1342
J . Org. Chem. 1998, 63, 1342-1343
NMR spectrum. In agreement with our previous work,
On e-step Syn th esis of Tyr om ycin A a n d
the facile syn elimination of the 2-pyridylthio group of
the intermidiate 4 on silica established the trans stereo-
chemical relationship of the 2-pyridylthio group and the
alkyl substituents, which is the result of a trans addition
of radical to citraconic anhydride.7,8 Tyromycin A was
obtained in 79% yield after irradiation of the thiohydrox-
amic ester 3a and stirring for 48 h to ensure complete
elimination of the 2-pyridylthio group followed by puri-
fication over C-18 reverse-phase.9 The other diacids
2b-e were successfully decarboxylated in the presence
of citraconic anhydride to furnish the desired tyromycin
analogues 1b-e in good yield. The results are sum-
marized in Table 1.
In conclusion, we have described the first total syn-
thesis of tyromycin and their analogues, in one step, from
readily available dicarboxylic acids. The facile elimina-
tion of the pyridylthio group, which avoids further
reactions (e.g., oxidation to sulfoxide and elimination),
and exceptionally mild reaction conditions offer a rapid
synthetic access to tyromycin analogues and will allow
further exploration of structure-activity relationships in
this area.
An a logu es
Ste´phane Poigny, Miche`le Guyot and
Mohammad Samadi*
Laboratoire de Chimie, URA 401 CNRS, Muse´um National
d’Histoire Naturelle, 63 rue Buffon, F-75 005 Paris, France
Received September 19, 1997
Among the enzymes bound to surfaces of mammalian
cells, aminopeptidases have been recognized as potential
target for immunomodulating drugs.1 Among inhibitors
of this class of enzymes, tyromycin A, an inhibitor of
leucine and cysteine aminopeptidases, was isolated from
mycelial cultures of the basidiomycete Tyromyces lacteus
(Fr.) Murr.2 Tyromycin A is the first naturally occurring
natural product containing two citraconic anhydride
units. Tyromycin A was found to inhibit the leucine and
cysteine aminopeptidases bound to the outer surface of
HeLa S3 cells and therefore may possess cytostatic
activity. Synthesis of this promising compound has not
been reported to date.
Exp er im en ta l Section
All the reactions were carried out under an argon atmosphere.
All reagents were obtained from commercial suppliers and used
without purification. Methylene chloride was distilled from
CaH2. Flash chromatography was effected on silica (Merck
Kieselgel 60, 230-400 mesh) with mixtures of ethyl acetate and
hexane as eluent. TLC analyses were performed on thin-layer
analytical plates 60 F254 (Merck). Elementary analyses were
carried out at the Institut de Chimie des Substances Naturelles,
Gif-sur-Yvette, France.
3
We recently reported an efficient one-step synthesis
of chaetomellic anhydride A, using Barton radical decar-
4,5
boxylation
In this paper we report further extension
of this reaction to total synthesis of tyromycin A and some
analogues using a double radical decarboxylation. Thus,
the readily available diacids 2 were converted to their
thiohydroxamic diesters 3, using Ph3P/2,2′-dithiobis-
(pyridine N-oxide) 5 coupling method
Gen er a l P r oced u r e. Note: The N-hydroxy-2-thiopyridone
derivatives are somewhat sensitive to daylight. It is advisable
to cover the reaction flask with an aluminum foil.
6
To a solution of dicarboxylic acid 2a -e (1 mmol) and 2,2′-
dithiobis(pyridine N-oxide) (2.2 mmol) in dry CH2Cl2 (10 mL)
was added Ph3P (2.2 mmol) under argon. The mixture was
stirred at room temperature for 30 min. Citraconic anhydride
(10 mmol) was then added, the aluminum foil removed, and the
mixture irradiated with a tungsten lamp (500 W) at 10-15 °C
for 30 min. The mixture was concentrated, and the residue was
dissolved in ether (100 mL), washed with 5% NaHCO3 (50 mL),
water (50 mL), and brine (50 mL), and dried over MgSO4. The
solvent was evaporated under reduced pressure, the excess of
citraconic anhydride removed in high vacuum, and the residue
subjected to flash chromatography on silica with hexanes-ethyl
acetate (9:1) as the eluent yielded the compounds 1c-e. In the
case of tyromycin 1a , and 1b, after 30 min of irradiation, the
mixture was stirred for 48 h at room temperature. Usual
workup as described for 1c-e, the residue was purified over C-18
reverse phase, using MeOH-H2O (9:1) as eluent.
(Scheme 1).
Irradiation in situ of the thiohydroxamic diesters 3, in
the presence of 10 equiv of citraconic anhydride, with a
tungsten light (500 W), during 30 min, gave the inter-
mediate addition products 4, which upon purification on
silica gel afforded the elimination products 1. The
nonisolable intermediate 4 could be observed by NMR
analysis of the crude mixture of the reaction run in
CDCl3. After 30 min irradiation, characteristic signals
for the presence of addition product 4 (δ 3.2 ppm, t, CH-
3′) and elimination product 1 (δ 2.5 ppm, t, CH2-1) were
seen, in a ratio 3:1. After 48 h stirring at room temper-
ature, complete disappearance of addition product 4 and
presence of the only signals corresponding to the elimina-
tion product 1, as the sole isomer, were observed in the
(7) Branchaud, B. P.; Slade, R. M. Tetrahedron Lett. 1994, 35, 4071.
(8) Barton, D. H. R.; Gateau-Olesker, A.; Gero, S. D.; Lacher, B.;
Tachdjian, C.; Zard, S. M. J . Chem. Soc., Chem. Commun. 1987, 1790.
(9) Purification of tyromycin A 1a (n ) 14), and its analogue 1b (n
) 12) over standard silica gel gave 48 and 46% yield, respectively. We
believe that an amount of dimaleic anhydrides 1a -e opened to their
dicarboxylic (1i) or tetracarboxylic (1ii) derivatives, particularly in the
case of tyromycin 1a and analogue 1b (n ) 12).
* Corresponding author. Phone: 33-1-40-79-31-44; Fax: 33-1-40-
79-31-45; E-mail: Samadi@mnhn.fr
(1) Aoyagi, T.; Suda, H.; Nagai, M.; Okagawa, K.; Suzuki, J .;
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Med. 1992, 58, 56-59.
(3) Poigny, S.; Guyot, M.; Samadi, M. J . Chem. Soc., Perkin Trans.
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(4) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J . Chem. Soc.,
Chem. Commun. 1983, 939. Barton, D. H. R.; Crich, D.; Motherwell,
W. B. Tetrahedron 1985, 41, 3901.
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Barton, S. Z. Zard, J anssen Chim. Acta 1987, 4, 3.
(6) Barton, D. H. R.; Samadi, M. Tetrahedron 1992, 41, 3901.
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