Stereogenic center formation catalysts

Preparation of enantiomerically enriched materials by use of chiral catalysts is also based on differences in transition-state energies. While the reactant is part of a complex or intermediate containing a chiral catalyst, it is in a chiral environment. The intermediates and complexes containing each enantiomeric reactant and a homochiral catalyst are diastereomeric and differ in energy. This energy difference can then control selection between the stereoisomeric products of the reaction. If the reaction creates a new stereogenic center in the reactant molecule, there can be a preference for formation of one enantiomer over the other. 

In the kinetic resolution, the yield of desired optically active product cannot exceed 50% based on the racemic substrate, even if the chiral-discriminating ability of the chiral catalyst is extremely high. In order to obtain one diastereomer selectively, the conversion must be suppressed to less than 50%, while in order to obtain one enantiomer of the starting material selectively, a higher than 50% conversion is required. If the stereogenic center is labile in the racemic substrate, one can convert the substrate completely to gain almost 100% yield of the diastereomer formation by utilizing dynamic stereomutation. 

The enantiomerically-pure intermediate 1 was prepared from the dioxolanone 4, available in three steps from L-malic acid. Lewis acid-mediated homologation converted 4, a 4 1 mixture of diastereomers, into 5 as a single diastereomer. After establishment of the alkenyl iodide, it necessary to maintain the lactone in its open form. A solution was found in the formation of the Weinreb amide. The final stereogenic center was established by Brown allylation of the derived aldehyde. The alkene metathesis to form 1 was carried out with the commercially-available Schrock Mo catalyst. The authors did not comment on the relative efficacy of alternative alkene metathesis catalysts. 

It is worthy of note that - similarly to the proline catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process in which two stereogenic centers are formed in one step, although using non-chiral starting materials (Scheme 5.16) [22, 23, 26, 27, 28]. In these reactions substituted acetone or acetaldehyde derivatives, rather than acetone, serve as donor. In contrast with the anti diastereoselectivity observed for the aldol reaction (Section 6.2.1.2), the proline-catalyzed Mannich reaction furnishes products with syn diastereoselectivity [23]. A proline-derived catalyst, which led to the formation of anti Mannich products has, however, been found by the Barbas group [29]. 

Desymmetrization via proline-catalyzed asymmetric intramolecular aldol reaction can, however, also be performed with acydic diketones of type 109 as has been reported by the Agami group [106], In the first step a prochiral acyclic diketone reacts in the presence of L-proline as catalyst (22-112 mol%) with formation of the aldol adduct 111 (Scheme 6.49). In this step reaction products with two stereogenic centers, 110, are formed. These chiral hydroxyketones 110 are subsequently converted, via dehydration, into the enones 111, by treatment with p-toluenesulfonic acid. 

Chiral templates can be considered a subclass of chiral auxiliaries. Unlike auxiliaries that have the potential for recycle, the stereogenic center of a template is destroyed during its removal. Although this usually results in the formation of simple by-products that are simple to remove, the cost of the template s stereogenic center is transferred to the product molecule. Under certain circumstances, chiral templates can provide a cost-effective route to a chiral compound (Chapter 25). Usually, the development of a template is the first step in understanding a specific transformation and the knowledge gained is used to develop an auxiliary or catalyst system. 

Substitution reactions allow for the introduction or change of functional groups but rely on the prior formation of the stereogenic center. The approach can allow for the correction of stereochemistry. Reactions of epoxides, and analogous systems such as cyclic sulfates, allow for 1,2-functionality to be set up in a stereospecific manner. Reactions of this type have been key to the applications of asymmetric oxidations. The use of chiral ligands for allylic substitutions does allow for the introduction of a new stereogenic center. With efficient catalysts now identified, it is surely just a matter of time before this methodology is used at scale. 

In addition to carbon-carbon bond formation, transition metal catalysts can also generate a stereogenic center. The first reaction of this type in which useful amounts of asymmetric induction were observed was an asymmetric hydrogenation to make phenylalanine and the method has been used for many years to synthesize the anti-Parkinsons drug, L-Dopa (3) (Fig. 7) (142, 143). 

Both biological and chemical-based catalysts are useful for a wide variety of reactions that range from carbon-carbon bond formation to the generation of a new stereogenic center. With the increasing awareness of green chemistry and the need to reduce waste in the pharmaceutical industry where this problem has been particularly bad, the use of catalytic reactions will surely continue to increase. 

The development of simple systems that allow for the asymmetric oxidation of allyl alcohols and simple alkenes to epoxides or 1,2-diols has had a great impact on synthetic methodology as it allows for the introduction of functionality with concurrent formation of one or two stereogenic centers. This functionality can then be used for subsequent reactions tliat usually fall into the substitution reaction class. Because these transition metal catalysts do not require the use of low temperatures to ensure high degrees of induction, they can be considered robust. However, the sometimes low catalyst turnover numbers and the synthesis of the substrate can still be crucial economic factors. Aspects of asymmetric oxidations are discussed in Chapter 12. 

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