Synthesis and peptide coupling of protected 2-pyrrolylalanine

Dörr, Aurélie A.; Lubell, William D.

doi:10.1016/j.tetlet.2010.11.089

Cited by 6 publications

(6 citation statements)

References 54 publications

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“…Although the 2-pyrrolylalanine targets were achieved because of sulfonamide protection, low yields were obtained in attempts to remove the sulfonyl group (i.e., TBAF in THF, SmI 2 in DMPU/THF, and Mg in MeOH), which plagued efforts to employ amino acids 3 and 10 in peptide synthesis. 17 To facilitate protecting group removal during peptide synthesis, N,N′-bis-(Boc)-3-(2-pyrrolyl)alanine 14 was subsequently targeted. Pyrrole 7 was protected with di-tert-butyl dicarbonate and catalytic 4-(dimethylamino)pyridine (DMAP) in acetonitrile to produce N-(Boc)pyrrole 12 in 98% yield (Scheme 3).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…8−14 Stabilization of the cis-isomer has been suggested to be due to an electrostatic interaction between the prolyl amide nitrogen and the Phe aromatic πsystem, 5a,f,9 in part because the prolyl amide isomer population has been modulated by varying the electronic density of the side chain of the residue N-terminal to proline in peptides. 15−17 For example, in Ac-Xaa-Pro-NHMe, the cis-amide isomer population was reduced on changing the Xaa residue from Phe to electron deficient arylalanine residues, 17 such as pyradizinylalanine. 16 Histidine analogs (i.e., thienylalanine, furylalanine, triazolylalanine, tetrazolylalanine, thiazolylalanine, imidazolylalanine, and pyrazolylalanine) have been used to study the importance of the hydrogen bond acceptor and donator properties of the imidazole side chain.…”

Section: ■ Introductionmentioning

confidence: 99%

“…23d (2S)-N-(Boc)-N′-Acetyl-3-(2pyrrolyl)alanine was also synthesized from L-aspartic acid by a route featuring ring-closing metathesis and aromatization to form the heterocycle. 23e Prior to our preliminary research, 17 the best of our knowledge, 22,23 pyrrolylalanine has been used only once in the synthesis of a peptide analog. Racemic N-Cbz-N′-(Boc)-3-(2-pyrrolyl)alanine was introduced into a thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NHMe) analog to investigate the role of the histidine residue; however, no biological activity was reported.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Recently, we communicated the synthesis of N,N′-bis-(phenylsulfonyl)-3-(2-pyrrolyl)alanine (3, Figure 1) by a route featuring a copper-catalyzed cascade addition of vinylmagnesium bromide to aspartic acid-derived βamino ester 4 (Scheme 1). 17 Although pyrrolylalanine was obtained in 13% overall yield from 4 and introduced into a dipeptide, attempts to remove the sulfonyl groups were unsuccessful. Alternative strategies have now been developed for the synthesis of enantiopure (2S)-3-(2-pyrrolyl)alanine derivatives, which are more suitable for peptide synthesis as validated by incorporation into Ac-Xaa-Pro-NHMe dipeptide models.…”

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis of Protected 2-Pyrrolylalanine for Peptide Chemistry and Examination of Its Influence on Prolyl Amide Isomer Equilibrium

Dörr

Lubell

2012

J. Org. Chem.

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Protected enantiopure 2-pyrrolylalanine was synthesized for application in peptide science as an electron-rich arylalanine (histidine) analog with π-donor capability. (2S)-N-(Boc)-N'-(Phenylsulfonyl)-, (2S)-N,N'-bis-(phenylsulfonyl)-, and (2S)-N,N'-bis-(Boc)-3-(2-pyrrolyl)alanines (10, 3, and 14, respectively) were made in 13-17% overall yields and six to seven steps from oxazolidine β-methyl ester 4. Homoallylic ketone 5 was prepared by a copper-catalyzed cascade addition of vinylmagnesium bromide to ester 4 and converted to pyrrolyl amino alcohol 7 by olefin oxidation and Paal-Knorr condensation. Protecting group shuffle and oxidation of the primary alcohol enabled the synthesis of pyrrolylalanines. The bis-Boc analog 14 proved useful in peptide chemistry and was employed to make N-acetyl-pyrrolylalaninyl-proline N''-methylamide 25. A study of the influence of the pyrrole moiety on the prolyl amide isomer equilibrium of 25 using (1)H NMR spectroscopy in chloroform, DMSO, and water demonstrated that the pyrrolylalanine peptide exhibited behavior and conformations different from those of other arylalanine analogs.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis of Protected 2-Pyrrolylalanine for Peptide Chemistry and Examination of Its Influence on Prolyl Amide Isomer Equilibrium

Dörr

Lubell

2012

J. Org. Chem.

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“…Aromatic side chains can have significant influence on peptide folding and recognition. 49 Aromatic effects on amide isomer equilibrium N-terminal to prolyl residues were studied by the synthesis and spectroscopic analysis of Ac-Xaa-Pro-NHMe dipeptide models 103−105 bearing π−enriched pyrrolylalanine, 15,50 π−deficient pyridazinylalanine, 14 and phenylalanine as control (Scheme 19).…”

Section: Peptidomimeticsmentioning

confidence: 99%

Applications of γ,δ-Unsaturated Ketones Synthesized by Copper-Catalyzed Cascade Addition of Vinyl Grignard Reagents to Esters

2018

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CONSPECTUS: γ,δ-Unsaturated ketones, so-called homoallylic ketones, have served as versatile building blocks for the synthesis of a variety of heterocycles, carbocycles, natural products, and reactive intermediates. Procured by a variety of processes, including conjugate addition of vinyl organometallic reagents to unsaturated ketones, allylation of silyl enol ethers, and rearrangements, homoallylic ketones are often synthesized by step-intensive methods. The cascade addition of 2 equiv of vinyl Grignard reagent to a carboxylate was reported by the Lubell laboratory in 2003 to give effective access to homoallylic ketones from a variety of aromatic, aliphatic, and α-amino methyl esters. Employing readily accessible vinyl magnesium halides in the presence of a catalytic amount of copper salt, this cascade reaction provides high yields of homoallylic ketones with minimal side product by a process featuring the assembly and collapse of a tetrahedral intermediate with expulsion of alkoxide ion, followed by conjugate addition to the resulting enone. Application of the cascade reaction to the synthesis of various homoallylic ketones has provided versatile building blocks for the synthesis of targets for different applications. For example, by employing (hetero)aryl di-and tricarboxylates as precursors, copper-catalyzed cascade additions have provided donor−acceptor and star-shaped monomers for optical-electronic materials. Amino ester starting materials have given homoallylic ketones for the synthesis of various peptidomimetics, including heteroarylalanines, hydroxyethylene isoesters, and diazepinone turn mimics. Moreover, anthranilate has served as building block to prepare various pyrrole, quinoline, benzodiazepine, and benzotriazepine heterocyles. In addition, cascade additions on hydroxyprolinates have given access to bipyrrole precursors of the prodigiosin family of natural products. In the interest to highlight the utility of the copper-catalyzed cascade addition of vinyl Grignard reagents to carboxylates, this Account provides details on the broad scope of substrates that deliver homoallylic ketone products as well as an overview of the wide range of applications in which this method may impact including materials and peptide science, heterocycle and natural product synthesis, and medicinal chemistry.

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Conjugated C3 symmetric aryl tripyrroles and aryl bipyrroles: synthesis, optical and electronic properties

Saroukou¹,

Skalski²,

Skene³

et al. 2014

Tetrahedron

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Synthesis and peptide coupling of protected 2-pyrrolylalanine

Cited by 6 publications

References 54 publications

Synthesis of Protected 2-Pyrrolylalanine for Peptide Chemistry and Examination of Its Influence on Prolyl Amide Isomer Equilibrium

Synthesis of Protected 2-Pyrrolylalanine for Peptide Chemistry and Examination of Its Influence on Prolyl Amide Isomer Equilibrium

Applications of γ,δ-Unsaturated Ketones Synthesized by Copper-Catalyzed Cascade Addition of Vinyl Grignard Reagents to Esters

Conjugated C3 symmetric aryl tripyrroles and aryl bipyrroles: synthesis, optical and electronic properties

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