Concise Total Synthesis of Antiarrhythmic Drug Dronedarone via a Conjugate Addition Followed Intramolecular Heck Cyclization

Background: The most frequently used chiral auxiliaries, oxazolidinones (Evans' oxazolidinones) have been employed in 1,4-congugate addition reactions to α,β-unsaturated carbonyl compounds. Supplementary to our previous reports in this mini-review, we attempted to underscore the applications of this strategy in a step (steps) in the total synthesis of some naturally occurring compounds exhibiting diverse biological activities. Objective: In this mini-review, we try to underscore the applications of oxazolidinones (Evans’ oxazolidinones) in 1,4-congugate addition reactions to α,β-unsaturated carbonyl in the total synthesis of some naturally occurring compounds exhibiting diverse biological activities. Conclusion: In spite of well-known superiority of asymmetric catalyzed reactions, the use of auxiliarycontrolled reactions are still considered as commanding, vital and sometimes as only tools in the generation of stereogenic centers during the construction of complex molecules and total synthesis of naturally occurring compounds. The commercial availability, or readily accessibility of a wide variety of chiral amino alcohols as starting materials to synthesize a wide range of oxazolidinones is the merits of them. In addition, the ease of removal and subjection to various and diverse stereoselective reactions make oxazolidinones as the ideal and superior chiral auxiliaries. In this regard, they were successfully used in asymmetric 1,4-conjugate addition reactions with high stereoselectivities. The high degree of asymmetric induction can be attributed to the rigid chelation of N-acyloxazolidinones with metal ions, as well as the covering of one face of the system by the bulkiness of 4-substituent. In summary, in this report, the importance of the applications of chiral oxazolidinones as suitable chiral auxiliaries in the stereoselective, 1,4-conjugate addition reactions in asymmetric synthesis and in particular, the total synthesis of naturally occurring compounds and some complex molecules were underscored. Noticeably, in these total syntheses, this chiral auxiliary is controlling the stereochemistry of a newly created stereogenic center as well as preserving the configuration of other chiral centers, which already have been presented in the precursor. General methods have been established for the attachment of the chiral auxiliary as a moiety to the substrate molecule in high to excellent yields. At the end of these reactions, this auxiliary can be easily removed leaving various desired reactive motifs for the next step in multi-step synthesis.

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A Concise Total Synthesis of (±)-Mesembrine

Synlett ◽

10.1055/s-0036-1591547 ◽

2018 ◽

Vol 29 (09) ◽

pp. 1203-1206 ◽

Cited By ~ 1

Author(s):

Hyoungsu Kim ◽

Hosam Choi ◽

Kiyoun Lee

Keyword(s):

Total Synthesis ◽

Claisen Rearrangement ◽

Addition Reaction ◽

Conjugate Addition ◽

Allylic Oxidation ◽

Quaternary Stereocenter

A concise total synthesis of (±)-mesembrine has been successfully accomplished in seven steps and 24% overall yield from commercially available 3-ethoxy-2-cyclohexen-1-one. Central to the assembly of the skeleton of mesembrine are a Johnson–Claisen rearrangement for the formation of the benzylic quaternary stereocenter and direct allylic oxidation to generate the substrate for the amidation/transannular aza-conjugate addition reaction.

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Metal-Mediated C–C Ring Construction: The Carreira Synthesis of (+)-Asperolide C

Organic Synthesis ◽

10.1093/oso/9780190646165.003.0073 ◽

2017 ◽

Author(s):

Douglass F. Taber

Keyword(s):

Conjugate Addition ◽

Ring Expansion ◽

Ethyl Acrylate ◽

Heck Cyclization ◽

University Of Oxford ◽

Silyl Enol Ether ◽

Emory University ◽

Institute Of Technology ◽

The University ◽

Technological University

Djamaladdin G. Musaev and Huw M. L. Davies of Emory University effected (Chem. Sci. 2013, 4, 2844) enantioselective cyclopropanation of ethyl acrylate 2 with the α-diazo ester 1 to give 3 in high ee. Philippe Compain of the Université de Strasbourg used (J. Org. Chem. 2013, 78, 6751) SmI2 to cyclize 4 to the cyclobutanol 5. Jianrong (Steve) Zhou of Nanyang Technological University effected (Chem. Commun. 2013, 49, 11758) enantioselective Heck addition of 7 to the prochiral ester 6 to give the cyclopentene 8. Liu-Zhu Gong of USTC, Hefei added (Org. Lett. 2013, 15, 3958) the Rh enolate from the enantioselective ring expansion of the α-diazo ester 9 to the nitroalkene 10, to give 11 in high de. Stephen P. Fletcher of the University of Oxford set (Angew. Chem. Int. Ed. 2013, 52, 7995) the cyclic quaternary center of 14 by the enantioselective conjugate addition to 12 of the alkyl zirconocene derived from 13. Alexandre Alexakis of the University of Geneva reported (Chem. Eur. J. 2013, 19, 15226) high ee from the conjugate addition of alkenyl Al reagents (not illustrated) to 12. Paultheo von Zezschwitz of Philipps-Universität Marburg prepared (Adv. Synth. Catal. 2013, 355, 2651) the silyl enol ether 17 by trapping the intermediate from the conjugate addition of 16 to 15. Stefan Bräse of the Karlsruhe Institute of Technology effected (Eur. J. Org. Chem. 2013, 7110) conjugate addition to the prochiral dienone 18 to give the highly substituted cyclohexenone 19. Ping Tian and Guo-Qiang Lin of the Shanghai Institute of Organic Chemistry cyclized (J. Am. Chem. Soc. 2013, 135, 11700) 20 to the kinetic, less stable epimer of the diketone 21. Rh-mediated intramolecular C–H insertion has been a powerful tool for the construction of cyclopentane derivatives. Douglass F. Taber of the University of Delaware found (J. Org. Chem. 2013, 78, 9772) that the Rh carbene derived from 22 was discriminating enough to target the more nucleophilic C–H bond, leading to the cyclohexanone 23. Kozo Shishido of the University of Tokushima observed (Org. Lett. 2013, 15, 3666) high diastereoselectivity in the intramolecular Heck cyclization of 24 to 25.

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Revision of the Structure and Total Synthesis of Topsentin C

Synthesis ◽

10.1055/s-0036-1588731 ◽

2017 ◽

Vol 49 (11) ◽

pp. 2562-2574 ◽

Cited By ~ 4

Author(s):

Nikita Golantsov ◽

Alexey Festa ◽

Alexey Varlamov ◽

Leonid Voskressensky

Keyword(s):

Total Synthesis ◽

Secondary Metabolite ◽

Conjugate Addition ◽

Solvent Free ◽

Synthetic Approach ◽

Protecting Group ◽

Marine Alkaloids ◽

Mild Reduction

An efficient synthetic approach to access (indol-3-yl)ethane-1,2-diamines with a protecting group at the indole N atom from readily available 3-(2-nitrovinyl)indoles is reported. This approach includes solvent-free conjugate addition of O-pivaloylhydroxylamines to 1-Boc-3-(2-nitrovinyl)indoles followed by mild reduction of the adducts. The obtained (indol-3-yl)ethane-1,2-diamines are convenient synthetic precursors for several classes of marine alkaloids. The first total synthesis of racemic topsentin C, a secondary metabolite from Hexadella sp., based on this approach is reported. The initially proposed structure for topsentin C has been revised.

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