Studies on the Synthesis of Tedanolide. 2. Stereoselective Synthesis of a Protected C(1)-C(12) Fragment

Article abstract of DOI:10.1021/ol0272343

(Matrix Presented) Highly diastereoselective syntheses of diketo esters 6a and 6b are described. These intermediates undergo efficient aldol reactions with protected C(13)-C(21) aldehydes 3 and 23, thereby providing advanced C(1)-C(21) tedanolide seco ester precursors 9a and 9b.

Full text of DOI:10.1021/ol0272343

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4739-4742
Studies on the Synthesis of Tedanolide.
2. Stereoselective Synthesis of a
Protected C(1)−C(12) Fragment
William R. Roush* and Jason S. Newcom
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
roush@umich.edu.
Received November 5, 2002
ABSTRACT
Highly diastereoselective syntheses of diketo esters 6a and 6b are described. These intermediates undergo efficient aldol reactions with
protected C(13)−C(21) aldehydes 3 and 23, thereby providing advanced C(1)−C(21) tedanolide seco ester precursors 9a and 9b.
Tedanolide (1, Scheme 1) is a highly cytotoxic macrolide
that was isolated from a Caribbean sponge species, Tedania
ignis, by Schmitz and co-workers in 1984.1 A structurally
related congener, 13-deoxytedanolide (2), was subsequently
number of tumor cell lines has stimulated considerable
interest in their synthesis. Thus far, studies on the synthesis
of tedanolide and 13-deoxytedanolide have been reported by
Yonemitsu,3 Taylor,4 Smith,5,6 Jung,7 Loh,8 and Masamune.9
In 1999 we described a highly stereoselective synthesis of
(3) (a) Katsuya, M.; Zhen, 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.; Madea, 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.
Scheme 1
(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.
isolated by Fusetani from a sponge species (Mycale adhaer-
ens) obtained from the western Pacific Ocean.2 The remark-
ably potent cytotoxicities of these compounds against a
(5) Smith, A. B.; Lodise, S. A. Org. Lett. 1999, 1, 1249.
(6) While this manuscript was in preparation, Prof. Amos Smith informed
us that he had completed the first total synthesis of 13-deoxytedanolide.
We thank him for making this information available to us prior to
publication.
(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.
(7) (a) Jung, M. E.; Lee, C. P. Org. Lett. 2001, 3, 1523. (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.
10.1021/ol0272343 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/02/2002

the tedanolide C(5)-C(21) fragment 5 via a highly stereo-
selective fragment assembly aldol reaction of chiral aldehyde
3 and the chiral â,γ-unsaturated methyl ketone 4 (Scheme
2).10 We report herein a highly stereoselective synthesis of
Scheme 4
Scheme 2
fully functionalized C(1)-C(12) methyl ketone fragments
6a,b and their elaboration to advanced tedanolide seco acid
precursors (9a and 9b) (Scheme 3).
Scheme 3
Reduction of 12 with LiAlH4 in THF at -78 °C provided
the corresponding 1,3-diol, which was converted to the 3,4-
dimethoxybenzylidene acetal 13 upon treatment with 3,4-
dimethoxylbenzaldehyde and catalytic p-TsOH in benzene.
DIBAL reduction14 of acetal 13 cleanly provided the primary
alcohol, which was oxidized to give aldehyde 14 using the
standard Swern protocol (64% overall yield from 11).15
Treatment of 14 with 3 equiv each of allylstannane 15 and
BF3‚Et2O in CH2Cl2 at -78 °C provided the 3,4-syn-4,5-
syn homoallylic alcohol 16 in 75% yield with g95:5 ds.16,17
Conversion of the hydroxyl group of 16 to a methyl ether
(MeOTf, 2,6-di-tert-butyl-4-methylpyridine (DBMePy), CH2-
Cl2, 23 °C)18 followed by standard oxidative cleavage of the
vinyl group provided aldehyde 17 (55% yield from 16).
Oxidation of the aldehyde to the corresponding carboxylic
acid was best accomplished by using the sodium chlorite
Our strategy for synthesis of the C(1)-C(12) methyl
ketone unit called for 6a to be assembled via the aldol
coupling of ethyl ketone 7a and R,â-unsaturated aldehyde
8. The synthesis of methyl ester 6a (Scheme 4) commenced
with the enantioselective hydrogenation11 of â-keto ester 10
using Taber’s protocol,12 which provided â-hydroxy ester
11 in almost quantitative yield and with g99% ee. Frater-
Seebach alkylation of 11 then provided the anti R-methyl-
â-hydroxy ester 12 in good yield and selectivity (g95:5 ds).13
(13) Frater, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron 1984, 40, 1269.
(14) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron 1990, 46, 4595.
(15) Tidwell, T. T. Org. React. 1990, 39, 297.
(16) Keck, G. E.; Abbott, D. E.; Wiley, M. R. Tetrahedron Lett. 1987,
28, 139.
(17) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem.
Soc. 1996, 118, 4322.
(8) (a) Loh, T.-P.; Feng, L.-C. Tetrahedron Lett. 2001, 42, 6001. (b)
Loh, T.-P.; Feng, L.-C. Tetrahedron Lett. 2001, 42, 3223.
(9) Liu, J.-F.; Abiko, A.; Pei, Z. H.; Buske, D. C.; Masamune, S.
Tetrahedron Lett. 1998, 39, 1873.
(10) Roush, W. R.; Lane, G. C. Org. Lett. 1999, 1, 95.
(11) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40.
(12) Taber, D. F.; Silverberg, L. J. Tetrahedron Lett. 1991, 32, 4227.
(18) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. Tetrahedron
Lett. 1994, 35, 7171.
4740
Org. Lett., Vol. 4, No. 26, 2002

procedure.19 It was essential that this oxidation be performed
at 0 °C and for the oxidation to be quenched with the addition
of Me2S in order to avoid competitive chlorination of the
dimethoxybenzyl (DMBM) ether. Esterification of the crude
(and relatively unstable) carboxylic acid with trimethylsily-
diazomethane then provided methyl ester 18a in 82% yield.
Deprotection of the DMPM20 ether and oxidation (TPAP,
NMO)21 of the alcohol (which is sensitive to lactonization)
to the ketone then completed the synthesis of the originally
targeted C(1)-C(6) methyl ester fragment 7a (70-73%
yield). Spectroscopic analysis of the lactone generated from
the alcohol prepared from 18a allowed us to verify the
stereochemistry of 16 and all intermediates derived there-
from.
Scheme 6
The C(7)-C(12) enal 8 was synthesized starting from the
readily available anti-â-hydroxy-R-methylbutyrate 1913 as
summarized in Scheme 5. Ester 19 was elaborated to the
Scheme 5
followed by deprotection20 of the DMPM ether and oxidation
of the resulting alcohol to the â,γ-unsaturated ketone using
TPAP and NMO21 then provided 6a in 67% overall yield.
Treatment of 6a with lithium hexamethyldisilazide (LiH-
DMS) in THF at -78 °C followed by addition of aldehyde
310 (1 equiv) proved to be highly stereoselective and provided
the Felkin aldol 9a as the only observed aldol product. The
stereochemistry of the new hydroxyl group of 9a was
assigned by application of our recently described NMR
method.25
Intermediate 9a represents the C(1)-C(21) fragment of
the natural product, with all functionality in the correct
oxidation state except for C(15), which ultimately must be
oxidized to a ketone. However, all attempts to deprotect the
methyl ester and the C(16)-acetoxymethyl groups were
unsuccessful, owing to the base sensitivity of 9a and
intermediates derived therefrom. Therefore, ongoing efforts
are focusing on the identification of a suitable set of
protecting groups for the C(1)-carboxylic acid and C(16)-
CH2OH groups that can be unmasked under mild conditions.
Toward this end, we have developed a synthesis of the C(1)-
C(21) aldol 9b, which possesses 2-chloroethyl ester at C(1)
and a 2-bromoethyl carbonate protecting group for C(16)-
CH2OH (see Scheme 7).
â-alkoxy aldehyde 20 in 87% overall yield by using a
sequence analogous to that described for the conversion of
12 to 14. Treatment of 20 with the stabilized ylid,
Ph3PdCH(Me)CO2Me, gave the R,â-unsaturated ester with
excellent selectivity. Reduction of the ester using DIBAL-H
in a mixture of CH2Cl2 and hexane at -78 °C and then
Parikh-Doering oxidation22 of the allylic alcohol provided
enal 8 in 70% overall yield.
Aldol coupling of 7a and 8 (1.5 equiv) was best ac-
complished by using the chlorotitanium enolate generated
by treatment of 7a with TiCl4 and i-Pr2NEt in CH2Cl2 at
-78 °C (Scheme 6).23 Under these conditions, aldol 21 was
obtained in 48% yield.24 Protection of 21 as a TBS ether
(19) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
(20) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(21) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625.
(22) Parikh, J. R.; von Doering, E. W. J. Am. Chem. Soc. 1967, 89, 5505.
(23) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047.
(24) The stereochemistry of aldol 21 was assigned by 1,3-anti reduction
(tetramethylammonium triacetoxyborohydride, CH3CN, HOAc, -10 °C,
86%) followed by conversion of the diol to the corresponding 1,3-anti
acetonide derivative. For the 1,3-anti reduction, see: Evans, D. A.; Chapman,
K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560. For the 1,3-diol
stereochemical assignment, see: Rychnovsky, S. D.; Rogers, B.; Yang, G.
J. Org. Chem. 1993, 58, 3511.
Chloroethyl ester 7b was prepared by Yamaguchi esteri-
fication26 of the carboxylic acid derived from 17 with
(25) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; VanNieuwehnze,
M. S.; Gustin, D. J.; Dilley, G. J.; Lane, G. C.; Scheidt, K. A.; Smith, W.
J., III. J. Org. Chem. 2002, 67, 4284.
(26) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Chem.
Bull. Jpn. 1979, 52, 1989.
Org. Lett., Vol. 4, No. 26, 2002
4741

2-chloroethanol (77%), followed by deprotection of the
DMPM ether and oxidation of the C(5)-hydroxyl group
(Scheme 4). Aldol coupling of 7b and 8 (1.5 equiv) using
the chlorotitanium enolate technology provided 22 in 62%
yield; 35% of 7b and 56% of 8 were recovered. Conversion
of 22 to 6b proceeded uneventfully (76% for the three steps).
The key aldol reaction of the lithium enolate generated from
9b and aldehyde 2327 (with a bromoethyl carbonate protect-
ing group for C(16)-CH2OH) then provided the Felkin aldol
9b in 67% yield along with 20% of recovered 6b and 17%
of recovered 8. However, we have not been able to develop
a workable procedure to generate the targeted seco acid by
deprotection of seco ester 9b. Consequently, efforts to
identify an appropriate protecting group combination for the
advanced seco ester intermediate are continuing.
Scheme 7
In summary, we have developed a highly stereoselective
syntheses of the C(1)-C(12) fragments 6a and 6b of
tedanolide and have demonstrated that these diketo esters
undergo efficient and stereoselective fragment coupling with
aldehydes 3 and 23, respectively. Further progress toward
completion of the total synthesis of tedanolide will be
reported in due course.
Acknowledgment. Support provided by the National
Institutes of Health (Grant GM 38436 to W.R.R. and
Training Grant GM 07767) is gratefully acknowledged. We
also thank Ms. Lisa Julian for providing samples of aldehyde
23 used in this work.
Supporting Information Available: Tabulated spectro-
scopic data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0272343
(27) The synthesis of 23 was performed by Lisa Julian, by appropriate
modifications of our previously published synthesis of 3 (ref 10).
4742
Org. Lett., Vol. 4, No. 26, 2002