The total synthesis of (+)-tedanolide

Article abstract of DOI:10.1021/ja0659572

The first total synthesis of the (+)-tedanolide is described. Pivotal steps are the Felkin-selective aldol coupling between C12 and C13 and an efficient Mitsunobu macrolactonization. Selective protecting group transformations and subsequent oxidations gen

Full text of DOI:10.1021/ja0659572

Published on Web 10/06/2006
The Total Synthesis of (+)-Tedanolide
Gunnar Ehrlich, Jorma Hassfeld,† Ulrike Eggert, and Markus Kalesse*
Institut fu¨r Organische Chemie, Leibniz UniVersita¨t HannoVer, Schneiderberg 1B, D-30167 HannoVer, Germany
Received August 23, 2006; E-mail: markus.kalesse@oci.uni-hannover.de
Scheme 1
(+)-Tedanolide (1) was isolated from the Caribbean sponge
Tedania ignis by Schmitz and co-workers1 in 1984. In 1991,
Fusetani and co-workers2 reported the isolation of (+)-13-deoxy-
tedanolide (2) from the sponge Mycale adhaerens. These two
closely related polyketides exhibit remarkable cytotoxicity against
P388 murine leukemia cells at pico- to nanomolar ranges, and
Fusetani et al. were able to identify the 60S large ribosomal subunit
as the molecular target of (+)-13-deoxytedanolide (2).3 Recently,
the isolation of a third metabolite, tedanolide C (Scheme 1), was
reported by Ireland et al.4 The challenging structural complexity
of the tedanolides in combination with the promising biological
profile has initiated several synthetic studies5 resulting in a variety
of fragment syntheses as well as fundamental studies. Consequently,
two total syntheses of (+)-13-deoxytedanolide (2) were reported
in 2003 and 2005 by Smith and Roush, respectively.6
Here we report the first total synthesis of (+)-tedanolide (1).
Even though both compounds (+)-tedanolide (1) and (+)-13-
deoxytedanolide (2) differ only in the presence of one hydroxyl
group at carbon 13, the concomitant retro aldol processes and
elimination, due to the 1,3 functional group distance of the hydroxy
ketone, are one major obstacle that requires substantial strategy
changes. Our retro synthetic analysis dissects tedanolide (1) such
that an aldol reaction between C12 and C13 serves as the juncture
between both key fragments 4 and 5 (Scheme 2). One key issue
responsible for the successful synthesis is the choice of the S
configuration at C15. This configuration prevents unfavorable
hemiacetal formation as already analyzed by Roush7 at the
ORCHEM meeting in 2004.
Scheme 2
Our synthesis utilized an aldol coupling between the methyl
ketone 48 and aldehyde 5. The synthesis of aldehyde 5 began with
known ketone 6,9 which can be accessed in large quantities starting
from the Roche ester. Before introducing the acid labile monomethoxy
trityl group (MMTr), the carbonyl group in 6 was reduced
stereoselectively with the aid of DIBAL-H followed by removal
of the TBS group. Protection of the allylic hydroxyl group was
achieved using TBSCl, and treatment with DDQ in the absence of
water produced the corresponding acetal. Reductive acetal opening
with DIBAL-H furnished the PMB-protected secondary alcohol,10
and the liberated primary hydroxyl group was subsequently oxidized
with TPAP/NMO11 to establish aldehyde 5 for the pivotal aldol
coupling (Scheme 3).
Scheme 3
The aldol coupling between ketone 4 and aldehyde 5 gave best
selectivity (7:1) in favor of the Felkin product when KHMDS was
used as the base. As described earlier for a model aldehyde,8 the
selectivity was governed by the methyl ketone and varied depending
on the counterion used with the base. The synthesis continued by
protecting the secondary alcohol as the TBS ether. This step induced
a retro aldol reaction, which is responsible for the low yield
observed in this transformation. Next, the MMTr group was
removed with hexafluoroisopropanol and MeOH in order to trap
the liberated MMTr cation.12 The subsequent ester cleavage was
achieved in quantitative yield with Pd(PPh3)2Cl2 and Bu3SnH. The
elegant use of the allyl protecting group for the carboxylate was
also presented in the synthesis of (+)-13-deoxytedanolide (2) by
† Present address: Schering AG, Mu¨llerstr. 178, D-13342 Berlin, Germany.
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10.1021/ja0659572 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
In summary, the first total synthesis of (+)-tedanolide has been
achieved through a convergent route using an aldol reaction, a
Mitsunobu lactonization, and a final step epoxidation.
Acknowledgment. This work was supported by the DFG (KA
913/9-1, KA 913/9-2). The authors thank Myriam Roy (Taylor
group, University of Notre Dame) for helpful discussions.
Supporting Information Available: Spectroscopic and analytical
data for compounds 1, 10, and 11, and selected experimental procedures
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.; Hossain, M. B.; van
der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251.
(2) Fusetani, N.; Sugawara, T.; Matsunaga, S.; Hirota, H. J. Org. Chem. 1991,
56, 4971.
(3) (a) Nishimura, S.; Matsunaga, S.; Yoshida, M.; Hirota, H.; Yokoyama,
S.; Fusetani, N. Bioorg. Med. Chem. 2005, 13, 449. (b) Nishimura, S.;
Matsunaga, S.; Yoshida, M.; Nakao, Y.; Hirota, H.; Fusetani, N. Bioorg.
Med. Chem. 2005, 13, 455.
(4) Chevallier, C.; Bugni, T. S.; Feng, X.; Harper, M. K.; Orendt, A. M.;
Ireland, C. M. J. Org. Chem. 2006, 71, 2510.
(5) (a) Matsushima, T.; Horita, K.; Nakajima, N.; Yonemitsu, O. Tetrahedron
Lett. 1996, 37, 385. (b) Matsushima, T.; Mori, M.; Nakajima, N.; Maeda,
H.; Uenishi, J.; Yonemitsu, O. Chem. Pharm. Bull. 1998, 46, 1335. (c)
Liu, J.-F.; Abiko, A.; Pei, Z.; Buske, D. C.; Masamune, S. Tetrahedron
Lett. 1998, 39, 1873. (d) Taylor, R. E.; Ciavarri, J. P.; Hearn, B. R.
Tetrahedron Lett. 1998, 39, 9361. (e) Roush, W. R.; Lane, G. C. Org.
Lett. 1999, 1, 95. (f) Matsushima, T.; Mori, M.; Zheng, B.-Z.; Maeda,
H.; Nakajima, N.; Uenishi, J.; Yonemitsu, O. Chem. Pharm. Bull. 1999,
47, 308. (g) Jung, M. E.; Karama, U.; Marquez, R. J. Org. Chem. 1999,
64, 663. (h) Matsushima, T.; Zheng, B.-Z.; Maeda, H.; Nakajima, N.;
Uenishi, J.; Yonemitsu, O. Synlett 1999, 780. (i) Smith, A. B., III; Lodise,
S. A. Org. Lett. 1999, 1, 1249. (j) Zheng, B.-Z.; Maeda, H.; Mori, M.;
Kusaka, S.-i.; Yonemitsu, O.; Matsushima, T.; Nakajima, N.; Uenishi, J.
Chem. Pharm. Bull. 1999, 47, 1288. (k) Jung, M. E.; Marquez, R.
Tetrahedron Lett. 1999, 40, 3129. (l) Matsushima, T.; Nakajima, N.;
Zheng, B.-Z.; Yonemitsu, O. Chem. Pharm. Bull. 2000, 48, 855. (m)
Zheng, B.-Z.; Yamauchi, M.; Dei, H.; Kusaka, S.-i.; Matsui, K.;
Yonemitsu, O. Tetrahedron Lett. 2000, 41, 6441. (n) Zheng, B.-Z.;
Yamauchi, H.; Dei, H.; Yonemitsu, O. Chem. Pharm. Bull. 2000, 48, 1761.
(o) Jung, M. E.; Marquez, R. Org. Lett. 2000, 2, 1669. (p) Jung, M. E.;
Lee, C. P. Org. Lett. 2001, 3, 333. (q) Loh, T.-P.; Feng, L.-C.; Tetrahedron
Lett. 2001, 42, 6001. (r) Loh, T.-P.; Feng, L.-C. Tetrahedron Lett. 2001,
42, 3223. (s) Matsui, K.; Zheng, B.-Z.; Kusaka, S.-i.; Kuroda, M.;
Yoshimoto, K.; Yamada, H.; Yonemitsu, O. Eur. J. Org. Chem. 2001,
3615. (t) Hearn, B. R.; Ciavarri, J. P.; Taylor, R. E. Org. Lett. 2002, 4,
2953. (u) Wong, C.-M.; Loh, T.-P. Tetrahedron Lett. 2006, 47, 4485.
(6) (a) Smith, A. B., III; Adams, C. M.; Barbosa, S. A. L.; Degnan, P. J. Am.
Chem. Soc. 2003, 125, 350. (b) Smith, A. B., III; Adams, C. M.; Barbosa,
S. A. L.; Degnan, P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12042. (c)
Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc. 2005, 127,
6186.
Roush.6c,7 For the subsequent macrolactonization, best yields were
observed when seco-acid 9 was subjected to the Mitsunobu
protocol13 directly after Pd-catalyzed deprotection of the allyl ester.
Other lactonizations, such as the Keck-Boden protocol14 or the
Yamaguchi esterification,15 did not generate comparable yields.
To establish the remaining two ketones, the PMB group was
removed with DDQ followed by Dess-Martin oxidation.16 These
two transformations could only be performed with moderate yields.
Next, the TES group was selectively deprotected with PPTS17 in
the presence of four TBS ethers, and again a Dess-Martin oxidation
provided triketone 11 (Scheme 4). The last steps to be accomplished
were the global TBS deprotection and the critical final step
epoxidation. Thorough experimentation using combinations of
fluoride and proton sources revealed the combination of HF-Et3N
to be the superior combination for the TBS deprotection, as
described by Roush.6c Under these conditions, the deprotection of
four silyl ethers only proceeded sluggishly to half-conversion after
4 days. By separation of the partial deprotected material through
column chromatography and re-subjecting to the deprotection
conditions, full conversion was achieved. Finally, the last step
epoxidation remained to be accomplished. Since Smith and co-
workers6a had shown that a late-stage epoxidation of (+)-13-
deoxytedanolide (2), with the C7 hydroxyl protected, occurs with
the desired face selectivity, we were encouraged to take on this
transformation as the final step. Additionally, Taylor and co-workers
reported on the epoxidation of myriaporone, a related natural
product.18 Following their experimental procedure, using mCPBA
(-40 °C, 2 days) gave clean conversion of the C18-C19 double
bond to the monoepoxide and traces of the diepoxide. The
spectroscopic data (1H NMR, 13C NMR, HRMS, optical rotation)
were in all respect identical to the data originally reported by
Schmitz and co-workers.1
(7) Julian, L. D. Studies toward the total synthesis of the tedanolides: Total
synthesis of 13-deoxytedanolide; Ph.D. Thesis, University of Michigan,
2005.
(8) Kalesse, M.; Hassfeld, J.; Eggert, U. Synthesis 2005, 1183.
(9) Ehrlich, G.; Kalesse, M. Synlett 2005, 655.
(10) Pilli, R. A.; de Andrade, C. K. Z.; Souto, C. R. O.; de Meijere, A. J. Org.
Chem. 1998, 63, 7811.
(11) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(12) Leonard, N. J.; Neelima. Tetrahedron Lett. 1995, 36, 7833.
(13) Mitsunobu, O. Synthesis 1981, 1.
(14) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989.
(15) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394.
(16) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(17) Pakrash, C.; Saleh, S.; Blair, I. A. Tetrahedron Lett. 1989, 30, 19.
(18) Fleming, K. N.; Taylor, R. E. Angew. Chem.. 2004, 116, 1760; Angew.
Chem., Int. Ed. 2004, 43, 1728.
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