Novel intramolecular cyclizations of Diels-Alder adducts derived from hexachlorocyclopentadiene and allylic alcohols

The Streptomyces metabolite (-)-FR182877 3 binds to and stabilizes microtubules, showing the same potency of anticancer activity as Taxol (paclitaxel). Masahisa Nakada of Waseda University assembled (Angew. Chem. Int. Ed. 2009, 48, 2580) the hexacyclic ring system of 3 by the tandem intramolecular Diels-Alder–intramolecular hetero Diels-Alder cyclization of 1, generating seven new stereogenic centers in a single step. The construction of the pentaene substrate 1 started with the known aldehyde 4, prepared by homologation of commercial ethyl 3-methyl-4-oxocrotonate. Addition of the propionyl oxazolidine anion 5 proceeded with high diastereocontrol, to give 6. The acyl oxazolidinone was not an efficient acylating agent, so it was converted to the Weinreb amide. Protection and deprotection then delivered the allylic acetate 7. The key step in the pentaene assembly was the carefully optimized Negishi-Wipf methylation of 8, followed by Pd-mediated coupling of the alkenyl organometallic so generated with the allylic acetate, to give 9. Condensation of the derived keto phosphonate 11 with the known aldehyde 12 then delivered the enone 13. The Nakada group has worked extensively on the intramolecular Diels-Alder reaction of substrates such as 1. They have shown that protected anti diols such as 1 cyclize with substantial diastereocontrol and in the desired sense. In contrast, cyclizations of protected syn diols proceed with poor diastereocontrol. The enone 13 was therefore reduced to the anti diol and protected, leading to 14 . Oxidation of 14 at room temperature led to a complex mixture, but slow oxidation at elevated temperature delivered 2 . Although the yield of 2 was not much better than if the reactions were carried out sequentially, first the intramolecular Diels-Alder cyclization, then the intramolecular hetero Diels-Alder cyclization, with the cascade protocol pure 2 was more readily separated from the reaction matrix. With 2 in hand, there was still the challenge of assembling the seven-membered ring. Cyclization was effected with an intramolecular Heck protocol. The two diastereomers of the allylic alcohol 15 cyclized with comparable efficiency. Ir-catalyzed alkene migration then converted the allylic alcohols to a mixture of ketones, which was equilibrated to give the more stable diasteromer.

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Control of regiospecificity in ionic Diels-Alder reactions. The use of allylic alcohols and allylic ethers as precursors of dienophilic allyl cations

The Journal of Organic Chemistry ◽

10.1021/jo00365a048 ◽

1986 ◽

Vol 51 (15) ◽

pp. 3075-3076 ◽

Cited By ~ 35

Author(s):

Paul G. Gassman ◽

Daniel A. Singleton

Keyword(s):

Diels Alder ◽

Allylic Alcohols ◽

Allylic Ethers

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Enantioselective Synthesis of Allylic Alcohols via an Oxazaborolidinium Ion Catalyzed Diels−Alder/Retro-Diels−Alder Sequence

Organic Letters ◽

10.1021/ol902280d ◽

2009 ◽

Vol 11 (22) ◽

pp. 5358-5361 ◽

Cited By ~ 19

Author(s):

Simon Jones ◽

Damien Valette

Keyword(s):

Diels Alder ◽

Enantioselective Synthesis ◽

Allylic Alcohols

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A Review on Onychine and its Analogs: Synthesis and Biological Activity

Current Organic Synthesis ◽

10.2174/1570179417666191218112842 ◽

2020 ◽

Vol 17 (1) ◽

pp. 3-22

Author(s):

Claudia R.B. Gomes ◽

Marcus V.N. de Souza ◽

Victor Facchinetti

Keyword(s):

Biological Activity ◽

Multicomponent Reactions ◽

Diels Alder ◽

Synthetic Methods ◽

Reaction Conditions ◽

Low Concentrations ◽

Wide Range ◽

Intramolecular Cyclizations ◽

Synthetic Approaches ◽

Operational Simplicity

Background: Onychine is a 4-azafluorenone alkaloid isolated from the Annonaceae family, in low concentrations. Onychine and its analogs exhibit a wide range of pharmacological activities such as antifungal, antibacterial, anticancer, and antimalarial. Because of the high bioactivity of some 4-azafluorenone derivatives, several synthetic methods have been developed for their procurement. Objective: Considering the importance of these alkaloids, we aim to present the main synthetic approaches to onychines and its derivatives and the biological activity of some 4-azafluorenones. Methods: The most prominent methodologies for the synthesis of onychines were reviewed. Results: In this work, we cover many synthetic approaches for the synthesis of onychine and 4-azafluorenone derivatives including intramolecular cyclizations, multicomponent reactions, microwave-assisted multicomponent reactions, Diels-alder reactions, among others. Moreover, we also review the biological activity of 4-azafluorenones. Conclusion: 4-azafluorenones have risen as prominent structures in medicinal chemistry; however, most of the time, access to new derivatives involves toxic catalysts, harsh reaction conditions, and long-step procedures. Therefore, the development of new synthetic routes with more operational simplicity, simple purification procedure, good yields, and low environmental impact, is desirable.

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Functionalization and elaboration of ring A taxoid building blocks

Canadian Journal of Chemistry ◽

10.1139/v97-186 ◽

1997 ◽

Vol 75 (11) ◽

pp. 1542-1551 ◽

Cited By ~ 6

Author(s):

Michael W. Tjepkema ◽

Timothy Wong ◽

Peter D. Wilson ◽

Alex G. Fallis

Keyword(s):

Building Blocks ◽

Diels Alder ◽

Allylic Alcohols ◽

Organolithium Reagents

The elaboration of the ring A aldehydes 1, 7, and 11 into more highly functionalized intermediates for taxoid synthesis is described. An improved route to the triene 4 and the adduct 28b is reported. Additional condensations of selected aldehydes (1,7) with the organolithium reagents derived from the substituted halodienes 8 and 14 afforded the allylic alcohols 10 and 15 with a diastereoselectivity of ~5:1. Further manipulation of these products by the installation of an α-keto-acetylenic dienophile provided a taxoid precursor with the C2, C9, C10, C13, and C20 oxygens installed in the case of 23 (from 7), and the less functionalized systems 27 and 27a (from 1). Keywords: taxoid, paclitaxel, Diels–Alder, cyclohexene, dienes.

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