Enantioselective total synthesis of amphidinolide F

Article abstract of DOI:10.1002/anie.201203935

A common-intermediate approach is utilized in the total synthesis of amphidinolide F (see scheme, left) to access both the C1-C8 and the C18-C25 portions of the macrolide. A silver-catalyzed rearrangement/cyclization was employed to construct the two tetrahydrofuran rings. A Felkin-controlled, dienyl lithium addition to an α-chiral aldehyde incorporated both the C9-C11 diene and the alcohol at C8. An umpolung sulfone alkylation/oxidative desulfurization sequence is employed to couple the two moieties. Copyright

Full text of DOI:10.1002/anie.201203935

Angewandte
Chemie
DOI: 10.1002/anie.201203935
Hidden Symmetry
Enantioselective Total Synthesis of Amphidinolide F**
Subham Mahapatra and Rich G. Carter*
Over 30 members of the diverse amphidinolide family of
biologically active macrolides have been isolated from the
dinoflagellate Amphidinium sp.[1] From this family, amphidi-
nolides C (1–2)[2] and F(3)[3] are among the most complex and
densely functionalized members (Scheme 1).[4] These natural
5 and iodide 6 through an umpolung strategy,[7] involving
a sulfone alkylation/oxidative desulfurization sequence,[6a,8]
which would mask the otherwise challenging 1,4-dicarbonyl
functionality. We noticed considerable “hidden” symmetry
within the tetrahydrofuran (THF) portions of fragments 5 and
6. Specifically, the C1–C8 and the C18–C25 portions contain
nearly identical functionalization, oxidation states, and ste-
reochemistry. This observation led us to propose that com-
pounds 5 and 6 might be accessible via common intermediate
7. Ketone 7 should provide access to over half of the carbon
backbone of the macrocycle as well as the majority of the
stereochemistry present in amphidinolide F.
Synthesis of common intermediate
7 is shown in
Scheme 3. Starting from known alcohol 8,[9] oxidation and
Ohira–Bestmann reaction[10] cleanly provided alkyne 10.
Removal of the benzylidine acetal under acidic conditions
followed by protection and Sonogashira cross-coupling pro-
vided enyne 13. Sharpless asymmetric dihydroxylation gave
diol 14 in excellent yield and diastereoselectivity.[11] Building
on the work from Gagosz[12] and Krause,[13] we had hoped to
use a gold-catalyzed cyclization to generate enol ether 16. The
presence of the 1,2-diol moiety complicates any cyclization
conditions, as both furan and pyran formation might be
possible. Unfortunately, all attempts to facilitate this trans-
formation under Au catalysis failed to generate the desired
product. Fortunately, we found that AgBF4[14] nicely provided
desired dihydrofuran 16 in good yield and complete stereo-
selectivity (d.r. > 20:1). This transformation was routinely
performed on 5-gram scale and provided sufficient quantities
Scheme 1. Structurally complex amphidinolide natural products.
products 1–3 contain eleven stereogenic centers embedded
within a 25-membered macrolactone including two trans-
disposed tetrahydrofuran ring systems, a 1,4-diketone motif,
and a highly substituted diene moiety at C9–C11. In addition
to the sizable structural challenges present in 1–3, these
macrolides have shown significant cytotoxic activity.[2,3] Con-
sequently, compounds 1–3 have attracted considerable syn-
thetic attention from numerous laboratories,[5] including our
own.[6] Despite these sizable endeavors,[5,6] neither amphidi-
nolide C nor amphidinolide F have been successfully synthe-
sized in the more than 20 years since their isolation. It should
be noted that the stereochemical assignment of compound 3 is
based on analogy to compound 1 and isolation from the same
organism. Herein, we disclose the first total synthesis of
amphidinolide F (3), and thus confirm both the absolute and
relative stereochemistry of the natural product.
Our initial disconnection in the retrosynthesis involved
cleavage of the macrolactone linkage at C1 to provide ketone
4 (Scheme 2). This ketone 4 should be accessible from sulfone
[*] S. Mahapatra, Prof. Dr. R. G. Carter
Chemistry Department, Oregon State University
Corvallis, OR 97331 (USA)
E-mail: rich.carter@oregonstate.edu
[**] Financial support was provided by the National Institutes of Health
(NIH) (GM63723) and Oregon State University (Harris and
Shoemaker Fellowships for SM). Prof. Takaaki Kubota and Jun’ichi
Kobayashi (Hokkaido University) are acknowledged for providing
a copy of the 1H NMR spectra for compound 3, and Prof. Max
Deinzer and Jeff Morrꢀ (OSU) for mass spectra data. Dong Su is
acknowledged for assistance in the synthesis of additional amounts
of early building block fragment 11 and Somdev Banerjee for
synthesis of known iodide 12. Finally, the authors are grateful to
Prof. James D. White (OSU) and Dr. Roger Hanselmann (Rib-X
Pharmaceuticals) for their helpful discussions
Scheme 2. Retrosynthetic analysis of amphidinolide F. EE=ethox-
yethyl, Piv=pivaloyl, TBS=tert-butyldimethylsily, TES=triethylsilyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203935.
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Scheme 3. Synthesis of common intermediate. Bz=benzyl, CSA=10-
camphorsulfonic acid, DMAP=4-dimethylaminopyridine, DMSO=di-
methyl sulfoxide, 2,6-Lut=2,6-lutidine, Pyr=pyridine, Tf=trifluorome-
thylsulfonyl.
Scheme 4. Synthesis of the C1–C14 subunit. AIBN=azobisisobutyroni-
trile, DMP=Dess–Martin periodinane, DMPU=1,3-dimethyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidinone, Im=imidazole, LDA=lithium diiso-
propylamide, TMS=trimethylsilyl.
of 16, which might serve as a building block for a variety of
trans-disposed furan-containing natural products. Subsequent
silyl protection and removal of the enol benzoate with
MeLi·LiBr[15] produced common intermediate 7.
this rearrangement occurring under the reaction conditions.
Generation of a related vinyllithium species via a hydrazone
using Shapiro conditions led to extensive decomposition.
After silylation at C8, incorporation of the iodide at C14
through a two-step sequence provided fragment 6.
Synthesis of the C1–C14 subunit is shown in Scheme 4. We
had hoped to directly trap the enolate derived from ketone 7
with methyl iodide to generate the C4-methyl derivative 20;
however, the stereochemistry at C6 appeared to be the
dominant stereocontrolling element in the alkylation and
resulted in the undesired C4-methyl stereochemistry. Fortu-
nately, we were able to exploit this directing effect to our
advantage through hydrogenation of the exo-methylene
compound 19 using Wilkinsonꢀs catalyst to provide the
correct stereochemical combination 20. Deoxygenation of
the carbonyl group at C5 followed by deprotection and
oxidation at C8 generated aldehyde 22. Next, we required the
stereoselective addition of a 2-metallo-1,3-diene species to a-
silyloxy aldehyde 22. Precursor 27 was prepared in four steps
from previously reported iodide 24[6a] through a regioselective
hydrostannylation of enyne 25. This regiochemistry is counter
to what is typically observed with most Pd-catalyzed hydro-
stannylations.[16] Treatment of iodide 27 with nBuLi followed
by addition to aldehyde 22 provided the C8–C9 coupled
material in good yield and reasonable diastereoselectivity
(d.r. = 3:1).[17] We had been concerned that the organolithium
species might undergo 1,3-metallotropic shifts[18] to generate
allenyl metallo species as well as scramble the E/Z olefin
geometry at C10–C11; however, we did not see evidence of
The construction of the second major fragment was also
accomplished with common intermediate 7 (Scheme 5). As
before, deoxygenation at C22 easily provided tetrahydrofuran
28. Removal of the pivolate at C18 followed by oxidation
generated aldehyde 29. Addition of the organolithium species
derived from known iodide 30[19] provided secondary alcohols
31 and 32 as an inseparable mixture of stereoisomers. We
initially had hoped to convert the alcohol at C18 into its
corresponding dimethyl ketal by oxidation followed by
ketalization under Noyori conditions. This approach had
proven productive in our prior model system.[6] While the
oxidation was effective, we were never able to ketalize the
corresponding ketone under a diverse array of conditions.
Consequently, we chose protection of alcohol(s) 31 and/or 32
as its/their ethoxyethyl (EE) ether as a viable alternative.
While we believe that both C18 alcohols 31 and 32 are viable
compounds for the synthetic sequence, we proceeded forward
with C18-S isomer 31[17] for practicality reasons, including
simplification of NMR spectra. Oxidation of the mixture of 31
and 32 with TPAP and NMO followed by reduction with
lithium tri-sec-butylborohydride (L-Selectride) gave C18-S
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key a-oxy aldehyde 35. We
had initially planned to
exploit Julia–Kocienski–Bla-
kemore olefination[20] of this
aldehyde with the known PT
sulfone;[21] however, this reac-
tion showed a preference for
the undesired cis alkene.
While alternate, multi-step
solutions have been devel-
oped to circumvent this prob-
lem,[5c,j] we continued to look
for a direct solution. Fortu-
nately, use of the Vedejs-type
tributyl phosphonium salt
36[22]
cleanly
generated
desired E alkene 37 in good
selectivity (97% yield, E:Z =
11:1). Exchange of the silyl
protecting groups at C24 pro-
vided C15–C29 fragment 5.
The completion of the
total synthesis of amphidino-
lide F is shown in Scheme 6.
The key coupling of the major
fragments was accomplished
by treatment of sulfone 5 with
Scheme 5. Synthesis of the C15–C29 subunit. Bn=benzyl, IPA=isopropyl alcohol, NMO=4-methylmorpho-
line-N-oxide, TPAP= tetra-n-propylammonium perruthenate, PPTS=pyridinium toluene-p-sulfonate, TBAF=
tetra-n-butylammonium fluoride.
isomer 31 in high distereoselectivity (31:32 = 15:1, 85% yield
over two steps). After EE protection of alcohol 31, debenzy-
lation, and incorporation of the sulfone moiety at C15
provided compound 34. Selective deprotection of the primary
TBS ether using HF·Pyr followed by Swern oxidation gave
LHMDS and HMPA followed by the addition of alkyl halide
6, smoothly forming C14–C15 coupled material 38.[6a] The
nucleophilicity of sulfone carbanions was instrumental in the
success of this challenging coupling between an a-branched
alkyl iodide and an a-branched nucleophile.[23] Next, oxida-
Scheme 6. Total synthesis of amphidinolide F. brsm=based on recovered starting material, HMPA= hexamethylphosphoramide, LAH=lithium
aluminum hydride, LHMDS=lithium hexamethyldisilazanide.
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data (1H NMR, 13C NMR, [a]D).[3]
In summary, the total synthesis of amphidinolide F has
been accomplished in 34 steps (longest linear sequence).
Highlights of the synthetic sequence include a silver-catalyzed
dihydrofuran formation, use of common intermediate 7 to
access both the C1–C8 and C18–C25 fragments, regioselective
hydrostannylation of enyne 25, diasteroselective addition of
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Received: May 22, 2012
Published online: && &&, &&&&
Keywords: asymmetric synthesis · diene · macrolide ·
.
silver catalysis · umpolung
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4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Hidden Symmetry
S. Mahapatra,
R. G. Carter*
&&&& — &&&&
Enantioselective Total Synthesis of
Amphidinolide F
A common-intermediate approach is uti-
lized in the total synthesis of amphidi-
nolide F (see scheme, left) to access both
the C1–C8 and the C18–C25 portions of
the macrolide. A silver-catalyzed rear-
rangement/cyclization was employed to
construct the two tetrahydrofuran rings. A
Felkin-controlled, dienyl lithium addition
to an a-chiral aldehyde incorporated both
the C9–C11 diene and the alcohol at C8.
An umpolung sulfone alkylation/oxidative
desulfurization sequence is employed to
couple the two moieties.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!