DEGRADABLE POLYMERS

Abstract

A polymer that is degradable and contains an acetyl group and a saccharide group. The acetyl group and the saccharide group are bonded to each other through an ester bond. Also provided is a method of preparing the polymer.

Claims

1. A polymer comprising at least 10 repeat units, each of which contains an acetyl moiety CR.sub.1R.sub.2C(O) and a saccharide moiety, wherein the acetyl moiety and the saccharide moiety are bonded to each other through an ester bond C(O)O, C(O) being a part of the acetyl moiety and O being a part of the saccharide moiety, and each of R.sub.1 and R.sub.2, independently, is H, halo, C.sub.1-C.sub.3 alkyl, or phenyl.

2. The polymer of claim 1, wherein the saccharide moiety is derived from glucose, mannose, galactose, rhamnose, xylose, arabinose, lactose, maltose, or glucosamine.

3. The polymer of claim 1 having the following repeat units containing a pyranose ring and the acetyl moiety: ##STR00019## in which each of the bonds connecting to the pyranose ring is either axial or equatorial; and R.sub.3 is H, CH.sub.3, or CH.sub.2OR.sub.3, R.sub.4 is OR.sub.4, R.sub.5 is OR.sub.5, and each of R.sub.3, R.sub.4, and R.sub.5, independently, is H, acetyl, benzyl, pivaloyl, benzoyl, C.sub.1-C.sub.6 alkyl, or a monosaccharide substituent.

4. The polymer of claim 3, wherein the monosaccharide substituent is a glucose substituent or a galactose substituent.

5. The polymer of claim 3, wherein each of R.sub.1 and R.sub.2 is H, R.sub.3 is H, CH.sub.3, or CH.sub.2OR.sub.3, R.sub.4 is OR.sub.4, R.sub.5 is OR.sub.5, and R.sub.3 is H, acetyl, benzyl, pivaloyl, benzoyl, methyl, or ethyl; R.sub.4 is H, acetyl, benzyl, pivaloyl, benzoyl, methyl, ethyl, a glucose substituent, or a galactose substituent; and R.sub.5 is H, acetyl, benzyl, pivaloyl, benzoyl, methyl, or ethyl.

6. The polymer of claim 1, wherein each of the repeat units is ##STR00020##

7. The polymer of claim 1, wherein the number average molecular weight of the polymer is 3,000 Da to 50,000 Da.

8. The polymer of claim 1, wherein the polymer is a co-polymer further comprising one or more repeat units derived from a vinyl monomer.

9. The polymer of claim 8, wherein the vinyl monomer is an acrylate, an acrylamide, an maleimide, a styrene, vinyl acetate, or vinyl amide.

10. The polymer of claim 1, wherein the polymer is a co-polymer further comprising (i) one or more repeat units derived from methyl acrylate, ethyl acrylate, 2-ethylhexyl acrylate, butyl acrylate, trimethylolpropane triacrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate, hydroxyethyl methacrylate, glycidyl methacrylate, N,N-dimethyl acrylamide, styrene, vinyl acetate, or N-vinylcarbazole and (ii) one or more repeat units derived from N-phenylmaleimide or N-methylmaleimide.

11. The polymer of claim 10, wherein the polymer has the following structure: ##STR00021## in which Ac is acetyl, Ph is phenyl, m:n:q is 1:(0-10):(0-30), and n and q are not both 0.

12. The polymer of claim 11, wherein the number average molecular weight is 3,000 Da to 1,000,000 Da.

13. A method of preparing the polymer of claim 1, the method comprising the steps of: (i) providing a reaction mixture containing a saccharide-ketene acetal comprising a saccharide moiety and a ketene acetal moiety, wherein the saccharide moiety has a pyranose or furanose ring having C1 and C2 positions, and the ketene acetal moiety connects to the saccharide moiety through two ether bonds on the C1 and C2 positions, and (ii) initiating a radical ring-opening polymerization reaction, thereby obtaining the polymer of claim 1.

14. The method of claim 13, wherein the saccharide moiety is derived from a monosaccharide having a pyranose ring and the ketene moiety is bonded to the pyranose ring on both the C1 and C2 positions to form a five membered cyclic ketene acetal.

15. The method of claim 13, wherein the saccharide moiety is derived from glucose, mannose, galactose, rhamnose, xylose, arabinose, lactose, maltose, or glucosamine.

16. The method of claim 13, wherein the reaction mixture further comprising a vinyl monomer and a maleimide monomer.

17. The method of claim 13, wherein the reaction mixture contains a RAFT reagent that is ##STR00022##

18. The method of claim 13, wherein the saccharide-ketene acetal is prepared by reacting a saccharide halide having a halide on the C1 position and O-acetyl on the C2 position, and the halide and O-acetyl are on the same side of the pyranose ring.

19. The method of claim 13, wherein the initiating step is achieved through adding a radical initiator at a temperature of 35 C. or higher.

20. The method of claim 19, wherein the radical initiator is 2.2-azobisisobutyro-nitrile (AIBN) and the temperature is 40 C. to 140 C.

Description

DETAILED DESCRIPTION

[0026] The polymers of this invention are prepared by polymerization of certain saccharide-CKA monomers such as a five-membered CKA fused with a saccharide furanose or pyranose ring at C1 and C2 position. Saccharide-CKA monomers are activated probably due to the anomeric effect and the additional twist of the ring structure caused by the 1,2-cis substitution on C1 and C2, leading to higher reactivity in polymerization including both homopolymerization and copolymerization. In homopolymerization, a radical initiator generates a free radical e.g., by heat or by irradiation, which then activates the CKA monomer thereby starting a chain reaction to produce a polymer. In a copolymerization, a maleimide is preferably added to the mixture together with vinyl monomers to improve the incorporation of CKA monomers to vinyl monomers and maleimide monomers.

[0027] Exemplary saccharide-CKA monomers have the following formula:

##STR00005##

[0028] In the formula above, each of R.sub.1-R.sub.5 has been defined above in the Summary section. Each carbon atom on the pyranose ring has been numbered as shown in formula VI. The five-membered CKA ring is fused to the saccharide pyranose ring through two ether bonds, each connects to one of the C1 and C2 carbon atoms. The two ether bonds are in the cis conformation, e.g., they are on the same side of the pyranose ring. As shown in formula VI, the two ether bonds are at the bottom of the pyranose ring. On the other hand, they can be on the top of the pyranose ring. Due to their cis conformation, it is preferable that one of the ether bonds is axial and the other is equatorial on the ring.

[0029] As to R.sub.3, R.sub.4, and R.sub.5, they can also be either axial or equatorial. Nevertheless, their conformation might have a positive or negative impact on the reaction rate or the product yield of a polymer prepared therefrom in view of their hindrance effect to the polymerization reaction. Preferably, each of R.sub.3, R.sub.4, and R.sub.5 is in an equatorial conformation.

[0030] Exemplary saccharide-CKA monomers include those derived from glucose, mannose, and galactose with structures shown below.

##STR00006##

[0031] In addition to glucose, mannose, and galactose, other monosaccharides are also suitable. Examples include rhamnose, xylose, arabinose, and glucosamine.

[0032] Other than the pyranose structure above, it is possible to use a five-membered furanose structure of a saccharide-CKA for preparing the polymer of this invention.

[0033] Preferably as shown above, the saccharide is a monosaccharide. Nevertheless, it is possible to use a disaccharide, an oligosaccharide (i.e., having at least two monosaccharide monomers) or a polysaccharide (i.e., having 10 or more monosaccharide monomers) in the saccharide-CKAs in preparing polymers of the invention. The polymers prepared from these CKAs will have disaccharide, oligosaccharide, or polysaccharide segments as repeat units in the backbone of the polymers.

[0034] Monosaccharides, disaccharides, oligosaccharides, and polysaccharides include their derivatives modified by protecting the OH groups such as alkylated carbohydrates (e.g., one or more hydroxyl groups that are methylated, ethylated, acetylated, or benzoylated).

[0035] The saccharide CKAs can be prepared using methods well known in the art. See, for example, R. Larock, Comprehensive Organic Transformations (2.sup.nd Ed., VCH Publishers 1999); P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis (4th Ed., John Wiley and Sons 2007); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons 1994); L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (2nd ed., John Wiley and Sons 2009); Agarwal, Polym. Chem. 1, 953-964 (2010); Tardy et al., Chem. Rev. 117, 1319-1406 (2017); Pesenti et al., ACS Macro Lett. 9, 1812-35 (2020); Sznaidman et al., J. Org. Chem. 60, 3942-43 (1995); and Ko et al., Org. Lett. 11, 609-612 (2009).

[0036] Saccharide-CKAs have been prepared through acid-catalyzed transacetalization-elimination process such as reported by Agarwal (2010), Tardy et al. (2017), and Psenti et al. (2020). Moreover, a preferred preparation method starts from commercially available saccharides (such as D-glucose pentaacetate, D-mannose pentaacetate, and D-galactose pentaacetate) via anomeric bromination followed by nucleophilic attack by the neighboring 2-O-acetate group and subsequent deprotonation. The two-step synthesis is readily scalable under mild conditions with high yields.

[0037] Homopolymerization is typically achieved by a free radical polymerization of a saccharide-CKA initiated by a free radical initiator such as azobisisobutyronitrile (AIBN), 2,2-azobis-(2,4-dimethylvaleronitrile), and a peroxide compound (e.g., benzoyl peroxide (BPO) and di-t-butyl peroxide (DTBP)). A typical polymerization reaction is performed in a solvent such as benzene at a temperature in the range of 35-165 C. (e.g., 40-150 C., 45-135 C., 50-120 C., 60-110 C., 70-100 C., 75 C., 80 C., and 90 C.) for 1 hour to 100 hours (e.g., 2-50 hours, 4-45 hours, 6-40 hours, 8-32 hours, 12 hours, 18 hours, 24 hours, and 28 hours).

[0038] The completion of the reaction can be monitored by conventional methods such as HPLC and NMR. The product is optionally purified by an appropriate method useful for separate polymers such as washing with solvents, filtration, centrifuge, and the like.

[0039] The polymers thus prepared can be readily evaluated using known analytical technologies, e.g., .sup.1H and .sup.13C NMR spectra. Through these analyses, the exemplary homopolymer of P(Glu-CKA) was found that the C2-O bond of Glu-CKA was quantitatively cleaved and a new CC bond was formed at C2 for connecting to a neighboring repeat unit. Undesirable ring-retaining byproducts can also be detected by .sup.1H and .sup.13C NMR spectra. The method of this invention generates insignificant amount of the ring-retaining byproducts that most likely not detectable in the homopolymerization of the saccharide-CKAs through the method as described above.

[0040] Polymers of this invention can also be prepared from copolymerization of saccharide-CKAs and vinyl monomers (e.g., acrylates and acrylamides). A third monomer is added in some embodiments. Preferred third monomers are maleimides such as N-phenyl maleimide.

[0041] Certain terminology is used in the following description for convenience only and is not limiting.

[0042] A range expressed as being between two numerical values, one as a low endpoint and the other as a high endpoint, includes the values between the numerical values and the low and high endpoints. Embodiments herein include subranges of a range herein, where the subrange includes a low and high endpoint of the subrange selected from any increment within the range selected from each single increment of the smallest significant figure, with the condition that the high endpoint of the subrange is higher than the low endpoint of the subrange.

[0043] Further embodiments herein include replacing one or more including or comprising in an embodiment with consisting essentially of or consisting of. Including and comprising, as used herein, are open ended, include the elements recited, and do not exclude the addition of one or more other elements. Consisting essentially of means that addition of one or more element compared to what is recited is within the scope, but the addition does not materially affect the basic and novel characteristics of the combination of explicitly recited elements. Consisting of refers to the recited elements, but excludes any element, step, or ingredient not specified.

[0044] The words a and one, as used in the claims and in the corresponding portions of the specification, are defined as including one or more of the referenced items unless specifically stated otherwise. This terminology includes the words above specifically mentioned, derivatives thereof, and words of similar import. The phrase at least one followed by a list of two or more items, such as A, B, or C or A, B, and C means any individual one of A, B or C as well as any combination thereof.

[0045] The term axial refers to a substituent on a pyranose or similar ring that point perpendicular to the plane of the ring. The term equatorial refers to a substituent that lie in the plane of the ring.

[0046] The term alkyl as used herein, means a straight or branched chain, monovalent or divalent hydrocarbon. An alkyl group herein may have from 1 to 30 carbon atoms (e.g., 1-25, 2-20, 3-16, 5-8, 1-6, and 1-4) unless otherwise specified. An alkyl group may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms, or a number of carbon atoms in a range from a first of the foregoing values to a second of the foregoing values, where the first and second values selected are any two of the foregoing values and the first value is less than the second. Examples include methyl (Me), methylene, ethyl, ethylene, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

[0047] The term acetyl refers to CH.sub.3C(O) or CR.sub.1R.sub.2C(O), each of R.sub.1 and R.sub.2, independently, being H, halo, C.sub.1-C.sub.20 alkyl (e.g., C.sub.1-C.sub.3 alkyl such as methyl, ethyl, and propyl), C.sub.2-C.sub.20 alkenyl (e.g., vinyl), C.sub.2-C.sub.20 alkynyl, C.sub.3-C.sub.10 cycloalkyl, 3-20 membered heterocycloalkyl, aryl (e.g., phenyl), or heteroaryl. The term acetal refers to a functional group represented by

##STR00007##

in which R is H, C.sub.1-C.sub.20 alkyl (e.g., C.sub.1-C.sub.3 alkyl such as methyl, ethyl, and propyl), C.sub.2-C.sub.20 alkenyl (e.g., vinyl), C.sub.2-C.sub.20 alkynyl, C.sub.3-C.sub.10 cycloalkyl, 3-20 membered heterocycloalkyl, aryl (e.g., phenyl), or heteroaryl. The term ketene acetal refers to

##STR00008##

R.sub.1 and R.sub.2 as defined above. A cyclic ketene acetal has a ring formed from the two ether functional groups (O) and the atoms (e.g, carbon) to which they are bonded.

[0048] The term alkenyl refers to a linear or branched monovalent or divalent hydrocarbon moiety that contains at least one double bond.

[0049] The term alkynyl refers to a linear or branched monovalent or divalent hydrocarbon moiety that contains at least one triple bond.

[0050] The term cycloalkyl refers to a saturated or unsaturated, cyclic, nonaromatic, monovalent or divalent hydrocarbon moiety, such as cyclohexyl and cyclohexylene.

[0051] The term heterocycloalkyl refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic, monovalent or divalent ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include aziridinyl, azetidinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydro-2-H-thiopyran-1,1-dioxidyl, piperazinyl, piperidinyl, morpholinyl, imidazolidinyl, azepanyl, dihydrothiadiazolyl, dioxanyl, and quinuclidinyl. Both cycloalkyl and heterocyclyl also include fused, bridged, and spiro ring systems. They further include substituted groups such as halocycloalkyl and haloheterocyclyl.

[0052] The term aryl herein refers to a monocyclic, bicyclic or tricyclic aromatic, monovalent or divalent ring system. Examples include phenyl, biphenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, and indanyl. Aryl can be unsubstituted or substituted with alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, ether, ester, and the like. The term aralkyl refers to alkyl substituted with aryl, i.e., aryl-alkyl.

[0053] The term heteroaryl herein refers to an aromatic monocyclic, bicyclic, tricyclic, and tetracyclic ring system having one or more heteroatoms (such as O, S or N). Examples include pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl, pyrazolyl, triazolyl, oxazolyl, thiadiazolyl, tetrazolyl, oxazolyl, isoxazolyl, carbazolyl, furyl, imidazolyl, thienyl, thiazolyl, and benzothiazolyl. The term heteroaralkyl refers to alkyl substituted with heteroaryl, i.e., heteroaryl-alkyl.

[0054] The term monosaccharide refers to a sugar having a five- or six-membered carbon backbone (i.e., a hexose). Monosaccharides also include hexoses substituted with hydroxy groups, oxo groups, amino groups, acetamido groups, and other functional groups. Monosaccharides further include deoxy monosaccharides having one or more carbon atoms in the hexose backbone having only hydrogen substituents. Examples of monosaccharides include, but are not limited to, glucose (Glu), galactose (Gal), mannose (Man), glucuronic acid (GlcA), iduronic acid (IdoA), allose, altrose, arabinose, cladinose, erythrose, erythrulose, fructose, D-fucitol, L-fucitol, fucosamine, fucose, foculose, D-galactosaminitol, glucosaminitol, glucose-6-phosphate, gulose glyceraldehyde, L-glycero-D-mannos-heptose, glycerol, glycerone, gulose, idose, lyxose, mannosamine, mannose-6-phosphate, psicose, quinovose, quinovosamine, rhamnitol, rhamnosamine, rhamnose, ribose, ribulose, sedoheptulose, sorbose, tagatose, talose, tartaric acid, threose, xylose, xylulose, glucosamine (2-amino-2-deoxy-glucose; GlcN), N-acetylglucosamine (2-acetamido-2-deoxy-glucose; GlcNAc), galactosamine (2-amino-2-deoxy-galactose; GalN), N-acetylgalactosamine (2-acetamido-2-deoxy-galactose; GalNAc), mannosamine (2-amino-2-deoxy-mannose; ManN), and N-acetylmannosamine (2-acetamido-2-deoxy-mannose; ManNAc).

[0055] The monosaccharide can be in D- or L configuration. The monosaccharide may further be an amino sugar (alcoholic hydroxy group replaced by amino group), a thio sugar (alcoholic hydroxy group replaced by thiol, or CO replaced by CS, or a ring oxygen of cyclic form replaced by sulfur), a seleno sugar, a telluro sugar, an aza sugar (ring carbon replaced by nitrogen), an imino sugar (ring oxygen replaced by nitrogen), a phosphano sugar (ring oxygen replaced with phosphorus), a phospha sugar (ring carbon replaced with phosphorus), a C-substituted monosaccharide (hydrogen at a non-terminal carbon atom replaced with carbon), an unsaturated monosaccharide, an alditol (carbonyl group replaced with CHOH group), aldonic acid (aldehydic group replaced by carboxy group), a ketoaldonic acid, a uronic add, an aldaric acid, and so forth. Amino sugars include amino monosaccharides. In some embodiments, an amino monosaccharide is mannosamine, fucosamine, quinovosamine, neuraminic acid, muramic acid, lactosediamine, acosamine, bacillosamine, daunosamine, desosamine, forosamine, garosamine, kanosamine, kansosamine, mycaminose, mycosamine, perosamine, pneumosamine, purpurosamine, or rhodosamine. It is understood that the monosaccharide and the like can be further substituted.

[0056] The term oligosaccharide refers to a compound containing at least two monosaccharides covalently linked together. Oligosaccharides include disaccharides (two monosaccharides), trisaccharides, tetrasaccharides, pentasaccharides, hexasaccharides, heptasaccharides, octasaccharides, and the like. Covalent linkages for linking sugars generally consist of glycosidic linkages (i.e., COC bonds) formed from the hydroxyl groups of adjacent sugars. Linkages can occur between the 1-carbon (the anomeric carbon) and the 4-carbon of adjacent sugars (i.e., a 1-4 linkage), the 1-carbon (the anomeric carbon) and the 3-carbon of adjacent sugars (i.e., a 1-3 linkage), the 1-carbon (the anomeric carbon) and the 6-carbon of adjacent sugars (i.e., a 1-6 linkage), or the 1-carbon (the anomeric carbon) and the 2-carbon of adjacent sugars (i.e., a 1-2 linkage). A sugar can be linked within an oligosaccharide such that the anomeric carbon is in the - or -configuration. Examples include abequose, acrabose, anucetose, amylopectin, amylose, apiose, arcanose, ascarylose, ascorbic acid, boivinose, cellobiose, cellobiose, cellulose, chacotriose, chalcose, chitin, colitose, cyclodextrin, cymarose, dextrin, 2-deoxyribose, 2deoxyglucose, diginose, digitalose, digitoxose, evalose, evemitrose, fructooligosaccharides, galto-oligosaccharide, gentianose, gentiobiose, glucan, glucogen, glycogen, hamamelose, heparin, inulin, isolevoglucosenone, isomaltose, isomaltotriose, isopanose, kojibiose, lactose, lactosamine, lactosediamine, laminaribiose, levoglucosan, levoglucosenone, P-maltose, maltriose, mannan-oligosaccharide, manninotnose, melezitose, melibiose, muramic acid, mycarose, mycinose, neuraminic acid, nigerose, nojirimycin, noviose, oleandrose, panose, paratose, planteose, pnmeverose, raffinose, rhodinose, rutinose, sarmentose, sedoheptulose, sedoheptulosan, solatriose, sophorose, stachyose, streptose, sucrose, am-trehalose, trehalosamine, turanose, tyvelose, xylobiose, umbelliferose and the like. Further, it is understood that the disaccharide, trisaccharide and polysaccharide and the like can be further substituted. They also include amino sugars and their derivatives, e.g., mycaminose.

[0057] As used herein, the term isomer refers to a compound having the same bond structure as a reference compound but having a different three-dimensional arrangement of the bonds. An isomer can be, for example, an enantiomer or a diastereomer.

[0058] The term amino refers to primary (NH.sub.2), secondary (NH), tertiary

##STR00009##

or quaternary

##STR00010##

amine group bonding to or being included in one or more of C.sub.1-C.sub.30 (e.g., C.sub.2-C.sub.20 and C.sub.4-C.sub.16) alkyl, C.sub.1-C.sub.30 (e.g., C.sub.2-C.sub.20 and C.sub.4-C.sub.16) heteroalkyl, aryl, or heteroaryl moieties. Examples include alkyl amino, dialkyl amino, alkenyl amino, etc. Aliphatic amino examples include C.sub.1-C.sub.30 alkyl amino, C.sub.2-C.sub.30 alkenyl amino, C.sub.2-C.sub.30 alkynyl amino, and C.sub.3-C.sub.30 cycloalkyl, C.sub.1-C.sub.30 heterocycloalkyl amino is an example of heteroaliphatic amino.

[0059] The term ketone refers to RC(O)R, in which each of R and R, independently, is (e.g., C.sub.2-C.sub.20 and C.sub.4-C.sub.16) alkyl, C.sub.1-C.sub.30 (e.g., C.sub.2-C.sub.20 and C.sub.4-C.sub.16) heteroalkyl, aryl, or heteroaryl.

[0060] The term carbonyl refers to C(O)R, in which R is defined above.

[0061] The term carboxylate refers to OC(O)R or C(O)OR, in which R is define above.

[0062] The term halo refers to H, F, Cl, Br, or I.

[0063] The term heteroatom refers to an atom that is not C or H, such as O, N, S, and P.

[0064] Alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, amino, carbonyl, carboxylate, carbamate, aryl, aralkyl, sulfonic, and phosphoric mentioned herein include both substituted and unsubstituted moieties, unless specified otherwise. Examples of a substituent include deuterium (D), hydroxyl (OH), halo (e.g., F and Cl), amino (NH.sub.2), cyano (CN), nitro (NO.sub.2), alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acylamino, alkylamino, aminoalkyl, haloalkyl (e.g., trifluoromethyl), heterocyclyl, alkoxycarbonyl, amido, carboxyl (COOH), alkanesulfonyl, alkylcarbonyl, alkenylcarbonyl, carbamido, carbamyl, carboxyl, thioureido, thiocyanato, sulfonamido, aryl, arylamino, aralkyl, and heteroaryl. All substitutes can be further substituted.

[0065] The term RAFT reagent refers to a chemical useful for reversible addition-fragmentation chain-transfer polymerization to afford control of the molecular weight and polydispersity of a polymer as prepared during a free-radical polymerization.

[0066] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0067] All publications, including patent documents, cited herein are incorporated by reference in their entirety.

EXAMPLES

[0068] Exemplary polymers were prepared and evaluated as described below. All manipulations of air- and moisture-sensitive materials were carried out under nitrogen in a glovebox or by using standard Schlenk line techniques. Solvent for polymerization, anhydrous benzene, was purchased from Sigma-Aldrich (catalog No. 401765, St Louis, MO) and stored in a nitrogen gas-filled glovebox. Other solvents (acetone, toluene, EtOAc, MeOH, Et.sub.2O) were used as received. Chemicals were purchased from Alfa Aesar (Haverhill, MA), Sigma-Aldrich, Fisher Scientific (Waltham, MA), Oakwood Chemical (Estill, SC), or Strem Chemicals (Newburyport, MA) and used as received without further purification. Concentrations unless otherwise indicated refer to solution volumes at 22 C. Evaporation and concentration in vacuo were performed using house vacuum (ca. 40 mm Hg). Column chromatography was performed with SiliaFlash 60 (40-63 micron) silica gel from Silicycle Inc. (Quebec City, Canada).

[0069] Nuclear magnetic resonance (NMR) spectra were obtained including .sup.1H, .sup.13C, COSY, HSQC, NOESY, DOSY NMR. Spectra were recorded on 600 MHz Varian/Agilent NMR spectrometer or 500 MHz VNMRS Varian/Agilent NMR spectrometer or 500 MHz Bruker Prodigy system or 500 MHz Bruker system with a helium CryoProbe and autosampler at the Boston College nuclear magnetic resonance facility. Chemical shifts for protons are reported in parts per million downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent. Chemical shifts for carbon are reported in parts per million downfield from tetramethylsilane and are referenced to the carbon resonances of the solvent. The solvent peak was referenced to 0 ppm for 1H for tetramethylsilane and 77.0 ppm for .sup.13C for CDCl.sub.3. Data are represented as follows: chemical shift, integration, multiplicity (br=broad, s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet, sp=septet, m=multiplet), coupling constants in Hertz (Hz).

[0070] High-Resolution Mass SpectrometryHigh-resolution mass spectrometry was performed on a JEOL AccuTOF-DART (positive mode) or Agilent 6220 TOF-ESI (positive mode) at the Mass Spectrometry Facility, Boston College.

[0071] Size-exclusion chromatography (SEC)Analyses were carried out using a Tosoh's high performance SEC system HLC-8420GPC with a refractive index detector and WYATT miniDAWN MALS detector or a Tosoh's high performance SEC system HLC-8320GPC with a refractive index detector. The Tosoh HLC-8420GPC SEC system was equipped with two TSKgel GMH.sub.HR-N columns (5 m, 7.8 mm I.D.30 cm), which were eluted with CHCl.sub.3 at 40 C. at a rate of 0.5 mL/min and calibrated using polystyrene standards (ReadyCal Kit, Sigma-Aldrich #81434). The Tosoh HLC-8320GPC SEC system was equipped with three TSKgel a-M columns (13 m, 7.8 mm I.D.30 cm), which were eluted with DMF at 50 C. at a rate of 0.5 mL/min and calibrated using polystyrene standards (ReadyCal Kit, Sigma-Aldrich #81434).

[0072] A facile procedure developed by Tosoh Bioscience described as follows was used to measure the specific refractive index dn/dc, which requires a standard with known dn/dc and a solution of the analyte. First, a polystyrene standard solution in CHCl.sub.3 with the concentration C.sub.inj of 1.08 mg/mL was run through SEC system with the injection volume V.sub.inj of 100 L. The integrated area RI.sub.area was calculated as 7498.275 mV.Math.sec, and the dn/dc of polystyrene in CHCl.sub.3 at 40 C. is 0.161 mL/g. Thus, the RI constant KRI for the system was calculated to be 431.233 based on the following equation.

KRI=RI.sub.area/(C.sub.inj.Math.V.sub.inj.Math.dn/dc)

[0073] For the measurement of dn/dc of polymer, the analyte solution was run through the SEC system with the injection volume V.sub.inj from 20 L to 100 L with the interval of 20 L. Thus, SEC elution profiles of polymer with different injection volumes were obtained and a plot of RI.sub.area/(KRI.Math.C.sub.inj) to V.sub.inj was made, and the slope of the plot is the dn/dc value. Using this method, the dn/dc values of P(Glu-CKA), P(Man-CKA), P(Gal-CKA) were measured as 0.0343 mL/g, 0.0278 mL/g and 0.0371 mL/g, respectively.

[0074] Thermogravimetric Analysis (TGA)Thermal gravimetric analysis was obtained using Netzsch Instruments STA 449 F1 Jupiter. Analysis was performed on 10 mg of a given sample at a heating rate of 10 C./min from 35 to 500 C. under nitrogen and argon gas.

[0075] Differential Scanning calorimetry (DSC)Data was recorded on Netzsch instruments DSC 214 Polyma using 5-20 mg samples. All T.sub.g values were obtained from a second scan after the thermal history was removed from the first scan. The second heating rate was 10 C./min and cooling rate was 10 C./min.

[0076] Abbreviations UsedAgClO.sub.4=Silver perchlorate, AIBN=Azobisisobutyronitrile, CDCl.sub.3=Deuterated chloroform, CHCl.sub.3=Chloroform, CH.sub.2Cl.sub.2=Methylene chloride, C.sub.6D.sub.6=Deuterated benzene, DMA=N,N-Dimethylacrylamide, DMF=Dimethylformamide, Et.sub.2O=diethyl ether HBr=Hydrobromic acid, MA=Methyl acrylate, MeOH=Methanol, MeONa=Sodium methoxide, MMA=Methyl methacrylate, Na.sub.2SO.sub.4=Sodium sulfate, PTLC=preparation thin layer chromatography, rt=Room temperature, TFA=trifluoroacetic acid.

Saccharide-CKA Monomers

[0077] Saccharide-CKA Monomers were synthesized according to Scheme I below.

##STR00011## ##STR00012## ##STR00013##

[0078] General Procedure for Monosaccharide CKAs SynthesisMonosaccharide CKA monomers were synthesized as follows. To a dry 100 mL round bottom flask, pentaacetate glucose (S1, 5 g, 12.8 mmol) and stir bar were added. Then 15 mL 33% HBr solution in acetic acid was added slowly. The resulting mixture was allowed to stir at room temperature for 1 hour. After 1 hour, .sup.1H NMR of the crude reaction mixture was performed to assure the full conversion of the starting material. The reaction mixture was diluted by 200 mL Et.sub.2O and washed by 200 mL water 5 times to remove excess HBr and acetic acid. Next, the organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, and concentrated by rotary evaporation to give S2 as a white solid in quantitative yield.

[0079] To a 500 mL round bottom three neck flask, 30 g 4 molecular sieves (powder) and stir bar were added. Under vacuum, the flask was flame-dried for 20 minutes and cooled to room temperature under vacuum. Under the nitrogen protection, all S2 from last step, diisopropyl ethyl amine (7.8 mL, 3.5 eq), and 350 mL dry toluene were added, and reaction mixture was allowed to stir for 5 minutes. Next, under nitrogen protection, AgClO.sub.4 (3.98 g, 1.5 eq) was added in one portion. The reaction flask was covered by aluminum foil to protect from light, and the mixture was vigorously stirred in dark at room temperature for 1 hour. After 1 hour, .sup.1H NMR of the crude reaction mixture was performed to ensure full conversion of the starting material. The reaction mixture was subsequently filtered with celite to remove excess silver salt, washed with 200 mL water twice to remove the remaining sliver salt, and dried over anhydrous Na.sub.2SO.sub.4, concentrated using rotary evaporation to give Glu-CKA as a pale yellow sticky liquid, which can be directly used for polymerization (4 g, 94% yield for two steps). For storage and use, all monosaccharide CKAs are dissolved in anhydrous benzene to prepare 1 M stock solution and stored in glove box freezer (40 C.). With this storage method, no NMR detectable decomposition after two months.

[0080] Glu-CKA: .sup.1H NMR (500 MHz, CDCl.sub.3) 5.80 (d, J=5.3 Hz, 1H), 5.25 (t, J=3.7 Hz, 1H), 4.96 (dd, J=9.6, 3.7 Hz, 1H), 4.43 (t, J=4.4 Hz, 1H), 4.28-4.17 (m, 2H), 4.00-3.93 (m, 1H), 3.46 (d, J=3.5 Hz, 1H), 3.40 (d, J=3.5 Hz, 1H), 2.12 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) 170.6, 169.6, 169.2, 161.9, 96.8, 74.0, 69.8, 68.4, 67.4, 62.5, 56.5, 20.7; HRMS (DART) m/z Calcd for C.sub.14H.sub.19O.sub.9 [M+H.sup.+]: 331.10236; found: 331.10270.

[0081] Following same procedure as described above except that pentaacetate mannose was used, Man-CKA was obtained as a white solid (3.4 g, 81% yield for two steps), which was directly used for polymerization. Optionally, it was purified by recrystallization with ethyl acetate/hexanes or benzene. .sup.1H NMR (500 MHZ, CDCl.sub.3) 5.65 (d, J=3.4 Hz, 1H), 5.33-5.24 (m, 1H), 5.24-5.17 (m, 1H), 4.64 (t, J=3.6 Hz, 1H), 4.27-4.16 (m, 2H), 3.86-3.81 (m, 1H), 3.56-3.48 (m, 2H), 2.14 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 170.6, 170.2, 169.3, 161.9, 96.4, 76.1, 72.4, 69.6, 65.4, 62.7, 58.3, 20.7, 20.6, 20.6. HRMS (DART) m/z Calcd for C.sub.14H.sub.19O.sub.9 [M+H.sup.+]: 331.10236; found: 331.10285.

[0082] Gal-CKA was obtained with a similar procedure as a pale red sticky liquid (3.8 g, 90% yield for two steps). For second step, 2.5 equiv. AgClO.sub.4 and 7 equiv. diisopropyl ethyl amine was used, and reaction was stirred in room temperature for 2 h. .sup.1H NMR (500 MHZ, CDCl.sub.3) 5.84 (d, J=5.0 Hz, 1H), 5.47-5.40 (m, 1H), 5.04 (dd, J=7.7, 3.3 Hz, 1H), 4.40-4.31 (m, 2H), 4.20-4.10 (m, 2H), 3.51-3.40 (m, 2H), 2.14 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 170.4, 169.9, 169.8, 160.0, 98.5, 71.9, 69.8, 69.1, 65.7, 61.4, 58.6, 20.7, 20.7, 20.6. HRMS (DART) m/z Calcd for C.sub.14H.sub.19O.sub.9 [M+H.sup.+]: 331.10236; found: 331.10292.

Polymerization

[0083] General Procedure of HomopolymerizationTo a flame-dried 100 mL round bottom flask, stir bar, monosaccharide CKA (1.98 g, 6 mmol), AIBN (19.7 mg, 0.12 mmol), and anhydrous benzene (30 mL) was added in glove box under nitrogen atmosphere. Then, the flask was capped with rubber stopper and sealed with tape in the glove box. Next, the flask was transferred out of the glove box, heated to 80 C., and stirred for 24 hours. After the reaction was finished by checking the crude .sup.1H NMR, reaction mixture was cooled to room temperature and diluted by 50 mL methylene chloride. The methylene chloride solution was then added dropwise into 500 mL diethyl ether under vigorous stirring in a 1000 mL round bottom flask to result in a cloudy suspension. The crude polymer was collected by vacuum filtration. The crude polymer was then dissolved in 30 mL methylene chloride and the precipitation process was repeated two more times. The resulting polymer was dried under high vacuum overnight to a constant weight, before being subjected to NMR analyses in CDCl.sub.3 and SEC analysis in CHCl.sub.3 solvent.

[0084] General Procedure of CopolymerizationTo an oven-dried 8 mL culture tube, monomers, AIBN, anhydrous benzene, and a stir bar were added in the glove box under nitrogen atmosphere. The culture tube was capped, sealed with tape, and transferred out of the glove box. Then, the reaction mixture was allowed to stir in the oil bath preheated to 80 C. for 1 hour. After reaction finished, the tube was cooled to room temperature. The crude polymer was dissolved in 5 mL CHCl.sub.3 and then precipitated into diethyl ether, centrifuged, discarded the solvent, and redissolve in methylene chloride. This procedure was repeated three times to ensure any catalyst residue or unreacted monomer was removed. The polymer was dried under high vacuum overnight to a constant weight. The resulting polymer was analyzed by NMR, SEC, TGA and DSC. The composition of the copolymer was determined by integration of peaks in .sup.1H NMR.

Example 1: Poly(GLU-CKA)

##STR00014##

[0085] P(Glu-CKA) (1.2 g, 61% yield white solid) was obtained from Glu-CKA (1.98 g, 6 mmol) with General Procedure of Homopolymerization. Crude .sup.1H NMR shows 69% conversion. .sup.1H NMR (500 MHZ, CDCl.sub.3) 6.46-6.07 (m, 1H), 5.57-5.37 (m, 1H), 5.29-5.05 (m, 1H), 4.32-3.99 (m, 3H), 2.99-2.37 (m, 3H), 2.13-2.01 (m, 9H). .sup.13C NMR (126 MHZ, CDCl.sub.3) 170.5, 169.7, 169.5, 169.3, 93.2, 70.5, 68.7, 65.5, 61.9, 38.3, 29.9, 20.8, 20.7, 20.6. SEC (CHCl.sub.3) M.sub.n, MALS=21.0 kDa, =1.58, dn/dc=0.0343 mL/g; M.sub.n, RI=10.7 kDa, =2.00. DSC T.sub.g=104 C. TGA T.sub.d=228 C.

Example 2: Poly(Man-CKA)

##STR00015##

[0086] P(Man-CKA) (1.14 g, 58% yield white solid) was obtained from Man-CKA (1.98 g, 6 mmol) with General Procedure of Homopolymerization. Crude .sup.1H NMR shows 66% conversion. .sup.1H NMR (500 MHZ, CDCl.sub.3) 6.11-5.37 (m, 1H), 5.36-4.92 (m, 2H), 4.59-4.19 (m, 1H), 4.19-3.95 (m, 1H), 3.95-3.58 (m, 1H), 3.21-2.16 (m, 3H), 2.15-1.92 (m, 9H). .sup.13C NMR (126 MHZ, CDCl.sub.3) 170.6, 170.2, 169.7, 169.1, 93.6, 72.5, 68.9, 65.6, 61.9, 41.2, 31.2, 20.7. SEC (CHCl.sub.3) M.sub.n, MALS=16.7 kDa, =1.63, dn/dc=0.0278 mL/g; M.sub.n, RI=5.8 kDa, =1.59. DSC T.sub.g=102 C. TGA T.sub.d=225 C.

Example 3: Poly(Gal-CKA)

##STR00016##

[0087] P(Gal-CKA) (0.8 g, 40% yield yellow solid) was obtained from Gal-CKA (1.98 g, 6 mmol) with General Procedure of Homopolymerization. Crude .sup.1H NMR shows 71% conversion. .sup.1H NMR (500 MHZ, CDCl.sub.3) 6.47-5.66 (m, 1H), 5.61-4.98 (m, 2H), 4.46-3.89 (m, 3H), 3.01-2.29 (m, 3H), 2.29-1.94 (m, 9H). .sup.13C NMR (126 MHz, CDCl.sub.3) 170.3, 170.0, 169.8, 169.6, 93.9, 92.8, 68.5, 65.8, 65.3, 61.3, 36.2, 30.9, 20.9, 20.7, 20.5. SEC (CHCl.sub.3) M.sub.n, MALS=11.8 kDa, =1.38, dn/dc=0.0371 mL/g; M.sub.n, RI=5.8 kDa, =1.38. DSC T.sub.g=72 C. TGA T.sub.d=220 C.

Example 4: Copolymer 1 (coP1)

[0088] Copolymer 1 (coP1) was synthesized with 1 M stock solution of Glu-CKA in benzene (0.4 mL, 0.4 mmol), MI (138.5 mg, 0.8 mmol), MMA (200.2 mg, 213.2 L, 2 mmol) and AIBN (1.31 mg, 8 mol) using the General Procedure of Copolymerization (334.5 mg, 71% yield), which was analyzed by NMR, SEC, TGA and DSC. The incorporation molar ratio of each monomer in the copolymer was determined to be Glu-CKA: MI: MMA=1:3.1:9.3 as calculated from NMR peaks, namely 6.27-3.90 (br, 6H) for Glu-CKA, 7.44 (s) for MI, and 3.60 (s) for MMA. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.55-7.32 (br, 9H), 7.26-7.10 (br, 6H), 6.27-3.90 (br, 6H), 3.89-3.24 (br, 28H), 3.10-0.70 (br, 62H). Certain NMR peaks were combined to simplify reporting of the data. SEC (DMF) M.sub.n, RI=70.3 kDa, =2.34. DSC T.sub.g=153 C. TGA T.sub.d=294 C.

Example 5: Copolymer 2 (coP2)

[0089] Copolymer 2 (coP2, 342 mg, 92% yield)) was synthesized with 1 M stock solution of Glu-CKA in benzene (0.2 mL, 0.2 mmol), MI (103.9 mg, 0.6 mmol), MMA (200.2 mg, 213.2 L, 2 mmol), and AIBN (1.31 mg, 8 mol) using the General Procedure of Copolymerization, which was analyzed by NMR, SEC, TGA and DSC. The ratio of each of each monomer in the copolymer was determined to be Glu-CKA: MI: MMA=1:4.4:15.2 using NMR peaks, namely, 6.42-3.88 (br) for Glu-CKA, 7.44 (s) for MI, and 3.61 (s) for MMA. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.58-7.32 (br, 13H), 7.26-7.11 (br, 9H), 6.42-3.88 (br, 6H), 3.87-3.32 (br, 46H), 3.28-0.62 (br, 95H). Certain NMR peaks were combined to simplify reporting of the data. SEC (DMF) M.sub.n, RI=81.4 kDa, =2.59. DSC T.sub.g=144 C. TGA T.sub.d=253 C.

Example 6: Copolymer 4 (coP4)

[0090] Copolymer 4 (coP4) was synthesized with 1 M stock solution of Glu-CKA in benzene (0.2 mL, 0.2 mmol), MI (103.9 mg, 0.6 mmol), MA (172.2 mg, 180.1 L, 2 mmol), and AIBN (1.31 mg, 8 mol) using the General Procedure of Copolymerization (325 mg, 95% yield), which was analyzed by NMR, SEC, TGA and DSC. The ratio of each monomer in the copolymer was determined to be Glu-CKA:MI:MA=1:3.3:10.7 using NMR peaks, namely 6.22-4.98 (br) for Glu-CKA, 7.44 (s) for MI, and 3.62 (s) for MA. .sup.1H NMR (500 MHZ, CDCl.sub.3) 7.52-7.33 (br, 10H), 7.29-7.18 (br, 7H), 6.22-3.89 (br, 6H), 3.88-3.46 (br, 32H), 3.46-1.18 (br, 50H). SEC (DMF) M.sub.n, RI=74.7 kDa, f)=3.17. DSC T.sub.g=96 C. TGA T.sub.d=322 C.

Example 7: Copolymer 5 (coP5)

[0091] Copolymer 5 (coP5) was synthesized with 1 M stock solution of Glu-CKA in benzene (0.2 mL, 0.2 mmol), MI (103.9 mg, 0.6 mmol), DMA (198.3 mg, 206.1 L, 2 mmol), and AIBN (1.31 mg, 8 mol) using the General Procedure of Copolymerization (324 mg, 88% yield), which was analyzed by NMR, SEC, TGA and DSC. The ratio of each monomer in the copolymer was determined to be Glu-CKA: MI: DMA=1:4.3:12.6 using NHR peaks, namely, 6.40-3.80 (br) for Glu-CKA, 7.42 (s) for MI, and 2.92 (s) for DMA. .sup.1H NMR (500 MHZ, CDCl.sub.3) 7.49-7.30 (br, 13H), 7.27-7.00 (br, 8H), 6.40-3.80 (br, 6H), 3.76-1.07 (br, 134H). SEC (DMF) M.sub.n, RI=55.1 kDa, f)=2.73. DSC T.sub.g=168 C. TGA T.sub.d=281 C.

General Procedure for Examples 8-12

[0092] To a 7-mL vial, monomers, AIBN (1.31 mg, 8 mol) and C.sub.6D.sub.6 (0.4 mL) were added and shaken until fully dissolved. The resulting solution was transfer to an oven-dried NMR tube and sealed with a rubber NMR cap with tape. After .sup.1H NMR confirming the ratio of monomers in solution, the NMR tube was connected to Schlenk line by a needle and was subjected to freeze-pump-thaw degassing three times with nitrogen under 78 C. The NMR spectrometer was pre-equilibrated pre-shimmed at 80 C. before the injection of the sample. Continuous .sup.1H NMR analyses of the reaction were performed at 80 C. to monitor the conversion vs time.

Example 8: Copolymer of Glu-CKA and Methyl Methacrylate (MMA)

[0093] Copolymerization was performed with Glu-CKA (66.1 mg, 0.2 mmol) and MMA (20 mg, 21.3 L, 0.2 mmol) at the 1:1 feed ratio using the General Procedure for EXAMPLES 8-12. The NMR results showed that both Glu-CKA and MMA were successfully incorporated into copolymer of Glu-CKA and MMA. Nevertheless, the conversion rate of Glu-CKA was lower than MMA, indicating that the copolymer has significant MMA segments.

Example 9: Copolymer of Glu-CKA and N-Phenyl Maleimide (MI)

[0094] Copolymerization was performed with Glu-CKA (66.1 mg, 0.2 mmol) and MI (34.6 mg, 0.2 mmol) at the 1:1 feed ratio. The NMR results showed that both Glu-CKA and MI were successfully incorporated into copolymer of Glu-CKA and MI. The conversion rate of Glu-CKA was the same as that of MI, indicating that the copolymer has a 1:1 ratio of Glu-CKA and MI.

Example 10: Copolymer of Glu-CKA, MI, and MMA at 1:1:1

[0095] Copolymerization was performed with Glu-CKA (66.1 mg, 0.2 mmol), MI (34.6 mg, 0.2 mmol), and MMA (20 mg, 21.3 L, 0.2 mmol) at the 1:1:1 ratio. All three monomers showed similar conversion rates throughout the copolymerization reaction, indicating that the copolymer has 1:1:1 ratio of Glu-CKA, MI, and MMA. As compared to Example 8, the addition of MI improved the incorporation of Glu-CKA in the copolymerization with MMA.

Example 11: Copolymer of Glu-CKA, MI, and MMA at 1:1:5

[0096] Copolymerization was performed with Glu-CKA (18.9 mg, 57.1 mol), MI (9.9 mg, 57.1 mol) and MMA (28.6 mg, 30.4 L, 285.5 mol) at the 1:1:5 ratio. The NMR results showed that monomers Glu-CKA, MI, and MMA were successfully incorporated into the copolymer. The conversion rate of Glu-CKA was lower than MI and MMA.

Example 12: Copolymer of Glu-CKA, MI, and MMA at 1:2:5

[0097] Copolymerization was performed with Glu-CKA (16.5 mg, 50 mol), MI (17.3 mg, 100 mol), and MMA (25 mg, 26.6 L, 250 mol) at a ratio of 1:2:5. The NMR results demonstrated similar conversion rates for all three monomers throughout the entire reaction, producing a copolymer coP1 in 71% yield. As calculated from .sup.1H NMR data, the copolymer incorporated the three monomers at the ratio of 1:3.1:9.3 for Glu-CKA: MI: MMA.

Comparative Copolymer

[0098] Comparative copolymer coP3 was synthesized with (173.2 mg, 1 mmol) MI, (500.6 mg, 533 L, 5 mmol) MMA and (1.31 mg, 8 mol) AIBN using the General Procedure of Copolymerization (476 mg, 71% yield), which was analyzed by NMR, SEC, TGA and DSC. The ratio of each monomer in the polymer was determined to be MI: MMA=1:5.4. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.57-7.32 (br, 3H), 7.26-7.10 (br, 2H), 3.85-3.41 (br, 16H), 3.07-1.67 (br, 13H), 1.67-0.72 (br, 18H). SEC (DMF) M.sub.n, RI=158.8 kDa, =3.95. DSC T.sub.g=150 C. TGA T.sub.d=347 C.

Degradation of Homopolymers

##STR00017##

[0099] General Procedure of Acidic Degradation of HomopolymersTo a 7 mL vial, homopolymer (20 mg, 60 mol of repeating units), 0.3 mL methylene chloride, and 0.3 mL trifluoroacetic acid added. The resulting mixture was allowed to stir at room temperature for 30 hours. Then the reaction mixture was concentrated by rotary evaporation. Next, mesitylene was added as internal standard and NMR yield was obtained from crude NMR. Different diastereomers were separated by PTLC.

[0100] Compound 3 was obtained in 84% NMR yield from P(Glu-CKA) and 16% NMR yield from P(Man-CKA) using the General Procedure of Acidic Degradation of Homopolymers, separated by PTLC with Hex: EA=1:1 as eluent.

[0101] .sup.1H NMR (500 MHz, CDCl.sub.3) 5.63 (d, J=3.8 Hz, 1H), 5.24 (dd, J=9.4, 6.5 Hz, 1H), 5.18 (t, J=9.5 Hz, 1H), 4.28 (dd, J=12.3, 5.1 Hz, 1H), 4.14 (dd, J=12.3, 2.4 Hz, 1H), 3.71 (m, 1H), 3.22-3.15 (m, 1H), 2.77 (dd, J=17.5, 11.8 Hz, 1H), 2.45 (dd, J=17.5, 8.6 Hz, 1H), 2.09 (s, 3H), 2.06 (s, 3H), 2.06 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 173.4, 170.6, 170.0, 169.6, 98.2, 71.4, 70.4, 65.3, 61.8, 40.1, 27.3, 20.7, 20.6, 20.6. HRMS (DART) m/z Calcd for C.sub.14H.sub.19O.sub.9 [M+H.sup.+]: 331.10236; found: 331.10253.

[0102] Compound 4 was obtained in 9% NMR yield from P(Glu-CKA) and 62% NMR yield from P(Man-CKA) using the General Procedure of Acidic Degradation of Homopolymers, separated by PTLC with Hex: EA=1:1 as eluent. .sup.1H NMR (500 MHZ, C.sub.6D.sub.6) 5.09-5.02 (m, 2H), 4.86 (t, J=8.2 Hz, 1H), 4.27 (dd, J=12.5, 4.2 Hz, 1H), 3.88 (dd, J=12.4, 2.3 Hz, 1H), 3.45 (dt, J=9.7, 3.2 Hz, 1H), 2.25 (d, J=16.8 Hz, 1H), 1.77-1.63 (m, 5H), 1.61 (s, 3H), 1.58 (s, 3H). .sup.13C NMR (126 MHZ, C.sub.6D.sub.6) 170.9, 169.9, 169.5, 169.2, 100.1, 71.9, 70.2, 67.2, 61.4, 40.1, 34.2, 20.3, 20.1, 20.1. HRMS (DART) m/z Calcd for C.sub.14H.sub.22NO.sub.9 [M+NH.sub.4.sup.+]: 348.12891; found: 348.12840.

[0103] Compound 5 was obtained in 78% NMR yield from P(Gal-CKA) using the General Procedure of Acidic Degradation of Homopolymers, separated by PTLC with Hex: Et2O=1:1 as eluent for five times. .sup.1H NMR (600 MHZ, CDCl.sub.3) 5.63 (d, J=4.0 Hz, 1H), 5.37 (d, J=3.9 Hz, 1H), 5.24 (dd, J=6.5, 3.9 Hz, 1H), 4.16 (qd, J=11.5, 6.6 Hz, 2H), 3.95 (td, J=6.6, 1.4 Hz, 1H), 3.09 (dd, J=17.4, 11.4 Hz, 1H), 2.94-2.86 (m, 1H), 2.47 (dd, J=17.4, 8.5 Hz, 1H), 2.15 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 174.5, 170.4, 169.7, 169.6, 98.5, 70.8, 66.8, 65.4, 61.6, 37.7, 28.3, 20.7, 20.6, 20.6. HRMS (DART) m/z Calcd for C.sub.14H.sub.19O.sub.9 [M+H.sup.+]: 331.10236; found: 331.10315.

[0104] Compound 6 was obtained in 20% NMR yield from P(Gal-CKA) using the General Procedure of Acidic Degradation of Homopolymers, separated by PTLC with Hex: Et2O=1:1 as eluent for five times. .sup.1H NMR (600 MHZ, CDCl.sub.3) 5.92 (d, J=4.1 Hz, 1H), 5.39 (d, J=2.9 Hz, 1H), 4.80 (dd, J=10.6, 3.0 Hz, 1H), 4.27 (t, J=6.5 Hz, 1H), 4.18-4.11 (m, 2H), 2.82-2.70 (m, 2H), 2.55 (d, J=16.7 Hz, 1H), 2.15 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 171.4, 170.4, 170.1, 169.9, 101.1, 69.7, 69.5, 64.7, 61.6, 35.4, 34.6, 20.7, 20.6, 20.6. HRMS (DART) m/z Calcd for C.sub.14H.sub.19O.sub.9 [M+H.sup.+]: 331.10236; found: 331.10300.

Basic Degradation of P(Glu-CKA)

##STR00018##

[0105] To a 7 mL vial, P(Glu-CKA) (100 mg, 300 mol of repeating units), 1.5 mL methylene chloride, and sodium methoxide (1.64 mg, 30 mol) in 1.5 mL methanol was added sequentially. The resulting mixture was allowed to stir at room temperature for 1 h, then concentrated by rotary evaporation. Next, .sup.1H NMR of the crude reaction mixture with added mesitylene as the internal standard showed 68% conversion and 61% NMR yield of 5 as a:b=5.3:1. Crude mixture was purified by column chromatography with 10% to 20% acetone in hexane as eluent to obtain compound S7 as a transparent liquid (35.8 mg, 50% yield). Other diastereomers were not observed after the basic degradation.

[0106] In CDCl.sub.3, compound S7 exists at a 1:0.19 mixture of a: diastereomers. .sup.1H NMR (600 MHz, CDCl.sub.3) 5.53 (dd, J=9.7, 5.4 Hz, 1H), 5.27 (dd, J=3.4, 1.2 Hz, 1H), 5.15 (dd, J=10.0, 5.1 Hz, 0.2H), 5.07 (t, J=9.7 Hz, 1H), 5.05-4.98 (m, 0.4H), 4.68 (d, J=5.1 Hz, 0.2H), 4.23-4.11 (m, 3.6H), 3.72 (s, 0.6H), 3.70 (s, 3H), 3.68-3.65 (m, 0.2H), 3.08-3.04 (m, 1H), 2.95-2.91 (m, 0.2H), 2.90-2.80 (m, 1.2H), 2.69 (dd, J=17.0, 4.4 Hz, 1H), 2.60 (dd, J=16.7, 4.0 Hz, 0.2H), 2.48 (dd, J=17.1, 9.8 Hz, 1H), 2.11 (s, 3H), 2.10 (s, 0.6H), 2.04 (s, 3H), 2.03 (s, 1.2H), 2.02 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 174.7, 172.4, 170.8, 170.8, 169.9, 169.8, 169.7, 94.9, 94.2, 72.5, 71.9, 69.4, 68.3, 66.3, 65.8, 62.5, 62.5, 52.4, 51.9, 40.4, 39.8, 30.3, 26.9, 20.9, 20.8, 20.8, 20.7, 20.7. HRMS (DART) m/z Calcd for C.sub.15H.sub.26NO.sub.10 [M+NH.sub.4.sup.+]: 380.15512; found: 380.15494.

Degradation Experiments of Copolymers

[0107] General Procedure of Degradation of CopolymersTo an oven-dried 8 mL culture tube, 20 mg copolymer, 0.5 mL CH.sub.2Cl.sub.2, and a stir bar was added. Next, a solution of MeONa (20 mg) in 0.5 mL MeOH was added. The culture tube was capped, and the reaction mixture was allowed to stir at room temperature for 16 hours. After the reaction finished, ion exchange resin (the proton form, 200 mg) was added, and reaction tube was shacked. Next, filtrate was collected after filtration with cotton to remove resin. The filtrate was concentrated by rotary evaporation and analyzed by SEC with DMF as the mobile phase.

[0108] Copolymers coP1, coP2, coP3, coP4, and coP5 were degraded following the procedure described above. All of copolymers and degradation product results were obtained by DMF GPC using the same methods.

[0109] Degradation of coP1 resulted in significant reduction of molecular weight from 70.3 KDa (M.sub.n) to 9.2 KDa (M.sub.n), indicating that ester groups were efficiently incorporated into the polymer backbone. Similarly, coP2, coP4, and coP5 showed, respectively, a reduction of M.sub.n from 81.4 kDa to 16.3 kDa, 74.5 kDa to 6.7 kDa, and 55.1 kDa to 11.3 kDa. Further, the polydispersity index of coP1 was increased from 2.34 to 4.84 after the degradation. The same trend was observed when coP5 was degraded.

[0110] By contrast, comparative copolymer coP3 containing only MI and MMA, was poorly degradable in the same degradation study, showing a decrease of M.sub.n from 158.8 kDa to 119 kDa, and a decrease of the polydispersity index from 3.95 to 2.93.

OTHER EMBODIMENTS

[0111] All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

[0112] From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the claims.