First Total Synthesis of Hinckdentine A

Higuchi, Kazuhiro; Sato, Yukihiro; Tsuchimochi, Mei; Sugiura, Kenta; Hatori, Masatoshi; Kawasaki, Tomomi

doi:10.1021/ol802394n

Cited by 104 publications

(51 citation statements)

References 26 publications

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“…42 Under these conditions, we were able to obtain the first synthetic sample of (−)-trigonoliimine A ( 1 ), albeit in low yield (16%). A possible pathway for the formation of (−)-trigonoliimine A ( 1) (Path A) and byproduct (+)- 52 (Path B) from azepane (−)- 5 is shown in Scheme 8.…”

Section: Resultsmentioning

confidence: 93%

“…46 Similarly, when tryptophol derivative 68 was subjected to Miller’s asymmetric oxidation 23 followed by base mediated 1,2-alkyl shift sequence, indoxyl (−)- 70 was obtained in 79% ee, providing a formal synthesis of (−)-hinckdentine ( 67 , Scheme 13). 42 Notably, the indoxyl 70 in racemic form has served as a key intermediate in Kawasaki’s total synthesis of (±)-hinckdentine ( 67 ). 42 …”

Section: Resultsmentioning

confidence: 99%

“…42 Notably, the indoxyl 70 in racemic form has served as a key intermediate in Kawasaki’s total synthesis of (±)-hinckdentine ( 67 ). 42 …”

Section: Resultsmentioning

confidence: 99%

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Total Synthesis, Stereochemical Assignment, and Biological Activity of All Known (−)-Trigonoliimines

et al. 2013

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A full account of our concise and enantioselective total syntheses of all known (−)-trigonoliimine alkaloids is described. Our retrobiosynthetic analysis of these natural products enabled identification of a single bistryptamine precursor as a precursor to all known trigonoliimines through a sequence of transformations involving asymmetric oxidation and reorganization. Our enantioselective syntheses of these alkaloids enabled the revision of the absolute stereochemistry of (−)-trigonoliimines A, B, and C. We report that trigonoliimines A, B, C, and structurally related compounds showed weak anticancer activities against HeLa and U-937 cells.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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Total Synthesis, Stereochemical Assignment, and Biological Activity of All Known (−)-Trigonoliimines

et al. 2013

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“…[2] Notably,o ur procedure is also applicable to the synthesis of an ovel type of nitrogen-containing tricyclic molecular structure bearing an a-tetrasubstituted carbon stereocenter,w hich is an important structural motif in many biologically active natural alkaloids,s uch as hinckdentine A. [18] Therefore, treatment of 2a with excess Bi(NO 3 ) 3 ·(5 H 2 O) yielded the desired urea 5, [19] which was smoothly oxidized with [bis(trifluoroacetoxy)iodo]benzene (PIFA) into tricyclic amine 6 in 64 %yield without adecrease in the ee value (Scheme 3c). [20] In conclusion, we have developed the first highly enantioselective Brønsted acid catalyzed hydroamination of alkenes that provides access to av ariety of pyrrolidine derivatives with an a-tetrasubstituted carbon stereocenter with good to excellent yields and enantioselectivities under mild reaction conditions.Athiourea group that acts as both the activating and directing group is crucial for the hydroamination to proceed with high levels of stereoinduction by cooperative multiple hydrogen bonding with the Brønsted acid and the double bond.…”

Section: Methodsmentioning

confidence: 99%

Brønsted Acid Catalyzed Asymmetric Hydroamination of Alkenes: Synthesis of Pyrrolidines Bearing a Tetrasubstituted Carbon Stereocenter

et al. 2015

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The first highly enantioselective Brønsted acid catalyzedi ntramolecular hydroamination of alkenes enables the efficient construction of as eries of chiral (spirocyclic) pyrrolidines with an a-tetrasubstituted carbon stereocenter with excellent functional group tolerance.Aunique feature of this strategy is the use of at hiourea group acting as both the activating and the directing group through cooperative multiple hydrogen bonding with aB r ø nsted acid and the double bond. The utility of this method is highlighted by the facile construction of chiral synthetic intermediates and important structural motifs that are widely found in organic synthesis.Chiral amines bearing an a-tetrasubstituted carbon stereocenter are important structural motifs in numerous biologically active compounds and potent pharmaceutical agents. [1] Consequently,m ethods that enable their asymmetric construction are in great demand, [1,2] as this process still remains af ormidable synthetic challenge because of the difficulties associated with overcoming the steric hindrance and controlling the correct orientation of the four attached substituents. Recent years have witnessed as ignificant increase in the utilization of asymmetric intramolecular hydroamination reactions of alkenes as ah ighly valuable synthetic approach for the construction of chiral azaheterocycles with applications as biologically active compounds and powerful organocatalysts or ligands.[3] Numerous elegant metal-catalyzed asymmetric intramolecular olefin hydroaminations have been developed that either proceed by olefin activation through coordination to increase the electrophilicity of the olefin or by N À Hb ond activation to increase the nucleophilicity of the amine. [3,4] Despite these studies,amethod with which the more challenging hydroamination products that bear ac hiral quaternary center can be obtained with high enantioselectivity has not been reported to date. [5] On the other hand, unlike the well-established metalcatalyzed counterparts,t he organocatalytic hydroamination of alkenes still represents aformidable challenge.[3d,6] Thefirst enantioselective variant of this transformation, which involved the use of ac hiral phosphoric acid as the catalyst, resulted in poor stereocontrol with up to 17 % ee.[6a] However, only recently Toste et al. achieved asignificant breakthrough by using ad ithiophosphoric acid to enable the hydroamination of dienes and allenes.T heir approach involved the transient covalent attachment of achiral leaving group to the allylic system to obtain high enantioselectivities, [3d,6b] which was supported by the findingt hat the presence of the sulfur atom in the catalyst was necessary because the oxygenated analogues of the dithiophosphoric acid were less efficient. Alternatively,J acobsen and co-workers have developed asymmetric thiourea-catalyzed Cope-type alkene hydroamination reactions that proceed through dipolar transition states with multiple hydrogen bonding interactions.[6c] Although these pioneering reports provide str...

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“…Kawasaki accordingly employed a protected cyclic aminal intermediate for selective C2, C8, and C10 tribromination, and succeeded in the rst racemic total synthesis of 5. 58 Hence, we selected indoline/anilide 77 as our key intermediate. Compound 77 was expected to favor ortho para dibromination at C8 and C10 on the left hand indoline (as drawn in Scheme 5) as well as single para bromination at C2 on the right hand anilide prior to the introduction of the amidine unit.…”

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confidence: 99%

Synthetic Studies on Heteropolycyclic Natural Products: Strategies via Novel Reactions and Reactivities

Shimokawa¹,

Fukuyama

2017

J. Synth. Org. Chem. Jpn.

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Five total syntheses of heteropolycyclic natural products, namely hyalodendrin, tryprostatins, spirotryprostatin A, the core of the stemofoline alkaloids, and hinckdentine A, are outlined. These syntheses share common characteristics; the sequences of transformations are facilitated through the development of new synthetic reactions and the discoveries of unknown molecular reactivities. Brief descriptions of new reactions, the mechanistic details of key transformations, and the resulting shortcuts and ef ciencies made possible in relation to the overall picture of these total syntheses are described.

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First Total Synthesis of Hinckdentine A

Abstract: We have accomplished the first total synthesis of (+/-)-hinckdentine A (1). The key steps are m-CPBA oxidation of 2-arylindole followed by acid-mediated Mannich-type C-C bond formation of 2-hydroxyindolin-3-one, seven-membered ring closure, and regioselective tribromination.

Cited by 104 publications

References 26 publications

Total Synthesis, Stereochemical Assignment, and Biological Activity of All Known (−)-Trigonoliimines

Total Synthesis, Stereochemical Assignment, and Biological Activity of All Known (−)-Trigonoliimines

Brønsted Acid Catalyzed Asymmetric Hydroamination of Alkenes: Synthesis of Pyrrolidines Bearing a Tetrasubstituted Carbon Stereocenter

Synthetic Studies on Heteropolycyclic Natural Products: Strategies via Novel Reactions and Reactivities

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