.
Angewandte
Communications
DOI: 10.1002/anie.201205728
Biology-Oriented Synthesis
A Natural Product Inspired Tetrahydropyran Collection Yields Mitosis
Modulators that Synergistically Target CSE1L and Tubulin**
Tobias Voigt, Claas Gerding-Reimers, Tuyen Thi Ngoc Tran, Sabrina Bergmann,
Hugo Lachance, Beate Schçlermann, Andreas Brockmeyer, Petra Janning, Slava Ziegler, and
Herbert Waldmann*
In biology-oriented synthesis (BIOS) biological relevance
and prevalidation are employed as key criteria for the design
and synthesis of focused compound collections for chemical
biology and medicinal chemistry research.[1] The scaffolds of
natural products are privileged, biologically relevant molec-
ular frameworks and natural products, and analogues thereof
have served as efficient probes in chemical research, for
example, in the study of processes related to cancer, in
particular mitosis.[2]
Tetrahydropyrans occur widely in nature (for examples,
see Figure S1 in the Supporting Information) and are
endowed with pronounced biological activities.[3] Their syn-
thesis has received intense attention, in particular when
a Prins cyclization is employed as the key step.[3b,4]
a synthetic route in which the tetrahydropyran 1 is generated
in one step from a polymer-bound aldehyde 2 and a readily
available homoallylic alcohol 3 (Scheme 1a). Immobilization
and, thereby, limited exposure of the electron-rich hydroxy-
aromatic aldehyde to Lewis acids should reduce side reactions
which have been encountered in related systems.[6]
For the solid-phase synthesis by means of the IRORI/
MacroKan technology, reactors were loaded with chloro-
methyl-derivatized polystyrene resin 4 and heated with
hydroxybenzaldehydes 5 (R1 or R2 = OH) for immobilization
(Scheme 2, loading 1.05–1.51 mmolgÀ1; see the Supporting
Information).[7] Eleven homoallylic alcohols 3 were synthe-
sized in solution by asymmetric allylation of the correspond-
ing aldehydes with Brownꢀs allylborane.[8]
Here we report the synthesis of a natural product inspired
compound collection based on the 4-hydroxytetrahydropyran
scaffold. Evaluation in a phenotypic screen revealed structur-
ally novel modulators of mitosis termed tubulexins which
target the chromosome segregation 1-like protein (CSE1L,
CAS, exportin-2) and the vinca alkaloid binding site of a/b-
tubulin.
The Prins cyclization carried out in the presence of
BF3·OEt2, TMSOAc, and acetic acid in dichloromethane or
tetrahydrofuran at room temperature[6b] (Scheme 2) selec-
tively yielded substituted 4-tetrahydropyranyl acetates 6 with
all-equatorial substituents (see also below). The esters could
readily be hydrolyzed to yield alcohols 9 for further trans-
formation.
For the synthesis of a compound collection based on the 4-
hydroxytetrahydropyran scaffold by means of the Prins
cyclization as the key transformation[4,5] we envisioned
Protected tetrahydropyrans 7 were released from the solid
support in high yields by treatment with trifluoroacetic acid/
dichloromethane (1:1) in the presence of 0.4% thioanisol
(cleavage conditions A) for 2 h at room temperature
(Scheme 2, see Table S2 in the Supporting Information).
Tetrahydropyrans with unprotected phenolic hydroxy groups
were obtained by treatment of immobilized tetrahydropyrans
9 with freshly prepared 2-bromobenzo[d][1,3,2]dioxaborole
(B-bromocatecholborane, 8) in combination with BF3.OEt2
(cleavage conditions B).[9]
These methods yielded 54 4-tetrahydropyranyl acetates 7
in overall yields of 3–35% based on the polymer-bound
aldehydes 2 (see Table S2, entries 1–54 in the Supporting
Information). In general, the structure of the polymer-bound
aldehyde appeared to influence the yield only to a minor
extent. The yields of a doubly benzyl-protected homoallylic
alcohol (3e) and a thienyl-substituted homoallylic alcohol
(3k; see Table S1 in the Supporting Information) were low
most likely because of undesired side reactions under the
acidic conditions.
[*] Dr. T. Voigt,[+] Dr. C. Gerding-Reimers,[+] M. Sc. T. T. Ngoc Tran,[+]
M. Sc. S. Bergmann, Dr. H. Lachance, B. Schçlermann,
Dipl.-Ing. A. Brockmeyer, Dr. P. Janning, Dr. S. Ziegler,
Prof. Dr. H. Waldmann
Max-Planck-Institut fꢀr molekulare Physiologie
Abt. Chemische Biologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
Dr. T. Voigt,[+] Dr. C. Gerding-Reimers,[+] M. Sc. T. T. Ngoc Tran,[+]
Dr. H. Lachance, Prof. Dr. H. Waldmann
Technische Universitꢁt Dortmund, Fakultꢁt Chemie
Lehrbereich Chem. Biologie
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
[+] These authors contributed equally to this work.
[**] Generous financial support by the MPG and the Fonds der
Chemischen Industrie is gratefully acknowledged. We would like to
thank Aymelt Itzen for helpful discussions on affinity measurements
and the Dortmund Protein Facility (DPF) for cloning pOPIN-His/
EGFP-CSE1L. This research was funded by the European Research
Council under the European Union’s Seventh Framework Pro-
gramme (FP7/2007-2013)/ERC Grant agreement no. 268309 and
the Max Planck Gesellschaft.
NOE spectroscopic investigation of a representative 4-
tetrahydropyranyl acetate (see Table S1, entry 1 in the
Supporting Information) proved the all-cis configuration of
this product and equatorial position of the substituents. The
results revealed that the axial 4-H proton in the tetrahydro-
pyran is in proximity to the axial 2’-H and the axial 6’-H
Supporting information for this article is available on the WWW
410
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 410 –414