Nucleophilic prochiral carbonyl compound

A nucleophilic addition to a prochiral carbonyl compound R -CO-R gives a racemic mixture of alcohols. If the substituent R is chiral, the two faces of the carbonyl become... 

A number of reports involving the addition of chiral nucleophiles to prochiral carbonyl compounds have appeared in Ae literature. While many of these examples involve the use of stabili carbanions... 

Alcohols can be obtained from many other classes of compounds such as alkyl halides, amines, al-kenes, epoxides and carbonyl compounds. The addition of nucleophiles to carbonyl compounds is a versatile and convenient methc for the the preparation of alcohols. Regioselective oxirane ring opening of epoxides by nucleophiles is another important route for the synthesis of alcohols. However, stereospe-cific oxirane ring formation is prerequisite to the use of epoxides in organic synthesis. The chemistry of epoxides has been extensively studied in this decade and the development of the diastereoselective oxidations of alkenic alcohols makes epoxy alcohols with definite configurations readily available. Recently developed asymmetric epoxidation of prochiral allylic alcohols allows the enantioselective synthesis of 2,3-epoxy alcohols. 

Scheme 2.131 Enantioselective nucleophilic trifluoromethylation of prochiral carbonyl compounds with chiral fluoride sources [78].

Scheme 2.2.13 Nucleophilic addition to a prochiral carbonyl compound to form a new asymmetric C-atom with two enantiomers.

In a series of reports between 1991 and 1997 Yamaguchi showed that rubidium salts of L-proline (9) catalysed the conjugate addition of both nitroalkanes [29, 30] andmalonates [31-33] to prochiral a,p-unsaturated carbonyl compounds in up to 88% ee (Scheme 1). Rationalisation of the selectivities observed involved initial formation of an iminium ion between the secondary amine of the catalyst and the a,p-unsaturated carbonyl substrate. Subsequent deprotonation of the nucleophile by the carboxylate and selective delivery using ion pair... 

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. 

In general, reactions involving prochiral nucleophiles are rare however, examples using activated dicarbonyl compounds and carbonyl compounds that can form only a single enolate under the base-mediated reaction conditions have recently been reported. 

Synthesis of a chiral compormd from an achiral compound requires a prochiral substrate that is selectively transformed into one of the possible stereoisomers. Important prochiral substrates are, for example, alkenes with two different substituents at one of the two C-atoms forming the double bond. Electrophilic addition of a substitutent different from the three existing ones (the two different ones above and the double bond) creates a fourth different substituent and, thus, an asymmetric carbon atom. Another class of important prochiral substrates is carbonyl compounds, which form asymmetric compounds in nucleophilic addition reactions. As exemplified in Scheme 2.2.13, prochiral compounds are characterized by a plane of symmetry that divides the molecule into two enantiotopic halves that behave like mirror images. The side from which the fourth substituent is introduced determines which enantiomer is formed. In cases where the prochiral molecule already contains a center of chirality, the plane of symmetry in the prochiral molecules creates two diastereotopic halves. By introducing the additional substituent diasterom-ers are formed. 

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