Towards the combinatorial synthesis of spongistatin fragment libraries by using asymmetric aldol reactions on solid support

Article abstract of DOI:10.1039/b505746a

By relying on asymmetric boron-mediated aldol reactions, solid phase methodology for the stereoselective synthesis of highly substituted spiroacetals was developed and applied to the preparation of a complex AB-spiroacetal subunit of the antimitotic agent

Full text of DOI:10.1039/b505746a

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Towards the combinatorial synthesis of spongistatin fragment libraries
by using asymmetric aldol reactions on solid support{
Ian Paterson,* Dirk Gottschling and Dirk Menche
Received (in Cambridge, UK) 26th April 2005, Accepted 3rd June 2005
First published as an Advance Article on the web 15th June 2005
DOI: 10.1039/b505746a
where purification procedures are simplified and automation may
become feasible.
By relying on asymmetric boron-mediated aldol reactions, solid
phase methodology for the stereoselective synthesis of highly
substituted spiroacetals was developed and applied to the
preparation of a complex AB-spiroacetal subunit of the
antimitotic agent spongistatin 1 (altohyrtin A).
As part of our studies towards the synthesis of polyketide-like
analogues,8,9 herein we report versatile methodology for the solid
phase synthesis of architecturally complex spiroacetals, which is
demonstrated by its successful application to the C1–C15 AB-
subunit 2 of spongistatin.10 This method relies on the preparation
of differently substituted linear precursors, such as 3, by
performing asymmetric boron-mediated aldol reactions on poly-
mer support,11 with subsequent cleavage from the resin and in situ
spiroacetalisation.
Spiroacetals are key structural elements in many bioactive
polyketide natural products and related analogues.1–4 As exempli-
fied by the potent anticancer agent spongistatin 1/altohyrtin A (1,
Fig. 1), they are characterised by having diverse arrays of
stereocentres, combined with a high level of oxygenation. While
methods for the solution phase synthesis of such pharmacophore
scaffolds have been developed,5,6 solid phase approaches remain a
challenging task, in particular when used within the realm of
complex natural product synthesis.7 By allowing extensive
As a first target for developing appropriate solid phase methods,
we chose to assemble the model resin-bound ketone 4 (Scheme 1)
that already contains the stereochemical pattern required for
generating the representative AB-spiroacetal subunit 5 of spongi-
statin. Our synthetic strategy called for first constructing its
‘eastern’ side, i.e. tetraketide 6, and subsequently performing an
aldol addition of this methyl ketone with chiral aldehyde 7. In
turn, it was planned that the ketone component 6 would be
prepared by an aldol reaction of acetone with aldehyde 8, attached
at the C3 position through a suitable silyl ether linker to a resin
support. Thus, this preliminary study would serve to test the
variation of the configuration and substitution pattern,
a
combinatorial strategy to construct elaborate spiroacetal libraries
is attractive, especially if this can be accomplished on solid phase,
Fig. 1 Spiroacetals: a key structural element of the spongistatins.
{ Electronic supplementary information (ESI) available: experimental
procedures, spectroscopic data for new compounds and copies of the
NMR spectra for 2. See http://dx.doi.org/10.1039/b505746a
University Chemical Laboratory, Lensfield Road, Cambridge, UK
CB2 1EW. E-mail: ip100@cam.ac.uk; Fax: +44 1223 336362;
Tel: +44 1223 336407
Scheme 1 Retrosynthetic analysis for the solid phase preparation of
spongistatin AB-spiroacetal subunit 5.
*ip100@cam.ac.uk
3568 | Chem. Commun., 2005, 3568–3570
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viability of performing such complex aldol coupling reactions with
either the aldehyde or the enolate linked to the polymer support.
The synthesis of methyl ketone 6 and its subsequent aldol
coupling with different b-silyloxy aldehydes, including 7, are
summarised in Scheme 2. This work was carried out both on solid
phase (series a) and in solution (series b). To allow a facile
characterisation of the resin-bound intermediates by gel-phase 13C-
NMR and FT-IR spectroscopy, benzyl alcohol was used in the
equivalent solution phase chemistry as a mimic for the resin. In the
first step, homoallylic alcohol 9 was attached to a hydroxymethy-
lene-modified Merrifield resin by a diisopropylsilyl linker,9a,12 via
intermediate 10, to give 11a (loading: 0.6 mmol g21 after capping),
which was then oxidatively cleaved to give aldehyde 8a in a
straightforward fashion, either by ozonolysis or using a two-step
protocol [OsO4, Pb(OAc)4]. In agreement with our previous studies
on similar systems in solution phase,13 enolisation of acetone with
(2)-Ipc2BCl/Et3N constituted a matched case in its aldol reaction
with the chiral aldehyde 8a and led to the desired 1,3-syn-adduct
12a with high diastereoselectivity (ca. 20:1 dr). After TBS
protection of the newly installed hydroxyl group (TBSCl,
imidazole, DMF), a second aldol chain extension now required
formation of the boron enolate 13a of the resin-bound methyl
ketone 6a. After extensive optimisation, this was best achieved
using a preformed solution of (2)-Ipc2BCl (3.0 equiv.) and Et3N
(3.7 equiv.) in Et2O, followed by addition of aldehyde 7 (6 equiv.).
Comparison of the 13C-NMR spectrum of the resulting aldol
adduct 4a with that for 4b, the corresponding model in solution,
again indicated a high level of diastereoselectivity (ca. 20:1 dr),
resulting from matched triple asymmetric induction.11,13,14
11-epi aldol adduct 15a with a similar level of stereocontrol. A key
example employed the aldol coupling of enolate 13a with the
aldehyde 14 to generate the required linear precursor for the more
elaborate AB-spiroacetal subunit 2 (Fig. 1), as employed in our
recent total synthesis of spongistatin 1.6a This reaction proceeded
smoothly on solid support and gave hexaketide 3a15,16 with high
stereoselectivity, again benefiting from triple asymmetric induction.
Having assembled the linear polyketide-type intermediates on
solid support, it remained to demonstrate that they could indeed
deliver the required spiroacetal segments. For realizing both the
projected cleavage from the resin and in situ cyclisation, HF?pyr
was chosen as a suitable reagent as it had previously shown its
usefulness in similar transformations, allowing the TBS ether at C5
to be retained.13 Gratifyingly, this enabled a one-pot process to be
accomplished for ketone 4a, allowing for cleavage of the silyl
linker, the TES ether and spiroacetalisation (Scheme 3).
Equilibration of the initial product mixture in solution,17 by
treatment with PPTS in MeOH–CH2Cl2, produced the desired,
thermodynamically preferred, spiroacetal 5. Overall, the spiroace-
tal 5 was produced in an acceptable 17% yield over the 7 steps
performed on solid support and cleavage.
After this initial validation of our strategy, we then turned our
attention to assembling a more challenging spongistatin inter-
mediate on solid support, i.e. the authentic C1–C15 AB-spiroacetal
subunit 2 (Scheme 4). Using again the HF?pyr conditions, both
cleavage of the TES ether and the silyl linker of 3a could be
accomplished while retaining the TBS and TIPS ethers. A similar
acid-mediated equilibration step then led to the isolation of the
required spiroacetal 2, obtained in 5% yield over 7 steps on solid
support.16,18
This two-directional aldol approach was then diversified and
applied to access other potential linear precursors to spiroacetals
on solid support. For example, the enantiomeric aldehyde ent-7
was combined with the resin-bound enolate 13a to generate the
In conclusion, we have completed the stereocontrolled synthesis
of some representative open-chain spiroacetal precursors related to
spongistatin fragment libraries on solid support. Cleavage from the
Scheme 2 Synthesis of linear b-hydroxy ketone precursors: series a on solid support; series b solution phase equivalent.
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D. O’Hagan, Nat. Prod. Rep., 1995, 12, 1; (c) R. D. Norcross and
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5 For leading references to other completed total syntheses of the
spongistatins, see: (a) D. A. Evans, B. W. Trotter, B. Cote, P. J.
Coleman, L. C. Dias and A. N. Tyler, Angew. Chem., Int. Ed. Engl.,
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Synthesis, ed. M. Harmata, Elsevier, Oxford, 2004, vol. 4, ch. 8, p. 211.
7 For reviews on the generation of natural product-type libraries, see: (a)
C. Watson, Angew. Chem. Int. Ed., 1999, 38, 1903; (b) K. C. Nicolaou
and J. A. Pfefferkorn, Biopolymers, 2001, 60, 171; (c) D. G. Hall,
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8 For our earlier work on the solution phase synthesis of spongistatin
analogues, see: I. Paterson, J. L. Acena, J. Bach, D. Y.-K. Chen and
M. J. Coster, Chem. Commun., 2003, 462.
Scheme 3 Cleavage of the linear precursor 4a from the solid support and
concomitant spiroacetalisation to give the model AB-spiroacetal 5 of
spongistatin.
9 (a) I. Paterson and T. Temal-Laib, Org. Lett., 2002, 4, 2473; (b)
I. Paterson, M. Donghi and K. A. Gerlach, Angew. Chem. Int. Ed.,
2000, 39, 3315; (c) C. Gennari, S. Ceccarelli, U. Piarulli, K. Aboutayab,
M. Donghi and I. Paterson, Tetrahedron, 1998, 54, 14999; (d) I. Paterson
and J. P. Scott, J. Chem. Soc., Perkin Trans. 1, 1999, 1003.
10 The Waldmann group have recently reported an aldol-based solid phase
approach to spiroacetals: O. Baran, S. Sommer and H. Waldmann,
Angew. Chem. Int. Ed., 2004, 43, 3195.
11 For a review on asymmetric boron aldol reactions, see: C. J. Cowden
and I. Paterson, Org. React., 1997, 51, 1.
12 K. A. Savin, J. C. G. Woo and S. J. Danishefsky, J. Org. Chem., 1999,
64, 4183.
Scheme 4 Cleavage of the linear precursor 3a from the solid support and
concomitant spiroacetalisation to give the fully elaborated C1–C15
fragment 2 of spongistatin.
13 I. Paterson, R. M. Oballa and R. D. Norcross, Tetrahedron Lett., 1996,
37, 8581.
14 A. J. Duplantier, M. H. Nantz, J. C. Roberts, R. P. Short, P. Somfai
and S. Masamune, Tetrahedron Lett., 1989, 30, 7357.
15 In preliminary studies directed towards the solid phase synthesis of the
CD-spiroacetal of spongistatin, the C22–C28 subunit 18 was prepared:
Homoallylic alcohol 16 was attached to the resin via a diisopropylsilyl
linker to access 17. Ozonolysis, aldol reaction, and subsequent TBS
protection gave resin-bound ketone 18, again with a high level of
diastereoselectivity. See ESI.{
resin and selective removal of protecting groups then led to the
isolation of the required spiroacetals, as in 3a A 2 and 4a A 5. The
use of different homoallylic alcohols and aldehydes as building
blocks should enable the extension of this methodology to access
many different spiroacetal scaffolds. In more general terms, a large
variety of different starter units and a wide range of aldehydes may
be used in a polymer-supported parallel synthesis fashion to
generate large and structurally diverse libraries of polyketide
sequences.9 Current efforts are being directed to extend this
methodology to the solid phase synthesis of other, structurally
diverse, natural polyketide-like libraries.
We thank the DAAD (Deutscher Akademischer
Austauschdienst; Postdoctoral Fellowship for D. G.), the
European Commission (IHP Network HPRN-CT-2000-00014;
Postdoctoral Fellowship for D. M.) and Merck for support.
16 The additional methyl group attached to C9 in spongistatin is best
introduced at a later stage, see: I. Paterson and R. M. Oballa,
Tetrahedron Lett., 1997, 38, 8241.
17 The initial product mixture contains 5, its C7-epimer and partially
cyclised hemiacetals (ratio y1:2:2): see ESI{.
18 The lower yield obtained here compared to 5 may be attributable to
Notes and references
1 For reviews on polyketide natural products, see: (a) D. O’Hagan, The
Polyketide Metabolites, Ellis Horwood, Chichester, 1991; (b)
partial deprotection of the TIPS ether.
3570 | Chem. Commun., 2005, 3568–3570
This journal is ß The Royal Society of Chemistry 2005