Intramolecular, addition aldol reaction, acid

Krische reported an intramolecular version of the tandem conjugate addition-aldol reaction. The reaction of enone-ketone 58 with phenylboronic acid 2 m occurs in diox-... 

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. 

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... 

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). 

Chiral Auxiliary for Asymmetric Induction. Numerous derivatives of (—)-8-phenylmenthol have been utilized for asymmetric induction studies. These include inter- and intramolecular Diels-Alder reactions, dihydroxylations, and intramolecular ene reactions of a,p-unsaturated 8-phenylmenthol esters. These reactions usually proceed in moderate to good yield with high diastereofacial selectivity. a-Keto esters of 8-phenylmenthol (see 8-Phenylmenthyl Pyruvate) have been used for asymmetric addition to the keto group, as well as for asymmetric [2 -F 2] photoadditions and nucleophilic alkylation. Ene reactions of a-imino esters of 8-phenylmenthol with alkenes provide a direct route to a-amino acids of high optical purity. Vinyl and butadienyl ethers of 8-phenylmenthol have been prepared and the diastereofacial selectivity of nitrone and Diels-Alder cycloadditions, respectively, have been evaluated. a-Anions of 8-phenylmenthol esters also show significant diastereofacial selectivity in aldol condensations and enantiose-lective alkene formation by reaction of achiral ketones with 8-phenylmenthyl phosphonoacetate gives de up to 90%. ... 

The first enantioselective total synthesis of tetracyclic sesquiterpenoid (+)-cyclomyltaylan-5a-ol, isolated from a Taiwanese liverwort, was accomplished by H. Hagiwara and co-workers. They started out from Hajos-Parrish ketone analogue, (S)-(+)-4,7a-dimethyl-2,3,7,7a-tetrahydro-6/-/-indene-1,5-dione, that could be synthesized from 2-methylcyclopentane-1,3-dione and ethyl vinyl ketone in an acetic acid-catalyzed Michael addition followed by an intramolecular aldol reaction. The intramolecular aldol reaction was carried out in the presence of one equivalent (S)-(-)-phenylalanine and 0.5 equivalent D-camphorsulfonic acid. The resulting enone was recrystallized from hexane-diethyl ether to yield the product in 43% yield and 98% ee. Since the absolute stereochemistry of the natural product was unknown, the total synthesis also served to establish the absolute stereochemistry. 

The isoquinuclidine ring system is readily accessible through various synthetic routes. The most widely used approach to the construction of the ISQ ring system is through Diels-Alder or 4+2 cycloaddition reactions. Dihydropyridines (DHPs) or 1,3-cyclohexadienes are most commonly employed as diene components and various dienophiles have been employed based on the substitution pattern of the final desired product. Intramolecular cyclizations, tandem-Michael addition/aldolizations or cyclization via tricyclic aziridines or perhydro / -aminobenzoic acid derivatives have also been reported. Several synthetic routes employing asymmetric or chiral synthetic approaches have also been reported. Most recently, solution-phase parallel synthesis of ISQ derivatives using several of these approaches has been reported [49,50,51]. 

Aldol reactions involving aluminum species are considered to be of less synthetic value because of the ambiguous isomerization of the aldol products, under the influence of the Lewis-acidic aluminum species. Efforts have been made to generate an aluminum enolate in a regiospecific manner. Addition of dialkylchloroalane and zinc to a mixture of an a-halo ketone (126) and an aldehyde leads to the formation of enolate (127), which subsequently reacts with the aldehyde, as shown in Scheme 53.71 This method is applicable to the construction of medium to large rings by intramolecular aldol cyclization of various a-bromocarboxylates of u)-hydroxy aldehydes (e.g. BiCHRC02(CH2) CH0 where — 9, 11 or 12 and R = H or Me). The macrolactonization proceeds in reasonable yield, as shown in Scheme 53. 

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