Unlocking the Potential of Poly(Ortho Ester)s: A General Catalytic Approach to the Synthesis of Surface‐Erodible Materials

Abstract Poly(ortho ester)s (POEs) are well‐known for their surface‐eroding properties and hence present unique opportunities for controlled‐release and tissue‐engineering applications. Their development and wide‐spread investigation has, however, been severely limited by challenging synthetic requirements that incorporate unstable intermediates and are therefore highly irreproducible. Herein, the first catalytic method for the synthesis of POEs using air‐ and moisture‐stable vinyl acetal precursors is presented. The synthesis of a range of POE structures is demonstrated, including those that are extremely difficult to achieve by other synthetic methods. Furthermore, application of this chemistry permits efficient installation of functional groups through ortho ester linkages on an aliphatic polycarbonate.

Mathieu J.-L. Tschan + ,N ga SzeI eong + ,R ichardT odd, Jack Everson † ,and Andrew P. Dove* In memory of Jack Everson Abstract: Poly(ortho ester)s (POEs) are well-known for their surface-eroding properties and hence present unique opportunities for controlled-release and tissue-engineering applications.T heir development and wide-spread investigation has, however,b een severely limited by challenging synthetic requirements that incorporate unstable intermediates and are therefore highly irreproducible.H erein, the first catalytic method for the synthesis of POEs using air-a nd moisturestable vinyl acetal precursors is presented. The synthesis of arange of POE structures is demonstrated, including those that are extremely difficult to achieve by other synthetic methods. Furthermore,a pplication of this chemistry permits efficient installation of functional groups through ortho ester linkages on an aliphatic polycarbonate.
The use of biodegradable polymers for controlled drug release and tissue engineering represents one of the most important advances in biomedicine. [1][2][3] An ideal material would display as urface erosion profile in which hydrolysis occurs faster than water ingress into the materials and results in sequential erosion of the surface layers. [4,5] Such profiles enable idealized zero-order release profiles and predictable materials properties throughout degradation. [6] Despite these benchmark requirements,t he paucity of easily accessible surface eroding materials have led to extensive study of bulk eroding materials,s uch as poly(lactic acid) and poly(ecaprolactone), [7,8] in which water diffusion into the material occurs at acomparable or faster rate to hydrolysis.This results in anon-linear mass loss over time,amplified by autocatalysis from trapped degradation products,w hich in turn leads to non-linear release by encapsulants,s ignificant burst effects, and uncontrolled loss of mechanical stability.
Despite the clear potential advantages of surface erodible polymers,examples are limited to only afew families,such as poly(anhydride)s [9,10] and poly(ortho ester)s (POEs). [11,12] Them ilder degradation products present POEs as ap otentially more attractive choice for in vivo applications and, indeed, POE types III and IV ( Figure 1) have shown significant promise in ocular [11][12][13][14] as well as gene delivery. [11,12] However,their synthesis typically involves either step-growth polymerization of the highly air-a nd moisture-sensitive diketene acetal (3,9-bis(ethylidene-2,4,8,10-tetraoxaspiro- [5,5]undecane (DETSOU;S cheme 1) with ad iol, [15] or transesterification between at riorthoester and triol. [16] Both procedures present significant synthetic challenges when it comes to producing repeatable polymer characteristics,which likely results because the highly reactive ketene acetal monomers compromises the high levels of purity required for successful step-growth polymerization. More recently, some success was achieved by preparing ortho-ester-containing monomers by multistep syntheses to create poly(ortho ester amide)s and poly(ortho ester urethane)s. [17] Despite these advances,f urther development of general routes to POE-based materials is required to enable wider study;i n particular,t echniques are needed to overcome challenges associated with the synthesis of such materials.  Herein, we present af acile,c atalytic method for the synthesis of POEs via easy-to-access,air-and moisture-stable intermediates.Furthermore,wedemonstrate that this unique approach is the only general synthetic pathway that can yield POEs of types II, III, and IV.M oreover,t he procedure is amenable to alarge range of potential feedstocks,aswell as to functionalization of other materials.T he development of am ore general and simple synthetic method to access POEs will more readily enable wider study and hence potentially address some of the outstanding problems that face the biomedical industry,i ncluding enhancing control over drug release rates and increasing the efficiencyofdelivery systems.
Inspired by the wealth of ruthenium-based double-bondmigration catalysis in the literature, [18,19] including for the synthesis of ketene acetals, [20,21] we postulated that a1 ,3dihydride shift of av inyl acetal with catalysts such as [RuHCOCl(PPh 3 ) 3 ]( 2) [20] and [RuHCl(PPh 3 ) 3 ] [18] (3)w ould enable in situ olefin isomerization catalysts in the presence of alcohols without the need to isolate the highly sensitive ketene acetal intermediate.Initially,model reactions focused on the in situ isomerization of the commercially available 5,5dimethyl-2-vinyl-1,3-dioxane,t hus avoiding isolation of the highly reactive DETSOU monomer (Scheme 1). With excess 1,6-hexanediol it was found that, while 2 catalyzed the formation of the diorthoester to 99.7 %c onversion at 45 8 8C in 6.5 h, using an analogous catalyst loading of 3 only gave similar conversion at the same rate when carried out at 85 8 8C (Supporting Information). Moreover,n os ide products/reactions could be observed by 1 Ha nd 13 CNMR spectroscopic analysis of the model reaction crude mixture,a nd only the expected product was formed.
Theo ptimal conditions found for each catalyst in the model reaction were then applied to the step-growth polymerization of the difunctional monomers 1 and 1,6-hexandiol (Scheme 1). Notably, 1 is obtained in as traightforward onestep reaction in 56 %y ield while DETSOU was obtained by ad ifficult two-step synthetic procedure in an approximately 40 %o verall yield. [15] Initially,t he polymerization was attempted using catalyst 2. While 2 was active at al ower temperature and hence limited the chance of polymer degradation, only oligomers were isolated (< 1kDa as determined by size-exclusion chromatography (SEC) analysis in CHCl 3 ). Interestingly,P OE(II) of significantly higher molecular weight was only achieved when catalyst 3 was employed at an increased temperature. Monitoring the reaction by SEC analysis revealed that the molecular weight of the polymer plateaued after about 4h, reaching aw eight-averaged molecular weight (M w )o f 9.5 kDa (Supporting Information, Figure S2). Thegenerality of the approach was demonstrated by the polymerization of 1 with 1,10-decanediol under comparable conditions and yielded ap olymeric material that displayed M w = 8.1 kDa (Supporting Information, Figures S3 and S4). Thus POE(II) type materials were accessible without requiring synthesis and isolation of the DETSOU intermediate.
To showcase extension of this method to awider range of POE structures,a nd to take advantage of the relatively low molecular weights,w es ought to extend our studies to the polymerization of monomers that would yield POEs of type III. At low molecular weights,the inherently flexible polymer backbone equates to POE(III) materials that are typically semisolids with low glass transition temperatures (T g ), which permits convenient mixing with adrug without heating and/or ap rocessing solvent;t his property is particularly important for incorporation of sensitive therapeutics. [12,22] Despite offering numerous advantages,t he potential to use such materials is limited by difficulties in polymer synthesis and the reproducibility of the materials;t hese limitations largely curtailed development of POE(III) from the late 1990s. [11,12] We postulated that our method could be applicable across all POE platforms and sought to investigate this further.
Preparation of bifunctional A-B monomers (7)(8)(9), that consist of both the cyclic vinyl acetal and alcohol moieties, was achieved in two simple steps (Scheme 2). Following success with POE(II) from 1,i nitially we focused on the retention of the six-membered ring precursors.F irstly,t he triols (4-6)were synthesized by simple esterification between bis(hydroxymethyl)propionica cid (bis-MPA) and the corresponding bromoalkanol in N,N-dimethylformamide (DMF). This reaction reached maximum conversion at approximately 85 %( with 15 %b is-MPAs tarting material). Thec rude mixture was ring-closed directly in the subsequent reaction with acrolein to yield the bifunctional monomers 7-9.T he 1 HNMR spectra of the bifunctional monomers (Supporting Information, Figure S5-S7) showed the appearance of vinyl protons (d = 5.89-5.26 ppm), which indicated asuccessful ring closure.N otably,a sac onsequence of the existence of two chiral centers in the 1,3-dioxane ring, two diastereomers were observed in each case,w hich was made evident by the occurrence of two distinct sets of vinyl signals and dioxane ring proton resonance.P olymerization of the bifunctional monomers was undertaken with the optimized conditions for catalyst 3 (Table 1). All materials were characterized by 1 HNMR spectroscopy (Supporting Information, Figures S9, S11, and S13) and SEC (Supporting Information, Figures S10, S12, and S14), which demonstrated that the polymers displayed M w in the range of 8t o1 1kDa. Thef ormation of endo and exo isomers of the ortho ester unit, by addition of the alcohol function above or below the planar ketene acetal function, is indicated by the splitting of the hydrogen atom signals of the 1,3-dioxane ring in the 1 HNMR spectra of the polymers.Each polymerization was repeated to demonstrate reproducibility-in stark contrast to typical POE(III) by transesterification, which cannot be prepared reproducibly. [11,12] Thea bility to apply air-stable vinyl acetal potentially allows access to aw ide range of novel materials that would otherwise be inaccessible by traditional routes.N otably,t he instability of ketene acetal precursors to excipient nucleophiles,s uch as water,i ncreases as the ring size is contracted from six to five. [23,24] To further demonstrate the utility of this method for the synthesis of new materials,the five-membered vinyl-acetal-containing ring bifunctional monomer (10)w as isolated directly from the commercially available 1,2,6hexanetriol (Figure 2A). [25] Thesubsequent in-situ-generated ketene acetal was able to undergo successful step-growth polymerization ( Figures 2B;S upporting Information, Figures S15 and S16) to yield polymer with M w up to 21 kDa.
Finally,t he mild nature of the process has been further demonstrated by the side-chain functionalization of an ovel degradable aliphatic polycarbonate.T he application of ortho

Angewandte Chemie
Communications esters as pH-responsive side chains [21,28] has received increased interest over the past few years.W hile cyclic ketene acetals have been applied for the functionalization of hydroxy-containing polymers (or derived monomers), the application of such am ethod to degradable polymers would require protection-deprotections trategies to be employed to overcome the incompatibilities of functional groups with polymerization methods typically required in their synthesis.
Thev inyl acetal side chains of P15 were functionalized with 1-hexanol and benzyl alcohol as model alcohols (Scheme 3). Initial application of catalyst 3 at the higher temperatures required for catalytic operation led to degradation of the polycarbonate backbone.However,application of catalyst 2,w hich is highly active at lower temperatures, resulted in polycarbonates with pendant hexyl or benzyl moieties linked through an ortho ester.S uccessful functionalization was evident from the 1 HNMR spectrum (Supporting Information, Figure S40), showing ad istinct upfield shift of the proton resonances from the vinylic (d = 5.85-5.25 ppm) to alkyl regions (d = 1.72 and 0.92 ppm) and the appearance of the signal (d = 3.38 ppm), which is indicative of the attachment of hexyl groups on the side chain of the polycarbonate backbone.SEC analysis (Supporting Information, Figure S41) revealed as ingle distribution with ac omparable dispersity to that of the original P15,which indicates that no observable degradation of the polycarbonate backbone occurred. To our knowledge,t his is the first report describing generation of an ortho ester functional group by addition of alcohol. In turn, this procedure presents am uch more versatile method for generating side-chain substituents that are linked to apolymer backbone by an ortho ester.
In summary,t he application of RuHCl(PPh 3 ) 3 as catalyst for the synthesis of surface erodible POEs was reported for the first time by asimple and accessible in situ 1,3-(di)hydride shift of stable (di)vinylacetal moieties in di(bi)functional monomers.Inaddition, application to bifunctional monomer systems enabled the preparation of POEs that would be extremely difficult, or impossible to prepare in ac onsistent manner by any other method. As with typical POE(III), the semi-solid nature of P7-P10 means that these materials may be useful as injectable materials for biomedical applications where viscosity can be easily tuned within awide range of T g (À39 to 18 8 8C) simply by varying the lengths of the alkyl chain in the bifunctional monomers.Wehave also demonstrated the versatility of this method by functionalizing an aliphatic polycarbonate by formation of ortho ester linkages.The facile nature of this synthetic procedure and the stability of the monomers (compared to other synthetic methods) provide as imple synthetic route to further research into these interesting and highly applicable materials.O ur work can potentially provide access to hitherto unprecedented surface erodible materials to potentially enhance the efficacya nd control of the current drug delivery systems that rely on bulk degrading materials.