Synthesis of tetrahydropyrans and related heterocycles via prins cyclization; extension to aza-prins cyclization

Title reaction proceeds in the absence of transition metal catalysts, is operationally simple and tolerates a wide variety of functional groups like cyano, amide, aromatic halide, ether, ketone groups and C—C double bonds.

Bu4NI‐Catalyzed C ? O Bond Formation by Using a Cross‐Dehydrogenative Coupling (CDC) Reaction

Dirhodium compounds are emerging as highly efficient catalysts for diverse reactions, and those with carboxamidate ligands have the broadest applications. The unique features of these compounds are their structural rigidity, ease of ligand exchange, open diaxial sites for coordination with Lewis bases, and their low oxidation potential. As consequences of this, dirhodium carboxamidates are efficient and effective catalysts for metal carbene reactions, Lewis acid-catalyzed processes, and chemical oxidations. With chiral carboxamidate ligands these dirhodium compounds show exceptional enantiocontrol for intramolecular cyclopropanation and carbon-hydrogen insertion reactions of diazoacetates, and they are also highly efficient and selective for hetero-Diels-Alder reactions. Their limitations lie in their moderate reactivities for metal carbene generation and Lewis acid catalysis and in the cost of the precious metal rhodium.

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Perspective on dirhodium carboxamidates as catalysts.

Prins-type macrocyclizations have recently emerged as a successful strategy in the synthesis of polyketide-derived natural products. This reaction provides a concise and selective means to form tetrahydropyran-containing macrocyclic rings of varying size. A high degree of functionality within the macrocycle is tolerated and the yields for these transformations are typically good to excellent. Since the initial report of a Prins macrocyclization reaction in 1979, examples of this approach did not re-emerge until 2008. However, the use of this method in natural product synthesis has rapidly gained momentum in the synthetic community, with multiple examples of this macrocyclization tactic reported in the recent literature.

Prins-type macrocyclizations as an efficient ring-closing strategy in natural product synthesis.

Prins-Type Cyclization Reactions in Natural Product Synthesis

Prins cyclizations are intramolecular electrophilic additions of oxocarbenium ions. They lead to tetrahydropyrans with a heteroatom at the 4-position, and usually show moderate-to-high selectivity for equatorial substitution. We have found that Prins cyclizations carried out under specific conditions produce tetrahydropyrans with almost exclusive formation of the axial 4-substituent. TMSBr, AcBr, and TMSI all lead to axial-selective Prins cyclizations with α-acetoxy ether substrates in the presence lutidine. The mechanism appears to involve solvolysis of the intermediate α-bromo ether rather than specific or Lewis acid-catalyzed rearrangement. The scope of the reaction, the high yields, and the stereoselectivity make this a valuable new method for tetrahydropyran formation.

Justin P. Vitale

Papers

Axial-Selective Prins Cyclizations by Solvolysis of α-Bromo Ethers

Formation of macrocycles by catalytic intramolecular aromatic cycloaddition of metal carbenes to remote arenes

Enantiocontrolled Macrocycle Formation by Catalytic Intramolecular Cyclopropanation.

Formation of Macrocycles by Catalytic Intramolecular Aromatic Cycloaddition of Metal Carbenes to Remote Arenes.

Axial-Selective Prins Cyclizations by Solvolysis of α-Bromo Ethers.