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A Modular Biomimetic Strategy for the Synthesis of Macrolide P

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A Modular Biomimetic Strategy for the Synthesis of Macrolide P ARTICLE https://doi.org/10.1038/s41467-020-16084-0 OPEN A modular biomimetic strategy for the synthesis of macrolide P-glycoprotein inhibitors via Rh-catalyzed C-H activation ✉ Lu Chen1,2,5, Haitian Quan 1,2,5, Zhongliang Xu1,2, Hao Wang1,2, Yuanzhi Xia3, Liguang Lou 1,2 & ✉ Weibo Yang 1,2,4 1234567890():,; One of the key challenges to overcome multidrug resistance (MDR) in cancer is the devel- opment of more effective and general strategies to discover bioactive scaffolds. Inspired by natural products, we describe a strategy to achieve this goal by modular biomimetic synthesis of scaffolds of (Z)-allylic-supported macrolides. Herein, an Rh(III)-catalyzed native carboxylic acid-directed and solvent-free C−H activation allylation with high stereoselectivity and chemoselectivity is achieved. The generated poly-substituted allylic alcohol as a multi- functional and biomimetic building block is crucial for the synthesis of (Z)-allylic-supported macrolides. Moreover, the unique allylic-supported macrolides significantly potentiate the sensitivity of tumor cells to cytotoxic agents such as vinorelbine and doxetaxel by reversing p170-glycoprotein-mediated MDR. Our findings will inspire the evolution of synthetic chemistry and open avenues for expedient and diversified synthesis of bioactive macrocyclic molecules. 1 Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China. 2 University of Chinese Academy of Sciences, Beijing 100049, China. 3 College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China. 4 Key Laboratory for Functional Material, Educational Department of Liaoning Province, University of Science and ✉ Technology Liaoning, Anshan 114051, China. 5These authors contributed equally: Lu Chen, Haitian Quan. email: [email protected]; [email protected] NATURE COMMUNICATIONS | (2020)11:2151 | https://doi.org/10.1038/s41467-020-16084-0 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-16084-0 any natural macrocyclic small molecules based on controlling stereoselectivity of poly-substituted allylic alcohols Munique scaffolds have served as an inspiration and remained a formidable challenge. Third, the branch/linear resource in drug discovery, or been harnessed as probes regioselectivity represented a common issue (Fig. 1c). for targets validation in chemical biology1. For instance, the drug Herein, we realize these ideas by Rh (III)-catalyzed C–H ally- for Cushing’s disease Pasireotide2, Histone Deacetylase (HDAC) lation of carboxylic acids and report a biomimetic modularization inhibitor Romidepsin3 and cGAS-STING inhibitor Astin C4 strategy, which utilizes the readily available building blocks to (Fig. 1a). It is notable that most of the natural macrocyclic small assemble allylic-supported macrolides that would be difficult or molecules are encoded with fundamental building blocks, such as impossible to obtain by other methods. Importantly, these allylic- natural amino acids, at a proper position. Since these building supported macrolides successfully transfer pharmacologically blocks inherently possess structural biology information, the relevant features and efficiently surmount P-glycoprotein(P-gp)- natural macrocyclic molecules derived from them could exert mediated multidrug resistance (MDR) in cancer chemotherapy. multifunctional biological activities when they interact with dif- ferent targets5–9. Although they possess valuable characteristics, gene expression limitation of microbes or plants and difficulty of Results resupply could limit both the number and types of macrocyclic Reaction optimization. Stimulated by the aforementioned chal- compounds accessible. lenges, we commenced our building blocks assembly by opti- With these issues in mind, we want to develop a short and mizing C–C bond formation (Table 1). The readily available 2- modular biomimetic strategy, which simply utilizes the funda- methylbenzoic acid 1a and 4-phenyl-4-vinyl-1,3-dioxolan-2-one mental building blocks from living organism’s endogenous ligand, 2a were chosen as the model substrates. When 1a and 2a were • such as amino acids, to expeditiously access and enrich diverse treated with a low valent Pd2(dba)3 CHCl3 catalyst in dimethyl- natural macrocycle-like chemical space. Macrolides could provide formamide (DMF) at 60 °C, an exclusive C–O bond instead of an excellent opportunity for validating this strategy, as they are C–C bond formation product 4aa was obtained in 45% NMR prevalent across all major natural molecules10. Inspired by NPs yield. Interestingly, replacement of low valent Pd (dba) •CHCl – 2 3 3 and our interest in construction of scaffold-diverse libraries11 14, catalyst to high valent Rh (III) catalyst dramatically changed the we set out to create a series of allylic-supported macrolides via an outcome of chemoselectivity, solely affording C–C bond forma- orchestrated assembly of readily available carboxylic acids, nat- tion product 3aa in 36% NMR yield albeit with low stereo- ural amino acids and vinylethylene carbonates15 using biomi- selectivity. The Z-geometry configuration of 3aa was confirmed metic modularization strategy (Fig. 1b). A retrosynthetic analysis by NOE analysis. The switchable chemoselectivity in this reaction indicated that a successive and concise C–H allylation, amidation, could be attributed to the nature of controlled reaction inter- and esterfication could translate these building blocks faithfully mediates, namely rhodacycle and π-allyl Pd intermediates19. into the target molecules. However, several challenging issues on Encouraged by these results, we next investigated different sol- native carboxylic acid-directed C–H activation allylation16,17 still vents and bases. It was found that the reaction was not compa- need to be addressed: First, chemoselectivity between C–C bond tible with 1,2-dichloroethane (DCE) or toluene and no desired and C–O bond formation should be a dilemma. While an ami- product 3aa could be afforded. Further screening of various bases – dation of carboxylic acid could avoid the C O allylation product revealed that K2CO3 was the optimal base, whereas other bases – – 18 and direct the C H bond activation C C allylations , an inevi- gave inferior results. Meanwhile, the amounts of the K2CO3 was fi table drawback is the need for additional synthetic steps for also optimized and the excess K2CO3 is not likely bene cial for installation and removal of the directing group. Second, 3aa formation. In contrast, the use of 0.5 equiv. K2CO3 led to a a HN O NH 2 O H N O O Polypeptides N O HN HN O O O O HN O NH HN O Assembled O O NH NH HO O HO 2 O O NH N NH NH H R HN S S Cl N N O O H N H N Cl Amino acids 2 H O O Fundamental building blocks of Endogenous ligands Pasireotide Romidepsin Astin C treat Cushing’s disease O HDAC inhibitor cGAS-STING inhibitor b A biomimetic modularization strategy c for synthesis of (Z)-allylic-supported macrocyclic peptides Design O Amidation O OH 2 Nu2 O Rh –CO R2 O R R O O 2 OH O O R + OH OH O N R1 H 3 NH H OH HN R 2 Nu1 R1 O O O Challenge I: Challenge II: Challenge III: O C-H allylation R1 Nu1-C and Nu2-O Z and E Branch and Linear Esterification O R1 Chemoselectivity Stereoselectivity Regioselectivity Potent MDR Inhibitors Fig. 1 Our design to create functional macrolides by a biomimetic modularization strategy. a Natural macrolides and macrocyclic peptides assembled by fundamental building blocks. b A biomimetic modularization strategy for synthesis of (Z)-allylic-supported macrocyclic peptides. c The design of Rh (III)- catalyzed C–H allylation of carboxylic acids. MDR: multidrug resistance, HDAC: histone deacetylase, cGAS: cyclic GMP-AMP synthase, STING: stimulator of interferon genes, Nu: nucleophile. 2 NATURE COMMUNICATIONS | (2020)11:2151 | https://doi.org/10.1038/s41467-020-16084-0 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-16084-0 ARTICLE Table 1 Optimization of building blocks assembly by chemoselective formation of C–C bond. O O OH O 1)Catalyst, Ligand O Base, Solvent OMe OH + O + O 60 °C Ph O Ph H Ph 2) MeI, K2CO3 OH 1a 2a 3aa 4aa Entrya Catalyst Ligand Base Solvent Yield(%)b (equiv.) 3aa 4aa 1Pd2(dba)3•CHCl3 PPh3 – CHCl3 N.D. 45 2 [Cp*RhCl2]2/AgSbF6 – Cs2CO3 (2.0) CHCl3 36 (1:1) N.D. 3 [Cp*RhCl2]2/AgSbF6 – Cs2CO3 (2.0) DCE N.D. N.D. 4 [Cp*RhCl2]2/AgSbF6 – Cs2CO3 (2.0) toluene N.D. N.D. 5 [Cp*RhCl2]2/AgSbF6 – CsOAc (2.0) CHCl3 21 (2:1) N.D. 6 [Cp*RhCl2]2/AgSbF6 – K2CO3 (2.0) CHCl3 40 (1:1) N.D. c 7 [Cp*RhCl2]2/AgSbF6 – K2CO3 (2.0) CHCl3 34 (2:1) N.D. d 8 [Cp*RhCl2]2/AgSbF6 – K2CO3 (2.0) – 46 (>20:1) N.D. d 9 [Cp*RhCl2]2/AgSbF6 – K2CO3 (1.0) – 56 (>20:1) N.D. d 10 [Cp*RhCl2]2/AgSbF6 – K2CO3 (0.5) – 79 (>20:1) N.D. 11 [Cp*RhCl2]2/AgSbF6 –— – N.D N.D a Reaction conditions: 1a (0.05 mmol), 2a (0.075 mmol), catalyst (5 mol %), ligand (20 mol %), AgSbF6 (20 mol%), solvent (0.5 mL), 60 °C, 12 h. After the reaction was complete,1 mL DMF, 0.15 mmol K2CO3 and 0.3 mmol MeI were added and the mixture was stirred at rt for 3 h. b 1 Yields were determined by the H NMR using CH2Br2 as the internal standard; Z/E ratios are given within parentheses. c Solvent (0.25 mL). d Solvent free. significantly improved yield, and 3aa could be formed in 79% on VECs could be extended from simple aryl to heteroaryl yield with an excellent Z/E stereoselectivity of 20:1 under solvent- without any stereoselectivity erosion (3al and 3am). The late- free conditions. (entry 10) Remarkably, to the best of our stage functionalization of Repaglinide which is an antidiabetic knowledge, transition metal-catalyzed native carboxylic acid- drug was successfully accomplished by introducing allylic alco- directed highly stereoselective C–H activation allylation was hols in a decent yield.
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