Highly Stereoselective Synthesis of a Compound Collection Based on the Bicyclic Scaffolds of Natural Products

Despite the great contribution of natural products in the history of successful drug discovery, there are significant limitations that persuade the pharmaceutical industry to evade natural products in drug discovery research. The extreme scarcity as well as structural complexity of natural products renders their practical synthetic access and further modifications extremely challenging. Although other alternative technologies, particularly combinatorial chemistry, were embraced by the pharmaceutical industry to get quick access to a large number of small molecules with simple frameworks that often lack three-dimensional complexity, hardly any success was achieved in the discovery of lead molecules. To acquire chemotypes beholding structural features of natural products, for instance high sp3 character, the synthesis of compound collections based on core-scaffolds of natural products presents a promising strategy. Here, we report a natural product inspired synthesis of six different chemotypes and their derivatives for drug discovery research. These bicyclic hetero- and carbocyclic scaffolds are highly novel, rich in sp3 features and with ideal physicochemical properties to display drug likeness. The functional groups on the scaffolds were exploited further to generate corresponding compound collections. Synthesis of two of these collections exemplified with ca. 350 compounds are each also presented. The whole compound library is being exposed to various biological screenings within the European Lead Factory consortium.

Materials and methods: Chemicals and solvents were obtained from commercial vendors and were used without further purification. All dry reactions were performed under argon atmosphere using commercial dry solvents. Column chromatography was performed on a silica column using 230−400 mesh silica gel. Thin-layer chromatography was performed on Macherey Nagel pre-coated TLC aluminum sheets with silica gel 60 UV254 (5-17 μm).
Compound visualization was effected with UV lamp, Iodine, phosphomolybdic acid in ethanol and aq. KMnO4 solution. 1 H NMR spectra were recorded at rt on a Bruker Avance spectrometer operating at 400 MHz. Chemical shifts are given in ppm (δ) from tetramethylsilane as an internal standard or residual solvent peak. Significant 1 H NMR data are tabulated in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad), coupling constant(s) in hertz, number of protons. Mass spectrometry was recorded using Agilent uHPLC (1290 Infinity) equipped with a Diode Array Detector and a Quadrupole MSD using mixture gradients of formic acid/water/acetonitrile as system solvent. High-resolution electrospray ionization mass spectra (ESI-FTMS) were recorded on a Thermo LTQ Orbitrap (high-resolution mass spectrometer from Thermo Electron) coupled to an "Accela" HPLC system supplied with a "Hypersil GOLD" column (Thermo Electron).
After completion of reaction, the reaction mixture was diluted with DCM, washed with couple of times with saturated aq. NaHCO 3 then water and brine solution. After concentration the crude residue was purified by column chromatography using 2-5% of EtOAc in pet-ether as an eluent to give the pure acetate (11b) 0.44 g (81% yield
Concentration of the filtrate afforded the pure product 3.0 g (96% yield      Found: 435.20.

) in DCM)
Experimental for the production phase of 8-deoxy serratinine based scaffolds: 35
NaHCO 3 and brine. After concentration, the crude residue was purified by column chromatography using 10-15% of EtOAc in cyclohexane as an eluent to give the carbamate
NaHCO 3 and brine. After concentration, the crude residue was purified by column chromatography using 10-15% of EtOAc in cyclohexane as an eluent to give the carbamate   was dissolved in analytical grade ethanol, was added methyl amine (33% in ethanol) (11.7 g;
The amino-ketone (11.7 g; 124.23 mmol) was dissolved in dry DCM (dilution is very important to get diastereo selectivity!!!) was added equivalent amount of oven dried powdered MS followed by NaBH(OEh) 3 (11.7 g; 124.23 mmol) in one portion, then allowed

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at rt. The reaction mixture was diluted with DCM, washed couple of times with saturated aq.