Organic Chemistry Portal
Organic Chemistry Highlights

Monday, December 19, 2005
Douglass Taber
University of Delaware

Stereoselective Construction of Carbocyclic Rings

Carbocyclic rings, unlike saturated heterocyclic rings, are not susceptible to the hepatic activation that is the basis of much drug toxicity. To pave the way for pharmaceutical discovery based on carbocyclic agents, much effort is going into the development of practical procedures for their stereocontrolled construction.

Intramolecular alkylation is an attractive method for ring construction. Helena M.C. Ferraz of the University of São Paulo and Marcos N. Eberlin of the State University of Campinas report (J. Org. Chem. 2005, 70, 110. DOI: 10.1021/jo048309e) that the intramolecular displacement of the iodide 1 proceeds by way of the tethered enamine 2, delivering the quaternary center of the keto ester 3 with high diastereocontrol.

Günter Helmchen of the Ruprecht-Karls-Universität, Heidelberg has reported (Chem. Commun. 2005, 2957. DOI: 10.1039/b503713a) the design of chiral ligands that direct the absolute sense of the Ir-catalyzed intramolecular alkylation of 4 to 5. Both 5- and 6-membered rings can be prepared in high ee using this procedure. The use of Ir, which is much less expensive than Pd or Rh, is particularly attractive.

The intramolecular aldol reaction can also proceed with high enantioselectivity. Daniel Romo of Texas A&M University has shown (J. Org. Chem. 2005, 70, 2835. DOI: 10.1021/jo050024u) that a quinine-derived organocatalyst Q+ works well for the cyclization of aldehyde acids such as 6 to the bicyclic β-lactone 8. Both 5- and 6-membered rings are formed with high enantioselectivity. The key to the success of the cyclization was the use of the modified Mukaiyama activating agent 7, having a non-nucleophilic counterion.

Tomislav Rovis of Colorado State University has reported (Angew. Chem. Int. Ed. 2005, 44, 3264. DOI: 10.1002/anie.200500088) the diastereoselective Lewis acid-mediated 1,3-rearrangement of dihydrooxepins such as 10 to the cyclopentene carboxaldehyde 11. It is particularly convenient that the precursor aldehyde 9 is also converted into 11 under the same conditions. As there are many ways to construct alkenyl cyclopropanes such as 9 with control of both relative and absolute configuration, this is an important addition to methods for the stereocontrolled construction of cyclopentanes.

The internal Diels-Alder cycloaddition has long been a workhorse for the construction of bicyclic systems, with substituents on the bridge between the diene and the dienophile directing the stereochemical course of the cyclization. In conjunction with a total synthesis of (+)-dihydrocompactin 16, Terek Sammakia of the University of Colorado has reported (J. Am. Chem. Soc. 2005, 127, 6504. DOI: 10.1021/ja043506g) the elegant use of the distal oxygenated stereogenic center of 12 to direct the stereochemical course of the ring formation. Since lactone formation by the SmI2 Molander protocol is highly diastereocontrolled, the initial oxygenated center of 12 is used to set every other stereogenic center in 16.

D. F. Taber, Org. Chem. Highlights 2005, December 19.