Synthesis of spirotetramates via a Diels-Alder approach

Article abstract of DOI:10.1021/ol200477s

Chemical equations presented. A study toward the unusual spirotetramate core of the pyrroindomycin antibiotics employing an intermolecular Diels-Alder reaction of an exo-methylene tetramic acid dienophile is described. The exo-methylene tetramate is readi

Full text of DOI:10.1021/ol200477s

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2224–2227
Synthesis of Spirotetramates via a
DielsÀAlder Approach
Nicholas A. Butt and Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park,
Nottingham NG7 2RD, U.K.
c.j.moody@nottingham.ac.uk
Received February 22, 2011
ABSTRACT
A study toward the unusual spirotetramate core of the pyrroindomycin antibiotics employing an intermolecular DielsÀAlder reaction of an exo-
methylene tetramic acid dienophile is described. The exo-methylene tetramate is readily synthesized from S-methylcysteine, and its reactivity as a
dienophile is compared with that of related dehydroalanine derivatives. An alternative approach to spirotetramates using a nitroalkene dienophile
is also reported.
Tetramic acids (pyrrolidine-2,4-diones) occur widely in
Nature as secondary metabolites produced by a wide range
of terrestrial and marine organisms.1À3 A large number of
these natural products carry acyl substituents at C-3, and
these 3-acyltetramates often have more pronounced bio-
logical activity, a fact ascribed to their potential ability to
act as ligands for metal ions and to mimic phosphate.2
3-Acyltetramates, which originate by mixed biosynthetic
routes involving nonribosomal peptide and polyketide
pathways, range in structural complexity from tenuazonic
acid 1,4À7 to equisetin 2,8À11 to cylindramide A 312À14
(Figure 1).
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4221.
Figure 1. Some naturally occurring 3-acyltetramic acids.
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Biomol. Chem. 2004, 2, 3524–3529.
However, it was the reports on the structurally unique
antibiotics, the pyrroindomycins 4,15,16 that captured our
attention. These compounds, isolated from fermentation
of culture LL42D005, a strain of Streptomyces rugosporus,
(8) Vesonder, R. F.; Tjarks, L. W.; Rohwedder, W. K.; Burmeister,
H. R.; Laugal, J. A. J. Antibiot. 1979, 32, 759–761.
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r
10.1021/ol200477s
Published on Web 04/06/2011
2011 American Chemical Society

during the screening for molecules active against Methi-
cillin-resistant Staphylococcus aureus (MRSA) and vanco-
mycin-resistant enterococci (VRE), not only contain the
unusual 1,8-dihydropyrroloindole heterocycle17 but also
differ from other 3-acyltetramic acid natural products in
that they contain a spirotetramate core (Figure 2). The
pyrroindomycins represent the first spirotetramates iso-
lated from Nature, although closely related spirotetronic
acids such as chlorothricin 5b are known (Figure 2).18
Although the stereochemistry of the pyrroindomycins
remains unknown their unusual architecture and structur-
al complexity make them interesting and challenging
targets for synthesis. We now report the first efforts in this
direction with an approach to the spirotetramate core
utilizing the DielsÀAlder reaction.
dehydroalanine type dienophiles in the synthesis of com-
plex natural products.20
The synthesis of the tetramic acid dienophile 12 started
from readily available S-methyl cysteine methyl ester 6
(Scheme 1). Protection of the amine functionality via
Scheme 1. Synthesis of the exo-Methylene Tetramate Dieno-
phile 12
reductive amination with 2,4-dimethoxybenzaldehyde
and NaBH(OAc)3 gave amine 7 in excellent yield. The
2,4-dimethoxybenzyl (DMB) group was chosen for its
capacity to tolerate conditions used further in the synthesis
and its proven ability to be readily removed from complex
tetramic acids.14 Formation of β-ketoamide 9 was
achieved in excellent yield by reaction of the protected
amine 7 with thioester 8 (prepared from cyclohexane
carboxylic acid and the lithium enolate of tert-butyl
thioacetate) using the Ley protocol of triethylamine and
silver trifluoroacetate.11 LaceyÀDieckmann cyclization
using standard conditions gave the desired 3-acyltetramic
acid 10. Sulfoxide 11 was readily prepared via oxidation
using hydrogen peroxide, and the final step was achieved
by a thermal elimination of the sulfoxide to give the
methylene tetramic acid 12 in good yield (Scheme 1). Long
reaction times and promotion of the elimination using
basic conditions led tothe degradation of starting material.
Tetramicacid12wasobtainedasa yellowoil and existsasa
mixture of enol forms at room temperature as observed in
its proton and carbon NMR spectra, presumably the
dominant species being the 2,4-diketo form with an
Figure 2. Structures of the spirotetramate pyrroindomycins and
related spirotetronates, chlorothricolide and chlorothricin.
Several methods have been employed to synthesize
tetramic acids in general,1 but the most common method
used for 3-acyltetramic acids is the LaceyÀDieckmann
cyclization of a β-ketoamide.19 However none of these
methods involve the synthesis of 3-acylspirotetramates,
and therefore we have developed a new approach to these
spiro compounds utilizing the exo-methylene 3-acyltetra-
mic acid 12 (containing a cyclohexyl group as a model for
the complex octalin system of the pyrroindomycins) as a
dienophile in an intermolecular DielsÀAlder reaction.
This strategy not only complements similar strategies used
for spirotetronic acids18 but also continues our use of
(17) Moody, C. J.; Ward, J. G. J. Chem. Soc., Perkin Trans. 1 1984,
2903–2909.
(18) Zografos, A. L.; Georgiadis, D. Synthesis 2006, 3157–3188.
(19) Lacey, R. N. J. Chem. Soc. 1954, 850–854.
(20) Hughes, R. A.; Thompson, S. P.; Alcaraz, L.; Moody, C. J.
J. Am. Chem. Soc. 2005, 127, 15644–15651.
(21) Steyn, P. S.; Wessels, P. L. Tetrahedron Lett. 1978, 4707–4710.
Org. Lett., Vol. 13, No. 9, 2011
2225

exocyclic enol in accord with previous observations on
3-acyltetramic acids.21
accord with literature precedent for dehydroalanine
derivatives.23 Attempts to improve the yield of the
DielsÀAlder reactions using Lewis acids and higher tem-
peratures were unsuccessful, resulting in degradation of
the tetramic acid dienophile. As expected, N-trifluoroace-
tyl dehydroalanine 13 underwent the corresponding
DielsÀAlder reactions satisfactorily to give the cyclohex-
enes 17 and 18 (Scheme 2). However, in contrast to 13, the
N-protected dehydroalanine 14 showed reduced activity
and only underwent a DielsÀAlder reaction with Da-
nishefsky’s diene to give 19 (after enone formation under
acidic conditions) in poor yield. Dehydroalanine deriva-
tives such as 7 are known to undergo a DielsÀAlder
reaction with a range of dienes,23À25 but it appears that
the steric and/or electronic effects of the N-2,4-dimethox-
ybenzyl group are detrimental to reactivity. The exo-
methylene tetramate 12 shows similar dienophilic reactiv-
ity to the N-2,4-dimethoxybenzyl dehydroalanine 14;
attempts to remove the DMB-protecting group from
tetramate 12 to enhance reactivity were not successful.
With the desired dienophile 12 in hand, its ability to
undergo a DielsÀAlder reaction with simple electron-rich
dienes was investigated and compared to that of the
structurally related known dehydroalanine 13,22 and the
corresponding DMB-derivative 14. Tetramic acid 12
proved a relatively modest dienophile but neverthe-
less reacted with 2,3-dimethyl-1,3-butadiene and with
Danishefsky’s diene to give the desired spirotetramates
15 and 16 in moderate yields (Scheme 2), as predominantly
Scheme 2. DielsÀAlder Reactins of exo-Methylene Tetramate
12 and Related Dehydroalanine Derivatives 13 and 14
Scheme 3. Alternative Synthesis of Spirotetramate 15
In view of the poor reactivity of the methylene tetramate
12 in the direct DielsÀAlder route to spirotetramates, we
also investigated an alternative route in which the cycload-
dition was effected before formation of the pyrrolidine-2,4-
dione, exemplified for the case of spirotetramate 15
(Scheme 3). At the same time, we also elected to increase
the reactivity of the dienophile by employing the highly
single enol tautomers. In the DielsÀAlder reaction with
Danishefsky’s diene, the initial adduct was not isolated
but converted into enone 16 under acidic conditions, and
the regiochemical outcome was confirmed by HMBC
spectroscopy (no correlation was observed between the
ketone carbon of the enone and the spirocenter) and is in
(24) Crossley, M. J.; Hambley, T. W.; Stamford, A. W. Aust. J.
Chem. 1990, 43, 1827–1837.
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G.; Peregrina, J. M.; Perez-Fernandez, M. New J. Chem. 2007, 31, 224–
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J. M. J. Chem. Soc., Perkin Trans. 1 1999, 3375–3379.
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Tetrahedron Lett. 2002, 43, 2585–2588.
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Org. Lett., Vol. 13, No. 9, 2011

reactive nitroalkene ester 20, generated in situ. Thus fol-
lowing a literature procedure,26 methyl nitroacetate was
condensed with formalin in acetic acid in the presence of
2,3-dimethyl-1,3-butadiene at 40 °C to give the cyclohex-
ene nitro ester 21 in 55% yield. Reduction of the nitro
group with zinc in acetic acid, followed by reductive
amination with 2,4-dimethoxybenzaldehyde using an
analogous procedure to that described previously, gave
the aminoester 22. Silver trifluoroacetate mediated reac-
tion of 22 with thioester 8 proceeded smoothly and gave
the β-ketoamide 23, subsequently subjected to LaceyÀ
Dieckmann cyclization to give the desired spirotetramate
15 (Scheme 3), identical to the sample prepared by the
DielsÀAlder reaction of tetramate 12. This method for
preparing spirotetramates has the advantage of being able
to use less reactive dienes for the DielsÀAlder reaction,
provided they are stable to acidic conditions, and will
enable the preparation of a range of 3-acylspirotetramates.
In conclusion we have developed new methodology for
the short and efficient syntheses of spirotetramates from
inexpensive starting materials, which will be directly ap-
plicable to spirotetramate containing natural products.
Acknowledgment. We thank theUniversity of Nottingham
for support of this work.
Supporting Information Available. Full experimental
1
details and characterization data, copies of H and 13C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 9, 2011
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