Conditions for a Rh(I)-catalyzed [2+2+1] cycloaddition reaction with methyl substituted allenes and alkynes

Wells, Sarah; Brummond, Kay M.

doi:10.1016/j.tetlet.2015.01.075

Cited by 10 publications

(6 citation statements)

References 22 publications

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“…With a number of α-methylene−γ-lactam tethered allene-ynes in hand, the feasibility of the APKR was tested. Because these substrates have a methyl-substituted allene, we used conditions previously developed in our group that minimize dimer formation by slowly adding the allene-yne to the Rh(I) catalyst . First, allene-yne 24a was diluted in toluene and added dropwise over 1 h to rhodium biscarbonyl chloride dimer ([Rh(CO) 2 Cl] 2 , 10 mol %) in toluene under carbon monoxide (1 atm) at 110 °C (eq 6).…”

Section: Resultsmentioning

confidence: 99%

“…1 4-((4S*,5S*)-3-Methylene-4-(3-methylpenta-3,4-dien-1-yl)-2oxo-5-(phenylethynyl)pyrrolidin-1-yl)benzonitrile (38). 38 was prepared according to General Procedure G. Lactam 24a (33 mg, 0.12 mmol), 4-iodobenzonitrile (38 mg, 0.17 mmol), copper iodide (5 mg, 0.02 mmol), N,N′-dimethylethylenediamine ( (39). 39 was prepared according to General Procedure G. Lactam 24a (24 mg, 0.087 mmol), 4-benzotrifluoromethyl iodide (0.02 mL, 0.1 mmol), copper iodide (2 mg, 0.02 mmol), N,N′-dimethylethylenediamine (4 μL, 0.04 mmol), cesium carbonate (57 mg, 0.17 mmol), and toluene (0.9 mL) provided lactam 39 (17 mg, 47%) as a clear oil after column chromatography (gradient elution with 5−10% ethyl acetate in hexanes).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Because these substrates have a methyl-substituted allene, we used conditions previously developed in our group that minimize dimer formation by slowly adding the allene-yne to the Rh(I) catalyst. 39 First, allene-yne 24a was diluted in toluene and added dropwise over 1 h to rhodium biscarbonyl chloride dimer ([Rh(CO) 2 Cl] 2 , 10 mol %) in toluene under carbon monoxide (1 atm) at 110 °C (eq 6). Heating the reaction for an additional 30 min after the addition of the allene-yne afforded lactam 45 in 72% yield (Table 2, entry 1).…”

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis of Guaianolide Analogues with a Tunable α-Methylene−γ-lactam Electrophile and Correlating Bioactivity with Thiol Reactivity

et al. 2020

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α-Methylene−γ-lactones are present in ∼3% of known natural products, and compounds comprising this motif display a range of biological activities. However, this reactive lactone limits informed structure−activity relationships for these bioactive molecules. Herein, we describe chemically tuning the electrophilicity of the α-methylene−γ-lactone by replacement with an α-methylene−γ-lactam. Guaianolide analogues having α-methylene−γ-lactams are synthesized using the allenic Pauson−Khand reaction. Substitution of the lactam nitrogen with electronically different groups affords diverse thiol reactivity. Cellular NF-κB inhibition assays for these lactams were benchmarked against parthenolide and a synthetic α-methylene−γ-lactone showing a positive correlation between thiol reactivity and bioactivity. Cytotoxicity assays show good correlation at the outer limits of thiol reactivity but less so for compounds with intermediate reactivity. A La assay to detect reactive molecules by nuclear magnetic resonance and mass spectrometry peptide sequencing assays with the La antigen protein demonstrate that lactam analogues with muted nonspecific thiol reactivities constitute a better electrophile for rational chemical probe and therapeutic molecule design.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis of Guaianolide Analogues with a Tunable α-Methylene−γ-lactam Electrophile and Correlating Bioactivity with Thiol Reactivity

et al. 2020

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“…Guaianolides (sesquiterpene lactones) are biologically important scaffolds as they possess many activities such as antitumor and anti-inflammatory activities [ 41 ]. Wells and Brummond reported the preparation of bicyclo [5.3.0]decadienones via rhodium(Ι)-catalyzed [2+2+1] cycloaddition of methyl substituted allenes with alkynes [ 42 ]. They first prepared allene-ynes starting from allenes in the following steps: (1) reduction with LiAlH 4 and then mesylation of resulting hydroxyl group, (2) treatment with sodium triethyl methanetricarboxylate followed by decarboxylation, (3) deprotonation of malonate derivative, and (4) addition of 1-bromo-2-butyne.…”

Section: Review Of Literaturementioning

confidence: 99%

Unveiling the Chemistry and Synthetic Potential of Catalytic Cycloaddition Reaction of Allenes: A Review

et al. 2023

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Allenes with two carbon–carbon double bonds belong to a unique class of unsaturated hydrocarbons. The central carbon atom of allene is sp hybridized and forms two σ-bonds and two π-bonds with two terminal sp2 hybridized carbon atoms. The chemistry of allenes has been well documented over the last decades. They are more reactive than alkenes due to higher strain and exhibit significant axial chirality, thus playing a vital role in asymmetric synthesis. Over a variety of organic transformations, allenes specifically undergo classical metal catalyzed cycloaddition reactions to obtain chemo-, regio- and stereoselective cycloadducts. This review briefly describes different types of annulations including [2+2], [2+2+1], [3+2], [2+2+2], [4+2], [5+2], [6+2] cycloadditions using titanium, cobalt, rhodium, nickel, palladium, platinum, gold and phosphine catalyzed reactions along with a mechanistic study of some highlighted protocols. The synthetic applications of these reactions towards the synthesis of natural products such as aristeromycin, ent-[3]-ladderanol, waihoensene(−)-vindoline and (+)-4-epi-vindoline have also been described.

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“…We envisioned that the cyclopentane ring system could be constructed rapidly via a Pauson−Khand reaction and the seven-membered ring closed by exploiting the nucleophilic terminal prenyl group. 13,14 Thus, (−)-linalool was converted into ester 32 via deprotonation and reaction with the mixed anhydride of 2-butynoic acid. This material underwent smooth Pauson−Khand (PK) reaction using dicobalt octacarbonyl, resulting in strained bicyclic lactone 33 (65% yield, 5:2 dr), which was rapidly reduced with DIBAL to afford triol 34.…”

Section: ■ Introductionmentioning

confidence: 99%

Allylative Approaches to the Synthesis of Complex Guaianolide Sesquiterpenes from Apiaceae and Asteraceae

Musacchio

Shen

et al. 2019

J. Am. Chem. Soc.

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With hundreds of unique members isolated to date, guaianolide lactones represent a particularly prolific class of terpene natural products. Given their extensive documented therapeutic properties and fascinating chemical structures, these metabolites have captivated the synthetic chemistry community for many decades. As a result of divergent biosynthetic pathways, which produce a wide array of stereochemical and oxidative permutations, a unifying synthetic pathway to this broad family of natural products is challenging. Herein we document the evolution of a chiral-pool-based synthetic program aimed at accessing an assortment of guaianolides, particularly those from the plant family Apiaceae as well as Asteraceae, members of which possess distinct chemical substructures and necessitate deviating synthetic platforms. An initial route employing the linear monoterpene linalool generated a lower oxidation state guaianolide but was not compatible with the majority of family members. A double-allylation disconnection using a carvone-derived fragment was then developed to access first an Asteraceae-type guaianolide and then various Apiaceae congeners. Finally, using these findings in conjunction with a tandem polyoxygenation cascade, we developed a pathway to highly oxygenated nortrilobolide. A variety of interesting observations in metal-mediated aldehyde allylation and alkene polyoxygenation are reported and discussed.

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Conditions for a Rh(I)-catalyzed [2+2+1] cycloaddition reaction with methyl substituted allenes and alkynes

Cited by 10 publications

References 22 publications

Synthesis of Guaianolide Analogues with a Tunable α-Methylene−γ-lactam Electrophile and Correlating Bioactivity with Thiol Reactivity

Synthesis of Guaianolide Analogues with a Tunable α-Methylene−γ-lactam Electrophile and Correlating Bioactivity with Thiol Reactivity

Unveiling the Chemistry and Synthetic Potential of Catalytic Cycloaddition Reaction of Allenes: A Review

Allylative Approaches to the Synthesis of Complex Guaianolide Sesquiterpenes from Apiaceae and Asteraceae

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