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Monday, December 12, 2005
Douglass Taber
University of Delaware

Recent Advances in Carbocyclic Ketone Construction

As the ketone is the central functional group of organic synthesis, so cyclic ketone construction has dominated carbocyclic construction. Several powerful methods for cyclic ketone construction have recently been put forward.

Several procedures are known, including Rh catalysis, for the exo cyclization of alkenyl aldehydes such as 1 to ketones such as 2. Kiyoshi Tomioka of Kyoto University recently reported (J. Org. Chem. 2005, 70, 681. ) that efficient cyclization can be achieved by merely heating the aldehyde with a catalytic amount of a tertiary thiol, with AIBN as the initiator. Addition takes place even to unactivated alkenes, and both five- and six-membered ring ketones can be formed. It is a measure of the mildness of the method that cyclization of 1 gives 2 as a 1:1 mixture, even though trans is much the more stable diasteromer.

Cyclic ketones can also be formed by intramolecular aldol condensation. Roger C. Whitehead of the University of Manchester found (Tetrahedron Lett. 2005, 46, 2803. ) that the cis ene dione 4, available by oxidation of the corresponding furan 3, underwent highly diasteroselective aldol condensation, to give untenone A (5).

The intramolecular aldol condensation can also be used to prepare enantiomerically-pure cyclic enones. Shigefumi Kuwahara of Tohoku University has shown (Tetrahedron Lett. 2005, 46, 547. ) that addition of 6 to 7, following the Evans procedure, followed by reduction and silylation delivered the bis-ether 8. Wacker oxidation followed by ozonolysis and exposure to aqueous NaOH in ether then led to the enone 9, without epimerization of the γ-center.

Scott G. Nelson of the University of Pittsburgh has developed (J. Org. Chem. 2005, 70, 4375. ) a highly diastereocontrolled route to substituted cyclohexanones using the intramolecular Sakurai reaction. The requisite allyl silane 12 was prepared by Claisen rearrangement of the allylic alcohol 10, followed by homologation. The Ti enolate from the Sakurai addition was trapped with isobutyraldehyde to give 13. Although 32 diastereomers of 13 are possible, the diastereomer illustrated was the dominant product from the cylization. Note that use of the enantiomerically-pure form of the alcohol 10 would have led to enantiomerically-pure 13.

One of the most powerful methods for bicyclic ketone construction is the intramolecular Pauson-Khand reaction (14 -> 15). Although catalytic methods for this transformation have been put forward, they are not always successful. Jihua Chen and Zhen Yang of Peking University have now found (Org. Lett. 2005, 7, 593. ) that the cyclization proceeds quickly and efficiently with 5 mol % of the commercial grade of Co2(CO)8 if it is run in the presence of the inexpensive tetramethylthiourea. The authors have also reported (Org. Lett. 2005, 7, 1657. ) that TMTU is beneficial to the Pd-catalyzed version of the reaction. These advances will make the Pauson-Khand cyclization a more generally practical procedure.

D. F. Taber, Org. Chem. Highlights 2005, December 12.