Total synthesis of (+)-13-deoxytedanolide

Article abstract of DOI:10.1021/ja050729d

A total synthesis of 13-deoxytedanolide is described. The synthesis features a highly stereoselective fragment assembly aldol reaction of methyl ketone 4 and aldehyde 5 to establish the complete carbon skeleton of the natural product in the form of aldol

Full text of DOI:10.1021/ja050729d

Published on Web 04/09/2005
Total Synthesis of (+)-13-Deoxytedanolide
Lisa D. Julian, Jason S. Newcom, and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
Received February 3, 2005; E-mail: roush@umich.edu
Scheme 1. Retrosynthetic Analysis
Tedanolide (1), was isolated in 1984 by Schmitz and co-workers
from the Carribean sponge Tedania ignis.1 In 1991, a closely related
macrolide, 13-deoxytedanolide (2), was isolated from Mycale
adhaerens by Fusetani and co-workers.2 Both compounds display
potent cytotoxicity against various cancer cell lines, and present
considerable challenges as targets for total synthesis.3-14 Smith and
co-workers have recently published the first total synthesis of 13-
deoxytedanolide.10
We have pursued a strategy that we anticipated would permit
the total synthesis of both 1 and 2 from a common precursor 3
(Scheme 1).15,16 We planned to assemble the complete carbon
skeletons of 1 and 2 and to set the stereochemistry of the C(13)-
OH (needed for 1) through a stereoselective methyl ketone aldol
reaction of ketone 4 and aldehyde 5. After considerable experi-
mentation, we elected to protect the C(1) acid of 4 as an allyl ester
and the C(16) hydroxymethyl group of 5 as an allyl carbonate
(Alloc), so that both units could be deprotected simultaneously prior
to macrolactonization. Although we have thus far been unable to
elaborate the aldol coupling product 4 and 5 to tedanolide (vide
infra), we have successfully utilized these intermediates in a total
synthesis of 13-deoxytedanolide (2), which is described herein.
Methyl ketone 4 was synthesized as summarized in Scheme 2.
Ethyl ketone 7 was prepared in four steps from known aldehyde
616 in 66% yield, via chlorite oxidation of the aldehyde,17 Mitsunobu
esterification of the resulting carboxylic acid,18 deprotection of the
DMPM ether,19 and TPAP oxidation of the resulting alcohol.20 The
aldol reaction of 7 and known aldehyde 816 was best performed by
exposure of 7 to TiCl4 and i-Pr2NEt for 8 min at -78 °C prior to
addition of 8 (-78 °C with warming to 0 °C).21 The targeted aldol
9 was obtained in 73% yield (10:1 ds). However, longer exposure
of 7 to TiCl4 and i-Pr2NEt consistently led to low yields (30%) of
9. Elaboration of aldol 9 to methyl ketone 4 proceeded in 65%
over three standard transformations.
Scheme 2. Synthesis of Methyl Ketone 4
Scheme 3. Synthesis of Aldehyde 5
Synthesis of the Alloc-protected aldehyde fragment 5 proved
more challenging (Scheme 3). The Alloc group could not be
installed directly at the stage of 10 due to its incompatibility with
subsequent olefin oxidative cleavage steps. Therefore, the primary
alcohol of 1015 was initially protected as a bromoethyl carbonate
(BEC), via treatment with 2-bromoethyl chloroformate. Subsequent
oxidative cleavage of the olefin and asymmetric crotylboration using
(S,S)-1122 in toluene at -78 °C provided 12 in 71% yield over
four steps. Protection of the free hydroxyl group of 12 as a TES
ether, dihydroxylation of the vinyl group, and temporary protection
of the resulting diol as bis-R-methoxyacetates then provided 13 as
a ca. 5:1 mixture of diol diastereomers in 83% yield. It was
necessary to functionalize the C(13) olefin prior to installing the
C(21-22) (Z)-olefin, again due to problems encountered in attempts
to cleave the terminal vinyl group in the presence of the C(21-
22) (Z)-olefin (data not shown). Deprotection of the PMB ether of
13 and oxidation of the resulting alcohol with the Dess-Martin
periodinane reagent23 gave a highly sensitive â,γ-epoxyaldehyde.
Treatment of the crude aldehyde with ethylidene(triphenyl)-
phosphorane then provided 14 with >20:1 selectivity. Next,
subjection of 14 to H2CdCHCH2OMgBr in Et2O-THF at 23 °C
effected simultaneous cleavage of the labile methoxyacetates and
trans-esterification of the bromoethyl carbonate to the targeted Alloc
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10.1021/ja050729d CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Fragment Assembly Aldol Reaction
ester and Alloc protecting groups by using Pd(PPh3)4 and n-Bu3-
SnH28 and subsequent modified-Yamaguchi macrolactonization29
of the seco acid intermediate afforded the penultimate intermediate
19 in 31% over these two steps. Finally, deprotection of the three
TBS ethers of 19 with Et3N‚(HF)3 and Et3N30,31 (thereby generating
Et3N‚(HF)2 in situ) provided (+)-13-deoxytedanolide in 66% yield.
Synthetic 13-deoxytedanolide was identical in all respects (1H NMR,
13C NMR, HRMS, IR, optical rotation) with an authentic sample.
Our continuing studies on the synthesis of tedanolide itself will
be reported in due course.
Acknowledgment. This research was supported by a grant from
the National Institutes of Health (GM 38436), and a Bristol-Myers
Squibb Graduate Fellowship to L.D.J. We thank Professors Fusetani
and Matsunaga for supplying an authentic sample of 13-deoxy-
tedanolide.
Scheme 5. Completion of the Total Synthesis
Supporting Information Available: Experimental procedures and
NMR data for selected intermediates. This material is available free of
charge via the Internet at http://pubs.acs.org.
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