A 2nd-generation scalable synthesis of the HIV-1 entry inhibitor CJF-III-288 enabled by photoredox catalysis

Herein is reported the development and optimization of a 2nd-Generation process synthesis for the human immunodeficiency virus-1 entry inhibitor CJF-III-288 bis-trifluoroacetate salt 1. The key transformations of the synthesis include a decatungstate-catalyzed diastereoselective Giese addition to set the stereogenecity of the indoline core and install the guanidine motif, followed by a high-yielding photoredox-nickel dual-catalyzed Csp3–Csp2 cross coupling to append the methyl-amino methyl aryl side chain. The route eliminates the use of noble metals, decreases the step count nearly by half, reduces the number of flash column purifications, and increases the overall yield of 1 tenfold. The route has yielded 5.7 grams of 1 for use in in vivo studies. , Proton (1H) and carbon (13C) NMR spectra were recorded on a Bruker Avance III 500-MHz spectrometer, a Bruker DRX500 500-MHz spectrometer, a Bruker NEO600 600-MHz spectrometer, or a Bruker NEO400 400-MHz spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) relative to methanol (δ 3.31), acetone (δ 2.05), chloroform (δ 7.26), and dimethyl sulfoxide (δ 2.50) for 1H NMR, and methanol (δ 49.15), acetone (δ 29.8), chloroform (δ77.16), and dimethyl sulfoxide (δ39.52) for 13C NMR. , , # Data from: A 2nd-generation scalable synthesis of the HIV-1 entry inhibitor CJF-III-288 enabled by photoredox catalysis ## FID_for_Publication.zip The folder FID_for_Publication.zip contains all of the raw FID files for the spectra included in the supplementary information. The files are organized into separate folders by compound, and the compounds are numbered the same way they are in the manuscript and supplementary information. The FID files are named by what type of NMR experiment was performed (1H or 13C). For compounds for which variable temperature experiments were performed, there is a separate folder within the compound's folder titled \"Variable Temperature Experiments\". This folder contains the raw FID files for the variable temperature experiment spectra, separated by nuclei (1H/13C). Compound Descriptions: **Compound 1** * SMILES: `[NH2-]C(NC[C@H]([C@H]1NC(C(NC2=[C+]C=C(Cl)C(F)=C2)=O)=O)N(C(OCCC)=O)C3=C1C=CC(C[NH2+]C)=C3)=[NH2].[2CF3CO2]` * Role: Final product * D...,本研究报道了人类免疫缺陷病毒1型（human immunodeficiency virus-1，简称HIV-1）入胞抑制剂CJF-III-288双三氟乙酸盐1的第二代工艺合成路线的开发与优化工作。该合成路线的关键转化步骤包括：以十钨酸盐（decatungstate）催化的非对映选择性Giese加成反应构建吲哚啉（indoline）母核的立体构型并引入胍基（guanidine）结构单元，随后通过高产率的光氧化还原-镍双催化（photoredox-nickel dual-catalyzed）Csp3–Csp2交叉偶联反应接入甲氨基甲基芳基侧链。该路线摒弃了贵金属的使用，将反应步骤缩减近一半，减少了快速柱层析纯化次数，并将化合物1的总收率提升了10倍。依托该路线已成功制备5.7克化合物1，用于体内药理学研究。 氢谱（¹H NMR）与碳谱（¹³C NMR）谱图均通过布鲁克Avance III 500 MHz、布鲁克DRX500 500 MHz、布鲁克NEO600 600 MHz或布鲁克NEO400 400 MHz核磁共振波谱仪采集。化学位移（δ）以百万分比（ppm）为单位报道，¹H NMR以甲醇（δ 3.31）、丙酮（δ 2.05）、三氯甲烷（δ 7.26）及二甲基亚砜（δ 2.50）为参比溶剂；¹³C NMR则以甲醇（δ 49.15）、丙酮（δ 29.8）、三氯甲烷（δ 77.16）及二甲基亚砜（δ 39.52）为参比溶剂。 # 数据来源：基于光氧化还原催化的HIV-1入胞抑制剂CJF-III-288第二代可放大合成路线 FID_for_Publication.zip FID_for_Publication.zip压缩包包含补充材料中所有谱图的原始FID文件。文件按化合物分类存放于独立子文件夹，化合物编号与手稿及补充材料中的编号保持一致。FID文件以其所对应的核磁共振实验类型（¹H或¹³C）命名。对于开展了变温实验的化合物，其对应子文件夹内设有名为"变温实验"的独立子文件夹，该文件夹内按原子核类型（¹H/¹³C）分类存放变温实验谱图的原始FID文件。 化合物说明： **Compound 1** * SMILES: `[NH2-]C(NC[C@H]([C@H]1NC(C(NC2=[C+]C=C(Cl)C(F)=C2)=O)=O)N(C(OCCC)=O)C3=C1C=CC(C[NH2+]C)=C3)=[NH2].[2CF3CO2]` * 作用：终产物 * D...,