Robinson annulation aldol reaction

In addition to these intermolecular processes, intramolecular versions of the Claisen (Dieckmann) reaction and the mixed Claisen and the aldol reaction (Robinson annulation) are also well known. In all cases the same structural classes of products are formed. 

The Wacker reaction provides a method for the preparation of 1,4-dicarbonyl compounds, by formation of an enolate, allylation with an allyl halide, followed by palladium-catalysed oxidation of the terminal alkene. The product 1,4-dicarbonyl compounds can be treated with base to promote intramolecular aldol reaction (Robinson annulation - see Section 1.1.2) to give cyclopentenones. Thus, in a synthesis of pentalenene, Wacker oxidation of the 2-aUyl ketone 115 gave the 1,4-diketone 116, which was converted to the cyclopentenone 117 (5.115). ... 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

Fig. 13.71. Tandem reaction I, consisting of a Michael addition and an aldol condensation Robinson annulation reaction for the synthesis of six-membered rings that are condensed to an existing ring.

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

Robinson annulation reaction (Section 23.12) A synthesis of cyclohexenones by sequential Michael reaction and intramolecular aldol reaction. 

A particularly important example of the intramolecular aldol reaction is the Robinson annulation, a procedure that constructs a new six-membered ring from a ketone.171 The reaction sequence starts with conjugate addition of the enolate to methyl... 

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. 

Johnson has developed two linear approaches to synthesize the C-nor-D-homosteroid skeleton (Scheme 2.2). In his first approach [21], tetralone 19, obtained from reduction of 2,5-dimethoxynaphthalene, was used as the source of the C,D-rings. The B- and A-rings were constructed by sequential Robinson annulations (19 —> 20 —> 21). The Cl 1,12 olefin was then introduced to provide 22. Ozonolysis of 22 followed by an aldol reaction of the resulting dialdehyde gave 23. Subsequent deformylation and deoxygenation afforded the cyclopamine skeleton 24. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

A rather nice example of enolate anion chemistry involving the Michael reaction and the aldol reaction is provided by the Robinson annulation, a ring-forming sequence used in the synthesis of steroidal systems (Latin annulus, ring). 

The reactions described in this chapter include some of the most useful synthetic methods for carbon-carbon bond formation the aldol and Claisen condensations, the Robinson annulation, and the Wittig reaction and related olefination methods. All of these reactions begin by the addition of a carbon nucleophile to a carbonyl group. The product which is isolated depends on the nature of the substituent (X) on the carbon nucleophile, the substituents (A and B) on the carbonyl group, and the ways in which A, B, and X interact to control the reaction pathways available to the addition intermediate. 

Another version of the Robinson annulation procedure involves the use of methyl 1-trimethylsilylvinyl ketone. The reaction follows the normal sequence of conjugate addition, aldol cyclization, and dehydration. 

The sequence that follows illustrates how a conjugate aldol addition (Michael addition) followed by a simple aldol condensation may be used to build one ring onto another. This procedure is known as the Robinson annulation (ring forming) reaction (after the English chemist Sir Robert Robinson, who won the Nobel Prize in Chemistry in 1947 for his research on naturally occurring compounds). 

Aldol reactions are often used to close five- and six-membered rings. Because of the favorable entropy (p. 211), such ring closures generally take place with ease, even where a ketone condenses with a ketone. An important example is the Robinson annulation reaction which has often been used in the synthesis of steroids and terpenes. In this reaction a cyclic ketone is converted to another cyclic ketone, with one additional six-membered ring containing a double bond. The substrate is treated with methyl vinyl ketone (or a simple derivative of methyl vinyl ketone) and a base.551 The enolate ion of the substrate adds to the methyl vinyl ketone in a Michael reaction (5-17) to give a diketone that undergoes or... 

As with Michael additions to activated alkenes, the initial adducts with activated alkynes can be trapped by various processes. An aldol reaction can occur if a carbonyl is properly situated in the starting material (Scheme 71).123 However, the use of methyl ethynyl ketone (509) and its homologs in the Robinson annulation process to give cyclohexadienones (510 equation 110) usually proceeds in poor... 

The Robinson Annulation is a useful reaction for the formation of six-membered rings in polycyclic compounds, such as steroids. It combines two reactions the Michael Addition and the Aldol Condensation... 

Another key event in the history of organocatalytic reaction was the discovery of efficient r-proline-mediated asymmetric Robinson annulation reported during the early 1970s. The so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction (an intramolecular aldol reaction) allowed access to some of the key intermediates for the synthesis of natural products (Scheme 1.4) [37, 38], and offered a practical and enantioselective route to the Wieland-Miescher ketone [39]. It is pertinent to note, that this chemistry is rooted in the early studies of Langenbeck and in the extensive investigations work of Stork and co-workers on enamine chemistry... 

Enolate D of Figure 13.71 can undergo an aldol reaction with the C=0 double bond of the ketone. The bicyclic compound A is formed as the condensation product. It is often possible to combine the formation and the consecutive reaction of a Michael adduct in a one-pot reaction. The overall reaction then is an annulation of a cyclohexenone to an enolizable ketone. The reaction sequence of Figure 13.71 is the Robinson annulation, an extraordinarily important synthesis of six-membered rings. 

The Michael reaction in combination with an aldol condensation provides a useful method for the construction of six-membered rings in a process termed the Robinson annulation. In the following example a tertiary amine is used as the base to catalyze the conjugate addition. Then, treatment with sodium hydroxide causes an intramolecular aldol condensation to occur. 

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