CROSS REFERENCE TO RELATED APPLICATIONS

The presently application claims priority to United States provisional patent application serial no. 61/528,307, filed August 29, 2011, the entire contents of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention pertains to the field of poly(hydroxyalkanoate) polymers. More particularly, the invention pertains to poly(hydroxyalkanoate) co-polymers of hydroxy alkanoate isomers.

BACKGROUND OF THE INVENTION

Poly- -hydroxybutyrate (PHB) is a biodegradable, biocompatible, thermoplastic made by microorganisms. (Baptist, J.N., 1962, U.S. Patent 3,036,959) Microbial synthesis of PHB, specifically R-PHB, through fermentation is known in the art. For example, Takao et al. (Japanese Patent Publication No. 60-251889 A2, entitled "Preparation of Poly (β-Hydroxybutyric Acid)", published December 12, 1985, incorporated herein by reference) discloses production of R-PHB using Azotobactor vinelandi. Microbial synthesis of PHB is capable of producing R-PHB with 100% optical purity, but this polymer is crystalline, brittle, and difficult to process.

Using microbial syntheses, the incorporation of structural modifications to R-PHB to improve its processing characteristics has been difficult. It is possible to feed fermentations with alternate monomers to change the polymer composition, but such processes can be difficult to control. One success in this regard is the microbial synthesis of poly(3-hydroxybutyrate-co-3 -hydroxy valerate) (PHBV) through fermentation. PHBV is similar to R-PHB, but incorporates a minor amount of valerate monomer. The presence of the ethyl side chains of the valerate monomer decreases the crystallinity of the polymer. PHBV is less brittle than R-PHB and has a melting temperature of about 160 °C leading to improved processing characteristics relative to R-PHB. Chemical synthesis of PHB is also known in the art. Hori et al. (European Patent Application Pub. No. 0 612 780 A2, entitled "Process for producing poly(3- hydroxybutyric acid)", published August 24, 1994) disclose a ring opening polymerization of β-butyrolactone with a tin catalyst to produce a high molecular weight PHB. The polymerization maintains the stereochemistry of the β-butyrolactone, so the

stereochemistry of the PHB product is dependent upon the optical purity of the β- butyrolactone reagent. Gross et al. (Macromolecules. 21, pp. 2657-2668, 1988) disclose a process of synthesizing PHB using a triethylaluminum/water catalyst. Zhang et al.

(Macromolecules, 23, pp. 3206-3212, 1990) disclose a process of synthesizing PHB using an aluminum-porphyrin catalyst. The above-mentioned references are all incorporated herein by reference.

SUMMARY OF THE INVENTION

The poly(hydroxy alkanoate) (PHA) product is a co-polymer of two or more hydroxy alkanoates where at least two of the hydroxy alkanoates are regioisomers of each other. The polymer product has a reduced melting point, a reduced crystallinity, and a reduced brittleness in comparison to a pure polymer of either of the two carboxylate isomers. The process for forming a poly(hydroxycarboxylate) product includes forming a mixture of two lactones and forming the polymer by ring opening polymerization of the mixture of lactones.

In certain embodiments of the present invention, the PHA polymer product includes a plurality of monomer units where at least two of the monomer units are regioisomers of each other.

In other embodiments, the invention includes methods for forming a poly(hydroxy alkanoate) polymer product from a lactone mixture including a plurality of lactones, at least two of which are regioisomers of each other.

In certain embodiments of the present invention, the lactone mixtures are made by physically mixing portions of two lactones while in other embodiments, the mixtures of lactones are formed directly by one or more chemical reactions. In certain embodiments, the lactone mixtures are formed directly by carbonylation of epoxide substrates. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the 1H nuclear magnetic resonance spectrum of a sample of polymer P4 according to the present invention: the small doublet at 1.18ppm indicates the presence of 2-methyl 3 -hydroxy propionate monomer in the polymer.

Fig. 2 shows the ^l H nuclear magnetic resonance spectrum of prior art poly(hydroxyl butyrate), no doublet at 1.18 ppm is present.

Fig. 3 shows the thermal thermogravimetric analysis data indicating the thermal

decomposition profile of the sample from Fig. 1.

Fig. 4 shows the digital scanning calorimetry profile of the sample from Fig. 1.

DEFINITIONS

Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of

Chemistry and Physics, 75 ^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March 's Advanced Organic Chemistry, 5 ^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 ^rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

Certain compounds of the present invention can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. Thus, inventive compounds and compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of enantiomers or diastereomers are provided.

Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of enantiomers. In addition to the above-mentioned compounds per se, this invention also encompasses pharmaceutically acceptable derivatives of these compounds and

compositions comprising one or more compounds. As used herein, the term "isomers" includes any and all geometric isomers and stereoisomers. For example, "isomers" include cis- and trans-isomers, E- and Z- isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. For instance, an stereoisomer may, in some embodiments, be provided substantially free of one or more corresponding stereoisomers, and may also be referred to as

"stereochemically enriched."

Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the opposite enantiomer, and may also be referred to as "optically enriched." "Optically enriched," as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques, et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al, Tetrahedron 33 :2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds

(McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical

Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). As used herein, the term "regioisomer" and derivatives of the term such as "regioisomers", and "regioisomeric" refer to compounds having the same core structure, but differing in the atom of the core structure on which a substituent resides. For example, regioisomeric lactones have the same lactone ring but have substituents on different carbon atoms of the rings. The term regioisomeric does not place any limitation on the stereochemistry of the compounds being referred to. Therefore one or more regioisomeric compounds may be racemic or enantioenriched, and if enantio enriched, the relative stereochemistry of the regioisomers may be the same or different. In some cases one regioisomer may be racemic, while another regioismer may be enantioenriched. The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), and iodine (iodo, -I).

The term "aliphatic" or "aliphatic group", as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spiro-fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-30 carbon atoms. In certain embodiments, aliphatic groups contain 1-12 carbon atoms. In certain embodiments, aliphatic groups contain 1-8 carbon atoms. In certain embodiments, aliphatic groups contain 1-6 carbon atoms. In some embodiments, aliphatic groups contain 1-5 carbon atoms, in some embodiments, aliphatic groups contain 1^1 carbon atoms, in yet other embodiments aliphatic groups contain 1-3 carbon atoms, and in yet other embodiments aliphatic groups contain 1-2 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The term "unsaturated", as used herein, means that a moiety has one or more double or triple bonds.

The terms "cycloaliphatic", "carbocycle", or "carbocyclic", used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic or polycyclic ring systems, as described herein, having from 3 to 12 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, adamantyl, norbornyl, and cyclooctadienyl. In some

embodiments, the cycloalkyl has 3-6 carbons. The terms "cycloaliphatic", "carbocycle" or "carbocyclic" also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring.

The term "alkyl," as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals derived from an aliphatic moiety containing between one and six carbon atoms by removal of a single hydrogen atom. Unless otherwise specified, alkyl groups contain 1-12 carbon atoms. In certain embodiments, alkyl groups contain 1-8 carbon atoms. In certain embodiments, alkyl groups contain 1-6 carbon atoms. In some embodiments, alkyl groups contain 1-5 carbon atoms, in some embodiments, alkyl groups contain 1-4 carbon atoms, in yet other embodiments alkyl groups contain 1-3 carbon atoms, and in yet other embodiments alkyl groups contain 1-2 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec- hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like.

The term "alkenyl," as used herein, denotes a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Unless otherwise specified, alkenyl groups contain 2-12 carbon atoms. In certain embodiments, alkenyl groups contain 2-8 carbon atoms. In certain embodiments, alkenyl groups contain 2-6 carbon atoms. In some embodiments, alkenyl groups contain 2-5 carbon atoms, in some embodiments, alkenyl groups contain 2-\ carbon atoms, in yet other embodiments alkenyl groups contain 2-3 carbon atoms, and in yet other embodiments alkenyl groups contain 2 carbon atoms. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2- buten-l-yl, and the like.

The term "alkynyl," as used herein, refers to a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. Unless otherwise specified, alkynyl groups contain 2-12 carbon atoms. In certain embodiments, alkynyl groups contain 2-8 carbon atoms. In certain embodiments, alkynyl groups contain 2-6 carbon atoms. In some embodiments, alkynyl groups contain 2-5 carbon atoms, in some embodiments, alkynyl groups contain 2-\ carbon atoms, in yet other embodiments alkynyl groups contain 2-3 carbon atoms, and in yet other embodiments alkynyl groups contain 2 carbon atoms.

Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and poly cyclic ring systems having a total of five to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to twelve ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more additional rings, such as benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, and the like. The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refer to groups having 5 to 14 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term

"heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring",

"heteroaryl group", or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-14-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), ΝΗ (as in pyrrolidinyl), or ¾fR (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,

pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH ₂ )o-4R°; -(CH ₂ )o- ₄ 0R°; -0-(CH ₂ )o- ₄ C(0)OR°; -(CH ₂ )o^CH(OR ⁰ ) ₂ ; -(CH ₂ ) ₀ ^SR°; -(CH ₂ ) ₀ - ₄ Ph, which may be substituted with R°; which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -N0 ₂ ; -CN; -N ₃ ; -(CH ₂ ) _C N(R ⁰ ) ₂ ; -(CH ₂ ) ₀ ^N(R ^O )C(O)R°; - N(R°)C(S)R°; -(CH ₂ )o^N(R°)C(0)NR° ₂ ; -N(R°)C(S)NR° ₂ ; -(CH ₂ ) ₀ ^N(R°)C(O)OR°; - N(R°)N(R°)C(0)R°; -N(R°)N(R°)C(0)NR° ₂ ; -N(R°)N(R°)C(0)OR°; -(CH ₂ ) ₀ - ₄ C(O)R°; -C(S)R°; -(CH ₂ )o^C(0)OR°; -(CH ₂ ) ₀ - ₄ C(O)N(R°) ₂ ; -(CH ₂ )C C(0)SR ⁰ ; -(CH ₂ )O- ₄ C(0)OSiR° ₃ ; -(CH ₂ ) _C OC(0)R ⁰ ; -OC(0)(CH ₂ ) ₀ - ₄ SR- SC(S)SR°; -(CH ₂ ) _C SC(0)R ⁰ ; - (CH ₂ )o- ₄ C(0)NR° ₂ ; -C(S)NR° ₂ ; -C(S)SR°; -SC(S)SR°, -(CH ₂ ) ₀ - ₄ OC(O)NR° ₂ ; - C(0)N(OR°)R°; -C(0)C(0)R°; -C(0)CH ₂ C(0)R°; -C(NOR°)R°; -(CH ₂ ) ₀ ^SSR°; - (CH ₂ )o-4S(0) ₂ R°; -(CH ₂ )o-4S(0) ₂ OR°; -(CH ₂ ) ₀ ^OS(O) ₂ R°; -S(0) ₂ NR° ₂ ; -(CH ₂ y

4S(0)R°; -N(R°)S(0) ₂ NR° ₂ ; -N(R°)S(0) ₂ R°; -N(OR°)R°; -C( H)NR° ₂ ; -P(0) ₂ R°; - P(0)R° ₂ ; -OP(0)R° ₂ ; -OP(0)(OR°) ₂ ; SiR° ₃ ; -(Ci^ straight or branched alkylene)0- N(R°) ₂ ; or -(Ci^ straight or branched alkylene)C(0)0-N(R°) ₂ , wherein each R° may be substituted as defined below and is independently hydrogen, Ci_s aliphatic, -CH ₂ Ph, - 0(CH ₂ )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having C heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or polycyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH ₂ y ₂ R ^e , -(haloR*), -(CH ₂ y ₂ OH, -(CH ₂ y ₂ OR ^e , -(CH ₂ y ₂ CH(OR') ₂ ; -

O(haloR'), -CN, -N ₃ , -(CH ₂ y ₂ C(0)R ^e , -(CH ₂ y ₂ C(0)OH, -(CH ₂ y ₂ C(0)OR ^e , -(CH ₂ y ₄ C(0)N(R°) ₂ ; -(CH ₂ y ₂ SR ^e , -(CH ₂ y ₂ SH, -(CH ₂ y ₂ NH ₂ , -(CH ₂ y ₂ NHR ^e , -(CH ₂ y

2NR" ₂ , -N0 ₂ , -SiR's, -OSiR's, -C(0)SR ^e -(C _1-4 straight or branched

alkylene)C(0)OR", or -SSR* wherein each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from Ci^ aliphatic, -CH ₂ Ph, -0(CH ₂ )o_iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0M heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S. Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR ^* ₂ , = NHC(0)R ^* ,

= NHC(0)OR ^* , = NHS(0) ₂ R ^* , =NR ^* , =NOR ^* , -0(C(R ^* ₂ )) ₂ _ ₃ 0-, or -S(C(R ^* ₂ )) ₂ _ ₃ S-, wherein each independent occurrence of R is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted" group include: -0(CR 2)2- ₃ 0-, wherein each independent occurrence of R is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R ^* include halogen, -R", -(haloR"), -OH, -OR", -O(haloR'), -CN, -C(0)OH, -C(0)OR ^e , -NH ₂ , -NHR", -NR' ₂ , or -N0 ₂ , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_4 aliphatic, -CH ₂ Ph, -0(CH ₂ )o iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0^1 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ^† , -NR ^† ₂ , -C(0)R ^† , -C(0)OR ^† , -C(0)C(0)R ^† , -C(0)CH ₂ C(0)R ^† , - S(0) ₂ R ^† , -S(0) ₂ NR ^† ₂ , -C(S)NR ^† ₂ , -C( H)NR ^† ₂ , or -N(R ^† )S(0) ₂ R ^† ; wherein each R ^† is independently hydrogen, Ci_6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0^1 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ^† , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms

independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R ^† are independently halogen, -R", -(haloR*), -OH, -OR", -O(haloR'), -CN, -C(0)OH, -C(0)OR ^e , -NH ₂ , -NHR", -NR' ₂ , or -NO2, wherein each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_4 aliphatic, -CH ₂ Ph, -0(CH ₂ )o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0^1 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

As used herein, the term "tautomer" includes two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to-(a different) enamine tautomerizations.

In the catalyst structures described hereinbelow, the substituents may be defined as

follows:

R ¹ and R ¹ are independently selected from the group consisting of: -H, Ci to C12 alkyl; C ₂ to C ₁₂ alkenyl; C ₂ to C ₁₂ alkynyl; -C(R ¹³ ) _z H ₍₃ - _z) ; -(CH^R ¹⁴ ; and -(CH ₂ ) _r Z-R ¹⁴ ,

R ² , R ² R ³ , and R ^3' are independently selected from the group consisting of:

a) Ci-Ci ₂ alkyl; b) C ₂ -Ci ₂ alkenyl; c) C ₂ -Ci ₂ alkynyl; d) Cs to Ci ₂ carbocycle; e) C ₃ to C heterocycle; f) -(ΟΗ ₂ )^ ^14; g) R ²⁰ ; and

where each of (i) through (v) may optionally be further substituted with one or more R ²⁰ groups; and where R ² and R ² , and R ³ and R ³ may optionally be taken together with the carbon atoms to which they are attached to form one or more rings which may in turn be substituted with one or more R ²⁰ groups; and

R ⁴ is selected from the group consisting of:

, where

R ^c at each occurrence is independently selected from the group consisting of: a) C1-C12 alkyl; b) C ₂ -C ₁₂ alkenyl, c) C ₂ -C ₁₂ alkynyl;

e) C3 to C ₁₂ carbocycle, f) C3 to C ₁₂ heterocycle; g) R ²⁰ ; and

Where: two or more R ^c groups may be taken together with the carbon atoms to which they are attached to form one or more rings, when two R ^c groups are attached to the same carbon atom, they may be taken together to form a moiety selected from the group consisting of: a 3 - to 8-membered spirocyclic ring; a carbonyl (C=0), an oxime (C=NOR ¹⁰ ); a hydrazone (C= R ⁿ R ¹² ); an imine (C=NR ⁿ ); and an alkenyl group (C=CR ^U R ¹² ), and where any of (a) through (f) may optionally be further substituted with one or more R groups,

R ^d at each occurrence is independently selected from the group consisting of: a) -H; b) Ci-Ci ₂ alkyl; c) C ₂ -Ci ₂ alkenyl, d) C ₂ -Ci ₂ alkynyl; e) halogen; f) -OR ¹⁰ ; g) -OC(0)R ¹³ ; h) -OC(0)OR ¹³ ; i) -OC(0)NR ⁿ R ¹² ; j) -CN; k) -CNO; 1) -C(0)R ¹³ ; m) -C(R ¹³ ) _z H ₍₃ - _z) ; n) -C(0)OR ¹³ ;

0) -C(0)NR ⁿ R ¹² ; p) -NR ⁿ R ¹² ; q) -NR ⁿ C(0)R ¹⁰ ; r) -NR ⁿ C(0)OR ¹³ ; s) -NR ⁿ S0 ₂ R ¹³ ; t) -NCO; u) -N ₃ ; v) -N0 ₂ ; w) -S(0) _x R ¹³ ;

x) -S0 ₂ NR ^u R ¹² ; y) -C(R ¹³ ) _z H ₍₃ - _z) ; z) -(CH^R ¹⁴ ;

aa) -(CH^-Z-R ¹⁶ -; and ab) -(ΟΗ ₂ ) ₄ -Ζ-(ΟΗ ₂ ) _Μ ^ ¹⁴ , R at each occurrence is independently selected from the group consisting of: a) -H; b) halogen; c) -OR ¹⁰ ; d) -OC(0)R ¹³ ; e) -OC(0)OR ¹³ ;

f) -OC(0)NR ^u R ¹² ; g) -CN; h) -CNO; i) -C(0)R ¹³ ; j) -C(0)OR ¹³ ;

k) -C(0)NR ⁿ R ¹² ; 1) -C(R ¹³ ) _z H ₍₃ - _z) ; m) -NR ⁿ R ¹² ; n) -NR ⁿ C(0)R ¹⁰ ; o) -NR ⁿ C(0)OR ¹⁰ ; p) -NCO; q) -NR ¹² S0 ₂ R ¹³ ; r) -S(0) _x R ¹³ ;

s)-S(0) ₂ NR ⁿ R ¹² ; t) -N0 ₂ ; u) -N ₃ ; v) -(CH ₂ R ¹⁴ ; w) -(CH ₂ -Z-R ¹⁶ ; and x) -(CR2)k-Z-(CR ₂ ) _m -R ^U , and where,

R ¹⁰ at each occurrence is independently selected from the group consisting of: a) -C(R ¹³ ) _Z H(3- _Z) ; b) d-C ₁₂ alkyl; c) C ₂ to C ₁₂ alkenyl; d) C ₂ to C ₁₂ alkynyl; e) C3 to C ₁₂ carbocycle; f) C3 to C ₁₂ heterocycle, g) -S(0) ₂ R ¹³ ; h) -Si(R ¹⁵ ) ₃ ; i) -H; and j) a hydroxyl protecting group,

R ¹¹ and R ¹² at each occurrence are independently selected from the group consisting of: a) -H; b) Ci to C ₁₂ alkyl; c) C ₂ to C ₁₂ alkenyl;

d) C ₂ to C12 alkynyl; and e) -C(R ¹³ ) _z H ₍₃ - _z) ; where R ¹¹ and R ¹² ; when both present, can optionally be taken together with the atom to which they are attached to form a 3- to 10-membered ring,

R ¹³ at each occurrence is independently selected from the group consisting of: a) -H; b) Ci-Ci ₂ alkyl; c) C ₂ to C ₁₂ alkenyl; d) C ₂ to C ₁₂ alkynyl; e) C3 to C ₁₂ carbocycle; f) C3 to C ₁₂ heterocycle,

R ¹⁴ at each occurrence is independently selected from the group consisting of: a) halogen; b) -OR ¹⁰ ; c) -OC(0)R ¹³ ; d) -OC(0)OR ¹³ ; e)-OC(0)NR ^u R ¹² ; f) -CN; g) -CNO; h) -C(R ¹³ ) _z H ₍₃ - _z) ; i) -C(0)R ¹³ ; j) -C(0)OR ¹³ ; k) -C(0)NR ⁿ R ¹² ; m) -NR ⁿ C(0)R ¹³ ;

n) -NR ^u C(0)OR ¹⁰ ; 0) -NR ⁿ S0 ₂ R ¹³ ; p) -NCO; q) -N ₃ ; r) -N0 ₂ ; s) -S(0) _x R ¹³ ; t) -S0 ₂ NR ⁿ R ¹² ; u) C ₃ to C ₁₂ heterocycle; and v) C ₃ to C ₁₂ carbocycle, R ¹⁵ at each occurrence is independently selected from the group consisting of: Ci-Ce alkyl, C2 to Ce alkenyl, C2 to Ce alkynyl, and C3 to C ₁₂ substituted or unsubstituted carbocycle,

R ¹⁶ at each occurrence is independently selected from the group consisting of: b) C1-C12 alkyl; c) C ₂ to C ₁₂ alkenyl; d) C ₂ to C ₁₂ alkynyl; C ₃ to

C12 heterocyle; C3 to C ₁₂ carbocycle; and -C(R ¹³ ) _Z H(3_ _Z ),

Z is a divalent linker selected from the group consisting of -(CH=CH) _a - ;

-(CH≡CH) _a -; -C(O)-; -C(=NOR ⁿ )-; -C(=NNR ^U R ¹² )-; -0-; -N(R ⁿ )-; -N(C(0)R ¹³ )-; -S(0) _x -; a polyethyler; and a polyamine, a is 1, 2, 3, or 4, k is an integer from 1 to 8 inclusive, m is an integer from 1 to 8 inclusive, x is 0, 1, or 2, and z is 1, 2, or 3.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

In certain embodiments, the present invention encompasses poly(hydroxyl alkanoate) compositions (PHAs) that are copolymers of at least one 3 -substituted-3 - hydroxy propionate and at least one 2-substituted-3 -hydroxy propionate. In certain embodiments, the 3 -substituted-3 -hydroxy propionate and the 2-substituted-3 -hydroxy propionate have different substituents (i.e. the group at the 3-position of the 3-substituted- 3 -hydroxy propionate is not identical to the group at the 2-position of the 2-substituted-3- hydroxy propionate). In certain other embodiments, the 3 -substituted-3 -hydroxy propionate and the 2-substituted-3 -hydroxy propionate have identical substituents (i.e. the group at the 3-position of the 3 -substituted-3 -hydroxy propionate is the same as the group at the 2-position of the 2-substituted-3-hydroxy propionate). For example, in certain embodiments, one monomer unit is a 3-substituted-3-hydroxypropionate (Ml), and another monomer is a 2-substituted-3-hydroxypropionate (M2) where the substituent R ^s on each monomer is the same. bodiment, one monomer unit Ml has the structure:

Ml , and another monomer unit M2 has the structure:

In certain embodiments, each R ^s is independently selected from the group consisting of: optionally substituted Ci to C2 ₀ aliphatic; optionally substituted Ci to C2 ₀ heteroaliphatic; optionally substituted C3 to C12 carbocyclic; and C3 to C12 optionally substituted heterocyclic.

In certain embodiments, the molar ratio of 3-substituted-3-hydroxypropionate (Ml) to 2-substituted-3-hydroxypropionate (M2) in the polymer is greater than 1 : 1. In one embodiment, the molar ratio ofMl to M2 is greater than 5: 1. In another embodiment, the molar ratio ofMl to M2 is greater than 10: 1. In another embodiment, the molar ratio of Ml to M2 is greater than 20: 1. In another embodiment, the molar ratio ofMl to M2 is greater than 50: 1. In another embodiment, the molar ratio ofMl to M2 is greater than 100: 1. In another embodiment, the molar ratio ofMl to M2 is greater than 1000: 1.

In certain embodiments of the invention, monomers with the structure M2 comprise 5 to 20% of the polymer, and monomers having structure Ml comprise 80 to 95% of the polymer. In other embodiments, monomers having structure M2 comprise 1 to 5% of the polymer and monomers having structure Ml comprise 95 to 99% of the polymer. In other embodiments, monomers having structure M2 comprise 0.01 to 1% of the polymer and monomers having structure Ml comprise 99 to 99.99% of the polymer.

In certain embodiments, the stereochemistry of the 3-substituted-3- hydroxypropionate is the opposite of the stereochemistry of the 2-substituted-3- hydroxypropionate. In other embodiments, the stereochemistry of the 3 -substituted-3 - hydroxypropionate is the same as the stereochemistry of the 2-substituted-3- hydroxypropionate. In certain embodiments, one of the monomers is enantio-enriched, and another monomer is racemic. In one embodiment, the 3 -substituted-3 -hydroxypropionate monomer is enantioenriched and the 2 -substituted-3 -hydroxypropionate monomer is not enantioenriched.

In other embodiments, polymers of the present invention encompass random copolymers, tapered copolymers, or block copolymers incorporating at least one monomer from Table la, and at least one monomer from Table lb. In certain embodiments, polymers of the present invention encompass random copolymers, tapered copolymers, or block copolymers incorporating at least one monomer from Table 1 a, and at least one monomer from Table lb where the substituent on the monomer from Table la and the substituent on the monomer from Table lb are the same.

Table la: 3-substituted-3-h droxy-propionate monomers

Table lb: 2-substituted-3-hydroxy-propionate monomers

In one embodiment, one monomer unit in the polymer has the structure M3:

R ^s O

M3 and another monomer unit in the polymer has the structure M4:

where R ^s is as defined above.

In another embodiment, one monomer unit in the polymer has the structure M5:

R ^s O

M5

, and the second monomer unit in the polymer has the structure M6:

, where R ^s is as defined above,

bodiment, one monomer unit in the polymer has the structure M7:

M7

and another monomer unit in the polymer has the structure M8: In certain embodiments, the present invention encompasses polymers having structure PI :

, where Ml, M2, and R ^s are as defined above.

In other embodiments, the invention includes methods for forming a poly(hydroxy alkanoate) polymer product from a lactone mixture including a plurality of lactones, where the mixture contains at least one 2-substituted propiolactone and at least one 3-substituted propiolactone. In certain embodiments, the 2-substituted propiolactone and the 3- substituted propiolactone have different substituents. In other embodiments, at least one 2- substituted propiolactone and at least one 3-substituted propiolactone have the same substituent.

In one embodiment the method includes the steps of forming a lactone mixture including a first lactone LI and a second lactone L2: , where R ^s is as defined above,

and treating the mixture with at least one material capable of catalyzing the ring-opening polymerization of the lactones to form a polymer PI incorporating monomer units Ml and M2, derived from LI and L2 respectively, for example, as shown in Scheme 1 :

Scheme 1

In another embodiment, provided methods include the steps of forming a lactone mixture including a first lactone L3 and a second lactone L4: , where R ^s is as defined above,

and treating the mixture with a material capable of catalyzing the ring-opening polymerization of the lactones to form polymer chains incorporating monomers derived from both L3 and L4, as shown in Scheme 2:

P2

Scheme 2.

In another embodiment, provided methods include the steps of forming a lactone mixture including a first lactone L5 and a second lactone L6:

, where R ^s is as defined above,

and treating the mixture with a material capable of catalyzing the ring-opening polymerization of the lactones to form a polymer P3 incorporating monomers derived from both L5 and L6, as shown in Scheme 3 :

Scheme 3.

In one embodiment, provided methods include the steps of forming a mixture including (R)- -butyrolactone L7 and a (R)-2-methyl-propiolactone L8:

and treating the mixture with a material capable of catalyzing the ring-opening polymerization of the lactones to form polymer chains incorporating monomers derived from both L7 and L8, as shown in Scheme 4:

P4

Scheme 4.

In another embodiment, provided methods include the steps of forming a lactone utyrolactone L9 and a rac-2-methyl-propiolactone L10:

and treating the mixture with a material capable of catalyzing the ring-opening polymerization of the lactones to form polymer chains incorporating monomers M7 and M9 derived from both L7 and L9, respectively, as shown in Scheme 5:

Scheme 5.

In another embodiment, provided methods include the steps of forming a lactone mixture including rac-3 -substituted propiolactone Lll and a rac-2-substituted- propiolactone L12:

R Lll R ^s L12 _{s where R} s _{ig as defmed abov6j}

and treating the mixture with a stereospecific catalyst capable of catalyzing the ring- opening polymerization of a single enantiomers of one or both of the lactones to form enantio-enriched polymer chains incorporating monomers derived from both Lll and L12, as shown in Scheme 6: f

+ I I

^RS enatioenriched Lll

P6

-OR-

P6'

Scheme 6.

In some instances, the polymerizations shown in Scheme 6 may occur such that both Lll and L12 are stereos electively polymerized. In that case, the reaction would yield polymer along with enantioenriched Lll and L12. In other cases, the catalyst may act such that only one lactone Lll or L12 is enantioselectively polymerized, while the other lactone is incorporated without enantioselectivity.

In another embodiment, provided methods include the steps of forming a lactone mixture including rac-3 -substituted propiolactone Lll and a rac-2-substituted- propiolactone L12: , where R ^s is as defined above,

and treating the mixture with a stereospecific catalyst capable of catalyzing the ring- opening polymerization of both of the enantiomers of one or both of the lactones to form isotactically-enriched polymer chains incorporating monomers derived from both Lll and L12, as shown in Scheme 6a:

Scheme 6a. In another embodiment, provided methods include the steps of forming a mixture including (R)-3-ethyl-propiolactone L13 and a (R)-2-ethyl-propiolactone L14:

and treating the mixture with a material capable of catalyzing the ring-opening polymerization of the lactones to form polymer chains incorporating monomers from both L13 and L14, as shown in Scheme 7:

Scheme 7.

In another embodiment, provided methods include the steps of forming a mixture including β-butyrolactone L15, 2-methyl-propiolactone L16, and 3-ethyl-propiolactone

and treating the mixture with a material capable of catalyzing the ring-opening polymerization of the lactones to form polymer chains incorporating monomers from all of L15 through L17, as shown in Scheme 8:

Scheme 8.

In another embodiment, provided methods include the steps of forming a mixture including β-butyrolactone L15, 2-methyl-propiolactone L16, 3-ethyl-propiolactone L17, and 2-ethyl-propiolactone L18:

and treating the mixture with a material capable of catalyzing the ring-opening polymerization of the lactones to form polymer chains incorporating monomers derived from all of L15 through L18, as shown in Scheme 9: ring-opening

polymerization

L15 through L18 — »

P9

Scheme 9.

In certain embodiments of the present invention, the polymers PI through P9 are random copolymers. In other embodiments, the polymers PI through P5 are tapered copolymers.

Catalysts suitable for the ring-opening polymerization step of the methods disclosed herein are disclosed, for example, in: Journal of the American Chemical Society (2002), 124(51), 15239-15248 Macromolecules. vol. 24, No. 20, pp. 5732-5733, Journal of Polymer Science. Part A-l, vol. 9, No. 10, pp. 2775-2787; Inoue, S., Y. Tomoi, T. Tsuruta & J. Furukawa; Macromolecules. vol. 26, No. 20, pp. 5533-5534;

Macromolecules. vol. 23, No. 13, pp. 3206-3212; Polymer Preprints (1999), 40(1), 508- 509; Macromolecules. vol. 21, No. 9, pp. 2657-2668; and Journal of Organometallic Chemistry, vol. 341, No. 1-3, pp. 83-9; and in US Patent Nos. 6, 133,402; 5,648,452; 6,316,590; 6,538,101 ; and 6,608, 170. The entirety of each of which is hereby incorporated herein by reference.

In certain embodiments of the present invention, the lactone mixtures are made by physically mixing portions of two or more lactones. The lactones that are thus mixed may be obtained by any methods known in the art. Suitable methods for making lactones suitable for the present invention are described, for example, in Catalytic Asymmetric Synthesis of β-Lactones and Application to the Total Synthesis of (-)-Pironetin (Xiaoqiang Shen, 2007 Ph.D. dissertation, University of Pittsburgh) the entirety of which is hereby incorporated herein by reference.

Therefore, in some embodiments, methods of the present invention include the steps of mixing a plurality of lactones, at least two of which are regioisomers of each other, and contacting the mixture with a polymerization catalyst to form a PHA polymer incorporating both of the regioisomeric lactones. In certain embodiments, the methods of the present invention include the step of combining lactones LI and L2 to form a mixture, and treating the mixture with a polymerization catalyst C2 to form a polymer PI, as shown in Scheme 10.

Scheme 10

In other embodiments of the present invention, the mixtures of lactones are formed by carbonylation of epoxide substrates. Suitable conditions for such carbonylations may be found, for example, in US Patent Application Serial No. US 2005-0014977 and in US Patent Nos. 6,852,865 and 7,569,709, the entirety of each of which are incorporated herein by reference.

Therefore, in some embodiments, methods of the present invention include the steps of contacting a mixture containing one or more epoxides with a carbonylation catalyst CI to produce a mixture of lactone products, at least two of which are regioisomers of each other, and contacting the mixture with a polymerization catalyst to form a PHA polymer incorporating both of the regioisomeric lactones. In certain embodiments, methods of the present invention include the steps of: a) contacting an epoxide El with carbon monoxide and a carbonylation catalyst CI to provide a mixture of lactones comprising LI and L2, and b) treating the mixture of lactones with a

polymerization catalyst C2 to provide the polymer PI as shown in Scheme 10a.

Scheme 10a

In some embodiments, methods of the present invention include one or more additional steps of isolating or purifying the mixture of LI and L2 prior to treating the mixture with the polymerization catalyst. In other embodiments, the mixture of products formed by the carbonylation step are treated directly with the polymerization catalyst C2. In certain embodiments of the present invention, the carbonylation step and the polymerization step are carried out sequentially on the same reaction mixture. In certain embodiments, the carbonylation step and the polymerization step are carried out sequentially in the same reaction vessel. In certain embodiments, the carbonylation step and the polymerization step are carried out concomitantly.

In some embodiments of the invention, mixtures of three or more lactones are produced from mixtures of two or more epoxides. For example, a mixture of two different epoxides El and El' is treated with a carbonylation catalyst CI to produce a mixture of products including at least two products derived from El that are regioisomers of each other (such as LI and L2). In addition, the products of such mixtures include one or more carbonylation products such as LI' derived from El'. The carbonylation of El' may also yield a mixture of regioisomers such that the mixture of lactones includes four lactones: two regioisomeric lactones derived from El, plus two regioisomeric lactones derived from

El'.

Scheme 11 In certain embodiments of the present invention, R ^s of the epoxide El is as defined hereinabove. In certain embodiments of the present invention, the epoxide El, has a structure selected from those in Table 2.

TABLE 2

In certain embodiments of the present invention, the epoxide El employed in the first step is enantioenriched. In other embodiments, the epoxide El employed in the first step is racemic. In certain embodiments of the present invention, the epoxide El is racemic, and the carbonylation catalyst CI is enantioselective such that the one or both of the lactones LI and L2 resulting from the carbonylation step are enantioenriched.

In certain embodiments of the present invention, the carbonylation catalyst CI comprises a Lewis acid in combination with a carbonyl complex of a transition metal. The term Lewis acid as used herein refers to any electrophilic species that is capable of accepting an electron pair and that is not a Bronsted-Lowry acid. Preferably, the Lewis acid portion of the catalyst includes an element from groups 3 through 14 of the periodic table or contains a lanthanide metal. Lewis acids useful for the invention may either be neutral (e.g. compounds such as AICI ₃ , CrCi ₃ , ZnCl ₂ , BF ₃ , and Yb(OTf) ₃ etc.) or they may be cationic (for instance, metal complexes of the formula [M( ) _X ] ^Z+ where M is a metal, each L is a ligand, x is an integer from 1 to 6 inclusive, and z is 0, 1, 2, or 3, and where, if more than one L is present, each L may be the same or different). Preferably, M is a transition metal, a group 13 or 14 metal, or a lanthanide. More preferably, M is a transition metal or a group 13 metal. Still more preferably, M is aluminum, chromium, indium or gallium, with aluminum and chromium being particularly preferred. Similarly, a range of ligands (L) can be present in the metallo Lewis acid component of the catalyst CI. A preferred class of ligands includes dianionic tetradentate ligands.

Suitable ligands for the metallo Lewis acid component of the catalyst CI include, but are not limited to: porphyrin derivatives 1, salen derivatives 2,

dibenzotetramethyltetraaza[14]annulene (tmtaa) derivatives 3, phthalocyaninate derivatives 4, and derivatives of the Trost ligand 5, with porphyrin, salen, and tmtaa derivatives being particularly preferred ligands. In some cases, a mixture of more than one Lewis acid component can be present in the catalyst CI.

The transition metal carbonyl complex included in the carbonylation catalyst CI may be neutral or anionic. Preferably, the metal carbonyl complex is anionic. Preferred anionic metal carbonyl complexes include monoanionic carbonyl complexes of metals from groups 5, 7 or 9 of the periodic table and dianionic carbonyl complexes of metals from groups 4 or 8 of the periodic table. More preferably, the metal carbonyl complex contains a metal from groups 7 or 9 of the periodic table, more preferably cobalt, manganese or rhodium. Examples of suitable anionic metal carbonyl complexes include, but are not limited to: [Co(CO) ₄ ] ^~ and [Mn(CO) ₅ ] ^~ with [Co(CO) ₄ ] ^" being particularly preferred. In some cases, a mixture of two or more transition metal carbonyl complexes may be present in the catalyst.

Turning next to the polymerization catalyst C2, there are numerous catalysts known to promote the ring-opening polymerization of lactones such as LI and L2. Any such known catalysts can be employed in methods of the present invention. Because some catalysts are more sensitive to parameters such as substrate steric hindrance than others, the choice of the catalyst C2 can affect the proportions of LI and L2 incorporated into the polymer formed. The ratio of incorporation of LI to L2 in the polymer formed by a particular catalyst can be determined by routine analytical techniques such as ¹³ C NMR spectroscopy. Modifications such as selection of the different catalysts C2 to optimize the polymerization of a particular mixture of lactones are encompassed by the present invention.

Catalysts C2 suitable for the polymerization step of the present invention are disclosed, for example, in: Journal of the American Chemical Society (2002), 124(51), 15239-15248 Macromolecules. vol. 24, No. 20, pp. 5732-5733, Journal of Polvmer Science. Part A-l, vol. 9, No. 10, pp. 2775-2787; Inoue, S., Y. Tomoi, T. Tsuruta & J. Furukawa; Macromolecules. vol. 26, No. 20, pp. 5533-5534; Macromolecules. vol. 23, No. 13, pp. 3206-3212; Polvmer Preprints (1999), 40(1), 508-509; Macromolecules. vol. 21, No. 9, pp. 2657-2668; and Journal of Organometallic Chemistry, vol. 341, No. 1-3, pp. 83-9; and in US Patent Nos. 6,133,402; 5,648,452; 6,316,590; 6,538, 101 ; and 6,608, 170. The entirety of each of which is hereby incorporated herein by reference.

It is to be understood that the embodiments of the invention herein described are merely illustrative of the application of the principles of the invention. Reference herein to details of the illustrated embodiments is not intended to limit the scope of the claims, which themselves recite those features regarded as essential to the invention.