Exploiting hidden symmetry in natural products: Total syntheses of amphidinolides C and F

Article abstract of DOI:10.1021/ja404796n

The total synthesis of amphidinolide C and a second-generation synthesis of amphidinolide F have been accomplished through the use of a common intermediate to access both the C₁-C₈ and the C₁₈-C ₂₅ sections. The development of a Ag-catalyzed cyclization of a propargyl benzoate diol is described to access both trans-tetrahydrofuran rings. The evolution of a Felkin-controlled, 2-lithio-1,3-dienyl addition strategy to incorporate C₉-C₁₁ diene as well as C₈ stereocenter is detailed. Key controlling aspects in the sulfone alkylation/oxidative desulfurization to join the major subunits, including the exploration of the optimum masking group for the C₁₈ carbonyl motif, are discussed. A Trost asymmetric alkynylation and a stereoselective cuprate addition to an alkynoate have been developed for the rapid construction of the C₂₆-C₃₄ subunit. A Tamura/Vedejs olefination to introduce the C₂₆ side arm of amphidnolides C and F is employed. The late-stage incorporation of the C₁₅, C₁₈ diketone motif proved critical to the successful competition of the total syntheses.

Full text of DOI:10.1021/ja404796n

Article
pubs.acs.org/JACS
Exploiting Hidden Symmetry in Natural Products: Total Syntheses of
Amphidinolides C and F
Subham Mahapatra and Rich G. Carter*
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, United States
S
* Supporting Information
ABSTRACT: The total synthesis of amphidinolide C and a
second-generation synthesis of amphidinolide F have been
accomplished through the use of a common intermediate to
access both the C1−C8 and the C18−C25 sections. The
development of a Ag-catalyzed cyclization of a propargyl
benzoate diol is described to access both trans-tetrahydrofuran
rings. The evolution of a Felkin-controlled, 2-lithio-1,3-dienyl
addition strategy to incorporate C9−C11 diene as well as C8
stereocenter is detailed. Key controlling aspects in the sulfone
alkylation/oxidative desulfurization to join the major subunits, including the exploration of the optimum masking group for the
C18 carbonyl motif, are discussed. A Trost asymmetric alkynylation and a stereoselective cuprate addition to an alkynoate have
been developed for the rapid construction of the C26−C34 subunit. A Tamura/Vedejs olefination to introduce the C26 side arm of
amphidnolides C and F is employed. The late-stage incorporation of the C15, C18 diketone motif proved critical to the successful
competition of the total syntheses.
INTRODUCTION
■
Natural products continue to yield medicinally relevant leads
for the treatment of human disease1 as well as an inspiration for
the development of new synthetic strategy and chemical
methodology for their construction.2 Macrolides such as
epothilones,3 apoptolidins4 and bryostantins5 historically have
provided a rich source of inspiration in both of these areas. The
amphidinolide family of macrolides embodies another such
collection of natural products that provides synthetic
inspiration through their challenging architecture with equally
intriguing biological functionparticularly cytotoxic activity
against multiple cancer cell lines.6
While multiple total syntheses of many members of this
family have been reported,7 certain important subfamilies
remain unaddressed. Of these unaddressed subfamilies, our
laboratory became particularly interested in amphidinolides C
and F, as they possess challenging (and identical) macrocyclic
core and intriguing biological profile (Figure 1). Both
amphidinolides C and F have attracted considerable synthetic
attention8 including from our own laboratory;9 however, no
total synthesis of either compound had been reported prior to
our efforts.10,11 Amphidinolide C was isolated from the genus
Amphidinium (Y-5, Y-56, Y-59 and Y-71 stains) in extremely
small amounts (0.0015% yield) by Kobayashi and co-workers.12
The relative stereochemistry of 1 was determined by 1D and
2D NMR techniques and the absolute stereochemistry was
Figure 1. Amphidinolides C, F and U.
have been identified which bear esterification or oxidation at
C29.13 Kobayashi has also reported the isolation of
amphidinolide U (5). This compound contains the same side
established through degradation and Mosher ester analysis.12
1
exhibits impressive cytotoxic activity in multiple cancer cell
lines (murine lymphoma L1210 cells: IC50 = 5.8 ng/mL and
human epidermoid carcinoma KB cells: IC50 = 4.6 ng/mL).12
Subsequently, additional variants (amphidinolides C2 and C3)
Received: May 13, 2013
Published: July 11, 2013
© 2013 American Chemical Society
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arm as amphidinolide C (1), but a simplified version of the
macrocyclic core and has shown significantly reduced
cytotoxicity data.14 Amphidinolide F (4) has also been isolated
in limited qualities (0.00001% wet weigh yield) bearing an
identical macrcocyclic core, but with a simplified side arm.15
Interestingly, amphidinolide F shows greatly reduced cytotoxic
activity as compared to 1.15 While the relative and absolute
configurations of amphidinolide C had been established by
Kobayashi, the definitive confirmation of the absolute stereo-
chemistry of amphidinolide F and its relationship to
amphidinolide C was not established until our laboratory
completed its total synthesis in 2012.10 In this article, we
provide a full account of our synthetic efforts toward
amphidinolide F as well as the first reported total synthesis of
amphidinolide C.
has received comparatively limited attention for the synthetic
community.19 This umpolung approach also would allow us to
regulate when the C15 carbonyl is incorporated while avoiding
potential complications with dithiane chemistry.20 The iodide 9
could be accessed from the vinyl iodide 11 and Weinreb amide
10 by an organolithium coupling followed by methylenation.
Prior to embarking on the total syntheses of compounds 1−4,
we felt it would be prudent to study both our C9−C11 diene
strategy and sulfone alkylation/oxidative desulfurization
sequence on a C7−C20 model compound 12.
Our successful studies9a on model compound 12 embarked
from the readily available dienyl iodide 1321 (Scheme 2).
Scheme 2. Synthesis of C7−C20 Segment: A Model Study
RESULTS AND DISCUSSION
Our retrosynthetic strategy for accessing amphidinolides C and
F is shown in Scheme 1. We envisioned formation of the 25-
■
Scheme 1. Retrosyntheses for Amphidinolides C−C3 and F
Sharpless epoxidation22 followed by silyl protection produced
14. Me3Al-mediated opening of vinyl iodide/allyl epoxide 14
provided preferential SN opening at C12.23 Our originally
2
published conditions proved somewhat scale dependent,9a but
we found that modified conditions (portion-wise addition of
reduced equivalents of AlMe3 and lowered reaction temper-
ature to −90 °C) gave reliable results on gram scale (>1.5 g
scale, 98%, 10:1 dr). Subsequent silylation of C13 alcohol
provided 11. Halogen/metal exchange and coupling with the
Weinreb amide 159a followed by methenylation using Petasis
conditions yielded the diene 16 with no observable E/Z
isomerization. 1D NOE analysis confirmed that the desired
olefin geometry was present after methylenation. Selective
membered macrocycle through Yamaguchi macrolactonization.
Next, we planned to join the two major subunits and
incorporate the C15 carbonyl through a sulfone alkylation/
oxidative desulfurization sequence.16 The nucleophilicity of
sulfone carbanions is a powerful tool for the construction of
sterically congested linkages such as the C14−C15 bond, in
which branching at neighboring C13 and C16 would normally
inhibit such strategies.17 Oxidative desulfurization is a chemical
transformation that has been known for decades;18 however, it
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removal of the C14 TBS ether and conversion to iodide
provided the requisite coupling partner 17. Next, our attention
turned to the key sulfone alkylation/oxidative desulfurization
sequence. The sulfone 18 (prepared in 9 steps from 3-hydroxy-
(2R)-methylpropionic acid methyl ester9a) was lithiated with
LHMDS in the presence of HMPA and added to iodide 17 to
cleanly provide the C14−C15 coupled material 19 in good yield
as a mixture of diastereomers at C15. Given the sterically
congested nature of both the nucleophile and electrophile, the
high efficiency of this coupling was rewarding. Next, the
oxidative desulfurization on sulfone 19 was examined. After
some experimentation, we found that deprotonation with LDA
in the presence of DMPU followed by the addition of
TMSOOTMS produced the desired ketone 12 in 51% isolated
yield (87% borsm).
Scheme 4. Synthesis of Cyclization Precursor
With an understanding that our strategy for the diene
portion and coupling the two major subunits was likely to
prove successful, we started our efforts toward the synthesis of
the two THF segments (Scheme 3). Central to this strategy
Scheme 3. Common Intermediate Approach to Major
Subunits
THF, 69% over 2 steps). Diol deprotection and subsequent
esterifications provided the propargyl benzoate 22. Sonogashira
coupling27 with known vinyl iodide 2328 generated the enyne
27. While this seven-step route provided access to the enyne 27
in multigram quantities, a more expedient route was feasible
through the known aldehyde 2829 and enyne 2930 using
Carreira’s asymmetric alkynylation31 with in situ benzoate ester
formation to provide 27 in four fewer steps (LLS). Sharpless
dihydroxylation with AD Mix β32,33 provided the cyclization
precursor 21 in high yield and excellent dr.
We were pleased to find that the desired metal-catalyzed
cyclization could be cleanly effected by treatment of 21 with
AgBF4 (10 mol %) in degassed benzene at 80 °C to produce
the trans-DHF 33 in 65−70% yield on 5 g scale (Scheme 5).
Interestingly, Au-catalyzed versions of this cyclization proved
unsuccessful in our hands. Key to this transformation was the
absence of light; performing this transformation in a lighted
room led to greatly diminished yield (∼25%). Selection of the
pivaloyl protecting group was also key as use of electron-rich
moieties (e.g., PMB, DMB) led to reduced yield (0−30%). In
addition to the desired DHF 33, a small amount (15%) of the
furan byproduct 35 was also produced. We hypothesize that
nucleophilic attack by the benzoate oxygen (marked in red) on
activated alkyne 30 might produce the allene species 32 via
stabilized carbocationic intermediate 31. Another silver-
mediated activation of allene 32 could promote the
nucleophilic attack by proximal alcohol moiety to deliver the
DHF 33 after protodemetalation. Alternately, byproduct 35
might arise from a competitive attack by the distal hydroxyl
nucleophile on activated alkyne 30 (marked in blue) to
generate the vinyl silver intermediate 34. Protodemetalation
followed by Lewis (or Bronsted) acid-activated aromatization
would produce the furan 35.
was the observation that a hidden symmetry element was
present within the macrocyclic core. The functionality and
stereochemistry of C1−C8 mapped nicely on the C18−C25
subunit. The lone exception to this correlation was the
presence of the C4 methyl moiety. We identified that both
the major fragments 9 and 8 could arise from a common
subunit 20. This subunit in turn should be accessible from the
propargyl benzoate/diol 21 through a metal-catalyzed cycliza-
tion. Pioneering work by Krause24 and Gagosz25 had
demonstrated that Au- or Ag-catalyzed processes were feasible;
however, neither Krause nor Gagosz has tested the potential of
this chemistry on diol systems such as 21 or in the presence of
considerable additional functionality.
Synthesis of the cyclization precursor 21 is shown in Scheme
4. Starting from the known alcohol 24 (available in two steps
from D-malic acid),26 Swern oxidation followed by alkyne
formation using the Ohira-Bestmann reagent 25 provided 26.
The alkyne 26 could also be accessed from the aldehyde via the
two-step Corey-Fuchs protocol (Ph3P, CBr4, CH2Cl2; n-BuLi,
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Scheme 5. Silver-catalyzed Cyclization to Dihydrofuran
Scheme 7. Initial Approach for C1−C14 Subunit
Synthesis of the common intermediate 20 is shown in
Scheme 6. While alcohol 33 proved to be unstable to prolonged
storage, protection as its TBS ether 36 quickly addressed that
shortcoming. Removal of the benzoate ester in presence of the
pivaloate (Piv) moiety was problematic. Fortunately, we found
that treatment with modulated methyl lithium (MeLi•LiBr)34
provided conditions that selectively cleaved the benzoate
moiety to reveal the in situ enolate 37 which was protonated
with aqueous ammonium chloride to provide the common
intermediate 20. A small amount of the pivaloate deprotected
product (∼10%) was observed under these conditions;
however, use of MeLi instead of MeLi•LiBr led to significantly
larger amount of depivaloated product.
Scheme 6. Synthesis of the Common Intermediate
stereocenter overrode the more proximate C3 position to
control the stereochemistry of this transformation. This
stereochemical bias was successfully harnessed by first
methylenation of the ketone 20 using Eschenmoser’s salt
followed by hydrogenation with Wilkinson’s catalyst to give the
desired stereochemical combination in 10:1 dr. In both cases 38
and 40, the C4 stereochemistry was determined by nOe
analysis. Next, deoxygenation of ketone 40 was first explored
using a Wolff−Kishner strategy. Myers had recently reported an
elegant improvement35 to the traditional harsh conditions for
this transformation that appeared well-suited to our substrate.
While we were able to form the TBS-hydrazone intermediate,
we were unable to effect the necessary reductionleading only
to decomposition or no reaction under a variety of conditions.
We next turned to a Barton-McCombie strategy.36 Reduction
of the ketone to alcohol followed by conversion to the thioate
and Bu3SnH-mediated reduction cleanly provided the deoxy-
genated product 41 in excellent overall yield.37 It was important
that the Bu3SnH reduction be conducted in deoxygenated
solvent. Next, removal of the C8 TBS ether was cleanly effected
using HF•pyr. conditions followed by Swern oxidation to yield
the aldehyde 42. In order to access the presumed coupling
partner (e.g., 10), it was required to incorporate the C9
Weinreb amide and to establish the C8 stereocenter. Nemoto
With the common intermediate 20 in hand, we first set out
to develop a general approach to the C1−C14 portion of both
amphidinolides C and F (Scheme 7). While we had hoped that
simple alkylation of the enolate 37 (e.g., generated in situ from
MeLi•LiBr treatment of benzoate 36) would provide the
desired stereochemical outcome, we experimentally observed
the undesired C4 stereochemistry in 5:1 dr. Interestingly, the C6
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has reported an elegant potential solution for this challenge,
which utilized a silyoxy malononitrile nucleophile.38 We were
pleased to see that these conditions nicely proceeded via the
presumed intermediate 4339 to provide the Weinreb amide 10
in good yield and modest diastereoselectivity. While stereo-
chemical outcome of this experiment was expected to be the
Felkin (syn) product, we did not rigorously determine the C8
stereochemistry. Unfortunately, despite considerable efforts
using either the major or minor C8 diastereomers, we were
unable to facilitate the subsequent coupling experiment
between the organolithium species derived from iodide 11
and the Weinreb amide 10 using a variety of halogen/metal
exchange conditions (e.g., n-BuLi, t-BuLi) and solvents (THF,
Et2O, THF/hexanes). On the basis of these unexpected results,
a revised approach was needed to circumvent the iterative
formation of the C8−C9 and the C9−C10 bonds.
The successful synthesis of the C1−C14 subunit is shown in
Scheme 8. In order to circumvent the problematic addition
chemistry with Weinreb amide 10, we chose to utilize a
nucleophilic 1,3-diene motif (e.g., organolithium 49) for
diastereoselective addition to aldehyde 42. We were unaware
of any prior example of exploiting similar strategy with 2-lithio-
1,3-dienes. While a related vinyl iodide have been employed in
cross coupling strategy to form the diene motif present in
amphidinolide B,40 the organolithium strategy brought with its
potential for metallotropic rearrangement41 of 49. We initially
explored accessing this lithio species via a Shapiro process from
the corresponding hydrazone 52; however, this approach led to
rapid decomposition. We hypothesized that proportionately
milder halogen-metal exchange process at lower temperature
might circumvent this decomposition process. Thus, we
targeted 2-iodo-1,3-diene 48 as a suitable precursor for
accessing the lithiated species. In preparation for this strategy,
Sonogashira coupling27 between iodide 11 and TMS-acetylene
(45) cleanly furnished the enyne 46 in excellent chemical yield.
Use of a Pd(II) salts [e.g., (Ph3P)2PdCl2] gave reduced
chemical yields as compared to (Ph3P)4Pd. Next, Pd(0)-
catalyzed hydrostannylation42 followed by iodination produced
the dienyl iodide 48. To our delight, halogen−metal exchange
followed by addition of aldehyde 42 cleanly provided the
targeted allylic alcohol 50 in 62% yield and 3:1 dr (50:51). This
strategy allowed us to produce the 1,3-diene and secure the C8
stereochemistry in a single operation. The C8 stereochemistry
was confirmed by advanced Mosher ester analysis.43 After TBS
protection at C8, selective desilylation at C14 and conversion to
the corresponding iodide provided the C1−C14 subunit 9.
With a viable, unified route to the C1−C14 domain, our
attention shifted to construction of the remaining sulfone
subunit (Scheme 9). Starting from the common ketone
Scheme 8. Synthesis of the C1−C14 Subunit
Scheme 9. Synthesis of the Silyl Enol-ethers
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intermediate 20, borohydride reduction provided correspond-
ing alcohol as a 1.7:1 mixture at C22. Thiolate formation under
basic conditions led to silyl migration, but use of thermolysis in
presence of thiocarbonyldiimidazole cleanly yielded the
thiolate. Barton-McCombie deoxygenation proceeded
smoothly to provide THF 53. After, pivaloate deprotection
and Swern oxidation to yield aldehyde 54, coupling with the
organolithium species derived from iodide 5544 produced the
alcohols 56/57 as a inseparable mixture of diastereomers.
Attempted coupling the C15 thiophenyl version45 of 55 proved
problematic in our hands. Oxidation generated the C18 ketone
58. As we had done previously,9a we planned to mask the C18
ketone as ketal 62. Despite our considerable efforts, we were
unable to affect this process. Consequently, it was necessary to
develop an alternate method for masking the C18 carbonyl
moiety. One option was to construct a silyl enol-ether that
should be readily cleavable under mild fluoride conditions;
however, its utility was potentially complicated due to the
possibility for formation of four different isomers. Fortunately,
after conversion to the sulfone 59, treatment with TBSOTf
under mildly basic conditions cleanly produced just two of the
four possible isomers in excellent yield.
Scheme 11. Synthesis of the Tetrahydropyranyl Series
We next set out to test the viability of our coupling strategy
on the enol-ethers 60 and 61 (Scheme 10). After modification
Scheme 10. Exploration of Silyl Enol-ether Series in Sulfone
Alkylation/Oxidative Desulfurization Sequence
(4) first due to the C25 simplified side arm with the expectation
that lessons learned could be applied to amphidinolide C (1).
Given the presumed acid sensitivity of the macrolactone, our
choices were likely limited to protecting groups readily
removable under mild conditions. We initially selected a
THP protecting group at C18 as it is well-known to be labile
under mildly acidic conditions.47 Starting from ketone 58, L-
Selectride reduction cleanly provided the 18S isomer 56 as
determined by advanced Mosher ester analysis.43 Protection at
C
18 using DHP generated the mixed acetal 65 in excellent yield.
Subsequent removal of the benzyl ether under hydrogenative
conditions followed by sulfide incorporation and oxidation
using TPAP, NMO in acetonitrile yielded the C15 sulfone 66.
Selective removal of the C25 TBS ether followed by Swern
oxidation yielded the α-oxy aldehyde 67. Olefination using the
Tamura/Vedejs-type tributylphosphonium salt 6848 cleanly
produced the desired diene 69 with high E/Z selectivity and
chemical yield (96%, 11:1 E/Z). C24 protecting group exchange
produced the necessary coupling partner 70 in excellent yield.
With both the major subunits in hand, we set out to explore
the critical sulfone alkylation/oxidative desulfurization se-
quence (Scheme 12). To our delight, treatment of sulfone 70
with LHMDS in presence of HMPA followed by addition of
the iodide 9 yielded the C14−C15 coupled material 71 in a
gratifying 72% yield. Only one equivalent of base with respect
to sulfone 70 was necessary to effect the transformation. For
the oxidative desulfurization, a modification of our original
conditions provided the desired ketone in excellent overall
yield. Davis’ oxaziridine appeared to be key to this trans-
formation as use of alternate oxidants (e.g., MoOPH,
TMSOOTMS etc.) gave inferior results. Presence of the C18
chelating protecting group is likely key to the success of both
the alkylation and the oxidative desulfurization. Both the C1
of the stoichiometry of base as compared to previously
developed conditions, we were able to once again facilitate
the key C−C bond-forming event. While the yields were
modest in the coupling process [52% yield for 60 and 45% yield
for 61 (not shown)46], we were more focused on the critical
oxidative desulfurization. We were disappointed to observe only
decomposition under a range of conditions for this critical step
using 63 as well as its silyl enol-ether isomer (not shown). One
possible explanation for the divergence in reactivity between
our model system 19 and the silyl enol-ether series was the
absence of a chelatable group at C18 to help direct lithiation at
C15 and stabilize any resultant anion.
Based on this speculative C18-chelation hypothesis, we
embarked on the synthesis of a fully functionalized C15−C29
system containing an appropriately selected protecting group at
C18 (Scheme 11). We strategically targeted amphidinolide F
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Scheme 12. Initial Construction of Amphidinolide F Macrocycle
Scheme 13. Total Synthesis of Amphidinolide F
Piv-protected and deprotected products (72 and 73 respec-
tively) were obtained from this transformation (likely due to
adventitious water facilitating its saponification); however, both
compounds were productive contributors to the synthetic
sequence. For 73, Swern oxidation directly produced the
aldehyde 74. For 72, LiAlH4 reduction removed the pivaloate
with concomitant reduction of the C15 carbonyl and subsequent
oxidation under Swern conditions generated the same aldehyde
74. Pinnick oxidation provided the carboxylic acid. Next, we
required the selective deprotection of the C24 TES ether in
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presence of multiple 2° TBS ethers and a OTHP moiety.
Fortunately, mild acidic conditions (PPTS, MeOH) selectively
removed the C24 TES ether to provide seco acid 75. We
speculated that the sterically congested nature of the C18
OTHP group inhibited its deprotection under these conditions.
Little did we know that this positive short-term accomplish-
ment was foreboding of future events. Next, macrolactonization
of seco-acid 75 under Shina conditions49 provided the 25-
membered macrolactone 77 in good yield (69% over 2 steps).
Yamaguchi macrolactonization conditions50 were also effective
in this transformationalbeit in a slightly lower chemical yield
(65%). Despite the THP moiety’s well-known lability under
Brønsted and Lewis acidic conditions, we were unable to
successfully facilitate its removal under a range of conditions
5:1:1 AcOH/THF/H2O, MgBr2,51 Me2AlCl,52 BF3•OEt2/1,2-
ethanedithiol53ultimately leading to decomposition in each
case. We speculated that the acid sensitivity of the macrocycle
77 was due to preferential ionization at C24, which would
generate a highly stabilized dienyl cation.
Despite this significant setback to our campaign toward
amphidinolide F, two negative results provided a possible
pathway to circumvent this reactivity. Unlike other conditions
screened, treatment of 77 with either 4:2:1 AcOH/THF/H2O
or PPTS/MeOH54 did not decompose the macrocycle (nor
was any appreciable deprotection of the C18 OTHP observed).
We hypothesized if we could identify a more acid labile
protecting group at C18 that could be cleaved with these mildly
acidic conditions, we could access the needed alcohol at that
position. We cautiously turned to the underutilized ethoxyethyl
ether (OEE) protecting group as a possible candidate. The
OEE moiety is known to be significantly more labile than an
OTHP group (ca. 250 times in one study)47 while maintaining
the necessary chelating ability for the sulfone alkylation/
oxidative desulfurization sequence.
amphidinolide F (4) in 56% isolated yield. Spectral comparison
of synthetic amphidinolide F was in good agreement with the
spectral data (1H, 13C, [α]D) reported by Kobayashi and co-
workers. It should be noted that both Kobayashi58 and our own
laboratory observed some concentration dependent shifts to
the NMR spectra; however, comparison at 0.0036 M
concentration (0.4 mg 4 in 0.18 mL CDCl3) proved optimum.
Thus, the total synthesis of 4 was achieved starting from 1,3-
propanediol in 29 steps longest linear sequence (LLS) based on
our second-generation route employing the Carreira asym-
metric alkynylation sequence (Scheme 4).
We next set out to apply this overall strategy to the synthesis
of the most bioactive member of this subfamily 1−4,
amphidinolide C (1). In fact, macrolide 1 is one of the most
biologically potent members of the entire amphidinolide family
of >35 macrolides. Our approach toward this compound
employs the identical C1−C14 subunit 9, but a more
complicated sulfone coupling partner 99. Starting from
known aldehyde 89 [available in one-step from hexanal
(88)59], Trost asymmetric alkynylation60 with commercially
available alkyne 90 gave the desired propargyl alcohol 92 in
high yield and enantioselectivity (Scheme 14). After silyl
Scheme 14. Synthesis of the Phosphonium Salt
The successful execution of this C18 OEE strategy for the
total synthesis of amphidinolide F is shown in Scheme 13.
Acetalization was best accomplished with PPTS and ethox-
yvinyl ether in high yield. We quickly became concerned with
the viability of this route, as the next required transformation
(C15 debenzylation) proved problematic under our prior Pd/C,
H2 conditions (see Supporting Information). Use of the
Freeman reagent55 nicely circumvented the problem. Fortu-
nately, the subsequent sequence principally followed our prior
OTHP route. After formation of the required sulfone 81,
sulfone alkylation/oxidation proceeded in near identical yields
to our OTHP route. For the macrocyclization, it was found the
Yamaguchi conditions50 to be optimum for accessing 86 in 65%
yield over 2 steps. With the key macrocycle 86 in hand, we
returned to the previously problematic C18 deprotection. We
were thrilled to find that our OEE hypothesis proved valid as
aqueous acetic acid conditions smoothly provided the
corresponding C18 alcohol 78. This alcohol 78 existed as a
mixture of the hydroxyl ketone and C15 hemiketal; however, the
equilibrium could be driven to the C15, C18 diketone 87 by
oxidation using Dess-Martin’s periodinane (DMP). It is
important to note that while macrolactonization, EE depro-
tection and DMP oxidation proceeded smoothly, NMR analysis
of the corresponding macrolactones often generated broaden
spectral patternsindicating a conformational equilibrium
likely existed on the NMR time scale. We explored multiple
deprotection conditions for the three remaining TBS ethers
(e.g., HF•pyr., TASF56); however, prolonged exposure to
Et3N•3HF57 ultimately proved to be effectiveyielding
protection at C29, cuprate addition to the alkynoate 93
generated the desired E-alkene 94 in complete stereoselectivity.
LiAlH4 reduction produced the allyl alcohol 95 in 89% yield
over two steps. This compound was employed to determine the
absolute configuration at C29 by desilylation (TBAF) and
advanced Mosher ester analysis.43 Conversion of alcohol 95 to
the corresponding tributylphosphonium salt 96 was accom-
plished by treatment with CBr4, Ph3P followed by displacement
with PBu3 in high overall yield. The overall route proved highly
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efficient (6 steps, 68% overall yield) yielding the salt 96 in
multigram quantity.
Synthesis of the C15−C34 sulfone 99 is shown in Scheme 15.
Starting from previously made bis-TBS ether 80, TBAF
salt 96 (1.5 to 2.2 equiv) led to excellent conversion to the
desired triene 99 (96% yield, 10:1 E/Z).
The completion of the total synthesis of amphidinolide C is
shown in Scheme 16. Lithiation of sulfone 99 followed by
addition of the iodide 9 generated the C14−C15 coupled
material in excellent yield (84%). Oxidative desulfurization
proceeded smoothly using LDA, DMPU and Davis’ oxaziridine
to produce 59% of 102 and 16% of 103. As before, both
compounds were useful for accessing the aldehyde 104. Pinnick
oxidation of aldehyde 104 followed by careful removal of the
C24 TES ether generated the seco acid. Yamaguchi macro-
lactonization produced the 25-membered macrolactone 105 in
63% yield over two steps. Aqueous acetic acid conditions again
proved effective for selective removal of the C18 OEE moiety.
Subsequent oxidation using DMP yielded tetra-TBS protected
amphidinolide C. Gratifyingly, global deprotection using
Et3N•3HF produced the natural product 1, which was matched
nicely with the observed spectra (1H, 13C NMR in C6D6).12b,c
Additionally, the optical rotation data was in agreement with
Scheme 15. Synthesis of the Sulfone Subunit
23
the literature value [Synthetic: [α]D = −98.5° (c = 0.21,
CHCl3); Natural:12 [α]D = −106° (c = 1.0, CHCl3)]. This
26
approach constitutes a 28-step synthesis (LLS) of amphidino-
lide C (1).
CONCLUSION
■
The total syntheses of amphidinolides C and F have been
accomplished (28 and 29 LLS respectively). Central to these
syntheses is the use of a common intermediate strategy to
access approximately 65% of the macrocyclic core and the THF
rings present in the two natural products. A stereoselective
silver-catalyzed cyclization of a propargyl benzoate/diol was
employed to construct the needed trans-stereochemistry of the
THF rings. A Felkin-controlled, 2-lithio-1,3-dienyl addition to
an α-silyloxy aldehyde incorporated the C9−C11 diene and
established the C8 stereocenter in single operation. An efficient
6-step sequence provided access to the C26−C34 aphidinolide C
subunit and the Tamura-Vedejs olefination incorporated the
C25−C29 side arm of amphidinolide F and the C25−C34 side
arm of amphidinolide C. A sterically congested sulfone
mediated desilylation followed by bis-TES protection produced
97. Next, tandem C25 deprotection and oxidation using Swern
conditions produced the α-oxy aldehyde 98. We initially
screened our previously optimized Tamura/Vedejs olefination
conditions for attaching the necessary side arm; however, only
decomposition was observed. This outcome was not entirely
unexpected as base-induced elimination of ylide 100 would
generate a conjugated triene 101. Fortunately, reduction of the
reaction temperature and an increase in the equivalence of the
Scheme 16. Total Synthesis of Amphidinolide C
10800
dx.doi.org/10.1021/ja404796n | J. Am. Chem. Soc. 2013, 135, 10792−10803

Journal of the American Chemical Society
Article
2002, 41, 508−511. (e) Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.;
alkylation/oxidative desulfurization sequence was utilized to
couple the major subunits and incorporate the C15 ketone. The
presence of chelating moiety at C18 was critical to the success of
the oxidative desulfurization step. A carefully orchestrated
sequence for stepwise revealing of the C24 alcohol followed by
macrolactonization, C18 deprotection and oxidation provided
access to the protected amphidinolide natural products. The
final global deprotection was uniquely feasible utilizing
Et3N•3HF as desilylating agent. With a viable route to
accessing the amphidinolide C/F subfamily, this work opens
the door to exploring the pronounced influence of the C25 side
arm on biological activity. These studies will be reported in due
course.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Complete experimental procedures are provided, including H
and 13C spectra, of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
1093. (u) Furstner, A.; Kattnig, E.; Lepage, O. J. Am. Chem. Soc. 2006,
̈
AUTHOR INFORMATION
Corresponding Author
rich.carter@oregonstate.edu
128, 9194−9204. (v) Nicoloau, K. C.; Brenzovich, W. E.; Bulger, P. G.;
Francis, T. M. Org. Biomol. Chem. 2006, 4, 2119−2157. (w) Nicolaou,
K. C.; Bulger, P. G.; Brenzovich, W. E. Org. Biomol. Chem. 2006, 4,
2158−2183. (x) Deng, L.-S.; Huang, X.-P.; Zhao, G. J. Org. Chem.
2006, 71, 4625−4635. (y) Jin, J.; Chen, Y.; Li, Y.; Wu, J.; Dai, W.-M.
Org. Lett. 2007, 9, 2585−2588. (z) Va, P.; Roush, W. R. Tetrahedron
■
Notes
The authors declare no competing financial interest.
2007, 63, 5768−5796. (aa) Furstner, A.; Bouchez, L. C.; Funel, J.-A.;
̈
ACKNOWLEDGMENTS
Liepins, V.; Poree, F.-H.; Gilmour, R.; Beaufils, F.; Laurich, D.;
Tamiya, M. Angew. Chem., Int. Ed. 2007, 46, 9265−9270. (bb) Dai, W.-
M.; Chen, Y.; Jin, J.; Wu, J.; Lou, J.; He, Q. Synlett 2008, 1737−1741.
(cc) Barbazanges, M.; Meyer, C.; Cossy, J. Org. Lett. 2008, 10, 4489−
4492. (dd) Kim, C. H.; An, H. J.; Shin, W. K.; Yu, W.; Woo, S. K.;
Jung, S. K.; Lee, E. Chem. Asian. J. 2008, 3, 1523−1534.
(ee) Rodriquez-Escrich, C.; Urpi, F.; Vilarrasa, J. Org. Lett. 2008, 10,
5191−5194. (ff) Lu, L.; Zhang, W.; Carter, R. G. J. Am. Chem. Soc.
2008, 130, 7253−7255. (gg) Lu, L.; Zhang, W.; Carter, R. G. J. Am.
■
Financial support was provided by the National Institutes of
Health (NIH) (GM63723) and Oregon State University
(Harris and Shoemaker Fellowships for S.M.). Prof. Takaaki
Kubota and Jun’ichi Kobayashi (Hokkaido University) are
acknowledged for assistance with the NMR spectra for
compounds 1 and 4, and Prof. Claudia Maier and Jeff Morre
(OSU) are acknowledged for for mass spectra data. Finally, the
authors are grateful to Prof. James D. White (OSU) and Dr.
Roger Hanselmann (Rib-X Pharmaceuticals) for their helpful
discussions.
́
Chem. Soc. 2008, 130, 11834. (hh) Furstner, A.; Bouchez, L. C.;
̈
Morency, L.; Funel, J.-A.; Liepins, V.; Poree, F.-H.; Gilmour, R.;
Laurich, D.; Beaufils, F.; Tamiya, M. Chem.Eur. J. 2009, 15, 3983−
4010. (ii) Hangyou, M.; Ishiyama, H.; Takahashi, Y.; Kobayashi, J. Org.
Lett. 2009, 11, 5046−5049. (jj) Ko, H. M.; Lee, C. W.; Kwon, H. K.;
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