Crossed aldol reactions synthetically useful

Conclusion When two different aldehydes have a hydrogens, a crossed aldol reaction is not synthetically useful. 

The use of lanthanide metal enolates in the aldol reaction has, to date, only been developed to a synthetically useful level in the case of cerium (Scheme S and Table 7). Stereoselectivities are no better than those of lithium enolates, but the cerium enolates of ketones woik well in crossed aldol additions to ketones (Table 7, entries 1-7) and sterically hindered aldehydes (Table 7, entries 9 and 10). Such crossed aldol reactions do not often work well with lithium enolates as enolate equilibration, retroaldolization and steric retardation of addition occur. Imamoto et al. have shown that cerium enolates (44), formed from anhydrous CeCb (1.2 equiv.) and the preformed lithium enolates of ketones in THF at -78 C, undergo such aldol reactions to give the corresponding p-hydroxy ketones (46), usually in high yield. The cerium suppresses the retroaldol reaction by efficient chelation of the aldolate (45). A similar effect is known for zinc halide mediated aldol reactions (Volume 2, (Chapter 1.8). The stereoselectivity of the... 

Crossed-aldol reaction (Section 19.5) An aldol reaction involving two different aldehyde or ketone reactants. If both aldol reactants have a hydrogens, four products can result. Crossed aldol reactions are synthetically useful when one reactant has no a hydrogens, such that it can serve only as an electrophile that is subject to attack by the enolate from the other reactant. 

The aldol reaction has long been recognized as one of the most useful synthetic tools. Under classical aldol reaction conditions, in vhich basic media are usually employed, dimers, polymers, self-condensation products, or a,j5-unsaturated carbonyl compounds are invariably formed as byproducts. The lithium enolate-mediated aldol reaction is regarded as one useful synthetic means of solving these problems. Besides the vell-studied aldol reaction based on lithium enolates, very versatile regio- and stereoselective carbon-carbon bond forming aldol-type reactions have been established in our laboratory by use of boron enolates (1971), silicon enolates-Le vis acids (1973), and tin(II) enolates (1982). Here we describe the first t vo topics, boron and silicon enolate-mediated crossed aldol reactions, in sequence. 

Most enzymes used by Nature for carbon-carbon bond formation and cleavage ( lyases ) catalyze a crossed aldol reaction in the form of a reversible, stereocontrolled addition of a nucleophilic ketone donor to an electrophilic aldehyde acceptor. Synthetically the most useful and most extensively studied enzymes use aldol donors comprising 2-carbon or 3-carbon fragments and can be grouped into fom categories depending on the structure of their nucleophilic component (Figme 5.2) (i) pyruvate-... 

Enolates and their Equivalents. The generation of regiospecific enolates is another problem of considerable synthetic importance. Use of lithium bis(2-propyl)amide as base at low temperature is recommended "- for formation of trilithio derivatives of 2,4,6-triketones and for synthesis with little loss of optical activity of the enolate of (14). The highly hindered base (15) is even better for carrying out in situ crossed aldol reactions between methyl ketones and aldehydes. 

Transition metal-catalyzed transformations are of major importance in synthetic organic chemistry [1], This reflects also the increasing number of domino processes starting with such a reaction. In particular, Pd-catalyzed domino transformations have seen an astounding development over the past years with the Heck reaction [2] - the Pd-catalyzed transformation of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - being used most often. This has been combined with another Heck reaction or a cross-coupling reaction [3] such as Suzuki, Stille, and Sonogashira reactions. Moreover, several examples have been published with a Tsuji-Trost reaction [lb, 4], a carbonylation, a pericyclic or an aldol reaction as the second step. 

Carreira and co-workers have also extended the scope of aldehydes that may be utilized in catalytic addition reactions to include stannylpropenal 108 as a substrate (Table 8B2.12, Entry 7). The adduct produced from the aldol addition of 105 is isolated with 92% ee and serves as a useful building block, as it is amenable for further synthetic elaboration (Scheme 8B2.9). Thus, vinylstannane 109 is a substrate for Stille cross-coupling reactions to give a diverse family of protected acetoacetate adducts 110. Following deprotection of the masked keto ester, the corresponding hydroxy keto ester 111 may be converted to either the syn or anti skipped polyols 112 or 113. A recent total synthesis of macrolactin A by Carreira and co-workers utilizes aldol... 

The aldol reaction is synthetically useful because it forms new carbon-carbon bonds, generating products with two functional groups. Moreover, the P-hydroxy carbonyl compounds formed in aldol reactions are readily transformed into a variety of other compounds. Figure 24.3 illustrates how the crossed aldol product obtained from cyclohexanone and formaldehyde (CH2=0) can be converted to other compounds by reactions learned in earlier chapters. 

In the study of catalytic, dienolate addition reactions, the use of stannyl prope-nal 50 as a substrate in aldol methodology has been introduced (Scheme 8-4). The adduct 51 produced from the process is isolated in 92% ee and, importantly, serves as a useful building block for subsequent synthetic elaboration. It is amenable for further manipulations such as Stille cross-coupling reactions to give a diverse family of protected acetoacetate adducts 52. 

The preceding reaction is called a mixed aldol addition or a crossed aldol addition. The four products have similar physical properties, making them difficult to separate. Consequently, a mixed aldol addition that forms four products is not a synthetically useful reaction. 

Group 4 Titanium and Zirconium. The titanium tetrachloride mediated aldol reaction of silyl enol ethers with aldehydes was first reported in early of 1970s (16,17). It proceeds in a highly regioselective manner for cross or direct aldol reactions in high yields (18-20). Since the pioneer contribution by Mukaiyama s group, numerous synthetically useful procedures were developed in titanium- and zirconium-catalyzed aldol reaction of broad substrates (21-23). 

If two different carbonyl compounds are used in an aldol addition— known as a crossed aldol addition—four products can be formed because reaction with hydroxide ion can form two different enolate ions (A and B ) and each enolate ion can react with either of the two carbonyl compounds (A or B). A reaction that forms four products clearly is not a synthetically useful reaction. 

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