Total Synthesis and Structural Revision of (+)-Amphidinolide W

Article abstract of DOI:10.1021/ja049754u

An enantioselective first total syntheis of amphidinolide W (2) and a revision of its C6 absolute stereochemistry (1) are described. Amphidinolide W (1), a 12-membered macrolide isolated from Amphidinium sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. The synthesis is convergent, and four of the five chiral centers were derived through asymmetric synthesis. The synthesis features Sharpless asymmetric dihydroxylation, diastereoselective alkylation, efficient cross metathesis of functionalized substrates, and novel functional group transformations using selective lipase-catalyzed hydrolysis of the primary acetate group. Of particular note, the C6 absolute stereochemistry of amphidinolide W (1) has now been revised through our current synthesis. Copyright

Full text of DOI:10.1021/ja049754u

Published on Web 03/04/2004
Total Synthesis and Structural Revision of (+)-Amphidinolide W
Arun K. Ghosh* and Gangli Gong
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607
Received January 14, 2004; E-mail: arunghos@uic.edu
Amphidinolides are a family of cytotoxic macrolides with
significant antitumor properties.1 However, the natural abundance
of amphidinolides is very limited and as a consequence, biological
studies have been severely hampered. Amphidinolide W, a novel
12-membered macrolide, has been recently isolated from the marine
dinoflagellate Amphidinolide sp.2 The chemical structure of 1 was
elucidated mainly on the basis of spectroscopic studies. The absolute
configurations of the five chiral centers of 1 have been determined
by using NMR studies of the MTPA esters of 1 and its degradation
products. Amphidinolide W exhibited potent cytotoxicity against
murine lymphoma L1210 cells. Also, it is quite unique as it is the
first and only macrolide in its family without an exomethylene unit.3
Herein, we report the first total synthesis of amphidinolide W (2)
and a revision of its C6 absolute stereochemistry (1).
As outlined in Figure 1, our synthetic strategy for amphidinolide
W involves the assembly of C1-C9 segment 3 and C10-C20
segment 4 by cross metathesis of two terminal olefins, functional
group transformation, followed by macrolactonization. Further
disconnection of fragment 3 at the C3-C4 bond leads to keto-
phosphonate 5 and aldehyde 6. Subunit 4 was planned to be derived
Figure 1. Retrosynthetic analysis of amphidinolide W.
from lactone 7, which would be synthesized using asymmetric
dihydroxylation and alkylation as the key steps.
Scheme 1 a
The synthesis of segment 3 is outlined in Scheme 1. The synthesis
began with methylation of oxazolidinone derivative 84 at -78 °C
to provide 9 diastereoselectively (ratio 15:1). Basic hydrolysis of
9 and subsequent amidation afforded Weinreb amide 10. Treatment
of 10 with lithiated phosphonate gave â-ketophosphonate 5.
Horner-Emmons reaction between 5 and aldehyde 65 furnished
the corresponding E-enone exclusively without any epimerization.6
Reduction of the resulting enone with Red-Al gave the correspond-
ing ketone7 which was protected as a dioxalane to afford 3.
Synthesis of 4 is outlined in Scheme 2. Asymmetric dihydroxyl-
ation8 of diene 119 with AD-mix-R furnished the hydroxy-γ-
lactone10 which was protected as a TIPS-ether to furnish lactone
12. Alkylation of 12 with LDA and MeI at -78 °C afforded 7 as
the major diastereomer (11:1 dr).11 Dibal-H reduction of 7 and
subsequent Wittig reaction of the resulting hemiacetal provided
E-olefin 13 exclusively. Alcohol 13 was converted to 4 by formation
of the MOM-ether, deprotection of the TIPS-ether, followed by
acetylation of the resulting alcohol.
Our assembly of the above subunits 3 and 4 by the key cross
metathesis12 is shown in Scheme 3. Among various protecting
groups and catalysts surveyed, we found that the acetate protecting
group and second generation Grubbs’ catalyst13 gave the optimum
result, affording 14 along with its Z-isomer (E:Z ratio 11:1) in 85%
yield. Dibal-H reduction of 14, protection of the primary alcohol
as the pivalate and the secondary alcohol as a TIPS ether, followed
by reduction of pivalate with Dibal-H afforded 15 in 78% yield
for four steps. Alcohol 15 was then converted to allylic bromide
16. Formation of the phosphonium salt and subsequent Wittig
reaction with propionaldehyde exclusively furnished E-olefin 17.
This was converted to acid 18 by deprotection of both TIPS groups,
a Conditions: (a) NaHMDS, MeI, -78 °C, 87%; (b) LiOOH, aqueous
THF, 0 °C; (c) MeONHMe‚HCl, N-methylpiperidine, iBuOCOCl, -15 °C,
92% (two steps); (d) nBuLi, MePO(OMe)2, -78 °C, 96%; (e) Ba(OH)2, 6,
THF/H2O, 85%; (f) Red-Al, CuBr, -20 °C, 90%; (g) p-TsOH, HOCH2-
CH2OH, (EtO)3CH, 55 °C, 90%.
protection of the resulting diol as a diacetate, lipase PS-30-catalyzed
selective removal of the primary acetate, followed by PDC oxidation
of the resulting alcohol. Hydrolysis of acetate provided acid 19.
Macrolactonization of 19 under Yamaguchi conditions14 afforded
macrolactone 20 along with its C2-epimer 21 in 47% combined
yield (3:1 mixture). Treatment of 20 with PPTS in aqueous acetone
followed by BF3‚OEt2 removed the oxalane and MOM groups,
furnish the presumed structure of amphidinolide W (1). Unfortu-
nately, the 1H and 13C NMR spectra for 1 and for its C2-epimer 22
are not identical to those reported for natural amphidinolide W.2
Further comparison of the spectra of our synthetic proposed am-
phidinolide W (1) and the reported spectra of natural amphidinolide
W revealed subtle discrepancies in the chemical shifts for the C6-
chiral center. On the basis of these chemical shifts variations, we
elected to synthesize the C6-epimer (R-configuration) of the
9
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J. AM. CHEM. SOC. 2004, 126, 3704-3705
10.1021/ja049754u CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
Scheme 4 a
a Conditions: (a) AD-mix-R, MeSO2NH2, t-BuOH, H2O, 0 °C, 43%;
(b) TIPSOTf, 2,6-lutidine, 99%; (c) LDA, MeI, -78 °C, 82%; (d) Dibal-
H, CH2Cl2, -78 °C; (e) Ph3PdC(CH3)CO2Et, CH2Cl2, 45 °C, 92% (two
steps); (f) MOMCl, iPr2NEt, 94%; (g) TBAF, THF, 98%; (h) Ac2O, Et3N,
DMAP, 94%.
Scheme 3 a
i
a Conditions: (a) NaHMDS, MeI, -78 °C, 87%; (b) Pr2NEt, 2,4,6-
Cl3C6H2COCl, then DMAP, PhH 80 °C, 50%; (c) PPTS, acetone/H2O, 40
°C; (d) BF3‚OEt2, Me2S, -20 °C, 50% (two steps).
amphidinolide W (2, [R]23 +8.1, c 1, CHCl3),15 whose spectral
D
data (1H and 13C NMR) are identical to those of natural amphi-
dinolide W.2
In summary, we have achieved the first total synthesis of
amphidinolide W (2) and made a revision of the C-6 stereochemistry
of structure 1 originally proposed for natural amphidinolide W.
Acknowledgment. We thank the University of Illinois at
Chicago for financial support.
Supporting Information Available: Experimental procedures and
1H and 13C NMR spectra for compounds 1-26 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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a Conditions: (a) (H2IMes)(PCy3)(Cl)2RudCHPh (5 mol %), CH2Cl2,
45 °C, 85%; (b) Dibal-H, -78 °C, 88%; (c) PivCl, Py, 93%; (d) TIPSOTf,
2,6-lutidine, 99%; (e) Dibal-H, -78 °C, 96%; (f) CBr4, PPh3, 0 °C, 95%;
t
(g) PBu3, CH3CN; then BuOK, CH3CH2CHO, PhH/THF, 0 °C, 90%; (h)
TBAF, THF, 99%; (i) Ac2O, Et3N, DMAP, 94%; (j) lipase PS-30, pH )
7.4, 95%; (k) PDC, DMF, 75%; (l) K2CO3, MeOH, 89%; (m) iPr2NEt, 2,4,6-
Cl3C6H2COCl, then DMAP, PhH 80 °C, 47%; (n) PPTS, acetone/H2O, 40
°C, 87%; (o) BF3‚OEt2, Me2S, -20 °C, 60%.
(7) The desired 1,4 addition product was obtained in 90% yield along with
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proposed structure 1. As shown in Scheme 4, asymmetric alkylation
of ent-8 provided epi-9 as a 12:1 mixture which was converted to
C6-epimeric seco acid 23 following the synthetic steps described
in Schemes 1 and 3. Macrolactonization14 of 23 provided macro-
lactones 24 and 25 as a 1:1 mixture in 50% combined yield. Many
attempts to improve the ratio for 24 have been so far unsuccessful.
The stereochemical identities of the C2-methyl group of 24 and 25
were established by NOESY experiments. To our delight, removal
of oxalane and MOM-protecting groups of 24 provided synthetic
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(11) The trans-stereochemistry is assigned on the basis of NOESY experiments.
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(15) Optical rotation for natural amphidinolide W has not been reported.
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