Synthesis of two diastereomeric C1-C22 fragments of spirastrellolide A

Article abstract of DOI:10.1039/b700827a

The optimisation of a synthetic strategy towards the ABC segment of the cytotoxic macrolide spirastrellolide A is reported, together with its application to the synthesis of two diastereomeric C₁-C₂₂ fragments for stereochemical corr

Full text of DOI:10.1039/b700827a

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Synthesis of two diastereomeric C1–C22 fragments of spirastrellolide A{
Ian Paterson,* Edward A. Anderson, Stephen M. Dalby, Julien Genovino, Jong Ho Lim and
Christian Moessner
Received (in Cambridge, UK) 18th January 2007, Accepted 29th January 2007
First published as an Advance Article on the web 14th February 2007
DOI: 10.1039/b700827a
Andersen group, until recently4 the relative stereochemistry
The optimisation of a synthetic strategy towards the ABC
between four stereoclusters (C3–C7, C9–C24, C27–C38 and C46),
and the absolute configuration, remained unknown, leading to 16
possible stereoisomers. In view of this ambiguity, we had
previously tried to determine the relative configuration between
the C3–C7 cis-2,6-disubstituted tetrahydropyran (A ring) and the
C9–C24 BC spiroacetal-containing subunit by comparison of
NMR data of two synthetic C1–C25 diastereomeric fragments to
that of spirastrellolide A methyl ester 2.5–7 Unfortunately, due to
the presumed conformational differences between the macrocyclic
natural product and our linear fragments, it was difficult to
confirm the relative stereochemistry in this region.
segment of the cytotoxic macrolide spirastrellolide A is
reported, together with its application to the synthesis of two
diastereomeric C1–C22 fragments for stereochemical correlation
purposes with a putative spirastrellolide degradation product.
The novel cytotoxic polyketide spirastrellolide A (1, Scheme 1),
was isolated by Andersen and co-workers from the Caribbean
sponge Spirastrella coccinea in 2003. Synthetic interest in
spirastrellolide derives not only from its unique molecular
architecture, but also from its potential development as an
antitumour therapeutic agent, as it is a potent and selective
inhibitor of protein phosphatase 2A (PP2A, IC50 = 1 nM).1,2 As
such, it appears to possess a similar mode of action to other
Ser/Thr phosphatase inhibitors, including fostriecin, okadaic acid,
and the calyculins, which induce premature cell mitosis. Given the
central regulatory role of PP2A in the cell, spirastrellolide may also
find further applications as a lead in the treatment of neurological
and metabolic disorders.3
At this juncture, a collaborative effort with the Andersen group
was conceived towards the correlation of fragments from chemical
degradations of spirastrellolide A with independently synthesised
intermediates of defined stereochemistry. A C1–C22 fragment 3 or
4 (Scheme 1) could potentially be prepared by oxidative cleavage
of the C22–C23 bond followed by reduction of the resulting
carbonyl groups. Laboratory syntheses of both 3 and 4, followed
by comparison with the spirastrellolide degradation fragment,
should then enable the assignment of the relative stereochemistry
between C3–C7 and C9–C24, and also the absolute configuration.
In addition, this project represented an opportunity to develop
both an improved approach to the C1–C16 alkyne 5 by removing
our reliance on stoichiometric chiral reagents,5 and also to
optimise our spiroacetalisation strategy. We report herein the
synthesis of the two C1–C22 diastereomeric fragments 3 and 4, and
the improvements to our synthetic strategy.
Although extensive NMR spectroscopic analysis of the
spirastrellolide methyl ester derivative 2 was performed by the
Our retrosynthetic analysis of degradation fragment 3 is
outlined in Scheme 2. According to our initial studies,6 a double
PMB deprotection/in situ spiroacetalisation strategy could be
adopted for the construction of the BC spiroacetal from the (Z)-
enone 6. This enone might itself be derived from the coupling of
Scheme 1 Spirastrellolide A and potential degradation route to frag-
ments 3 and 4.
University Chemical Laboratory, Lensfield Road, Cambridge, UK
CB2 1EW. E-mail: ip100@cam.ac.uk; Fax: +44 1223 336362;
Tel: +44 1223 336407
{ Electronic supplementary information (ESI) available: Compounds 5, 7,
3, 4. See DOI: 10.1039/b700827a
Scheme 2 Retrosynthesis of the C1–C22 subunit 3.
1852 | Chem. Commun., 2007, 1852–1854
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the lithiated alkyne 5 with aldehyde 7, followed by reoxidation at
17 and Lindlar reduction. Alkyne 5 contains a modified array of
C
protecting groups, which we hoped would allow selective
deprotection/BC spiroacetalisation without recourse to harsh
conditions.5
Our original approach to the C1–C11 aldehyde 13 (Scheme 3)
utilised two Brown allylations; we envisaged that the first of these
(to control the C3 stereocentre) could be replaced with a Jacobsen
hydrolytic kinetic resolution (HKR).8 Enantiopure epoxide 8
(46%, .99% ee), thus prepared by HKR of the corresponding
racemic epoxide,8 was subjected to ring-opening with 3-butenyl-
magnesium bromide to afford the secondary alcohol 9 (96%).
Cross-metathesis9 of 9 with methyl acrylate gave enoate 10 (91%),
which underwent intramolecular Michael addition and oxidation
state adjustment to give the cis-2,6-disubstituted tetrahydropyran
aldehyde 11 as a single diastereomer (92%, three steps). The second
Brown allylation of our original synthesis could be successfully
replaced by a substrate-controlled allylation10 with allyltrimethyl-
silane to give 12 (80%, 86 : 14 dr), which was subjected to TBS
protection and ozonolysis to provide aldehyde 13 (85%, two
steps).5
Scheme 4 Reagent and conditions: (i) 14, (2)-Ipc2BCl, Et3N, Et2O, 0 uC;
13, 278 uC; (ii) Me4NBH(OAc)3, MeCN–AcOH (3 : 1), 230 uC; (iii)
˚
DDQ, 4 A MS, DCM; (iv) TBSOTf, 2,6-lutidine, DCM; (v) BH3?Me2S,
The synthesis of the targeted alkyne 5 was completed as depicted
in Scheme 4. A boron-mediated 1,4-syn-aldol reaction of ketone 14
with aldehyde 13 provided aldol adduct 15 (75%, .95 : 5 dr).11
Selective 1,3-anti-reduction,12 followed by hydroxyl-differentiating
PMP acetal formation (DDQ) and TBS protection, then gave
PMP acetal 16 (51%). Although DIBALH proved ineffective in
initial attempts to cleave this PMP acetal, reductive acetal-opening
(to 17) was successfully achieved with borane at high temperature
(100 uC).13 A small amount of over-reduced diol 18 was also
isolated (20%), which could be recycled by reprotection to PMP
acetal 16 (99%). Oxidation of alcohol 17, followed by Corey–
Fuchs alkynylation,14 provided the C1–C16 alkyne 6 (76%). This
scalable route to 5 proceeded in 11% overall yield (16 steps) from
epoxide 8.
toluene, 100 uC; (vi) PMPCH(OMe)2, p-TsOH, DCM; (vii) Dess–Martin
periodinane, DCM; (viii) CBr4, PPh3, Et3N, DCM, 278 uC; (ix) n-BuLi,
THF.
Barbier-type allylation15 gave allylic alcohol 20 (88%) as an
inseparable mixture of diastereomers (3 : 1). Fortunately,
separation by flash column chromatography proved possible after
methylation (21, 88%). Functional group manipulation completed
the preparation of aldehyde 7.
With 5 and 7 in hand, we were now ready to prepare C1–C22
diastereomer 3. Lithiation of alkyne 5, followed by addition of
aldehyde 7, gave the desired coupled propargylic alcohols as a 1 : 1
epimeric mixture at C17 (Scheme 6). Dess–Martin oxidation
followed by Lindlar reduction delivered (Z)-enone 5 (44%, three
steps).
The synthesis of aldehyde coupling partner 7 commenced with
commercially available 1,2:5,6-di-O-isopropylidene-D-mannitol 19
(Scheme 5). Oxidative cleavage of the glycol and subsequent
The key spiroacetalisation was then realised by DDQ deprotec-
tion of the PMB groups at both C13 and C21, smooth
spiroacetalisation to a single isomer being observed in situ.
Gratifyingly, from the viewpoint of our long term synthetic
strategy, this transformation could be achieved without affecting
Scheme 5 Reagents and conditions: (i) NaIO4/silica gel, DCM; (ii)
allylBr, Zn, THF, NH4Cl; (iii) NaH, MeI, THF; (iv) p-TsOH, MeOH;
(v) TBSCl, imidazole, DCM; (vi) PMBTCA, TfOH, DCM; (vii) 9-BBN,
THF; H2O2, pH 7 buffer; (vii) Dess–Martin periodinane, NaHCO3,
DCM.
Scheme 3 Reagents and conditions: (i) 3-butenylMgBr, CuI (cat.), THF;
(ii) Grubbs catalyst (second generation, 0.5 mol%), methyl acrylate, DCM;
(iii) KOt-Bu, THF, 220 uC; (iv) LiAlH4, Et2O; (v) Dess–Martin
periodinane, DCM; (vi) allyltrimethylsilane, TiCl4, DCM, 278 uC; (vii)
TBSCl, imidazole, DMAP (cat.), DMF; (viii) O3, DCM, 278 uC; PPh3.
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At this point, the Andersen group reported the isolation of a
new member of the spirastrellolide family, spirastrellolide B, and
its degradation/conversion to a p-bromophenacyl ester.16 The
resulting X-ray crystal structure of this derivative has solved the
stereochemical ambiguities within the spirastrellolide macrocycle,
thereby validating structure 1 (Scheme 1) for spirastrellolide A.
In conclusion, we have developed syntheses of two diastereo-
meric C1–C22 subunits corresponding to a potential degradation
fragment from spirastrellolide A. In addition, we have further
optimised our synthetic route to the ABC region of spirastrellolide
by exploiting Jacobsen HKR and cross-metathesis methodology to
access the pivotal alkyne 5, and by developing an improved BC
spiroacetalisation strategy. Ongoing work is directed towards the
extension of this approach to encompass the DEF segment and
completion of the total synthesis of spirastrellolide A.
We thank the EPSRC (EP/C541677/1), Merck Research
Laboratories, Homerton College, Cambridge (Research
Fellowship to E. A. A.), SK Corporation (J. H. L.) and the
German Academic Exchange Service (DAAD, Postdoctoral
Fellowship to C. M.) for support and Professor Raymond
Andersen (University of British Columbia) for helpful discussions.
Scheme 6 Reagents and conditions: (i) n-BuLi, THF, 220 uC; 7, 278 uC;
(ii) Dess–Martin periodinane, NaHCO3, DCM; (iii) H2, Pd/CaCO3/Pb,
quinoline, EtOH; (iv) DDQ, pH 7 buffer/DCM; (v) TBAF, THF.
Notes and references
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T. Tarling, M. Roberge and R. J. Andersen, Org. Lett., 2004, 6, 2607.
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R. E. Honkanen and T. Golden, Curr. Med. Chem., 2002, 9, 2055.
4 The studies reported herein were completed before an additional
stereochemical assignment was reported by Andersen, see ref. 16.
5 I. Paterson, E. A. Anderson, S. M. Dalby and O. Loiseleur, Org. Lett.,
2005, 7, 4125.
6 Initial studies on the ABC fragment: I. Paterson, E. A. Anderson and
S. M. Dalby, Synthesis, 2005, 3225.
7 For other synthetic studies towards spirastrellolide, see: J. Liu and
R. P. Hsung, Org. Lett., 2005, 7, 2273; I. Paterson, E. A. Anderson,
S. M. Dalby and O. Loiseleur, Org. Lett., 2005, 7, 4121; Y. Pan and J. K.
De Brabander, Synlett, 2006, 853; C. Wang and C. J. Forsyth,
Org. Lett., 2006, 8, 2997; A. Fu¨rstner, M. D. B. Fenster, B. Fasching,
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K. Radkowski, Angew. Chem., Int. Ed., 2006, 45, 5510; J. Liu,
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I. Paterson, E. A. Anderson, S. M. Dalby, J. H. Lim, P. Maltas and
C. Moessner, Chem. Commun., 2006, 4186.
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2002, 124, 1307. Epoxide 8 was prepared from rac-8 using (S,S)-
(salen)Co(II) (5 mol%), AcOH (0.2 eq.) and H2O (0.55 eq.).
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Scheme 7 Reagents and conditions: (i) n-BuLi, THF, 220 uC, then 21,
278 uC; (ii) Dess–Martin periodinane, NaHCO3, DCM; (iii) H2,
Pd/CaCO3/Pb, quinoline, EtOH; (iv) DDQ, pH 7 buffer/DCM; (v) 40%
aq. HF, MeCN.
any of the silyl protecting groups. Finally, global TBS-deprotection
with TBAF provided the (3R,7S)-C1–C22 fragment 3 (45%).
The preparation of the complementary (3S,7R)-fragment 4 was
conveniently achieved using alkyne 22 (Scheme 7), which had been
prepared previously. As above, addition of alkyne 22 to aldehyde
7, followed by Dess–Martin oxidation and Lindlar reduction, gave
(Z)-enone 23. Stepwise deprotections of the PMB ether (DDQ),
followed by the acetonide and TBS groups (HF/MeCN), provided
the (3S,7R)-C1–C22 fragment 4. The completion of 3 and 4 thus
enabled a potential correlation with a suitable degradation product
from spirastrellolide A (Scheme 1).
1854 | Chem. Commun., 2007, 1852–1854
This journal is ß The Royal Society of Chemistry 2007