Synthetic studies of tedanolide, a marine macrolide displaying potent antitumor activity. Stereoselective synthesis of the C(13)-C(23) segment

Article abstract of DOI:10.1021/ol050569a

(Chemical Equation Presented) A highly stereoselective synthesis of the C(13)-C(23) segment of tedanolide (1), an 18-membered macrolide isolated from the Caribbean sponge Tedania ignis, displaying significant cytotoxicity against KB and PS tumor cell line

Full text of DOI:10.1021/ol050569a

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2341-2344
Synthetic Studies of Tedanolide, a
Marine Macrolide Displaying Potent
Antitumor Activity. Stereoselective
Synthesis of the C(13)−C(23) Segment
Yasuhiro Iwata, Keiji Tanino, and Masaaki Miyashita*
DiVision of Chemistry, Graduate School of Science, Hokkaido UniVersity,
Sapporo 060-0810, Japan
miyasita@sci.hokudai.ac.jp
Received March 16, 2005
ABSTRACT
A highly stereoselective synthesis of the C(13)−C(23) segment of tedanolide (1), an 18-membered macrolide isolated from the Caribbean
sponge Tedania ignis, displaying significant cytotoxicity against KB and PS tumor cell lines, is described which involves two stereoselective
epoxidations of regioisomeric trisubstituted double bonds and a stereospecific SN2′ methylation reaction of a trans-γ,δ-epoxy-cis-r,â-unsaturated
ester as the key steps.
Tedanolide (1), a structurally complex 18-membered mac-
rolide, was isolated from the Caribbean sponge Tedania ignis
in 1984,1 which was referred to as “fire sponge” because
contact with the skin induced a localized burning sensation.
Tedanolide (1) has demonstrated potent antitumor activity
as well as cytotoxicity against KB and PS cell lines (ED50
values of 0.25 ng/mL and 16 pg/mL, respectively).1 In 1991,
13-deoxytedanolide (2) was discovered from the Japanese
sponge Mycale adhaerens, and 2 was also revealed to exhibit
strong antitumor activity as well as significant cytotoxicity
against P388 murine leukemia cells.2
so far Smith5a,5b and very recently Roush8a have reported
successful total syntheses of 13-deoxytedanolide (2). How-
ever, the synthesis of tedanolide (1) has been impeded owing
(3) (a) Katsuya, M.; Zheng, B.-Z.; Kusaka, S.-I.; Kuroda, M.; Yoshimoto,
K.; Yamada, H.; Yonemitsu, O. Eur. J. Org. Chem. 2001, 3615. (b) Zheng,
B.-Z.; Yamauchi, M.; Dei, H.; Kusaka, S.-I.; Matsui, K.; Yonemitsu, O.
Tetrahedron Lett. 2000, 41, 6441. (c) Matsushima, T.; Nakajima, N.; Zheng,
B.-Z.; Yonemitsu, O. Chem. Pharm. Bull. 2000, 48, 855. (d) Zheng, B.-Z.;
Maeda, H.; Mori, M.; Kusaka, S.-I.; Yonemitsu, O.; Matsushima, T.;
Nakajima, N.; Uenishi, J.-I. Chem. Pharm. Bull. 1999, 47, 1288. (e)
Matsushima, T.; Zheng, B.-Z.; Maeda, H.; Nakajima, N.; Uenishi, J.-I.;
Yonemitsu, O. Synlett 1999, 780. (f) Matsushima, T.; Mori, M.; Zheng,
B.-Z.; Maeda, H.; Nakajima, N.; Uenishi, J.-I.; Yonemitsu, O. Chem. Pharm.
Bull. 1999, 47, 308. (g) Matsushima, T.; Mori, M.; Nakajima, N.; Maeda,
H.; Uenishi, J.-I.; Yonemitsu, O. Chem. Pharm. Bull. 1998, 46, 1335. (h)
Matsushima, T.; Horita, K.; Nakajima, N.; Yonemitsu, O. Tetrahedron Lett.
1996, 37, 385.
(4) (a) Taylor, R. E.; Hearn, B. R.; Ciavarri, J. P. Org. Lett. 2002, 4,
2953. (b) Taylor, R. E.; Ciavarri, J. P.; Hearn, B. R. Tetrahedron Lett. 1998,
39, 9361. For the synthesis of the myriaporones, a related class of natural
products, see: Fleming, K. N.; Taylor, R. E. Angew. Chem., Int. Ed. 2004,
43, 1728.
(5) (a) Smith, A. B.; Adams, C. M.; Barbosa, S. A. L.; Degnan, A. P.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12042. (b) Smith, A. B.; Adams,
C. M.; Barbosa, S. A. L.; Degnan, A. P. J. Am. Chem. Soc. 2003, 125, 350.
(c) Smith, A. B.; Lodise, S. A. Org. Lett. 1999, 1, 1249.
These distinctive biological properties, combined with
complex stereostructures, make the tedanolide macrolides
extremely attractive targets for synthetic chemists,3-10 and
(1) Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.; Hossain, M. B.;
van der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251.
(2) (a) Nishimura, S.; Matsunaga, S.; Yoshida, M.; Hirota, H.; Yokoyama,
S.; Fusetani, N. Bioorg. Med. Chem. 2005, 449. (b) Nishimura, S.;
Matsunaga, S.; Yoshida, M.; Nakao, Y.; Hirota, H.; Fusetani, N. Bioorg.
Med. Chem. 2005, 455. (c) Fusetani, N.; Sugawara, T.; Matsunaga, S.;
Hirota, H. J. Org. Chem. 1991, 56, 4971.
10.1021/ol050569a CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/13/2005

to its densely functionalized complex stereostructure, despite
great synthetic efforts.
We set about synthetic studies of tedanolide (1) that aimed
at developing an efficient synthetic route flexible enough to
provide access to the tedanolide macrolides. Our retrosyn-
thesis of tedanolide (1) is shown in Scheme 1.
stereoselective synthesis of the C(13)-C(23) segment 3
having seven contiguous asymmetric carbon centers. The
strategy is highlighted by two stereoselective epoxidation
reactions of trisubstituted olefins and a stereospecific SN2′
methylation reaction of a trans-γ,δ-epoxy-cis-R,â-unsat-
urated ester11 as the key steps.
At first, the C(13)-C(21) polypropionate chain containing
five stereogenic centers and a trans-trisubstituted double bond
was elaborated according to Scheme 2. Thus, reduction of
ester 512 with DIBAH in THF furnished the allyl alcohol in
95% yield, which was then subjected to the Katsuki-
Sharpless asymmetric epoxidation13 resulting in the formation
of the â-epoxy alcohol 6 (R/â ) 5: 95) in 96% yield.
Treatment of 6 with vinylmagnesium chloride and copper(I)
bromide-dimethyl sulfide complex14 in ether at 0 °C
provided 7 stereoselectively. Interestingly, vinylmagnesium
chloride was found to be much more effective than vinyl-
magnesium bromide in this substitution reaction. Protection
of the resulting 1,3-diol as the acetonide followed by
oxidative cleavage of the vinyl group using standard condi-
tions furnished aldehyde 8 in 68% overall yield from 6.
Aldehyde 8 was then converted to the trisubstituted allyl
alcohol 9 by a Wittig reaction with Ph3PdC(CH3)CO2Et in
toluene followed by reduction of the ester with DIBAH in
THF (97% yield for the two steps). Epoxidation of 9 with
m-CPBA in CH2Cl2 at 0 °C gave the expected R-epoxy
alcohol 10 with remarkably high stereoselectivity (R/â )
98:2) in 92% yield.
Scheme 1. Retrosynthesis of Tedanolide (1)
In turn, to introduce an R secondary methyl group at the
C(20) position stereoselectively, we envisaged the use of the
stereospecific SN2′ methylation reaction of γ,δ-epoxy-R,â-
unsaturated esters recently developed in our laboratory.11 For
this purpose, the requisite cis-R,â-unsaturated ester 11 was
synthesized by a two-step reaction sequence: (1) oxidation
of the primary alcohol 10 with Dess-Martin periodinane15
to the aldehyde and (2) Horner-Wadsworth-Emmons reac-
Namely, 1 was divided into the C(13)-C(23) segment 3
and the C(1)-C(12) segment 4, and both segments were
designed to connect by an aldol reaction at the C(12) and
C(13) positions under Felkin-Anh control. We also designed
a synthetic route for the C(13)-C(23) segment 3 starting
from a chiral unsaturated ester 5. We report herein the
Scheme 2. Stereoselective Synthesis of the C(13)-C(21) Polypropionate Chain
2342
Org. Lett., Vol. 7, No. 12, 2005

Scheme 3. Stereoselective Synthesis of C(13)-C(23) Segment
tion with the Ando reagent (o-CH3C6H4O)2P(O)CH2CO2Et16
methyl group newly introduced at the C(20) position20 as
well as the stereochemistry of the previous trisubstituted
epoxide 10.
and KHMDS in THF at -78 °C (81% yield for the two
steps). The key SN2′ methylation reaction of 11 with
Me2Zn-CuCN reagent stereospecifically occurred in DMF,
as we expected, giving rise to 12 as a single product in 74%
yield.
It should be pointed out that other organocopper reagents,
e.g., the Gilmann reagent17 and Knochel’s conditions,18 were
totally ineffective in this particular reaction. To confirm the
stereochemistry of the product at this stage, 12 was trans-
formed into acetonide 13 by the following reaction se-
quence: (1) removal of the acetonide in 12 by aq AcOH;
(2) protection of the primary alcohol with TBSCl; (3)
formation of isopropylidene acetal on the anti-1,3-diol moiety
(54% for the three steps). As the acetal carbon in 13 appeared
at δ 100.5 ppm in its 13C NMR spectrum, the stereo-
chemistry of the anti-1,3-diol was unequivocally con-
firmed.19 This also proved the configuration of the secondary
With the synthesis of the C(13)-C(21) polypropionate
chain in hand, we focused on the conversion of 12 into the
C(13)-C(23) segment 3 (Scheme 3). Namely, protection of
the secondary hydroxyl group in 12 with TBSCl followed
by reduction of the ester with DIBAH in THF produced the
primary alcohol 14 in 89% yield. At this stage, the requisite
terminal (Z)-olefin was installed by oxidation of alcohol 14
with Dess-Martin periodinane15 followed by a Wittig
reaction of the resulting aldehyde with Ph3PCH2CH3Br and
KHMDS in THF (75% yield for the two steps). Removal of
the MPM group in 15 with DDQ in CH2Cl2 and subsequent
removal of the TBS group with TBAF furnished diol 16 in
98% yield. The crucial epoxidation of the allyl alcohol with
m-CPBA occurred stereoselectively by the neighboring
participation of the hydroxyl group, as we expected,
giving rise to the R-epoxide 17 (R/â ) 94: 6) in 72% yield.
Finally, protection of two hydroxyl groups in 17 with TESCl
followed by a Swern oxidation according to the Spur
protocol21 afforded the targeted C(13)-C(23) segment 18
in 75% yield.
(6) (a) Jung, M. E.; Lee, C. P. Org. Lett. 2001, 3, 333. (b) Jung, M. E.;
Lee, C. P. Tetrahedron Lett. 2000, 41, 9719. (c) Jung, M. E.; Marquez, R.
Org. Lett. 2000, 2, 1669. (d) Jung, M. E.; Marquez, R. Tetrahedron Lett.
1999, 40, 3129.
(7) (a) Loh, T.-P.; Feng, L.-C.; Tetrahedron Lett. 2001, 42, 6001. (b)
Loh, T.-P.; Feng, L.-C. Tetrahedron Lett. 2001, 42, 3223.
(8) (a) Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc.
2005, 127, 6186. (b) Roush, W. R.; Newcom, J. S. Org. Lett. 2002, 4, 4739.
(c) Roush, W. R.; Lane, G. C. Org. Lett. 1999, 1, 95.
(9) Liu, J.-F.; Abiko, A.; Pei, Z. H.; Buske, D. C.; Masamune, S.
Tetrahedron Lett. 1998, 39, 1873.
(10) (a) Ehrlich, G.; Kalesse, M. Synlett 2005, 655. (b) Hassfeld, J.;
Kalesse, M. Synlett 2002, 2007.
(11) Hirai, A.; Matsui, A.; Komatsu, K.; Tanino, K.; Miyashita, M. Chem.
Commun. 2002, 1970.
(12) Dias, L. C.; Jardim, L. S. A.; Ferreira, A. A.; Soarez, H. U. J. Braz.
Chem. Soc. 2001, 12, 463.
(13) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974.
(14) Tius, M. A.; Fauq, A. H. J. Org. Chem. 1983, 48, 4131.
(15) Dess, P. B.; Martin, J. C. J. Am. Chem. Soc. 1978, 100, 300.
(16) (a) Ando, K.; Tetrahedron Lett. 1995, 36, 4105. (b) Ando, K. J.
Org. Chem. 1997, 62, 1934.
(17) (a) Marshall, J. A.; Blough, B. E. J. Org. Chem. 1990, 55, 1540.
(b) Marshall, J. A.; Trometer, J. D.; Blough, B. E.; Crute, T. D. Tetrahedron
Lett. 1988, 29, 913. (c) Marshall, J. A.; Trometer, J. D.; Blough, B. E.;
Crute, T. D. J. Org. Chem. 1988, 53, 4274.
In summary, we have achieved the straightforward, highly
stereoselective synthesis of the C(13)-C(23) segment of
tedanolide (1) through an original strategy based on acyclic
stereocontrol without use of any aldol methodologies, in
which two stereoselective epoxidations of regioisomeric
trisubstituted double bonds and the stereospecific SN2′
methylation reaction of the trans-γ,δ-epoxy-cis-R,â-unsatu-
rated ester 10 are involved as the key steps. Studies toward
total synthesis of tedanolide (1) are in progress in our
laboratory.
(19) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9.
(20) We unambiguously confirmed the configuration of C(20) by
degradation of compound 14 into (S)-2-methyl-3-(triisopropylsilyl)oxy-1-
propanol followed by conversion into (+)-MTPA ester and its identification
with a chiral authentic sample by NMR analyses.
(18) (a) Soorukram, D.; Knochel, P. Org. Lett. 2004, 6, 2409. (b)
Harrington-Frost, N.; Leuser, H.; Calaza, M. I.; Kneisel, F. F.; Knochel, P.
Org Lett. 2003, 5, 2111.
(21) Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron
Lett. 1999, 40, 5161.
Org. Lett., Vol. 7, No. 12, 2005
2343

Acknowledgment. Financial support from the Ministry
of Education, Culture, Sports, Science and Technology, Japan
(a Grant-in-Aid for Scientific Research (A) (No. 12304042)
and a Grant-in-Aid for Scientific Research (B) (No. 16350049)
is gratefully acknowledged.
Supporting Information Available: Experimental details
and characterization data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL050569A
2344
Org. Lett., Vol. 7, No. 12, 2005