Organic Letters
Letter
Scheme 5. Synthesis and Ki-Values of Representative Derivatives 21−25 and Unsubstituted Bicycle 3a
protection of the hydroxyl group and subsequent acidic
deprotection of the Boc- and tBu-groups. However, it turned
out that the acid could not be released without concomitant
cleavage of the silyl ether. Eventually, it was found that the
hydroxyl group could be protected with simultaneous
deprotection of the Boc- and tBu-groups in a single step, by
employing excess TESOTf and 2,6-lutidine.12 The so formed
amino acid was then cyclized under high dilution conditions (5
× 10−3 M) using HATU to afford the orthogonally protected
bicycle 18 in 60% yield over two steps. Finally, to elaborate the
core structure of the bicycle, the Cbz-group was cleaved and the
3,5-dichlorobenzenesulfonyl moiety was introduced as an
exemplary sulfonamide which had previously shown superior
affinity for FKBP51.3e,f Subsequently, the TES-group was
cleaved with TBAF to give 21 in a 70% overall yield over three
steps.
corresponding atoms of the precursor scaffold 3 (Figure 3).
The N-methoxyethyl substituent of 23 closely mimicked the
With the core structure 21 in hand we tested its binding
affinity to the FK506-binding protein 51, a promising novel
target for stress-related disorders. Using a fluorescence
polarization assay3a we were pleased to observe an affinity of
596 nM, making 21 the most efficient FKBP51 ligand known so
far.13
Figure 3. Cocrystal structure of 23 in complex with the FK506-
binding domain of FKBP51. The position of a superimposed
unsubstituted [4.3.1] bicycle 3 from Figure 2 is indicated as thin lines.4
To further explore the binding properties of the novel
scaffold in more detail we prepared representative derivatives.
Compound 21 was reacted with NaHMDS and iodomethane to
give the N,O-dimethylated derivative 22 accompanied by an
inseparable mixture of the two respective monomethylated
products (Scheme 5). Likewise, alkylation of 21 with 2-
bromoethyl methyl ether afforded the bis-alkylated derivative
23. We also installed a 2-(3,4-dimethoxyphenoxy)ethyl subunit,
a preferred R2 substituent for FKBPs, to allow a direct
comparison between type 3 and type 4 bicyclic ligands (Figure
1). Toward this end, alcohol 21 was MOM-protected to give 24
followed by alkylation with 4-(2-bromoethoxy)-1,2-dimethoxy-
benzene and acidic cleavage of the protecting group to give 25.
Compounds 22 to 25 all potently bound to FKBP51, with 25
exceeding the affinity of the prototypical FKBP ligand FK506
(Ki(FKBP51) = 104 nM, LE = 0.17).3a Compound 25 also
allows a direct comparison with a corresponding unsubstituted
analog 3a,3f which shows that the additional hydroxyl group in
the C5-position, enabled by the new synthetic approach,
enhances the affinity for FKBP51 by more than 100-fold.
To determine the molecular binding mode of the novel
FKBP ligands we solved the cocrystal structure of 23 with the
FK506-binding domain of FKBP51 at a resolution of 1.0 Å.3b,14
The [4.3.1] bicyclic core nearly perfectly superimposed with
conformation of the larger (dimethoxyphenoxy)ethyl residue in
3 and serves as a hydrogen bond acceptor for Tyr113. The
additional O-methoxyethyl substituent of 23 extends in a
staggered/gauche conformation and engages in van der Waals
interactions with Tyr57, Asp68, Arg73, and Phe77.
In summary, we have developed a concise and stereoselective
procedure for the construction of the C5-hydroxy derivatized
diazabicyclo[4.3.1]decane-2-one scaffold. Additional substitu-
ents in the 5-position substantially enhance affinity and ligand
efficiency for FKBPs such as the psychiatric risk factor FKBP51.
ASSOCIATED CONTENT
* Supporting Information
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S
Experimental procedures, spectroscopic data, and NMR spectra
for all compounds. This material is available free of charge via
AUTHOR INFORMATION
Corresponding Author
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dx.doi.org/10.1021/ol5023195 | Org. Lett. 2014, 16, 5254−5257