Total synthesis of spirastrellolide A methyl ester - Part 2: Subunit union and completion of the synthesis

Article abstract of DOI:10.1002/anie.200705566

(Figure Presented) Succumbing to synthesis: The stereocontrolled total synthesis of spirastrellolide A methyl ester is reported. The union of two key C1-C16 and C17-C40 subunits is followed by macrolactonization and late-stage side chain attachment by a cross-metathesis reaction anda π-allyl Stille coupling reaction with a C43-C47 stannane, thus confirming the 46R configuration. The full configuration and conformation of the 38-membered macrolide is revealed by single-crystal X-ray analysis of an advanced pentaol intermediate.

Full text of DOI:10.1002/anie.200705566

Angewandte
Chemie
DOI: 10.1002/anie.200705566
Natural Product Synthesis
Total Synthesis of Spirastrellolide A Methyl Ester—Part 2: Subunit
Union and Completion of the Synthesis**
Ian Paterson,* Edward A. Anderson, Stephen M. Dalby, Jong Ho Lim, Julien Genovino,
Philip Maltas, and Christian Moessner
The marine macrolide spirastrellolide A (1, Scheme 1) is a
potent and selective protein phosphatase inhibitor, causing
premature cell entry into mitosis.[1] Synthetic interest[2] in the
spirastrellolides derives not only from their unique molecular
architecture, but also from their potential as lead structures
for the development of novel anticancer agents.[3] In the
preceding communication,[2] we described our optimized and
scalable approach to the construction of the key C17–C40 bis-
spiroacetal intermediate 3, which forms the foundation of our
strategy towards these challenging natural products. Herein,
we report the completion of the first total synthesis of
spirastrellolide A methyl ester (2, Scheme 1), as well as the
single-crystal X-ray diffraction analysis of an advanced
intermediate that reveals the conformation of the spirastrel-
lolide macrocycle and plays a vital role in our end-game
strategy.
A summary of our synthetic plan, which was designed to
provide maximum flexibility in terms of fragment coupling
and diastereomer selection, is outlined in Scheme 1. This
optimized retrosynthesis leads to three key subunits—the
C17–C40 aldehyde 3, the C1–C16 alkyne 4, and the C43–C47
stannane 5. The planned completion of the total synthesis of
spirastrellolide A methyl ester (2) would thus proceed
through the union of aldehyde 3 with alkyne 4, with
subsequent elaboration to introduce the BC spiroacetal
domain, and macrolactonization to generate the 38-mem-
bered macrolide core. A series of manipulations at C40 (in the
truncated side chain) would precede the end game of the
synthesis, which would involve a cross-coupling reaction with
stannane 5 to install concurrently the 40E and 43Z double
bonds as well as the terminal a-hydroxy ester in structure 2.
Scheme 1. Spirastrellolide A (1), its methyl ester (2), and retrosynthetic
analysis leading to key building blocks 3–5. PMB=para-methoxyben-
zyl, TBS=tert-butyldimethylsilyl, TES=triethylsilyl.
The first requirement for this synthetic plan was the
preparation of the C1–C16 alkyne 4. We have previously
reported the synthesis of a close relative of this alkyne[4] by
using Jacobsenꢀs hydrolytic kinetic resolution of epoxides.[5]
Building on this earlier work, installation of a PMB ether was
now required at C1 such that our envisaged BC-spiroacetal-
ization step would result in simultaneous deprotection at this
position. The most convenient point to undertake this
modification was deemed to be the vinyl dibromide 6
(Scheme 2). Thus, selective desilylation at C1 was followed
by formation of the PMB ether under mild conditions by
using PMB trichloroacetimidate. Subsequent conversion of
the vinyl dibromide into the alkyne 4 proceeded uneventfully
on treatment with base (66% yield, over 3 steps).[6]
[*] Prof. Dr. I. Paterson, Dr. E. A. Anderson, S. M. Dalby, J. H. Lim,
J. Genovino, P. Maltas, Dr. C. Moessner
University Chemical Laboratory
University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax: (+44)1223-336-362
E-mail: ip100@cam.ac.uk
Homepage: http://www-paterson.ch.cam.ac.uk
[**] This work was supported by the EPSRC (GR/C541677/1), Merck
Research Laboratories, Homerton College, Cambridge (E.A.A.), SK
Corporation (J.H.L.), and the German Academic Exchange Service
(C.M.). We thank Prof. R. J. Andersen (University of British
Columbia) for an authenticsample of spirastrellolide A methyl ester
and for helpful discussions, as well as Dr. J. Davies (Cambridge) for
solving the X-ray crystal structure of pentaol 12.
The union of the C1–C16 and C17–C40 subunits through
addition of the lithium anion of alkyne 4 to the DEF aldehyde
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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3 was now addressed. In this key step, deprotonation of 4 with
treatment of enone 7 with DDQ (CH2Cl2/pH 7 buffer, 08C)
did indeed cleave all three PMB ethers, while also achieving
selective BC spiroacetalization with complete control over
the C17 acetal stereocenter (resulting from a double anomeric
effect).[7] Unexpectedly, this transformation was accompanied
by cleavage of the TES ether at C23, with some minor by-
products detected in which this silyl ether had migrated to C1.
Nevertheless, we were able to remove both these by-products
and the minor C23,C24 diastereomer (arising from the earlier
hydroboration reaction)[2] by flash chromatography, such that
the pure ABCDEF hexacyclic diol 8 was isolated in 58%
yield from enone 7. The synthesis of the seco acid 10 was
completed through oxidation of the C1 hydroxy group in 8 to
the corresponding acid 9 (TEMPO/BAIB; NaClO2), and then
selective cleavage of the C37 TES ether (TBAF, AcOH; 64%
brsm). The latter transformation was best halted prior to
completion, as some over-deprotection involving the C40
TBS or C22 TES ether moieties occurred under prolonged
reaction times.
nBuLi followed by addition to aldehyde 3 (THF, À788C to
À208C) led cleanly to an inconsequential mixture of epimeric
C17 alcohols in 92% yield. Lindlar reduction of these
propargylic alcohols, followed by oxidation (Dess–Martin
periodinane), then provided the (Z)-enone 7 in 89% yield.
Formation of the BC spiroacetal domain, and the
simultaneous liberation of the C1 hydroxy group in readiness
for oxidation to the seco acid, was now required. Gratifyingly,
At this point, we had reached the much anticipated and
crucial macrolactonization step which would form the first
fully synthetic spirastrellolide analogue. Gratifyingly, acid 10
underwent a rapid and efficient macrocyclization by using the
Yamaguchi protocol,[8] to provide the corresponding 38-
membered macrolide 11 in excellent yield (79%), thus
suggesting a favorable conformational preorganization of
the seco acid. In principle, all that remained was a series of
selective manipulations at C40 to install the required side
chain. However, this proved fraught with difficulty, as it was
not possible to selectively cleave the C40 TBS ether of 11 or
indeed other intermediates. One apparent solution to this
problem would be the complete cleavage of all the silyl ether
groups, followed by reprotection or selective reaction at C40.
We were able to achieve this global deprotection using HF·Py
(Scheme 3), and recrystallization (CH2Cl2/heptane) of the
crude product gave the remarkable pentaol 12 as colorless
needles (83%, m.p. 1748C). Importantly, these crystals were
of sufficient size and quality to obtain the X-ray crystal
structure shown.[9] This structure served to confirm that the
relative and absolute configuration was indeed as we had
intended and corresponded to that recently reported for the
natural spirastrellolide macrocycle.[1c] Notably, the pentaol 12
features a distinctive hydrogen-bond network, which leads to
Scheme 2. Preparation of the C1–C16 alkyne 4, its union with the C17–
C40 aldehyde 3, and conversion into the macrocycle 11. a) HF·Py/Py,
THF, 73%; b) PMBTCA, Ph3CBF4, THF, 08C, 90%; c) nBuLi, THF,
À788C to À208C, 100%; d) nBuLi, THF, À208C; 3, À788C to À208C,
92%; e) Pd/CaCO3/Pb, quinoline, H2, EtOAc; f) DMP, NaHCO3,
CH2Cl2, 89% (over 2 steps); g) DDQ, CH2Cl2/pH 7 buffer (9:1), 08C,
58%; h) TEMPO, BAIB, CH2Cl2/pH 7 buffer (5:1); NaClO2,
NaH2PO4·H2O, 2-methyl-2-butene, tBuOH/H2O (1:1), 88%; i) TBAF,
AcOH, THF, 49% (64% brsm); j) 2,4,6-trichlorobenzoyl chloride, Et3N,
toluene; DMAP, toluene, 79%. BAIB=[bis(acetoxy)iodo]benzene,
brsm=based on recovered starting material, DDQ=2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, DMAP=4-(dimethylamino)pyridine,
DMP=Dess–Martin periodinane, PMBTCA=para-methoxybenzyl-
2,2,2-trichloroacetimidate, Py=pyridine; TBAF=tetra-n-butylammo-
nium fluoride, TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy, free
radical.
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Scheme 4. Preparation of the side chain stannanes 13 and 5. a) CBr4,
PPh3, Et3N, CH2Cl2, 08C, 81%; b) nBu3SnH, [Pd(PPh3)4], benzene,
408C; (Me3Sn)2, iPr2NEt, 808C, 74%; c) K2CO3, MeOH, 81%.
(S)-malic acid. Methanolysis of 13 then provided the free a-
hydroxy ester 5.
Our exploratory Stille cross-coupling studies are shown in
Scheme 5. We were mindful that the intermediate p-allylpal-
ladium complex 16 could arise from the two regioisomeric
carbonates 17 and 18, and furthermore that the configuration
of both the internal C40 carbonate of 17 (at the allylic
stereocenter) and terminal C42 carbonate of 18 (olefin
Scheme 3. Deprotection of the macrocycle 11 to the crystalline pentaol
12 and X-ray crystal structure of 12 (shown with ellipsoids at 50%
probability). a) HF·Py/Py, THF, 83%.
a well-defined conformation of the macrolide core. Interest-
ingly, an inexact match between 12 and the macrolide region
of spirastrellolide Awas revealed in the 1H NMR spectrum.[10]
This finding is consistent with our observations that small
changes in the side chain could lead to substantial differences
in the chemical shifts in the 1H NMR spectrum of the
macrocycle, thereby emphasizing its proximity to this ring
and hence restricting its accessibility.
Attachment of the full side chain of the spirastrellolides
was planned (Scheme 1) using a p-allyl Stille cross-coupling
reaction[11] of stannane 5 with a suitable allylic carbonate
derived from the advanced intermediate 12. It was decided to
first model this crucial transformation with a simplified DEF
analogue. At this stage of the project, rapid access to both
enantiomers of stannane 5 and its acetonide derivative 13
were required (Scheme 4). To this end, the aldehyde 14,
prepared in three steps from (R)-malic acid,[12] was converted
into the corresponding vinyl dibromide 15 (81%).[6] Pleas-
ingly, a palladium-catalyzed one-pot debromination/stanny-
lation protocol, which exploits the differing reactivity of the
trans- and cis-bromides through selective reductive (E)-
debromination[13] ([Pd(PPh3)4], Bu3SnH, 408C) followed by
buffered bromine-tin exchange (Me6Sn2, 808C),[14] provided
solely the (Z)-alkenyl stannane 13 (74%); the antipodal
stannane ent-13 was obtained in an analogous fashion from
Scheme 5. Synthesis of carbonates 17 and 18, and their coupling with
=
stannane ent-13. a) H2C CHI, CrCl2, NiCl2, DMF, 71%; b) ClCO2Me, Py,
CH2Cl2, 43%; c) [PdCl2(MeCN)2], ent-13, DMF/H2O (4:1), 59% (for 17),
=
80% (for 18); d) Ph3P CH2, THF, À788C to RT, 71%; e) 2nd generation
Grubbs catalyst, 21, CH2Cl2, 408C, 99% (E/Z 7:1). DMF=N,N-dimethyl-
formamide.
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isomers) may well be important, as the rate of isomerization
of p-allyl species derived from such precursors depend
strongly on the choice of reaction conditions.[11a] In the
present system, the combination of a hindered Z stannane
combined with the bulky nature of the tricyclic DEF system
was anticipated to favor terminal substitution and formation
of an E olefin. Thus, we addressed the formation of the p-
allylpalladium complex 16 by both routes, starting from the
common C26–C40 aldehyde 19 obtained from the corre-
sponding alcohol.[15] The preparation and reaction of the
internal carbonate 17 was first examined. Aldehyde 19
underwent a smooth Nozaki–Hiyama–Kishi coupling[16] with
vinyl iodide to provide an epimeric mixture of internal allylic
alcohols, which were then converted into 17. We were now
faced with the key p-allyl Stille cross-coupling reaction,[11] for
which (because the C46 configuration was unknown at the
time of these studies) we arbitrarily employed the (S)-
stannane ent-13. Treatment of the carbonates 17 with ent-13
and [PdCl2(MeCN)2] led to the isolation of a single product 20
(59%), which corresponds to the desired 40E,43Z diene
(JH40,H41 = 14.6 Hz). The regioisomeric carbonates 18 were
prepared by Wittig methylenation of aldehyde 19, followed by
cross-metathesis[17] with the bis-methyl carbonate 21 to
generate the terminal allylic carbonates 18 as a 7:1 E/Z
mixture. (E)-18 was also prepared exclusively through Wittig
olefination (Ph3PCHCO2Me), followed by reduction with
DIBALH and carbonate formation. Pleasingly, these carbo-
nates 18 also proved to be viable substrates for the cross-
coupling reaction with ent-13, and the C26–C47 diene 20 was
again isolated as a single isomer, in an improved yield of 80%.
Confident that we were now equipped with two comple-
mentary strategies for installing the side chain, we refocused
our attention on the pentaol 12, and embarked on the
concluding steps of the total synthesis (Scheme 6). These
steps commenced with formation of the corresponding
trisacetonide of 12 (which contained a mixed acetal at C40)
by warming 12 with 2,2-dimethoxypropane and PPTS. It was
then possible to cleave the C40 mixed acetal—a reaction that
was inevitably accompanied by some competing deprotection
at C9 or C11 to give a recyclable monoacetonide—giving the
bis-acetonide in an overall yield of 78% after one recycle. The
residual primary alcohol at C40 was oxidized using Dess–
Martin periodinane to give aldehyde 22, which represented
the point at which to test our two coupling strategies. In the
event, our concerns over this side chain introduction proved
justified, as the Nozaki–Hiyama–Kishi vinyl iodide addition,
which had proved facile in our model system 19, failed in the
current setting. Fortunately, we were able to exploit our
alternative strategy through Wittig methylenation of alde-
hyde 22 to provide the terminal alkene 23. In contrast,
attempts to extend the sterically encumbered side chain
Scheme 6. Completion of the total synthesis of spirastrellolide A
methyl ester (2). a) PPTS, (MeO)2CMe2/CH2Cl2 (2:1), 358C, 95%;
b) PPTS, CH2Cl2/MeOH (12:1), 08C, 78% after one recycle; c) DMP,
=
NaHCO3, CH2Cl2, 80%; d) Ph3P CH2, THF, À788C to RT, 75%; e) 2nd
generation Grubbs catalyst, 21, benzene, 808C, 57% (99% brsm);
f) [PdCl2(MeCN)2], 5, DMF/H2O (4:1), 358C, 96%; g) PPTS, MeOH,
358C, 60%. PPTS=pyridinium para-toluenesulfonate.
=
further using stabilized Wittig reagents (e.g. Ph3P CHCHO)
proved unrewarding, despite the remarkable thermal stability
of the aldehyde 22 (e.g. prolonged heating to 1108C in
toluene).
At this point we were faced with a narrow window of
synthetic opportunity, as our plan now relied on the success of
a contemporary cross-metathesis reaction[17] to overcome the
limitations of classical olefination chemistry. The steric
demands of the C40–C41 terminal alkene were again in
evidence, as the cross-metathesis of 23 required substantially
harsher conditions than had our model substrates. Pleasingly,
and despite the requirement for elevated temperatures
(second-generation Grubbs catalyst, 808C, benzene, 4 h)
and excess 21 (16 equiv), the reaction afforded the desired
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6, 2607; c) K. Warabi, D. E. Williams, B. O. Patrick, M. Roberge,
product 24 (99% brsm, typical conversion 60%, E/Z 6:1).
Crucially, the resulting allylic carbonate 24 then underwent a
p-allyl Stille cross-coupling reaction with the (R)-stannane 5
to give the (40E,43Z)-bis-acetonide 25, which was isolated as
the sole geometric isomer in excellent yield (96%). The
benefit of our late-stage protecting group switch was now
revealed, as this bis-acetonide correlated in all respects (1H
and 13C NMR spectra, mass spectra, and optical rotation) with
that formed by Andersen and co-workers from spirastrello-
lide A itself,[1b,10] thereby confirming the 46R configuration.[1d]
With 25 in hand, the completion of the total synthesis
required only the cleavage of the acetonide groups. Heating a
solution of 25 in methanol in the presence of PPTS (358C,
12 h) did indeed remove both acetonide groups, and provided
(+)-spirastrellolide A methyl ester (2) in 60% yield, [a]2D0 =
+ 28.6 (c = 0.007, CH2Cl2). Comparison with an authentic
sample (provided by Professor Andersen) revealed matching
NMR spectra (in several solvents), IR and mass spectra,
HPLC retention time, optical rotation, and CD spectra,
thereby conclusively defining the full configuration of the
spirastrellolides.[10]
In conclusion, we have completed the first total synthesis
of spirastrellolide A methyl ester by using a modular and
convergent strategy, which proceeds in 36 linear steps, with a
19-step sequence from the C26–C40 DEF subunit.[18] We
anticipate that this work will in turn allow the preparation of
significant quantities of spirastrellolide A itself for detailed
biological evaluation as well as leading to the synthesis of its
congeners spirastrellolides B–G[1d] along with unnatural ana-
logues for structure–activity relationship studies. Further-
more, the X-ray crystal structure of the unprotected macro-
lide core of spirastellolide A should enable protein phospha-
tase 2A docking studies to be performed, thereby permitting
the rational design of analogues with improved efficacy.
R. J. Andersen, J. Am. Chem. Soc. 2007, 129, 508; d) D. E.
Williams, R. A. Keyzers, K. Warabi, K. Desjardine, J. L. Riffell,
M. Roberge, R. J. Andersen, J. Org. Chem. 2007, 72, 9842.
[2] For leading references to previous synthetic work towards the
spirastrellolides, see Refs. [4] and [5] in I. Paterson, E. A.
Anderson, S. M. Dalby, J. H. Lim, J. Genovino, P. Maltas, C.
Moessner, Angew. Chem. 2008, DOI: 10.1002/ange.200705565;
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Koehn, G. T. Carter, Nat. Rev. Drug Discovery 2005, 4, 206.
[4] I. Paterson, E. A. Anderson, S. M. Dalby, J. Genovino, J. H. Lim,
C. Moessner, Chem. Commun. 2007, 1852.
[5] S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga, K. B.
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[6] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769.
[7] For related examples of this strategy from our research group,
see a) I. Paterson, E. A. Anderson, S. M. Dalby, Synthesis 2005,
3225; b) Ref. [4].
[8] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
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[9] CCDC 669312 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[10] See the Supporting Information for details.
[11] a) A. M. Castaꢁo, A. M. Echavarren, Tetrahedron Lett. 1996, 37,
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Faron, S. R. Gilbertson, R. W. Kaesler, D. C. Yang, C. K.
Murray, J. Org. Chem. 1986, 51, 277; b) W. J. Scott, J. K. Stille,
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[15] The alcohol precursor to aldehyde 19 is reported in Refs. [2] in
the preceding communication.
Received: December 5, 2007
Published online: February 28, 2008
[16] a) K. Takai, K. Kimura, T. Kuroda, T. Hiyama, H. Nozaki,
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Keywords: antitumor agents · enzyme inhibitors · macrolides ·
spiroacetals · total synthesis
.
[1] a) D. E. Williams, M. Roberge, R. Van Soest, R. J. Andersen, J.
Am. Chem. Soc. 2003, 125, 5296; b) D. E. Williams, M. Lapawa,
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[18] Compound 11 in the preceding communication, see Ref. [2].
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