Synthesis and Stereochemical Assignment of (+)-Chamuvarinin

Florence, Gordon J.; Morris, Joanne C.; Murray, Ross G.; Osler, Jonathan D.; Reddy, Vanga R.; Smith, Terry

doi:10.1021/ol1028699

Cited by 29 publications

(28 citation statements)

References 43 publications

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“…[13,40] This three-step sequence only required a single chromatographic purification of the final product, which was identical to an authentic sample in all respects. [8,19] By implementation of this revised coupling strategy, we were able to improve the overall step efficiency (the longest linear sequence being 17 steps from 13, compare with 20 steps in our initial approach), although the overall yield was only slightly improved (2.2 % overall yield), in part due to the challenging C20-C21 bond construction. This revised approach also enabled access to a range of advanced structural analogues, which are detailed in the following section.…”

Section: Resultsmentioning

confidence: 95%

“…In turn, compound 38 could be assembled by adaptation of the C8-C9 Julia-Kocienski olefination developed in our initial synthesis. [19,24,25,36,37] As shown in Scheme 9, the C9-C20 sulfone 39 was readily prepared in three steps from intermediate 22 in 50 % yield, involving C9-debenzylation, Mitsunobu thioetherification, and oxidation to the sulfone. The Julia-Kocienski olefination between aldehyde 5 and sulfone 39 by using NaHMDS in THF proceeded smoothly to provide 40 in excellent yield as a single E isomer.…”

Section: Resultsmentioning

confidence: 99%

“…[a] 20 D = À11.9 (c = 0.52 in CHCl 3 ); synthetic 1: [a] 20 D = + + 9.9 (c = 0.1 in CHCl 3 ); [19] natural 1: [a] D = + + 25 (c = 0.026 in CHCl 3 ) [8] ].…”

Section: Resultsmentioning

confidence: 99%

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Total Synthesis, Stereochemical Assignment, and Biological Activity of Chamuvarinin and Structural Analogues

Florence

Morris

Murray

et al. 2013

Chemistry A European J

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A highly stereocontrolled synthesis of (+)-chamuvarinin has been completed in 1.5% overall yield over 20 steps. The key fragment coupling reactions were the addition of alkyne 8 to aldehyde 7 (under Felkin-Anh control), followed by the two step activation/cyclization to close the C20-C23 2,5-cis-substituted tetrahydrofuran ring and a Julia-Kocienski olefination at C8-C9 to introduce the terminal butenolide. The inherent flexibility of our coupling strategy led to a streamlined synthesis with 17 steps in the longest sequence (2.2% overall yield), in which the key bond couplings are reversed. In addition, a series of structural analogues of chamuvarinin have been prepared and screened for activity against HeLa cancer cell lines and both the bloodstream and insect forms of Trypanosoma brucei, the parasitic agent responsible for African sleeping sickness.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

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Total Synthesis, Stereochemical Assignment, and Biological Activity of Chamuvarinin and Structural Analogues

Florence

Morris

Murray

et al. 2013

Chemistry A European J

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“…Starting from our established THP building block syn ‐ 16 and anti ‐ 17 ,, Swern oxidation followed by diastereoselective Carreira alkynylation gave the corresponding propargyl alcohols 18 and 19 , respectively. While the stereochemical control of the alkynylation reactions was inconsequential for the downstream synthesis, these conditions proved more efficient compared with lithium TMS‐acetylide addition to the respective aldehydes .…”

Section: Resultsmentioning

confidence: 99%

“…With alkyne precursors 20 and 21 in hand along with the ethyl‐terminated variant 22 (used in our initial synthesis of 1 ), we were in a position to begin the modular assembly of first the key 1,4‐alkyne diol framework followed by the Williams Ru‐catalysed heterocyclisation to access furan derivatives with both diastereomeric and terminal functionality variations, as detailed in Scheme . Access to the intermediate 1,4‐alkyne diol precursors was achieved by n BuLi deprotonation of the respective alkyne 20 , 21 or 22 followed by addition of the respective THP‐aldehyde 23–26 to give precursors 27–35 (entries 1–9) after silyl group cleavage in modest but workable yields over two steps.…”

Section: Resultsmentioning

confidence: 99%

Structure‐Based Design, Synthesis and Biological Evaluation of Bis‐Tetrahydropyran Furan Acetogenin Mimics Targeting the Trypanosomatid F1 Component of ATP Synthase

et al. 2019

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The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for the severely debilitating neglected Tropical diseases of African sleeping sickness, Chagas disease and leishmaniasis, respectively. As part of our ongoing programme exploring the potential of simplified analogues of the acetogenin chamuvarinin we identified the T. brucei FoF1‐ATP synthase as a target of our earlier triazole analogue series. Using computational docking studies, we hypothesised that the central triazole heterocyclic spacer could be substituted for a central 2,5‐substituted furan moiety, thus diversifying the chemical framework for the generation of compounds with greater potency and/or selectivity. Here we report the design, docking, synthesis and biological evaluation of new series of trypanocidal compounds and demonstrate their on‐target inhibitory effects. Furthermore, the synthesis of furans by the modular coupling of alkyne‐ and aldehyde‐THPs to bis‐THP 1,4‐alkyne diols followed by ruthenium/xantphos‐catalysed heterocyclisation described here represents the most complex use of this method of heterocyclisation to date.

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The J ulia– K ocienski Olefination

Blakemore¹,

Sephton

Ciganek

2018

Organic Reactions

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The Julia–Kocienski olefination is a direct connective synthesis of alkenes via the addition of metalated aryl alkyl sulfones to carbonyl compounds. The activating aromatic group associated with the sulfone must possess electrophilic character, and alkene formation occurs via β‐alkoxy sulfone formation, transfer of the aryl group from sulfur to oxygen via a Smiles rearrangement, and then elimination of sulfur dioxide and an aryloxide anion from the resulting β‐aryloxy sulfinate anion. The olefination process itself and the methods used to prepare the requisite sulfone substrates are tolerant of a wide variety of functional groups, and a variety of alkene targets can be prepared. Stereoselectivity is dependent on the nature of the sulfone, the carbonyl compound, the activating aryl moiety, and the reaction conditions. This chapter describes theoretical and operational aspects of the Julia–Kocienski olefination such that the reader will be able to obtain optimal results in his/her own research. A detailed mechanistic overview is included to account for the factors that influence stereoselectivity and yield. Methods for introducing sulfone activators into fragments of interest, best practices for generating sulfone anions, and optimal strategies for targeting different classes of alkene targets are discussed. Functional group compatibilities, reaction variants, and a comparison to other methods of alkene synthesis are also presented. Tabular surveys are organized according to type of alkene synthesized, with an emphasis on the degree of substitution and the level of conjugation about the newly formed double bond. The literature is covered from the initial disclosure of the Julia–Kocienski olefination in 1991 to the first quarter of 2016.

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Synthesis and Stereochemical Assignment of (+)-Chamuvarinin

Cited by 29 publications

References 43 publications

Total Synthesis, Stereochemical Assignment, and Biological Activity of Chamuvarinin and Structural Analogues

Total Synthesis, Stereochemical Assignment, and Biological Activity of Chamuvarinin and Structural Analogues

Structure‐Based Design, Synthesis and Biological Evaluation of Bis‐Tetrahydropyran Furan Acetogenin Mimics Targeting the Trypanosomatid F1 Component of ATP Synthase

The J ulia– K ocienski Olefination

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