Enolates and Aldehydes

The application of asymmetric synthesis through reaction of chiral enolates with aldehydes is commanding a great deal of current interest, and aspects of this topic have been the subject of a number of recent 

Given the chiral moiety X., there are a limited number of positional permutations for the substitution of this ligand on the enolate system (eqs. [89]-[92]). When Xc is attached to the carbon framework 

As a corollary to the cases above, the aldehyde may also contain a proximal center of asymmetry. In these cases the resident chirality in both the enolate and the aldehyde can influence the generation of new asymmetry in either a mutually cooperative (consonant) or an antagonistic (dissonant) fashion. The consonant or dissonant diastere oface selection imparted to both condensation partners has been referred to as double stereodifferentiation (83,109). This issue becomes important in the lasalocid A aldol bond construction illustrated in eq. [93]. This pivotal aldol condensation has been examined in detail 

Aldol Diostereomer Ratios KishI (llOo) Ireland (llOd) 

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Additionally, various zirconium-assisted aldol condensations between different types of zirconium enolates and aldehydes have been reported.141-145... 

R3 R2 and R2 Ri gauche interactions however, for the same set of substituents, an increase in the steric requirements of either Rj or R3 will influence only one set of vicinal steric interactions (Rj R2 or R3 R2). Some support for these conclusions has been cited (eqs. [6] and [7]). These qualitative arguments may also be relevant to the observed populations of hydrogen- and nonhydrogen-bonded populations of the aldol adducts as well (see Table 1, entries K, L). Unfortunately, little detailed information exists on the solution geometries of these metal chelates. Furthermore, in many studies it is impossible to ascertain whether the aldol condensations between metal enolates and aldehydes were carried out under kinetic or thermodynamic conditions. Consequently, the importance of metal structure and enolate geometry in the definition of product stereochemistry remains ill defined. This is particularly true in the numerous studies reported on the Reformatsky reaction (20) and related variants (21). 

Table 9 Vinylogous aldol reactions using enolate and aldehyde activation ...

Tab. 3.2. Diastereoselectivity in the aldol reactions between ( )- or (Z)-/ -silyl ester enolates and aldehydes (Scheme 3.7).

Phenoxide anions have been proved to be good Lewis base catalysts to promote syn-selective aldol reaction between TMS enolates and aldehydes.31... 

In 1997, Yamamoto, Yanagisawa, and others reported the asymmetric reaction catalyzed by a BINAP-AgOTf catalyst (Table 9.7).16 The reaction was conducted with tributyltin enolate and aldehydes in the presence of the BINAP-AgOTf catalyst to afford the corresponding adduct with high enantioselectivity. The observed... 

Ester enolates and aldehydes normally undergo aldol additions, as illustrated in the example Side Note 13.5. 

Reaction conditions 5 imol [Rh(CO)2(acac)], P/Rh = 6, 30 bar CO/H2 (1 1), 100 °C for 1-decene and 1-hexadecane, 80 °C for styrene and n-butyl acrylate, hexane/toluene/perfluoromethylcyclohexane = 4/2/4 (mL), 15 h reaction time. The products were analysed by H NMR and the conversion and selectivity confirmed by GC. To aldehyde, olefin isomerisation accounts for the product balance. c Linear to branched aldehyde ratio, determined by HNMR. The branched product was a 1 1 mixture of enol and aldehyde, the linear aldehyde was < 1%. 

This computational study revealed the mechanism of the reaction between trialkyltin enolates and aldehydes or organic halides, both without and with coordinating ligands. High coordination of trialkyltin enolates causes an increase of their nucleophilicity and decrease of Lewis acidity of the tin center, which control the course of reaction . In the reaction of tin enolates with aldehydes, a noncoordinated tin enolate gives a cyclic TS in sled conformation whereas an acyclic TS leading to deactivation of the process is shown in the case of a highly coordinated enolate. Both theoretical and experimental results of... 

In recent years the synthetic potential and mechanistic aspects of asymmetric catalysis with chiral Lewis base have been investigated. Aldol addition reactions between trichlorosilyl enolates with aldehydes have been also intensively studied. Now, full investigations of the trichlorosilyl enolates derived from achiral and chiral methyl ketones, in both uncatalysed and catalysed reactions with chiral and achiral aldehyde acceptors have been reported. The aldol addition is dramatically accelerated by the addition of chiral phosphoramides, particularly (137) and proceed with good to high enantioselectivity with achiral enolates and aldehydes (Scheme 34). ... 

The orientation of the enolate and aldehyde in the transition state of the aldol reaction, open transition state vs. the ordered, chelate-controlled transition state... 

Abu-Hasanayn, F., Streitwieser, A. Kinetics and Isotope Effects of the Aldol-Tishchenko Reaction between Lithium Enolates and Aldehydes. J. Org. Chem. 1998, 63, 2954-2960. 

The ratio between enol and aldehyde isomers is about 1.4. The chain-transfer constant in eq 49 (Cc = 700) is an order of magnitude less than that of MMA. One may conclude that this value reflects steric obstruction of the methylene group by the OH group and that there is no significant enthalpy gain in the enol structure shown in eq 50 relative to a PMMA terminal double bond. 

Three-component coupling reaction of a-enones, silyl enolates, and aldehydes by successive Mukaiyama-Michael and aldol reactions is a powerful method for stereoselective construction of highly functionahzed molecules valuable as synthetic intermediates of natural compounds [231c]. Kobayashi et al. recently reported the synthesis of y-acyl-d-lactams from ketene silyl thioacetals, a,/l-urisalu-rated thioesters, and imines via successive SbCl5-Sn(OTf)2-catalyzed Mukaiyama-Michael and Sc(OTf)3-catalyzed Mannich-type reactions (Scheme 10.87) [241]. 

The relationship between enolate geometry and aldol stereochemistry has now been well established for many aldol reactions. The geometry of lithium enolates expresses itself through the so-called Zimmerman-Traxler5 transition state which is nothing more than the six-membered cyclic transition state that we met in the last chapter. When a lithium enolate reacts with an aldehyde, both the enolate and aldehyde oxygen atoms coordinate to the lithium atom 10 so that the transition state 11 is a partly unsaturated six-membered ring. 

A second distinct process disclosed by Denmark involves the Lewis base-catalyzed addition of enol trichlorosilanes 36 to aldehydes (Eq. 3) [30b]. Remarkably, despite the fact that the imcatalyzed addition of such enol silanes to aldehydes is rapid at -78 C, the use of optically active phosphoramides substantially accelerates the addition reaction and leads to the formation of optically active products. As a consequence of stereochemical studies involving substituted enol trichlorosilanes, Denmark has proposed a hexacoordinated silicon atom as the organizational locus about which enolate and aldehyde are arranged in a cyclic array 37. 

Aldehyde enolates and aldehydes are extremely reactive and therefore, to avoid undesirable side reactions, fast and quantitative conversion of aldehydes to enolates is necessary. Strong bases are needed, e.g. potassium amide in liquid ammonia or potassium hydride in THF. Aldehyde enolates are very rarely used in organic synthesis. 

The foregoing results clearly constitute an encouraging lead, and represent the best that has yet been done with chiral auxiliaries for lithium enolate aldol reactions. Although the chiral auxiliary is not covalently attached to either reactant, it is still used stoichiometrically. Furthermore, the process has only been demonstrated with the aldol reaction in equation (133). It will be interesting to see if the efficacy of this method will extend to other enolates and aldehydes. 

Table 14 Condensations of A/-(a-Bromoacetyl)oxazolidinone Enolates and Aldehydes ...

A.ii. Diastereoselection in the Aldol Condensation. In addition to the alkylation reaction, enolates react with other carbonyl compounds to give aldol or Claisen products, as discussed in previous sections. An aldol condensation with the enolate of 1-phenyl-1-propanone and benzaldehyde generates two new stereocenters and gives two racemic diastereomers (four stereoisomers). These two diastereomers are the racemic anti diastereomer (340 and 343) and the racemic syn diastereomer (341 and 342). Diastereoselectivity in this reaction is dependent on the reaction conditions and the enolate and aldehyde partners, and this section will explore the origins of that diastereoselection. 

In aldol condensations involving preformed lithium enolates and aldehydes, complete kinetic stereoselection is observed (as illustrated in Scheme 39). When is bulky (e.g. t-butyl or trimethylsilyl) the (Z)-enolate gives the erythro-aldol and the ( )-enolate gives the threo-aldol. When R is smaller, the stereoselectivity diminishes or disappears. In contrast, a tetra-alkylammonium enolate reacts with benzaldehyde with equally high but opposite kinetic stereoselectivity. 

Scheme 2. Transition state models for reactions between enolates and aldehydes with a stereogenic center at the a-position (valid as long as RL>Me).

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