REACTIONS THAT FORM DIASTEREOMERS

In the hydrogenation of an alkene using a transition metal catalyst, the planar molecule binds to the surface of the metal. If the alkene is achiral, the side presented to the surface of the metal is not important. The alkene can be hydrogenated from the top or bottom to give the hydrogenated product. If the alkene contains a chiral carbon atom near the double bond, however, two products are possible. Consider the catalytic hydrogenation of (i )-2-methyhnethylenecyclo-hexane. Two stereoisomers, S,2R and R,2R, form, but in unequal amounts. Approximately 70% of the product is the cis isomer (15,2./ ). 

Because the alkene is chiral, there is a difference between the steric environment of the two faces of the double bond. The methyl group above the plane decreases the probability of hydrogenation from that face of the double bond. Hydrogenation from the less hindered bottom side pushes the newly formed methyl group up, and the cis isomer results. The two stereoisomers form in unequal amounts as a consequence of the chiral center. The reaction is stereoselective. 

Similar observations show that one enantiomer reacts with an achiral reagent to give unequal amounts of diastereomeric products. The relative yields of the diastereomers often depend on the structure of the existing stereogenic center and its proximity to the newly formed stereogenic center. Many stereogenic centers are present in an enzyme catalyst. They create a chiral environment, which leads to high stereoselectivity. Usually, only one diastereomer forms in enzyme-catalyzed reactions. 

Write the structure of the oxirane (epoxide) that forms when (.Z)-2-butene reacts with w-chloroper-benzoic acid. Assign the configurations of the stereogenic centers. 

Free radical chlorination of (5)-2-bromobutane yields a mixture of compounds with chlorine substituted at any of the four carbon atoms. Write the structure(s) of the 2-bromo-3-chlorobutane formed. Assign the configuration of the stereogenic center(s). Is the product optically active  

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Some reactions afford mixtures of products. Mixtures include diastereomers, such as endo and exo products (10.1 and 10.2) of a Diels-Alder cycloaddition, and regioisomers, such as ortho and para products (10.3 and 10.4) from an electrophilic aromatic substitution (Scheme 10.1). Even a reaction that forms products as subtly similar as enantiomers is technically a mixture of products. Isomeric mixtures violate the spirit of one compound, one well in combinatorial chemistry. Isomeric mixtures, however, are often unavoidable and therefore tolerated in compound libraries. Mixtures are also tolerated in libraries of compounds that have been derived from natural sources. Examples include extracts from finely ground vegetation and microbial broths. 

The synthesis of a chiral amino acid from an achiral precursor by any of the methods described in the previous section yields a racemic mi.xture— an equal mixture of S and R products. To use these synthetic amino acids for the laboratory synthesis of naturally occurring proteins, however, the racemic mixture must first be resolved into pure enantiomers. Sometimes this resolution can he done by allowing the racemic amino acid to undergo a reaction that forms two diastereomers, which are then separated and converted back to the amino acid (Section 9.10). 

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... 

After identifying the optimal etherification conditions, our attention turned to isolation of 18 in diastereomerically pure form. Diastereomers 18 and 19 were not crystalline, but, fortunately, the corresponding carboxylic acid 71 was crystalline. Saponification of the crude etherification reaction mixture of 18 and 19 with NaOH in MeOH resulted in the quantitative formation of carboxylic acids 71 and 72 (17 1) (Scheme 7.22). Since the etherification reaction only proceeded to 75-80% conversion, there still remained starting alcohol 10. Unfortunately, all attempts to fractionally crystallize the desired diastereomer 71 from the crude mixture proved unfruitful. It was reasoned that crystallization and purification of 71 would be possible via an appropriate salt. A screen of a variety of amines was then undertaken. During the screening process it was discovered that when NEt3 was added... 

Another attractive domino approach starts with an aldol reaction of preformed enol ethers and carbonyl compounds as the first step. Rychnovsky and coworkers have found that unsaturated enol ethers such as 2-237 react with different aldehydes 2-238 in the presence of TiBr4. The process consists of an aldol and a Prins-type reaction to give 4-bromotetrahydropyrans 2-239 in good yields, and allows the formation of two new C-C-bonds, one ring and three new stereogenic centers (Scheme 2.56) [131]. In the reaction, only two diastereomers out of eight possible isomers were formed whereby the intermediate carbocation is quenched with a bromide. 

Tsuji has reported the cyclization/distannylation of bis( 1,3-dienes) that form bis(functionalized) 1,2-dialkenyl-cycloalkanes, although the scope of the transformation was quite limited.In one example, reaction of ( , )-6,6-bis(ethoxycarbonyl)-l,3,8,10-undecatetraene and hexamethyldistannane (1.2equiv.) catalyzed by Pd(DBA)2 in toluene at room temperature for 20h gave /ra/ i--( ,Z)-l,2-bis-[2-(trimethylstannyl)vinyl]cyclopentane trans- E,Z)-108] in 90% yield as a single regioisomer and diastereomer (Equation (69)). 

Oxidatively generated oxocarbenium ions have been used for intramolecular epoxide activation. Cascade reactions to form oligotetrahydrofuran products that demonstrated a strong preference for the exo-cyclization pathway were achieved in good yields when disubstituted epoxides were used as substrates. High stereoselectivity was observed in these reactions, with complementary diastereomers being formed from diastereomeric (g) epoxides.257... 

Here we are primarily concerned with the fact that this ortho -adduct may occur in the form of two diastereomers. The diastereomers are formed as a 57 43 cis/trans-mixtme in the absence of A1C13, but a 95 5 cis/trans-mixture is obtained in the presence of A1C13. In the latter case, thus, one is dealing with a Diels-Alder reaction that exhibits a substantial simple diastereoselectivity (see Section 11.1.3 for a definition of the term). Here, the simple diastereoselectivity is due to kinetic rather than thermodynamic control, since the preferentially formed ds-disubstituted cyclohexene is less stable than its irans-isomer. 

Step [1] is just an acid-base reaction in which the racemic mixture of A -acetyl alanines reacts with the same enantiomer of the resolving agent, in this case (7 )-methylbenzylamine. The salts that form are diastereomers, not enantiomers, because they have the same configuration about one stereogenic center, but the opposite configuration about the other stereogenic center. 

As we have seen, the Diels-Alder reaction can be both stereoselective and regioselective. In some cases, the Diels-Alder reaction can be made enantioselective Solvent effects are important in such reactions. The role of reactant polarity on the course of the reaction has been examined. Most enantioselective Diels-Alder reactions have used a chiral dienophile (e.g., 199) and an achiral diene,along with a Lewis acid catalyst (see below). In such cases, addition of the diene to the two faces of 199 takes place at different rates, and 200 and 201 are formed in different amounts. An achiral compound A can be converted to a chiral compound by a chemical reaction with a compound B that is enantiopure. After the reaction, the resulting diastereomers can be separated, providing enantiopure compounds, each with a bond between molecule A and chiral compound B (a chiral auxiliary). Common chiral auxiliaries include chiral carboxylic acids, alcohols, or sultams. In the case illustrated, hydrolysis of the product removes the chiral R group, making it a chiral auxiliary in this reaction. Asymmetric Diels-Alder reactions have also been carried out with achiral dienes and dienophiles, but with an optically active catalyst. Many chiral catalysts... 

A further step was taken when first Halpern [28] and then Brown [29] were able to identify a further intermediate, the rhodium alkyl hydride formed by addition of dihydrogen to the enamide complex with transfer of a single hydride to the benzylic carbon. For the simple dppe complex studied by Halpern, the interpretation of the experiment was straightforward, but the intermediate derived from DIPAMP by Brown and Chaloner provided a major surprise only the disfavored minor diastereomer of the enamide complex was reactive towards H2. The major/minor equilibrium is so strongly biased towards the former below -50 °C that reaction with H2 is undetected. Only when the solvate complex is allowed to react with the dehydroamino acid derivative under H2, well below -50 °C (under which conditions up to 35% of the minor diastereomer is initially observed) is the alkyl hydride observed, concomitant with disappearance of that minor diastereomer. This reactive intermediate was characterized by its H-NMR (hydride), the distinctive P-NMR and by both heteronuclear coupling and chemical shifts in the C-NMR spectra of alkyl hydrides derived from singly and doubly labeled dehydroamino esters. 

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. 

Results from competition kinetics indicate that major diastereomers in stereoselective 5-ev o-trig cyclizations are formed in elementary reactions which are by a factor of 1.5-3 faster than the reference reaction 5 — 6 (Scheme 3). Likewise,... 

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