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

Abstract

Upon exposure of 3,4-benzannulated 1,5-diynes (benzo-endiynes) to α-ketols (α-hydroxyketones) in the presence of ruthenium(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 oxaruthana-cycles that suffer α-ketol mediated transfer hydrogenolysis. This process provides a new, convergent means of assembling Type II polyketide substructures.

Ruthenium-Catalyzed Transfer Hydrogenation for C–C Bond Formation: Hydrohydroxyalkylation and Hydroaminoalkylation via Reactant Redox Pairs

“…85 Here, redox-neutral couplings using α-ketols are essential, as diols require a sacrificial hydrogen acceptor, which contributes to partial reduction of the diyne reactant. Regioselective cycloaddition is achieved using nonsymmetric diynes with alkyne termini substituted by n -propyl and t -butyl groups.…”

Ruthenium(0)‐Catalyzed [4+2] Cycloaddition of Acetylenic Aldehydes with α‐Ketols: Convergent Construction of Angucycline Ring Systems

“…However, rather than carbonylating, as in Pauson–Khand‐type reactions, the oxaruthenacycles undergo reduction by dehydrogenating alcohol reactants, releasing product, and regenerating the carbonyl partner required for oxidative coupling. This pattern of reactivity served as the basis for the design of novel [4+2] cycloadditions of 1,2‐diols with dienes, and α‐ketols with 3,4‐benzannulated 1,5‐diynes . Herein, we report that zero‐valent ruthenium catalysts promote the [4+2] cycloaddition of α‐ketols with ortho ‐acetylenic benzaldehydes, and demonstrate how this transformation enables concise construction of ring systems found in type II polyketides of the angucycline class .…”

“…This pattern of reactivity served as the basis for the design of novel [4+2] cycloadditions of 1,2-diols with dienes [5a] and α-ketols with 3,4-benzannulated 1,5-diynes. [5b] Here, we report that zero-valent ruthenium catalysts promote the [4+2] cycloaddition of α-ketols with ortho -acetylenic benzaldehydes and demonstrate how this transformation enables concise construction of ring systems found in type II polyketides of the angucycline class. [6] This cycloaddition is unique among metal catalyzed reactions of ortho -acetylenic benzaldehydes (Scheme 1).…”

“…Our initial experiments were guided by earlier studies conducted from our laboratory on the ruthenium(0)-catalyzed [4+2] cycloadditions of α-hydroxyketones with 3,4-benzannulated 1,5-diynes, [5b] which involved exposure of the reactants to the ruthenium(0) catalyst generated in situ from Ru 3 (CO) 12 (2 mol%) and CyJohnPhos (12 mol%) (Figure 2) in m -xylene-H 2 O at 60–85 o C. Gratifyingly, upon application of these conditions to the cycloaddition of ortho -acetylenic arylaldehyde 1a with the para -fluorophenyl α-ketol 2a , the targeted product of [4+2] cycloaddition 3a could be isolated as a single stereoisomer in 75% yield (Table 1). The syn -diol and ( E )-olefin stereochemistry were corroborated by single crystal X-ray diffraction analysis.…”

Ruthenium-Catalyzed Transfer Hydrogenation for C–C Bond Formation: Hydrohydroxyalkylation and Hydroaminoalkylation via Reactant Redox Pairs

“…85 Here, redox-neutral couplings using α-ketols are essential, as diols require a sacrificial hydrogen acceptor, which contributes to partial reduction of the diyne reactant. Regioselective cycloaddition is achieved using nonsymmetric diynes with alkyne termini substituted by npropyl and t-butyl groups.…”