3804
J . Org. Chem. 1997, 62, 3804-3805
Sch em e 1a
Stu d ies tow a r d Th iostr ep ton An tibiotics:
Assem bly of th e Cen tr a l P yr id in e-Th ia zole
Clu ster of Micr ococcin s
Marco A. Ciufolini* and Yong Chun Shen
Department of Chemistry, MS 60, Rice University,
6100 Main Street, Houston, Texas 77005-1892
Received March 11, 1997
Micrococcin P1, 1,1 is a member of the thiostrepton
family of antibiotics,2 and it is a potent inhibitor of
protein synthesis, seemingly as a result of interaction
with ribosomal RNA.3 Thiostrepton itself 4 and other
members of the the same family5 have been found to
induce expression of various genes of unknown function
in Streptomyces species. This property has not yet been
reported for micrococcin, but because 1 and thiostrepton
appear to have very similar biological properties,3 it
seems likely that 1 may also be a gene inducer. Despite
these exciting reports, almost no synthetic work has been
recorded in the thiostrepton area. Some of the difficulties
inherent to the construction of the complex pyridine-
thiazole clusters present in these substances have been
addressed in the synthesis of a degradation product of
1, termed micrococcinic acid,6 which, however, lacks the
delicate threonine-derived array evident in one of the
thiazole subunits. We now describe a convergent syn-
thesis of 2, the complete heterocyclic core of micrococcins.
a
Key: (a) H2S, H2O; (b) ethyl bromopyruvate, EtOH, heat, 95%
a-b; (c) NH3, MeOH; (d) Ac2O, pyridine, 67% c-d; (e) Lawesson
reagent, toluene, reflux; (f) K2CO3, EtOH; (g) PCC, CH2Cl2; 40%
from 5; (h) CH2dCHMgBr; (i) MnO2, 72% h-i.
suitable modifications of our pyridine-forming chemistry.7
Compounds 8 and 15 were prepared as follows. Reaction
of glycolonitrile, 3, with gaseous H2S afforded the ex-
pected thioamide in essentially quantitative yield. In
crude form, this material reacted with ethyl bromopy-
ruvate (EBP) to furnish thiazole 4 (Scheme 1). Sequen-
tial ammonolysis, O-acetylation, treatment with the
Lawesson reagent,8 and condensation with EBP yielded
bithiazole 6. This compound was advanced to the sensi-
tive enone 8 by selective acetate cleavage, oxidation of
the resulting carbinol to an aldehyde, vinyl Grignard
addition, and again oxidation with MnO2.9
The route to compound 15 commenced with am-
monolysis of L-threonine derivative 910 and chemoselec-
tive conversion of the amide into thioamide 10 with the
Lawesson reagent. Best results were obtained when the
thionation reaction was run in refluxing benzene (Scheme
2).11 Condensation of 10 with EBP yielded thiazole (-)-
11, which reacted with 3 equiv of the carbanion arising
upon treatment of thiazole 14 with n-BuLi to form ketone
15 in high yield.12
The fusion of 8 and 15 into a pyridine by variants of
our chemistry7 was not straightforward, while more
traditional methods were marred by technical difficulties.
In particular, the formal Michael addition of the enolate
of 15 into 8 was plagued by the great sensitivity of the
enone to basic agents (polymerization). Numerous ex-
periments ultimately unveiled an outstanding solution
in the form of catalysis by a heterogeneous system. Thus,
the long-sought Michael adduct 16 emerged in nearly
quantitative yield upon reaction of 8 and 15 in ethyl
acetate at room temperature in the presence of (insoluble)
It seemed plausible that the pyridine nucleus with its
full complement of thiazoles could be manufactured
through the merger of fragments 8 and 15, possibly by
(7) Cf. (a) Ciufolini, M. A.; Roschangar, F. J . Am. Chem. Soc. 1996,
118, 12082. (b) Ciufolini, M. A.; Shen, Y. C.; Bishop, M. J . J . Am. Chem.
Soc. 1995, 117, 12460. (c) Ciufolini, M. A. In Advances in Heterocyclic
Natural Product Synthesis; Pearson, W. H., Ed.; J AI Press: Greenwich,
CT, 1996; Vol. 3, p 1.
(1) Structure: (a) Bycroft, B. W.; Gowland, M. S. J . Chem. Soc.,
Chem. Commun. 1978, 256. Review: (b) Pestka, S. In Antibiotics;
Corcoran, J . W., Hahn, F. E., Eds.; Springer-Verlag: New York, 1975;
Vol. 3, p 480 ff.
(2) Review: Pestka, S.; Bodley, J . W. In Antibiotics; Corcoran, J .
W., Hahn, F. E., Eds.; Springer-Verlag: New York, 1975; Vol. 3, p 531
ff.
(8) Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S. O. In
Organic Syntheses; Freeman, J . P., Ed.; J ohn Wiley & Sons: New York,
NY, 1990; Collect. Vol. VII, p 372 and references cited therein.
(9) Prepared according to: Attenburrow, J .; Cameron, A. F. B.;
Chapman, J . H.; Evans, R. M.; Hems, B. A.; J ansen, A. B. A.; Walker,
T. J . Chem. Soc. 1952, 1094. Other oxidants (PCC, PDC, Swern, TPAP/
NMO) gave poor results.
(3) (a) Rosendahl, G.; Douthwaite, S. Nucleic Acids Res. 1994, 22,
357. (b) Cundliffe, E.; Thompson, J . Eur. J . Biochem. 1981, 118, 47.
(4) (a) Murakami, T.; Holt, T. G.; Thompson, C. T. J . Bacteriol. 1989,
171, 1459. (b) Holmes, D. G.; Caso, J . L.; Thompson, C. T. EMBO J .
1993, 8, 3183.
(5) Yun, B.-S.; Hidaka, T.; Furihata, K.; Seto, H. J . Antibiot. 1994,
47, 510.
(10) Obtained from L-threonine in 97% yield by: (a) COCl2, NaOH
(cf. Xi, N.; Ciufolini, M. A. Tetrahedron Lett. 1995, 36, 6595); (b) MeOH,
cat. H2SO4.
(11) A complex mixture of products was obtained when this reaction
was run under standard conditions (refluxing xylenes, ca. 135 °C).
(12) This material existed as a 1:3 ratio mixture of ketone and one
geometric isomer of the enol form (NMR, probably the Z isomer due
to intramolecular H bonding).
(6) Kelly, T. R.; J agoe, C. T.; Gu, Z. Tetrahedron Lett. 1991, 32, 4263.
S0022-3263(97)00442-8 CCC: $14.00 © 1997 American Chemical Society
Ciufolini, Marco A.
