A Gram‐Scale Batch and Flow Total Synthesis of Perhydrohistrionicotoxin

Brasholz, Malte; MacDonald, James M.; Saubern, Simon; Ryan, John H.; Holmes, Andrew B.

doi:10.1002/chem.201001435

Cited by 65 publications

(46 citation statements)

References 59 publications

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“…Hydrogen is commonly used in flow synthesis, 99,100 usually in excess amounts. When hydrogenation is followed by other steps, 9,26,29,33,101,102 a simple buffer flask allows the outgassing of hydrogen, after the pressure is reduced. However, in some cases the applied chemistry did not tolerate this method.…”

Section: In-line Work-upmentioning

confidence: 99%

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

Bana

Örkényi

Lövei

et al. 2017

Bioorganic & Medicinal Chemistry

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a b s t r a c tRecent advances in the field of continuous flow chemistry allow the multistep preparation of complex molecules such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of laboratory-scale applications are described, which are pointing towards novel manufacturing processes of pharmaceutical compounds, in accordance with recent regulatory, economical and quality guidances. The chemical and technical knowledge gained during these studies is considerable; nevertheless, connecting several individual chemical transformations and the attached analytics and purification holds hidden traps. In this review, we summarize innovative solutions for these challenges, in order to benefit chemists aiming to exploit flow chemistry systems for the synthesis of biologically active molecules.

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Section: In-line Work-upmentioning

confidence: 99%

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

Bana

Örkényi

Lövei

et al. 2017

Bioorganic & Medicinal Chemistry

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“…[2] The detailed understanding of nitrone [3+ +2]-cycloadditions and methods for ring-opening isoxazolines and isoxazolidines that has been complied in the literaturehas promoted the use of these transformations in the synthesis of natural products and active pharmaceutical reagents that contain amino acid, 1,3-aminoa lcohol, and b-lactam functionalities. [3] Twos pecific examples shown in Scheme 1B and 1C are the synthesis of (À)-perhydrohistrionicotoxin, ap oison-arrow frog alkaloid that is an oncompetitive inhibitoro fa cetylcholine receptors, and the synthesis of ezetimibe, ad rug that lowers cholesterol. [3f,g] Additional examples include the synthesis of the antibiotic (+ +)-negamycin, the cytotoxic alkaloid lepadiformine, and tubulin polymerization inhibitor tubulysin D. [3a,b,e] While nitrones are best known for their [3+ +2]-dipolar cycloaddition reactivity,t he applicationo fn itrone intermediates to the synthesis of heterocyclesi sn ot limited to these transformations.T his review will focus on several alternative transformations of nitrones that can be used to form ad iversea rray of heterocyclic compounds.T he transformationst hat will be discussed include formal [3+ +3]-and[ 4 + +2]-cycloadditions of nitrones (section 2), metal-catalyzed internal redox cyclizations of nitrones (section 3), electrocyclizations, metal-catalyzed cyclizations, and rearrangements of nitrones (section4), and cascade reactions initiated by [3+ +2]-cycloadditions of nitrones (section 5).…”

Section: Overviewmentioning

confidence: 99%

“…Further optimization of the addition of nitrones to cyclopropane diesters by the Kerr group showedt hat the transformation could be realized as am ulticomponent coupling process through generation of the nitrone from am ixture of aldehyde and hydroxylamine in the presence of Yb(OTf) 3 prior to the addition of the cyclopropane diester (Scheme12B). [27] It could also be achieved as either as ingle-step or multicomponent coupling process in the presence of MgI 2 insteado fY b(OTf) 3 (Scheme 12 C). [28] The multicomponent coupling process showeds imilars ubstrate tolerance and diastereoselectivity to the single-step, Yb(OTf) 3 -catalyzed transformation.…”

Section: Formal[3+ +3] Cycloadditions Of Nitronesa Nd Cyclopropane DImentioning

confidence: 99%

Diverse Applications of Nitrones for the Synthesis of Heterocyclic Compounds

Anderson

2015

Asian J Org Chem

133

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Although best known for their [3+ +2]-dipolar cycloaddition reactivity and use in the preparationo fi soxazolines and isoxazolidines,n itrones are versatile reagents that undergo av ariety of transformationsf or the synthesis of ad iverse array of heterocyclic compounds. Theb readth of heterocycle synthesis using nitrone reagentsi ncludes: 1) stepwise [3+ +3]-cycloaddition reactions of nitrones with vinyl diazoacetates, transition-metal-coordinated cycloisomerization intermediates, trimethylenem ethanes, and cyclopropane diesters to form dihydro-a nd tetrahydro-1,2-oxazines;2 )internal redox cyclization reactions of alkyne-tetheredn itrones to provide access to azabicyclooctanes,i soindoles, aminoindanones, and isoquinolones;3 )electrocyclizationso fi ns itu generated N-allenylnitrones to form pyridines and azetidine-N-oxides, as well as metal-catalyzed cyclizationsa nd rearrangements of nitrones to form azepine-N-oxides, spirocyclic isoxazolines, and a,b-epoxyimines;a nd 4) the use of [3+ +2]cycloaddition reactions of nitrones to trigger cascade reactions for the formationo ft etrahydrooxazepines, dihydrocarbazoles, and benzoindolizines. This Focus Review aims to highlight these diverse applicationso fn itrones for the synthesis of heterocyclest oe mphasize the broad utility of these reactive intermediates andt oi nspire their furtherd evelopment as important synthons beyond the scope of traditional [3+ +2]-dipolar cycloaddition reactions. Scheme1.[3+ +2]-Dipolar cycloadditions of nitrones and their application to the synthesis of naturalproducts and biologically active compounds:Diverse applicationsofn itrones for the synthesis of heterocyclic compounds.[a] Prof. Dr.L.L.A nderson 2. Formal [3+ +3]-Cycloadditions of Nitrones and [4+ +2]-Cycloadditions of N-Alkenylnitrones.Formal [3+ +3]-cycloadditions of nitrones have been investigated as alternative methods for the synthesis of dihydro-and tetrahydro-1,2-oxazines and offer new routes to these heterocycles that are unique from traditional [4+ +2]-cycloadditions of dienes and nitrosobenzenes. [8] The nitrone cycloaddition partners discussed below include vinyldiazoacetates, alkenyl gold complexes,m etal carbenoids generated through cycloisomerization processes, trimethylene methanes, and cyclopropane diesters (Scheme 3A). The synthesiso fN-alkenylnitrones has also prompted an investigation of these electron-deficient azadienesa si nverse-demand cycloaddition partners for the synthesis of six-membered-ring nitrones that are poised to undergo furtherf unctionalization (Scheme 3B). Prof. Laura L. Anderson receivedh er B.A. from Knox College in 2000 and moved to the University of California, Berkeley,f or her graduate studies where she worked with Prof. John Arnold and Prof. Robert G. Bergman developing new hydroamination catalystsa nd studying the reactivity of transition metal imido complexes. After obtaining her Ph.D. in 2005, Prof. Anderson movedt ot he Universityo f California, Irvine, wheres he completed aR uth L. Kirschstein NIH postdoctoral fellowship with Pr...

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“…One such sequence involves a cyclization followed by in situ intramolecular cycloaddition to give three new rings in a single transformation [2–8]. We have been studying the intramolecular dipolar cycloaddition of azomethine ylides in synthesis [9–16] and were able to show that the azomethine ylide could be prepared in situ by a cyclization step [17–18]; for example, by heating the aldehyde 1 (R = Et) with glycine ethyl ester to give the tricyclic product 2 [19–20] (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of fused tricyclic amines unsubstituted at the ring-junction positions by a cascade condensation, cyclization, cycloaddition then decarbonylation strategy

Coldham¹,

Burrell²,

Guerrand³

et al. 2012

Beilstein J. Org. Chem.

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SummaryHeating aldehydes that contain a protected hydroxymethyl group, a tethered alkyl chloride and a tethered alkenyl group at the α-position of the aldehyde with an amine sets up a cascade (tandem) reaction sequence involving condensation to an intermediate imine, then cyclization and formation of an intermediate azomethine ylide and then intramolecular dipolar cycloaddition. The fused tricyclic products are formed with complete or very high stereochemical control. The hydroxymethyl group was converted into an aldehyde – which could be removed to give the tricyclic amine products that are unsubstituted at the ring junction positions – or was converted into an alkene, which allowed the formation of the core ring system of the alkaloids scandine and meloscine.

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A Gram‐Scale Batch and Flow Total Synthesis of Perhydrohistrionicotoxin

Cited by 65 publications

References 59 publications

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

Diverse Applications of Nitrones for the Synthesis of Heterocyclic Compounds

Synthesis of fused tricyclic amines unsubstituted at the ring-junction positions by a cascade condensation, cyclization, cycloaddition then decarbonylation strategy

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