Synthesis of tedanolide and 13-deoxytedanolide. Assembly of a common C(1)-C(11) subtarget

Article abstract of DOI:10.1021/ol9909233

(matrix presented) In this Letter we describe a synthetic strategy and an efficient assembly of a common C(1)-C(11) subtarget, (-)-3, for (+)-tedanolide (1) and (+)-13-deoxytedanolide (2), architecturally complex marine macrolides displaying potent antitu

Full text of DOI:10.1021/ol9909233

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1249-1252
Synthesis of Tedanolide and
13-Deoxytedanolide. Assembly of a
Common C(1)−C(11) Subtarget
Amos B. Smith, III,* and Stephanie A. Lodise
Department of Chemistry, Laboratory for Research on the Structure of Matter, and
Monell Chemical Senses Center, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received August 9, 1999
ABSTRACT
In this Letter we describe a synthetic strategy and an efficient assembly of a common C(1)−C(11) subtarget, (−)-3, for (+)-tedanolide (1) and
(+)-13-deoxytedanolide (2), architecturally complex marine macrolides displaying potent antitumor activity. Key elements of the synthesis
include two iterations of the Evans aldol protocol to construct the C(1)−C(6) moiety and a stereocontrolled vinyl anion addition to generate
the C(8,9) trisubstituted olefin incorporating stereogenicity at C(7). Alkylation with a model epoxide demonstrates that (−)-3 is a competent
dithiane for further elaboration of the macrolide skeleton.
In 1984 Schmitz and co-workers1 isolated (+)-tedanolide (1),
a structurally complex 18-membered macrolide, from Teda-
nia ignis, a prevalent Caribbean sponge commonly referred
to as “fire sponge” due to the sensation induced upon human
contact.2,3 The relative and absolute stereochemistry of 1 was
determined by X-ray diffraction, exploiting the anomalous
dispersion of oxygen.1 More recently (1991), Fusetani and
co-workers4 disclosed the isolation and structural elucidation
of the 13-deoxy congener (2) from the Japanese sponge
Mycale adhaerens.
respectively)1 and in vivo antitumor activity, increasing the
lifespan of mice implanted with lymphocytic leukemia cells
(23% at 1.56 µg/kg).5 Deoxytedanolide (2) also displays
significant antineoplastic activity (P388: T/C, 189%; 0.125
mg/kg).4
Tedanolide and deoxytedanolide represent unusual mac-
rolides in that lactonization occurs at a primary hydroxyl
instead of the customary secondary hydroxyl;6 equally
intriguing is the high level of oxygen functionality. Not
surprisingly, this combination of structural complexity and
antitumor activity has engendered considerable interest on
the part of the synthetic community.7 In this Letter, we
outline a unified synthetic strategy and disclose an efficient
Tedanolide (1) displays in vitro cytotoxicity against KB
and PS cell lines (ED50’s: 0.25 ng/mL and 16 pg/mL,
(1) Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.; Hossain, M. B.;
van der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251.
(2) de Laubenfels, M. W. Trans. Zool. Soc. London 1950, No. 27, 1.
(3) Yaffee, H. L. S. L.; Sturgardter, F. Arch. Dermatol. 1963, 87, 601.
(4) Fusetani, N.; Sugawara, T.; Matsunaga, S.; Hirota, H. J. Org. Chem.
1991, 56, 4971.
(5) Schmitz, F. J.; Genasekera, S. P.; Hossain, M. B.; van der Helm, D.;
Yalamanchili, G. U.S. Patent Application 87-7347 870127.
(6) Masamune, S.; Bates, G. S.; Corcoran, J. W. Angew. Chem., Int. Ed.
Engl. 1977, 16, 585.
10.1021/ol9909233 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/16/1999

assembly of a common advanced C(1)-C(11) subtarget (3)
for tedanolide (1) and 13-deoxytedanolide (2).
1 and 2 leads to dithiane 3, a common subtarget for union
with 5 for tedanolide (1) and with 6 for 13-deoxytedanolide
(2). Further disconnection of 3 at C(7,8) yields aldehyde 7
and vinyl iodide 8.
The synthesis of aldehyde 7 began with (S)-(-)-2,2-
dimethyl-1,3-dioxolane-4-carboxaldehyde (9), available in
three steps from ascorbic acid (Scheme 2).9 Iterative Evans
Scheme 1
Scheme 2
aldol10 condensations incorporating silyl protection (TBSOTf/
2,6-lutidine) and conversion via the thioester to aldehyde (+)-
1211 were followed by LiBH4 reduction and acetal formation
to furnish (+)-13.11 Due to the observed lability of a methoxy
group at C(3), we chose to forestall methylation of the C(3)
hydroxyl in (+)-1111 until after both the second Evans aldol
and installation of the p-methoxyphenyl acetal. Removal of
the silyl group at C(3) in (+)-13 with TBAF and methylation
(NaH, MeI) then provided (+)-14.11
Selective reduction of the acetal in (+)-14 was initially
accompanied by reduction of the acetonide (ca. 50%). This
unanticipated process was eliminated by treatment with
DIBAL-H (3 equiv) for only 15 min; adherence to this
protocol furnished primary alcohol (-)-1511 in excellent
yield. Parikh-Doering oxidation (SO3‚pyr, DMSO, Et3N)
then completed the construction of aldehyde (+)-7.11,12
Turning to the synthesis of vinyl iodide (-)-8, Swern
Consistent with concurrent investigations on the utility of
dithianes8 as linchpins for complex molecule construction,
disconnectionat the C(29) lactone and C(11,12) σ-bonds of
(7) (a) Yonemitsu, O. J. Synth. Org. Chem. Jpn. 1994, 52, 946. (b)
Matsushima, T.; Horita, K.; Nakajima, N.; Yonemitsu, O. Tetrahedron Lett.
1996, 37, 385. (c) Matsushima, T.; Mori, M.; Nakajima, N.; Maeda, H.;
Uenishi, J.; Yonemitsu, O. Chem. Pharm. Bull. 1998, 46, 1335. (d)
Matsushima, T.; Mori, M.; Zheng, B.-Z.; Maeda, H.; Nakajima, N.; Uenishi,
J.; Yonemitsu, O. Chem. Pharm. Bull. 1999, 47, 308. (e) Matsushima, T.;
Zheng, B. Z.; Maeda, H.; Nakajima, N.; Uenishi, J.; Yonemitsu, O. Synlett
1999, 6, 780. (f) Liu, J.-F.; Abiko, A.; Pei, Z. H.; Buske, D. C.; Masamune,
S. Tetrahedron Lett. 1998, 39, 1873. (g) Taylor, R. E.; Ciavarri, J. P.; Hearn,
B. R.; Tetrahedron Lett. 1998, 39, 9361. (h) Jung, M. E., Karama, U.,
Marquez, R. J. Org. Chem. 1999, 64, 663. (i) Jung, M. E., Marquez, R.
Tetrahedron Lett. 1999, 40, 3129. (j) Roush, W. R.; Lane, G. C. Org. Lett.
1999, 1, 95.
(9) Hubschwerlen, C. Synthesis 1986, 962.
(10) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
(11) The structure assigned to each new compound is in accord with its
1
infrared, 500-MHz H NMR, and 125-MHz 13C NMR spectra, as well as
(8) Smith, A. B., III; Condon, S. M.; McCauley, J. A. Acc. Chem. Res.
1998, 31, 35.
appropriate parent ion identification by high-resolution mass spectrometry.
(12) Parikh, J. R.; von Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
1250
Org. Lett., Vol. 1, No. 8, 1999

oxidation13 of known alcohol (+)-16,14 available in five steps
from methyl (S)-(+)-3-hydroxyl-2-methylpropionate, was
followed by the Corey-Fuchs15 protocol (CBr4/PPh3) to
furnish dibromide (-)-1711 (Scheme 3). Conversion to the
Scheme 4
Scheme 3
terminal alkyne (n-BuLi; -78 °C, THF) followed by
alkylation with MeI led to (-)-18.11 Attempts to generate
alkyne (-)-18 in one operation resulted at best in only
modest yields. Hydrostannylation exploiting the conditions
of Guibe´16 then furnished a mixture of (E)- and (Z)-
vinylstannanes (6:1, 85% yield), separable by column chro-
matography.
Coupling the major (E)-vinylstannane with (+)-7 (n-BuLi,
-78 °C, THF) proved problematic. Quenching experiments
employing MeOH-d1 revealed that after 30 min at -78 °C
transmetalation had proceeded only to 30% conversion;
unfortunately, warming the metalation reaction mixture to
-50 °C led to decomposition. To circumvent this problem,
the stannane was converted to the corresponding vinyl iodide
(I2, CH2Cl2); metalation with t-BuLi at -78 °C followed by
treatment with MeOH-d1 demonstrated complete vinyl anion
formation with no decomposition.
Final elaboration of subtarget 3 (Scheme 5) was achieved
via treatment with TIPSOTf and 2,6-lutidine to provide silyl
ether (-)-3.11
Scheme 5
With efficient approaches to the requisite fragments
available, treatment of vinyl iodide (-)-811 with t-BuLi at
-78 °C for ca. 30 min, followed by low-temperature cannula
addition to aldehyde (+)-7 at -100 °C, led to a mixture of
(-)-2011 and (-)-2111 (Scheme 4). With THF as solvent, a
2.7:1 mixture of 20 and 21 was obtained, favoring the desired
isomer, (-)-20.17 Less polar solvents (Et2O and tert-
butylmethyl ether) afforded improved selectivity, with best
results (ca. 4:1) obtained with a 4:1 mixture of Et2O and
pentane; the yield in this case was 65%.
Since the generation of highly oxygenated d1 dithiane
anions18 can be capricious,19 we decided to explore the
coupling of (-)-3 with a model epoxide (Scheme 6). To this
end, treatment of (-)-3 in THF at -78 °C with t-BuLi for
5 min followed by addition of benzyl (S)-(+)-glycidyl ether
(-)-22 provided (-)-2311 in 78% yield, thereby demonstrat-
ing the viability of dithiane (-)-3 as a linchpin.
(13) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(14) Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L.,
Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1997, 119, 947.
(15) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(16) Zhang, H. X.; Guibe´, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857.
(17) The stereochemistry was determined via a combination of the
Mosher ester analysis of secondary alcohols with application of the
Kakisawa test (Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092) and the Rychnovsky-Evans 13C NMR 1,3-
acetonide empirical correlation [Rychnovsky, S. D.; Skalitzky, D. J.
Tetrahedron Lett. 1990, 31, 945. Rychnovsky, S. D.; Rogers, B.; Yang, G.
J. Org. Chem. 1993, 58, 3511. Evans, D. A.; Rieger, D. L.; Gage, J. R.
Tetrahedron Lett. 1990, 31, 7099.]
(18) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
(19) (a) Oppong, I.; Pauls, H. W.; Liang, D.; Fraser-Reid, B. J. Chem.
Soc., Chem. Commun. 1986, 1241. (b) Konishita, M.; Taniguchi, M.;
Morioka, M.; Takami, H.; Mizusawa, Y. Bull. Chem. Soc. Jpn. 1988, 61,
1, 2147.
Org. Lett., Vol. 1, No. 8, 1999
1251

rolide skeleton. The synthesis of (-)-3, requiring 13 steps,
proceeded efficiently in 15% overall yield. Studies to
assemble 5 and 6, their union with (-)-3, and conversion to
tedanolide (1) and 13-deoxytedanolide (2) continue in our
laboratory.
Scheme 6
Acknowledgment. Support was provided by the National
Institutes of Health (Institute of General Medical Sciences)
through Grant GM-29028 and by an American Chemical
Society Division of Organic Chemistry Fellowship to S.A.L.
Supporting Information Available: Spectroscopic and
analytical data for (+)-11, (+)-12, (+)-13, (+)-14, (-)-15,
(+)-7, (-)-17, (-)-18, (-)-8, (-)-20, (-)-21, and (-)-23
and selected experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
In summary, we have developed an efficient synthesis of
a common C(1)-C(11) dithiane (3) for tedanolide (1) and
13-deoxytedanolide (2) and demonstrated that this dithiane
is a competent linchpin for future elaboration of the mac-
OL9909233
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Org. Lett., Vol. 1, No. 8, 1999