Carbonyl compounds acyclic, diastereoselective reactions

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

Any explanation of facial selectivity must account for the diastereoselection observed in reactions of acyclic aldehydes and ketones and high stereochemical preference for axial attack in the reduction of sterically unhindered cyclohexanones along with observed substituent effects. A consideration of each will follow. Many theories have been proposed [8, 9] to account for experimental observations, but only a few have survived detailed scrutiny. In recent years the application of computational methods has increased our understanding of selectivity and can often allow reasonable predictions to be made even in complex systems. Experimental studies of anionic nucleophilic addition to carbonyl groups in the gas phase [10], however, show that this proceeds without an activation barrier. In fact Dewar [11] suggested that all reactions of anions with neutral species will proceed without activation in the gas phase. The transition states for reactions such as hydride addition to carbonyl compounds cannot therefore be modelled by gas phase procedures. In solution, desolvation of the anion is considered to account for the experimentally observed barrier to reaction. 

The Mukaiyama version of the aldol reaction is well known a carbonyl-titanium tetrachloride complex reacts with a trimethylsilyl enol ether. Under these conditions there is no titanium enolate involved. Another procedure has been reported a trimethylsilyl enol ether reacts with titanium tetrachloride to give the titanium enolate addition of the carbonyl compound generates the aldol product (although with slightly lower diastereoselectivity than with Mukaiyama s procedure). (Z)-Enolsilanes from acyclic ketones react rapidly and stereospecifically with TiCU to form (Z)-configured CbTi enolates, while the ( )-isomers react slowly to afford low yields of mixtures of ( )- and (Z)-Cl3Ti enolates (Scheme 41). 

Miscellaneous Reactions. In addition to the key reactions above, DDQ has been used for the oxidative removal of chromium, iron, and manganese from their complexes with arenes and for the oxidative formation of imidazoles and thiadia-zoles from acyclic precursors. Catal)ftic amounts of DDQ also offer a mild method for the oxidative regeneration of carbonyl compounds from acetals, which contrasts with their formation from diazo compounds on treatment with DDQ and methanol in nonpolar solvents. DDQ also provides effective catalysis for the tetrahydropyranylation of alcohols. Furthermore, the oxidation of chiral esters or amides of arylacetic acid by DDQ in acetic acid provides a mild procedure for the synthesis of chiral a-acetoxy derivatives, although the diastereoselectivity achieved so far is only 65-67%. ... 

In 1973, Mukaiyama and his co-workers reported the use of silyl enol ethers as ketone enolate equivalents. Silyl enol ethers react with aldehydes in the presence of a stoichiometric amount of TiCU as a Lewis acid (Scheme 3-78). The Lewis acid is considered to electrophilically activate aldehydes. Since this landmark discovery, many efforts have been made to improve the original protocol, especially focusing on the use of a catalytic amount of Lewis acid catalysts.A wide variety of metal complexes and nonmetallic cationic compounds is now applicable to this reaction as a catalyst. Not only aldehydes but also acetals, ketones, and imines have been extensively employed as electrophiles for the aldol reactions. The reaction generally proceeds via an acyclic transition state, in which the electron-rich double bond of enol silyl ethers approach carbonyls activated by a Lewis acid (Scheme 3-79). In most cases, acyclic transition state with an antiperiplanar orientation of reactants well accounts for observed diastereoselectivities. ... 

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