Chiral-Anion-Dependent Inversion of Diastereo- and Enantioselectivity in Carbonyl Crotylation via Ruthenium-Catalyzed Butadiene Hydrohydroxyalkylation

The ruthenium catalyst generated in situ from H₂Ru­(CO)­(PPh₃)₃, (<i>S</i>)-SEGPHOS, and a TADDOL-derived phosphoric acid promotes butadiene hydrohydroxyalkylation to form enantiomerically enriched products. Notably, the observed diastereo- and enantioselectivity is the opposite of that observed using BINOL-derived phosphate counterions in combination with (<i>S</i>)-SEGPHOS, the same enantiomer of the chiral ligand. Match/mismatch effects between the chiral ligand and the chiral TADDOL-phosphate counterion are described. For the first time, single-crystal X-ray diffraction data for a ruthenium complex modified by a chiral phosphate counterion are reported

Ruthenium-Catalyzed Hydrohydroxyalkylation of Acrylates with Diols and α‑Hydroxycarbonyl Compounds To Form Spiro- and α‑Methylene-γ-butyrolactones

Under the conditions of ruthenium(0)-catalyzed hydrohydroxyalkylation, vicinal diols <b>1a</b>–<b>1l</b> and methyl acrylate <b>2a</b> are converted to the corresponding lactones <b>3a</b>–<b>3l</b> in good to excellent yield. The reactions of methyl acrylate <b>2a</b> with hydrobenzoin <b>1f</b>, benzoin <i>didehydro</i>-<b>1f</b>, and benzil <i>tetradehydro</i>-<b>1f</b> form the same lactone <b>3f</b> product, demonstrating that this process may be deployed in a redox level-independent manner. A variety of substituted acrylic esters <b>2a</b>–<b>2h</b> participate in spirolactone formation, as illustrated in the conversion of <i>N</i>-benzyl-3-hydroxyoxindole <b>1o</b> to cycloadducts <b>4a</b>–<b>4h</b>. Hydrohydroxyalkylation of hydroxyl-substituted methacrylate <b>2i</b> with diols <b>1b</b>, <b>1f</b>, <b>1j</b>, and <b>1l</b> forms α-<i>exo</i>-methylene-γ-butyrolactones <b>5b</b>, <b>5f</b>, <b>5j</b>, and <b>5l</b> in moderate to good yield. A catalytic cycle involving 1,2-dicarbonyl–acrylate oxidative coupling to form oxaruthenacyclic intermediates is postulated. A catalytically competent mononuclear ruthenium­(II) complex was characterized by single-crystal X-ray diffraction. The influence of electronic effects on regioselectivity in reactions of nonsymmetric diols was probed using <i>para</i>-substituted 1-phenyl-1,2-propanediols <b>1g</b>, <b>1m</b>, and <b>1n</b> and density functional theory calculations

Ruthenium-Catalyzed Hydrohydroxyalkylation of Acrylates with Diols and α‑Hydroxycarbonyl Compounds To Form Spiro- and α‑Methylene-γ-butyrolactones

Under the conditions of ruthenium(0)-catalyzed hydrohydroxyalkylation, vicinal diols <b>1a</b>–<b>1l</b> and methyl acrylate <b>2a</b> are converted to the corresponding lactones <b>3a</b>–<b>3l</b> in good to excellent yield. The reactions of methyl acrylate <b>2a</b> with hydrobenzoin <b>1f</b>, benzoin <i>didehydro</i>-<b>1f</b>, and benzil <i>tetradehydro</i>-<b>1f</b> form the same lactone <b>3f</b> product, demonstrating that this process may be deployed in a redox level-independent manner. A variety of substituted acrylic esters <b>2a</b>–<b>2h</b> participate in spirolactone formation, as illustrated in the conversion of <i>N</i>-benzyl-3-hydroxyoxindole <b>1o</b> to cycloadducts <b>4a</b>–<b>4h</b>. Hydrohydroxyalkylation of hydroxyl-substituted methacrylate <b>2i</b> with diols <b>1b</b>, <b>1f</b>, <b>1j</b>, and <b>1l</b> forms α-<i>exo</i>-methylene-γ-butyrolactones <b>5b</b>, <b>5f</b>, <b>5j</b>, and <b>5l</b> in moderate to good yield. A catalytic cycle involving 1,2-dicarbonyl–acrylate oxidative coupling to form oxaruthenacyclic intermediates is postulated. A catalytically competent mononuclear ruthenium­(II) complex was characterized by single-crystal X-ray diffraction. The influence of electronic effects on regioselectivity in reactions of nonsymmetric diols was probed using <i>para</i>-substituted 1-phenyl-1,2-propanediols <b>1g</b>, <b>1m</b>, and <b>1n</b> and density functional theory calculations

Ruthenium(0)-Catalyzed C–C Coupling of Alkynes and 3‑Hydroxy-2-oxindoles: Direct C–H Vinylation of Alcohols

Upon exposure to a ruthenium(0) catalyst, <i>N</i>-benzyl-3-hydroxy-2-oxindoles react with diverse alkynes to form products of C–H vinylation with complete control of regioselectivity and olefin geometry. This method contributes to a growing body of catalytic processes that enable direct conversion of lower alcohols to higher alcohols in the absence of stoichiometric organometallic reagents

Synthesis of Nirmatrelvir: Development of an Efficient, Scalable Process to Generate the Western Fragment

Nirmatrelvir (1), a novel and specific inhibitor of the SARS-CoV-2 3C-like protease, was developed by Pfizer scientists in mid 2020. Efforts to develop a scalable process to manufacture nirmatrelvir were undertaken with a great sense of urgency, as there were no effective treatments available for the worldwide patient population at that time. We used a convergent approach to generate this molecule. The first two steps used to generate the western fragment of nirmatrelvir from l-tert-leucine, ethyl trifluoroacetate, and a [3.1.0] bicyclic proline derivative are described here. This is the first of a series of four papers describing the commercial process of the development of nirmatrelvir