K. Ohata, S. Terashima / Bioorg. Med. Chem. Lett. 17 (2007) 4070–4074
4073
2003, 47, 297; (b) Jones, S. M.; Urch, J. E.; Brun, R.;
Harwood, J. L.; Berry, C.; Gilbert, I. H. Bioorg. Med.
Chem. 2004, 12, 683.
until the number of carbon atoms reaches five and to
slightly decrease when it exceeds five. This tendency
was most apparent for ent-4a–f. In addition, it was
found that, as the C5-vinyl side chain becomes longer,
the absolute configuration renders less effect on type I
FAS inhibitory activity (see the cases for R1 = n-Pr, n-
Bu, and n-Hex).
5. (a) Jackowski, S.; Murphy, C. M.; Cronan, J. E.; Rock, C.
O. J. Biol. Chem. 1989, 264, 7624; (b) Price, A. C.; Choi,
K-H.; Heath, R. J.; Li, Z.; White, S. W.; Rock, C. O.
J. Biol. Chem. 2001, 276, 6551.
6. (a) Hayashi, T.; Yamamoto, O.; Sasaki, H.; Kawaguchi,
A.; Okazaki, H. Biochem. Biophys. Res. Commun. 1983,
115, 1108; (b) Nishida, I.; Kawaguchi, A.; Yamada, M.
J. Biochem. (Tokyo) 1986, 99, 1447.
In conclusion, we have succeeded in synthesizing twelve
enantiomeric pairs of 5-vinyl TLM congeners (3a–f, ent-
3a–f, 4a–f, and ent-4a–f) using our efficient synthetic
route previously explored for the total synthesis of
TLM (1), 3-demethyl TLM (2), and their enantiomers
(ent-1 and ent-2).10 Among them, (S)-3-demethyl-5-
(pent-1-enyl) TLM [(S)-4-hydroxy-5-methyl-5-(pent-1-
enyl)-5H-thiophen-2-one] (ent-4d) was found to exhibit
inhibitory activity against mammalian type I FAS equal
to that of C75, the potent inhibitor so far reported.7,11
From the studies on biological activity carried out using
optically active TLM and its congeners, it appeared evi-
dent that in vitro antibacterial and mammalian type I
FAS inhibitory activity can be cleanly separated by
changing not only the structure but also the absolute
configuration of the side chain at the C5-position of 1
and its congeners. Studies aiming at further exploring
the characteristic features of biological activity for
TLM are in progress.
7. McFadden, J. M.; Medghalchi, S. M.; Thupari, J. N.;
Pinn, M. L.; Vadlamudi, A.; Miller, K. I.; Kuhajda, F. P.;
Townsend, C. A. J. Med. Chem. 2005, 48, 946.
8. (a) Sakya, S. M.; Suarez-Contreras, M.; Dirlam, J. P.;
O’Connell, T. N.; Hayashi, S. F.; Santoro, S. L.; Kam-
icker, B. J.; George, D. M.; Ziegler, C. B. Bioorg. Med.
Chem. Lett. 2001, 11, 2751; (b) Senior, S. J.; Illarionov, P.
A.; Gurcha, S. S.; Campbell, I. B.; Schaeffer, M. L.;
Minnikin, D. E.; Besra, G. S. Bioorg. Med. Chem. Lett.
2003, 13, 3685; (c) Senior, S. J.; Illarionov, P. A.; Gurcha,
S. S.; Campbell, I. B.; Schaeffer, M. L.; Minnikin, D. E.;
Besra, G. S. Bioorg. Med. Chem. Lett. 2004, 14, 373; (d)
Kamal, A.; Shaik, A. A.; Sinha, R.; Yadav, J. S.; Arora, S.
K. Bioorg. Med. Chem. Lett. 2005, 15, 1927; (e) Jones, S.
M.; Urch, J. E.; Kaiser, M.; Brun, R.; Harwood, J. L.;
Berry, C.; Gilbert, I. H. J. Med. Chem. 2005, 48, 5932.
9. For the total synthesis of optically active thiolactomycin
so far reported, See (a) Chambers, M. S.; Thomas, E. J.
J. Chem. Soc. Chem. Commun. 1989, 23; (b) Chambers, M.
S.; Thomas, E. J. J. Chem. Soc. Perkin Trans. 1 1997, 417;
(c) McFadden, J. M.; Frehywot, G. L.; Townsend, C. A.
Org. Lett. 2002, 4, 3859; (d) Totama, K.; Tanchi, T.;
Mase, N.; Yoda, H.; Takabe, K. Tetrahedron Lett. 2006,
47, 7163; (e) Kamal, A.; Shark, A.; Azeecla, S.; Malik, M/
S.; Sandbhor, M. Tertrahedron Assymm. 2006, 17, 2890; (f)
Darmann, K. L.; Bruckner, R. Angew. Chem. Int. Ed.
2007, 46, 1160.
10. Ohata, K.; Terashima, S. Tetrahedron Lett. 2006, 47, 2787.
11. Kuhajda, F. P.; Pizer, E. S.; Li, J. N.; Mani, S.; Frehywot,
G. L.; Townsend, C. A. Proc. Natl. Acad. Sci. U.S.A.
2000, 97, 3450.
12. Being different from the previous case in which (R)-N-
acyloxazolidin-2-one derived from (R)-4-benzyloxazolidin-
2-one provided (R)-a-sulfenylated product by way of the
non-chelated (E)-trienolate (I),10 asymmetric deconjugative
a-sulfenylation of (S)-N-acyloxazolidin-2-one 6a–f pre-
pared from (S)-4-benzyloxazolidin-2-one gave (R)-sulfeny-
lated products 7a–f. The latter reaction carried out in the
absence of HMPA was anticipated to proceed through the
chelated (E)-dienolate (II) due to the absence of HMPA.
Acknowledgments
We are grateful to Dr. T. Ishizaki of Kyorin Pharmaceu-
tical Co., Ltd., for extensive support and Dr. Y. Fukuda
of Kyorin Pharmaceutical Co., Ltd., for valuable sugges-
tions and discussions. In vitro antibacterial and mamma-
lian type I FAS inhibitory activity assay were carried out
by Dr. M. Takei and Ms. H. Gomori, and by Dr. T. Ide
and Dr. M. Tsunoda, Kyorin Pharmaceutical Co. Ltd.,
respectively, to whom the authors’ thanks are due.
References and notes
1. Oishi, H.; Noto, T.; Sasaki, H.; Suzuki, K.; Hayashi, T.;
Okazaki, H.; Ando, K.; Sawada, M. J. Antibiot. 1982, 35,
391.
2. (a) Noto, T.; Miyakawa, S.; Oishi, H.; Endo, H.; Okazaki,
H. J. Antibiot. 1982, 35, 401; (b) Miyakawa, S.; Suzuki,
K.; Noto, T.; Harada, Y.; Okazaki, H. J. Antibiot. 1982,
35, 411.
3. (a) Kremer, L.; Douglas, J. D.; Baulard, A. R.; More-
house, C.; Guy, M. R.; Alland, D.; Dover, L. G.; Lakey, J.
H.; Jacobs, W. R.; Brennan, P. J.; Minnikin, D. E.; Besra,
G. S. J. Biol. Chem. 2000, 275, 16857; (b) Slayden, R. A.;
Lee, R. E.; Armour, J. W.; Cooper, A. M.; Orme, I. M.;
Brennan, P. J.; Besra, G. S. Antimicrob. Agents Chemo-
ther. 1996, 40, 2813; (c) Kim, P.; Zhang, Y-M.; Shenoy,
G.; Nguyen, Q-A.; Boshoff, H. I.; Manjunatha, U. H.;
Goodwin, M. B.; Lonsdale, J.; Price, A. C.; Miller, D. J.;
Duncan, K.; White, S. W.; Rock, C. O.; Barry, C. E., III;
Dowd, C. S. J. Med. Chem. 2006, 49, 159.
O
O
Ph
R1
Ph
O
K
O
N
N
O
O
S
S
MeSO2
R
MeSO2
R
II
I
13. The absolute stereochemistry of 7a–f was rigorously
assigned to have (R)-configuration by preliminary synthe-
1
sis of known (S)-3b9b from ent-7b as well as the H NMR
spectra of 7a and 7c–f similar to that of 7b. Based on these
preliminary results, (S)-4-benzyloxazolidin-2-one was
employed as a chiral auxiliary for preparing 3 and 4
instead of its (R)-enantiomer.
4. (a) Waller, R. F.; Ralph, S. A.; Reed, M. B.; Su, V.;
Douglas, J. D.; Minnikin, D. E.; Cowman, A. F.; Besra,
G. S.; McFadden, G. I. Antimicrob. Agents Chemother.