The Exocyclic Effect:  Protecting Group Strategy to Enhance Stereoselectivity in Hydrogen Transfer Reactions of Acyclic Free Radicals

Abstract

To enhance the diastereoselectivity of the hydrogen transfer reaction of acyclic substrates bearing 1,2- or 1,3-diols, the feasibility of a strategy employing bifunctional protecting groups has been demonstrated. This strategy is based upon the “exocyclic effect” or the significant improvement of anti-selectivity exhibited by the reductions of substrates in which the two substituents (R1 and Y) at the stereogenic center α to the radical center are linked together. A rationale for the excellent facial discrimination of these exocyclic radicals is offered based on an analysis of transition state models, which considers both steric and electronic factors.

Diastereoselective Hydrogen‐Transfer Reactions: An Experimental and DFT Study

“…Taking advantage of this effect allowed for the reliable synthesis of 2,3‐ anti propionate relationships9 found within numerous ionophores bearing tetrahydropyran (THP) rings or tetrahydrofuran rings (THF) 5. 8a–c, e, f…”

“…To overcome the limitations observed with less substituted acyclic compounds, such as 4 a , b , we next studied the reduction of C3C5 diol radical precursors temporarily protected as acetonides or benzylidenes to take advantage of the exocyclic effect [Eq. (3)] 8c. The high 2,3‐ anti inductions obtained then encouraged us to develop single‐pot methodologies with boron Lewis acids to form in situ cyclic boronates and borinates [Eq.…”

Enantioselective Total Synthesis of Octalactin A Using Asymmetric Aldol Reactions and a Rapid Lactonization To Form a Medium‐Sized Ring

“…[3] Results and Discussion Synthesis of aldol-type fragments by desulfurization: The optically active aldol syn-16 was synthesized with high stereoselectivity by the asymmetric aldol reaction of tetrasubstituted KSA 13, derived from ethyl 2-methylthiopropanoate, with b-siloxyaldehyde 14. The catalyst for the reaction was a chiral Lewis acid consisting of Sn(OTf) 2 [16,17] The ester group was reduced by LiAlH 4 and halogenation of the resulting primary alcohol afforded the corresponding iodoalkane. Successive reductive cleavage of the benzylidene acetal part and protection of the primary alcohol produced the desired righthand segment 9, which was further converted to the phosphonium salt 19 by a conventional method.…”

Phenylselenoethers as Precursors of Acyclic Free Radicals. Creating Tertiary and Quaternary Centers Using Free Radical-Based Intermediates

“…Indeed, the amplification of the anti selectivity was noticed when two of the substituents of the stereogenic center to the radical are embedded in a ring [28]. The product ratios are better in the cases of the cyclic ethers, as illustrated in Scheme 9, in comparison to their acyclic counterpart (Scheme 8, entries 1 and 2).…”