The stereocontrolled total synthesis of spirastrellolide A methyl ester. Expedient construction of the key fragments

Article abstract of DOI:10.1039/c2ob25100k

Due to a combination of their promising anticancer properties, limited supply from the marine sponge source and their unprecedented molecular architecture, spirastrellolides represent attractive and challenging synthetic targets. A modular strategy for the synthesis of spirastrellolide A methyl ester, which allowed for the initial stereochemical uncertainties in the assigned structure was adopted, based on the envisaged sequential coupling of a series of suitably functionalised fragments; in this first paper, full details of the synthesis of these fragments are described. The pivotal C26-C40 DEF bis-spiroacetal was assembled by a double Sharpless asymmetric dihydroxylation/acetalisation cascade process on a linear diene intermediate, configuring the C31 and C35 acetal centres under suitably mild acidic conditions. A C1-C16 alkyne fragment was constructed by application of an oxy-Michael reaction to introduce the A-ring tetrahydropyran, a Sakurai allylation to install the C9 hydroxyl, and a 1,4-syn boron aldol/directed reduction sequence to establish the C11 and C13 stereocentres. Two different coupling strategies were investigated to elaborate the C26-C40 DEF fragment, involving either a C17-C25 sulfone or a C17-C24 vinyl iodide, each of which was prepared using an Evans glycolate aldol reaction. The remaining C43-C47 vinyl stannane fragment required for introduction of the unsaturated side chain was prepared from (R)-malic acid.

Full text of DOI:10.1039/c2ob25100k

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Organic &
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PAPER
The stereocontrolled total synthesis of spirastrellolide A methyl ester.
Expedient construction of the key fragments†‡§
Ian Paterson,* Edward A. Anderson, Stephen M. Dalby, Jong Ho Lim, Philip Maltas, Olivier Loiseleur,
Julien Genovino and Christian Moessner
Received 13th January 2012, Accepted 8th March 2012
DOI: 10.1039/c2ob25100k
Due to a combination of their promising anticancer properties, limited supply from the marine sponge
source and their unprecedented molecular architecture, spirastrellolides represent attractive and
challenging synthetic targets. A modular strategy for the synthesis of spirastrellolide A methyl ester,
which allowed for the initial stereochemical uncertainties in the assigned structure was adopted, based on
the envisaged sequential coupling of a series of suitably functionalised fragments; in this first paper, full
details of the synthesis of these fragments are described. The pivotal C26–C40 DEF bis-spiroacetal was
assembled by a double Sharpless asymmetric dihydroxylation/acetalisation cascade process on a linear
diene intermediate, configuring the C31 and C35 acetal centres under suitably mild acidic conditions.
A C1–C16 alkyne fragment was constructed by application of an oxy-Michael reaction to introduce the
A-ring tetrahydropyran, a Sakurai allylation to install the C9 hydroxyl, and a 1,4-syn boron aldol/directed
reduction sequence to establish the C11 and C13 stereocentres. Two different coupling strategies were
investigated to elaborate the C26–C40 DEF fragment, involving either a C17–C25 sulfone or a C17–C24
vinyl iodide, each of which was prepared using an Evans glycolate aldol reaction. The remaining
C43–C47 vinyl stannane fragment required for introduction of the unsaturated side chain was prepared
from (R)-malic acid.
macrolides for the treatment of metastatic breast cancer, constitu-
Introduction
tes a compelling proof-of-concept.3 The Novartis large-scale
Marine organisms, particularly sponge invertebrates and their
associated bacteria, continue to be an important source of novel
biologically active compounds, both in terms of their significant
therapeutic potential and as novel molecular probes for chemical
biology studies.1,2 In particular, marine macrolides that exhibit
exceptional levels of antimitotic activity, combined with unique
modes of action, represent valuable lead structures for the devel-
opment of new generation anticancer drugs. Furthermore, as the
promising biological activity exhibited by many complex marine
macrolides is often mirrored by their scarce natural supply, and
complicated by the challenge of full stereochemical determi-
nation, chemical synthesis represents a critically important exer-
cise. In this regard, the successful development of Halaven by
Eisai, as a fully synthetic analogue of the halichondrin marine
synthesis of discodermolide, a rare polyketide of marine sponge
origin, also represents an impressive example of what can be
achieved towards the development of complex marine natural
products as anticancer drugs in a pharmaceutical setting.4
The spirastrellolides constitute a structurally unprecedented
family of antimitotic macrolides, initially isolated by bioassay-
guided fractionation from extracts of the Caribbean sponge Spir-
astrella coccinea collected off reef walls near Capucin, Domin-
ica.5 The most abundant member of this family is spirastrellolide
A (1), which was first reported by the Andersen group in 2003,5a
followed by six structurally related congeners (spirastrellolides
B–G, 2–7).6 As shown in Fig. 1, the spirastrellolide scaffold
with its signature 38-membered macrolactone and embedded
spiroacetal motifs displays considerable architectural complexity,
with variation in the degree of chlorination at C4 and C28, olefi-
nation at Δ15,16, methylation at the C46-OH in the unsaturated
side-chain and hydroxylation at C8. While the spirastrellolides
are C47 carboxylic acids, conversion to the corresponding
methyl esters 8–14 proved necessary to enable the complete sep-
aration of the congeners and final purification, and the majority
of the physical and biological data for the spirastrellolides has
been collected for these purified methyl esters and their deriva-
tives. More recently, the Matsunaga group7 have isolated
University Chemical Laboratory, University of Cambridge, Lensfield
Road, Cambridge CB2 1EW, UK. E-mail: ip100@cam.ac.uk; Fax: +44
1223 336 362
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
‡Electronic supplementary information (ESI) available: this provides the
entire Experimental section for this paper. See DOI: 10.1039/
c2ob25100k
§Dedicated to Professor Ian Fleming.
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Fig. 2 Derivative 15 of spirastrellolide B prepared by the Andersen
group for structure elucidation by single crystal X-ray diffraction.
by degradation studies on spirastrellolide D and correlation with
dimethyl (R)-malate.6b In the meantime, we and other groups
had initiated synthetic studies based on the 2004 spirastrellolide
A structure of Andersen,5b which had 16 possible stereochemical
permutations. Soon after the disclosure of the full stereostructure
by the Andersen group,6b we communicated our first total
synthesis of spirastrellolide A methyl ester (8) which validated
the configurational assignment.13 This was followed by the
Fürstner group’s two total syntheses of spirastrellolide F methyl
ester (the 15,16-dihydro congener 13, Fig. 1).14 In this and the
accompanying paper,15 we now provide full details and discus-
sion of our total synthesis, concentrating on the ongoing stereo-
chemical issues and the evolution of efficient fragment assembly
strategies that ultimately proved successful in preparing spira-
strellolide A methyl ester. In this first paper, we provide a
full account of the development and optimisation of scaleable
and highly stereocontrolled routes to the key spirastrellolide
fragments.
Fig. 1 Structures of spirastrellolides A–G and their corresponding
methyl esters.
spirastrellolide A from a different sponge collected off the coast
of Nagannu Island, Okinawa, suggesting that the spirastrellolides
may be secondary metabolites produced by symbiotic bacteria.
Spirastrellolide A (1) was found to accelerate cell entry into
mitosis from S-phase, prior to initiating cell-cycle arrest during
M-phase, which is thought to be mediated through potent and
selective inhibition of protein phosphatase 2A (IC50 = 1 nM).5
Drugs that target the inhibition of either protein kinases (PKs,
mediating phosphorylation of proteins) or protein phosphatases
(PPs, governing dephosphorylation of proteins) have shown con-
siderable therapeutic potential in fields tackling cancer, obesity,
organ transplant rejection and the formation of Alzheimer’s
plaques.8 The methyl ester 8 also exhibited potent antiprolifera-
tive activity against a panel of cancer cell lines. This promising
biological profile marks out the spirastrellolides as exciting lead
structures for drug discovery,9 and combined with the scarcity of
the natural supply and the initial uncertainties over the full
stereochemistry, has stimulated considerable synthetic interest,
with numerous studies towards fragments reported.10–12
Initial synthetic efforts and strategy evolution
The spirastrellolides clearly present a significant synthetic chal-
lenge due to the array of functional groups and the high level of
oxygenation, which necessitates careful attention to chemoselec-
tivity issues and the selection of a robust but flexible protecting
group strategy. However, of arguably greater significance for the
synthetic chemist is the issue of stereochemistry which must be
addressed.
Spirastrellolide A (1, Fig. 3) bears 20 stereogenic centres dis-
tributed around the 38-membered macrocycle, which also incor-
porates three cyclic subunits: a cis-fused tetrahydropyran
(A-ring), a [6,6]-spiroacetal (BC-rings) and a [5,6,6]-bis-
spiroacetal (DEF-rings), with the latter two benefiting from
double anomeric effect stabilisation. From the outset, we
reasoned that these well-defined spiroacetal ring systems might
be obtained via acid-catalysed acetalisation under thermodyn-
amic control from suitable linear precursors. In addition, there is
a remote stereocentre at C46 within the unsaturated side-chain.
Initially, the configurational relationship between the C3–C7
tetrahydropyran A-ring (red), C9–C24 BC-spiroacetal (green),
The continuing efforts of the Andersen group to elucidate the
full stereostructure finally led in 2007 to a definitive assignment
of the configuration of the macrolide core of spirastrellolide B
through single crystal X-ray diffraction studies on the p-bromo-
phenacyl derivative 15 (Fig. 2).6a This was followed by the
assignment of the remote C46 stereocentre within the side chain
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Fig. 3 Initial target structure with key bond disconnections at C42–
C43, C25–C26 and C1–OC37; where the configurational relationship
between the four coloured stereoclusters was not defined.
DEF-bis-spiroacetal (blue) and C46 hydroxyl stereocentre
(purple) was not confidently assigned by the Andersen group,
such that there were 16 possible stereoisomers to be considered.
Our synthetic plan therefore needed to be highly flexible due to
this configurational uncertainty, and should also allow for access
to novel structural analogues for SAR studies. Hence, the adop-
tion of a modular approach, combining the different stereoclus-
ters in suitably functionalised fragments to progressively
assemble the northern and southern spiroacetal-containing
regions and the macrolide core, lay at the heart of our synthesis
plan. Taking the above factors into consideration, our initial stu-
dies12a–d targeted the construction of fully elaborated northern
and southern hemispheres with the objective of narrowing down
the number of stereochemical permutations by NMR compari-
sons with the available data for the natural product. Disconnec-
tion of the side-chain at C42–C43, allowing for the undefined
C46 stereocentre, would be used to reduce the stereoconundrum
to the three highlighted macrocyclic domains (C3–C7, C9–C24,
C27–C38) in Fig. 3. Following disconnection across the macro-
lactone bridge, a C25–C26 bond scission would then isolate the
DEF-spiroacetal as a single region of known stereochemistry
together with the C1–C25 ABC-region.
Before discussing the details of the synthetic strategy which
ultimately proved successful, it is helpful to first summarise
some of the key results from intelligence gathering exercises
directed towards the construction of the northern and southern
hemisphere regions, where the selection of suitable protecting
groups was found to be a critical issue. In early exploratory
work, we targeted the synthesis of both possible diastereomers
of the C1–C25 southern hemisphere in 16 and 17 (Scheme 1).12b
The precursor C1–C25 enones 18 and 19 were constructed incor-
porating either the (3R,7S)- or (3S,7R)-configuration of the A-
ring tetrahydropyran from the diastereomeric alkynes 20 and 21,
combined with the same aldehyde 22. In order to achieve the
removal of the two acetonides and induce controlled spirocycli-
sation, rather forcing conditions were found to be required (aq.
HF, MeCN), leading to complete desilylation and generation of
Scheme 1 Initial synthesis of two diastereomers 16 and 17 of southern
hemisphere C1–C25 region.
pentaol spiroacetals 16 and 17. Both these pentaols showed
excellent spectroscopic correlation with the natural product,
where on balance the (3R,7S) diastereomer 16 appeared to corre-
late more closely to the spirastrellolide NMR data than counter-
part 17. However, an unequivocal conclusion could not be
reached at this stage. This result was not entirely unexpected as
the macrocycle and the appended side-chain are likely to
strongly affect the molecular conformation and resultant NMR
spectra compared to these simpler fragments, particularly in the
C7–C9 region. Nevertheless, this work provided a preliminary
indication that 16 was the better match, which was pursued and
ultimately proved to be correct. As discussed later, whilst some
aspects of the synthesis of spiroacetal 16 would be retained, the
conditions required for acetonide deprotection were somewhat
harsh and capricious. Consequently, our preferred longer term
strategy for BC-spiroacetalisation would incorporate PMB ethers
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Scheme 2 Initial synthesis of southern hemisphere C1–C21 region 24.
Scheme 4 Examples of unsuccessful attempts at C25–C26 bond for-
mation with tetracyclic DEF components.
Scheme 3 Initial synthesis of tetracyclic C26–C40 DEF-bis-spiroacetal
29.
Nevertheless, detailed 1H and 13C NMR comparison of 29
with the analogous data reported for spirastrellolide A methyl
ester revealed excellent homology, confirming the structural and
stereochemical assignment for this key region. While the sub-
sequent examination of alternative routes to the DEF-bis-spiro-
acetal led to some improvements,12d,f it became clear that a
complete revision of our synthetic strategy for the northern hemi-
sphere region was required to enable access to adequate stocks
of material to advance the total synthesis.
In addition to issues associated with accessing C26–C40
DEF-bis-spiroacetal 29 in useful quantities, preliminary explora-
tory investigations into the formation of the C25–C26 bond to
connect the northern and southern hemisphere regions were
carried out (Scheme 4). For this challenging union, two strat-
egies were pursued using substrates which could be readily
derived from tetracycle 29: an alkylation of tosylate 30 or iodide
at C13 and C21, following the success of a DDQ-mediated
deprotection and spirocyclisation of 23 in constructing the
related C1–C21 spiroacetal 24 (Scheme 2).12c
In our early studies on the assembly of the northern hemi-
sphere region, incorporating the characteristic DEF-bis-spiroace-
tal of spirastrellolide A, the C26–C40 ketone 25, which we
envisaged to be a precursor to this spiroacetal was prepared by
HWE coupling between acetonide-containing phosphonate 26
and aldehyde 27 (Scheme 3).12a Deprotection again proved pro-
blematic, with the strongly acidic conditions required for clea-
vage (e.g. HCl or CSA) leading to competitive elimination of the
F-ring to furan 28. Even under optimised conditions (Dowex
50Wx8, MeOH–H2O, 70 °C), at best only a 40% yield of the
required tetracyclic C26–C40 DEF subunit 29 could be obtained.
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Scheme 5 Revised synthesis plan for spirastrellolide A methyl ester based on either (a) Julia olefination to form C25–C26 bond or (b) Suzuki coup-
ling and hydroboration to form C24–C25 bond in aldehyde 40.
31 with sulfone 32, and a Julia olefination of aldehyde 33 with
model sulfone 34.16 Unfortunately, neither of these approaches
proved successful, and in all cases complete degradation of the
DEF-component was observed without isolation of any required
coupled products 35 or 36, thought to be due to the sensitive
nature of the C40 δ-lactone functionality. Overall, these frustrat-
ing setbacks prompted a reconsideration of our approach to not
only constructing the DEF-region but the macrocycle as a whole,
leading to the following strategy evolution and identification of
more suitable fragments and protecting groups.
Stille coupling of side-chain stannane 37 to a preformed macro-
cycle, which would be closed by macrolactonisation between the
C1 carboxylic acid and C37 hydroxyl group in truncated seco-
acid 38. Now however, the C1–C16 alkyne 39 containing the
Δ15,16 unsaturation was excised, revealing fully elaborated C17–
C40 aldehyde 40. Coupling of alkyne 39 with aldehyde 40 and
formation of the BC-spiroacetal would now use the successful
approach developed earlier for spiroacetal 24 (Scheme 2), which
relies on the selective and mild removal of PMB ethers at C13
and C21 with in situ spiroacetalisation.12c,e A modified Julia
olefination17 was initially considered for C25–C26 bond for-
mation, utilising the sulfone fragment 41 which incorporates all
five contiguous stereocentres spanning C20–C24 for coupling to
the DEF-aldehyde fragment 42. Hydroboration of the resulting
terminal alkene to afford a C17 alcohol would then be followed
by reduction of the internal alkene. Alternatively, a B-alkyl
Suzuki coupling reaction18 of DEF-alkene 43 with the simpler
C17–C24 vinyl iodide 44 would provide a C17–C40 diene,
upon which it was proposed that the C23/C24 stereocentres and
C17 oxygenation in aldehyde 40 might be installed through an
adventurous substrate-controlled double hydroboration reaction.
The relative merits of these two complementary coupling strat-
egies would be determined by experiment, as discussed in the
accompanying paper.15 Notably, it was only during the latter
stages of this work that the stereochemical uncertainties within
the macrocycle were resolved by the Andersen group,6a which
Revised synthesis plan
The presence of the Δ15,16 alkene in the B-ring of spirastrellolide
A meant that our original fragment coupling strategy,12a,b invol-
ving the union of preformed ABC- and DEF-subunits, was
rather inflexible, with chemoselectivity issues arising from any
coupling methods that would introduce additional unsaturation.
It was recognised that the convergency of the original strategy
would have to be sacrificed for an alternative approach, whereby
the Δ15,16 alkene could be introduced subsequent to elaboration
at the C26 position of the DEF-subunit, which might now be
achieved under suitably mild conditions.
As shown in our revised synthesis plan outlined in Scheme 5,
spirastrellolide A methyl ester (8) would arise from the late-stage
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Scheme 7 Synthesis of methyl ketone 48 by asymmetric
chloroallylation.
(Z)-(γ-chloroallyl)borane 51, derived in situ from allyl chloride
and (−)-Ipc2BOMe, afforded syn-chlorohydrin 52 (>20 : 1 dr) in
51% yield and 92% ee (1H NMR analysis of the corresponding
Mosher esters).22 The dimethyl acetal of 50 is conveniently
unmasked during this process, and subsequent methyl ether for-
mation from 52 with Meerwein’s salt delivered methyl ketone
48. Although operationally demanding, this process could be
performed on a reasonably large scale, providing access to multi-
gram quantities of this C26–C32 building block.
Scheme 6 Retrosynthetic analysis of DEF-bis-spiroacetal 45 based
on a double asymmetric dihydroxylation/acetalisation cascade from
diene 47.
A suitable C33–C40 component 49 was now required for
aldol coupling with 48. For this purpose, aldehyde 53 was sub-
mitted to a modified Knoevenagel reaction23 with malonic acid
to access β,γ-unsaturated carboxylic acid 54 (Scheme 8). Oxi-
dation state adjustment provided aldehyde 56, which could not
be purified by column chromatography on SiO2 due to the pro-
pensity for isomerisation to the conjugated enal. Under our stan-
dard conditions,20c reaction of the (E)-boron enolate of ethyl
ketone 5724 with crude aldehyde 56 provided the anti-aldol
adduct 58, which following oxidative work-up, was isolated
cleanly and in high yield (83%, >20 : 1 dr). Silyl protection of
aldol adduct 58 (TBSOTf) to give 59, followed by cleavage of
the lactate auxiliary under standard conditions,20c afforded alde-
hyde 49 in 85% overall yield.
fortuitously validated the decision to pursue stereoisomer 8, as
originally depicted for spirastrellolide A methyl ester.5b
Results and discussion
The C26–C40 DEF-bis-spiroacetal 45
Due to the limitations of our originally reported12a route to C26–
C40 fragment 29 (Scheme 3), an improved synthesis of a new
DEF-bis-spiroacetal fragment 45 was devised as shown in
Scheme 6, with the principle aim of reducing the susceptibility
of the F-ring to furan formation by removing the appended
γ-lactone. Importantly, we also recognised that the sense of
asymmetric induction in the Sharpless dihydroxylation reac-
tions19 that would be used to install the C37/C38 and C26/C27
diols in the acyclic precursor 46 was the same.12e This would
enable us to install all four hydroxyl groups in 46 from the C26–
C40 diene 47 with a total avoidance of protecting groups, and
subsequent spiroacetalisation might therefore be induced under
particularly mild acidic conditions. In turn, diene 47 would be
accessed through aldol coupling of C26–C32 methyl ketone 48
and C33–C40 aldehyde 49 (prepared using our lactate aldol
methodology20 to set the C34/C35 anti-relationship) in prefer-
ence to the HWE coupling protocol used previously. In practice,
the implementation of these measures greatly streamlined the
synthesis and improved the scalability of the preparation of the
pivotal DEF-subunit of spirastrellolide A.
With scaleable routes to both ketone 48 and aldehyde 49
established, their coupling to form C26–C40 diene 47 could now
be pursued (Scheme 9). Again a boron aldol reaction was con-
veniently employed for this purpose, which provided an inconse-
quential mixture of epimeric alcohols 60 in excellent yield
(98%). Treatment of 60 with MsCl and Et3N induced an E1cb
elimination to give the corresponding (E)-enone. Conjugate
reduction25 under the catalytic conditions reported by Lip-
shutz,26 requiring only
3
mol% of Stryker’s reagent
([Ph3PCuH]6), provided diene 61 in excellent yield (94%).
Acid-mediated desilylation of 61 and Dess–Martin oxidation of
the ensuing C35 alcohol then provided 47 in 66% yield on small
scale (ca. 50 mg), however repetition of this two-step process on
larger scales delivered the desired diketone 47 in much
lower yields, with predominant formation of dihydropyran 62
instead being observed. To circumvent this side-reaction, a three-
step procedure was developed in which the C31 ketone in 61
was reduced prior to desilylation at C35, thus preventing cyclisa-
tion. The resulting diol 63 could then be converted cleanly to
diketone 47 using a double Swern oxidation, in a reliable 87%
yield.
Following our earlier studies,12a the Oehlschlager–Brown
asymmetric chloroallylation reaction21 was selected to configure
a syn-α-vinylchlorohydrin and hence provide a route to the
chlorinated D-ring of spirastrellolide A. Accordingly, treatment
of readily available aldehyde 50 (Scheme 7) with
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Scheme 8 Synthesis of aldehyde 49 using an asymmetric boron aldol
reaction.
With C26–C40 diene 47 in hand, the key tandem double
asymmetric dihydroxylation and bis-spiroacetalisation sequence
was addressed. Submission of diene 47 to Sharpless con-
ditions,19 utilising (DHQ)2PYR as ligand, effected a stereo-
selective double dihydroxylation but did not lead directly to
Scheme 9 Synthesis of linear diene 47, the substrate for double asym-
metric dihydroxylation.
C26–C40 DEF-bis-spiracetal 64 (Scheme 10). Instead,
a
product, desired bis-spiroacetal 64, adopts the expected anomeric
effect-stabilised configuration, the resulting cage-like structure
shown may suffer from destabilising steric interactions. By con-
trast, other C31/C35 configurations, although less favourable
stereoelectronically, may result in reduced steric crowding.
Importantly, it was found that these minor DEF isomers could be
resubmitted to the spiroacetalisation conditions (PPTS, CH2Cl2–
MeOH), leading to desilylation and epimerisation at the spiro-
cyclic centres (C31 and C35) which, upon TES reprotection,
generated further quantities of 45. In this fashion, the required
C26–C40 bis-spiroacetal 45 could be accessed in a reliable 81%
yield after two equilibrations of the mixed isomer by-products.
The success of this approach owes much to the increased stab-
ility of DEF-spiroacetal 64 with respect to furan formation,
allowing access to the thermodynamic equilibrium mixture of
products rather than the kinetic outcome.
complex mixture of products was isolated, considered to be the
C26–C40 hemi-acetals 65, which were fully cyclised under
mildly acidic conditions (PPTS, CH2Cl2–MeOH). Per-silylation
of the crude diol product facilitated purification, giving access to
targeted DEF-bis-spiroacetal 45 in 43% yield (chromatographi-
cally separable from other spirocyclic isomers). Clear nOe
enhancements between key protons in bis-spiroacetal diol 6427
confirmed the major product of the double dihydroxylation/bis-
spirocyclisation sequence to contain the desired double anomeri-
cally stabilised configurations at C31 and C35.
In our earlier work, in which these asymmetric dihydroxyla-
tions were performed on the individual alkenes in separate frag-
ments, the diastereoselectivity of each dihydroxylation was
found to be around 20 : 1 dr in each case.12b Notably, the dihy-
droxylation of the terminal Δ26,27 alkene corresponds to a re-
inforcing situation based on the inherent 1,2-anti stereoinduction
from the allylic chloride (which acts in a manner comparable to
an allylic alcohol).28 Therefore, the minor isomers obtained in
the double asymmetric dihydroxylation of 47 were assigned as
epimers at the C31 and C35 acetal centres. Although the major
The development of this expedient double asymmetric dihy-
droxylation/acetalisation cascade process ensured that we could
now prepare multi-gram quantities of DEF-bis-spiroacetal 45 to
go forward with the total synthesis effort. Importantly, selective
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Scheme 10 Double asymmetric dihydroxylation/spiroacetalisation
cascade sequence to give C26–C40 DEF-bis-spiroacetal 45.
deprotection of the primary TES ether provided C26 alcohol 66
for further elaboration to aldehyde 42 and alkene 43 for fragment
coupling (described in the following paper15). Based on the two
alternative strategies proposed in Scheme 5, we now required
access to both the C17–C25 sulfone fragment 41 for the planned
Julia olefination approach, and the simpler C17–C24 vinyl
iodide 44 for exploration of the Suzuki cross-coupling approach.
Scheme 11 Synthesis of C17–C25 sulfone fragment 41.
aldehyde 68 via Dess–Martin oxidation buffered by pyridine.
For the purpose of establishing the syn-diol relationship between
C21 and C22 in the targeted C17–C25 sulfone 41 (Scheme 11),
whilst simultaneously installing a PMB ether at C21 for the
planned BC-spiroacetalisation, an Evans glycolate aldol reac-
tion was selected.31 This strategy would also allow the requi-
site C20 methoxy-bearing stereocentre to be installed by
reduction of an ensuing ketone, utilising this PMB ether for
chelation control.
In the event, glycolate imide 72 was accessed using a con-
venient three-step process from (R)-benzyloxazolidinone.32 Eno-
lisation of 72 (n-Bu2BOTf, Et3N, PhMe), followed by addition
of aldehyde 68 then gave syn-aldol adduct 73 (76%, >20 : 1 dr).
Transamination with N,O-dimethylhydroxylamine hydrochloride
and subsequent TES ether formation followed by addition of
allylmagnesium bromide produced ketone 74 (68%, 3 steps).
Chelation-controlled reduction33 of 74 was best achieved using
Zn(BH4)2, which gave alcohol 75 (78%, 19 : 1 dr).
The C17–C25 sulfone 41
The polyoxygenated C20–C24 region in spirastrellolide A con-
tains five contiguous stereocentres. The construction of this
stereopentad commenced with dimethyl (S)-malate (67), which
was converted into aldehyde 68 by adaptation of a literature pro-
cedure.29 Thus, a Fráter–Seebach-type enolate alkylation with
methyl iodide afforded the expected anti-isomer 69 (61%, 9 : 1
dr). Reduction of 69 with LiAlH4 then gave triol 70, which
proved too water soluble to be isolated from the aqueous phase
during work up. To circumvent this, addition of anhydrous acetic
acid in place of an aqueous work up, followed by in situ acety-
lation, enabled efficient isolation of the tris-acetate of 70.30
Without exposure to water, triol 70 was then easily obtained by
methanolysis (NaOMe, MeOH). Regioselective acetalisation
then produced the thermodynamically preferred six-membered
benzylidene acetal 71 (77%, 4 steps), which was converted to
With all of the necessary stereocentres now installed, the sec-
ondary alcohol in 75 was converted into its methyl ether 76 by
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reaction with Me3OBF4 in the presence of proton sponge.34
For the purpose of obtaining a suitable substrate for introduc-
tion of the required sulfone group by a Mitsunobu reaction, a
selective three step protecting group manipulation of 76 was
performed. This involved acidic cleavage of the acetal and
silyl ether of 76, followed by tris-TES protection and cleavage
of the primary silyl ether of 77. This latter step proved chal-
lenging, but following a screen of various conditions, treat-
ment with HF·py/py in THF was found to selectively liberate
the primary alcohol, and a Mitsunobu reaction with 2-mercap-
tobenzothiazole (BTSH) gave sulfide 78 (99%). Finally, the
synthesis of the Julia coupling partner was completed by oxi-
dation of sulfide 78 using H2O2 in the presence of an
ammonium molybdate catalyst, affording the desired C17–C25
sulfone 41 (70%).
procedure, vinyl iodide 44 could be efficiently accessed on
multi-gram scales, in seven steps and 37% yield from aldehyde
80. Notably, this expedient sequence proved to be more con-
venient than the much lengthier route to the corresponding
sulfone 41.
The C1–C16 alkyne 39
The optimised synthetic route to the C1–C16 alkyne 39
(Scheme 13), containing the remaining carbon atoms required
for the spirastrellolide A macrocycle, evolved from strategies we
had previously developed for construction of a range of related
ABC-ring fragments (e.g., 16 and 17 in Scheme 1).12b,e Alkyne
39 would now come from β-hydroxy ketone 84, itself generated
from a 1,4-syn aldol reaction38,39 between C1–C11 aldehyde 85
and methyl ketone 86. In turn, aldehyde 85 would arise from an
intramolecular oxy-Michael addition of C1–C9 enoate 87, with
subsequent chelation-controlled allylation to set the C9
stereocentre.
The synthesis of aldehyde 85 commenced with the opening of
epoxide 88 (obtained in >95 : 5 er using Jacobsen hydrolytic
kinetic resolution)40 with butenylmagnesium bromide
(Scheme 14). Cross metathesis41 of the ensuing alkene with
methyl acrylate (Grubbs II, 0.5 mol%) gave (E)-enoate 87,
which then underwent a hetero-Michael reaction on treatment
with t-BuOK, giving C1–C9 cis-tetrahydropyran 89 in good
yield and selectivity (83%, >20 : 1 dr). Oxidation state adjust-
ment at C9 afforded C1–C9 aldehyde 90, which proved a good
substrate for allylation under Sakurai-type conditions42 (TiCl4,
80%, 6 : 1 dr). This last step replaced previous reliance on stoi-
chiometric chiral reagents to set the C9 stereocentre,12b with the
The C17–C24 vinyl iodide 44
For the alternative Suzuki coupling approach, access to C17–
C24 vinyl iodide fragment 44 was required. In practice, this (E)-
vinyl iodide was installed through hydrotitanation of but-3-ynol
(79) according to the procedure developed by the Sato group
(Scheme 12).35 Dess–Martin oxidation then afforded aldehyde
80 (89%).36
As in the earlier case, an Evans glycolate aldol coupling
between imide 72 and aldehyde 80 (n-Bu2BOTf, Et3N, PhMe)
proceeded smoothly to afford syn-aldol adduct 81 (77%, >20 : 1
dr). With the C21/C22 stereocentres in place, transamination of
81, with subsequent silyl protection, gave Weinreb amide 82.
Treatment of 82 with allylmagnesium bromide and chelation-
controlled reduction of the resulting ketone with Zn(BH4)2, then
afforded alcohol 83 (90%, 19 : 1 dr). The required C17–C24
vinyl iodide fragment 44 was then completed through methyl-
ation of the C20 alcohol (Me3OBF4) and desilylation under
mildly acidic conditions (PPTS, MeOH).37 Using the above
Scheme 12 Synthesis of C17–C24 vinyl iodide fragment 44.
Scheme 13 Retrosynthetic analysis of C1–C16 alkyne fragment 39.
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Scheme 14 Synthesis of C1–C11 aldehyde 85.
diastereoselectivity attributed to a π-facial bias for pseudo-axial
attack of allyltrimethylsilane onto a β-alkoxy-chelated intermedi-
ate. Silyl protection of alcohol 91 and ozonolysis completed the
C1–C11 aldehyde 85 in 62% overall yield from epoxide 88.
Using our standard conditions, aldehyde 85 underwent
smooth aldol coupling38 with the diisopinocamphenylboron
enolate derived from methyl ketone 86, to give the expected 1,4-
syn adduct 84 with good yield and selectivity (75%, >20 : 1 dr)
(Scheme 15).43 Next, an Evans–Saksena reduction44 of ketone
84 afforded the corresponding 1,3-anti diol (92%, >20 : 1 dr).
Subsequent formation of the PMP acetal 92 under oxidative con-
ditions (DDQ) and silylation of the residual C11 alcohol then
gave the fully protected polyol. Regioselective opening of the
PMP acetal to reveal the terminal C15 alcohol in 93 proved
difficult, with many conditions (including standard treatment
with DIBAL) resulting in over-deprotection to afford 1,3-diol
94. Under optimised conditions using BH3·SMe2 at 100 °C,45
the ratio of desired alcohol 93 to diol 94 was at best 3 : 1,
although 94 could be easily recycled. While Corey–Fuchs alky-
nylation46 could then be used to complete the C1–C16 alkyne
fragment in good yield (not shown), the sequence was amended
to include a protecting group exchange, in order to mitigate any
late-stage selectivity issues with respect to deprotection at C1 in
the presence of TBS ethers at C37 and C40. This entailed selec-
tively cleaving the TBS ether at C1 (HF·py, py) to give alcohol
95, followed by PMB ether formation and conversion of the
dibromoalkene to the alkyne 39 (73%, 5 steps). The newly-
formed C1 PMB ether should then be cleaved to reveal the
primary alcohol during the planned DDQ-mediated BC-spiroace-
talisation step. This reaction sequence proved sufficiently robust
to be able to afford multi-gram quantities of the C1–C16 alkyne
fragment 39.
Scheme 15 Synthesis of C1–C16 alkyne fragment 39.
The C43–C47 vinyl stannane 37
Either the (R)- or (S)-configuration of the C46 stereocentre in the
side-chain stannane fragment 37 could be obtained by starting
from the appropriate enantiomer of malic acid. The synthesis of
(46R)-37 from (R)-malic acid (96) is shown in Scheme 16,
where its antipode was prepared in an analogous fashion.
Following a literature procedure,47 aldehyde 97 was prepared
from 96,48 and a Corey–Fuchs reaction46 afforded vinyl dibro-
mide 98. In order to prepare (Z)-vinyl stannane 99, selective
reduction of the trans-bromide of 98 with n-Bu3SnH was investi-
gated in the presence of catalytic Pd(PPh3)4,49 with the reaction
1
monitored using H NMR spectroscopy. After isolation of the
(Z)-vinyl bromide product, tin–halogen exchange was carried out
with (Me3Sn)2 and the same Pd(0) catalyst.50 By following this
two-step procedure, the (Z)-vinyl stannane 99 could be isolated
5870 | Org. Biomol. Chem., 2012, 10, 5861–5872
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Experimental
Full experimental and characterisation details are provided in the
ESI.§
Acknowledgements
Financial support was provided by the EPSRC, Homerton
College (Research Fellowship to E. A. A.), Clare College
(Research Fellowship to S. M. D.), SK Innovation (J. H. L.),
Syngenta (O. L.) and the DAAD (C. M.). We thank Professor
R. J. Andersen (University of British Columbia) for helpful dis-
cussions throughout this project and the EPSRC National Mass
Spectrometry Service (Swansea) for providing mass spectra.
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This journal is © The Royal Society of Chemistry 2012