
cyclized and the ester moiety was hydrolyzed. Reesterification with
trimethylsilyl diazomethane gave the N-amino oxazolidinone 9a.
9
2420 VOL. 124, NO. 11, 2002 J. AM. CHEM. SOC.
10.1021/ja0175486 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Enantioselective R-Aminiation Reaction of 2-Keto Ester
1a with Azo Dicarboxylates 2a-d Catalyzed by Copper
Complexes 4-7
11, formed by the present catalytic enantioselective direct R-ami-
nation methodology, shows the applicability of this new reaction.
These syn-â-amino-R-hydroxy ester fragments are present in many
different important compounds of pharmaceutical interest such as
Bestatin and Valinoctin A,11 and the side chain of Taxol analogues.12
The formation of 10b,k and 11 leads to an assignment of the
chiral carbon atom formed in the catalytic enantioselective reaction
as the (S)-enantiomer.13 The absolute configuration leads us to
propose transition state 12 to account for the enantioselectivity of
entry
azo dicarboxylate
cat.
solvent
product
yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
2a (R2 ) Et)
2b (R2 ) Bn)
2c (R2 ) i-Pr)
2d (R2 ) t-Bu)
2a (R2 ) Et)
2b (R2 ) Bn)
2b (R2 ) Bn)
2b (R2 ) Bn)
2b (R2 ) Bn)
4
4
4
4
4
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
THF
THF
9a
9b
9c
9d
9a
9b
9b
9b
9b
55
68
39
90
n.d.c
n.d.c
47
n.d.c
n.d.c
35
60
31
57
58
82
7
89
88
THF
THF
a Isolated yield after 4 reaction steps (see Scheme 1). b Ee determined
by chiral HPLC. c Not determined
Table 2. Direct Enantioselective R-Aminiation Reaction of 2-Keto
Esters 1a-h with Dibenzyl Azodicarboxylate 2b Catalyzed by
Chiral Copper Complexes 4, 6, and 7 in THF and CH2Cl2
a
THF
CH Cl2a
yield/ee
the reactions. The first step in the reaction is the generation of the
enol (red in 12) from the 2-keto ester. This reaction is suggested
to be copper-catalyzed and leads to the enol, which is coordinated
to the metal either in a mono- or bidentate fashion. It is proposed
that the azo dicarboxylate also coordinates to the chiral catalyst
(blue in 12) and that a six-membered chairlike transition state is
formed, with the R-substituent of the enol-form of the 2-keto ester
in the less crowded pseudoequatorial position.
In conclusion we have developed a catalytic highly enantiose-
lective direct R-amination of 2-keto esters catalyzed by chiral
bisoxazoline-copper(II) complexes. The reaction gives an easy
entry to optically active masked syn-â-amino-R-hydroxy esters.
Further work utilizing this new concept is in progress.
2
1
entry
2-keto ester R
cat.
product
yield/ee
1
2
3
4
5
6
7
8
9
10
11
12
13
14
benzyl (1a)
4
6
7
4
6
7
4
6
7
6
6
6
6
6
9b
9b
9b
9e
9e
9e
9f
9f
9f
9g
9h
9i
60/82
57/89
58/88
44/86
29/90
44/92
78/92
48/97
50/95
38/90
36/94
51/95
60/95b
72/96
39/90
55/77
50/70
33/78
45/90
36/78
40/93
63/93
52/85
62/93
52/92
53/96
78/95b
54/96
benzyl (1a)
benzyl (1a)
methyl (1b)
methyl (1b)
methyl (1b)
pentyl (1c)
pentyl (1c)
pentyl (1c)
allyl (1d)
but-3-enyl (1e)
isobutyl (1f)
isopropyl (1g)
9j
9k
c-hexylmethyl (1h)
a Yield and ee in %; ee determined by chiral HPLC. b Ee determined by
chiral-GC after removal of the Cbz group.
Acknowledgment. This work was made possible by a grant
from The Danish National Research Foundation.
Supporting Information Available: Complete experimental pro-
cedure and characterization (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 2
References
(1) See e.g.: Genet, J.-P.; Greck, C.; Lavergne, D. In Modern Amination
Methods; Ricci, A., Ed.; Wiley-VCH: Wienheim, 2000; Chapter 3.
(2) (a) Gennari, C.; Colombo, L.; Bertolini, G. J. Am. Chem. Soc. 1986, 108,
6394. (b) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F., Jr.
J. Am. Chem. Soc. 1986, 108, 6395. (c) Trimble, L. A.; Vederas, J. C. J.
Am. Chem. Soc. 1986, 108, 6397. (d) Oppolzer, W.; Moretti, R. HelV.
Chim. Acta 1986, 69, 1923. (e) See also: Clarina, J.; Ga´lvez, N.; Marchi,
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7331.
esters substituted with allyl (1d), but-3-enyl (1e), isobutyl (1f),
isopropyl (1g), and cyclohexyl methyl (1h) all reacted with 2b in
the presence of 6 as the catalyst to give the corresponding
R-aminated products 9g-k in moderate to high yields and excellent
enantioselectivities.
(3) (a) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595. (b) Yamishita,
Y.; Ishitani, H.; Kobayashi, S. J. Can. Chem. 2000, 666.
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(5) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Commun. 2000, 2211.
(6) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001,
40, 2995.
An important application of this direct R-amination reaction is
the formation of syn-â-amino-R-hydroxy esters. Treatment of the
N-amino oxazolidinones 9b,k with first H2-Pd/C, followed by
treatment with Zn-acetone in acetic acid shows the scope of this
direct R-amination reaction as the syn-â-amino-R-hydroxy esters
masked as oxazolidinones 10b,k are formed in 88% and 89% yield,
respectively, and without detectable decrease in enantiomeric excess
(Scheme 2, eq 2).
The N-Boc protected syn-â-amino-R-hydroxy ester 11 can be
formed directly from 8: Both the Cbz groups and the nitrogen-
nitrogen bond are easily cleaved and reduced, respectively, by H2-
Raney-Ni and subsequent protection of the amino group by Boc2O-
DMAP gives 11 in good yield (Scheme 2, eq 3). It should be noted
that the enantiomeric excess of 8b is maintained during the reaction
sequence.
(7) Metal-induced keto to enol tautomerization has previous been observed:
El-Dissouky, A.; Refaaat, L. S. Inorg. Chim. Acta 1984, 87, 213.
(8) For reviews on C2-bisoxazoline-Lewis acid complexes as catalysts see:
(a) Ghosh, A. K.; Matahvivan, P.; Capiello, J. Tetrahedron: Asymmetry
1998, 9, 1. (b) Jørgensen, K. A.; Johannsen, M.; Yao, S.; Audrian, H.;
Thorhauge, J. Acc. Chem. Res. 1999, 32, 605. (c) Johnson, J. S.; Evans,
D. A. Acc. Chem. Res. 2000, 33, 325.
(9) Racemization of 3-amino-2-keto-amides and 3-amino-2-keto-esters has
previously been observed: (a) Slee, D. H.; Laslo, K. L.; Elder, J. H.;
Ollmann, I. R.; Gustchina, A.; Kervinnen, J.; Zdanov, A.; Wong, C.-H.
J. Am. Chem. Soc. 1995, 117, 11867 and references therein (b) Bunnage,
M. E.; Chernega, A. N.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc.,
Perkin Trans. 1 1994, 2373.
(10) Hubbard, J. L. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley and Sons: Chichester, 1995; Vol. 5, p
3172.
(11) Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1999, 64, 2852 and
references therein.
(12) Li, L.; Thomas, S. A.; Klein, L. L.; Yeung, C. M.; Maring, C. J.; Gram-
povnik, D. J.; Lartey, P. A.; Plattner, J. J. J. Med. Chem. 1994, 37, 2655.
(13) The assignment of the stereochemistry is based on 1H NMR, optical
rotation, and literature values; see Supporting Information.
The easy accessibility of both masked syn-â-amino-R-hydroxy
esters 10 and the N-Boc protected syn-â-amino-R-hydroxy ester
JA0175486
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J. AM. CHEM. SOC. VOL. 124, NO. 11, 2002 2421