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Interest in therapeutic discovery typically drives the preparation of natural product analogs, but these undertakings contribute significant advances for synthetic chemistry as well. The need for a highly efficient and scalable synthetic route to a complex molecular scaffold for diversification frequently inspires new methodological development or unique application of existing methods on structurally intricate systems. Additionally, synthetic planning with an aim toward late-stage diversification can provide access to otherwise unavailable compounds or facilitate preparation of complex molecules with diverse patterns of substitution around a shared carbon framework. For these reasons among others, programs dedicated to the diversification of natural product frameworks and other complex molecular scaffolds have been increasing in popularity, a trend likely to continue given their fruitfulness and breadth of impact. In this Perspective, we discuss our experience using late-stage diversification as a guiding principle for the synthesis of natural product analogs and reflect on the impact such efforts have on the future of complex molecule synthesis.

Dienogest (DIE) and drospirenone (DRO) are two fourth-generation synthetic progestins widely used as oral contraceptives. Despite their increasing detection in wastewaters and surface waters, their fate during biological wastewater treatment is unclear. Here, we investigated DIE and DRO biotransformation with representative activated sludge batch incubations and identified relevant transformation products (TPs) using high-resolution mass spectrometry. DIE exhibited slow biotransformation (16-30 h half-life) and proceeded through a quantitative aromatic dehydrogenation to form TP 309 (molar yields of ∼55%), an aromatic TP ∼30% estrogenic as 17β-estradiol. DRO experienced more rapid biotransformation (

The desire for maximally efficient transformations in complex molecule synthesis has contributed to a surge of interest in C–H functionalization methods development in recent years. In contrast to the steady stream of methodological reports, however, there are noticeably fewer studies comparing the efficacies of different C–H functionalization protocols on a single structurally intricate substrate. Recognizing the importance of heteroatom incorporation in complex molecule synthesis, this report discloses a comparative examination of diverse strategies for C–O, C–N, and C–X bond formation through late-stage C–H oxidation of the tricyclic cyanthiwigin natural product core. Methods for allylic C–H acetoxylation, tertiary C–H hydroxylation, tertiary C–H amination, tertiary C–H azidation, and secondary C–H halogenation are explored. These efforts highlight the robustness and selectivities of many well-established protocols for C–H oxidation when applied to a complex molecular framework, and the findings are relevant to chemists aiming to employ such strategies in the context of chemical synthesis.

An improved synthesis of the cyanthiwigin natural product core enabled by new catalytic technology is reported. The key double catalytic enantioselective alkylation has been reoptimized using a recently developed protocol employing low loadings of palladium catalyst, thereby facilitating large-scale production of the tricyclic cyanthiwigin framework. Additionally, preparation of the penultimate aldehyde intermediate is expedited through the application of anti-Markovnikov Tsuji–Wacker oxidation.

A family of Ag complexes of the type [{BnN(CH2CH2RIm)2}Ag]·[AgX2] (X = I, RIm = 1-methylimidazole (3a); X = Cl, RIm = 1-tert-butylimidazole (3b), 1-benzylimidazole (3c) or 1-methylbenzimidazole (3d)) or [{BnN(CH2CH2CH2RIm)2}Ag]·[AgCl2] (RIm = 1-methylimidazole (4a), 1-tert-butylimidazole (4b), 1-benzylimidazole (4c) or 1-methylbenzimidazole (4d)) with a flexible unsaturated linker connecting the two NHC ligands has been prepared. These silver complexes undergo facile transmetalliation with [Ir(COD)Cl]2 to generate the bimetallic species (COD)ClIr{BnN(CH2CH2RIm)2}IrCl(COD) (RIm = 1-methylimidazole (5a), 1-tert-butylimidazole (5b), 1-benzylimidazole (5c) or 1-methylbenzimidazole (5d)) or (COD)ClIr{BnN(CH2CH2CH2RIm)2}IrCl(COD) (RIm = 1-methylimidazole (6a), 1-tert-butylimidazole (6b), 1-benzylimidazole (6c) or 1-methylbenzimidazole (6d)) with a bridging bidentate NHC ligand. A similar reaction can be performed using [Rh(COD)Cl]2 to generate the analogous Rh species (COD)ClRh{BnN(CH2CH2CH2RIm)2}RhCl(COD) (RIm = 1-methylimidazole (7a), 1-benzylimidazole (7c) or 1-methylbenzimidazole (7d)). Complexes 5d, 6d and 7d were characterized by X-ray crystallography. All of our new Rh and Ir species possess axial chirality and are prepared as a mixture of isomers. However, crystals of 5d, 6d and 7d contain only one diastereomer. Dissolution of the diastereometrically pure crystals results in epimerization and the formation of an equilibrium mixture. Our new Ir complexes are active catalysts for both olefin and transfer hydrogenation and we present a comparison of their catalytic activity based on the linker length of the ligand.

Enantioselective catalytic allylic alkylation for the synthesis of 2-alkyl-2-allylcycloalkanones and 3,3-disubstituted pyrrolidinones, piperidinones and piperazinones has been previously reported by our laboratory. The efficient construction of chiral all-carbon quaternary centers by allylic alkylation was previously achieved with a catalyst derived in situ from zero valent palladium sources and chiral phosphinooxazoline (PHOX) ligands. We now report an improved reaction protocol with broad applicability among different substrate classes in industry-compatible reaction media using loadings of palladium(II) acetate as low as 0.075 mol % and the readily available chiral PHOX ligands. The novel and highly efficient procedure enables facile scale-up of the reaction in an economical and sustainable fashion.

The decarbonylative dehydration of fatty acids shows a good functional group tolerance and provides linear alpha olefins with only small amounts of internal olefins as side products.

A highly efficient palladium-catalyzed decarbonylative dehydration reaction of carboxylic acids is reported. This method transforms abundant and renewable even-numbered natural fatty acids into valuable and expensive odd-numbered alpha olefins. Additionally, the chemistry displays a high functional group tolerance. The process employs a low loading of palladium catalyst and proceeds under solvent-free and relatively mild conditions.