This application claims the benefit of U.S. Provisional Application No. 63/270,638, filed October 22, 2021 , the entire content of which is incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under grant number CHE21 17246 awarded by the National Science Foundation. The government has certain rights in the invention.

BACKGROUND

Polysaccharides are among the most abundant biopolymers on Earth. In addition to their essential functions in biology ¹ , the utilization of polysaccharide-based biomass in renewable energy ² and sustainable materials ³ is also critical to reducing carbon emissions worldwide. However, polysaccharides isolated from biological sources are often heterogeneous ⁴ , imposing significant constraints on their characterization and utilization for emerging technologies. Therefore, the development of synthetic approaches to polysaccharides has been one of the main research areas in glycoscience ⁵ . For example, enzymatic synthesis has emerged as a promising method for polysaccharide synthesis owing to the perfect regio- and stereoselectivity of the enzymatic glycosylation, and the elimination of the need for protecting groups ⁶ . However, limited enzyme availability and high specificity generally restrict them to specific substrates or reactions. Iterative assembly strategies have been developed to prepare synthetic polysaccharides with precise sequence and length ⁷ . Notably, the automated glycan assembly (AGA) techniques developed by Seeberger has enabled the construction of complex polysaccharides (FIG. 1 a) ⁸ ’ ⁹ . Nevertheless, the stepwise assembly methods require significant investments in equipment and reagents, and often have modest scalability. Chemical polymerization is an efficient method for the scalable synthesis of polysaccharides and glycomimetic polymers ¹⁰ . Over the last ten years, many carbohydrate-derived monomers have been used to generate carbohydrate polymers, such as isosorbide ¹¹ , xylose ¹² , isohexide ¹³ , and levoglucosenyl ether ¹⁴ (FIG. 1 a). Particularly worth noting are the living anionic ring-opening polymerization of monosaccharide-derived cyclic carbonate and b-lactam reported by Wooley ¹⁵ and Grinstaff ¹⁶ , respectively. However, these polymers all consist of non-glycosidic linkages, and in some cases, control over the polymerization remains challenging. While the cationic ring-opening polymerization (CROP) of 1 ,6-anhydrosugars has been employed to produce polysaccharides since the 1960s ¹⁷ , achieving control over this polymerization remains a formidable challenge.

Synthetic polymers play an essential role in the modern human society due to their low cost, high stability, and excellent material properties. However, they impose increasingly serious environmental issue, caused by unsustainable generation (~320 Mt in 2015) and disposal of single-used commodity plastics, pushing people to find numerous approaches to address this challenge from the perspective of circular economy. Among them, chemical recycling via depolymerization to their constituent monomer, where polymer-to-polymer closed-loop recycling would be achieved, represents an ideal solution to the end-of-use issue of plastics. Although tremendous advances have been made in the last decades, the chemical recycling approach still faces challenges, such as, relatively complicated monomer syntheses, energy-intensive polymerization conditions (typically low temperature) and uncomplete recycling of the precursor motif chemicals. In addition, the material properties of the virgin and recycled polymers, including thermostability, crystallinity and mechanical behaviors, must be concerned as well.

Thus, there is a need to develop chemically recyclable polymers with novel structures and encouraging properties from more environmentally friendly biomass- derived feedstocks. Polysaccharides with inherent structural rigidity and stereoregularity prognosticate remarkable stability and crystallinity, as well as other unexpected material properties. In addition, not only can polysaccharides be readily prepared from abundant and sustainable natural monosaccharides, but also their potentially labile glycosylic bond will help to unzip the polymer chain to achieve complete chemical recycling. Hence, extensive efforts have been made to pursue efficient polysaccharides synthesis. State- of-the-art iterative glycosylation has been widely used to construct complex polysaccharides, and glycans more than 100-mer have been successfully obtained by Seeberger and Yu lab, but tedious protection/deprotection steps used therein offset the benefits associated with the renewable feedstocks. Polymerization represent another powerful strategy to prepare polysaccharides, despite free from lab-consuming tasks, but poor control over the polymerization hamper their application in the precision polysaccharides synthesis. The present disclosure provides efficient synthetic routes to precision polysaccharides to satisfy these needs and other needs.

SUMMARY

In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure provides a chemical approach to produce stereoregular polysaccharides from abundant natural resources of 1 ,6-anhydrosugars with precise control over molecular weights. The resulting polysaccharides possess excellent chemical stabilities against strong acid, base, and under high temperature, but can be readily recycled and depolymerized into the starting monomers in the presence of the catalyst. Existing strategies do not offer the level of control over polymer structures and molecular weights achieved by the method of the present disclosure and cannot achieve a circular life cycle demonstrated in the present disclosure.

In one aspect, the present disclosure provides a method of controlled synthesizing and chemical recycling of a stereoregular polysaccharide comprising reacting a biomass- derived anhydrosugar having Formula I: wherein R is a group selected from C1 -C6 alkyl group, with an initiator in the presence of a synergy of a catalyst and the initiator. In certain embodiments, the R is a group selected from C1 -C6 alkyl group, C1 -C5 alkyl group, C1 -C4 alkyl group, C1 -C3 alkyl group, C1 -C2 alkyl group, and/or a methyl group.

In certain embodiments, the initiator is glucosyl halide having a structure represented by the formula: wherein the halide is a group selected from fluoride, chloride, bromide or iodide. The initiator provides the polysaccharide with high chain end fidelity and an excellent molecular weight distribution in a controlled manner. In certain embodiments, the polysaccharide of the present disclosure has 1 -95% chain end fidelity, 50-95% chain end fidelity, or about 90%-95% chain end fidelity.

In certain embodiments, the catalyst is a Lewis acid, including but not limited to, Cu(OTf)2, BFs or Boron trifluoride complex, such as boron trifluoride diethyl etherate.

The present disclosure further provides that the polysaccharides are made by the method described herein. In certain embodiments, the polysaccharide of the present disclosure has a molecular weight that ranges from 2.6 to 32.2 kDa. The polysaccharide of the present disclosure can replace polyethylene glycol (PEG), a widely used polymer in drug delivery applications ranging from anti-cancer drugs to mRNA vaccines.

Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments are combinable and interchangeable with one another.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood with reference to the drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views. A better understanding of the features and advantages of the invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

FIGs. 1a-1c. Living cationic ring-opening polymerization of 1,6- anhydrosugars. FIG. 1a. Established pathways to polysaccharides (Prior Art). FIG. 1 b. Representative reaction scheme of living cationic ring-opening polymerization of 1 ,6- anhydrosugars in this work. FIG. 1c. Proposed mechanism. LG, leaving group; PG, protecting group; tPG, temporary protecting group; Bn, benzyl; Me, methyl; R, alkyl/allyl group.

FIGs. 2a-2f. Preparation and characterization of precision polysaccharides. FIG. 2a. Development of living CROP of 1 ,6-anhydrosugars. FIG. 2b. MALDI-TOF MS spectrum of P(Me-D-Glc). FIG. 2c. ¹ H NMR spectra of P(Me-D-Glc). FIG. 2d. (i) Plots of M _n and D as a function of monomer conversion and (ii) Plots of Mi and D as a function of the [M]o/[l]o ratio. FIG. 2e. Synthesis of block copolysaccharide P("Bu-D-Glc)-b-P(Me-D- Glc). FIG. 2f , Chain end modification of P(Me-D-Glc). Et, ethyl; "Bu, n-butyl; Glc, glucose; OTf, trifluoromethanesulfonate.

FIGs. 3a-3b. Monomer scope and computational studies. FIG. 3a. Monomer scope: polymerization reactions were performed at in dichloromethane for six hours; more experimental details are provided in Supplementary Information. FIG. 3b. Energy profile of reversible deactivation and propagation process. Free energies (kcal mol ^-1 ) are obtained at the level of wB97X-2-D3(BJ)/ma-def2-TZVPP-def2- TZVPP/SMD(DCM)//B3LYP-D3(BJ)/ma-def2-SVP-def2-SVP/PCM(DCM). The DFT calculations were performed starting from a methyl-protected glucosyl fluoride 1 to mimic the dormant species during living CROP and simplify the calculations. "Pr, n-propyl; "Pen, n-pentyl; All, allyl.

FIGs. 4a-4c. Synthesis of biologically relevant precision polysaccharides. FIG. 4a. Synthesis of a-1 ,6-D-glucan P(OH-D-Glc) and comparison to natural a-1 ,6-D- glucan. FIG. 4b. Enzymatic degradation studies of P(OH ^Bn -D-Glc) and P(OH ^Bn -L-Glc). FIG. 4c. Synthesis of a-1 ,6-D-mannan P(OH-D-Man). Pd, Pd(PPh 3)4 and Pd(OH)2; Man, mannose.

FIGs. 5a-5e. Chemical recycling and material properties of precision polysaccharides. FIG. 5a. Polymerization-depolymerization cycles. FIG. 5b. (i) SEC trace overlays of P(Me-D-Glc) treated by various additives and (ii) TGA curves of P(R-D- Glc) (R = Me, Et, "Pr, "Bu, "Pen). FIG. 5c. (i) DSC curve and powder XRD profile (inset) of P(Me-D-Glc) and (ii) overlays of DSC curves of P(R-D-Glc) (R = Et, "Pr, "Bu, "Pen). FIG. 5d. Stress-strain curves of PN1 (green) and PN2 (magenta). FIG. 5e. Depolymerization of materials and reprepared materials PN1' and PN2' from recovered monomers.

Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

Petroleum-based plastics are currently produced in a massive scale worldwide and contribute to a significant portion of the plastic waste accumulation in the environment. While much effort has been made to develop sustainable and degradable polymers (e.g., polyesters and polylactides) as potential replacements for traditional vinyl plastics, they are still single-use plastics that cannot be chemically recycled. The present disclosure provides a promising solution to this challenge. Starting from 1 ,6-anhydrosugar, an abundant natural product, a novel class of polysaccharides can be generated with precisely controlled molecular weight and stereochemistry. This unprecedented capability is of immediate and broad interest to the polymer industry, which has seen a significant surge of interest in addressing the global crisis of plastic pollution.

Disclosed herein is a novel approach that can achieve polysaccharides with high chain end fidelity and an excellent molecular weight distribution via polymerization of biomass-derived anhydrosugars in a controlled manner. The resulting polysaccharides possess excellent chemical stabilities against strong acid, base, and under high temperature. As a significant conceptual advance, the novel approach described herein has, surprisingly, enabled a fully closed recycling loop for the biomass-derived anhydrosugars using the same catalysts both in the polymerization to obtain the polysaccharides and unzipping thereof.

In one aspect, the disclosed methods provides that the anhydrosugars react with an initiator in the presence of a synergy of a catalyst and the initiator achieving the polysaccharides with high chain end fidelity and an excellent molecular weight distribution in a controlled manner. In a further aspect, the polysaccharides obtained by such methods can be recycled and depolymerized into the starting monomers in the presence of the catalyst.

Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.

DEFINITIONS

As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of. As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a monomer,” “a catalyst,” or “a polymer,” includes, but is not limited to, mixtures or combinations of two or more such monomers, catalysts, or polymers, and the like.

It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

When a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g., the phrase “x to y” includes the range from ‘x ’to ‘y ’as well as the range greater than ‘x ’and less than ‘y’. The range can also be expressed as an upper limit, e.g., ‘about x, y, z, or less ’and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z ’as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater ’should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z ’as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x ’to ‘y’”, where ‘x ’and ‘y ’are numerical values, includes “about ‘x ’to about ‘y’”.

It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1 % to 5%” should be interpreted to include not only the explicitly recited values of about 0.1 % to about 5%, but also include individual values (e.g., about 1 %, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1 .1 %; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

Unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e., one atmosphere).

The composition, sequence, length, and type of glycosidic linkages of polysaccharides profoundly affect their biological and physical properties. However, investigation of the structure-function relationship of polysaccharides is hampered by accessing well-defined polysaccharides in sufficient quantities. Here, the present disclosure provides a chemical approach to precision polysaccharides with native glycosidic linkages via living cationic ring-opening polymerization of 1 ,6-anhydrosugars. In certain embodiments, well-defined polysaccharides with tunable molecular weight, low dispersity, and excellent regio- and stereoselectivity were synthesized using a boron trifluoride etherate catalyst and glycosyl fluoride initiators. Computational studies revealed that the reaction propagated through the monomer a-addition to the oxocarbenium and was controlled by the reversible deactivation of the propagating oxocarbenium to form the glycosyl fluoride dormant species. The method disclosed herein afforded a facile and scalable pathway to multiple biologically relevant precision polysaccharides, including D-glucan, D-mannan, and an unusual L-glucan. It is demonstrated that catalytic depolymerization of precision polysaccharides efficiently regenerated monomers, suggesting their utility as a class of chemically recyclable materials with tailored thermal and mechanical properties.

In certain embodiments, the synergistic combination of a glycosyl donor initiator and a mild Lewis acid catalyst were leveraged to achieve living CROP of 1 ,6- anhydrosugars (FIG. 1 b). Native polysaccharides with controlled molecular weight and excellent regio- and stereoselectivity could be readily prepared from these biorenewable monomers. The mechanism of the disclosed method is centered on reversible deactivation of the propagating oxocarbenium ¹⁸ , which is generated by the fluoride abstraction from glycosyl fluoride initiator by boron trifluoride catalyst. Addition of the 1 ,6- anhydrosugar monomer to oxocarbenium from the less sterically demanding a-face affords an a-oxonium ¹⁹ . Followed by a rapid ring opening process, the oxocarbenium was regenerated. An equilibrium between oxocarbenium species and dormant glycosyl fluoride is established to achieve controlled chain growth (FIG. 1 c). It is worth noting that Coates et al. recently harnessed a similar strategy to accomplish the controlled polymerization of cyclic acetals ²⁰ .

The present disclosure provides a chemical approach to precision native polysaccharides through living polymerization of 1 ,6-anhydrosugars. The generality of this method enabled the facile synthesis of a variety of polysaccharides and oligo-glycans with excellent regio- and stereoselectivity, precise molecular weight control, and high fidelity of the chain end groups. In addition, the obtained materials displayed excellent chemical recyclability and tunable thermal and mechanical properties. Overall, the method disclosed herein created a new paradigm for the chemical synthesis of polysaccharides with strong implications in a range of applications spanning from materials science to bioengineering.

Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure.

EXAMPLES

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

EXAMPLE 1

Materials and Methods

All manipulations of air- and moisture-sensitive materials were carried out under nitrogen in a glovebox or by using standard Schlenk line techniques. Solvents for polymerization, such as Dichloromethane (DCM), chloroform (CHCh) and acetonitrile (CH3CN), were dried over calcium hydride for 24 hrs, distillated to an oven-dried Schlenk flask, and stored in a nitrogen gas-filled glovebox. Solvents for air sensitive reactions, such as tetrahydrofuran (THF), dimethylformamide (DMF), were purchased from Fisher Scientific and used after purification by a dry solvent system (Pure Process Technology). Otherwise, solvents (hexane, acetone, toluene, EtOAc, MeOH, DMSO) were used as received. BF3*Et2O was dried over calcium hydride for 24 hrs, vacuum distillated to an oven-dried Schlenk flask, and stored under nitrogen in a glovebox freezer at -30 °C. All other chemicals were purchased from Alfa Aesar, Sigma-Aldrich, Acros, Fisher Scientific, or TCI chemical companies and used as received without further purification.

¹ H, ¹³ C, ¹⁹ F NMR — Spectra were recorded on either a Varian Gemini-600 (600 MHz) or Varian lnova-500 (500 MHz) NMR spectrometer Chemical shifts (5) for ¹ H and ¹³ C NMR spectra were referenced to protons of the residual solvent (for ¹ H) or deuterated solvent itself (for ¹³ C).

Powder X-Ray Diffraction (PXRD) — Analyses were performed on a Rigaku MiniFlex diffractometer. The voltage was set to 40 kV, and the current was 40 mA. The detector collected data over the range 20 = 5-50°.

Specific Rotation — Analyses were performed on a Rudolph Analytical Research Autopol IV Polarimeter. The wavelength of the light used is 589 nanometers (the sodium D line), and the path length is 0.5 dm. The data was collected at 20 °C.

High-resolution mass spectrometry (HRMS) — Analyses were performed on JEOL AccuTOF DART Micromass LCT ESI-MS.

Matrix-Assisted Laser Desorption/lonization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) — Analyses were performed on a Bruker Auto Flex Max instrument (positive mode). a-Cyano-4-hydroxycinnamic acid was used as matrix with Nal added as the cation source.

Size-exclusion chromatography (SEC) — Analyses were carried out using a Tosoh’s high performance SEC system HLC-8320GPC with a refractive index detector. The Tosoh SEC system was equipped with two TSKgel GMHHR-N columns (5 pm, 7.8 mm ID), which were eluted with and calibrated using polystyrene standards (ReadyCal Kit, Sigma-Aldrich #81434). Deprotected polymer molecular weights were determined by SEC using DMF (0.01 M LiBr) as the eluent at a flow rate of 0.5 mL/min through three TSKgel AlphaM columns (13 μm, 7.8 mm ID) at 50 °C with a refractive index detector.

Thermogravimetric Analysis (TGA) — Thermal gravimetric analysis was obtained using a Netzsch Instruments STA 449 F1 Jupiter. Analysis was performed on ~10 mg of a given sample at a heating rate of under nitrogen gas.

Differential Scanning Calorimetry {DSC) — Data was recorded on a Netzsch instruments DSC 214 Polyma using ~10 mg samples. All T _m and T _g values were obtained from a second scan after the thermal history was removed from the first scan. The second heating rate was

Uniaxial Tensile Elongation Tests — Analyses were performed on an Instron 5567 universal testing system equipped with a 1 kN load cell and manual grips, at a crosshead speed of 5 mm/min. A pre-strain of 0.1 N was also applied. The samples were prepared in Teflon molds with cavity dimensions of (63.5x9.5x3.2 mm ³ ). Grip separation was used as the gauge length for the purposes of calculating strain. Extension to failure was performed using three parallel samples and the data were analyzed using the Bluehill Universal Software. The Young’s modulus was calculated using the slope of the stressstrain curve from 0 to 1% strain. solvent was removed under reduced pressure. DCM was added, successively washed with water and brine, and then dried over Na2SO4. After filtration, all the volatiles were removed under vacuum and the crude was purified by flash chromatography to afford the desired product. To a solution of CL-Me-S2 (2.0 g, 8.6 mmol, 1 .0 equiv) in MeOH (20 mL) at , was added MeONa (46.5 mg, 0.86 mmol, 0.1 equiv). The reaction was stirred at for 2 hrs and neutralized by Amberlite resin IR-120 (H ⁺ ). After filtration, the solvent was removed in vacuo to furnish the desired product CL-Me-S 3 as a colorless syrup, the syrup was used for next step without further purification.

Prepared according to a modified literature procedure ⁵⁴ . To a solution of 1 ,4- butanediol dimethanesulfonate (740 mg, 3.0 mmol, 1.0 equiv) and CL-Me-S3 (860 mg, 4.5 mmol, 1 .5 equiv) in toluene (2.5 mL) and dimethyl sulfoxide (10 mL) was added KOH (675 mg, 12.0 mmol, 4.0 equiv). The reaction was stirred at s, after cooled down to room temperature, the mixture was diluted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. After filtration, the solvent was removed in vacuo and the crude was purified by flash chromatography (hexane/ethyl acetate = 1/2) to afford the desired product CL-Me as a colorless syrup (800 mg, 81% yield). ¹ H NMR (500 MHz, CDCI ₃ ): δ 5.46 (s, 2H), 4.62 (dd, J= 6.0, 1 .6 Hz, 2H), 3.93 (dd, J= 7.2, 1 .2 Hz, 2H), 3.71 (dd, J = 7.2, 6.0 Hz, 2H), 3.61 -3.51 (m, 4H), 3.46 (s, 6H), 3.45 (s, 6H), 3.41 - 3.39 (m, 2H), 3.13-3.11 (m, 2H), 3.09-3.07 (m, 2H), 1.67-1.63 (m, 4H). ¹³ C NMR (125 MHz, CDCI ₃ ): δ 99.87, 79.52, 78.61 , 76.74, 73.10, 69.99, 65.14, 57.80, 57.12, 26.71. HRMS (DART-MS) m/z calcd. for C20H35O10 [M+H] ⁺ 435.22247 found: 435.22181 .

Polymer Synthesis

General procedure: In a glovebox under a nitrogen atmosphere, an oven-dried vial was charged with [M], [I] and DCM (or CDCI ₃ ), BF3*Et2O was added. After 6 hrs, the reaction vial was removed from the glovebox and quenched with two drops of methanol. The polymer solution was precipitated into cold hexane or MeOH/H2O (v/v, 1/1 ), centrifuged, discarded the solvent, and redissolve in CHCI ₃ . 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. Chain End Modifications

P(Me-D-Glc) was prepared according to the general procedure with [M]o:[l]o = 15.

P(Me-D-Glc) (34 mg) was dissolved in CDCb (0.2 mL), alkenyl alcohol (0.5 M, 27 μL, 13.5 pmol) and BF3*Et2O (0.2 M, 25 μL, 5 pmol) was sequentially added. After 1 hr, the reaction was quenched with two drops of methanol. The polymer solution was precipitated into cold hexane to give P(Me ⁰¹ -D-Glc) as a white powder. P(Me ⁰² -D-Glc) was prepared through a similar procedure, except alkynyl was used as a nucleophile. The ¹ H-NMR and MALDI-TOF MS analyses indicated that the transformations of co-F chain end were quantitative.

Enzymatic Degradation Studies

Adapted from a literature report ⁵⁶ : P(OH ^Bn -D-Glc) or P(OH ^Bn -L-Glc) solutions (1 .0 mg, 10 mg/mL) in ammonium acetate (100 μL, 5 mM, pH 5.5) were degraded by dextranase (from Penicillium funiculosum, . The mixtures were lyophilized to provide white foams. The molecular weights were determined by SEC using DMF (0.01 M LiBr) as the eluent. SEC analyses revealed complete degradation of D-glucan, while L-glucan remained intact.

Conditions Optimization

General procedure: In a glovebox under a nitrogen atmosphere, an oven-dried vial was charged with Me-D-GIc (20.5 mg, 0.1 mmol), 1-3 (0.2 M, 10 pμ, 2 pmol), and solution of Lewis acid in DCM or CH ₃ CN was added to give a final reaction concentration of 2.0 M. After 3 hrs, the reaction vial was removed from the glovebox and quenched with two drops of methanol. The polymer solution was precipitated into cold hexane, centrifuged, discarded the solvent, and redissolve in CHCI ₃ . 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 experimental results were summarized in Table 1 below.

EXAMPLE 2

Preparation and characterization of precision polysaccharides

From the outset, O-methylated 1 ,6-anhydro-b-D-glucopyranose Me-D-GIc was utilized as a model monomer, which can be readily obtained after a one-step methylation of the biomass-derived and commercially available 1 ,6-anhydro-b-D-glucopyranose ($1 .3/g) in high yield and decagram scale (94%, 1 1 .8 g). Previous works by Kamigaito ²¹ and Fors ²² have shown that thiocarbamate chain transfer agents could regulate the propagation of oxocarbenium ions, which are structurally like the proposed propagating species in the polymerization of 1 ,6-anhydrosugars (FIG. 1 c). Separately, glycosyl thiocarbamate also served as a good glycosyl donor in catalytic glycosylation reactions ²³ . Based on these seminal reports, a series of glycosyl donors were evaluated, including glycosyl thiocarbamate 1-1 , glycosyl trithiocarbonate I-S1 , and glycosyl xanthate I-S2, for their ability to initiate the CROP of 1 ,6-anhydrosugars by mild Lewis acid catalysts (Table 1 ).

Table 1. Summary of conditions optimization results for Me-D-GIc. Monomer conversion was determined by ¹ H NMR spectroscopy; were determined by SEC analysis calibrated to polystyrene standard; w-chain end fidelity was determined by

fidelity of the w-chain end suggested poor control over the polymerization (FIG. 2a (i)). The low level of control may be attributed to the lability of C-S bond in these glycosyl donors under acidic condition and that more stable glycosyl donors could lead to improved control. Indeed, glycosyl chloride 1-2 was found to afford a polysaccharide with a 60% fidelity of the w-chain end (FIG. 2a (ii)). Encouragingly, a more stable glycosyl fluoride 1-3 provided an excellent w-chain end fidelity (90%) when boron trifluoride etherate (BF3*Et2O) was used as the catalyst (FIG. 2a (iii)). Size-exclusion chromatography (SEC) analysis of the sample, P(Me-D-Glc), revealed a monomodal

41

SUBSTITUTE SHEET ( RULE 26)

EXAMPLE 2

Monomer scope

With the initiator/catalyst pair identified, the monomer scope of this polymerization was explored (FIG. 3a). O-alkylated 1 ,6-anhydrosugars with various alkyl side chains, including ethyl, n-propyl, n-butyl, n-pentyl, and allyl all exhibited good reactivities and excellent control over the polymerization (FIG. 3a, entry 2-6). Notably, ¹ H, ¹³ C NMR, and high positive specific rotation values consistently supported exclusive a-1 ,6-D-glycosidic linkages in these polysaccharides. Remarkably, a polysaccharide with a degree of polymerization (DP) of 185 was obtained with relatively low dispersity when 0- ethyl monomer Et-D-GIc was polymerized (FIG. 3a, entry 2). For the 1 ,6-anhydrosugars with long O-alkyl side chains (e.g., n-butyl and n-pentyl), the addition of external fluoride ions further improved control over the polymerization (FIG. 3a, entry 4-5). Furthermore, this methodology was not limited to 1 ,6-anhydroglucose. O-allyl 1 ,6-anhydromannose All-D-Man and O-ethyl 1 ,6-anhydrogalactose Et-D-Gal could also be polymerized with high efficiency and excellent control (FIG. 3a, entry 9-10), yielding well-defined a-1 ,6- polymannose and a-1 ,6-polygalactose, respectively.

EXAMPLE 3

Computational investigations

Density functional theory (DFT) calculations were performed to gain more mechanistic insights into the reversible deactivation process in the living CROP and the origin of the excellent a-selectivity during the propagation step (FIG. 3b). The energy surface of activation of the dormant glycosyl fluoride 1 was first calculated, showing that the reaction readily gave an active oxocarbenium species 2 with an energy barrier of 7.1 kcal mol' ¹ . The facile activation of glycosyl fluoride chain end was attributed to the hardness of the fluorine atom, making it more readily to be abstracted by hard Lewis acid boron trifluoride. On the other hand, the reverse reaction, namely the deactivation of oxocarbenium species 2 by BF4' counterion, occurred with a low energy barrier of 4.4 kcal mol' ¹ , and the fast deactivation process might arise from the strong anomeric effect of the glycosyl fluoride. In short, the synergy of glycosyl fluoride and boron trifluoride results in an equilibrium between the active and dormant species, with the ratio of propagating oxocarbenium: dormant species being 0.01. The low concentration of the propagating oxocarbenium results in livingness in the polymerization.

As for the propagation process, two sequential steps were then considered. A monomer first attacked the oxocarbenium to form an oxonium species 3, and then a subsequent ring opening reaction occurred to regenerate the propagating oxocarbenium. According to the DFT calculations, the energy barrier of the a-addition was lower than that of the b-addition (TS2_3a = 4.9 kcal mol' ¹ versus TS2_3b = 9.9 kcal mol' ¹ ). The difference in transition state energies is primarily attributed to the steric repulsion between the incoming anhydrosugar monomer and oxocarbenium species. This a-selectivity is consistent with the experimental results, where the single anomeric carbon signal was observed in ¹³ C NMR spectra of the precision polysaccharides. A ring opening process was identified after the formation of oxonium intermediate 3a, which is considerably exergonic by 6.7 kcal mol ^-1 , indicative of the facile regeneration of the oxocarbenium. It is noteworthy that the direct addition to oxonium 3a by the anhydrosguar monomer proposed by Schuerch ¹⁷ yielded no computationally viable transition states despite extensive searches. This result is consistent with a recent work by Reineke ¹⁹ .

EXAMPLE 4

Chain extension and chain end modifications

Synthesizing advanced polymeric architectures, such as block copolymers, represents one of the greatest advantages of living polymerization. Building upon this method, block copolysaccharides that are otherwise laborious to synthesize were accessed. First, polymerization of ⁿ Bu-D-Glc was carried out in the presence of 1-3 to give a macroinitiator P( ⁿ Bu-D-Glc) (Mi = 3.2 kg/mol, D = 1.15) with an excellent fidelity of the w-chain end. Next, chain extension of P( ⁿ Bu-D-Glc) by Me-D-GIc yielded a diblock copolysaccharide P( ⁿ Bu-D-Glc)-d-P(Me-D-Glc). A shift to higher molecular weight, monomodal distribution with low D (1.17) and little to no tailing in SEC traces (FIG. 2e), as well as a single peak in the diffusion-ordered spectroscopy (DOSY) NMR analysis firmly supported the successful chain-extension.

Furthermore, as glycosyl fluoride has been widely used as a glycosyl donor in catalytic glycosylation reactions, the w-F chain end presents a versatile handle for further functionalization. As a proof of this principle, glycosylation of alkenyl and alkynyl alcohol by the w-F chain end of P(Me-D-Glc) was examined using BF3*Et2O as an activator (FIG. 2f). The ¹ H NMR and MALDI-TOF MS analyses indicated that the transformations of w-F chain end were quantitative, creating an opportunity for the post-polymerization functionalization of precision polysaccharides via thiol-ene and Cu(l)-catalyzed azidealkyne cycloaddition (CuAAC) click chemistries.

EXAMPLE 5

Synthesis of native polysaccharides

Oligomeric a-1 ,6-glycans play significant roles in many biological processes ²⁵ . Therefore, the current polymerization method was applied to access these biologically important glycans. Because of the facile removal of allyl groups, O-allyl 1 ,6-D- anhydroglucose AII-D-GIc was chosen as the monomer. Polymerization of AII-D-GIc at [M]o:[l]o ratio of 10:1 yielded a precision polysaccharide P(AII-D-Glc) with excellent molecular weight control (FIG. 3a, entry 6). Notably, this synthetic procedure was readily scalable (FIG. 4a): 1.1 grams of precise polysaccharide P(AII-D-Glc) was obtained without loss of control as indicated by a monomodal SEC peak and low D (1 .24). Followed by Pd-catalyzed deprotection, a well-defined a-1 ,6-D-glucan P(OH-D-Glc) was prepared. The obtained a-1 ,6-D-glucan showed identical ¹ H NMR and ¹³ C NMR spectra to the natural a-1 ,6-D-glucan (FIG. 4a), which further verified the excellent regio- and stereoselectivity of this method. Importantly, the w-F chain end was still observed in synthetic glucan, which could potentially be used as a glycosyl donor in enzymatic glycosylation to access more complex glycans ²⁶ .

Biosynthetic pathways of polysaccharides predominantly produce D-enantiomers which are susceptible to enzymatic degradation ²⁷ . In contrast, a chemical polymerization process does not discriminate either D- or L-anhydrosugars, providing a good opportunity to generate physiologically stable all-L-polysaccharides. Indeed, in the presence of a L- glycosyl fluoride initiator , 1 ,6-anhydro-b-L-glucopyranose ⁿ Bu-L-Glc and All-L- Glc could be polymerized to give the corresponding all-L-polysaccharide without any erosion in efficiency and livingness (FIG. 3a, entry 7-8). Applying the same deprotection protocol to P(AII-L-Glc), a rare a-1 ,6-L-glucan was obtained. Equal but opposite-in-sign specific rotation values were observed for D- and L-glucans (FIG. 4b), confirming the stereoregularity and enantiopurity of both polysaccharides. To the best of our knowledge, the a-1 ,6-L-glucan prepared herein represents the first example of precision all-L-glycans. Both D- and L-glucans were treated with dextranase from Penicillium funiculosum. SEC analyses of the degradation reaction revealed complete degradation of D-glucan, while L-glucan remained intact (FIG. 4b). The remarkable resistance of L-glucans against glycosidase-mediated degradation suggested their potential physiological stability for future biomedical applications.

Furthermore, it was demonstrated the synthetic utility of the current living CROP strategy to synthesize a-1 ,6-D-mannan, a polysaccharide that exists in the cell wall of Mycobacterium tuberculosis and is implicated in the human immune response to pathogens ²⁸ . To produce precision a-1 ,6-D-mannan, All-D-Man was first polymerized into a well-defined polysaccharide After removing the allyl groups, a well-defined a-1 ,6-D-mannan was readily generated (FIG. 4c), which was determined to be composed of a-1 ,6-D-glycosidic linkages by ¹ H and ¹³ C NMR. Therefore, the current polymerization pathway becomes a promising alternative to the labor/equipment-demanding stepwise glycan assembly strategies for constructing biologically relevant polysaccharides ²⁹ . EXAMPLE 6 Depolymerization and repolymerization

Beyond biologically active polysaccharides, renewable materials were also explored based on precision polysaccharides. One of the most desired properties of the next-generation sustainable polymers is their inherent chemical recyclability, which enables a closed-loop life cycle ^30-33 . Given that 1 ,6-anhydroglucose was produced by the thermolysis of starch or cellulose, precision polysaccharide P(Me-D-Glc) was first subjected to thermolysis conditions (450 °C, 30 mmHg). Indeed, monomer Me-D-GIc could be recovered in 34% yield. Despite the low yield, this result suggested the chemical recyclability of precision polysaccharides. Further thermodynamic analysis via variabletemperature ¹ H NMR revealed the standard state thermodynamic parameters of the living

SUBSTITUTE SHEET ( RULE 26) Table 4. Kinetic studies for [Et-D-GIc] polymerization. Experiments were performed according to general polymerization procedure, [Et-D-Glc]o = 1.5 M, [Et-D- Glc]o:[l-3]o = 200. Time-point aliquots were taken during polymerization for ¹ H NMR and SEC analyses.

EXAMPLE 7

Material properties

Labile main-chain groups (e.g., acetal, ester, enamine) are often incorporated into the existing chemically recyclable polymers to enable depolymerization ²⁰³⁴ ' ³⁸ , rendering these polymers unstable under harsh conditions (e.g., strong acid/base, high temperature, etc.). In contrast, the precision polysaccharides exhibited remarkable chemical and thermal stability. Little to no change in molecular weight and dispersity was found when exposing P(Me-D-Glc) to an excessive amount of Br^nsted acid (e.g., acetic acid or trifluoroacetic acid) or base (e.g., pyridine, triethylamine, or 1 ,8- diazabicyclo[5.4.0]undec-7-ene) for 24 h (FIG. 5b (i)). Thermogravimetric analysis (TGA) revealed an onset decomposition temperature Td (defined by 5% weight loss) greater than 345°C (FIG. 5b (ii)). Impressively, the morphology and thermal performance of precision polysaccharides were readily tunable by side chain modifications. P(Me-D-Glc) turned out to be highly crystalline with well-defined diffraction patterns as revealed by powder X- ray diffraction (PXRD) spectrum, in which three major diffraction signals at and 18.9 ^Q were observed (FIG. 5c (i), inset). Additionally, a high melting temperature ( Tm) of 284 °C was detected in differential scanning calorimetry (DSC) analysis (FIG. 5c (i)). In contrast, a Tmwas not found in the polysaccharides carrying longer alkyl groups. At the same time, their glass-transition temperatures when varying the O-alkyl substitution from ethyl to n-pentyl (FIG. 5c (ii)). The precision polysaccharides represent a rare example that significant changes in the polymer morphology and thermal properties can be induced by simply altering the side chains ^{19 39} .

The chemical recyclability, together with good chemical and thermal stabilities make these polysaccharides promising candidates for sustainable materials (FIG. 5d). In particular, a copolysaccharide PN1 consisting of 65 mol% ⁿ Pen-D-Glc, 30 mol% Me-D- Glc, and 5 mol% crosslinker CL displayed mechanical properties typical for an elastomer: a Young’s modulus of 106.63 ±16.17 MPa, a tensile strength of 4.06 ±0.09 MPa, and elongation at break reaching 138 ±15%. In contrast, a completely different material (PN2) was obtained when the copolysaccharide composition changed to 30 mol% ⁿ Pen-D-Glc, 65 mol% Me-D-GIc, and 5 mol% crosslinker CL. As a glassy material, PN2 showed higher Young’s modulus (0.82 ±0.10 GPa) and ultimate tensile strength (19.17 ±1.92 MPa), with elongation at break of 2.6 ±0.3%. The drastic change in the mechanical properties was attributed to the different which lead to elastic (PN1 ) or glassy (PN2) characteristics, respectively. Both copolysaccharide-based materials could be depolymerized completely (FIG. 5e), with the monomers and crosslinker recovered in excellent yield (85%). The recovered 1 ,6-anhydrosugars were repolymerized, and the resulting copolysaccharides PN1' and PN2' showed identical tensile properties to pristine PN1 and PN2, respectively.

Table 6. Stress, strain, and Young’s modulus values of tensile tests at a strain rate of 5 mm/min for PN1 and PN1' (sample 4).

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It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations set forth for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the above-described embodiment(s) without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.