Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: Synthesis of (–)-flustramine B

Austin, Joel F.; Kim, Sung Gon; Sinz, Christopher J.; Xiao, Wen; MacMillan, David W. C.

doi:10.1073/pnas.0308177101

Cited by 441 publications

(123 citation statements)

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“…8 In 2004, MacMillan et al reported the enantioselective synthesis of (-)-flustramine B, using 6-bromotryptamine and acrolein as starting materials, and compound 2 as organocatalyst, by a cascade addition-cyclization strategy (Scheme 1). 9 More recently, the same research group used imidazolidinone 2 for aldehyde-aldehyde aldol reactions obtaining as major compound the enantiomer of the most favored product in the proline catalyzed process. 10 List and coworkers have also obtained good yields and enantioselectivities in asymmetric hydrogenations of α,β-unsaturated aldehydes using amine 2 as organocatalyst.…”

Section: Introductionmentioning

confidence: 99%

Origins of Stereoselectivity in Diels−Alder Cycloadditions Catalyzed by Chiral Imidazolidinones

2006

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B3LYP/6-31G(d) density functional theory has been used to study Diels-Alder reactions of cyclopentadiene with α,β-unsaturated aldehydes and ketones organocatalyzed by MacMillan's chiral imidazolidinones. Preferred conformations of transition structures and reaction intermediates have been located. The dramatically different reactivities and enantioselectivities exhibited by two similar chiral imidazolidinones are rationalized.

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Section: Introductionmentioning

confidence: 99%

Origins of Stereoselectivity in Diels−Alder Cycloadditions Catalyzed by Chiral Imidazolidinones

2006

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“…Furthermore, all of the newly isolated flustramines described here exhibited levorotation. Although we only report the relative configuration for the novel flustramines, it is worth noting that enantioselective syntheses of derivatives of flustramine B 16,17,24 and flustramine A 24 have consistently shown levorotatory species having an absolute configuration equivalent to that shown for 1-10, 12, and 13, although the R and S designations vary with the types of substituents at C-3a and N-8.…”

Section: Flustra Alkaloids From the Bryozoan Flustra Foliaceamentioning

confidence: 99%

“…15 The later synthesis of ent-debromoflustramine B established the configuration of natural flustramine B as being 3aS,8 a R. 16 More recently, Austin et al reported the synthesis of chiral flustramine B identical to the natural product using a cascade addition-cyclization approach. 17 Other studies have targeted racemic debromodihydroflustramine C, 18,19 racemic flustramine C, 20 various racemic flustramines, 21 racemic dihydroflustramine C and flustramine E, 22 racemic flustramines A and C, 23 and scalemic flustramines A and B. 24 We report here studies building on our previous work with F. foliacea collected from Canadian waters.…”

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confidence: 99%

Further Studies on the Chemistry of the Flustra Alkaloids from the Bryozoan Flustra foliacea

et al. 2009

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“…[2] Not surprisingly, the majority of studies in this field have been focused on the Friedel-Crafts reaction of indoles with a range of electrophiles. [3] Indeed, even C3-substituted indoles demonstrate high nucleophilicity; [4] C3-selective reactions have been realized by means of electrophilic compounds and subsequent tandem addition to the newly formed imine group. This processes lead to the construction of fused indolines having C3-quaternary stereocenters.…”

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Lewis Acid Catalyzed Intramolecular Direct Ene Reaction of Indoles

et al. 2010

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Synthetic modifications on indole skeletons have provoked increasing interest because the related heterocyclic systems are present in numerous alkaloid products, pharmaceuticals, and agrochemicals.[1] Indole heterocycles, which basically consist of a benzo [b]pyrrole framework, are considered electron-rich compounds that exhibit substantial reactivity, especially at the C3-position.[2] Not surprisingly, the majority of studies in this field have been focused on the Friedel-Crafts reaction of indoles with a range of electrophiles.[3] Indeed, even C3-substituted indoles demonstrate high nucleophilicity;[4] C3-selective reactions have been realized by means of electrophilic compounds and subsequent tandem addition to the newly formed imine group. This processes lead to the construction of fused indolines having C3-quaternary stereocenters. In addition, C3-substituted indoles also show reactivity at the C2-position, [5] and the most well-established reaction is the Pictet-Spengler reaction.[6] On the other hand, the heteroaromatic indolyl structure contains an enamine functionality, which is likely to isomerize to an electrophilic imine (or iminium) group through proton transfer under the proper reaction conditions (such as by the activation of Brønsted or Lewis acids).[7] As a consequence, a chemoselective, direct nucleophilic C2-functionalization pathway could be developed for the synthesis of indoline compounds, as proposed in Equation (1; Nu = nucleophile). Nevertheless, such a synthetic approach has not yet been addressed.Recently, our research group [8] has reported an a-regioand stereoselective Michael addition of g,g-disubstituted a,bunsaturated aldehydes to nitroolefins through dienamine catalysis.[9] We further found that this activation mode was quite successful in the direct asymmetric alkylation reaction of 3-indolylmethanols [10] and g,g-disubstituted a,b-unsaturated aldehydes. As shown in Scheme 1, under the catalysis of a,a-diphenylprolinol O-TMS ether 1 (5 mol %) and AcOH (10 mol %), the exclusive a-regioselective alkylation product 4 a could be smoothly isolated in a diastereomerically pure form from 3-indolylphenylmethanol 2 a and 4-methyl-2-pentenal 3 a after reduction with NaBH 4 , and the reaction also gave excellent enantioselectivity. [11] In an attempt to conduct Friedel-Crafts annulation of 4 a under the catalysis of a Lewis acid such as AlCl 3 (1.0 equiv), we discovered that an unexpected and highly substituted cyclopentyl[b]indoline [12] compound 5 a could be cleanly obtained with complete diastereocontrol within 30 minutes, [13,14] while the FriedelCrafts product A was not detected (Scheme 1).[15] We recognized that an unprecedented and unique intramolecular imino-ene reaction of the indole heterocycle had occurredprobably through AlCl 3 -promoted enamine-imine isomerization and a subsequent ene cyclization (Scheme 1; intermediate B). The efficient participation of the inactivated imine in the relatively less explored imino-ene-type reaction was an unusual result. [16] To gain some insigh...

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Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: Synthesis of (–)-flustramine B

Cited by 441 publications

References 65 publications

Origins of Stereoselectivity in Diels−Alder Cycloadditions Catalyzed by Chiral Imidazolidinones

Origins of Stereoselectivity in Diels−Alder Cycloadditions Catalyzed by Chiral Imidazolidinones

Further Studies on the Chemistry of the Flustra Alkaloids from the Bryozoan Flustra foliacea

Lewis Acid Catalyzed Intramolecular Direct Ene Reaction of Indoles

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