K. Tatsuta et al. / Tetrahedron Letters 53 (2012) 422–425
425
TMSO
TBSO
SMe OMe
6
Toyama Prefectural University for providing hibarimicinone and
its NMR spectra. Authors are grateful for the financial support
to GCOE program ‘Center for Practical Chemical Wisdom’, and
The Ministry of Education, Culture, Sports, Science and Technol-
ogy (MEXT).
Me
H
TMSO
OMe
MOMO
7
8
H
O
O
OTMS
17'
15'
OTBS
TBSO
TMSO
15
17
O
O
OMOM
MeO
7'
H
8'
OTBS
OTMS
6'
OTMS
H
Me
MeO
OnBu
Supplementary data
SMe
22
HMBC
The spectrum data of compounds 5–11, 14, 15, 17, 18, 180, 19,
20, 22, 24, 27, and 1, 1H NMR spectrum of synthetic hibarimici-
none (400 MHz in CD3OD), 13C NMR spectrum of synthetic hiba-
rimicinone (150 MHz in CD3OD) and the CD spectrum of
synthetic hibarimicinone. Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
Figure 3. HMBC of the octacyclic 22.
Therefore, bisthiolactone 20 was treated with base in the mixed sol-
vent including THF, toluene, and pyridine to promote double Mi-
chael–Dieckmann type cyclization to give eight rings, and the
resulting thiolates were methylated to provide compounds 21 and
22. The labile trione 21, the keto form in G ring, was smoothly con-
verted into the enol form 22 in the presence of LiCl. Formation of
the octacycllic skeleton was confirmed by HMBC with 22 (Fig. 3).
Hydrolysis of semithioacetal was performed with AgNO3, and the
subsequent treatment with DBU gave the hydroquinone at the C ring
of 23. Oxidation of the C ring and aromatization of F ring, including
elimination of thioether and tautomerization, were attained with
Ag2CO3 and MeI to afford 24 in one pot. The ether acrossing AB rings
formed with excess amounts of LiI by enolization at BC rings and
conjugate addition to the resulting enone 25. The simultaneous
de-O-methoxymethylation gave free phenols (rings D and E) in 26.
The resulting 26 was immediately oxidized to quinone 27. The cor-
relation between H8’ and C130 in 27 made sure the transannular
ether formation. Finally, de-O-silylation as well as de-O-methyla-
tion and tautomerization at CD rings were achieved by treatment
of 27 under the acidic conditions to give hibarimicinone (1). The
spectral data of the synthetic 1 including the 1H NMR and the CD
spectra were identical with those of the natural hibarimicinone.
In conclusion, we have achieved the total synthesis of hibarim-
icinone (1). The synthesis features the chemistry of a chiral biaryl
thiolactone including double Michael–Dieckmann type cyclization
and aromatization. The ether acrossing AB rings in 26 was formed
via enolization and conjugate addition in BC rings of 24. Removal
of protective groups and tautomerization under the acidic condi-
tions gave hibarimicinone (1).
References and notes
1. Hibarimicins: (a) Hori, H.; Kajiura, T.; Igarashi, Y.; Furumai, T.; Higashi, K.;
Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55, 46–52; (b)
Kajiura, T.; Furumai, T.; Igarashi, Y.; Hori, H.; Higashi, K.; Ishiyama, T.; Uramoto,
M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55, 53–60; (c) Igarashi, Y.; Kajiura, T.;
Furumai, T.; Hori, H.; Higashi, K.; Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J.
Antibiot. 2002, 55, 61–70; (d) Kajiura, T.; Furumai, T.; Igarashi, Y.; Hori, H.;
Higashi, K.; Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 1998, 51,
394–401; (e) Hori, H.; Igarashi, Y.; Kajiura, T.; Furumai, T.; Higashi, K.; Ishiyama,
T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 1998, 51, 402–417; (f) Hori, H.;
Higashi, K.; Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. Tetrahedron Lett. 1996,
37, 2785–2788; (g) Uehara, Y.; Li, P.; Fukazawa, H.; Mizuno, S.; Nihei, Y.; Nishio,
M.; Hanada, M.; Yamamoto, C.; Furumai, T.; Oki, T. J. Antibiot. 1993, 46, 1306–
1308.
2. Cho, S. I.; Fukazawa, H.; Honma, Y.; Kajiura, T.; Hori, H.; Igarashi, Y.; Furumai, T.;
Oki, T.; Uehara, Y. J. Antibiot. 2002, 55, 270–278.
3. (a) Hori, H.; Igarashi, Y.; Kajiura, T.; Sato, S.; Furumai, T.; Higashi, K.; Ishiyama,
T.; Uehara, Y.; Oki, T. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 2004, 46,
49–54; For the discussion on hibarimicin atropisomers: (b) Romaine, I. M.;
Hempel, J. E.; Shanmugam, G.; Hori, H.; Igarashi, Y.; Polavarapu, P. L.; Sulikowski,
G. A. Org. Lett. 2011, 13, 4538–4541.
4. Recent application of this method to the total synthesis of natural products: (a)
Tatsuta, K.; Tokishita, S.; Fukuda, T.; Kano, T.; Komiya, T.; Hosokawa, S.
Tetrahedron Lett. 2011, 52, 983–986; (b) Tatsuta, K.; Tanaka, H.; Tsukagoshi, H.;
Kashima, T.; Hosokawa, S. Tetrahedron Lett. 2010, 51, 5546–5549; For a review: (c)
Mal, D.; Pahari, P. Chem. Rev. 2007, 107, 1892–1918; Precedent examples of
Hauser annulation with thiophthalides shows low to moderate yields: (d) Mal, D.;
Pal, R.; Murty, K. V. S. N. J. Chem. Soc. Commun. 1992, 821–822; (e) Majumdar, G.;
Pal, R.; Murty, K. V. S. N.; Mal, D. J. Chem. Soc., Perkin Trans. 1 1994, 309–316; (f)
Mal, D.; Majumdar, G.; Pal, R. J. Chem. Soc., Perkin Trans. 1 1994, 1115–1116.
5. Tatsuta, K.; Takahashi, M.; Tanaka, N. J. Antibiot. 2000, 53, 88–91.
6. Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135–1138.
7. Crystallographic data (excluding structure factors) for the structures of 19 have
been deposited with the Cambridge Crystallographic Data Center as
supplementary publication numbers CCDC 843601 for 19.
Acknowledgments
Authors thank Professor Hiroshi Hori in Tamagawa University,
Professor Yasuhiro Igarashi and Professor Tamotsu Furumai in
Tatsuta, Kuniaki
