Total Synthesis of the Marine Macrolide Amphidinolide F

Article abstract of DOI:10.1021/acs.orglett.8b01020

A new and efficient convergent approach toward the synthesis of amphidinolide F is described through the assembly of three fragments. The two trans-tetrahydrofurans were built by a diastereoselective C-glycosylation with titanium enolate of bulky N-acetyloxazolidinethiones. The side chain was inserted by a Liebeskind-Srogl cross-coupling reaction. A sulfone condensation/desulfonylation sequence, a Stille cross-coupling, and a macrolactonization were applied to connect the fragments.

Full text of DOI:10.1021/acs.orglett.8b01020

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of the Marine Macrolide Amphidinolide F
Laurent Ferrie,* Johan Fenneteau, and Bruno Figadere*
́
̀
BioCIS, Univ. Paris-Sud, CNRS, Universite
́
Paris-Saclay, 92290 Chat
̂
enay-Malabry, France
S
* Supporting Information
ABSTRACT: A new and efficient convergent approach toward
the synthesis of amphidinolide F is described through the
assembly of three fragments. The two trans-tetrahydrofurans
were built by a diastereoselective C-glycosylation with titanium
enolate of bulky N-acetyloxazolidinethiones. The side chain was
inserted by a Liebeskind−Srogl cross-coupling reaction. A sulfone
condensation/desulfonylation sequence, a Stille cross-coupling,
and a macrolactonization were applied to connect the fragments.
Scheme 1. Retrosynthetic Analysis of Amphidinolide F (1)
mphidinolides are part of a large family of macrolides
Acontaining more than 30 members, all isolated from
different strains or species of the dinoflagellate Amphidinium.1
Amphidinolides F (1),2 C (2),3 C2 (3),4 and C35 (4)
particularly drew our attention due to the presence of two
trans-tetrahydrofurans, 11 to 12 stereogenic centers, and two
diene frameworks at C9−C11 and at C25−C28, which make
these molecules unique in their family. These marine natural
products are very similar in terms of structure, exhibiting the
same macrolactone. As a consequence, the stereochemical
assignment of amphidinolide F (1) was originally deduced from
its analogy with amphidinolide C (2). The differences rely only
on the side chain, amphidinolide F (1), being six carbons
shorter. On the other hand, amphidinolide C (2) contains one
more stereogenic center at C29, and natural derivatives C2 (3)
and C3 (4) show differences only at this position, with the
hydroxyl group being acylated for 3 and oxidized for 4 (Figure
1).
These amphidinolides show significant cytotoxic activities
against some cancer cell lines. Amphidinolide C (2) is
particularly active on murine lymphoma L1210 and human
epidermoid carcinoma KB cells lines (IC50 of 5.8 and 4.6 ng/
mL respectively),3 while a reduced cytotoxicity is observed for
1 (1.5 and 3.2 μg/mL),2 3 (0.8 and 3.0 μg/mL),4 4 (7.6 and
10.0 μg/mL).5 Amphidinolides F (1) and C (2) have received a
great interest from organic chemists, producing numerous
synthetic approaches6 to these macrolides and finally
culminating to two total syntheses of both amphidinolide F
(1) and C (2).7,8 We describe herein our achievement of the
total synthesis of amphidinolide F (1).
From a retrosynthetic point of view, we initially planned to
construct the THF ring using a C-glycosylation to form the
Received: March 30, 2018
Figure 1. Structures of amphidinolide F, C, C2, and C3.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01020
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Organic Letters
Letter
Scheme 2. Synthesis of the C18−C29 Fragment (5)
Scheme 3. Synthesis of the C10−C17 Fragment (6)
trans selectivity because of steric bulk,12 favoring the reaction
on the most reactive oxonium conformer. Thus, when ketal 10
reacted with titanium enolate of oxazolidinethione 11, trans-
THF 12 was isolated after methanolysis of the auxiliary as
almost the sole diastereomer (86%, dr ≥ 95:5). As we
envisioned, construction of a thioester moiety was required to
directly introduce the corresponding dienic side chain using a
chemoselective Liebeskind−Srogl cross coupling.13 Therefore,
the hydroxyl group was deprotected and oxidized into
carboxylic acid 13 with in situ generation of ruthenium
tetroxide.14 Carboxylic acid 13 was then transformed into
thioester 14, through activation into an acyl chloride followed
by reaction with thiocresol. As we initially carried out the cross
coupling with the corresponding boronic acid derivative 15a6r
in the presence of CuTC (copper thiophene carboxylate) and
Pd2dba3/P(OMe)3, we observed nonreproducible results (15−
61%) in the formation of dienone 16 due to the instability of
boronic acid 15a. However, ketone 16 was obtained in a 70%
yield when more stable stannane 15b was used for the cross-
coupling in conjunction with the use of CuDPP (copper
diphenylphosphinate) and Pd2dba3/P(o-fur)3.15 Moreover, we
also experienced that the synthesis of 15b is shorter and more
practical than that of 15a (three steps vs six). Reduction of
dienone 16 using Luche conditions16 at −78 °C gave us the syn
product 17 in a polar Felkin−Anh fashion selectivity (dr ≥
90:10).6n Finally, the hydroxyl group was etherified with a
C19−C20 bond.6i,r Unfortunately, we found from model
experiments that the diene framework was not compatible
with the generated oxonium intermediate during this reaction.
Therefore, we changed this disconnection in order to perform
the C-glycosylation reaction prior to the diene installation.
Following this idea, we envisioned forging the macrolactone
core with a sulfone condensation/desulfonylation sequence to
connect 5 (C18−C29) to 6 (C10−C17) and a Stille cross
coupling to attach the subunit 7 (C1−C9), followed by a
macrolactonization (Scheme 1). Fragments 5, 6, and 7 could be
synthesized through high diastereoselective reactions from
chiral synthons easily accessible from the chiral pool or from
well-known asymmetric reactions (e.g., Sharpless asymmetric
epoxidation of allylic alcohol).
The synthesis of C18−C29 subunit 5 started from chiral
lactone 8,9 which was protected as a TBDPS (tert-
butyldiphenylsilyl) ether, and compound 9 was then subjected
to DIBALH reduction/acetylation to lead to activated ketal
10.10 C-Glycosylation of ketals derived from 5-substituted THF
is known to usually be a low selective process due to a
competition between the lowest energy oxonium conformer,
leading to the cis-THF, and the most reactive oxonium
conformer, leading to the trans-THF.11 Nevertheless, the use
of the titanium enolate of oxazolidinethione 11 showed a good
B
DOI: 10.1021/acs.orglett.8b01020
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Scheme 4. Synthesis of Amphidinolide F (1)
fragile TMS protecting group, and the ester was converted into
aldehyde 5 by using a selective reduction with DIBALH
(Scheme 2).
protection with TES ether, compound 24 was obtained.
Functionalization of the terminal alkyne present in compound
24 was troublesome. Negishi’s zirconium catalyzed carboalumi-
nation21 or stannylcupration followed by iodolysis22 did not
allow us to set up the required functionalities. Thus, a reported
four-step approach23 was successfully applied to our substrate,
giving rise to the accomplishment of the synthesis of fragment
C10−C17 (6). A palladium mediated regio- and stereoselective
trimethylsilyl-stannylation of alkyne 24 gave product 25.24
Then iodolysis of the stannane, followed by a substitution of
iodide by dimethylcuprate, afforded compound 26. Final
iodolysis of TMS with NIS25 in MeCN/CH2Cl2 ended the
sequence toward subunit 6 (Scheme 3).
The linkage of subunits 5 and 6 was briefly studied. It was
found that base, concentration, and temperature were
important parameters for the success of the sulfone
condensation. Therefore, sulfone 6 was best deprotonated at
0 °C26 with LDA and aldehyde 5 was then added at −78 °C,
followed by a slow warming to 0 °C delivering a complex
mixture of four diastereomers. A two-step sequence including
2,6-lutidine buffered Dess-Martin oxidation of C18 alcohol and
SmI2 mediated desulfonylation at −78 °C, afford compound 27
(Scheme 4, box).
In parallel, the synthesis of subunit C10−C17 (6) was
conducted. The inherent symmetry of the C12−C16 segment
could be advantageously exploited by using ring-openings of
epoxides with different nucleophiles. The use of an
orthogonally protected hydroxyl group at C15 would selectively
generate the ketone function in a later stage. Thus, commercial
alkyne 18 was selectively reduced to the corresponding (Z)-
olefin with Pd/BaSO4−quinoline, and a Sharpless asymmetric
epoxidation was performed using cumyl hydroperoxide to
obtain epoxy alcohol 19 (er = 93:7) (Scheme 3).17 The
protection/activation of the hydroxyl group as tosylate 20
allowed us to accomplish the ring-opening of the epoxide
exclusively on its less hindered side with the help of a
trimethylaluminum “ate” complex derived from TMS-acetylene
in combination with BF3·OEt2.18 The tosylate was then
internally displaced by the generation of sodium alkoxide to
give terminal epoxide 21. A second epoxide ring−opening was
carried out with (Z)-propenyl Grignard in the presence of CuI
giving (Z)-homo allyl alcohol 22. The two new stereogenic
centers were installed by a VO(acac)2 directed−epoxidation
and gave almost exclusively a single diastereomer (dr = 43:1).19
The protection of the hydroxyl as a TBS ether and
methanolysis of TMS alkyne protecting group afforded
compound 23. The last epoxide ring opening was performed
with lithiated methylphenylsulfone in synergy with BF3·OEt2.20
The transformation was quantitative, but a mixture of
regioisomers, in a separable 71:29 ratio, was obtained.
Fortunately the lithium anion added preferentially on the less
hindered face of the epoxide, and after an orthogonal
The next step was the introduction of the last C1−C9
fragment. Subunit C1−C9 was synthesized using a strategy
reported by us based on a vinylogous Mukaiyama aldol reaction
followed by a C-glycosylation with an oxazolidinethione.6i Early
studies indicated that the Stille cross-coupling with methyl ester
28 was effective using the copper-mediated Liebeskind’s
protocol27 with a 45−55% yield range depending on the
coupling partners. However, we later experienced some
difficulties to cleanly saponify the corresponding methyl ester
C
DOI: 10.1021/acs.orglett.8b01020
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Organic Letters
Letter
of such complex molecules. Thus, we decided to perform the
Stille coupling between the free acid 7, obtained by reaction of
28 with TMSOK,28 and vinyl iodide 27 (Scheme 4). As we
anticipated proto-demetalation issues between the free acid and
the in situ generated vinyl copper species, we decided to treat
first free acid 7 with NaH in DMF followed by addition of vinyl
iodide 27 and other reagents needed. We were pleased to note
that the cross-coupling was very effective, although it resulted in
a partial TMS deprotection. Therefore, treatment of the crude
reaction mixture with dilute HCl selectively removed TMS
ether and afforded, after purification, compound 29 (72%
yield). The macrolactonization took place using Yamaguchi
reagent,29 affording compound 30 as a 3:1 mixture of at least
two major conformers detectable by NMR.7,8 The TES group
at C15 was selectively cleaved employing HF·pyridine in THF/
pyridine30 giving a complex mixture of hydroxyketone and
ketals in equilibrium. The probable presence of conformers
makes this intermediate very difficult to characterize. Never-
theless, we can establish that the ketal form seems predominant
due to the absence of the ketone absorption band (νC=O) at
1715 cm−1 in the infrared spectrum. The oxidation of hydroxyl
Bruno Figadere: 0000-0003-4226-8489
Notes
̀
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by ANR through AMPHICTOT
program (ANR-11-BS07-0028). We thank Karine Leblanc
■
(BioCIS, Chat
our gratitude to ICSN and especially Jean-Franco
̂
enay-Malabry) for HRMS analysis. We express
is Gallard
̧
(CNRS, Gif-sur-Yvette, France) for experiments of our
synthetic sample of amphidinolide F on a 800 MHz NMR
spectrometer.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: laurent.ferrie@u-psud.fr.
*E-mail: bruno.figadere@u-psud.fr.
ORCID
Laurent Ferrie: 0000-0002-1171-205X
́
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Johan Fenneteau: 0000-0003-4181-3035
D
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