A concise, asymmetric synthesis of tetramic acid derivatives

Article abstract of DOI:10.1021/ol026599k

(graph presented) A simple, asymmetric synthesis of tetramic acid derivatives is described in this paper. The key step is a carbonyl transfer from carbonyldiimidazole (CDI) to α-diimines (I) to form N-alkyl-4-alkylamino-5-methylenepyrrol-2-ones (II). In t

Full text of DOI:10.1021/ol026599k

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3651-3654
A Concise, Asymmetric Synthesis of
Tetramic Acid Derivatives
Santos Fustero,* Marta Garc´ıa de la Torre,§ Juan F. Sanz-Cervera,
Carmen Ram´ırez de Arellano,‡ Julio Piera, and Antonio Simo´n
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia,
E-46100 Burjassot, Spain
santos.fustero@uV.es
Received July 24, 2002
ABSTRACT
A simple, asymmetric synthesis of tetramic acid derivatives is described in this paper. The key step is a carbonyl transfer from carbonyldiimidazole
(CDI) to r-diimines (I) to form N-alkyl-4-alkylamino-5-methylenepyrrol-2-ones (II). In turn, these compounds can be easily transformed into
tetramic acid derivatives (III) in two additional steps.
CDI has been widely used in organic synthesis as a transfer
reagent of both the imidazole ring and the carbonyl group.1
One of the most frequent applications of CDI is as carbo-
nylating agent in processes that imply formation of two
carbon-heteroatom bonds.2 In contrast, CDI has been used
much less frequently in the formation of one or two carbon-
carbon bonds. To the best of our knowledge, only four
examples have been reported related to such processes.3 In
the most recent case,3d our research group was able to prepare
â-enamino esters and thioesters through the reaction of
ketimines with CDI, followed by reaction with an alkoxide.
In this paper, we are reporting a novel carbonyl transfer from
CDI to R-diimines that constitutes the key step for a synthesis
of tetramic acid derivatives.
A number of natural products with a wide range of
biological activities, which include antiviral, antitumoral,
antibiotic, and antimicrobial activities, include the core
structure of tetramic acid (1, pyrrolidin-2,4-dione). Some
examples of these substances are tirandamycine (2), disidine
(3), and magnesidine (4).4
Natural products that derive from tetramic acid and include
an acyl group on C-3 are called 3-acyltetramic acids. Their
biological activity is essentially due to the presence of the
pyrrolidin-2,4-dione ring, the carbonyl group on C-3, and
the stereocenter on C-5, together with the ability to form
complexes with metallic ions.5
§ Current address: Eli Lilly & Co., Alcobendas, Madrid, Spain.
‡ X-ray analysis.
(1) (a) Staab, H. A. Liebigs Ann. Chem. 1957, 609, 75-83. (b) Staab,
H. A. Angew. Chem. 1962, 74, 407-423; Angew. Chem., Int. Ed. Engl.
1962, 1, 351-367. (c) Paul, R.; Anderson, G. W. J. Am. Chem. Soc. 1960,
82, 4596-4600. (d) Kno¨lker, H. J.; El-Ahl, A. A. Heterocycles 1993, 36,
1381-1385. (e) Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew. Chem.,
Int. Ed. Engl. 1979, 18, 72-74. (f) Armstrong, A. In Encyclopedia of
Reagents for Organic Synthesis; Paquete, L. A., Ed.; Wiley & Sons: New
York, 1995; Vol. 4, p 1006.
(2) (a) Buntain, I. G.; Suckling, C. J.; Wood, H. C. S. J. Chem. Soc.,
Perkin Trans. 1 1988, 3175-3182. (b) Staab, H. A.; Benz, W. Liebigs Ann.
Chem. 1961, 648, 72-82. (c) Walsh, D. A.; Green, J. B.; Franzyschen, S.
K.; Nolan, J. C.; Janni, J. M. J. Med. Chem. 1990, 33, 2028-2032. (d)
Zhang, X.; Rodrigues, J.; Evans, L.; Hinkle, B.; Ballantyne, L.; Pen˜a, M.
J. Org. Chem. 1997, 62, 6420-6423.
(3) (a) Jerris, P. J.; Wovkulich, P. M.; Smith, A. B., III Tetrahedron
Lett. 1979, 20, 4517-4520. (b) Garigpati, R. S.; Tschaen, D. M.; Weinreb,
S. M. J. Am. Chem. Soc. 1990, 112, 3475-3482. (c) Barluenga, J.; Gonza´lez,
F.; Fustero, S.; Pe´rez, R. J. Org. Chem. 1991, 56, 6751-6754. (d) Fustero,
S.; Garc´ıa de la Torre, M.; Jofre´, V.; Pe´rez Carlo´n, R.; Navarro, A.; Simo´n
Fuentes, A. J. Org. Chem. 1998, 63, 8825-8836.
(4) For a review on tetramic acid derivatives, see: Royles, B. J. L. Chem.
ReV. 1995, 95, 1981-2001.
(5) (a) Markopolou, O.; Markopoulos, J.; Nicholls, D. J. Inorg. Biochem.
1990, 39, 307-316. (b) Heaton, B. T.; Jacob, C.; Markopoulos, J.;
Markopoulou, O.; Na¨hring, J.; Skylaris, C.-K.; Smith, A. K. J. Chem. Soc.,
Dalton Trans. 1996, 1701-1706.
10.1021/ol026599k CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/19/2002

Table 1. Results for the Reaction between R-Diimines 7 and
CDI
entry R-diimine
R
product
yield (%)a
1
2
3
4
7a
7b
7c
7d
c-C6H11
(()-sec-Bu
R-(+)-C6H5(Me)CH
S-(-)-C6H5(Me)CH
8a
8b
8c
8d
40
58
47
51
a Isolated yields.
either through the formation of a C-C bond or a C-N bond
as a first step. Although the acyclic intermediate has never
been isolated, the results obtained in related reactions3d,8
seem to point to the first hypothesis, as represented in
Scheme 2.
A variety of procedures using either standard solution4 or
solid-phase6 chemistry have been used to prepare optically
pure tetramic acid derivatives. In all of them a chiral R-amino
acid source is a useful precursor to induce asymmetry.
Our synthesis of the tetramic acid derivatives begins with
the double condensation of a primary amine (5) with
butanedione (6) in dichloromethane at room temperature, in
the presence of 98% formic acid and 4 Å molecular sieves.7
After 7 days, the corresponding R-diimines 7 were obtained
in 47-56% yield (Scheme 1).
Scheme 2
Scheme 1
The preparation of the desired tetramic acid derivatives
implies two steps: reduction of the exocyclic double bond
and hydrolysis of the N-protected enamine to a carbonyl
group. In principle, either of these two reactions could be
done first. However, hydrolysis of the derivatives 8a-d in
aqueous acidic conditions yielded complex reaction mixtures,
from which isolation of the desired products was not possible.
In contrast, the alternative route (reduction followed by
hydrolysis) was successful. Thus, catalytic hydrogenation of
compounds 8a-d in MeOH solution under atmospheric
pressure with hydrogen and 10% Pd/C as catalyst at room
temperature gave derivatives 9a-d in good yields (Scheme
3 and Table 2).
The second step consists of a carbonyl transfer from N,N′-
carbonyldiimidazole (CDI) (2.0 equiv) in the presence of
BF3‚OEt2 (2,0 equiv)3d to the diimines 7a-d (1.0 equiv) to
give the cyclic derivatives 8a-d in moderate yields (Scheme
1 and Table 1).
The achiral compound 8a was obtained in 40% yield (entry
1, Table 1). However, we were mainly interested in exploring
the possibility of an asymmetric synthesis through chiral
induction of the R group in the subsequent steps. For that
reason, a chiral substituent was also introduced (entries 2-4,
Table 1) in compounds 7b-d to yield 8b-d. The formation
of the condensation compounds 8 might be rationalized
Scheme 3
(6) (a) Matthews, J.; Rivero, R. A. J. Org. Chem. 1998, 63, 4808-4810
and literature cited therein. (b) Romoff, T. T.; Ma, L.; Wang, Y.; Campbell,
A. Synlett 1998, 12, 1341-1342.
While for compound 8a a single product was obtained
(9a), in the case of 8b-d a mixture of diastereomers resulted
3652
Org. Lett., Vol. 4, No. 21, 2002

Scheme 4
Table 2. Results for the Reduction of Compounds 8
entry
R
product
d.r. (R/â)
yielda (%)
1
2
3
4
c-C6H11
(()-sec-Bu
R-(+)-C6H5(Me)CH
S-(-)-C6H5(Me)CH
9a
9b
9c
9d
84
86
84 (60)c
98 (60)c
16 (58:42)b
76 (12:88)b
80 (90:10)b
a Yield for the purified product or diastereomeric mixture. b Diastereo-
meric ratio as determined through 1H NMR of the reaction crude.
c The yield of the major reaction product after purification appears in
parentheses.
pound by simply using 9câ instead of 9dr as starting
material for this reaction.
(Table 2). As expected, the sec-butyl group in compound
8b did not cause a significant asymmetric induction (only
16% d.e.). However, in enantiomers 8c and 8d, where R is
the phenylethyl group in configurations R and S, respectively,
the asymmetric induction worked well, yielding the mixture
of diastereomers 9cr + 9câ, and 9dr + 9dâ with diaster-
eomeric ratios of ca. 80%. The corresponding diastereomers
were easily separated by means of column chromatography,
and their structures secured through extensive spectroscopic
analysis and X-ray crystallographic analysis of compound
9câ. As a result, the absolute configuration of 9câ was shown
to be (R,R,R)9 (Figure 1).
Aside from their own interest, chiral N-protected tetramic
acid derivatives are important precursors of â-hydroxy-γ-
amino acids, which in turn constitute useful building blocks
in the synthesis of different classes of biologically active
molecules.11 Thus, compound 11d was easily prepared in
78% yield and diastereomeric excess of >95% (Scheme 5)
Scheme 5
when a CH2Cl2:AcOH (9:1) solution of 10dr was treated
with 2.0 equiv of NaBH4 at 0 °C for 1.5 h. The structure of
11d was ascertained by means of spectroscopic analysis and
agreed with the results of NOE experiments. These results
coincided with others previously reported for the reduction
of chiral tetramic acid derivatives.11a
In summary, we have presented a simple, asymmetric
synthesis of tetramic acid derivatives that can easily furnish
both enantiomers in only four steps from easily available,
inexpensive materials and in which the key step is a carbonyl
transfer from CDI to an R-ketodiimine.
(9) Crystal data for 9câ: C21H24N2O; crystals from n-hexane/CHCl3 (1:
1). Colorless block of dimensions 0.62 × 0.46 × 0.42 mm3 size, monoclinic,
P21, a ) 8.656(1) Å, b ) 6.843(1) Å, c ) 16.820(2) Å, â ) 93.19(1)°, V
) 994.8(2) Å3, Z ) 2, Dc ) 1.070 g cm-3, 2θmax ) 55°, diffractometer
Siemens P4, Mo KR λ ) 0.71073 Å, ω-scan, T ) 291(2) K, 9000 reflections
collected of which 4525 were independent (Rint ) 0.087), direct primary
solution and refinement on F2 (SHELXL-97, G. M. Sheldrick, University
of Go¨ttingen, 1997), 208 refined parameters, amino hydrogen atom located
in a difference Fourier synthesis and refined with restrained N-H bond
length, other hydrogen atoms riding, R1[I > 2σ(I)] ) 0.0608, wR2(all data)
) 0.2382, residual electron density 0.158 (-0.196) eÅ-3, both the C9 methyl
group and the C21-C26 phenyl group are disordered over two sites, absolute
structure could not be determined.
(10) Interestingly, when THF was used as solvent, the reaction gave only
ill-defined products, and the desired product 10dr was not detected.
(11) See, for example: (a) Galeotti, N.; Poncet, J.; Chiche, L.; Jouin, P.
J. Org. Chem. 1993, 58, 5370-5376. (b) Palomo, C.; Cossio, F.; Rubiales,
G.; Aparicio, D. Tetrahedron Lett. 1991, 32, 3115-3118. (c) Ma, D.; Ma,
J.; Ding, W.; Dai, L. Tetrahedron: Asymmetry 1996, 7, 2365-2370. (d)
Ba¨nziger, M.; McGarrity, J. F.; Meul, T. J. Org. Chem. 1993, 58, 4010-
4012.
Figure 1. Thermal ellipsoid plot of (R,R,R)-9câ.
Finally, the preparation of compound 10dr was achieved
by means of treatment of a solution of compound 9dr in
diethyl ether10 with aqueous 6 N H2SO4 at room temperature
for 7 h. This procedure gave enantiomerically pure tetramic
acid 10dr in 90% yield (Scheme 4). This method would
also allow the preparation of the enantiomer of this com-
(7) Dieck, H. T.; Dietrich, J. Chem. Ber. 1984, 117, 694-701.
(8) Garc´ıa de la Torre, M. Ph.D. Dissertation, Universidad de Valencia,
Burjassot (Valencia), Spain, 1999.
Org. Lett., Vol. 4, No. 21, 2002
3653

Acknowledgment. We thank the Ministerio de Ciencia
y Tecnolog´ıa of Spain for financial support. M.G.T. and J.P.
thank the fundacio´n Ramo´n Areces and the Ministerio de
Educacio´n y Cultura, respectively, for predoctoral fellow-
ships.
Supporting Information Available: Spectroscopic data,
experimental details for 8, 9, 10, and 11 and crystal data for
compound 9câ in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL026599K
3654
Org. Lett., Vol. 4, No. 21, 2002