Aldol addition reactions crossed

The aldol addition reaction is one of the most versatile carbon-carbon bond forming processes available to synthetic chemists. The addition reaction involves readily accessed starting materials and can provide )9-hydroxy carbonyl adducts possessing up to two new stereocenters. The previous decade witnessed many substantive advances in the crossed aldol addition reaction as a result of the development of a variety of well-defined enolization protocols and the evolution of highly sophisticated understanding of the reaction mechanism. Moreover, the design of highly effective chiral auxiliary-based systems has allowed for impressive levels of stereocontrol in a number of asymmetric aldol processes. 

A crossed Claisen condensation is a condensation reaction between two different esters. Like a crossed aldol addition, a crossed Claisen condensation is a useful reaction only if it is carried out under conditions that foster the formation of primarily one product. Otherwise, the reaction will form a mixture of products that are difficult to separate. 

Hydroxymethylation is achieved by crossed aldol addition reaction (Section 18-6) of the malonic ester enolate with formaldehyde. 

Recent developments in this area have considerably expanded the scope of the process to include a wide range of ketone and aldehyde components [98-100). Direct proline-catalyzed cross-coupling aldol reactions from ketones (Equation 16) [98] and aldehydes (Equation 17) [101] have been reported. Moreover, domino processes are possible thus, the proline-catalyzed aldol addition reaction of acetaldehyde proceeds through a double aldol addition and elimination to give useful building blocks for asymmetric synthesis (Equation 18) [100], As with any catalytic process, these processes are in essence multivariable problems, consisting of multiple steps and reactive intermediates, the reactivities and stabilities of which are finely balanced. 

Pentaerythritol is produced by reaction of formaldehyde [50-00-0] and acetaldehyde [75-07-0] in the presence of a basic catalyst, generally an alkah or alkaline-earth hydroxide. Reaction proceeds by aldol addition to the carbon adjacent to the hydroxyl on the acetaldehyde. The pentaerythrose [3818-32-4] so produced is converted to pentaerythritol by a crossed Cannizzaro reaction using formaldehyde. All reaction steps are reversible except the last, which allows completion of the reaction and high yield industrial production. 

Butyraldehyde undergoes stereoselective crossed aldol addition with diethyl ketone [96-22-0] ia the presence of a staimous triflate catalyst (14) to give a predominantiy erythro product (3). Other stereoselective crossed aldol reactions of //-butyraldehyde have been reported (15). 

Fig. 13). The cross-linked scandium-modified dendrimer was tested in a number of Lewis acid-catalyzed reactions, including Mukaiyama aldol additions to aldehydes and aldimines, Diels-Alder reactions, and Friedel-Crafts acylations. The dendritic catalyst was recovered by a simple filtration. The Mukaiyama aldol... 

In the Mukaiyama aldol additions of trimethyl-(l-phenyl-propenyloxy)-silane to give benzaldehyde and cinnamaldehyde catalyzed by 7 mol% supported scandium catalyst, a 1 1 mixture of diastereomers was obtained. Again, the dendritic catalyst could be recycled easily without any loss in performance. The scandium cross-linked dendritic material appeared to be an efficient catalyst for the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene. The Diels-Alder adduct was formed in dichloromethane at 0°C in 79% yield with an endo/exo ratio of 85 15. The material was also used as a Friedel-Crafts acylation catalyst (contain-ing7mol% scandium) for the formation of / -methoxyacetophenone (in a 73% yield) from anisole, acetic acid anhydride, and lithium perchlorate at 50°C in nitromethane. 

The aldol addition of formaldehyde in the presence of sodium hydroxide for the introduction of a hydroxymethyl branch was first applied to l,2 3,4-di-0-isopropylidene-aWefiydo-L-arabinose, and the product (143), formed by a crossed-Cannizzaro reaction, was converted into 1 by... 

Catalyzed aldol additions do not generally proceed with high diastereoselectivity at ambient temperature. Improved stereoselectivity can be achieved by using preformed, diastereomerically pure enolates at low temperatures (Entry 5, Table 7.2). This strategy enables the solid-phase preparation of stereochemically defined polyketides. On cross-linked polystyrene, the observed diastereoselectivity in the addition of boron enolates to aldehydes is the same as that in the homogeneous phase reaction [14,18]. 

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... 

Only one of the aldol condensations of Table 13.7 (top, center) concerns the reaction of a carbonyl compound with itself. In all other reactions of Table 13.7, the ,/i-unsaturated carbonyl compounds are formed by two different carbonyl compounds. Such aldol condensations are referred to as crossed aldol condensations (cf. the discussion of crossed aldol additions in Section 13.3.1). 

Other examples The addition reaction of lithium enolates of ketones to 1,2-epoxides to afford the a-alkyl-y-hydroxyketones. (a) P. Crotti, V. D. Bussolo, L. Favero, M. Pineschi, M. Pasero, J. Org. Chem. 1996, 61, 9548-9552. The cross-aldol reactions between ketones and aldehydes, (b) S. Fuku-zawa, T. Tsuchimoto, T. Kanai, Bull. Chem. Soc. Jpn. 1994, 67, 2227-2232. 

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. 

Additionally, organocatalytic cross-aldol reactions catalyzed by cyclic secondary amines in aqueous media provide a direct route to a variety of aldols, including carbohydrate derivatives, and may warrant consideration as a prebiotic route to sugars [12a],... 

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... 

The stereoselectivity of the aldol additions shown in Schemes 5.25 and 5.26 are obviously the result of a complex series of factors, among which are the Felkin-Anh preference dictated by the a-substituent on the aldehyde, the proximal stereocenters on the enolate, etc. Additionally, the more remote stereocenters, such as at the p-position of the aldehyde, may influence the selectivity of these types of reactions. Evans has begun an investigation into some of the more subtle effects on crossed aldol selectivity, such as protecting groups at a remote site on the enolate [131], and of P-substituents on the aldehyde component [132], and also of matched and mismatched stereocenters at the a and P positions of an aldehyde (double asymmetric induction) [133]. Further, the effect of chiral enolates adding to a,P-disubstituted aldehydes has been evaluated [134]. The latter turns out to be a case of triple asymmetric induction, with three possible outcomes fully matched, partially matched, and one fully mismatched trio. 

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. 

Claisen condensation (p. 810) condensation reaction (p. 807) crossed aldol addition (p. 809)... 

We shall therefore consider crossed aldol condensations by two general approaches that allow control over the distribution of products. The first approach hinges on structural factors of the carbonyl reactants and the role that favorable or unfavorable aldol addition equilibria play in determining the product distribution. In this approach relatively weak bases such as hydroxide or an alkoxide are used in a protic solvent such as water or an alcohol. The second approach, called a directed aldol reaction, involves use of a strong base such as LDA in an aptotic solvent. With a strong base, one reactant can be converted essentially completely to its enolate, which can then be allowed to react with the other carbonyl reactant. 

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