A Total Synthesis of Millingtonine A

Wegner, Jens; Ley, Steven V.; Kirschning, Andreas; Hansen, Anne-Lene L.; Montenegro, Javier; Baxendale, Ian R.

doi:10.1021/ol203158p

Cited by 39 publications

(18 citation statements)

References 20 publications

(14 reference statements)

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“…Finally, removal of the pivaloyl groups under basic conditions gave over 50 mg of millingtonine ( 1 ) in 67 % yield. Thus we had successfully synthesized millingtonine ( 1 ) in a longest linear sequence of seven steps from commercially available materials (ten steps in total), which compares favorably to the previous state‐of‐the‐art …”

Section: Methodsmentioning

confidence: 78%

“…There has been one previous total synthesis of millingtonine ( 1 ), reported in 2012 by the research groups of Ley, Kirschning, and Baxendale . The execution of a total synthesis of this alkaloid is an impressive achievement, with the intermediate structures en route to millingtonine ( 1 ) reported to be “exceedingly prone” to rearrangement reactions.…”

Section: Methodsmentioning

confidence: 99%

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Total Synthesis of Millingtonine

Brown

Lawrence

2016

Angewandte Chemie

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Millingtonine is ag lycosidic alkaloid that exists as apair of pseudo-enantiomeric diastereomers.Consideration of the likely biosynthetic origins of this unusual natural product has resulted in the development of aseven-step total synthesis. Results from this synthetic work provideevidence in support of aproposed network of biosynthetic pathwaysthat can account for the formation of several phenylethanoid natural products.Scheme 4. Biomimetic total synthesis of millingtonine (1). Boc = tert-butyloxycarbonyl, TMSOTf = trimethylsilyl trifluoromethanesulfonate, Glc = dglucopyranosyl, Piv = pivaloyl, TFA = trifluoroacetic acid.

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Section: Methodsmentioning

confidence: 78%

Section: Methodsmentioning

confidence: 99%

Total Synthesis of Millingtonine

Brown

Lawrence

2016

Angewandte Chemie

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“…2,5‐Dihydropyrroles– and 2,3‐dihydropyrroles,, are privileged structural cores of bioactive natural (for example, thrombin inhibitors) and unnatural products (for example, Sibiromycin gene cluster and others), which exhibit important biological activity. In addition, 2,3‐dihydropyrroles can be widely employ as important intermediates in the synthesis of natural alkaloids and other complex molecules . For these reasons, the development of methods for the facile and efficient synthesis of dihydropyrroles is a hot topic in modern organic chemistry, which has received considerable attention…”

Section: Five‐membered N‐heterocyclesmentioning

confidence: 99%

α,β‐Unsaturated Aldehydes in the Synthesis of Five‐Membered Heterocyclic Compounds with One Heteroatom: Recent Advances from Developments in Metal‐ and Organocatalysis

Keiko

Вчисло

2016

Asian J Org Chem

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The ever-increasing interest in the chemistry of five-membered heterocyclic compounds is due to their paramount importance in such essentialf ields as pharmacology, medicine, biology,o rganic synthesis of fine chemicals, agricultural chemistry,a nd the chemical industry.T his Review summarizesa nd highlights methodsf or the synthesis of five-membered O-, N-, and S-heterocycles based on transformations of a,b-enals. Over the last decade, these reactions, which often differ from the processes involving other a,bunsaturated carbonyl compounds in methodology andr esults, have been gathering momentum. Many of the catalytic and technological novelties discussed in the review,s uch as asymmetricm etal-and organocatalysis, multiple catalysts, one-pot multicomponent reactions proceeding through domino,c ascade, or tandem reactions, andm icrowave activation, promote the formation of diverset arget products, the structures of which becomes clear from the mechanistic schemesg iven in the review.T he mechanisms discussed reflect great advances in the chemo-, regio-, and stereoselectivity of the reactions with participation of a,b-alkenals, achieved in the last 15 years, which allowsn ew five-membered heteroarenes and related compounds (pyrroles, dihydropyrroles, pyrrolidines,f urans, thiophenes) to be synthesized.

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confidence: 99%

Rhodium‐Catalyzed Asymmetric Arylative Cyclization of meso‐1,6‐Dienynes Leading to Enantioenriched cis‐Hydrobenzofurans

et al. 2013

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Chiral cis-hydrobenzofurans represent a unique motif existing in numerous natural products, for instance, isoambrox, [1] haterumaimide I, [2] rosenonolactone, [3] incarviditone, [4] and millingtonine A [5] (Scheme 1 a). Owing to their diverse biological activities, [1][2][3][4][5] a great deal of attention has been paid to the development of efficient methods toward their enantioselective syntheses. One of the most straightforward and powerful ways to construct such a framework is the catalytic asymmetric desymmetrization of cyclohexadienones (Scheme 1 b). In recent elegant reports, Rovis and co-workers demonstrated the feasibility of using chiral-NHC-catalyzed intramolecular Stetter reactions for the asymmetric desymmetrization of cyclohexadienones to prepare chiral cis-hydrobenzofuranones. [6] Very recently, Sasai and co-workers described the use of bifunctional chiral phosphinothiourea catalysts in a intramolecular Rauhut-Currier reaction for the enantioselective discrimination of cyclohexadienones. [7] Although these protocols [6][7][8] proved to be highly effective, their efforts were mainly focused on the application of chiral organocatalysts in intramolecular reactions with a limited substrate scope. Moreover, transition metal catalyzed asymmetric desymmetrization of cyclohexadienones is quite scarce. [9] During our continuous efforts in exploring rhodium/chiral diene-catalyzed asymmetric arylation, [10] we envisioned that a rhodium-catalyzed tandem arylrhodation/conjugate addition reaction of cyclohexadienone-containing [13,14] 1,6-dienynes, [11,12] which are accessible from dearomatization of corresponding phenols, [15] would provide a novel approach to these enantioenriched cis-hydrobenzofurans (Scheme 1 c). However, two major concerns need to be addressed in this rhodium-catalyzed asymmetric desymmetrization process.One is the competitive reaction between the arylrhodation of the carbon-carbon triple bond and two conjugate addition reactions of the cyclohexadienone with the arylboronic acid. The other is whether the chiral ligand coordinating to rhodium could efficiently discriminate between the mesocyclohexadienones in the cyclization step.With this in mind, several varieties of chiral ligands (Scheme 2) were evaluated for this rhodium-catalyzed asymmetric tandem arylrhodation/conjugate addition of (4-Scheme 1. Catalytic asymmetric desymmetrization of cyclohexadienones for preparing chiral cis-hydrobenzofurans. a) cis-Hydrobenzofurans as structural motifs in natural products. b) Organocatalytic asymmetric desymmetrization of cyclohexadienones. c) Our approach to enantioenriched cis-hydrobenzofurans.

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A Total Synthesis of Millingtonine A

Cited by 39 publications

References 20 publications

Total Synthesis of Millingtonine

Total Synthesis of Millingtonine

α,β‐Unsaturated Aldehydes in the Synthesis of Five‐Membered Heterocyclic Compounds with One Heteroatom: Recent Advances from Developments in Metal‐ and Organocatalysis

Rhodium‐Catalyzed Asymmetric Arylative Cyclization of meso‐1,6‐Dienynes Leading to Enantioenriched cis‐Hydrobenzofurans

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