Chemical ligation from O-acyl isopeptides via 8- and 11-membered cyclic transition states

Panda, Siva S.; Elagawany, Mohamed; Marwani, Hadi M.; Çalışkan, Eray; El-Katib, Mirna; Oliferenko, Alexander A.; Alamry, Khalid A.; Katritzky, Alan R.

doi:10.3998/ark.5550190.p008.632

Cited by 6 publications

(2 citation statements)

References 25 publications

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“…A feature of the homologated (β 3 ) amino acids used in 9 is that the size of the NCL [S–N] trans -acyl shift transition states differs from those used in the previously reported α-peptide-forming rotaxane machines . Katritzky found that NCLs requiring 15- or 19-membered [S–N] acyl-transfer transition states, the size employed in the operation of 9 , are significantly slower than NCLs involving 11-, 14-, and 17-membered transition states (which featured in the operation of the α-peptide-forming machines) . We attribute the longer reaction time necessary for complete operation of 9 (7 days, cf., 3 days for α-peptide-forming machines) to these less favorable transition-state sizes.…”

Section: Resultsmentioning

confidence: 99%

Sequence-Specific β-Peptide Synthesis by a Rotaxane-Based Molecular Machine

Gall

Kitching

et al. 2017

J. Am. Chem. Soc.

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We report on the synthesis and operation of a three-barrier, rotaxane-based, artificial molecular machine capable of sequence-specific β-homo (β) peptide synthesis. The machine utilizes nonproteinogenic β-amino acids, a class of amino acids not generally accepted by the ribosome, particularly consecutively. Successful operation of the machine via native chemical ligation (NCL) demonstrates that even challenging 15- and 19-membered ligation transition states are suitable for information translation using this artificial molecular machine. The peptide-bond-forming catalyst region can be removed from the transcribed peptide by peptidases, artificial and biomachines working in concert to generate a product that cannot be made by either machine alone.

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Section: Resultsmentioning

confidence: 99%

Sequence-Specific β-Peptide Synthesis by a Rotaxane-Based Molecular Machine

Gall

Kitching

et al. 2017

J. Am. Chem. Soc.

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“…Homocysteine-containing isopeptide 19 was also prepared, and ligation via a 6-membered cyclic transition state was studied. The formation of ligated product with 98% abundance was observed by HPLC-MS analysis, showing that S → N -acyl group migration via a 6-membered transition state is preferred over intermolecular acylation (Scheme ) …”

Section: Chemical Ligations From Cysteine Isopeptidesmentioning

confidence: 99%

Traceless Chemical Ligation from S-, O-, and N-Acyl Isopeptides

et al. 2014

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Peptides are ubiquitous in nature where they play crucial roles as catalysts (enzymes), cell membrane ion transporters, and structural elements (proteins) within biological systems. In addition, both linear and cyclic peptides have found use as pharmaceuticals and components of various conjugate molecular systems. Small wonder then that chemists throughout the ages have sought to mimic nature by synthesis of the amide polymers known as peptides and proteins. The fundamental reaction in the formation of a peptide bond is condensation of an amine of one amino acid with the activated carbonyl group of another. This "fragment condensation" has been achieved in many ways both in solution and by solid-phase peptide synthesis (SPSS) on resin. The most successful method for in-solution coupling is known as native chemical ligation (NCL), and the technique dates back to the pioneering work of Wieland (1953) and subsequently Kent (1994) among many others. This Account builds on the established principles of NCL as applied specifically to S-, O-, and N-isopeptides, molecules that are generally more soluble and less prone to aggregation than native peptides. This Account also covers NCL of isopeptides containing terminal and nonterminal S-acylated cysteine units, reactions that enable the synthesis of native peptides from S-acyl peptides without the use of auxiliaries. With C-terminal S-acyl isopeptides, NCL was carried out under microwave irradiation in phosphate buffer (pH 7.3) at 50 °C. Intramolecular acyl migration was observed through 5-19-membered transition states with relative rates, as assessed by product analysis, in the order, 5 > 10 > 11 > 14, 16, or 17 > 12 > 13, 15, or 19 > 18 ≫ 9 > 8. The rate/pH profile for the 15-membered TS showed a maximum for ligated product versus transacylation at pH 7.0-7.3 presumably associated with the pKa of the N-nucleophile in the hydrogen-bonded TS. Cysteine occurs at low abundance (1.7%) in natural peptides and is rarely available in a terminal position thus limiting the utility of the method. This Account reports, however, NCL at nonterminal acyl cysteine through 5-, 8-, 11-, and 14-membered TSs with relative rates of ligation in the order, 5 ≫ 14 > 11 ≫ 8, thus paralleling the results with acylated terminal cysteine residues. In an obvious sequel to the work with acylated cysteine, we discuss intramolecular O- to N-acyl shift in O-acyl serine and O-acyl tyrosine isopeptides where the story becomes more complex in terms of viable conditions and optimum size of the cyclic TS. N- to N-acyl migration in acyl tryptophan isopeptides is described, and finally, chemical ligation is applied to the synthesis of cyclic peptides. Conformational analysis and quantum chemical calculations are used to rationalize ligation through a range of cyclic transition states. This Account highlights the fact that NCL of acyl isopeptides is an extremely useful strategy for the synthesis of a wide variety of native peptides in good yields and under mild conditions. Mechanistic aspects of the ligations a...

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Amide‐Forming Ligation Reactions

2019

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One of the long‐standing pursuits of synthetic organic chemists is the development of chemical methods for the synthesis of peptides and proteins as tools for understanding biological processes and providing therapeutic solutions to human diseases. The advent of chemoselective ligation reactions for the chemical synthesis of peptides and proteins has enabled synthetic chemists to realize this long‐held dream. In an amide‐forming ligation reaction, two uniquely placed functional groups within the peptide allow peptide or protein segments to be joined in a chemoselective manner with an amide bond. In this chapter, some of the early methods based on principles of the capture/rearrangement strategy for ligation of peptides are catalogued, followed by some of the most versatile and well‐established contemporary methods for the preparation of linear/cyclic peptides and proteins such as the native chemical ligation (NCL) and the α‐ketoacid–hydroxylamine (KAHA) ligation. The chapter concludes with some of the most promising new generation ligation methods such as the potassium acyltrifluoroborate–hydroxylamine (KAT) ligation. The tremendous progress in the past two decades in the development of several ligation methods that rely on a pair of unique functional groups is set to expand the horizons of fully functional proteins and multi‐protein assemblies that are purely synthetically prepared. Although contemporary ligation reactions do not match the speed and efficiency at which proteins are assembled in biological systems, the repertoire of chemoselective amide‐forming ligation methods has already enabled synthetic protein chemistry to surpass biology in terms of chemical and structural diversity.

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Chemical ligation from O-acyl isopeptides via 8- and 11-membered cyclic transition states

Cited by 6 publications

References 25 publications

Sequence-Specific β-Peptide Synthesis by a Rotaxane-Based Molecular Machine

Sequence-Specific β-Peptide Synthesis by a Rotaxane-Based Molecular Machine

Traceless Chemical Ligation from S-, O-, and N-Acyl Isopeptides

Amide‐Forming Ligation Reactions

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