Reactions That Produce Diastereomers

StereospecIfIc reactions were Introduced in connection with syn and anti additions to alkenes in Section 6.2. 

Once we grasp the idea of stereoisomerism in molecules with two or more chirality centers, we can explore further details of addition reactions of alkenes. 

When bromine adds to (Z)- or ( )-2-butene, the product 2,3-dibromobutane contains two equivalently substituted chirality centers  

Three stereoisomers are possible a pair of enantiomers and a meso form. 

Two factors combine to determine which stereoisomers are actually formed in the reaction. 

Bromine addition to alkenes is a stereospecific reaction, a reaction in which stereo-isomeric starting materials yield products that are stereoisomers of each other. In this case the starting materials, in separate reactions, are the E and Z stereoisomers of 2-butene. The chiral dibromides formed from (Z)-2-butene are stereoisomers (diastereomers) of the meso dibromide from ( )-2-butene. 

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The introduction of branches also makes it possible to have stereoisomers. Compounds with a single methyl branch at any position other than carbon 2 or the exact center of the chain can exist as one of two possible enantiomers, whereas compounds with two or more branches have a number of different stereoisomers (e.g., enantiomers, me so isomers, or diastereomers). Generic reactions that produce racemic mixtures or mixtures of stereoisomers will be discussed first, followed by descriptions of methods used to make individual stereoisomers. 

This reaction was first reported by Marckwald in 1904. It is the synthesis of chiral L-valeric acid (a-methyl propanoic acid) from the pyrolysis of brucine salt of racemic o -methyl-o -ethylmalonic acid. Therefore, it is generally known as the Marckwald asymmetric synthesis. Occasionally, it is also referred to as the Marckwald method. In this reaction, the brucine salts of racemic a-methyl-a-ethylmalonic acid essentially exist as a pair of diastereomers that are separated by fractional crystallization the one with lower solubility is isolated. Upon pyrolysis of such crystalline salt at 170°C, the corresponding brucine salt of L-valeric acid forms upon decarboxylation, resulting in a 10% e.e. In addition, Marckwald defined the asymmetric synthesis as reactions that produce optically active molecules from symmetrically constituted compounds with the use of optically active materials and exclusion of any analytical processes, such as resolution. However, this work was challenged as not being a trae asymmetric synthesis because the procedure was similar to that of Pasteur. In fact, the If actional crystallization of the diastereomers is a resolution process. This process is used as base for many other preparations of chiral molecules, such as tartaric acid and under its influence, the kinetic resolution and tme asymmetric synthesis have been developed in modem organic synthesis. The asymmetric synthesis has been redefined by Morrison and Mosher as the reaction by which an achiral unit of the substrate is converted into a chiral unit in such a manner that the two resulting stereoisomers are produced in unequal amounts. ... 

Diastereoselective reaction A reaction that produces one diastereomer in preference to all others. 

A reaction that introduces a second chirality center into a starting material that already has one need not produce equal quantities of two possible diastereomers Con sider catalytic hydrogenation of 2 methyl(methylene)cyclohexane As you might expect both CIS and trans 1 2 dimethylcyclohexane are formed... 

Three general methods exist for the resolution of enantiomers by Hquid chromatography (qv) (47,48). Conversion of the enantiomers to diastereomers and subsequent column chromatography on an achiral stationary phase with an achiral eluant represents a classical method of resolution (49). Diastereomeric derivatization is problematic in that conversion back to the desired enantiomers can result in partial racemization. For example, (lR,23, 5R)-menthol (R)-mandelate (31) is readily separated from its diastereomer but ester hydrolysis under numerous reaction conditions produces (R)-(-)-mandehc acid (32) which is contaminated with (3)-(+)-mandehc acid (33). 

Treatment of all four diasteromers of 72 with sodium or potassium bases yielded stilbenes with high stereoselectivity (Scheme 15) <2003T255>. Two of the diastereomers gave rise to some retro-aldol products. In two cases, hexacoordinate species were identified by the upheld 31P chemical shift (5—112 ppm). It was noted that phosphoranes that ring-closed to form hexacoordinate tricyclic species were the ones that did not undergo the retro-aldol reaction to produce aldehydes. The ring closure was disfavored for intermediates with steric repulsion between trifluoromethyl and phenyl groups. 

Once this process is explored with the model system to assess the level of enantioselectivity, we will then prepare alkyl zinc reagent 48 from 44 using standard methods - - and cross couple 48 to aryl bromide 18 using the appropriate chiral catalysts (Scheme 7). Although the acetonide stereocenter in 48 is somewhat remote from the coupling site, the stereocenter may serve to enhance the stereoselectivity of the cross-coupling process because the two possible products are diastereomers, not simply enantiomers. This reaction will produce 49 from (S)-48 and 30 from (R)-48 that can then be converted to epoxides 31 and 32 using standard methods. Epoxide 31 leads to heliannuol D 4 after base-promoted epoxide cyclization and deprotonation. Similarly, epoxide 32 leads to heliannuol A 1 after acid-promoted cyclization. 

Rhodium( I)-catalyzed hydroformylation of cyclic enol acetals 1 leads to acetal-protected syn-3,5-dihydroxyalkanals 2 with extraordinarily high levels (>50 1) of diastereoselectivity (Scheme 5.2) [2]. The diastereoselectivity cannot be ascribed to any obvious steric bias, and serves as a powerful demonstration that the hydroformylation reaction may be subject to exquisite stereoelectronic control. Indeed, while the addition of a pseudo-axial methyl group to the acetal carbon (as in acetonide 3) has a deleterious effect on the rate of the reaction, the sy -diastereomer 4 is still produced selectively, in what is surely a contra-steric hydroformylation reaction. 

One of the most direct ways to produce diastereomers is by addition reactions across carbon-carbon double bonds. If the structure of the olefin substrate is such that two new chiral centers are produced by the addition of a particular reagent across the double bond, then diastereomers will result. For example, the addition of HBr to Z-3-chloro-2-phenyl-2-pentene produces 2-bromo-3-chloro-2-phenylpentane as a mixture of four diastereomers. Assuming only Markovnikov addition, the diastereomers are produced by the addition of a proton to C-3 followed by addition of bromide to the carbocation intermediate at C-2. Since the olefin precursor is planar, the proton can add from either face, and since the carbocation intermediate is also planar and freely rotating, the bromide can add to either face to give diastereomeric products. The possibilities are delineated schematically (but not mechanistically) below. 

The thermally promoted reaction of an enantiomerically pure a-alkoxyallylstan-nane with achiral aldehydes was first reported by Thomas in 1984 [100]. The a-alkoxyallylstannane 145 (prepared from menthol and a racemic stannol) is heated with the aldehyde at 130°C to produce the homoallylic alcohol 146 as a single diastereomer in good yield (Scheme 10-62). Chairlike, six-membered transition structures can account for the observed diastereoseleetivity in these reactions. The a-alkoxy group prefers to adopt an axial position in the transition structure, ensuring that the diastereomers 145 and 147 react selectively with the aldehyde from only one face of the carbonyl group. 

Several workers have studied platinum(II) complexes of olefins containing chiral amine or amino-acid ligands. Panunzi(9) observed stereoselectivity in the reaction between cis-(S - a-methylbenzylamine)dichloroplatinum (II) and trans-2-butene with the major diastereomer formed to the extent of 70% of total complex. More recently (10), it has been shown that the replacement of coordinated trans-2-butene by free olefin in (S-prolinato) dichloroplatinum (II) complexes takes place more easily with retention than with inversion. Addition of a large excess of trans-2-butene to solutions of the corresponding ethylene complexes produced first an increase and then a gradual decrease in their circular dichroism. The kinetic stereoselectivity in this reaction (that is, the differing reaction rates of the two prochiral faces of trans-but-2-ene) was 3 1, but at equilibrium the ratio of major and minor diastereomers was 64 36 in the cis-isomer and 59 41 in the trans-isomer. 

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