Angew. Chem. Int. Ed. http://doi.org/f277mq (2015)

The tetrahydrofuran ring is widely found as a substructure in natural products; a recent review listed in excess of 30 such marine natural products, some of which display interesting antimicrobial, antibacterial and anticancer properties. Stereoselective routes to substituted tetrahydrofurans are thus in demand, but despite much attention from the synthetic community, the most highly substituted compounds remain difficult to access. Now, Christopher Moody and co-workers from the University of Nottingham have reported a method in which either a rhodium or copper catalyst directs the combination of diazocarbonyls and β-hydroxyketones to form these sought after products. The second of these starting materials are, of course, readily accessible by aldol reactions.

Moody and co-workers have long had an interest in O–H insertion reactions of metallocarbenes. The tetrahydrofuran products appear — on paper — to be the result of an intramolecular aldol reaction after such an insertion reaction on the β-hydroxyketone starting material. Exposure of this apparent intermediate to the reaction conditions did not, however, result in the formation of any tetrahydrofuran product. It is proposed, instead, that an initially formed oxonium ylide (which may or may not first dissociate from the metal) undergoes an intramolecular cyclization to the tetrahydrofuran rather than the 1,2-H-shift that would result in the insertion product. Hydrogen bonding results in a well-ordered transition state for this process and explains the high observed diastereoselectivity.

The rhodium and copper catalysts seem to offer complementary reactivity — with rhodium working best with electron-rich diazoacetates and copper working best with electron-poor substrates. A variety of β-hydroxyketones substrates were studied, with rhodium catalysts found to be superior when these were secondary or tertiary alcohols. When catalysts with chiral ligands were used, those with rhodium resulted in essentially no chiral induction while those with copper gave low enantiomeric excess. This suggests that the key intermediate remains at least loosely bound to the metal in the case of copper while reactions with rhodium proceed through a metal-free intermediate.