Synthesis of β-amino acids based on oxidative cleavage of dihydropyridone derivatives

Article abstract of DOI:10.1021/ol0485518

(Chemical Equation Presented) A new method for the synthesis of β-amino acids based on 2,3-dihydropyridones as starting materials is presented. Conversions of 2,3-dihydropyridones with NaIO₄ and subsequently with base gave the corresponding β-amino acids in a one-pot procedure. The reactions have been monitored by ¹H NMR indicating that the β-amino acids were formed in quantitative yields mostly. This method appears to be of broad scope, as 2-substituted 2,3-dihydropyridones are easily accessible via N-acyliminium ions generated from 4-methoxypyridine.

Full text of DOI:10.1021/ol0485518

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3553-3556
Synthesis of
Oxidative Cleavage of Dihydropyridone
Derivatives
â-Amino Acids Based on
Markus Ege and Klaus T. Wanner*
Department Pharmazie, Zentrum fu¨r Pharmaforschung, LMU Mu¨nchen,
Butenandtstr. 5-13, Haus C, 81377 Mu¨nchen, Germany
klaus.wanner@cup.uni-muenchen.de
Received July 26, 2004
ABSTRACT
A new method for the synthesis of
dihydropyridones with NaIO4 and subsequently with base gave the corresponding
been monitored by 1H NMR indicating that the
-amino acids were formed in quantitative yields mostly. This method appears to be of broad
scope, as 2-substituted 2,3-dihydropyridones are easily accessible via N-acyliminium ions generated from 4-methoxypyridine.
â
-amino acids based on 2,3-dihydropyridones as starting materials is presented. Conversions of 2,3-
â
-amino acids in a one-pot procedure. The reactions have
â
In recent years, â-amino acid derivatives gained much
attention1 by being key components of a variety of bioactive
molecules such as the antitumor agent taxol,2a the antifungal
jasplakinolide,2b the enzyme inhibitor bestatin,2c and many
others.1 Furthermore, â-amino acid derivatives are of high
interest as precursors for peptidomimetics3 and â-lactams.4
In addition, they may also display useful biological activities
as free amino acids.5
of general methods for the stereoselective construction of
highly substituted and functionalized â-amino acid deriva-
tives. We became aware of 4-methoxypyridine as a putative
building block of high versatility for the synthesis of this
type of compound (see Scheme 1).
Transformation reactions of 4-methoxypyridine to dihydro-
pyridones bearing substituents at the ring nitrogen as well
as in positions 2 and 3 of the heterocycle are well established.
N-Acyliminium ion chemistry gives access to 2,3-dihydro-
pyridones 3 possessing a substituent at the 2-position.
Subsequently, a broad array of different substituents ranging
from aliphatic6a,b and aromatic residues6a,b to heteroatomic
groups6c-f may be introduced at the 3-position via the
corresponding enolate of the N-acyl-2,3-dihydropyridone.
This may be accomplished in a diastereoselective fashion
when a substituent in the 2-position of 2,3-dihydropyridone
3 is present.6 Finally, substitution reactions at the ring
In the context of a study aimed at the development of new
GABA uptake inhibitors, we realized that there is still a lack
(1) For reviews, see: (a) EnantioselectiVe Synthesis of â-Amino Acids;
Juaristi, E., Ed.; Wiley-VCH: New York, 1997. (b) Liu, M.; Sibi, P.
Tetrahedron 2002, 58, 7991-8035. (c) Abele, S.; Seebach, D. Eur. J. Org.
Chem. 2000, 1-15. (d) Juaristi, E.; Lo´pez-Ruiz, H. Curr. Med. Chem. 1999,
6, 983-1004.
(2) (a) Rowinsky, E. K.; Donehower, R. C. Pharmacol. Ther. 1991, 52,
35-84. (b) Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett. 1986,
27, 2797-2800. (c) Roers, R.; Verdine, G. L. Tetrahedron Lett. 2001, 42,
3563-3565.
(3) Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar, M.-I.
Curr. Med. Chem. 2002, 9, 811-822.
(4) (a) The Chemistry of â-Lactams; Page, M. I., Ed.; Chapman and
Hall: London, 1992. (b) The Organic Chemistry of â-Lactams; Georg, G.
I., Ed.; Verlag Chemie: New York, 1993.
(5) (a) Shinagawa, S.; Kanamaru, T.; Harada, S.; Asai, M.; Okazaki, H.
J. Med. Chem. 1987, 30, 1458-1463. (b) Casiraghi, G.; Colombo, L.; Rassu,
G.; Spanu, P. J. Org. Chem. 1991, 56, 6523-6527.
(6) (a) Al-awar, R. S.; Joseph, S. P.; Comins, D. L. J. Org. Chem. 1993,
58, 7732-7739. (b) Kuethe, J. T.; Wong, A.; Davies, I. W.; Reider, P. J.
Tetrahedron Lett. 2002, 43, 3871-3874. (c) Beifuss, U.; Feder, G.; Bes,
T.; Uson, I. Synlett 1998, 6, 649-651. (d) Kiely, J. S.; Huang, S.; Lesheski,
L. E. J. Heterocycl. Chem. 1989, 26, 1675-81. (e) Comins, D. L.; Fulp,
A. B. Tetrahedron Lett. 2001, 42, 6839-6841. (f) Comins, D. L.; Huang,
S.; McArdle, C. L.; Ingalls, C. L. Org. Lett. 2001, 3, 469-471.
10.1021/ol0485518 CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/09/2004

The synthesis of racemic dihydropyridones 5a-c was
accomplished according to standard procedures by trapping
reactions of N-acylpyridinium salt 49 with appropriate
nucleophiles providing the required compounds in yields of
84-88%. To remove the benzoyl group, 5a-c were treated
with 3.5 equiv of NaOMe at room temperature,8a,b,10 yielding
dihydropyridones 6a-c in 82-86%. We observed that this
reaction could be clearly improved when only catalytic
amounts of NaOMe (0.5 equiv) were employed and the
temperature was lowered to 0 °C, leading to compounds
6a-c in almost quantitative yields (91-95%). Finally,
deprotonation of 6a,b with NaHMDS and subsequent treat-
ment with MeI afforded compounds 7a,b as precursors for
N-substituted â-amino acids (7a, 91%; 7b, 94%).
Scheme 1. Synthetic Strategy
Initial attempts focused on the oxidation of the N-acyl-
protected dihydropyridones 5a-c. However, all oxidizing
agents employed, KMnO4, KMnO4/NaIO4, RuCl3/NaIO4,
OsO4/NaIO4, and NaIO4, required harsh reaction conditions
and led to mixtures of products providing the desired N-acyl-
protected amino acid even after extensive optimization
studies only in low to moderate yields. The best result were
obtained using NaIO4 as a single oxidant. As NaIO4 does
not interfere with free amines, it seemed quite promising to
undertake oxidative cleavage reactions of the N-unprotected
dihydropyridones 6a-c or 7a,b with this reagent.
Thus, when the N-unprotected dihydropyridone 6b was
treated with NaIO4, the starting material was rapidly con-
sumed, even at room temperature, and following workup,
the amino acid 10b‚HCl was obtained in a yield of 51%.
However, in addition, the N-formyl amino acid 8b was also
isolated in 28% yield. Monitoring the reaction by 1H NMR
spectroscopy revealed that 8b and the amino acid 10b were
the only products formed and that the ratio of these two
products (8b/10b) did not change significantly during the
course of the reaction. Therefore, the N-formyl derivative
8b and the free â-amino acid 10b might be formed by two
competing reaction pathways and not by a stepwise process
nitrogen via the corresponding anion of the N-unprotected
dihydropyridone (e.g., 2) leading to N-substituted dihydro-
pyridones7 are also well-known. Thus, when aiming at the
synthesis of â-amino acids, the oxidative breakdown of the
substituted 2,3-dihydropyridone ring represents the crucial
step to be established. Successful oxidative transformation
would pave the way to various series of â-amino acids, in
which substituents either in the â-position or in R- and
â-positions are present, and to compounds bearing additional
N-substituents as well.
Besides, an asymmetric synthesis of â-amino acids could
follow the same line, as the set up of the first stereocenter
in the 2-position of the 2,3-dihydropyridone ring may be
efficiently accomplished in a stereoselective manner by
utilizing well-established chiral N-acyliminium ion chemistry
featuring N-acyl groups as chiral auxiliaries.8 In this paper,
we describe the successful implementation of this plan for
the synthesis of â-mono- and N,â-disubstituted â-amino acids
1.
Scheme 2. Synthesis of the Amino Acid Precursors 6 and 7a
3554
Org. Lett., Vol. 6, No. 20, 2004

Scheme 3. Transformation of Dihydropyridones to â-amino
Scheme 4. Synthesis of the N-Fmoc-Protected Amino Acids
Acidsa
12a
each case a clean reaction product was obtained. According
1
to the H NMR spectra of the crude reaction mixtures in
addition to the free amino acids 10a,c and 11a, only a second
product had been formed in each case. The latter are likely
to be the N-formyl derivatives 8a,c and 9a, as their 1H NMR
data corresponded well with those of the N-formyl amino
acid 8b, though these compounds were not isolated and
further characterized. However, in line with this assumption,
these compounds disappeared when the reaction mixtures
were treated with sodium hydroxide, and the amino acids
10a,c and 11a remained as single products.
To convert the sterically more demanding dihydropyridone
7b to the amino acid 11b, the reaction time for the oxidative
cleavage and the subsequent saponification had to be
increased from 2 to 22 h and from 24 to 65 h, respectively.
Thereby, the starting material had been completely con-
sumed. However, in addition to the desired â-amino acid
11b, this time small amounts of unidentified side products
were also present in the crude product obtained after the
alkaline hydrolysis.
where the N-formyl derivative 8b represents a precursor of
10b. Consequently, we tried to solve this problem by simply
subjecting the crude reaction mixture resulting from the
oxidation process to an alkaline hydrolysis, as this should
transform the N-formyl derivative 8b into the desired
compound 10b, thus leaving only the latter as the final
compound. Indeed, when the crude product consisting of 8b
and 10b was treated with NaOH at room temperature for 24
h the reaction product became uniform, with the free amino
acid 10b being the only product detectable by H NMR
spectroscopy.
Fortunately, the above-mentioned procedure worked well
also for the oxidative degradation of dihydropyridones 6a,c
and 7a,b. For the oxidation of 6a,c and 7a with NaIO4, in
1
Notably, N-substituents as present in compounds 7a and
7b do not hamper the oxidation reaction, though their
presence may significantly slow the reaction rate, which is
likely a result of steric hindrance, as indicated by the long
reaction time necessary for the conversion of 7b (22 h for
7b as compared to 2 h for 7a). Moreover, the amino function
of the dihydropyridone ring may also be part of a benzylic
(7) Comins, D. L.; Zhang, Y.-M. J. Am. Chem. Soc. 1996, 118, 12248-
12249.
(8) (a) Hoesl, C. E.; Maurus, M.; Pabel, J.; Polborn, K.; Wanner, K. T.
Tetrahedron 2002, 58, 6757-6770. (b) Comins, D. L. J. Heterocycl. Chem.
1999, 36, 1491-1500. (c) Streith, J.; Boiron, A.; Sifferlen, T.; Strehler, C.;
Tschamber, T. Tetrahedron Lett. 1994, 35, 3927-3930.
(9) Pabel, J.; Hoesl, C. E.; Maurus, M.; Ege, M.; Wanner, K. T. J. Org.
Chem. 2000, 65, 9272-9275.
(10) Alkahatlan, H. Z. Synth. Commun. 1992, 22, 2659-2671.
Org. Lett., Vol. 6, No. 20, 2004
3555

or an allylic system, and as such commonly highly suscep-
tible to oxidative degradation, without interfering with the
NaIO4 oxidation, which is best demonstrated by the clean
conversion of 6b and 6c into 10b and 10c, respectively. Thus,
this method should be of broad applicability and prove to
be useful even for the synthesis of â-amino acids with
functional groups sensitive to oxidizing agents.
To remove inorganic salts resulting from the oxidation
reaction, the crude reaction mixtures were purified by anion
and subsequent cation exchange chromatography providing
the free amino acid hydrochlorides 10a-c‚HCl and 11a,b‚
HCl in almost quantitative yields (83-95%, see Scheme 3).
Alternatively, the amino acids may also be isolated as
N-Fmoc derivatives, as demonstrated for 10a and 10c. Direct
treatment of the crude reaction mixtures resulting from the
oxidation of 6a and 6c with FmocCl afforded the desired
Fmoc-protected amino acids 12a and 12c in 73 and 71%
yield, respectively (see Scheme 4). However, under these
conditions the reaction mixtures became highly viscous,
which, besides hampering the isolation procedure, might have
had a negative impact on the reaction. When the crude
reaction mixtures were first purified by cation exchange
chromatography to remove inorganic salts present in high
amount, this problem vanished and the Fmoc-protected amino
acids 12a and 12c were obtained in even better yields (12a,
85%; 12c, 82%).
In summary, a mild and efficient method for the prepara-
tion of â-amino acids based on the oxidative cleavage of
suitably substituted dihydropyridones, e.g., 6a-c and 7a,b,
has been developed. Further applications exploiting the scope
of this new reaction for the synthesis of highly functionalized
â-amino acids are in progress.
Acknowledgment. Financial support of this work by the
Deutsche Forschungsgemeinschaft, the Fonds der Chemis-
chen Industrie, and the BMBF is gratefully acknowledged.
Supporting Information Available: Experimental details
and analytical data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0485518
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Org. Lett., Vol. 6, No. 20, 2004