Asymmetric synthesis of 2-azabicyclo[3.3.1]nonanes by a microwave-assisted organocatalysed tandem desymmetrisation and intramolecular aldolisation

Diaba, Fai͏̈za; Bonjoch, Josep

doi:10.1039/b906835j

Cited by 40 publications

(25 citation statements)

References 44 publications

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“…4-tert-Butyldiphenylsilyloxyproline (186a) was the most efficient catalyst able to promote the intramolecular desymmetrization of prochiral 4-N-protected aminocyclohexane acetaldehyde derivative 187, allowing the synthesis of chiral morphan scaffold 188 with complete diastereoselectivity, which is present in many biologically active products. The reaction rate was accelerated by using microwave activation (300 W), and the best results were achieved in the presence of water (10 equiv) in acetonitrile as solvent (Scheme 3.45) [252].…”

Section: Intramolecular Reactionsmentioning

confidence: 99%

Organocatalyzed Aldol Reactions

Guillena¹

2013

Modern Methods in Stereoselective Aldol Reactions

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The use of catalytic enantioselective methods to perform an aldol reaction provides a direct entry for the synthesis of chiral compounds and is probably the most attractive way to achieve this goal with high control of the chemo-, regio-, diastereo-, and enantioselectivity. The application of biochemical methods based on enzyme aldolases or antibodies, which are discussed in other chapters, avoid the use of preformed enolates or their equivalents for enhancing the global atom efficiency of the process [1] for which the narrow substrate scope is a major drawback. The discovery of methodologies to carry out the enantioselective direct aldol reaction [2] has eluded the production of stoichiometric by-products increasing the substrate scope. This task could be accomplished by using small molecules as catalysts, such as metal complexes (which are covered along this book) and organic molecules, also known as organocatalysts [3]. The growth of this last research area and the direct aldol reaction are closely linked [4], with the report on the use of (S)-proline as catalyst for the intermolecular aldol [5] definitely being the push for the development of the organocatalytic methods as a competitive methodology for the synthesis of chiral compounds.In a strict sense, an organocatalyzed reaction is a process in which all the involved reagents and catalysis are purely organic compounds of low-molecular weight, excluding boron-and silicon-containing derivatives. However, in some cases, the presence of a silyl group only plays a steric role and therefore can also be considered as an organocatalyzed process. Also, if the organocatalyst involved in a reaction is immobilized in a polymer, a dendrimer, or even an inorganic material that serves only as a support to facilitate its recovery [6], it could still be considered as an organocatalyst, although those types of derivatives have been scarcely used in the natural product synthesis and therefore will be excluded from this chapter. Therefore, a comprehensive overview of the direct aldol reaction [7], emphasizing the reactivity, scope, selectivity, and limitations of the methodology and giving several examples of their application to the synthesis of biologically active compounds, is discussed in this chapter.

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Section: Intramolecular Reactionsmentioning

confidence: 99%

Organocatalyzed Aldol Reactions

Guillena¹

2013

Modern Methods in Stereoselective Aldol Reactions

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“…and Bonjoch group, though very few methods are currently available to synthesize enantiopure morphans (equation 6) 46. Products Scheme 10 Intramolecular transannular aldol reactions.…”

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confidence: 99%

2.07 The Aldol Reaction: Organocatalysis Approach

Mase

Hayashi²

2014

Comprehensive Organic Synthesis II

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“…15 Only recently, catalytic asymmetric versions of this reaction, consisting in the condensation of 2-aminoaryl aldehydes with a carbonyl compounds, were reported, either using enamine catalysis mediated by trans-4-hydroxyproline, [16][17] or a chiral phosphoric acid derivative in combination with an achiral amines 18 as promoters, both in high levels of enantioselectivities. Although, the organocatalyzed aldol reaction [19][20][21][22][23][24][25] has been deeply studied in the last ten years, only a few reports dealing with the desymmetrization of the prochiral ketones [26][27][28][29][30][31][32][33][34][35][36][37] used as nucleophiles, which is one of the prerequisite for the success of the synthesis of the chiral quinoline analogues, have been reported. Furthermore, the synthesis of the quinolines required the use of o-aminobenzaldehydes as electrophiles, which are less reactive than the generally activated aromatic aldehydes used in the enamine-catalyzed aldol reaction.…”

Section: Figure 1 Tacrine and Analoguesmentioning

confidence: 99%

Solvent-Free Enantioselective Friedländer Condensation with Wet 1,1′-Binaphthalene-2,2′-diamine-Derived Prolinamides as Organocatalysts

2013

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Unsupported and supported-binam-derived prolinamides are efficient organocatalysts under solvent-free conditions at room temperature to perform the synthesis of chiral tacrine analogues in good yields (up to 93%) and excellent enantioselectivies (up to 96%). The Friedländer reaction involved in this process takes place using several cyclohexanone derivatives and 2-aminoaromatic aldehydes and it is compatible with the presence of either electron-withdrawing or electron-donating groups at the aromatic ring of the 2-aminoaryl aldehydes derivatives used as electrophiles. The reaction can be extended to cyclopentanone derivatives affording a regioisomeric but separable mixture of products. The use of the silica gel supported organocatalyst, under solvent-free conditions, for this process led to the expected product up to (87% ee), with its reused being possible at least up to five times.

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Asymmetric synthesis of 2-azabicyclo[3.3.1]nonanes by a microwave-assisted organocatalysed tandem desymmetrisation and intramolecular aldolisation

Abstract: The six-membered nitrogen-containing ring of the morphan scaffold, ubiquitous in natural products, is formed by an intramolecular aldol process of an aza-tethered dicarbonyl compound, leading to the first asymmetric synthesis of a morphan derivative using organocatalysis.

Cited by 40 publications

References 44 publications

Organocatalyzed Aldol Reactions

Organocatalyzed Aldol Reactions

2.07 The Aldol Reaction: Organocatalysis Approach

Solvent-Free Enantioselective Friedländer Condensation with Wet 1,1′-Binaphthalene-2,2′-diamine-Derived Prolinamides as Organocatalysts

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