C4 side-chain modified nodulisporic acid analogs

BACKGROUND OF THE INVENTION

[0001] Nodulosporic acid A and related component nodulisporic acid A1 are antiparasitic agents and ectoparasiticidal agents isolated from the fermentation culture of Nodulisporium sp. MF-5954 (ATCC 74245). These two compounds have the following structures as disclosed in U.S. Pat. No. 5,399,582 and J. G. Ondeyka et al. J. Am. Chem. Soc. 1997, 119(38), 8809-8816.

[0002] nodulisporic acid A (compound A)

[0003] nodulisporic acid A1 (compound B)

[0004] Derivatives of nodulisporic acid are disclosed in U.S. Pat. No. 5,962,499.

SUMMARY OF THE INVENTION

[0005] This invention relates to new acaricidal, antiparasitic, insecticidal and anthelmintic agents related to the nodulisporic acids, to processes for their preparation, compositions thereof, their use in the treatment of parasitic infections, including helminthiasis, in human and animals, and their use in the treatment of parasitic infections in plants or plant products.

DETAILED DESCRIPTION OF THE INVENTION

[0006] The present invention provides compounds having the formula I:

[0007] wherein

[0008] R1 is

[0009] (1) hydrogen,

[0010] (2) optionally substituted C1-C10 alkyl,

[0011] (3) optionally substituted C2-C10 alkenyl,

[0012] (4) optionally substituted C2-C10 alkynyl,

[0013] (5) optionally substituted C3-C8 cycloalkyl,

[0014] (6) optionally substituted C5-C8 cycloalkenyl

[0015] where the substitutents on the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are 1 to 3 groups independently selected from

[0016] (i) C1-C5 alkyl,

[0017] (ii) X—C1-C10 alkyl,

[0018] (iii) C3-C8 cycloalkyl,

[0019] (iv) hydroxy,

[0020] (v) halogen,

[0021] (vi) cyano,

[0022] (vii) carboxy,

[0023] (viii) NY1Y2,

[0024] (ix) C1-C10 alkanoylamino, and

[0025] (x) aroyl amino wherein said aroyl is optionally substituted with 1 to 3 groups independently selected from Rf

[0026] (7) aryl C0-C5 alkyl wherein said aryl is optionally substituted with 1 to 3 groups independently selected from Rf,

[0027] (8) C1-C5 perfluoroalkyl

[0028] (9) a 5- or 6-membered heterocycle optionally substituted by 1 to 3 groups independently selected from hydroxy, oxo, C1-C10 alkyl and halogen;

[0029] R2, R3, and R4 are independently ORa, OCO2Rb, OC(O)NRcRd; or

[0030] R1+R2 represent ═O, ═NORa, ═N—NRcRd, ═CCO2Ra, ═CC(O)NRcRd, ═CCN ═CC(O)Ra, or ═CRaRa;

[0031] R5 is hydrogen, ORa or

[0032] R4+R5 represent ═O, ═NORa, ═N—NRCRd or ═CRaRa;

[0033] R6 is

[0034] (1) the fragment

[0035] (2) the fragment

[0036] where A is a 5- or 6-membered heterocycle optionally substituted with 1 to 4 groups independently selected from C1-C5 alkyl, C2-C5 alkenyl, C1-C5 perfluoroalkyl, aryl, ORa, NRcRd, oxo, thiono, C(O)Ra, C(O)NRcRd, cyano, CO2Rb and halogen, and where a ring nitrogen is present, it is substituted with a group selected from Rc; the two Z groups are each OH or together form a bond across the two carbon atoms to which they are attached;

[0037] (3) the fragment

[0038] wherein A is as defined above; or

[0039] R6, R4 and the atoms to which they are attached together form the fragment

[0040] R7 is

[0041] (1) hydrogen,

[0042] (2) optionally substituted C1-C10 alkyl,

[0043] (3) optionally substituted C2-C10 alkenyl,

[0044] (4) optionally substituted C2-C10 alkynyl,

[0045] (5) optionally substituted aryl,

[0046] (6) optionally substituted C3-C8 cycloalkyl,

[0047] (7) optionally substituted C5-C8 cycloalkenyl,

[0048] (8) halogen,

[0049] (9) CN,

[0050] (10) C(O)Ra,

[0051] (11) CH═NORa,

[0052] (12) CO2Rb,

[0053] (13) C(O)NRcRd,

[0054] (14) C(O)N(ORb)Rc,

[0055] (15) C(O)NRcNRcRd,

[0056] (16) C(O)NRcSO2Rb,

[0057] (17) NRcRd

[0058] (18) NRcC(O)Ra,

[0059] (19) NRcC(O)ORb,

[0060] (20) NRcC(O)NRcRd,

[0061] (21) NRcC(O)SRb,

[0062] (22) NRcC(O)P(O)(Ra)2,

[0063] (23) NRcS(O)2Ra,

[0064] (24) N═C═O,

[0065] (25) XRa,

[0066] (26) OC(O)Ra,

[0067] (27) OSO2Ra,

[0068] (28) P(O)(ORa)2,

[0069] (29) 4- to 8-membered heterocycle optionally substituted by 1 to 4 groups independently selected from C1-C5 alkyl, C2-C5 alkenyl, C1-C5 perfluoroalkyl, NRcRd, oxo, thiono, C(O)NRcRd, cyano, aryl, C(O)Ra, CO2Rb and halogen,

[0070] where the substituents on the optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl and cycloalkenyl are from 1 to 10 groups independently selected from

[0071] (a) halogen,

[0072] (b) C3-C7 cycloalkyl,

[0073] (c) C1-C7 alkyl optionally substituted with from 1 to 3 groups independently selected from ORa, oxo, NRcRd, N3, NRcC(O)Ra, NRcSO2Ra, O2CNRcRd, NRcC(O)NRcRd, CO2Rb, C(O)NRcRd, or a 3- to 8-membered heterocycle optionally substituted with oxo or C(O)Ra,

[0074] (d) C1-C7 alkenyl optionally substituted with from 1 to 3 groups independently selected from ORa, oxo, NRcRd, N3, NRcC(O)Ra, NRcSO2Ra, O2CNRcRd, NRcC(O)RcRd, CO2Rb, C(O)NRcRd, or a 3- to 8-membered heterocycle optionally substituted with oxo or C(O)Ra,

[0075] (e) C1-C5 perfluoroalkyl,

[0076] (f) aryl optionally substituted with 1 to 3 groups selected from Rf,

[0077] (g) CN,

[0078] (h) C(O)Ra,

[0079] (i) CO2Rb,

[0080] (j) C(O)NRcRd,

[0081] (k) C(O)N(ORb)Rc,

[0082] (l) C(O)NRcNRcRd,

[0083] (m) C(O)NRcSO2Rb,

[0084] (n) N═C═O,

[0085] (o) N═N═N,

[0086] (p) NRcC(O)NRcRd,

[0087] (q) NRcC(O)P(O)Ra,

[0088] (r) NRcRd,

[0089] (s) NRcCO2Rb,

[0090] (t) NRcSO2Ra,

[0091] (u) NRcC(O)SRb,

[0092] (v) NRcC(O)Ra,

[0093] (w) ═NORa,

[0094] (x) ═NNRcRd,

[0095] (y) ═NNRcSO2Ra

[0096] (z) XRa,

[0097] (aa) oxo,

[0098] (bb) OCO2Rb,

[0099] (cc) OC(O)NRcRd,

[0100] (dd) OSO2Ra,

[0101] (ee) P(O)(ORa)2,

[0102] (ff) a 4- to 8-membered heterocycle optionally substituted by 1 to 4 groups independently selected from C1-C5 alkyl, C2-C5 alkenyl, C1-C5 perfluoroalkyl, NRcRd, oxo, thiono, XRa, C(O)NRcRd, cyano, (C0-C6-alkyl)aryl, CO2Rb and halogen;

[0103] R9 is a group selected from R7, with the proviso that R9 is not methyl when R7 is CN, C(O)ORb, C(O)N(ORb)Rc, C(O)NRcRd, NHC(O)ORb, NHC(O)NRcRd, CH2ORa, CH2OCO2Rb, CH2OC(O)NRcRd, C(O)NRcNRcRd, or C(O)NRcSO2Rb;

[0104] R20 is a group selected from R7;

[0105]

___
prepresents a single or a double bond;

[0106] Ra is

[0107] (1) hydrogen,

[0108] (2) optionally substituted C1-C10 alkyl,

[0109] (3) optionally substituted C3-C10 alkenyl,

[0110] (4) optionally substituted C3-C10 alkynyl,

[0111] (5) optionally substituted C1-C10 alkanoyl,

[0112] (6) optionally substituted C3-C10 alkenoyl,

[0113] (7) optionally substituted C3-C10 alkynoyl,

[0114] (8) optionally substituted aroyl,

[0115] (9) optionally substituted aryl,

[0116] (10) optionally substituted C3-C7 cycloalkanoyl,

[0117] (11) optionally substituted C5-C7 cycloalkenoyl,

[0118] (12) optionally substituted C1-C10 alkylsulfonyl,

[0119] (13) optionally substituted C3-C8 cycloalkyl,

[0120] (14) optionally substituted (C1-C6 alkyl)aryl,

[0121] (15) optionally substituted C5-C8 cycloalkenyl,

[0122] (16) C1-C5 pefluoroalkyl,

[0123] (17) arylsulfonyl optionally substituted with 1 to 3 groups independently selected from C1-C5 alkyl, C1-C5 perfluoroalkyl, nitro, halogen and cyano,

[0124] (18) a 4- to 8-membered heterocycle optionally substituted with 1 to 4 groups independently selected from C1-C5 alkyl, C2-C5 alkenyl, C1-C5 perfluoroalkyl, NRgRh, oxo, thiono, OH, C1-C5 alkoxy, C1-C5 alkanoyl, C(O)NRgRh, cyano, CO2H, CO2-C1-C6 alkyl and halogen;

[0125] where the substituents on the optionally substituted alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, alkynoyl, aroyl, aryl, cycloalkanoyl, cycloalkenoyl, alkylsulfonyl, cycloalkyl and cycloalkenyl are from 1 to 10 groups independently selected from OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl, aryl C1-C3 alkoxy, NRgRh, CO2H, CO2C1-C6 alkyl, C(O)NRgRh, NRgC(O)C1-C6 alkyl and halogen,

[0126] Rb is

[0127] (1) H,

[0128] (2) optionally substituted aryl,

[0129] (3) optionally substituted C1-C10 alkyl,

[0130] (4) optionally substituted C3-C10 alkenyl,

[0131] (5) optionally substituted C3-C10 alkynyl,

[0132] (6) optionally substituted C3-C15 cycloalkyl,

[0133] (7) optionally substituted C0-C6 alkyl S(O)2Ri,

[0134] (8) optionally substituted C2-C6 alkanoyl,

[0135] (9) optionally substituted C5-C10 cycloalkenyl, or

[0136] (10) optionally substituted 4- to 8-membered heterocycle;

[0137] where the substituents on the optionally substituted aryl, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, or alkynyl are from 1 to 10 groups independently selected from

[0138] (a) C1-C6 alkyl optionally substituted with aryl, hydroxy or amino,

[0139] (b) C1-C5 perfluoroalkyl;

[0140] (c) C3-C7 cycloalkyl optionally substituted with 1 to 4 groups independently selected from Re,

[0141] (d) C5-C7 cycloalkenyl,

[0142] (e) halogen,

[0143] (f) cyano,

[0144] (g) OH,

[0145] (h) XC1-C6 alkyl optionally substituted with amino, hydroxy or aryl optionally substituted with 1,2-methylenedioxy or 1 to 5 groups independently selected from Re,

[0146] (i) OC(O)C1-C5 alkyl,

[0147] (j) aryl C1-C6 perfluoroalkoxy,

[0148] (k) oxo,

[0149] (l) SO2NRgRh,

[0150] (m)C(O)Ri,

[0151] (n) CO2Ri,

[0152] (o) C(O)NRgRh,

[0153] (p) NRgRh,

[0154] (q) N(Rg)CO2Ri,

[0155] (r) N(Rc)C(S)ORi,

[0156] (s) 4- to 8-membered heterocycle optionally substituted with 1 to 5 groups independently selected from Re, and

[0157] (t) aryl optionally substituted with 1,2-methylenedioxy or 1 to 5 groups independently selected from Re,

[0158] Rc and Rd are independently selected from Rb; or

[0159] Rc and Rd together with the N to which they are attached form a 3- to 10-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and NRg, optionally substituted with 1 to 3 groups independently selected from Rg, hydroxy, thiono and oxo;

[0160] Re is

[0161] (1) halogen,

[0162] (2) C1-C7 alkyl,

[0163] (3) C1-C3 perfluoroalkyl,

[0164] (4) cyano,

[0165] (5) nitro,

[0166] (6) RiX(CH2)v—,

[0167] (7) RiCO2(CH2)v—,

[0168] (8) RiOCO(CH2)v,

[0169] (9) aryl optionally substituted with from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy,

[0170] (10) SO2NRgRh,

[0171] (11) amino, or

[0172] (12) oxo;

[0173] Rf is

[0174] (1) C1-C4 alkyl,

[0175] (2) C2-C4 alkenyl,

[0176] (3) C2-C4 alkynyl,

[0177] (4) C1-C3-perfluoroalkyl,

[0178] (5) NY1Y2,

[0179] (6) NHC(O)C1-C5 alkyl,

[0180] (7) OH,

[0181] (8) X—C1-C4 alkyl, or

[0182] (9) halogen,

[0183] Rg and Rh are independently

[0184] (1) hydrogen,

[0185] (2) C1-C6 alkyl optionally substituted with hydroxy, amino, C1-C5 alkanoyl or CO2Ri

[0186] (3) C0-C6aryl optionally substituted with halogen, 1,2-methylene-dioxy, C1-C7 alkoxy, C1-C7 alkyl or C1-C3 perfluoroalkyl,

[0187] (4) C(O)OC1-C5 alkyl optionally substituted with aryl,

[0188] (5) C(O)C1-C5 alkyl,

[0189] (6) C(O)NY1Y2, or

[0190] Rg and Rh together with the N to which they are attached form a 3- to 7-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and NRi, optionally substituted with 1 to 3 groups independently selected from halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, cyano, nitro, RiX(CH2)v—, RiCO2(CH2)v—, RiOCO(CH2)v, aryl optionally substituted with from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy, and oxo;

[0191] Ri is

[0192] (1) hydrogen,

[0193] (2) C1-C3 perfluoroalkyl,

[0194] (3) C1-C6 alkyl,

[0195] (4) optionally substituted aryl C0-C6 alkyl, where the aryl substituents are from 1 to 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxy;

[0196] X is O or S(O)m,

[0197] Y1 and Y2 are independently hydrogen or C1-C5 alkyl,

[0198] m is O to 2;and

[0199] v is O to 3;or

[0200] a pharmaceutically acceptable salt thereof.

[0201] In one subset of compounds of formula I, R6 is the fragment.

[0202] In one embodiment thereof, R20 is hydrogen or C1-C5 alkyl, R7 is CN, CO2Rb or CO2NRcRd, and Rg is other than methyl, and may be for example, hydrogen, ethyl, n-propyl, 3-dihydroxy-1-propyl, 2-oxoethyl, 2-hydroxyethyl, 2-(methylcarbamoyloxy)ethyl, 2-aminoethyl, 2-(ethylcarbamoylamino)ethyl, 2-(ethylamino)ethyl, fluorine, hydroxymethyl, methoxy, n-butyl, allyl, cyano, 4-(1-butenyl), 3-oxopropyl, 3,4-dihydroxybutyl, benzyloxycarbonylamino, trifluoromethyl, acetyl, 2-(ethylcarbamoyloxy)ethyl, 2-(methylcarbamoyloxy)ethyl, 2-(isopropyl-carbamoyloxy)ethyl, 2-(t-butylcarbamoyloxy)ethyl, phenyl, 4-fluorophenyl, methoxycarbonylamino, difluorochloroacetyl, isobutylaminocarbonylmethyl.

[0203] In another embodiment thereof R20 is hydrogen or C1-C5 alkyl, R7 is selected from hydrogen, NRcC(O)Ra, NRcC(O)NRcRd, NRcC(O)ORb, C(O)Ra, P(O)(ORa)2, optionally substituted heterocycle, optionally substituted aryl, CH═NORa, OSO2Ra, NRcC(O)P(O)(Ra)2, NRcC(O)SRb, substituted methyl wherein the substitutents are selected from CO2Rb, C(O)Ra, NRcRd, XRa. Aryl are for example, tetrazolyl, thienyl, isoxazolyl, oxazolyl, and thiazolyl; heterocycles are for example, oxazolinyl or thiazolinyl.

[0204] In another subset of compounds of formula I, R6 is the fragment

[0205] wherein the two Z groups together form a bond across the carbon atoms to which they are attached, and R20 is hydrogen. In one embodiment thereof A

[0206] In another subset of compounds of formula I are compounds of formula Ia:

[0207] The present invention provides in another aspect pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. Such compositions may further comprise one or more other active ingredients such as anthelmintic agents, insect regulators, ecdosyne agonists and fipronil.

[0208] The present invention provides in another aspect a method for treating parasitic diseases in a mammal which comprises administering an antiparasitic amount of a compound of Formula I. The treatment may further comprise co-administering one or more other active ingredients such as anthelmintic agents, insect regulators, ecdosyne agonists and fipronil.

[0209] “Alkyl” as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. “Alkenyl”, “alkynyl” and other like terms include carbon chains containing at least one unsaturated C—C bond.

[0210] The term “cycloalkyl” means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as benzofused carbocycles and spirofused carbocycles. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene and the like. Similarly, “cycloalkenyl” means carbocycles containing no heteroatoms and at least one non-aromatic C—C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.

[0211] The term “halogen” is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.

[0212] The term “heterocycle”, unless otherwise specified, means mono- or bicyclic compounds that are saturated or partly unsaturated, as well as benzo- or heteroaromatic ring fused saturated heterocycles or partly unsaturated heterocycles, and containing from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Examples of saturated heterocycles include morpholine, thiomorpholine, piperidine, piperazine, tetrahydropyran, tetrahydrofuran, dioxane, tetrahydrothiophene, oxazolidine, pyrrolidine; examples of partly unsaturated heterocycles include dihydropyran, dihydropyridazine, dihydrofuran, dihydrooxazole, dihydropyrazole, dihydropyridine, dihydropyridazine and the like. Examples of benzo- or heteroaromatic ring fused heterocycle include 2,3-dihydrobenzofuranyl, benzopyranyl, tetrahydroquinoline, tetrahydroisoquinoline, benzomorpholinyl, 1,4-benzodioxanyl, 2,3-dihydrofuro(2,3-b)pyridyl and the like.

[0213] The term “aryl” is intended to include mono- and bicyclic aromatic and heteroaromatic rings containing from 0 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “aryl” is also meant to include benzofused cycloalkyl, benzofused cycloalkenyl, and benzofused heterocyclic groups, wherein the point of attachment is on the aryl portion. Examples of “aryl” groups include phenyl, pyrrolyl, isoxazolyl, pyrazinyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, naphthyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furo(2,3-B)pyridyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzothiophenyl, quinolinyl, indolyl, 2,3-dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalene and the like.

[0214] Aroyl means arylcarbonyl in which aryl is as defined above.

[0215] Examples of NRcRd or NRgRh forming a 3- to 10- membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m and N are aziridine, azetidine, pyrrolidine, piperidine, thiomorpholine, morpholine, piperazine, octahydroindole, tetrahydroisoquinoline and the like.

[0216] The term “optionally substituted” is intended to include both substituted and unsubstituted; thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring.

[0217] The term “composition”, as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

[0218] Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other; thus, for example, ORa at C24 may represent OH and at C7 represent O-acyl.

[0219] Compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is intended to include all possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and all possible geometric isomers. In addition, the present invention includes all pharmaceutically acceptable salts thereof. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0220] When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

[0221] Compounds of the present invention are named based on the trivial name of the parent compound, nodulisporic acid A (compound A), and their position numbers are those as indicated in compound A.

[0222] Compounds of the present invention are prepared from two nodulisporic acids (Compounds A and B), which in turn are obtained from the fermentation culture of Nodulisporium sp. MF-5954 (ATCC74245). The description of the producing microorganism, the fermentation process, and the isolation and purification of the three nodulisporic acids are disclosed in U.S. Pat. No. 5,399,582, issued Mar. 21, 1995, and Ondeyka, J. G. et al., (J. Am. Chem. Soc. 1997, 119(38), 8809-8816) which is hereby incorporated by reference in its entirety.

[0223] The above structural formula is shown without a definitive stereochemistry at certain positions. However, during the the course of the synthetic procedures used to prepare such compounds, or using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. In particular, the stereoisomers at C7, C24, C1′, C2′, C1″, C2″, C3″, C4″ and C5″ may be oriented in either the alpha- or beta-position, representing such groups oriented below or above the plane of the molecule, respectively. In each such case, and at other positions in the molecule, both the alpha- and beta-configurations are intended to be included within the ambit of this invention.

[0224] Compounds of formula I wherein the allyl group at position 2′ is in the epi configuration may be obtained by treatment of the appropriate precursor with a bases such as hydroxide, methoxide, imidazole, triethylamine, potassium hydride, lithium diisopropylamide and the like in protic or aprotic solvents (as appropriate) such as water, methanol, ethanol, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide and the like. The reaction is complete at temperatures from −78° C. to the reflux temperature of the solution in from 15 minutes to 12 hours.

[0225] During certain reactions described below, it may be necessary to protect the groups at C24 and C7. With these positions protected, the reactions may be carried out at other positions without affecting the remainder of the molecule. Subsequent to any of the described reactions (vida infra), the protecting group(s) may be removed and the unprotected product isolated. The protecting groups employed at C24 and C7 are those which may be readily synthesized, not significantly affected by the reactions at the other positions, and may be removed without significantly affecting any other functionality of the molecule. One preferred type of protecting group is the tri-substituted silyl group, preferably the tri-loweralkyl silyl group or di-loweralkyl-aryl silyl group. Especially preferred examples are the trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl and dimethylphenylsilyl groups.

[0226] The protected compound may be prepared with the appropriately substituted silyl trifluoromethanesulfonate, BSTFA, hexamethyldisilazane or silyl halide, preferably the silyl chloride. The reaction is carried out in an aprotic solvent such as methylene chloride, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran, dimethylformamide and the like. In order to minimize side reactions, there is included in the reaction mixture a base to react with the acid released during the course of the reaction. Preferred bases are amines such as imidazole, pyridine, triethylamine or diisopropylethylamine and the like. The base is required in amounts equimolar to the amount of hydrogen halide liberated, however, generally several equivalents of the amine are employed. The reaction is stirred at from 0° C. to the reflux temperature of the reaction mixture and is complete from 1 to 24 hours.

[0227] The silyl group is removed by treatment of the silyl compound with anhydrous pyridine-hydrogen fluoride in tetrahydrofuran or dimethylsulfoxide or with tetraalkylammonium fluoride in tetrahydrofuran. The reaction is complete in from 1 to 24 hours at from o° C. to 50° C. Alternatively, the silyl group may be removed by stirring the silylated compound in lower protic solvents such as methanol, ethanol, isopropanol and the like catalyzed by an acid, preferably a sulfonic acid monohydrate such as para-toluenesulfonic acid, benzenesulfonic acid, pyridinium para-toluenesulfonate or carboxylic acids such as acetic acid, propionic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid and the like. The reaction is complete in 1 to 24 hours at from 0° C. to 50° C.

[0228] Protecting groups that may also be suitably used in the preparation of compounds of the present invention may be found in standard textbooks such as Greene and Wutz, Protective Groups in Organic Synthesis, 1991, John Wiley & Sons, Inc.

[0229] Compounds of formula I where R1 and R2 together represent an oxime, ═NORa, may be prepared by treating the appropriate oxo analog with H2NORa to produce the corresponding oxime. Oxime formation may be accomplished using techniques known to those skilled in the art, including, but not restricted to, the use of H2NORa either as the free base or as an acid addition salt such as the HCl salt, or an O-protected hydroxylamine such as O-trialkylsilylhydroxylamine, in a protic solvent such as methanol, ethanol, isopropanol and the like or aprotic solvents such as methylene chloride, chloroform, ethyl acetate, isopropyl acetate, tetrahydrofuran, dimethylformamide, benzene, toluene and the like, as appropriate. The reactions may by catalyzed by the addition of sulfonic acids, carboxylic acids or Lewis acids, including, but not limited to, benzenesulfonic acid monhydrate, para-toluenesulfonic acid monohydrate, acetic acid, zinc chloride and the like.

[0230] Similarly, compounds of formula I wherein R1 and R2 together represent ═NNRcRd may be prepared by treating the appropriate oxo analog with H2NNRcRd to give the corresponding hydrazones using conditions directly analogous to those described for oxime formation.

[0231] Compounds of formula I wherein R6 contains CO2Rb may be transesterified by heating the solution in an alcoholic solvent with a Lewis acid catalyst from 50° C. to 200° C., or most preferably 120° C. Suitable alcohols include methanol, ethanol, allyl alcohol, propanol, benzyl alcohol, 2-trimethylsilylethylalcohol and the like. These reactions may also be performed using a co-solvent such as benzene or toluene. Suitable Lewis acids include MgCl2, MgBr2, AlCl3, ZnI2 and the like, or most preferably, Ti(OiPr)4. Standard conditions for these reactions are described in Seebach, D. et al., Synthesis (1982), 138-141.

[0232] Compounds of formula I wherein one or both of the ___ bonds represent a single bond may be prepared from the corresponding compound wherein ______ is a double bond by conventional hydrogenation procedures. The double bonds may be hydrogenated with any of a variety of standard precious metal hydrogenation catalysts such as Wilkinson's catalyst, Pearlman's catalyst, 1-25% palladium on carbon, 1-25% platinum on carbon and the like. The reaction is generally carried out in a non-reducible solvents (either protic or aprotic) such as methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, isopropyl acetate, benzene, toluene, dimethylformamide and the like. The hydrogen source may be hydrogen gas from 1 to 50 atmospheres of pressure or other hydrogen sources such as ammonium formate, cyclohexene, cyclohexadiene and the like. The reduction also may be carried out using sodium dithionite and sodium bicarbonate in the presence of a phase transfer catalyst, in particular a tetraalkylammonium phase transfer catalyst, and the like. The reactions may be run from 0° C. to 100° C. and are complete in from 5 min to 24 hours.

[0233] Compounds of formula I wherein R2 is OH and R1 is H may be prepared from the corresponding ketone by treating the appropriate oxo analog with standard reducing agents including, but not restricted to, sodium borohydride, lithium borohydride, lithium aluminum hydride, potassium tri-sec-butyl borohydride, diisobutylaluminum hydride, diborane oxazaborolidines and alkylboranes (both achiral and chiral). These reactions are performed in a manner known to those skilled in the art and are carried out in non-reducible solvents such as methanol, ethanol, diethyl ether, tetrahydrofuran, hexanes, pentane, methylene chloride and the like. The reactions are complete in from 5 minutes to 24 hours at temperatures ranging from −78° C. to 60° C. Compounds of formula I wherein R2 is OH, R1 is H and R6 contains CH2OH may be obtained by reacting the appropriate carboxylic acid or ester analog (e.g., where R6 contains CO2H or CO2Ra) with the more reactive reducing agents as described above, including lithium aluminum hydride, lithium borohydride and the like. Compounds of formula I wherein R2 and R1 together are oxo and R6 contains CH2OH may be obtained by reacting the appropriate carboxylic acid (e.g., where R6 contains CO2H) with less reactive reducing agents such as diborane and the like.

[0234] Compounds of formula I wherein R2 is OH and R1 is other than H, may be prepared from the corresponding ketone by treating the appropriate oxo analog with a Grignard reagent R1MgBr, or with a lithium reagent R1Li. These reactions are performed in a manner known to those skilled in the art and preferably are performed in aprotic solvents such as diethyl ether, tetrahydrofuran, hexanes or pentanes. The reactions are complete in from 5 minutes to 24 hours at temperatures ranging from −78° C. to 60° C.

[0235] Compounds of formula I where R6 contains C(O)N(ORb)Rc or C(O)NRcRd are prepared from the corresponding carboxylic acid using standard amide-forming reagents known to those skilled in the art. The reaction is carried out using at least one equivalent of an amine nucleophile, HN(ORb)Rc or HNRcRd, although preferably ten to one hundred equivalents of amine nucleophiles are employed. Amide-forming reagents include, but are not restricted to, dicyclohexyl-carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), diisopropylcarbodiimide, benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorphosphate (BOP), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), chloro-tris-pyrrolidino-phosphonium hexafluorophosphate (PyCloP), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP), diphenylphosphoryl azide (DPPA), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HBTU), O-benzotriazol-1-yl-N,N,N′,N′-bis(penta-methylene)uronium hexafluorophosphate and 2-chloro-1-methylpyridinium iodide. The amide-forming reactions may be facilitated by the optional addition of N-hydroxybenzotriazole or N-hydroxy-7-aza-benzotriazole. The amidation reaction is generally performed using at least one equivalent (although several equivalents may be employed) of amine bases such as triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine and the like. The carboxyl group may be activated for amide bond formation via its corresponding acid chloride or mixed anhydride, using conditions known to those skilled in the art. These amide-forming reactions are carried out in aprotic solvents such as methylene chloride, tetrahydrofuran, diethyl ether, dimethylformamide, N-methylpyrrolidine and the like at −20° C. to 60° C. and are complete in 15 minutes to 24 hours.

[0236] Compounds of formula I where R6 contains CO2Rb are prepared from the corresponding carboxylic acid using standard ester-forming reagents known to those skilled in the art. The esterification reaction is carried out using at least one equivalent of an alcohol, HORb, although preferably ten to one hundred equivalents of alcohol are used; the esterification also may be carried out using the alcohol as solvent. Esterification reagents include, but are not restricted to, dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), diisopropylcarbodiimide, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorphosphate (BOP), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), chloro-tris-pyrrolidino-phosphonium hexafluorophosphate (PyCloP), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP), diphenylphosphoryl azide (DPPA), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazol-1-yl-N,N,N′,N′-bis(pentamethylene)uronium hexafluorophosphate and 2-chloro-1-methyl-pyridinium iodide. The ester-forming reactions may be facilitated by the optional addition of N-hydroxybenzotriazole, N-hydroxy-7-aza-benzotriazole, 4-(N,N-dimethylamino)pyridine or 4-pyrrolidinopyridine. The reaction is generally performed using at least one equivalent (although several equivalents may be employed) of amine bases such as triethylamine, diisopropylethylamine, pyridine and the like. The carboxyl group may be activated for ester bond formation via its corresponding acid chloride or mixed anhydride, using conditions known to those skilled in the art. These ester-forming reactions are carried out in aprotic solvents such as methylene chloride, tetrahydrofuran, diethyl ether, dimethylformamide, N-methylpyrrolidine and the like at temperatures ranging from −20° C. to 60° C. and are complete in 15 minutes to 24 hours.

[0237] Compounds of formula I wherein one or more of R2, R3, R4, and R9 is ORa, OCO2Rb or OC(O)NRcRd, and/or where R9 is CH2ORa, CH2OCO2Rb or CH2OC(O)NRcRd may be prepared using known methods for acylation, sulfonylation and alkylation of alcohols. Thus, acylation may be accomplished using reagents such as acid anhydrides, acid chlorides, chloroformates, carbamoyl chlorides, isocyanates and amine bases according to general procedures known to those skilled in the art. Sulfonylations may be carried out using sulfonylchlorides or sulfonic anhydrides. The acylation and sulfonylation reactions may be carried out in aprotic solvents such as methylene chloride, chloroform, pyridine, benzene, toluene and the like. The acylation and sulfonylation reactions are complete in from 15 minutes to 24 hours at temperatures ranging from −20° C. to 80° C. The degree of acylation, sulfonylation and alkylation will depend on the amount of the reagents used. Thus, for example, using one equivalent of an acylating reagent and one equivalent of nodulisporic acid results in a product mixture containg 4- and 20-acylated nodulisporic acid; such a mixture may be separated by conventional techniques such as chromatography.

[0238] Compounds of formula I wherein one or more of R2, R3, R4 is ORa and/or where R6 contains CH2ORa, may be prepared using methods known to those skilled in the art for the alkylation of alcohols. Thus, alkylation may be accomplished using reagents including, but not restricted to, halides IRa, BrRa, ClRa, diazo reagents N2Ra, trichloroacetimidates RaOC(NH)CCl3, sulfates RaOSO2Me, RaOSO2CF3, and the like. The alkylation reactions may be facilitated by the addition of acid, base or Lewis acids, as appropriate. The reactions are performed in aprotic solvents such as methylene chloride, chloroform, tetrahydrofuran, benzene, toluene, dimethylformamide, N-methyl-pyrrolidine, dimethyl sulfoxide, hexamethylphosphoramide and are complete at from 0° C. to the reflux temperature of the solution from 15 minutes to 48 hours.

[0239] The 3″ -aldehyde (Compound II) may be prepared as described in Schemes I and II. Thus, compound A or compound B may be treated with potassium permanganate under conditions known to those skilled in the art to yield the aldehyde product, Compound II. The potassium pernanganate may be used stoichiometrically or in excess and in the presence of a solid support including but not restricted to, Celite, basic alumina, neutral alumina, acidic alumina, silica gel, clays and the like. Sodium permanganate or tetraalkylammonium permanganate (either preformed or generated in situ from a tetraalkylamonium salt and potassium permanganate) may be substituted for potassium permanganate. Suitable tetraalkylammonium salts include, but are not restricted to (n-Bu)4NX, (PhCH2)3NMeX, (n-heptyl)4NX, (PhCH2)N(n-Bu)3X, (n-dodecyl)3NMeX, Adogen 464 and the like and where X═HO, SO4, PF6 and the like. The reaction to form Compound II may be performed in a variety of solvents or mixtures of solvents. These include both protic and aprotic solvents such as water, methylene chloride, chloroform, dichloroethane, methanol, ethanol, tert-butanol, ether, tetrahydrofuran, benzene, pyridine, acetone and the like. The reactions may be performed at from −78° C. to 80° C. and are complete in from 5 minutes to 24 hours.

[0240] Compound II, the 3″ -aldehyde, may also be produced by treating Compound III with osmium tetroxide under conditions known to those skilled in the art as shown in Scheme II below. Also produced during this reaction is the diol product IV. Mono- and disubstituted amides of compound III may be used in this reaction. These include, but are not restricted to, monosubstituted amides such as N-methyl, N-ethyl, N-propyl, N-butyl, N-tert-butyl, N-phenyl and the like or disubstituted amides such as N,N-dimethyl, N,N-diethyl, N-methyl-N-ethyl, N-methyl-N-phenyl and the like. Osmium tetroxide may be used either stoichiometrically or catalytically in the presence of an ocidant, including, but not restricted to, morpholine N-oxide, trimethylamine N-oxide, hydrogen peroxide, tert-butyl hydroperoxide and the like. The dihydroxylation reactions may be performed in a variety of solvents or mixtures of solvents. These include both protic and aprotic solvents such as water, methanol, ethanol, tert-butanol, ether, tetrahydrofuran, benzene, pyridine, acetone and the like. The reactions may be performed at from −78° C. to 80° C. and are complete in from 5 minutes to 24 hours. Diol product IV may be converted into 3″ -aldehyde II by treatment with an oxidizing agent, including, but restricted to, NaIO4, HIO4, MnO2, Amberlite 904-NaIO4 and the like, or preferably Pb(OAc)4. These oxidative cleavage reactions may be performed in a variety of solvents or mixtures of solvents. These include both protic and aprotic solvents such as water, methanol, ethanol, tert-butanol, ether, tetrahydrofuran, benzene, pyridine, acetone and the like. The reactions may be performed at from −78° C. to 80° C. and are complete in from 5 minutes to 24 hours.

[0241] Compounds of formula V may be prepared by reacting Compound II with appropriate olefin-forming reaction conditions known to those skilled in the art as shown in Scheme III below. Reagents for these reactions include, but are not restricted to, the use of stabilized and unstabilized Wittig reagents, Horner-Emmons reagents, Tebbe reagent, Petassis reagent, aldol reactions, Knoevenagel reactions, Peterson olefinations and the like. Starting Compound II may have its C7- and C24-hydroxyl groups protected with silyl protecting groups. The compounds of formula I shown below may be acyclic or cyclic, depending on the chain-extending reagents utilized. Alternatively, compounds of formula V may be acyclic but further modified to yield cyclic products. The olefination reactions may be performed in a variety of solvents or mixtures of solvents. These include both protic and aprotic solvents such as water, methanol, ethanol, tert-butanol, ether, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, 1,2-dichloroethane, benzene, toluene, pyridine, acetone and the like. Suitable bases include, but are not limited to, NaOH, KOH, NaOEt, KOtBu, LDA, LHMDS, NaHMDS, KHMDS, pyridine, piperidine, morpholine, lutidine, DMAP, DBU and the like. The reactions may be performed at from −78° C. to 80° C. and are complete in from 5 minutes to 24 hours. The compounds of formula V may be further elaborated by Stille, Heck and Suzuki couplings where R6 contains OTf, B(OH)2, Sn(n-Bu)3, SnMe3, OP(O)(OPh)2, I, Br, or Cl.

[0242] Wittig reagents may be readily prepared by reacting Ph3P with an appropriate halide under conditions known to those skilled in the art, such as those described by Ikuta, H. et al. (J. Med. Chem. 1987, 30, 1995-1998) or Larock, R. C. (Comprehensive Organic Transformations, VCH Publishers: Inc. New York, N.Y., 1989, Chapter 4). Alternatively, stabilized Wittig reagents may be prepared as described by Bestmann, H. J. and Schulz, H. (Chem. Ber. 1964, 97, 11) wherein an appropriate unstabilized Wittig reagent Ph3P═C(Ra)2 is reacted with a suitable chloroformate to yield Ph3P═C(Ra)2CO2Rb or as described by the conjugate addition of Ph3P to N—Rc substituted maleimides.

[0243] Compounds of formula VI may be prepared as illustrated in Scheme IV by the addition of an appropriate nucleophile to the 3″ -aldehyde of compound II. The C7 and C24 hydroxyls of compound II may be optionally protected with R3Si groups as previously described. The nucleophilic addition reaction may produce a mixture of stereoisomers at 3″. Suitable nucleophiles include, but are not restricted to, Grignard reagents and organolithium, organocuprates organozinc reagents, organosodium reagents, organopotassium reagents and organocerium reagents and the like. These reagents include, but are not restricted to, MeMgBr, EtLi, PhMgCl, (nPr)2CuMgI, H2C═CHMgBr, 2-furfuryl lithium, BrZnCH2CO2Me, NaCH2C(O)Ph(4-Br) and the like. Suitable solvents, or mixtures of solvents for this reaction include, but are not restricted to, toluene, tetrahydrofuran, hexanes, dioxane, 1,2-dimethoxyethane, DMSO, HMPA, DMPU and the like or most preferably diethyl ether. The reactions proceed at from −100° C. to 80° C. and are complete in from 5 min to 12 h. Oxidation of the newly formed 3″ -hydroxyl to form the corresponding 3″ -ketone may be accomplished using reagents known to those skilled in the art. These reagents include, but are not restricted to TPAP, Dess-Martin reagent, Mn(OAc)2, CuCl, SeO2, NaOCl/HOAc, DMSO/Ac2O, DDQ, and the like or most preferably MnO2. Suitable solvents for this oxidation reaction include, but are not restricted to, EtOAc, CHCl3, benzene, toluene, THF, and the like or most preferably CH2Cl2. Compounds of formula VI may be prepared by reacting the intermediate 3″ -ketone thus prepared with appropriate olefin-forming reaction conditions known to those skilled in the art as described previously.

[0244] Compounds of formula V (or formula VI) where R4″ a (or b) is CO2Rb are useful as intermediates in the preparation of certain compounds of formula V (or formula VI) where R4″ a (or b) is C(O)NRcRd. The esters where R4 a (or b) is CO2Rb may be hydrolyzed by treatment with hydroxide or ammonium hydroxide in a protic solvent such as methanol, ethanol, water, tetrahydrofuran/water or dimethylformamide/water and the like at from 0° C. to the reflux temperature of the solution. Alternatively, the resultant esters may be transesterified by treatment with a Lewis acid, including, but not restricted to, magnesium chloride, magnesium bromide, aluminum chloride, zinc chloride, Otera's catalyst, and the like, or preferably titanium tetra-isopropoxide in a protic solvent such as methanol, ethanol, isopropanol, 2-trimethylsilylethyl alcohol and the like, or preferably allyl alcohol. The transesterification reactions are complete in from 1 to 24 hours at 0° C. to the reflux temperature of the solution, preferably 110° C. The allyl ester (e.g. Rb═—CH2CH═CH2) may be removed by treatment with Pd° using conditions known to those skilled in the are to generate the free carboxylic acid (e.g. Rb═H). Pd° reagents include, but are not restricted to, PdCl2(PPh3)2, Pd(OAc)2(PPh3)2, PdCl2(PhCN)2, Pd(OAc)2, PdCl2(P(o-tolyl)3)2, PdCl2(DDPF), Pd2(dba)3, and the like, or preferably Pd(PPh3)4. Amides (where R4′ a (or b) is C(O)NRcRd) are prepared as described (vide supra) from the corresponding carboxylic acids.

[0245] Compounds of formula VIII where R4″ a(or b) contains NRcC(O)NRcRd (compond VIIIa), NRcCO2Rb (compond VIIIb), NRcC(O)SRa (compond VIIIC), or NRcC(O)Ra (compond VIIId), may be prepared from the corresponding carboxylic acids as shown in Scheme V. Thus, compounds of formula V where R4″ a(or b) is CO2His treated with diphenylphosphoryl azide to provide the acyl azide VIIa. Heating of compound VIIa in an aprotic solvent such as benzene, toluene, dimethylformamide and the like results in a rearrangement yielding compound VIIb, an isocyanate. The isocyanate-forming reactions may be performed from 0° C. to 120° C., preferably at 80° C., and are complete in 15 min to 24 hours.

[0246] Compounds of formula VIIIa may be prepared when compounds of formula VIIb are reacted with an appropriate amine HNRcRd in an aprotic solvent such as methylene chloride, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, benzene, toluene and the like. The urea-forming reactions may be performed from 0° C. to 100° C. and are complete in 15 minutes to 24 hours.

[0247] Compounds of formula VIIb may be reacted in an aprotic solvent such as benzene, toluene, methylene chloride, 1,2-dichloroethylene, dimethylformamide and the like, with an alcohol RbOH, such as methanol, ethanol, benzyl alcohol, 2-trimethylsilylethanol, 2,2,2-trichloroethanol, methyl glyocolate, phenol and the like to yield carbamates of formula VIIIb. Similarly, compounds of formula VIIIc may be prepared by substituting HSRb for HORb in the reaction. The addition of one or more equivalents of an amine base such as triethylamine, diisopropylethylamine, pyridine and the like may be employed to accelerate carbamate formation. The carbamate-forming reactions may be performed from 0° C. to 100° C. and are complete in 15 minutes to 24 hours.

[0248] Compounds of formula VIIId may be prepared by treatment of compounds of formula VIIb with RaMgI, RaMgCl, RaLi, (Ra)2CuLi or preferably RaMgBr, as illustrated below. Compounds of formula VIIb may be reacted in an aprotic solvent, or mixture of solvents, such as including, but not restricted to, dioxane, pentane, hexane, DMSO, HMPA, or NMP, and the like, or preferably tetrahydrofuran. The reactions may be performed from −78° C. to 100° C. and is complete in from 5 minutes to 12 hours.

[0249] Compounds of formula I may be further modified as illustrated in Scheme VI. For instance, the allyl ester at C5″ of compounds of formula IX may be converted into the corresponding 5″ -amide (compounds of formula Xa) as shown and the propenyl group at C4″ modified by treatment with osmium tetroxide (step 3) to generate the corresponding diol (compounds of formula Xb). The diol of formula Xb may be subjected to oxidative cleavage (step 4) with lead tetraacetate to form aldehydes of formula Xc. The aldehyde of compounds of formula Xc may be reduced to generate the corresponding intermediate alcohol (not shown) which may be acylated (steps 5 or 6) to form compounds of formula Xd or Xe. The aldehyde of Xc may be converted into an amine of formula Xf (step 7) via reductive amination with HNRcRd and an appropriate reducing agent, and the resultant amine (Xf where Rd is hydrogen) may be optionally acylated to form compounds of formula Xg (step 8) or sulfonylated. In addition, the aldehyde of Xc may be reacted with chain extending olefinating reagents such as Wittig reagents, Horner-Emmons reagents and the like as described previously (compounds not shown).

[0250] Alternatively, the aldehyde of Xc may be treated with an acid such as PPTS in an alcoholic solvent such as methanol, ethanol, n-propanol and the like to generate cyclic compounds of formula XIa and XIb as illustrated in Scheme VII.

[0251] Compounds of formula XIIIa may be prepared using the Passerrini reaction wherein compounds of formula XII are treated with a carboxylic acid, an isonitrile in a protic solvent as shown in Scheme VIII. Suitable isonitriles for the Passerrini reaction, include, but are not limited to, methyl, ethyl, isopropyl, tert-butyl, cyclohexenyl, benzyl and ethyl isonitriloacetate and the like. The Passerrini reaction may be performed in protic solvents or mixtures of solvents, including, but not limited to, methanol, ethanol, isopropanol, tert-butanol or water as well as aprotic solvents, including, but not limited to methylene chloride, DMSO, DMF, NMP, THF, chloroform, toluene and the like at temperatures from 0° C. to 80° C. but most preferably at room temperature. Suitable carboxylic acids include, but are not limited to acetic acid, proprionic acid, formic acid, alpha-chloroacetic acid, alpha-methoxyacetic acid, butyric acid, benzoic acid and the like. Substitution of a sulfonic acid and an amine base for the carboxylic acid leads to the formation of compounds of formula XIIIb. Suitable sulfonic acids include, but are not limited to benzene sulfonic acid or methane sulfonic acid, and the like or most preferably toluene sulfonic acid. Suitable amine bases include, but are not limited to, Et3N, DIEA, DBU, lutidine, imidazole, quinoline and the like, or most preferably pyridine. Suitable protic solvents for the formation of compound XMb include, but are not limited to, water, methanol, ethanol, n-propanol, butanol, isopropanol, allyl alcohol, tert-butanol, 2,2,2-trifluoroethanol, phenol, benzyl alcohol, ethylene glycol, methyl glycolate and the like.

[0252] The instant compounds are potent endo- and ecto-antiparasitic agents, particularly against helminths, ectoparasites, insects, and acarids, infecting man, animals and plants, thus having utility in human and animal health, agriculture and pest control in household and commercial areas.

[0253] The disease or group of diseases described generally as helminthiasis is due to infection of an animal host with parasitic worms known as helminths. Helminthiasis is a prevalent and serious economic problem in domesticated animals such as swine, sheep, horses, cattle, goats, dogs, cats, fish, buffalo, camels, llamas, reindeer, laboratory animals, furbearing animals, zoo animals and exotic species and poultry. Among the helminths, the group of worms described as nematodes causes widespread and often times serious infection in various species of animals. The most common genera of nematodes infecting the animals referred to above are Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Habronema, Druschia, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. Certain of these, such as Nematodirus, Cooperia, and Oesophagostomum attack primarily the intestinal tract while others, such as Haemonchus and Ostertagia, are more prevalent in the stomach while still others such as Dictyocaulus are found in the lungs. Still other parasites may be located in other tissues and organs of the body such as the heart and blood vessels, subcutaneous and lymphatic tissue and the like. The parasitic infections known as helminthiases lead to anemia, malnutrition, weakness, weight loss, severe damage to the walls of the intestinal tract and other tissues and organs and, if left untreated, may result in death of the infected host. The compounds of this invention have activity against these parasites, and in addition are also active against Dirofilaria in dogs and cats, Nematospiroides, Syphacia, Aspiculuris in rodents, arthropod ectoparasites of animals and birds such as ticks, mites such as scabies lice, fleas, blowflies, and other biting insects in domesticated animals and poultry, such as Tenophalides, Ixodes, Psoroptes, and Hemotobia, in sheep Lucilia sp., biting insects and such migrating dipterous larvae as Hypoderma sp. in cattle, Gastrophilus in horses, and Cuterebra sp. in rodents and nuisance flies including blood feeding flies and filth flies.

[0254] The instant compounds are also useful against parasites which infect humans. The most common genera of parasites of the gastro-intestinal tract of man are Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris, and Enterobius. Other medically important genera of parasites which are found in the blood or other tissues and organs outside the gastrointestinal tract are the filiarial worms such as Wuchereria, Brugia, Onchocerca and Loa, Dracunuculus and extra intestinal stages of the intestinal worms Strongyloides and Trichinella. The compounds are also of value against arthropods parasitizing man, biting insects and other dipterous pests causing annoyance to man.

[0255] The compounds are also active against household pests such as the cockroach, Blatella sp., clothes moth, Tineola sp., carpet beetle, Attagenus sp., the housefly Musca domestica as well as fleas, house dust mites, termites and ants.

[0256] The compounds of this invention are also useful in combatting agricultural pests that inflict damage upon crops while they are growing or while in storage. The compounds are applied using known techniques as sprays, dusts, emulsions and the like, to the growing or stored crops to effect protection from such agricultural pests.

[0257] The compounds are also useful against insect pests of stored grains such as Tribolium sp., Tenebrio sp. and of agricultural plants such as aphids, (Acyrthiosiphon sp.); against migratory orthopterans such as locusts and immature stages of insects living on plant tissue. The compounds are useful as a nematocide for the control of soil nematodes and plant parasites such as Meloidogyne sp. which may be of importance in agriculture. The compounds are also highly useful in treating acreage infested with fire ant nests. The compounds are scattered above the infested area in low levels in bait formulations which are brought back to the nest. In addition to a direct-but-slow onset toxic effect on the fire ants, the compound has a long-term effect on the nest by sterilizing the queen which effectively destroys the nest.

[0258] The compounds of this invention may be administered in formulations wherein the active compound is intimately admixed with one or more inert ingredients and optionally including one or more additional active ingredients. The compounds may be used in any composition known to those skilled in the art for administration to humans and animals, for application to plants and for premise and area application to control household pests in either a residential or commercial setting. For application to humans and animals to control internal and external parasites, oral formulations, in solid or liquid or parenteral liquid, implant or depot injection forms may be used. For topical application dip, spray, powder, dust, pour-on, spot-on, jetting fluid, shampoos, collar, tag or harness, may be used. For agricultural premise or area application, liquid spray, powders, dust, or bait forms may be used. In addition “feed-through” forms may be used to control nuisance flies that feed or breed in animal waste. The compounds are formulated, such as by encapsulation, to lease a residue of active agent in the animal waste which controls filth flies or other arthropod pests.

[0259] Accordingly, the present invention provides a method for the treatment or prevention of diseases caused by parasites which comprises administering to a host in need of such treatment or prevention an antiparasitic effective amount of a compound of Formula I. The parasites may be, for example, arthropod parasites such as ticks, lice, fleas, mites and other biting arthropods in domesticated animals and poultry. The parasites also include helminths such as those mentioned above.

[0260] Compounds of formula I are effective in treatment of parasitic diseases that occur in other animals including humans. The optimum amount to be employed for best results will, of course, depend upon the particular compound employed, the species of animal to be treated and the type and severity of parasitic infection or infestation. Generally good results are obtained with our novel compounds by the oral administration of from about 0.001 to 500 mg per kg of animal body weight, such total dose being given at one time or in divided doses over a relatively short period of time such as 1-5 days. With the preferred compounds of the invention, excellent control of such parasites is obtained in animals by administering from about 0.025 to 100 mg per kg of body weight in a single dose. Repeat treatments are given as required to combat re-infections and are dependent upon the species of parasite and the husbandry techniques being employed. Repeat treatments may be given daily, weekly, biweekly, monthly, or longer for example up to six months, or any combination thereof, as required. The techniques for administering these materials to animals are known to those skilled in the veterinary field.

[0261] Compounds of formula I may be co-administered or used in combination with one or more other agents to the host. Co-administration or combination use includes administering all active ingredients in one formulation, for example a tablet, capsule, feed stuff, or liquid containing a compound of formula I and one or more said other agents; administering each ingredient in a separate formulation; and combinations thereof. When one or more of a compound of formula I or said other agent(s) is contained in a separate formulation, any order of administration as well as any interval between the administration of the active ingredients are within the meaning of co-administration or combination use.

[0262] Agents that may be co-administered or used in combination with compounds of formula I include any that are used in the treatment or prevention of human or animal diseases or conditions, or used in agricultural applications, or for pest control. In a preferred embodiment, the co-administered agents are used in veterinary medicine, particularly those used in domesticated animals such as dogs and cats or other companion animals. Examples of other agents that may be co-administered with compounds of formula I are provided below. It is to be understood that the specific agents enumerated are illustrative only, and are not meant to be restrictive in any manner.

[0263] Accordingly, compounds of the present invention may be co-administered or used in combination with anthelmintic agents. These anthelmintic agents are meant to include, but not be restricted to, compounds selected from the avermectin and milbemycin class of compounds such as ivermectin, avermectin, abamectin, emamectin, eprinamectin, doramectin, milbemycin derivatives described in EPO 357460, EPO 444964 and EPO 594291, moxidectin, Interceptor™ and nemadectin. Additional anthelmintic agents include the benzimidazoles such as thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate and the like. Additional anthelmintic agents include imidazothiazoles and tetrahydropyrimidines such as tetramisole-levamisole, butamisole, pyrantel, pamoate, oxantel or morantel.

[0264] Compounds of this invention may be co-administered or used in combination with fipronil (FRONTLINE™); or with an insect growth regulator with molt inhibiting activity such as lufenuron (PROGRAM™ or SENTINEL™) and the like; or with ecdysone agonists such as tebufenozide and the like, which induces premature molt and causes feeding to cease; or with imidacloprid (ADVANTAGE™).

[0265] Compounds of this invention may be co-administered or used in combination with avermectin or milbemycin or doramectin derivatives such as those described in U.S. Pat. No. 5,015,630, WO 94/15944, WO95/22552, including selamectin (REVOLUTION™).

[0266] Compounds of this invention may be co-administered or used in combination with cyclic depsipeptides that exhibit anthelmintic efficacy such as those described in WO96/11945, WO93119053, WO 93/25543, EP 626375, EP 382173, WO 94/19334, EP 382173 and EP 503538.

[0267] Compounds of this invention may be used in combination or be co-administered with derivatives and analogs of the general class of dioxomorpholine antiparasitic and anthelmintic agents as illustrated by WO 9615121; or with pyrethroids or organophosphates or insecticidal carbamates, such as those described in “Chemotherapy of Parasitic Diseases”, Campbell, W. C. and Rew, R. S, Eds., 1986; or with derivatives and analogs of the general class of paraherquamide and macfortine anthelmintic agents.

[0268] The co-administered compounds are given via routes, and in doses, that are customarily used for those compounds.

[0269] Compounds of formula I may be administered orally in a unit dosage form such as a capsule, bolus or tablet including chewable tablet, or as a liquid drench where used as an anthelmintic in mammals. The drench is normally a solution, suspension or dispersion of the active ingredient usually in water together with a suspending agent such as bentonite and a wetting agent or like excipient. Generally, the drenches also contain an antifoaming agent. Drench formulations generally contain from about 0.001 to 0.5% by weight of the active compound. Preferred drench formulations may contain from 0.01 to 0.1% by weight. The capsules and boluses comprise the active ingredient admixed with a carrier vehicle such as starch, talc, magnesium stearate, or di-calcium phosphate.

[0270] Where it is desired to administer the instant compounds in a dry, solid unit dosage form, capsules, boluses or tablets containing the desired amount of active compound usually are employed. These dosage forms are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, fillers, disintegrating agents, and/or binders such as starch, lactose, talc, magnesium stearate, vegetable gums and the like. Such unit dosage formulations may be varied widely with respect to their total weight and content of the antiparasitic agent depending upon factors such as the type of host animal to be treated, the severity and type of infection and the weight of the host.

[0271] When the active compound is to be administered via an animal feedstuff, it is intimately dispersed in the feed or used as a top dressing or in the form of pellets or liquid which may then be added to the finished feed or optionally fed separately. Alternatively, feed based individual dosage forms may be used such as a chewable treat. Alternatively, the antiparasitic compounds of this invention may be administered to animals parenterally, for example, by intraruminal, intramuscular, intravascular, intratracheal, or subcutaneous injection in which the active ingredient is dissolved or dispersed in a liquid carrier vehicle. For parenteral administration, the active material is suitably admixed with an acceptable vehicle, preferably of the vegetable oil variety such as peanut oil, cotton seed oil and the like. Other parenteral vehicles such as organic preparation using solketal, glycerol formal, propylene glycol, and aqueous parenteral formulations are also used. The active compound or compounds are dissolved or suspended in the parenteral formulation for administration; such formulations generally contain from 0.0005 to 5% by weight of the active compound.

[0272] When the compounds described herein are administered as a component of the feed of the animals, or dissolved or suspended in the drinking water, compositions are provided in which the active compound or compounds are intimately dispersed in an inert carrier or diluent. By inert carrier is meant one that will not react with the antiparasitic agent and one that may be administered safely to animals. Preferably, a carrier for feed administration is one that is, or may be, an ingredient of the animal ration.

[0273] Suitable compositions include feed premixes or supplements in which the active ingredient is present in relatively large amounts and which are suitable for direct feeding to the animal or for addition to the feed either directly or after an intermediate dilution or blending step. Typical carriers or diluents suitable for such compositions include, for example, distillers' dried grains, corn meal, citrus meal, fermentation residues, ground oyster shells, wheat shorts, molasses solubles, corn cob meal, edible bean mill feed, soya grits, crushed limestone and the like. The active compounds are intimately dispersed throughout the carrier by methods such as grinding, stirring, milling or tumbling. Compositions containing from about 0.005 to 50% weight of the active compound are particularly suitable as feed premixes. Feed supplements, which are fed directly to the animal, contain from about 0.0002 to 0.3% by weight of the active compounds.

[0274] Such supplements are added to the animal feed in an amount to give the finished feed the concentration of active compound desired for the treatment and control of parasitic diseases. Although the desired concentration of active compound will vary depending upon the factors previously mentioned as well as upon the particular compound employed, the compounds of this invention are usually fed at concentrations of between 0.00001 to 10% in the feed in order to achieve the desired anti-parasitic result.

[0275] In using the compounds of this invention, the individual compounds may be prepared and used in that form. Alternatively, mixtures of the individual compounds may be used, or they may be combined with other active compounds not related to the compounds of this invention.

[0276] Also included in the present invention are pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention may further comprise a second active ingredient such as those described above for co-administration. The preferred second ingredient is selected from an anthelmintic agent, fipronil, imidocloprid, an insect growth regulator, or a ecdysone agonist. Said second ingredient is preferably selected from the group consisting of ivermectin, avermectin 5-oxime, abamectin, emamectin, eprinamectin, doramectin, doramectin monosaccharide 5-oximes, fulladectin, milbemycin, milbemycin 5-oxime, moxidectin, Interceptor™, nemadectin, imidacloprid, fipronil, lufenuron, thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate, tetramisole-levamisole, butamisole, pyrantel, pamoate, oxantel and morantel.

[0277] Preparation of Intermediates

[0278] (a) Synthesis from Nodulisporic acid A:

[0279] To KMnO4 (3 g) at 25° C. was added water (5 mL). The KMnO4 solution was cooled to 0° C. and Al2O3 (weakly acidic, 10.8 g) was added and stirred for 5 min until thoroughly mixed. A solution of nodulisporic acid A (3 g) in CH2Cl2 (300 mL) was added dropwise via an addition funnel over 20 min. The solution was aged for an additional 20 min at 0° C. then at 25° C. for 90 min. The solution was filtered through a 3 inch pad of Celite using CH2Cl2 as eluant followed by EtOAc. The solvents were removed under reduced pressure at ambient temperature to yield pure title compound (2.234 g, 82%) without any additional purification.

[0280] (b) Synthesis from N-tert-butyl Nodulisporamide

[0281] To N-tert-butyl nodulisporamide A (50 mg) in CH2Cl2 (2 mL) at 25° C. was added N-methylmorpholine N-oxide (50 mg) followed by 0.024 M Os04 in water (0.31 mL). After aging the solution for 16 hr, TLC showed the presence of the desired compound and the R,R- and S,S-3″,4″ -diols of N-tert-butyl nodulisporamide A. Intermediate 1 (10.5 mg) and the diols (36 mg) were isolated in pure form by PTLC on silica gel using 2:1 EtOAc:hexanes as eluant. The R,R- and S,S-diols were combined. To a mixture of diols (10 mg) in acetone (0.9 mL) at 25° C. was added NaIO4 (25 mg) and the solution was allowed to age for 12 h. The solution was poured into saturated aqueous NaHCO3, extracted with EtOAc and dried (Na2SO4). Pure Intermediate 1 (7 mg) was obtained following PTLC on silica gel using 1/1 hexanes/EtOAc as eluant.

[0282] To Intermediate I (560 mg) in acetonitrile (10 mL) at 25° C. was added (Me3Si)2NH (1.8 mL) and the the solution was aged for 12 h. Additional (Me3Si)2NH (1.5 mL) and acetonitrile (3 mL) were then added. After 3 h, the solvent was removed under reduced pressure and the residue dried in vacuo for 1 h to yield pure title compound (870 mg, 100%) which required no purification. The product was characterized by proton NMR.

[0283] To Intermediate 1 (750 mg) in pyridine/DNF (30 rnL, 1/1) at room temperature was added Et3SiOSO2CF3 (3.2 g) and aged for 20 min. The solution was diluted with ethyl acetate, washed with saturated CuSO4(aq) (4 ×), water (1 ×), brine (1 ×), and dried (Na2SO4). The solution was filtered, concentrated under reduced pressure and pure product was obtained following flash chromatography on silica gel using 7/93 acetone/hexanes as eluant. The title compound thus obtained was characterized by 1H NMR.

[0284] To Intermediate I (420 mg) and imidazole (540 mg) in CH2Cl2 (15 mL) at 0° C. was added (nPr)3SiCl (1 mL) dropwise. After stirring for 30 min, the solution was warmed to room temperature for an additional 30 min and then quenched with ice-water. The organic phase was separated and washed with water, dried (NaSO4), filtered and concentrated to give the pure product as a foam (620 mg). The product thus obtained was characterized by proton NMR.

[0285] Method A

[0286] To Intermediate III (1 g) in tBuOH (25 mL) at 25° C. was added 2-methyl-2-butene (6 mL) and stirred for 5 min. A solution of NaOCl2 (954 mg) and NaH2PO4.2H2O (1.28 g) in water (10 mL) was then added. After 4 h, the solution was poured into saturated NH4Cl(aq), extracted with CH2Cl2 (3×) and dried (Na2SO4). The solution was filtered and concentrated to dryness under reduced pressure. Pure title compound (725 mg) was obtained following flash chromatography on silica gel using gradient elution (5% to 25% EtOAc in hexanes).

[0287] Method B

[0288] A solution of KMnO4 (1.3 g) in acetone (64 mL) and pH 7 phosphate buffer (21 mL) was prepared. To Intermediate III (3.63 g) in acetone (64 mL) was added the KMnO4/buffer solution (˜20 mL) and the solution was aged for 30 min. Additional KMnO4 solution (˜20 mL) was added every 30 min for 2 h. The solution was then cooled to 0° C. and 1M Na2SO3 was added until all of the KMnO4 was reacted. The mixture was filtered and washed with 15/85 MeOH/acetone (2×). The filtrate was concentrated under reduced pressure to dryness and redissolved in water. The aqueous solution was extracted with 3/7 iPrOH/CHCl3 (3×) and the organic layers were dried (Na2SO4). The solids were removed by filtration and the solution was evaporated to drynesss under reduced pressure. Pure title product (1.29 g) along with recovered starting aldehyde (˜1.3 g) was obtained following flash chromatography on silica gel using 2/8 EtOAc/hexanes as eluant.

[0289] Preparation of Intermediate Vb.

[0290] Following the procedure described for Intermediate Va and using Intermediate II, Intermediate Vb was prepared.

[0291] Method A

[0292] To Intermediate II (821 mg) in tetrahydrofuran (THF, 8 niL) at −78° C. was added L-Selectride® (Adrich, 1.07 mL, 1 M solution in THF) dropwise over 5 min. After 20 min, the solution was quenched by addition of saturated NH4Cl(aq), extracted with CH2Cl2, washed with brine and dried (Na2SO4). The solution was filtered, concentrated under reduced pressure and purifed by flash chromatography on silica gel using 15/85 EtOAc/hexanes as eluant. The pure Intermediate VIa (571 mg) thus obtained was characterized by 1H NMR.

[0293] Method B

[0294] To Intermediate II (1.0 g) in EtOAc (50 mL) at room temperature was added 10% Pd/C and a balloon atmosphere of hydrogen was established. After 5.5 h, the solution was filtered through Celite using EtOAc as eluant. The solution was concentrated under reduced pressure and purifed by MPLC chromatography on silica gel using 4/6 EtOAc/hexanes as eluant. The pure Intermediate VIa (726 mg, mobile product) and pure Intermediate VIb (70 mg, polar product) thus obtained were characterized by 1H NMR.

[0295] To (N-diphenylmethylene)amino acetonitrile (75 mg) in THF (0.5 mL) at −78° C. was added LiN(SiMe3)2 (340 μL, 1.0 M solution). The yellow solution was stirred at −78° C. for 5 min, placed in a 0° C. ice bath for 5 min and then recooled to −78° C. for 15 min. A solution of Intermediate II (65 mg in 0.8 niL THF) was added at −78° C. After 25 min, MeSO2Cl (60 μL) was added. After 10 min, triethylamine (36 μL) was added and the reaction warmed first to 0° C. for 20 min and then room temperature of 2 h. The solution was rapidly filtered without workup through a 1 inch pad of silica gel using CH2Cl2 followed by 15/85 EtOAc/hexanes as eluant. The solution was concentrated to dryness under reduced pressure and used in the next step without any further manipulation or characterization.

[0296] Step A. To Intermediate 1 (128 mg) in CH2Cl2 (10 mL) at 25° C. was added Ph3P═C(Et)CO2CH2CH═CH2 (320 mg). The solution was aged for 2 days and then additional Ph3P═C(Et)CO2CH2CH═CH2 (320 mg) was added. After one additional hour, the solution was purified without workup by flash chromatography on silica gel using 6/4 EtOAc/hexanes as eluant to yield pure allyl ester of Intermediate VIIIb (124 mg, 84%). The purified allyl ester of Intermediate VIIIa was characterized by proton NMR and mass spectrometry [m/z: 734.1. (M++1)].

[0297] Step B. To the 5″ -allyl ester of Step A (160 mg) in 1/3 THF/CH2Cl2 (8 mL) at 25° C. was added (Ph3P)4Pd (13 mg) and morpholine (160 mg). The solution was aged for 6 h and the solution was purified without workup by flash chromatography on silica gel using 1/9 MeOH/CH2Cl2 as eluant to yield pure Intermediate VIIIa (112 mg, 74%). The purified Intermediate VIIIa was characterized by proton NMR and mass spectrometry [m/z: 693.4 (M++1)].

[0298] Intermediates VIIIb and VIIIc were similarly prepared following the procedure for Intermediate VIIIa and using Ph3P═C(n-Pr)CO2CH2CH═CH2 and Ph3P═C(n-Bu)CO2CH2CH═CH2, respectively.

[0299] General Procedures for the Preparation of Stabilized Wittig Reagents

[0300] To a solution of Ph3PCH2CH2CH2CH3.Br (20 g) in toluene (80 mL) at −78° C. was added nBuLi (31.3 mL, 1.6 M in hexane) over 10 min. The cooling bath was removed and the solution was allowed to warm to 25° C. After 1 h at 25° C., the deep red solution was heated to reflux and a solution of allyl chloroformate (3.01 g) in toluene (10 mL) was then added dropwise. A white solid precipitated immediately. After 5 min, the mixture was cooled to 25° C. and the white solid was collected by filtration and discarded. The filtrate was concentrated under reduced pressure to yield an off-white solid (7.89 g, 78%) that was dried in vacuuo and used with no further purification. The purified product was characterized by proton NMR.

[0301] (2) 1-Ethyl-3-triphenylphosphoranylidine-pyrrolidin-2-one (reference: J. Med. Chem. 1987, v30, pl995-1998).

[0302] A mixture of γ-butyrolactone (100 g) and PBr3 (2 mL) was heated at 110° C. while Br2 (50 mL) was added slowly dropwise below the surface of the solution. The solution was cooled to 50° C. and DMF (0.1 ImL) was added. The solution was heated to 90° C. and SOCl2 (100 mL) was added dropwise and the solution was aged for 3 h. The BrCH2CH2CH(Br)C(O)Cl thus prepared was used with no purification. Ethylamine (17 mL, 70 weight % in water) was diluted with water (50 mL) and CHCl3 (30 mL) and cooled to 12° C. A portion of the acid chloride solution (20 g) was diluted with CHCl3 (30 mL) and added dropwise to the EtNH2 solution. After 30 min, the solution was poured into brine, extracted with CHCl3 and dried (MgSO4). The solution was filtered and concentrated to dryness and the residue (10.15 g) was used with no further purification. To the BrCH2CH2CH(Br)C(O)NHEt (10 g) thus obtained at 0° C. was added DMF (20 nL), benzene (60 mL) and treated with NaH (1.36 g, 60% dispersion in oil) in portions over 10 min. After 30 min, the solution was poured into water and extracted with EtOAc. The combined organic layers were washed with water, brine and dried (MgSO4). The solution was filtered and concentrated to dryness to yield crude product (4.7 g) which was used with no further purification. To the 3-bromo-1-ethyl-pyrrolidinone (4.7 g) in THF (15 mL) was added Ph3P (6.82 g) and the solution heated at reflux for 16 h. The volatiles were removed under reduced pressure and residue was dissolved in EtOH (30 niL) to which was added iPr2NEt (15 mL). The solution was heated to reflux for 3 h and concentrated to dryness to yield the desired Wittig reagent which was used with no further purification. The Wittig reagent thus obtained was characterized by 1H NMR.

[0303] (3) 1-Cyclopentyl-3-triphenylphosphoranylidine-succinamide (reference: Tetrahedron, 1968, 24, 2241).

[0304] To Ph3P (3.7 g) in glacial acetic acid (40 mL) was added 1-cyclopentyl-maleimide and the solution was heated to reflux for 1 h. The volatiles were removed under reduced pressure and the residue was dissolved in CH2Cl2 (100 mL). The CH2Cl2 solution was washed with saturated NaHCO3(aq), brine and dried (MgSO4). The solution was filtered, concentrated to dryness to yield the desired Wittig reagent which was used with no further purification. The Wittig reagent thus obtained was characterized by 1H NMR.

[0305] (4) 3-triphenylphosphoranylidine-glutaramide (reference: Synthesis, 1998, 325).

[0306] To alpha-chloroacetamide (3.8 g) in nitromethane (100 mL) was added Ph3P (10.4 g) and the solution was refluxed for 30 h. The volatiles were removed under reduced pressure and MeOH (10 mL) was added followed by NaOMe (11.24 niL, 0.5 M solution in MeOH) and the solution was aged for 1 h. To this solution was then added ethyl acrylate (0.61 mL) and the solution was aged for 48 h. The volatiles were removed under reduced pressure and the residue was partioned between CH2Cl2 and water. The organic layer was separated, dried (MgSO4), filtered and concentrated to dryness. The Wittig reagent (1.68 g) thus prepared was characterized by 1H NMR and was used with no further purification.

[0307] The following examples are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any manner.

EXAMPLE 1

[0308]

[0309] Step a:

[0310] To the 3″ -aldehyde (Intermediate I, 128 mg) in CH2Cl2 (10 mL) at 25° C. was added Ph3P═C(Et)CO2CH2CH═CH2 (320 mg). The solution was aged for 2 days and then additional Ph3P═C(Et)CO2CH2CH═CH2 (320 mg) was added. After one additional hour, the solution was purified without workup by flash chromatography on silica gel using 6/4 EtOAc/hexanes as eluant to yield pure 1a (124 mg, 84%). The purified product was characterized by proton NMR and mass spectrometry (m/z: 734.1 (M++1)).

[0311] Step b:

[0312] To the product of step a (160 mg) in 1:3 THF/CH2Cl2 (8 mL) at 25° C. was added (Ph3P)4Pd (13 mg) and morpholine (160 mg). The solution was aged for 6 h and the solution was purified without workup by flash chromatography on silica gel using 1/9 MeOHICH2Cl2 as eluant to yield pure product (112 mg, 74%). The purified product was characterized by proton NMR and mass spectrometry (m/z: 693.4 (M++1)).

EXAMPLE 2

[0313]

[0314] To a stirred solution of 2a (200 mg, prepared following the general procedure of Example 1, step a) in CH2Cl2 (10 mL) was added N-methylmorpholine-N-oxide (198 mg) followed by OSO4 (0.34 mL, 4% solution in water). The solution was aged at 25° C. for 4 h and then poured into saturated Na2S2O3(aq), extracted with CH2Cl2 and dried (Na2SO4). The solvents were removed in vacuo and pure product (182 mg, 86%) was obtained following flash chromatography on silica gel using 1/9 MeOH/CH2Cl2 as eluant. The purified product was characterized by proton NMR and mass spectrometry (m/z: 754.2 (M++1)).

EXAMPLE 3

[0315]

[0316] To a solution of the product of Example 2 (100 mg) in MeOH (6 mL) at 0° C. was added pyridine (11 μL) followed by Pb(OAc)4 (60 mg) and the cooling bath was removed. After 10 min at 25° C., the solution was diluted with CH2Cl2 (30 mL) and poured into saturated Na2S2O3(aq). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Pure product (93 mg, 96%) was obtained following flash chromatography on silica gel using 1/9 MeOHI/CH2Cl2 as eluant. The purified product was characterized by proton NMR and mass spectrometry (m/z: 722.1 (M++1)).

EXAMPLE 4

[0317]

[0318] To the product of Example 3 (72 mg) in MeOH (3 mL) at 25° C. was added NaBH3CN (8 mg). After 1 h, the solution was diluted with CH2Cl2, poured into saturated brine and dried (Na2SO4). The solution was filtered, concentrated under reduced pressure and pure products (60 mg 5a, 83%; 5 mg 5b) were obtained following preparative TLC on silica gel using 5/95 MeOH/CH2Cl2 as eluant. The purified product was characterized by proton NMR and mass spectrometry (m/z: 741.2 (M++1) for 4a and m/z: 709.1 (M++1) for 4b).

EXAMPLE 5

[0319]

[0320] To compound 4a (18 mg) in CH2Cl2 (1 mL) at 0° C. was added (p-NO2)PhOC(O)Cl (6 mg) followed by pyridine (3 μL). After 2 h, additional (p-NO2)PhOC(O)Cl (6 mg) was added and the solution aged for 2 h. The reaction then was warmed to RT and methylamine (5 drops, 1 M solution in CH2Cl2) was added. After 1 h, the reaction was quenched by addition of saturated brine, extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated under reduced pressure. Pure product was obtained following PTLC (1×1000 μm silica gel plate) using 6/4 EtOAc/hexanes as eluant. Pure product (3.3 mg) was characterized by 1H NMR and mass spectrometry [m/z: 781.4 (M++1)].

EXAMPLE 6

[0321]

[0322] To the product of Example 3 (40 mg) in MeOH (5 mL) at 0° C. was added NH4OAc (854 mg) and 3 Å molecular sieves (400 mg) followed by NaBH3CN (4.2 mg) and the cooling bath was removed. After 30 min at 25° C., the solution was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (4×1000 μm plates) using 1/9 MeOH/CH2Cl2 as eluant. The purified product (13 mg, 33%) was characterized by proton NMR and mass spectrometry (m/z: 723.5 (M++1)).

EXAMPLE 7

[0323]

[0324] To the product of Example 6 (5 mg) in CH2Cl2 (1 mL) at RT was added ethyl isocyanate (10 μL). After 1 h, the reaction was quenched by addition of saturated brine, extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated under reduced pressure. Pure product was obtained following PTLC (1×500 μm silica gel plate) using 6/4 EtOAc/hexanes as eluant. Pure product was characterized by 1H NMR and mass spectrometry (m/z: 795.4 (M++1)).

EXAMPLE 8

[0325]

[0326] To (EtO)2P(O)CH(F)CO2Et (47 μL) in THF (1 mL) at −78° C. was added KN(SiMe3)2 (0.445 mL, 0.5 M in toluene) dropwise. After 15 min, the (EtO)2P(O)CF(Li)CO2Et solution (0.77 mL) was added dropwise over 5 min to 7,24-bis-O-trimethylsilyl-3″ -aldehyde (Intermediate II, 90 mg) in THF (1.8 mL) at 0° C. After 5 min, the solution was poured into saturated brine:saturated NaHCO3 (˜1:1), extracted with CH2Cl2 and dried (Na2SO4). The solution was filtered and concentrated under reduced pressure. The residue was dissolved in 200° EtOH (1 mL) at 25° C. and pyridinium para-toluenesulfonate (23 mg) was added. After 10 min, the solvent was removed under a stream on nitrogen. Pure product (66 mg, 65%) as a mixture of E,E and E,Z isomers (˜1:1) was obtained following preparative TLC purification on silica gel (1×1500 μm plate) using 1/1 EtOAc/hexanes as eluant. The purified product was characterized by proton NMR.

EXAMPLE 9

[0327]

[0328] To the product of Example 9 (51 mg) was added allyl alcohol (2 mL) followed by Ti(OiPr)4 (10 μL) and the solution was heated to 140° C. for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and filtered through a 1.5 inch pad of silica gel using EtOAc as eluant and then concentrated. The product thus purified (52 mg, 100%) was characterized by proton NMR and mass spectrometry (m/z: 724.2 (M++1)).

EXAMPLE 10

[0329]

[0330] To Ph3PCH2SPh.Br (106 mg) in toluene (1 mL) at −78° C. was added KN(SiMe3)2 (0.5 mL, 0.5 M solution in toluene). The solution was then warmed to 0° C. and stirred for 30 min. To a solution of 7,24-bis-O-trimethylsilyl-3″-aldehyde (Intermediate II, 30 mg) in toluene (1 mL) at 0° C. was then added the Ph3P═CHSPh solution (0.24 mL) dropwise. After 20 min at 0° C., additional Ph3P═CHSPh solution (0.24 mL) was added. After 20 min, the solution was poured into saturated NaHCO3, extracted with CH2Cl2 and dried (Na2SO4). The solution was filtered and concentrated under reduced pressure. Pure product (9 mg, 26%) was obtained following preparative TLC on silica gel (1×1500 μm plate) using 1/9 EtOAc/hexanes as eluant. The product thus purified was characterized by proton NMR.

[0331] To the carboxylic acid product of Example 1 (30 mg) in CH2Cl2 (2 mL) at 25° C. was added N-hydroxybenzotriazole (5.8 mg) and diisopropylethylamine (8 μL) and the solution cooled to 0° C. To this solution was added BOP (22 mg) followed 15 min later by HNMe2 (0.30 mL) and the cooling bath was removed. After 1 h at 25° C., the solution was poured into saturated NaHCO3(aq), extracted with CH2Cl2 and dried (Na2SO4). The solution was filtered and concentrated under reduced pressure. Pure product (24 mg, 77%) was obtained following preparative TLC purification on silica gel (1×1000 μm plate) using 6/4 EtOAc/hexanes as eluant. The product thus purified was characterized by proton NMR and mass spectrometry (m/z: 721.5 (M++1)).

EXAMPLE 12

[0332]

[0333] Step a:

[0334] To the 4″-carboxylic acid (90 mg, prepared following the general procedure of Example 1) in CH2Cl2 (6 mL) at 25° C. was added diisopropylethylamine (600 μL) followed by (PhO)2P(O)N3 (600 μL) and the solution was heated to reflux for 1 h. The solution was cooled to 25° C. and purified without workup by preparative TLC on silica gel using 4/6 EtOAc/hexanes as eluant to yield pure acyl azide 12a (68 mg, 71%). The product thus obtained was characterized by proton NMR.

[0335] Step b:

[0336] To the product of step a (68 mg) in MeCN (5 mL) was added HN(SiMe)3 (0.1 mL) and aged for 1 h. The volatiles were removed under reduced pressure and pure product was obtained following preparative TLC on silica gel using 1/9 EtOAc/hexanes as eluant. The product thus obtained was characterized by proton NMR.

[0337] Step c:

[0338] To the product of step b (12 mg) was added PhMe (2 mL) and the solution was heated to 80° C. for 30 min. The solvent was removed under reduced pressure and the product obtained was characterized by proton NMR without workup or purification.

[0339] Step d:

[0340] To the product of step c (10 mg) in THF (0.4 mL) at −78° C. was added MeMgCl (15 μL, 3 M solution in THF). The solution was aged for 30 min and was then quenched by addition of saturated NH4Cl(aq), extracted with CH2Cl2 and dried (Na2SO4). Pure product was obtained following preparative TLC on silica gel using 3/7 EtOAc/hexanes as eluant. The product thus obtained was characterized by proton NMR.

[0341] Step e:

[0342] To the product of step d (18 mg) at 25° C. in absolute ethanol (1 mL) was added pyridinium para-toluenesulfonate (11 mg). After 10 min, the solvent was removed under reduced pressure and pure product (10 mg, 69%) was obtained following preparative TLC on silica gel (1×1000 μm plate) using 4/6 acetone/hexanes as eluant. The product thus obtained was characterized by proton NMR and mass spectrometry (m/z: 679.4 (M++1)).

EXAMPLE 13

[0343]

[0344] To the product of Example 12, step c (12c) in methylene chloride at RT was added benzyl alcohol and triethyl amine. The solution was aged for 2 h at RT and then the volatiles were removed under reduced pressure. Pure product was obtained following preparative TLC on silica gel using 2/8 EtOAc/hexanes as eluant. The product thus obtained was characterized by proton NMR.

EXAMPLE 14

[0345]

[0346] To the 7,24-bis-O-trimethylsilyl 3″ -aldehyde (Intermediate II, 25 mg) in THF (0.65 mL) at 25° C. was added (Cp)2TiMe2 (0.20 mL, 1M in toluene) and the solution was heated to 70° C. for 2 h. The golden dark-orange solution was cooled to 25° C. and purified without workup by centrifugal TLC (chromatatron) eluting first with hexanes, then 3/7 EtOAc/hexanes. The purified product (10 mg, 40%) was characterized by proton NMR.

EXAMPLE 15

[0347]

[0348] To a solution of CH2[PO(OEt)2]2 (19 mg) in THF (0.5 nL) at −78° C. was added a (IM) solution of lithium hexamethyldisilazane (0.066 mL), and the mixture was stirred for 30 min. A solution of Intermediate IV (14 mg) in THF (0.5 mL) was then added to the anion of CH2[PO(OC2H5)2]2 at −78° C. and the solution was aged for 2h. The reaction was quenched with 10% citric acid, and the crude product isolated after a work-up was purified by PTLC on silica gel (Analtech 1000 μm plates) using EtOAc/Hexane (2/1) as the eluant. Yield: 8 mg (55%). The product obtained was characterized by proton NMR and mass spectrometry [m/z: 758.3 (M++1) and 682.8 (M-75)].

EXAMPLE 16

[0349]

[0350] To Intermediate VII (25 mg) in MeOH (2 mL) at RT was added 2N HCl (50 μL) and the solution was aged for 30 min. The solution was aged for 30 min, cooled to 0° C. and neutralized with saturated NaHCO3(aq). The solution was extracted with EtOAc, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude 4″ -amine (18 mg) thus obtained was dissolved in CH2Cl2 (0.35 mL) at rt and dimethylpyrocarbonate (0.1 mL) was added. The solution was aged for 56 h. The volatiles were removed under reduced pressure and two pure, isomeric products were obtained following PTLC on silica gel (2×1000 μm plates) using 1/2 acetone/hexanes as eluant. The E and Z olefinic products were characterized by 1H NMR and MS [m/z: 720.5 (M++1) for each]. Yield: 5.4 mg mobile isomer A and 5.6 mg polar isomer B.

EXAMPLE 17

[0351]

[0352] To Intermediate II (10 mg) in EtOAc (1 mL) at RT was added 10% Pd/C (1 mg) and an atmosphere of hydrogen was established using a balloon. After 4 h, the catalyst was removed by filtration through Celite using EtOAc as eluant and the solvent was removed under reduced pressure. Pure product (4 mg) was obtained following PTLC on silica gel (1×500 μm plate) using 2/8 acetone/hexanes as eluant. The product thus obtained was characterized by 1H NMR.

EXAMPLE 18

[0353]

[0354] To Intermediate I (20 mg) in benzene (2 mL) at rt was added 3-methyl-1-phenyl-2-pyrazolin-5-one (40 mg). After 1 h, the solution was purified without workup by PTLC on silica gel (2×1000 μm plates) using 4/6 acetone/hexanes to yield pure product (19 mg). The product thus obtained was characterized by 1H NMR and MS (m/z: 781.3 (M++1)).

EXAMPLE 19

[0355]

[0356] To 2-dimethylphosphonato-[1,3]dithiane (105 mg) in THF (0.75 mL) at −78° C. was added nBuLi (0.26 mL, 1.6M in hexanes). The solution was warmed to 0° C. over 30 min and then re-cooled to −78° C. To the ylide thus generated was added Intermediate I (100 mg) as a solution in THF (0.75 mL) and the solution was aged for 2 h at −78° C. Water was added to quench the reaction, the aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. Pure dithiane product (82 mg) was obtained following PTLC on silica gel (2×1000 μm plates) using 1/9 EtOAc/hexanes as eluant. The product thus obtained was characterized by 1H NMR.

[0357] Following the general descriptions of the previous examples and using appropriate 3″ -aldehyde precursors, the following compounds were prepared and deprotected as previously described. All compounds were characterized by mass spectrometry and/or 1H NMR.

EXAMPLE 20

[0358]

Entry
R4″ Group***
Mass Spec

20a
H

20b
H(1′ = CH2)

20c
CN

20d
CN (Z isomer)

20e
CN (2′-nat and 2′-epi)

20f
C(O)CH3

20g
CO2H
648.7(M+ + 1-H2O)

20h
CO2CH2CH═CH2

20i
CO2CH2Ph

20j
CO2Et

20k
CO2tBu

20l
CO2tBu(1′-CHCO2tBu)

20m
C(O)NH2
665.3(M+ + 1)

20n
C(O)(N-1-piperidinyl)
733.5(M+ + 1)

20o
C(O)(N-1-pyrrolidinyl)
719.4(M+ + 1)

20p
C(O)N(Me)CH2CH3
707.4(M+ + 1)

20q
C(O)N(Me)CH2Ph(4-Cl)
803.4(M+ + 1)

20r
C(O)NH2 (Z isomer)
665.1(M+ + 1)

20s
C(O)NHCH2CH2F
711.4(M+ + 1)

20t
C(O)NHCH2Ph
755.4(M+ + 1)

20u
C(O)NH—Et

20v
C(O)NH-tBu
721.8(M+ + 1)

20w
C(O)NMe2
693.4(M+ + 1)

20x
NHAc (Z isomer)
679.4(M+ + 1)

20y
NHC(O)Et
693.4(M+ + 1)

20z
NHC(O)Et (Z isomer)
693.4(M+ + 1)

20aa
NHC(O)nBu
721.5(M+ + 1)

20bb
NHC(O)nPr
707.4(M+ + 1)

20cc
NHC(O)nPr (Z isomer)
707.4(M+ + 1)

20dd
P(O)(OEt)2
758.3(M+ + 1)

20ee
SPh
730.0(M+ + 1)

***(E isomer unless indicated)

EXAMPLE 21

[0359]

Entry
R4″ Group***
Mass Spec

21a
2-(4,5-dihydro-4-(R)-isopropyl-oxazolinyl)
747.0(M+ + 1)

21b
2-(4,5-dihydro-4-(S)-C(O)NHEt-thiazolinyl)
776.0(M+ + 1)

21c
2-(4,5-dihydro-4-(S)-C(O)NHMe-

thiazolinyl)

21d
2-(4,5-dihydro-4-(S)-C(O)NHtBu-
804.0(M+ + 1)

thiazolinyl)

21e
2-(4,5-dihydro-4-(S)-C(O)NHtBu-

thiazolinyl) (Z isomer)

21f
2-(4,5-dihydro-4-(S)-C(O)NMe2-thiazolinyl)

21g
2-(4,5-dihydro-4-(S)-C(O)NMe2-thiazolinyl)
776.0(M+ + 1)

(Z isomer)

21h
2-(4,5-dihydro-4-(S)-isopropyl-oxazolinyl)
747.0(M+ + 1)

21i
2-(4,5-dihydro-4-(spiro-cyclopentyl)-
759.0(M+ + 1)

oxazolinyl)

21j
2-(4,5-dihydro-4-CO2Me-thiazolinyl)
779.0(M+ + 1)

21k
2-(4,5-dihydro-5-(R)-methyl-oxazolinyl)
719.0(M+ + 1)

21l
2-(4,5-dihydro-5-(S)-methyl-oxazolinyl)
719.0(M+ + 1)

21m
2-(4,5-dihydro-oxazolinyl)
705(M+ + 1)

21n
2-furfuryl (E & Z)

21o
2-thienyl

21p
5-(1-Ph-tetrazolyl)

21q
5-(1-Ph-tetrazolyl) (Z isomer)

21r
5-(N-1-(2-cyanoethyl)-tetrazolyl)

21s
5-(N-1-(2-cyanoethyl)-tetrazolyl) (Z isomer)

21t
5-(N—Et-tetrazolyl)

21u
5-[3-(Ph(3,5-CF3))-isoxazolyl]

21v
5-[3-(Ph(4-tBu))-isoxazolyl]

21w
5-tetrazolyl

21x
CH═NNHSO2Ph(4-Me)

21y
CH═NOCH2Ph

21z
CH═NOMe

21aa
CH2CO2allyl
734.6(M+ + 1)

21bb
CH2CO2Me
708.5(M+ + 1)

21cc
CH2CO2nPr
736.4(M+ + 1)

21dd
CN

21ee
CN (Z isomer)

21ff
N-1-(5-Me-tetrazolyl)
718.2(M+ + 1)

21gg
NHC(O)Et

21hh
NHC(O)Me
617.4(M − 75)

21ii
NHC(O)Me(1″,2″-dihydro)
635.5(M − 75)

21jj
NHC(O)nBu

21kk
NHC(O)nPr
645.6(M − 75)

21ll
NHC(O)P(O)Ph2
879.2(M+ + 1)

21mm
NHC(O)Ph(2,4,6-Me)
797.2(M+ + 1)

21nn
NHC(O)Ph(4-Cl)
713.4(M − 75)

21oo
NHC(O)S(CH2)3Ph

21pp
NHC(O)SEt

21qq
OSO2CF3

21rr
OSO2CF3 (2′-nat and 2′-epi)

***(E isomer unless indicated)

EXAMPLE 22

[0360]

Entry
R4″a Group
R4″b Group
Mass Spec

22a
C(O)(N-1-piperidinyl)
Et
761.5(M+ + 1)

22b
C(O)(N-1-pyrrolidinyl)
Et
747.5(M+ + 1)

22c
C(O)CF2Cl
CO2Me

22d
C(O)Me
C(O)NEt2

22e
C(O)Me
CF3

22f
C(O)Me
NH—Me

22g
C(O)Me
NHPh(2-OMe)

22h
C(O)Me
NMe2

22i
C(O)N(Me)CH2Ph(4-Cl)
Et
831.4(M+ + 1)

22j
C(O)N(Me)Et
CH2OH

22k
C(O)NH2
CH2CH═CH2
705.3(M+ + 1)

22l
C(O)NH2
Et
693.4(M+ + 1)

22m
C(O)NH2
nBu
721.3(M+ + 1)

22n
C(O)NH2
nPr
707.4(M+ + 1)

22o
C(O)NH2
OMe
677.3(M+ + 1)

22p
C(O)NH2
OMe
695.4(M+ + 1)

22q
C(O)NH2 (2′-nat and 2′-
CH2CH═CH2
705.3(M+ + 1)

epi)

22r
C(O)NH2 (2′-nat and 2′-
nPr
707.4(M+ + 1)

epi)

22s
C(O)NHC(Me)2C≡CH
CH2C(O)NHC(Me)2C≡CH

22t
C(O)NHCH2CF3
CH2CH═CH2
787.4(M+ + 1)

22u
C(O)NHCH2CF3
Et
775.4(M+ + 1)

22v
C(O)NHCH2CH2F
CH2CH(OH)CH2OH
785.4(M+ + 1)

22w
C(O)NHCH2CH2F
CH2CH═CH2
751.4(M+ + 1)

22x
C(O)NHCH2Ph(4-F)
CH2CH(OH)CH2OH
847.5(M+ + 1)

22y
C(O)NHCH2Ph(4-F)
CH2CH═CH2
813.5(M+ + 1)

22z
C(O)NH—Et
CH2CH(OH)CH2OH
767.4(M+ + 1)

22aa
C(O)NH—Et
CH2CH═CH2
733.4(M+ + 1)

22bb
C(O)NH—Et
Et
721.4(M+ + 1)

22cc
C(O)NH—Et
nBu
749.4(M+ + 1)

22dd
C(O)NH—Et
nPr
735.5(M+ + 1)

22ee
C(O)NH—Et
OMe
705.4(M+ + 1)

22ff
C(O)NH—Et (2′-nat and
CH2CH═CH2
733.3(M+ + 1)

2′-epi)

22gg
C(O)NH—Et (2′-nat and
F
711.1(M+ + 1)

2′-epi)

22hh
C(O)NH—Et (2′-nat and
nPr
735.5(M+ + 1)

2′-epi)

22ii
C(O)NHiBu
CH2C(O)NH-iBu

22jj
C(O)NH-iPr
CH2CH(OH)CH2OH
781.4(M+ + 1)

22kk
C(O)NH-iPr
CH2CH═CH2
747.3(M+ + 1)

22ll
C(O)NHMe
CH2CH(OH)CH2OH
753.4(M+ + 1)

22mm
C(O)NH—Me
CH2CH═CH2
719.4(M+ + 1)

22nn
C(O)NH—Me
CH2CH2-epoxide

22oo
C(O)NH—Me
Et

Z2pp
C(O)NH—Me (2′-nat and
Et
707.4(M+ + 1)

2′-epi)

22qq
C(O)NHMe (E & Z)
C(O)Me

22rr
C(O)NHPh(2-OMe)
C(O)Me

(E & Z)

22ss
C(O)NH-tBu
CH2CH(OH)CH2OH
795.3(M+ + 1)

22tt
C(O)NH-tBu
CH2CH═CH2
761.3(M+ + 1)

22uu
C(O)NH-tBu
Et
749.5(M+ + 1)

22vv
C(O)NH-tBu
F
739.0(M+ + 1)

22ww
C(O)NH-tBu
nBu
777.4(M+ + 1)

22xx
C(O)NH-tBu
nPr
764.4(M+ + 1)

22yy
C(O)NH-tBu
OMe

22zz
C(O)NH-tBu (2′-nat and
CH2CH═CH2

2′-epi)

22aaa
C(O)NH-tBu (2′-nat and
nPr
763.5(M+ + 1)

2′-epi)

22bbb
C(O)NMe2
CH2CH(OH)CH2OH
767.5(M+ + 1)

22ccc
C(O)NMe2
CH2CH═CH2
733.4(M+ + 1)

22ddd
C(O)NMe2
CH2CH3
721.5(M+ + 1)

22eee
C(O)NMe2 (E & Z)
C(O)Me

22fff
C(O)Ph
OMe
726.1(M+ + 1)

22ggg
C(O)Ph (Z isomer)
C(O)Me

22hhh
C(O)Ph(4-F) (E & Z)
CO2Me

22iii
CF3
C(O)Me

22jjj
CF3 (23,24-dehydro)
C(O)Me

22kkk
CH2CH2NHC(O)NH—Et
CO2Me
795.4(M+ + 1)

22lll
CH2CH2OC(O)NH-iPr
CO2Me
809.4(M+ + 1)

22mmm
CH2CH2OC(O)NH-tBu
CO2Me
823.4(M+ + 1)

22nnn
CN
CN

22ooo
CN
CO2CH2CH═CH2

22ppp
CO2CH2CH═CH2
F

22qqq
CO2H
Et
693.4(M+ + 1)

22rrr
CO2H
F

22sss
CO2H
nBu
722.3(M+ + 1)

22ttt
CO2H
nPr
708.4(M+ + 1)

22uuu
CO2H
OMe
696.1(M+ + 1)

22vvv
CO2H (2′-nat and 2′-epi)
CH2CH═CH2
706.2(M+ + 1)

22www
CO2Me

789.1(M+ + 1)

22xxx
CO2Me

803.1(M+ + 1)

22yyy
CO2Me

861.9(M + NH4)

22zzz
CO2Me

847.9(M + NH4)

22aaaa
CO2Me
CH2CH(OH)CH2OH
754.2(M+ + 1)

22bbbb
CO2Me
CH2CH═CH2
702.1(M − H20)

22cccc
CO2Me
CH2CH2CH(OH)CH2OH
769.1(M+ + 1)

22dddd
CO2Me
CH2CH2CH═CH2
751.4(M + NH4)

22eeee
CO2Me
CH2CH2NH2
723.5(M+ + 1)

22ffff
CO2Me
CH2CH2NHC(O)NH—Et
795.4(M+ + 1)

22gggg
CO2Me
CH2CH2OC(O)NH—Et
795.5(M+ + 1)

22hhhh
CO2Me
CH2CH2OC(O)NH-iPr
809.4(M+ + 1)

22iiii
CO2Me
CH2CH2OC(O)NH—Me
781.4(M+ + 1)

22jjjj
CO2Me
CH2CH2OC(O)NH-tBu
823.4(M+ + 1)

22kkkk
CO2Me
CH2CH2OH
741.2(M + NH4)

22llll
CO2Me
CH2CHO
722.1(M+ + 1)

22mmmm
CO2Me
CN

22nnnn
CO2Me
NHCO2CH2Ph
845.9(M + NH4)

22oooo
CO2Me
Ph(4-F)

22pppp
CO2Me (2′-nat and 2′-epi)
CH2CH2CH═CH2
—

22qqqq
CO2Me (2′-nat and 2′-epi)
CH2CH2CHO
736.1(M+ + 1)

22rrrr
CO2Me (2′-nat and 2′-epi)
CH2CH2NH—Et
751.6(M+ + 1)

22ssss
CO2Me (2′-nat and 2′-epi)
CN

22tttt
CO2Me (2′-nat and 2′-epi)
NHCO2CH2Ph
846.0(M + NH4)

22uuuu
F
C(O)NH—Et
711.0(M+ + 1)

22vvvv
F (2′-nat and 2′-epi)
C(O)NH—Et
711.0(M+ + 1)

22wwww
F (2′-nat and 2′-epi)
C(O)NH-tBu
739.2(M+ + 1)

22xxxx
NHC(O)Et
Et
721.5(M+ + 1)

22yyyy
NHC(O)Me
Et
707.4(M+ + 1)

22zzzz
NHC(O)Me
Et
709.5(M+ + 1)

22aaaaa
NHC(O)Me (E & Z)
CN

22bbbbb
NHC(O)nBu
H
721.5(M+ + 1)

22ccccc
NHC(O)NH-tBu
nBu
778.1(M+ + 1)

22ddddd
NHC(O)N-morpholinyl
nBu
806.2(M+ + 1)

22eeeee
NHC(O)OMe
CN

22fffff
NHC(O)OMe (Z isomer)
CN

22ggggg
NHCO2CH2Ph
CO2Me

***(E isomer unless indicated)

EXAMPLE 23

[0361]

Entry
R6″
O or NR
5″ - 6″
Mass Spec

23a
H
N-(2-pyridyl)
single
768.4(M+ + 1)

23b
H
N-allyl
single
731.4(M+ + 1)

23c
oxo
N-allyl
single
745.4(M+ + 1)

23d
H
N-cC5H9
single
759.5(M+ + 1)

23e
oxo
N-cC5H9
single
755.1(M − H20)

23f
oxo
N-cC6H11
single
769.0(M − H20)

23g
oxo
N—CH2CH2F
single
751.6(M+ + 1)

23h
oxo
N—CH2Ph
single
777.1(M − H20)

23i
H
N-cPr
single
731.4(M+ + 1)

23j
oxo
N-cPr
single
745.2(M+ + 1)

23k
oxo
NEt
single
733.3(M+ + 1)

23l
oxo
N-(1-pyrrolidinyl)
single
774.6(M+ + 1)

23m
oxo
N-(4-morpholinyl)
single
790.4(M+ + 1)

23n
oxo
N-[3-(5-Me-
single
785.4(M+ + 1)

isoxazolyl)]

23o
oxo
N-nBu
single
761.4(M+ + 1)

23p
H
NC(O)Me
single
691.4(M+ + 1)

23q
oxo
NCH2CH2CN
single
757.4(M+ + 1)

23r
H
NCH2CH2F
single
737.4(M+ + 1)

23s
OH
NCH2CH2F
single
753.4(M+ + 1)

23t
OMe
NCH2CH2F
single
767.4(M+ + 1)

23u
H
NCH2CH2OH
single
735.4(M+ + 1)

23v
OH
NCH2Ph(4-F)
single
815.4(M+ + 1)

23w
H
N—Et
double
717.4(M+ + 1)

23x
H
N—Et
single
719.5(M+ + 1)

23y
OH
N—Et
single
735.4(M+ + 1)

23z
H
NH
single
691.4(M+ + 1)

23aa
oxo
NH
single
705.3(M+ + 1)

23bb
H
NH (2′-epi)
single

23cc
H
N-iBu
single
747.5(M+ + 1)

23dd
H
N-iPr
single
733.5(M+ + 1)

23ee
OH
N-iPr
single
749.4(M+ + 1)

23ff
oxo
NMe
single
701.1(M − H20)

23gg
H
N—Me
single
705.4(M+ + 1)

23hh
OH
N—Me
single
721.4(M+ + 1)

23ii
H
N-tBu
double
745.5(M+ + 1)

23jj
H
N-tBu
single
747.5(M+ + 1)

23kk
OMe
N-tBu
single
777.4(M+ + 1)

23ll
H
O
single

23mm
oxo
N—Ph
single
763.1(M − H2O)

23nn
oxo
N—Ph(2-F)
single
799.4(M+ + 1)

23oo
oxo
N—Ph(3,5-diMe)
single
810.6(M+ + 1)

23pp
oxo
N—Ph(3-F)
single
799.4(M+ + 1)

23qq
oxo
N—Ph(3-Me)
single
795.5(M+ + 1)

23ff
oxo
N—Ph(4-Ac)
single
823.6(M+ + 1)

23ss
oxo
N—Ph(4-Cl)
single
815.4(M+ + 1)

23tt
oxo
N—Ph(4-Et)
single
809.6(M+ + 1)

23uu
oxo
N—Ph(4-F)
single
799.4(M+ + 1)

23vv
oxo
N—Ph(4-Me)
single
795.4(M+ + 1)

23ww
oxo
N—Ph(4-OMe)
single
811.6(M+ + 1)

23xx
oxo
N-tBu
single
744.0(M − H2O)

EXAMPLE 24

[0362]

[0363] Following the general descriptions of Example 1 using the Intermediate I and 3-triphenylphosphoranylidine-glutaramide, the title compound was prepared as previously described and characterized by 1H NMR and mass spectrometry (m/z: 719.3 (M++1))

EXAMPLE 25

[0364] Following the general descriptions of previous examples and using the appropriate 3″ -aldehyde precursor, the following compounds were prepared and deprotected as previously described. All compounds were characterized by mass spectrometry and/or 1H NMR.

EntryR6Mass Spec25a

739.3(M+ + 1)25b

739.4(M+ + 1)25c

767.3(M+ + 1)25d

779.3(M+ + 1)25e

722.3(M+ + 1)25f

781.3(M+ + 1)25g

735.3(M+ + 1)25h

705.2 (M − H2O)25i

774.2(M+ + 1)25j

25k

830.2(M+ + 1)25l

732.3(M+ + 1)25m

746.3(M+ + 1)25n

746.3(M+ + 1)25o

760.3(M+ + 1)25p

816.0 (M − H2O)25q

772.2(M+ + 1)25r

815.3(M+ + 1)25s

25t

781.3(M+ + 1)25u

880.3(M+ + 1)25v

885.1(M+ + 1)25w

822.4(M+ + 1)25x

1006.2 (M+ + 1)25y

704.3(M+ + 1)1:2 mixture of E and Z isomers25z

855.3(M+ + 1)1 1 mixture of E and Z isomers25aa

859.3(M+ + 1)25bb

825.3(M+ + 1)

EXAMPLE 26

[0365]

[0366] To a solution of N-(1,1-dimethylethyl)-nodulisporamide (50 mg) and Pd(OAc)2 (3 mg) in CH2Cl2 (2 mL), a solution of CH2N2 in ether (generated from N-nitrosomethylurea) (0.5 mL) was added dropwise at room temperature. The resulting dark colored (N2 evolution was observed) mixture was stirred for 16 h at room temperature and then filtered through a celite pad. The filtrate was concentrated in vacuo, and the residue was purified by PTLC using EtOAc/hexane (1/1) (three developments) to give the desired cyclopropane compounds: fast moving Isomer A (8 mg) and slower moving Isomer B (23 mg).

EXAMPLE 27

[0367]

[0368] Step a:

[0369] To a stirred solution of Intermediate II (3.24 g) in diethyl ether (100 mL) at −78° C. was added MeMgBr (2.78 mL, 3.0 M solution in diethyl ether) over 10 min. After 30 min at −78° C., the mixture was quenched with methanol (1 mL), washed once with saturated NH4Cl(aq) and the aqueous layer was extracted with diethyl ether (2×). The combined organic layers were washed with saturated NaHCO3, brine and dried (Na2SO4). The solution was filtered and concentrated under reduced pressure. The intermediate 27a thus obtained was used with no further purification.

[0370] Step b:

[0371] The 3″ -alcohol 27a (3.05 g) was placed in methylene chloride (50 mL) at RT to which was added MnO2 (5 g) and the solution was aged with vigorous stirring for 3 d. The solution was filtered and the filtrate evaporated under reduced pressure. Pure 27b (2.6 g) was obtained following flash chromatography on silica gel using 1/9 EtOAc/hexanes as eluant. The product was characterized by proton NMR.

[0372] Step c

[0373] To a stirred solution of (EtO)2P(O)CH2CO2CH2CH═CH2 (0.5 g) in THF/DMF (2 mL, 1/1) was added NaH (43 mg, 60% dispersion in oil) and the solution was aged for 1 h. The 3″ -methyl ketone 27b (165 mg) was added to the NaH/phosphonate solution and the mixture was heated to 60° C. for 4 h. The solution was cooled to RT and diluted with methylene chloride, washed with water (3×), brine (1×) and dried (Na2SO4). The solution was filtered and concentrated to dryness under reduced pressure. The residue was filtered through a 1.5″ thick pad of silica gel to remove baseline contaminants using 1/9 EtOAc/hexanes as eluant. The bis-protected product thus obtained was placed in ethanol (5 mL) at RT to which was added PPTS (2 mg). After 1 h, the solution was concentrated to dryness and was purified by flash chromatography to yield a mixture of 2′-epi (fast-moving product) and 2′-nat (slow moving product) stereoisomers. The products thus obtained were characterized by proton NMR.

EXAMPLE 28

[0374]

[0375] The 2′-epi allyl ester product (60 mg) of Example 27 was placed in methylene chloride (6 mL) to which was adde PdCl2(PPh3)2 (5 mg) followed by nBu3SnH (0.15 mL). After 30 min, the solution was purified by flash chromatography on silica gel without workup to yield pure carboxylic acid derivative (35 mg) which was characterized by proton NMR and MS (m/z: 680.3 (M++1-H2O).

EXAMPLE 29

[0376]

[0377] The 2′-nat-carboxylic product (8 mg) of Example 27 was placed in methylene chloride (2 mL) at RT to which was added HOBT (1.9 mg), (iPr)2NEt (20.5 mg) and cyclopropyl amine (3.4 mg) followed by the addition of BOP reagent (15.6 mg). After 10 min, the solution was diluted with methylene chloride, washed with brine and dried (Na2SO4). The solution was filtered and concentrated under reduced pressure. Pure amide product (5.3 mg) was obtained following PTLC (1×1000 μm plate) on silica gel using 1/1 acetone/hexanes as eluant. The product thus obtained was characterized by proton NMR and MS (m/z: 719.3 (M++1).

EXAMPLE 30

[0378] Following the general procedure of Example 29, the following compounds were prepared and were characterized by mass spectrometry and/or proton NMR.

EntryR5″ GroupMass Spec30aNH-(N-1-piperizinyl)30bNHCH2CH2F725.3(M+ + 1)30cNH—Et707.3(M+ + 1)30dNH-iPr721.4(M+ + 1)30eNH-iPr (2′-epi)721.4(M+ + 1)30fNH—Me693.3(M+ + 1)30gNH—Me (2′-epi)693.3(M+ + 1)30hNHtBu735.4(M+ + 1)30iNH-tBu (2′-epi)735.5(M+ + 1)30jOH662.3(M+ + 1-H2O)

EXAMPLE 31

[0379] The following derivatives were obtained by osmium-catalyzed dihydroxylation using the appropriate unsaturated precursor and following the general procedure used for the preparation of Intermediate I (method b). The cis-diol products thus obtained, which could be optionally separated (both R,R and S,S diastereomers were produced), were characterized by proton NMR.

EntryR1″ Group31a

31b

31c

31d

31e

100

EXAMPLE 32

[0380]

101

[0381] Step a:

[0382] To the 4″ -n-propyl substituted carboxylic acid (25 mg, prepared following the general procedures used for the preparation of the product of Example 2) in CH2Cl2 (2 mL) at 25° C. was added diisopropylethylamine (62 μL) followed by (PhO)2P(O)N3 (61 μL) and the solution was heated to reflux for 1 h. Pure acyl azide product 32a (21 mg, 81%) was obtained without workup following preparative TLC purification on silica gel (2×1000 μm plates) using 6/4 EtOAc/hexanes as eluant. The product thus purified was characterized by proton NMR.

[0383] Step b:

[0384] To the acyl azide of step a (21 mg) was added PhMe (2 mL) and the solution was heated to reflux for 1.5 h. The solution was cooled to 25° C. and concentrated to dryness to yield desired isocyanate 32b (18.6 mg) which was used with no further purification. The product thus obtained was characterized by proton NMR.

[0385] Step c:

[0386] To the isocyanate product of step b (10 mg) in methylene chloride (1 mL) was added morpholine (0.1 mL) and the solution was aged for 10 min. Pure urea product (7.9 mg) was obtained without workup following preparative TLC on silica gel (1×1000 μm plate) using 6/4 EtOAc/hexanes as eluant. The product thus obtained was characterized by proton NMR and mass spectrometry (m/z: 806.2 (M++1)).

EXAMPLE 33

[0387]

102

[0388] Nodulisporic acid A1 (Compound B) was converted into the corresponding 3″ -aldehyde following the general procedure as described for the preparation of Intermediate I. The product thus obtained was characterized by 1H NMR and MS [m/z: 654.2 (M++1)].

EXAMPLE 34

[0389]

103

[0390] The product of Example 33 was converted into the corresponding enoate following the general conditions described for the preparation of the product of Example 1. During purification, transferring and concentration of the reaction product using methanol led to incorporation of a methoxyl at C7. The title product thus obtained was characterized by 1H NMR and MS [m/z: 710.3 (M++1)].

EXAMPLE 35

[0391]

104

[0392] To the product of Example 34 (26 mg) in a mixture of THF (1 mL) and water (0.5 mL) was added PPTS (30 mg) and the solution was aged for 18 h at room temperature. The reaction was then diluted with ethyl acetate, washed with sat. NaHCO3 and water. The crude product obtained was purified on silica-gel by PTLC using ETOAc-hexane (1/2) as the eluent. The title product thus obtained was characterized by 1H NMR and MS [m/z: 696.3 (M++1)].

105

EntryR7R2″Mass Spec36aMeCH═CHC(O)Me694.4(M+ + 1)36bMeCH═CHCHO680.2(M+ + 1)36cMeCH═CHCO2Me710.3(M+ + 1)36dMeCH═CHCO2CH2CH═CH2736.5(M+ + 1)36eMe

106

763.4(M+ + 1)36fMe

107

797.6(M+ + 1)36gHCH═CHCHO666.5(M+ + 1)36hHCH═CHCO2Me696.3(M+ + 1)36iHCH═CHCO2CH2CH═CH2722.3(M+ + 1)36jH

108

731.4(M+-H2O + 1)36kH

109

783.3(M+ + 1)

EXAMPLE 37

[0393]

110

[0394] Following the general procedure of Example 29 using ethane thiol instead of cyclopropyl amine, nodulisporic acid A (compound A) was converted into the corresponding ethyl thioester. To the 5″ thioester (650 mg) thus obtained at RT was added acetone (50 mL) followed by Et3SiH (0.75 mL) and Lindlar catalyst (1.3 g). After 20 min at RT, the solids were filtered through Celite and the volatiles were removed under reduced pressure. Pure 5″ -aldehyde product 37a (420 mg) and pure 1″, 2″, 3″, 4″-tetrahydro-5″-aldehdye product 37b (70 mg) were obtained following PTLC chromatography on silica gel (5×1000 μm plates). The aldehydes thus prepared were characterized by proton NMR.

EXAMPLE 38

[0395] Following the general olefination procedure described in Example 1 and using the aldehyde 37a, the following compounds were prepared and characterized by proton NMR:

111

EntryR6″ Group38aPh(4-Br) (E only)38bCO2Et (E & Z)38cMe (2′-epi) (E & Z)38dMe (E & Z)

EXAMPLE 39

[0396]

112

[0397] Following the general description for the preparation of Intermediate II, the C7 and C24 hydroxyl groups of compound 37a were protected as trimethylsilyl ethers. This intermediate ether was treated with 2,4,6-trimethylphenyl Grignard as described in Example 27 (step a) to form a separable mixture of 5″ -alcohol isomers. The trimethylsilyl groups were removed as described previously and the pure products (mobile isomer A; polar isomer B) obtained following PTLC were characterized by proton NMR.

EXAMPLE 40

[0398] Following the general procedure of Example 39 and using the appropriate nucleophile, the following compounds were prepared and were characterized by proton NMR:

113

EntryR5″ Group5″ Isomer40atBuB40btBuA40cEtA & B40dC≡CHA & B40eCH2C(O)tBuA40fCH2C(O)tBuB40gCH2C(O)Ph(4-Br)A40hCH2C(O)Ph(4-Br)B40iCH2C(O)[2-(5-Me-furyl)]A40jCH2C(O)[2-(5-Me-furyl)]B40kCH2C(O)[3-(2,5-Me-thienyl)]A401CH2C(O)[3-(2,5-Me-thienyl)]B

EXAMPLE 41

[0399] Following the general procedure of Example 27 (steps a and b) using the appropriate nucleophile, the following compounds were obtained and deprotected as described previously. The compounds thus obtained were characterized by proton NMR.

114

EntryR5″ Group41aCH2CO2Ph(4-NO2)41bCH2CH═CH2(1′-CH2CH═CH2)41cEt41dtBu41ePh(4-tBu)

EXAMPLE 42

[0400]

115

[0401] To the 5″-aldehyde 37a was placed in methanol at 0 C to which was added glacial acetic acid and benzyl amine. To the cooled solution was added NaBH3CN. The solution was aged for 3 h at 0 C and then warmed to RT. The solution was then poured into saturated brine, extracted with EtOAc and dried (Na2SO4). Pure product, as a mixture of olefin isomers at C4″ were obtained following PTLC and the pure product thus obtained was characterized by proton NMR.

EXAMPLE 43

[0402] Following the general procedure of Example 42 and using an appropriate amine, the following compounds were prepared and were characterized by proton NMR:

116

EntryNRcRd***R4″ Group43aNHCH2PhMe43bNHCH2Ph(4-OMe)Me43cNHCH2Ph(4-OMe)(Z isomer)Me43dNH-tBu(E & Z isomers)Me43eNH-tBuMe43fNH-tBu(Z isomer)Me43gNH2Me43hN-4-morpholinylMe43iN-4-morpholinyl(Z isomer)Me43jNHCH2Ph(4-OCF3)Me43kNHCH2Ph(4-OCF3)(Z isomer)Me431N(Me)EtMe43mNHCH2CF2CF3Me43nN(CH2CF3)2Me43oN(AC)CH2CF2CF3Me43pN(Ac)CH2Ph(4-OMe)Me43qNCH2CH2CH2(N-4-morpholinyl)Me43rNCH2CH2CH2(N-4-morpholinyl)(Z isomer)Me43sNMe2(2′-nat and 2′-epi)H***E isomer unless indicated

EXAMPLE 44

[0403]

117

[0404] Nodulisporic acid A (compound A) was converted to the corresponding 5″-amide using H2NCH(CH2OH)C(O)NHMe and protected as its 7,24-bis-OSiMe3 ethers as previously described. To the 7,24-bis-OSiMe3-protected-5″-amide (15 mg) thus prepared in dioxane (1.5 mL) at RT was added Burgess reagent (19 mg) and the solution was aged for 4 h. Additional Burgess reagent (19 mg) was added and the solution was aged for 12 h. Additional Burgess reagent (19 mg) was added and the solution was aged for 24 h (this was repeated twice). The volatiles were removed under reduced pressure and the pure 7,24-bis-OSiMe3-protected-4″-oxazolines were obtained following PTLC purification on silica gel (1×500 μm plate) using 2/8 acetone/hexanes as eluant. Cis (2 mg) and trans (2 mg) isomers at 4″ were isolated from this reaction. Deprotection of the trans product was accomplished as described to yield pure product (1 mg) which was characterized by 1H NMR.

EXAMPLE 45

[0405] Using the general strategy illustrated in Example 44, the following compounds were prepared and deprotected as previously described. The products thus obtained were characterized by proton NMR and mass spectrometry.

118

EntryR1 GroupR2 GroupMass Spec45aHH705.0 (M+ + 1)45b(R)-iPrH747.0 (M+ + 1)45c(S)-iPrH747.0 (M+ + 1)45dH(S)-Me719.0 (M+ + 1)45eH(R)-M719.0 (M+ + 1)45fspiro-cyclopentylH759.0 (M+ + 1)

EXAMPLE 46

[0406]

119

[0407] Nodulisporic acid A (Compound A) was converted to the corresponding 5″-N,N-diethyl amide as described and protected as described for Intermediate III as its 7,24-bis-OSiEt3 ether. To the bis-protected 5″-N,N-diethyl amide (40 mg) thus obtained was added pyridine (35 μL) in CH2Cl2 (1 mL) and the solution was cooled to −50° C. and Tf2O (10 μL) was then added. The solution was warmed slowly to 0° C. and aged for 12 h. The solution was re-cooled to −30° C. and HSCH2CH2NH2 (10 mg) was added followed by pyridine (35 μL). The solution was allowed to warm to RT. Pure 7,24-bis-OSiEt3-protected-4″-thiazoline (16 mg) was obtained following PTLC purification on silica gel (1×1500 μm plate) using 2/8 acetone/hexanes as eluant. The 7,24-bis-OSiEt3-protected-4″-thiazoline was deprotected as described previously to yield the desired 4″-thiazoline which was characterized by 1H NMR.

EXAMPLE 47

[0408] Using the general strategy illustrated in Example 46, the following compounds were prepared. The compounds thus obtained were characterized by mass spectrometry and/or proton NMR.

120

EntryR1 Group***Mass Spec47a(S)—C(O)NH-Me47b(S)—C(O)NH-Et776.0 (M+ 1)47c(S)—C(O)NMe2(Z isomer)776.0 (M+ + 1)47d(S)—C(O)NMe247e(S)—C(O)NH-tBu(Z isomer)47f(S)—C(O)NH-tBu804.0 (M+ + 1)47g(S)—C(O)NH-tBu721.0 (M+ + 1)47hCO2Me779.0 (M+ + 1)***(E isomer at 4″ unless indicated)

EXAMPLE 48

[0409] The following 4″-heterocyclic substituted derivatives were prepared and were characterized by mass spectrometry and/or proton NMR.

121

EntryR1″ GroupMass Spec48a

122

48b

123

48c

124

48d

125

48e

126

48f

127

48g

128

718.2 (M+ + 1)48h

129

719.0 (M+ + 1)48i

130

48j

131

EXAMPLE 49

[0410]

132

[0411] Step a:

[0412] To a solution of nodulisporic acid A (compound A, 400 mg) in THF (8 mL) maintained between 0° C. and −5° C. was added (iPr)2NEt (0.63 mL) followed by MeSO2Cl (0.23 mL). After 30 min at this temperature, diazomethane (excess) in diethyl ether was added and after 15 min, the solution was stirred at RT overnight. The volatiles were removed under reduced pressure and the residue was purified by radial preparative thin layer chromatography using hexanes:EtOAc (1/1) as eluant to yield pure product 49a (63 mg, 63%). The product thus obtained was characterized by proton NMR.

[0413] Step b:

[0414] The diazoketone product of step a (6.6 mg) was placed in glacial acetic acid (0.7 mL) at 0° C. to which was added LiCl (2.1 mg). After 1 h, the solution was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with brine and dried (Na2SO4), filtered and concentrated under reduced pressure. Pure methyl ketone product 49b and alpha-hydroxy ketone product 49c were isolated following PTLC purification. The products thus obtained were characterized by proton NMR and mass spectrometry (m/z: 678.8 M++1) for 49b; m/z: 694.5 M++1) for 49c).

EXAMPLE 50

[0415]

133

[0416] To the 4″-alpha diazoketone product of Example 49, step a (8 mg) in anhydrous methanol (0.5 mL) at RT was added triethylamine (0.04 m L) followed by PhCO2Ag (2 mg) and the solution was aged for 1 h. The solution was filtered through a pad of Celite, concentrated to dryness under reduced pressure and the residue was washed with water, then 10% aqueous citric acid solution and then water again and then dried (Na2SO4). Pure product was obtained following PTLC on silica gel (1×500 m plate). The product (3 mg) thus obtained was characterized by proton NMR and mass spectrometry (m/z: 708.5 (M++1).

EXAMPLE 51

[0417] Following the general procedure of Example 50 but substituting n-propanol or allyl alcohol for methanol yielded the following ester derivatives. These compounds were characterized by proton NMR and mass spectrometry.

134

EntryRb GroupMass Spec51anPr736.4 (M+ + 1)51bCH2CH═CH2734.6 (M+ + 1)

EXAMPLE 52

[0418]

135

[0419] To 12.5 mg of the 5″-aldehyde 37a in methanol (0.1 mL) at RT was added water (0.01 mL), glacial acetic acid (0.02 mL) and tert-butyl isonitrile (0.02 mL). The solution was aged for 24 h at RT and then the volatiles were removed under reduced pressure. Pure product (1 mg), as a mixtures of 5″-stereoisomers was obtained following PTLC purification using EtOAc:hexanes (1/1) as eluant. The product thus obtained was characterized by proton NMR.

EXAMPLE 53

[0420]

136

[0421] To the 5″-aldehyde 37a (9 mg) was added glacial acetic acid (0.2 mL) followed by NaBH3CN (20 mg). After 30 min, saturated aqueous NaHCO3 was added followed by EtOAc extraction. Pure 5″-hydroxylmethyl product (5 mg) was obtained following PTLC purification using hexanes:acetone (6/4) as eluant. The product thus obtained was characterized by proton NMR. To the 5″-hydroxymethyl derivative (3 mg) thus obtained at RT was added acetic anhydride (0.1 mL) followed by (iPr)2NEt (0.1 ImL). After 30 min, the volatiles were removed under reduced pressure and pure 5″-acetoxymethyl derivative was obtained following PTLC chromatography on silica gel using hexanes:EtOAc (2:1) as eluant. The product thus obtained was characterized by proton NMR.

EXAMPLE 54

[0422]

137

[0423] To the 5″-acetoxymethyl product (12 mg) of Example 53 at RT in a one dram glass vial was added methanol (1 mL) followed by PhSO2Na (20 mg) and Pd(PPh3)4 (10 mg) and an argon atmosphere was established. The vial was tightly sealed and then heated to 65° C. for 2 h. The solution was cooled to RT and the volatiles were removed under reduced pressure. Pure 5″-sulfone product (4.6 mg) was obtained following PTLC purification on silica gel using hexanes:EtOAc (2/1) as eluant. The product thus obtained was characterized by proton NMR.

EXAMPLE 55

[0424] Following the general procedure of Example 54 and using an appropriate sulfenic acid salt, the following compounds were prepared and were characterized by proton NMR.

138

EntryAr Group55aPh(4-Br)55bPh(3,4-Cl)55cPh(3-OAc)

EXAMPLE 56

[0425]

139

[0426] Step A.

[0427] To the 4″-oxazoline product of Example 45d (100 mg) at RT in pyridine/DMF (5 mL, 1/1) add Et3SiOSO2CF3 (460 mg) and stir for 30 min. Dilute the solution with EtOAc, wash with saturated CuSO4(aq), water, brine and dry the organic layer (Na2SO4). Filter and concentrate the residue under reduced pressure. Pure 7,24-bis-OSiEt3 protected 52d may be obtained following flash chromatography on silica gel.

[0428] Step B.

[0429] Place the 7,24-bis-OSiEt3 protected 52d (17 mg) thus prepared in methylene chloride (0.3 mL) at 0° C. add BrCCl3 (3 μL) followed by DBU (3.6 μL) and age for 12 h. Pour the solution into saturated NaHCO3(aq), extract with CH2Cl2 and dry (Na2SO4). Filter the solution and then concentrate under reduced pressure. Pure 7,24-bis-OSiEt3 protected oxazole-containing product may be obtained following PTLC on silica gel. The 7,724-bis-OSiEt3 protecting groups may be removed as previously described to yield the desired deprotected title oxazolyl product.

EXAMPLE 57

[0430] Using the general strategy illustrated in Example 56 and the appropriate oxazoline precursors prepared as described in Example 44, the following oxazolyl compounds may be prepared. In addition, the allyl groups of 57h, 57i or 57j may be removed to liberate the corresponding carboxylic acids and the resultant carboxylic acids may be converted into the corresponding amide derivatives as previously described. The products thus obtained may be characterized by proton NMR and mass spectrometry.

140

EntryR1 GroupR2 Group57aHH57biPrH57cHiPr57dMeH57eHMe57fHC(O)NH-Me57gHPh57hCO2CH2CH═CH2H57iHCO2CH2CH═CH257jMeCO2CH2CH═CH257kHCO2H57lHC(O)NH257mMeC(O)NH257nHC(O)NH-Me57oC(O)NH-EtH57pHC(O)NH-iPr57qHC(O)NH-cPr57rHC(O)NH-tBu57sHC(O)NHCH2CH2F57tMeC(O)NHCH2CH2F57uHC(O)NHCH2CF357vHC(O)NHCH2CN57wHC(O)NHCH2C(Me)═CH257xHC(O)NHC(Me)2C≡CH57yHC(O)NHC(Me)2C(O)NMe257zHC(O)NHCH2Ph(4-OMe)57aaHC(O)NMe257bbHC(O)NEt257ccHC(O)N(Me)Et57ddHC(O)N(Me)iPr57eeHC(O)N(Et)iPr57ffHC(O)(N-1-piperidinyl)57ggHC(O)(N-1-pyrrolidinyl)57hhHC(O)(N-4-morpholinyl)

EXAMPLE 58

[0431] Using the general strategy illustrated in Example 56 and the appropriate thiazoline precursors (in lieu of the oxazoline precursors) prepared as described in Example 46, the following thiazolyl compounds may be prepared. In addition, the allyl groups of 58h, 58i or 58j may be removed to liberate the corresponding carboxylic acids and the resultant carboxylic acids may be converted into the corresponding amide derivatives as previously described. The products thus obtained may be characterized by proton NMR and mass spectrometry.

141

EntryR1 GroupR2 Group58aHH58biPrH58cHiPr58dMeH58eHMe58fHC(O)NH-Me58gHPh58hCO2CH2CH═CH2H58iHCO2CH2CH═CH258jMeCO2CH2CH═CH258kHCO2H58lHC(O)NH258mMeC(O)NH258nHC(O)NH-Me58oC(O)NH-EtH58pHC(O)NH-iPr58qHC(O)NH-cPr58rHC(O)NH-tBu58sHC(O)NHCH2CH2F58tMeC(O)NHCH2CH2F58uHC(O)NHCH2CF358vHC(O)NHCH2CN58wHC(O)NHCH2C(Me)═CH258xHC(O)NHC(Me)2C≡CH58yHC(O)NHC(Me)2C(O)NMe258zHC(O)NHCH2Ph(4-OMe)58aaHC(O)NMe258bbHC(O)NEt258ccHC(O)N(Me)Et58ddHC(O)N(Me)iPr58eeHC(O)N(Et)iPr58ffHC(O)(N-1-piperidinyl)58ggHC(O)(N-1-pyrrolidinyl)58hhHC(O)(N-4-morpholinyl)

C4 side-chain modified nodulisporic acid analogs

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