Abstract
An efficient Pd/ETM (ETM = electron transfer mediator)-cocatalyzed stereoselective oxidative carbocyclization of dienallenes under aerobic oxidation conditions has been developed to afford six-membered heterocycles. The use of a bifunctional cobalt complex [Co(salophen)-HQ] as hybrid ETM gave a faster aerobic oxidation than the use of separated ETMs, indicating that intramolecular electron transfer between the hydroquinone unit and the oxidized metal macrocycle occurs. In this way, a class of important cis-1,4-disubstituted six-membered heterocycles, including dihydropyran and tetrahydropyridine derivatives were obtained in high diastereoselectivity with good functional group compatibility. The experimental and computational (DFT) studies reveal that the pendent olefin does not only act as an indispensable element for the initial allene attack involving allenic C(sp3)–H bond cleavage, but it also induces a face-selective reaction of the olefin of the allylic group, leading to a highly diastereoselective formation of the product. Finally, the deuterium kinetic isotope effects measured suggest that the initial allenic C(sp3)–H bond cleavage is the rate-limiting step, which was supported by DFT calculations.
Highlights
Six-membered heterocycles are ubiquitous core structures in various natural products, as well as in pharmacologically active substances.1 Glucose, the monosaccharide made during photosynthesis from water and carbon dioxide, is one of the most important compounds in the life sciences.2 α-Dglucopyranose bears the core structure of tetrahydropyran with substituents stereochemically arranged, including 1,2, 1,3, and 1,4-cis configurations of two different hydroxyl groups (Scheme 1a)
We found that the pendent olefin unit is an indispensable element for the subsequent allene attack via C(sp3)−H bond cleavage (Scheme 3a)
The pendent olefin was shown to be an indispensable element by comparative experiments, and its role is to trigger the initial allenic C(sp3)−H bond cleavage and to control the stereochemical outcome of the carbocyclization as confirmed by the density functional theory (DFT) calculations
Summary
Six-membered heterocycles are ubiquitous core structures in various natural products, as well as in pharmacologically active substances. Glucose, the monosaccharide made during photosynthesis from water and carbon dioxide, is one of the most important compounds in the life sciences. α-Dglucopyranose bears the core structure of tetrahydropyran with substituents stereochemically arranged, including 1,2-, 1,3-, and 1,4-cis configurations of two different hydroxyl groups (Scheme 1a). For 1,2- and 1,4-disubstituted six-membered rings, a cis configuration will have one substituent in the equatorial position and the other one in the axial position, where the latter suffers from 1,3diaxial interaction(s) with the axial C−H bond(s) (Scheme 1b).. (a) Selected Natural Products Bearing the Core Structure of Six-Membered Heterocycles with 1,2-, 1,3-, or 1,4-cis Configuration. (b) Comparison of the Difficulties on the Selectivity Control for the Synthesis of cis-1,2-, 1,3-, and 1,4-Disubstituted Six-Membered Rings (X, Y = C, O, N. etc.). The corresponding reaction of the less favored intermediate Int-B′ would give the trans-1,4-disubstituted heterocycle Int-C′. In this overall transformation, both the ring-closing reaction and the installation of a new functional group (FG) can be efficiently realized in a one-step manner
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