Aldol-type reaction stereocontrolled

The activation of the carbonyl group by Lewis acids was another leap made in the 1960s as typified by Mukaiyama-aldol reaction. In sharp contrast to the conventional carbonyl addition reactions that had been run under basic conditions, this new method allowed the addition of various nucleophiles under acidic conditions with high chemo- and stereocontrol and, consequently, the scope of the carbonyl addition reaction was extensively expanded. The Lewis acid-promoted ally-lation with allylmetals and ene reaction also received as much attention as the aldol-type reaction. It should be further pointed out that the catalytic versions of asymmetric reactions, which represent one of the most exciting topics in recent synthetic chemistry, owe their development strongly to the Lewis acid activation protocol. The design of a variety of chiral ligands for metals has produced luxuriant fruits in this field. 

Thus, boron enolates prepared under mild conditions enable aldol-type reactions essentially under neutral conditions. Stereocontrolled synthesis of acyclic molecules has been achieved by employing boron enolate-mediated aldol reactions this method has been extensively applied to the synthesis of natural products. 

Some of the most impressive advances in the area of catalytic, enantioselective aldol addition reactions have taken place in the development of catalytic methods for enantioselective acetate aldol additions, a reaction type that has long been recalcitrant. Thus, although prior to 1992 a number of chiral-auxiliary based and catalytic methods were available for diastereo- and enantiocontrol in propionate aldol addition reactions, there was a paucity of analogous methods for effective stereocontrol in the addition of the simpler acetate-derived enol silanes. However, recent developments in this area have led to the availability of several useful catalytic processes. Thus, in contrast to the state of the art in 1992, it is possible to prepare acetate-derived aldol fragments utilizing asymmetric catalysis with a variety of transition-metal based complexes of Ti(IV), Cu(II), Sn(II), and Ag(I). 

Intermolecular aldol-type 1,2-addition reactions are an important means by which stereocontrolled chain elaboration can be performed. Such reactions are widely used in synthesis of complex molecules and some leading examples are herein provided. 

In 2008, Zhang et al. succeeded in a three-component cascade reaction using achiral Ru and chiral Zr catalysis [14]. Under the influence of achiral Rh(OAc)j, oxonium ylide was generated from diazo compound 37 and alcohol 38. Consequently, this reactive intermediate was trapped by aldehyde 39 through a Lewis acid-promoted enantioselective aldol-type addition, yielding the chiral building blocks 40 with high levels of stereocontrol (Scheme 9.11). It should be noted that the presence of acidic Zr catalyst can also suppress the undesired irreversible intramolecular proton transfer of the oxonium ylide to benefit reaction pathway control. 

The enamine geometry 32 is cmcial for the stereocontrol in organocatalytic aldehyde-aldehyde couplings amines of type 31 are convenient catalysts for enantioselective enamine-aldol reactions. Examples are shown in Scheme 24 [126,131,132,133,134,135]. 

Indeed, the forwards reaction uses a boron triflate and a bulky base of the type we have seen in order to make the cis boron enolate and achieve exactly this control. There are, of course, two. wn-aldol products possible here, 58 and 60, by virtue of the chiral centres present in the aldehyde fragment, and both do indeed form (in a 16 84 ratio). Trying to achieve selective formation of one of these syn diastereomers rather than the other syn diastereomer is beyond the scope of this chapter, even though that too is relative stereocontrol. It is complicated because it involves enantio-merically pure reagents in combination with the enantiomerically pure aldehyde and a match/mis-match issue. These issues are explored more fully in Chapter 30. Examples include combinations of chiral or achiral aldehydes with both achiral and chiral boron reagents. 

One of the most classical reactions for the formation of C-C bonds is the aldolic condensation. In nature, such stereocontrolled reactions are catalyzed by enzymes of the class of lyases (EC 4). The majority of these enzymes can be found in the biosynthesis of carbohydrates, and are used for the synthesis of natural and unnatural carbohydrates. Aldolases (and transketolases) have been intensively investigated and their scope of applications has been evaluated and reviewed by the groups of Whitesides and Wong [16, 21,142-145] (see also Chapter B4 in [22]). Aldolases can be divided into three main types ... 

Enantiomerically pure oxazolines and oxazolidinones have found widespread application in organic synthesis as chiral auxiliaries. They have been mainly used for the synthesis of enantiomerically pure amino acids but also as chiral auxiliaries to produce non-racemic enolates as pioneered by Evans.The reaction types proceeding with high stereocontrol include enolate alkylation, enolate oxidation, enolate halogenation, enolate amination, enolate acylation, aldol reaction and Diels-Alder reactions. 

Recently, Dong and Sun disclosed an unprecedented intermolecular asymmetric a-aldol reaction of vinylogous NHC-enolates, a type of versatile but less explored species relative to simple NHC-enolates. In contrast to the known C—C bond formation at the y-position of vinylogous NHC-enolates, this reaction exhibits complete a-selectivity. Unlike most cycloaddition reactions of NHC-enolates with external carbonyl electrophiles, this reaction does not involve a cycloaddition step. Notably, two challengingstereocenters, one quaternary and the other labile tertiary (both allylic and a-carbonyl), are also established in an acyclic product with excellent stereocontrol. A range of highly enantioenriched p,y-unsaturated P -fluoroalkylated esters have been synthesized with high efficiency under mild conditions. These products can be easily transformed into other useful molecules, such as densely functionalized tetrahydrofurans (Scheme 7.90). 

Kobayashi et al. reported that a chiral barium complex prepared from a 3,3 -disilyl-substituted BINOF derivative was promising in asymmetric reactions [23]. By using the barium catalyst, direct-type aldol reactions of imides were investigated. Basically, a stereocontrolled direct-type aldol reaction between an... 

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