Total Synthesis of (+)-SCH 351448: Efficiency via Chemoselectivity and Redox-Economy Powered by Metal Catalysis

The polyketide natural product (+)-SCH 351448, a macrodiolide ionophore bearing 14 stereogenic centers, is prepared in 14 steps (LLS). In eight prior syntheses, 22–32 steps were required. Multiple chemoselective and redox-economic functional group interconversions collectively contribute to a step-change in efficiency

Regioselective Ruthenium Catalyzed Hydrohydroxyalkylation of Dienes with 3‑Hydroxy-2-oxindoles: Prenylation, Geranylation, and Beyond

The direct conversion of secondary to tertiary alcohols <i>via</i> ruthenium(0) catalyzed C–C coupling of substituted 3-hydroxy-2-oxindoles with various dienes is described. Coupling occurs in a completely regioselective manner in the absence of stoichiometric byproducts

Formal Synthesis of Premisakinolide A and C(19)–C(32) of Swinholide A via Site-Selective C–H Allylation and Crotylation of Unprotected Diols

Using stereo- and site-selective C–H allylation and crotylation of unprotected diols, an intermediate in the synthesis of premisakinolide A (bistheonellic acid B) that was previously made in 16–27 (LLS) steps is now prepared in only nine steps. This fragment also represents a synthesis of C(19)–C(32) of the actin-binding macrodiolide swinholide A

Hydroxymethylation beyond Carbonylation: Enantioselective Iridium-Catalyzed Reductive Coupling of Formaldehyde with Allylic Acetates via Enantiotopic π‑Facial Discrimination

Chiral iridium complexes modified by SEGPHOS catalyze the 2-propanol-mediated reductive coupling of branched allylic acetates <b>1a</b>–<b>1o</b> with formaldehyde to form primary homoallylic alcohols <b>2a</b>–<b>2o</b> with excellent control of regio- and enantioselectivity. These processes, which rely on enantiotopic π-facial discrimination of σ-allyliridium intermediates, represent the first examples of enantioselective formaldehyde C–C coupling beyond aldol addition

Redox-Triggered C–C Coupling of Alcohols and Vinyl Epoxides: Diastereo- and Enantioselective Formation of All-Carbon Quaternary Centers <i>via tert</i>-(Hydroxy)-Prenylation

Iridium catalyzed primary alcohol oxidation triggers reductive C–O bond cleavage of isoprene oxide to form aldehyde-allyliridium pairs that combine to form products of <i>tert</i>-(hydroxy)-prenylation, a motif found in >2000 terpenoid natural products. Curtin–Hammett effects are exploited to enforce high levels of <i>anti</i>-diastereo- and enantioselectivity in the formation of an all-carbon quaternary center. The present redox-triggered carbonyl additions occur in the absence of stoichiometric byproducts, premetalated reagents, and discrete alcohol-to-aldehyde redox manipulations

Total Synthesis of Swinholide A: An Exposition in Hydrogen-Mediated C–C Bond Formation

Diverse hydrogen-mediated C–C couplings enable construction of the actin-binding marine polyketide swinholide A in only 15 steps (longest linear sequence), roughly half the steps required in two prior total syntheses. The redox-economy, chemo- and stereo­selectivity embodied by this new class of C–C couplings are shown to evoke a step-change in efficiency

Ruthenium(0) Catalyzed Endiyne−α-Ketol [4 + 2] Cycloaddition: Convergent Assembly of Type II Polyketide Substructures via C–C Bond Forming Transfer Hydrogenation

Upon exposure of 3,4-benzannulated 1,5-diynes (benzo-endiynes) to α-ketols (α-hydroxyketones) in the presence of Ru(0) catalysts derived from Ru₃(CO)₁₂ and RuPhos or CyJohnPhos, successive redox-triggered C–C coupling occurs to generate products of [4 + 2] cycloaddition. The proposed catalytic mechanism involves consecutive alkyne-carbonyl oxidative couplings to form transient oxaruthanacycles that suffer α-ketol mediated transfer hydrogenolysis. This process provides a new, convergent means of assembling Type II polyketide substructures

Redox-Triggered C–C Coupling of Alcohols and Vinyl Epoxides: Diastereo- and Enantioselective Formation of All-Carbon Quaternary Centers <i>via tert</i>-(Hydroxy)-Prenylation

Iridium catalyzed primary alcohol oxidation triggers reductive C–O bond cleavage of isoprene oxide to form aldehyde-allyliridium pairs that combine to form products of <i>tert</i>-(hydroxy)-prenylation, a motif found in >2000 terpenoid natural products. Curtin–Hammett effects are exploited to enforce high levels of <i>anti</i>-diastereo- and enantioselectivity in the formation of an all-carbon quaternary center. The present redox-triggered carbonyl additions occur in the absence of stoichiometric byproducts, premetalated reagents, and discrete alcohol-to-aldehyde redox manipulations

Modular Terpenoid Construction via Catalytic Enantioselective Formation of All-Carbon Quaternary Centers: Total Synthesis of Oridamycin A, Triptoquinones B and C, and Isoiresin

Total syntheses of orida­mycin A, tripto­quinones B and C, and iso­iresin are accomplished from a common intermediate prepared via iridium-catalyzed alcohol C–H <i>tert</i>-(hydroxy)­prenylation - a byproduct-free process that forms an all-carbon quaternary stereocenter with excellent control of diastereo- and enantio­selectivity

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