The efficacy and synthetic versatility of asymmetric organocatalysis have contributed enormously to the field of organic synthesis since the early 2000s. As asymmetric organocatalytic methods mature, they have extended beyond the academia and undergone scale-up for the production of chiral drugs, natural products, and enantiomerically enriched bioactive molecules. This review provides a comprehensive overview of the applications of asymmetric organocatalysis in medicinal chemistry. A general picture of asymmetric organocatalytic strategies in medicinal chemistry is firstly presented, and the specific applications of these strategies in pharmaceutical synthesis are systematically described, with a focus on the preparation of antiviral, anticancer, neuroprotective, cardiovascular, antibacterial, and antiparasitic agents, as well as several miscellaneous bioactive agents. The review concludes with a discussion of the challenges, limitations and future prospects for organocatalytic asymmetric synthesis of medicinally valuable compounds.

Asymmetric organocatalysis: an enabling technology for medicinal chemistry

Podophyllotoxin and its related aryltetralin cyclolignans belong to a family of important products that exhibit various biological properties (e.g., cytotoxic, insecticidal, antifungal, antiviral, anti-inflammatory, neurotoxic, immunosuppressive, antirheumatic, antioxidative, antispasmogenic, and hypolipidemic activities). This Review provides a survey of podophyllotoxin and its analogues isolated from plants. In particular, recent developments in the elegant total chemical synthesis, structural modifications, biosynthesis, and biotransformation of podophyllotoxin and its analogues are summarized. Moreover, a deoxypodophyllotoxin-based chemosensor for selective detection of mercury ion is described. In addition to the most active podophyllotoxin derivatives in each series against human cancer cell lines and insect pests listed in the tables, the structure-activity relationships of podophyllotoxin derivatives as cytotoxic and insecticidal agents are also outlined. Future prospects and further developments in this area are covered at the end of the Review. We believe that this Review will provide necessary information for synthetic, medicinal, and pesticidal chemistry researchers who are interested in the chemistry and biology of podophyllotoxins.

Recent Advances in the Chemistry and Biology of Podophyllotoxins.

H8-BINOL Chiral Imidodiphosphoric Acids Catalyzed Enantioselective Synthesis of Dihydroindolo-/-pyrrolo[1,2-a]quinoxalines

An efficient and convenient iron-catalyzed protocol has been developed for the synthesis of substituted pyrrolo[1,2-a]quinoxalines from 1-(N-arylpyrrol-2-yl)ethanone O-acetyl oximes through N–O bond cleavage and intramolecular directed C–H arylation reactions in acetic acid.

Iron-Catalyzed Intramolecular C(sp(2))-N Cyclization of 1-(N-Arylpyrrol-2-yl)ethanone O-Acetyl Oximes toward Pyrrolo[1,2-a]quinoxaline Derivatives.

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, we have prepared three series of novel 4α-(acyloxy)-2'(2',6')-(di)halogenopodophyllotoxin derivatives modified in the C and E rings of podophyllotoxin, which is a naturally occurring aryltetralin lignan isolated from the roots and rhizomes of Podophyllum hexandrum . Their structures were well characterized by (1)H NMR, HRMS, ESI-MS, optical rotation, and mp. The stereochemical configurations of compounds 5s, 6b, 6d, and 7q were unambiguously confirmed by single-crystal X-ray diffraction. Their insecticidal activity was evaluated against the pre-third-instar larvae of oriental armyworm, Mythimna separata Walker, in vivo at a concentration of 1 mg/mL. These derivatives likely displayed the antimolting hormone effect. Among all the derivatives, especially compounds 5a, 5n, 7f, 7n, and 7w exhibited the most potent insecticidal activity with final mortality rates of 70% or so. This suggested that a chlorine or bromine atom introduced at the C2' or C2' and C6' positions on the E ring of podophyllotoxin was necessary for obtaining the potent compounds. This will pave the way for further design, structural modification, and development of podophyllotoxin derivatives as insecticidal agents.

Synthesis of novel 4α-(acyloxy)-2'(2',6')-(di)halogenopodophyllotoxin derivatives as insecticidal agents.

In continuation of our program to find compounds with potent anti-human immunodeficiency virus type 1 (HIV-1) activities, seventeen 5,6-dihydro-indolo[1,2-a]quinoxaline derivatives (1-17) were preliminarily evaluated as HIV-1 inhibitors in vitro. Among all the derivatives, especially compounds 10 and 17 showed the most potent anti-HIV-1 activities with EC50 values of 2.42 and 3.39 mu g/mL, and TI values of 63.76 and 53.60, respectively.

Discovery of 5,6-Dihydro-indolo[1,2-a]quinoxaline Derivatives as New HIV-1 Inhibitors In Vitro

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, we have synthesized three series of novel 4-acyloxy compounds derived from podophyllotoxin modified in the A and C rings, which is isolated as the main secondary metabolite from the roots and rhizomes of Podophyllum hexandrum. Their insecticidal activity was preliminarily evaluated against the pre-third-instar larvae of Mythimna separata in vivo. Compound 9g displayed the best promising insecticidal activity. It revealed that cleavage of the 6,7-methylenedioxy group of podophyllotoxin will lead to a less active compound and that the C-4 position of podophyllotoxin was the important modification location. A quantitative structure–activity relationship (QSAR) model was developed by genetic algorithm combined with multiple linear regression (GA-MLR). For this model, the squared correlation coefficient (R2) is 0.914, the leave-one-out cross-validation correlation coefficient (Q2LOO) is 0.881, an...

Synthesis and quantitative structure-activity relationship (QSAR) study of novel 4-acyloxypodophyllotoxin derivatives modified in the A and C rings as insecticidal agents

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Discovery of 5,6-Dihydro-indolo[1,2-a]quinoxaline Derivatives as New HIV-1 Inhibitors In Vitro

Synthesis and quantitative structure-activity relationship (QSAR) study of novel 4-acyloxypodophyllotoxin derivatives modified in the A and C rings as insecticidal agents