Lead-oriented synthesis: Investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library

Synthesis and functionalisation of a bifunctional normorphan 3D building block for medicinal chemistry

“…The mixture was extracted with CH2Cl2 (3 × 20 mL) and the combined organic extracts were washed with brine (50 mL), dried (Na2SO4) and evaporated under reduced pressure to give the crude product. Purification by flash column chromatography on silica with 4:6 to 7:3 Et2O-hexane as eluent gave trichloroacetamide 8 (9.45 13 C NMR (101 MHz, CDCl3) (mixture of rotamers) δ 208.4 (C=O, ketone), 160.7 (C=O, amide), 160.1 (ipso-Ar), 157.2 (ipso-Ar), 128.7 (Ar, only resolved in HMQC), 127.1 (Ar), 117.4 (ipso-Ar), 104.3 (ipso-Ar), 98.5 (Ar), 93.8 (CCl3), 57.2 (NCH), 55.5 (OMe), 46.9 (NCH), 42.1 (NCH2), 39.8 (CH2), 29.3 (CH2) (1 × OMe resonance not resolved); HRMS (ESI) m/z calcd for C17H20 35 Cl3NO4 (M + Na) + 430.0350, found 430.0344 (+1.4 ppm error).…”

“…Purification by flash column chromatography on silica with 1:1 EtOAc-hexane as eluent gave arylated normorphan 13 (565 mg, 86%) as a clear oil, RF Using general procedure A, vinyl MIDA boronate 1 (100 mg, 0.234 mmol, 1.0 eq), Pd(OAc)2 (3.00 mg, 0.012 mmol, 0.05 eq), SPhos (10.0 mg, 0.023 mmol, 0.1 eq), 4-bromobenzotrifluoride (63.0 mg, 0.280 mmol, 1.2 eq) and 3 M K3PO4(aq) (0.59 mL, 1.755 mmol, 7.5 eq) in dioxane (2.34 mL) gave the crude product. Purification by flash column chromatography on silica with 4:1 to 3:2 hexane-EtOAc as eluent gave arylated normorphan 14 (60.0 mg, 61%) as a clear oil, RF 13 C NMR (101 MHz, CDCl3) δ 176.4 (C=O), 160.6 (ipso-Ar), 158.6 (ipso-Ar), 144.2 (ipso-Ar), 139.6 (=C), 130.7 (Ar), 129.1 (q, J = 32.5 Hz, ipso-Ar), 125.6 (Ar), 125.5 (q, J = 4.0 Hz, Ar), 124.4 (q, J = 272.0 Hz, CF3), 123.8 (=CH), 117.8 (ipso-Ar), 104.…”

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As part of our ongoing interest in exploring 3D lead-like 13,14 and fragment 15,16 medicinal chemistry space, we have become interested in the design, synthesis and further functionalisation of bifunctional 3D building blocks for use in medicinal chemistry. With building block design in mind, the normorphan core was of particular interest as a result of its rigidity, 3-dimensionality, high Fsp 3 and low molecular weight.

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Organocatalytic Access to Enantioenriched Spirooxindole-Based 4-Methyleneazetidines

“…Since the most widely exploited scaffolds so far involve the spiro junction of oxindoles with five-membered and six-membered rings, we recently aimed to contribute to greater diversity in this field turning our attention to four membered rings. With the notable exception of β-lactams, four-membered rings have received limited attention from medicinal chemists until recently, with only a few spirocyclic azetidine scaffolds proposed as new potential lead compounds [ 9 , 10 ].…”

Highly diastereoselective entry into chiral spirooxindole-based 4-methyleneazetidines via formal [2+2] annulation reaction

“…In particular, only a few novel spirocyclic azetidine scaffolds have been recently proposed, 7 which are able to access unexplored chemical space and act as potential new lead compounds. 8 Our long-standing interest in the asymmetric synthesis of 3,3-disubstituted oxindole derivatives and related spiro compounds, 9 combined with the growing interest in hybrid drugs as therapeutic agents, inspired us to combine the two biologically active oxindole and azetidine moieties, by means of a spiro arrangement of the two ring systems. 10 We conceived of the synthesis of chiral spirooxindole-based 4-methyleneazetidines as an unprecedented, intriguing combination of pharmacologically relevant motifs.…”