Efficient synthesis of the C1-C11 fragment of the tedanolides. The nonaldol aldol process in synthesis

Article abstract of DOI:10.1021/ol005675l

(matrix presented) The nonaldol aldol process developed in our laboratories has been applied to the synthesis of a C₁-C₁₁ fragment 22 of the novel macrocyclic cytotoxic agents tedanolide and 13-deoxytedanolide 1 and 2. The commercially available hydroxy ester 7 was converted in 24 steps into compound 22 using two nonaldol aldol reactions.

Full text of DOI:10.1021/ol005675l

ORGANIC
LETTERS
2000
Vol. 2, No. 12
1669-1672
Efficient Synthesis of the C −C
Fragment of the Tedanolides. The
1
11
Nonaldol Aldol Process in Synthesis
Michael E. Jung* and Rodolfo Marquez
Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, California 90095-1569
jung@chem.ucla.edu
Received February 15, 2000
ABSTRACT
The nonaldol aldol process developed in our laboratories has been applied to the synthesis of a C −C fragment 22 of the novel macrocyclic
1
11
cytotoxic agents tedanolide and 13-deoxytedanolide 1 and 2. The commercially available hydroxy ester 7 was converted in 24 steps into
compound 22 using two nonaldol aldol reactions.
Since their isolation and characterization1,2 in the mid 1980s
and early 1990s, the cytotoxic marine macrocycles tedanolide
1 and 13-deoxytedanolide 2 have attracted a great deal of
synthetic interest due to their strong biological activity and
structural complexity.3 Tedanolide 1 has shown ED50’s of
250 pg/mL (vs the KB human carcinoma cell line) and 16
pg/mL (vs PS lymphocytic leukemia). Preliminary data also
suggest that tedanolide 1 may induce terminal cell dif-
ferentiation at the S phase at concentrations as low as 10
ng/mL, which offers the possibility of using it as a mecha-
nism-based drug lead. 13-Deoxytedanolide 2, on the other
hand, has shown a T/C of 189% at a dose of 125 µg/kg vs
p388 cell lines.1,2 No mechanistic studies have been published
for 13-deoxytedanolide 2 to date.
Structurally, both macrocycles are composed of an 18-
membered macrocyclic lactone with a polypropionate skel-
eton, an internal trisubstituted E olefin, and 12 or 13
stereocenters, making their synthesis extremely challenging.
We now report our high yielding and highly stereoselective
synthesis of the C1-C11 fragment common to both tedanolide
and 13-deoxytedanolide using the first practical synthetic
application of the highly efficient nonaldol aldol methodolgy
recently developed in our laboratories.4 Using the nonaldol
aldol transformation, it is possible to obtain highly enantio-
and diastereospecific propionate units 6 via the Lewis acid
(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) 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. Phar. Bull. 1998, 46,
1335. (c) Liu, J. F.; Abiko, A.; Pei, Z.-H.; 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) Matsushima, T.; Mori, M.;
Zheng, B. Z.; Maeda, H.; Nakajima, N.; Uenishi, J.; Yonemitsu, O. Chem.
Phar. Bull. 1999, 47, 308. (f) Zheng, B. Z.; Maeda, H.; Mori, M.; Kusaka,
S.; Yonemitsu, O.; Matsushima, T.; Nakajima, N.; Uenishi, J. Chem. Phar.
Bull. 1999, 47, 1288. (g) Matsushima, T.; Zheng, B. Z.; Maeda, H.;
Nakajima, N.; Uenishi, J.; Yonemitsu, O. Synlett 1999, 780. (h) Roush, W.
R.; Lane, G. C. Org. Lett. 1999, 1, 95. (i) Smith, A. B., Lodise, S. A.
Abstracts of Papers, 218th National Meeting of the American Chemical
Society, New Orleans, LA, Aug 22-26, 1999; Amercian Chemical
Society: Washington, DC, 1999; p 549. Org. Lett. 1999, 1, 1249.
(4) (a) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993, 115, 12208
and references therein. (b) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc.
1995, 117, 7379. (c) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1997,
119, 12150. (d) D’Amico, D. C. Ph.D. Thesis, UCLA, 1995. (e) Jung, M.
E.; Lee, W. S.; Sun, D. Org. Lett. 1999, 1, 307. (f) Jung, M. E.; Sun, D.
Tetrahedron Lett. 1999, 40, 8343.
10.1021/ol005675l CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/19/2000

catalyzed rearrangement of chiral epoxy alcohols 5 without
the use of chiral auxiliaries in the key step (obviously the
step that produces the epoxy alcohols uses chiral reagents).
Our convergent retrosynthetic analysis for the synthesis of
both tedanolide and 13-deoxytedanolide called for the
cleavage of the macrocyclic ring at the C1-C17 ester
functionality and the C12-C13 bond, generating the C1-C12
fragment 3 and the C13-C24 fragment 4 (Scheme 1).
Wittig olefination,5 and 1,2-reduction proceeded in good yield
to produce the desired allylic alcohol 9. TBS protection of
alcohol 9 followed by DMTr group removal afforded the
desired homoallylic alcohol 10 in excellent yield. NBS-
promoted cyclization6 of the free homoallylic alcohol onto
the double bond generated the bromotetrahydrofuran 11 in
good yield as a single diastereomer with the stereochemistry
proven by NOE analysis. Our decision to proceed via the
bromotetrahydrofuran functionality was based on previous
results,7 which demonstrated the utility of this protecting
group as a masked homoallylic methyl ketone.
Scheme 1
Deprotection of the TBS ether 11, followed by Swern
oxidation and Wittig olefination, produced the desired
E-conjugated ester 12 in good yield over three steps (Scheme
3). 1,2-Reduction of conjugated ester 12 afforded the
Scheme 3
The synthesis of the top fragment 3 began with com-
mercially available methyl R (-)-3-hydroxy-2-methylpro-
pionate 7 (Scheme 2), which was protected with a dimethox-
expected allylic alcohol 13 in high yield as a single product.
With the allylic alcohol 13 in hand, we attempted to take
advantage of the stereochemical information present in the
bromotetrahydrofuran ring to influence the stereochemical
outcome of the epoxidation. Unfortunately, all of the
substrate-controlled epoxidation conditions attempted yielded
the undesired epoxide 14 as the major product. However,
the use of Sharpless asymmetric epoxidation conditions8
provided a 10:1 mixture of epoxides 14 and 15 with the
desired epoxide 15 being the major diastereomer.
Scheme 2
(5) Fleck, F.; Schinz, H. HelV. Chim. Acta 1950, 33, 146.
(6) (a) Parker, K. A.; O’Fee, R. J. Am. Chem. Soc. 1983, 105, 654. (b)
Rychnovsky, S. D.; Barlett, P. A. J. Am. Chem. Soc. 1981, 103, 3963. (c)
Mihailovic, M. Lj.; Marinkovic, D. J. Serb. Chem. Soc. 1985, 50, 5. (d)
Harding, K. E.; Tiner, T. H. Electrophilic Heteroatom Cyclizations. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford,
1991; Vol. IV, p 363.
(7) Jung, M. E.; Karama, U.; Marquez, R. J. Org. Chem. 1999, 64, 663.
(8) (a) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136. (b) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(c) Rossitier, B. E.; Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1981,
103, 464. (d) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.
ytrityl group (DMTr) and reduced to afford the monoprotected
diol 8 in quantitative yield. Swern oxidation, followed by
1670
Org. Lett., Vol. 2, No. 12, 2000

Crucial nonaldol aldol rearrangement of epoxide 15
provided the pivotal aldehyde aldol product 16 as a single
diastereomer in excellent yield and without any need for
purification (Scheme 4). The stereochemistry of the aldehyde
steps. Epoxidation of alcohol 20 under substrate-controlled
conditions yielded, after silylation of the free hydroxyl, the
desired epoxide 21 in 65% yield.
Once the desired epoxide 21 was in hand, the final
nonaldol aldol rearrangement required to complete the C1-
C11 fragment of tedanolide was carried out (Scheme 6).
Scheme 4
Scheme 6
Treatment of epoxide 21 with trimethylsilyl triflate, followed
by Still-Wittig olefination conditions9,10 afforded the desired
C1-C11 Z-conjugated ester 22 in 80% yield as a 1:1 mixture
with the pyran derivative 23.
Formation of the pyran side-product 23 was rationalized
as originating from the attack of the tetrahydrofuran oxygen
on the tertiary carbon of the activated epoxide 24 to generate
the bicyclic intermediate 25. Intermediate 25 is then hydro-
lyzed during aqueous workup to give the observed pyran 23
(Scheme 7).
16 was confirmed via NOE and J-value analysis of the
acetonide derivative 17 which was readily prepared in three
steps from aldehyde 16 (Scheme 4).
Wittig olefination of aldehyde 16 proceeded in excellent
yield and with complete stereoselectivity to produce the
E-conjugated ester 18 (Scheme 5). 1,2-Reduction, followed
Scheme 5
Scheme 7
In conclusion, we have demonstrated the feasibility of
using the nonaldol aldol methodology toward an efficient
synthesis of tedanolide 1 and 13-deoxytedanolide 2. With
its ease of use, no purification requirements and no need for
expensive chiral auxiliaries, we have shown that the nonaldol
aldol methodology is a viable and economic alternative to
by deprotection of the secondary silyl group and subsequent
protection of the primary alcohol of the resulting diol,
afforded the desired secondary alcohol intermediate 19 in
good yield over three steps. Mesylation of the free secondary
hydroxyl group followed by silyl group removal produced
the required allylic alcohol 20 in excellent yield over both
(9) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(10) We find that it is often advantageous to use the aldehydes
immediately upon their formation rather than to isolate and try to purify
them since one often observes some decomposition upon purification.
Org. Lett., Vol. 2, No. 12, 2000
1671

traditional asymmetric aldol methods. Further developments
in our approach toward the total synthesis of tedanolide and
13-deoxytedanolide will be published in due course.
Supporting Information Available: The NMR data and
experimental procedures for compounds 8-23 are available
as Supporting Information. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the National Institutes of
Health (CA-72684) for generous financial support. R.M.
would like to thank the University of California President’s
Office for a fellowship.
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Org. Lett., Vol. 2, No. 12, 2000