Acid Aldol, intramolecular

Base-catalyzed aldol reactions have been carried out intramole-cularly.241 The aqueous acid-catalyzed intramolecular aldol condensation of 3-oxocyclohexaneacetaldehyde proceeded diastereoselectively (Eq. 8.95).242... 

A tandem enzymatic aldol-intramolecular Homer-Wadsworth-Emmons reaction has been used in the synthesis of a cyclitol.310 The key steps are illustrated in Scheme 8.33. The phosphonate aldehyde was condensed with dihydroxyacetone phosphate (DHAP) in water with FDP aldolase to give the aldol adduct, which cyclizes with an intramolecular Horner-Wadsworth-Emmons reaction to give the cyclo-pentene product. The one-pot reaction takes place in aqueous solution at slightly acidic (pH 6.1-6.8) conditions. The aqueous Wittig-type reaction has also been investigated in DNA-templated synthesis.311... 

Substituted, 2,3-disubstituted, and 2,3-annulated thiophenes can be prepared by reactions of ketone enolates with carbonodithioic acid O-ethyl 5-(2-oxoethyl)ester. Hydrolysis of the resulting aldols, intramolecular addition of thiol group to the carbonyl group, and elimination of two molecules of water lead to the thiophenes (116) (Scheme 38) (92HCA907). 

The roles of proline and primary amino acids in intramolecular aldol cyclizations are compared in the previous section. 

Lewis acid catalyzed intramolecular vinylogous aldol reaction of 5-substituted furoic acids afforded spiro compounds with high diastereoselectivity, which were converted to the zaragozic acids <02JOC4200>. 

The antiviral marine natural product, (-)-hennoxazole A, was synthesized in the laboratory of F. Yokokawa." The highly functionalized tetrahydropyranyl ring moiety was prepared by the sequence of a Mukaiyama aldol reaction, cheiation-controiied 1,3-syn reduction, Wacker oxidation, and an acid catalyzed intramolecular ketalization. The terminal olefin functionality was oxidized by the modified Wacker oxidation, which utilized Cu(OAc)2 as a co-oxidant. Interestingly, a similar terminal alkene substrate, which had an oxazole moiety, failed to undergo oxidation to the corresponding methyl ketone under a variety of conditions. 

A second, less used, strategy encompasses the Lewis acid catalyzed intramolecular reaction of a silyl enol ether with a propargyl cation. The latter can be conveniently generated by a cobalt complexed propargyl ether. This complexation strongly helps the carbocation formation. By using cobalt complexation, intramolecular aldol type reactions (for R = OR ) have been accomplished. ... 

In this volume we present five selected contributions by well-known authors, each an authority in his field. The first chapter deals with construction of isoxazolines (dihydroisoxazoles) via 1,3-dipolar cycloadditions of nitronates or of nitrile oxides generated from nitroalkanes. This includes inter- as well as intramolecular processes. Many of these heterocycles possess important synthetic and biological properties and are shown to lead to stereo- and re-gioselective introduction of multifunctional molecules such as amino alcohols, )6-amino acids, aldols, nitriles, and others. 

The acid-catalysed intramolecular aldolization of 3-oxocyclohexaneacetaldehydes (56) yields an 85 15 mixture of 6-endo- and 6-exo-hydroxybicyclo[2.2.2]octan-2-ones (57a, 57b), under thermodynamic control." The origin of the diastereoselectivity is not, apparently, due to intramolecular hydrogen-bonding in (57a), but rather to an unfavourable steric interaction in (57b). 

New methods for the elaboration of the gibbane carbon skeleton and related Structures continue to be developed. Chiral gibbane derivatives can be prepared by asymmetric aldol condensations using L-proline as catalyst, or by building up the carbon skeleton from a chiral precursor. Examples have already been quoted which bear witness to the considerable synthetic potential of acid-catalysed intramolecular cyclizations of olehnic diazoketones. Mander etal. have given full details of their studies in this area with anisole derivatives such as... 

Scheme 28.13 Phosphoric acid-catalyzed intramolecular aldol reactions.

The first application of the Wynberg process to employ nonactivated aldehydes was reported in 2001 by Romo and coworkers and introduced the nucleophile-catalyzed aldol-lactonization (NCAL) methodology (Scheme 3.17) [40]. In this manifold an in situ generated ammonium enolate, formed via an activated acid, undergoes intramolecular formal [2+2] cycloaddition with an aldehyde moiety to generate the... 

Aldol, intramolecular Dicarbonyl compound. Acid or base p-Hydroxyaldehyde Only 5- or... 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

Comforth has reviewed literature reports and independently studied the special cases of reaction of 1 with salicylaldehyde and with 2-acetoxybenzaldehyde. Coumarins (10) are afforded in the condensation of 1 with salicylaldehyde or its imine, whereas when 2-acetoxybenzaldehyde is used, acetoxy oxazolone 12 is the major product. The initial aldol condensation product between the oxazolone and 2-acetoxybenzaldehyde is the 4-(a-hydroxybenzyl)oxazolone 11, in which base-catalyzed intramolecular transacetylation is envisioned. The product 9 (R = Ac) can either be acetylated on the phenolic hydroxy group, before or after loss of acetic acid, to yield the oxazolone 12, or it can rearrange, by a second intramolecular process catalyzed by base and acid, to the hydrocoumarin, which loses acetic acid to yield 10. When salicylaldehyde is the starting material, aldol intermediate 9 (R = H) can rearrange directly to a hydrocoumarin. Comforth also accessed pure 4-(2 -hydroxyphenylmethylene)-2-phenyloxazol-5(4//)-one (13) through hydrolysis of 12 with 88% sulfuric acid. 

Several cyditol derivatives of varying ring size, for example, (69)/(70), have been prepared based on an enzymatic aldolization as the initial step. Substrates carrying suitably installed C,H-acidic functional groups such as nitro, ester, phosphonate (or halogen) functionalities made use of facile intramolecular nucleophilic (or radical) cyclization reactions ensuing, or subsequent to, the enzyme-catalyzed aldol addition (Figure 10.27) [134—137]. 

Microbial degradation of validamycin A (8) with a cell suspension of Pseudomonas dentrificans afforded validamine (202) and valienamine (203). Hydrogenolysis of validamycin B, followed by acid hydrolysis, yielded hydroxy validamine (204). Valiolamine (205) was isolated and shown to be a component of validamycin G. ° Biosynthesis of these carba-glycosylamines was extensively studied, and the intramolecular aldol addition of the... 

The aldol reaction can be applied to dicarbonyl compounds in which the two groups are favorably disposed for intramolecular reaction. Kinetic studies on cyclization of 5-oxohexanal, 2,5-hexanedione, and 2,6-heptanedione indicate that formation of five-membered rings is thermodynamically somewhat more favorable than formation of six-membered rings, but that the latter is several thousand times faster.170 A catalytic amount of acid or base is frequently satisfactory for formation of five- and six-membered rings, but with more complex structures, the techniques required for directed aldol condensations are used. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Copper hydride species, notably Stryker s reagent [Ph3PCuH]6, are capable of promoting the conjugate reduction of a,( >-unsalurated carbonyl compounds [42], Taking advantage of this trustworthy method, Chiu et al. demonstrated in 1998 an intramolecular reductive aldol reaction in the synthesis of novel terpenoid pseudolaric acids isolated from Chinese folk medicine (Scheme 28) [43]. Two equivalents of [Ph3PCuH]6 enabled cycli-zation of keto-enone 104 to provide the bicyclic diastereomers 105 (66%) and 106 (16%). The reaction also was applied to the transformation of 107... 

We have already discussed a large group of reactions in which carbanions add to the C=0 group (cf. pp. 221-234), including examples of intramolecular carbanion addition, e.g. an aldol reaction (p. 226), Dieckmann reaction (p. 230), and the benzilic acid rearrangement (p. 232), and also to the C=C—C=O system, the Michael reaction... 

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