Catalytic enantioselective transamination of alpha-keto esters: an organic approach to enzymatic reactions.

Article abstract of DOI:10.1039/b308395k

The half-transamination reaction of alpha-keto esters with pyridoxamine or 4-picolylamine was found to be catalysed by different metal catalysts in organic solvents giving moderate yields and enantioselectivities of up to 37% ee for methyl-3-indole pyruvate.

Full text of DOI:10.1039/b308395k

Catalytic enantioselective transaminiation of a-keto esters: an organic
approach to enzymatic reactions
Kristian Rahbek Knudsen, Stephan Bachmann and Karl Anker Jørgensen*
Danish National Research Foundation: Centre for Catalysis, Department of Chemistry, Aarhus University,
DK-8000 Aarhus C, Denmark. E-mail: kaj@chem.au.dk; Fax: +45 8619 6199; Tel: +45 8942 3910
Received (in Cambridge, UK) 22nd July 2003, Accepted 29th August 2003
First published as an Advance Article on the web 19th September 2003
The half-transamination reaction of a-keto esters with
pyridoxamine or 4-picolylamine was found to be catalysed
by different metal catalysts in organic solvents giving
moderate yields and enantioselectivities of up to 37% ee for
methyl-3-indole pyruvate.
Scheme 2 Half-transamination of ethyl pyruvate with pyridoxamine 2.
The development of biomimetic reactions is one of the major
We observe a moderate ligand accelerating effect for this
challenges for synthetic chemists. These reactions are generally
reaction if catalyst 7a (Fig. 1) is used, and 37% of the Boc-
protected alanine derivative was isolated (Table 1, entry 3)
very complicated and the mechanisms are often only partly
elucidated. Therefore an approach dealing with classical
compared to the reaction with Zn(OTf)2 as catalyst where a 28%
organic or organometallic chemistry is challenging.
yield was found (entry 2) and in the absence of a catalyst (entry
The biological transamination of a-keto acids to give a-
1) where very low conversion was found.
amino acids is catalysed by the vitamin B6-dependent amino-
transferase, and proceeds via several protonation/isomerisation
steps going from the ketimine 3 to the aldimine 4 (Scheme
1).1
Fig. 1 Suitable chiral catalysts for asymmetric half-transamination reac-
tions.
The change from CH3OH to a solvent with a higher pKa such
as CH3NO2 does not affect the yield (40%, entry 4). It is well
known that additives such as 1,1,1,3,3,3-hexafluoroisopropanol
(HFIP) can promote the release of the product from the
catalyst,5 but no effect of e.g. HFIP (20 mol%) on the reaction
yield was found (entry 5).
A higher activity for this transamination was detected when
the reaction temperature was increased to 50 °C (66% yield,
entry 6). Interestingly Cu(II) does not catalyse the reaction
(entry 7), but Cu( ), Ag( ), Al(III) and In(III) are active Lewis
acid catalysts for this kind of transformation, giving up to 51%
yield for Cu( ) in combination with dppe (1,2-diphenylphosphi-
noethane) (entries 8–11). A reasonable explanation for the
unreactivity of Cu(II) could be the electron configuration at the
metal centre. The unreactive Cu(II) has a d9 configuration,
Scheme 1 Mechanism of the natural half-transamination (Enz = en-
zyme).
I
I
I
The mechanism of the transamination of a-keto acids with
pyridoxamine to give a-amino acids (or the reversed reaction)
in the presence of stoichiometric amounts of different metal
ions has been intensively studied.2 Different approaches have
been investigated, including chiral versions,3 however, to the
best of our knowledge no catalytic and enantioselective method
has been presented up until now.
Table 1 Results of the metal catalysed half-transamination of ethyl pyruvate
with pyridoxamine 2
We present here the first catalytic† and enantioselective half-
transamination1c reaction of a-keto esters and pyridoxamine or
4-picolylamine, based on (chiral) Lewis acid catalysts to
activate the pyruvate derivatives and protic solvents, such as
CH3OH or CH3NO2, as a proton source for the isomerisation
steps. For the first time isolated yields of the a-amino acid
derivatives are given, whereas most of the known half-
transaminations are based on kinetic studies of reaction rates.2,4
The half-transamination of a-keto esters with pyridoxamine
derivatives is a reversible process and therefore in an equilib-
rium with the reverse reaction (half-transamination of the a-
amino acids with pyridoxal 5). Hence high reaction yields and
enantioselectivities are difficult to achieve. Despite this fact
different metal salts, such as Zn(OTf)2, CuPF6·4CH3CN,
AgOTf, AlMe3 or InCl3·3H2O (see Table 1) are able to catalyse
the half-transamination of ethyl pyruvate with pyridoxamine 2
in protic solvents (Scheme 2).
Entry
Catalyst
T/°C
Solvent
Yield (%) a
1
2
—
Zn(OTf)2
7a
7a
7a
RT
RT
RT
RT
RT
50
RT
RT
RT
RT
RT
MeOH
MeOH
MeOH
MeNO2
MeOH
MeOH
MeOH
MeOH
MeOH
MeNO2
MeOH
0
28
37
40
41
66
0
51
49
35
37
3b
4b
5b,c
6b
7
7a
Cu(OTf)2
[Cu(dppe)]PF6
[Ag(dppe)]OTf
AlMe3
8
9
10
11
InCl3·3H2O
a Isolated yield after protection of the free amine with (Boc)2O. b Due to the
low UV-absorbance of the product and the fragmentation under mild GC
separation conditions, the enantiomeric excess could not be determined.
c 20 mol% 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as additive.
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CHEM. COMMUN., 2003, 2602–2603
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whereas all transamination catalysts, with the exception of
Al(III), are isolelectronic and possess a d10 configuration at the
metal centre.
equilibrium between the two half-transamination reactions we
are dealing with, as mentioned above.
We suggest that the pKa of the solvent and the geometry of
the metal intermediate are the key factors to obtain enantiose-
lective reactions. As soon as a distortion of the optimal
geometry of the intermediate occurs, due to coordination of the
solvent or other factors, the selectivity is diminished. In our
further investigations we will try to find an ideal catalytic
system with the help of molecular modelling to improve the
enantioselectivity and reaction yields in parallel.
Changing from ethyl pyruvate to methyl-3-indole pyruvate
the reactivity in CH3OH was low and only 19% of the product
was isolated. Surprisingly, the use of 4-picolylamine 6 as amine
source instead of pyridoxamine 2 (Scheme 3) gave good yields
(Table 2, entry 1) whereas 6 was unreactive in combination with
ethyl pyruvate. The pyridine N-atom has an important role
during the isomerisation steps since benzylamine was un-
reactive under the standard reaction conditions.
In summary, a new catalytic and enantioselective approach to
chiral a-amino acids has been developed using Cu( ) or Zn(II)
I
Lewis acid catalysts in combination with different chiral
ligands. The reaction gives optically active alanine and
tryptophan derivatives in low to moderate yields with low
enantioselectivities. The enantiomeric excess shows a moderate
dependency on the size of the functionality on the bisoxazoline
rings of the ligands. Enantioselectivities can only be obtained
when solvents with high pKa values, such as CH3NO2 are used,
indicating that the protonation step is probably the key factor to
obtain enantioselectivity. The improvement of the enantiose-
lectivity in combination with good reaction yields will be the
object of future studies.
Scheme 3 Half-transamination of 3-methyl-indole pyruvate with 4-picoly-
lamine and different (chiral) Lewis acid catalysts.
Matsushima and Matsumoto tried to use 6 in the transamina-
tion of pyruvic acid, but no conversion was observed.2g
Therefore this is the first report of a transamination of a
pyruvate derivative with 6 as the amine source, however, with
a variety of different chiral catalysts no enantioselectivity could
be induced with CH3OH being the solvent.
This work was made possible by a grant from the Danish
National Research Foundation.
Notes and references
To our delight, we have found that in a solvent with a higher
pKa than CH3OH, such as CH3NO2, enantioselectivity can be
induced with several chiral Lewis acid catalysts (see Table 2).
By changing the solvent from CH3OH to CH3NO2 19% ee
was found for the tryptophan derivative using 7a as the catalyst
(Table 2, entry 3). The change of solvent has a positive effect on
the enantioselectivity, but in general poor yields are obtained in
† Typical catalytic procedure: The metal salt (0.1 mmol, 20 mol% versus
the amine source) and the (chiral) ligand (0.11 mmol, 22 mol%) were stirred
for 30 min under vaccum. Then 2 ml of solvent were added and the solution
was stirred for 1 h before the amine source (2 or 6, 0.5 mmol) and the a-keto
ester (1 mmol, 2 eq.) were added. The resulting mixture was stirred for 20
h and hydrolysed by the addition of water (2 eq.) and trifluoroacetic acid (1
eq.). The free amino group was protected by adding NEt3 (210 ml, 3 eq.) and
(Boc)2O (218 mg, 2 eq.) to the methanol solution and stirring for 30 min at
50 °C. After cooling the mixture to room temperature the solvent was
removed and the oily residue was purified by FC using CH2Cl2/Et2O (9 : 1)
as eluent. The enantiomeric excess was determined by HPLC on a Chiralpak
CH3NO2. With catalyst 7b where Cu( ) is the central atom the
I
same enantioselectivity was found as with 7a (20% ee, entry 4).
Modifying the R group from Ph (7a) to Bn (8a) in the oxazoline
ring of the ligands shows a significant influence on the
enantioselectivity and the product with 8a as the catalyst was
racemic (entry 5). With the bulky 1-naphthyl group at the
oxazoline moiety the enantioselectivity is improved to 27% ee
(entry 6). The most selective catalyst for the enantioselective
transamination of methyl-3-indole pyruvate with 6 is catalyst 9,
having an indole substituent (Fig. 1). This catalyst gives 37% ee
(entry 7), the highest enantioselectivity we observed up until
now for this type of reaction.
AS column with hexane/i-PrOH (80 : 20) as eluent. Rt(min), 5.7 (
7.3 ( -isomer). The absolute configuration was assigned by comparision
with a commercially available sample of ( )-tryptophan that had been
D-isomer),
L
L
derivatised to the Boc-protected tryptophan methylester.
1 For an overview on enzymatic transaminations see: (a) A. E. Braunstein,
in The Enzymes, P. D. Boyer, ed., Academic Press, New York, 1973, vol.
9; (b) Transaminases, P. Christen and D. E. Metzler, eds., John Wiley,
New York, 1985; (c) Y. Murakami, J.-i. Kikuchi, Y. Hisaeda and O.
Hayashida, Chem. Rev., 1996, 96, 721.
2 Selected papers: (a) Y. Matsushima and A. M. Martell, J. Am. Chem.
Soc., 1967, 89, 1331; (b) Y. Tachibana, M. Ando and H. Kuzuhara, Chem.
Lett., 1982, 1765; (c) Y. Tachibana, M. Ando and H. Kuzuhara, Bull.
Chem. Soc. Jpn., 1983, 56, 2263; (d) D. Metzler and E. E. Snell, J. Am.
Chem. Soc., 1952, 74, 979; (e) D. Metzler, M. Ikawa and E. E. Snell, J.
Am. Chem. Soc., 1954, 76, 648; (f) J. B. Longenecker and E. E. Snell,
Biochemistry, 1956, 42, 221; (g) S. Matsumoto and Y. Matsushima, J.
Am. Chem. Soc., 1972, 94, 722; (h) E. Fasella, S. D. Dong and R.
Breslow, Bioorg. Med. Chem., 1999, 7, 709.
3 (a) Y. Tachibana, M. Ando and H. Kuzuhara, Chem. Lett., 1982, 1765;
(b) Y. Tachibana, M. Ando and H. Kuzuhara, Bull. Chem. Soc. Jpn.,
1983, 56, 3652; (c) K. Bernauer, R. Deschenaux and T. Taura, Helv.
Chim. Acta, 1983, 66, 2049; (d) R. Deschenaux and K. Bernauer, Helv.
Chim. Acta, 1984, 67, 373; (e) S. C. Zimmermann and R. Breslow, J. Am.
Chem. Soc., 1984, 106, 1490.
In general enantioselectivity is observed only in combination
with low yields. This fact can be a consequence of the
Table 2 Summary of the metal catalysed half-transamination of methyl-
3-indole pyruvate with 4-picolylamine 6
Entry
Catalyst
t/h
Solvent
Yield (%)a Ee (%)b
1
2
3
4
5
6
7
Zn(OTf)2
20
20
20
40
40
40
40
MeOH
MeOH
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
66
50
10
15
36
22
15
—
7a
7a
7b
8a
8b
9
Rac
19 (
20 (
Rac
27 (
37 (
D
)
)
D
D
)
)
D
4 O. A. Gansow and R. H. Holm, J. Am. Chem. Soc., 1968, 90, 5629.
5 (a) H. Kitajima, K. Ito and T. Katsuki, Tetrahedron, 1997, 53, 17015; (b)
R. Takita, T. Ohshima and T. Katsuki, Tetrahedron Lett., 2002, 43,
4661.
a Isolated yield after protection of the free amine with (Boc)2O. b The
enantiomeric excess was determined by HPLC using a Chiralpak AS
column.
CHEM. COMMUN., 2003, 2602–2603
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