Aldol-type reactions intermolecular

Intermolecular Aldol-type Reactions with Sml2... 

The tin(IV) enolate can be quenched with a variety of electrophiles to form new carbon-carbon bonds, including carbonyl addition (aldol-type) reactions, alkylations and conjugate additions of tin(IV) enolates. Tin(IV) enolates react readily with aldehydes in both intra- and intermolecular aldol-type reactions [5J]. The best conditions for the intermolecular aldol condensation reaction were to initially generate the tin enolate by reacting the desired enone with tributyltin hydride and then... 

Intermolecular aldol-type 1,2-addition reactions are an important means by which stereocontrolled chain elaboration can be performed. Such reactions are widely used in synthesis of complex molecules and some leading examples are herein provided. 

Intermolecular Michael addition [4.1] Intermolecular aldol reaction [6.2.1] Intramolecular aldol reaction [6.2.2] Aldol-related reactions (e.g. vinylogous Mukaiyama-type aldol) [6.2.3]... 

In contrast to the mechanism discussed in the previous section, catalytic, enantioselective aldol addition processes have been described which proceed through an intermediate aldolate that undergoes subsequent intermolecular silylation. Denmark has discussed this possibility in a study of the triarylmethyl-cation-catalyzed Mukaiyama aldol reaction (Scheme 10) [73]. The results of exploratory experiments suggested that it would be possible to develop a competent catalytic, enantioselective Lewis-acid mediated process even when strongly Lewis acidic silyl species are generated transiently in the reaction mixture. A system of this type is viable only if the rate of silylation of the metal aldolate is faster than the rate of the competing silyl-catalyzed aldol addition reaction (ksj>> ksi-aidoi Scheme 10). A report by Chen on the enantioselective aldol addition reaction catalyzed by optically active triaryl cations provides support for the mechanistic conclusions of the Denmark study [74]. 

The observed excellent stereoselectivities (dr=91 9 to >95 5, 94 to >99% ee) could be ascribed to the steric hindrance created by the employed catalyst in each step of the catalytic cycle reported below (Scheme 2.56). Once the chiral amine (S)-70 activates the acrolein 131 as electrophile by generating the vinylogous iminium ion A, the indole 171 performs an intermolecular Friedel-Crafts-type reaction. The resulting enamine B acts as nucleophile in the Michael addition of the nitroalkene 140 leading to the iminium ion D, which upon hydrolysis liberates the catalyst and yields the intermediate aldehyde 173. The latter compound enters in the second cycle by reacting with the iminium ion A, previously formed by the free catalyst. The subsequent intramolecular enamine-mediated aldol reaction of E completes the ring closure generating the intermediate F, which after dehydration and hydrolysis is transformed in the desired indole 172. 

With this new methodology in hands, Hu et al. [166] explored the trapping of the 1,4-addition intermediate with a different electrophile for the development of a new MCR. RhjCOAc) was again the most active catalyst in the 1,4-addition/aldol-type intramolecular cascade reaction. Under the optimized reaction conditions, this three-component reaction worked well with a broad family of bifunctional substrates 135 bearing different substituents on the aryl group next to the enone moiety and a variety of alcohols 136 (Scheme 3.63). In all cases, 1-indanols 137 were obtained in 60-83% yield and with complete diastereoselectivity. Enantiopure 1-indanol was obtained employing a L-menthol-derived diazo compound. The intermolecular four-component version was also attempted, but the formation of the desired product was not observed. 

Aldol-type condensations are useful for making the c connection in 3-pyrroHn-2-ones, hence it makes sense to combine an aldol reaction with an amidation to form a straightforward intermolecular-type ac approach to 3-pyrrolin-2-ones. It turns out that not many aldol-lactamiza-tion approaches have been reported for making (non-tetramic acid) 3-pyr-rohn-2-ones. One example, reported by Yao and coworkers, involves the synthesis of lactam-terminated polyketides (Scheme 63 2007BMCL3426). 1,3,5-Trisubstituted 3-pyrrolin-2-ones 257 were prepared by treating esters... 

Aldol reactions using phosphoramides as organocatalysts The organic base-catalyzed asymmetric intermolecular aldol reaction with ketone-derived donors can be successfully applied to the construction of aldol products with two stereogenic centers [82-86]. Trichlorosilyl enolates of type 51 have been used as nucleophiles. Such enolates are strongly activated ketone derivatives and react spontaneously with several aldehydes at —80 °C. A first important result was that in the aldol reaction of 51 catalytic amounts of HMPA led to acceleration of the rate of reaction. After screening several optically active phosphoramides as catalysts in a model reaction the aldol product anti-53 was obtained with a diastereomeric... 

Computational studies suggest that the mechanism of the proline catalyzed aldol cyclization is best described by the nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide. A metal-free partial Zimmerman-Traxler-type transition state involving a chair-like arrangement of enamine and carbonyl atoms and the participation of only one proline molecule has been established [118,119]. On the basis of density functional theory (DFT) calculations Cordova and co-workers [120,121] have studied the primary amino acid intermolecular aldol reaction mechanism. They demonstrated that only one amino acid molecule is involved in the... 

The originally proposed stereochemical model by Hajos and Parrish" was rejected by M.E. Jung and A. Eschenmoser. They proposed a one-proline aldolase-type mechanism involving a side chain enamine. The most widely accepted transition state model to account for the observed stereochemistry was proposed by C. Agami et al. suggesting the involvement of two (S)-(-)-proline molecules. " " Recently, K.N. Houk and co-workers reexamined the mechanism of the intra- and intermolecular (S)-(-)-proline catalyzed aldol reactions. Their theoretical studies, kinetic, stereochemical and dilution experiments support a one-proline mechanism where the reaction goes through a six-membered chairlike transition state. 

Metal Free Transition metal catalysts are highly effective for C—H bond activation. However, transition metal complexes are not only expensive, but also difficult to remove from the reaction products, resulting in toxicity concerns. DDQ is a well-known oxidant in organic chemistry [33]. For many years, it has been used for the oxidation of alcohols to ketones and aromatization. The first intermolecular C—C bond formation was realized by DDQ-mediated Mukaiyama-type aldol reactions [34], The reactions of electron-rich benzyl ethers and silyl enol ethers afforded 3-alkoxy-3-phenylpropionyl derivatives at ambient temperature with moderate to excellent yields (Equation 11.12). 

The r-BuOK-catalyzed reaction of a terminal alkyne with cyclohexanone in DMSO to give a tertiary alcohol in 91% yield (eq 47) provides a straightforward illustration of an addition to a carbonyl compound. The same type of addition takes place in the nonpolar solvent benzene but the rate is slower and the yield lower. Treatment of cyclohexanone with ethynylbenzene under the same reaction conditions yields l-(phenylethynyl)cyclohexanol in 83% yield when the reaction is carried out using 1.0 equiv of r-BuOK in the absence of solvent the yield of the tertiary alcohol is 93%. Other aliphatic and aromatic ketones give similar results. Ketones with relatively acidic a hydrogens are capable of undergoing intermolecular aldol additions in the presence of the base but, apparently, the reversibility of this reaction allows the irreversible addition of the acetyUde anion to compete favorably. ... 

Prior to the advent of organocatalysis, the asymmetric direct a-allqtlation reaction was relatively unknown. Classical methods to access a-allq lated carbonyl products required stoichiometric amounts of preformed aldehyde metal enolates. Additionally, side reactions such as aldol, Canizzaro- or Tischenko-type processes diminished the efficiency of these reactions. In this sense the asymmetric intermolecular Sjj2 a-alkylation of aldehydes with simple allq l halides has been a difficult feat to achieve. 

Recently, Dong and Sun disclosed an unprecedented intermolecular asymmetric a-aldol reaction of vinylogous NHC-enolates, a type of versatile but less explored species relative to simple NHC-enolates. In contrast to the known C—C bond formation at the y-position of vinylogous NHC-enolates, this reaction exhibits complete a-selectivity. Unlike most cycloaddition reactions of NHC-enolates with external carbonyl electrophiles, this reaction does not involve a cycloaddition step. Notably, two challengingstereocenters, one quaternary and the other labile tertiary (both allylic and a-carbonyl), are also established in an acyclic product with excellent stereocontrol. A range of highly enantioenriched p,y-unsaturated P -fluoroalkylated esters have been synthesized with high efficiency under mild conditions. These products can be easily transformed into other useful molecules, such as densely functionalized tetrahydrofurans (Scheme 7.90). 

After development of the proline-catalyzed intermolecular aldol reaction by List, Lemer and Barbas in 2000 [16], which led to intense world-wide investigation, List himself developed a further intramolecular proline catalyzed cyclization which was enol-exo in nature as opposed to the enol-endo type cyclization of the Hajos-Parrish-Eder-Sauer-Wiechert process (Scheme 1.15). A range of substrates were applied using the methodology and excellent enantioselectivities were obtained [17]. 

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