Radical Reactions of Carbohydrates

Volume II: Radical Reactions in Carbohydrate Synthesis

Chapter 19: Compounds with Carbon-Carbon Multiple Bonds II: Cyclization Reactions

Chapter 19 is in a portable document file (pdf) and can be viewed by clicking the blue, Chapter 19 button below. The drawing underneath the button pictures a radical cyclization that forms a five-membered ring. Beside the drawing is a description of the reaction. Below the drawing and its description is a summary of Chapter 19.

Chapter 19: Compounds with Carbon-Carbon Multiple Bonds II: Cyclization Reactions

This drawing pictures a radical cyclization reaction.

Drawing Description

Radical cyclization is nearly always a kinetically con-trolled process. Kinetic control often leads to regio-specific formation of the less stable cyclic radical. In the reaction shown in the drawing on the left (Scheme 1 in Chapter 19)  even though cyclization to give a six-membered ring is possible and would gen­erate a more stable radical, the only reaction pathway followed leads to the smaller ring and the less stable radical.

Summary of Chapter 19

Forming a new ring by internal addition of a carbon-centered radical to a multiple bond is a powerful tool in carbohydrate synthesis. Regioselectivity and stereoselectivity are vital aspects of this type of reaction. Being able to predict regioselectivity is critical because a cyclization reaction potentially can form rings of two sizes. Since the newly formed ring nearly always has an additional chiral center (sometimes two), understanding stereoselectivity is essential in predicting stereochemistry in the cyclic product.

Compounds with five-membered rings are the ones most often produced by radical cycli­zation. Reactions that form five-membered rings are capable of generating six-membered rings also, but rarely do so because the transition state leading to the larger ring has greater ring strain. Compounds with six-membered rings are the major products when cyclization is capable of forming either six- or seven-membered rings consisting only of second row elements. Larger rings (seven or more members) are created when a radical center and a distant multiple bond are linked by a tether, usually one containing a silicon–oxygen bond.

The stereoselectivity of reactions that produce five- and six-membered rings usually can be rationalized by assuming that the reaction passes through a chair-like transition state. The lowest energy transition state for such a reaction has as many substituents as possible in pseudoequatorial positions. A variety of factors (pseudo-1,3-diaxial interaction, allylic strain, hydrogen bonding, conformation of an existing ring) affect transition-state energy and can, on occasion, cause a boat-like transition state to be more stable than a chair-like one.

Various types of unsaturated carbohydrates, often α,β-unsaturated esters, undergo radical cyclization. Also prominent among reactive compounds are those in which the radical-forming part of the molecule and the portion containing the multiple bond are connected by a silicon–oxygen tether. A third group of compounds that cyclize readily includes allyl and propargyl ethers and related compounds.