Aldol and related reaction

SCHEME 116. Asymmetric aldol-type reaction between aldehydes and a-isocyanoac-etates. 

SCHEME 117. Asymmetric aldol-typc reaction between aldehydes and a-isocyano-phosphonates. 

SCHEME 119. Lewis acid-catalyzed asymmetric aldol-type reaction of end silyl ethers. 

Although phase-hansfer catalyhc enanhoselechve direct aldol reachons of glycine donor with aldehyde acceptors could provide an ideal method for the simultaneous construchon of the primary structure and stereochemical integrity of P-hydroxy- 

Entry Catalyst (X mol%) R Base Solvent T(X) Yield (%) ee (%) (config.) Reference 

Herrera and Bernard have developed a new catalyhc enantioselechve approach to the asymmetric nucleophilic addition of nitromethane to N-carbamoyl imines generated from a-amido sulfones (aza-Henry reachon) [64]. The chiral phase-hansfer catalyst 85a acts in a dual fashion, first promohng the formation of the imine under mild reachon condihons and then achvahng the nucleophile for asymmetric addihon. This new strategy for the catalyhc aza-Henry reaction was 

The directed aldol reaction is an important means of selective carbon-carbon bond formation. This reaction is efficiently achieved by the transformation of one carbonyl group to a silylated enol derivative, which subsequently couples with another carbonyl compound with the aid of a Lewis acid, typically TiCl4, as formulated in Eq. (2). This type of directed aldol reaction is called the Mukaiyama aldol reaction, a standard and practical synthetic protocol with broad application which has, accordingly, been reviewed extensively [38-42] in addition to the reviews cited in the introductory section. The fundamental reactions between enol silyl ethers and an aldehyde or a ketone 

Although both aldehydes and ketones also participate in the directed aldol reaction, the former are generally more reactive, as is exemplified in Eq. (6) [45]. Thus, the aldol reaction of an enol silyl ether with an aldehyde could be performed in the presence of a ketone. Equation (6) also demonstrates that the base (LDA)-mediated aldol reaction and the Mukaiyama-type reaction took place at the different position in a complementary manner to give the isomeric aldols. 

The directed aldol reaction in the presence of TiC found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anft-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47]. 

In addition to enol silyl ethers, other derivatives of aldehydes and ketones, i.e. enol ethers (Eq. 8) [48] and enol esters (Eq. 9) [49, 50], serve as a partners for the cross aldol reaction, although the lower reactivity of these compounds compared with enol silyl ethers often makes the reaetion more complicated. For example, the products isolated in Eq. (8) were ether derivatives or a,y8-unsaturated carbonyl compounds rather than the expected aldol itself. 

Acetals are a versatile alternative to aldehydes and ketones which have wide applicability in the titanium-mediated aldol reaction [51], Equation (10) shows the difference between an acetal and the parent aldehyde in the diastereoselective aldol reaction [52]. In this example the latter results in better diastereoselectivity than the former. The reactivity of an aldehyde and its acetal have been compared (Eq. 11) [53]. More examples of the directed aldol reaction starting from enol derivatives of aldehydes and ketones are summarized in Table 1. 

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This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

These enolates are important in organic synthesis in providing a source of nucleophilic enol for use in aldol and related reactions, and this is covered in Volume 9. 

In contrast to the "classical solution" we have just discussed, we will now consider the aldol condensation -one of the most important carbon-carbon bond formation reactions [3], in both the laboratory and Nature l - as an example of the "contemporary solution" to the problem of acyclic stereoselection. As a reversible reaction, the design of highly stereoselective aldol and related reactions demands that all the stereochemical aspects involved in the C-C bond formation are kinetically controlled. 

C—C Bond Formation and Fission Aldol and Related Reactions. 10... 

Aldol and Related Reactions involving Fluoroenolates and Equivalents... 

For an excellent discussion of diastereoselectivity in the aldol and related reactions see M. B. Smith, Organic Synthesis, McGraw-Hill, New York, 1994, Chapter 9, pp. 857-964. 

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