1-tert-Butyl 2-methyl 4-(R)-hydroxypyrrolidine-1,2-(2S)-dicarboxylate

Clegg, William; Deboves, Hervé J. C.; Elsegood, Mark R. J.

doi:10.1107/s1600536803026412

Cited by 3 publications

(5 citation statements)

References 5 publications

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“…The most common 4-substituted Pro is the naturally occurring Hyp. With the electron-withdrawing hydroxyl group occupying the 4R position, Hyp prefers the exo ring pucker and adopts either the α R (Clegg et al 2003;Lübben et al 2014) or the P II conformation (Panasik et al 1994), exhibiting the trans imide bond. In contrast, 4S-hydroxyproline (hyp), which does not occur in nature, prefers the endo ring pucker with a cis amide bond and appears mostly in the δ-basin (Shoulders et al 2010).…”

Section: Crystal Structures Of Terminally Blocked 4-substituted Prolinementioning

confidence: 99%

Conformational landscape of substituted prolines

Ganguly

Basu

2020

Biophys Rev

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The cyclic side chain of the amino acid proline confers unique conformational restraints on its backbone and side chain dihedral angles. This affects two equilibria-one at the backbone (cis/trans) and the other at the side chain (endo/exo). Substitutions on the proline ring impose additional steric and stereoelectronic effects that can further modulate both these equilibria, which in turn can also affect the backbone dihedral angle (ϕ, ψ) preferences. In this review, we have explored the conformational landscape of several termini capped mono-(2-, 3-, 4-, and 5-) substituted proline derivatives in the Cambridge Structural Database, correlating observed conformations with the nature of substituents and deciphering the underlying interactions for the observed structural biases. The impact of incorporating these derivatives within model peptides and proteins are also discussed for selected cases. Several of these substituents have been used to introduce bioorthogonal functionality and modulate structure-specific ligand recognition or used as spectroscopic probes. The incorporation of these diversely applicable functional groups, coupled with their ability to define an amino acid conformation via stereoelectronic effects, have a broad appeal among chemical biologists, molecular biophysicists, and medicinal chemists.

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Section: Crystal Structures Of Terminally Blocked 4-substituted Prolinementioning

confidence: 99%

Conformational landscape of substituted prolines

Ganguly

Basu

2020

Biophys Rev

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“…This ϕ torsion angle would also be compatible with polyproline II conformation and with the conformation at the i +1 position of type II and type VIa1 β-turns (( ϕ , ψ ) ~ (−60°, +120°)), which is the observed ( ϕ , ψ ) for other proline amino acids with electron-withdrawing 4 R -substitutents. 7a, 7e, 17a, 22a, 23a These data indicate the ability of this amino acid to promote compact conformations of proline and trans amide bonds ( ω = 180°).…”

Section: Figurementioning

confidence: 84%

“…7a, b, 21 These data, including the compact ϕ ~ −60°, suggest the application of 4 R -iodophenyl hydroxyproline in contexts where a more compact proline conformation (α R or PPII) is preferred, including at the i +1 position of type I, type II, or type VIa1 β-turns. 12a, b, 14, 22 Indeed, Raines and coworkers observed that related 4 R -hydroxyproline derivatives (-OH, -OMe, -OAc) can alternatively adopt α R or PPII conformations, with both conformations exhibiting favorable n→π* interactions. 22 These data also emphasize the conformational control possible with the judicious use of appropriate 4 R - and 4 S -substituted prolines, with each stereoisomer exhibiting divergent presentation of its functional group and distinct conformational preferences, suitable for structurally orthogonal applications (Figure 7).…”

Section: Resultsmentioning

confidence: 99%

“…12a, b, 14, 22 Indeed, Raines and coworkers observed that related 4 R -hydroxyproline derivatives (-OH, -OMe, -OAc) can alternatively adopt α R or PPII conformations, with both conformations exhibiting favorable n→π* interactions. 22 These data also emphasize the conformational control possible with the judicious use of appropriate 4 R - and 4 S -substituted prolines, with each stereoisomer exhibiting divergent presentation of its functional group and distinct conformational preferences, suitable for structurally orthogonal applications (Figure 7). 7–8, 16b, c, 17c, 23 …”

Section: Resultsmentioning

confidence: 99%

“…This conformation is consistent in ϕ with that observed for 4 R -hydroxyprolines in collagen and for various other prolines with electron-withdrawing 4 R -substituents. 7a, b, 17a, 22–23, 35 This work represents the first crystal structure of a trans-substituted diastereomer (i.e. 2 S ,4 R - or 2 R ,4 S -) of an aryloxyproline.…”

Section: Discussionmentioning

confidence: 99%

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4R- and 4S-iodophenyl hydroxyproline, 4R-pentynoyl hydroxyproline, and S-propargyl-4-thiolphenylalanine: conformationally biased and tunable amino acids for bioorthogonal reactions

et al. 2016

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Bioorthogonal reactions allow the introduction of new functionalities into peptides, proteins, and other biological molecules. The most readily accessible amino acids for biooorthogonal reactions have modest conformational preferences or bases for molecular interactions. Herein we describe the synthesis of 4 novel amino acids containing functional groups for bioorthogonal reactions. (2S,4R)- and (2S,4S)-iodophenyl ethers of hydroxyproline are capable of modification via rapid, specific Suzuki and Sonogashira reactions in water. The synthesis of these amino acids, as Boc-, Fmoc- and free amino acids, was achieved through succinct sequences. These amino acids exhibit well-defined conformational preferences, with the 4S-iodophenyl hydroxyproline crystallographically exhibiting β-turn (ϕ, ψ ~ −80°, 0°) or relatively extended (ϕ, ψ ~ −80°, +170°) conformations, while the 4R- diastereomer prefers a more compact conformation (ϕ ~ −60°). The aryloxyproline diastereomers present the aryl groups in a highly divergent manner, suggesting their stereospecific use in molecular design, medicinal chemistry, and catalysis. Thus, the 4R- and 4S-iodophenyl hydroxyprolines can be differentially applied in distinct structural contexts. The pentynoate ester of 4R-hydroxyproline introduces an alkyne functional group within an amino acid that prefers compact conformations. The propargyl thioether of 4-thiolphenylalanine was synthesized via copper-mediated cross-coupling reaction of thioacetic acid with protected 4-iodophenylalanine, followed by thiolysis and alkylation. This amino acid combines an alkyne functional group with an aromatic amino acid and the ability to tune aromatic and side chain properties via sulfur oxidation. These amino acids provide novel loci for peptide functionalization, with greater control of conformation possible than with other amino acids containing these functional groups.

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The Distinct Conformational Landscapes of 4S‐Substituted Prolines That Promote an endo Ring Pucker

Costantini

Ganguly

Martin

et al. 2019

Chemistry A European J

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4-Substitution on prolined irectly impactsp rotein main chain conformational preferences.T he structurale ffects of N-acyl substitution and of 4-substitution were examined by NMR spectroscopy and X-ray crystallography on minimal molecules with ap roline 4S-nitrobenzoate.T he effects of N-acyl substitution on conformation werea ttenuated in the 4S-nitrobenzoate context, duet ot he minimal role of the n!p*i nteraction in stabilizing extended conformations. By X-ray crystallography,a ne xtended conformation was observedf or most molecules. The formyl derivative adopted a d conformation that is observed at the i + 2p osition of b-turns.C omputational analysis indicated that the structures observed crystallographically represent the inher-ent conformational preferences of 4S-substituted prolines with electron-withdrawing4-position substituents. The divergent conformational preferences of 4R-a nd 4S-substituted proliness uggest their wider structure-specific application in molecular design. In particular,t he proline endo ring pucker favored by 4S-substituted prolines uniquelyp romotes the d conformation [(f, y) % (À808,0 8)] found in b-turns.I nc ontrast to other acyl capping groups, the pivaloyl group strongly promoted trans amide bond and polyproline II helix conformation, with ac lose n!p*i nteraction in the crystalline state, despite the endo ring pucker,s uggesting its special capabilities in promoting compactc onformations in f due to its strongly electron-donatingc haracter.[a] N.Supporting information (including experimentalprocedures, NMR data on 3-9,N OESY spectra for 7 and 9,X -ray crystallographic data, additional analysis of computational data, 1 Ha nd 13 CNMR spectraf or all new compounds, and coordinates for all geometry-optimized structures) and the ORCID identification number(s) for the author(s) of this article can be found under:https://doi.

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1-tert-Butyl 2-methyl 4-(R)-hydroxypyrrolidine-1,2-(2S)-dicarboxylate

Abstract: Key indicatorsSingle-crystal X-ray study T = 160 K Mean '(C±C) = 0.002 A Ê R factor = 0.030 wR factor = 0.075 Data-to-parameter ratio = 11.2 For details of how these key indicators were automatically derived from the article, see

Cited by 3 publications

References 5 publications

Conformational landscape of substituted prolines

Conformational landscape of substituted prolines

4R- and 4S-iodophenyl hydroxyproline, 4R-pentynoyl hydroxyproline, and S-propargyl-4-thiolphenylalanine: conformationally biased and tunable amino acids for bioorthogonal reactions

The Distinct Conformational Landscapes of 4S‐Substituted Prolines That Promote an endo Ring Pucker

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