Synthesis of a Fully Functionalized Protected C1-C11 Fragment for the Synthesis of the Tedanolides

Article abstract of DOI:10.1021/ol000329p

(Matrix Presented) The use of several non-aldol aldol processes allows one to prepare a fully functionalized and completely protected C1-C11 fragment that should be useful for the total synthesis of the tedanolides.

Full text of DOI:10.1021/ol000329p

ORGANIC
LETTERS
2001
Vol. 3, No. 3
333-336
Synthesis of a Fully Functionalized
Protected C1−C11 Fragment for the
Synthesis of the Tedanolides
Michael E. Jung* and Christopher P. Lee
Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, California 90095-1569
jung@chem.ucla.edu
Received October 26, 2000
ABSTRACT
The use of several non-aldol aldol processes allows one to prepare a fully functionalized and completely protected C1−C11 fragment that
should be useful for the total synthesis of the tedanolides.
The highly cytotoxic macrolide tedanolide (1, R ) OH) was
isolated by Schmitz and co-workers in 1984 from the
Caribbean sponge Tedania ignis,1 while the analogous
cytotoxic compound 13-deoxytedanolide (2, R ) H) was
isolated from the Japanese sponge Mycale adhaerens by
Fusetani and co-workers in 1991.2 Because of their potent
antitumor activity and their complex structures, the tedano-
lides 1 and 2 have generated considerable synthetic work,3
including that of our group, which has used the non-aldol
aldol process4 in our approach to these molecules.
aldol reaction of the aldehyde derived from 3 (for tedanolide
1) or an alkylation of the tosylate derived from 3 (for
deoxytedanolide 2) followed by removal of protecting
groups, oxidation, and macrolactonization (Scheme 1).
Recently we discussed our approach to the C1-C11 fragment
4, in which the key step was a non-aldol aldol process.5
Thus, the epoxy mesylate 6 bearing a lactol methyl ether
(prepared in several steps from the commercially available
hydroxy ester 5) underwent the desired non-aldol aldol
The straightforward retrosynthetic disconnection of the
tedanolide skeleton by cleavage at the lactone moiety and
at the C12-C13 bond affords the intermediates 3 and 4,
which could be combined in the forward sense by either an
Scheme 1
(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. J. Org. Chem. 1991, 56,
4971.
(3) (a) Yonemitsu, O. J. Synth. Org. Chem. Jpn. 1994, 52, 946. (b)
Matsushima, T.; Horita, K.; Nakajima, N.; Yonemitsu, O. Tetrahedron Lett.
1996, 37, 185. (c) Matsushima, T.; Mori, M.; Nakajima, N.; 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) Roush, W. R.; Lane, G. C. Org. Lett.
1999, 1, 95. (i) Smith, A. B., III; Lodise, S. A. Org. Lett. 1999, 1, 1249.
10.1021/ol000329p CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/12/2001

rearrangement on treatment with TMSOTf and Hunig’s base
to give the desired aldehyde, which was then converted into
the hydroxy ester 7 in very good overall yield and selectivity
(Scheme 2). We now report the conversion of this hydroxy
as its TBS ether, and final protection of the secondary alcohol
as its PMB ether 9 in 75% yield. The installation of the last
two stereocenters in the C1-C11 fragment of tedanolide
required removal of the mesylate protecting group of 9,
which was accomplished by a slight modification of our
earlier route, namely, using methyllithium in THF,4e,6 to give
the alcohol, which was then protected as the triethylsilyl
(TES) ether.7 The steric hindrance of the secondary TES ether
allowed for selective removal of the primary TBS ether to
give the alcohol 10 in modest overall yield. MCPBA
epoxidation of 10 occurred stereoselectively to give epoxide
11 in 84% yield and a 6:1 diastereomeric ratio.8 The
diastereoselectivity is the result of allylic 1,3 strain and the
directing ability of the PMB ether. We hoped to open the
epoxide with methanol to furnish the desired diol 12, since
Sharpless has reported the formation of 1,2-diols from epoxy
alcohols in the presence of Ti(OiPr)4 using a variety of
nucleophiles including alcohols.9 However, we observed no
reaction of 11 with methanol, even at reflux. Several other
Lewis and Bronsted acids were investigated, but none gave
the desired product. When the Lewis acid was changed to
BF3 etherate,10 TES deprotection exposed a free hydroxyl
group that readily cyclized to provide the tetrahydropyran
Scheme 2
ester into the fully functionalized protected C1-C11 frag-
ment 24 for the synthesis of the tedanolides.
Since the natural products have a ketone at C5, the
hydroxyl group at C5 of 7 must eventually be transformed
into a ketone. For this reason, it would be advantageous to
protect this alcohol with an orthogonal protecting group such
as a PMB ether. Unfortunately, the usual procedure of PMB
ether formation (PMBCl, NaH, THF) afforded the lactone 8
in 94% yield (Scheme 3). We opted instead for a three-step
13 in 63% yield. Thus, as seen in our earlier synthesis,4e
a
somewhat nucleophilic oxygen atom (even a silyl ether) six
atoms away from a developing positive charge leads to
cyclization.
We therefore decided to look at other ether protecting
groups that might be less likely to participate in cyclizations
of this sort (Scheme 4). The TBS ether 9 was converted via
Scheme 3
Scheme 4
a similar three-step route into the benzyl ether 14 in 61%
overall yield. Kishi epoxidation again produced mainly the
desired epoxide 15. This benzyl ether epoxide could now
be opened with methanol in the presence of BF3 etherate to
route, namely, reduction of the Z-enoate of 7 using DIBAL-
H, regioselective protection of the primary hydroxyl group
334
Org. Lett., Vol. 3, No. 3, 2001

give a methoxy diol in 59% yield. However, surprisingly,
the desired 1,2-diol 16 was not obtained, but rather the
unexpected 1,3-diol 17.11 Thus the steric hindrance of the
chain outweighs that of the hydroxymethyl group, and no
directing effect of the alcohol was observed with BF3. We
hypothesized that if we added another alcohol such as benzyl
or allyl alcohol to the diastereomeric epoxide, then after
methylation and removal of the benzyl or allyl group, the
desired methoxy diol would be produced (in a sense using
benzyl or allyl alcohol as a surrogate for water). The allylic
alcohol 14 was epoxidized with DMDO (formed in situ from
oxone and acetone) to give a 3:1 ratio favoring the desired
syn epoxide 18 (Scheme 5). Opening with benzyl alcohol
Scheme 6
Scheme 5
gave the desired carbonate 20 in 74% yield.15 No methyl
lactol ether deprotection was observed during the acidic
hydrolysis step. Formation of the anion of the alcohol of 20
with NaH, even in the presence of methyl iodide or triflate,16
gave only the product of carbonate migration 22 rather than
the desired methyl ether 21. However, alkylation with methyl
triflate in the presence of the very hindered base 2,6-di-tert-
butylpyridine in refluxing dichloromethane furnished the
desired methyl ether 21 in 43% yield.
To prepare the compound for regeneration of the trisub-
stituted alkene and methyl ketone formation, we first had to
adjust the protecting groups. Basic hydrolysis of the carbon-
ate 21 provided the diol 23 in 83% yield (Scheme 7). A tert-
was unsuccessful, but we were able to form the allyloxy diol
19 from 18 on treatment with allyl alcohol and BF3 etherate.12
However, because of the low yield we discontinued this
route.
The solution to the formation of the desired methoxy diol
involved an intramolecular strategy.13 Thus the nucleophilic
carbamate was attached to the hydroxyl group of 18 by
treatment with phenyl isocyanate in 95% yield (Scheme 6).
Treatment of this carbamate with 5% HClO4 in acetonitrile14
(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, Los Angeles, CA,
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. (g) Jung, M. E.;
Karama, U.; Marquez, R. J. Org. Chem. 1999, 64, 663. (h) Jung, M. E.;
Marquez, R. Tetrahedron Lett. 1999, 40, 3129. (i) Jung, M. E.; Marquez,
R. Org. Lett. 2000, 2, 1669.
Scheme 7
(5) Jung, M. E.; Lee, C. P. Tetrahedron Lett. 2000, 41, 9719.
(6) Cossy, J.; Ranaivosata, J.-L.; Bellosta, V.; Wietzke, R. Synth.
Commun. 1995, 25, 3109.
(7) The alcohol is too hindered to allow easy introduction of the TBS
ether.
(8) Johnson, M. R.; Nakata, T.; Kishi, Y. Tetrahedron Lett. 1979, 20,
4343. Johnson, M. R.; Kishi, Y. Tetrahedron Lett. 1979, 20, 4347.
(9) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557.
(10) Liu, Y.-J.; Chu, T.-Y.; Engel, R. Synth. Commun. 1992, 22, 2367.
(11) The position of the methyl ether was determined by constructing
two derivatives, the cyclic carbonate, which had the characteristic IR stretch
of a six-membered carbonate (1755 cm-1), and the p-methoxybenzylidene
acetal formed by oxidative cyclization with DDQ, which showed the
expected NOE between 1,3 diaxial protons.
(12) The structure of 19 was again inferred, since the cyclic carbonate
formed from it had the characteristic IR stretch of a six-membered carbonate
(1748 cm-1).
(13) (a) Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107,
1691. (b) Wang, Z.; Schreiber, S. L. Tetrahedron Lett. 1990, 31, 31.
(14) Horita, K.; Nagato, S.; Oikawa, Y.; Yonemitsu, O. Chem. Pharm.
Bull. 1989, 37, 1705.
butyldiphenylsilyl (TPS) ether was then attached to the
primary alcohol in 72% yield, allowing the secondary alcohol
to be protected as its benzyl ether to give 24 in 50% yield,
along with the bisbenzyl ether formed presumably as a result
(15) The IR spectrum of 20 showed an absorption at 1798 cm-1
,
indicative of a five-membered carbonate.
(16) (a) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 2050. (b)
Jung, M. E.; Nichols, C. J. Tetrahedron Lett. 1998, 39, 4615.
Org. Lett., Vol. 3, No. 3, 2001
335

of some hydrolysis of the TPS ether prior to or during the
benzylation. Further reactions of 24, namely, reductive
debromination and formation of the methyl ketone to produce
4 are currently underway in our laboratories.
In conclusion, we have developed a good method for the
preparation of a fully functionalized protected C1-C11
fragment for the synthesis of the tedanolides in several steps
from the commercially available hydroxy ester 5.
Acknowledgment. We thank the National Institutes of
Health (CA72684) for generous financial support.
Supporting Information Available: Spectral data and
experimental procedures for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL000329P
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