Department of Chemistry, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, University Park Campus, Los Angeles, California 90089, United States.
J Org Chem. 2020 Nov 20;85(22):14592-14609. doi: 10.1021/acs.joc.0c01204. Epub 2020 Oct 30.
Nucleoside 5'-triphosphate (dNTP) analogues in which the β,γ-oxygen is mimicked by a CXY group (β,γ-CXY-dNTPs) have provided information about DNA polymerase catalysis and fidelity. Definition of CXY stereochemistry is important to elucidate precise binding modes. We previously reported the ()- and ()-β,γ-CHX-dGTP diastereomers (X = F, Cl), prepared via P,C-dimorpholinamide CHCl (, ) and CHF (, ) bisphosphonates (BPs) equipped with an ()-mandelic acid as a chiral auxiliary, with final deprotection using H/Pd. This method also affords the β,γ-CHCl-dTTP (, ), β,γ-CHF (, ), and β,γ-CHCl (, ) dATP diastereomers as documented here, but the reductive deprotection step is not compatible with dCTP or the bromo substituent in β,γ-CHBr-dNTP analogues. To complete assembly of the toolkit, we describe an alternative synthetic strategy featuring ethylbenzylamine or phenylglycine-derived chiral BP synthons incorporating a photolabile protecting group. After acid-catalyzed removal of the ()-(+)-α-ethylbenzylamine auxiliary, coupling with activated dCMP and photochemical deprotection, the individual diastereomers of β,γ-CHBr- (, ), β,γ-CHCl- (, 3), β,γ-CHF-dCTP (, ) were obtained. The β,γ-CH(CH)-dATPs (, ) were obtained using a methyl ()-(-)-phenylglycinate auxiliary. P and F NMR Δδ values are correlated with CXY stereochemistry and p values for 13 CXY-bisphosphonic acids and imidodiphosphonic acid are tabulated.
核苷 5'-三磷酸 (dNTP) 类似物中，β,γ-氧被 CXY 基团模拟 (β,γ-CXY-dNTPs)，为 DNA 聚合酶催化和保真度提供了信息。CXY 立体化学的定义对于阐明精确的结合模式很重要。我们之前报道了通过 P,C-二吗啉酰胺 CHCl（，）和 CHF（，）双膦酸酯（BPs）制备的（）-和（）-β,γ-CHX-dGTP 非对映异构体（X = F, Cl），其中（）-扁桃酸作为手性助剂，最后使用 H/Pd 脱保护。该方法还提供了β,γ-CHCl-dTTP（，），β,γ-CHF（，）和β,γ-CHCl（，）dATP 非对映异构体，如本文所述，但还原脱保护步骤与 dCTP 或β,γ-CHBr-dNTP 类似物中的溴取代基不兼容。为了完成工具包的组装，我们描述了一种替代的合成策略，其特点是使用含有光保护基团的乙基苄胺或苯甘氨酸衍生的手性 BP 合成子。在酸催化去除（）-（+）-α-乙基苄基胺助剂后，与活化的 dCMP 偶联并进行光化学脱保护，得到了β,γ-CHBr-（，），β,γ-CHCl-（，3），β,γ-CHF-dCTP（，）的各个非对映异构体。使用（）-（-）-苯甘氨酸甲酯作为手性助剂获得β,γ-CH(CH)-dATPs（，）。P 和 F NMR Δδ 值与 CXY 立体化学相关，并且列出了 13 CXY-双膦酸和亚膦酸二酰胺的 p 值。
