Aldol reaction chelation effects

Several reactions of carbonyl groups in an LPDE system have been examined. Mukaiyama aldol reactions are effectively promoted in an LPDE solution, and remarkable chelating effects of oxygen functional groups at the a-positions of aldehydes are observed (Scheme 4).16,17 Regarding... 

Cerium enolate complexes of type Cl2Ce(OCR=CHR) achieve higher yields in stoichiometric cross-aldol reactions of sterically crowded substrates than the corresponding lithium enolates (Scheme 26). The larger cerium is assumed to be more effective in the inital aldol chelate formation. Formation of oc-bromo-/ -hydroxyketones is also catalyzed [249]. 

The mechanism of the Mukaiyama aldol reaction largely depends on the reaction conditions, substrates, and Lewis acids. Linder the classical conditions, where TiCl4 is used in equimolar quantities, it was shown that the Lewis acid activates the aldehyde component by coordination followed by rapid carbon-carbon bond formation. Silyl transfer may occur in an intra- or intermolecular fashion. The stereochemical outcome of the reaction is generally explained by the open transition state model, and it is based on steric- and dipolar effects. " For Z-enol silanes, transition states A, D, and F are close in energy. When substituent R is small and R is large, transition state A is the most favored and it leads to the formation of the anf/-diastereomer. In contrast, when R is bulky and R is small, transition state D is favored giving the syn-diastereomer as the major product. When the aldehyde is capable of chelation, the reaction yields the syn product, presumably via transition state h. ... 

Aldol reaction. The chelation effect of Mglj is critical to the aldol reaction between an aldehyde and a silyl ketene acetal which establishes a stereocenter in an intermediate of lactacystin. ... 

The Eu-catalyst Eu(dppm)3 provides a remarkable level of chemoselectivity but is only effective for the Mukaiyama-aldol reaction of aldehydes with several ketene silyl acetals (KSA) (Table 2-3) [55]. When ketones and aldehydes are treated, respectively, with KSA and ketone-derived silyl enol ethers, no reaction results. The rate enhancement by chelation control (entry 4, Table 2-3) is intriguing. This is a feature common to other Lewis acids such as TiC [56] or LiC104 [57],... 

Under kinetic control the aldol reaction is very stereospecifie (Fig. 8.5). The lithium enolate is generated in an aprotic solvent, and then the carbonyl compound is added. The reaction proceeds via the metal-chelated minor path 6e. The minimization of steric effects in the chair transition state and the stereochemistry of the enolate (Section 9.3) determine the stereochemistry of the product. 

Eujimura, on the other hand, reported that chiral Pt complexes 69 prepared from the chelating acyl Pt(II) complexes 68 and TfOH in the presence of air and water are effective in the asymmetric aldol reaction of mefhyl isobutyrate TMS enolate with primary aliphatic aldehydes (Scheme 10.58) [158]. In this reaction, 2,6-lutidine is used as proton scavenger, to avoid fhe effects of residual acid, and a free aldol and its TMS efher are obtained wifh fhe same enantioselectivity. IR and... 

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 coupling of 96 with 77 was followed by the epoxidation to give 98. Aldol reaction of lithium enolate of ethyl acetate was conducted by the remote chelation effect with the C7-oxygen atom as well as by a steric bulkiness of the Cg-methyl group at the transition state. As a result of this unexpected bonus, the product 99 was stereochemically pure at the C3 position. The operation to... 

Transition metal catalyzed aldol reactions are attractive methods due to their high catalytic activity, privileged chelation effects of controlling stereoselectivity, and mild or neutral reaction conditions. Except group 5-7, most of transition metals have been shown as efficient catalyst in homogeneous aldol reactions with variants of substrates. Thus and correspondingly, the catalytic aldol reactions will be emphasized herein with representative transition metal based complexes in group 4 and 8-11. 

One can infer from this mechanism that a chelating effect (fig. 6) governs the key intermediate this is similar to the mechanism later applied to cerium(IIl)-assisted reductions, and is also closely related to the intermediate proposed as part of the first example of a cross-aldol reaction of cerium enolates (section 4.4). 

Trimethylsilyloxyfuran 338 has shown promise as a masked butenolide fragment To fuUy exploit these qualities, the threo versus erythro (339 vs 340) diastereoselectivity in aldol-type additions has to be controlled. In fact it has been shown that this is easily achieved by appropriate reaction conditions. Applying Mukaiyama conditions (i.e., using the silyl enol ether as the donor in the presence of a Lewis acid such as TESOTf to generate oxonium species) leads to threo preference for 339, presumably via an open transition state, whereas desilylation with TBAF generates the erythro-diastereomer 340, this time via a closed Diels-Alder (or Zimmerman-Traxler)-like transition state. In both cases, chelating effects can be ruled out... 

Although a majority of the catalytic complexes employed in the aldol reaction are bidentate, Carreira and coworkers published the synthesis of a new chiral tridentate chelating ligand for the efficient asymmetric induction of stereochemistry in aldol adducts. The Ti(IV) complex 68, an analog of the BINOL catalyst previously mentioned, was further stabilized by 3,5-di-tert-butylsalicyclic acid as a counterion to increase the yields, selectivity, and efficiency of the asymmetric reaction. This new catalyst is particularly effective in the addition of either O-trimethylsilyl, or O-ethyl, or O-methyl ketene to both aliphatic and aromatic aldehydes enantioselectively to obtain the respective aldol adduct. For example, the reaction of the silylketene acetal 90 with the aromatic aldehyde 89 in the presence of 68 obtains the aldol adduct 91 in high yield (91%) and excellent enantioselectivity (97% ee). 

In the discussion of the stereochemistry of aldol and Mukaiyama reactions, the most important factors in determining the syn or anti diastereoselectivity were identified as the nature of the TS (cyclic, open, or chelated) and the configuration (E or Z) of the enolate. If either the aldehyde or enolate is chiral, an additional factor enters the picture. The aldehyde or enolate then has two nonidentical faces and the stereochemical outcome will depend on facial selectivity. In principle, this applies to any stereocenter in the molecule, but the strongest and most studied effects are those of a- and (3-substituents. If the aldehyde is chiral, particularly when the stereogenic center is adjacent to the carbonyl group, the competition between the two diastereotopic faces of the carbonyl group determines the stereochemical outcome of the reaction. 

One of the most spectacular and useful template reactions is the Curtis reaction , in which a new chelate ring is formed as the result of an aldol condensation between a methylene ketone or inline and an imine salt. The initial example of this reaction was the formation of a macrocyclic nickel(II) complex from tris(l,2-diaminoethane)nickel(II) perchlorate and acetone (equation 53).182 The reaction has been developed by Curtis and numerous other workers and has been reviewed.183 In mechanistic terms there is some circumstantial evidence to suggest that the nucleophile is an uncoordinated aoetonyl carbanion which adds to a coordinated imine to yield a coordinated amino ketone (equation 54). If such a mechanism operates then the template effect is largely, if not wholly, thermodynamic in nature, as described for imine formation. Such a view is supported by the fact that the free macrocycle salts can be produced by acid catalysis alone. However, this fact does not... 

Wittig-Horner olefination. This reaction can be effected with LiCl (I equiv.) and either diisopropylethylamine or DBU (1 equiv.) in CH,CN at room temperature. This variation is particularly useful in reactions with aldehydes or phosphonates that can undergo epimerization or aldol-type reactions under standard conditions (NaH or K,CO,). Yields are usually >80%. The reaction also shows a high (E)-selectivity. Presumably a chelated lithium enolate of the phosphonate is the reactive species. 

The use of Al(III) complexes as catalysts in Lewis acid mediated reactions has been known for years. However, recent years have witnessed interesting developments in this area with the use of ingeiuously designed neutral tri-coordinate Al(lll) chelates. Representative examples involving such chelates as catalysts include (1) asymmetric acyl halide-aldehyde cyclocondensations, " (2) asymmetric Meerwein-Schmidt-Ponndorf-Verley reduction of prochiral ketones, (3) aldol transfer reactions and (4) asymmetric rearrangement of a-amino aldehydes to access optically active a-hydroxy ketones. It is important to point out that, in most cases, the use of a chelating ligand appears critical for effective catalytic activity and enantioselectivity. 

Stereoselective reduction of a-alkyl-3-keto acid derivatives represents an attractive alternative to stereoselective aldol condensation. Complementary methods for pr uction of either diastereoisomer of a-alkyl-3-hydroxy amides from the corresponding a-alkyl-3-keto amides (53) have been developed. Zinc borohydride in ether at -78 C gave the syn isomer (54) with excellent selectivity ( 7 3) in high yield via a chelated transition state. A Felkin transition state with the amide in the perpendicular position accounted for reduction with potassium triethylborohydride in ether at 0 C to give the stereochemi-cally pure anti diastereoisomer (55). The combination of these methods with asymmetric acylation provided an effective solution to the asymmetric aldol problem (Scheme 6). In contrast, the reduction of a-methyl-3-keto esters with zinc borohydride was highly syn selective when the ketone was aromatic or a,3-unsaturated, but less reliable in aliphatic cases. Hydrosilylation also provided complete dia-stereocontrol (Scheme 7). The fluoride-mediated reaction was anti selective ( 8 2) while reduction in trifluoroacetic acid favored production of the syn isomer (>98 2). No loss of optical purity was observed under these mild conditions. 

Since it had been determined that ketone or aldehyde functionality was not directly accessible from chiral A/-acyloxazolidinones, the transamination-metal alkyl addition procedure provided a conveniently expeditious alternative. The first step, transamination, proceeded in high yield by introduction of the N-acyloxazolidinone into a solution of the aluminum amide in dichloromethane at -IS C. The reaction is favored by the presence of a-heteroatom substituents and by -alcohol functionality (aldol adducts). Acceleration of the transamination in the latter case is most likely due to formation of a chelated intermediate (5) which serves to activate only the exocyclic carbonyl towards attack (equation 4). Because of the indicated activation, these aldol adducts are often the best substrates for this permutation. The effectiveness of the transamination in the case of (4) is noteworthy, as retroaldol fragmentation of this substrate usually occurs under mild base catalysis. 

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