Enantioselective Functional Group Interconversions

The ability to interconvert one functional group into another is of fundamental importance in organic synthesis. Often, these interconversions involve reduction or oxidation of a functional group, and such transformations also may either create or destroy a stereogenic center. The first part of Section 12-1 will explore transition metal-catalyzed hydrogenations of C=C and C=0 bonds, which can exhibit a high degree of stereoselectivity. The second part will consider oxidation reactions that are also catalyzed by transition metal complexes, which can lead to enantioenriched products. 

The double bond in an alkene is rich in its chemistry, and it undergoes transformation to alcohols, alkyl halides, and alkanes depending upon reaction conditions. Although C=0 and C=C bonds are planar and provide an achiral reaction site, the interaction of these functional groups with specific reagents often creates one or more stereogenic centers in the reaction product, as reaction 12.1 shows. 

In this case, the achiral reagents reacting via an achiral (or racemic) intermediate in an achiral solvent should produce racemic product. Over 40 years ago, this is all we could expect of such a reaction in terms of stereoselectivity. If the purpose of the transformation was to obtain one or the other enantiomer, then special and often tedious methods were required to resolve the racemic product. Today, the goal of synthesis chemists often is to produce molecules that are not only chiral, but also enantiomerically pure. Biologically active molecules typically exist in only one enantiomeric form. Efficacious drugs are also often most effective if they exist as only one enantiomer in order to interact properly with a chiral active site. A racemic drug is a mixture of enantiomers, only 50% of which is usually efficacious. The other 50% is at best worthless and at worst toxic, sometimes severely so.2 

With the goal in mind of mimicking Nature or producing materials even more efficacious than those naturally occurring, chemists have discovered several methods for obtaining a particular enantiomer of a chiral compound. Among these are the following  

Method 1 represents the oldest technique for producing selectively one enantiomer, and readers should already be familiar with it.3 A chromatography column normally is an achiral environment elution of a racemate through the column should result in no separation into enantiomers. In Method 2, however, columns are modified by attaching chiral, enantioenriched groups to the solid support. Now a chiral environment does exist such that the two enantiomers exhibit diastereomerically different interactions with the column this is the basis for separation. Chiral column chromatography can sometimes resolve 

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Hydrogen atom transfer implies the transfer of hydrogen atoms from the chain carrier, which is the stereo-determining step in enantioselective hydrogen atom transfer reactions. These reactions are often employed as a functional group interconversion step in the synthesis of many natural products wherein an alkyl iodide or alkyl bromide is converted into an alkane, which, in simple terms, is defined as reduction [ 19,20 ]. Most of these reactions can be classified as diastereoselective in that the selectivity arises from the substrate. Enantioselective H-atom transfer reactions can be performed in two distinct ways (1) by H-atom transfer from an achiral reductant to a radical complexed to a chiral source or alternatively (2) by H-atom transfer from a chiral reductant to a radical. 

Compared to reductions the oxidation reactions constitute an area that is still relatively unexplored from a large-scale point of view. In spite of the enormous efforts which have been spent on basic research, applications at scale are still scarce. The reasons for this could be that the asymmetric procedures currently at hand are deemed to be inefficient, that the types of functional group interconversions addressed with oxidations are far less in demand than is the case for reductions, or the existence of competitive stoichiometric methods (mostly based on the use of metal oxides and salts, such as fTO, and KM 1104) that are considered to be sufficient for most purposes. Another factor that needs to be included is the intrinsic difficulty in designing a catalyst that is stable under the relatively aggressive oxidative conditions (compare reactivity of [H] and [O]). Nonetheless, the capabihty of enantioselective oxidations has been unambiguously proven at the manufacturing level in enough cases to make this approach a viable option for commercial production (see Sections 2.2 and 2.3). 

A chemoselective reaction is a reaction in which a reagent reacts with one functional group in preference to another. An enantioselective reaction forms more of one enantiomer than of another. Converting one functional group into another is called functional group interconversion. 

Baeyer-Villiger oxidation (p. 853) catalytic hydrogenation (p. 844) chemoselective reaction (p. 848) dissolving-metal reduction (p. 846) enantioselective reaction (p. 857) epoxidation (p. 855) functional group interconversion (p. glycol (p. 858)... 

The enantioselective hydrocyanation of alkenes has the potential to serve as an efficient method to generate optically active nitriles, as well as amides, esters, and amines after functional group interconversions of the nitrile group. As in asymmetric hydroformylation, asymmetric hydrocyanation requires control of both regiochemistry and stereochemistry because simple olefins tend to generate achiral terminal nitrile products. The hydrocyanation of norbomene will give a single constitutional isomer and was studied initially. However, modest enantioselectivities were obtained, and the synthetic value is limited. ... 

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