Total Synthesis of (+)-Cocaine via Desymmetrization of a <i>meso</i>-Dialdehyde

Mans, Douglas M.; Pearson, William H.

doi:10.1021/ol048777a

Cited by 64 publications

(28 citation statements)

References 59 publications

(28 reference statements)

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“…This used for the preparation of (+)-cocaine starting a meso-dialdehyde, which provided the tropane ring skeleton in 86% ee [25].…”

Section: Proline As Organocatalyst 157mentioning

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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“…This used for the preparation of (+)-cocaine starting a meso-dialdehyde, which provided the tropane ring skeleton in 86% ee [25].…”

Section: Proline As Organocatalyst 157mentioning

confidence: 99%

Organocatalyzed Aldol Reactions

Guillena¹

2013

Modern Methods in Stereoselective Aldol Reactions

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“…42 Therefore, Pearson and Mans reported an efficient and rapid access to (+)-cocaine 85 40 using amine catalyzed asymmetric desymmetrization of mesodialdehyde 81 (Scheme 17). 43 The tropane skeleton 82 was established in 91% yield as 1:1 mixture of epimers by the reaction of dialdehyde 81 with proline 2 (20 mol%) through enolexo-aldolization, which was quickly converted to (+)-cocaine 45 in additional five steps with over all high enantioselectivity (86% ee). This represents the first use of the intramolecular prolinecatalyzed aldol reaction to generate aza-bridged bicyclic skeleton and additionally synthesis of various enantioenriched cocaine analogues could be achieved.…”

Section: Miscellaneous Examplesmentioning

confidence: 99%

Linear dialdehydes as promising substrates for aminocatalyzed transformations

et al. 2015

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Organocatalytic domino reactions involving amine activation of carbonyl compounds have become the latest chemical technology towards the design and development of useful synthetic methods. In this direction, linear dialdehydes such as succinaldehyde, glutaraldehyde, and other homologous compounds have attracted considerable attention as suitable substrates for amine catalyzed transformations. Due to their unique structural features, dialdehydes can easily engage in recreation of cascade/tandem transformations for the synthesis of valuable natural products and drug molecules. In this review article we discuss the current scenario and potential applications of linear dialdehydes as adequate synthetic substrates for amine catalyzed transformations to access biologically important complex scaffolds.

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“…36 In 2004, Pearson group utilized intramolecular aldol reaction to achieve the desymmetrization of meso-dialdehyde 69 for the total synthesis of (+)-Cocaine 71. 37 Using the conditions reported by List, the L-proline catalyzed aldol reaction afforded products 70 ax/eq as a 1:1 mixture. They synthesized the natural product (+)-Cocaine 71 in three steps from the 70 ax/eq mixture (Scheme 20).…”

Section: A-carbonylmentioning

confidence: 99%

Recent advances of desymmetrization protocol applied in natural product total synthesis

Wang

Feng

Tang

et al. 2014

Tetrahedron Letters

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a b s t r a c tDesymmetrization synthesis strategy has simplified and improved the efficiency of synthesis, which attracted great attention in the past few decades. Since the strategy has been developed rapidly and got a wide range of applications in natural product total synthesis, the rules are urgent to be summarized. In this Letter, the recent developments of desymmetrization protocol in natural product total synthesis were summarized.

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Total Synthesis of (+)-Cocaine via Desymmetrization of a meso-Dialdehyde

Cited by 64 publications

References 59 publications

Organocatalyzed Aldol Reactions

Organocatalyzed Aldol Reactions

Linear dialdehydes as promising substrates for aminocatalyzed transformations

Recent advances of desymmetrization protocol applied in natural product total synthesis

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