Stereoselectivity of Radical Reactions

Inhibited by a perceived complexity, the study of diastereoselective processes involving free radicals did not begin until the late 1980s. Studies involving the stereoselectivity of radical reactions under the influence of Lewis acid soon followed. This chapter will review the effect of Lewis acid on the diastereoselectivity of substrate-controlled radical reactions. Reactions involving chiral Lewis acids and chiral hydrogen donors (reagent control) will be reviewed in another chapter [Volume 1, Chapter 4.5]. 

Intermolecular radical bond formations with companally high yields and stereoselectivities are still very rare in the total synthesis of bioactive compounds. One exception is Curran s camptothecin synthesis. However, progress in acyclic stereoselection of radical reactions [11] should soon help to formulate new solutions for these synthetic challenges. 

The MOVB theory of stereoselection of "real" radical electrocyclic reactions destroys the impasse which has been reached in the field of radical chemistry with regards to the stereoselectivity of radical reactions, in general. 

As is the case with the Wittig and Peterson olefinations, there is more than one point at which the stereoselectivity of the reaction can be determined, depending on the details of the mechanism. Adduct formation can be product determining or reversible. Furthermore, in the reductive mechanism, there is the potential for stereorandomization if radical intermediates are involved. As a result, there is a degree of variability in the stereoselectivity. Fortunately, the modified version using tetrazolyl sulfones usually gives a predominance of the E-isomer. 

Crich and Gastaldi investigated the nucleophilic trapping of a dihydronaphthalene radical cation by octyl alcohol and noted that the stereoselectivity of the reaction, while not high, was a function of the substrate stereochemistry (Scheme 19) [134]. In terms of the general mechanism for fragmentation... 

The general concepts of stereoselectivity in radical reactions have been illustrated in a number of recent books. Readers are referred to those books for a thorough treatment [1,2]. The following sections deal with a collection of applications where silanes act as mediators for smooth and selective radical strategies, based on consecutive reactions. 

We refer the readers to a useful body of books and reviews in the bibliography which will prove helpful to investigators determining the mechanism of radical reactions. The early two-volume compendium edited by Kochi has much valuable information, even though 30 years old, and most modern texts on radicals provide excellent guidance to radical synthesis and mechanism. We shall not discuss stereochemistry explicitly which now forms an important part of the mechanisms of radical reactions except to note that excellent stereoselectivities can be obtained in radical reactions with a clear understanding of the mechanisms involved. Many concepts in radical polymerisations are equally applicable to small molecule reactions and we refer the reader to an excellent account on the subject by Moad and Solomon. 

Alkynes reacted with (dichloroiodo)benzene under free radical conditions to give trans- 1,2-dichloro adducts. The stereoselectivity of the reaction was much better than with elemental chlorine yields were also improved. An example is provided by the chlorination of cyclopropylacetylene under photochemical conditions [11] ... 

Since the reduction is believed to proceed via a radical mechanism, it seems plausible that these cyclisations are in fact radical-mediated. However, strong evidence against this comes from the stereoselectivity of the reaction the trans selectivity of these cyclisations contrasts powerfully with the cis selectivity of the corresponding radical reactions. 

The key to the high stereoselectivity of these reactions, relative to their radical counterparts, is their late, product-like transition state.152 As early as 1974, it was suggested by Oliver that cyclisations of organolithiums onto unactivated alkenes was promoted by an interaction between the lithium atom and the C=C double bond. There is now plenty of evidence that this is the case in 1991, ab initio calculations by Bailey and coworkers125 showed that not only is there a sound theoretical basis for treating structures such as 338-340 as reasonable... 

Enzyme selectivity is usually limited because it depends on the interaction between the substrate and hydrophobic and hydrophilic amino acid residues at the active site, but here the degree of substrate immobilization is generally low. After the electron transfer process has occurred, the substrate is transformed into a radical compound that diffuses to the bulk of the solution and evolves according to its chemical properties, generally independently of the enzyme. This implies that the peroxidases rule the yield and the rate of radical formation but, once the latter species has been formed, the product composition and the stereoselectivity of the reaction are essentially dependent on the radical chemical structure and, to some extent, on the solvent and temperature of the reaction. 

In order to explain the high stereoselectivity of these reactions, it was suggested that out of the two possible conformers 27 and 28 of the adduct radicals, only conformer 27 is involved in the transition state, as the reaction of conformer 28 would be less stereoselective. The absence of conformer 28 may be due to the steric repulsion between groups CH2EWG and NR2 which destabilize 28. Alternatively, if 28 is the more stable conformer, the ring flip of the initially formed 27 may be slower than hydrogen atom abstraction from Bu3SnH. 

Although the subsequent discussion describes the stereoselection at the steady state through the example of radical reactions, the analysis and principles are general for any reaction profile that fits into the scheme of complex stereoselective reactions. In the process proposed and analyzed by Curran et al., the activation of compounds of type 1 is done, for example, by radical formation. The group selectivity in this first step has again no effect on the stereomeric nature of the product. To obtain a stereoconvergent process it is crucial, however, that the reaction is operating at the steady state. This means that the concentrations of the radial intermediates (compounds in brackets in Scheme 2) is low and stationary, while their absolute concentrations are determined by the different rates of reaction. 

For reviews on the stereoselectivity of radical pair combinations, see (a) Curran, D. P. Porter, N. A. Giese, B. Stereochemistry of Radical Reactions Concepts, Guidelines, and Synthetic Applications, VCH Weinheim, 1995 p 242, and references cited therein, (b) John, L. E. An Introduction to Free Radicals, Wiley New York, 1993 p 56 and references cited therein. 

Radical chemistry has been widely exploited for the modification of carbohydrates. In particular, tributyltin hydride-promoted deoxygenation provides a convenient method for the effective removal of hydroxyl groups without intervention of other functionalities. Stereoselective carbon-carbon bond formation at the anomeric center has also revealed its apphcability for the preparation of carbon analogues of 0-glycosides. The majority of this work has been reviewed in earlier publications and hence will not be covered in this account. Instead a selection of newer appHcations is provided here, which have been categorized according to the type of radical reaction carried out. 

The use of Lewis acids to impart chemoselectivity and stereoselectivity to free-radical polymerization and copolymerization is well documented [670]. Recent progress in radical reactions in organic synthesis has revealed the importance of Lewis acids in selective transformations [671,672]. Lewis acids have also been found to enhance the reactivity both of radical acceptors [673-675] and of radicals themselves [676], thus increasing the efficiency of radical reactions. 

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