An Overview of Saturated Cyclic Ethers: Biological Profiles and Synthetic Strategies

Saturated oxygen heterocycles are widely found in a broad array of natural products and other biologically active molecules. In medicinal chemistry, small and medium rings are also important synthetic intermediates since they can undergo ring-opening and -expansion reactions. These applications have driven numerous studies on the synthesis of oxygen-containing heterocycles and considerable effort has been devoted toward the development of methods for the construction of saturated oxygen heterocycles. This paper provides an overview of the biological roles and synthetic strategies of saturated cyclic ethers, covering some of the most studied and newly discovered related natural products in recent years. This paper also reports several promising and newly developed synthetic methods, emphasizing 3–7 membered rings.

Synthesis of Aza-polyquinanes via Fischer Indolization and Ring-Rearrangement Metathesis as Key Steps

Herein, we describe a simple synthetic strategy to assemble aza-polyquinane systems containing an indole motif by employing the Fischer indolization and ring-rearrangement metathesis as key steps. The precursor used here is exo-dicyclopentadienone, which is derived from less explored exo-dicyclopentadiene. By using this approach, several aza-polyquinanes that contain indole units and fused medium rings (eight- and nine-membered rings) were synthesized in good yields.

Templated assembly of medium cyclic ethers via exo-trig nucleophilic cyclization of cyclopropenes

A novel method for the assembly of medium heterocycles via an intramolecular nucleophilic addition to cyclopropenes is described. The exo-trig nucleophilic cyclizations were shown to proceed very efficiently and in a highly diastereoselective fashion affording cis-fused bicyclic products possessing 7 to 10-membered medium rings; starting from a diastereomeric mixtures of bromocyclopropanes.

Metal-Mediated C–C Ring Construction: (+)-Shiromool (Baran)

Seiji Iwasa of the Toyohashi University of Technology devised (Adv. Synth. Catal. 2012, 354, 3435) a water-soluble Ru catalyst for enantioselective intramolecular cyclopropanation that could be separated from the product and recycled by simple water/ether extraction. Minoru Isobe of the National Tsing Hua University combined (Org. Lett. 2012, 14, 5274) the Nicholas and Hosomi-Sakurai reactions to close the cyclobutane ring of 4. Kazunori Koide of the University of Pittsburgh established (Tetrahedron Lett. 2012, 53, 6637) that the activity of a Ru metathesis catalyst, shut down by the presence of TBAF, could be restored by the inclusion of TMS2O. Jan Streuff of Albert-Ludwigs-Universität Freiburg demonstrated (Angew. Chem. Int. Ed. 2012, 51, 8661) that the enantiomerically pure Brintzinger complex mediated the reductive cyclization of 7 to 8. Huw M.L. Davies of Emory University prepared (J. Am. Chem. Soc. 2012, 134, 18241) the cyclopentenone 11 by the Rh-mediated addition of 10 to 9 followed by elimination. Christophe Meyer and Janine Cossy of ESPCI ParisTech showed (Angew. Chem. Int. Ed. 2012, 51, 11540) that the Rh-mediated rearrangement of 12 to 13 proceeded with substantial diastereocontrol. Jian-Hua Xie and Qi-Lin Zhou of Nankai University observed (Org. Lett. 2012, 14, 6158) that the enantioselective hydrogenation of 14 followed by Claisen rearrangement established the cyclic quaternary center of 17 with high stereocontrol. Ken Tanaka of the Tokyo University of Agriculture and Technology devised (Angew. Chem. Int. Ed. 2012, 51, 13031) the Rh-mediated addition of the enyne 18 to 19 to give the highly substituted cyclohexene 20. Daesung Lee of the University of Illinois at Chicago showed (Chem. Sci. 2012, 3, 3296) that the ring-opening/ring-closing metathesis of 21 delivered 22 with high diastereocontrol. Andreas Speicher of Saarland University cyclized (Org. Lett. 2012, 14, 4548) 23 to 24 with significant atropisomeric induction. Erick M. Carreira of the Eidgenössische Technische Hochschule Zürich effected (J. Am. Chem. Soc. 2012, 134, 20276) the polycyclization of racemic 25 to 26 with high enantiomeric excess. Medium rings are often the most difficult to construct, because of the inherent congestion across the forming ring. Phil S. Baran of Scripps/La Jolla effected (Angew. Chem. Int. Ed. 2012, 51, 11491) the cyclization of 27 to 28 as a single dominant diastereomer.