DOI: 10.1002/chem.201601275
Communication
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Total Synthesis |Hot Paper|
Total Synthesis of (Æ)-Integrifolin
Katsuya Shimomaki,[a] Hiroyuki Kusama,[a, b] and Nobuharu Iwasawa*[a]
methylamide 3[7] in the synthesis of (Æ)-dehydrocostus lactone
(Scheme 1A);[6a] however, the yield of this transformation was
low because of facile ring-opening of the lactone ring through
enolization of the C-4 ketone moiety. Lei’s group utilized ring-
opening of the epoxide moiety with aluminum isopropoxide in
Abstract: The total synthesis of (Æ)-integrifolin has been
achieved for the first time through the stereoselective
preparation of the bicyclo[5.3.0]decane skeleton based on
the tungsten-catalyzed cyclization of acyclic trienynes
under photoirradiation conditions. Further key transforma-
tions of the cyclized product are the Tamao oxidation
through cyclic silyl ether, the introduction of two oxygen
functionalities by the oxidation of the diene and the con-
struction of three exo-methylene moieties.
Integrifolin 1 is a guaianolide isolated as a major constituent of
Andryala integrifolia, found in Mediterranean Europe by the re-
search group of Vergara in 1984 (Figure 1).[1,2] Integrifolin has
a significant inhibitory effect on the proliferation of cultured
human cancer cell lines[3] as well as a characteristic structure
with three exo-methylene moieties and six asymmetric centers
on the bicyclo[5.3.0]decane skeleton.
Scheme 1. Synthesis of guaianolides containing three exo-methylene moiet-
ies.
toluene under microwave conditions in the synthesis of 3-epi-
zaluzanin C; however, the conversion efficiency was rather low
(Scheme 1B).[6d] Thus, it is essential for the success of the total
synthesis of integrifolin to introduce the three exo-methylene
moieties efficiently in an appropriate order, along with stereo-
selective construction of the carbon skeleton containing ap-
propriate functionalities.
Figure 1. Guaianolide skeleton and integrifolin 1.
The exo-methylene moieties in guaianolides present several
difficulties in their synthesis due to the high reactivity of a-
methylene lactones as a Michael acceptor[4] and also to facile
isomerization of the double bond under acidic or basic condi-
tions.[5,6a] In fact, the syntheses of guaianolides containing
three exo-methylenes such as integrifolin have rarely been re-
ported.[6] Rigby’s group reported the methylenation of dike-
tone 2 at C-4 and C-10 with (lithiomethyl)phosphinothionic di-
As a useful method for stereoselective synthesis of bicy-
clo[5.3.0]decane derivatives 5,[8] we already reported the tung-
sten-catalyzed cyclization of acyclic trienynes 4 under photoir-
radiation conditions (Scheme 2).[9] It is expected that by utiliz-
ing the stereospecific nature of this cyclization, bicyclo[5.3.0]-
decane derivatives bearing desired stereochemistry would be
synthesized selectively by choosing an appropriate geometrical
isomer of the siloxydiene and enyne moieties.
[a] K. Shimomaki, Prof. Dr. H. Kusama, Prof. Dr. N. Iwasawa
Department of Chemistry, Tokyo Institute of Technology
2-12-1, O-okayama, Meguro-ku, Tokyo, 152-8851 (Japan)
[b] Prof. Dr. H. Kusama
Present address: Department of Chemistry, Faculty of Science
Gakushuin University, 1-5-1, Mejiro, Toshima-ku, Tokyo, 171-8588 (Japan)
Supporting Information for this article (including synthetic procedures and
characterization of the compounds) can be found under
Scheme 2. Tungsten-catalyzed cyclization of acyclic trienynes.
Chem. Eur. J. 2016, 22, 1 – 6
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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