1,4-Oxazepan-7-one trifluoroacetate: a modular monomer precursor for the synthesis of functional and biodegradable poly(amino esters)

Abstract

N-Acylated poly(amino esters) (PAEs) synthesized via organocatalytic ring-opening polymerization (ROP) offer potential for tailored, functional and degradable polymers. In this study, a universal monomer precursor toward N-acylated-1,4-oxazepan-7-ones (OxP)s was synthesized using a three-step approach, allowing for the introduction of various functional groups. Two novel oxidation sensitive OxP monomers bearing a double bond and a sulfide group were designed, as well as two monomers with alkyl moieties. The organocatalytic ROP of the OxP monomers using 1,8-diazabicyclo[5.4.0]undec-7-en (DBU) and 1-(3,5-bis(trifluoromethyl)phenyl)-3-cyclohexyl thiourea (TU) as catalysts was investigated. Polymerizations were performed under ambient temperature, affording homopolymers with narrow dispersities (Ð = 1.09-1.13). As a proof of concept, a post-polymerization thiol-ene functionalization of the allyl functional PAE was performed via photo-rheology experiments. Finally, the (bio)degradability of the N-acylated poly(amino esters) was evaluated through a series of degradation studies under mild enzymatic catalysis, in neutral phosphate-buffered saline solution and under accelerated conditions.

Fig. 1. (a) Three-step synthetic route toward 1,4-oxazepan-7-one trifluoroacetate (OxP_TFA) starting from 4-piperidone. [1] Boc protection, quantitative yield; [2] Bayer-Villiger ring-expansion, 64%; [2′] oxidation with OXONE®, 80%; [3] Boc-deprotection; 95%. (b) One-step acylation of OxP_TFA for the synthesis of four N-acylated-1,4-oxazepan-7-one (OxP) monomers with different side chains and functional groups.

Fig. 2. ¹H NMR spectrum of 4-(But-3-enoyl)-1,4-oxazepan-7-one (OxP_propylene).

Scheme 1. Organocatalytic ROP of N-acylated-1,4-oxazepan-7-ones.

Fig. 3. (a) ¹H NMR spectrum of P(OxP_propylene) with assigned signals. (b) SEC elution traces of OxP_propylene organocatalytic ROP after given reaction times (green to purple gradient, solid lines). Purified P(OxP_propylene) sample from the t = 80 min sample (pink, dashed line). RI signal; eluent: THF, 25 °C; standard: PMMA.

Fig. 4. DSC thermogram of POxP homopolymers: POxP_But, POxPEtS_Me, POxP_propylene, POxP_Me.

Fig. 5. Kinetic plot of organocatalytic ROP of OxPs in DCM. Semilogarithmic plots over the reaction time (dots with varying shapes and colors for every OxP homopolymer), fitted by linear regression (line with varying color for every OxP homopolymer).

Fig. 6. SEC elution traces of P(OxP_Me) degradation under enzymatic conditions: [P(OxP_Me)] = 5 mg mL⁻¹, [LPC] = 100 U mL⁻¹, PBS, 37 °C (DMF, standard: PMMA).

Fig. 7. Storage and loss moduli (G′ and G′′) as a function of time for POxP_propylene photo-induced cross-linking with DTT before and after irradiation (10 min) with 365 nm UV light.