Highly Stereoselective Radical Cyclization of Haloacetals Controlled by the Acetal Center

Abstract

A systematic investigation of radical haloacetal cyclizations (Ueno-Stork reaction) where the acetal center is the unique stereogenic element is reported. This highly diastereoselective reaction can be used for the preparation of polysubstituted tetrahydrofurans and gamma-lactones. We report herein the full experimental details of reactions where up to three new chiral centers are created. To demonstrate the potential of this approach, short syntheses of (+)-eldanolide and of tricyclic acetals related to biologically active lignans have been achieved.

A Computational Study of Radical Haloacetal Cyclizations Controlled by the Acetal Center

“…In order to save computational cost, the methoxy substituted radical 1 a was used as a model for the ethoxy derivative used experimentally. [16,20] Five possible transition states were identified: a chair-axial, a twist-axial, a boat-axial, a chair-equatorial and a twistequatorial ( Figure 1). Interestingly, the twist transition state has not been reported so far.…”

“…[20] In order to provide a further level of understanding of this chemistry, we began to explore the mechanistic details of these radical ring closures using computational techniques. We now report that ab initio and other computational techniques are able to accurately predict the outcome of the reactions in question.…”

“…98:2). [20] Calculation using the 3-21G basis set. In addition, higher-level single point calculations were performed on these optimized structures, the results of which are listed in Table 3.…”

Diastereoselective Radical‐Mediated Hydrogen‐Atom Abstraction

“…For instance, by using acetals of type 1 and 3, it is possible to activate alcohols at the b position. The chromatographic resolution of the starting acetals and the use of a chiral auxiliary to control the absolute stereochemistry at the acetal chiral center [11,13,[21][22][23] should facilitate access to optically pure polysubstituted tetrahydrofurans and g-lactones. Further work toward this goal is currently underway.…”

“…[10] The stereochemical outcome of these reactions will be then compared with that of the selective cyclization of the related systems D to E, which has been thoroughly investigated by us (Scheme 1 b). [11][12][13] The radical precursors were readily prepared from the corresponding alcohols, 1-methoxyallene, and N-bromo-or N-iodosuccinimide, according to Equation (1). [14] The reaction conditions for the hydrogen abstraction were optimized with substrate 1 a [Eq.…”