Stereoselective Halogenation in Natural Product Synthesis

Chung, Won‐jin; Vanderwal, Christopher D.

doi:10.1002/anie.201506388

Cited by 248 publications

(145 citation statements)

References 297 publications

(390 reference statements)

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“…1,2 Of these, about 4700 are halogenated, 3 and just 5 contain a fluorine atom, 4−7 with no reports of natural fluorometabolites derived from fungi. Nature has been a fertile source for drug leads, particularly in the realms of anticancer and antimicrobial agents.…”

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confidence: 99%

Biosynthesis of Fluorinated Peptaibols Using a Site-Directed Building Block Incorporation Approach

et al. 2017

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Synthetic biological approaches, such as site-directed biosynthesis, have contributed to the expansion of the chemical space of natural products, making possible the biosynthesis of unnatural metabolites that otherwise would be difficult to access. Such methods may allow the incorporation of fluorine, an atom rarely found in nature, into complex secondary metabolites. Organofluorine compounds and secondary metabolites have both played pivotal roles in the development of drugs; however, their discovery and development are often via nonintersecting tracks. In this context, we used the biosynthetic machinery of Trichoderma arundinaceum (strain MSX70741) to incorporate a fluorine atom into peptaibol-type molecules in a site-selective manner. Thus, fermentation of strain MSX70741 in media containing ortho- and meta-F-phenylalanine resulted in the biosynthesis of two new fluorine-containing alamethicin F50 derivatives. The fluorinated products were characterized using spectroscopic (1D and 2D NMR, including 19F) and spectrometric (HRESIMS/MSn) methods, and their absolute configurations were established by Marfey’s analysis. Fluorine-containing alamethicin F50 derivatives exhibited potency analogous to the nonfluorinated parent when evaluated against a panel of human cancer cell lines. Importantly, the biosynthesis of fluorinated alamethicin F50 derivatives by strain MSX70741 was monitored in situ using a droplet–liquid microjunction–surface sampling probe coupled to a hyphenated system.

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confidence: 99%

Biosynthesis of Fluorinated Peptaibols Using a Site-Directed Building Block Incorporation Approach

et al. 2017

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“…The structural variety within the halogenated chamigrenes is complemented by diverse biological activities, with noteworthy examples including antibacterial, [2] antifungal, [3] antiviral, [4] anthelmintic, [5] and anticancer [6] effects. To date, the total synthesis of (+)-elatol 6 by Stoltz and Grubbs [7a] constitutes the only enantioselective synthesis of a member of the halogenated chamigrene sesquiterpenes. A general enantioselective approach for the synthesis of this class of molecules has yet to be reported .…”

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confidence: 99%

A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes

2016

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The brominated chamigrene sesquiterpenes constitute a large subclass of bromocyclohexane containing natural products, yet no general enantioselective strategy for the synthesis of these small molecules exists. Herein we report a general strategy for accessing this family of secondary metabolites including the enantioselective synthesis of (−)-α- and (−)-ent-β-bromochamigrene, (−)-dactylone, and (+)-aplydactone. Access to these molecules is enabled by a stereospecific bromopolyene cyclization initiated by the solvolysis of an enantioenriched vicinal bromochloride.

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“…238–240 Furthermore, halogens are a versatile functional group, enabling further transformations such as cross-coupling. 241 Despite their utility, less work has been reported on site-selective halogenation as compared to C–H oxidation. The presence of a myriad of halogenated natural products makes the discovery of novel and selective techniques to halogenate compounds a worthy endeavor.…”

Section: C–h Oxidationmentioning

confidence: 99%

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

2017

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The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogs of natural products by this approach is then described as a quintessential “late-stage functionalization” exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this review is on the recent studies of non-enzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C–H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C–C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry.

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Stereoselective Halogenation in Natural Product Synthesis

Cited by 248 publications

References 297 publications

Biosynthesis of Fluorinated Peptaibols Using a Site-Directed Building Block Incorporation Approach

Biosynthesis of Fluorinated Peptaibols Using a Site-Directed Building Block Incorporation Approach

A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

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