Amphotericin B (AmB) is a prototypical small molecule natural product that can form ion channels in living eukaryotic cells and has remained refractory to microbial resistance despite extensive clinical utilization in the treatment of life-threatening fungal infections for more than half a century. It is now widely accepted that AmB kills yeast primarily via channel-mediated membrane permeabilization. Enabled by the iterative cross-coupling-based synthesis of a functional group deficient derivative of this natural product, we have discovered that channel formation is not required for potent fungicidal activity. Alternatively, AmB primarily kills yeast by simply binding ergosterol, a lipid that is vital for many aspects of yeast cell physiology. Membrane permeabilization via channel formation represents a second complementary mechanism that further increases drug potency and the rate of yeast killing. Collectively, these findings (i) reveal that the binding of a physiologically important microbial lipid is a powerful and clinically validated antimicrobial strategy that may be inherently refractory to resistance, (ii) illuminate a more straightforward path to an improved therapeutic index for this clinically vital but also highly toxic antifungal agent, and (iii) suggest that the capacity for AmB to form proteinlike ion channels might be separable from its cytocidal effects.small molecules | protein-like functions | N-methyliminodiacetic acid boronates
This communication describes the discovery of air-stable and highly versatile B-protected haloalkenylboronic acid building blocks for iterative cross-coupling. These reagents enable the total synthesis of polyene natural products with extraordinary levels of simplicity, efficiency, and modularity. Specifically, all-trans-retinal, β-parinaric acid, and one-half the amphotericin B macrolide skeleton were prepared using only the Suzuki-Miyaura reaction in an iterative manner to bring together collections of simple and readily-accessible building blocks. In contrast to their boronic acid counterparts, the intermediate polyenylboronate esters are remarkably stable (to both column purification and storage), which is critical to their successful utilization. Moreover, the reactive boronic acids can be cleanly liberated using very mild aqueous base. These advances have enabled preparation of the longest polyene ever synthesized using the SM reaction. We additionally report, to the best of our knowledge, the first triply metal selective (Zn vs. Sn and B) cross-coupling reaction, the first selective cross-coupling with a differentially-ligated diboron reagent, and the first cross-couplings between polyenylchlorides and vinylboronic acids. Collectively, these new building blocks and methods can dramatically improve the way polyene natural products and their derivatives are synthesized in the laboratory.Most biologically active small molecules exert their effects via the perturbation of macromolecular targets. 1 There are a few, however, that operate via higher-order mechanisms that lie outside this paradigm. The class of "polyene natural products" 2 is particularly rich with examples. Perhaps most notable is the antifungal heptaene macrolide amphotericin B (AmB, 1, Figure 1A), which self-assembles into a membrane-spanning channel complex with functional properties reminiscent of protein-based ion channels. 3,4 Other polyenes are known to provide structural support for cell membranes, 5 transduce solar energy into mechanical energy, 6 serve as pigments for efficient light harvesting 7 and/or species-specific coloration, 8 act as fluorescent probes, 9 and/or quench reactive oxygen species. 10 The existence of these natural prototypes suggests that the potential for small molecules to perform useful functions in living systems likely extends far beyond that which is currently utilized. Unfettered synthetic access to these compounds and their derivatives is paramount for realizing this potential.The synthesis of polyenes is made challenging by the sensitivity of conjugated double bond frameworks to light, oxygen, and many common synthetic reagents, especially protic and
Optimization of the route to the sap-feeding insecticidal candidate tyclopyrazoflor featuring [3 + 2] cyclization of 3-hydrazinopyridine·2HCl and methyl acrylate is described. The key impurities in the [3 + 2] cyclization were identified and successfully controlled after optimization. The hazards associated with oxidation of an intermediate pyrazolidin-3-one using the incompatible combination of potassium persulfate and N,N-dimethylformamide (DMF) were avoided by using potassium ferricyanide in the presence of potassium hydroxide in water. The two elimination impurities in the ethylation step to produce tyclopyrazoflor were successfully minimized using ethyl iodide in the presence of cesium carbonate in DMF at 0 °C. The overall yield for this seven-step synthesis of tyclopyrazoflor was improved from 10% to 41% after the optimization detailed herein.
The potential safety hazards associated with the Suzuki–Miyaura cross-coupling of aryl bromides with vinylboron species were evaluated. In the Suzuki–Miyaura cross-coupling of 1-bromo-3-(trifluoromethyl)benzene with potassium vinyltrifluoroborate in the presence of potassium carbonate (K2CO3) in 9:1 dimethyl sulfoxide (DMSO)/water at 80 °C, the thermal profile revealed a significant exotherm upon the addition of catalytic 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride [Pd(dppf)Cl2]. Further investigations indicated that the exotherm was consistently higher and the reactions were faster in the studied aqueous systems compared to anhydrous conditions. Although under anhydrous conditions the exotherms were comparable among the studied cases, the rate of the exotherm was highly dependent on the choice of aryl electrophile, solvent, base, catalyst, as well as vinylboron species. In many of the studied cases the maximum temperature of a synthesis reaction (MTSR) was considerably higher than the boiling point of the solvent and/or the onset temperature of the DMSO decomposition, indicating that in the absence of active cooling the system could quickly exceed the boiling point of the solvent or trigger the decomposition of the reaction mixture to result in a runaway reaction.
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