Aldol additions double asymmetric induction

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. 

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). 

Asymmetric induction is reported in the addition of enolates of methyl ketones to aldehydes.55 Double stereo-differentiation—in which simultaneous 1,3-control can be obtained hi the aldehyde moiety—is shown to be achievable with proper selection of the aldol type. 

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