Hydroxyl‐tolerated polymerization of N‐phenoxycarbonyl α‐amino acids: A simple way to polypeptides bearing hydroxyl groups

Abstract

Differing from the moisture‐sensitive α‐amino acid N‐carboxyanhydrides (AA‐NCAs) monomers, N‐phenoxycarbonyl α‐amino acids (AA‐NPCs) can be prepared and stored in open air. In this contribution, we report that the controlled polymerizations of AA‐NPC monomers of O‐tert‐butyl‐dl‐serine (BRS‐NPC), Nε‐benzyloxycarbonyl‐l‐lysine (ZLL‐NPC) and Nε‐trifluoroacetyl‐l‐lysine (FLL‐NPC) initiated by amines are surprisingly able to tolerate common nucleophilic impurities such as water and alcohols at a level of monomer concentration. The structures of polypeptides synthesized in the presence of water or alcohols agree well with the designed ones in the case of repeated chain extensions. Detailed mechanism study and density functional theory calculation reveal that the low concentration of AA‐NCA and the high activity of amines are the key factors to the controllability of AA‐NPC polymerizations. The water‐ and alcohol‐tolerant property in polymerizations of AA‐NPCs encourages the following studies on unprotected (phenolic) hydroxyl groups containing AA‐NPCs. The controllable polymerizations of N‐phenoxycarbonyl l‐tyrosine (LT‐NPC) and N‐phenoxycarbonyl S‐(3‐hydroxypropyl)‐l‐cysteine (HLC‐NPC) initiated by amines are confirmed and reported for the first time, which extends the library of AA‐NPCs and polypeptides as well. All the universality of library, the convenience of monomer preparation, and the controllability and water‐ and alcohol‐tolerant property of polymerization of AA‐NPCs significantly enhance the feasibility of polypeptide synthesis, making AA‐NPC approach a promising synthetic method of polypeptides. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 907–916

Well-Defined Construction of Functional Macromolecular Architectures Based on Polymerization of Amino Acid Urethanes

“…The acetal linkage is cleaved under acidic conditions to produce poly(L-serine). Urethane 2t bearing the hydroxyl group [28] and urethane 2u bearing the acetal moiety [29] are synthesized and polymerized into the corresponding polypeptides.…”

“…These highly electrophilic initiating ends and the amino group at the propagating end of PP1 are readily attacked by amines such as butylamine, leading to the formation of PP1 with increased molecular weights. Recently, the high tolerance of polymerization to OH-containing compounds has been elucidated (Scheme 15) [28]. Even in the presence of benzyl alcohol, the corresponding polypeptides with predictable M n s and narrow molecular weight distributions can be obtained.…”

“…The tolerance of the polypeptide synthesis using the urethane derivatives to alcohols and water demonstrates its potential as a powerful and versatile tool for the construction of a wide range of macromolecular architectures containing polypeptide segments. Recently, the high tolerance of polymerization to OH-containing compounds has been elucidated (Scheme 15) [28]. Even in the presence of benzyl alcohol, the corresponding polypeptides with predictable Mns and narrow molecular weight distributions can be obtained.…”

“…Recently, the high tolerance of polymerization to OH-containing compounds has been elucidated ( Scheme 15 ) [ 28 ]. Even in the presence of benzyl alcohol, the corresponding polypeptides with predictable M n s and narrow molecular weight distributions can be obtained.…”

“…In contrast, urethane 2u derived from L-serine does not polymerize, but undergoes cyclization to a chemically robust five-membered urethane (Scheme 21). The polypeptide synthesis using urethane derivatives of amino acids can be used in the direct syntheses of polypeptides bearing hydroxyl-functionalized side chains of the corresponding urethanes [28]. For example, L-cysteine-derived urethane 2t can be converted to the corresponding polypeptide without hydroxyl group protection, because of the tolerance of polymerization to the presence of alcohols (Scheme 20).…”