Aldol transform

Under the same conditions, tricyclo[5.3.1.0]undecanes are accessible from 5-sub-stituted 2-cyclohexen-l-one as 2-370 with a shorter tether by one CH2-group. Recently, another Michael/Michael/aldol transformation was employed by Paulsen and coworkers to obtain access to the central aromatic core of compounds as 2-376 (Scheme 2.89) [206]. It is of value that such products are thought to act as cholesterol ester transfer protein (CETP) inhibitors, and the application of these drugs should prevent reduction of the HDL-cholesterol level and therefore reduce the risk of coronary heart diseases [207]. 

Thiopyran derivatives may be formed when a sulfide participates in an aldol transformation. An excellent example is the formation of 2H-thiopyran-5-carbaldehyde (19a) from benzaldehyde and acetaldehyde in the presence of sodium disulfide (Scheme 11 A).196... 

The venerable aldol addition has been one of the most widely used synthetic methods for the construction of stereochemically complex natural and nonnatural products. Its versatility is evident in the innumerable syntheses in which the aldol transform has served indispensably as the focus of convergent syntheses. It has been utilized at a variety of strategic points in syntheses such as in the construction of basic building blocks early in a synthetic plan or in the constitutive assembly of large, stereochemically complex fragments late in the synthetic plan [1,2]. 

This review covers the catalytic literature on condensation reactions to form ketones, by various routes. The focus is on newer developments from the past 15 years, although some older references are included to put the new work in context. Decarboxylative condensations of carboxylic acids and aldehydes, multistep aldol transformations, and condensations based on other functional groups such as boronic acids are considered. The composition of successful catalysts and the important process considerations are discussed. The treatment excludes enantioselective aldehyde and ketone additions requiring stoichiometric amounts of enol silyl ethers (Mukaiyama reaction) or other silyl enolates, and aldol condensations catalyzed by enzymes (aldolases) or catalytic antibodies with aldolase activity. It also excludes condensations catalyzed at ambient conditions or below by aqueous base. Recent reviews on these topics are those of Machajewski and Wong, Shibasaki and Sasai, and Lawrence. " The enzymatic condensations produce mainly polyhydroxyketones. The Mukaiyama and similar reactions require a Lewis acid or Lewis base as catalyst, and the protecting silyl ether or other group must be subsequently removed. However, in some recent work the silane concentrations have been reduced to catalytic amounts (or even zero) this work is discussed. 

Fig. 2) [34]. These aluminium systems, the most commonly used example being given the acronym ALB for aluminium-lithium-binaphthol, were found to be equally effective for many phospho-aldol transformations as their lanthanide cousins, a little less reactive overall, but especially useful on electron-withdrawing carbonyl substrates (e.g., compare entries 2 and 3 in Table 1 and Table 3).

Figure 5 shows excerpts taken from the aldol transform to illustrate ALCHEM statements. Lines 2-5 represent the NAME, REFERENCE, SUBSTRUCTURE, PRIORITY, and CHARACTER, respectively. Group 1 is the DGROUP and Group 2 is the WGROUP. Atom 1 refers to the first atom on the path, the location of the DGROUP. 

The aldol reaction is an important carbon-carbon bond formation reaction. The general concept of the reaction involves the nucleophilic addition of a ketone enolate to an aldehyde to form a P-hydroxy ketone, or aldol , a structural unit found in many naturally occurring molecules and pharmaceuticals. Since the aldol addition reaction creates two new stereocenters, up to four stereoisomers may result. The Evans aldol reaction performs a diasteroselective aldol transformation using an Evans s acyl oxazolidinone (also known as Evans chiral auxiliary), a chiral carbonyl compound that creates a temporary chiral enolate for the aldol addition. Upon subsequent removal of the auxiliary, the desired aldol stereoisomer is revealed. ... 

Asymmetric syn and anti aldol reactions have been used for synthesis of the following natural products containing lactone moieties. A titanium enolate-based aldol reaction has also been utilized in the aldol dehydration sequence during the synthesis of pyrone natural products mxyopyronin A and B. The following syntheses of lactone-containing natural products highlight the variety of aldol transformations. 

Even with more atom-economical, catalytic, asymmetric aldol options available, the use of chiral auxiliaries on large scale should not always be avoided based on the perception of poor AE. The following example toward discodermolide (82) from Novartis Process Chemistry, where AE, process greenness, and waste minimization are of great concern, demonstrates that aldol transformations with auxiliaries are possible on multi-kg scale [66] (Scheme 13.12). After aldol reaction and cleavage of the chiral controller to produce 80, they were able to recover 81 in 67% yield via crystallization. 

To improve the efficiency and selectivity of the tandem aldol process, Cdrdova s group also isolated the 3-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction. The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 1.8). The two-step synthetic protocol made it possible to investigate both (l)- and (D)-catalysts in stereocontrol. The synthesis of hexoses proceeded with excellent chemo-, diastereo-, and enantioselectivity. In all cases except one, the corresponding hexoses were isolated as single diastereomers with >99% ee [10],... 

Reversing the position of the aldol electrophile, Enders and coworkers developed a type ce approach to complex 3-pyrrolin-2-ones that involved a quadruple cascade process (Scheme 91 2014S1539). Treatment of cinnamaldehyde (353) and the a-ketoamide 354 with pyrrolidine catalyst 355 and NaOAc gives the fused 3-pyrrolin-2-one 357. The mechanism of the reaction includes a Michael addition by the amide followed by aldol condensation to generate the 3-pyrrolin-2-one intermediate 356 subsequent Michael and aldol transformations with a second equivalent of 353 then gives the fused cyclopentene ring. 

First reported in 1838, the aldol reaction has remained one of the most powerful tools for the formation of carbon-carbon bonds in organic chemistry. In order to induce diastereoselectivity in an aldol transformation, both enolate geometry and facial selectivity must be controlled. Oxazolidinone auxiliaries facilitate control over both of these parameters. By varying the Lewis aeid in oxazolidinone controlled aldol reaetions, both 1,2-syn and 1,2-anti stereoehemistries can be obtained. ... 

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