Asymmetric Synthesis - Stereochemistry and Conformation - Introduction - March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

Part I. Introduction

Chapter 4. Stereochemistry and Conformation

4.G. Asymmetric Synthesis

Organic chemists often wish to synthesize a chiral compound in the form of a single enantiomer or diastereomer, rather than as a mixture of stereoisomers. There are two basic ways in which this can be done.137 The first way, which is more common, is to begin with a single stereoisomer, and to use a synthesis that does not affect the stereogenic center (or centers). The optically active starting compound can be obtained by a previous synthesis, or by resolution of a racemic mixture (Sec. 4.I). If possible, the starting material is obtained from Nature, since many compounds (e.g., amino acids, sugars, and steroids), are present in Nature in the form of a single enantiomer or diastereomer. These compounds have been referred to as a chiral pool; that is, readily available compounds that can be used as starting materials.138 This term is not used much now.

The other basic method is called asymmetric synthesis,139 or stereoselective synthesis. As mentioned earlier, optically active materials cannot be created from inactive starting materials and conditions, except in the manner previously noted.97 However, when a new stereogenic center is created, the two possible enantiomers need not be formed in equal amounts if anything is present that is not symmetric. Asymmetric synthesis may be categorized into four headings:

1. Active Substrate. If a new stereogenic center is created in a molecule that is already optically active, the product will generate diastereomers and the two diastereomers may not (except fortuitously) be formed in equal amounts. The reason is that the direction of attack by the reagent is determined by the groups already there. For certain additions to the carbon–oxygen double bond of ketones containing an asymmetric α carbon, Cram's rulepredicts which of two diastereomers will predominate (diastereoselectivity).140,141 The reaction of 46, which has a stereogenic center at the α-carbon, and HCN can generate two possible diastereomers (47 and 48).

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If 46 is observed along its axis, it may be represented as in 49 (Sec. 4.O.i), where S, M, and L stand for small, medium, and large, respectively. The oxygen of the carbonyl orients itself between the small- and the medium-sized groups. The rule requires that the incoming group preferentially attacks on the side of the plane containing the small group. By this rule, it can be predicted that 48 will be formed in larger amounts than 47.

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Another model uses transition state models 50 and 51 to predict diastereoselectivity in what is known as the Felkin–Anh model.142. This model assumes the favored transition state will be that with the greatest separation between the incoming group and any electronegative substituent at the α-carbon. The so-called Cornforth model has also been presented as a model for carbonyl addition to halogenated compounds,143 and it assumes that the electron pairs on the carbonyl oxygen and on the halogen repel and assume an anti-conformation.

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Many reactions of this type are known, and in some the extent of favoritism approaches 100% (e.g., see Reaction 12-12).144 The farther away the reaction site is from the chiral center, the less influence the latter has and the more equal the amounts of diastereomers formed. There are many examples of asymmetric induction via nucleophilic acyl addition to carbonyl compounds (Reactions 16-24 and 16-25). Enolborane addition to α-heteroatom substituted aldehydes has been evaluated using the Cornforth and the Felkin–Anh models.145

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In a special case of this type of asymmetric synthesis, a compound (52) with achiral molecules, but whose crystals are chiral, was converted by UV light to a single enantiomer of a chiral product (53).146

It is often possible to convert an achiral compound to a chiral compound by (1) addition of a chiral group; (2) running an asymmetric synthesis, and (3) cleavage of the original chiral group. The original chiral group is called a chiral auxiliary. An example is conversion of the achiral 2-pentanone to the chiral 4-methyl-3-heptanone, (55).147 In this case, >99% of the product was the (S) enantiomer. As noted, compound 54 is called a chiral auxiliarybecause it is used to induce asymmetry and is then removed.

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2. Active Reagent. A pair of enantiomers can be separated by an active reagent that reacts faster with one of them than it does with the other (this is also a method of resolution). If the absolute configuration of the reagent is known, the configuration of the enantiomers can often be determined by a knowledge of the mechanism and

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by determining which diastereomer is preferentially formed.148 Creation of a new stereogenic center in an inactive molecule can also be accomplished with an optically active reagent, although it is rare for 100% selectivity to be observed. An example149,150 is the reduction of methyl benzoylformate with optically active N-benzyl-3-(hydroxymethyl)-4-methyl-1,4-dihydropyridine (56) to produce mandelic acid (after hydrolysis) that contained ~97.5% of the (S)-(+) isomer and 2.5% of the (R)-(−) isomer (for another example, see Reaction 15-16). Note that the other product, (57), is not chiral. Reactions like this, in which one reagent (in this case 56) gives up its chirality to another, are called self-immolative. In another example:

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chirality is transferred from one atom to another in the same molecule.151

A reaction in which an inactive substrate is converted selectively to one of two enantiomers is called an enantioselective reaction, and the process is called asymmetric induction. These terms apply to reactions in this category and in categories 3 and 4.

When an optically active substrate reacts with an optically active reagent to form two new stereogenic centers, it is possible for both centers to be created in the desired sense. This type of process is called double asymmetric synthesis152 (for an example, see Reaction 16-34).

3. Optically Active Catalyst or Solvent.153 Many such examples are found in the literature, among them reduction of ketones and substituted alkenes to optically active (though not optically pure) secondary alcohols and substituted alkanes by treatment with hydrogen and a chiral homogeneous hydrogenation catalyst (reactions 16-23 and 15-11),154 the treatment of aldehydes or ketones with organometallic compounds in the presence of a chiral catalyst (see Reaction 16-24), and the conversion of alkenes to optically active epoxides by treatment with a hydroperoxide and a chiral catalyst (see Reaction 15-50). In some instances, the ratio of enantiomers prepared in this way is 99:1 or more.155 Other examples of the use of a chiral catalyst or solvent are the conversion of chlorofumaric acid (in the form of its diion) to the (−)-threo isomer of the diion of chloromalic acid by treatment with H2O and the enzyme fumarase,156 as well as the preparation of optically active aldols (aldol condensation, see Reaction 16-35) by the condensation of enolate anions with optically active substrates.157

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4. Reactions in the Presence of Circularly Polarized Light.158 If the light used to initiate a photochemical reaction (see Chap. 07) of achiral reagents is circularly polarized, then, in theory, a chiral product richer in one enantiomer might be obtained. However, such experiments have not proved fruitful. In certain instances, the use of left- and right-circularly polarized light has given products with opposite rotations159 (showing that the principle is valid), but up to now the extent of favoritism has always been <1%.