Intramolecular Staudinger Ligation: A Powerful Ring-Closure Method To Form Medium-Sized Lactams (original) (raw)
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2021
Strategies for one-pot peptide ligation enable chemists to access synthetic proteins at a high yield in a short time. Herein, we report a new one-pot multi-segments ligation strategy using N-terminal thiazolidine (Thz) peptide and a formaldehyde scavenger. Among our designed 2-aminobenzamide-based aldehyde scavengers, 2-amino-5-methoxy-N’,N’-dimethylbenzohydrazide showed a good ability to capture formaldehyde from Thz at pH 4.0. This scavenger had compatibility with the conditions of native chemical ligation at pH 7.5. Using this scavenger for a model peptide ligation system, we performed one-pot four-segment ligation at a high yield without significant side reactions.
Chemical ligation from O-acyl isopeptides via 8- and 11-membered cyclic transition states
Arkivoc, 2014
Unprotected O-acylated serine and O-acylated threonine isopeptides have been synthesized, and their conversion to native tripeptides and tetrapeptides by O-to N-terminus transfer investigated. Ligations involving 8-and 11-membered cyclic transition states are shown experimentally and computationally to be more favorable than intermolecular cross-ligations. transition state resulting in the native peptide bond. The bifunctional nature of the N-terminal cysteine 1,2-mercaptoamine moiety is responsible for the observed chemoselectivity in NCL. 14 NCL development as a synthetic tool for building peptides depends on additives to increase ligation rates and yields. Ligations depend on factors such as steric demand, the exogenous thiol reactivity and the nature of the solvent. 14-17 In addition, the low abundance of cysteine (1.7% of the residues in protein sequences) is a major drawback of this methodology since NCL is restricted to Cys residues.
Sequential peptide chemical ligation by the thioester method and extended chemical ligation
Tetrahedron Letters, 2005
The sequential chemical ligation of peptide thioesters by a combination of the thioester method and extended chemical ligation using a photoremovable auxiliary, 2-mercapto-1-(2-nitrophenyl)ethyl group, is described. The thiazolidine ring was used as a protecting group for the N-terminal 1,2-aminoethanethiol moiety of the auxiliary in the middle peptide thioester. After the first thioester coupling, the thiazolidine ring was opened by treatment with O-methylhydroxylamine. Second coupling by extended chemical ligation followed by UV irradiation gave the target polypeptide.
Study of Chemical Ligation Via 17-, 18- and 19-Membered Cyclic Transition States
Chemical Biology & Drug Design, 2012
Unprotected S-acylated cysteine isopeptides containing a-, b-or c-amino acid units have been synthesized, and their conversion to native hexapeptides by S-to the N-terminus ligations involving 17-, 18and 19-membered cyclic transition states have been demonstrated both experimentally and computationally to be more favorable than intermolecular cross-ligations.
Methods and strategies of peptide ligation*
Peptide Science, 2001
This review focuses on the concept, methods, and strategies of orthogonal peptide ligation. It updates our previous review in 1999 on the same subject matter in Biopolymers (Peptide Science, 1999, Vol. 51, p. 311). Orthogonal peptide ligation is an amino terminal specific method to couple chemically unprotected peptides or proteins derived from synthetic or biosynthetic sources. Unlike conventional chemical methods, peptide ligation methods do not require coupling reagents or protection schemes, but are achieved through a variable chemoselective capture step and then an invariable intramolecular acyl transfer reaction. It is also a convergent method with the fewest steps. More than a dozen orthogonal ligation methods have been developed based on captures by either imine or thioester chemistries to afford native and unusual amino acids at ligation sites of linear, branched, or cyclic peptides. The ligation strategies for multiple segments including sequential and tandem ligations are also discussed.
Stereoselective Construction of β-, γ-, and δ-Lactam Rings via Enzymatic C–H Amidation
Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Given their widespread presence in bioactive molecules, methods for the asymmetric synthesis of these molecules, in particular through the selective functionalization of ubiquitous yet unreactive aliphatic C–H bonds, are highly desirable. In this study, we report the development of a novel strategy for the asymmetric synthesis of 4-, 5-, and 6-membered lactams via an unprecedented hemoprotein-catalyzed intramolecular C-H amidation reaction with readily available dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation producing an array of β-, γ-, and δ-lactam molecules in high yields, with high enantioselectivity, and on preparative scale. Mechanistic and computational studies elucidate the nature of the C–H amination and enantiodetermining steps in these reactions and provide insights into protein-me...
ChemBioChem, 2013
Scheme 3. Synthesis of synthetic precursors 2-5. a) LiAlH 4 , THF, 95 %; b) Ms-Cl, DIPEA, CH 2 Cl 2 , 88 %; c) NaN 3 , DMF, 100 %; d) LiAlH 4 , THF, 95 %; e) LiOH, THF/H 2 O, 100 %; f) 11, DCC, DMAP, CH 2 Cl 2 , 26 %; g) TIPS, TFA/CH 2 Cl 2 , 100 %; h) HONHBoc, DBU, DMF, 89 %; i) TIPS, TFA/CH 2 Cl 2 , 100 %; j) 12, CuSO 4 , NaAsc, CH 2 Cl 2 /H 2 O, 72 %; k) TIPS, TFA/CH 2 Cl 2 , 100 %; l) 13, HBTU, DIPEA, CH 2 Cl 2 , 55 %; m) TIPS, TFA/CH 2 Cl 2 , 100 %.
The introductiono fm acrocyclic constraints in peptides (peptide stapling) is an important tool within pep-tide medicinalc hemistry for stabilising and pre-organising peptides in ad esired conformation.I nr ecent years, the copper-catalysed azide–alkyne cycloaddition (CuAAC) has emerged as ap owerfulm ethodf or peptidestapling. However ,t od ate CuAAC stapling has not provided as imple methodf or obtaining peptidest hat are easily diversified further .I nt he present study,w er eport an ew diversity-oriented peptides tapling (DOPS) methodology based on CuAAC chemistry.S tapling of peptides incorporating two azide-modified amino acids with 1,3,5-triethynylbenzene efficiently provides (i, i + 7)-and (i, i + 9)-stapled peptides with as ingle free alkyne positioned on the staple, which can be further conjugated or dimerised. Au nique feature of the present method is that it provides easy access to radiolabelled stapled peptidesb yc atalytic tritiation of the alkyne positioned on the staple.