Stereogenic center formation aldol reactions

In a chiral aldehyde or a chiral ketone, the carbonyl faces are diastereotopic. Thus, the addition of an enolate leads to the formation of at least one stereogenic center. An effective transfer of chirality from the stereogenic center to the diastereoface is highly desirable. In most cases of diastereoface selection of this type, the chiral aldehyde or ketone was used in the racemic form, especially in early investigations. However, from the point of view of an HPC synthesis, it is indispensable to use enantiomerically pure carbonyl compounds. Therefore, this section emphasizes those aldol reactions which are performed with enantiomerically pure aldehydes. 

Note also the stereochemistry. In some cases, two new stereogenic centers are formed. The hydroxyl group and any C(2) substituent on the enolate can be in a syn or anti relationship. For many aldol addition reactions, the stereochemical outcome of the reaction can be predicted and analyzed on the basis of the detailed mechanism of the reaction. Entry 1 is a mixed ketone-aldehyde aldol addition carried out by kinetic formation of the less-substituted ketone enolate. Entries 2 to 4 are similar reactions but with more highly substituted reactants. Entries 5 and 6 involve boron enolates, which are discussed in Section 2.1.2.2. Entry 7 shows the formation of a boron enolate of an amide reactions of this type are considered in Section 2.1.3. Entries 8 to 10 show titanium, tin, and zirconium enolates and are discussed in Section 2.1.2.3. 

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. 

An interesting pericyclic-anionic-pericyclic domino reaction showing a high stereoselectivity is the cycloaddition-aldol-retro-ene process depicted in scheme 20.1581 The procedure presumably starts with a [4+2]-cycloaddition of diene 98 and S02 in presence of a Lewis acid. After opening of the formed adduct reaction with (Z)-silyl vinyl ether 99 leads to a mixture of alk-2-enesulfinic acids 101. It follows a retro-ene reaction which affords a 7 3 mixture of the products 102 and 103. The reaction described by Vogel et al is a nice example for the efficient generation of polypropionate chains with the stereoselective formation of three stereogenic centers and one (0-double bond in a three-component domino reaction in its strict definition. 

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]. 

Intermolecular Aldol Reaction With Formation of One Stereogenic Center... 

Intermolecular Aldol Reaction with Formation of Two Stereogenic Centers... 

The basic principles of the mechanism of this Lewis-base-catalyzed aldol reaction have already been described in Section 6.2.1.1. With regard to the course of the enantio- and diastereoselective formation of aldol adducts with two stereogenic centers, it is proposed that synthesis of anti-products proceeds via a chair-like transition structure. A distinctive feature of the cationic transition state complex is a hexacoordinated silicon atom bearing two chiral phosphoramide molecules as ligands (Scheme 6.30). 

An alternative concept is asymmetric desymmetrization of a prochiral molecule of type 83. The starting materials 83 have three keto groups and one carbon atom bearing at least three substituents. A prerequisite is the presence of a prochiral carbon atom with two identical substituents bearing a keto functionality (Scheme 6.39, Eq. (2)). This type of asymmetric intramolecular aldol reaction proceeds with formation of cyclic ketols of type 84 with two stereogenic centers. Dehydration can subsequently be performed, leading to optically active enones of type 85. The two types of intramolecular aldol reaction are shown conceptually in Scheme 6.39. 

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. 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

Methods that involve C—C bond formation with the establishment of two new stereogenic centers are of considerable interest in this context. The aldol reaction has proven very useful in this regard, particularly in view of die development of powerful chiral enolates capable of controlling the stereochemical course of reactions with chiral aldehydes via the principle of double asymmetric synthesis. ... 

---