MACROCYCLIC PICOLINAMIDES AS FUNGICIDES

BACKGROUND & SUMMARY

[0001] Fungicides are compounds, of natural or synthetic origin, which act to protect and/or cure plants against damage caused by agriculturally relevant fungi. Generally, no single fungicide is useful in all situations. Consequently, research is ongoing to produce fungicides that may have better performance, are easier to use, and cost less.

[0002] The present disclosure relates to macrocyclic picolinamides and their use as fungicides. The compounds of the present disclosure may offer protection against ascomycetes, basidiomycetes, deuteromycetes and oomycetes.

[0003] One embodiment of the resent disclosure may include compounds of Formula I:

wherein

X is H or C(0)R ₂ ;

Y is H, C(0)R ₂ , or Q;

Q is

Ri is selected from the group consisting of OR ₅ ;

R ₂ is alkoxy, each optionally substituted with 0, 1 or multiple R ₈ ;

R ₃ is selected from the group consisting of hydrogen and alkoxy;

R ₄ is hydrogen, -C(0)R ₆ , or -CH ₂ OC(0)R ₆ ; R5 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, or -C(0)R ₇ , each optionally substituted with 0, 1 or multiple R ₈ ;

R ₆ is alkyl or alkoxy, each optionally substituted with 0,1 or multiple R9; R ₇ is alkyl, optionally substituted with 0, 1, or multiple R ₈ .

R ₈ is alkyl, aryl, alkoxy, acyl, halo, each optionally substituted with 0, 1, or multiple R ₉ ;

R9 is alkyl, alkoxy, acyl _, halo, or haloalkyl.

[0004] Another embodiment of the present disclosure may include a fungicidal composition for the control or prevention of fungal attack comprising the compounds described above and a phytologically acceptable carrier material.

[0005] Yet another embodiment of the present disclosure may include a method for the control or prevention of fungal attack on a plant, the method including the steps of applying a fungicidally effective amount of one or more of the compounds described above to at least one of the fungus, the plant, and an area adjacent to the plant.

[0006] It will be understood by those skilled in the art that the following terms may include generic "R"-groups within their definitions, e.g., "the term alkoxy refers to an -OR substituent". It is also understood that within the definitions for the following terms, these "R" groups are included for illustration purposes and should not be construed as limiting or being limited by substitutions about Formula I.

[0007] The term "alkyl" refers to a branched, unbranched, or saturated cyclic carbon chain, including, but not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0008] The term "alkenyl" refers to a branched, unbranched or cyclic carbon chain containing one or more double bonds including, but not limited to, ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

[0009] The term "alkynyl" refers to a branched or unbranched carbon chain containing one or more triple bonds including, but not limited to, propynyl, butynyl and the like.

[0010] The term "aryl" refers to any aromatic, mono- or bi-cyclic, containing 0 heteroatoms. [0011] The term "heterocycle" refers to any aromatic or non-aromatic ring, mono- or tricyclic, containing one or more heteroatoms

[0012] The term "alkoxy" refers to an -OR substituent.

[0013] The term "hydroxyl" refers to an -OH substituent.

[0014] The term "arylalkoxy" refers to -0(CH ₂ ) _n Ar where n is an integer selected from the list 1, 2, 3, 4, 5, or 6.

[0015] The term "haloalkoxy" refers to an -OR-X substituent, wherein X is CI, F, Br, or I, or any combination thereof.

[0016] The term "haloalkyl" refers to an alkyl, which is substituted with CI, F, I, or Br or any combination thereof.

[0017] The term "halogen" or "halo" refers to one or more halogen atoms, defined as F, CI, Br, and I.

[0018] Throughout the disclosure, reference to the compounds of Formula I is read as also including diastereomers, enantiomers, and mixtures thereof. In another embodiment, Formula (I) is read as also including salts or hydrates thereof. Exemplary salts include, but are not limited to: hydrochloride, hydrobromide, and hydroiodide.

[0019] It is also understood by those skilled in the art that additional substitution is allowable, unless otherwise noted, as long as the rules of chemical bonding and strain energy are satisfied and the product still exhibits fungicidal activity.

[0020] Another embodiment of the present disclosure is a use of a compound of Formula I, for protection of a plant against attack by a phytopathogenic organism or the treatment of a plant infested by a phytopathogenic organism, comprising the application of a compound of Formula I, or a composition comprising the compound to soil, a plant, a part of a plant, foliage, and/or roots.

[0021] Additionally, another embodiment of the present disclosure is a composition useful for protecting a plant against attack by a phytopathogenic organism and/or treatment of a plant infested by a phytopathogenic organism comprising a compound of Formula I and a phytologically acceptable carrier material. DETAILED DESCRIPTION

[0022] The compounds of the present disclosure may be applied by any of a variety of known techniques, either as the compounds or as formulations comprising the compounds. For example, the compounds may be applied to the roots or foliage of plants for the control of various fungi, without damaging the commercial value of the plants. The materials may be applied in the form of any of the generally used formulation types, for example, as solutions, dusts, wettable powders, flowable concentrate, or emulsifiable concentrates.

[0023] Preferably, the compounds of the present disclosure are applied in the form of a formulation, comprising one or more of the compounds of Formula I with a phytologically acceptable carrier. Concentrated formulations may be dispersed in water, or other liquids, for application, or formulations may be dust-like or granular, which may then be applied without further treatment. The formulations can be prepared according to procedures that are conventional in the agricultural chemical art.

[0024] The present disclosure contemplates all vehicles by which one or more of the compounds may be formulated for delivery and use as a fungicide. Typically, formulations are applied as aqueous suspensions or emulsions. Such suspensions or emulsions may be produced from water-soluble, water-suspendible, or emulsifiable formulations which are solids, usually known as wettable powders; or liquids, usually known as emulsifiable concentrates, aqueous suspensions, or suspension concentrates. As will be readily appreciated, any material to which these compounds may be added may be used, provided it yields the desired utility without significant interference with the activity of these compounds as antifungal agents.

[0025] Wettable powders, which may be compacted to form water-dispersible granules, comprise an intimate mixture of one or more of the compounds of Formula I, an inert carrier and surfactants. The concentration of the compound in the wettable powder may be from about 10 percent to about 90 percent by weight based on the total weight of the wettable powder, more preferably about 25 weight percent to about 75 weight percent. In the preparation of wettable powder formulations, the compounds may be compounded with any finely divided solid, such as prophyllite, talc, chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein, gluten, montmorillonite clays, diatomaceous earths, purified silicates or the like. In such operations, the finely divided carrier and surfactants are typically blended with the compound(s) and milled. [0026] Emulsifiable concentrates of the compounds of Formula I may comprise a convenient concentration, such as from about 1 weight percent to about 50 weight percent of the compound, in a suitable liquid, based on the total weight of the concentrate. The compounds may be dissolved in an inert carrier, which is either a water-miscible solvent or a mixture of water-immiscible organic solvents, and emulsifiers. The concentrates may be diluted with water and oil to form spray mixtures in the form of oil-in-water emulsions. Useful organic solvents include aromatics, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, for example, terpenic solvents, including rosin derivatives, aliphatic ketones, such as cyclohexanone, and complex alcohols, such as 2- ethoxyethanol.

[0027] Emulsifiers which may be advantageously employed herein may be readily determined by those skilled in the art and include various nonionic, anionic, cationic and amphoteric emulsifiers, or a blend of two or more emulsifiers. Examples of nonionic emulsifiers useful in preparing the emulsifiable concentrates include the polyalkylene glycol ethers and condensation products of alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or fatty acids with ethylene oxide, propylene oxides such as the ethoxylated alkyl phenols and carboxylic esters solubilized with the polyol or polyoxyalkylene. Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts. Anionic emulsifiers include the oil-soluble salts (e.g., calcium) of alkylaryl sulphonic acids, oil-soluble salts or sulfated polyglycol ethers and appropriate salts of phosphated polyglycol ether.

[0028] Representative organic liquids which may be employed in preparing the emulsifiable concentrates of the compounds of the present disclosure are the aromatic liquids such as xylene, propyl benzene fractions; or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids such as dioctyl phthalate; kerosene; dialkyl amides of various fatty acids, particularly the dimethyl amides of fatty glycols and glycol derivatives such as the n-butyl ether, ethyl ether or methyl ether of diethylene glycol, the methyl ether of Methylene glycol, petroleum fractions or hydrocarbons such as mineral oil, aromatic solvents, paraffinic oils, and the like; vegetable oils such as soy bean oil, rape seed oil, olive oil, castor oil, sunflower seed oil, coconut oil, corn oil, cotton seed oil, linseed oil, palm oil, peanut oil, safflower oil, sesame oil, tung oil and the like; esters of the above vegetable oils; and the like. Mixtures of two or more organic liquids may also be employed in the preparation of the emulsifiable concentrate. Organic liquids include xylene, and propyl benzene fractions, with xylene being most preferred in some cases. Surface-active dispersing agents are typically employed in liquid formulations and in an amount of from 0.1 to 20 percent by weight based on the combined weight of the dispersing agent with one or more of the compounds. The formulations can also contain other compatible additives, for example, plant growth regulators and other biologically active compounds used in agriculture.

[0029] Aqueous suspensions comprise suspensions of one or more water-insoluble compounds of Formula I, dispersed in an aqueous vehicle at a concentration in the range from about 1 to about 50 weight percent, based on the total weight of the aqueous suspension. Suspensions are prepared by finely grinding one or more of the compounds, and vigorously mixing the ground material into a vehicle comprised of water and surfactants chosen from the same types discussed above. Other components, such as inorganic salts and synthetic or natural gums, may also be added to increase the density and viscosity of the aqueous vehicle.

[0030] The compounds of Formula I can also be applied as granular formulations, which are particularly useful for applications to the soil. Granular formulations generally contain from about 0.5 to about 10 weight percent, based on the total weight of the granular formulation of the compound(s), dispersed in an inert carrier which consists entirely or in large part of coarsely divided inert material such as attapulgite, bentonite, diatomite, clay or a similar inexpensive substance. Such formulations are usually prepared by dissolving the compounds in a suitable solvent and applying it to a granular carrier which has been preformed to the appropriate particle size, in the range of from about 0.5 to about 3 mm. A suitable solvent is a solvent in which the compound is substantially or completely soluble. Such formulations may also be prepared by making a dough or paste of the carrier and the compound and solvent, and crushing and drying to obtain the desired granular particle.

[0031] Dusts containing the compounds of Formula I may be prepared by intimately mixing one or more of the compounds in powdered form with a suitable dusty agricultural carrier, such as, for example, kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1 to about 10 weight percent of the compounds, based on the total weight of the dust.

[0032] The formulations may additionally contain adjuvant surfactants to enhance deposition, wetting and penetration of the compounds onto the target crop and organism. These adjuvant surfactants may optionally be employed as a component of the formulation or as a tank mix. The amount of adjuvant surfactant will typically vary from 0.01 to 1.0 percent by volume, based on a spray-volume of water, preferably 0.05 to 0.5 volume percent. Suitable adjuvant surfactants include, but are not limited to ethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols, salts of the esters or sulphosuccinic acids, ethoxylated organosilicones, ethoxylated fatty amines, blends of surfactants with mineral or vegetable oils, crop oil concentrate (mineral oil (85%) + emulsifiers (15%)); nonylphenol ethoxylate; benzylcocoalkyldimethyl quaternary ammonium salt; blend of petroleum hydrocarbon, alkyl esters, organic acid, and anionic surfactant; C ₉ - Cn

alkylpolyglycoside; phosphated alcohol ethoxylate; natural primary alcohol (C ₁₂ - C ₁₆ ) ethoxylate; di-sec-butylphenol EO-PO block copolymer; polysiloxane-methyl cap; nonylphenol ethoxylate + urea ammonium nitrrate; emulsified methylated seed oil; tridecyl alcohol (synthetic) ethoxylate (8EO); tallow amine ethoxylate (15 EO); PEG(400) dioleate-99. The formulations may also include oil-in-water emulsions such as those disclosed in U.S. Patent Application Serial No. 11/495,228, the disclosure of which is expressly incorporated by reference herein.

[0033] The formulations may optionally include combinations that contain other pesticidal compounds. Such additional pesticidal compounds may be fungicides, insecticides, herbicides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the compounds of the present disclosure in the medium selected for application, and not antagonistic to the activity of the present compounds. Accordingly, in such embodiments, the other pesticidal compound is employed as a supplemental toxicant for the same or for a different pesticidal use. The compounds of Formula I and the pesticidal compound in the combination can generally be present in a weight ratio of from 1:100 tol00:l.

[0034] The compounds of the present disclosure may also be combined with other fungicides to form fungicidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure are often applied in conjunction with one or more other fungicides to control a wider variety of undesirable diseases. When used in conjunction with other fungicide(s), the presently claimed compounds may be formulated with the other fungicide(s), tank-mixed with the other fungicide(s) or applied sequentially with the other fungicide(s). Such other fungicides may include 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol, 8-hydroxyquinoline sulfate, ametoctradin, amisulbrom, antimycin, Ampelomyces quisqualis, azaconazole, azoxystrobin, Bacillus subtilis, Bacillus subtilis strain QST713, benalaxyl, benomyl, benthiavalicarb-isopropyl, benzylaminobenzene- sulfonate (BABS) salt, bicarbonates, biphenyl, bismerthiazol, bitertanol, bixafen, blasticidin-S, borax, Bordeaux mixture, boscalid, bromuconazole, bupirimate, calcium polysulfide, captafol, captan, carbendazim, carboxin, carpropamid, carvone, chlazafenone, chloroneb, chlorothalonil, chlozolinate, Coniothyrium minitans, copper hydroxide, copper octanoate, copper oxychloride, copper sulfate, copper sulfate (tribasic), cuprous oxide, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, dazomet, debacarb, diammonium ethylenebis-

(dithiocarbamate), dichlofluanid, dichlorophen, diclocymet, diclomezine, dichloran, diethofencarb, difenoconazole, difenzoquat ion, diflumetorim, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinobuton, dinocap, diphenylamine, dithianon, dodemorph, dodemorph acetate, dodine, dodine free base, edifenphos, enestrobin, enestroburin, epoxiconazole, ethaboxam, ethoxyquin, etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fenpyrazamine, fentin, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumorph, fluopicolide, fluopyram, fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutianil, flutolanil, flutriafol, fluxapyroxad, folpet, formaldehyde, fosetyl, fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine, guazatine acetates, GY-81, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imazalil sulfate, imibenconazole, iminoctadine, iminoctadine triacetate, iminoctadine tris(albesilate), iodocarb, ipconazole, ipfenpyrazolone, iprobenfos, iprodione, iprovalicarb, isoprothiolane, isopyrazam, isotianil, kasugamycin, kasugamycin hydrochloride hydrate, kresoxim-methyl, laminarin, mancopper, mancozeb, mandipropamid, maneb, mefenoxam, mepanipyrim, mepronil, meptyl-dinocap, mercuric chloride, mercuric oxide, mercurous chloride, metalaxyl, metalaxyl-M, metam, metam-ammonium, metam-potassium, metam-sodium, metconazole, methasulfocarb, methyl iodide, methyl isothiocyanate, metiram, metominostrobin, metrafenone, mildiomycin, myclobutanil, nabam, nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic acid (fatty acids), orysastrobin, oxadixyl, oxine-copper, oxpoconazole fumarate, oxycarboxin, pefurazoate, penconazole, pencycuron, penflufen, pentachlorophenol,

pentachlorophenyl laurate, penthiopyrad, phenylmercury acetate, phosphonic acid, phthalide, picoxystrobin, polyoxin B, polyoxins, polyoxorim, potassium bicarbonate, potassium

hydroxyquinoline sulfate, probenazole, prochloraz, procymidone, propamocarb, propamocarb hydrochloride, propiconazole, propineb, proquinazid, prothioconazole, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyriofenone, pyroquilon, quinoclamine, quinoxyfen, quintozene, Reynoutria sachalinensis extract, sedaxane, silthiofam, simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodium pentachlorophenoxide, spiroxamine, sulfur, SYP-Z048, tar oils, tebuconazole, tebufloquin, tecnazene, tetraconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazoxide, tricyclazole, tridemorph, trifloxystrobin, triflumizole, triforine, triticonazole, validamycin, valifenalate, valiphenal, vinclozolin, zineb, ziram, zoxamide, Candida oleophila, Fusarium oxysporum, Gliocladium spp.,

Phlebiopsis gigantea, Streptomyces griseoviridis, Trichoderma spp., (7¾>)- V-(3,5-dichlorophenyl)-

2-(methoxymethyl)-succinimide, 1,2-dichloropropane, l,3-dichloro-l,l,3,3-tetrafluoroacetone hydrate, 1 -chloro-2,4-dinitronaphthalene, 1 -chloro-2-nitropropane, 2-(2-heptadecyl-2-imidazolin- 1 - yl)ethanol, 2,3-dihydro-5-phenyl-l,4-dithi-ine 1,1,4,4-tetraoxide, 2-methoxyethylmercury acetate,

2-methoxyethylmercury chloride, 2-methoxyethylmercury silicate, 3-(4-chlorophenyl)-5- methylrhodanine, 4-(2-nitroprop-l-enyl)phenyl thiocyanateme, ampropylfos, anilazine, azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox, bentaluron, benzamacril; benzamacril- isobutyl, benzamorf, binapacryl, bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate, cadmium calcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone,

chloraniformethan, chlorfenazole, chlorquinox, climbazole, copper bis(3-phenylsalicylate), copper zinc chromate, cufraneb, cupric hydrazinium sulfate, cuprobam, cyclafuramid, cypendazole, cyprofuram, decafentin, dichlone, dichlozoline, diclobutrazol, dimethirimol, dinocton, dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin, drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf, fenapanil, fenitropan, fluotrimazole, furcarbanil, furconazole, furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin, halacrinate, Hercules 3944, hexylthiofos,

ICIA0858, isopamphos, isovaledione, mebenil, mecarbinzid, metazoxolon, methfuroxam, methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride, myclozolin, N-3,5- dichlorophenyl-succinimide, N-3-nitrophenylitaconimide, natamycin, N-ethylmercurio-4- toluenesulfonanilide, nickel bis(dimethyldithiocarbamate), OCH, phenylmercury

dimethyldithiocarbamate, phenylmercury nitrate, phosdiphen, prothiocarb; prothiocarb

hydrochloride, pyracarbolid, pyridinitril, pyroxychlor, pyroxyfur, quinacetol; quinacetol sulfate, quinazamid, quinconazole, rabenzazole, salicylanilide, SSF-109, sultropen, tecoram, thiadifluor, thicyofen, thiochlorfenphim, thiophanate, thioquinox, tioxymid, triamiphos, triarimol, triazbutil, trichlamide, urbacid, zarilamid, and any combinations thereof.

[0035] Additionally, the compounds described herein may be combined with other pesticides, including insecticides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the compounds of the present disclosure in the medium selected for application, and not antagonistic to the activity of the present compounds to form pesticidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure may be applied in conjunction with one or more other pesticides to control a wider variety of undesirable pests. When used in conjunction with other pesticides, the presently claimed compounds may be formulated with the other pesticide(s), tank-mixed with the other pesticide(s) or applied sequentially with the other pesticide(s). Typical insecticides include, but are not limited to: 1,2-dichloropropane, abamectin, acephate, acetamiprid, acethion, acetoprole, acrinathrin, acrylonitrile, alanycarb, aldicarb, aldoxycarb, aldrin, allethrin, allosamidin, allyxycarb, alpha-cypermethrin, alpha-ecdysone, alpha-endosulfan, amidithion, aminocarb, amiton, amiton oxalate, amitraz, anabasine, athidathion, azadirachtin, azamethiphos, azinphos-ethyl, azinphos-methyl, azothoate, barium hexafluorosilicate, barthrin, bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin, bifenthrin, bioallethrin, bioethanomethrin, biopermethrin, bistrifluron, borax, boric acid, bromfenvinfos, bromocyclen, bromo-DDT, bromophos, bromophos-ethyl, bufencarb, buprofezin, butacarb, butathiofos, butocarboxim, butonate, butoxycarboxim, cadusafos, calcium arsenate, calcium polysulfide, camphechlor, carbanolate, carbaryl, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, cartap, cartap hydrochloride, chlorantraniliprole, chlorbicyclen, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorethoxyfos,

chlorfenapyr, chlorfenvinphos, chlorfluazuron, chlormephos, chloroform, chloropicrin,

chlorphoxim, chlorprazophos, chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, chromafenozide, cinerin I, cinerin Π, cinerins, cismethrin, cloethocarb, closantel, clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate, copper oleate, coumaphos, coumithoate, crotamiton, crotoxyphos, crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S- methylsulphon, diafenthiuron, dialifos, diatomaceous earth, diazinon, dicapthon, dichlofenthion, dichlorvos, dicresyl, dicrotophos, dicyclanil, dieldrin, diflubenzuron, dilor, dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dimethylvinphos, dimetilan, dinex, dinex-diclexine, dinoprop, dinosam, dinotefuran, diofenolan, dioxabenzofos, dioxacarb, dioxathion, disulfoton, dithicrofos, d- limonene, DNOC, DNOC-ammonium, DNOC -potassium, DNOC-sodium, doramectin, ecdysterone, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothion, endrin,

EPN, epofenonane, eprinomectin, esdepallethrine, esfenvalerate, etaphos, ethiofencarb, ethion, ethiprole, ethoate-methyl, ethoprophos, ethyl formate, ethyl-DDD, ethylene dibromide, ethylene dichloride, ethylene oxide, etofenprox, etrimfos, EXD, famphur, fenamiphos, fenazaflor, fenchlorphos, fenethacarb, fenfluthrin, fenitrothion, fenobucarb, fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin, fensulfothion, fenthion, fenthion-ethyl, fenvalerate, fipronil, flonicamid, flubendiamide, flucofuron, flucycloxuron, flucythrinate, flufenerim, flufenoxuron, flufenprox, fluvalinate, fonofos, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosmethilan, fospirate, fosthietan, furathiocarb, furethrin, gamma- cyhalothrin, gamma-HCH, halfenprox, halofenozide, HCH, HEOD, heptachlor, heptenophos, heterophos, hexaflumuron, HHDN, hydramethylnon, hydrogen cyanide, hydroprene, hyquincarb, imidacloprid, imiprothrin, indoxacarb, iodomethane, IPSP, isazofos, isobenzan, isocarbophos, isodrin, isofenphos, isofenphos-methyl, isoprocarb, isoprothiolane, isothioate, isoxathion, ivermectin, jasmolin I, jasmolin Π, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone ΠΙ, kelevan, kinoprene, lambda-cyhalothrin, lead arsenate, lepimectin, leptophos, lindane, lirimfos, lufenuron, lythidathion, malathion, malonoben, mazidox, mecarbam, mecarphon, menazon, mephosfolan, mercurous chloride, mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion, methiocarb, methocrotophos, methomyl, methoprene,

methoxychlor, methoxyfenozide, methyl bromide, methyl isothiocyanate, methylchloroform, methylene chloride, metofluthrin, metolcarb, metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime, mipafox, mirex, molosultap, monocrotophos, monomehypo, monosultap, morphothion, moxidectin, naftalofos, naled, naphthalene, nicotine, nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron, noviflumuron, omethoate, oxamyl, oxydemeton- methyl, oxydeprofos, oxydisulfoton, para-dichlorobenzene, parathion, parathion-methyl, penfluron, pentachlorophenol, permethrin, phenkapton, phenothrin, phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor, phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite, potassium thiocyanate, pp'-

DDT, prallethrin, precocene I, precocene Π, precocene ΠΙ, primidophos, profenofos, profluralin, promacyl, promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos, prothoate, protrifenbute, pyraclofos, pyrafluprole, pyrazophos, pyresmethrin, pyrethrin I, pyrethrin Π, pyrethrins, pyridaben, pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyrimitate, pyriprole, pyriproxyfen, quassia, quinalphos, quinalphos-methyl, quinothion, rafoxanide, resmethrin, rotenone, ryania, sabadiUa, schradan, selamectin, silafluofen, silica gel, sodium arsenite, sodium fluoride, sodium hexafluorosilicate, sodium thiocyanate, sophamide, spinetoram, spinosad, spiromesifen, spirotetramat, sulcofuron, sulcofuron- sodium, sulfluramid, sulfotep, sulfoxaflor, sulfuryl fluoride, sulprofos, tau-fluvalinate, tazimcarb, TDE, tebufenozide, tebufenpyrad, tebupirirnfos, teflubenzuron, tefluthrin, temephos, TEPP, terallethrin, terbufos, tetrachloroethane, tetrachlorvinphos, tetramethrin, tetramethylfluthrin, theta-cypermethrin, thiacloprid, thiamethoxam, thicrofos, thiocarboxime, thiocyclam, thiocyclam oxalate, thiodicarb, thiofanox, thiometon, thiosultap, thiosultap-disodium, thiosultap-monosodium, thuringiensin, tolfenpyrad, tralomethrin, transfluthrin, transpermethrin, triarathene, triazamate, triazophos, trichlorfon, trichlormetaphos-3, trichloronat, trifenofos, triflumuron, trimethacarb, triprene, vamidothion, vaniliprole, XMC, xylylcarb, zeta-cypermethrin, zolaprofos, and any combinations thereof.

[0036] Additionally, the compounds described herein may be combined with herbicides that are compatible with the compounds of the present disclosure in the medium selected for application, and not antagonistic to the activity of the present compounds to form pesticidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure may be applied in conjunction with one or more herbicides to control a wide variety of undesirable plants. When used in conjunction with herbicides, the presently claimed compounds may be formulated with the herbicide(s), tank-mixed with the herbicide(s) or applied sequentially with the herbicide(s). Typical herbicides include, but are not limited to: 4-CPA; 4-CPB; 4-CPP; 2,4-D; 3,4-DA; 2,4-DB; 3,4-DB;

2,4-DEB; 2,4-DEP; 3,4-DP; 2,3,6-TBA; 2,4,5-T; 2,4,5-TB; acetochlor, acifluorfen, aclonifen, acrolein, alachlor, allidochlor, alloxydim, allyl alcohol, alorac, ametridione, ametryn, amibuzin, amicarbazone, amidosulfuron, aminocyclopyrachlor, aminopyralid, amiprofos-methyl, amitrole, ammonium sulfamate, anilofos, anisuron, asulam, atraton, atrazine, azafenidin, azimsulfuron, aziprotryne, barban, BCPC, beflubutamid, benazolin, bencarbazone, benfluralin, benfuresate, bensulfuron, bensulide, bentazone, benzadox, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzoylprop, benzthiazuron, bicyclopyrone, bifenox, bilanafos, bispyribac, borax, bromacil, bromobonil, bromobutide, bromofenoxim, bromoxynil, brompyrazon, butachlor, butafenacil, butamifos, butenachlor, buthidazole, buthiuron, butralin, butroxydim, buturon, butylate, cacodylic acid, cafenstrole, calcium chlorate, calcium cyanamide, cambendichlor, carbasulam, carbetamide, carboxazole chlorprocarb, carfentrazone, CDEA, CEPC, chlomethoxyfen,

chloramben, chloranocryl, chlorazifop, chlorazine, chlorbromuron, chlorbufam, chloreturon, chlorfenac, chlorfenprop, chlorflurazole, chlorflurenol, chloridazon, chlorimuron, chlornitrofen, chloropon, chlorotoluron, chloroxuron, chloroxynil, chlorpropham, chlorsulfuron, chlorthal, chlorthiamid, cinidon-ethyl, cinmethylin, cinosulfuron, cisanilide, clethodim, cliodinate, clodinafop, clofop, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, cloransulam, CMA, copper sulfate, CPMF, CPPC, credazine, cresol, cumyluron, cyanatryn, cyanazine, cycloate,

cyclosulfamuron, cycloxydim, cycluron, cyhalofop, cyperquat, cyprazine, cyprazole, cypromid, daimuron, dalapon, dazomet, delachlor, desmedipham, desmetryn, di-allate, dicamba, dichlobenil, dichloralurea, dichlormate, dichlorprop, dichlorprop-P, diclofop, diclosulam, diethamquat, diethatyl, difenopenten, difenoxuron, difenzoquat, diflufenican, diflufenzopyr, dimefuron, dimepiperate, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimexano, dimidazon, dinitramine, dinofenate, dinoprop, dinosam, dinoseb, dinoterb, diphenamid, dipropetryn, diquat, disul, dithiopyr, diuron, DMPA, DNOC, DSMA, EBEP, eglinazine, endothal, epronaz, EPTC, erbon, esprocarb, ethalfluralin, ethametsulfuron, ethidimuron, ethiolate, ethofumesate, ethoxyfen, ethoxysulfuron, etinofen, etnipromid, etobenzanid, EXD, fenasulam, fenoprop, fenoxaprop, fenoxaprop-P, fenoxasulfone, fenteracol, fenthiaprop, fentrazamide, fenuron, ferrous sulfate, flamprop, flamprop-

M, flazasulfuron, florasulam, fluazifop, fluazifop-P, fluazolate, flucarbazone, flucetosulfuron, fluchloralin, flufenacet, flufenican, flufenpyr, flumetsulam, flumezin, flumiclorac, flumioxazin, flumipropyn, fluometuron, fluorodifen, fluoroglycofen, fluoromidine, fluoronitrofen, fluothiuron, flupoxam, flupropacil, flupropanate, flupyrsulfuron, fluridone, flurochloridone, fluroxypyr, flurtamone, fluthiacet, fomesafen, foramsulfuron, fosamine, furyloxyfen, glufosinate, glufosinate-P, glyphosate, halosafen, halosulfuron, haloxydine, haloxyfop, haloxyfop-P, hexachloroacetone, hexaflurate, hexazinone, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, imazosulfuron, indanofan, indaziflam, iodobonil, iodomethane, iodosulfuron, ioxynil, ipazine, ipfencarbazone, iprymidam, isocarbamid, isocil, isomethiozin, isonoruron, isopolinate, isopropalin, isoproturon, isouron, isoxaben, isoxachlortole, isoxaflutole, isoxapyrifop, karbutilate, ketospiradox, lactofen, lenacil, linuron, MAA, MAMA, MCPA, MCPA-thioethyl, MCPB, mecoprop, mecoprop-

P, medinoterb, mefenacet, mefluidide, mesoprazine, mesosulfuron, mesotrione, metam, metamifop, metamitron, metazachlor, metazosulfuron, metflurazon, methabenzthiazuron, methalpropalin, methazole, methiobencarb, methiozolin, methiuron, methometon, methoprotryne, methyl bromide, methyl isothiocyanate, methyldymron, metobenzuron, metobromuron, metolachlor, metosulam, metoxuron, metribuzin, metsulfuron, molinate, monalide, monisouron, monochloroacetic acid, monolinuron, monuron, morfamquat, MSMA, naproanilide, napropamide, naptalam, neburon, nicosulfuron, nipyraclofen, nitralin, nitrofen, nitrofluorfen, norflurazon, noruron, OCH, orbencarb, o/t zo-dichlorobenzene, orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxapyrazon, oxasulfuron, oxaziclomefone, oxyfluorfen, parafluron, paraquat, pebulate, pelargonic acid, pendimethalin, penoxsulam, pentachlorophenol, pentanochlor, pentoxazone, perfluidone, pethoxamid,

phenisopham, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenylmercury acetate, picloram, picolinafen, pinoxaden, piperophos, potassium arsenite, potassium azide, potassium cyanate, pretilachlor, primisulfuron, procyazine, prodiamine, profluazol, profluralin, profoxydim, proglinazine, prometon, prometryn, propachlor, propanil, propaquizafop, propazine, propham, propisochlor, propoxycarbazone, propyrisulfuron, propyzamide, prosulfalin, prosulfocarb, prosulfuron, proxan, prynachlor, pydanon, pyraclonil, pyraflufen, pyrasulfotole, pyrazolynate, pyrazosulfuron, pyrazoxyfen, pyribenzoxim, pyributicarb, pyriclor, pyridafol, pyridate, pyriftalid, pyriminobac, pyrimisulfan, pyrithiobac, pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine, quinonamid, quizalofop, quizalofop-P, rhodethanil, rimsulfuron, saflufenacil, S- metolachlor, sebuthylazine, secbumeton, sethoxydim, siduron, simazine, simeton, simetryn, SMA, sodium arsenite, sodium azide, sodium chlorate, sulcotrione, sulfallate, sulfentrazone, sulfometuron, sulfosulfuron, sulfuric acid, sulglycapin, swep, TCA, tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim, terbacil, terbucarb, terbuchlor, terbumeton, terbuthylazine, terbutryn, tetrafluron, thenylchlor, thiazafluron, thiazopyr, thidiazimin, thidiazuron, thiencarbazone-methyl, thifensulfuron, thiobencarb, tiocarbazil, tioclorim, topramezone, tralkoxydim, triafamone, tri-allate, triasulfuron, triaziflam, tribenuron, tricamba, triclopyr, tridiphane, trietazine, trifloxysulfuron, trifluralin, triflusulfuron, trifop, trifopsime, trihydroxytriazine, trimeturon, tripropindan, tritac, tritosulfuron, vernolate, and xylachlor.

[0037] Another embodiment of the present disclosure is a method for the control or prevention of fungal attack. This method comprises applying to the soil, plant, roots, foliage, or locus of the fungus, or to a locus in which the infestation is to be prevented (for example applying to cereal or grape plants), a fungicidally effective amount of one or more of the compounds of Formula I. The compounds are suitable for treatment of various plants at fungicidal levels, while exhibiting low phytotoxicity. The compounds may be useful both in a protectant and/or an eradicant fashion.

[0038] The compounds have been found to have significant fungicidal effect particularly for agricultural use. Many of the compounds are particularly effective for use with agricultural crops and horticultural plants.

[0039] It will be understood by those in the art that the efficacy of the compound for the foregoing fungi establishes the general utility of the compounds as fungicides.

[0040] The compounds have broad ranges of activity against fungal pathogens. Exemplary pathogens may include, but are not limited to, causing agent of wheat leaf blotch (Mycosphaerella graminicola; impect stage: Septoria tritici), wheat brown rust (Puccinia triticina), wheat stripe rust (Puccinia striiformis), scab of apple (Venturia inaequalis), powdery mildew of grapevine {Uncinula necator), barley scald (Rhynchosporium secalis), blast of rice {Magnaporthe grisea), rust of soybean (Phakopsora pachyrhizi), glume blotch of wheat (Leptosphaeria nodorum), powdery mildew of wheat (Blumeria graminisf. sp.tritici), powdery mildew of barley (Blumeria graminisf. sp. hordei), powdery mildew of cucurbits (Erysiphe cichoracearum), anthracnose of cucurbits (Glomerella lagenarium), leaf spot of beet {Cercospora beticola), early blight of tomato {Alternaria solani), and spot blotch of barley {Cochliobolus sativus). The exact amount of the active material to be applied is dependent not only on the specific active material being applied, but also on the particular action desired, the fungal species to be controlled, and the stage of growth thereof, as well as the part of the plant or other product to be contacted with the compound. Thus, all the compounds, and formulations containing the same, may not be equally effective at similar concentrations or against the same fungal species.

[0041] The compounds are effective in use with plants in a disease-inhibiting and phytologically acceptable amount. The term "disease-inhibiting and phytologically acceptable amount" refers to an amount of a compound that kills or inhibits the plant disease for which control is desired, but is not significantly toxic to the plant. This amount will generally be from about 0.1 to about 1000 ppm (parts per million), with 1 to 500 ppm being preferred. The exact concentration of compound required varies with the fungal disease to be controlled, the type of formulation employed, the method of application, the particular plant species, climate conditions, and the like. A suitable application rate is typically in the range from about 0.10 to about 4 pounds/acre (about 0.01 to 0.45 grams per square meter, g/m ).

[0042] Any range or desired value given herein may be extended or altered without losing the effects sought, as is apparent to the skilled person for an understanding of the teachings herein.

[0043] The compounds of Formula I may be made using well-known chemical procedures. Intermediates not specifically mentioned in this disclosure are either commercially available, may be made by routes disclosed in the chemical literature, or may be readily synthesized from commercial starting materials utilizing standard procedures.

GENERAL SCHEMES

[0044] The following schemes illustrate approaches to generating picolinamide compounds of Formula (I). The following descriptions and examples are provided for illustrative purposes and should not be construed as limiting in terms of substituents or substitution patterns.

[0045] Compounds of Formula 1.2, can be prepared by the method shown in Scheme 1, steps a - b . Compounds of Formula 1.1 , can be prepared from compounds of Formula 1.0, by treatment with chlorotriisopropylsilane in the presence of a base, such as imidazole, in a solvent such as dichloromethane, and at a temperature between 0 and 23 °C. Compounds of Formula 1.2, can be prepared from compounds of Formula 1.1, by treatment with a reducing agent, such as

diisobutylaluminum hydride (DIBAL-H), in a solvent such as dichloromethane, and at a

temperature from about -78 and to about 23 °C. Scheme 1

1.0 1.1 1.2

[0046] Compounds of Formula 2.1, can be prepared by the method shown in Scheme 2, steps a - b. Compounds of Formula 2.0, can be prepared from compounds of Formula 1.2, by treatment with (+)-Ipc ₂ -allylborane, as described by Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401-404, in a solvent such as diethylether, and at cryogenic temperatures such as -78 °C.

Compounds of Formula 2.1 , can be prepared from compounds of Formula 2.0, by treatment with a base, such as sodium hydride, and 4-methoxybenzyl bromide in the presence of a catalyst, such as tetrabutylammonium iodide, in a solvent such as dimethylformamide (DMF), and at a temperature from about 0 and to about 23 °C. Alternatively, compounds of Formula 2.1 can be prepared from compounds of Formula 1.3 by treatment with a base, such as sodium hydride, and benzyl bromide, in a solvent such as DMF, and at a temperature from about 0 and to about 23 °C.

Scheme 2

2.0 2.1

[0047] Compounds of Formula 3.2, can be prepared by the method shown in Scheme 3, steps a - b. Compounds of Formula 3.1, where Y is as originally defined, can be prepared from compounds of Formula 2.1, by treatment with an alkylborane reagent, such as 9- borabicyclo[3.3.1]nonane (9-BBN), in a solvent such as THF, at a temperature between ambient temperature and about 50 °C, followed by treatment with an alkaline aqueous solution, such as aqueous potassium phosphate (K ₃ P0 ₄ ), a brominated olefin, such as a compound of Formula 3.0, where Y is as originally defined, prepared as described in Collier, P. N. et. al. J. Org. Chem. 2002, 67, 1802-1815, and a palladium catalyst, such as [l,l-bis(diphenylphosphino)ferrocene] dichloropalladium(II) [PdCl ₂ (dppf)] at ambient room temperature to about 55 °C, as shown in step a. Compounds of Formula 3.2, where Y is as originally defined, can be prepared from enamides, generalized by Formula 3.1, where Y is as originally defined, using an asymmetric hydrogenation reaction as described in Stammers, T. A.; Burk, M. J. Tet. Lett. 1999, 40, 3325-3328, employing a catalyst such as (+)-l,2-bis((2S,5S)-2,5-diethylphospholano)benzene(l,5-cyclo octadiene) rhodium(I) trifluoromethanesulfonate ((S,S)-Et-DuPHOS-Rh) under a hydrogen gas (H ₂ ) atmosphere at a pressure between 40 and 200 pounds per square inch (psi) in a solvent such as methanol (MeOH), as shown in step b.

Scheme 3

[0048] Compounds of Formula 4.1, can be prepared by the method shown in Scheme 4, steps a - b. Compounds of Formula 4.0, where Y is C(0)iBu, herein referred to as Boc, can be prepared from compounds of Formula 3.2, by treatment with a desilylating agent, such as tetrabutylammonium fluoride (TBAF), in a solvent such as THF, at a temperature between 0 °C and ambient temperature, as shown in step a. Compounds of Formula 4.1, where Y is Boc, can be prepared from compounds of 4.0, where Y is Boc, by treatment with a hydroxide base, such as lithium hydroxide monohydrate (LiOH ^» H ₂ 0), in an aqueous MeOH solvent mixture, as shown in step b.

[0049] Compounds of of Formula 5.0, where Y is Boc, can be prepared according to the method outlined in Scheme 5, step a. Compounds of Formula 5.0, can be obtained from

compounds of Formula 4.1, where Y is Boc, by the addition of a solution of compounds of Formula 4.1 in a halogenated solvent, such as DCM, or an aromatic solvent, such as toluene, to a mixture of a base, such as DMAP, and a mixed anhydride, such as 2-methyl-6-nitrobenzoic anhydride (MNBA), in a halogenated solvent, such as DCM, or an aromatic solvent, such as toluene, at a temperature between about 21 °C and about 60 °C over a period of 4 - 12 hours (h), as shown in step a.

[0050] Compounds of Formula 6.1, 6.2 and 6.3, where X and Y are Boc, can be prepared according to the method outlined in Scheme 6, steps a - b. Compounds of Formula 6.1, can be obtained from compounds of Formula 5.0, where Y is as originally defined, according to the method described in Example 2, Step lb in US 2015/0094341 Al. Compounds of Formula 6.2, can be obtained from compounds of Formula 5.0, where X and Y are Boc, by treatment with an oxidizing agent, such as eerie ammonium nitrate (CAN), in a solvent such as aqueous acetonitrile, at a temperature of about 0 °C, as shown in step b. Compounds of Formula 6.3, where X and Y are Boc, can be prepared from compounds of Formula 6.1, where X and Y are Boc, by treatment with an oxidizing agent, such as CAN, in a solvent, such as aqueous acetonitrile, at a temperature of about 0 °C, as shown in step b.

Scheme 6

6.2 6.3 [0051] Compounds of of Formula 7.0, 7.1 and 7.2, where Y is Boc, can be prepared according to the method outlined in Scheme 7, steps a - c. Compounds of Formula 7.0, can be obtained from compounds of Formula 6.2, where Y is Boc, according to the method described in Example 6, in US 2015/0094341A1, as shown in step a. Compounds of Formula 7.1, can be obtained from compounds of Formula 6.2, where Y is Boc, according to the method described in Example 5, in US 2015/0094341A1, as shown in step b. Compounds of Formula 7.2, where Y is Boc, can be prepared from compounds of Formula 6.2, where Y is Boc, according to the method described in Example 1, Step 2a in US 2015/0094341 Al, as shown in step c.

Scheme 7

7.2

[0052] Compounds of of Formula 8.0 and 8.1, where X and Y are Boc, and Ri is as originally defined, can be prepared according to the method outlined in Scheme 8, steps a - b. Compounds of Formula 8.0, can be obtained from compounds of Formula 6.3, where X and Y are Boc, according to the method described in Example 3, Step 1 in US 2015/0094341A1, as shown in step a. Compounds of Formula 8.1, can be obtained from compounds of Formula 6.3, where X and Y are Boc, according to the method described in Example 3, Step 2a in US 2015/0094341 Al or Example 4, Step 2 in US 2015/0094341 Al, as shown in step b.

[0053] Compounds of of Formula 9.0 and 9.1, where X and Y are Boc, can be prepared according to the method outlined in Scheme 9, steps a - b. Compounds of Formula 9.0, can be obtained from compounds of Formula 6.3, where X and Y are Boc, according to the method described in Example 4, Step 1 in US 2015/0094341A1, as shown in step a. Compounds of Formula 9.1, can be obtained from compounds of Formula 6.3, where X and Y are Boc, according to the method described in Example 3, Step 2a in US 2015/0094341A1 or Example 4, Step 2 in US 2015/0094341 Al, as shown in step b.

[0054] Compounds of of Formula 10.0, 10.1 10.2, where X and Y are Boc, can be prepared according to the method outlined in Scheme 10, steps a - c. Compounds of Formula 10.0, can be obtained from compounds of Formula 6.3, where X and Y are Boc, according to the method described in Example 4, Step 1 in US 2015/0094341A1, as shown in step a. Compounds of Formula 10.1, can be obtained from compounds of Formula 6.3, where X and Y are Boc, according to the method described in Example 3, Step 2a in US 2015/0094341A1 or Example 4, Step 2 in US 2015/0094341A1, as shown in step b. Compounds of Formula 10.2, can be obtained from compounds of Formula 6.3, where X and Y are Boc, according to the method described in Example 4, Step 3 in US 2015/0094341A1, as shown in step c.

Scheme 10

[0055] Compounds of of Formula 11.3 and 11.2, where Ri is as originally defined, can be prepared according to the method outlined in Scheme 11, steps a - c. Compounds of Formula 11.2, can be obtained from compounds of Formula 11.0, where Y is Boc and Ri is not PMB, by treatment with an acid, such as a 4.0 Molar (M) hydrogen chloride (HCl) solution in dioxane, in a solvent such as dichloromethane, at ambient temperature, as shown in step a. Alternatively, compounds of Formula 11.2, can be obtained from compounds of Formula 11.0, where Y is Boc and Ri is PMB, by treatment with trimethylsilyl trifluoromethanesulfonate (TMSOTf), as described in Zhang, A. J. et. al. Tet. Lett. 1998, 39, 7439-7442, in the presence of a base such as 2,6-lutidine, in a solvent such as dichlormethane, at ambient temperature, as shown in step b. Compounds of Formula 11.2, can be obtained from compounds of Formula 11.1, where X and Y are Boc, by treatment with an acid, such as a 4.0 Molar (M) hydrogen chloride (HCl) solution in dioxane, at ambient temperature, as shown in step a. Compounds of Formula 11.3, can be obtained from compounds of Formula 11.2, where Ri is as originally defined, by treatment with 3-hydroxy- 4-methoxypicolinic acid, in the presence of a base, such as N-ethyl-N-isopropylpropan-2-amine (DIPEA), and a peptide coupling reagent, such as benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), in an aprotic solvent such as DCM, as shown in c. Scheme 11

1 1 .3

[0056] Compounds of of Formula 12.0, where Ri and R ₃ are as originally defined, can be prepared by the method shown in Scheme 12, step a. Compounds of Formula 12.0, where Ri and R ₃ are as originally defined, can be prepared from compounds of Formula 11.3, where Ri is as originally defined, by treatment with the appropriate alkyl halide with or without a reagent such as sodium iodide (Nal) and an alkali carbonate base, such as sodium carbonate (Na ₂ C0 ₃ ) or potassium carbonate (K ₂ C0 ₃ ), in a solvent such as acetone, or by treatment with an acyl halide in the presence of an amine base, such as pyridine, Et ₃ N, DMAP, or mixtures thereof, in an aprotic solvent such as DCM, as shown in step a. Scheme 12

11.3 12.0

[0057] The following examples are presented to illustrate the various aspects of the compounds of the present disclosure and should not be construed as limitations to the claims.

EXAMPLES

[0058] Example 1: Preparation of (S)-ethyl 2-((triisopropylsilyl)oxy)propanoate:

[0059] In a 500 mL round-bottom flask, (S)-ethyl 2-hydroxypropanoate (9.71 mL, 85 mmol) and imidazole (13.83 g, 203 mmol) were dissolved in DCM (220 mL) under N ₂ and cooled to 0 °C in an ice/water bath. Chlorotriisopropylsilane (21.74 mL, 102 mmol) was then added via syringe over 30 minutes. The reaction mixture was allowed to warm to room temperature as the ice melted and stirred overnight. After 18 h, TLC indicated consumption of starting material. The reaction mixture was poured into a separatory funnel and washed with H ₂ 0 (100 mL), saturated aqueous NaHC0 ₃ (100 mL), brine (100 mL), 1M HC1 (100 mL), then brine (100 mL). The organic layer was passed through a phase separator and concentrated to afford a clear, colorless oil. The oil was purified by flash column chromatography (silica gel (Si0 ₂ ), 0~ 10% ethyl acetate in hexanes) to afford the title compound (21.68 g, 79 mmol, 93 % yield) as a clear, colorless oil: 1H NMR (400 MHz, CDC1 ₃ ) δ 4.41 (q, J = 6.7 Hz, 1H), 4.18 (qd, J = 7.1, 2.7 Hz, 2H), 1.43 (d, J = 6.7 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.17 0.97 (m, 21H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 174.23, 68.55, 60.66, 21.80, 17.85, 14.22, 12.16; R _f = 0.73 in 10% Ethyl acetate : hexanes, one UV-inactive spot (KMn0 ₄ stain).

[0060] Example 2: Preparation of (S)-2-((triisopropylsilyl)oxy)propanal:

[0061] In a 1 L round-bottom flask, (S)-ethyl 2-((triisopropylsilyl)oxy)propanoate (21.68 g, 79 mmol) was dissolved in DCM (395 mL) under N ₂ and cooled to -78 °C in an dry ice/acetone bath. Diisobutylaluminum hydride (1 M in hexanes, 158 mL, 158 mmol) was added via syringe over 4 hours. The reaction was stirred at -78 °C for an additional 30 min. After 30 min, ethyl acetate (75 mL) was added to quench the reaction, and the reaction mixture was warmed to 0 °C in an ice/water bath. A solution of saturated aqueous potassium sodium tartrate (-200 mL) was added, and the reaction was vigorously stirred overnight, slowly warming to room temperature as the ice bath melted. After 18 h, the biphasic mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (3 x 150 mL). The combined organic layers were passed through a phase separator and concentrated to afford a clear, colorless oil. The oil was purified by flash column chromatography (silica gel (Si0 ₂ ), 0-^20% ethyl acetate in hexanes) to afford the title compound (15.85 g, 69 mmol, 87% yield) as a clear, colorless oil: 1H

NMR (400 MHz, CDCI ₃ ) δ 9.66 (d, = 1.7 Hz, 1H), 4.18 (qd, = 6.8, 1.7 Hz, 1H), 1.31 (d, = 6.8 Hz, 3H), 1.11 1.01 (m, 21H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 204.54, 73.83, 18.95, 17.89, 12.14; R _f = 0.73 in 10% Ethyl acetate : hexanes, one UV-inactive spot (KMn0 ₄ stain). [0062] Example 3: Preparation of (2S,3 ?)-2-((triisopropylsilyl)oxy)hex-5-en-3-ol:

[0063] A 500 mL round bottom flask was charged with (+)-Ipc ₂ -allylborane (1M in pentane, 25.0 mL, 25.00 mmol) under N ₂ and diluted with Et ₂ 0 (100 mL). The resultant clear, colorless solution was cooled to -78 °C in an acetone/dry ice bath. (S)-2-((triisopropylsilyl)oxy)propanal (4.61 g, 20.01 mmol) was added as a solution in anhydrous Et ₂ 0 (60 mL) via syringe over 1.5 h. The clear, colorless reaction was cooled for an additional 1.5 h at -78 °C, after which TLC indicated consumption of starting material. MeOH (50 mL) was then added, and the reaction was stirred for 5 min at -78 °C. pH 7 buffer (70 mL) was added, and the reaction was warmed to 0 °C in an ice/water bath. H ₂ 0 ₂ (30%, 60 mL) was then added, and the resulting biphasic reaction mixture was vigorously stirred at 0 °C for 2.5 h, and then warmed to room temperature as the ice melted and stirred for 30 h. The layers were separated, and the aqueous phase was extracted with El^O (3 x 100 mL). The aqueous layer was carefully quenched with saturated aqueous Na^O _g on ice until KI- starch test paper indicated the disappearance of residual H ₂ 0 ₂ . The combined organic layers were dried over MgS0 ₄ , filtered, and concentrated to a clear oil. The oil was purified by flash column chromatography (Si0 ₂ , 0" 5% ethyl acetate in hexanes) to afford the title compound (5.00 g, 18.33 mmol, 92% yield) as a clear, light rose colored oil: 1H NMR (400 MHz, CDC1 ₃ ) δ 5.85 (ddt, = 17.2, 10.2, 7.0 Hz, 1H), 5.22 - 4.97 (m, 2H), 3.93 (qd, J = 6.2, 3.3 Hz, 1H), 3.70 (ddt, J = 8.3, 5.7, 2.9 Hz, 1H), 2.34 (d, 7 = 2.6 Hz, 1H), 2.30 - 2.09 (m, 2H), 1.14 (d, J = 6.3 Hz, 3H), 1.12 - 1.03 (m, 21H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 134.91, 117.07, 74.48, 70.77, 36.72, 18.06, 16.59, 12.37; IR (neat) 3480, 2943, 2866, 1463, 1067, 881 cm ^_1 ; HRMS-ESI (mJz) calcd for [Ci ₅ H ₃₃ 0 ₂ Si] ⁺ ,

274.2270; found, 274.2274; R _f = 0.53 in 20% Ethyl acetate : hexanes, one UV-inactive purple spot (p-anisaldehyde stain). [0064] Example 4A: Preparation of triisopropyl(((2S,3 ?)-3-((4-methoxybenzyl)oxy)hex-5- en-2-yl)oxy) silane :

[0065] In a 250 mL round-bottom flask, a suspension of sodium hydride (0.441 g, 11.04 mmol) was prepared in DMF (45.7 mL) under an atmosphere of N ₂ and cooled to 0 °C in an ice/water bath. After 5 min, (2S,3 ?)-2-((triisopropylsilyl)oxy)hex-5-en-3-ol (2.005 g, 7.36 mmol) was added via syringe as a solution in DMF (6 mL with 2 x 3 mL washes) over 5 min. The resulting bright yellow reaction mixture was brought to room temperature and stirred for 2 h, during which time bubbling was observed and the reaction progressed from bright yellow to orange. The reaction was cooled to 0 °C and tetrabutylammonium iodide (0.272 g, 0.736 mmol) was added in one portion followed by 4-methoxybenzyl bromide (1.716 mL, 11.77 mmol), after which the reaction underwent a distinct color change to light yellow. The reaction mixture was warmed to room temperature and stirred for 2 h. TLC indicated incomplete consumption of starting material and additional tetrabutylammonium iodide (0.272 g, 0.736 mmol) and 4-methoxybenzyl bromide (1.716 mL, 11.77 mmol) was added. The resulting yellow reaction mixture was stirred at room

temperature overnight. TLC indicated near consumption of starting material. The yellow reaction mixture was cooled to 0 °C and diethylamine (2.283 mL, 22.07 mmol) was added over 10 seconds. The reaction was warmed to room temperature and stirred for 1 h, after which the reaction was poured over saturated aqueous NH ₄ C1 (75 mL) and extracted with Et ₂ 0 (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over MgS0 ₄ , filtered, and concentrated to afford a yellow oil. The oil was purified by flash column chromatography (Si0 ₂ , 0"M5% MTBE in petroleum ether) to afford the title compound (2.605 g, 6.63 mmol, 90% yield) as a clear, colorless oil: 1H NMR (400 MHz, CDC1 ₃ ) δ 7.28 (d, = 8.6 Hz, 2H), 6.86 (d, = 8.6 Hz, 2H), 5.99 - 5.76 (m, 1H), 5.15 - 4.98 (m, 2H), 4.70 (d, = 11.1 Hz, 1H), 4.52 (d, = 11.1 Hz, 1H), 3.98 (qd, = 6.2, 3.5 Hz, 1H), 3.79 (s, 3H), 3.45 (ddd, = 7.5, 5.3, 3.5 Hz, 1H), 2.38 - 2.19 (m, 2H), 1.23 (d, J = 6.2 Hz, 3H), 1.10 - 1.02 (m, 21H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 159.02, 135.76, 131.34, 129.32, 116.52, 113.65, 83.67, 72.77, 71.11, 55.27, 36.43, 18.69, 18.22, 12.53; IR (neat) 3075, 2942, 2892, 2865, 1641, 1613, 1587, 1513, 1463, 1382, 1301, 1246, 1171, 1093, 1067, 1038, 1012, 997, 965, 914, 882, 820, 762, 677, 574 cm ^"1 ; HRMS-ESI (m/z) calcd for [C ₂ 3H ₄₀ O ₃ SiNa] ⁺ , 415.26389; found, 415.26297; R _f = 0.57 in 10% Ethyl acetate : hexanes, one UV-active dark blue spot (p-anisaldehyde stain).

[0066] Example 4B: Preparation of (((2S,3tf)-3-(benzyloxy)hex-5-en-2- yl)oxy)triisopropylsilane:

[0067] A slurry of NaH (0.549 g, 13.7 mmol) and DMF (50 mL) was cooled to 0 °C. A solution of (2S,3tf)-2-((triisopropylsilyl)oxy)hex-5-en-3-ol (3.40 g, 12.5 mmol) in DMF (50 mL) was added via cannula, and the reaction mixture was brought to rt and stirred for 4 h. The reaction mixture was cooled to 0 °C, and benzyl bromide (1.78 mL, 15.0 mmol) was added by syringe. The reaction mixture was allowed to warm to rt and stirred for 2 h, then poured over saturated aqueous NH ₄ C1 (100 mL), extracted with Et ₂ 0 (3 X 100 mL), washed with H ₂ 0 (3 X 75 mL), and dried over MgS0 ₄ . The combined organic layers were evaporated to yield a colorless oil that was purified by flash column chromatography (100% hexanes to 8% ethyl acetate : hexanes) to afford (((2S,3 ?)-3- (benzyloxy)hex-5-en-2-yl)oxy)triisopropylsilane (4.02 g, 11.09 mmol, 89 % yield) as a clear, colorless oil (Si0 ₂ , 0-^8% ethyl acetate in hexanes) to afford the title compound (4.02 g, 11.1 mmol, 89% yield) as a clear, colorless oil: 1H NMR (400 MHz, CDC1 ₃ ) δ 7.47 - 7.21 (m, 5H), 5.88 (dqd, = 17.1, 7.2, 3.9 Hz, 1H), 5.27 - 5.00 (m, 2H), 4.78 (d, = 11.5 Hz, 1H), 4.59 (d, = 11.5 Hz, 1H), 3.99 (tq, = 6.3, 3.4 Hz, 1H), 3.47 (ddd, = 8.0, 5.1, 3.1 Hz, 1H), 2.60 - 2.01 (m, 2H), 1.24 (d, = 6.3 Hz, 3H), 1.15 - 0.97 (m, 21H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 135.70, 128.26, 128.23, 127.73, 127.34, 116.60, 84.00, 73.12, 71.13, 36.44, 18.64, 18.23, 12.55; HRMS-ESI (m/z) calcd for [C ₂ 2H ₃₉ 0 ₂ Si] ⁺ , 364.2741; found, 364.2742; R _f = 0.69 in 10% Ethyl acetate : hexanes, one UV-active purple spot (p-anisaldehyde stain). [0068] Example 5: Preparation of (77?,8S,Z)-methyl 2-((tert-butoxycarbonyl)amino)-7-((4- methoxybenzyl)oxy)-8-((triisopropylsilyl)oxy)non-2-enoate:

[0069] In a 25 mL vial, triisopropyl(((2S,3 ?)-3-((4-methoxybenzyl)oxy)hex-5-en-2- yl)oxy)silane (542 mg, 1.380 mmol) was dissolved in THF (3451 μί) under an atmosphere of N ₂ . To this solution was added 9-BBN (0.5 M in THF, 5245 μί, 2.62 mmol) via syringe over 30 seconds. The resulting clear, colorless solution was stirred at room temperature overnight. After 16 h, TLC indicated consumption of starting material and the formation of several new spots. To the reaction was added K ₃ P0 ₄ (3 M aqueous solution, 920 μί, 2.76 mmol) slowly, and the evolution of hydrogen gas was observed. (Z)-methyl 3-bromo-2-((tert-butoxycarbonyl)amino)acrylate (391 mg, 1.394 mmol) was then added as a solution in DMF (2 mL w/ 2 x 0.75 mL washes) via syringe followed by PdCl ₂ (dppf) (101 mg, 0.138 mmol). The reaction was fitted with a reflux condensor and flushed with N ₂ . The resulting red colored reaction was then heated to 55 °C and stirred for 6 h, producing a deep black colored reaction mixture. After 6 h, TLC indicated consumption of starting material, and the reaction was quenched with saturated aqueous NaHC0 ₃ (10 mL). The aqueous layer was extracted with El^O (3 x 10 mL). The combined organic layers were dried over MgS0 ₄ , filtered and concentrated to afford an orange colored oil. The oil was purified by flash column chromatography (Si0 ₂ , 0-^20% ethyl acetate in hexanes) to afford the title compound (707.4 mg, 1.191 mmol, 86% yield) as a pale yellow oil: ¹ H NMR (400 MHz, CDC1 ₃ ) δ 7.35 - 7.19 (m, 2H), 6.93 - 6.79 (m, 2H), 6.53 (t, = 7.3 Hz, 1H), 6.02 (s, 1H), 4.84 - 4.70 (m, 1H), 4.58 - 4.31 (m, 1H), 3.95 (qd, = 6.1, 2.8 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.40 (dt, = 8.3, 3.3 Hz, 1H), 2.19 (td, = 8.2, 7.8, 5.9 Hz, 2H), 1.95 - 1.74 (m, 2H), 1.74 - 1.57 (m, 2H), 1.58 - 1.32 (m, 12H), 1.21 (d, = 6.2 Hz, 3H), 1.08 (s, 18H); JR (neat) 3335, 2938, 2865, 1709, 1658, 1613, 1587, 1513, 1463, 1437, 1412, 1366, 1341, 1299, 1246, 1163, 1104, 1038, 1013, 917, 882, 821, 764, 732, 677, 575 cm ^"1 ; ESEVIS m/z 616.5 [C ₃ 2H ₅₅ N0 ₇ SiNa] ⁺ ; R _f = 0.33 in 20% Ethyl acetate : hexanes, one UV-active black spot (p-anisaldehyde stain).

[0070] Example 6: Preparation of (2S,7R,8S)-methyl 2-((tert-butoxycarbonyl)amino)-7-((4- methoxybenzyl)oxy)-8-((triisopropylsilyl)oxy)nonanoate:

[0071] A high pressure reactor was charged with a solution of (7 ?,8S,Z)-methyl 2-((tert- butoxycarbonyl)amino)-7-((4-methoxybenzyl)oxy)-8-((triisopro pylsilyl)oxy)non-2-enoate (0.626 g,

I.054 mmol) in anhydrous methanol (10.54 mL). The resulting solution was sparged with N ₂ using a needle for 20 min. (S,S)-Et-DUPHOS-Rh (0.023 g, 0.032 mmol) was added in one portion, and the reaction vessel was sealed. The vessel was flushed with H ₂ gas three times and then pressurized with H ₂ to 200 psi. The reaction was then stirred at room temperature overnight. After 16 h, TLC indicated consumption of starting material and conversion to a slightly higher R _f spot. The reaction was concentrated under reduced pressure to yield an orange oil. The oil was purified by flash column chromatography (Si0 ₂ , 0-^30% ethyl acetate in hexanes) to afford the title compound (613.6 mg, 1.030 mmol, 98% yield) as a clear, colorless oil: 1H NMR (400 MHz, CDC1 ₃ ) δ 7.32 - 7.21 (m, 2H), 6.92 - 6.82 (m, 2H), 5.02 (d, J = 8.4 Hz, 1H), 4.77 (d, J = 11.0 Hz, 1H), 4.46 (d, / =

I I .1 Hz, 1H), 4.27 (td, J = 8.1, 5.2 Hz, 1H), 3.94 (qd, J = 6.2, 2.8 Hz, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.38 (dt, J = 8.4, 3.4 Hz, 1H), 1.94 - 1.71 (m, 2H), 1.71 - 1.55 (m, 2H), 1.44 (m, 11H), 1.36 - 1.24 (m, 3H), 1.21 (d, J = 6.2 Hz, 3H), 1.08 (m, 20H); IR (neat) 3364, 2941, 2865, 1745, 1716, 1613, 1586, 1513, 1463, 1390, 1365, 1301, 1246, 1210, 1168, 1103, 1038, 1012, 917, 882, 821, 760, 732, 678, 586 cm ^"1 ; HRMS-ESI (m/z) [M-Boc+H]+ calcd for [C ₂₇ H ₅ oN0 ₅ Si] ⁺ , 496.3458; found, 496.3455; R _f = 0.29 in 20% Ethyl acetate : hexanes, one UV-active purple spot (p- anisaldehyde stain).

[0072] Example 7: Preparation of (2S,7R,8S)-methyl 2-((tert-butoxycarbonyl)

hydroxy-7-((4-methoxybenzyl)oxy)nonanoate:

[0073] In a small vial, (2S,7R,8S)-methyl 2-((tert-butoxycarbonyl)amino)-7-((4- methoxybenzyl)oxy)-8-((triisopropylsilyl)oxy)nonanoate (207.1 mg, 0.348 mmol) was dissolved in THF (3476 μί) under N ₂ and cooled to 0 °C in an ice/water bath. After ~5 min,

tetrabutylammonium fluoride (1M in THF, 417 μί, 0.417 mmol) was added via syringe over 2 min. The reaction mixture was then allowed to warm to room temperature as the ice melted and stirred overnight. After 20 h, TLC indicated consumption of starting material. The reaction was quenched with saturated aqueous NH ₄ C1 (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were passed through a phase separator and concentrated to afford a clear, colorless oil. The oil was purified by flash column chromatography (Si0 ₂ , 0-^80% ethyl acetate in hexanes) to afford the title compound (107.6 mg, 0.245 mmol, 70% yield) as a clear, colorless oil: ¹ H NMR (400 MHz, CDC1 ₃ ) δ 7.31 - 7.20 (m, 2H), 6.94 - 6.83 (m, 2H), 5.13 - 4.93 (m, 1H), 4.61 - 4.38 (m, 2H), 4.36 - 4.19 (m, 1H), 3.95 (dtd, J = 9.3, 6.6, 3.3 Hz, 1H), 3.81 (s, 3H), 3.73 (d, J = 1.0 Hz, 3H), 3.29 (dt, J = 7.8, 3.7 Hz, 1H), 2.20 - 2.01 (m, 1H), 1.79 (ddt, = 14.7, 9.9, 5.4 Hz, 1H), 1.69 - 1.41 (m, 4H), 1.44 (s, 9H), 1.30 (dddd, J = 21.5, 11.2, 7.4, 3.6 Hz, 3H), 1.18 - 1.11 (m, 3H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 173.39, 159.26, 155.36, 130.61, 129.41, 129.21, 113.86, 82.30, 71.75, 67.85, 55.28, 53.34, 52.21, 32.74, 28.68, 28.33, 25.44, 25.25, 17.80; IR (neat) 3360, 2935, 2862, 1741, 1707, 1612, 1586, 1512, 1455, 1391, 1365, 1301, 1245, 1032, 912, 821, 780, 731, 647, 879, 564, 553, 531 cm ^"1 ; HRMS-ESI (m/z) calcd for [C ₂₃ H ₃₇ NNa0 ₇ ] ⁺ , 462.2462; found, 462.2466; R _f = 0.13 in 40% Ethyl acetate : hexanes, one UV-active purple spot (p-anisaldehyde stain).

[0074] Example 8, Step 1 : Preparation of (2S,7tf ,8S)-2-((tert-butoxycarbonyl)

hydroxy-7-((4-methoxybenzyl)oxy)nonanoic acid:

[0075] In a small vial, (2S,7R,8S)-methyl 2-((tert-butoxycarbonyl)amino)-8-hydroxy-7-((4- methoxybenzyl) oxy)nonanoate (302.3 mg, 0.688 mmol) was dissolved in THF (4585 μί)Λ\¾εΓ (2293 μί). To this solution, lithium hydroxide hydrate (87 mg, 2.063 mmol) was added in one portion and the reaction was stirred at room temperature for 3 h. TLC indicated conversion to a more polar spot. UPLC supported formation of a product corresponding to the desired molecular weight. The reaction was diluted with EtOAc (30 mL) and then washed with 0.2 M HC1 (30 mL) followed by brine (30 mL). The organic layer was dried over Ν¾80 ₄ , filtered and concentrated to afford the title compound as a colorless, cloudy oil that was used directly in the next step without further purification: 1H NMR (400 MHz, CDC1 ₃ ) δ 7.31 - 7.19 (m, 2H), 6.93 - 6.82 (m, 2H), 5.13 (d, 7 = 8.2 Hz, 1H), 4.50 (q, = 11.2 Hz, 2H), 4.29 (q, 7 = 6.9 Hz, 1H), 3.97 (qd, J = 6.5, 3.4 Hz, 1H), 3.79 (s, 3H), 3.30 (dt, J = 7.3, 3.5 Hz, 1H), 1.90 - 1.71 (m, 1H), 1.71 - 1.20 (m, 8H), 1.44 (s, 9H), 1.14 (d, J = 6.4 Hz, 3H), no COOH observed; IR (neat) 2934, 2364, 1711, 1612, 1513, 1456, 1393, 1367, 1302, 1247, 1170, 1034, 912, 822, 734, 641 631, 621, 604, 594 cm ^"1 ; HRMS-ESI (m/z) calcd for [C ₂₂ H ₃₅ NNa0 ₇ ] ⁺ , 448.2306; found, 448.2308; R _f = baseline in 40% Ethyl acetate : hexanes, one UV-active purple spot (p-anisaldehyde stain).

[0076] Example 8, Step 2: Preparation of tert-butyl ((3S,8tf ,9S)-8-((4-methoxybenzyl)oxy)- 9-methyl-2-oxooxonan-3-yl)carbamate:

[0077] In a 500 mL round-bottom flask, 2-methyl-6-nitrobenzoic anhydride (0.479 g, 1.391 mmol) and N^V-dimethylpyridin-4-amine (0.510 g, 4.17 mmol) was dissolved in DCM (79 mL) under N ₂ . (2S,7 ?,8S)-2-((tert-butoxycarbonyl)amino)-8-hydroxy-7-((4- methoxybenzyl)oxy)nonanoic acid (0.296 g, 0.696 mmol) was then added as a solution in DCM (60 mL) via syringe over 4 hours. The reaction was stirred at room temperature overnight. After 18 h, TLC indicated consumption of starting material and conversion to a major higher R _f spot and a small amount of byproduct. The reaction was quenched with 100 mL 0.2 M HC1 and the layers were separated. The organic phase was washed with one-half aqueous saturated NaHC0 ₃ (100 mL). The organic phase was then passed through a phase separator and concentrated to afford a clear, colorless oil. The oil purified by flash column chromatography (Si0 ₂ , 0-^20% ethyl acetate in hexanes) to afford the title compound (107.0 mg, 0.263 mmol, 38% yield over two steps) as a pale yellow oil: 1H NMR (400 MHz, CDC1 ₃ ) δ 7.26 - 7.20 (m, 2H), 6.93 - 6.84 (m, 2H), 5.19 (d, / = 8.0 Hz, 1H), 5.03 (dq, J = 8.9, 6.3 Hz, 1H), 4.53 (d, J = 11.3 Hz, 1H), 4.33 (d, J = 11.3 Hz, 1H), 4.20 - 4.05 (m, 1H), 3.80 (s, 3H), 3.20 - 3.11 (m, 1H), 2.27 - 2.09 (m, 1H), 1.74 (ddt, = 15.2, 13.1, 4.5 Hz, 2H), 1.53 (dddt, J = 17.3, 13.8, 7.7, 3.5 Hz, 3H), 1.43 (s, 10H), 1.34 (d, J = 6.3 Hz, 3H), 1.30 - 1.20 (m, 1H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 173.64, 159.27, 154.91, 130.05, 129.45, 113.81, 82.58, 79.74, 73.40, 70.77, 55.27, 53.87, 32.59, 28.92, 28.33, 28.03, 21.83, 18.21 ; IR (neat) 3371, 2935, 1710, 1512, 1247, 1160, 1063 cm ^"1 ; HRMS-ESI (m/z) calcd for [C ₂₂ H ₃₃ N0 ₆ Na] ⁺ , 430.22001; found, 430.22118; R _f = 0.29 in 20% Ethyl acetate : hexanes, one UV-active purple spot p- anisaldehyde stain). [0078] Example 9: Preparation of tert-butyl N-[((3S,8tf ,9S)-8-((4-methoxybenzyl)oxy)-9- methyl-2-oxooxonan-3-yl)]-N-tert-butoxycarbonyl-carbamate:

[0079] The reaction can be conducted as in Example 2, Step lb in US 2015/0094341 Al. 1H NMR (400 MHz, CDC1 ₃ ) δ 7.26 - 7.18 (m, 2H), 6.92 - 6.83 (m, 2H), 4.88 (dq, J = 9.0, 6.3 Hz, 1H), 4.71 (dd, J = 11.8, 5.4 Hz, 1H), 4.54 (d, J = 11.3 Hz, 1H), 4.33 (d, 7 = 11.2 Hz, 1H), 3.80 (s, 3H), 3.18 - 3.10 (m, 1H), 2.27 (dddd, J = 13.9, 11.8, 7.3, 1.9 Hz, 1H), 2.00 (dddd, J = 14.1, 10.4, 5.4, 1.9 Hz, 1H), 1.87 - 1.74 (m, 2H), 1.73 - 1.52 (m, 4H), 1.50 (s, 18H), 1.33 (d, J = 6.3 Hz, 3H); ¹³ C NMR (101 MHz, CDCI3) δ 171.21, 159.27, 152.93, 130.23, 129.42, 113.82, 82.76, 82.56, 73.64, 70.75, 58.93, 55.29, 30.64, 29.62, 29.01, 27.98, 23.24, 18.32; IR (thin film) 2978, 2934, 1743, 1703, 1353, 1246, 1171 cm ^"1 ; HRMS-ESI (m/z) calcd for 530.2724; found, 530.2726; R _f = 0.37 in 20% Ethyl acetate : hexanes, one UV-active blue/purple spot (p-anisaldehyde stain).

[0080] Example 10: Preparation of tert-butyl ((3S,8 ?,9S)-8-hydroxy-9-methyl-2-oxooxonan- 3-yl)carbamate:

[0081] In a small vial flask, tert-butyl ((3S,8tf ,9S)-8-((4-methoxybenzyl)oxy)-9-methyl-2- oxooxonan-3-yl)carbamate (107 mg, 0.263 mmol) was dissolved in acetonitrile (4774 μί) and water (477 μί). The resulting clear solution was cooled to 0 °C in an ice water bath. After 5 minutes, eerie ammonium nitrate (720 mg, 1.313 mmol) was added in one portion. The

yellow/orange colored solution was stirred at 0 °C for 2 hrs. After 2 hrs, TLC indicated

consumption of starting material. The reaction was diluted with CH ₂ C1 ₂ (25 mL) and H ₂ 0 (25 mL), and the layers were separated. The aqueous layer was extracted with CH ₂ C1 ₂ (3 x 25 mL). The combined organic layers were washed with saturated aqueous NaHC0 ₃ (50 mL), brine (50 mL), and then passed through a phase separator. The oil was purified by flash column chromatography (Si0 ₂ , 0-^60% ethyl acetate in hexanes) to afford the title compound (51.8 mg, 0.180 mmol, 67% yield) as a clear, colorless oil: 1H NMR (400 MHz, CDC1 ₃ ) δ 5.17 (d, = 8.0 Hz, 1H), 4.94 (dq, = 8.3, 6.3 Hz, 1H), 4.16 (ddd, 7 = 10.8, 7.9, 5.5 Hz, 1H), 3.50 (dtd, J = 8.3, 6.3, 5.8, 2.2 Hz, 1H), 2.28 - 2.07 (m, 1H), 1.95 (d, J = 6.0 Hz, 1H), 1.87 - 1.51 (m, 6H), 1.44 (s, 9H), 1.39 (d, J = 6.4 Hz, 3H), 1.32 - 1.20 (m, 1H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 173.91, 154.95, 79.86, 75.84, 74.95, 53.71, 33.52, 32.97, 28.33, 26.81, 22.08, 18.09; IR (neat) 3373, 2977, 2935, 2251, 1689, 1505, 1454, 1367, 1319, 1252, 1200, 1160, 1045, 911, 862, 783, 730 cm ^"1 ; HRMS-ESI (m/z) calcd for [Ci ₄ H ₂₅ NNa0 ₅ ] ⁺ , 310.1625; found, 310.1625; R _f = 0.24 in 50% Ethyl acetate : hexanes, one UV-inactive purple spot (p-anisaldehyde stain).

[0082] Example 11A: Preparation of (2S,3 ?,8S)-8-((tert-butoxycarbonyl)amino)-2-methyl-9- oxooxonan-3-yl isobutyrate:

[0083] The reaction can be conducted as in Example 5, in US 2015/0094341A1: 1H NMR (400 MHz, CDC1 ₃ ) δ 5.29 (d, J = 7.9 Hz, 1H), 5.15 (dq, / = 9.0, 6.3 Hz, 1H), 4.54 (ddd, / = 9.1, 6.7, 2.5 Hz, 1H), 4.18 (ddd, / = 10.8, 8.0, 5.4 Hz, 1H), 2.54 (hept, = 7.0 Hz, 1H), 2.33 - 2.08 (m, 1H), 1.80 (ddt, = 15.1, 9.4, 5.1 Hz, 2H), 1.72 - 1.51 (m, 3H), 1.44 (s, 9H), 1.41 - 1.32 (m, 1H), 1.30 (d, = 6.3 Hz, 4H), 1.16 (dd, = 7.0, 3.7 Hz, 6H); IR (thin film) 3379, 2976, 1714, 1366, 1152 cm ^"1 ; HRMS-ESI (m/z) calcd for [Ci ₈ H ₃ iNNa0 ₆ ] ⁺ , 380.2044; found, 380.2044; R _f = 0.67 in 30% Ethyl acetate : hexanes, one UV-inactive black spot (p-anisaldehyde stain).

[0084] Example 11B: Preparation of tert-butyl ((3S,8 ?,9S)-8-(4-fluorophenoxy)-9-methyl-2- oxooxonan-3-yl)carbamate:

[0085] The reaction can be conducted as in Example 1, Step 2a in US 2015/0094341 Al: 1H NMR (400 MHz, CDC1 ₃ ) δ 7.02 - 6.91 (m, 2H), 6.84 - 6.71 (m, 2H), 5.23 (dq, 7 = 8.6, 6.3 Hz, 2H), 4.21 (ddd, 7 = 11.1, 8.0, 5.3 Hz, 1H), 3.91 (ddd, 7 = 8.8, 7.3, 1.3 Hz, 1H), 2.32 - 2.19 (m, 1H), 1.90 - 1.55 (m, 5H), 1.55 - 1.47 (m, 1H), 1.45 (s, 9H), 1.41 (d, 7 = 6.3 Hz, 3H), 1.37 - 1.21 (m, 1H); ¹³ C NMR (126 MHz, CDCI3) δ 173.62, 157.41 (d, 7 = 239.2 Hz), 154.91, 153.29 (d, 7 = 2.3 Hz), 116.87 (d, 7 = 7.9 Hz), 116.01 (d, 7 = 23.1 Hz), 82.10, 79.86, 72.76, 53.92, 32.69, 28.84, 28.33, 27.70, 21.97, 18.25; ¹⁹ F NMR (471 MHz, CDC1 ₃ ) δ -123.23; IR (thin film) 3373, 2937, 1705, 1502, 1159, 1047 cm ^"1 ; HRMS-ESI (m/z) calcd for [C ₂ oH ₂₈ FNNa0 ₅ ] ⁺ , 404.1844; found, 404.1842; R _f = 0.55 in 30% Ethyl acetate : hexanes, one UV-active red spot (p-anisaldehyde stain).

[0086] Example 11C, Step 1 : Preparation of tert-butyl N- [((3S,8tf ,9S)-8-(allyloxy)-9-methyl- 2-oxooxonan-3 -yl)] -N-tert-butoxycarbonyl-carbamate:

[0087] The reaction can be conducted as in Example 3, Step 1 in US 2015/0094341A1. 1H NMR (400 MHz, CDCI3) δ 6.40 (ddtd, 7 = 15.7, 6.1, 3.8, 2.1 Hz, 1H), 6.01 - 5.81 (m, 1H), 4.90 (dq, 7 = 8.6, 6.3 Hz, 1H), 4.74 (dd, 7 = 11.6, 5.5 Hz, 1H), 4.23 - 4.11 (m, 1H), 4.05 - 3.92 (m, 1H), 3.13 (ddd, 7 = 8.6, 5.3, 1.4 Hz, 1H), 2.28 (dddd, 7 = 13.8, 11.6, 7.6, 1.9 Hz, 1H), 2.02 (dddd, 7 = 14.2, 10.3, 5.6, 1.9 Hz, 1H), 1.90 - 1.76 (m, 1H), 1.77 - 1.61 (m, 1H), 1.61 - 1.47 (m, 22H), 1.36 (d, 7 = 6.3 Hz, 3H); ¹³ C NMR (101 MHz, CDCI3) δ 171.12, 152.94, 136.45 (q, 7 = 6.4 Hz), 123.06 (q, 7 = 269.0 Hz), 118.71 (q, 7 = 33.8 Hz), 84.22, 82.65, 73.17, 66.80, 58.84, 30.74, 29.55, 28.59, 27.99, 23.39, 18.33; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -64.27; IR (thin film) 2981, 2939, 1744, 1705, 1263, 1123 cm ^"1 ; HRMS-ESI (m/z) calcd for [CisHseFsNNaCyT, 518.2336; found, 518.2335; R _f = 0.56 in 30% Ethyl acetate : hexanes, one UV-inactive purple spot (p-anisaldehyde stain).

[0088] Example 11C, Step 2: Preparation of tert-butyl N-[((3S,8tf ,9S)-9-methyl-2-oxo-8- propoxyoxonan-3-yl)]-N-tert-butoxycarbonyl-carbamate:

[0089] The reaction can be conducted as in Example 3 , Step 2a in US 2015/0094341 A 1. 1H NMR (400 MHz, CDC1 ₃ ) d 4.83 (dq, 7 = 8.8, 6.3 Hz, 1H), 4.72 (dd, 7 = 11.7, 5.4 Hz, 1H), 3.58 (dt, 7 = 9.2, 5.9 Hz, 1H), 3.34 (dt, 7 = 9.2, 6.0 Hz, 1H), 3.03 (ddd, 7 = 8.8, 7.4, 1.4 Hz, 1H), 2.36 - 2.09 (m, 3H), 2.01 (dddd, 7 = 14.2, 10.4, 5.5, 1.9 Hz, 1H), 1.90 - 1.74 (m, 3H), 1.74 - 1.61 (m, 2H), 1.51 (s, 21H), 1.33 (d, 7 = 6.3 Hz, 3H); ¹³ C NMR (101 MHz, CDCI3) δ 171.21, 152.95, 131.75 - 122.83 (m), 84.08, 82.60, 73.36, 67.26, 58.88, 30.77 (q, 7 = 28.9 Hz), 30.68, 29.59, 28.88, 27.97, 23.26, 22.71 (q, 7 = 3.0 Hz), 18.29; IR (thin film) 2980, 2936, 1743, 1704, 1354, 1249, 1144 cm ^"1 ; HRMS- ESI (m/z) calcd for [C ₂₃ H ₃₈ F ₃ NNa0 ₇ ] ⁺ , 520.2493; found, 520.2496; R _f = 0.56 in 30% Ethyl acetate : hexanes, one UV-inactive dark purple spot (p-anisaldehyde stain).

[0090] Example 11D, Step 1: Preparation of tert-butyl N-[((3S,8tf ,9S)-9-methyl-2-oxo-8- (((E)-3-oxobut- 1-en- 1 -yl)oxy)oxonan-3-yl)] -N-tert-butoxycarbonyl-carbamate:

The reaction can be conducted as in Example 4, Step 1 in US 2015/0094341A1. 1H NMR (400 MHz, CDCI3) δ 7.41 (d, 7 = 12.8 Hz, 1H), 5.58 (d, 7 = 12.7 Hz, 1H), 5.00 (dq, 7 = 8.9, 6.3 Hz, 1H), 4.76 (dd, 7 = 11.6, 5.6 Hz, 1H), 3.77 - 3.64 (m, 1H), 2.29 (dddd, 7 = 13.6, 11.5, 6.1, 2.3 Hz, 1H), 2.18 (s, 3H), 2.05 (dddd, 7 = 14.2, 10.4, 5.6, 1.7 Hz, 1H), 1.95 - 1.79 (m, 1H), 1.70 (tdd, 7 = 11.2, 8.7, 5.5 Hz, 3H), 1.56 - 1.49 (m, 20H), 1.34 (d, J = 6.3 Hz, 3H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 197.13, 171.00, 160.75, 152.89, 108.61, 85.69, 82.77, 72.14, 58.73, 30.57, 30.17, 28.20, 28.16, 27.99, 23.24, 18.12; IR (thin film) 2981, 2935, 1745, 1705, 1356, 1169, 1144 cm ^"1 ; HRMS-ESI (m/z) calcd for [C ₂₃ H ₃₇ NNa0 ₈ ] ⁺ , 478.2411 ; found, 478.2417; R _f = 0.26 in 30% Ethyl acetate : hexanes, one UV-active red spot (p-anisaldehyde stain).

[0091] Example 11D, Step 2: Preparation of tert-butyl N-[((3S,8tf ,9S)-9-methyl-2-oxo-8-(3- oxobutoxy)oxonan-3-yl)]-N-tert-butoxycarbonyl-carbamate:

[0092] The reaction can be conducted as in Example 4, Step 2 in US 2015/0094341A1. 1H NMR (400 MHz, CDC1 ₃ ) δ 4.79 (dq, / = 9.0, 6.3 Hz, 1H), 4.71 (dd, / = 11.7, 5.4 Hz, 1H), 3.79 (dt, = 9.3, 6.0 Hz, 1H), 3.56 (dt, / = 9.3, 6.2 Hz, 1H), 3.04 (ddd, = 8.9, 7.7, 1.3 Hz, 1H), 2.67-2.61 (m, 2H), 2.26 (dddd, / = 13.9, 11.7, 7.3, 1.9 Hz, 1H), 2.18 (s, 3H), 2.00 (dddd, / = 14.3, 10.5, 5.5, 1.9 Hz, 1H), 1.81 (tdd, = 11.0, 5.4, 1.9 Hz, 1H), 1.76-1.62 (m, 3H), 1.61- 1.40 (m, 2H), 1.51 (s, 18H), 1.31 (d, = 6.3 Hz, 3H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 207.06, 171.23, 152.92, 84.35, 82.56, 73.36, 64.21, 58.89, 43.68, 30.69, 30.61, 29.42, 29.00, 27.96, 23.19, 18.21 ; IR (neat) 2978.60, 1742.12, 1702.41, 1353.21, 1108.97 cm ^"1 ; HRMS-ESI (m/z) calcd for [C ₂₃ H ₃₉ NNa0 ₈ ] ⁺ , 480.2568; found, 480.2573.

[0093] Example 11D, Step 3: Preparation of tert-butyl N-[((3S,8 ?,9S)-8-(3,3- difluorobutoxy)-9-methyl-2-oxooxonan-3-yl)]-N-tert-butoxycar bonyl-carbamate:

[0094] The reaction can be conducted as in Example 4, Step 3 in US 2015/0094341A1. 1H NMR (400 MHz, CDC1 ₃ ) δ 4.82 (dq, / = 8.8, 6.3 Hz, 1H), 4.72 (dd, / = 11.7, 5.4 Hz, 1H), 3.70 (dt, 7 = 9.5, 6.5 Hz, 1H), 3.46 (dt, 7 = 9.5, 6.5 Hz, 1H), 3.04 (ddd, 7 = 8.9, 7.5, 1.4 Hz, 1H), 2.27 (dddd, 7 = 13.8, 11.7, 7.4, 1.9 Hz, 1H), 2.19-1.96 (m, 3H), 1.82 (dddd, 7 = 17.0, 11.1, 4.8, 2.6 Hz, 1H), 1.76-1.56 (m, 6H), 1.51 (s, 20H), 1.34 (d, 7 = 6.3 Hz, 3H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 171.21, 152.92, 123.40 (t, 7 = 237.9 Hz), 84.28, 82.57, 73.32, 63.27 (t, 7 = 6.2 Hz), 58.87, 38.33 (t, 7 = 25.5 Hz), 30.64, 29.42, 28.91, 27.95, 23.99 (t, 7 = 27.4 Hz), 23.23, 18.25; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -88.67 (d, 7 = 241.5 Hz), -89.51 (d, 7 = 241.6 Hz); ffi. (neat) 2978.73, 1742.76, 1702.63, 1336.74, 1141.25, 1122.27 cm ^"1 ; HRMS-ESI (m/z) calcd for [C ₂ H ₃ 9F ₂ NNa0 ₇ ] ⁺ , 502.2587; found, 502.2597.

[0095] Example HE: Preparation of tert-butyl ((3S,8tf ,9S)-8-methoxy-9-methyl-2- oxooxonan-3-yl)carbamate:

[0096] The reaction can be conducted as in Example 6, in US 2015/0094341A1. 1H NMR (400 MHz, CDC1 ₃ ) δ 5.22 (d, 7 = 8.0 Hz, 1H), 4.97 (dq, 7 = 8.7, 6.3 Hz, 1H), 4.15 (ddd, 7 = 10.9, 7.9, 5.2 Hz, 1H), 3.31 (s, 3H), 2.96 (ddd, 7 = 8.6, 6.9, 1.6 Hz, 1H), 2.35 - 2.04 (m, 1H), 1.82 - 1.66 (m, 2H), 1.66 - 1.52 (m, 2H), 1.44 (s, 11H), 1.36 (d, 7 = 6.3 Hz, 3H), 1.34 - 1.23 (m, 1H); IR (thin film) 3353, 2935, 1711, 1366, 1160, 1104, 1089 cm ^"1 ; HRMS-ESI (m/z) calcd for

[Ci ₅ H ₂₇ NNa0 ₅ ] ⁺ , 324.1781; found, 324.1784; Rf = 0.59 in 30% Ethyl acetate : hexanes, one UV- inactive black spot (p-anisaldehyde stain).

[0097] Example 12A, Step 1 : Preparation of (3S,8tf ,9S)-3-amino-8-((4-methoxybenzyl)oxy)- 9-methyloxonan-2-one :

[0098] In a 20 mL vial, tert-butyl ((3S,8tf ,9S)-8-((4-methoxybenzyl)oxy)-9-methyl-2- oxooxonan-3-yl)carbamate (242.8 mg, 0.596 mmol) was dissolved in DCM (5958 μί) and 2,6- lutidine (275 μί, 2.383 mmol) was added in one portion followed by trimethylsilyl

trifluoromethanesulfonate (269 μί, 1.490 mmol). The resulting yellow solution was stirred at room temperature for 2 hrs. After 2 h, TLC indicated consumption of starting material. Methanol (3 mL) was added and the reaction was stirred overnight. The reaction was concentrated under a stream of N ₂ and dried in an oven to provide the title compound (185 mg, 0.596 mmol, 100% yield) as a crude dark yellow oil that was used directly in the next step: IR (neat) 3528, 2954, 1736, 1241, 1213 cm ^"1 ; HRMS-ESI (m z) calcd for [Ci ₇ H ₂₆ N0 ₄ ] ⁺ , 308.1856; found, 308.1862; R _f = baseline in 20% Ethyl acetate : hexanes, one UV-active dark blue/black spot (p-anisaldehyde stain).

[0099] Example 12A, Step 2: Preparation of 3-hydroxy-4-methoxy-N-((3S,8tf ,9S)-8-((4- methoxybenzyl)oxy)-9-methyl-2-oxooxonan-3-yl)picolinamide:

[00100] To a vial containing (3S,8tf ,9S)-3-amino-8-((4-methoxybenzyl)oxy)-9- methyloxonan-2-one (183 mg, 0.595 mmol) was added 3-hydroxy-4-methoxypicolinic acid (111 mg, 0.655 mmol) and ((lH-benzo[d][l,2,3]triazol-l-yl)oxy)tri(pyrrolidin-l-yl)pho sphonium hexafluorophosphate(V) (341 mg, 0.655 mmol). DCM (5953 μί) was added followed by N-ethyl-

N-isopropylpropan-2-amine (342 μί, 1.965 mmol) dropwise over 45 seconds. After 10 min, all solids solubilized and the resulting rose colored reaction was stirred at room temperature overnight.

TLC indicated formation of a higher R _f product that glowed light blue under UV light. The reaction was concentrated under reduced pressure to yield a tan yellow colored oil. The oil was purified by flash column chromatography (Si0 ₂ , 0- 100% ethyl acetate in hexanes) to afford the title compound (134.6 mg, 0.294 mmol, 49% yield) as a colorless opaque oil: 1H NMR (400 MHz,

CDC1 ₃ ) δ 12.12 (s, 1H), 8.61 (d, J = 8.0 Hz, 1H), 8.00 (dd, J = 10.6, 5.2 Hz, 1H), 7.35 - 7.17 (m,

2H), 6.96 - 6.81 (m, 2H), 5.10 (dq, J = 8.8, 6.3 Hz, 1H), 4.63 - 4.47 (m, 2H), 4.35 (d, 7 = 11.1 Hz, 1H), 3.93 (s, 3H), 3.81 (s, 3H), 3.27 - 3.14 (m, 1H), 2.33 (dddd, J = 14.2, 10.7, 5.4, 2.0 Hz, 1H), 2.04 - 1.75 (m, 3H), 1.75 - 1.42 (m, 5H), 1.37 (d, J = 6.3 Hz, 3H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 172.56, 168.58, 159.30, 155.30, 148.68, 140.54, 130.44, 129.99, 129.48, 113.83, 109.44, 82.55, 73.75, 70.85, 56.06, 55.28, 52.44, 32.05, 28.95, 27.97, 21.89, 18.22; IR (neat) 3492, 3090, 2983, 1747, 1238, 1162, 1027 cm ^"1 ; HRMS-ESI (m/z) calcd for [C ₂₄ H ₃ iN ₂ 0 ₇ ] ⁺ , 459.2126; found,

459.2126.

[00101] Example 12B, Step 1: Preparation of (3S,8tf ,9S)-8-methoxy-9-methyl-2-oxooxonan- 3-aminium chloride:

[00102] Te/t-butyl ((3S,8tf ,9S)-8-methoxy-9-methyl-2-oxooxonan-3-yl)carbamate (291.9 mg, 0.969 mmol) was dissolved in DCM (2.0 mL) in a 20 mL vial and hydrogen chloride hydrogen chloride (4M in dioxane, 2.91 mL, 11.62 mmol) was added. The resulting clear, colorless solution was stirred at room temperature for 2 hrs, during which time the reaction became progressively cloudier. After 2 h, TLC indicated consumption of starting material. The reaction was concentrated under a stream of N ₂ and dried in an oven overnight to provide the title compound (230 mg, 0.969 mmol, 100% yield) as a crude pale yellow oil that was used directly in the next step: JR (neat) 3406, 2934, 1745, 1240, 1090 cm ^"1 ; HRMS-ESI (m/z) calcd for [CioH ₂₀ N0 ₃ ] ⁺ , 202.1438; found,

202.1440; R _f = baseline in 20% Ethyl acetate : hexanes, one UV-inactive pink/purple spot (p- anisaldehyde stain)

[00103] Example 12B, Step 2: Preparation of 3-hydroxy-4-methoxy-N-((3S,8tf ,9S)-8- methoxy-9-methyl-2-oxooxonan-3-yl)picolinamide:

[00104] To a vial containing (3S,8 ?,9S)-8-methoxy-9-methyl-2-oxooxonan-3-arninium chloride (230 mg, 0.969 mmol) was added 3-hydroxy-4-methoxypicolinic acid (197 mg, 1.163 mmol) and ((lH-benzo[d][l,2,3]triazol-l-yl)oxy)tri(pyrrolidin-l-yl)pho sphonium

hexafluorophosphate(V) (605 mg, 1.163 mmol). DCM (9689 μί) was added followed by N-ethyl- N-isopropylpropan-2-amine (608 μί, 3.49 mmol) dropwise over 45 seconds. After 10 min, all solids solubilized and the resulting rose colored reaction was stirred at room temperature for 2 h. TLC indicated formation of a higher R _f product that glowed light blue under UV light. The reaction was concentrated under reduced pressure to yield a tan yellow colored oil. The oil was purified by flash column chromatography (Si0 ₂ , 0~ 100% ethyl acetate in hexanes) to afford the title compound (332.3 mg, 0.943 mmol, 97% yield) as a pale yellow oil: 1H NMR (400 MHz,

CDC1 ₃ ) δ 12.12 (d, J = 0.7 Hz, 1H), 8.62 (d, = 7.9 Hz, 1H), 7.98 (d, = 5.2 Hz, 1H), 6.87 (d, = 5.2 Hz, 1H), 5.04 (dq, = 8.6, 6.3 Hz, 1H), 4.56 (ddd, / = 10.9, 7.9, 5.3 Hz, 1H), 3.94 (d, = 1.1 Hz, 3H), 3.34 (s, 3H), 3.01 (ddd, / = 8.6, 6.9, 1.6 Hz, 1H), 2.34 (dddd, = 14.2, 10.5, 5.3, 2.0 Hz, 1H), 2.05 - 1.78 (m, 2H), 1.79 - 1.44 (m, 5H), 1.39 (d, = 6.3 Hz, 3H); ¹³ C NMR (101 MHz, CDCI ₃ ) δ 172.55, 168.60, 155.28, 148.65, 140.55, 130.40, 109.47, 85.40, 73.60, 56.85, 56.06, 52.38, 31.99, 28.26, 27.77, 21.97, 18.24; IR (neat) 3368, 2937, 1740, 1648, 1526, 1263 cm ^"1 ; HRMS-ESI (m/z) calcd for [Ci ₇ H ₂₅ N ₂ 0 ₆ ] ⁺ , 353.1707; found, 353.1716.

[00105] Example 13A: Preparation of 4-methoxy-2-(((3S,8tf ,9S)-8-methoxy-9-methyl-2- oxooxonan-3-yl)carbamoyl)pyridin-3-yl acetate:

[00106] To a small vial, 3-hydroxy-4-methoxy-N-((3S,8tf ,9S)-8-methoxy-9-methyl-2- oxooxonan-3-yl)picolinamide (107.3 mg, 0.304 mmol) was dissolved in DCM (2 mL). To this solution was added triethylamine (0.127 mL, 0.913 mmol) followed by acetyl chloride (0.032 mL, 0.457 mmol). The resulting orange colored reaction was stirred at room temperature for 2 h. After 2 h, TLC indicated consumption of starting material. The reaction was quenched with saturated aqueous NH ₄ C1 (2 mL) and extracted with CH ₂ C1 ₂ (5 x 2 mL). The combined organic layers were passed through a phase separator and concentrated to afford an oil. The oil was purified by flash column chromatography (Si0 ₂ , 0-^50% acetone in hexanes) to afford the title compound (90.9 mg, 0.230 mmol, 76% yield) as a yellow oil: 1H NMR (400 MHz, CDC1 ₃ ) δ 8.65 (d, / = 8.0 Hz, 1H), 8.33 (d, J = 5.4 Hz, 1H), 7.00 (d, J = 5.4 Hz, 1H), 5.01 (dq, J = 8.7, 6.3 Hz, 1H), 4.56 (ddd, J = 10.9, 8.1, 5.3 Hz, 1H), 3.90 (s, 3H), 3.33 (s, 3H), 2.99 (ddd, / = 8.7, 6.9, 1.6 Hz, 1H), 2.40 (s, 3H), 2.31 (dddd, = 14.0, 10.3, 4.7, 2.0 Hz, 2H), 1.87 - 1.73 (m, 2H), 1.73 - 1.39 (m, 4H), 1.37 (d, = 6.3 Hz, 3H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 173.05, 168.89, 162.33, 159.40, 146.72, 141.51, 137.43, 109.76, 85.49, 73.34, 56.83, 56.28, 52.50, 32.27, 28.33, 27.97, 22.00, 20.76, 18.22; IR (neat) 3379, 2938, 1770, 1740, 1675, 1507, 1173 cm ^"1 ; HRMS-ESI (m/z) calcd for [Ci ₉ H ₂₇ N ₂ 0 ₇ ] ⁺ , 395.1813; found, 395.1823; R _f = 0.39 in 80% Ethyl acetate : hexanes, one UV-active purple spot (p- anisaldehyde stain).

[00107] Example 13B: Preparation of ((4-methoxy-2-(((3S,8tf ,9S)-8-methoxy-9-methyl-2- oxooxonan-3-yl)carbamoyl)pyridin-3-yl)oxy)methyl acetate:

[00108] In a small vial, 3-hydroxy-4-methoxy-N-((3S,8tf ,9S)-8-methoxy-9-methyl-2- oxooxonan-3-yl)picolinamide (99.1 mg, 0.281 mmol) and potassium carbonate (50.5 mg, 0.366 mmol) were dissolved in acetone (2 mL). To this was solution was added bromomethyl acetate (0.036 mL, 0.366 mmol). The resulting cloudy white reaction was stirred at 50 °C for 1.5 h. After 1.5 h, TLC indicated consumption of starting material. The reaction was concentrated under a stream of N ₂ to afford a white cloudy oil. The oil was purified by flash column chromatography (Si0 ₂ , 0-^50% acetone in hexanes) to afford the title compound (79.0 mg, 0.186 mmol, 66% yield) as a clear, colorless oil: 1H NMR (400 MHz, CDC1 ₃ ) δ 8.44 (d, J = 7.8 Hz, 1H), 8.28 (d, / = 5.4 Hz, 1H), 6.95 (d, J = 5.4 Hz, 1H), 5.79 - 5.70 (m, 2H), 5.02 (dq, J = 8.7, 6.3 Hz, 1H), 4.58 (ddd, J = 10.9, 7.8, 5.3 Hz, 1H), 3.91 (s, 3H), 3.33 (s, 3H), 3.00 (ddd, J = 8.5, 6.8, 1.6 Hz, 1H), 2.34 (dddd, = 14.1, 10.5, 5.4, 2.0 Hz, 1H), 2.07 (s, 3H), 1.89 - 1.41 (m, 7H), 1.38 (d, J = 6.3 Hz, 3H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 173.16, 170.27, 162.92, 160.26, 145.78, 143.92, 142.55, 109.56, 89.59, 85.48, 73.37, 56.85, 56.18, 52.75, 32.13, 28.34, 27.91, 22.03, 20.88, 18.25; IR (neat) 3379, 2937, 1743, 1674, 1503, 1200 cm ^"1 ; HRMS-ESI (m/z) calcd for [C ₂₀ H ₂₉ N ₂ O ₈ ] ⁺ , 425.1918; found, 425.1929; R _f = 0.20 in 80% Ethyl acetate : hexanes, one UV-active dark blue spot (p- anisaldehyde stain).

[00109] Example 13C: Preparation of ((4-methoxy-2-(((3S,8tf ,9S)-8-methoxy-9-methyl-2- oxooxonan-3-yl)carbamoyl)pyridin-3-yl)oxy)methyl 2-ethoxyacetate:

[00110] In a small vial, 3-hydroxy-4-methoxy-N-((3S,8tf ,9S)-8-methoxy-9-methyl-2- oxooxonan-3-yl)picolinamide (97.9 mg, 0.278 mmol) and sodium carbonate (58.9 mg, 0.556 mmol) were dissolved in acetone (2 mL). To this solution was added chloromethyl 2-ethoxyacetate (0.071 mL, 0.556 mmol) and sodium iodide (4.16 mg, 0.028 mmol). The resulting cloudy yellow reaction was stirred at 55 °C overnight. After 16 h, TLC indicated near complete consumption of starting material. The reaction was concentrated under a stream of N ₂ to afford a white cloudy oil. The oil was purified by flash column chromatography (0-^50% acetone in hexanes) to afford the title compound (82.8 mg, 0.177 mmol, 64% yield) as a clear, colorless oil: 1H NMR (400 MHz, CDC1 ₃ ) δ 8.45 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 5.4 Hz, 1H), 6.95 (d, = 5.4 Hz, 1H), 5.89 - 5.75 (m, 2H), 5.02 (dq, = 8.7, 6.3 Hz, 1H), 4.56 (ddd, / = 10.8, 7.8, 5.3 Hz, 1H), 4.10 (s, 2H), 3.90 (s, 3H), 3.59 (q, = 7.0 Hz, 2H), 3.33 (s, 3H), 3.00 (ddd, / = 8.7, 6.7, 1.6 Hz, 1H), 2.33 (dddd, = 14.2, 10.6, 5.3, 2.0 Hz, 1H), 1.88 - 1.41 (m, 7H), 1.38 (d, = 6.3 Hz, 3H), 1.23 (t, = 7.0 Hz, 3H); ¹³ C NMR (101 MHz, CDCI ₃ ) δ 173.13, 170.05, 162.87, 160.18, 145.83, 143.86, 142.43, 109.68, 89.57, 85.50, 73.38, 67.80, 67.18, 56.84, 56.22, 52.75, 32.11, 28.33, 27.90, 22.04, 18.24, 15.01; IR (neat) 3376, 2935, 1749, 1505, 1120 cm ^"1 ; HRMS-ESI (m/z) calcd for [CiiHssNiOg]*, 469.2181; found,

469.2195; R _f = 0.23 in 80% Ethyl acetate : hexanes, one UV-active purple spot (p-anisaldehyde stain).

[00111] Example A: Evaluation of Fungicidal Activity: Leaf Blotch of Wheat (Mycosphaerella graminicola; Anamorph: Zymoseptoria tritici; Bayer code SEPTTR):

[00112] Technical grades of materials were dissolved in acetone, which were then mixed with nine volumes of water containing 110 ppm Triton X-100. The fungicide solutions were applied onto wheat seedlings using an automated booth sprayer to run-off. All sprayed plants were allowed to air dry prior to further handling. All fungicides were evaluated using the aforementioned method for their activity vs. all target diseases. Wheat leaf blotch and brown rust activity were also evaluated using track spray applications, in which case the fungicides were formulated as EC formulations, containing 0.1% Trycol 5941 in the spray solutions.

[00113] Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50% mineral soil/50% soil-less Metro mix until the first leaf was fully emerged, with 7-10 seedlings per pot. These plants were inoculated with an aqueous spore suspension of Zymoseptoria tritici either prior to or after fungicide treatments. After inoculation the plants were kept in 100% relative humidity (one day in a dark dew chamber followed by two to three days in a lighted dew chamber at 20 °C) to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse set at 20 °C for disease to develop. When disease symptoms were fully expressed on the I ^s leaves of untreated plants, infection levels were assessed on a scale of 0 to 100 percent disease severity.

Percent disease control was calculated using the ratio of disease severity on treated plants relative to untreated plants.

[00114] Example B: Evaluation of Fungicidal Activity: Wheat Brown Rust (Puccinia triticina; Synonym: Puccinia reconditaf. sp. tritici; Bayer code PUCCRT):

[00115] Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50% mineral soil/50% soil-less Metro mix until the first leaf was fully emerged, with 7-10 seedlings per pot. These plants were inoculated with an aqueous spore suspension of Puccinia triticina either prior to or after fungicide treatments. After inoculation the plants were kept in a dark dew room at 22 °C with 100% relative humidity overnight to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse set at 24 °C for disease to develop. Fungicide formulation, application and disease assessment followed the procedures as described in the Example A.

[00116] Example C: Evaluation of Fungicidal Activity: Grape Powdery Mildew (Uncinula necator; Bayer code UNCINE):

[00117] Grape seedlings (variety Carignane) were grown in soil-less Metro mix, with one plant per pot, and used in the test when approximately one month old. Plants were inoculated 24 hr after fungicide treatment by shaking spores from infected leaves over test plants. Plants were maintained in a greenhouse set at 20 °C until disease was fully developed. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.

[00118] Example D: Evaluation of Fungicidal Activity: Powdery Mildew of Cucumber (Erysiphe cichoracearum; Bayer code ERYSCI):

[00119] Cucumber seedlings (variety Bush Pickle) were grown in soil-less Metro mix, with one plant per pot, and used in the test when 12 to 14 days old. Plants were inoculated with a spore suspension 24 hr following fungicide treatments. After inoculation the plants remained in the greenhouse set at 20 °C until disease was fully expressed. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A. [00120] Example E: Evaluation of Fungicidal Activity: Leaf Spot of Sugar Beets (Cercospora beticola; Bayer code CERCBE):

[00121] Sugar beet plants (variety HH88) were grown in soil-less Metro mix and trimmed regularly to maintain a uniform plant size prior to test. Plants were inoculated with a spore suspension 24 hr after fungicide treatments. Inoculated plants were kept in a dew chamber at 22 °C for 48 hr then incubated in a greenhouse set at 24 °C under a clear plastic hood with bottom ventilation until disease symptoms were fully expressed. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.

[00122] Example F: Evaluation of Fungicidal Activity: Asian Soybean Rust (Phakopsora pachyrhizi; Bayer code PHAKPA):

[00123] Technical grades of materials were dissolved in acetone, which were then mixed with nine volumes of water containing 0.011% Tween 20. The fungicide solutions were applied onto soybean seedlings using an automated booth sprayer to run-off. All sprayed plants were allowed to air dry prior to further handling.

[00124] Soybean plants (variety Williams 82) were grown in soil-less Metro mix, with one plant per pot. Two weeks old seedlings were used for testing. Plants were inoculated either 3 days prior to or 1 day after fungicide treatments. Plants were incubated for 24 h in a dark dew room at 22 °C and 100 % RH then transferred to a growth room at 23 °C for disease to develop. Disease severity was assessed on the sprayed leaves.

[00125] Example G: Evaluation of Fungicidal Activity: Barley Scald (Rhyncosporium secalis; Bayer code RHYNSE):

[00126] Barley seedlings (variety Harrington) were propagated in soil-less Metro mix, with each pot having 8 to 12 plants, and used in the test when first leaf was fully emerged. Test plants were inoculated by an aqueous spore suspension of Rhyncosporium secalis 24 hr after fungicide treatments. After inoculation the plants were kept in a dew room at 20°C with 100% relative humidity for 48 hr. The plants were then transferred to a greenhouse set at 20 °C for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.

[00127] Example H: Evaluation of Fungicidal Activity: Rice Blast (Magnaporthe grisea; Anamorph: Pyricularia oryzae; Bayer code PYRIOR):

[00128] Rice seedlings (variety Japonica) were propagated in soil-less Metro mix, with each pot having 8 to 14 plants, and used in the test when 12 to 14 days old. Test plants were inoculated with an aqueous spore suspension of Pyricularia oryzae 24 hr after fungicide treatments. After inoculation the plants were kept in a dew room at 22 °C withl00% relative humidity for 48 hr to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse set at 24 °C for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.

[00129] Example I: Evaluation of Fungicidal Activity: Tomato Early Blight (Alternaria solani; Bayer code ALTESO):

[00130] Tomato plants (variety Outdoor girl) were propagated in soil-less Metro mix, with each pot having one plant, and used when 12 to 14 days old. Test plants were inoculated with an aqueous spore suspension of Alternaria solani 24 hr after fungicide treatments. After inoculation the plants were kept in 100% relative humidity (one day in a dark dew chamber followed by two to three days in a lighted dew chamber at 20 °C ) to permit spores to germinate and infect the leaf. The plants were then transferred to a growth room at 22 °C for disease to develop. Fungicide

formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.

[00131] Example J: Evaluation of Fungicidal Activity: Cucumber Anthracnose (Glomerella lagenarium; Anamorph: Colletotrichum lagenarium; Bayer code COLLLA):

[00132] Cucumber seedlings (variety Bush Pickle) were propagated in soil-less Metro mix, with each pot having one plant, and used in the test when 12 to 14 days old. Test plants were inoculated with an aqueous spore suspension of Colletotrichum lagenarium 24 hr after fungicide treatments. After inoculation the plants were kept in a dew room at 22 °C with 100% relative humidity for 48 hr to permit spores to germinate and infect the leaf. The plants were then transferred to a growth room set at 22 °C for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.

Table 1. Compound Structure and Appearance

3 3 Example 11B. Prepared

Cmpd. No. - Compound Number

Table 2. Analytical Data

*

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDC1 ₃ ) δ 5.14 (tt, = 9.1, 4.6 Hz, 2H), 4.53 (ddd, / = 9.2, 6.5, 2.8

Hz, 1H), 4.18 (ddd, / = 11.0, 8.0, 5.3 Hz,

IR (thin 1H), 2.53 (hept, = 7.0 Hz, 1H), 2.33 - 2.08 film) (m, 1H), 1.79 (tdd, = 13.3, 6.6, 4.3 Hz, 2H), 3379, 1.71 - 1.50 (m, 3H), 1.44 (s, 9H), 1.41 - 1.32

ESIMS mJz 358.4

4 2976, (m, 1H), 1.30 (d, = 6.4 Hz, 3H), 1.28 - 1.22

([M+H] ⁺ )

1714, (m, 1H), 1.16 (dd, / = 7.0, 3.5 Hz, 6H). 1366,

1152 ¹³ C NMR (101 MHz, CDCI ₃ ) δ 176.13,

173.71, 154.89, 79.86, 76.58, 72.16, 53.90, 34.05, 32.84, 30.36, 28.33, 27.04, 21.87,

18.88, 18.78, 17.87.

1H NMR (400 MHz, CDCI ₃ ) δ 5.00 (dq, = 9.1, 6.3 Hz, 1H), 4.75 (dd, / = 11.7, 5.5 Hz, 1H), 4.52 (ddd, = 9.2, 6.5, 2.7 Hz, 1H), 2.71

IR (thin

(tt, / = 8.7, 7.1 Hz, 1H), 2.28 (dddd, = 13.7, film)

HRMS-ESI (mJz) 11.7, 7.6, 1.8 Hz, 1H), 2.04 (dddd, = 14.1, 2938,

[(M+Na) ⁺ ] calcd for 10.2, 5.7, 2.0 Hz, 1H), 1.96 - 1.64 (m, 9H), 1736,

5 C ₂₅ H ₄₁ NNa0 ₈ , 1.64 - 1.54 (m, 4H), 1.52 (s, 18H), 1.48 - 1703,

506.2724; found, 1.38 (m, 1H), 1.28 (d, = 6.3 Hz, 3H). 1367,

506.2734

1143,

¹³ C NMR (101 MHz, CDCI ₃ ) δ 175.82, 1124

171.30, 152.92, 82.63, 72.44, 58.90, 43.86, 31.04, 30.76, 29.93, 29.78, 27.97, 25.80,

25.75, 23.19, 17.99.

1H NMR (400 MHz, CDCI ₃ ) δ 4.83 (dq, = 9.0, 6.2 Hz, 1H), 4.71 (dd, = 11.8, 5.3 Hz,

IR (thin 1H), 3.31 (dd, = 8.8, 6.2 Hz, 1H), 3.01 (ddd, film) = 10.9, 9.0, 7.2 Hz, 2H), 2.27 (dddd, = 2977, HRMS-ESI (mJz) 13.9, 11.8, 7.3, 2.0 Hz, 1H), 2.01 (dddd, = 2934, [(M+Na) ⁺ ] calcd for 14.2, 10.4, 5.4, 2.0 Hz, 1H), 1.89 - 1.62 (m,

6 1744, C ₂₅ H ₄₁ NNa0 ₇ , 4H), 1.62 - 1.39 (m, 21H), 1.35 (d, = 6.3 1704, 466.2775; found, Hz, 3H), 0.89 (t, = 6.5 Hz, 6H).

1367, 466.2783

1170, ¹³ C NMR (101 MHz, CDCI ₃ ) δ 171.28, 1122 152.95, 84.13, 82.54, 76.32, 73.76, 58.94,

30.63, 29.62, 29.24, 28.74, 27.96, 23.15,

19.46, 19.40, 18.31. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDC1 ₃ ) δ 7.33 - 7.24 (m, 2H), 7.18 (tq, 7 = 4.5, 1.6 Hz, 3H), 4.85 (dq, 7 = 9.0, 6.3 Hz, IH), 4.72 (dd, 7 = 11.8,

5.4 Hz, IH), 3.54 (dt, 7 = 9.2, 6.1 Hz, IH),

IR (thin 3.29 (dt, 7 = 9.2, 6.3 Hz, IH), 3.02 (ddd, 7 = film) 8.8, 7.3, 1.4 Hz, IH), 2.76 - 2.61 (m, 2H), 2978, HRMS-ESI (mJz) 2.27 (dddd, 7 = 13.9, 11.8, 7.3, 2.0 Hz, IH), 2933, [(M+Na) ⁺ ] calcd for 2.01 (dddd, 7 = 14.2, 10.4, 5.4, 2.0 Hz, IH),

7 1743, C ₂₈ H ₄₃ NNa0 ₇ , 1.92 - 1.75 (m, 3H), 1.75 - 1.60 (m, 2H), 1703, 528.2932; found, 1.60 - 1.42 (m, 21H), 1.37 (d, 7 = 6.2 Hz, 1367, 528.2943 3H).

1123,

1109 ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 171.26,

152.94, 141.87, 128.43, 128.32, 125.79, 83.98, 82.56, 73.66, 68.34, 58.92, 32.37, 31.57, 30.63, 29.71, 29.12, 27.96, 23.17,

18.36.

IR (thin

1H NMR (400 MHz, CDC1 ₃ ) δ 4.83 (dq, 7 = film)

8.8, 6.3 Hz, IH), 4.72 (dd, 7 = 11.7, 5.4 Hz, 2980, HRMS-ESI (mJz)

IH), 3.58 (dt, 7 = 9.2, 5.9 Hz, IH), 3.34 (dt, 7 2936, [(M+Na) ⁺ ] calcd for

= 9.2, 6.0 Hz, IH), 3.03 (ddd, 7 = 8.8, 7.4, 1.4

8 1743, C ₂₃ H ₃₈ F ₃ NNa0 ₇ ,

Hz, IH), 2.36 - 2.09 (m, 3H), 2.01 (dddd, 7 = 1704, 520.2493; found,

14.2, 10.4, 5.5, 1.9 Hz, IH), 1.90 - 1.74 (m, 1354, 520.2496

3H), 1.74 - 1.61 (m, 2H), 1.51 (s, 21H), 1.33 1249,

(d, 7 = 6.3 Hz, 3H).

1144

1H NMR (400 MHz, CDC1 ₃ ) δ 4.81 (tq, 7 =

IR (thin

9.4, 6.3 Hz, IH), 4.72 (ddd, 7 = 11.8, 5.4, 1.9 film)

Hz, IH), 3.52 (dt, 7 = 9.1, 6.4 Hz, IH), 3.36 - 2977, HRMS-ESI (mJz)

3.22 (m, IH), 3.21 - 3.07 (m, IH), 3.01 (ddd, 2934, [(M+Na) ⁺ ] calcd for

7 = 9.0, 7.4, 1.3 Hz, IH), 2.26 (dddd, 7 =

9 1744, C ₂₄ H4 ₃ NNa0 ₇ ,

14.0, 11.8, 7.3, 1.9 Hz, IH), 2.00 (dddd, 7 = 1705, 480.2932; found,

14.2, 10.4, 5.4, 2.0 Hz, IH), 1.81 (ddtd, 7 = 1353, 480.2936

14.6, 6.1, 4.5, 2.3 Hz, IH), 1.76 - 1.63 (m, 1209,

2H), 1.51 (s, 22H), 1.39 - 1.20 (m, 6H), 0.97 1123

- 0.82 (m, 4H). *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDC1 ₃ ) δ 4.82 (dq, =

IR (thin 9.1, 6.2 Hz, 1H), 4.71 (dd, = 11.8, 5.4 Hz, film) HRMS-ESI (mJz) 1H), 3.55 - 3.43 (m, 1H), 3.25 (dt, / = 9.0, 2977.26, [(M+Na) ⁺ ] calcd for 6.6 Hz, 1H), 3.01 (ddd, = 9.0, 7.5, 1.3 Hz,

10 1743.97, C22H ₃₉ NNa07, 1H), 2.26 (dddd, = 14.0, 11.8, 7.3, 1.9 Hz, 1704.59, 452.2619; found, 1H), 2.00 (dddd, / = 14.2, 10.4, 5.5, 2.1 Hz, 1353.42, 452.2623 1H), 1.88 - 1.62 (m, 4H), 1.62 - 1.45 (m, 1143.94 4H), 1.51 (s, 18H), 1.35 (d, = 6.2 Hz, 3H),

0.91 (t, = 7.4 Hz, 3H).

IR (thin 1H NMR (400 MHz, CDC1 ₃ ) δ 4.78 (dq, = film) HRMS-ESI (mJz) 9.2, 6.2 Hz, 1H), 4.71 (dd, = 11.9, 5.4 Hz, 2976.99, [(M+Na) ⁺ ] calcd for 1H), 4.00 - 3.90 (m, 1H), 3.07 (ddd, / = 9.0,

11 1743.43, C ₂₄ H ₄ iNNa0 ₇ , 7.5, 1.3 Hz, 1H), 2.26 (dddd, / = 14.0, 11.9, 1704.62, 478.2775; found, 7.3, 2.0 Hz, 1H), 2.00 (dddt, = 14.2, 10.3, 1367.40, 478.2776 5.4, 2.2 Hz, 1H), 1.94 - 1.40 (m, 14H), 1.51 1122.58 (s, 18H), 1.32 (d, = 6.2 Hz, 3H).

1H NMR (400 MHz, CDC1 ₃ ) δ 4.80 (dq, =

IR (thin 8.8, 6.2 Hz, 1H), 4.71 (dd, = 11.7, 5.4 Hz, film) HRMS-ESI (mJz) 1H), 3.81 (dt, = 9.1, 6.0 Hz, 1H), 3.69 (s, 2978.59, [(M+Na) ⁺ ] calcd for 3H), 3.59 (dt, / = 9.0, 6.1 Hz, 1H), 3.06 (ddd,

12 1740.85, C ₂₃ H ₃₉ NNa09, = 9.0, 7.6, 1.5 Hz, 1H), 2.60 - 2.50 (m, 2H), 1353.01, 496.2517; found, 2.26 (dddd, = 13.9, 11.6, 7.3, 2.1 Hz, 1H), 1243.79, 496.2518 2.01 (dddd, = 14.2, 10.4, 5.4, 2.1 Hz, 1H), 1122.46 1.90 - 1.62 (m, 4H), 1.62 - 1.39 (m, 2H),

1.51 (s, 18H), 1.32 (d, = 6.3 Hz, 3H).

1H NMR (400 MHz, CDC1 ₃ ) δ 4.82 (dq, = 8.8, 6.3 Hz, 1H), 4.72 (dd, = 11.7, 5.4 Hz,

IR (thin

1H), 3.70 (dt, = 9.5, 6.5 Hz, 1H), 3.46 (dt, film)

HRMS-ESI (mJz) = 9.5, 6.5 Hz, 1H), 3.04 (ddd, = 8.9, 7.5, 1.4 2978.73,

[(M+Na) ⁺ ] calcd for Hz, 1H), 2.27 (dddd, = 13.8, 11.7, 7.4, 1.9 1742.76,

13 C ₂₃ H ₃ 9F ₂ NNa07, Hz, 1H), 2.19 - 1.96 (m, 3H), 1.82 (dddd, = 1702.63,

502.2587; found, 17.0, 11.1, 4.8, 2.6 Hz, 1H), 1.76 - 1.56 (m, 1336.74,

502.2597 6H), 1.51 (s, 20H), 1.34 (d, = 6.3 Hz, 3H). 1141.25,

1122.27

¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -88.67 (d, = 241.5 Hz), -89.51 (d, = 241.6 Hz). *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

IR (thin 1H NMR (400 MHz, CDC1 ₃ ) δ 7.37 - 7.21 film) (m, 2H), 6.95 (tt, = 7.4, 1.1 Hz, 1H), 6.88 -

HRMS-ESI (mJz)

3380, 6.72 (m, 2H), 5.24 (ddt, = 9.5, 6.3, 2.6 Hz,

([M+Na] ⁺ ) calcd for

2936, 2H), 4.21 (ddd, / = 11.2, 8.0, 5.3 Hz, 1H),

14 C2oH ₂₉ NNa05,

1707, 3.98 (ddd, / = 8.8, 7.5, 1.2 Hz, 1H), 2.24 (tdd,

386.1938; found,

1493, = 10.8, 6.2, 2.1 Hz, 1H), 1.92 - 1.56 (m,

386.1945

1159, 5H), 1.56 - 1.43 (m, 10H), 1.40 (d, = 6.3 1047 Hz, 3H), 1.37 - 1.28 (m, 1H).

1H NMR (400 MHz, CDC1 ₃ ) δ 7.02 - 6.91 (m, 2H), 6.84 - 6.71 (m, 2H), 5.23 (dq, / =

8.6, 6.3 Hz, 2H), 4.21 (ddd, = 11.1, 8.0, 5.3

Hz, 1H), 3.91 (ddd, = 8.8, 7.3, 1.3 Hz, 1H),

IR (thin

2.32 - 2.19 (m, 1H), 1.90 - 1.55 (m, 5H), film)

HRMS-ESI (mJz) 1.55 - 1.47 (m, 1H), 1.45 (s, 9H), 1.41 (d, J = 3373,

[(M+Na) ⁺ ] calcd for 6.3 Hz, 3H), 1.37 - 1.21 (m, 1H). ¹³ C NMR 2937,

15 C ₂₀ H ₂₈ FNNaO ₅ , (126 MHz, CDC1 ₃ ) δ 173.62, 157.41 (d, =

1705,

404.1844; found, 239.2 Hz), 154.91, 153.29 (d, / = 2.3 Hz), 1502,

404.1842 116.87 (d, = 7.9 Hz), 116.01 (d, = 23.1 1159,

Hz), 82.10, 79.86, 72.76, 53.92, 32.69, 28.84, 1047

28.33, 27.70, 21.97, 18.25.

¹⁹ F NMR (471 MHz, CDC1 ₃ ) δ -123.23 (dq,

= 8.1, 4.1 Hz).

Ή NMR (400 MHz, CDC1 ₃ ) δ 8.65 (s, 2H), 7.38 - 7.27 (m, 5H), 5.01 (dt, = 12.3, 6.2

IR (neat) Hz, 1H), 4.58 (d, = 11.5 Hz, 1H), 4.37 (d,

HRMS-ESI (mJz)

3398, = 11.5 Hz, lH), 4.02 (d, = 8.2 Hz, 1H), 3.16

([M+H] ⁺ ) calcd for

2933, (dd, = 9.1, 5.0 Hz, 1H), 2.52 (s, 1H), 1.96 -

16 Ci ₆ H ₂₄ N0 ₃ ⁺ ,

1744, 1.65 (m, 3H), 1.67 - 1.42 (m, 4H), 1.35 (d,

278.1751; found,

1239, = 6.2 Hz, 3H) ¹³ C NMR (101 MHz, CDC1 ₃ ) δ

278.1751

1070, 730 170.65, 137.86, 128.42, 127.87, 127.79,

82.94, 74.50, 71.14, 53.28, 29.70, 28.84,

27.80, 21.48, 18.15. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

IR (thin

film) HRMS-ESI (mJz)

3528, ([M+H] ⁺ ) calcd for

17 2954, C ₁₇ H ₂₆ N0 ₄ ,

1736, 308.1851; found,

1241, 308.1856

1213

IR (thin

film) HRMS-ESI (mJz)

3406, ([M+H] ⁺ ) calcd for

18 2934, CioH ₂₀ N0 ₃ ,

1745, 202.1438; found,

1240, 202.1440

1090

IR (thin

film)

HRMS-ESI (mJz)

3436,

([M+H] ⁺ ) calcd for

2927,

19 Ci ₃ H ₂₄ N0 ₄ ,

1727,

258.1700; found,

1476,

258.1708

1196,

1060

IR (thin

film)

HRMS-ESI (mJz)

3451,

([M+H] ⁺ ) calcd for

2953,

20 C ₁₅ H ₂₆ N0 ₄ ,

2870,

284.1856; found,

1750,

284.1864

1728,

1190

IR (thin

film)

HRMS-ESI (mJz)

3405,

([M+H] ⁺ ) calcd for

2953,

21 C ₁₃ H ₂₆ N0 ₃ ,

2872,

244.1907; found,

1747,

244.1907

1240,

1092 *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

IR (thin

film)

HRMS-ESI (m/z)

3416,

([M+H] ⁺ ) calcd for

2933,

22 Ci ₈ H ₂₈ N0 ₃ ,

2871,

306.2064; found,

1747,

306.2070

1240,

1091

IR (thin

film) HRMS-ESI (m/z)

3406, ([M+H] ⁺ ) calcd for

23 2938, Ci ₃ H ₂₃ F ₃ N0 ₃ ,

2876, 298.1625; found,

1748, 298.1626

1233

IR (thin

film)

HRMS-ESI (m/z)

3406,

([M+H] ⁺ ) calcd for

2932,

24 C ₁₄ H ₂₈ N0 ₃ ,

2873,

258.2064; found,

1748,

258.2066

1240,

1092

ESIMS m/z 230.2

25

([M+H] ⁺ )

ESIMS m/z 256.2

26

([M+H] ⁺ )

ESIMS m/z 274.2

27

([M+H] ⁺ )

ESIMS m/z 280.2

28

([M+H] ⁺ )

*

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDC1 ₃ ) δ 12.12 (d, = 0.7 Hz, 1H), 8.62 (d, = 7.9 Hz, 1H), 7.98 (d, = 5.2 Hz, 1H), 6.87 (d, = 5.2 Hz, 1H),

IR (thin

5.04 (dq, / = 8.6, 6.3 Hz, 1H), 4.56 (ddd, / = film)

10.9, 7.9, 5.3 Hz, 1H), 3.94 (d, = 1.1 Hz, 3368, HRMS-ESI (mJz)

3H), 3.34 (s, 3H), 3.01 (ddd, / = 8.6, 6.9, 1.6 2937, ([M+H] ⁺ ) calcd for

Hz, 1H), 2.34 (dddd, / = 14.2, 10.5, 5.3, 2.0

32 1740, C ₁₇ H ₂₅ N ₂ 0 ₆ ,

Hz, 1H), 2.05 - 1.78 (m, 2H), 1.79 - 1.44 (m, 1648, 353.1707; found,

5H), 1.39 (d, = 6.3 Hz, 3H).

1526, 353.1716

1263,

¹³ C NMR (101 MHz, CDC1 ₃ ) δ 172.55, 1221

168.60, 155.28, 148.65, 140.55, 130.40, 109.47, 85.40, 73.60, 56.85, 56.06, 52.38, 31.99, 28.26, 27.77, 21.97, 18.24.

1H NMR (400 MHz, CDC1 ₃ ) δ 12.09 (d, = 0.7 Hz, 1H), 8.56 (d, = 7.9 Hz, 1H), 8.00 (d, = 5.2 Hz, 1H), 6.87 (d, = 5.2 Hz, 1H), 5.21 (dq, = 9.0, 6.3 Hz, 1H), 4.66 - 4.52 (m,

IR (thin

2H), 3.94 (s, 3H), 2.55 (hept, = 7.0 Hz, 1H), film)

HRMS-ESI (mJz) 2.36 (dddd, / = 14.1, 10.4, 5.6, 2.1 Hz, 1H), 3367,

([M+H] ⁺ ) calcd for 1.96 - 1.79 (m, 2H), 1.79 - 1.55 (m, 3H), 2972,

33 C ₂ o¾9N ₂ 0 ₇ , 1.56 - 1.36 (m, 2H), 1.34 (d, = 6.3 Hz, 3H),

2939,

409.1969; found, 1.17 (dd, = 7.0, 3.5 Hz, 6H).

1732,

409.1976

1650,

¹³ C NMR (101 MHz, CDCI ₃ ) δ 176.14, 1528

172.58, 168.62, 155.36, 148.74, 140.54, 130.40, 109.48, 76.49, 72.52, 56.08, 52.44, 34.04, 32.31, 30.40, 27.00, 21.93, 18.89,

18.78, 17.90.

*

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

^X H NMR (400 MHz, CDC1 ₃ ) δ 12.12 (s, IH), 8.61 (d, = 8.0 Hz, IH), 8.00 (dd, = 10.6, 5.2 Hz, IH), 7.35 - 7.17 (m, 2H), 6.96 - 6.81

IR (thin (m, 2H), 5.10 (dq, / = 8.8, 6.3 Hz, IH), 4.63 film) - 4.47 (m, 2H), 4.35 (d, = 11.1 Hz, IH), 3492, HRMS-ESI (mJz) 3.93 (s, 3H), 3.81 (s, 3H), 3.27 - 3.14 (m, 3090, ([M+H] ⁺ ) calcd for IH), 2.33 (dddd, = 14.2, 10.7, 5.4, 2.0 Hz,

34 2983, C2 ₄ H ₃ iN ₂ 07, IH), 2.04 - 1.75 (m, 3H), 1.75 - 1.42 (m,

1747, 459.2126; found, 5H), 1.37 (d, = 6.3 Hz, 3H).

1238, 459.2126

1162, ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 172.56, 1027 168.58, 159.30, 155.30, 148.68, 140.54,

130.44, 129.99, 129.48, 113.83, 109.44, 82.55, 73.75, 70.85, 56.06, 55.28, 52.44, 32.05, 28.95, 27.97, 21.89, 18.22.

1H NMR (400 MHz, CDC1 ₃ ) δ 12.12 (s, IH),

IR (thin 8.61 (d, = 7.9 Hz, IH), 7.99 (d, = 5.2 Hz, film) IH), 6.86 (d, = 5.2 Hz, IH), 5.05 (dq, / =

HRMS-ESI (mJz)

3368.34, 9.0, 6.3 Hz, IH), 4.55 (ddd, / = 11.1, 8.0, 5.4

([M+H] ⁺ ) calcd for

2936.48, Hz, IH), 3.94 (s, 3H), 3.52 (dt, / = 9.1, 6.4

35 C19H29N2O6,

1739.52, Hz, IH), 3.27 (dt, / = 9.0, 6.6 Hz, IH), 3.08

381.2020; found,

1648.80, (ddd, / = 9.0, 7.4, 1.2 Hz, IH), 2.38 - 2.27

381.2028

1526.02, (m, IH), 1.88 - 1.64 (m, 4H), 1.64 - 1.43 (m, 1242.33 5H), 1.40 (d, = 6.3 Hz, 3H), 0.93 (t, = 7.4

Hz, 3H).

IR (thin

1H NMR (400 MHz, CDC1 ₃ ) δ 12.12 (s, IH), film)

8.61 (d, = 7.9 Hz, IH), 7.99 (d, = 5.2 Hz, 3368.41, HRMS-ESI (mJz)

IH), 6.86 (d, = 5.0 Hz, IH), 5.00 (dq, = 2940.84, ([M+H] ⁺ ) calcd for

9.1, 6.3 Hz, IH), 4.54 (ddd, = 11.2, 7.9, 5.3

36 1739.41, C ₂ iH ₃ iN ₂ 0 ₆ ,

Hz, IH), 4.00 - 3.95 (m, IH), 3.94 (s, 3H), 1648.88, 407.2177; found,

3.14 (ddd, = 8.9, 7.0, 1.5 Hz, IH), 2.33 1526.09, 407.2177

(dddd, = 14.1, 10.4, 5.3, 2.0 Hz, IH), 1.89 - 1438.08,

1.41 (m, 15H), 1.37 (d, = 6.3 Hz, 3H). 1054.61 *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDCI ₃ ) δ 12.11 (s, IH),

IR (thin

8.59 (d, = 7.9 Hz, IH), 7.99 (d, = 5.2 Hz, film)

IH), 6.87 (d, = 5.2 Hz, IH), 5.02 (dq, / = 3368.87, HRMS-ESI (mJz)

9.0, 6.3 Hz, IH), 4.55 (ddd, / = 11.0, 7.9, 5.3 2940.14, ([M+H] ⁺ ) calcd for

Hz, IH), 3.94 (s, 3H), 3.83 (dt, / = 9.3, 6.0

37 1736.36, C20H29N2O8,

Hz, IH), 3.70 (s, 3H), 3.61 (dt, / = 9.2, 6.2 1648.37, 425.1918; found,

Hz, IH), 3.12 (ddd, / = 8.8, 6.9, 1.6 Hz, IH), 1526.50, 425.1925

2.56 (t, = 6.1 Hz, 2H), 2.33 (dddd, / = 14.3, 1436.99,

10.6, 5.4, 2.0 Hz, IH), 1.91 - 1.42 (m, 7H), 1176.07

1.37 (d, = 6.3 Hz, 3H).

1H NMR (400 MHz, CDC1 ₃ ) δ 12.11 (s, IH),

IR (thin 8.60 (d, = 7.9 Hz, IH), 7.99 (d, = 5.2 Hz, film) IH), 6.87 (d, = 5.2 Hz, IH), 5.04 (dq, / =

HRMS-ESI (mJz)

3360.90, 8.8, 6.3 Hz, IH), 4.56 (ddd, = 11.0, 7.9, 5.3

([M+H] ⁺ ) calcd for

2973.21, Hz, IH), 3.94 (s, 3H), 3.73 (dt, = 9.6, 6.6

38 C20H29F2N2O6,

1729.23, Hz, IH), 3.49 (dt, = 9.6, 6.5 Hz, IH), 3.11

431.1988; found,

1650.09, (ddd, = 8.6, 6.8, 1.6 Hz, IH), 2.34 (dddd,

431.1992

1524.43, = 14.2, 10.5, 5.4, 1.9 Hz, IH), 2.22 - 2.05 (m, 1138.29 2H), 1.83 (tdt, = 10.2, 5.0, 3.1 Hz, IH), 1.78

- 1.43 (m, 9H), 1.39 (d, = 6.3 Hz, 3H).

1H NMR (400 MHz, CDC1 ₃ ) δ 12.09 (d, = 0.6 Hz, IH), 8.56 (d, = 7.9 Hz, IH), 7.99 (d, = 5.2 Hz, IH), 6.88 (d, = 5.2 Hz, IH), 5.21 (dq, = 9.0, 6.3 Hz, IH), 4.58 (dtd, =

IR (thin

11.0, 5.4, 3.0 Hz, 2H), 3.94 (s, 3H), 2.73 (tt, film)

HRMS-ESI (mJz) = 8.7, 7.1 Hz, IH), 2.36 (dddd, = 14.0, 10.3, 3370,

([M+H] ⁺ ) calcd for 5.5, 2.0 Hz, IH), 1.99 - 1.83 (m, 5H), 1.83 - 2944,

39 C ₂₂ H ₃₁ N ₂ O ₇ , 1.54 (m, 8H), 1.54 - 1.36 (m, 2H), 1.34 (d,

2870,

435.2126; found, = 6.4 Hz, 3H).

1730,

435.2133

1527,

¹³ C NMR (101 MHz, CDCI ₃ ) δ 175.75, 1174

172.58, 168.61, 155.34, 148.72, 140.53, 130.38, 109.48, 76.50, 72.55, 56.07, 52.44, 43.83, 32.29, 30.42, 29.95, 29.79, 27.03, 25.80, 25.75, 21.92, 17.92. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDCI ₃ ) δ 12.13 (d, = 0.7 Hz, 1H), 8.61 (d, = 7.9 Hz, 1H), 7.99 (d, = 5.2 Hz, 1H), 6.87 (dd, / = 5.3, 0.6 Hz, 1H), 5.05 (dq, / = 8.9, 6.3 Hz, 1H), 4.55 (ddd,

IR (thin

= 11.0, 7.9, 5.3 Hz, 1H), 3.94 (s, 3H), 3.33 film)

(dd, / = 8.7, 6.2 Hz, 1H), 3.06 (qd, / = 6.5, 3369, HRMS-ESI (mJz)

3.2 Hz, 2H), 2.33 (dddd, = 14.1, 10.5, 5.3, 2937, ([M+H] ⁺ ) calcd for

2.0 Hz, 1H), 1.92 - 1.64 (m, 4H), 1.64 - 1.43

40 1740, C20H31N2O6,

(m, 4H), 1.40 (d, = 6.3 Hz, 3H), 0.91 (t, = 1649, 395.2177; found,

6.7 Hz, 6H).

1526, 395.2185

1264,

¹³ C NMR (101 MHz, CDCI ₃ ) δ 172.58, 1221

168.58, 155.30, 148.68, 140.53, 130.44, 109.44, 83.95, 76.42, 73.89, 56.06, 52.46, 32.08, 29.02, 28.74, 28.17, 21.87, 19.46,

19.40, 18.23.

1H NMR (400 MHz, CDC1 ₃ ) δ 12.12 (d, = 0.6 Hz, 1H), 8.61 (d, = 7.9 Hz, 1H), 7.99 (d, = 5.2 Hz, 1H), 7.32 - 7.26 (m, 2H), 7.24 - 7.13 (m, 3H), 6.86 (dd, = 5.3, 0.7 Hz, 1H), 5.07 (dq, / = 8.8, 6.2 Hz, 1H), 4.55 (ddd, / =

IR (thin 10.9, 7.9, 5.3 Hz, 1H), 3.93 (s, 3H), 3.57 (dt, film) 7 = 9.1, 6.1 Hz, 1H), 3.32 (dt, J = 9.1, 6.3 Hz,

HRMS-ESI (mJz)

3368, 1H), 3.16 - 3.00 (m, 1H), 2.69 (dd, J = 8.6,

([M+H] ⁺ ) calcd for

2937, 6.7 Hz, 2H), 2.33 (dddd, = 14.2, 10.5, 5.4,

41 C25H33N2O6,

1740, 2.0 Hz, 1H), 1.88 (dq, = 8.5, 6.3 Hz, 2H),

457.2333; found,

1649, 1.83 - 1.63 (m, 3H), 1.63 - 1.45 (m, 4H),

457.2341

1527, 1.41 (d, = 6.3 Hz, 3H). 1450

¹³ C NMR (101 MHz, CDC1 ₃ ) δ 172.58, 168.58, 155.30, 148.68, 141.80, 140.53, 130.45, 128.42, 128.34, 125.82, 109.44, 83.82, 73.79, 68.46, 56.05, 52.44, 32.37, 32.07, 31.54, 29.09, 28.04, 21.88, 18.28. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDCI ₃ ) δ 12.11 (d, J = 0.6 Hz, 1H), 8.60 (d, = 7.9 Hz, 1H), 7.99 (d, = 5.2 Hz, 1H), 6.87 (dd, / = 5.2, 0.6 Hz, 1H), 5.04 (dq, = 8.8, 6.3 Hz, 1H), 4.56 (ddd, = 10.9, 7.9, 5.3 Hz, 1H), 3.94 (s, 3H), 3.61

IR (thin

(dt, / = 9.1, 5.9 Hz, 1H), 3.37 (dt, / = 9.1, 6.1 film)

Hz, 1H), 3.10 (ddd, / = 8.6, 6.8, 1.6 Hz, 1H), 3370, HRMS-ESI (mJz)

2.34 (dddd, / = 14.2, 10.5, 5.4, 1.9 Hz, 1H), 2940, ([M+H] ⁺ ) calcd for

2.28 - 2.10 (m, 2H), 1.82 (ddt, = 11.5, 8.3,

42 1741, C20H28F3N2O6,

5.7 Hz, 3H), 1.76 - 1.42 (m, 6H), 1.38 (d, J = 1650, 449.1894; found,

6.3 Hz, 3H).

1528, 449.1895

1450,

¹³ C NMR (101 MHz, CDC1 ₃ ) δ 172.55, 1252

168.62, 155.34, 148.71, 140.57, 130.44, 127.23 (q, = 276.1 Hz), 109.48, 83.95, 73.53, 67.36, 56.08, 52.40, 32.06, 30.75 (q, = 28.9 Hz), 28.96, 27.80, 22.72 (q, = 3.0

Hz), 21.93, 18.24.

1H NMR (400 MHz, CDC1 ₃ ) δ 12.13 (dd, = 3.0, 0.6 Hz, 1H), 8.61 (dd, = 7.9, 3.6 Hz, 1H), 7.99 (dd, = 5.2, 0.9 Hz, 1H), 6.92 - 6.81 (m, 1H), 5.11 - 4.97 (m, 1H), 4.55 (dddd, = 11.0, 7.8, 5.3, 2.3 Hz, 1H), 3.94 (s,

IR (thin

3H), 3.55 (dt, = 9.1, 6.4 Hz, 1H), 3.30 (dt, film)

= 9.0, 6.6 Hz, 1H), 3.23 - 3.13 (m, 1H), 3.07 3368, HRMS-ESI (mJz)

(ddd, = 8.7, 6.8, 1.6 Hz, 1H), 2.33 (dddd, 2934, ([M+H] ⁺ ) calcd for

= 14.1, 10.5, 5.3, 2.0 Hz, 1H), 1.90 - 1.64 (m,

43 1740, C21H33N2O6,

3H), 1.64 - 1.42 (m, 6H), 1.39 (d, = 6.3 Hz, 1649, 409.2333; found,

3H), 1.37 - 1.26 (m, 2H), 0.98 - 0.80 (m, 1527, 409.2339

4H).

1449,

1264

¹³ C NMR (101 MHz, CDC1 ₃ ) δ 172.58, 168.58, 155.31, 148.69, 140.53, 130.47, 109.43, 83.82, 73.83, 69.56, 56.06, 52.47, 32.09, 29.64, 29.19, 28.38, 28.22, 22.49,

21.88, 18.19, 14.04. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDCI ₃ ) δ 12.11 (s, IH),

IR (thin

8.63 (d, = 7.9 Hz, IH), 7.99 (d, = 5.2 Hz, film)

HRMS-ESI (mJz) IH), 7.37 - 7.21 (m, 2H), 6.96 (tt, = 7.4, 1.1 3367,

([M+H] ⁺ ) calcd for Hz, IH), 6.91 - 6.78 (m, 3H), 5.32 (dq, / = 2938,

44 C22H27N2O6, 8.8, 6.3 Hz, IH), 4.61 (ddd, / = 11.1, 7.9, 5.3

1742,

415.1864; found, Hz, IH), 4.03 (ddd, / = 8.7, 7.3, 1.2 Hz, IH), 1648,

415.1868 3.94 (s, 3H), 2.38 (dddd, / = 14.1, 10.4, 5.3, 1598,

2.0 Hz, IH), 2.02 - 1.63 (m, 5H), 1.63 - 1.47 1209

(m, 2H), 1.44 (d, = 6.3 Hz, 3H).

1H NMR (400 MHz, CDCI ₃ ) δ 12.10 (d, = 0.6 Hz, IH), 8.62 (d, = 7.9 Hz, IH), 8.00 (d,

IR (thin = 5.1 Hz, IH), 7.03 - 6.93 (m, 2H), 6.88 film) (dd, = 5.2, 0.7 Hz, IH), 6.82 - 6.72 (m,

HRMS-ESI (mJz)

3369, 2H), 5.29 (dq, / = 8.7, 6.3 Hz, IH), 4.61 (ddd,

([M+H] ⁺ ) calcd for

2939, = 11.0, 7.9, 5.3 Hz, IH), 3.99 - 3.89 (m,

45 C22H26FN2O6,

1743, 4H), 2.38 (dddd, / = 14.1, 10.4, 5.3, 2.0 Hz,

433.1769; found,

1649, IH), 2.05 - 1.84 (m, 2H), 1.84 - 1.62 (m,

433.1771

1502, 3H), 1.53 (dddd, = 18.3, 9.2, 7.0, 3.5 Hz, 1199 2H), 1.44 (d, = 6.3 Hz, 3H).

¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -123.13.

^X H NMR (400 MHz, CDCI ₃ ) δ 12.12 (s, IH), 8.61 (d, = 8.0 Hz, IH), 7.99 (d, = 5.2 Hz, IH), 7.46 - 7.26 (m, 5H), 6.86 (d, = 5.2 Hz,

IH), 5.74 (m, 2H), 5.12 (dq, = 8.8, 6.3 Hz, IH), 4.62 (d, = 11.5 Hz, IH), 4.55 (ddd, =

IR (neat) 11.0, 7.9, 5.4 Hz, IH), 4.42 (d, = 11.5 Hz, 3379, HRMS-ESI (mJz) IH), 3.94 (s, 3H), 3.24 (ddd, = 8.5, 6.5, 1.7 2938, ([M+H] ⁺ ) calcd for Hz, IH), 2.46 - 2.27 (m, IH), 2.07 (s, IH),

46 1745, C26H33N20g ⁺ , 1.90 - 1.75 (m, 2H), 1.71 - 1.56 (m, 4H), 1.55

1675, 501.2231; found, - 1.45 (m, 2H), 1.40 (d, = 6.3 Hz, 3H). 1503, 501.2242

1201 ¹³ C NMR (101 MHz, CDCI ₃ ) δ 173.17,

170.26, 162.91, 160.25, 145.78, 143.90, 142.51, 137.99, 128.41, 127.84, 127.76, 109.58, 89.56, 83.05, 73.47, 71.18, 56.18, 52.79, 32.12, 28.96, 28.01, 21.96, 20.88,

18.26. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

^X H NMR (400 MHz, CDC1 ₃ ) δ 8.65 (d, = 8.3 Hz, 1H), 8.33 (d, = 5.4 Hz, 1H), 7.42 - 7.26 (m, 5H), 6.99 (d, = 5.4 Hz, 1H), 5.10 (dq, / = 8.9, 6.3 Hz, 1H), 4.61 (d, = 11.6

IR (neat) Hz, 1H), 4.55 (ddd, / = 11.0, 8.0, 5.3 Hz, 3380, HRMS-ESI (mJz) 1H), 4.41 (d, = 11.5 Hz, 1H), 3.89 (s, 3H), 2940, ([M+H] ⁺ ) calcd for 3.21 (ddd, / = 8.5, 6.5, 1.7 Hz, 1H), 2.39 (s,

47 1771, C ₂₅ H ₃ iN ₂ 0 ₇ ⁺ , 3H), 2.37 - 2.20 (m, 1H), 1.89 - 1.71 (m, 2H),

1677, 471.2126; found, 1.72 - 1.42 (m, 5H), 1.37 (d, = 6.3 Hz, 3H). 1508, 471.2132

1199 ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 173.07,

168.88, 162.33, 159.39, 146.73, 141.49, 137.99, 137.43, 128.42, 127.84, 127.76, 109.78, 83.07, 73.46, 71.17, 56.28, 52.54, 32.27, 28.96, 28.07, 21.94, 20.76, 18.23.

Ή NMR (400 MHz, CDC1 ₃ ) δ 8.50 (d, = 7.8 Hz, 1H), 8.27 (d, = 5.3 Hz, 1H), 7.41 - 7.28 (m, 5H), 6.93 (d, = 5.4 Hz, 1H), 5.78 (d, = 6.4 Hz, 1H), 5.76 (d, = 6.4 Hz, 1H), 5.10 (dq, / = 8.8, 6.3 Hz, 1H), 4.62 (d, = 11.6 Hz, 1H), 4.56 (ddd, = 10.9, 7.8, 5.3 Hz, 1H), 4.42 (d, = 11.5 Hz, 1H), 3.88 (s,

IR (neat)

HRMS-ESI (mJz) 3H), 3.26 - 3.20 (m, 1H), 2.55 (hept, / = 7.1 3379,

([M+H] ⁺ ) calcd for Hz, 1H), 2.34 (dddd, = 14.0, 10.6, 5.5, 2.0 2937,

48 C28H ₃ 7N ₂ 08 ⁺ , Hz, 1H), 1.90 - 1.74 (m, 2H), 1.74 - 1.42 (m,

1743,

529.2544; found, 5H), 1.38 (d, = 6.3 Hz, 3H), 1.14 (d, = 7.0 1676,

529.2553 Hz, 6H).

1502

¹³ C NMR (101 MHz, CDC1 ₃ ) δ 176.23, 173.17, 162.89, 160.24, 145.64, 144.13, 142.17, 137.99, 128.41, 127.84, 127.76, 109.51, 89.93, 83.05, 73.46, 71.18, 56.13, 52.79, 33.85, 32.13, 28.97, 28.04, 21.96,

18.68, 18.25. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDCI ₃ ) δ 8.61 (d, = 7.7 Hz, 1H), 8.34 (d, = 5.4 Hz, 1H), 7.01 (d, = 5.5 Hz, 1H), 5.19 (dq, / = 9.1, 6.3 Hz, 1H), 4.65 - 4.50 (m, 2H), 3.91 (s, 3H), 2.60 -

IR (thin

2.47 (m, 1H), 2.40 (s, 3H), 2.38 - 2.25 (m, film)

HRMS-ESI (mJz) 1H), 1.83 (tdd, = 10.8, 5.0, 3.2 Hz, 2H), 3378,

([M+H] ⁺ ) calcd for 1.77 - 1.52 (m, 3H), 1.49 - 1.34 (m, 2H), 2940,

49 C22H31N2O8, 1.31 (d, = 6.4 Hz, 3H), 1.17 (dd, / = 7.0, 3.5

1732,

451.2075; found, Hz, 6H).

1676,

451.2085

1507,

¹³ C NMR (101 MHz, CDC1 ₃ ) δ 176.14, 1174

173.08, 168.89, 162.35, 159.43, 146.71, 141.45, 137.49, 109.80, 76.58, 72.24, 56.29, 52.54, 34.05, 32.55, 30.45, 27.12, 21.96, 20.75, 18.89, 18.78, 17.87.

1H NMR (400 MHz, CDCI ₃ ) δ 8.40 (d, = 7.8 Hz, 1H), 8.29 (d, = 5.4 Hz, 1H), 6.95 (d, = 5.4 Hz, 1H), 5.75 (d, J = 1.1 Hz, 2H), 5.19 (dq, = 9.0, 6.3 Hz, 1H), 4.68 - 4.49 (m,

IR (thin 2H), 3.91 (s, 3H), 2.54 (hept, = 7.0 Hz, 1H), film) 2.36 (dddd, = 14.0, 10.3, 5.4, 2.1 Hz, 1H),

HRMS-ESI (mJz)

3378, 2.08 (s, 3H), 1.92 - 1.78 (m, 2H), 1.78 - 1.52

([M+H] ⁺ ) calcd for

2940, (m, 3H), 1.43 (dddt, = 15.2, 13.4, 8.0, 4.0

50 C ₂₃ H ₃₃ N ₂ O9,

1732, Hz, 2H), 1.32 (d, = 6.3 Hz, 3H), 1.17 (dd,

481.2181; found,

1675, = 7.0, 3.5 Hz, 6H).

481.2194

1503,

1199 ¹³ C NMR (101 MHz, CDCI ₃ ) δ 176.15,

173.19, 170.29, 162.94, 160.29, 145.75, 144.02, 142.45, 109.60, 89.59, 76.60, 72.25, 56.19, 52.81, 34.05, 32.38, 30.45, 27.10, 21.99, 20.88, 18.89, 18.79, 17.90. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDCI ₃ ) δ 8.65 (d, = 8.0 Hz, IH), 8.33 (d, = 5.4 Hz, IH), 7.00 (d, = 5.4 Hz, IH), 5.01 (dq, / = 8.7, 6.3 Hz,

IR (thin IH), 4.56 (ddd, / = 10.9, 8.1, 5.3 Hz, IH), film) 3.90 (s, 3H), 3.33 (s, 3H), 2.99 (ddd, = 8.7, 3379, HRMS-ESI (mJz) 6.9, 1.6 Hz, IH), 2.40 (s, 3H), 2.31 (dddd, / = 2938, ([M+H] ⁺ ) calcd for 14.0, 10.3, 4.7, 2.0 Hz, 2H), 1.87 - 1.73 (m,

51 1770, C ₁ 9H ₂₇ N ₂ O ₇ , 2H), 1.73 - 1.39 (m, 4H), 1.37 (d, = 6.3 Hz,

1740, 395.1813; found, 3H).

1675, 395.1823

1507, ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 173.05, 1173 168.89, 162.33, 159.40, 146.72, 141.51,

137.43, 109.76, 85.49, 73.34, 56.83, 56.28, 52.50, 32.27, 28.33, 27.97, 22.00, 20.76,

18.22.

1H NMR (400 MHz, CDCI ₃ ) δ 8.44 (d, = 7.8 Hz, IH), 8.28 (d, = 5.4 Hz, IH), 6.95 (d, = 5.4 Hz, IH), 5.79 - 5.70 (m, 2H), 5.02 (dq, / = 8.7, 6.3 Hz, IH), 4.58 (ddd, = 10.9,

IR (thin

7.8, 5.3 Hz, IH), 3.91 (s, 3H), 3.33 (s, 3H), film)

HRMS-ESI (mJz) 3.00 (ddd, = 8.5, 6.8, 1.6 Hz, IH), 2.34 3379,

([M+H] ⁺ ) calcd for (dddd, = 14.1, 10.5, 5.4, 2.0 Hz, IH), 2.07 2937,

52 C20H29N2O8, (s, 3H), 1.89 - 1.41 (m, 7H), 1.38 (d, = 6.3

1743,

425.1918; found, Hz, 3H).

1674,

425.1929

1503,

¹³ C NMR (101 MHz, CDC1 ₃ ) δ 173.16, 1200

170.27, 162.92, 160.26, 145.78, 143.92, 142.55, 109.56, 89.59, 85.48, 73.37, 56.85, 56.18, 52.75, 32.13, 28.34, 27.91, 22.03,

20.88, 18.25.

*

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDCI ₃ ) δ 8.45 (d, = 7.8 Hz, IH), 8.27 (d, = 5.4 Hz, IH), 6.95 (d, = 5.4 Hz, IH), 5.89 - 5.75 (m, 2H), 5.02 (dq, / = 8.7, 6.3 Hz, IH), 4.56 (ddd, = 10.8,

7.8, 5.3 Hz, IH), 4.10 (s, 2H), 3.90 (s, 3H),

IR (thin

3.59 (q, = 7.0 Hz, 2H), 3.33 (s, 3H), 3.00 film) HRMS-ESI (mJz)

(ddd, / = 8.7, 6.7, 1.6 Hz, IH), 2.33 (dddd, 3376, ([M+H] ⁺ ) calcd for

= 14.2, 10.6, 5.3, 2.0 Hz, IH), 1.88 - 1.41 (m,

53 2935, C ₂₂ H ₃₃ N ₂ O9,

7H), 1.38 (d, = 6.3 Hz, 3H), 1.23 (t, = 7.0 1749, 469.2181; found,

Hz, 3H).

1505, 469.2195

1120

¹³ C NMR (101 MHz, CDCI ₃ ) δ 173.13, 170.05, 162.87, 160.18, 145.83, 143.86, 142.43, 109.68, 89.57, 85.50, 73.38, 67.80, 67.18, 56.84, 56.22, 52.75, 32.11, 28.33, 27.90, 22.04, 18.24, 15.01.

1H NMR (400 MHz, CDC1 ₃ ) δ 8.44 (d, = 7.7 Hz, IH), 8.27 (d, = 5.3 Hz, IH), 7.26 - 7.20 (m, 2H), 6.94 (d, = 5.4 Hz, IH), 6.92 - 6.85 (m, 2H), 5.84 - 5.65 (m, 2H), 5.08 (dq, = 8.9, 6.3 Hz, IH), 4.63 - 4.49 (m, 2H), 4.35

IR (thin

(d, = 11.1 Hz, IH), 3.90 (s, 3H), 3.81 (s, film)

HRMS-ESI (mJz) 3H), 3.25 - 3.13 (m, IH), 2.34 (dddd, / = 3378,

([M+H] ⁺ ) calcd for 14.1, 10.6, 5.4, 2.0 Hz, IH), 2.07 (s, 3H), 2937,

54 C ₂₇ H ₃₅ N ₂ O9, 1.89 - 1.73 (m, 3H), 1.73 - 1.38 (m, 4H),

1746,

531.2337; found, 1.36 (d, = 6.3 Hz, 3H).

1676,

531.2344

1511,

¹³ C NMR (101 MHz, CDC1 ₃ ) δ 173.17, 1202

170.26, 162.90, 160.25, 159.28, 145.77, 143.91, 142.53, 130.06, 129.47, 113.82, 109.56, 89.58, 82.63, 73.50, 70.83, 56.17, 55.28, 52.80, 32.14, 29.01, 28.08, 21.95,

20.88, 18.22. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDCI ₃ ) δ 8.64 (d, = 8.7 Hz, IH), 8.33 (d, = 5.4 Hz, IH), 7.32 - 7.18 (m, 2H), 6.99 (d, = 5.5 Hz, IH), 6.94 - 6.83 (m, 2H), 5.07 (dq, = 9.0, 6.3 Hz, IH),

IR (thin

4.61 - 4.47 (m, 2H), 4.34 (d, = 11.2 Hz, film)

IH), 3.90 (s, 3H), 3.81 (s, 3H), 3.25 - 3.11 3380, HRMS-ESI (mJz)

(m, IH), 2.39 (s, 3H), 2.37 - 2.23 (m, IH), 2938, ([M+H] ⁺ ) calcd for

1.91 - 1.71 (m, 2H), 1.71 - 1.38 (m, 5H),

55 1770, C26H33N2O8,

1.35 (d, = 6.3 Hz, 3H).

1740, 501.2231; found,

1676, 501.2239

¹³ C NMR (101 MHz, CDC1 ₃ ) δ 173.07, 1510,

168.89, 162.32, 159.39, 159.28, 146.72, 1173

141.51, 137.43, 130.06, 129.48, 113.83, 109.75, 82.65, 73.49, 70.82, 56.27, 55.29, 52.55, 32.29, 29.00, 28.15, 21.92, 20.75,

18.20.

1H NMR (400 MHz, CDC1 ₃ ) δ 8.44 (d, = 7.8 Hz, IH), 8.28 (d, = 5.4 Hz, IH), 6.95 (d,

IR (thin = 5.4 Hz, IH), 5.75 (d, = 6.5 Hz, IH), film) 5.73 (d, = 6.4 Hz, IH), 5.02 (dq, / = 8.9, 6.3

HRMS-ESI (mJz)

3379.51, Hz, IH), 4.57 (ddd, / = 11.0, 7.8, 5.3 Hz,

([M+H] ⁺ ) calcd for

2936.73, IH), 3.91 (s, 3H), 3.52 (dt, / = 9.1, 6.5 Hz,

56 C22H33N2O8,

1742.36, IH), 3.27 (dt, / = 9.0, 6.6 Hz, IH), 3.07 (ddd,

453.2231; found,

1674.97, = 8.7, 6.9, 1.6 Hz, IH), 2.34 (dddd, / =

453.2239

1502.53, 14.0, 10.5, 5.4, 2.0 Hz, IH), 2.07 (s, 3H), 1199.64 1.87 - 1.63 (m, 4H), 1.63 - 1.41 (m, 5H),

1.38 (d, = 6.3 Hz, 3H), 0.93 (t, = 7.4 Hz,

3H).

1H NMR (400 MHz, CDCI ₃ ) δ 8.44 (d, =

IR (thin 7.8 Hz, IH), 8.28 (d, = 5.3 Hz, IH), 6.94 (d, film) = 5.4 Hz, IH), 5.75 (d, = 6.5 Hz, IH),

HRMS-ESI (mJz)

3379.74, 5.73 (d, = 6.5 Hz, IH), 4.98 (dq, = 8.9, 6.3

([M+H] ⁺ ) calcd for

2942.16, Hz, IH), 4.56 (ddd, = 10.8, 7.8, 5.3 Hz,

57 C 4H35N2O8,

1743.08, IH), 4.02 - 3.92 (m, IH), 3.91 (s, 3H), 3.13

479.2388; found,

1675.28, (ddd, = 8.9, 7.2, 1.7 Hz, IH), 2.34 (dddd,

479.2393

1502.78, = 13.8, 10.6, 5.4, 1.9 Hz, IH), 2.07 (s, 3H), 1200.06 1.86 - 1.38 (m, 15H), 1.36 (d, = 6.3 Hz,

3H). *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDCI ₃ ) δ 8.43 (d, = 7.8 Hz, 1H), 8.28 (d, = 5.4 Hz, 1H), 6.95 (d,

IR (thin

= 5.4 Hz, 1H), 5.75 (d, = 6.5 Hz, 1H), film)

HRMS-ESI (mJz) 5.73 (d, = 6.4 Hz, 1H), 5.00 (dq, / = 8.9, 6.3 3379.81,

([M+H] ⁺ ) calcd for Hz, 1H), 4.56 (ddd, / = 10.9, 7.8, 5.3 Hz, 2942.41,

58 C23H33N2O10, 1H), 3.91 (s, 3H), 3.83 (dt, = 9.2, 6.0 Hz, 1737.27,

497.213; found, 1H), 3.70 (s, 3H), 3.61 (dt, / = 9.2, 6.3 Hz, 1674.43,

497.2132 1H), 3.11 (ddd, / = 8.8, 6.9, 1.5 Hz, 1H), 2.56 1503.15,

(t, = 6.1 Hz, 2H), 2.33 (dddd, = 14.0, 10.5, 1198.23

5.4, 2.0 Hz, 1H), 2.07 (s, 3H), 1.86 - 1.37 (m, 7H), 1.35 (d, = 6.3 Hz, 3H).

1H NMR (400 MHz, CDCI ₃ ) δ 8.43 (d, = 7.8 Hz, 1H), 8.28 (d, = 5.4 Hz, 1H), 6.95 (d,

IR (thin

= 5.4 Hz, 1H), 5.75 (d, = 6.4 Hz, 1H), film)

5.73 (d, = 6.4 Hz, 1H), 5.02 (dq, / = 8.7, 6.3 3391.75, HRMS-ESI (mJz)

Hz, 1H), 4.58 (ddd, = 10.8, 7.8, 5.3 Hz, 2941.62, ([M+H] ⁺ ) calcd for

1H), 3.91 (s, 3H), 3.72 (dt, = 9.5, 6.5 Hz,

59 1761.98, C23H33F2N2O8,

1H), 3.48 (dt, = 9.6, 6.5 Hz, 1H), 3.10 (ddd, 1736.35, 503.2199; found,

= 8.5, 6.7, 1.6 Hz, 1H), 2.34 (dddd, = 1674.56, 503.2212

13.9, 10.5, 5.3, 1.9 Hz, 1H), 2.14 (dddd, = 1501.63,

15.3, 13.5, 6.7, 5.3 Hz, 2H), 2.07 (s, 3H), 1126.28

1.87 - 1.39 (m, 10H), 1.37 (d, = 6.3 Hz,

3H).

1H NMR (400 MHz, CDCI ₃ ) δ 8.40 (d, = 7.8 Hz, 1H), 8.28 (d, = 5.4 Hz, 1H), 6.95 (d, = 5.4 Hz, 1H), 5.75 (d, = 1.0 Hz, 2H),

IR (thin 5.19 (dq, = 9.1, 6.3 Hz, 1H), 4.68 - 4.50 (m, film) 2H), 3.91 (s, 3H), 2.73 (tt, = 8.7, 7.1 Hz, 3380, HRMS-ESI (mJz) 1H), 2.36 (dddd, = 14.1, 10.4, 5.5, 2.2 Hz, 2946, ([M+H] ⁺ ) calcd for 1H), 2.07 (s, 3H), 1.97 - 1.51 (m, 13H), 1.51

60 1731, C ₂₅ H ₃₅ N ₂ O9, - 1.35 (m, 2H), 1.32 (d, = 6.3 Hz, 3H).

1677, 507.2337; found,

1503, 507.2341 ¹³ C NMR (101 MHz, CDCI ₃ ) δ 175.77, 1200, 173.20, 170.28, 162.93, 160.29, 145.75, 1175 144.01, 142.44, 109.59, 89.58, 76.61, 72.28,

56.19, 52.81, 43.86, 32.38, 30.46, 29.95, 29.80, 27.13, 25.81, 25.75, 21.98, 20.88,

17.92. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDCI ₃ ) δ 8.44 (d, 7 = 7.8 Hz, 1H), 8.28 (d, 7 = 5.4 Hz, 1H), 6.94 (d,

7 = 5.4 Hz, 1H), 5.83 - 5.68 (m, 2H), 5.03 (dq, 7 = 9.0, 6.3 Hz, 1H), 4.57 (ddd, 7 = 11.0,

IR (thin 7.8, 5.3 Hz, 1H), 3.91 (s, 3H), 3.33 (dd, 7 = film) 8.7, 6.2 Hz, 1H), 3.05 (dtd, 7 = 8.8, 4.2, 2.2

HRMS-ESI (mJz)

3379, Hz, 2H), 2.34 (dddd, 7 = 14.1, 10.4, 5.3, 2.0

([M+H] ⁺ ) calcd for

2952, Hz, 1H), 2.07 (s, 3H), 1.88 - 1.63 (m, 4H),

61 C23H35N2O8,

1743, 1.63 - 1.40 (m, 4H), 1.38 (d, 7 = 6.3 Hz, 3H),

467.2388; found,

1675, 0.90 (t, 7 = 6.8 Hz, 6H).

467.2395

1504,

1201 ¹³ C NMR (101 MHz, CDCI ₃ ) δ 173.20,

170.27, 162.90, 160.26, 145.77, 143.91, 142.57, 109.54, 89.59, 84.00, 76.41, 73.65, 56.18, 52.82, 32.19, 29.08, 28.74, 28.28, 21.92, 20.88, 19.47, 19.40, 18.23.

1H NMR (400 MHz, CDC1 ₃ ) δ 8.44 (d, 7 = 7.8 Hz, 1H), 8.28 (d, 7 = 5.4 Hz, 1H), 7.34 - 7.24 (m, 2H), 7.24 - 7.13 (m, 3H), 6.94 (d, 7 = 5.4 Hz, 1H), 5.83 - 5.67 (m, 2H), 5.05 (dq, 7 = 8.9, 6.3 Hz, 1H), 4.57 (ddd, 7 = 11.0, 7.8, 5.3 Hz, 1H), 3.90 (s, 3H), 3.56 (dt, 7 = 9.2,

IR (thin

6.1 Hz, 1H), 3.31 (dt, 7 = 9.1, 6.3 Hz, 1H), film)

HRMS-ESI (mJz) 3.14 - 3.03 (m, 1H), 2.76 - 2.61 (m, 2H), 3379,

([M+H] ⁺ ) calcd for 2.34 (dddd, 7 = 14.1, 10.4, 5.3, 2.0 Hz, 1H), 2938,

62 C28H37N2O8, 2.07 (s, 3H), 1.88 (dq, 7 = 8.5, 6.4 Hz, 2H),

1742,

529.2544; found, 1.84 - 1.61 (m, 3H), 1.61 - 1.42 (m, 4H), 1675,

529.2552 1.40 (d, 7 = 6.3 Hz, 3H).

1503,

1201

¹³ C NMR (101 MHz, CDC1 ₃ ) δ 173.19, 170.27, 162.91, 160.26, 145.77, 143.92, 142.55, 141.83, 128.43, 128.34, 125.82, 109.55, 89.59, 83.87, 73.55, 68.45, 56.18, 52.80, 32.38, 32.17, 31.56, 29.15, 28.15,

21.94, 20.88, 18.29. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDCI ₃ ) δ 8.64 (d, = 8.1 Hz, 1H), 8.33 (d, = 5.4 Hz, 1H), 7.00 (d, = 5.4 Hz, 1H), 5.02 (dq, / = 9.0, 6.3 Hz, 1H), 4.55 (ddd, / = 11.0, 8.1, 5.3 Hz, 1H),

IR (thin

3.90 (s, 3H), 3.32 (dd, = 8.7, 6.2 Hz, 1H), film)

3.04 (ddd, / = 8.8, 6.8, 1.9 Hz, 2H), 2.40 (s, 3379, HRMS-ESI (mJz)

3H), 2.30 (dddt, = 12.0, 10.4, 5.2, 2.5 Hz, 2952, ([M+H] ⁺ ) calcd for

1H), 1.88 - 1.61 (m, 5H), 1.61 - 1.40 (m,

65 1771, C ₂₂ H ₃₃ N ₂ O ₇ ,

3H), 1.37 (d, = 6.3 Hz, 3H), 0.90 (t, = 6.8 1676, 437.2282; found,

Hz, 6H).

1507, 437.2295

1197,

¹³ C NMR (101 MHz, CDCI ₃ ) δ 173.09, 1174

168.88, 162.32, 159.39, 146.72, 141.53, 137.43, 109.75, 84.01, 76.39, 73.63, 56.28, 52.57, 32.33, 29.07, 28.74, 28.33, 21.90, 20.76, 19.47, 19.40, 18.20.

1H NMR (400 MHz, CDC1 ₃ ) δ 8.64 (d, = 8.1 Hz, 1H), 8.34 (d, = 5.4 Hz, 1H), 7.00 (d, = 5.4 Hz, 1H), 5.01 (dq, / = 8.8, 6.3 Hz, 1H), 4.55 (ddd, = 10.9, 8.1, 5.3 Hz, 1H), 3.90 (s, 3H), 3.60 (dt, / = 9.1, 5.9 Hz, 1H),

IR (thin

3.35 (dt, / = 9.1, 6.0 Hz, 1H), 3.08 (ddd, = film)

8.6, 6.7, 1.7 Hz, 1H), 2.40 (s, 3H), 2.37 - 3377, HRMS-ESI (mJz)

2.25 (m, 1H), 2.25 - 2.09 (m, 2H), 1.88 - 2941, ([M+H] ⁺ ) calcd for

1.73 (m, 3H), 1.73 - 1.38 (m, 6H), 1.36 (d,

66 1771, C ₂₂ H ₃₀ F ₃ N ₂ O ₇ ,

= 6.3 Hz, 3H).

1676, 491.2000; found,

1508, 491.2003

1197,

¹³ C NMR (101 MHz, CDCI ₃ ) δ 173.05, 1175

168.89, 162.35, 159.42, 146.73, 141.50, 137.45, 127.22 (q, = 276.0 Hz), 109.78, 84.01, 73.25, 67.33, 56.29, 52.50, 32.30, 30.76 (q, = 28.9 Hz), 29.00, 27.97, 22.71 (q, = 3.0 Hz), 21.95, 20.76, 18.21. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (400 MHz, CDCI ₃ ) δ 8.47 (d, = 7.8 Hz, 1H), 8.29 (d, = 5.3 Hz, 1H), 7.34 -

7.24 (m, 2H), 7.01 - 6.91 (m, 2H), 6.89 - 6.80 (m, 2H), 5.83 - 5.70 (m, 2H), 5.30 (dq,

IR (thin = 8.9, 6.3 Hz, 1H), 4.63 (ddd, / = 11.1, 7.8, film) 5.3 Hz, 1H), 4.02 (ddd, = 8.8, 7.3, 1.3 Hz,

HRMS-ESI (mJz)

3376, 1H), 3.91 (s, 3H), 2.38 (dddd, / = 14.1, 10.3,

([M+H] ⁺ ) calcd for

2939, 5.3, 2.0 Hz, 1H), 2.08 (s, 3H), 1.97 - 1.61 (m,

70 C25H31N2O8,

1748, 5H), 1.61 - 1.45 (m, 2H), 1.43 (d, = 6.3 Hz,

487.2075; found,

1676, 3H).

487.2083

1494,

1201 ¹³ C NMR (101 MHz, CDCI ₃ ) δ 173.16,

170.27, 162.95, 160.28, 157.21, 145.79, 143.96, 142.47, 129.63, 121.10, 115.69, 109.60, 89.57, 81.16, 73.00, 56.19, 52.88, 32.28, 29.05, 27.82, 22.10, 20.88, 18.26.

1H NMR (400 MHz, CDC1 ₃ ) δ 8.48 (d, = 7.8 Hz, 1H), 8.28 (d, = 5.4 Hz, 1H), 7.35 -

7.23 (m, 2H), 7.01 - 6.91 (m, 2H), 6.89 - 6.80 (m, 2H), 5.87 - 5.80 (m, 2H), 5.30 (dq,

= 8.9, 6.3 Hz, 1H), 4.61 (ddd, = 11.1, 7.8,

IR (thin 5.3 Hz, 1H), 4.11 (s, 2H), 4.02 (ddd, = 8.7, film) 7.3, 1.2 Hz, 1H), 3.91 (s, 3H), 3.60 (q, = 7.0

HRMS-ESI (mJz)

3381, Hz, 2H), 2.37 (dddd, / = 14.1, 10.4, 5.3, 2.0

([M+H] ⁺ ) calcd for

2938, Hz, 1H), 1.97 - 1.61 (m, 6H), 1.61 - 1.45 (m,

71 C ₂₇ H ₃₅ N ₂ O9,

1745, 2H), 1.43 (d, = 6.3 Hz, 3H), 1.22 (d, = 7.0

531.2337; found,

1676, Hz, 2H).

531.2345

1494,

1127 ¹³ C NMR (101 MHz, CDCI ₃ ) δ 173.13,

170.06, 162.89, 160.18, 157.20, 145.84, 143.90, 142.33, 129.63, 121.10, 115.68, 109.71, 89.55, 81.15, 73.00, 67.79, 67.18, 56.23, 52.87, 32.25, 29.03, 27.83, 22.09,

18.26, 15.01. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (500 MHz, CDCI ₃ ) δ 8.46 (d, = 7.8 Hz, 1H), 8.29 (d, = 5.3 Hz, 1H), 7.02 -

6.92 (m, 3H), 6.83 - 6.75 (m, 2H), 5.80 - 5.71 (m, 2H), 5.27 (dq, = 8.8, 6.3 Hz, 1H), 4.62 (ddd, / = 11.0, 7.8, 5.3 Hz, 1H), 3.95 (ddd, / = 8.8, 7.3, 1.4 Hz, 1H), 3.91 (s, 3H),

IR (thin

2.38 (dddd, / = 14.2, 10.6, 5.4, 1.9 Hz, 1H), film)

HRMS-ESI (mJz) 2.08 (s, 3H), 1.87 (dddt, = 12.3, 7.0, 5.1, 2.0 3381,

([M+H] ⁺ ) calcd for Hz, 1H), 1.83 - 1.61 (m, 4H), 1.61 - 1.45 (m, 2939,

72 C25H30FN2O8, 2H), 1.43 (d, = 6.3 Hz, 3H).

1748,

505.1981; found,

1675,

505.1990 ¹³ C NMR (126 MHz, CDCI ₃ ) δ 173.13, 1502,

170.27, 162.95, 160.28, 157.41 (d, = 239.1 1198

Hz), 153.32, 145.79, 143.96, 142.42, 116.89

(d, = 8.0 Hz), 116.01 (d, = 23.0 Hz), 109.63, 89.55, 82.12, 72.85, 56.20, 52.83,

32.21, 28.90, 27.72, 22.09, 20.88, 18.27.

¹⁹ F NMR (471 MHz, CDC1 ₃ ) δ -123.24.

1H NMR (500 MHz, CDC1 ₃ ) δ 8.47 (d, = 7.8 Hz, 1H), 8.28 (d, = 5.3 Hz, 1H), 7.03 -

IR (thin 6.90 (m, 3H), 6.83 - 6.73 (m, 2H), 5.83 (d, film) = 2.0 Hz, 2H), 5.27 (dq, = 8.8, 6.3 Hz, 1H), 3381, HRMS-ESI (mJz) 4.61 (ddd, 7 = 11.0, 7.8, 5.3 Hz, 1H), 4.11 (s, 2938, ([M+H] ⁺ ) calcd for 2H), 3.94 (ddd, J = 8.7, 7.2, 1.3 Hz, 1H), 3.91

73 1745, C ₂₇ H ₃₄ FN ₂ O9, (s, 3H), 3.60 (q, J= 7.0 Hz, 2H), 2.37 (dddd,

1675, 549.2243; found, J = 14.2, 10.6, 5.4, 1.9 Hz, 1H), 1.87 (dddd, 1502, 549.2243 = 14.2, 10.8, 5.4, 2.9 Hz, 1H), 1.82 - 1.60 (m, 1199, 4H), 1.60 - 1.44 (m, 2H), 1.43 (d, J = 6.3 Hz, 1127 3H), 1.23 (t, 7 = 7.0 Hz, 3H).

¹⁹ F NMR (471 MHz, CDC1 ₃ ) δ -123.25. *

Cmpd. NMR

IR (cm ¹ ) MASS

No. (1H, ¹³ C or ¹⁹ F)

1H NMR (500 MHz, CDCI ₃ ) δ 8.66 (d, =

IR (thin 7.8 Hz, 1H), 8.34 (d, = 5.4 Hz, 1H), 7.05 - film) 6.91 (m, 3H), 6.83 - 6.74 (m, 2H), 5.27 (dq,

HRMS-ESI (mJz)

3378, = 8.8, 6.3 Hz, 1H), 4.60 (ddd, = 11.1, 8.1,

([M+H] ⁺ ) calcd for

2939, 5.3 Hz, 1H), 3.98 - 3.86 (m, 4H), 2.40 (s,

74 C ₂ . ₄ H ₂₈ FN ₂ O ₇ ,

1769, 3H), 2.39 - 2.10 (m, 1H), 1.86 (dtt, J = 15.5,

475.1875; found,

1675, 7.0, 3.5 Hz, 1H), 1.81 - 1.62 (m, 4H), 1.59 - 475.1879

1502, 1.44 (m, 2H), 1.42 (d, = 6.3 Hz, 3H). 1196

¹⁹ F NMR (471 MHz, CDCI ₃ ) δ -123.26.

Cmpd. No. - Compound Number

lH NMR were run at 400 MHz unless noted otherwise

C NMR were run at 101 MHz unless noted otherwise

F NMR were run at 376 MHz unless noted otherwise

Table 3. Biological Testing Rating Scale

Table 4. Biological Activity -High- Volume Cereal Activity at 100 ppm

PUCCRT - Wheat Brown Rust {Puccinia triticina)

SEPTTR - Wheat Leaf Blotch {Zymoseptoria tritici)

1DP - 1 Day Protectant

3DC - 3 Day Curative Table 5. Biological Activity - Low- Volume Cereal Activity at 121.5 g H

PUCCRT* SEPTTR*

Cmpd No. 1DP* 3DC* 1DP* 3DC*

65 A A B A

66 A A A A

67 A A B A

68 A A B A

69 A A A A

70 A A A A

71 A A A A

72 A A A A

73 A A A A

74 A A A A

PUCCRT - Wheat Brown Rust {Puccinia triticina)

SEPTTR - Wheat Leaf Blotch {Zymoseptoria tritici)

1DP - 1 Day Protectant

3DC - 3 Day Curative

Table 6. Biological Activity - Disease Control at 100 ppm

ALTESO - Tomato Early Blight (Alternaria solani)

CERCBE - Leaf Spot of Sugar Beets (Cercospora beticola)

COLLLA - Cucumber Anthracnose (Glomerella lagenarium; Anamorph: Colletotricum lagenarium)

ERYSCI - Powdery Mildew of Cucumber (Erysiphe cichoracearum)

PYRIOR- Rice Blast (Magnaporthe grisea)

RHYNSE - Barley Scald (Rhyncosporium secalis)

UNCINE - Grape Powdery Mildew (Uncinula necator)

Table 7. Biological Activity - Disease Control at 25 ppm

PHAKPA - Asian Soybean Rust (Phakopsora pachyrhizi) 1DP - 1 Day Protectant

3DC - 3 Day Curative