Selective modification of sulfamidate-containing peptides

Abstract

<p>Hybrid peptides whose N-terminal residues are activated in the form of α-methylisoserine cyclic sulfamidates exhibit rich reactivity as electrophiles, allowing site- and stereoselective modifications at different backbone and side chain positions.</p>

Thermal Safety and Structure-Related Reactivity Investigation of Five-Membered Cyclic Sulfamidates

“…1,5 This makes cyclic sulfamidates of special interest in organic chemistry because of their key role as intermediates in the synthesis of numerous products having heteroatomic functional groups. Five-membered cyclic sulfamidates find, among others, application as excellent chiral building blocks for the synthesis of α-methylated β-amino acids, 2,4,6,7 radiolabeled amino acids, 8 sequence-defined macromolecules, 9 for the selective modification of sulfamidate-containing peptides, 10 as vehicles for the synthesis of substituted lactams 3,5 or as precursors to serine derivatives, 11 thiomorpholines, 12 piperazines, 12 and N-heterocycles. 1,13 Based on this wide range of practical applications, these molecule classes are widely used throughout the academia and fine chemical industries.…”

“…The reactivity profile of cyclic sulfamidates is comparable to those of activated aziridines and azetidines. , Several added advantages of using cyclic sulfamidates are to be mentioned, such as more regiospecific ring opening, related to the higher reactivity of the C–O bond, no significant reliance on ring strain since activation toward nucleophilic attack is “in-built”, and finally no requirement for the presence (and subsequent removal) of an additional activating substituent on the nitrogen. , This makes cyclic sulfamidates of special interest in organic chemistry because of their key role as intermediates in the synthesis of numerous products having heteroatomic functional groups. Five-membered cyclic sulfamidates find, among others, application as excellent chiral building blocks for the synthesis of α-methylated β-amino acids, ,,, radiolabeled amino acids, sequence-defined macromolecules, for the selective modification of sulfamidate-containing peptides, as vehicles for the synthesis of substituted lactams , or as precursors to serine derivatives, thiomorpholines, piperazines, and N-heterocycles. , Based on this wide range of practical applications, these molecule classes are widely used throughout the academia and fine chemical industries. Within the pharmaceutical sector, cyclic sulfamidates are typically used as chiral building blocks. − They have been notably employed for the preparation of an enantiopure intermediate toward levofloxacin or as the lactam precursor for the synthesis of (−)-aphanorphine, which incorporates a scaffold close to a benzomorphan analgesic (Figure ).…”

Conformationally Restricted β‐Sheet Breaker Peptides Incorporating Cyclic α‐Methylisoserine Sulfamidates

“…[10][11][12][13][14][15][16][17] The reactivity of sulfamidate-containing peptides has been extensively studied, [11] including short peptides incorporating α-methylisoserine-derived sulfamidate by our group. [18][19][20][21] However, although such chiral scaffolds can be regarded as structural analogs of cyclic amino acids (Pro or βPro), [22,23] their structural properties have been much less explored. Analysis of reported crystallographic [18,24] and quantum mechanical [25] structures reveals that amide-substituted α-methylisoserine sulfamidates show highly conserved conformational features, particularly at the C-terminal amide bond.…”

Synthesis of Fluorescent Lanthipeptide Cytolysin S Analogues by Late-Stage Sulfamidate Ring Opening

“…First, we synthesized the linear model peptide that previously led to transacylation (i.e., 1a-Ala-His-Asn-Cys-Gly) 22 by microwave (MW)-assisted SPPS, 27 and its Nterminus was reacted with dansyl (DNS) chloride (Figure 1B). Upon cleavage and deprotection, peptide 2 was dissolved in a 96:4 mixture of CD 3 CN and D 2 O and base-promoted cyclization was monitored by 1 H NMR spectroscopy (Figure 1C).…”

“…Cyclic sulfamidates have been extensively used for the regio- and stereoselective synthesis of a wide variety of chemicals through regioselective nucleophilic ring-opening reactions. − In particular, the intermolecular S-alkylation of five-membered ring sulfamidates has been exploited for the synthesis of orthogonally protected Lan and MeLan analogues. − For instance, the thioether ring B of haloduracin β as well as mimetics has been synthesized by intermolecular ring opening of sulfamidates with short cysteine-containing peptides. , However, attempts to achieve the intramolecular ring opening of peptides containing N -carbonyl sulfamidates and cysteine residues produced an unexpected N → S acyl shift …”