Aldol reaction double asymmetric induction

Double asymmetric induction (See section 1.5.3) can also be employed in aldol reactions. When chiral aldehyde 15 is treated with achiral boron-mediated enolate 14, a mixture of diastereomers is obtained in a ratio of 1.75 1. However, when the same aldehyde 15 is allowed to react with enolates derived from Evans auxiliary 8, a syn-aldol product 16 is obtained with very high stereo-... 

Now, we examine the interaction of chiral aldehyde (-)-96 with chiral enolate (S )-lOOb. This aldol reaction gives 104 and 105 in a ratio of 104 105 > 100 1. Changing the chirality of the enolate reverses the result Compound 104 and 105 are synthesized in a ratio of 1 30 (Scheme 3-38).66 The two reactions (—)-96 + (S )-lOOb and (—)-96 + (7 )-100b are referred to as the matched and mismatched pairs, respectively. Even in the mismatched pair, stereoselectivity is still acceptable for synthetic purposes. Not only is the stereochemical course of the aldol reaction fully under control, but also the power of double asymmetric induction is clearly illustrated. 

There is an important difference between Horeau s and Heathcock s examples in that the aldol reaction generates two chirality elements in the bond-forming step. In principle, analysis of such a reaction requires evaluation of two aspects, i.e., the effect of double asymmetric induction on simple and induced diastereoselectivity. The aldol reaction is not particularly suited for this... 

Masamune et al. have reviewed in detail the effects of double asymmetric induction not only for epoxidation, but also for the aldol, Diels-Alder, and catalytic hydrogenation reactions. The merits of this strategy are illustrated by an analysis of Woodward s synthesis" of erythromycin A (1), which has 10 chiral centers. 

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. 

The stereochemical outcome of an aldol reaction involving more than one chiral component is consistent with the rule of approximate multiplicativity of diastereofacial selectivities intrinsic to the chiral reactants. For a matched case, the diastereoselectivity approximates (substrate DS) X (reagent DS). For a mismatched case, the diastereoselectivity is (substrate DS) (reagent DS). Double asymmetric induction also can be used to enforce the inherent facial selectivity of a chiral aldehyde, as shown below. 

Masamune s synthesis of bryostatin 7 (114) [36] contains early examples of double asymmetric induction, where the aldol reaction of chiral ketones could be... 

In Masamune s initial synthesis of the C -Cn polyacetate region of the bryo-statins (Scheme 9-37), the chiral reagents (S)- and (R)-53 were used to control the stereocenters at C3, C7 and Cn [36], The first of these reactions used R)-53 to set the C3 center in 115 and then two subsequent double asymmetric induction aldol reactions, to give 116 and 117, set the remaining stereocenters. 

In order to understand the phenomenon of double asymmetric induction, we need to have a clear picture of the inherent selectivities of each of the chiral partners in closely related single asymmetric induction processes. Consider for example the kinetically controlled aldol addition reactions shown in Scheme 1.5... 

Scheme 1.5. Examples of single and double asymmetric induction in the aldol addition reaction, (a) Reaction of a chiral enolate and an achiral aldehyde (b) Reaction of an achiral enolate with a chiral aldehyde (c) Matched pair double asymmetric induction with a chiral enolate and a chiral aldehyde (d) Mismatched pair double asymmetric induction with a chiral enolate and the aldehyde enantiomeric to that shown in (a). (After ref. [58]).

The stereoselectivity of the aldol additions shown in Schemes 5.25 and 5.26 are obviously the result of a complex series of factors, among which are the Felkin-Anh preference dictated by the a-substituent on the aldehyde, the proximal stereocenters on the enolate, etc. Additionally, the more remote stereocenters, such as at the p-position of the aldehyde, may influence the selectivity of these types of reactions. Evans has begun an investigation into some of the more subtle effects on crossed aldol selectivity, such as protecting groups at a remote site on the enolate [131], and of P-substituents on the aldehyde component [132], and also of matched and mismatched stereocenters at the a and P positions of an aldehyde (double asymmetric induction) [133]. Further, the effect of chiral enolates adding to a,P-disubstituted aldehydes has been evaluated [134]. The latter turns out to be a case of triple asymmetric induction, with three possible outcomes fully matched, partially matched, and one fully mismatched trio. 

Masamune [91]. It is recognized as particularly relevant in the context of stereoselective aldol reactions. Masamune developed the chiral ketones (J )-and (S)-179, derived from each enantiomer of mandelic acid, to conduct dia-stereoselective aldol reactions with both achiral and chiral aldehydes (Scheme 4.19) [91-93]. Subsequent to aldol addition, desilylation and oxidative cleavage of the chiral controlling group provides a carboxylic acid. The synthesis of the macrolide aglycon 6-deoxyerythronolide B (187) showcases the use of these ketones and represents the first successful application of double asymmetric induction in the context of a complex target [91, 93, 94). 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

The boron-aldol reaction of the p-methoxyben-zyl(PMB)-protected methylketone 16 proceeds with excellent 1,5-anti-selectivity (Scheme 4). In cases where the asymmetric induction is lower it may be improved by a double stereodifferential aldol reaction with chiral boron ligands [7]. The reason for this high stereoselectivity is currently unknown. Ab initio calculations suggest the involvement of twisted boat structures rather than chair transition structures [6]. 

In accordance with this model one finds diastereoselectively anti products on reaction of aldehydes with ( )-allyl compounds, whereas allyl systems with the (Z)-configuration give mainly syn products and it is even possible to effect asymmetric induction. As the double bond of the product can be oxidatively cleaved to a CW3 group, the reaction can be regarded as a stereoselective aldol reaction, an aspect which explains the widespread interest in this type of reaction. With heterosubstituted allylic anions it is sometimes possible to effect predominantly y-attack with different electrophiles by the choice of the heteroatom.2 For instance it is well known that with sulfur substituents like —SR, —SOR or —SOjR the a-attack dominates, but doubly lithiated allenethiol possesses high y-reactivity and can be used as a homoenolate anion equivalent in reaction with electrophiles such as alkyl halides (Scheme 7). ... 

These aldols have all had just one chiral centre in the starting material. Should there be more than one, double diastereomeric induction produces matched and mismatched pairs of substrates and reagents, perfectly illustrated by the Evans aldol method applied to the syn and anti aldol products 205 themselves derived from asymmetric aldol reactions. The extra chiral centre, though carrying just a methyl group, has a big effect on the result. The absolute stereochemistry of the OPMB group is the same in both anti-205 and yvn-205 but the stereoselectivity achieved is very different. The matched case favours Felkin selectivity as well as transition state 201 but, with the mismatched pair, the two are at cross purposes. It is interesting than 1,2-control does not dominate in this case.33... 

Stork and coworkers [624e] have introduced enamines as a nucleophilic substitute of enols, and a few asymmetric aldol reactions have been performed with enamines. Scolastico and coworkers [1311] have reacted morpholine enamines with chiral oxazolidine 1.84 (EWG = Ts), and in some cases they obtained higher sdectivities than those obtained from enoxysilanes ( 6.9.3) (Figure 6.102). Chiral enamines derived from pyrrolidine 1.64 (R = MeOCI ) react with acyliminoesters of chiral alcohols at -100°C [1313], Double diastereodifferentiation is at work so that from matched reagents, for example the pyrrolidine enamine and iminoester 6.126 shown in Figure 6.102, P-keto-a-aminoesters are obtained with a high diastereo- and enantioselectivity. The esters of either enantiomer of menthol or of achiral alcohols give mediocre asymmetric induction. 

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