Analogues of pleuromutilin antibiotics

Abstract

A novel class of antibiotic compounds has been developed based on synthetic variations of the naturally occurring diterpenoid antibiotic pleuromutilin. The pleuromutilin analogues are stereochemically and structurally diverse and can be prepared by Pd-catalyzed coupling between the Pd-glycosyl donors and pleuromutilin, followed by various post-coupling modifications. Synthesized compounds were tested against several strains of bacteria, and compare well in potency to pleuromutilin. The new antibiotic compounds are expected to avoid the development of resistance and to be useful against a wide variety of Gram-positive and Gram-negative bacteria and the infections they cause.

Description

[0001] TITLE Analogues of Pleuromutilin Antibiotics CROSS REFERENCE TO RELATED APPLICATIONS This application claims the priority of U.S. Provisional Application No.63 / 704,184 filed 7 October 2024 and entitled “Glycosylated Analogues of Pleuromutilin Antibiotics”, the whole of which is hereby incorporated by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. R01AI154860 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Drug resistance in bacteria has been a growing concern in the public health community. Several decades of irresponsible use of excessively dispensed antibiotics has caused rapid development of resistant strains.1The World Health Organization (WHO) has updated its list of high priority pathogens where there is a dire need for new antibiotics for both Gram-positive and Gram-negative infections.2The use of legacy antibiotics as last-resort drugs is not sustainable and results in rapid resistance development in the already defensively-robust bacterial strain being treated with said last-resort antibiotic. Thus, new antibiotic drug molecules that are unaffected by current bacterial-resistance mechanism are desperately needed. Pleuromutilins are well-known to have antibacterial properties against both gram- positive and some gram-negative bacteria.3,4Pleuromutilins have been approved for veterinary use and more recently human use. Retapamulin was approved for topical use in infected wounds and lefamulin was approved for intravenous and oral use against community- acquired bacterial pneumonia infections. Pleuromutilins remain promising antibacterials due to the lack of resistance development. This can be attributed to their highly specific mode of action, where binding to domain V of the 50S ribosomal subunit at the peptidyl transfer center inhibits bacterial protein synthesis.5Given the ability of bacteria to develop resistance to antibiotics, and given that different antibiotics have different uses according to their effectiveness against different bacterial pathogens, safety profile, and pharmacokinetics, there is a need to develop further analogues of pleuromutilins. SUMMARY The invention provides a novel class of antibiotic compounds which are synthetic analogues of the naturally occurring antibiotic pluromutilin. The compounds disclosed herein are structurally rearranged pleuromutilins, glycosylated pleuromutilins, or pleuromutilins modified by, for example, glycosylation or esterification. The synthesized compounds were tested for inhibition of bacterial growth and found to be as highly potent as pleuromutilin or its previously described variants, such as lefamulin. The synthesized compounds were also shown to be highly specific for inhibiting bacterial over eukaryotic protein synthesis in cell-free translation assays. The compounds show low cytotoxicity for mammalian cells, and are also capable of uptake as siderophores, thereby enhancing bacterial cell uptake. An aspect of the present technology is an antibiotic compound having a structure according to any of the following formulas:

[0002] ; wherein for Formulas I, Va, Vb, and Vc, T is O, S, NR, or CR2, wherein R is H, alkyl, hydroxyalkyl, aminoalkyl, or perfluoroalkyl, (S or R); and wherein for Formulas IIa, IIb, IIc, III, and IV, W is H, OH, halogen, OR, N3, NRH, or NR2, wherein R is H, alkyl, hydroxyalkyl, aminoalkyl, or perfluoroalkyl, (S or R); wherein T is O, S, NR, or CR2, wherein R is H, alkyl, hydroxyalkyl, aminoalkyl, or perfluoroalkyl, (S or R). The linker portion can be any of the following: CO(CHCH)ntrans or cis, n = 1-10; (CH2)n, n = 1-10; (CHCH)n cis or trans, n = 1-10; CO(CH2)n, n = 0-10; ; (CH2CH2O)n, n = 1-10; CO(CH2CH2O)n, n = 1-10; or no linker. In alternative embodiments of any of the linkers, n = 2, 3, 4, 5, 6, 7, 8, 9, or 10, or 2-3, 2-4, 2-5, or 3-5. The modifier portion can be any of the following:

[0003] a . For modifiers having optional portions having l, m, or n repeating structural units, l, m, and / or n can be 1-10 or can be 2, 3, 4, 5, 6, 7, 8, 9, or 10, or 2-3, 2-4, 2-5, or 3-5. In a preferred embodiment, the compound has the structure of Formula I, wherein T is S, and wherein the modifier is selected from the group consisting of: . BRIEF DESCRIPTION OF THE DRAWINGS Fig.1 shows a scheme for the synthesis of several pleuromutilin analogues using pyranones A-E as modifiers. Fig.2 shows the synthesis of compound TTPM2 from pleuromutilin. Fig.3 shows a scheme for the synthesis of several pleuromutilin analogues. Fig.4 shows a scheme for the synthesis of several pleuromutilin analogues. Fig.5 shows a scheme for the synthesis of several pleuromutilin analogues. Fig.6 shows a scheme for the synthesis of several pleuromutilin analogues. Fig.7 shows a scheme for the synthesis of several pleuromutilin analogues. Fig.8 shows a scheme for the synthesis of several pleuromutilin analogues. Fig.9 shows a scheme for the synthesis of several pleuromutilin analogues. Fig.10 shows a scheme for the synthesis of several pleuromutilin analogues. Fig.11 shows a scheme for the synthesis of several pleuromutilin analogues. Fig.12A shows dose-response curves for inhibition of protein synthesis in a cell-free bacterial expression system for lefamulin and several of the present pleuromutilin analogues. Fig. 12B shows dose-response curves for inhibition of protein synthesis in a cell-free eukaryotic expression system for lefamulin and pleuromutilin analogue TT-906. Fig.12C shows a comparison of the IC50 for E. coli in vitro translation extract inhibition and E. coli MIC values for lefamulin and several of the present pleuromutilin analogues. DETAILED DESCRIPTION The present technology provides a new structural class of antibiotics based on the pleuromutilin class of antibiotics. The new pleuromutilin analogues and derivatives include: 1) structurally rearranged pleuromutilins, 2) glycosylated pleuromutilins, 3) modified pleuromutilins (e.g., glycosylation and esterification products), and 4) modified rearranged pleuromutilins (e.g., glycosylation and esterification products). Members of this new structural class have been shown to possess antibacterial activity comparable with two currently used pleuromutilin antibiotics, retapamulin and lefamulin. The technology addresses antibiotic resistance and provides novel compounds with antibiotic activity against the ESKAPE pathogens (i.e., Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.). The present technology provides new analogues with improved activity and penetrance into Gram negative organisms, which can be accomplished with aminosugar motifs. The series of novel compounds described herein have improved activity over pleuromutilin. Importantly, this is accomplished without introducing an ionizable amine group, reducing the risk of toxicity and development of bacterial resistance. The new analogues were generated by reacting pleuromutilin or related compounds with sugars (which can be any known monosaccharides, disaccharides, or trisaccharides), substituted pyran rings, substituted aromatic 5 and 6 membered ring carbocycles, substituted 5 and 6 membered ring non-aromatic heterocycles, substituted 5 and 6 membered ring aromatic heterocycles, substituted triazoles, substituted benzotriazoles, for example through glycosidic linkages, esters, or thioesters. As used herein, a “substituent”, unless otherwise specified, can be any of the following: hydrogen, hydroxy, sulfoxy, halo, acyl, acyloxy, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, arylhalo, arylhydroxy, arylcyano, aryltrifluoromethyl, aryltrifluoromethoxy, arylnitro, aryltrifluoromethoxy, arylnitro, and arylether, arylester, arylsulfonyl, arylsulfinyl, arylsulfonamidyl, arylsulfonate, arylsulfoxyl, arylphosphate ester, arylcarbonyl, arylcarboxylate, arylcarbamate, arylamine, arylimide, heteroaryl, heteroarylalkyl, heteroarylhalo, heteroarylhydroxy, heteroarylcyano, heteroaryltrifluoromethyl, aryltrifluoromethoxy, arylnitro, heteroaryltrifluoromethoxy, heteroarylnitro, and heteroarylether, heteroarylester, heteroarylsulfonyl, heteroarylsulfinyl, heteroarylsulfonamidyl, heteroarylsulfonate, heteroarylsulfoxyl, heteroarylphosphate ester, heteroarylcarbonyl, heteroarylcarboxylate, heteroarylcarbamate, heteroarylamine, heteroarylimide, quinidine, morpholine, and any ring structure is optionally substituted with any of the substituents described herein, with the proviso that any two adjacent substituents can come together to form a carbocyclic or heterocyclic ring system. A hydrocarbon or heterocyclic ring system can be phenyl, thienyl, furanyl, pyrimidinyl, oxazoyl, thiazolyl, pyridyl, naphthyl, quinolinyl, indolyl, benzothiophenyl, benzofuranyl, pyrrolyl, imidazolyl, pyrazole, triazolyl, isoxazolyl, pyridazinyl, pyzazinyl, pyrimidinyl, oxadiazolyl, benzimidazolyl, or triazinyl. A heterocyclic ring system may contain one or more heteroatoms selected from the group consisting of oxygen, sulfur, nitrogen, and combinations thereof. The new class of non-natural antibiotics is based on the polyterpenoid natural product pleuromutilin. The new glycosylated pleuromutilins are referred to herein as saccharomutilins. In addition, a new class of pleuromutilin esters has been synthesized. The efficacy of this approach was demonstrated by a series of activity screens. The screens include: 1) determination of minimum inhibitory concentration (MIC) for antibacterial activity against a range of pathogenic bacteria (S. aureus, E. coli (wild-type tolC), E. coli (tolC knockout), E. coli (lptD mutant), Enterococcus faecalis, Enterococcus faecium, Bacillus anthracis)(see Table 1); 2) prokaryotic over eukaryotic selectivity in an in vitro ribosome translation assay (Figs.12A- 12B); and 3) a mammalian cytotoxicity assay (Table 1). Analysis of the MIC data shows that members of both the ester and glycosylation modification improved the antibacterial activity of the base pleuromutilin structure. This improvement in activity is comparable with the antibacterial activity of two FDA-approved pleuromutilin-based antibiotics, retapamulin and lefamulin. The antibacterial activities of the two best pyranone based saccharomutilins (TT-906 and TT-907) were linked to selective inhibition of the bacterial ribosome in in vitro translation assays comparing prokaryotic translation inhibition and eukaryotic translation inhibition (Figs.12A-12C). Minimum inhibitory concentrations (MICs) were determined using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution reference method. See Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, 12th ed (CLSI Standard M07). Wayne, PA: Clinical and Laboratory Standards Institute; 2024. Frozen bacterial stocks were sub-cultured on sheep blood agar, incubated for 18–24 hours, and adjusted to a 0.5 McFarland standard (~1 × 10⁸ CFU / mL). The suspension was diluted 1:300 into cation-adjusted Mueller–Hinton broth to achieve a final inoculum of approximately 5 × 10⁵ CFU / mL per well in 384-well microplates. Antimicrobials were dispensed by using the D300 inkjet digital dispensing technology in doubling dilutions ranging from 0.125 to 256 µg / mL. Plates were incubated for 16–20 hours, and MICs were recorded as the lowest concentration without visible growth. The digital dispensing method was validated as equivalent or superior in precision to standard manual dilution procedures. See Smith KP, Kirby JE. Verification of an Automated, Digital Dispensing Platform for At-Will Broth Microdilution-Based Antimicrobial Susceptibility Testing. J Clin Microbiol.2016 Sep;54(9):2288-93. doi: 10.1128 / JCM.00932-16. Prokaryotic and eukaryotic nanoluciferase (Nluc) reporter constructs were generated for coupled in vitro transcription / translation studies. For bacterial assays, the E. coli S30 Extract System for Circular DNA from Promega was combined with 100 ng of the T7Nluc plasmid and tested compounds dispensed into 384-well plates. Following 60 minutes of incubation at 37 °C, furimazine substrate was added, and luminescence was quantified. Eukaryotic translation was measured using the TnT-T7 Quick Coupled Transcription / Translation System with 100 ng of the corresponding Nluc plasmid DNA and methionine, incubated at 30 °C for 80 minutes. Luminescence readings reflected inhibition of translation activity. See Morgan CE, Kang YS, Green AB, Smith KP, Dowgiallo MG, Miller BC, Chiaraviglio L, Truelson KA, Zulauf KE, Rodriguez S, Kang AD, Manetsch R, Yu EW, Kirby JE. Streptothricin F is a bactericidal antibiotic effective against highly drug-resistant gram-negative bacteria that interacts with the 30S subunit of the 70S ribosome. PLoS Biol. 2023 May 16;21(5):e3002091. doi: 10.1371 / journal.pbio.3002091. Cytotoxicity was assessed in a J774A.1 murine macrophage cell line plated in 384- well plates at densities of approximately 7 × 10⁵ cells / cm², respectively. Cells were cultured inin RPMI 1640 medium with 9% fetal bovine serum, day 2, 1st 7 compounds125 nM SYTOX Green. After 24 hours, cells were treated with two-fold serial dilutions of test compounds dispensed via HP D300 digital system. SYTOX Green fluorescence, indicative of cell membrane integrity loss, was monitored using a TECAN M1000 plate reader (excitation 485 nm / emission 535 nm) over 2 days at 37 °C in 5% CO₂. See Chiaraviglio L, Kirby JE. Evaluation of impermeant, DNA-binding dye fluorescence as a real-time readout of eukaryotic cell toxicity in a high throughput screening format. Assay Drug Dev Technol. 2014 May;12(4):219-28. doi: 10.1089 / adt.2014.577. Several new saccharomutilins were identified with promising activity (see Table 1). From the screens, two potent compounds (α-L-TT-906, β-D-TT-944) were identified as having an aculose sugar (e.g., MIC: 0.25 to 2 µM against S. aureus, Enterococcus faecium and Bacillus anthracis). Importantly, a third potent compound (TT-907) had the enone of the aculose reduced. With regards to stereochemistry, all three compounds shared the absolute stereochemistry of the C-1 position of the sugar (i.e., α-L / β-D share the same C-1 stereochemistry). In an in vitro ribosome translation assay for both prokaryotic (i.e., Pseudomonas, E. coli, A. baumannii, and Klebsiella) and eukaryotic ribosomes it could be shown that the antibacterial activity was the result of ribosome inhibition, and the inhibition was selective for the bacterial ribosome. With a Pd-p-allyl leaving group at C1 of the pyranone and a proper nucleophile, the O’Doherty group has shown the utility of Pd-catalyzed glycosylations. With this methodology, various sugar diastereomers, as well as diverse biomolecules of interest can be accessed (such as oligosaccharides, nucleosides, glycosylated natural products, etc.).6Using a Pd- glycosylation reaction sequence, pleuromutilin and its dihydro-congener can be converted into two sets of four diastereomeric saccharomutilins; the process is illustrated in Figs. 1-10. Analysis of the activity spectrum from this series of compounds shows the importance of the aglycon vinyl-group for antibacterial activity and the stereospecificity of the improvement in antibacterial activity associated with glycosylation. The results of screening of exemplary embodiments of the present antibiotic compounds are presented in Tables 1 and 2 below. Table 1 lists compounds with sugars as modifiers and Table 2 lists compounds with esters as modifiers.

[0004]

[0005]

[0006] The antibiotic compounds of the present technology can be administered as pharmaceutical compositions. The pharmaceutical compositions include one or more pharmaceutically acceptable excipients in addition to one or more active agents, such as the present antibiotic compound and optionally one or more additional active agents. The pharmaceutical excipients or carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water, saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any agent described herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents. Where necessary, the compositions can also include a solubilizing agent. The compositions of the present technology can be present in various formulations. Any compound and composition (and / or additional agents) described herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see, e.g., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington’s Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed.1995), incorporated herein by reference. The pharmaceutical compositions can be administered by any known method consistent with maintaining their structure and function, and allowing the antibiotic compounds contained therein to reach their target, such as bacterial cells, and the ribosomes contained therein, within or upon the subject’s body. Administration can be, for example, parenteral, by intravenous or subcutaneous injection, by surgical implantation of a sustained release formulation, oral (with suitable polymeric nanoparticles capable of protecting the active agents), or by topical administration. The subject can be any mammalian subject, and is preferably a human subject. The compositions can be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. In some embodiments, the composition is administered orally. In some embodiments, the administration is by absorption through epithelial or mucocutaneous linings. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. In some embodiments, the compositions are in the form of a capsule, tablet, patch, or lozenge. The compositions can be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. In some embodiments, the composition is administered orally. In some embodiments, the administration is by absorption through epithelial or mucocutaneous linings. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. In some embodiments, the compositions are in the form of a capsule, tablet, patch, or lozenge. EXAMPLES Example 1. Synthesis of Pyranone Analogues of Pleuromutilin Starting materials and reagents used were of commercial grade and used without further purification. All reactions were monitored via thin-layer chromatography (TLC) with glass plates coated with Silica Gel 60 (F254, 250 µm thickness). Spots were detected with UV light, cerium molybdate stain, and / or potassium permanganate stain. Flash column chromatography was conducted using silica gel (specs). All NMR spectra were acquired at ambient temperature using a Bruker 500 MHz FT-NMR spectrometer. Chemical shifts are reported in ppm (δ) relative to the 1H signal of residual CDCl3 at δ 7.26 ppm. The reactions of Pyranones A-E with pleuromutilin are shown in Fig.1. Example 2. Synthesis of 19,20-Dihydropleuromutilin (TTPM2) See Fig.2. To a solution of Pleuromutilin (1.00 g, 2.64 mmol) in EtOAc (50 mL) was added Pd / C (100 mg) at RT. A balloon charged with H2 was added and the reaction mixture was stirred at RT for 24h. The Pd / C was filtered and the filtrate was concentrated in vacuo to yield TTPM2 as a white solid (980 mg, 98%); 1H NMR (500 MHz, CDCl3) δ 5.70 (d, J = 8.2 Hz, 1H), 4.08 – 3.96 (m, 2H), 3.40 (d, J = 6.0 Hz, 1H), 2.39 (p, J = 7.0 Hz, 1H), 2.28 – 2.07 (m, 3H), 1.79 – 1.69 (m, 3H), 1.66 – 1.52 (m, 3H), 1.45 (ddd, J = 12.9, 9.2, 3.0 Hz, 1H), 1.41 – 1.28 (m, 5H), 1.25 – 1.20 (m, 1H), 1.15 – 1.05 (m, 1H), 0.97 – 0.89 (m, 6H), 0.73 (t, J = 7.4 Hz, 3H), 0.66 (d, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 217.2, 172.3, 70.0, 61.3, 58.4, 41.9, 41.0, 40.9, 36.6, 34.4, 34.4, 30.2, 26.8, 26.3, 24.9, 20.6, 16.4, 14.8, 11.1, 8.2. Example 3. Synthesis of 22-O-(α-D-aculo-pyranosyl)pleuromutilin (TT901) To a solution of Pleuromutilin (100 mg, 0.264 mmol) and Pyranone A (242 mg, 1.06 mmol) in THF (1 mL) at RT was added a mixture of Pd2(dba)3^CHCl3(6.8 mg, 0.0066 mmol) and PPh3 (6.9 mg, 0.26 mmol) in DCM (0.2 mL). The reaction mixture was stirred at RT for 2h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (1:1 hexane:EtOAc, Rf= 0.5) to yield TT901 as a yellow oil (82 mg, 64%);1H NMR (500 MHz, CDCl3) δ 6.83 (dd, J = 10.2, 3.5 Hz, 1H), 6.41 (dd, J = 17.4, 11.0 Hz, 1H), 6.05 (d, J = 10.4 Hz, 1H), 5.78 (d, J = 8.4 Hz, 1H), 5.27 (dd, J = 11.0, 1.6 Hz, 1H), 5.20 (d, J = 3.5 Hz, 1H), 5.13 (dd, J = 17.4, 1.6 Hz, 1H), 4.59 (q, J = 6.7 Hz, 1H), 4.23 (d, J = 16.7 Hz, 1H), 4.07 (d, J = 16.7 Hz, 1H), 3.31 (dd, J = 10.3, 6.5 Hz, 1H), 2.28 (dq, J = 7.0, 7.0 Hz, 1H), 2.23 – 2.09 (m, 2H), 2.07 – 1.99 (m, 2H), 1.72 (dq, J = 14.5, 3.1 Hz, 1H), 1.59 (m, 2H), 1.50 (qd, J = 13.2, 3.4 Hz, 1H), 1.38 (m, 4H), 1.33 – 1.22 (m, 5H), 1.10 (m, 4H), 0.83 (d, J = 7.0 Hz, 3H), 0.68 (d, J = 7.1 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.0, 196.6, 168.7, 142.5, 138.9, 127.7, 117.3, 93.4, 74.5, 70.7, 69.0, 65.8, 58.1, 45.4, 44.8, 43.9, 41.8, 36.7, 36.1, 34.4, 30.4, 26.8, 26.5, 24.9, 16.6, 15.1, 14.8, 11.6. Example 4.22-O-(α-D-2,3-didehydro-6-deoxy-erytho-hexo-pyranosyl)pleuromutilin (TT902) To a solution of TT901 (198 mg, 0.405 mmol) in DCM (2 mL) and 0.4 M CeCl3^(H2O)7in MeOH (2 mL) at –78 ^C was added NaBH4(23 mg, 0.608 mmol). The reaction mixture was allowed to warm to 0 ^C and stirred for 1h, at which time the reaction mixture was diluted with DCM (25 mL) and washed with H2O (2 x 20 mL) and brine (2 x 10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf= 0.3) to yield TT902 as a white solid (106 mg, 53%);1H NMR (500 MHz, CDCl3) δ 6.43 (dd, J = 17.4, 11.0 Hz, 1H), 5.90 (dt, J = 10.0, 1.4 Hz, 1H), 5.79 – 5.71 (m, 2H), 5.27 (dd, J = 10.9, 1.6 Hz, 1H), 5.13 (dd, J = 17.4, 1.6 Hz, 1H), 4.95 – 4.91 (m, 1H), 4.13 (d, J = 16.7 Hz, 1H), 4.01 (d, J = 16.7 Hz, 1H), 3.77 (t, J = 7.9 Hz, 1H), 3.70 (dq, J = 9.0, 6.1 Hz, 1H), 3.29 (dd, J = 10.6, 6.5 Hz, 1H), 2.28 (dq, J = 6.9, 6.9 Hz, 1H), 2.24 – 2.08 (m, 2H), 2.07 – 1.96 (m, 2H), 1.79 (t, J = 7.2 Hz, 1H), 1.71 (dq, J = 14.5, 3.1 Hz, 1H), 1.65 – 1.48 (m, 2H), 1.48 – 1.15 (m, 9H), 1.10 (m, 4H), 0.82 (d, J = 7.0 Hz, 3H), 0.68 (d, J = 7.0 Hz, 3H).;13C NMR (126 MHz, CDCl3) δ 217.2, 169.1, 138.9, 134.1, 125.8, 117.4, 94.4, 74.6, 69.5, 68.7, 68.4, 65.3, 58.2, 45.5, 44.8, 43.9, 41.8, 36.8, 36.1, 34.5, 30.5, 26.8, 26.3, 24.9, 17.9, 16.7, 14.9, 11.6. Example 5. 22-O-(α-D-rhamno-pyranosyl)pleuromutilin A (TT903): To a solution of TT902 (100 mg, 0.204 mmol) in tert-butanol (1 mL), acetone (1 mL), and (50 / 50 w / w) N-methylmorpholine N-oxide in H2O (0.3 mL) at RT was carefully added a tiny crystal of solid osmium tetroxide. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was purified via loading directly onto flash column chromatography on silica gel (4 / 1 DCM:MeOH, Rf= 0.5) to yield TT903 as white crystals (57 mg, 50%);1H NMR (500 MHz, MeOD) δ 5.82 (d, J = 7.2 Hz, 1H), 4.74 (d, J = 1.7 Hz, 1H), 4.16 – 4.00 (m, 3H), 3.86 (dd, J = 3.4, 1.7 Hz, 1H), 3.82 (dd, J = 11.6, 5.5 Hz, 1H), 3.64 (dd, J = 9.5, 3.4 Hz, 1H), 3.60 (dd, J = 9.5, 6.2 Hz, 1H), 3.48 (dd, J = 11.6, 7.0 Hz, 1H), 3.45 (d, J = 5.9 Hz, 1H), 3.34 (t, J = 9.6 Hz, 1H), 2.47 (dq, J = 6.9, 6.9 Hz, 1H), 2.37 (m, 1H), 2.23 (m, 1H), 2.11 (m, 1H), 1.83 – 1.75 (m, 2H), 1.74 – 1.56 (m, 4H), 1.46 – 1.32 (m, 5H), 1.20 (d, J = 6.3 Hz, 3H), 1.12 (td, J = 14.0, 4.7 Hz, 1H), 0.97 (s, 3H), 0.94 (d, J = 6.9 Hz, 3H), 0.70 (d, J = 6.4 Hz, 3H);13C NMR (126 MHz, MeOD) δ 219.6, 171.6, 101.7, 75.4, 73.7, 72.1, 72.1, 71.9, 70.4, 70.3, 65.7, 65.1, 59.8, 49.9, 47.1, 46.0, 43.0, 37.9, 36.4, 35.2, 31.4, 28.1, 25.7, 21.6, 18.0, 16.9, 15.2, 11.8; Example 6. 22-O-(α-D-amecieto-pyranosyl)pleuromutilin (TT905) To a mixture of TT901 (50 mg, 0.102 mmol) and copper(II) acetylacetonate (8.1 mg, 0.031 mmol) in DCM (1 mL) and MeOH (1 mL) at RT was carefully added NaBH4(7.7 mg, 0.20 mmol). The reaction mixture stirred at RT for 1h, at which time the reaction mixture was diluted with DCM (10 mL) and washed with H2O (2 x 10 mL) and brine (2 x 5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf = 0.2) to yield TT905 as a white solid (50 mg, 22%);1H NMR (500 MHz, CDCl3) δ 6.49 (dd, J = 17.4, 10.9 Hz, 1H), 5.82 (d, J = 8.4 Hz, 1H), 5.34 (dd, J = 11.0, 1.6 Hz, 1H), 5.19 (dd, J = 17.4, 1.6 Hz, 1H), 4.80 (d, J = 2.5 Hz, 1H), 4.14 – 3.98 (m, 2H), 3.58 (dq, J = 9.1, 6.2 Hz, 1H), 3.35 (dd, J = 10.7, 6.5 Hz, 1H), 3.25 (dq, J = 9.5, 4.6 Hz, 1H), 2.34 (dq, J = 7.0, 7.0 Hz, 1H), 2.29 – 2.14 (m, 2H), 2.11 – 2.04 (m, 2H), 1.96 (m, 1H), 1.86 (m, 1H), 1.82 – 1.73 (m, 2H), 1.71 – 1.50 (m, 4H), 1.49 – 1.41 (m, 4H), 1.36 (dq, J = 14.4, 3.4 Hz, 1H), 1.31 (d, J = 16.2 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H), 1.18 – 1.08 (m, 4H), 0.87 (d, J = 7.0 Hz, 3H), 0.73 (d, J = 7.0 Hz, 3H); NMR (126 MHz, CDCl3) δ 217.1, 169.2, 138.9, 117.4, 96.1, 74.6, 71.9, 69.9, 68.6, 64.0, 58.2, 45.5, 44.8, 44.0, 41.8, 36.8, 36.1, 34.5, 30.5, 29.2, 27.4, 26.8, 26.3, 24.9, 17.9, 16.7, 14.9, 11.5; Example 7. 22-O-(α-D-amecieto-pyranosyl)pleuromutilin A (TT910) To a solution of TT905 (42 mg, 0.085 mmol) in tert-butanol (0.5 mL), acetone (0.5 mL), and (50 / 50 w / w) N-methylmorpholine N-oxide in H2O (0.2 mL) at RT was carefully added a tiny crystal of solid osmium tetroxide. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was purified via loading directly onto flash column chromatography on silica gel (9:1 DCM:MeOH, Rf = 0.5) to yield TT910 as a white solid (26 mg, 58%);1H NMR (500 MHz, MeOD) δ 6.16 (d, J = 8.2 Hz, 1H), 4.83 (m, 1H), 4.56 (dd, J = 8.3, 3.0 Hz, 1H), 4.26 – 4.10 (m, 2H), 3.64 (dq, J = 9.1, 6.2 Hz, 1H), 3.48 (td, J = 12.1, 7.3 Hz, 2H), 3.25 (dd, J = 11.6, 3.0 Hz, 1H), 3.18 (m, 1H), 2.29 (m, 1H), 2.21 – 2.13 (m, 2H), 1.99 (d, J = 15.9 Hz, 1H), 1.93 (m, 1H), 1.87 – 1.70 (m, 6H), 1.64 (m, 1H), 1.55 – 1.42 (m, 5H), 1.29 – 1.14 (m, 9H), 0.92 (s, 3H), 0.83 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, MeOD) δ 218.5, 172.3, 97.8, 72.9, 72.5, 71.3, 70.0, 65.6, 65.5, 60.2, 56.9, 49.9, 47.0, 45.3, 43.2, 40.2, 38.5, 35.3, 31.1, 30.3, 28.1, 27.9, 25.6, 18.3, 17.3, 17.1, 15.4, 13.8; Example 8. 22-O-(α-D-2,3-dihydro-aculo-pyranosyl)pleuromutilin (TT947) To a solution of TT901 (500 mg, 1.02 mmol) in toluene (15 mL) at RT was added (Triphenylphosphine)copper hydride hexamer (100 mg, 0.0510 mmol). After stirring for 5 min, polymethylhydrosiloxane (5 mL) was added at RT and the reaction was stirred at RT for 16h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (1:1 hexane:EtOAc, Rf = 0.5) to yield TT947 as a colourless oil (92 mg, 18%);1H NMR (500 MHz, CDCl3) δ 6.48 (dd, J = 17.3, 11.0 Hz, 1H), 5.82 (d, J = 8.5 Hz, 1H), 5.33 (dd, J = 10.9, 1.6 Hz, 1H), 5.19 (dd, J = 17.5, 1.6 Hz, 1H), 5.04 (t, J = 5.0 Hz, 1H), 4.32 (q, J = 6.7 Hz, 1H), 4.25 – 4.04 (m, 2H), 3.35 (d, J = 6.5 Hz, 1H), 2.56 – 2.37 (m, 2H), 2.37 – 2.29 (m, 2H), 2.28 – 2.16 (m, 2H), 2.16 – 2.00 (m, 3H), 1.76 (dq, J = 14.6, 3.1 Hz, 1H), 1.70 – 1.61 (m, 2H), 1.54 (qd, J = 13.6, 3.5 Hz, 1H), 1.48 – 1.40 (m, 4H), 1.36 (dq, J = 14.3, 3.6 Hz, 1H), 1.29 (d, J = 16.1 Hz, 1H), 1.24 (d, J = 6.7 Hz, 3H), 1.18 – 1.07 (m, 4H), 0.87 (d, J = 6.9 Hz, 3H), 0.73 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 216.1, 209.2, 168.1, 138.0, 116.4, 96.3, 73.7, 70.5, 68.0, 64.1, 57.3, 44.6, 44.0, 43.1, 41.0, 35.9, 35.2, 33.6, 32.5, 29.6, 27.5, 25.9, 25.5, 24.0, 15.8, 14.0, 13.9, 10.7. Example 9. 22-O-(α-L-aculo-pyranosyl)pleuromutilin (TT906) To a solution of Pleuromutilin (100 mg, 0.264 mmol) and Pyranone C (242 mg, 1.06 mmol) in THF (1 mL) at RT was added a mixture of Pd2(dba)3^CHCl3(6.8 mg, 0.0066 mmol) and PPh3 (6.9 mg, 0.026 mmol) in DCM (0.2 mL). The reaction mixture was stirred at RT for 2h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (1:1 hexane:EtOAc, Rf= 0.5) to yield TT906 as a yellow oil (95 mg, 74%);1H NMR (500 MHz, CDCl3) δ 6.88 (ddd, J = 10.2, 3.5, 0.8 Hz, 1H), 6.50 (ddd, J = 17.5, 11.0, 1.0 Hz, 1H), 6.10 (d, J = 10.2 Hz, 1H), 5.81 (d, J = 8.6 Hz, 1H), 5.34 (dt, J = 11.1, 1.3 Hz, 1H), 5.25 – 5.17 (m, 2H), 4.63 (q, J = 6.7 Hz, 1H), 4.27 – 4.14 (m, 2H), 3.35 (dd, J = 10.7, 6.5 Hz, 1H), 2.32 (dq, J = 7.0, 7.0 Hz, 1H), 2.27 – 2.16 (m, 2H), 2.13 – 2.05 (m, 2H), 1.76 (dq, J = 14.5, 3.1 Hz, 1H), 1.65 (m, 2H), 1.54 (m, 1H), 1.46 – 1.29 (m, 9H), 1.19 – 1.08 (m, 4H), 0.87 (d, J = 7.0 Hz, 3H), 0.71 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 216.9, 196.6, 168.7, 142.4, 138.8, 127.8, 117.5, 93.4, 74.6, 70.8, 69.2, 65.8, 58.1, 45.4, 44.8, 44.0, 41.9, 36.6, 36.0, 34.4, 30.4, 26.8, 26.3, 24.8, 16.7, 15.2, 14.8, 11.5. Example 10. 22-O-(α-L-2,3-didehydro-6-deoxy-erytho-hexo-pyranosyl)pleuromutilin (TT907) To a solution of TT906 (250 mg, 0.512 mmol) in DCM (3 mL) and 0.4 M CeCl3^(H2O)7 in MeOH (3 mL) at –78 ^C was added NaBH4 (50 mg, 1.32 mmol). The reaction mixture was allowed to warm to 0 ^C and stirred for 2h, at which time the reaction mixture was diluted with DCM (25 mL) and washed with H2O (2 x 20 mL) and brine (2 x 10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf = 0.3) to yield TT907 as a colorless oil (204 mg, 81%); 1H NMR (500 MHz, CDCl3) δ 6.46 (dd, J = 17.4, 11.0 Hz, 1H), 5.90 (dt, J = 10.2, 1.4 Hz, 1H), 5.80 – 5.71 (m, 2H), 5.29 (dd, J = 11.0, 1.6 Hz, 1H), 5.15 (dd, J = 17.4, 1.6 Hz, 1H), 4.92 (m, 1H), 4.13 – 4.00 (m, 2H), 3.78 (m, 1H), 3.69 (dq, J = 8.9, 6.1 Hz, 1H), 3.29 (dd, J = 10.8, 6.5 Hz, 1H), 2.27 (dq, J = 7.0, 7.0 Hz, 1H), 2.23 – 2.08 (m, 2H), 2.04 – 1.97 (m, 2H), 1.70 (dq, J = 14.5, 3.1 Hz, 1H), 1.59 (m, 2H), 1.51 (m, 1H), 1.43 – 1.20 (m, 9H), 1.13 – 1.03 (m, 4H), 0.81 (d, J = 7.0 Hz, 3H), 0.66 (d, J = 7.1 Hz, 3H).;13C NMR (126 MHz, CDCl3) δ 217.2, 169.2, 138.9, 134.3, 125.6, 117.4, 94.4, 74.5, 69.4, 68.8, 68.3, 65.3, 58.1, 45.4, 44.7, 44.0, 41.8, 36.6, 36.0, 34.5, 30.4, 26.8, 26.4, 24.8, 18.0, 16.7, 14.8, 11.5. Example 11. 22-O-(α-L-amecieto-pyranosyl)pleuromutilin (TT908) To a mixture of TT906 (250 mg, 0.507 mmol) and copper(II) acetylacetonate (40 mg, 0.15 mmol) in DCM (3 mL) and MeOH (3 mL) at RT was carefully added NaBH4 (50 mg, 1.32 mmol). The reaction mixture stirred at RT for 1h, at which time the reaction mixture was diluted with DCM (25 mL) and washed with H2O (2 x 20 mL) and brine (2 x 10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf= 0.2) to yield TT908 as a colourless oil (120 mg, 48%);1H NMR (500 MHz, CDCl3) δ 6.52 (dd, J = 17.4, 11.0 Hz, 1H), 5.81 (d, J = 8.5 Hz, 1H), 5.36 (dd, J = 11.0, 1.5 Hz, 1H), 5.21 (dd, J = 17.4, 1.6 Hz, 1H), 4.80 (d, J = 2.5 Hz, 1H), 4.07 (d, J = 1.6 Hz, 2H), 3.59 (dq, J = 9.2, 6.2 Hz, 1H), 3.36 (dd, J = 10.9, 6.5 Hz, 1H), 3.26 (dp, J = 10.0, 5.2 Hz, 1H), 2.34 (dq, J = 7.0, 7.0 Hz, 1H), 2.30 – 2.15 (m, 2H), 2.12 – 2.05 (m, 2H), 1.97 (ddt, J = 10.4, 3.8, 2.0 Hz, 1H), 1.87 (m, 1H), 1.77 (m, 2H), 1.69 – 1.52 (m, 3H), 1.47 – 1.42 (m, 5H), 1.38 (ddd, J = 11.1, 5.9, 3.5 Hz, 1H), 1.32 (d, J = 16.0 Hz, 1H), 1.23 (d, J = 6.2 Hz, 3H), 1.19 – 1.09 (m, 4H), 0.87 (d, J = 7.0 Hz, 3H), 0.73 (d, J = 7.1 Hz, 3H).;13C NMR (126 MHz, CDCl3) δ 217.1, 169.3, 138.9, 117.4, 96.1, 74.6, 71.8, 70.0, 68.8, 64.1, 58.1, 45.4, 44.8, 44.0, 41.8, 36.7, 36.0, 34.5, 30.4, 29.2, 27.3, 26.8, 26.3, 24.8, 17.9, 16.7, 14.8, 11.5. Example 12. 22-O-(α-L-rhamno-pyranosyl)pleuromutilin A (TT911)

[0007] To a solution of TT907 (46 mg, 0.094 mmol) in tert-butanol (0.7 mL), acetone (0.7 mL), and (50 / 50 w / w) N-methylmorpholine N-oxide in H2O (0.2 mL) at RT was carefully added a tiny crystal of solid osmium tetroxide. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was purified via loading directly onto flash column chromatography on silica gel (5:1 DCM:MeOH, Rf= 0.5) to yield TT911 as a colourless oil (52 mg, 27%);1H NMR (500 MHz, MeOD) δ 6.09 (d, J = 8.2 Hz, 1H), 4.77 (d, J = 1.7 Hz, 1H), 4.50 (dd, J = 8.2, 2.9 Hz, 1H), 4.16 (d, J = 2.3 Hz, 2H), 3.88 (dd, J = 3.5, 1.7 Hz, 1H), 3.63 (dd, J = 9.5, 3.4 Hz, 1H), 3.55 (dd, J = 9.4, 6.2 Hz, 1H), 3.44 – 3.38 (m, 2H), 3.35 (t, J = 9.5 Hz, 1H), 3.19 (dd, J = 11.6, 3.0 Hz, 1H), 2.23 (m, 1H), 2.15 – 2.07 (m, 2H), 1.93 (d, J = 15.8 Hz, 1H), 1.82 – 1.64 (m, 5H), 1.59 (dqd, J = 13.8, 6.6, 2.7 Hz, 1H), 1.49 – 1.37 (m, 5H), 1.27 – 1.17 (m, 4H), 1.10 (d, J = 6.4 Hz, 3H), 0.86 (s, 3H), 0.77 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, MeOD) δ 218.5, 172.0, 101.4, 73.7, 72.9, 72.2, 71.9, 70.4, 70.3, 65.6, 65.2, 60.1, 57.0, 49.8, 47.0, 45.3, 43.2, 40.2, 38.5, 35.2, 31.1, 27.9, 25.6, 18.0, 17.4, 17.1, 15.4, 13.8; Example 13. 22-O-(α-L-amecieto-pyranosyl)pleuromutilin A (TT912) To a solution of TT908 (30 mg, 0.061 mmol) in tert-butanol (0.5 mL), acetone (0.5 mL), and (50 / 50 w / w) N-methylmorpholine N-oxide in H2O (0.1 mL) at RT was carefully added a tiny crystal of solid osmium tetroxide. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was purified via loading directly onto flash column chromatography on silica gel (9:1 DCM:MeOH, Rf= 0.5) to yield TT912 as a colourless oil (32 mg, 37%);1H NMR (500 MHz, MeOD) δ 6.08 (d, J = 8.2 Hz, 1H), 4.78 (d, J = 2.6 Hz, 1H), 4.51 (dd, J = 8.3, 3.0 Hz, 1H), 4.20 – 4.07 (m, 2H), 3.52 (dq, J = 9.2, 6.2 Hz, 1H), 3.47 – 3.37 (m, 2H), 3.18 (dd, J = 11.6, 3.0 Hz, 1H), 3.12 (m, 1H), 2.23 (dt, J = 12.3, 9.8 Hz, 1H), 2.15 – 2.07 (m, 2H), 1.95 – 1.85 (m, 2H), 1.78 – 1.67 (m, 6H), 1.58 (m, 1H), 1.49 – 1.36 (m, 5H), 1.28 – 1.06 (m, 9H), 0.86 (s, 3H), 0.77 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, MeOD) δ 218.5, 172.5, 97.3, 72.9, 72.5, 71.3, 70.2, 65.6, 65.1, 60.1, 57.0, 49.8, 47.0, 45.3, 43.2, 40.2, 38.5, 35.2, 31.1, 30.3, 28.0, 27.9, 25.5, 18.4, 17.4, 17.1, 15.4, 13.8; Example 14. 22-O-(α-L-2,3-dihydro-aculo-pyranosyl)pleuromutilin (TT946) To a solution of TT906 (500 mg, 1.02 mmol) in toluene (15 mL) at RT was added (Triphenylphosphine)copper hydride hexamer (100 mg, 0.0510 mmol). After stirring for 5 min, polymethylhydrosiloxane (5 mL) was added at RT and the reaction was stirred at RT for 16h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (1:1 hexane:EtOAc, Rf = 0.5) to yield TT946 as a colourless oil (76 mg, 15%);1H NMR (500 MHz, CDCl3) δ 6.51 (dd, J = 17.4, 11.0 Hz, 1H), 5.80 (d, J = 8.6 Hz, 1H), 5.35 (dd, J = 11.0, 1.5 Hz, 1H), 5.21 (dd, J = 17.4, 1.6 Hz, 1H), 5.04 (t, J = 5.0 Hz, 1H), 4.33 (p, J = 6.7 Hz, 1H), 4.22 – 4.08 (m, 2H), 3.36 (d, J = 6.5 Hz, 1H), 2.59 – 2.38 (m, 2H), 2.38 – 2.29 (m, 2H), 2.29 – 2.15 (m, 2H), 2.15 – 2.04 (m, 3H), 1.77 (dq, J = 14.5, 3.2 Hz, 1H), 1.72 – 1.60 (m, 2H), 1.54 (m, 1H), 1.49 – 1.42 (m, 4H), 1.40 – 1.30 (m, 2H), 1.24 (d, J = 6.8 Hz, 3H), 1.19 – 1.08 (m, 4H), 0.87 (d, J = 7.0 Hz, 3H), 0.73 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 216.9, 210.2, 169.0, 138.8, 117.4, 97.1, 74.5, 71.4, 69.0, 65.0, 58.1, 45.5, 44.8, 44.0, 41.9, 36.7, 36.0, 34.5, 33.4, 30.4, 28.4, 26.9, 26.3, 24.8, 16.7, 14.9, 14.8, 11.5; Example 15. 22-O-(α-D-aculo-pyranosyl)-19,20-Dihydropleuromutilin (TT915): To a solution of TTPM2 (166 mg, 0.436 mmol) and Pyranone A (400 mg, 1.74 mmol) in THF (2 mL) at RT was added a mixture of Pd2(dba)3^CHCl3 (23 mg, 0.022 mmol) and PPh3 (23 mg, 0.087 mmol) in DCM (0.2 mL). The reaction mixture was stirred at RT for 2h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (1:1 hexane:EtOAc, Rf = 0.5) to yield TT915 as a colourless oil (137 mg, 64%);1H NMR (500 MHz, CDCl3) δ 6.87 (dd, J = 10.2, 3.5 Hz, 1H), 6.07 (d, J = 10.2 Hz, 1H), 5.69 (d, J = 8.2 Hz, 1H), 5.21 (d, J = 3.5 Hz, 1H), 4.61 (q, J = 6.8 Hz, 1H), 4.28 (d, J = 16.7 Hz, 1H), 4.09 (d, J = 16.7 Hz, 1H), 3.38 (t, J = 5.2 Hz, 1H), 2.38 (dq, J = 7.0, 7.0 Hz, 1H), 2.26 – 2.13 (m, 2H), 2.08 (m, 1H), 1.80 – 1.66 (m, 4H), 1.64 – 1.48 (m, 3H), 1.47 – 1.26 (m, 9H), 1.08 (td, J = 13.8, 4.4 Hz, 1H), 0.93 – 0.87 (m, 6H), 0.75 – 0.61 (m, 6H);13C NMR (126 MHz, CDCl3) δ 217.3, 196.7, 168.9, 142.6, 127.7, 93.4, 76.4, 70.8, 69.3, 65.6, 58.5, 45.5, 41.8, 41.0, 40.8, 36.7, 34.4, 34.430.2, 26.8, 26.3, 24.9, 20.6, 16.5, 15.2, 14.8, 11.1, 8.2; Example 16. 22-O-(α-D-amecieto-pyranosyl)-19,20-Dihydropleuromutilin (TT917) To a mixture of TT915 (40 mg, 0.082 mmol) and copper(II) acetylacetonate (6.4 mg, 0.024 mmol) in DCM (1 mL) and MeOH (1 mL) at RT was carefully added NaBH4(10 mg, 0.26 mmol). The reaction mixture stirred at RT for 1h, at which time the reaction mixture was diluted with DCM (10 mL) and washed with H2O (2 x 10 mL) and brine (2 x 5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf = 0.2) to yield TT917 as a colourless oil (12 mg, 30%);1H NMR (500 MHz, CDCl3) δ 5.70 (d, J = 8.1 Hz, 1H), 4.79 (d, J = 2.6 Hz, 1H), 4.14 (d, J = 16.7 Hz, 1H), 4.03 (d, J = 16.7 Hz, 1H), 3.58 (dq, J = 9.3, 6.3 Hz, 1H), 3.41 (t, J = 4.9 Hz, 1H), 3.26 (m, 1H), 2.43 (dq, J = 6.9, 6.9 Hz, 1H), 2.30 – 2.08 (m, 3H), 1.96 (m, 1H), 1.87 (dt, J = 7.5, 4.2 Hz, 1H), 1.83 – 1.68 (m, 4H), 1.67 – 1.39 (m, 8H), 1.38 – 1.29 (m, 2H), 1.27 – 1.19 (m, 4H), 1.12 (td, J = 13.9, 4.5 Hz, 1H), 0.97 – 0.91 (m, 6H), 0.80 – 0.68 (m, 6H);13C NMR (126 MHz, CDCl3) δ 217.2, 169.4, 96.0, 76.6, 72.0, 69.9, 68.9, 63.9, 58.6, 45.6, 41.9, 41.2, 40.9, 36.7, 34.5, 34.4, 30.3, 29.3, 27.4, 26.8, 26.3, 25.0, 20.7, 17.9, 16.5, 14.8, 11.1, 8.3; Example 17. 22-O-(α-D-2,3-didehydro-6-deoxy-erytho-hexo-pyranosyl)-19,20- Dihydropleuromutilin (TT919) To a solution of TT915 (65 mg, 0.132 mmol) in DCM (1 mL) and 0.4 M CeCl3^(H2O)7in MeOH (1 mL) at –78 ^C was added NaBH4(20 mg, 0.52 mmol). The reaction mixture was allowed to warm to 0 ^C and stirred for 2h, at which time the reaction mixture was diluted with DCM (10 mL) and washed with H2O (2 x 10 mL) and brine (2 x 5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf= 0.3) to yield TT919 as a colourless oil (62 mg, 95%);1H NMR (500 MHz, CDCl3) δ 5.97 (dt, J = 10.2, 1.4 Hz, 1H), 5.83 (dt, J = 10.3, 2.5 Hz, 1H), 5.71 (d, J = 8.1 Hz, 1H), 4.98 (m, 1H), 4.24 (d, J = 16.7 Hz, 1H), 4.07 (d, J = 16.9 Hz, 1H), 3.84 (t, J = 8.4 Hz, 1H), 3.76 (dq, J = 8.9, 6.1 Hz, 1H), 3.41 (d, J = 6.6 Hz, 1H), 2.43 (dq, J = 6.9, 6.9 Hz, 1H), 2.30 – 2.13 (m, 2H), 2.10 (d, J = 2.8 Hz, 1H), 1.86 – 1.68 (m, 3H), 1.68 – 1.52 (m, 4H), 1.48 (m, 1H), 1.41 (s, 3H), 1.36 – 1.23 (m, 5H), 1.12 (td, J = 13.8, 4.4 Hz, 1H), 0.95 (d, J = 8.0 Hz, 6H), 0.80 – 0.67 (m, 6H);13C NMR (126 MHz, CDCl3) δ 217.2, 169.3, 133.9, 126.0, 94.3, 76.6, 69.6, 69.0, 68.4, 65.2, 58.6, 45.6, 41.9, 41.1, 40.9, 36.7, 34.5, 34.4, 30.3, 26.8, 26.3, 25.0, 20.7, 17.9, 16.5, 14.9, 11.1, 8.3; Example 18. 22-O-(α-D-rhamno-pyranosyl)-19,20-Dihydropleuromutilin (TT920) To a solution of TT919 (35 mg, 0.071 mmol) in tert-butanol (0.5 mL), acetone (0.5 mL), and (50 / 50 w / w) N-methylmorpholine N-oxide in H2O (0.1 mL) at RT was carefully added a tiny crystal of solid osmium tetroxide. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was purified via loading directly onto flash column chromatography on silica gel (9:1 DCM:MeOH, Rf = 0.3) to yield TT920 as a colourless oil (16 mg, 43%);1H NMR (500 MHz, MeOD) δ 5.72 (d, J = 8.1 Hz, 1H), 4.74 (d, J = 1.7 Hz, 1H), 4.21 – 3.95 (m, 2H), 3.87 (dd, J = 3.4, 1.7 Hz, 1H), 3.64 (dd, J = 9.5, 3.4 Hz, 1H), 3.58 (dq, J = 9.5, 6.1 Hz, 1H), 3.46 – 3.32 (m, 2H), 2.38 – 2.29 (m, 2H), 2.22 (m, 1H), 2.11 (dt, J = 19.2, 9.4 Hz, 1H), 1.83 – 1.71 (m, 3H), 1.69 – 1.47 (m, 4H), 1.44 – 1.37 (m, 4H), 1.35 – 1.25 (m, 2H), 1.21 (d, J = 6.2 Hz, 3H), 1.11 (td, J = 13.8, 4.3 Hz, 1H), 0.94 – 0.87 (m, 6H), 0.75 – 0.66 (m, 6H);13C NMR (126 MHz, MeOD) δ 219.8, 170.8, 101.6, 76.7, 73.7, 72.1, 71.9, 70.6, 70.4, 65.3, 59.4, 46.8, 43.1, 41.9, 41.7, 38.1, 36.0, 35.3, 31.5, 28.1, 26.8, 25.8, 21.3, 18.0, 17.0, 15.4, 11.8, 8.6; Example 19. 22-O-(α-L-aculo-pyranosyl)-19,20-Dihydropleuromutilin (TT916) To a solution of TTPM2 (400 mg, 1.05 mmol) and Pyranone B (960 mg, 4.20 mmol) in THF (3 mL) at RT was added a mixture of Pd2(dba)3^CHCl3(54 mg, 0.053 mmol) and PPh3(55 mg, 0.21 mmol) in DCM (0.2 mL). The reaction mixture was stirred at RT for 2h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (1:1 hexane:EtOAc, Rf= 0.5) to yield TT916 as a yellow oil (393 mg, 76%);1H NMR (500 MHz, CDCl3) δ 6.87 (ddd, J = 10.2, 3.5, 1.1 Hz, 1H), 6.06 (d, J = 10.1 Hz, 1H), 5.65 (m, 1H), 5.23 (d, J = 3.5 Hz, 1H), 4.57 (m, 1H), 4.24 – 4.12 (m, 2H), 3.38 (t, J = 4.6 Hz, 1H), 2.36 (dq, J = 7.0, 7.0 Hz, 1H), 2.25 – 2.05 (m, 3H), 1.79 – 1.66 (m, 4H), 1.64 – 1.48 (m, 3H), 1.47 – 1.25 (m, 9H), 1.07 (td, J = 13.9, 4.2 Hz, 1H), 0.94 – 0.88 (m, 6H), 0.76 – 0.70 (m, 3H), 0.68 – 0.64 (m, 3H);13C NMR (126 MHz, CDCl3) δ 217.1, 196.6, 168.8, 142.7, 127.6, 93.1, 76.3, 70.7, 69.4, 65.5, 58.4, 45.5, 41.9, 41.2, 40.9, 36.6, 34.4, 34.4, 30.2, 26.8, 26.3, 24.9, 20.8, 16.5, 15.2, 14.8, 11.1, 8.3; Example 20. 22-O-(α-L-amecieto-pyranosyl)-19,20-Dihydropleuromutilin (TT918) To a mixture of TT916 (80 mg, 0.16 mmol) and copper(II) acetylacetonate (13 mg, 0.049 mmol) in DCM (1 mL) and MeOH (1 mL) at RT was carefully added NaBH4 (20 mg, 0.52 mmol). The reaction mixture stirred at RT for 1h, at which time the reaction mixture was diluted with DCM (10 mL) and washed with H2O (2 x 10 mL) and brine (2 x 5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf = 0.2) to yield TT918 as a colourless oil (81 mg, 26%);1H NMR (500 MHz, CDCl3) δ 5.68 (d, J = 8.2 Hz, 1H), 4.81 (d, J = 2.8 Hz, 1H), 4.07 (s, 2H), 3.57 (dq, J = 9.1, 6.2 Hz, 1H), 3.41 (t, J = 5.4 Hz, 1H), 3.26 (dq, J = 10.0, 4.6 Hz, 1H), 2.42 (dq, J = 6.9, 6.9 Hz, 1H), 2.29 – 2.08 (m, 3H), 1.95 (m, 1H), 1.86 (m, 1H), 1.79 – 1.69 (m, 4H), 1.62 – 1.53 (m, 4H), 1.49 – 1.40 (m, 5H), 1.38 – 1.28 (m, 2H), 1.26 – 1.19 (m, 4H), 1.11 (td, J = 13.8, 4.3 Hz, 1H), 0.97 – 0.91 (m, 6H), 0.77 (t, J = 7.4 Hz, 3H), 0.71 (d, J = 6.8 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.2, 169.4, 95.9, 76.6, 71.9, 69.9, 69.0, 63.9, 58.5, 45.6, 41.9, 41.2, 40.9, 36.7, 34.5, 34.3, 30.3, 29.2, 27.4, 26.8, 26.3, 24.9, 20.9, 17.9, 16.5, 14.8, 11.0, 8.3. Example 21. 22-O-(α-L-2,3-didehydro-6-deoxy-erytho-hexo-pyranosyl)-19,20- Dihydropleuromutilin (TT921) To a solution of TT916 (195 mg, 0.397 mmol) in DCM (3 mL) and 0.4 M CeCl3^(H2O)7 in MeOH (3 mL) at –78 ^C was added NaBH4 (40 mg, 1.0 mmol). The reaction mixture was allowed to warm to 0 ^C and stirred for 2h, at which time the reaction mixture was diluted with DCM (20 mL) and washed with H2O (2 x 20 mL) and brine (2 x 10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf = 0.3) to yield TT921 as a colourless oil (196 mg, 63%);1H NMR (500 MHz, CDCl3) δ 5.95 (dt, J = 10.1, 1.4 Hz, 1H), 5.81 (dt, J = 10.2, 2.4 Hz, 1H), 5.67 (d, J = 8.2 Hz, 1H), 4.98 (m, 1H), 4.19 – 4.08 (m, 2H), 3.82 (t, J = 7.1 Hz, 1H), 3.72 (dq, J = 9.0, 6.1 Hz, 1H), 3.40 (d, J = 5.9 Hz, 1H), 2.40 (dq, J = 6.9, 6.9 Hz, 1H), 2.27 – 2.13 (m, 2H), 2.09 (m, 1H), 1.90 (d, J = 7.7 Hz, 1H), 1.79 – 1.68 (m, 3H), 1.65 – 1.51 (m, 3H), 1.45 (ddd, J = 12.9, 9.2, 2.9 Hz, 1H), 1.40 (s, 3H), 1.37 – 1.30 (m, 2H), 1.29 (d, J = 6.1 Hz, 3H), 1.10 (td, J = 14.1, 4.3 Hz, 1H), 0.96 – 0.90 (m, 6H), 0.76 (t, J = 7.4 Hz, 3H), 0.69 (d, J = 6.8 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.3, 169.3, 134.0, 125.9, 94.1, 76.5, 69.5, 69.0, 68.4, 65.0, 58.5, 45.6, 41.9, 41.3, 40.9, 36.6, 34.5, 34.3, 30.2, 26.8, 26.3, 24.9, 20.9, 17.9, 16.5, 14.8, 11.1, 8.4; Example 22. 22-O-(α-L-rhamno-pyranosyl)-19,20-Dihydropleuromutilin (TT922) To a solution of TT921 (72 mg, 0.15 mmol) in tert-butanol (1 mL), acetone (1 mL), and (50 / 50 w / w) N-methylmorpholine N-oxide in H2O (0.2 mL) at RT was carefully added a tiny crystal of solid osmium tetroxide. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was purified via loading directly onto flash column chromatography on silica gel (9:1 hexane:EtOAc, Rf = 0.3) to yield TT922 as a colourless oil (77 mg, 34%);1H NMR (500 MHz, MeOD) δ 5.70 (d, J = 8.1 Hz, 1H), 4.73 (d, J = 1.7 Hz, 1H), 4.14 – 4.03 (m, 2H), 3.87 (dd, J = 3.5, 1.7 Hz, 1H), 3.63 (dd, J = 9.5, 3.4 Hz, 1H), 3.55 (dq, J = 9.5, 6.2 Hz, 1H), 3.41 (d, J = 6.1 Hz, 1H), 3.34 (t, J = 9.6 Hz, 1H), 2.37 – 2.31 (m, 2H), 2.22 (ddt, J = 19.5, 10.9, 1.8 Hz, 1H), 2.11 (dt, J = 19.2, 9.4 Hz, 1H), 1.84 – 1.71 (m, 3H), 1.69 – 1.48 (m, 4H), 1.45 – 1.37 (m, 4H), 1.36 – 1.27 (m, 2H), 1.21 (d, J = 6.2 Hz, 3H), 1.11 (td, J = 13.7, 4.3 Hz, 1H), 0.98 – 0.86 (m, 6H), 0.75 – 0.66 (m, 6H);13C NMR (126 MHz, MeOD) δ 219.7, 170.8, 101.3, 76.6, 73.7, 72.1, 71.9, 70.6, 70.4, 65.1, 59.4, 46.8, 43.1, 41.9, 41.7, 38.0, 35.9, 35.3, 31.5, 28.1, 26.8, 25.7, 21.4, 18.0, 17.0, 15.3, 11.8, 8.6. Example 23.22-O-(α-D-6’-dimethyl-tert-butylsiloxy-aculo-pyranosyl)-pleuromutilin (TT913)

[0008] To a solution of Pleuromutilin (100 mg, 0.264 mmol) and Pyranone E (332 mg, 0.925 mmol) in THF (2 mL) at RT was added a mixture of Pd2(dba)3^CHCl3(6.8 mg, 0.0066 mmol) and PPh3 (6.9 mg, 0.026 mmol) in DCM (0.1 mL). The reaction mixture was stirred at RT for 2h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:1 hexane:EtOAc, Rf= 0.3) to yield TT913 as a yellow oil (134 mg, 82%);1H NMR (500 MHz, CDCl3) δ 6.92 (dd, J = 10.3, 3.5 Hz, 1H), 6.47 (dd, J = 17.4, 11.0 Hz, 1H), 6.13 (d, J = 10.3 Hz, 1H), 5.82 (d, J = 8.5 Hz, 1H), 5.42 (d, J = 3.5 Hz, 1H), 5.33 (dd, J = 11.0, 1.6 Hz, 1H), 5.19 (dd, J = 17.4, 1.6 Hz, 1H), 4.46 (dd, J = 4.9, 2.7 Hz, 1H), 4.27 (d, J = 16.5 Hz, 1H), 4.13 (d, J = 16.6 Hz, 1H), 4.00 (qd, J = 11.3, 3.9 Hz, 2H), 3.35 (t, J = 7.9 Hz, 1H), 2.33 (dq, J = 6.9, 6.9 Hz, 1H), 2.29 – 2.13 (m, 2H), 2.11 – 2.04 (m, 2H), 1.77 (m, 1H), 1.70 – 1.60 (m, 2H), 1.56 – 1.42 (m, 5H), 1.37 (m, 1H), 1.30 (d, J = 16.1 Hz, 1H), 1.18 – 1.07 (m, 4H), 0.90 – 0.83 (m, 12H), 0.71 (d, J = 7.0 Hz, 3H), 0.04 (d, J = 4.4 Hz, 6H);13C NMR (126 MHz, CDCl3) δ 216.9, 194.2, 168.6, 143.0, 138.9, 128.6, 117.4, 93.0, 76.3, 74.6, 69.1, 65.3, 62.4, 58.2, 45.5, 44.8, 44.0, 41.8, 36.7, 36.1, 34.4, 30.4, 26.8, 26.4, 25.9, 24.9, 18.3, 16.7, 14.8, 11.6, -5.3, -5.4. Example 24. 22-O-(α-D-6’-hydroxy-amecieto-pyranosyl)-pleuromutilin (TT927) To a mixture of TT913 (100 mg, 0.162 mmol) and copper(II) acetylacetonate (13 mg, 0.48 mmol) in DCM (2 mL) and MeOH (2 mL) at RT was carefully added NaBH4(30 mg, 0.78 mmol). The reaction mixture stirred at RT for 1h, at which time the reaction mixture was diluted with DCM (10 mL) and washed with H2O (2 x 10 mL) and brine (2 x 5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was used in the next reaction without further purification. To the residue in THF (3 mL) at 0 ^C was added 1 M tetrabutylammonium fluoride in THF (0.3 mL). The reaction mixture was stirred at 0 ^C for 1h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (100% EtOAc, Rf = 0.5) to yield TT927 as a colourless oil (82 mg, 90%, two steps);1H NMR (500 MHz, CDCl3) δ 6.46 (dd, J = 17.4, 11.0 Hz, 1H), 5.79 (d, J = 8.4 Hz, 1H), 5.32 (dd, J = 11.0, 1.5 Hz, 1H), 5.18 (dd, J = 17.4, 1.6 Hz, 1H), 4.83 (d, J = 3.3 Hz, 1H), 4.13 – 3.99 (m, 2H), 3.83 – 3.70 (m, 2H), 3.65 – 3.51 (m, 2H), 3.34 (dd, J = 10.1, 6.3 Hz, 1H), 2.32 (dq, J = 6.9, 6.9 Hz, 1H), 2.28 – 2.11 (m, 2H), 2.10 – 2.02 (m, 2H), 1.94 (dt, J = 13.5, 3.4 Hz, 1H), 1.90 – 1.71 (m, 3H), 1.68 – 1.48 (m, 3H), 1.47 – 1.39 (m, 4H), 1.38 – 1.20 (m, 2H), 1.18 – 1.06 (m, 4H), 0.86 (d, J = 7.0 Hz, 3H), 0.70 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.2, 169.1, 139.0, 117.3, 96.3, 74.6, 73.4, 68.8, 66.8, 64.3, 62.9, 58.2, 45.5, 44.8, 44.0, 41.8, 36.7, 36.1, 34.5, 30.4, 28.9, 26.9, 26.8, 26.4, 24.9, 16.7, 14.9, 11.5. Example 25.22-O-(α-D-2,3-didehydro-6-deoxy-erytho-hexo-pyranosyl)-pleuromutilin (TT928) To a solution of TT913 (300 mg, 0.485 mmol) in DCM (4 mL) and 0.4 M CeCl3^(H2O)7 in MeOH (4 mL) at –78 ^C was added NaBH4 (80 mg, 2.1 mmol). The reaction mixture was allowed to warm to 0 ^C and stirred for 1h, at which time the reaction mixture was diluted with DCM (25 mL) and washed with H2O (2 x 20 mL) and brine (2 x 10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was used in the next reaction without further purification. To the residue in THF (10 mL) at 0 ^C was added 1 M tetrabutylammonium fluoride in THF (1 mL). The reaction mixture was stirred at 0 ^C for 1h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (100% EtOAc, Rf= 0.5) to yield TT928 as a colourless oil (226 mg, 92%, two steps);1H NMR (500 MHz, CDCl3) δ 6.39 (dd, J = 17.3, 10.9 Hz, 1H), 5.92 (dt, J = 10.2, 1.4 Hz, 1H), 5.76 – 5.68 (m, 2H), 5.25 (dd, J = 11.0, 1.6 Hz, 1H), 5.11 (dd, J = 17.4, 1.6 Hz, 1H), 4.95 (d, J = 2.7 Hz, 1H), 4.18 – 3.95 (m, 3H), 3.78 – 3.71 (m, 2H), 3.68 (dt, J = 8.2, 3.9 Hz, 1H), 3.29 (dd, J = 10.4, 6.4 Hz, 1H), 2.26 (dq, J = 7.0, 7.0 Hz, 1H), 2.22 – 2.06 (m, 2H), 2.06 – 1.95 (m, 2H), 1.74 – 1.63 (m, 2H), 1.62 – 1.53 (m, 2H), 1.47 (qd, J = 13.6, 3.5 Hz, 1H), 1.41 – 1.34 (m, 4H), 1.30 (dd, J = 14.4, 3.7 Hz, 1H), 1.22 (d, J = 16.2 Hz, 1H), 1.12 – 1.01 (m, 4H), 0.81 (d, J = 7.0 Hz, 3H), 0.65 (d, J = 6.9 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.3, 169.2, 138.9, 134.4, 125.1, 117.3, 94.7, 74.6, 71.8, 68.9, 65.7, 63.8, 62.3, 58.2, 45.5, 44.8, 43.9, 41.8, 36.7, 36.1, 34.5, 30.4, 26.7, 26.4, 24.9, 16.6, 14.9, 11.6; Example 26. 22-O-(α-D-erytho-hexo-pyranosyl)-pleuromutilin (TT929) To a solution of TT927 (55 mg, 0.11 mmol) in tert-butanol (1 mL), acetone (1 mL), and (50 / 50 w / w) N-methylmorpholine N-oxide in H2O (0.2 mL) at RT was carefully added a tiny crystal of solid osmium tetroxide. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was purified via loading directly onto flash column chromatography on silica gel (5:1 DCM:MeOH, Rf= 0.6) to yield TT929 as a colourless oil (18 mg, 31%);1H NMR (500 MHz, MeOD) δ 6.10 (d, J = 8.2 Hz, 1H), 4.87 (d, J = 3.0 Hz, 1H), 4.50 (dd, J = 8.2, 3.0 Hz, 1H), 4.27 – 4.10 (m, 2H), 3.74 (dd, J = 11.7, 2.5 Hz, 1H), 3.61 (dd, J = 11.7, 5.7 Hz, 1H), 3.51 (ddd, J = 9.7, 5.7, 2.5 Hz, 1H), 3.47 – 3.37 (m, 3H), 3.19 (dd, J = 11.6, 2.9 Hz, 1H), 2.23 (m, 1H), 2.16 – 2.07 (m, 2H), 1.93 (d, J = 15.9 Hz, 1H), 1.87 (m, 1H), 1.84 – 1.64 (m, 8H), 1.59 (m, 1H), 1.48 – 1.38 (m, 5H), 1.18 (td, J = 14.3, 4.5 Hz, 1H), 1.10 (d, J = 6.5 Hz, 3H), 0.86 (s, 3H), 0.77 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, MeOD) δ 218.6, 172.4, 97.5, 75.9, 72.9, 70.1, 66.9, 65.6, 65.3, 63.0, 60.2, 56.9, 49.8, 47.0, 45.3, 43.2, 40.2, 38.5, 35.3, 31.1, 29.9, 27.9, 27.9, 25.6, 17.4, 17.1, 15.4, 13.8; Example 27. 22-O-(α-D-manno-pyranosyl)-pleuromutilin A (TT930)

[0009] To a solution of TT928 (50 mg, 0.099 mmol) in tert-butanol (1 mL), acetone (1 mL), and (50 / 50 w / w) N-methylmorpholine N-oxide in H2O (0.2 mL) at RT was carefully added a tiny crystal of solid osmium tetroxide. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was purified via loading directly onto flash column chromatography on silica gel (4:1 DCM:MeOH, Rf= 0.3) to yield TT930 as a colourless oil (7 mg, 12%);1H NMR (500 MHz, MeOD) δ 5.88 (d, J = 7.3 Hz, 1H), 4.81 (m, 1H), 4.26 – 4.13 (m, 3H), 3.93 (dd, J = 3.4, 1.7 Hz, 1H), 3.88 (dd, J = 11.6, 5.5 Hz, 1H), 3.83 (dd, J = 11.8, 2.3 Hz, 1H), 3.77 – 3.68 (m, 3H), 3.64 (td, J = 9.5, 4.3 Hz, 1H), 3.58 (dd, J = 5.8, 2.4 Hz, 1H), 3.54 (dd, J = 11.6, 6.8 Hz, 1H), 3.51 (d, J = 5.9 Hz, 1H), 2.53 (dq, J = 6.8, 6.8 Hz, 1H), 2.44 (m, 1H), 2.28 (dd, J = 19.4, 10.6 Hz, 1H), 2.16 (dt, J = 19.2, 9.4 Hz, 1H), 1.89 – 1.81 (m, 2H), 1.79 – 1.63 (m, 3H), 1.54 – 1.38 (m, 5H), 1.19 (ddd, J = 13.9, 8.8, 4.5 Hz, 1H), 1.09 (d, J = 13.4 Hz, 1H), 1.04 – 0.98 (m, 6H), 0.76 (d, J = 6.2 Hz, 3H); Example 28. 22-O-(α-D-6’-dimethyl-tert-butylsiloxy-aculo-pyranosyl)-19,20- Dihydropleuromutilin (TT931) To a solution of TTPM2 (350 mg, 0.920 mmol) and Pyranone E (1.48 g, 4.14 mmol) in THF (4 mL) at RT was added a mixture of Pd2(dba)3^CHCl3 (48 mg, 0.046 mmol) and PPh3 (48 mg, 0.18 mmol) in DCM (0.2 mL). The reaction mixture was stirred at RT for 2h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:1 hexane:EtOAc, Rf = 0.4) to yield TT931 as a yellow oil (520 mg, 91%);1H NMR (500 MHz, CDCl3) δ 6.94 (dd, J = 10.3, 3.5 Hz, 1H), 6.13 (d, J = 10.3 Hz, 1H), 5.72 (d, J = 8.1 Hz, 1H), 5.41 (d, J = 3.4 Hz, 1H), 4.47 (dd, J = 4.8, 3.0 Hz, 1H), 4.32 (d, J = 16.7 Hz, 1H), 4.14 (d, J = 16.7 Hz, 1H), 4.06 – 3.97 (m, 2H), 3.41 (t, J = 5.8 Hz, 1H), 2.42 (dq, J = 7.0, 7.0 Hz, 1H), 2.29 – 2.14 (m, 2H), 2.10 (d, J = 2.8 Hz, 1H), 1.81 – 1.70 (m, 3H), 1.65 – 1.54 (m, 3H), 1.50 – 1.43 (m, 2H), 1.40 (s, 3H), 1.39 – 1.29 (m, 2H), 1.12 (td, J = 13.9, 4.4 Hz, 1H), 1.00 – 0.92 (m, 6H), 0.86 (s, 9H), 0.75 (t, J = 7.4 Hz, 3H), 0.70 (d, J = 7.0 Hz, 3H), 0.05 (d, J = 3.1 Hz, 6H);13C NMR (126 MHz, CDCl3) δ 217.1, 194.2, 168.8, 143.0, 128.5, 92.8, 76.5, 76.3, 69.3, 65.1, 62.4, 58.5, 45.5, 41.8, 41.1, 40.9, 36.6, 34.4, 34.4, 30.3, 26.8, 26.3, 25.9, 25.0, 20.6, 18.3, 16.5, 14.8, 11.1, 8.3, -5.3, -5.3; Example 29. 22-O-(α-D-6’-hydroxy-amecieto-pyranosyl)-19,20-dihydropleuromutilin (TT934) To a mixture of TT931 (100 mg, 0.161 mmol) and copper(II) acetylacetonate (13 mg, 0.048 mmol) in DCM (2 mL) and MeOH (2 mL) at RT was carefully added NaBH4(30 mg, 0.78 mmol). The reaction mixture stirred at RT for 1h, at which time the reaction mixture was diluted with DCM (10 mL) and washed with H2O (2 x 10 mL) and brine (2 x 5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was used in the next reaction without further purification. To the residue in THF (3 mL) at 0 ^C was added 1 M tetrabutylammonium fluoride in THF (0.3 mL). The reaction mixture was stirred at 0 ^C for 1h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (100% EtOAc, Rf= 0.5) to yield TT934 as a colourless oil (27 mg, 33%, two steps); 1H NMR (500 MHz, CDCl3) δ 5.69 (d, J = 8.1 Hz, 1H), 4.84 (d, J = 3.3 Hz, 1H), 4.16 – 3.99 (m, 2H), 3.78 (qd, J = 11.6, 3.9 Hz, 2H), 3.60 (dtd, J = 25.1, 9.4, 4.2 Hz, 2H), 3.40 (t, J = 5.0 Hz, 1H), 2.41 (dq, J = 6.9, 6.9 Hz, 1H), 2.28 – 2.12 (m, 2H), 2.10 (d, J = 2.8 Hz, 1H), 1.97 (dt, J = 13.5, 3.2 Hz, 1H), 1.92 – 1.68 (m, 6H), 1.65 – 1.51 (m, 4H), 1.46 (ddd, J = 13.0, 9.3, 2.7 Hz, 1H), 1.40 (d, J = 1.7 Hz, 3H), 1.37 – 1.29 (m, 2H), 1.11 (td, J = 13.9, 4.5 Hz, 1H), 0.98 – 0.91 (m, 6H), 0.74 (td, J = 7.4, 1.6 Hz, 3H), 0.71 – 0.67 (m, 3H);13C NMR (126 MHz, CDCl3) δ 217.3, 169.3, 96.2, 76.5, 73.3, 69.1, 67.0, 64.1, 63.0, 58.6, 45.6, 41.9, 41.1, 40.9, 36.7, 34.5, 34.4, 30.3, 28.9, 26.9, 26.8, 26.3, 25.0, 20.7, 16.5, 14.8, 11.1, 8.3. Example 30. 22-O-(α-D-2,3-didehydro-6-deoxy-erytho-hexo-pyranosyl)-19,20- dihydropleuromutilin (TT935) O O O O OH To a solution of TT931 (200 mg, 0.322 mmol) in DCM (4 mL) and 0.4 M CeCl3^(H2O)7in MeOH (4 mL) at –78 ^C was added NaBH4(60 mg, 1.6 mmol). The reaction mixture was allowed to warm to 0 ^C and stirred for 1h, at which time the reaction mixture was diluted with DCM (20 mL) and washed with H2O (2 x 20 mL) and brine (2 x 10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was used in the next reaction without further purification. To the residue in THF (5 mL) at 0 ^C was added 1 M tetrabutylammonium fluoride in THF (0.5 mL). The reaction mixture was stirred at 0 ^C for 1h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (100% EtOAc, Rf = 0.5) to yield TT935 as a colourless oil (69 mg, 42%, two steps);1H NMR (500 MHz, CDCl3) δ 5.98 (dt, J = 10.2, 1.5 Hz, 1H), 5.79 (dq, J = 10.2, 2.1 Hz, 1H), 5.68 (d, J = 8.1 Hz, 1H), 5.00 (m, 1H), 4.25 – 4.15 (m, 2H), 4.04 (dd, J = 16.8, 1.1 Hz, 1H), 3.81 (dd, J = 4.2, 1.5 Hz, 2H), 3.74 (m, 1H), 3.39 (t, J = 5.6 Hz, 1H), 2.39 (dq, J = 7.0, 7.0 Hz, 1H), 2.28 – 2.11 (m, 2H), 2.09 (d, J = 2.8 Hz, 1H), 1.81 – 1.65 (m, 4H), 1.64 – 1.49 (m, 3H), 1.45 (ddd, J = 12.5, 9.1, 2.7 Hz, 1H), 1.41 – 1.27 (m, 5H), 1.09 (td, J = 13.8, 4.3 Hz, 1H), 0.97 – 0.89 (m, 6H), 0.75 – 0.65 (m, 6H);13C NMR (126 MHz, CDCl3) δ 217.4, 169.4, 134.2, 125.3, 94.7, 76.5, 71.8, 69.2, 65.7, 64.0, 62.4, 58.5, 45.6, 41.8, 41.1, 40.9, 36.7, 34.5, 34.4, 30.3, 26.8, 26.3, 25.0, 20.6, 16.5, 14.8, 11.1, 8.3. Example 31. 22-O-(α-D-manno-pyranosyl)-19,20-dihydropleuromutilin A (TT936) O HO O O O O O OH To a solution of TT935 (43 mg, 0.085 mmol) in tert-butanol (1 mL), acetone (1 mL), and (50 / 50 w / w) N-methylmorpholine N-oxide in H2O (0.2 mL) at RT was carefully added a tiny crystal of solid osmium tetroxide. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was purified via loading directly onto flash column chromatography on silica gel (5:1 DCM:MeOH, Rf= 0.4) to yield TT936 as a colourless oil (11 mg, 24%);1H NMR (500 MHz, MeOD) δ 6.04 (d, J = 8.7 Hz, 1H), 4.83 (m, 1H), 4.29 – 4.09 (m, 2H), 3.88 (dd, J = 3.4, 1.7 Hz, 1H), 3.79 (dd, J = 11.8, 2.2 Hz, 1H), 3.73 – 3.62 (m, 2H), 3.62 – 3.46 (m, 3H), 2.30 – 2.24 (m, 1H), 2.21 – 2.09 (m, 3H), 2.02 (dd, J = 15.8, 8.8 Hz, 1H), 1.75 – 1.34 (m, 12H), 1.17 (ddd, J = 16.7, 12.9, 4.1 Hz, 1H), 1.05 (d, J = 6.5 Hz, 3H), 0.93 (s, 3H), 0.81 – 0.73 (m, 6H);13C NMR (126 MHz, MeOD) δ 219.8, 170.9, 101.4, 76.7, 75.2, 72.3, 71.8, 70.7, 68.4, 65.1, 62.8, 59.4, 46.8, 43.1, 41.9, 41.7, 38.1, 36.0, 35.3, 31.5, 28.1, 26.8, 25.7, 21.3, 17.0, 15.4, 11.8, 8.6. Example 32. 22-O-(b-D-aculo-pyranosyl)-pleuromutilin (TT944) O O O O O OH To a solution of Pleuromutilin (650 mg, 1.72 mmol) and Pyranone B (2.00 g, 8.72 mmol) in THF (15 mL) at RT was added a mixture of Pd2(dba)3^CHCl3 (75 mg, 0.072 mmol) and PPh3(150 mg, 0.57 mmol) in DCM (2 mL). The reaction mixture was stirred at RT for 2h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (1:1 hexane:EtOAc, Rf = 0.5) to yield TT944 as a orange oil (710 mg, 85%);1H NMR (500 MHz, CDCl3) δ 6.97 (dd, J = 10.3, 2.0 Hz, 1H), 6.48 (dd, J = 17.4, 11.0 Hz, 1H), 6.14 (dd, J = 10.3, 1.5 Hz, 1H), 5.82 (d, J = 8.6 Hz, 1H), 5.42 (m, 1H), 5.35 (dd, J = 11.0, 1.6 Hz, 1H), 5.20 (dd, J = 17.4, 1.6 Hz, 1H), 4.24 (d, J = 1.1 Hz, 2H), 4.18 (qd, J = 6.9, 0.8 Hz, 1H), 3.36 (d, J = 6.5 Hz, 1H), 2.33 (dq, J = 6.9, 6.9 Hz, 1H), 2.30 – 2.16 (m, 2H), 2.13 – 2.05 (m, 2H), 1.77 (dq, J = 14.4, 3.2 Hz, 1H), 1.69 – 1.61 (m, 2H), 1.54 (m, 1H), 1.48 – 1.41 (m, 7H), 1.38 (m, 1H), 1.31 (d, J = 16.1 Hz, 1H), 1.19 – 1.08 (m, 4H), 0.88 (dd, J = 7.1, 2.7 Hz, 3H), 0.72 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.0, 196.4, 168.6, 145.5, 138.8, 128.3, 117.4, 94.8, 75.4, 74.6, 69.1, 65.0, 58.1, 45.5, 44.8, 44.0, 41.8, 36.6, 36.1, 34.4, 30.4, 26.9, 26.4, 24.8, 17.3, 16.7, 14.8, 11.5. Example 33. 22-O-(b-D-2,3-dihydro-aculo-pyranosyl)-pleuromutilin (TT950) O O O O O OH To a solution of TT944 in toluene (3 mL) at RT was added (Triphenylphosphine)copper hydride hexamer (20 mg, 0.010 mmol). After stirring for 5 min, polymethylhydrosiloxane (1 mL) was added at RT and the reaction was stirred at RT for 16h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (1:1 hexane:EtOAc, Rf = 0.5) to yield TT950 as a colourless oil (17 mg, 17%);1H NMR (500 MHz, CDCl3) δ 6.50 (dd, J = 17.4, 11.0 Hz, 1H), 5.82 (d, J = 8.4 Hz, 1H), 5.36 (dd, J = 11.0, 1.6 Hz, 1H), 5.21 (dd, J = 17.4, 1.6 Hz, 1H), 5.03 (dd, J = 5.9, 3.5 Hz, 1H), 4.20 (d, J = 2.8 Hz, 2H), 4.05 (q, J = 7.0 Hz, 1H), 3.36 (d, J = 6.5 Hz, 1H), 2.66 (dt, J = 16.8, 6.9 Hz, 1H), 2.42 (ddd, J = 16.7, 8.3, 6.4 Hz, 1H), 2.37 – 2.04 (m, 7H), 1.78 (dq, J = 14.5, 3.1 Hz, 1H), 1.71 – 1.62 (m, 2H), 1.56 (m, 1H), 1.50 – 1.42 (m, 4H), 1.41 – 1.29 (m, 5H), 1.21 – 1.06 (m, 4H), 0.88 (d, J = 7.0 Hz, 3H), 0.73 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 216.9, 209.1, 168.9, 138.8, 117.5, 97.7, 76.2, 74.6, 68.9, 64.8, 58.1, 45.5, 44.8, 44.0, 41.9, 36.7, 36.1, 34.5, 33.4, 30.4, 29.1, 26.9, 26.4, 24.8, 17.1, 16.7, 14.8, 11.5. Example 34. 22-O-(b-D-chloroacetyl-amecito-pyranosyl)pleuromutilin (TT982A) and 22-O-(b-D-chloroacetyl-rhodino-pyranosyl)pleuromutilin (TT982B) O To a mixture of TT944 (1.00 g, 2.05 mmol) and copper(II) acetylacetonate (160 mg, 0.614 mmol) in DCM (10 mL) and MeOH (10 mL) at RT was carefully added NaBH4 (300 mg, 7.93 mmol). The reaction mixture stirred at RT for 1h, at which time the reaction mixture was diluted with DCM (75 mL) and washed with H2O (2 x 50 mL) and brine (2 x 25 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was used in the next reaction without further purification. To the residue (500 mg) in DCM (10 mL) at RT was added chloroacetic anhydride (150 mg, 0.877 mmol) and DMAP (11 mg, 0.088 mmol). The reaction mixture was stirred at RT for 2h, at which time the reaction mixture was diluted with EtOAc (50 mL). The organic phase was washed with 1M HCl (2 x 25 mL), sat. aq. NaHCO3 (3 x 25 mL), H2O (2 x 25 mL), and brine (2 x 25 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (3:2 hexane:EtOAc, Rf = 0.6 TT982A, Rf = 0.5 TT982B) to yield TT982A as a colourless oil (387 mg, 58%) and TT982B as a colourless oil (33 mg, 5%). TT982A 1H NMR (500 MHz, CDCl3) δ 6.46 (m, 1H), 5.78 (t, J = 7.5 Hz, 1H), 5.31 (ddd, J = 11.1, 7.4, 1.5 Hz, 1H), 5.18 (ddd, J = 17.5, 6.5, 1.6 Hz, 1H), 4.55 (ddd, J = 8.6, 5.7, 2.2 Hz, 1H), 4.49 (m, 1H), 4.18 – 4.14 (m, 2H), 4.02 – 4.00 (m, 2H), 3.48 (qd, J = 6.1, 2.6 Hz, 1H), 3.35 (dd, J = 6.6, 4.3 Hz, 1H), 2.32 (q, J = 6.7 Hz, 1H), 2.26 – 1.97 (m, 6H), 1.76 (m, 1H), 1.71 – 1.58 (m, 3H), 1.58 – 1.47 (m, 2H), 1.46 – 1.38 (m, 4H), 1.35 (dq, J = 14.1, 3.4 Hz, 1H), 1.28 (m, 1H), 1.18 (t, J = 6.3 Hz, 3H), 1.16 – 1.06 (m, 4H), 0.85 (t, J = 6.2 Hz, 3H), 0.69 (t, J = 6.6 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.0, 168.9, 166.5, 138.8, 117.4, 100.3, 74.5, 74.5, 73.0, 68.8, 65.1, 58.1, 45.4, 44.7, 43.9, 41.8, 40.8, 36.6, 36.0, 34.4, 30.4, 29.4, 26.8, 26.5, 26.4, 24.8, 18.0, 16.6, 14.8, 11.5. TT982B 1H NMR (500 MHz, CDCl3) δ 6.49 (m, 1H), 5.81 (d, J = 8.7 Hz, 1H), 5.34 (dd, J = 11.0, 1.5 Hz, 1H), 5.20 (dd, J = 17.4, 1.5 Hz, 1H), 4.81 (dt, J = 3.1, 1.8 Hz, 1H), 4.57 (dd, J = 8.9, 2.3 Hz, 1H), 4.27 – 4.16 (m, 2H), 4.11 (dd, J = 7.1, 2.3 Hz, 2H), 3.65 (qd, J = 6.5, 1.4 Hz, 1H), 3.35 (dd, J = 9.9, 6.1 Hz, 1H), 2.34 (dq, J = 6.9, 6.9 Hz, 1H), 2.29 – 2.16 (m, 2H), 2.08 (dd, J = 13.0, 3.3 Hz, 2H), 1.85 – 1.73 (m, 2H), 1.71 – 1.61 (m, 3H), 1.55 (m, 1H), 1.49 – 1.41 (m, 5H), 1.37 (m, 1H), 1.30 (m, 1H), 1.24 (m, 1H), 1.20 – 1.08 (m, 7H), 0.87 (dd, J = 7.0, 1.4 Hz, 3H), 0.72 (dd, J = 7.0, 1.8 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.0, 168.9, 167.2, 138.8, 117.4, 100.9, 74.6, 72.4, 70.5, 68.8, 65.0, 58.1, 45.5, 44.8, 44.0, 41.8, 41.0, 36.7, 36.0, 34.5, 30.4, 26.9, 26.8, 26.4, 25.5, 24.8, 17.0, 16.6, 14.8, 11.5; Example 35. 22-O-(b-D-chloroacetyl-2,3-didehydro-6-deoxy-erytho-hexo- pyranosyl)pleuromutilin (TT983A) and 22-O-(b-D-chloroacetyl-2,3-didehydro-6-deoxy-threo- hexo-pyranosyl)pleuromutilin (TT983B) O To a solution of TT944 (1.00 g, 2.05 mmol) in DCM (10 mL) and 0.4 M CeCl3^(H2O)7in MeOH (10 mL) at –78 ^C was added NaBH4(300 mg, 7.93 mmol). The reaction mixture was allowed to warm to 0 ^C and stirred for 1h, at which time the reaction mixture was diluted with DCM (75 mL) and washed with H2O (2 x 50 mL) and brine (2 x 25 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was used in the next reaction without further purification. To the residue (500 mg) in DCM (10 mL) at RT was added chloroacetic anhydride (150 mg, 0.877 mmol) and DMAP (11 mg, 0.088 mmol). The reaction mixture was stirred at RT for 2h, at which time the reaction mixture was diluted with EtOAc (50 mL). The organic phase was washed with 1M HCl (2 x 25 mL), sat. aq. NaHCO3 (3 x 25 mL), H2O (2 x 25 mL), and brine (2 x 25 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (3:2 hexane:EtOAc, Rf= 0.6 TT983A, Rf= 0.5 TT983B) to yield TT983A as a colourless oil (192 mg, 16%) and TT983B as a colourless oil (143 mg, 12%). TT983A 1H NMR (500 MHz, CDCl3) δ 6.43 (dd, J = 17.4, 11.0 Hz, 1H), 5.99 (dt, J = 10.3, 1.5 Hz, 1H), 5.92 (ddd, J = 10.3, 3.4, 1.7 Hz, 1H), 5.75 (d, J = 8.5 Hz, 1H), 5.28 (dd, J = 11.0, 1.6 Hz, 1H), 5.19 – 5.10 (m, 2H), 5.01 (td, J = 3.6, 1.7 Hz, 1H), 4.17 – 4.08 (m, 2H), 4.06 – 3.98 (m, 2H), 3.86 (m, 1H), 3.32 (d, J = 6.4 Hz, 1H), 2.29 (dq, J = 7.0, 7.0 Hz, 1H), 2.25 – 2.10 (m, 2H), 2.10 – 1.98 (m, 2H), 1.72 (dq, J = 14.5, 3.1 Hz, 1H), 1.60 (tdd, J = 10.8, 7.8, 5.3 Hz, 2H), 1.49 (qd, J = 13.1, 3.6 Hz, 1H), 1.43 – 1.36 (m, 4H), 1.32 (m, 1H), 1.25 (d, J = 6.6 Hz, 3H), 1.18 (m, 1H), 1.10 (s, 4H), 0.82 (d, J = 7.0 Hz, 3H), 0.66 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.1, 168.8, 166.8, 138.9, 130.5, 126.7, 117.3, 94.9, 74.6, 71.0, 70.7, 68.8, 64.4, 58.1, 45.4, 44.8, 43.9, 41.8, 40.8, 36.6, 36.0, 34.4, 30.4, 26.8, 26.4, 24.8, 18.6, 16.7, 14.8, 11.5; TT983B 1H NMR (500 MHz, CDCl3) δ 6.49 (dd, J = 17.4, 11.0 Hz, 1H), 6.12 – 6.04 (m, 2H), 5.81 (d, J = 8.5 Hz, 1H), 5.34 (dd, J = 11.0, 1.6 Hz, 1H), 5.22 – 5.17 (m, 2H), 5.04 (m, 1H), 4.27 – 4.15 (m, 2H), 4.12 – 4.07 (m, 2H), 3.89 (qd, J = 6.5, 2.5 Hz, 1H), 3.35 (d, J = 6.5 Hz, 1H), 2.33 (dq, J = 6.9, 6.9 Hz, 1H), 2.30 – 2.12 (m, 2H), 2.11 – 2.04 (m, 2H), 1.76 (dq, J = 14.5, 3.2 Hz, 1H), 1.70 – 1.61 (m, 2H), 1.54 (m, 1H), 1.48 – 1.40 (m, 4H), 1.36 (m, 1H), 1.28 (m, 1H), 1.24 (d, J = 6.6 Hz, 3H), 1.18 – 1.09 (m, 4H), 0.87 (d, J = 7.0 Hz, 3H), 0.72 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.1, 168.8, 167.2, 138.9, 132.8, 126.6, 117.4, 96.6, 74.6, 69.5, 68.8, 67.8, 64.6, 58.1, 45.5, 44.8, 44.0, 41.8, 40.8, 36.7, 36.0, 34.5, 30.4, 26.9, 26.3, 24.8, 16.7, 16.3, 14.8, 11.5. Example 36. 22-O-(b-D-amecieto-pyranosyl)-pleuromutilin (TT986A) O O O O O OH To a solution of TT982A (100 mg, 0.176 mmol) in THF (3 mL) at RT was added NaHCO3 (100 mg, 1.19 mmol) and tetrabutylammonium iodide (20 mg, 0.054 mmol). After stirring at RT for 5 min, thiourea (70 mg, 0.92 mmol) was added. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf= 0.5) to yield TT986A as a colourless oil (42 mg, 48%);1H NMR (500 MHz, CDCl3) δ 6.49 (dd, J = 17.4, 11.0 Hz, 1H), 5.80 (d, J = 8.5 Hz, 1H), 5.34 (dd, J = 11.0, 1.5 Hz, 1H), 5.20 (dd, J = 17.4, 1.6 Hz, 1H), 4.51 (dd, J = 9.3, 2.2 Hz, 1H), 4.25 – 4.14 (m, 2H), 3.35 (d, J = 6.5 Hz, 1H), 3.30 – 3.18 (m, 2H), 2.34 (dq, J = 6.9, 6.9 Hz, 1H), 2.30 – 2.14 (m, 2H), 2.12 – 2.03 (m, 3H), 2.00 (ddt, J = 13.1, 5.5, 2.6 Hz, 1H), 1.77 (dq, J = 14.5, 3.1 Hz, 1H), 1.70 – 1.52 (m, 4H), 1.52 – 1.41 (m, 5H), 1.37 (m, 1H), 1.30 (d, J = 16.1 Hz, 1H), 1.27 (d, J = 5.9 Hz, 3H), 1.17 – 1.09 (m, 4H), 0.87 (d, J = 7.1 Hz, 3H), 0.72 (d, J = 7.0 Hz, 3H).;13C NMR (126 MHz, CDCl3) δ 217.2, 169.0, 138.8, 117.4, 100.7, 76.0, 74.6, 71.3, 68.7, 65.2, 58.2, 45.4, 44.8, 44.0, 41.8, 36.7, 36.0, 34.5, 30.7, 30.4, 30.3, 26.9, 26.4, 24.8, 18.0, 16.6, 14.8, 11.5.. Example 37. 22-O-(b-D-rhodino-pyranosyl)-pleuromutilin (TT986B) To a solution of TT982B (135 mg, 0.237 mmol) in THF (3 mL) at RT was added NaHCO3 (140 mg, 1.67 mmol) and tetrabutylammonium iodide (30 mg, 0.081 mmol). After stirring at RT for 5 min, thiourea (90 mg, 1.2 mmol) was added. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf= 0.5) to yield TT986B as a colourless oil (26 mg, 22%);1H NMR (500 MHz, CDCl3) δ 6.49 (dd, J = 17.4, 11.0 Hz, 1H), 5.80 (d, J = 8.5 Hz, 1H), 5.34 (dd, J = 10.9, 1.6 Hz, 1H), 5.20 (dd, J = 17.5, 1.7 Hz, 1H), 4.51 (dd, J = 8.8, 2.6 Hz, 1H), 4.19 (s, 2H), 3.57 (qd, J = 6.5, 1.2 Hz, 1H), 3.47 (s, 1H), 3.35 (dd, J = 10.6, 6.5 Hz, 1H), 2.33 (dq, J = 7.0, 7.0 Hz, 1H), 2.29 – 2.14 (m, 2H), 2.13 – 2.01 (m, 3H), 1.98 (dq, J = 13.7, 3.3 Hz, 1H), 1.76 (m, 2H), 1.70 – 1.59 (m, 3H), 1.52 – 1.41 (m, 5H), 1.36 (dq, J = 14.5, 3.5 Hz, 1H), 1.30 (m, 1H), 1.21 (d, J = 6.5 Hz, 3H), 1.15 (m, 4H), 0.87 (d, J = 7.0 Hz, 3H), 0.71 (d, J = 7.0 Hz, 3H).;13C NMR (126 MHz, CDCl3) δ 217.0, 169.1, 138.8, 117.5, 101.3, 74.6, 74.1, 68.7, 66.6, 65.0, 58.2, 45.4, 44.8, 44.0, 41.8, 36.7, 36.0, 34.5, 30.4, 29.4, 26.9, 26.4, 25.0, 24.8, 17.0, 16.6, 14.8, 11.5. Example 38. 22-O-(α-D-2,3-didehydro-6-deoxy-erytho-hexo-pyranosyl)pleuromutilin (TT987A) To a solution of TT983A (92 mg, 0.16) in THF (2 mL) at RT was added NaHCO3(90 mg, 1.1 mmol) and tetrabutylammonium iodide (20 mg, 0.054 mmol). After stirring at RT for 5 min, thiourea (60 mg, 0.79 mmol) was added. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf= 0.5) to yield TT987A as a colourless oil (51 mg, 64%);1H NMR (500 MHz, CDCl3) δ 6.50 (ddd, J = 17.4, 11.0, 3.3 Hz, 1H), 6.00 (ddd, J = 10.2, 2.8, 1.7 Hz, 1H), 5.86 (dt, J = 10.2, 1.6 Hz, 1H), 5.81 (d, J = 8.5 Hz, 1H), 5.35 (dd, J = 11.0, 1.6 Hz, 1H), 5.24 – 5.16 (m, 2H), 4.17 (s, 2H), 3.89 (m, 1H), 3.63 (p, J = 6.4 Hz, 1H), 3.36 (dd, J = 10.4, 6.5 Hz, 1H), 2.35 (dq, J = 6.9, 6.9 Hz, 1H), 2.27 – 2.17 (m, 2H), 2.12 – 2.05 (m, 2H), 1.78 (dq, J = 14.5, 3.2 Hz, 1H), 1.70 – 1.62 (m, 2H), 1.55 (m, 1H), 1.49 – 1.43 (m, 4H), 1.40 – 1.28 (m, 5H), 1.19 – 1.12 (m, 4H), 0.88 (d, J = 7.1 Hz, 3H), 0.73 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.2, 169.0, 138.9, 132.8, 127.9, 117.4, 95.9, 74.6, 74.6, 68.8, 68.1, 64.4, 58.2, 45.4, 44.8, 44.0, 41.8, 36.7, 36.0, 34.5, 30.4, 26.8, 26.4, 24.8, 18.3, 16.7, 14.8, 11.5. Example 39. 22-O-(α-D-2,3-didehydro-6-deoxy-threo-hexo-pyranosyl)pleuromutilin (TT987B) O O O O O OH To a solution of TT983B (153mg, 0.270 mmol) in THF (3 mL) at RT was added NaHCO3 (150 mg, 1.79 mmol) and tetrabutylammonium iodide (30 mg, 0.081 mmol). After stirring at RT for 5 min, thiourea (100 mg, 1.31 mmol) was added. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf= 0.5) to yield TT987B as a colourless oil (69 mg, 52%);1H NMR (500 MHz, CDCl3) δ 6.47 (dd, J = 17.4, 11.0 Hz, 1H), 6.15 (ddd, J = 10.0, 5.0, 1.5 Hz, 1H), 5.88 (d, J = 10.0 Hz, 1H), 5.78 (d, J = 8.5 Hz, 1H), 5.32 (dd, J = 11.0, 1.6 Hz, 1H), 5.18 (dd, J = 17.5, 1.6 Hz, 1H), 5.09 (d, J = 1.8 Hz, 1H), 4.23 – 4.13 (m, 2H), 3.71 – 3.61 (m, 2H), 3.34 (dd, J = 10.4, 6.4 Hz, 1H), 2.31 (dq, J = 6.9, 6.9 Hz, 1H), 2.28 – 2.13 (m, 2H), 2.10 – 2.01 (m, 2H), 1.75 (dq, J = 14.5, 3.1 Hz, 1H), 1.68 – 1.59 (m, 2H), 1.56 (m, 1H), 1.45 – 1.40 (m, 4H), 1.37 – 1.27 (m, 2H), 1.24 (d, J = 6.4 Hz, 3H), 1.16 – 1.07 (m, 4H), 0.85 (d, J = 7.0 Hz, 3H), 0.70 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.1, 169.0, 138.9, 131.8, 129.6, 117.4, 97.4, 74.6, 71.6, 68.9, 65.2, 64.5, 58.1, 45.4, 44.7, 44.0, 41.8, 36.7, 36.0, 34.5, 30.4, 26.9, 26.4, 24.8, 16.7, 16.6, 14.8, 11.5; Example 40. 22-O-(b-L-aculo-pyranosyl)-pleuromutilin (TT938) O O O O O OH To a solution of Pleuromutilin (650 mg, 1.72 mmol) and Pyranone D (2.00 g, 8.72 mmol) in THF (15 mL) at RT was added a mixture of Pd2(dba)3^CHCl3(75 mg, 0.072 mmol) and PPh3 (150 mg, 0.57 mmol) in DCM (2 mL). The reaction mixture was stirred at RT for 2h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (1:1 hexane:EtOAc, Rf= 0.5) to yield TT938 as an orange oil (680 mg, 81%);1H NMR (500 MHz, CDCl3) δ 6.97 (dd, J = 10.3, 2.1 Hz, 1H), 6.50 (dd, J = 17.4, 11.0 Hz, 1H), 6.15 (dd, J = 10.4, 1.5 Hz, 1H), 5.84 (d, J = 8.5 Hz, 1H), 5.44 (t, J = 1.8 Hz, 1H), 5.35 (dd, J = 11.0, 1.6 Hz, 1H), 5.21 (dd, J = 17.4, 1.6 Hz, 1H), 4.31 – 4.19 (m, 3H), 3.36 (d, J = 6.5 Hz, 1H), 2.34 (dq, J = 7.0, 7.0 Hz, 1H), 2.30 – 2.15 (m, 2H), 2.10 (m, 2H), 1.78 (dq, J = 14.6, 3.2 Hz, 1H), 1.72 – 1.62 (m, 2H), 1.55 (qd, J = 13.3, 3.7 Hz, 1H), 1.50 – 1.43 (m, 7H), 1.41 – 1.30 (m, 2H), 1.20 – 1.10 (m, 4H), 0.89 (d, J = 7.0 Hz, 3H), 0.73 (d, J = 7.0 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 216.9, 196.4, 168.5, 145.4, 139.0, 128.3, 117.4, 94.8, 75.4, 74.6, 69.2, 65.2, 58.2, 45.5, 44.8, 44.0, 41.8, 36.7, 36.1, 34.4, 30.4, 26.8, 26.4, 24.9, 17.5, 16.8, 14.9, 11.5. Example 41. 22-O-(b-L-2,3-dihydro-aculo-pyranosyl)-pleuromutilin (TT949) To a solution of TT938 in toluene (3 mL) at RT was added (Triphenylphosphine)copper hydride hexamer (20 mg, 0.010 mmol). After stirring for 5 min, polymethylhydrosiloxane (1 mL) was added at RT and the reaction was stirred at RT for 16h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (1:1 hexane:EtOAc, Rf = 0.5) to yield TT949 as a colorless oil (26 mg, 26%);1H NMR (500 MHz, CDCl3) δ 6.51 (dd, J = 17.4, 11.0 Hz, 1H), 5.83 (d, J = 8.5 Hz, 1H), 5.35 (dd, J = 11.0, 1.6 Hz, 1H), 5.20 (dd, J = 17.4, 1.6 Hz, 1H), 5.04 (dd, J = 5.6, 3.6 Hz, 1H), 4.25 – 4.13 (m, 2H), 4.08 (q, J = 7.0 Hz, 1H), 3.36 (d, J = 6.5 Hz, 1H), 2.67 (ddd, J = 16.7, 7.7, 6.4 Hz, 1H), 2.42 (ddd, J = 16.8, 8.0, 6.3 Hz, 1H), 2.38 – 2.05 (m, 7H), 1.77 (dq, J = 14.6, 3.1 Hz, 1H), 1.70 – 1.62 (m, 2H), 1.55 (qd, J = 13.3, 3.6 Hz, 1H), 1.49 – 1.43 (m, 4H), 1.39 – 1.33 (m, 4H), 1.28 (d, J = 28.0 Hz, 1H), 1.20 – 1.10 (m, 4H), 0.88 (d, J = 6.9 Hz, 3H), 0.73 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 216.1, 208.3, 168.0, 138.1, 116.4, 96.9, 75.4, 73.7, 68.0, 64.2, 57.3, 44.6, 44.0, 43.1, 41.0, 35.9, 35.2, 33.6, 32.4, 29.6, 28.1, 25.9, 25.5, 24.0, 16.5, 15.9, 14.0, 10.6. Example 42. 22-O-(b-L-chloroacetyl-amecito-pyranosyl)pleuromutilin (TT980A) and 22-O-(b-L-chloroacetyl-rhodino-pyranosyl)pleuromutilin (TT980B) O To a mixture of TT938 (1.20 g, 2.46 mmol) and copper(II) acetylacetonate (214 mg, 0.818 mmol) in DCM (12 mL) and MeOH (12 mL) at RT was carefully added NaBH4 (360 mg, 9.52 mmol). The reaction mixture stirred at RT for 1h, at which time the reaction mixture was diluted with DCM (75 mL) and washed with H2O (2 x 50 mL) and brine (2 x 25 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was used in the next reaction without further purification. To the residue (500 mg) in DCM (10 mL) at RT was added chloroacetic anhydride (150 mg, 0.877 mmol) and DMAP (11 mg, 0.088 mmol). The reaction mixture was stirred at RT for 2h, at which time the reaction mixture was diluted with EtOAc (50 mL). The organic phase was washed with 1M HCl (2 x 25 mL), sat. aq. NaHCO3(3 x 25 mL), H2O (2 x 25 mL), and brine (2 x 25 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (3:2 hexane:EtOAc, Rf = 0.6 TT980A, Rf = 0.5 TT980B) to yield TT980A as a colourless oil (296 mg, 46%) and TT980B as a colourless oil (85 mg, 14%). TT980A1H NMR (500 MHz, CDCl3) δ 6.46 (dd, J = 17.4, 11.0 Hz, 1H), 5.77 (d, J = 8.4 Hz, 1H), 5.30 (dd, J = 11.0, 1.6 Hz, 1H), 5.16 (dd, J = 17.4, 1.7 Hz, 1H), 4.55 (dd, J = 8.7, 2.3 Hz, 1H), 4.49 (ddd, J = 10.2, 8.6, 4.6 Hz, 1H), 4.12 (s, 2H), 4.00 (d, J = 0.8 Hz, 2H), 3.50 (dq, J = 8.7, 6.2 Hz, 1H), 3.34 (d, J = 6.5 Hz, 1H), 2.30 (p, J = 6.9 Hz, 1H), 2.26 – 2.10 (m, 3H), 2.09 – 1.95 (m, 3H), 1.77 – 1.45 (m, 6H), 1.45 – 1.36 (m, 4H), 1.36 – 1.24 (m, 2H), 1.18 (d, J = 6.3 Hz, 3H), 1.15 – 1.02 (m, 4H), 0.84 (d, J = 7.0 Hz, 3H), 0.68 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.1, 168.9, 166.6, 139.0, 117.2, 100.7, 74.6, 74.5, 72.9, 68.9, 65.7, 58.2, 45.4, 44.8, 43.9, 41.8, 40.8, 36.7, 36.0, 34.4, 30.4, 29.3, 26.8, 26.4, 26.3, 24.8, 18.1, 16.7, 14.9, 11.5. TT980B 1H NMR (500 MHz, CDCl3) δ 6.52 (dd, J = 17.3, 10.9 Hz, 1H), 5.83 (d, J = 8.4 Hz, 1H), 5.35 (d, J = 10.9 Hz, 1H), 5.21 (m, 1H), 4.82 (d, J = 3.2 Hz, 1H), 4.58 (dd, J = 8.6, 2.3 Hz, 1H), 4.24 – 4.08 (m, 4H), 3.69 (m, 1H), 3.41 (s, 1H), 2.37 (m, 1H), 2.23 (m, 1H), 2.13 – 2.04 (m, 3H), 1.84 – 1.62 (m, 5H), 1.55 (m, 1H), 1.49 – 1.31 (m, 6H), 1.28 – 1.09 (m, 9H), 0.93 – 0.79 (m, 3H), 0.72 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.2, 169.0, 167.2, 139.1, 117.3, 101.4, 74.7, 72.4, 70.5, 68.9, 65.6, 58.2, 45.5, 44.8, 44.0, 41.9, 41.0, 36.8, 36.1, 34.5, 30.4, 26.8, 26.8, 26.3, 25.5, 24.9, 17.0, 16.8, 14.9, 11.6. Example 43. 22-O-(b-L-chloroacetyl-2,3-didehydro-6-deoxy-erytho-hexo- pyranosyl)pleuromutilin (TT981A) and 22-O-(b-L-chloroacetyl-2,3-didehydro-6-deoxy-threo- hexo-pyranosyl)pleuromutilin (TT981B) O To a solution of TT938 (1.20 g, 2.46 mmol) in DCM (12 mL) and 0.4 M CeCl3^(H2O)7in MeOH (12 mL) at –78 ^C was added NaBH4(360 mg, 9.52 mmol). The reaction mixture was allowed to warm to 0 ^C and stirred for 1h, at which time the reaction mixture was diluted with DCM (75 mL) and washed with H2O (2 x 50 mL) and brine (2 x 25 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was used in the next reaction without further purification. To the residue (680 mg) in DCM (12 mL) at RT was added chloroacetyl anhydride (200 mg, 1.17 mmol) and DMAP (14 mg, 0.11 mmol). The reaction mixture was stirred at RT for 2h, at which time the reaction mixture was diluted with EtOAc (50 mL). The organic phase was washed with 1M HCl (2 x 25 mL), sat. aq. NaHCO3 (3 x 25 mL), H2O (2 x 25 mL), and brine (2 x 25 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (3:2 hexane:EtOAc, Rf = 0.6 TT981A, Rf = 0.5 TT981B) to yield TT981A as a colourless oil (190 mg, 17%) and TT981B as a colourless oil (215 mg, 19%). TT981A 1H NMR (500 MHz, CDCl3) δ 6.51 (ddd, J = 17.4, 11.0, 2.0 Hz, 1H), 6.06 (dq, J = 10.3, 1.8 Hz, 1H), 5.99 (ddt, J = 10.3, 3.7, 1.9 Hz, 1H), 5.83 (dd, J = 8.6, 1.9 Hz, 1H), 5.35 (dt, J = 11.0, 2.0 Hz, 1H), 5.26 – 5.17 (m, 2H), 5.08 (ddq, J = 5.2, 3.5, 1.6 Hz, 1H), 4.24 – 4.12 (m, 2H), 4.08 (d, J = 2.0 Hz, 2H), 3.95 (dtd, J = 12.1, 6.0, 2.0 Hz, 1H), 3.36 (d, J = 6.4 Hz, 1H), 2.36 (m, 1H), 2.32 – 2.15 (m, 2H), 2.14 – 2.03 (m, 2H), 1.78 (dt, J = 14.4, 2.9 Hz, 1H), 1.72 – 1.62 (m, 2H), 1.59 – 1.28 (m, 10H), 1.23 – 1.09 (m, 4H), 0.89 (dd, J = 7.1, 2.0 Hz, 3H), 0.73 (dd, J = 7.1, 2.1 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.0, 168.8, 166.9, 139.0, 130.5, 126.6, 117.3, 94.9, 74.6, 71.1, 70.7, 68.9, 64.4, 58.2, 45.5, 44.8, 44.0, 41.8, 40.8, 36.7, 36.1, 34.5, 30.4, 26.8, 26.4, 24.9, 18.7, 16.7, 14.9, 11.5. TT981B 1H NMR (500 MHz, CDCl3) δ 6.50 (dd, J = 17.4, 11.0 Hz, 1H), 6.13 – 6.04 (m, 2H), 5.80 (d, J = 8.5 Hz, 1H), 5.34 (dd, J = 10.9, 1.6 Hz, 1H), 5.25 – 5.17 (m, 2H), 5.06 (m, 1H), 4.19 (s, 2H), 4.12 – 4.08 (m, 2H), 3.92 (qd, J = 6.5, 2.5 Hz, 1H), 3.37 (d, J = 6.4 Hz, 1H), 2.34 (dq, J = 7.0, 7.0 Hz, 1H), 2.30 – 2.14 (m, 2H), 2.13 – 2.05 (m, 2H), 1.77 (dq, J = 14.4, 3.2 Hz, 1H), 1.70 – 1.60 (m, 2H), 1.55 (m, 1H), 1.49 – 1.41 (m, 4H), 1.40 – 1.29 (m, 2H), 1.25 (d, J = 6.5 Hz, 3H), 1.19 – 1.08 (m, 4H), 0.88 (d, J = 7.0 Hz, 3H), 0.70 (d, J = 7.1 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.0, 168.8, 167.2, 139.0, 132.7, 126.8, 117.3, 96.8, 74.6, 69.5, 68.9, 67.7, 64.6, 58.2, 45.5, 44.8, 44.0, 41.8, 40.8, 36.7, 36.0, 34.5, 30.4, 26.8, 26.4, 24.8, 16.8, 16.4, 14.9, 11.5. Example 44. 22-O-(b-L-amecito-pyranosyl)pleuromutilin (TT984A) To a solution of TT980A (112 mg, 0.197 mmol) in THF (2 mL) at RT was added NaHCO3 (110 mg, 0.131 mmol) and tetrabutylammonium iodide (20 mg, 0.054 mmol). After stirring at RT for 5 min, thiourea (80 mg, 1.0 mmol) was added. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf= 0.5) to yield TT984A as a colourless oil (48 mg, 49%);1H NMR (500 MHz, CDCl3) δ 6.48 (dd, J = 17.4, 11.0 Hz, 1H), 5.79 (d, J = 8.5 Hz, 1H), 5.32 (dd, J = 11.0, 1.6 Hz, 1H), 5.17 (dd, J = 17.4, 1.7 Hz, 1H), 4.50 (dd, J = 9.2, 2.2 Hz, 1H), 4.14 (s, 2H), 3.33 (dd, J = 10.4, 6.5 Hz, 1H), 3.28 – 3.19 (m, 2H), 2.32 (dq, J = 6.9, 6.9 Hz, 1H), 2.27 – 2.13 (m, 2H), 2.10 – 2.00 (m, 3H), 2.00 – 1.91 (m, 2H), 1.75 (dq, J = 14.5, 3.1 Hz, 1H), 1.67 – 1.49 (m, 4H), 1.47 – 1.39 (m, 4H), 1.37 – 1.29 (m, 2H), 1.26 (d, J = 5.6 Hz, 3H), 1.16 – 1.06 (m, 4H), 0.85 (d, J = 7.0 Hz, 3H), 0.70 (d, J = 7.0 Hz, 3H).;13C NMR (126 MHz, CDCl3) δ 217.2, 169.0, 139.0, 117.2, 101.2, 76.0, 74.6, 71.2, 68.8, 65.8, 58.2, 45.5, 44.8, 44.0, 41.8, 36.8, 36.1, 34.5, 30.7, 30.4, 30.2, 26.8, 26.4, 24.9, 18.1, 16.8, 14.9, 11.5. Example 45. 22-O-(b-L-rhodino-pyranosyl)pleuromutilin (TT984B) To a solution of TT980B (44 mg, 0.077 mmol) in THF (1 mL) at RT was added NaHCO3(40 mg, 0.48 mmol) and tetrabutylammonium iodide (10 mg, 0.027 mmol). After stirring at RT for 5 min, thiourea (30 mg, 0.39 mmol) was added. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf = 0.5) to yield TT984B as a colourless oil (17 mg, 45%);1H NMR (500 MHz, CDCl3) δ 6.51 (dd, J = 17.4, 11.0 Hz, 1H), 5.82 (d, J = 8.4 Hz, 1H), 5.34 (dd, J = 11.0, 1.6 Hz, 1H), 5.19 (dt, J = 17.4, 1.4 Hz, 1H), 4.52 (dd, J = 8.3, 3.0 Hz, 1H), 4.18 (s, 2H), 3.56 (qd, J = 6.4, 1.2 Hz, 1H), 3.48 (dt, J = 3.5, 1.7 Hz, 1H), 3.35 (dd, J = 10.6, 6.6 Hz, 1H), 2.34 (dq, J = 7.0, 7.0 Hz, 1H), 2.29 – 2.14 (m, 2H), 2.12 – 2.02 (m, 3H), 1.99 (dt, J = 13.6, 3.5 Hz, 1H), 1.78 – 1.62 (m, 5H), 1.51 – 1.41 (m, 5H), 1.39 – 1.30 (m, 2H), 1.23 – 1.21 (m, 3H), 1.19 – 1.08 (m, 4H), 0.87 (d, J = 6.9 Hz, 3H), 0.72 (d, J = 7.0 Hz, 3H).;13C NMR (126 MHz, CDCl3) δ 217.1, 169.0, 139.1, 117.2, 101.8, 74.6, 74.1, 68.8, 66.6, 65.6, 58.2, 45.5, 44.8, 44.0, 41.8, 36.8, 36.1, 34.5, 30.4, 29.4, 26.8, 26.4, 25.0, 24.9, 17.1, 16.8, 14.9, 11.5. Example 46. 22-O-(b-L-2,3-didehydro-6-deoxy-erytho-hexo-pyranosyl)pleuromutilin (TT985A) To a solution of TT981A (99 mg, 0.17 mmol) in THF (2 mL) at RT was added NaHCO3(100 mg, 1.19 mmol) and tetrabutylammonium iodide (20 mg, 0.054 mmol). After stirring at RT for 5 min, thiourea (70 mg, 0.92 mmol) was added. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf = 0.5) to yield TT985A as a colorless oil (59 mg, 69%);1H NMR (500 MHz, CDCl3) δ 6.48 (dd, J = 17.4, 11.0 Hz, 1H), 5.98 (ddd, J = 10.2, 2.9, 1.7 Hz, 1H), 5.83 (dt, J = 10.2, 1.7 Hz, 1H), 5.79 (d, J = 8.5 Hz, 1H), 5.32 (dd, J = 11.0, 1.6 Hz, 1H), 5.22 – 5.14 (m, 2H), 4.19 – 4.05 (m, 2H), 3.85 (d, J = 6.6 Hz, 1H), 3.63 (p, J = 6.4 Hz, 1H), 3.33 (dd, J = 10.6, 6.5 Hz, 1H), 2.32 (dq, J = 7.0, 7.0 Hz, 1H), 2.28 – 2.16 (m, 2H), 2.09 – 2.01 (m, 2H), 1.75 (dq, J = 14.5, 3.1 Hz, 1H), 1.67 – 1.59 (m, 2H), 1.52 (m, 1H), 1.47 – 1.40 (m, 4H), 1.37 – 1.28 (m, 5H), 1.15 – 1.06 (m, 4H), 0.86 (d, J = 7.0 Hz, 3H), 0.70 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.2, 169.0, 139.0, 132.8, 127.8, 117.3, 95.9, 74.6, 74.6, 68.8, 68.0, 64.4, 58.2, 45.5, 44.8, 44.0, 41.8, 36.7, 36.0, 34.5, 30.4, 26.8, 26.4, 24.8, 18.4, 16.7, 14.9, 11.5. Example 47. 22-O-(b-L-2,3-didehydro-6-deoxy-threo-hexo-pyranosyl)pleuromutilin (TT985B) To a solution of TT981B (177 mg, 0.312 mmol) in THF (4 mL) at RT was added NaHCO3(180 mg, 2.14 mmol) and tetrabutylammonium iodide (30 mg, 0.081 mmol). After stirring at RT for 5 min, thiourea (120 mg, 1.58 mmol) was added. The reaction mixture was stirred at RT for 16h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:3 hexane:EtOAc, Rf = 0.5) to yield TT985B as a colorless oil (112 mg, 73%);1H NMR (500 MHz, CDCl3) δ 6.49 (dd, J = 17.4, 11.0 Hz, 1H), 6.17 (ddd, J = 10.0, 5.0, 1.5 Hz, 1H), 5.88 (dd, J = 10.1, 1.2 Hz, 1H), 5.80 (d, J = 8.4 Hz, 1H), 5.32 (dd, J = 11.0, 1.7 Hz, 1H), 5.18 (dd, J = 17.4, 1.7 Hz, 1H), 5.12 (q, J = 1.5 Hz, 1H), 4.18 (s, 2H), 3.71 (qd, J = 6.5, 2.1 Hz, 1H), 3.66 (d, J = 6.5 Hz, 1H), 3.35 (dd, J = 10.5, 6.5 Hz, 1H), 2.32 (dq, J = 7.0, 7.0 Hz, 1H), 2.29 – 2.13 (m, 2H), 2.09 – 2.05 (m, 2H), 1.76 (dq, J = 14.5, 3.1 Hz, 1H), 1.68 – 1.60 (m, 2H), 1.54 (m, 1H), 1.48 – 1.41 (m, 4H), 1.39 – 1.24 (m, 5H), 1.17 – 1.08 (m, 4H), 0.87 (d, J = 7.0 Hz, 3H), 0.71 (d, J = 7.0 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 217.1, 168.9, 139.0, 132.0, 129.6, 117.3, 97.6, 74.6, 71.6, 69.0, 65.4, 64.6, 58.2, 45.5, 44.8, 44.0, 41.8, 36.7, 36.1, 34.5, 30.4, 26.8, 26.4, 24.9, 16.8, 16.6, 14.9, 11.6. Example 48. 19-bromo-Pleuromutilin A (TT954) and 20-iso-bromo-Pleuromutilin A (TT955) O To a solution of Pleuromutilin (3.00 g, 7.94 mmol) DCM (100 mL) at RT was added N- bromosuccinimide (2.83 g, 15.9 mmol). The reaction mixture was stirred at RT for 36h, at which time the reaction mixture was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel (2:1 hexane:EtOAc, Rf = 0.5 TT954, Rf = 0.4 TT955) to yield TT954 as a colorless oil (1.30 g, 36%) and TT955 as a colourless oil (1.51 g, 42%). TT954 1H NMR (500 MHz, CDCl3) δ 5.63 (d, J = 9.1 Hz, 1H), 4.89 (t, J = 8.6 Hz, 1H), 4.26 (t, J = 9.1 Hz, 1H), 4.17 – 4.02 (m, 2H), 3.92 (dd, J = 9.5, 8.3 Hz, 1H), 3.71 (d, J = 10.5 Hz, 1H), 2.31 – 2.20 (m, 3H), 2.05 – 1.96 (m, 1H), 1.83 (d, J = 2.6 Hz, 1H), 1.78 (dq, J = 14.5, 3.1 Hz, 1H), 1.73 – 1.57 (m, 3H), 1.53 – 1.35 (m, 6H), 1.19 (s, 3H), 1.13 (td, J = 14.0, 4.6 Hz, 1H), 0.95 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 7.1 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 216.7, 172.6, 83.0, 70.3, 68.6, 61.2, 58.1, 53.5, 47.0, 44.8, 42.1, 38.3, 37.2, 36.9, 34.4, 31.0, 27.2, 26.7, 25.1, 17.1, 15.5, 13.0 TT955 1H NMR (500 MHz, CDCl3) δ 6.04 (d, J = 10.3 Hz, 1H), 5.18 (t, J = 7.2 Hz, 1H), 4.16 – 4.01 (m, 2H), 3.89 (d, J = 11.5 Hz, 1H), 3.41 (dd, J = 7.3, 2.8 Hz, 2H), 2.84 (dq, J = 12.6, 6.4 Hz, 1H), 2.23 (dd, J = 9.8, 6.3 Hz, 2H), 1.89 (dd, J = 16.0, 10.4 Hz, 1H), 1.77 (dq, J = 14.2, 2.9 Hz, 1H), 1.63 – 1.50 (m, 6H), 1.46 (s, 3H), 1.45 – 1.36 (m, 4H), 1.14 (td, J = 13.7, 4.4 Hz, 1H), 0.98 (d, J = 6.3 Hz, 3H), 0.78 (d, J = 6.5 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 216.5, 172.5, 91.7, 80.5, 69.8, 61.2, 58.8, 44.2, 42.4, 41.7, 41.5, 38.1, 38.0, 34.6, 30.6, 29.1, 26.7, 25.6, 23.9, 17.4, 16.3, 12.1. Example 49. 22-O-(E)-3’-(3”,4”-didimethyl-tert-butylsiloxyphenyl)acryloyl)pleuromutilin (WY- N2143-P-TBS-CA) TBS-Caffeic Acid (287.4 mg, 0.532 mmol, 1.2 equiv) and DMAP (5.5 mg, 0.044 mmol, 0.1 equiv) were dissolved in dry dichloromethane (1.0 mL) and cooled to 0^°C, followed by addition of EDCI (106.2 mg, 0.554 mmol, 1.25 equiv). After stirring at 0^°C for 10 min, pleuromutilin (167.7 mg, 0.443 mmol, 1.0 equiv) was added directly as a solid, and the reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction crude was diluted by ethyl acetate, purified by extraction with 1 M HCl (1.5 mL), sat. NaHCO3 (1.5 mL), and brine (1.5 mL), dried over Na2SO4, and evaporated under reduced pressure. The crude extract was purified by column chromatography (17.5% Ethyl acetate / Hexane) to afford white crystalline solid P-TBS-CA (302.4 mg, 92%). Rf=0.5 (30% ethyl acetate in hexane).1H NMR (500 MHz, CDCl3) δ 7.59 (dd, J = 8.4, 2.2 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.49 (dd, J = 17.4, 11.0 Hz, 1H), 5.81 (d, J = 8.5 Hz, 1H), 5.35 (dd, J = 11.0, 1.5 Hz, 1H), 5.22 (dd, J = 17.4, 1.5 Hz, 1H), 4.77 (d, J = 15.7 Hz, 1H), 4.65 (d, J = 16.0 Hz, 1H), 3.35 (dd, J = 10.4, 6.5 Hz, 1H), 2.32 (h, J = 7.3 Hz, 1H), 2.27 – 2.22 (m, 1H), 2.18 (dd, J = 19.4, 9.3 Hz, 1H), 2.11 – 2.02 (m, 2H), 1.76 (dq, J = 14.6, 3.1 Hz, 1H), 1.69 – 1.62 (m, 2H), 1.59 (d, J = 3.2 Hz, 1H), 1.53 (td, J = 13.2, 3.7 Hz, 1H), 1.45 (ddd, J = 12.5, 9.3, 3.3 Hz, 2H), 1.39 (s, 3H), 1.36 (d, J = 3.8 Hz, 1H), 1.25 (d, J = 2.0 Hz, 1H), 1.18 (s, 3H), 1.14 (dd, J = 14.3, 4.5 Hz, 1H), 0.99 (s, 9H), 0.98 (s, 9H), 0.87 (d, J = 7.2 Hz, 3H), 0.79 (d, J = 7.1 Hz, 3H), 0.23 (s, 6H), 0.21 (s, 6H).13C NMR (126 MHz, CDCl3) δ 216.96, 166.91, 165.42, 152.16, 146.76, 138.80, 124.04, 122.53, 122.27, 120.54, 117.35, 74.59, 69.54, 61.52, 58.11, 45.44, 44.54, 44.02, 41.85, 36.71, 36.02, 34.45, 30.42, 26.83, 26.34, 25.88, 25.84, 24.82, 18.51, 18.41, 16.68, 14.77, 11.45, -4.06, -4.16. Example 50. 22-O-(E)-3’-(3”,4”-dihydroxyphenyl)acryloyl)pleuromutilin (WY-N2134-P-CA) To a solution of the WY-N2143-P-TBS-CA (142.5 mg, 0.185 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (THF, 2.0 mL) was added tetra-n-butylammonium fluoride (TBAF, 1.0 M in THF, 0.81 mL, 0.81 mmol, 4.4 equiv) under a nitrogen atmosphere at room temperature. The reaction mixture was stirred for 1 h, and the progress was monitored by thin- layer chromatography (TLC, 60% ethyl acetate / hexanes, Rf = 0.50 for the product). Upon completion, the reaction was quenched with saturated aqueous ammonium chloride (3 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (2% MeOH in dichloromethane) to afford the deprotected alcohol (90.9 mg, 0.168 mmol, 90.9%) as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 15.9 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 8.3, 2.0 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.49 (s, 1H), 6.47 (dd, J = 17.4, 11.0 Hz, 1H), 6.33 (s, 1H), 6.26 (d, J = 15.9 Hz, 1H), 5.80 (d, J = 8.5 Hz, 1H), 5.34 (dd, J = 11.0, 1.5 Hz, 1H), 5.21 (dd, J = 17.4, 1.5 Hz, 1H), 4.69 (d, J = 16.1 Hz, 1H), 4.60 (d, J = 16.1 Hz, 1H), 3.37 (dd, J = 10.4, 6.5 Hz, 1H), 2.33 (p, J = 7.1 Hz, 1H), 2.28 – 2.23 (m, 1H), 2.19 (dd, J = 19.5, 9.3 Hz, 1H), 2.11 (d, J = 2.6 Hz, 1H), 2.10 – 2.06 (m, 1H), 1.81 – 1.75 (m, 1H), 1.68 – 1.63 (m, 1H), 1.61 – 1.56 (m, 1H), 1.56 – 1.45 (m, 1H), 1.45 (s, 3H), 1.38 (dd, J = 16.5, 3.1 Hz, 1H), 1.25 (d, J = 2.2 Hz, 1H), 1.18 (s, 3H), 1.13 (td, J = 14.1, 4.5 Hz, 1H), 0.97 (t, J = 7.3 Hz, 1H), 0.88 (d, J = 7.0 Hz, 3H), 0.79 (d, J = 7.1 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 217.8, 167.6, 166.8, 147.0, 146.7, 144.3, 138.7, 127.2, 122.8, 117.7, 115.6, 114.4, 113.9, 74.8, 70.1, 61.5, 58.3, 45.6, 44.7, 44.2, 42.0, 36.9, 36.1, 34.6, 30.6, 26.9, 26.5, 25.0, 16.8, 15.0, 11.7. Example 51. 22-O-(benzoyl)pleuromutilin (AA-280) In a 5 mL flask, dissolve Pleuromutilin (100 mg, 0.264 mmol) in 1 ml of dry dichloromethane. Followed by the addition of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (60.8 mg, 0.317 mmol) and N,N-dimethylpyridin-4-amine (1.3 mg, 0.026 mmol) at 0 ^C. After stirring for a few minutes, then follow the addition of benzoic acid (38 mg, 0.317 mmol). The solution was stirred for 24 hr at rt and monitored by TLC, until the reaction was complete. The mixture was filter and washed by Dichloromethane then concentrated under reduced pressure. The crude product was purified using column chromatography eluting with 20-30% EtOAc / hexane to give 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3- oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl benzoate as colorless oil (109 mg, 0.226 mmol, 85%). Rf (50% EtOAc / hexane) = 0.5; 1H NMR (500 MHz, CDCl3) δ 1H NMR (500 MHz, CDCl3) δ 8.09 (dd, J = 8.3, 1.4 Hz, 1H), 7.56 (tt, J = 6.9, 1.4 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 6.49 (dd, J = 17.4, 11.0 Hz, 1H), 5.82 (d, J = 8.5 Hz, 1H), 5.35 (dd, J = 11.0, 1.5 Hz, 1H), 5.22 (dd, J = 17.4, 1.5 Hz, 1H), 4.82 (d, J = 15.9 Hz, 1H), 4.71 (d, J = 16.0 Hz, 1H), 3.36 (dd, J = 10.7, 6.5 Hz, 1H), 2.32 (dq, J = 11.8, 6.0 Hz, 1H), 2.28 – 2.18 (m, 2H), 2.12 – 2.03 (m, 2H), 1.77 (dq, J = 14.5, 3.2 Hz, 1H), 1.73 – 1.58 (m, 2H), 1.55 (s, 3H), 1.49 – 1.36 (m, 1H), 1.41 (s, 4H), 1.18 (s, 5H), 1.12 (dd, J = 14.1, 4.5 Hz, 1H), 0.87 (d, J = 7.1 Hz, 3H), 0.81 (d, J = 7.0 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 217.34, 167.12, 166.21, 139.18, 133.84, 130.29, 129.60, 128.87, 117.82, 74.99, 70.12, 62.09, 58.51, 45.86, 44.98, 44.45, 42.28, 37.12, 36.44, 34.86, 30.83, 27.24, 26.75, 25.23, 17.10, 15.18, 11.86.

[0010] Example 52. 22-O-(nicotinoyl)pleuromutilin (AA-281) In a 5 mL flask, dissolve Pleuromutilin (100 mg, 0.264 mmol) in 1 ml of dry dichloromethane. Followed by the addition of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (60.8 mg, 0.317 mmol) and N,N-dimethylpyridin-4-amine (1.3 mg, 0.026 mmol) at 0 ^C. After stirring for a few minutes, then follow the addition of nicotinic acid (39 mg, 0.317 mmol). The solution was stirred for 24 hr at rt and monitored by TLC, until the reaction was complete. The mixture was filter and washed by Dichloromethane then concentrated under reduced pressure. The crude product was purified using column chromatography eluting with 30-40% EtOAc / hexane to give 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3- oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl nicotinate as colorless oil (112 mg, 0.232 mmol, 87%). Rf (50% EtOAc / hexane) = 0.3;1H NMR (500 MHz, CDCl3) δ 9.28 (d, J = 2.2 Hz, 1H), 8.81 (dd, J = 4.9, 1.8 Hz, 1H), 8.34 (dt, J = 7.9, 2.0 Hz, 1H), 7.42 (dd, J = 8.0, 4.9 Hz, 1H), 6.47 (dd, J = 17.4, 11.0 Hz, 1H), 5.83 (d, J = 8.5 Hz, 1H), 5.35 (dd, J = 10.9, 1.5 Hz, 1H), 5.22 (dd, J = 17.4, 1.5 Hz, 1H), 4.84 (d, J = 15.9 Hz, 1H), 4.74 (d, J = 15.9 Hz, 1H), 3.36 (dd, J = 10.7, 6.5 Hz, 1H), 2.37 – 2.27 (m, 1H), 2.26 – 2.15 (m, 2H), 2.10 (s, 2H), 1.77 (dq, J = 14.5, 3.2 Hz, 1H), 1.66 (ddt, J = 13.6, 11.0, 6.8 Hz, 2H), 1.57 (s, 4H), 1.48 – 1.35 (m, 6H), 1.19 (s, 3H), 1.14 (td, J = 14.1, 4.4 Hz, 1H), 0.87 (d, J = 7.0 Hz, 3H), 0.81 (d, J = 7.1 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 217.25, 166.71, 164.96, 154.32, 151.58, 139.12, 137.70, 125.60, 123.78, 117.87, 74.98, 70.40, 62.27, 58.47, 45.85, 45.02, 44.45, 42.28, 37.07, 36.45, 34.84, 30.80, 27.23, 26.78, 25.23, 17.08, 15.16, 11.86. Example 53. 22-O-(picolinoyl)pleuromutilin (AA-283) In a 5 mL flask, dissolve Pleuromutilin (100 mg, 0.264 mmol) in 1 ml of dry dichloromethane. Followed by the addition of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (60.8 mg, 0.317 mmol) and N,N-dimethylpyridin-4-amine (1.3 mg, 0.026 mmol) at 0 ^C. After stirring for a few minutes, then follow the addition of picolinic acid (39 mg, 0.317 mmol). The solution was stirred for 24 hr at rt and monitored by TLC, until the reaction was complete. The mixture was filter and washed by Dichloromethane then concentrated under reduced pressure. The crude product was purified using column chromatography eluting with 30-40% EtOAc / hexane to give 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro- 4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl picolinate white solid (120 mg, 0.249 mmol, 93%). Rf (60% EtOAc / hexane) = 0.3;1H NMR (500 MHz, CDCl3) δ 8.78 (ddd, J = 4.7, 1.8, 0.9 Hz, 1H), 8.18 (dt, J = 8.0, 1.0 Hz, 1H), 7.87 (td, J = 7.8, 1.8 Hz, 1H), 7.51 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 6.46 (dd, J = 17.4, 11.0 Hz, 1H), 5.83 (d, J = 8.5 Hz, 1H), 5.33 (dd, J = 11.0, 1.5 Hz, 1H), 5.21 (dd, J = 17.4, 1.5 Hz, 1H), 4.89 (d, J = 15.9 Hz, 1H), 4.80 (d, J = 15.9 Hz, 1H), 3.35 (dd, J = 10.6, 6.5 Hz, 1H), 2.32 (p, J = 6.5 Hz, 1H), 2.29 – 2.15 (m, 2H), 2.10 (s, 2H), 1.77 (dq, J = 14.4, 3.2 Hz, 1H), 1.72 – 1.61 (m, 2H), 1.56 (s, 5H), 1.50 – 1.34 (m, 6H), 1.22 – 1.11 (m, 4H), 0.87 (d, J = 7.1 Hz, 3H), 0.80 (d, J = 7.1 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 216.83, 166.13, 164.29, 149.92, 147.04, 138.59, 136.97, 127.21, 125.42, 117.33, 74.47, 69.76, 62.11, 57.98, 45.34, 44.51, 43.91, 41.76, 36.60, 35.92, 34.35, 30.31, 26.70, 26.27, 24.72, 16.56, 14.63, 11.34. Example 54. 22-O-(pyrazine-2-carboxyl)pleuromutilin (AA-284) In a 5 mL flask, dissolve Pleuromutilin (100 mg, 0.264 mmol) in 1 ml of dry dichloromethane. Followed by the addition of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (60.8 mg, 0.317 mmol) and N,N-dimethylpyridin-4-amine (1.3 mg, 0.026 mmol) at 0 ^C. After stirring for a few minutes, then follow the addition of pyrazine-2-carboxylic acid (39 mg, 0.317 mmol). The solution was stirred for 24 hr at rt and monitored by TLC, until the reaction was complete. The mixture was filter and washed by Dichloromethane then concentrated under reduced pressure. The crude product was purified using column chromatography eluting with 30-40% EtOAc / hexane to give 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12- tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl pyrazine-2-carboxylate white solid (122 mg, 0.252 mmol, 85%). Rf (60% EtOAc / hexane) = 0.45;1H NMR (500 MHz, CDCl3) δ 9.36 (d, J = 1.5 Hz, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.76 (dd, J = 2.4, 1.5 Hz, 1H), 6.45 (dd, J = 17.4, 11.0 Hz, 1H), 5.84 (d, J = 8.5 Hz, 1H), 5.34 (dd, J = 11.0, 1.5 Hz, 1H), 5.21 (dd, J = 17.4, 1.5 Hz, 1H), 4.91 (d, J = 15.8 Hz, 1H), 4.83 (d, J = 15.8 Hz, 1H), 3.35 (dd, J = 10.5, 6.5 Hz, 1H), 2.32 (p, J = 6.5 Hz, 1H), 2.29 – 2.15 (m, 2H), 2.10 (s, 2H), 1.77 (dq, J = 14.4, 3.2 Hz, 1H), 1.72 – 1.61 (m, 2H), 1.56 (s, 5H), 1.50 – 1.34 (m, 6H), 1.22 – 1.11 (m, 4H), 0.87 (d, J = 7.1 Hz, 3H), 0.80 (d, J = 7.1 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 216.74, 165.76, 163.10, 148.01, 146.44, 144.47, 142.50, 138.53, 117.40, 74.46, 70.05, 62.27, 57.95, 45.33, 44.52, 43.92, 41.77, 36.55, 35.93, 34.33, 30.29, 26.70, 26.29, 24.72, 16.55, 14.62, 11.35. Example 55. 22-O-(oxazole-4-carboxylate)pleuromutilin (AA-286) In a 5 mL flask, dissolve Pleuromutilin (100 mg, 0.264 mmol) in 1 ml of dry dichloromethane. Followed by the addition of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (60.8 mg, 0.317 mmol) and N,N-dimethylpyridin-4-amine (1.3 mg, 0.026 mmol) at 0 ^C. After stirring for a few minutes, then follow the addition of oxazole-4-carboxylic acid (39 mg, 0.317 mmol). The solution was stirred for 24 hr at rt and monitored by TLC, until the reaction was complete. The mixture was filter and washed by Dichloromethane then concentrated under reduced pressure. The crude product was purified using column chromatography eluting with 30-40% EtOAc / hexane to give 2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12- tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl oxazole-4-carboxylate as colorless oil (119 mg, 0.252 mmol, 85%). Rf (60% EtOAc / hexane) = 0.36;1H NMR (500 MHz, CDCl3) δ 8.34 (d, J = 1.0 Hz, 1H), 7.95 (d, J = 1.0 Hz, 1H), 6.45 (dd, J = 17.4, 11.0 Hz, 1H), 5.81 (d, J = 8.5 Hz, 1H), 5.34 (dd, J = 11.0, 1.5 Hz, 1H), 5.21 (dd, J = 17.4, 1.5 Hz, 1H), 4.80 (d, J = 15.9 Hz, 1H), 4.71 (d, J = 15.9 Hz, 1H), 3.35 (dd, J = 10.6, 6.5 Hz, 1H), 2.32 (p, J = 6.5 Hz, 1H), 2.29 – 2.15 (m, 2H), 2.10 (s, 2H), 1.77 (dq, J = 14.4, 3.2 Hz, 1H), 1.72 – 1.61 (m, 2H), 1.56 (s, 5H), 1.50 – 1.34 (m, 6H), 1.22 – 1.11 (m, 4H), 0.87 (d, J = 7.1 Hz, 3H), 0.80 (d, J = 7.1 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 217.29, 166.52, 160.38, 151.96, 145.18, 139.07, 132.75, 117.87, 74.97, 70.35, 61.97, 58.47, 45.84, 44.99, 44.42, 42.26, 37.07, 36.43, 34.84, 30.80, 27.20, 26.78, 25.22, 17.04, 15.13, 11.86. As used herein, "consisting essentially of" allows the inclusion of materials or steps that do not materially affect the basic and novel characteristics of the claim. Any recitation herein of the term "comprising", particularly in a listing of components of a composition or elements of a device, constitutes inclusion of alternative embodiments in which “comprising” is replaced with "consisting essentially of" or "consisting of". While the present invention has been described in conjunction with certain preferred embodiments, one of ordinary skill, after reading the foregoing specification, will be able to effect various changes, substitutions of equivalents, and other alterations to the compositions and methods set forth herein. References 1. Moyes, R. B.; Reynolds, J.; Curr. Protoc. Microbiol.2009, 15, 3. 2. WHO Bacterial Priority Pathogens List, 2024. Geneva: World Health Organization; 2024. 3. Kavanagh, F.; Hervey, A.; Robbins, W. J. Proc. Natl. Acad. Sci. USA.1951, 37(9), 570- 574. 4. Sader, H. S.; Biedenbach, D. J.; Paukner, S.; Ivezic-Schoenfeld, Z.; Jones, R. N. Antimicrob. Agents Chemother.2012, 56(3), 1619-1623. 5. Davidovich, C.; Bashan, A.; Auerbach-Nevo, T.; Yaggie, R. D.; Gontarek, R. R.; Yonath, A. Proc. Natl. Acad. Sci. USA.2007, 104(11), 4291-4296. 6. Guppi, S. R. et al. Org. Lett.2006, 8, 293-296. 7. Smith KP, Kirby JE. Verification of an Automated, Digital Dispensing Platform for At-Will Broth Microdilution-Based Antimicrobial Susceptibility Testing. J Clin Microbiol.2016 Sep;54(9):2288-93. doi: 10.1128 / JCM.00932-16. 8. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, 12th ed (CLSI Standard M07). Wayne, PA: Clinical and Laboratory Standards Institute; 2024. 9. Morgan CE, Kang YS, Green AB, Smith KP, Dowgiallo MG, Miller BC, Chiaraviglio L, Truelson KA, Zulauf KE, Rodriguez S, Kang AD, Manetsch R, Yu EW, Kirby JE. Streptothricin F is a bactericidal antibiotic effective against highly drug-resistant gram- negative bacteria that interacts with the 30S subunit of the 70S ribosome. PLoS Biol.2023 May 16;21(5):e3002091. doi: 10.1371 / journal.pbio.3002091. 10. Chiaraviglio L, Kirby JE. Evaluation of impermeant, DNA-binding dye fluorescence as a real-time readout of eukaryotic cell toxicity in a high throughput screening format. Assay Drug Dev Technol.2014 May;12(4):219-28. doi: 10.1089 / adt.2014.577.

Claims

CLAIMS What is claimed is:

1. An antibiotic compound having a structure of:; wherein for Formulas I, Va, Vb, and Vc, T is O, S, NR, or CR2, wherein R is H, alkyl, hydroxyalkyl, aminoalkyl, or perfluoroalkyl, (S or R); wherein for Formulas IIa, IIb, IIc, III, and IV, W is H, OH, halogen, OR, N3, NRH, or NR2, wherein R is H, alkyl, hydroxyalkyl, aminoalkyl, or perfluoroalkyl, (S or R); wherein T is O, S, NR, or CR2, wherein R is H, alkyl, hydroxyalkyl, aminoalkyl, or perfluoroalkyl, (S or R); wherein for any of Formulas I, IIa, IIb, IIc, III, IV, Va, Vb, or Vc shown above the Linker is selected from the group consisting of: CO(CHCH)ntrans or cis, n = 1-10; (CH2)n, n = 1-10; (CHCH)n cis or trans, n = 1-10; CO(CH2)n, n = 0-10; ; (CH2CH2O)n, n = 1-10; CO(CH2CH2O)n, n = 1-10; no linker; and wherein for any of Formulas I, IIa, IIb, IIc, III, IV, Va, Vb, or Vc shown above the Modifier is selected from the group consisting of:a.

2. The antibiotic compound of claim 1, wherein the compound has the structure of Formula I, and wherein T is not S.

3. The antibiotic compound of claim 1, wherein the compound has the structure of Formula I, wherein T is S, and wherein the Modifier is selected from the group consisting of:.

4. The antibiotic compound of claim 1 or claim 2, wherein the Modifier is selected from the group consisting of:

5. The antibiotic compound of claim 1 which is selected from the group consisting of:O O O O OO O O O O OO O O OOOc-08.

6. The antibiotic compound of claim 5 which is selected from the group consisting of: TT-901, TT-906, TT-907, TT-916, TT-902, TT-905, TT-908, TT915, TT918, , TT921, TT928, TT935, TT938, TT994, TT946, TT947, TT949, TT950, TT984A, TT984B, TT985A, TT985B, TT986A, TT986B, TT987A, TT987B, TT-1016, TT1017, TT1019, TT1020, TT-1021, TT1022B, TT1022A, and AA-deboc-08.

7. The antibiotic compound of claim 1 which is selected from the group consisting of:

8. The antibiotic compound of claim 7 which is selected from the group consisting of: AA-283, AA-287, AA-289, AA-289-deboc, AA-290-deboc, AA-291, AA-292, AA-293, AA-294, AA-deboc-291, AA-deboc-292, AA-deboc-293, AA-deboc-294, AA-deboc-02, AA-deboc-03, AA-deboc-04, AA-deboc-05, AA-deboc-09, AA-10, AA-11, AA-12, AA-13, AA-14, WY-N2-134-P-CA, WY-N2-136-P-HCA, WY-N2-139-P-DOPAC, and WY-N2-132-P-PCA.

9. The antibiotic compound of any of the preceding claims, wherein the compound is at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% enantiomerically pure.

10. The antibiotic compound of any of the preceding claims, wherein the compound exhibits antibiotic a minimum inhibitory concentration (MIC) for inhibiting the growth of bacteria of less than about 50µM, less than about 20µM, less than about 10µM, less than about 5µM, or less than about 1µM.

11. The antibiotic compound of claim 10, wherein said MIC is for inhibiting the growth of bacteria selected from the group consisting of Enterobacterales, including Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella aerogenes, Enterobacter cloacae, Citrobacter, Salmonella species, Shigella species, Serratia marcesens, Proteus mirabilis, Proteus vulgaris, and Yersinia pestis; Pseudomonas aeruginosa; Acinetobacter baumannii; Stenotrophomonas maltiphilia; Streptococcus pneumonia; Hemophilus influenza; Staphylococcus aureus; coagulase negative Staphylococcus species; Moraxella catarrhalis; Legionella species; Chlamydia pneumonia; Mycoplasma pneumonia; Streptococcus pyogenes; Enterococcus faecium; Enterococcus faecalis; Bacillus anthracis; Francisellatularensis; Brucella species; Neisseria gonorrhoeae; Chlamydia trachomatis; and Mycoplasma genitalium.

12. The antibiotic compound of any of the preceding claims, wherein the compound selectively inhibits cytotoxicity for bacterial over eukaryotic or mammalian cells at a ratio of at least 5, 10, 20, 30, 50, or 100.

13. The antibiotic compound of any of the preceding claims, wherein the compound selectively inhibits protein synthesis at bacterial ribosomes over protein synthesis at eukaryotic ribosomes at a ratio of at least 10, 20, 30, 50, 100, 300, 500, or 1000 based upon IC50 values using an E. coli in vitro translation assay vs. a rabbit reticulocyte in vitro translation assay.

14. The antibiotic compound of any of the preceding claims that binds to bacterial 23S ribosomal RNA.

15. The antibiotic compound of any of the preceding claims that has siderophore activity.

16. The antibiotic compound of any of the preceding claims that is taken up as a complex with iron into bacterial cells via their ATP-binding cassette transporters.

17. The antibiotic compound of any of the preceding claims that inhibits the survival and / or growth of bacterial cells in vitro or in vivo, such as in a bacterial cell culture, in a mammalian cell culture, or in an animal model of bacterial infection.

18. The antibiotic compound of claim 15, wherein the bacteria whose survival and / or growth are inhibited by the compound are selected from the group consisting of Enterobacterales, including Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella aerogenes, Enterobacter cloacae, Citrobacter, Salmonella species, Shigella species, Serratia marcesens, Proteus mirabilis, Proteus vulgaris, and Yersinia pestis; Pseudomonas aeruginosa; Acinetobacter baumannii; Stenotrophomonas maltiphilia; Streptococcus pneumonia; Hemophilus influenza; Staphylococcus aureus; coagulase negative Staphylococcus species; Moraxella catarrhalis; Legionella species; Chlamydia pneumonia; Mycoplasma pneumonia; Streptococcus pyogenes; Enterococcus faecium; Enterococcus faecalis; Bacillus anthracis; Francisella tularensis; Brucella species; Neisseria gonorrhoeae; Chlamydia trachomatis; and Mycoplasma genitalium.

19. A pharmaceutical composition comprising the antibiotic compound of any of the preceding claims and one or more excipients.

20. A pharmaceutical kit comprising the antibiotic compound of any of claims 1-18, or the pharmaceutical composition of claim 19, and at least one other component, such as another antibiotic compound, a therapeutic agent, or a diagnostic reagent or device.

21. A method for treating or preventing to any degree a bacterial infection in a mammalian subject in need thereof, the method comprising administering the compound of any of claims 1-18 or the pharmaceutical composition of claim 19 to a mammalian subject in need thereof.

22. The method of claim 21, wherein the subject has a bacterial infection by bacteria selected from the group consisting of Enterobacterales, including Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella aerogenes, Enterobacter cloacae, Citrobacter, Salmonella species, Shigella species, Serratia marcesens, Proteus mirabilis, Proteus vulgaris, and Yersinia pestis; Pseudomonas aeruginosa; Acinetobacter baumannii; Stenotrophomonas maltiphilia; Streptococcus pneumonia; Hemophilus influenza; Staphylococcus aureus; coagulase negative Staphylococcus species; Moraxella catarrhalis; Legionella species; Chlamydia pneumonia; Mycoplasma pneumonia; Streptococcus pyogenes; Enterococcus faecium; Enterococcus faecalis; Bacillus anthracis; Francisella tularensis; Brucella species; Neisseria gonorrhoeae; Chlamydia trachomatis; and Mycoplasma genitalium.

23. The method of claim 21 or 22 further comprising testing the antibiotic compound or the pharmaceutical composition for effectiveness in inhibiting growth of bacteria in a sample obtained from the mammalian subject.

24. The method of any of claims 21-23, wherein the bacteria causing the infection are resistant to at least one other antibiotic.

25. The method of any of claims 21-24, wherein the mammalian subject has a bacterial infection selected from the group consisting of bacterial pneumonia, including community acquired pneumonia, skin infections, soft tissue infections, intra-abdominal infections, urinary tract infection, acne, including acne vulgaris, infections caused by a bioterrorism agent, sexually transmitted infections, and infections caused by multidrug resistant bacteria.

26. The method of any of claims 21-25, wherein said administration is oral, by intravenous injection, parenteral, or topical.

27. The antibiotic compound of any of claims 1-18 for use in treating or preventing to any degree a bacterial infection selected from the group consisting of bacterial pneumonia, including community acquired pneumonia, skin infections, soft tissue infections, intra- abdominal infections, urinary tract infection, acne, including acne vulgaris, infections caused by a bioterrorism agent, sexually transmitted infections, and infections caused by multidrug resistant bacteria.

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