Haghighi Fatemeh, Jesikiewicz Luke T, Stahl Corrinne E, Nafie Jordan, Ortega-Vega Amanda, Liu Peng, Brummond Kay M
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
BioTools, Inc., Jupiter, Florida 33478, United States.
J Am Chem Soc. 2025 Jan 8;147(1):498-509. doi: 10.1021/jacs.4c11661. Epub 2024 Dec 19.
We report a stereo-differentiating dynamic kinetic asymmetric Rh(I)-catalyzed Pauson-Khand reaction, which provides access to an array of thapsigargin stereoisomers. Using catalyst-control, a consistent stereochemical outcome is achieved at C2─for both matched and mismatched cases─regardless of the allene-yne C8 stereochemistry. The stereochemical configuration for all stereoisomers was assigned by comparing experimental vibrational circular dichroism (VCD) and C NMR to DFT-computed spectra. DFT calculations of the transition-state structures corroborate experimentally observed stereoselectivity and identify key stabilizing and destabilizing interactions between the chiral ligand and allene-yne PKR substrates. The robust nature of our catalyst-ligand system places the total synthesis of thapsigargin and its stereoisomeric analogues within reach.
我们报道了一种立体区分的动态动力学不对称铑（I）催化的Pauson-Khand反应，该反应可用于制备一系列毒胡萝卜素立体异构体。通过催化剂控制，无论丙二烯-炔烃C8的立体化学如何，在C2位置（无论是匹配还是不匹配的情况）都能实现一致的立体化学结果。通过将实验振动圆二色性（VCD）和碳核磁共振（C NMR）与密度泛函理论（DFT）计算的光谱进行比较，确定了所有立体异构体的立体化学构型。过渡态结构的DFT计算证实了实验观察到的立体选择性，并确定了手性配体与丙二烯-炔烃PKR底物之间关键的稳定和不稳定相互作用。我们的催化剂-配体体系的稳健性质使得毒胡萝卜素及其立体异构类似物的全合成成为可能。
