The stereocontrolled total synthesis of spirastrellolide A methyl ester. Fragment coupling studies and completion of the synthesis

Article abstract of DOI:10.1039/c2ob25101a

The spirastrellolides are a novel family of structurally unprecedented marine macrolides which show promising anticancer properties due to their potent inhibition of protein phosphatase 2A. In the preceding paper, a modular strategy for the synthesis of spirastellolide A methyl ester which allowed for the initial stereochemical uncertainties was outlined, together with the synthesis of a series of suitably functionalised fragments. In this paper, the realisation of this synthesis is described. Two alternative coupling strategies were explored for elaborating the C26-C40 DEF bis-spiroacetal fragment: a modified Julia olefination of a C26 aldehyde with a C17-C25 sulfone, and a Suzuki coupling of a C25 trialkylborane with a C17-C24 vinyl iodide, which also required the development of a double hydroboration reaction to install the C23/C24 stereocentres. The latter proved a significantly superior strategy, and was fully optimised to provide a C17 aldehyde which was coupled with a C1-C16 alkyne fragment to afford the C1-C40 carbon framework. The BC spiroacetal was then installed within this advanced intermediate by oxidative cleavage of two PMB ethers with spontaneous spiroacetalisation, which also led to unanticipated deprotection of the C23 TES ether. The ensuing truncated seco-acid was cyclised in high yield to construct the 38-membered macrolactone under Yamaguchi macrolactonisation conditions, suggesting favourable conformational pre-organisation. Exhaustive desilylation provided a crystalline macrocyclic pentaol, revealing much about the likely conformation of the macrolactone in solution. Attachment of the remainder of the side chain proved challenging, potentially due to steric hindrance by this macrocycle; an olefin cross-metathesis to install an electrophilic allylic carbonate and subsequent π-allyl Stille coupling with a C43-C47 stannane achieved this goal. Global deprotection completed the first total synthesis of (+)-spirastrellolide A methyl ester which, following detailed NMR correlation with an authentic sample, validated the full configurational assignment. A series of simplified analogues of spirastrellolide incorporating the C26-C47 region were also prepared by π-allyl Stille coupling reactions.

Full text of DOI:10.1039/c2ob25101a

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PAPER
The stereocontrolled total synthesis of spirastrellolide A methyl ester.
Fragment coupling studies and completion of the synthesis†‡§
Ian Paterson,* Edward A. Anderson, Stephen M. Dalby, Jong Ho Lim and Philip Maltas
Received 13th January 2012, Accepted 8th March 2012
DOI: 10.1039/c2ob25101a
The spirastrellolides are a novel family of structurally unprecedented marine macrolides which show
promising anticancer properties due to their potent inhibition of protein phosphatase 2A. In the preceding
paper, a modular strategy for the synthesis of spirastellolide A methyl ester which allowed for the initial
stereochemical uncertainties was outlined, together with the synthesis of a series of suitably
functionalised fragments. In this paper, the realisation of this synthesis is described. Two alternative
coupling strategies were explored for elaborating the C26–C40 DEF bis-spiroacetal fragment: a modified
Julia olefination of a C26 aldehyde with a C17–C25 sulfone, and a Suzuki coupling of a C25
trialkylborane with a C17–C24 vinyl iodide, which also required the development of a double
hydroboration reaction to install the C23/C24 stereocentres. The latter proved a significantly superior
strategy, and was fully optimised to provide a C17 aldehyde which was coupled with a C1–C16 alkyne
fragment to afford the C1–C40 carbon framework. The BC spiroacetal was then installed within this
advanced intermediate by oxidative cleavage of two PMB ethers with spontaneous spiroacetalisation,
which also led to unanticipated deprotection of the C23 TES ether. The ensuing truncated seco-acid was
cyclised in high yield to construct the 38-membered macrolactone under Yamaguchi macrolactonisation
conditions, suggesting favourable conformational pre-organisation. Exhaustive desilylation provided a
crystalline macrocyclic pentaol, revealing much about the likely conformation of the macrolactone in
solution. Attachment of the remainder of the side chain proved challenging, potentially due to steric
hindrance by this macrocycle; an olefin cross-metathesis to install an electrophilic allylic carbonate and
subsequent π-allyl Stille coupling with a C43–C47 stannane achieved this goal. Global deprotection
completed the first total synthesis of (+)-spirastrellolide A methyl ester which, following detailed NMR
correlation with an authentic sample, validated the full configurational assignment. A series of simplified
analogues of spirastrellolide incorporating the C26–C47 region were also prepared by π-allyl Stille
coupling reactions.
esters.2 The intense synthetic interest,3–5 that the spirastrellolides
have generated derives not only from their unique molecular
architecture but also from their potential for development as lead
structures for novel anticancer agents due to the significant anti-
mitotic behaviour displayed in cell-based assays. Moreover, their
identification as potent and selective inhibitors of protein phos-
phatases may afford valuable molecular probes for cell biology,
as well as unique scaffolds for therapeutic development.6 As
with other promising antimitotic macrolides of marine sponge
origin however, there is a supply issue requiring the development
of a practical chemical synthesis to afford a more sustainable
source.7 In addition, the initial uncertainties reported by the
Andersen group1 over the full stereochemical assignment of the
spirastrellolides might be progressively resolved by synthetic
means.
Introduction
Spirastrellolide A (1, Scheme 1) was first isolated by Andersen
and co-workers from the Caribbean sponge Spirastrella coccinea
in 2003, and characterised as its methyl ester derivative 2.1 This
was followed by the isolation of six minor congeners, spirastrel-
lolides B–G, also characterised as their corresponding methyl
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. CCDC reference number
669312. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob25101a
In the preceding paper,8,9 we outlined a modular strategy for
the synthesis of spirastrellolide A methyl ester (2), allowing for
§Dedicated to Professor Ian Fleming.
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Scheme 1 Evolved synthetic strategy for spirastrellolide A based on either (a) Julia olefination to form C25–C26 bond or (b) Suzuki coupling and
hydroboration to form C24–C25 bond in aldehyde 9.
the initial stereochemical uncertainties, and described the
efficient synthesis of a series of suitably functionalised fragments
(C1–C16 alkyne 3, C17–C25 sulfone 4, C17–C24 vinyl iodide 5
and C26–C40 bis-spiroacetal 6, Scheme 1). Notably, the absolute
configuration of these fragments was selected on the basis of the
stereostructure shown in Andersen’s 2004 paper,1b with the flexi-
bility that the other enantiomeric form of each could be readily
accessed if required. As it turned out, we were fortunate that
these four fragments all had the absolute configuration required
for elaboration into the macrocyclic core of the spirastrellolides,
as revealed in late 2007 by the publication of the X-ray structure
of a derivative of spirastrellolide B.2a This meant that the
only remaining stereochemical ambiguity was the configuration
at C46 in the side-chain,2b and in recognition of this we had
prepared the two enantiomeric forms of the C43–C47 stannane
fragment 7 and 8.
The first of these (a) was based on a planned Julia-type olefina-
tion between sulfone 4 and DEF-bis-spiroacetal aldehyde 10, fol-
lowed by selective hydroboration of the terminal alkene and
reduction of the internal Δ25,26 alkene so formed. The second,
more adventurous approach (b), involved an sp2–sp3 B-alkyl
Suzuki coupling10 between vinyl iodide 5 and a trialkylborane
derived by hydroboration of the homologated DEF-bis-spiroace-
tal alkene 11. While the latter route has a clear advantage in that
vinyl iodide 5 is more readily available than the corresponding
sulfone 4, there was significant uncertainty in the sense and
degree of π-facial selectivity that would arise from hydroboration
of the resulting Δ23,24 alkene to install the C23/C24 stereocen-
tres. Assuming that one of these strategies could reliably afford
the advanced C17–C40 aldehyde 9, then an alkyne addition
which had proved robust in earlier work9b,c,d would be used to
couple the C1–C16 fragment 3, leading to a suitable precursor
for the planned BC-spiroacetalisation step which, based on our
earlier exploratory findings, would rely on DDQ-mediated PMB
ether cleavage.9c,d We would then plan to access the truncated
seco-acid 12 and explore its macrolactonisation to assemble the
38-membered macrolide core of the spirastrellolides. At this
point, we could diverge to install either the (46R)-stannane 7 or
its enantiomer (8) by a planned π-allyl Stille coupling11 with a
suitable appended allylic electrophile. Despite the apparent feasi-
bility of this synthesis plan, we fully expected that it would need
to be modified to circumvent unanticipated experimental
Evolved synthesis plan
With this groundwork in place, we now needed to identify a suit-
able coupling strategy to assemble the available fragments and
subsequently close the signature 38-membered macrocycle en
route to spirastrellolide A methyl ester (Scheme 1). As discussed
previously,8 our strategy evolved to consider two complementary
approaches to assembling the advanced C17–C40 aldehyde 9.
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bottlenecks and possible roadblocks we might encounter on the
uncharted way to spirastrellolide A.
labile DEF aldehyde 13 could not be recovered, suggesting that
it underwent decomposition under these strongly basic reaction
conditions.
We reasoned that replacement of the appended δ-lactone by a
suitably protected 1,4-diol in aldehyde 10 (Scheme 3) might be
more rewarding. This entailed a buffered Dess–Martin14 or
Swern15 oxidation of 6 to afford desired aldehyde 10, which
proved unstable to purification by chromatography and so was
routinely used directly in subsequent reactions. With aldehyde
10 in hand, we first explored the Julia coupling option using
model sulfone 18.16 Aldehyde 10 was added to a pre-mixed sol-
ution of sulfone 18 and LiHMDS at −78 °C, followed by
warming to room temperature. To facilitate product isolation, the
PMB ether was cleaved prior to purification by treatment with
DDQ. This afforded coupled alcohol 19 as solely the E-alkene
(28% over 3 steps from 6). Encouraged by this promising
outcome, we moved to examine the one-pot Julia olefination
between the fully-functionalised C17–C25 sulfone 48 and the
same aldehyde 10. Following the same procedure, aldehyde 10
was added to a pre-mixed solution of sulfone 4 and LiHMDS in
THF at −78 °C. After slow warming to room temperature, the
desired coupled product 20 was obtained, albeit in a modest
25% yield. It is likely that the considerable steric demands of
aldehyde 10 inhibit C25–C26 bond formation with the lithiated
sulfone, allowing competing degradation pathways to occur.
Although the yield for this Julia coupling was disappointing, the
planned synthesis of a fully elaborated C17–C40 fragment was
still pursued.
Results and discussion
The Julia coupling route
In previous studies,12 the first-generation tetracyclic DEF-bis-
spiroacetal aldehyde 13 had failed to undergo a Julia olefina-
tion13 with model sulfone 14 to give 15 (Scheme 2) using con-
ditions (KHMDS, THF, −78 °C) that had proven successful for a
simplified dihydropyran aldehyde (16 → 17). Unfortunately, the
Site-selective hydroboration of the terminal alkene in 20 was
initially attempted using 9-BBN, although repeated trials gave
only low conversion or unidentified by-products. Similarly dis-
appointing results were obtained using disiamylborane with or
without Wilkinson’s catalyst (ClRh(PPh3)3).17 Finally, treatment
of 20 with BH3·SMe2 at 0 °C gave the desired primary alcohol
Scheme 2 Exploratory studies for fragment coupling by Julia olefina-
tion using sulfone 14.
Scheme 3 Synthesis of C1–C20 fragment 22 by Julia coupling route.
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21 in 81% yield without disruption of the internal Δ25,26 alkene.
Hydrogenation of the latter was now required to complete the
fragment synthesis. Due to the presence of the benzyl and PMB
ethers in alcohol 21, care was taken to find a procedure that
would saturate only the internal double bond. Hydrogenation in
benzene using Wilkinson’s catalyst was attempted on the model
compound 19, but led only to several unidentifiable by-products.
However, when diimide reduction with (NCO2K)2 was tested,18
1H NMR spectroscopic analysis indicated the clean formation of
the desired saturated product. With a suitable reduction protocol
in hand, alcohol 21 was now submitted to (NCO2K)2 in pyridine
and acetic acid in methanol (which generates diimide in situ). In
contrast to 19, diimide reduction of 21 was slow and required a
greater excess of reagent. Although the steric effects around the
internal double bond were probably responsible for the reduced
reactivity, it was with great relief that the completed C17–C40
fragment 22 could be isolated in essentially quantitative yield
after 5 days. This advanced material, although prepared in
modest yield due to the inefficient Julia olefination step, proved
invaluable in establishing the stereochemistry of the coupled
product from the alternative Suzuki coupling/double hydrobora-
tion option.
Scheme 4 Model studies for hydroboration of allylic alcohol.
The Suzuki coupling route
methylenation method of Lebel23 was selected based on the sen-
sitivity of the DEF aldehyde substrate. This involved treatment
of freshly prepared aldehyde (from DMP oxidation of alcohol 6)
with a mixture of Wilkinson’s catalyst, PPh3, ethanol and
TMSCHN2. The targeted DEF-alkene 11 was isolated in
60–80% yield from 6, where the variability in yield was due
more to the rather capricious oxidation than to the methylenation
step. In reality, this reaction is a modification of the Wittig olefi-
nation, which proved a similarly effective method for the prep-
aration of 11 (60–80% from 6) and was ultimately the method of
choice due to its greater operational simplicity.
With both DEF-alkene 11 and vinyl iodide 5 in hand, their
union and the construction of the C17–C40 carbon skeleton of
spirastrellolide A could be investigated. Following a procedure
developed in model systems,12 DEF-alkene 11 was treated with
9-BBN to generate the corresponding trialkylborane 28. The
quality of this reagent proved critical to the reaction and
the success of the Pd-catalysed cross-coupling as a whole.24
Following slow addition of the intermediate trialkylborane to
vinyl iodide 5 under optimised Suzuki coupling conditions
(Pd(dppf)Cl2, Cs2CO3, Ph3As, aq DMF),25 the desired C17–C40
diene 29 was isolated in an excellent 83% yield. With a more
successful fragment coupling achieved, the crucial double hydro-
boration reaction was now needed to complete the C20–C24
stereopentad and reveal the required C17 oxygenation.
Our concerns over the limited success of the Julia olefination
strategy led us to reevaluate the original C25–C26 disconnection
altogether (disconnection (a), Scheme 1), and seek one that
might allow for a milder, more reliable mode of fragment coup-
ling, compatible with both the steric demands of the DEF-ring
system and the base sensitivity of the associated C26 aldehyde
10. A Suzuki-type fragment coupling at C24–C25 (disconnec-
tion (b)) was considered attractive due to the mild and chemose-
lective conditions under which it might be achieved,10 whilst
also potentially relieving the steric factors imposed by the DEF-
ring system through the insertion of an additional carbon in the
connecting chain. However, the planned introduction of the C23/
C24 stereocentres by subsequent hydroboration of the resulting
trisubstituted Δ23,24 alkene was an unknown factor.19 Somewhat
surprisingly, the hydroboration of internal allylic alcohols with
the alkene substitution pattern we required for this campaign has
not previously been investigated. Nevertheless, we conjectured
that, following Kishi’s empirical rule20 and the Stork/Houk–
Jäger model,21 hydroboration might occur preferentially on the
desired π-face as dictated by the ‘inside-alkoxy’ effect (see
insert, Scheme 4). Preliminary intelligence-gathering com-
menced by way of some initial model studies. With diol 23,22
hydroboration with BH3·SMe2 in THF, followed by standard oxi-
dative workup, provided a mixture of triols 24 and 25 with 3 : 1
dr, gratifyingly in favour of the desired isomer 24. Stereochemi-
cal determination was achieved by conversion into the corre-
In the event (Scheme 5), treatment of diene 29 with an excess
(10 equiv.) of BH3·SMe2 in THF for 2 h, followed by an oxi-
dative workup provided the triol 30 as a 3 : 1 mixture of diaster-
eomers by 1H NMR analysis. Chromatographic purification
enabled clean isolation of the major isomer. Determination of the
stereochemical outcome was achieved by derivatisation of this
triol as the corresponding cyclic carbonate 31. A diagnostic nOe
between H22 and H23 suggested the cis-configured carbonate,
corresponding to the required spirastrellolide stereochemistry in
1
sponding cyclic carbonates and H NMR nOe analysis. Further
model studies also identified the requirement for a free hydroxyl
at C22 for successful reaction.
Encouraged by this preliminary success, we turned to examin-
ation of the real system (Scheme 5), which required access to
DEF-bis-spiroacetal alkene 11 for the planned Suzuki coupling
with vinyl iodide 5. Initially, the mild, rhodium-catalysed
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Scheme 5 Suzuki coupling and double hydroboration to assemble C17–C40 fragment 32.
this region. Ultimately, rigorous proof of stereochemistry was
achieved by conversion of 32 into alcohol 22 (PPTS, CH2Cl2–
MeOH), and comparison with authentic material prepared by the
although it gave us confidence to go forward with the preferred
Suzuki coupling route with some redesign of the protecting
groups. In particular, the controlled late stage removal of the
benzyl ether at C40 would likely raise chemoselectivity issues in
the presence of the Δ15,16 olefin and the C28 chlorine substituent.
In its place, a TBS ether was chosen which should be inert to the
conditions used for manipulation of the C1 and C37 oxygenation
in preparation for macrolactonisation, yet might be selectively
removed after the macrolactone ring had been closed.
1
earlier Julia olefination route (Scheme 3). H NMR data for this
latter compound was in complete agreement with that for the
major isomer of the double hydroboration reaction, and substan-
tially different from the minor isomer, thus confirming the
stereochemical assignment at C23 and C24. To our delight,
double hydroboration of diene 29 had indeed given predomi-
nantly the desired stereochemistry at C23 and C24, which was a
major breakthrough in advancing the total synthesis effort.
Following this gratifying result, we concentrated on improving
the key double hydroboration step. In practice, the yield could be
increased by per-silylation of the crude hydroboration products,
which delivered tetra-TES ether 32 (as a 3 : 1 mixture with its
chromatographically inseparable minor diastereomer) in 77%
yield from diene 29. Significant enhancement in the diastereos-
electivity of this key transformation was then realised by exploit-
For rapid access to the modified DEF-bis-spiroacetal 34
(Scheme 6), the benzyl ether in C26–C40 fragment 33 was best
cleaved by hydrogenolysis with W-6 Raney nickel in EtOH to
cleanly afford the corresponding C40 alcohol.28 TBS protection
of this alcohol then gave tris-silyl ether 34 in good yield (86%
from 33). With 34 in hand, the same sequence employed pre-
viously was adapted to give alkene 35. Accordingly, selective
cleavage of the C26 TES ether was followed by oxidation to the
corresponding aldehyde under optimised Dess–Martin con-
ditions (dilute in wet CH2Cl2). Wittig methylenation then
afforded the revised DEF-alkene 35 in readiness for Suzuki
coupling with vinyl iodide 5. As before, hydroboration of 35
was performed with 9-BBN, the reaction was quenched with
water, and the crude trialkylborane was used directly in the
Suzuki coupling. As previously, the cross-coupling reaction was
performed by slow addition of trialkylborane to vinyl iodide 5 in
wet DMF,25 in the presence of Pd(dppf)Cl2, Cs2CO3 and
Ph3As.29 Due to the oxygen-sensitivity of the palladium catalyst,
all reaction solvents had to be carefully degassed before use,
under which conditions the desired product 36 was isolated in
83% yield. Using the optimum slow addition procedure devel-
oped for the double hydroboration of 29 (Scheme 5), diene 36
was converted into tris-silyl ether 37 in excellent yield and selec-
tivity (95%, 10 : 1 dr). At this juncture, selective cleavage of the
C17 TES ether in 37 was achieved by treatment with PPTS
ing
a marked substrate concentration dependence. Under
optimised conditions,26 diene 29 was added dropwise over 2 h
via syringe pump to a solution of BH3·SMe2 in THF at 0 °C.
Oxidative workup (H2O2, NaOH) and per-silylation of the crude
triol then provided the tetra-TES ether 32 in excellent yield and
diastereoselectivity (85%, 10 : 1 dr). Whilst it is tempting to
rationalise this highly stereoselective reaction using the stereo-
chemical model depicted in Scheme 4, the lack of stereoselectiv-
ity observed for other model systems27 suggests that
stereoinduction arises principally as a result of the DEF-ring
system, presumably through steric blocking of one of the alkene
π-faces in the reacting conformation of 29.
With the material prepared by this route, we explored its elab-
oration into truncated C1–C40 seco-acid 12 (Scheme 1) but ran
into difficulties in the critical macrolactonisation step. For the
sake of brevity, this phase of the project is not detailed here,12
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C1–C40 carbon framework of the spirastrellolides could now be
realised through a coupling reaction between alkyne fragment 38
and aldehyde 38 (Scheme 7). Lithiation of alkyne 3, followed by
addition of aldehyde 38 afforded the coupled product 39, iso-
lated as an inconsequential (ca. 1 : 1) mixture of epimeric C17
alcohols. Lindlar reduction30 followed by Dess–Martin oxidation
provided (Z)-enone 40 in 82% yield over 3 steps. At this stage,
the planned tris-PMB deprotection and in situ spirocyclisation
could be implemented to construct the BC-spiroacetal moiety in
spirastrellolide A. On submission of 40 to DDQ in CH2Cl2/pH 7
buffer, the fully functionalised ABCDEF-ring system was
obtained in 62% yield. Notably, 41 was isolated cleanly, with the
minor C23/C24 hydroboration diastereomer now able to be sep-
arated chromatographically. Based on the anticipated stabilisation
by the anomeric effect, the configuration at C17 of the newly
formed BC-spiroacetal in 41 was confirmed through a diagnostic
nOe correlation between protons at C13 and C21. It is also note-
worthy that the major product 41 was found to have a free
hydroxyl group at C23 due to an unexpected silyl deprotection.
At this point, it was decided to progress the synthesis with a free
hydroxyl at C23 in 41, a decision we later found to be crucial for
successful macrolactonisation.31
Having the complete C1–C40 component 41 now in hand,
elaboration into the truncated seco-acid was carried out in readi-
ness for macrolactonisation. From 41, the required seco-acid 42
was prepared via a 3-step sequence. For selective oxidation of
the primary alcohol at C1, the nitroxyl radical TEMPO was used
in the presence of PhI(OAc)2.32 Through this TEMPO oxidation,
the expected aldehyde was formed together with some material
which had been further oxidised to carboxylic acid. Notably, no
oxidation of the C23 secondary alcohol was observed. Without
purification, Lindgren–Pinnick oxidation33,34 was carried out to
convert all of this material to the carboxylic acid in 86% yield
over 2 steps. To complete the preparation of seco-acid 42, TES
deprotection of the C37 alcohol was carefully performed with a
mixture of TBAF–AcOH (1 : 3 molar ratio) in THF. It was
necessary to stop this reaction before full conversion of starting
material due to the lability of the other silyl ethers. Quenching of
the reaction after 45 min produced 42 in 57% yield, while 31%
of unreacted starting material could be recovered and reused.
Based on our extensive experience in macrolide total synthesis,35
the tried and tested method of Yamaguchi was selected to close
the 38-membered macrolactone of spirastrellolide A.36,37
Accordingly, a mixed anhydride of 42 was initially formed with
2,4,6-Cl3(C6H2)COCl and Et3N in THF; this was diluted with
PhMe and slowly added by syringe pump to a solution of
DMAP. Gratifyingly, clean macrolactonisation to afford 43 was
achieved in essentially quantitative yield within 2 h, without the
need for heating. The remarkable ease with which this highly
functionalised 38-membered macrolactone could be prepared,
together with the observation that no cyclisation was observed
involving the free alcohol at C23, suggests that the seco-acid 43
may favour a pre-organised pseudo-macrocyclic conformation.
We attribute this effect to the nature of the C22–C24 linker
region between the BC and DEF-spiroacetal ring systems, which
serves to orientate the BC and DEF spiroacetals in a productive
manner for closure of the 38-membered macrolactone. This con-
formational preference may derive from possible hydrogen
bonding of the free C23 alcohol with the C11 ether (see Fig. 1)
Scheme 6 Suzuki coupling in modified C40 TBS ether series.
(CH2Cl2, MeOH, 10 : 1), followed by Dess–Martin oxidation
to afford C17–C40 aldehyde 38, incorporating all of the
oxygenation required for spirastrellolide A, with the correct
stereochemistry.
Alkyne addition, BC-spiroacetalisation and macrolactonisation
Building on our early work on synthesising the southern hemi-
sphere in isolation,9b–d completion of the more elaborate
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Scheme 7 Alkyne addition, BC-spiroacetalisation and macrolactonisation to give 43.
or a subtle steric or stereoelectronic control over the C22/C24
rotamer distribution.38
followed by protecting group adjustment. Using HF·py/py (2 : 1
v/v) in THF (Scheme 8), all the silyl ethers were cleaved to
afford the remarkable macrocyclic pentaol 44, which was iso-
lated as colourless needle-shaped crystals (m.p. 174 °C). The
excellent quality of these crystals enabled X-ray diffraction
analysis, yielding the crystal structure shown in Fig. 1.39 Interest-
ingly, this revealed a network of both intermolecular and intra-
molecular hydrogen bonding, which leads to a well-defined
conformation within the 38-membered macrocycle. This first
solid-state structure40 of the exact macrocyclic core of spirastrel-
lolide A confirmed that the configuration of all the stereocentres
had been installed as planned and corresponded to that within
the natural product itself, and furthermore revealed the precise
location in space of the various macrocycle substituents – infor-
mation which is likely to prove invaluable in the design of spir-
astrellolide analogues.2a
Exploring the side-chain attachment
Delighted with the efficiency of the crucial macrolactonisation
step, completion of the synthesis seemed imminently possible
from advanced intermediate 43. The only remaining task
appeared to be attachment of the full side chain at the C40 pos-
ition. However, despite significant experimentation, selective
cleavage of the supposedly labile primary TBS ether in 43 to
reveal the free C40 hydroxyl could not be achieved. Most
attempts led to a mixture of non-selectively deprotected com-
pounds, revealing a variety of alcohols in the macrocycle. There-
fore, our preferred course of action became a global deprotection
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Fig. 1 Crystal structure39 of macrocyclic pentaol 44 and depiction of
internal hydrogen-bond network.
Inspired by the preparation of the bis-acetonide of spirastrello-
lide A methyl ester in the structural elucidation studies of the
Andersen group,1b acetonide protection of the C22/C23 and
C9/C11 diol regions in 44 was proposed in the anticipation that
this would lead to an opportunity for NMR correlation.
Bis-acetonide 45 having a primary alcohol at C40 was prepared
in a two-step sequence. Full protection of 44 with an excess of
2,2-dimethoxypropane in the presence of PPTS, followed by
cleavage of the accompanying mixed acetal group at C40,
produced the desired alcohol 45 (60%). The latter step also pro-
duced some over-deprotected compounds, which could be easily
recycled through the same reaction sequence. In general, an
overall yield of 78% for 45 was obtained after one recycle. Com-
Scheme 8 Preparation of macrocyclic pentaol 44 and bis-acetonide
derivative 45.
anticipated that both configurations could be generated and
hence the two possible diastereomers of the natural product
could be accessed. In order to establish suitable reaction con-
ditions, while conserving advanced material, this Stille coupling
sequence was explored starting out from already prepared C25–
C40 DEF-alkene 11 (Scheme 9). Hydrogenation of 11 with
Pearlman’s catalyst effected C40 debenzylation, alkene reduction
together with C37 desilylation, affording the corresponding diol
in near quantitative yield. Selective primary oxidation (TEMPO,
PhI(OAc)2) then gave γ-lactone 46 as a crystalline solid
(m.p. 153 °C). Reduction of γ-lactone 46 to the lactol with
DIBAL followed by addition of vinylmagnesium bromide pro-
vided allylic alcohol 47 (94%, 2 : 1 dr), which was subjected to
cyclic carbonate formation by treatment with triphosgene to
provide 48 (39%, 3 : 2 dr).41 The Stille cross-coupling between
48 and stannane 78 was carried out using catalytic
1
parison of the H NMR spectroscopic data of bis-acetonide 45
with the reported data for the bis-acetonide of spirastrellolide A
methyl ester (see ESI‡) now indicated a close correlation. In this
key synthetic intermediate, the conformation of the macrocyclic
core in solution appears to correlate closely with the derivatised
natural material within comparable regions.
With the fully functionalised macrocycle established, we
could now investigate various endgame options. From the outset,
our preferred approach called for the late-stage installation of the
full side chain of spirastrellolide A, incorporating the 1,4-diene
moiety and α-hydroxy methyl ester, as dictated by the initially
unknown configuration at C46. By use of C43–C47 stannane
fragment 7 (Scheme 1) and a π-allyl Stille coupling,11 it was
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Scheme 9 Synthesis of northern hemisphere analogues of spirastrellolide by π-allyl Stille coupling with cyclic carbonate 48.
Scheme 10 Synthesis of additional northern hemisphere analogues of spirastrellolide by π-allyl Stille coupling with acyclic carbonates 52 and 53.
PdCl2(MeCN)2 in wet DMF, which afforded methyl ester 49
(72%) via an intermediate π-allyl palladium species. Pleasingly,
this reaction proceeded with the expected conservation of the
(43Z)-alkene (3JH43,H44 = 10.8 Hz) and installation of the
required (40E)-alkene (3JH40,H41 = 14.6 Hz). Repeating the reac-
tion with structurally related stannane 50 was also successful,
affording the corresponding skipped diene 51 (57%). To increase
the flexibility of the synthesis endgame, we also prepared the
acyclic regioisomeric allylic carbonates 52 and 53 (incorporating
TES ethers at C26 and C37) as substrates for the π-allyl Stille
coupling reaction (Scheme 10). Dess–Martin oxidation of
alcohol 54 (from debenzylation of 33, Scheme 6) gave aldehyde
55. Vinylmagnesium bromide addition to 55 followed by acyla-
tion with methyl chloroformate produced a 1 : 1 epimeric
mixture of secondary allylic carbonates 52. As an alternative, an
HWE olefination42 of aldehyde 55 extended the side chain
giving (E)-enoate 56. Ester reduction followed by carbonate for-
mation produced coupling substrate 53 containing only the (E)-
alkene. In order to develop a strategy that might be more appli-
cable to the real system, which contains a potentially sensitive
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macrolactone functionality, an alternative route to 53 was also
devised to exclude the reduction step. Wittig methylenation of
55 to give 57, followed by cross-metathesis43 with bis-allylic
carbonate 5844 using Grubbs II catalyst (5 mol%, CH2Cl2,
40 °C) proceeded smoothly to afford alkene 53 in 95% yield as
an inseparable mixture of isomers (E/Z = 7 : 1). As the cross-
coupling is proposed to proceed via a π-allyl palladium inter-
mediate, this alkene geometry ought to be irrelevant (i.e., both
(E)- and (Z)-alkenes should give the same product), providing
the rate of stereochemical equilibration of the π-allyl complexes
to the more stable transoid configuration exceeds that of transme-
tallation. We were most gratified to find that Stille coupling
between stannane ent-50 and 53, using PdCl2(MeCN)2 (10 mol
%) in wet DMF, indeed gave 1,4-diene 59 as a single diastereo-
mer in 80% yield despite the mixture of E/Z isomers in 53. Car-
bonate 53 underwent coupling with 50 with equal facility (59a,
69% brsm). The isomeric carbonate 52 proved a somewhat
poorer substrate for cross-coupling however, providing 59 in
59% yield, and the methyl ester 60 on reaction with 8 in 33%
yield. The diastereoisomeric dioxolanone 59a could then be
smoothly converted into methyl ester 60a by methanolysis
(K2CO3, MeOH).45
As well as showing that Stille coupling of an in situ generated
π-allyl palladium species is a viable approach for elaborating the
characteristic C38 side chain of the spirastrellolides, this tempor-
ary detour also provided several simplified analogues (49, 51, 59
and 60) for future structure–activity relationship studies.
Completion of the total synthesis of spirastrellolide A methyl
ester
At this stage, we were ready to embark on the final stages of the
total synthesis campaign having established the viability of the
π-allyl Stille coupling process on northern hemisphere model
systems. In order to test out some of the protocols for introdu-
cing the allylic carbonate appendage on the full macrolactone
system, the alcohol 45 was oxidised by buffered Dess–Martin
periodinane to cleanly afford aldehyde 61 (Scheme 11).
Frustratingly, initial attempts to elaborate macrocyclic aldehyde
61 towards the targeted allylic carbonate proved unsuccessful.
These included a Nozaki–Hiyama–Kishi reaction with vinyl
iodide, a Grignard addition with vinylmagnesium bromide, and
a stabilised Wittig olefination with Ph3PvCHCHO. Although it
is difficult to pinpoint a single cause of failure in a structure as
complex as 61, it was considered that steric effects from the
macrocyclic cage-like environment around the C40 aldehyde (as
revealed by the X-ray crystal structure of 44, see Fig. 1) were
reducing its reactivity. Fortunately, a Wittig olefination of 61
with Ph3PvCH2 was successful, giving the terminal alkene 62
cleanly (87%, 2 steps). Studies towards the side chain attachment
were thus channelled towards olefin cross-metathesis43 of 62
with 58, which we hoped would afford a primary allylic carbon-
ate. Further evidence for the reduced reactivity at this site is
shown by the forcing conditions which were needed to achieve
this cross-metathesis, requiring 20 mol% loading of Grubbs II
catalyst and an elevated temperature of 80 °C. Moreover, the
desired product 63 was isolated in a modest 58% yield after 16 h
reaction, although fortunately the unreacted starting material 62
Scheme 11 Completion of the total synthesis of spirastrellolide A
methyl ester.
could be recovered in 42% yield (99% brsm for 63), this low
conversion again likely reflecting the steric encumbrance
imposed by the macrocycle on the truncated side chain. The
stereoselectivity of this coupling mirrored that of our earlier
model study, with allylic carbonate 63 being obtained as a
6 : 1 mixture of E/Z-isomers.
At this late stage of the campaign, the configuration of the
last remaining stereocentre at C46 was assigned in a timely
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Scheme 12 Summary of the intermediates and synthetic journey to spirastrellolide A methyl ester (2).
publication by the Andersen group.2b By oxidative degradation
of a newly found congener, spirastrellolide D methyl ester, and
subsequent methyl ester formation within the fragmentation
product, dimethyl malate was obtained as the (R)-enantiomer.
Consequently, spirastrellolide D was shown to have (R)-
configuration at C46 and hence, by analogy, it was assumed that
spirastrellolide Awould be the same.
With this knowledge of the full configuration of spirastrello-
lide A, the side chain attachment could now be completed with
confidence that the correct stereochemistry would be introduced.
Stille coupling was initiated between macrocyclic allylic carbon-
ates 63 and (46R)-stannane 7 using identical conditions to those
in the model system (PdCl2(MeCN)2 in wet DMF). From the
previous work to chain-extend at C40, it was expected that
the reactivity of the allylic carbonate would be lower than for the
model system. As such, it was disappointing yet unsurprising to
discover that once stannane 7 was added to a pre-mixed solution
of 63 and palladium catalyst in degassed DMF–H2O, the desired
cross-coupling reaction seemed to be prevented by competing
decomposition pathways, with more rapid formation of the
homo-coupling product of 7 and deposition of palladium black,
preventing productive turnover in the catalytic cycle. Fortunately,
this could be circumvented by the slow (portionwise) addition of
solutions of PdCl2(MeCN)2 catalyst and stannane 7 to substrate
63, which provided the desired coupled product 64 in 96% yield.
As expected from the model system, both isomers of the Δ40,41
olefin in 63 produced the desired (40E)-olefin following Stille
coupling. At this stage, a direct comparison could be made to
an identical bis-acetonide prepared by the Andersen group
from natural spirastrellolide A.1b Gratifyingly, this synthetic bis-
acetonide 64 correlated in all respects (1H and 13C NMR, mass
spectra, and optical rotation, see ESI‡) with the data reported,
unequivocally validating the complete stereostructure proposed
by the Andersen group.46
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To complete the total synthesis, the final acetonide deprotec-
tion was carried out on 64. With an excess of PPTS in MeOH,
spirastrellolide A methyl ester (2) could be obtained following
16 h reaction at 35 °C. At this stage, a sample of authentic
methyl ester of spirastrellolide Awas made available to us by the
Andersen group for correlation purposes. However, 1H NMR
comparison of the purified synthetic and natural samples proved
an inexact match on initial analysis. Even more remarkably,
repeated analysis of the same sample in benzene-d6 gave varied
spectra depending on the sample treatment. For example, spectra
of this sample differed before and after storage at −20 °C for
16 h, despite both spectra being recorded at room temperature.
Purification by HPLC also caused changes to the resonances in
by double hydroboration to install the C23/C24 stereocentres.
The derived C17 aldehyde 38 then underwent smooth coupling
with the lithium acetylide of alkyne 3. A DDQ-mediated BC-
spiroacetalisation was followed by a remarkably high yielding
macrolactonisation of a truncated seco-acid 42 to give, after
exhaustive desilylation, the crystalline macrocyclic core 44 of
the spirastrellolides. Finally, after investigations to chain-extend
the sterically hindered C40 region, a π-allyl Stille coupling was
employed to install the required skipped diene from a diastereo-
meric mixture of allylic carbonates 63. Global deprotection and
purification then afforded fully synthetic (+)-spirastrellolide A
methyl ester (2), which was validated by careful NMR corre-
lation with an authentic sample.
This first total synthesis of spirastrellolide A methyl ester
evolved alongside structure determination studies by the Ander-
sen group. As such initial stereochemical ambiguities influenced
our synthetic strategy, resulting in a modular approach to the
macrocyclic core and a late-stage side-chain attachment. We
anticipate that with the full configuration now secure, a more
streamlined and higher yielding synthetic route to the spirastrel-
lolides might evolve from the extensive groundwork reported in
these two papers.48 In closing, we emphasise that pursuing such
complex natural products as the spirastrellolides by total syn-
thesis has proved to be a learning experience par excellence, as
well as enabling a sustainable supply and access to novel
designed analogues to further explore the biology and thera-
peutic potential of these fascinating molecules.
1
the 3.1–4.8 ppm region of the H NMR spectra (see ESI‡). This
observation may suggest the adoption of different stable confor-
mers (i.e., atropisomers) of spirastrellolide in benzene-d6, where
the barrier to interconversion is set by the hydrogen bond-stabil-
ised framework. It is entirely conceivable that reverse phase
HPLC purification could interconvert such isomers via tempor-
ary disruption of this hydrogen bond network (polar/aqueous
conditions), and that the process of temporary incorporation of
the natural product in a frozen benzene matrix could exert
similar effects. Similar discrepancies between samples had been
observed by Andersen,47 and subsequent to our work by the
Fürstner group4b in their total synthesis of spirastrellolide F
methyl ester, as well as in our earlier NMR analysis of macro-
cyclic pentaol 44.40 To reinforce this hypothesis, a more polar
NMR solvent was used in order to disrupt the hydrogen-bonding
network. In acetonitrile-d3, despite the poorer dispersion, all
chemical shifts were now readily reproducible in both the syn-
thetic and natural sample. By careful trials, it was discovered that
an exact correlation in benzene-d6 could only be achieved by
subjecting both synthetic and natural samples to an identical
NMR sample preparation protocol. Thus, purification by HPLC,
preparation of NMR samples, and running of the NMR spectra
was carried out in parallel under identical conditions with both
samples. Gratifyingly, in this case, both the natural and synthetic
NMR spectra were now identical. Correlation was also obtained
in mass spectra, CD spectra, optical rotation and HPLC retention
time, thus confirming unequivocally the success of our total syn-
thesis, and providing for the first time a synthetic means to
access this captivating and important natural product.
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.) and SK Innovation (J. H. L.).
We thank Professor R. J. Andersen (University of British Colum-
bia) for helpful discussions throughout this project and for pro-
viding us with a precious sample of authentic spirastrellolide A
methyl ester. The EPSRC National Mass Spectrometry Service
(Swansea) are thanked for providing mass spectra.
Conclusions
References
Due to a combination of their promising anticancer properties,
the limited supply from the marine sponge source and their
unprecedented 38-membered macrolactone scaffold, the spiras-
trellolides represent attractive yet challenging synthetic targets.
By adopting a modular and flexible strategy, a highly stereocon-
trolled total synthesis of (+)-spirastrellolide A methyl ester (2)
was completed in 36 steps (ca. 0.3% overall yield, Scheme 12).
Following optimised syntheses of the key building blocks
(C1–C16 alkyne 3, C17–C24 vinyl iodide 5 and C25–C40 bis-
spiroacetal 6), controlled fragment coupling to access the macro-
cyclic core of spirastrellolide A proceeded with high efficiency.
In the preferred route, vinyl iodide 5 was coupled to bis-spiroa-
cetal 34 using B-alkyl Suzuki coupling methodology, followed
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25 In this reaction, the excess vinyl iodide coupling partner was recovered as
a mixture of 5 and 9-BBN derivative i, whilst the Suzuki coupling
product was never found to contain bound 9-BBN. Furthermore, reac-
tions in which the preformed trialkylborane was added in a single portion
failed to proceed to completion. Together this suggested the free hydroxyl
of 5 might be acting competitively as a base for the organoborane prior to
transmetallation, inhibiting subsequent cross-coupling due to steric
factors. Consistent with this hypothesis, dropwise syringe pump addition
of the preformed trialkylborane solution to a pre-mixed solution of vinyl
iodide 5 and reagents was required for smooth and complete consumption
of the trialkylborane.
9 For earlier work from our laboratory, see:
(a) I. Paterson,
26 J. H. Lim, PhD Thesis, University of Cambridge, 2009.
E. A. Anderson, S. M. Dalby and O. Loiseleur, Org. Lett., 2005, 7, 4121;
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C. Moessner, Chem. Commun., 2007, 1852; (f) I. Paterson,
E. A. Anderson, S. M. Dalby, J. H. Lim, O. Loiseleur, P. Maltas and
C. Moessner, Pure Appl. Chem., 2007, 79, 667; (g) I. Paterson,
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27 Notably, hydroboration of ii and iii both proceeded non-stereoselectively.
This suggests the stereoinduction observed for 23 to be a function of the
1,3-diol rather than C22-hydroxyl alone, and that potential internal hydro-
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ESI.‡.
17 D. A. Evans, G. C. Fu and A. H. Hoveyda, J. Am. Chem. Soc., 1988,
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28 Reagent quality proved critical, where older preparations of Ra-Ni led to
a sluggish reaction and competing desilylation. Reagent preparations of
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30 H. Lindlar, Helv. Chim. Acta, 1952, 35, 446.
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strate to 42 with a TES ether at C23 and a benzyl ether at C40, which
under Yamaguchi conditions (performed on a small scale and using elev-
ated temperatures) gave only a low yield of impure macrolactone (ref.
12). A free hydroxyl at C23 appears to be critical to ensure a productive
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18 (a) E. E. van Tamelen, M. Davis and M. F. Deem, Chem. Commun.,
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electivity. (a) G. Schmid, T. Fukuyama, K. Akasaka and Y. Kishi, J. Am.
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described in the ESI.‡.
23 H. Lebel and V. Paquet, J. Am. Chem. Soc., 2004, 126, 320.
24 The use of commercial 9-BBN led to poor conversion and on prolonged
exposure, to degradation. A much more active and successful reagent was
instead prepared and recrystallised from DME to afford a storable crystal-
line solid, with which a fresh THF solution was made up immediately
prior to hydroboration. Treatment of the alkene 10 with 1.5 equiv. of this
reagent then initiated smooth conversion to the corresponding
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R. Britton, G. Cecere, G. Chouraqui, G. J. Florence, H. Knust and
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38 The forcing conditions required by the Fürstner group (refluxing PhMe)
for achieving a Yamaguchi macrolactonisation on a related system were
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ascribed to a disadvantageous conformation imposed by having the
C22/C23 hydroxyls protected as an acetonide; see ref. 4b.
39 CCDC 669312 contains the supplementary crystallographic data for
42.‡
42 I. Paterson, K.-S. Yeung and J. B. Smaill, Synlett, 1993, 774.
43 (a) A. K. Chatterjee, T. L. Choi, D. P. Sanders and R. H. Grubbs, J. Am.
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40 Detailed 1H NMR analysis of 44 in C6D6 solution proved to be
a demanding task, where several different conformations of the macro-
cyclic pentaol may be present. The observation of variable chemical
shifts of some resonances on repeated submission of the same
sample and an inexact match between 44 and the macrolactone region
of spirastrellolide A methyl ester meant that the definitive evidence
from the X-ray structure was invaluable. All of the erratic
1H NMR signals correlate to the protons, which could be part
of the hydrogen-bonding network, based on the solid-state structure of
44.
44 T. Tsuda, T. Kiyoi and T. Saegusa, J. Org. Chem., 1990, 55, 3388.
45 See ESI‡ for structures and details.
46 Independently to the degradation study by the Andersen group (ref. 2b),
it was considered that the side-chain configuration could be established
through the synthesis of both C46-epimers and comparison to the
reported spectral data. To this end, we also prepared the 46-epi-bis-aceto-
nide of spirastrellolide A methyl ester by carrying out the Stille coupling
with ent-7; this product showed a distinctly different 1H NMR spectrum
to that of 64 and so could be ruled out.
47 D. E. Williams, personal communication, University of British Columbia,
November 2008.
48 I. Paterson, P. Maltas, S. M. Dalby, J. H. Lim and E. A. Anderson,
Angew. Chem., Int. Ed., 2012, 51, 2749.
41 A change in diastereomeric ratio at C40 in forming carbonates 48
is attributed to differential reactivity between the epimeric allylic
alcohols.
5886 | Org. Biomol. Chem., 2012, 10, 5873–5886
This journal is © The Royal Society of Chemistry 2012