Mild Thio‐Diversification of Bioactive Natural Products. Withaferin A: A Case study.

Abstract

A sustainable strategy was developed to create chemical diversity from bioactive scaffolds. The methodology comprises a set of simple reactions between the parent compound (i. e. withaferin A), and small sulfur nucleophiles in hydroalcoholic media, at room temperature and in open‐air atmosphere. Novel steroidal sulfur natural product‐analogs were obtained, featuring ring opening, ring formation, new stereocenters and modulation of parameters useful in medicinal chemistry.

Thiol-free multicomponent synthesis of non-racemic β-acyloxy thioethers from biocatalytically obtained chiral halohydrins

“…Regarding the multicomponent reaction mechanism, several [S → O] and [S → N] acyl migration examples employing transition metals such as Cu 41 and Pd, 42 or metal-free strategies, 43 have been reported. Based on a previously reported mechanism, 34 we proposed as a first step a S N 2 between the halohydrin and thioacetate anion, thus affording the corresponding β-hydroxy thioacetate.…”

A Homodimer of Withaferin A Formed by Base-Promoted Elimination of Acetic Acid from 27-O-Acetylwithaferin A Followed by a Diels–Alder Reaction

“…To a solution of 3 (2.0 mg, 4.4 μmol) in dry pyridine (0.2 mL) was added Ac 2 O (5.0 μL, 52.9 μmol), and the mixture was stirred at 25 °C until the reaction was completed (TLC control). Excess EtOH was added to the reaction mixture, which was evaporated under reduced pressure to give 6 (2.1 mg, 97%) as an amorphous solid; [α] D 25 +72 (c 0.1, CHCl 3 ); 1 H and 13 C NMR data, Table 1; HRESIMS: m/z 517.2558 [M + Na] + (calcd for C 30 H 38 NaO 6 , 517.2566).…”

“…Middle fractions were combined and purified by prep. TLC [R f = 0.6, silica gel, CH 2 Cl 2 /MeOH; 98:2 (double elution)] followed by recrystallization CH 2 Cl 2 /EtOH to give 8 (7.8 mg, 77%) as colorless crystals; [α] D 25 +140 (c 0.1, CHCl 3 ); 1 H and 13 C NMR data, Table 2.…”

“…ECD spectra were measured with a JASCO J-810 spectropolarimeter. 1D and 2D NMR spectra were recorded in CDCl 3 with a Bruker AVANCE III instrument at 400 MHz for 1 H NMR and 100 MHz for 13 C NMR using residual CHCl 3 as the internal standard, referenced to solvent peaks for CDCl 3 at δ H 7.24 and δ C 77.0. Bruker NEO 500 MHz NMR instrument was used to record the 1 H NMR spectra for monitoring the progress of reaction of 2 with DBU in an NMR tube.…”

“…Numerous biological activities associated with withaferin A have prompted several structure–activity relationship (SAR) studies utilizing the 2,3-en-1-one moiety and the secondary OH-4 group in ring A, the 5β,6β-oxirane moiety in ring B, and the α,β-unsaturated lactone ring and the OH-27 group in ring E of the side-chain. Modifications of these structural moieties of withaferin A ( 1 ) included esterification, − silylation, ,− and oxidation − of OH-4 and OH-27, reduction of the C-1 carbonyl, reduction of the 2,3-double bond, , intermolecular 1,3-dipolar azomethine-ylide cycloaddition, and chemoselective and diastereoselective 1,3-dipolar nitrone cycloaddition to the 2,3-double bond, Michael addition of a variety of nucleophiles to the 2,3-en-1-one moiety, ,,,, 5β,6β-oxirane ring opening followed by modifications of the resulting diol, ,, and modifications of the side-chain. One of the known side-chain modification reactions, except for derivatization of the OH-27, has involved treatment of withaferin A ( 1 ) and 4,27-di- O -acetylwithaferin A ( 5 ) with a strong base (KOH/MeOH or NaOMe/MeOH) resulting in α-methylene-δ-lactone moiety in ring E and concurrent Michael addition of the base to the 2,3-en-1-one moiety of ring A affording 11 . , As the 2,3-en-1-one moiety of 1 is known to be responsible for many of its biological activities, ,, such Michael adducts are of no interest.…”