Back to Table of Contents

44921-G4
Controlled Polymerization of Alpha-Amino Acid-N-Carboxyanhydrides

Jianjun Cheng, University of Illinois at Urbana-Champaign

Polypeptides are a class of important biomaterials that are extensively utilized in drug delivery, tissue engineering, sensing and catalysis. They are usually prepared through amine initiated ring-opening-polymerizations (ROP) of α-amino acid-N-carboxyanhydrides (NCAs). Although large-scale, high molecular weight (MW) polypeptides can be readily synthesized using this method, the resulting polypeptides typically have uncontrollable MWs and broad MW distributions. In the past several decades, tremendous efforts have been devoted to the development of initiators for controlled NCA polymerization, resulting in exciting achievements through the modification of conventional amine initiators or polymerization conditions, or by developing zero-valent transition metal catalysts. In conjunction with these studies, we report controlled NCA polymerizations mediated by hexamethyldisilazane (HMDS) and the identification of trimethylsilyl carbamate (TMS-CBM) as an unusual group- propagation group.

As an active silylation reagent, HMDS is widely used in organic synthesis. We found HMDS also gave remarkable control of polymerizations of NCAs and led to formation of poly(-benzyl-L-glutamate) (PBLG) with expected MWs. The NCA polymerizations initiated with HMDS were in sharp contrast to those initiated with conventional amine initiators in which elevated PBLG MWs by several folds were observed. The obtained PBLG MW (Mn = 2.18 × 104 g/mol) at monomer/iritiator ratio (M/I) of 100, for instance, agreed perfectly with the expected PBLG MW (Mn = 2.19 × 104 g/mol) in this HMDS mediated polymerization. On the contrary, Glu-NCA polymerization initiated with diethylamine (DEA) gave PBLG with a Mn more than four times higher than the expected Mn. Polymerization initiated by HMDS completed within 24 hrs at room temperature with quantitative monomer conversions and narrow MW distributions (MWDs). The MWs of PBLG had linear correlation with the conversions of Glu-NCA and accorded well with the expected MWs, demonstrating that PBLG chains propagated through living chain ends in the HMDS mediated NCA polymerizations. Block copolypeptides, such as poly(-benzyl-L-glutamate)-block-poly(-Cbz-L-lysine) (PBLG-b-PZLL), with expected MWs and narrow MWDs (MWD ~ 1.03 to 1.1) can be readily prepared.

As a secondary amine, HMDS can either function as nucleophile to open the NCA ring at CO-5 or behave like a base to deprotonate the NH-3. Because of the two bulky TMS groups around the nitrogen in HMDS, it is unlikely for HMDS to attack the CO-5 of NCA. Prior study also indicated that secondary amine (R2NH) with bulky R group exclusively HMDS is more basic than regular secondary and tertiary amines, therefore the first step likely involves the deprotonation of NCA in a manner similar to the first step of the “activated monomer” mechanism. Interestingly, the Si-N-Si band at 932 cm-1 in FT-IR disappeared after mixing equal molar Glu-NCA and HMDS, indicating the cleavage of N-Si bond during initiation and formation of a TMS-CBM group.

To confirm the formation of TMS-CBM end group, we mixed equal molar Glu-NCA and HMDS in DMSO-d6 and then analyzed the mixture (Glu(1)/HMDS(1)) using 13C-NMR and FAB-MS. The anhydride carbon peak of Glu-NCA at 172.0 ppm disappeared; a new peak at 155.3 ppm appeared, which was attributed to the formation of a carbamate bond. Interestingly, when the FAB-MS study was carried out with minimum exposure to air, Glu(1)/HMDS(1) and its decomposed derivatives were detected that matched exactly to the expected MWs of these compounds. Using high-resolution FAB-MS, we determined the molecular formula of Glu(1)/HMDS(1) to be C19H33O5N2Si2. The MS analysis of a mixture of Glu-NCA and HMDS (5:1 molar ratio) showed peaks of 644 Da and 863 Da that corresponded to the dimer and trimer of Glu peptides, respectively, with identical TMS carbamate terminal groups as Glu(1)/HMDS(1). These experiments indicated that polypeptide chains may propagate through the migration of TMS end groups to the incoming monomers. This reaction resembles to some extend the group-transfer polymerizations (GTPs) of acrylic monomers mediated by similar organosilicon compounds. To demonstrate that controlled NCA polymerization can be achieved using materials containing the same TMS-CBM group, we tested the polymerizations of Glu-NCA in the presence of trimethylsilyl dimethylcarbamate. As expected, polymerizations proceeded smoothly and gave PBLGs with anticipated MWs and narrow MWDs with less than 15% deviation.

In conclusion, with the support of ACS-PRF we discovered an unusual TMS-CBM propagating group that can control the living polymerization of NCAs. This organosilicon reagent mediated NCA polymerization offers a metal-free strategy for the convenient synthesis of homo- or block-polypeptides with predictable MWs and narrow MWDs.

Back to top