Cyclopenta‐, benzo‐, and cyclohepta[b]‐annulated azepane scaffolds were prepared in two steps from optically active cyclic α‐allyl‐β‐oxoesters. The first step was ruthenium‐catalyzed olefin cross metathesis with acrylonitrile. The second step was palladium‐catalyzed dihydrogenation which consists of three consecutive processes: The hydrogenation of the C−C double and C−N triple bonds was followed by the reductive amination via the iminium ion formed in situ from the primary amino function and the endocyclic carbonyl group. This last step gave, stereoselectively, the annulated azepanes with relative trans‐configuration. The amino function and the ester group define two points for further diversification of the scaffolds. The trifluoroacetyl derivatives allowed to establish the enantiopurity of the products to be 97–98 % ee by GLC on a chiral phase. The relative trans‐configurations and in one case also the absolute (R,R)‐configuration was established by X‐ray crystallography.
G-protein-coupled receptors are deactivated or desensitized by phosphorylation by respective G-protein-coupled receptor kinases (GRKs). In zebrafish rod and cone photoreceptor cells, four orthologous GRKs are expressed participating in the deactivation of rod and cone opsins. An important feature of GRKs in general is the consensus sites for lipid modification, which would allow the posttranslational attachment of isoprenoids facilitating membrane association and enzymatic performance. Because direct proof is missing for isoprenoid modification of zebrafish GRKs, we used a semichemical approach to study the incorporation of a farnesyl moiety into a GRK and its cellular consequences. The approach involves organic synthesis of a functionalized farnesyl derivative that is suitable for a subsequent alkyne–azide cycloaddition (click reaction). For this purpose, zebrafish GRK was expressed in HEK293 cells and modified in situ with the synthetic farnesyl moiety. Successful farnesylation by an endogenous farnesyltransferase was detected by immunoblotting and immunocytochemistry using a biotin–streptavidin-coupled assay and ligation with a fluorescence dye, respectively. Immunocytochemical detection of farnesylated GRK in different cell compartments indicates the applicability of the approach for studying the transport of cellular components.
Three regioisomeric thieno[c]azocine derivatives were prepared in six steps from bromothiophene carboxylic acids. The reaction sequence started with an esterification with isopropyl alcohol. The resulting esters were submitted to a Heck reaction with tert-butyl acrylate followed by catalytic hydrogenation. Subsequent Dieckmann condensation gave cyclopentathiophenes with a cyclic β-oxo ester motif, which were α-alkylated with phenacyl bromide to furnish 1,4-diketones. The latter were converted in the key step, a bismuth-catalyzed ring transformation with methylamine, yielding the racemic eightmembered ring lactams, that is, tetrahydrothieno[2,3-c]-, [3,2-c]-, and -[3,4-c]azocine derivatives in overall yields of 25%, 16% and 12%, respectively.Some years ago, a new, elegant, and relatively simple route to prepare unsaturated 2-azocanone derivatives 1 (1,2,3,4,5,6-hexahydroazocin-2-ones, Figure 1) was discovered. 2 The reaction proceeded by a bismuth-catalyzed ringtransformation of five-membered ring oxo esters 4 containing a 1,4-diketone moiety 3 and primary amines R 1 NH 2 . Since these products 1 exist in a folded conformation, they represent an attractive molecular scaffold for combinatorial chemistry. In our continuing efforts to identify sophisticated structural motifs as a basis for combinatorial library synthesis in drug discovery, we are interested in such nonplanar and easily accessible scaffolds that provide several points of diversification. Such three-dimensional scaffolds open additional opportunities for adapting the shape of drug molecules to the requirements of binding sites on biological targets. Therefore, we have already explored scaffolds 1 as the basis of library synthesis. 4 Two points of diversity in structures 1 are the residues R 1 at N-1 and R 2 at C-8 originating from diketones 4 and primary amines, respectively. As an additional site for further diversifying functionalization (R 3 ) the carboxylate moiety at C-6 was selected, which could be converted with another amine R 3 NH 2 to carboxamides after saponification. As an extension of molecular diversity of the scaffold heterocyclic oxo esters were considered as starting materials, which resulted in thiazocane (X = S) 5 and diazocane (X = NR 4 ) 6 scaffolds 2 and 3. We have furthermore accessed benzo[c]-and pyrido[c]-annulated azocanes when starting with indane 7 and azaindane derivatives. 8 Compound 5 represents one of three regioisomeric pyrido[c]azocane motifs prepared by us. Figure 1 Some azocanones 1-3 and 5, precursor compound 4, and the antipsychotic drug olanzapine (6) N N R 2 R 1 O CONHR 3 5 X N R 2 R 1 O CONHR 3
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