U.S. patent application number 15/457825 was filed with the patent office on 2017-06-29 for macrocyclic picolinamides compounds with fungicidal activity.
The applicant listed for this patent is DOW AGROSCIENCES LLC. Invention is credited to Timothy A. Boebel, Karla Bravo-Altamirano, Jessica Herrick, Fangzheng Li, Kevin G. Meyer, James M. Renga, Jeremy Wilmot, Chenglin Yao.
Application Number | 20170183324 15/457825 |
Document ID | / |
Family ID | 52740742 |
Filed Date | 2017-06-29 |
United States Patent
Application |
20170183324 |
Kind Code |
A1 |
Li; Fangzheng ; et
al. |
June 29, 2017 |
MACROCYCLIC PICOLINAMIDES COMPOUNDS WITH FUNGICIDAL ACTIVITY
Abstract
The invention relates to compounds of macrocyclic picolinamides
of Formula I suitable to control or prevent growth of fungi.
##STR00001##
Inventors: |
Li; Fangzheng; (Carmel,
IN) ; Meyer; Kevin G.; (Zionsville, IN) ;
Renga; James M.; (Spokane, WA) ; Yao; Chenglin;
(Westfield, IN) ; Wilmot; Jeremy; (Zionsville,
IN) ; Herrick; Jessica; (Zionsville, IN) ;
Bravo-Altamirano; Karla; (Carmel, IN) ; Boebel;
Timothy A.; (Indianapolis, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DOW AGROSCIENCES LLC |
Indianapolis |
IN |
US |
|
|
Family ID: |
52740742 |
Appl. No.: |
15/457825 |
Filed: |
March 13, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14500708 |
Sep 29, 2014 |
9629365 |
|
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15457825 |
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61885417 |
Oct 1, 2013 |
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61885409 |
Oct 1, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07F 7/1804 20130101;
A01N 43/40 20130101; C07D 405/14 20130101; C07D 493/04 20130101;
C07D 405/12 20130101; A01N 43/08 20130101; A01N 43/22 20130101;
A01N 43/90 20130101; A01N 53/00 20130101; C07D 313/00 20130101;
A01N 55/00 20130101; C07D 407/06 20130101; A01N 43/04 20130101;
A01N 47/18 20130101 |
International
Class: |
C07D 313/00 20060101
C07D313/00; A01N 43/40 20060101 A01N043/40; C07D 405/14 20060101
C07D405/14; A01N 43/08 20060101 A01N043/08; A01N 43/90 20060101
A01N043/90; A01N 47/18 20060101 A01N047/18; A01N 43/04 20060101
A01N043/04; C07D 407/06 20060101 C07D407/06; C07D 405/12 20060101
C07D405/12; C07D 493/04 20060101 C07D493/04 |
Claims
1. A compound of Formula I ##STR00067## wherein: X is C(O)R.sub.3,
or CH.sub.2OR.sub.3; Y is H, C(O)R.sub.3, R.sub.1 is chosen from H,
alkyl, alkenyl, aryl, --Si(R.sub.5).sub.3 or --C(O)R.sub.6, each
optionally substituted with 0, 1 or multiple R.sub.6; R.sub.2 is
chosen from CH.sub.2R.sub.8, aryl, alkyl, or alkenyl, each
optionally substituted with 0, 1, or multiple R.sub.6, R.sub.3 is
chosen from alkyl, alkoxy, benzyl, or benzyloxy, each optionally
substituted with 0, 1, or multiple R.sub.5; R.sub.5 is chosen from
alkyl, halo, or alkoxy; R.sub.6 is chosen from alkyl, alkenyl,
halo, haloalkyl, alkoxy, aryl, heteroaryl, heterocyclyl, thioalkyl,
or --C(O)R.sub.5; and R.sub.8 is chosen from H, alkyl, alkenyl,
aryl, thioalkyl, or heteroaryl, each optionally substituted with 0,
1, or multiple R.sub.6.
2. The compound according to claim 1, wherein X and Y are
independently chosen from H, C(O)R.sub.3, or CH.sub.2OR.sub.3.
3. The compound according to claim 2, wherein R.sub.1 is chosen
from H, alkyl, alkenyl, phenyl, --Si(R.sub.5).sub.3, or
--C(O)R.sub.6, each optionally substituted with 0, 1 or multiple
R.sub.6.
4. The compound according to claim 3, wherein R.sub.2 is chosen
from CH.sub.2R.sub.8, phenyl, alkyl, or alkenyl, each optionally
substituted with 0, 1, or multiple R.sub.6.
5. The compound according to claim 4, wherein R.sub.8 is chosen
from H, alkyl, alkenyl, phenyl, or heteroaryl, each optionally
substituted with 0, 1, or multiple R.sub.6.
6. A formulation for the control of a fungal pathogen, comprising:
at least one of the compounds of claim 1; and a phytologically
acceptable carrier material.
7. The formulation according to claim 6, wherein the formulation is
suitable for treating plants.
8. A formulation for the control of a fungal pathogen, comprising:
at least one of the compounds of claim 1; and at least one
agriculturally active ingredient selected from the group consisting
of: fungicides, insecticides, nematocides, miticides,
arthropodicides, bactericides and combinations thereof.
9. The formulation according to claim 8, wherein the formulation is
suitable for treating plants.
10. A formulation for the control of a fungal pathogen, comprising:
the formulation of claim 6; and at least one agriculturally active
ingredient selected from the group consisting of: fungicides,
insecticides, nematocides, miticides, arthropodicides, bactericides
and combinations thereof.
11. The formulation according to claim 10, wherein the formulation
is suitable for treating plants.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 14/500,708, titled Macrocyclic Picolinamide Compounds with
Fungicidal Activity, filed on Sep. 29, 2014, which claims the
benefit of U.S. Provisional Patent Application Ser. No. 61/885,409,
and U.S. Provisional Patent Application Ser. No. 61/885,417, each
filed Oct. 1, 2013, the disclosures of each of which is expressly
incorporated by reference herein.
BACKGROUND & SUMMARY
[0002] Fungicides are compounds, of natural or synthetic origin,
which act to protect and/or cure plants against damage caused by
agriculturally relevant fungi. Generally, no single fungicide is
useful in all situations. Consequently, research is ongoing to
produce fungicides that may have better performance, are easier to
use, and cost less.
[0003] The present disclosure relates to macrocyclic picolinamides
and their use as fungicides. The compounds of the present
disclosure may offer protection against ascomycetes,
basidiomycetes, deuteromycetes and oomycetes.
[0004] One embodiment of the present disclosure may include
compounds of Formula I:
##STR00002##
[0005] X is H, C(O)R.sub.3, or CH.sub.2OR.sub.3;
[0006] Y is H, C(O)R.sub.3, or Q;
[0007] Q is
##STR00003##
[0008] R.sub.1 is H, alkyl, alkenyl, aryl, --Si(R.sub.5).sub.3,
--C(O)R.sub.6, each substituted with 0, 1 or multiple R.sub.6;
[0009] R.sub.2 is CH.sub.2R.sub.8, aryl, alkyl, alkenyl, each
substituted with 0, 1, or multiple R.sub.6,
[0010] R.sub.3 is alkyl, alkoxy, benzyl, benzyloxy, each
substituted with 0, 1, or multiple R.sub.5;
[0011] R.sub.4 is H, --C(O)R.sub.7 or --CH.sub.2OC(O)R.sub.7;
[0012] R.sub.5 is alkyl, halo, alkoxy;
[0013] R.sub.6 is alkyl, alkenyl, halo, haloalkyl, alkoxy, aryl,
heteroaryl, heterocyclyl, thioalkyl, --C(O)R.sub.5;
[0014] R.sub.7 is alkyl or alkoxy, each substituted with 0, 1, or
multiple R.sub.6;
[0015] R.sub.8 is H, alkyl, alkenyl, aryl, heteroaryl, thioalkyl
each substituted with 0, 1, or multiple R.sub.6.
[0016] Another embodiment of the present disclosure may include a
fungicidal composition for the control or prevention of fungal
attack comprising the compounds described above and a
phytologically acceptable carrier material.
[0017] Yet another embodiment of the present disclosure may include
a method for the control or prevention of fungal attack on a plant,
the method including the steps of applying a fungicidally effective
amount of one or more of the compounds described above to at least
one of the fungus, the plant, and an area adjacent to the
plant.
[0018] It will be understood by the those skilled in the art that
the following terms may include generic "R"-groups within their
definitions, e.g., "the term alkoxy refers to an --OR substituent".
It is also understood that within the definitions for the following
terms, these "R" groups are included for illustration purposes and
should not be construed as limiting or being limited by
substitutions about Formula I.
[0019] The term "alkyl" refers to a branched, unbranched, or
saturated cyclic carbon chain, including, but not limited to,
methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl,
pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
the like.
[0020] The term "alkenyl" refers to a branched, unbranched or
cyclic carbon chain containing one or more double bonds including,
but not limited to, ethenyl, propenyl, butenyl, isopropenyl,
isobutenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the
like.
[0021] The term "alkynyl" refers to a branched or unbranched carbon
chain containing one or more triple bonds including, but not
limited to, propynyl, butynyl and the like.
[0022] The term "aryl" refers to any aromatic, mono- or bi-cyclic,
containing 0 heteroatoms.
[0023] The term "heterocycle" refers to any aromatic or
non-aromatic ring, mono- or bi-cyclic, containing one or more
heteroatoms
[0024] The term "alkoxy" refers to an --OR substituent.
[0025] The term "cyano" refers to a C.ident.N substituent.
[0026] The term "hydroxyl" refers to an --OH substituent.
[0027] The term "amino" refers to a --NH.sub.2 substituent.
[0028] The term "arylalkoxy" refers to --O(CH.sub.2).sub.nAr where
n is an integer selected from the list 1, 2, 3, 4, 5, or 6.
[0029] The term "haloalkoxy" refers to an --OR--X substituent,
wherein X is Cl, F, Br, or I, or any combination thereof.
[0030] The term "haloalkyl" refers to an alkyl, which is
substituted with Cl, F, I, or Br or any combination thereof.
[0031] The term "halogen" or "halo" refers to one or more halogen
atoms, defined as F, Cl, Br, and I.
[0032] The term "nitro" refers to a --NO.sub.2 substituent.
[0033] The term thioalkyl refers to an --SR substituent.
[0034] Throughout the disclosure, reference to the compounds of
Formula I is read as also including diastereomers, enantiomers, and
mixtures thereof. In another embodiment, Formula (I) is read as
also including salts or hydrates thereof. Exemplary salts include,
but are not limited to: hydrochloride, hydrobromide, and
hydroiodide.
[0035] It is also understood by those skilled in the art that
additional substitution is allowable, unless otherwise noted, as
long as the rules of chemical bonding and strain energy are
satisfied and the product still exhibits fungicidal activity.
[0036] Another embodiment of the present disclosure is a use of a
compound of Formula I, for protection of a plant against attack by
a phytopathogenic organism or the treatment of a plant infested by
a phytopathogenic organism, comprising the application of a
compound of Formula I, or a composition comprising the compound to
soil, a plant, a part of a plant, foliage, and/or roots.
[0037] Additionally, another embodiment of the present disclosure
is a composition useful for protecting a plant against attack by a
phytopathogenic organism and/or treatment of a plant infested by a
phytopathogenic organism comprising a compound of Formula I and a
phytologically acceptable carrier material.
DETAILED DESCRIPTION
[0038] The compounds of the present disclosure may be applied by
any of a variety of known techniques, either as the compounds or as
formulations comprising the compounds. For example, the compounds
may be applied to the roots or foliage of plants for the control of
various fungi, without damaging the commercial value of the plants.
The materials may be applied in the form of any of the generally
used formulation types, for example, as solutions, dusts, wettable
powders, flowable concentrate, or emulsifiable concentrates.
[0039] Preferably, the compounds of the present disclosure are
applied in the form of a formulation, comprising one or more of the
compounds of Formula I with a phytologically acceptable carrier.
Concentrated formulations may be dispersed in water, or other
liquids, for application, or formulations may be dust-like or
granular, which may then be applied without further treatment. The
formulations can be prepared according to procedures that are
conventional in the agricultural chemical art.
[0040] The present disclosure contemplates all vehicles by which
one or more of the compounds may be formulated for delivery and use
as a fungicide. Typically, formulations are applied as aqueous
suspensions or emulsions. Such suspensions or emulsions may be
produced from water-soluble, water-suspendible, or emulsifiable
formulations which are solids, usually known as wettable powders;
or liquids, usually known as emulsifiable concentrates, aqueous
suspensions, or suspension concentrates. As will be readily
appreciated, any material to which these compounds may be added may
be used, provided it yields the desired utility without significant
interference with the activity of these compounds as antifungal
agents.
[0041] Wettable powders, which may be compacted to form
water-dispersible granules, comprise an intimate mixture of one or
more of the compounds of Formula I, an inert carrier and
surfactants. The concentration of the compound in the wettable
powder may be from about 10 percent to about 90 percent by weight
based on the total weight of the wettable powder, more preferably
about 25 weight percent to about 75 weight percent. In the
preparation of wettable powder formulations, the compounds may be
compounded with any finely divided solid, such as prophyllite,
talc, chalk, gypsum, Fuller's earth, bentonite, attapulgite,
starch, casein, gluten, montmorillonite clays, diatomaceous earths,
purified silicates or the like. In such operations, the finely
divided carrier and surfactants are typically blended with the
compound(s) and milled.
[0042] Emulsifiable concentrates of the compounds of Formula I may
comprise a convenient concentration, such as from about 1 weight
percent to about 50 weight percent of the compound, in a suitable
liquid, based on the total weight of the concentrate. The compounds
may be dissolved in an inert carrier, which is either a
water-miscible solvent or a mixture of water-immiscible organic
solvents, and emulsifiers. The concentrates may be diluted with
water and oil to form spray mixtures in the form of oil-in-water
emulsions. Useful organic solvents include aromatics, especially
the high-boiling naphthalenic and olefinic portions of petroleum
such as heavy aromatic naphtha. Other organic solvents may also be
used, for example, terpenic solvents, including rosin derivatives,
aliphatic ketones, such as cyclohexanone, and complex alcohols,
such as 2-ethoxyethanol.
[0043] Emulsifiers which may be advantageously employed herein may
be readily determined by those skilled in the art and include
various nonionic, anionic, cationic and amphoteric emulsifiers, or
a blend of two or more emulsifiers. Examples of nonionic
emulsifiers useful in preparing the emulsifiable concentrates
include the polyalkylene glycol ethers and condensation products of
alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or
fatty acids with ethylene oxide, propylene oxides such as the
ethoxylated alkyl phenols and carboxylic esters solubilized with
the polyol or polyoxyalkylene. Cationic emulsifiers include
quaternary ammonium compounds and fatty amine salts. Anionic
emulsifiers include the oil-soluble salts (e.g., calcium) of
alkylaryl sulphonic acids, oil-soluble salts or sulfated polyglycol
ethers and appropriate salts of phosphated polyglycol ether.
[0044] Representative organic liquids which may be employed in
preparing the emulsifiable concentrates of the compounds of the
present disclosure are the aromatic liquids such as xylene, propyl
benzene fractions; or mixed naphthalene fractions, mineral oils,
substituted aromatic organic liquids such as dioctyl phthalate;
kerosene; dialkyl amides of various fatty acids, particularly the
dimethyl amides of fatty glycols and glycol derivatives such as the
n-butyl ether, ethyl ether or methyl ether of diethylene glycol,
the methyl ether of triethylene glycol, petroleum fractions or
hydrocarbons such as mineral oil, aromatic solvents, paraffinic
oils, and the like; vegetable oils such as soy bean oil, rape seed
oil, olive oil, castor oil, sunflower seed oil, coconut oil, corn
oil, cotton seed oil, linseed oil, palm oil, peanut oil, safflower
oil, sesame oil, tung oil and the like; esters of the above
vegetable oils; and the like. Mixtures of two or more organic
liquids may also be employed in the preparation of the emulsifiable
concentrate. Organic liquids include xylene, and propyl benzene
fractions, with xylene being most preferred in some cases.
Surface-active dispersing agents are typically employed in liquid
formulations and in an amount of from 0.1 to 20 percent by weight
based on the combined weight of the dispersing agent with one or
more of the compounds. The formulations can also contain other
compatible additives, for example, plant growth regulators and
other biologically active compounds used in agriculture.
[0045] Aqueous suspensions comprise suspensions of one or more
water-insoluble compounds of Formula I, dispersed in an aqueous
vehicle at a concentration in the range from about 1 to about 50
weight percent, based on the total weight of the aqueous
suspension. Suspensions are prepared by finely grinding one or more
of the compounds, and vigorously mixing the ground material into a
vehicle comprised of water and surfactants chosen from the same
types discussed above. Other components, such as inorganic salts
and synthetic or natural gums, may also be added to increase the
density and viscosity of the aqueous vehicle.
[0046] The compounds of Formula I can also be applied as granular
formulations, which are particularly useful for applications to the
soil. Granular formulations generally contain from about 0.5 to
about 10 weight percent, based on the total weight of the granular
formulation of the compound(s), dispersed in an inert carrier which
consists entirely or in large part of coarsely divided inert
material such as attapulgite, bentonite, diatomite, clay or a
similar inexpensive substance. Such formulations are usually
prepared by dissolving the compounds in a suitable solvent and
applying it to a granular carrier which has been preformed to the
appropriate particle size, in the range of from about 0.5 to about
3 mm. A suitable solvent is a solvent in which the compound is
substantially or completely soluble. Such formulations may also be
prepared by making a dough or paste of the carrier and the compound
and solvent, and crushing and drying to obtain the desired granular
particle.
[0047] Dusts containing the compounds of Formula I may be prepared
by intimately mixing one or more of the compounds in powdered form
with a suitable dusty agricultural carrier, such as, for example,
kaolin clay, ground volcanic rock, and the like. Dusts can suitably
contain from about 1 to about 10 weight percent of the compounds,
based on the total weight of the dust.
[0048] The formulations may additionally contain adjuvant
surfactants to enhance deposition, wetting and penetration of the
compounds onto the target crop and organism. These adjuvant
surfactants may optionally be employed as a component of the
formulation or as a tank mix. The amount of adjuvant surfactant
will typically vary from 0.01 to 1.0 percent by volume, based on a
spray-volume of water, preferably 0.05 to 0.5 volume percent.
Suitable adjuvant surfactants include, but are not limited to
ethoxylated nonyl phenols, ethoxylated synthetic or natural
alcohols, salts of the esters or sulphosuccinic acids, ethoxylated
organosilicones, ethoxylated fatty amines, blends of surfactants
with mineral or vegetable oils, crop oil concentrate (mineral oil
(85%)+emulsifiers (15%)); nonylphenol ethoxylate;
benzylcocoalkyldimethyl quaternary ammonium salt; blend of
petroleum hydrocarbon, alkyl esters, organic acid, and anionic
surfactant; C.sub.9-C.sub.11 alkylpolyglycoside; phosphated alcohol
ethoxylate; natural primary alcohol (C.sub.12-C.sub.16) ethoxylate;
di-sec-butylphenol EO-PO block copolymer; polysiloxane-methyl cap;
nonylphenol ethoxylate+urea ammonium nitrrate; emulsified
methylated seed oil; tridecyl alcohol (synthetic) ethoxylate (8EO);
tallow amine ethoxylate (15 EO); PEG(400) dioleate-99. The
formulations may also include oil-in-water emulsions such as those
disclosed in U.S. patent application Ser. No. 11/495,228, the
disclosure of which is expressly incorporated by reference
herein.
[0049] The formulations may optionally include combinations that
contain other pesticidal compounds. Such additional pesticidal
compounds may be fungicides, insecticides, herbicides, nematocides,
miticides, arthropodicides, bactericides or combinations thereof
that are compatible with the compounds of the present disclosure in
the medium selected for application, and not antagonistic to the
activity of the present compounds. Accordingly, in such
embodiments, the other pesticidal compound is employed as a
supplemental toxicant for the same or for a different pesticidal
use. The compounds of Formula I and the pesticidal compound in the
combination can generally be present in a weight ratio of from
1:100 to 100:1.
[0050] The compounds of the present disclosure may also be combined
with other fungicides to form fungicidal mixtures and synergistic
mixtures thereof. The fungicidal compounds of the present
disclosure are often applied in conjunction with one or more other
fungicides to control a wider variety of undesirable diseases. When
used in conjunction with other fungicide(s), the presently claimed
compounds may be formulated with the other fungicide(s), tank-mixed
with the other fungicide(s) or applied sequentially with the other
fungicide(s). Such other fungicides may include
2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol,
8-hydroxyquinoline sulfate, ametoctradin, amisulbrom, antimycin,
Ampelomyces quisqualis, azaconazole, azoxystrobin, Bacillus
subtilis, Bacillus subtilis strain QST713, benalaxyl, benomyl,
benthiavalicarb-isopropyl, benzylaminobenzene-sulfonate (BABS)
salt, bicarbonates, biphenyl, bismerthiazol, bitertanol, bixafen,
blasticidin-S, borax, Bordeaux mixture, boscalid, bromuconazole,
bupirimate, calcium polysulfide, captafol, captan, carbendazim,
carboxin, carpropamid, carvone, chlazafenone, chloroneb,
chlorothalonil, chlozolinate, Coniothyrium minitans, copper
hydroxide, copper octanoate, copper oxychloride, copper sulfate,
copper sulfate (tribasic), cuprous oxide, cyazofamid, cyflufenamid,
cymoxanil, cyproconazole, cyprodinil, dazomet, debacarb, diammonium
ethylenebis-(dithiocarbamate), dichlofluanid, dichlorophen,
diclocymet, diclomezine, dichloran, diethofencarb, difenoconazole,
difenzoquat ion, diflumetorim, dimethomorph, dimoxystrobin,
diniconazole, diniconazole-M, dinobuton, dinocap, diphenylamine,
dithianon, dodemorph, dodemorph acetate, dodine, dodine free base,
edifenphos, enestrobin, enestroburin, epoxiconazole, ethaboxam,
ethoxyquin, etridiazole, famoxadone, fenamidone, fenarimol,
fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil,
fenpropidin, fenpropimorph, fenpyrazamine, fentin, fentin acetate,
fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil,
flumorph, fluopicolide, fluopyram, fluoroimide, fluoxastrobin,
fluquinconazole, flusilazole, flusulfamide, flutianil, flutolanil,
flutriafol, fluxapyroxad, folpet, formaldehyde, fosetyl,
fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine,
guazatine acetates, GY-81, hexachlorobenzene, hexaconazole,
hymexazol, imazalil, imazalil sulfate, imibenconazole,
iminoctadine, iminoctadine triacetate, iminoctadine
tris(albesilate), iodocarb, ipconazole, ipfenpyrazolone,
iprobenfos, iprodione, iprovalicarb, isoprothiolane, isopyrazam,
isotianil, kasugamycin, kasugamycin hydrochloride hydrate,
kresoxim-methyl, laminarin, mancopper, mancozeb, mandipropamid,
maneb, mefenoxam, mepanipyrim, mepronil, meptyl-dinocap, mercuric
chloride, mercuric oxide, mercurous chloride, metalaxyl,
metalaxyl-M, metam, metam-ammonium, metam-potassium, metam-sodium,
metconazole, methasulfocarb, methyl iodide, methyl isothiocyanate,
metiram, metominostrobin, metrafenone, mildiomycin, myclobutanil,
nabam, nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic
acid (fatty acids), orysastrobin, oxadixyl, oxine-copper,
oxpoconazole fumarate, oxycarboxin, pefurazoate, penconazole,
pencycuron, penflufen, pentachlorophenol, pentachlorophenyl
laurate, penthiopyrad, phenylmercury acetate, phosphonic acid,
phthalide, picoxystrobin, polyoxin B, polyoxins, polyoxorim,
potassium bicarbonate, potassium hydroxyquinoline sulfate,
probenazole, prochloraz, procymidone, propamocarb, propamocarb
hydrochloride, propiconazole, propineb, proquinazid,
prothioconazole, pyraclostrobin, pyrametostrobin, pyraoxystrobin,
pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil,
pyriofenone, pyroquilon, quinoclamine, quinoxyfen, quintozene,
Reynoutria sachalinensis extract, sedaxane, silthiofam,
simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodium
pentachlorophenoxide, spiroxamine, sulfur, SYP-Z048, tar oils,
tebuconazole, tebufloquin, tecnazene, tetraconazole, thiabendazole,
thifluzamide, thiophanate-methyl, thiram, tiadinil,
tolclofos-methyl, tolylfluanid, triadimefon, triadimenol,
triazoxide, tricyclazole, tridemorph, trifloxystrobin,
triflumizole, triforine, triticonazole, validamycin, valifenalate,
valiphenal, vinclozolin, zineb, ziram, zoxamide, Candida oleophila,
Fusarium oxysporum, Gliocladium spp., Phlebiopsis gigantea,
Streptomyces griseoviridis, Trichoderma spp.,
(RS)-N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide,
1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone
hydrate, 1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane,
2-(2-heptadecyl-2-imidazolin-1-yl)ethanol,
2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide,
2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride,
2-methoxyethylmercury silicate,
3-(4-chlorophenyl)-5-methylrhodanine, 4-(2-nitroprop-1-enyl)phenyl
thiocyanateme, ampropylfos, anilazine, azithiram, barium
polysulfide, Bayer 32394, benodanil, benquinox, bentaluron,
benzamacril; benzamacril-isobutyl, benzamorf, binapacryl,
bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate,
cadmium calcium copper zinc chromate sulfate, carbamorph, CECA,
chlobenthiazone, chloraniformethan, chlorfenazole, chlorquinox,
climbazole, copper bis(3-phenylsalicylate), copper zinc chromate,
cufraneb, cupric hydrazinium sulfate, cuprobam, cyclafuramid,
cypendazole, cyprofuram, decafentin, dichlone, dichlozoline,
diclobutrazol, dimethirimol, dinocton, dinosulfon, dinoterbon,
dipyrithione, ditalimfos, dodicin, drazoxolon, EBP, ESBP,
etaconazole, etem, ethirim, fenaminosulf, fenapanil, fenitropan,
fluotrimazole, furcarbanil, furconazole, furconazole-cis,
furmecyclox, furophanate, glyodine, griseofulvin, halacrinate,
Hercules 3944, hexylthiofos, ICIA0858, isopamphos, isovaledione,
mebenil, mecarbinzid, metazoxolon, methfuroxam, methylmercury
dicyandiamide, metsulfovax, milneb, mucochloric anhydride,
myclozolin, N-3,5-dichlorophenyl-succinimide,
N-3-nitrophenylitaconimide, natamycin,
N-ethylmercurio-4-toluenesulfonanilide, nickel
bis(dimethyldithiocarbamate), OCH, phenylmercury
dimethyldithiocarbamate, phenylmercury nitrate, phosdiphen,
prothiocarb; prothiocarb hydrochloride, pyracarbolid, pyridinitril,
pyroxychlor, pyroxyfur, quinacetol; quinacetol sulfate, quinazamid,
quinconazole, rabenzazole, salicylanilide, SSF-109, sultropen,
tecoram, thiadifluor, thicyofen, thiochlorfenphim, thiophanate,
thioquinox, tioxymid, triamiphos, triarimol, triazbutil,
trichlamide, urbacid, zarilamid, and any combinations thereof.
[0051] Additionally, the compounds described herein may be combined
with other pesticides, including insecticides, nematocides,
miticides, arthropodicides, bactericides or combinations thereof
that are compatible with the compounds of the present disclosure in
the medium selected for application, and not antagonistic to the
activity of the present compounds to form pesticidal mixtures and
synergistic mixtures thereof. The fungicidal compounds of the
present disclosure may be applied in conjunction with one or more
other pesticides to control a wider variety of undesirable pests.
When used in conjunction with other pesticides, the presently
claimed compounds may be formulated with the other pesticide(s),
tank-mixed with the other pesticide(s) or applied sequentially with
the other pesticide(s). Typical insecticides include, but are not
limited to: 1,2-dichloropropane, abamectin, acephate, acetamiprid,
acethion, acetoprole, acrinathrin, acrylonitrile, alanycarb,
aldicarb, aldoxycarb, aldrin, allethrin, allosamidin, allyxycarb,
alpha-cypermethrin, alpha-ecdysone, alpha-endosulfan, amidithion,
aminocarb, amiton, amiton oxalate, amitraz, anabasine, athidathion,
azadirachtin, azamethiphos, azinphos-ethyl, azinphos-methyl,
azothoate, barium hexafluorosilicate, barthrin, bendiocarb,
benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin,
bifenthrin, bioallethrin, bioethanomethrin, biopermethrin,
bistrifluron, borax, boric acid, bromfenvinfos, bromocyclen,
bromo-DDT, bromophos, bromophos-ethyl, bufencarb, buprofezin,
butacarb, butathiofos, butocarboxim, butonate, butoxycarboxim,
cadusafos, calcium arsenate, calcium polysulfide, camphechlor,
carbanolate, carbaryl, carbofuran, carbon disulfide, carbon
tetrachloride, carbophenothion, carbosulfan, cartap, cartap
hydrochloride, chlorantraniliprole, chlorbicyclen, chlordane,
chlordecone, chlordimeform, chlordimeform hydrochloride,
chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron,
chlormephos, chloroform, chloropicrin, chlorphoxim, chlorprazophos,
chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, chromafenozide,
cinerin I, cinerin II, cinerins, cismethrin, cloethocarb,
closantel, clothianidin, copper acetoarsenite, copper arsenate,
copper naphthenate, copper oleate, coumaphos, coumithoate,
crotamiton, crotoxyphos, crufomate, cryolite, cyanofenphos,
cyanophos, cyanthoate, cyantraniliprole, cyclethrin, cycloprothrin,
cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyromazine,
cythioate, DDT, decarbofuran, deltamethrin, demephion, demephion-O,
demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl,
demeton-S, demeton-S-methyl, demeton-S-methylsulphon,
diafenthiuron, dialifos, diatomaceous earth, diazinon, dicapthon,
dichlofenthion, dichlorvos, dicresyl, dicrotophos, dicyclanil,
dieldrin, diflubenzuron, dilor, dimefluthrin, dimefox, dimetan,
dimethoate, dimethrin, dimethylvinphos, dimetilan, dinex,
dinex-diclexine, dinoprop, dinosam, dinotefuran, diofenolan,
dioxabenzofos, dioxacarb, dioxathion, disulfoton, dithicrofos,
d-limonene, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium,
doramectin, ecdysterone, emamectin, emamectin benzoate, EMPC,
empenthrin, endosulfan, endothion, endrin, EPN, epofenonane,
eprinomectin, esdepallethrine, esfenvalerate, etaphos,
ethiofencarb, ethion, ethiprole, ethoate-methyl, ethoprophos, ethyl
formate, ethyl-DDD, ethylene dibromide, ethylene dichloride,
ethylene oxide, etofenprox, etrimfos, EXD, famphur, fenamiphos,
fenazaflor, fenchlorphos, fenethacarb, fenfluthrin, fenitrothion,
fenobucarb, fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin,
fensulfothion, fenthion, fenthion-ethyl, fenvalerate, fipronil,
flonicamid, flubendiamide, flucofuron, flucycloxuron,
flucythrinate, flufenerim, flufenoxuron, flufenprox, fluvalinate,
fonofos, formetanate, formetanate hydrochloride, formothion,
formparanate, formparanate hydrochloride, fosmethilan, fospirate,
fosthietan, furathiocarb, furethrin, gamma-cyhalothrin, gamma-HCH,
halfenprox, halofenozide, HCH, HEOD, heptachlor, heptenophos,
heterophos, hexaflumuron, HHDN, hydramethylnon, hydrogen cyanide,
hydroprene, hyquincarb, imidacloprid, imiprothrin, indoxacarb,
iodomethane, IPSP, isazofos, isobenzan, isocarbophos, isodrin,
isofenphos, isofenphos-methyl, isoprocarb, isoprothiolane,
isothioate, isoxathion, ivermectin, jasmolin I, jasmolin II,
jodfenphos, juvenile hormone I, juvenile hormone II, juvenile
hormone III, kelevan, kinoprene, lambda-cyhalothrin, lead arsenate,
lepimectin, leptophos, lindane, lirimfos, lufenuron, lythidathion,
malathion, malonoben, mazidox, mecarbam, mecarphon, menazon,
mephosfolan, mercurous chloride, mesulfenfos, metaflumizone,
methacrifos, methamidophos, methidathion, methiocarb,
methocrotophos, methomyl, methoprene, methoxychlor,
methoxyfenozide, methyl bromide, methyl isothiocyanate,
methylchloroform, methylene chloride, metofluthrin, metolcarb,
metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin
oxime, mipafox, mirex, molosultap, monocrotophos, monomehypo,
monosultap, morphothion, moxidectin, naftalofos, naled,
naphthalene, nicotine, nifluridide, nitenpyram, nithiazine,
nitrilacarb, novaluron, noviflumuron, omethoate, oxamyl,
oxydemeton-methyl, oxydeprofos, oxydisulfoton,
para-dichlorobenzene, parathion, parathion-methyl, penfluron,
pentachlorophenol, permethrin, phenkapton, phenothrin, phenthoate,
phorate, phosalone, phosfolan, phosmet, phosnichlor, phosphamidon,
phosphine, phoxim, phoxim-methyl, pirimetaphos, pirimicarb,
pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite, potassium
thiocyanate, pp'-DDT, prallethrin, precocene I, precocene II,
precocene III, primidophos, profenofos, profluralin, promacyl,
promecarb, propaphos, propetamphos, propoxur, prothidathion,
prothiofos, prothoate, protrifenbute, pyraclofos, pyrafluprole,
pyrazophos, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins,
pyridaben, pyridalyl, pyridaphenthion, pyrifluquinazon,
pyrimidifen, pyrimitate, pyriprole, pyriproxyfen, quassia,
quinalphos, quinalphos-methyl, quinothion, rafoxanide, resmethrin,
rotenone, ryania, sabadilla, schradan, selamectin, silafluofen,
silica gel, sodium arsenite, sodium fluoride, sodium
hexafluorosilicate, sodium thiocyanate, sophamide, spinetoram,
spinosad, spiromesifen, spirotetramat, sulcofuron,
sulcofuron-sodium, sulfluramid, sulfotep, sulfoxaflor, sulfuryl
fluoride, sulprofos, tau-fluvalinate, tazimcarb, TDE, tebufenozide,
tebufenpyrad, tebupirimfos, teflubenzuron, tefluthrin, temephos,
TEPP, terallethrin, terbufos, tetrachloroethane, tetrachlorvinphos,
tetramethrin, tetramethylfluthrin, theta-cypermethrin, thiacloprid,
thiamethoxam, thicrofos, thiocarboxime, thiocyclam, thiocyclam
oxalate, thiodicarb, thiofanox, thiometon, thiosultap,
thiosultap-disodium, thiosultap-monosodium, thuringiensin,
tolfenpyrad, tralomethrin, transfluthrin, transpermethrin,
triarathene, triazamate, triazophos, trichlorfon,
trichlormetaphos-3, trichloronat, trifenofos, triflumuron,
trimethacarb, triprene, vamidothion, vaniliprole, XMC, xylylcarb,
zeta-cypermethrin, zolaprofos, and any combinations thereof.
[0052] Additionally, the compounds described herein may be combined
with herbicides that are compatible with the compounds of the
present disclosure in the medium selected for application, and not
antagonistic to the activity of the present compounds to form
pesticidal mixtures and synergistic mixtures thereof. The
fungicidal compounds of the present disclosure may be applied in
conjunction with one or more herbicides to control a wide variety
of undesirable plants. When used in conjunction with herbicides,
the presently claimed compounds may be formulated with the
herbicide(s), tank-mixed with the herbicide(s) or applied
sequentially with the herbicide(s). Typical herbicides include, but
are not limited to: 4-CPA; 4-CPB; 4-CPP; 2,4-D; 3,4-DA; 2,4-DB;
3,4-DB; 2,4-DEB; 2,4-DEP; 3,4-DP; 2,3,6-TBA; 2,4,5-T; 2,4,5-TB;
acetochlor, acifluorfen, aclonifen, acrolein, alachlor,
allidochlor, alloxydim, allyl alcohol, alorac, ametridione,
ametryn, amibuzin, amicarbazone, amidosulfuron,
aminocyclopyrachlor, aminopyralid, amiprofos-methyl, amitrole,
ammonium sulfamate, anilofos, anisuron, asulam, atraton, atrazine,
azafenidin, azimsulfuron, aziprotryne, barban, BCPC, beflubutamid,
benazolin, bencarbazone, benfluralin, benfuresate, bensulfuron,
bensulide, bentazone, benzadox, benzfendizone, benzipram,
benzobicyclon, benzofenap, benzofluor, benzoylprop, benzthiazuron,
bicyclopyrone, bifenox, bilanafos, bispyribac, borax, bromacil,
bromobonil, bromobutide, bromofenoxim, bromoxynil, brompyrazon,
butachlor, butafenacil, butamifos, butenachlor, buthidazole,
buthiuron, butralin, butroxydim, buturon, butylate, cacodylic acid,
cafenstrole, calcium chlorate, calcium cyanamide, cambendichlor,
carbasulam, carbetamide, carboxazole chlorprocarb, carfentrazone,
CDEA, CEPC, chlomethoxyfen, chloramben, chloranocryl, chlorazifop,
chlorazine, chlorbromuron, chlorbufam, chloreturon, chlorfenac,
chlorfenprop, chlorflurazole, chlorflurenol, chloridazon,
chlorimuron, chlornitrofen, chloropon, chlorotoluron, chloroxuron,
chloroxynil, chlorpropham, chlorsulfuron, chlorthal, chlorthiamid,
cinidon-ethyl, cinmethylin, cinosulfuron, cisanilide, clethodim,
cliodinate, clodinafop, clofop, clomazone, clomeprop, cloprop,
cloproxydim, clopyralid, cloransulam, CMA, copper sulfate, CPMF,
CPPC, credazine, cresol, cumyluron, cyanatryn, cyanazine, cycloate,
cyclosulfamuron, cycloxydim, cycluron, cyhalofop, cyperquat,
cyprazine, cyprazole, cypromid, daimuron, dalapon, dazomet,
delachlor, desmedipham, desmetryn, di-allate, dicamba, dichlobenil,
dichloralurea, dichlormate, dichlorprop, dichlorprop-P, diclofop,
diclosulam, diethamquat, diethatyl, difenopenten, difenoxuron,
difenzoquat, diflufenican, diflufenzopyr, dimefuron, dimepiperate,
dimethachlor, dimethametryn, dimethenamid, dimethenamid-P,
dimexano, dimidazon, dinitramine, dinofenate, dinoprop, dinosam,
dinoseb, dinoterb, diphenamid, dipropetryn, diquat, disul,
dithiopyr, diuron, DMPA, DNOC, DSMA, EBEP, eglinazine, endothal,
epronaz, EPTC, erbon, esprocarb, ethalfluralin, ethametsulfuron,
ethidimuron, ethiolate, ethofumesate, ethoxyfen, ethoxysulfuron,
etinofen, etnipromid, etobenzanid, EXD, fenasulam, fenoprop,
fenoxaprop, fenoxaprop-P, fenoxasulfone, fenteracol, fenthiaprop,
fentrazamide, fenuron, ferrous sulfate, flamprop, flamprop-M,
flazasulfuron, florasulam, fluazifop, fluazifop-P, fluazolate,
flucarbazone, flucetosulfuron, fluchloralin, flufenacet,
flufenican, flufenpyr, flumetsulam, flumezin, flumiclorac,
flumioxazin, flumipropyn, fluometuron, fluorodifen, fluoroglycofen,
fluoromidine, fluoronitrofen, fluothiuron, flupoxam, flupropacil,
flupropanate, flupyrsulfuron, fluridone, flurochloridone,
fluroxypyr, flurtamone, fluthiacet, fomesafen, foramsulfuron,
fosamine, furyloxyfen, glufosinate, glufosinate-P, glyphosate,
halosafen, halosulfuron, haloxydine, haloxyfop, haloxyfop-P,
hexachloroacetone, hexaflurate, hexazinone, imazamethabenz,
imazamox, imazapic, imazapyr, imazaquin, imazethapyr,
imazosulfuron, indanofan, indaziflam, iodobonil, iodomethane,
iodosulfuron, ioxynil, ipazine, ipfencarbazone, iprymidam,
isocarbamid, isocil, isomethiozin, isonoruron, isopolinate,
isopropalin, isoproturon, isouron, isoxaben, isoxachlortole,
isoxaflutole, isoxapyrifop, karbutilate, ketospiradox, lactofen,
lenacil, linuron, MAA, MAMA, MCPA, MCPA-thioethyl, MCPB, mecoprop,
mecoprop-P, medinoterb, mefenacet, mefluidide, mesoprazine,
mesosulfuron, mesotrione, metam, metamifop, metamitron,
metazachlor, metazosulfuron, metflurazon, methabenzthiazuron,
methalpropalin, methazole, methiobencarb, methiozolin, methiuron,
methometon, methoprotryne, methyl bromide, methyl isothiocyanate,
methyldymron, metobenzuron, metobromuron, metolachlor, metosulam,
metoxuron, metribuzin, metsulfuron, molinate, monalide, monisouron,
monochloroacetic acid, monolinuron, monuron, morfamquat, MSMA,
naproanilide, napropamide, naptalam, neburon, nicosulfuron,
nipyraclofen, nitralin, nitrofen, nitrofluorfen, norflurazon,
noruron, OCH, orbencarb, ortho-dichlorobenzene, orthosulfamuron,
oryzalin, oxadiargyl, oxadiazon, oxapyrazon, oxasulfuron,
oxaziclomefone, oxyfluorfen, parafluron, paraquat, pebulate,
pelargonic acid, pendimethalin, penoxsulam, pentachlorophenol,
pentanochlor, pentoxazone, perfluidone, pethoxamid, phenisopham,
phenmedipham, phenmedipham-ethyl, phenobenzuron, phenylmercury
acetate, picloram, picolinafen, pinoxaden, piperophos, potassium
arsenite, potassium azide, potassium cyanate, pretilachlor,
primisulfuron, procyazine, prodiamine, profluazol, profluralin,
profoxydim, proglinazine, prometon, prometryn, propachlor,
propanil, propaquizafop, propazine, propham, propisochlor,
propoxycarbazone, propyrisulfuron, propyzamide, prosulfalin,
prosulfocarb, prosulfuron, proxan, prynachlor, pydanon, pyraclonil,
pyraflufen, pyrasulfotole, pyrazolynate, pyrazosulfuron,
pyrazoxyfen, pyribenzoxim, pyributicarb, pyriclor, pyridafol,
pyridate, pyriftalid, pyriminobac, pyrimisulfan, pyrithiobac,
pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine,
quinonamid, quizalofop, quizalofop-P, rhodethanil, rimsulfuron,
saflufenacil, S-metolachlor, sebuthylazine, secbumeton, sethoxydim,
siduron, simazine, simeton, simetryn, SMA, sodium arsenite, sodium
azide, sodium chlorate, sulcotrione, sulfallate, sulfentrazone,
sulfometuron, sulfosulfuron, sulfuric acid, sulglycapin, swep, TCA,
tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim,
terbacil, terbucarb, terbuchlor, terbumeton, terbuthylazine,
terbutryn, tetrafluron, thenylchlor, thiazafluron, thiazopyr,
thidiazimin, thidiazuron, thiencarbazone-methyl, thifensulfuron,
thiobencarb, tiocarbazil, tioclorim, topramezone, tralkoxydim,
triafamone, tri-allate, triasulfuron, triaziflam, tribenuron,
tricamba, triclopyr, tridiphane, trietazine, trifloxysulfuron,
trifluralin, triflusulfuron, trifop, trifopsime,
trihydroxytriazine, trimeturon, tripropindan, tritac,
tritosulfuron, vernolate, and xylachlor.
[0053] Another embodiment of the present disclosure is a method for
the control or prevention of fungal attack. This method comprises
applying to the soil, plant, roots, foliage, or locus of the
fungus, or to a locus in which the infestation is to be prevented
(for example applying to cereal or grape plants), a fungicidally
effective amount of one or more of the compounds of Formula I. The
compounds are suitable for treatment of various plants at
fungicidal levels, while exhibiting low phytotoxicity. The
compounds may be useful both in a protectant and/or an eradicant
fashion.
[0054] The compounds have been found to have significant fungicidal
effect particularly for agricultural use. Many of the compounds are
particularly effective for use with agricultural crops and
horticultural plants.
[0055] It will be understood by those in the art that the efficacy
of the compound for the foregoing fungi establishes the general
utility of the compounds as fungicides.
[0056] The compounds have broad ranges of activity against fungal
pathogens. Exemplary pathogens may include, but are not limited to,
causing agent of wheat leaf blotch (Mycosphaerella graminicola;
impect stage: Septoria tritici), wheat brown rust (Puccinia
triticina), wheat stripe rust (Puccinia striiformis), scab of apple
(Venturia inaequalis), powdery mildew of grapevine (Uncinula
necator), barley scald (Rhynchosporium secalis), blast of rice
(Magnaporthe grisea), rust of soybean (Phakopsora pachyrhizi),
glume blotch of wheat (Leptosphaeria nodorum), powdery mildew of
wheat (Blumeria graminis f. sp. tritici), powdery mildew of barley
(Blumeria graminis f. sp. hordei), powdery mildew of cucurbits
(Erysiphe cichoracearum), anthracnose of cucurbits (Glomerella
lagenarium), leaf spot of beet (Cercospora beticola), early blight
of tomato (Alternaria solani), and spot blotch of barley
(Cochliobolus sativus). The exact amount of the active material to
be applied is dependent not only on the specific active material
being applied, but also on the particular action desired, the
fungal species to be controlled, and the stage of growth thereof,
as well as the part of the plant or other product to be contacted
with the compound. Thus, all the compounds, and formulations
containing the same, may not be equally effective at similar
concentrations or against the same fungal species.
[0057] The compounds are effective in use with plants in a
disease-inhibiting and phytologically acceptable amount. The term
"disease-inhibiting and phytologically acceptable amount" refers to
an amount of a compound that kills or inhibits the plant disease
for which control is desired, but is not significantly toxic to the
plant. This amount will generally be from about 0.1 to about 1000
ppm (parts per million), with 1 to 500 ppm being preferred. The
exact concentration of compound required varies with the fungal
disease to be controlled, the type of formulation employed, the
method of application, the particular plant species, climate
conditions, and the like. A suitable application rate is typically
in the range from about 0.10 to about 4 pounds/acre (about 0.01 to
0.45 grams per square meter, g/m.sup.2).
[0058] Any range or desired value given herein may be extended or
altered without losing the effects sought, as is apparent to the
skilled person for an understanding of the teachings herein.
[0059] The compounds of Formula I may be made using well-known
chemical procedures. Intermediates not specifically mentioned in
this disclosure are either commercially available, may be made by
routes disclosed in the chemical literature, or may be readily
synthesized from commercial starting materials utilizing standard
procedures.
GENERAL SCHEMES
[0060] The following schemes illustrate approaches to generating
picolinamide compounds of Formula (I). The following descriptions
and examples are provided for illustrative purposes and should not
be construed as limiting in terms of substituents or substitution
patterns.
[0061] Compounds of Formula 1.3, where R.sub.2 is as originally
defined, can be prepared by the method shown in Scheme 1, steps
a-b. Compounds of Formula 1.1, where R.sub.8 is as originally
defined and R.sub.9 is alkyl or alkoxy, can be prepared from
compounds of Formula 1.0, where R.sub.8 is as originally defined,
by treatment with an alkoxy borane such as pinacol borane in the
presence of a nickel catalyst, such as bis(cyclooctadiene)nickel(0)
(Ni(cod).sub.2), as described by Ely, R. J.; Morken, J. P. J. Am.
Chem. Soc. 2010, 132, 2534-2535, in a solvent such as toluene, and
at a temperature between 0 and 23.degree. C. Alternatively,
compounds of Formula 1.1, where R.sub.8 is as originally defined
and R.sub.9 is alkyl or alkoxy can be prepared as reported in
Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54,
1570. Compounds of Formula 1.3, where R.sub.2 is as originally
defined, can be prepared from compounds of Formula 1.1, where
R.sub.8 is as originally defined and R.sub.9 is as defined above by
treatment with a benzyl (Bn) or para-methoxybenzyl (PMB) protected
lactate-derived aldehyde such as compound 1.2, prepared as
described in Cheng and Brookhart Angew. Chem. Int. Ed. 2012, 51,
9422-9424 (see Takai, K.; Heathcock, C. H. J. Org. Chem. 1985, 50,
3247-3251 for characterization of Bn aldehyde and Terashima et al.
Bull. Chem. Soc. Jpn. 1989, 62, 3038-3040 for characterization of
PMB aldehyde).
##STR00004##
[0062] Compounds of Formulas 2.0, 2.1, and 2.2 can be prepared
using the methods shown in Scheme 2, steps a-c. Compounds of
Formula 2.0, where R.sub.1 is aryl and R.sub.2 is as originally
defined, can be prepared by the method shown in a, from compounds
of Formula 1.3, where R.sub.2 is as originally defined, by
treatment with a triarylbismuth reagent, prepared according to the
methods described by Hassan, A. et. al. Organometallics 1996, 15,
5613-5621, Moiseev, D. V. et al. J. Organomet. Chem. 2005, 690,
3652-3663, or Sinclair, P. J. et al. Bioorg. Med. Chem. Lett. 1995,
5, 1035-1038, in the presence of a copper catalyst, such as
diacetoxycopper, and an amine base, such as
N,N-dicyclohexyl-methylamine, in an aprotic solvent such as toluene
at 20-40.degree. C. Compounds of Formula 2.1, where R.sub.1 is
alkyl and R.sub.2 is as originally defined, can be prepared from
compounds of Formula 1.3, where R.sub.2 is as originally defined,
by treatment with a base, such as sodium hydride (NaH), in an
aprotic solvent such as tetrahydrofuran (THF), followed by
treatment with an alkyl halide or sulfonate, such as isobutyl
toluenesulfonate at 0-22.degree. C., as shown in b. Compounds of
Formula 2.2, where R.sub.1 is silyl and R.sub.2 is as originally
defined, can be prepared from compounds of Formula 1.3, where
R.sub.2 is as originally defined, by treatment with a silyl
trifluoromethanesulfonate, such as triisopropyl
trifluoromethanesulfonate, in the presence of a base, such as
2,6-lutidine, in a solvent such as dichloromethane
(CH.sub.2Cl.sub.2, DCM) at a reduced temperature, such as 0.degree.
C., as shown in c.
##STR00005##
[0063] Compounds of Formula 3.2, where R.sub.1 and R.sub.2 are as
originally defined and Y is tert-butoxy carbonyl (Boc), can be
prepared by the method shown in Scheme 3. Compounds of Formula 3.2
can be prepared from compounds of Formula 3.0, where R.sub.1 and
R.sub.2 are as originally defined, by treatment with an alkylborane
reagent, such as 9-borabicyclo[3.3.1]nonane (9-BBN), in a solvent
such as THF at 20-50.degree. C., followed by treatment with an
aqueous base, such as potassium phosphate (K.sub.3PO.sub.4), and a
bromoacrylate, such as a compound of Formula 3.1 where Y is Boc,
prepared as in Singh et al. Org. Lett. 2003, 17, 3155-3158, and a
catalyst, such as [1,1-bis(diphenylphosphino)ferrocene]
dichloropalladium(II) (PdCl.sub.2(dppf)) at 20-55.degree. C.
##STR00006##
[0064] Compounds of Formula 4.0, where R.sub.1 and R.sub.2 are as
originally defined and Y is Boc, can be prepared by the method
shown in Scheme 4. Compounds of Formula 4.0 can be prepared from
compounds of Formula 3.2, where R.sub.1 and R.sub.2 are as
originally defined and Y is Boc, by treatment with hydrogen (15-200
psi) in the presence of a catalyst such as
1,2-bis[(2S,5S)-2,5-diethyl-phospholano]benzene(1,5-cyclooctadiene)rhodiu-
m(I) trifluoromethanesulfonate ((S,S)-Et-DUPHOS-Rh) in an alcoholic
solvent such as methanol (MeOH).
##STR00007##
[0065] Compounds of Formula 5.3, where R.sub.1 and R.sub.2 are as
originally defined and Y is Boc can be prepared through a variety
of methods, as shown in Scheme 5, steps a-c. Compounds of Formula
5.0 and 5.1, where R.sub.1 and R.sub.2 are as originally defined
and Y is Boc, can be prepared from compounds of Formula 4.0, where
R.sub.1 and R.sub.2 are as originally defined, Y is Boc, and the
alcohol is protected as the PMB ether, by treatment with an
oxidant, such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in
an solvent mixture such as DCM and water (H.sub.2O), as shown in a.
Compounds of Formula 5.2, where R.sub.1 and R.sub.2 are as
originally defined and Y is Boc, can be prepared from compounds of
Formula 4.0, where R.sub.1 and R.sub.2 are as originally defined, Y
is Boc, and the alcohol is protected as the Bn ether, by
hydrogenolysis, i.e., treatment with hydrogen (H.sub.2; 15-500 psi)
in the presence of a catalyst, such as 5% or 10% w/w
palladium/carbon (Pd/C), in a solvent such as THF, as shown in b.
Compounds of Formula 5.3, where R.sub.1 and R.sub.2 are as
originally defined and Y is Boc, can be prepared from compounds of
Formulas 5.0 and 5.2, where R.sub.1, R.sub.2, and Y are as defined
above and the acid is protected as methyl (Me) ester, by treatment
with a base such as lithium hydroxide (LiOH) in a mixture of
H.sub.2O and a solvent such as THF, as shown in c. Compounds of
Formula 5.3, where R.sub.1 and R.sub.2 are as originally defined
and Y is Boc, can also be prepared from compounds of Formula 5.1,
where R.sub.1, R.sub.2, and Y are as defined above and the acid is
protected as the Bn ester, by hydrogenolysis or saponification, as
shown in b and c, respectively. Alternatively, compounds of Formula
5.3, where R.sub.1 and R.sub.2 are as originally defined and Y is
Boc, can be prepared directly from compounds of Formula 4.0, where
R.sub.1, R.sub.2, and Y are as defined above and the alcohol and
acid are protected as the Bn ether and Bn ester, respectively, by
the hydrogenolysis conditions described in b.
##STR00008##
[0066] Compounds of Formula 6.0, where R.sub.1 and R.sub.2 are as
originally defined and Y is Boc, can be prepared from compounds of
Formula 5.3, where R.sub.1 and R.sub.2 are as originally defined
and Y is Boc, by the addition of a solution of compounds of Formula
5.3 in a halogenated solvent such as DCM or an aromatic solvent
such as toluene to a mixture of a base, such as DMAP, and an
anhydride, such as 2-methyl-6-nitrobenzoic anhydride (MNBA), in
either a halogenated solvent such as DCM or an aromatic solvent
such as toluene over a period of 4-12 hours, as shown in Scheme
6.
##STR00009##
[0067] Compounds of Formula 7.1 can be prepared according to the
methods shown in Scheme 7, steps a-b. Compounds of Formula 7.0,
where R.sub.1 is triisopropylsilyl (TIPS), R.sub.2 is as originally
defined, Y is Boc, and X is methoxymethyl (MOM) can be prepared
from compounds of Formula 6.0, where R.sub.1, R.sub.2, and Y are as
defined above, by treatment with an aldehyde, such as
paraformaldehyde, in a solvent such as DCM in the presence of a
silyl chloride, such as trimethylsilyl chloride, at a reduced
temperature such as 0.degree. C., followed by addition of a
solution of a base such as triethylamine, in an alcoholic solvent
such as methanol, as shown in a. Compounds of Formula 7.1, where
R.sub.1 is H and R.sub.2, X, and Y are as defined above, can be
prepared from compounds of Formula 7.0, where R.sub.1, R.sub.2, X,
and Y are as defined above, by treatment with a fluoride salt such
as tetra-N-butylammonium fluoride (TBAF), in a solvent such as THF,
as shown in b.
##STR00010##
[0068] Compounds of Formulas 8.0-8.8 can be prepared through the
methods shown in Scheme 8, steps a-g. Compounds of Formula 8.0,
where R.sub.1 is allyloxy, R.sub.2 is as originally defined, X is
MOM, and Y is Boc, can be prepared from compounds of Formula 7.1,
where R.sub.1 is H, R.sub.2, X, and Y are as defined above, by
treatment with an allyl carbonate, such as a tert-butyl (allyl)
carbonate or a symmetric (allyl) carbonate, such as bis
(2-methylallyl) carbonate, in the presence of a palladium catalyst
and ligand, for example tris(dibenzylideneacetone)-dipalladium(0)
(Pd.sub.2(dba).sub.3) and 1,1'-bis(diphenylphosphino)ferrocene
(dppf), in a polar aprotic solvent like tetrahydrofuran (THF) at an
elevated temperature such as 60.degree. C., as shown in a.
Compounds of Formula 8.1, where R.sub.1 is alkyl, R.sub.2 is as
originally defined, X is MOM, and Y is Boc, can be prepared from
compounds of Formula 8.0, where R.sub.1, R.sub.2, X, and Y are
defined as above, by treatment with H.sub.2 (15-200 psi) in the
presence of a catalyst, such as 5% or 10% w/w Pd/C in a solvent
such as EtOAc, as shown in b. Compounds of Formula 8.2, where
R.sub.1 is an aliphatic aldehyde and R.sub.2, X, and Y are as
defined above, can be prepared from compounds of Formula 8.0, where
R.sub.1, R.sub.2, X, and Y are as defined above, by treatment with
ozone in the presence of a base, such as sodium bicarbonate
(NaHCO.sub.3) in a mixture of a halogenated and an alcoholic
solvent, such as DCM and MeOH, as shown in c. Compounds of Formula
8.3, where R.sub.1 is fluorinated alkyl and R.sub.2, X, and Y are
as defined above, can be prepared from compounds of Formula 8.2,
where R.sub.1, R.sub.2, X, and Y are as defined above, by treatment
with a fluorinating reagent, such as bis(2-methoxyethyl)aminosulfur
trifluoride (Deoxo-Fluor.RTM.) in a solvent such as DCM, as shown
in d.
[0069] Compounds of Formula 8.4, where R.sub.1 is an vinylogous
ester, R.sub.2 is as originally defined, X is MOM, and Y is Boc,
can be prepared from compounds of Formula 7.1, where R.sub.1 is H,
R.sub.2, X, and Y are as defined above, by treating solutions of
the compounds of Formula 7.1 in a solvent such as DCM with a
catalytic amount of 1,4-diazabicyclo[2.2.2]octane (DABCO), followed
by addition of a conjugated alkyne, such as but-3-yn-2-one at a
reduced temperature, for example 0.degree. C., as shown in e.
Compounds of Formula 8.5, where R.sub.1 is an aliphatic ketone,
R.sub.2 is as originally defined, X is MOM, and Y is Boc, can be
prepared from compounds of Formula 8.4, where R.sub.1, R.sub.2, X,
and Y are as defined above, by the reductive conditions described
in b. Compounds of Formula 8.6, where R.sub.1 is fluorinated alkyl,
R.sub.2 is as originally defined, X is MOM, and Y is Boc, can be
prepared from compounds of Formula 8.5, where R.sub.1, R.sub.2, X,
and Y are defined as above, by the fluorination conditions
described in d.
[0070] Compounds of Formula 8.7, where R.sub.1 is acyl, R.sub.2 is
as originally defined, X is MOM, and Y is Boc, can be prepared from
compounds of Formula 7.1, where R.sub.1 is H, R.sub.2 is as
originally defined, X is MOM, and Y is Boc, by treatment with a
base such as triethylamine and a catalyst such as (DMAP) in a
solvent such as DCM, followed by treatment with an acid chloride,
as shown in f.
[0071] Compounds of Formula 8.8, where R.sub.1 is alkyl, R.sub.2 is
as originally defined, X is MOM, and Y is Boc, can be prepared from
compounds of Formula 7.1, where R.sub.1 is H, R.sub.2 is as
originally defined, X is MOM, and Y is Boc, by treatment with a
base, such as 1,8-bis(dimethylamino)naphthalene (Proton
Sponge.RTM.) and an alkylating agent, such as trimethyloxonium
tetrafluoroborate, in a solvent such as DCM, as shown in g.
##STR00011##
[0072] Compounds of Formula 9.1, where R.sub.1 is as originally
defined and Y is Boc, can be prepared by the method shown in Scheme
9. Compounds of Formula 9.1 can be prepared from compounds of
Formula 9.0, where R.sub.1 is as originally defined and Y is Boc,
by treatment with a fluoride salt, such as TBAF, in a solvent such
as THF.
##STR00012##
[0073] Compounds of Formulas 10.0-10.7 can be prepared through the
methods shown in Scheme 10, steps a-h. Compounds of Formula 10.0,
where R.sub.1 is as originally defined and Y is Boc, can be
prepared from compounds of Formula 9.1, where R.sub.1 is as
originally defined and Y is Boc, by treatment with a triarylbismuth
reagent, prepared according to the methods described by Hassan, A.
et. al. Organometallics 1996, 15, 5613-5621, Moiseev, D. V. et al.
J. Organomet. Chem. 2005, 690, 3652-3663, or Sinclair, P. J. et al.
Bioorg. Med. Chem. Lett. 1995, 5, 1035-1038, in the presence of a
copper catalyst, such as diacetoxycopper, and an amine base, such
as N,N-dicyclohexyl-methylamine, in an aprotic solvent such as
toluene at an elevated temperature of about 50.degree. C., as shown
in a. Compounds of Formula 10.1, where R.sub.1 is as originally
defined and Y is Boc, can be prepared from compounds of Formula
9.1, where R.sub.1 and Y are as defined above, by treatment with a
base such as Proton Sponge.RTM. followed by an alkylating agent,
such as trimethyloxonium tetrafluoroborate, in a solvent such as
DCM, as shown in b. Compounds of Formula 10.2, where R.sub.1 is as
originally defined and Y is Boc, can be prepared from compounds of
Formula 9.1, where R.sub.1 and Y are as defined above, by treatment
with an oxidizing reagent, such as Dess-Martin periodinane, in a
solvent such as DCM, as shown in c. Compounds of Formula 10.3,
where R.sub.1 is as originally defined and Y is Boc, can be
prepared from compounds of Formula 10.2, where R.sub.1 and Y are as
defined above, by treatment with a fluorinating reagent, such as
Deoxo-Fluor.RTM., in a solvent such as DCM, as shown in d.
Compounds of Formula 10.4, where R.sub.1 is as originally defined
and Y is Boc, can be prepared from compounds of Formula 9.1, where
R.sub.1 and Y are as defined above, by treatment with a
fluorinating reagent, such as Deoxo-Fluor.RTM., in a solvent such
as DCM or through halogenation conditions, such as treatment with
perhalomethanes in the presence of triphenylphosphine in DCM at a
reduced temperature, such as 0.degree. C., as shown in e. Compounds
of Formula 10.5, where R.sub.1 is as originally defined and Y is
Boc, can be prepared from compounds of Formula 10.4, where R.sub.1
and Y are as defined above, by treatment with a reducing agent such
as tributyltin hydride in the presence of a radical initiator, such
as azobisisobutyronitrile (AIBN), in a solvent such as toluene at
an elevated temperature, for example 80.degree. C., as shown in f
Compounds of Formula 10.6, where R.sub.1 is as originally defined
and Y is Boc, can be prepared from compounds of Formula 9.1, where
R.sub.1 and Y are as defined above, by treatment with a
selenocyanate and a phosphine, such as tributylphosphine, in a
solvent such as THF at a temperature from about 0.degree. C. to
about 23.degree. C., as shown in g. Compounds of Formula 10.7,
where R.sub.1 is as originally defined and Y is Boc, can be
prepared from compounds of Formula 10.6, where R.sub.1 and Y are as
defined above, by treatment with an oxidizing agent, such as
hydrogen peroxide, in a solvent such as THF, as shown in h.
##STR00013##
[0074] Compounds of Formulas11.4 and 11.5 can be prepared through
the methods shown in Scheme 11, steps a-d. Compounds of Formula
11.4, where R.sub.1 and R.sub.2 are as originally defined, can be
prepared from a variety of precursors, including, but not limited
to, compounds of Formulas 11.0, 11.1, 11.2, and 11.3, where R.sub.1
and R.sub.2 are as originally defined, and Y is Boc (11.0), X and Y
are Boc (11.1), X is MOM and Y is Boc (11.2), and Y is CBz (11.3)
respectively. Treating compounds of Formulas 11.0-11.2 with an
acid, such as a 4.0 M hydrogen chloride (HCl) solution in dioxane,
in a solvent such as DCM affords the hydrochloride salt of
compounds of Formula 11.4, which may be neutralized in situ in step
d or neutralized prior to use to give the free amine, as shown in
a. Additionally, compounds of Formula 11.4, where R.sub.1 and
R.sub.2 are as originally defined, can be prepared from compounds
of Formulas 11.0 and 11.1, where R.sub.1, R.sub.2, X, and Y are as
originally defined, by treatment with trimethylsilyl
trifluoromethanesulfonate in the presence of a base, such
2,6-lutidine, in an aprotic solvent such as DCM, followed by
treatment with a protic solvent such as MeOH, as shown in b.
Alternatively, compounds of Formula 11.4, where R.sub.1 and R.sub.2
are as originally defined, can be prepared from compounds of
Formula 11.3, where R.sub.1 and R.sub.2 are as originally defined
and Y is CBz, by treatment with hydrogen in the presence of a
catalyst, such as 5% or 10% w/w Pd/C, in a solvent such as EtOAc,
as shown in c. Compounds of Formula 11.5, where R.sub.1 and R.sub.2
are as originally defined, can be prepared from compounds of
Formula 11.4, where R.sub.1 and R.sub.2 are as originally defined,
by treatment with 3-hydroxy-4-methoxypicolinic acid in the presence
of an amine base, such as 4-methylmorpholine or triethylamine
(TEA), and a peptide coupling reagent, such as
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) or
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
(PyBOP), in an aprotic solvent such as DCM, as shown in d.
##STR00014##
[0075] Compounds of Formula 12.0, where R.sub.1, R.sub.2 and
R.sub.4 are as originally defined, can be prepared by the method
shown in Scheme 12. Compounds of Formula 12.0 can be prepared from
compounds of Formula 11.5, where R.sub.1 and R.sub.2 are as
originally defined, by treatment with the appropriate alkyl halide
with or without a reagent such as sodium iodide (NaI) and an alkali
carbonate base such as sodium carbonate (Na.sub.2CO.sub.3) or
potassium carbonate (K.sub.2CO.sub.3) in a solvent such as acetone
or by treatment with an acyl halide in the presence of an amine
base, such as pyridine, triethylamine, DMAP, or mixtures thereof in
an aprotic solvent such as DCM, as shown in a.
##STR00015##
[0076] Compounds of Formula 13.0, where R.sub.1 and R.sub.4 are as
originally defined and R.sub.2 is cyclohexyl optionally substituted
with one or multiple R.sub.10, wherein R.sub.10 is halo or alkyl,
can be prepared by the method shown in Scheme 13. Compounds of
Formula 13.0 can be prepared from compounds of Formula 12.0, where
R.sub.1 and R.sub.4 are as originally defined and R.sub.2 is aryl
optionally substituted with one or multiple R.sub.10, wherein
R.sub.10 is halo or alkyl, by treatment with hydrogen gas in the
presence of a catalyst, such as rhodium on carbon (Rh/C), in a
solvent such as THF at an elevated temperature such as 70.degree.
C., as shown in a.
##STR00016##
[0077] The following examples are presented to illustrate the
various aspects of the compounds of the present disclosure and
should not be construed as limitations to the claims.
EXAMPLES
Example 1
Step 1: Preparation of
(2S,3R,4S)-2-((4-methoxybenzyl)oxy)-7-methyl-4-vinyloctan-3-ol
##STR00017##
[0079] Under a strict nitrogen atmosphere an oven-dried
round-bottomed flask with a magnetic stir bar was charged with
bis(1,5-cyclooctadiene)nickel(0) (0.297 grams (g), 1.080 millimole
(mmol)) and tricyclohexylphosphine (0.379 g, 1.35 mmol). Anhydrous
toluene (40 milliliters (mL)) followed by
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.34 ml, 57.5 mmol) and
(E)-6-methylhepta-1,3-diene (11.9 g, 54.0 mmol), prepared according
to the procedure disclosed in Wang, Y.; West, F. G. Synthesis 2002,
99-103, were added to the flask and the reaction was allowed to
stir at room temperature for 20 hours (h), as described in the
diene hydroboration conditions reported in Ely, R. J.; Morken, J.
P. J. Am. Chem. Soc. 2010, 132, 2534-2535. To the mixture was added
a solution of (S)-2-((4-methoxybenzyl)oxy)propanal (10.49 g, 54.0
mmol) in anhydrous toluene (5 mL) at -20.degree. C. The reaction
mixture was slowly warmed to room temperature and stirred at room
temperature for 40 h, then quenched with MeOH and stirred for an
additional 2 h. The crude mixture was concentrated under reduced
pressure and purified by column chromatography on silica gel
(SiO.sub.2; gradient, hexanes/ethyl acetate) to yield the title
compound as a colorless oil (11.3 g, 69%): IR (neat) 3467, 2925,
2868, 1513, 1247 cm.sup.-1; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.27-7.22 (m, 2H), 6.90-6.85 (m, 2H), 5.51-5.38 (m, 1H),
5.08-4.96 (m, 2H), 4.52-4.40 (m, 2H), 3.80 (s, 3H), 3.66 (ddd,
J=9.2, 3.1, 2.1 Hz, 1H), 3.59-3.49 (m, 1H), 2.26-2.20 (m, 1H),
2.04-1.95 (m, 1H), 1.90-1.80 (m, 1H), 1.59-1.43 (m, 1H), 1.29-1.14
(m, 2H), 1.13 (d, J=6.2 Hz, 3H), 1.10-0.99 (m, 1H), 0.87 (d, J=6.4
Hz, 3H), 0.86 (d, J=6.4 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3)
.delta. 159.19, 138.56, 130.59, 129.22, 116.59, 113.82, 75.89,
74.46, 70.11, 55.29, 47.18, 36.05, 28.57, 28.23, 22.98, 22.42,
12.17; ESIMS m/z 329.2 ([M+Na].sup.+).
Example 1
Step 2a: Preparation of
1-methoxy-4-((((2S,3R,4S)-7-methyl-3-phenoxy-4-vinyloctan-2-yl)oxy)methyl-
)benzene
##STR00018##
[0081] To a solution of
(2S,3R,4S)-2-((4-methoxybenzyl)oxy)-7-methyl-4-vinyloctan-3-ol (2.0
g, 6.53 mmol) in anhydrous toluene (30 mL) was added
bis(acetato-O)triphenylbismuth(V) (5.47 g, 9.79 mmol),
N-cyclohexyl-N-methylcyclohexanamine (2.10 mL, 9.79 mmol) and
anhydrous diacetoxycopper (0.237 g, 1.305 mmol) at room
temperature. The reaction was heated at 43.degree. C. for 5 h,
filtered through a Celite.RTM. pad, concentrated and purified by
column chromatography on SiO.sub.2 (gradient, hexanes/ethyl
acetate) to furnish the title product as a colorless oil (2.30 g,
92%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.27-7.21 (m, 2H),
7.19-7.13 (m, 2H), 7.03-6.97 (m, 2H), 6.94-6.88 (m, 1H), 6.86-6.81
(m, 2H), 5.64-5.51 (m, 1H), 5.07-5.00 (m, 2H), 4.54-4.33 (m, 2H),
4.26 (dd, J=6.5, 4.7 Hz, 1H), 3.79 (s, 3H), 3.79-3.72 (m, 1H),
2.44-2.31 (m, 1H), 1.74-1.61 (m, 1H), 1.52-1.38 (m, 1H), 1.34-1.25
(m, 1H), 1.23 (d, J=6.3 Hz, 3H), 1.22-1.11 (m, 1H), 1.09-0.98 (m,
1H), 0.84 (d, J=6.8 Hz, 3H), 0.82 (d, J=6.8 Hz, 3H); .sup.13C NMR
(101 MHz, CDCl.sub.3) .delta. 160.05, 159.04, 139.48, 129.42,
129.32, 129.19, 121.56, 120.67, 116.46, 113.67, 83.41, 75.26,
70.16, 55.26, 47.15, 36.47, 28.05, 27.64, 22.96, 22.34, 14.83;
ESIMS m/z 405.3 ([M+Na].sup.+).
Example 1
Step 2b: Preparation of
1-((((2S,3R,4S)-3-(cyclopropylmethoxy)-7-methyl-4-vinyloctan-2-yl)oxy)met-
hyl)-4-methoxybenzene
##STR00019##
[0083] A solution of
(2S,3R,4S)-2-((4-methoxybenzyl)oxy)-7-methyl-4-vinyloctan-3-ol (2.0
g, 6.53 mmol) in anhydrous DMF (12 mL) was added at room
temperature to a solution of NaH (NaH; 0.326 g, 8.16 mmol, 60%
dispersion in mineral oil) in anhydrous DMF (12 ml). The reaction
was stirred for 15 minutes (min) at room temperature, treated with
(bromomethyl)cyclopropane (0.823 ml, 8.48 mmol) at room
temperature, and then was heated to 40.degree. C. for and stirred
for 6 h. The reaction was cooled to room temperature and additional
NaH (0.131 g, 3.27 mmol) and (bromomethyl)cyclopropane (0.317 mL,
3.27 mmol) were added, and the reaction was heated at 45.degree. C.
for 4 h. The reaction was again cooled to room temperature and a
third batch of NaH (0.131 g, 3.27 mmol) followed by
(bromomethyl)cyclopropane (0.317 mL, 3.27 mmol) was added and the
reaction was heated at 45.degree. C. for 2 h. The reaction mixture
was quenched with saturated aqueous ammonium chloride (NH.sub.4Cl)
and the phases were separated. The aqueous phase was extracted with
diethyl ether (Et.sub.2O), and the combined organic phases were
washed with brine, dried over magnesium sulfate (MgSO.sub.4),
concentrated, and purified by column chromatography on SiO.sub.2
(gradient, hexanes/ethyl acetate) to furnish the title product as a
colorless oil (1.94 g, 82%): IR (neat) 2953, 2868, 1613, 1513,
1247, 1084 cm.sup.-1; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.25-7.20 (m, 2H), 6.89-6.81 (m, 2H), 5.52 (dt, J=17.0, 10.0 Hz,
1H), 5.03-4.92 (m, 2H), 4.52-4.32 (m, 2H), 3.78 (s, 3H), 3.65-3.56
(m, 2H), 3.34 (dd, J=10.0, 6.9 Hz, 1H), 3.28-3.22 (m, 1H), 2.09
(tdd, J=10.1, 7.7, 3.1 Hz, 1H), 1.81-1.67 (m, 1H), 1.55-1.42 (m,
1H), 1.28-1.13 (m, 2H), 1.19 (d, J=6.3 Hz, 3H), 1.13-0.95 (m, 2H),
0.87 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.56-0.45 (m, 2H),
0.25-0.14 (m, 2H); ESIMS m/z 383.4 ([M+Na].sup.+).
Example 1
Step 2b: Preparation of
1-((((2S,3R,4S)-3-isobutoxy-7-methyl-4-vinyloctan-2-yl)oxy)methyl)-4-meth-
oxybenzene
##STR00020##
[0085] A solution of
(2S,3R,4S)-2-((4-methoxybenzyl)oxy)-7-methyl-4-vinyloctan-3-ol (2.0
g, 6.53 mmol) in anhydrous DMF (15 mL) was added at room
temperature to a solution of NaH (0.326 g, 8.16 mmol, 60%
dispersion in mineral oil) in anhydrous DMF (6.0 mL). The reaction
was stirred for 15 min at room temperature, then isobutyl
4-methylbenzenesulfonate (1.66 mL, 8.16 mmol) was added at room
temperature and the reaction was heated at 50.degree. C. and
stirred for for 1 h. The reaction was cooled down to room
temperature and NaH (0.261 g, 6.53 mmol) followed by isobutyl
4-methylbenzenesulfonate (1.33 mL, 6.53 mmol) were added and
heating continued for 2 h at 50.degree. C., after which the
reaction was again cooled down to room temperature and a third
batch of NaH (0.131 g, 3.27 mmol) and isobutyl
4-methylbenzenesulfonate (0.67 mL, 3.27 mmol) were added and the
reaction was heated at 50.degree. C. for 7 h. The reaction mixture
was quenched with saturated NH.sub.4Cl and the phases were
separated. The aqueous phase was extracted with Et.sub.2O, and the
combined organic phases were washed with brine, dried over
MgSO.sub.4, concentrated, and purified by column chromatography on
SiO.sub.2 (gradient, hexanes/ethyl acetate) to furnish the title
product as a colorless oil (2.05 g, 87%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.29-7.21 (m, 2H), 6.90-6.83 (m, 2H), 5.61-5.49
(m, 1H), 5.04-4.89 (m, 2H), 4.53-4.33 (m, 2H), 3.80 (s, 3H),
3.64-3.51 (m, 2H), 3.28-3.16 (m, 2H), 2.15-2.02 (m, 1H), 1.90-1.77
(m, 1H), 1.76-1.60 (m, 1H), 1.54-1.41 (m, 1H), 1.28-1.11 (m, 2H),
1.17 (d, J=6.3 Hz, 3H), 1.08-0.96 (m, 1H), 0.95-0.88 (m, 6H), 0.86
(d, J=6.4 Hz, 3H), 0.85 (d, J=6.4 Hz, 3H); .sup.13C NMR (101 MHz,
CDCl.sub.3) .delta. 158.97, 140.43, 131.09, 129.06, 115.66, 113.67,
84.26, 79.58, 76.41, 70.05, 55.26, 47.38, 36.46, 29.13, 28.21,
27.85, 22.91, 22.47, 19.66, 19.55, 14.25; ESIMS m/z 385.4
([M+Na].sup.+).
Example 1
Step 2b: Preparation of
1-((2S,3R,4S)-3-(benzyloxy)-4-((4-methoxy-benzyl)oxy)-2-vinylpentyl)-2,4--
difluorobenzene
##STR00021##
[0087] An oven-dried 100 mL Schlenk flask was cooled under nitrogen
and was then charged with NaH (60% dispersion in mineral oil, 1.24
g, 31.0 mmol) and anhydrous DMF (50 mL). A solution of
(2S,3R,4S)-4-(2,4-difluorobenzyl)-2-((4-methoxybenzyl)oxy)hex-5-en-3-ol
(8.06 g, 22.2 mmol) in anhydrous DMF (10 mL) was added via canula
over a period of 6 min followed by an anhydrous DMF rinse (5 mL) of
the source flask and needle. Gas evolution was observed, and the
resulting white suspension was stirred at room temperature for 90
min, at which point the reaction color had turned red. Benzyl
bromide (4.23 mL, 35.6 mmol) was added and the reaction was heated
to 40.degree. C. After stirring for 3 hours, the heat source was
removed and the reaction was cooled to room temperature. Saturated
aqueous NH.sub.4Cl solution (20 mL) was added, and the mixture was
allowed to stir for 30 min, at which point gas evolution had
ceased. The crude mixture was then diluted with H.sub.2O (50 mL)
and extracted with Et.sub.2O (100 mL.times.3). The combined organic
extracts were washed with saturated aqueous NH.sub.4Cl solution
(100 mL), dried over anhydrous MgSO.sub.4, filtered, concentrated,
and the residue was purified by column chromatography on SiO.sub.2
(0%.fwdarw.10% methyl tert-butylether (MTBE)/hexane gradient) to
furnish the title product as white solid (90% Pure, 8.47 g, 84%):
mp 141-144.degree. C.; .sup.1H NMR (400 MHz, CDCl3) .delta.
7.41-7.30 (m, 4H), 7.30-7.24 (m, 3H), 7.05-6.96 (m, 1H), 6.90-6.84
(m, 2H), 6.76-6.67 (m, 2H), 5.57 (dddd, J=17.1, 10.3, 9.0, 1.3 Hz,
1H), 4.88 (dd, J=10.2, 1.9 Hz, 1H), 4.87 (d, J=11.4 Hz, 1H), 4.72
(ddd, J=17.2, 1.8, 0.5 Hz, 1H), 4.63 (d, J=11.4 Hz, 1H), 4.53 (d,
J=11.3 Hz, 1H), 4.40 (d, J=11.3 Hz, 1H), 3.79 (s, 3H), 3.70 (qd,
J=6.2, 3.8 Hz, 1H), 3.52 (dd, J=6.9, 3.9 Hz, 1H), 3.09 (d, J=10.4
Hz, 1H), 2.59-2.44 (m, 2H), 1.25 (d, J=6.3 Hz, 3H); .sup.13C NMR
(101 MHz, CDCl3) .delta. 161.24 (dd, J=245.7, 11.9 Hz), 161.09 (dd,
J=247.0, 11.6 Hz), 159.11, 138.90, 138.24, 132.05 (dd, J=9.4, 6.7
Hz), 130.92, 129.17, 128.33, 127.97, 127.53, 123.45 (dd, J=15.9,
3.7 Hz), 116.95, 113.78, 110.59 (dd, J=20.8, 3.7 Hz), 103.33 (dd,
J=26.5, 25.0 Hz), 83.67, 76.56, 74.18, 70.41, 55.28, 47.98, 29.75,
14.24; .sup.19F NMR (376 MHz, CDCl3) .delta. -113.06 (d, J=6.8 Hz),
-113.95 (d, J=6.4 Hz); ESIMS: m/z 475 ([M+Na].sup.+).
Example 1
Step 2b: Preparation of
1-((((2S,3R,4S)-4-benzyl-3-(2-methoxyethoxy)-hex-5-en-2-yl)oxy)methyl)-4--
methoxybenzene
##STR00022##
[0089] To a suspension of NaH (0.088 g, 3.68 mmol) in DMF (10mL)
was added dropwise a solution of
(2S,3R,4S)-4-benzyl-2-((4-methoxybenzyl)oxy)hex-5-en-3-ol (1 g,
3.06 mmol) in DMF (5 mL). The mixture was stirred at room
temperature for 20 min and then 1-bromo-2-methoxyethane (0.852 g,
6.13 mmol) was added. The reaction mixture was heated to 60.degree.
C. for 5 h. The reaction was cooled to room temperature and another
portion of NaH (0.088 g, 3.68 mmol) and 1-bromo-2-methoxyethane
(0.852 g, 6.13 mmol) were added, and the reaction mixture was
heated to 60.degree. C. and stirred overnight. The reaction mixture
was quenched with saturated NH.sub.4Cl and the phases were
separated. The aqueous phase was extracted with EtOAc (2.times.40
mL), and the combined organic phases were dried over MgSO.sub.4,
concentrated, and purified by column chromatography on SiO.sub.2
(EtOAc/hexanes) to furnish the title product as as colorless oil
(0.730 g, 62%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30-7.06
(m, 7H), 6.86 (dd, J=8.6, 0.9 Hz, 2H), 5.68-5.47 (m, 1H), 4.95-4.69
(m, 2H), 4.60-4.26 (m, 2H), 4.04-3.91 (m, 1H), 3.79 (s, 3H),
3.73-3.69 (m, 1H), 3.68-3.60 (m, 1H), 3.59-3.53 (m, 2H), 3.39 (d,
J=0.8 Hz, 3H), 3.38-3.36 (m, 1H), 3.15 (d, J=10.4 Hz, 1H),
2.70-2.42 (m, 2H), 1.30-1.17 (m, 3H); .sup.13C NMR (101 MHz,
CDCl.sub.3) .delta. 159.05, 140.67, 138.83, 130.95, 129.56, 129.11,
127.92, 125.60, 116.61, 113.74, 84.59, 76.46, 72.41, 71.76, 70.26,
58.96, 55.28, 48.55, 36.96, 14.01; ESIMS m/z 407.2
([M+Na].sup.+).
Example 1
Step 2c: Preparation of
triisopropyl(((2S,3R,4S)-2-((4-methoxybenzyl)-oxy)-7-methyl-4-vinyloctan--
3-yl)oxy)silane
##STR00023##
[0091] To an ice-cooled solution of
(2S,3R,4S)-2-((4-methoxybenzyl)oxy)-7-methyl-4-vinyloctan-3-ol
(3.70 g, 12.07 mmol) in anhydrous CH.sub.2Cl.sub.2 (60.4 ml) were
added 2,6-dimethylpyridine (1.97 ml, 16.9 mmol) and
triisopropylsilyl trifluoromethanesulfonate (3.89 ml, 14.5 mmol),
and the mixture was allowed to warm to room temperature while
stirring overnight. The reaction mixture was poured into saturated
aqueous sodium bicarbonate (NaHCO.sub.3) solution and mixed
thoroughly. The phases were separated and the aqueous phase was
extracted with CH.sub.2Cl.sub.2, and the combined organic phases
were washed with brine, dried over MgSO.sub.4, concentrated, and
purified by column chromatography on SiO.sub.2 (gradient,
hexanes/ethyl acetate) to furnish the title product as as a
colorless oil (4.76 g, 85%): .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.26-7.19 (m, 2H), 6.88-6.81 (m, 2H), 5.63-5.50 (m, 1H),
5.05-4.89 (m, 2H), 4.51-4.29 (m, 2H), 3.84 (dd, J=6.6, 3.0 Hz, 1H),
3.79 (s, 3H), 3.55-3.46 (m, 1H), 2.11-1.98 (m, 1H), 1.75-1.61 (m,
1H), 1.56-1.41 (m, 1H), 1.24-1.17 (m, 1H), 1.15 (d, J=6.2 Hz, 3H),
1.13-0.97 (m, 20H), 0.85 (d, J=6.8 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H);
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 158.88, 139.86, 131.19,
129.19, 115.64, 113.50, 78.34, 76.39, 70.08, 55.24, 49.46, 36.94,
28.35, 28.23, 22.83, 22.51, 18.43, 18.41, 13.71, 13.18; ESIMS m/z
485.4 ([M+Na].sup.+).
Example 1
Step 3: Preparation of (6R,7R,8S,Z)-benzyl
2-((tert-butoxycarbonyl)amino)-7-(cyclopropylmethoxy)-6-(4-fluorobenzyl)--
8-((4-methoxybenzyl)-oxy)non-2-enoate
##STR00024##
[0093] A 0.5 M solution of 9-borabicyclo[3.3.1]nonane in anhydrous
THF (7.0 mL, 3.50 mmol) was added to a solution of
1-((2S,3R,4S)-3-(cyclopropylmethoxy)-4-((4-methoxybenzyl)oxy)-2-vinylpent-
yl)-4-fluorobenzene (960 milligrams (mg), 2.409 mmol) in anhydrous
THF (5 mL) at 0.degree. C. The resulting solution was warmed to
room temperature and stirred for 1 h, then heated to 50.degree. C.
for 2 h. The reaction was cooled to room temperature, a solution of
K.sub.3PO.sub.4 (3 M aqueous, 1.61 mL, 4.82 mmol) was added, and
the reaction was stirred for 15 min at room temperature. To the
mixture was added a solution of (Z)-benzyl
3-bromo-2-((tert-butoxycarbonyl)amino)acrylate (870 mg, 2.44 mmol),
prepared using a similar procedure to that disclosed in Singh, J.
et al. Org. Lett. 2003, 5, 3155-3158, in degassed DMF (2 mL) and
PdCl.sub.2(dppf) (88.0 mg, 0.120 mmol). The reaction was heated
overnight at 60.degree. C., cooled, diluted with Et.sub.2O, and
washed with saturated aqueous NaHCO.sub.3. The phases were
separated and the aqueous phase was extracted with Et.sub.2O. The
combined organic phases were washed with saturated aqueous
NH.sub.4Cl and water, dried over MgSO.sub.4, concentrated, and
purified by column chromatography on SiO.sub.2 (gradient,
hexanes/ethyl acetate) to furnish the title product as a pale
yellow oil (1.43 g, 88%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.38-7.26 (m, 5H), 7.26-7.19 (m, 2H), 6.97-6.89 (m, 2H), 6.88-6.78
(m, 4H), 6.39 (t, J=7.2 Hz, 1H), 6.29 (s, 1H), 5.24-5.10 (m, 2H),
4.61-4.25 (m, 2H), 3.73 (s, 3H), 3.64-3.53 (m, 1H), 3.45-3.31 (m,
2H), 3.22 (dd, J=7.2, 2.8 Hz, 1H), 2.79 (dd, J=14.0, 4.8 Hz, 1H),
2.37 (dd, J=14.0, 9.5 Hz, 1H), 2.25-2.08 (m, 2H), 1.92-1.79 (m,
1H), 1.57-1.43 (m, 1H), 1.43 (s, 9H), 1.39-1.28 (m, 1H), 1.28 (d,
J=6.0 Hz, 3H), 1.09-0.96 (m, 1H), 0.53-0.44 (m, 2H), 0.21-0.13 (m,
2H); .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 164.48, 160.91 (d,
J=243.2 Hz), 158.99, 153.40, 136.94 (d, J=3.2 Hz), 136.82, 135.55,
130.26, 130.24 (d, J=7.7 Hz), 129.39, 128.31, 128.04, 128.00,
126.23, 114.62 (d, J=20.9 Hz), 113.58, 82.58, 80.01, 76.69, 74.41,
69.70, 66.72, 54.94, 40.81, 34.83, 28.49, 27.99, 25.75, 16.00,
11.01, 2.86, 2.78; .sup.19F NMR (376 MHz, CDCl.sub.3) .delta.
-117.70; ESIMS m/z 676.4 ([M+H].sup.+).
Example 1
Step 4:
(2S,6R,7R,8S)-methyl-2-((tert-butoxycarbonyl)amino)-6-(4-methoxybe-
nzyl)-8-((4-methoxybenzyl)oxy)-7-((triisopropylsilyl)oxy)nonanoate
##STR00025##
[0095] The title compound was prepared using a procedure adapted
from Jones et al. Tetrahedron Lett. 1999, 40, 1211-1214. A high
pressure reactor was charged with (6R,7R,8S,Z)-methyl
7-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-8-((4-methoxybenzyl)oxy)-6-(-
4-methylbenzyl)non-2-enoate (2.72 g, 3.82 mmol) and anhydrous MeOH
(20 mL) and the solution was sparged with nitrogen using a needle
for 10 min. To the solution was added
(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene-(cyclooctadiene)rhodiu-
m(I) trifluoromethanesulfonate (28 mg, 0.038 mmol) and the reactor
was sealed, pressurized with H.sub.2 (200 psi) and stirred at room
temperature for 3 h. The pressure was released and the crude
reaction mixture was filtered through a pad of Celite.RTM.,
concentrated, and purified by column chromatography on SiO.sub.2
(0.fwdarw.100% EtOAc/hexanes gradient) to furnish the title product
as a colorless oil (2.73 g, 100%): IR (neat) 3377, 2941, 2865,
1744, 1715, 1511, 1245, 1164 cm.sup.-1; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.31-7.22 (m, 2H), 7.01 (d, J=8.5 Hz, 2H), 6.87
(d, J=8.6 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 4.90 (d, J=8.5 Hz, 1H),
4.51 (d, J=11.2 Hz, 1H), 4.33 (d, J=11.3 Hz, 1H), 4.25 (q, J=7.2
Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.70 (s, 3H), 3.63-3.52 (m,
1H), 2.77 (dd, J=13.8, 7.2 Hz, 1H), 2.43 (dd, J=13.8, 7.4 Hz, 1H),
1.78 (d, J=7.7 Hz, 1H), 1.70 (s, 1H), 1.52 (d, J=10.7 Hz, 2H), 1.44
(s, 9H), 1.35-1.07 (m, 7H), 1.07-0.93 (m, 21H); .sup.13C NMR (101
MHz, CDCl.sub.3) .delta. 173.40, 158.94, 157.67, 155.35, 133.91,
131.04, 130.15, 129.21, 113.63, 113.58, 79.80, 76.44, 76.36, 70.18,
55.29, 55.26, 53.37, 52.16, 45.89, 36.12, 33.12, 29.50, 28.32,
23.81, 18.27, 16.23, 13.02; HRMS-ESI (m/z) ([M].sup.+) calcd for
C.sub.40H.sub.65NO.sub.8Si, 715.448; found, 715.4479.
Example 1
Step 5a: Preparation of (2S,6R,7R,8S)-methyl
2-((tert-butoxycarbonyl)-amino)-8-hydroxy-7-isobutoxy-6-(2-(methylthio)et-
hyl)nonanoate
##STR00026##
[0097] To a mixture of (2S,6R,7 R,8S)-methyl
2-((tert-butoxycarbonyl)amino)-7-isobutoxy-8-((4-methoxybenzyl)oxy)-6-(2--
(methylthio)ethyl)nonanoate (536 mg, 0.941 mmol) and 0.85 mL
H.sub.2O in CH.sub.2Cl.sub.2 (9.4 mL) at 0.degree. C. (icewater
bath) was added DDQ (214 mg, 0.941 mmol). The resulting dark
mixture was stirred at 0.degree. C. for 3 h, then another portion
of DDQ (41 mg, 0.180 mmol) were added and the reaction was stirred
for 1 h. The reaction was quenched with sodium hydroxide (NaOH; 1.3
ml of 1M aqueous, 1.3 mmol) and stirred for 10 min. The reaction
was then diluted with H.sub.2O (20 mL) and extracted with
CH.sub.2Cl.sub.2 (3.times.20 mL). The combined organic extracts
were dried over Na.sub.2SO.sub.4, filtered, and concentrated to
provide a red oil which was purified by column chromatography on
SiO.sub.2 (5.fwdarw.35% acetone/hexanes gradient) to furnish the
title product as a clear, colorless oil (353 mg, 83%): .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 5.02 (d, J=8.0 Hz, 1H), 4.31 (d,
J=5.2 Hz, 1H), 3.95-3.83 (m, 1H), 3.74 (d, J=1.6 Hz, 3H), 3.36 (dd,
J=8.5, 6.3 Hz, 1H), 3.22 (dd, J=8.5, 6.6 Hz, 1H), 3.05 (dd, J=5.6,
3.9 Hz, 1H), 2.58 (ddd, J=14.0, 8.7, 5.3 Hz, 1H), 2.47 (ddd,
J=12.8, 8.3, 7.4 Hz, 1H), 2.10 (s, 3H), 1.96-1.68 (m, 4H),
1.68-1.49 (m, 3H), 1.45 (s, 9H), 1.39 (s, 4H), 1.21 (d, J=6.3 Hz,
3H), 0.91 (dd, J=6.7, 1.9 Hz, 6H); .sup.13C NMR (101 MHz,
CDCl.sub.3) .delta. 173.36, 155.36, 84.83, 79.93, 79.24, 68.10,
53.20, 52.27, 38.01, 33.20, 33.05, 32.76, 30.90, 29.21, 28.83,
28.33, 22.83, 19.52, 19.46, 19.11, 15.43; ESIMS m/z 450.4 ([M+H]+),
472.4 ([M+Na].sup.+).
Example 1
Step 5b: Preparation of
(2S,6R,7R,8S)-2-((tert-butoxycarbonyl)amino)-8-hydroxy-6-(4-methylbenzyl)-
-7-phenoxynonanoic acid
##STR00027##
[0099] A 25 mL screw top vial was charged with (2S,6R,7R,8S)-benzyl
8-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-6-(4-methylbenzyl)-7-phenoxy-
nonanoate (741 mg, 1.11 mmol), EtOAc (10 mL), and 10% Pd/C (61 mg,
0.057 mmol). The vial was sealed with a septum-cap, and the
reaction was briefly degassed under high vacuum, and then
repressurized under about 1 atmosphere of H.sub.2 (balloon
pressure). This process was repeated 2.times., and the reaction was
stirred at room temperature under balloon pressure of hydrogen.
After stirring for 19 h, the solids were removed by filtration
through a pad of Celite.RTM., rinsing with excess EtOAc. The
filtrate was concentrated and then dried under high vacuum to
afford the title compound as a white solid (516 mg, 91%): mp
48-51.degree. C.; .sup.1H NMR (400 MHz, CDCl3) .delta. 7.30-7.17
(m, 2H), 7.09 (s, 4H), 6.97-6.83 (m, 3H), 6.69-6.02 (m, 2H), 5.00
(d, J=8.3 Hz, 1H), 4.33-3.96 (m, 3H), 3.03 (dd, J=13.8, 5.3 Hz,
1H), 2.49 (dd, J=13.9, 8.9 Hz, 1H), 2.33 (s, 3H), 2.19-2.08 (m,
1H), 1.78-1.62 (m, 1H), 1.59-1.15 (m, 17H); .sup.13C NMR (101 MHz,
CDCl3) .delta. 176.73, 159.43, 155.73, 138.03, 135.33, 129.57,
129.10, 129.06, 120.88, 115.85, 82.16, 80.24, 68.15, 53.26, 41.47,
35.46, 32.45, 29.53, 28.35, 22.51, 21.05, 20.01; ESIMS: m/z 486
([M+H].sup.+).
Example 1
Step 5b: Preparation of
(2S,6R,7R,8S)-2-((tert-butoxycarbonyl)amino)-8-hydroxy-6-(4-methoxybenzyl-
)-7-(triisopropylsilyl)oxy)nonanoic acid
##STR00028##
[0101] A high pressure reactor was charged with Pd/C (212 mg, 0.199
mmol) and a solution of
(2S,6R,7R,8S)-benzyl-2-((tert-butoxycarbonyl)amino)-8-hydroxy-6-(4-methox-
ybenzyl)-7-((triisopropylsilyl)oxy)nonanoate (2.02 g, 3.01 mmol) in
THF (10 mL). The flask was pressurized to 500 psi and stirred for 2
days (d). The reaction mixture was filtered through a pad of
Celite.RTM. and concentrated to give the title compound as a sticky
semi solid (1.730 g, 99%): IR (neat) 3337, 2941, 2865, 1714, 1511,
1462, 1245, 1165 cm.sup.-1; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.13-6.90 (m, 2H), 6.88-6.67 (m, 2H), 4.87 (d, J=8.0 Hz,
1H), 4.22 (s, 1H), 3.96 (qd, J=6.4, 4.0 Hz, 1H), 3.79 (s, 3H),
3.76-3.62 (m, 1H), 2.93 (dd, J=14.0, 5.9 Hz, 1H), 2.44 (dd, J=13.9,
8.7 Hz, 1H), 1.92-1.65 (m, 2H), 1.62-1.48 (m, 2H), 1.44 (s, 9H),
1.34-1.14 (m, 6H), 1.14-0.71 (m, 21H); .sup.13C NMR (101 MHz,
CDCl.sub.3) .delta. 175.71, 157.74, 155.72, 133.62, 130.02, 113.74,
70.38, 60.42, 55.27, 53.21, 43.79, 35.95, 32.41, 29.79, 28.30,
23.72, 19.11, 18.28, 14.20, 13.03; HRMS-ESI (m/z) ([M].sup.+) calcd
for C.sub.31H.sub.55NO.sub.7Si, 581.3748; found, 581.3744.
Example 1
Step 5b: Preparation of
(2S,6R)-2-((tert-butoxycarbonyl)amino)-6-((1R,2S)-2-hydroxy-1-((triisopro-
pylsilyl)oxy)propyl)-9-methyldecanoic acid
##STR00029##
[0103]
(2S,6R)-2-((tert-Butoxycarbonyl)amino)-6-((1R,2S)-2-((4-methoxybenz-
yl)oxy)-1-((triisopropylsilyl)oxy)propyl)-9-methyldecanoic acid
(8.55 g, 13.1 mmol) was dissolved in THF (40 ml) in a high pressure
reactor with a stir bar. To the resulting solution was added 5%
Pd/C (1.40 g, 0.656 mmol) was added, the reactor was sealed and
purged with H.sub.2 (4.times.), and then charged to 600 psi with
H.sub.2 at room temperature. The reactor was heated to 50.degree.
C. for 12 h and then stirred at room temperature overnight. The
reaction mixture was filtered through a pad of Celite.RTM. and
concentrated to yield the title compound as a colorless oil
contaminated with 20% p-methoxytoluene (7.76 g, 89: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 5.05-4.92 (m, 1H), 4.37-4.22 (m, 1H),
3.89 (qd, J=6.4, 3.5 Hz, 1H), 3.83-3.78 (m, 1H), 1.93-1.77 (m, 2H),
1.74-1.45 (m, 5H), 1.45 (s, 9H), 1.45-1.19 (m, 2H), 1.19 (d, J=5.1
Hz, 3H), 1.14-1.02 (m, 24H), 0.87 (d, J=6.6 Hz, 6H); ESIMS m/z
554.5 ([M+Na].sup.+).
Example 1
Step 5c: Preparation of
(2S,6R,7R,8S)-7-(benzyloxy)-2-((tert-butoxy-carbonyl)amino)-6-(2,4-difluo-
robenzyl)-8-hydroxynonanoic acid
##STR00030##
[0105] A 250 mL round bottom flask was charged with
(2S,6R,7R,8S)-benzyl
7-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-6-(2,4-difluorobenzyl)-8-hyd-
roxynonanoate (2.10 g, 3.43 mmol), THF (24 mL) and H.sub.2O (6 mL).
LiOH.H.sub.2O (153 mg, 3.64 mmol) was added, and the resulting
mixture was allowed to stir at room temperature. After stirring for
2.5 h, the reaction mixture was heated to 50.degree. C. and was
stirred for an additional 17 h at that temperature. Additional
portions of water (3 mL) and LiOH.H.sub.2O (152 mg, 3.62 mmol) were
added and the reaction was stirred at room temperature for 4.5 h.
The reaction mixture was diluted with 1.0 M aqueous HCl (50 mL) and
extracted with EtOAc (3.times.50 mL). The combined organic extracts
were washed with saturated aqueous sodium chloride solution (NaCl,
brine; 50 mL), dried over anhydrous MgSO.sub.4, filtered,
concentrated, and dried under high vacuum to obtain the title
compound as a colorless oil contaminated with 10% BnOH (1.55 g,
87%): .sup.1H NMR (400 MHz, CDCl3) .delta. 7.39-7.26 (m, 5H),
7.15-7.05 (m, 1H), 6.82-6.69 (m, 2H), 5.03 (d, J=8.3 Hz, 1H), 4.64
(d, J=11.5 Hz, 1H), 4.55 (d, J=11.6 Hz, 1H), 4.20 (q, J=7.4 Hz,
1H), 4.03 (p, J=6.2 Hz, 1H), 3.37-3.24 (m, 1H), 2.99 (dd, J=14.0,
4.6 Hz, 1H), 2.51 (dd, J=14.0, 9.9 Hz, 1H), 2.01-1.90 (m, 1H),
1.75-1.60 (m, 1H), 1.56-1.15 (m, 17H); 13C NMR (101 MHz, CDCl3)
.delta. 176.51 , 161.26 (dd, J=246.7, 12.7 Hz), 161.07 (dd,
J=247.1, 12.0 Hz), 155.60 , 138.35 , 131.98 (dd, J=9.3, 6.9 Hz),
128.37, 127.77, 126.97, 124.00 (dd, J=15.8, 3.8 Hz), 110.83 (dd,
J=20.8, 3.6 Hz), 104.38 102.95 (m), 83.36, 80.11, 73.75, 68.11,
53.17, 39.82, 32.49, 29.71, 28.85, 28.25, 22.55, 19.22; 19F NMR
(376 MHz, CDCl3) .delta. -113.45 (d, J=7.0 Hz), -113.63 (d, J=6.7
Hz); ESIMS: m/z 522 ([M+H].sup.+).
Example 1
Step 5c: Preparation of
(2S,6R)-2-((tert-butoxycarbonyl)amino)-6-((1R,2S)-2-((4-methoxybenzyl)oxy-
)-1-((triisopropylsilyl)oxy)propyl)-9-methyldecanoic acid
##STR00031##
[0107] To a solution of (2S,6R)-methyl
2-((tert-butoxycarbonyl)amino)-6-((1R,2S)-2-((4-methoxybenzyl)oxy)-1-(tri-
isopropylsilyl)oxy)propyl) -9-ethyldecanoate (8.76 g, 13.2 mmol) in
a mixture of THF and H.sub.2O (125 mL/62.5 mL) was added LiOH
(2.047 g, 85.0 mmol) and the resulting mixture was stirred for 24 h
at 40.degree. C. and then for another 24 h at room temperature. The
reaction mixture was diluted with EtOAc and washed with 1.0 M
aqueous HCl. The phases were separated and the aqueous phase was
extracted with EtOAc. The combined organic phase was washed with
brine, dried over MgSO.sub.4, and concentrated to furnish the title
compound as a pale yellow oil (8.55 g, 100%): IR (neat) 2943, 2866,
1715, 1513, 1392, 1247, 1162, 1038 cm.sup.-1; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.26-7.20 (m, 2H), 6.88-6.82 (m, 2H), 4.96-4.83
(m, 1H), 4.51-4.31 (m, 2H), 4.31-4.20 (m, 1H), 3.88 (t, J=3.8 Hz,
1H), 3.80 (s, 3H), 3.52-3.43 (m, 1H), 1.91-1.72 (m, 2H), 1.68-1.46
(m, 5H), 1.45 (s, 9H), 1.44-1.19 (m, 2H), 1.18 (d, J=6.2 Hz, 3H),
1.18-0.98 (m, 24H), 0.86-0.80 (m, 6H); ESIMS m/z 674.6
([M+Na].sup.+).
Example 1
Step 5c: Preparation of
(2S,6R,7R,8S)-2-((tert-butoxycarbonyl)amino)-8-hydroxy-7-isobutoxy-6-(2-(-
methylthio)ethyl)nonanoic acid
##STR00032##
[0109] To a mixture of (2S,6R,7R,8S)-methyl
2-((tert-butoxycarbonyl)amino)-8-hydroxy-7-isobutoxy-6-(2-(methylthio)eth-
yl)nonanoate (326 mg, 0.725 mmol) in THF (2.4 ml) and H.sub.2O (1.2
ml was added LiOH.H.sub.2O (91 mg, 2.2 mmol). The resulting mixture
was stirred at room temperature for 3 h, quenched with 2N HCl (3
mL), diluted with H.sub.2O (20 mL), and extracted with EtOAc
(3.times.20 mL). The organic extracts were combined, dried over
Na.sub.2SO.sub.4, filtered, and concentrated to provide the title
compound as a sticky colorless oil (307 mg, 97%): .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 5.05 (d, J=7.3 Hz, 1H), 4.31 (s, 1H), 3.88
(p, J=6.3 Hz, 1H), 3.36 (dd, J=8.5, 6.3 Hz, 1H), 3.23 (dd, J=8.6,
6.6 Hz, 1H), 3.07 (dd, J=5.7, 3.9 Hz, 1H), 2.59 (ddd, J=13.9, 8.6,
5.3 Hz, 1H), 2.48 (dt, J=12.8, 7.5 Hz, 1H), 2.10 (s, 3H), 1.84 (tt,
J=13.2, 7.1 Hz, 3H), 1.78 1.62 (m, 2H), 1.55 (dd, J=13.6, 5.8 Hz,
1H), 1.46 (s, 12H), 1.22 (d, J=6.3 Hz, 3H), 0.91 (dd, J=6.7, 2.0
Hz, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 155.81, 99.99,
84.81, 79.35, 68.26, 38.01, 32.80, 30.94, 29.22, 28.80, 28.32,
22.88, 19.51, 19.46, 19.13, 15.44; ESIMS m/z 436.3 ([M+H].sup.+),
458.3 ([M+Na].sup.+).
Example 1
Step 6: Preparation of tert-butyl ((3S,7
R,8R,9S)-7-isopentyl-9-methyl-2-oxo-8-((triisopropylsilyl)oxy)oxonan-3-yl-
)carbamate
##STR00033##
[0111] A solution of
(2S,6R)-2-((tert-butoxycarbonyl)amino)-6-((1R,2S)-2-hydroxy-1-((triisopro-
pylsilyl)oxy)propyl)-9-methyldecanoic acid (7.76 g, 13.1 mmol) in
anhydrous CH.sub.2Cl.sub.2 (500 mL) was added to a solution of MNBA
(9.04 g, 26.3 mmol) and DMAP (12.8 g, 105.0 mmol) in anhydrous
CH.sub.2Cl.sub.2 (2.5 L) at room temperature over the course of 4
h. After the addition was complete, the reaction was stirred for 12
h at room temperature, concentrated and purified by column
chromatography on SiO.sub.2 (gradient, hexanes/ethyl acetate) to
furnish the title product as a sticky pale yellow solid (3.98 g,
59%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.14 (d, J=8.2 Hz,
1H), 4.90-4.78 (m, 1H), 4.20-4.09 (m, 1H), 3.61 (t, J=7.6 Hz, 1H),
2.26-2.10 (m, 1H), 1.79-1.65 (m, 1H), 1.65-1.40 (m, 3H), 1.44 (s,
9H), 1.37 (d, J=6.5 Hz, 3H), 1.32-0.97 (m, 28H), 0.884 (d, J=6.7
Hz, 3H), 0.878 (d, J=6.7 Hz, 3H); .sup.13C NMR (101 MHz,
CDCl.sub.3) .delta. 173.12, 154.92, 79.62, 78.59, 75.82, 60.33,
53.07, 45.68, 36.92, 34.17, 28.64, 28.58, 28.31, 27.27, 22.82,
22.49, 18.95, 18.86, 18.38, 18.33, 13.75; ESIMS m/z 536.5
([M+Na].sup.+).
Example 2
Step 1a-1: Preparation of tert-butyl
((3S,7R,8R,9S)-7-(4-methoxybenzyl)-9-methyl-2-oxo-8-((triisopropylsilyl)o-
xy)oxonan-3-yl)(methoxymethyl)carbamate
##STR00034##
[0113] A 4 mL vial was charged with tert-butyl
((3S,7R,8R,9S)-7-(4-methoxybenzyl)-9-methyl-2-oxo-8-((triisopropylsilyl)o-
xy)oxonan-3-yl)carbamate (42.0 mg, 0.074 mmol), paraformaldehyde
(3.13 mg, 0.104 mmol) and CH.sub.2Cl.sub.2 (0.5 mL), then cooled to
0.degree. C. under N.sub.2. Chlorotrimethylsilane (0.026 mL, 0.201
mmol) was added to the reaction mixture, which was stirred for 45
min, then quenched by the addition of 9:1 MeOH/Et.sub.3N (0.5 mL).
The mixture was warmed to room temperature and stirred overnight.
The reaction was diluted with H.sub.2O (2 mL) and passed through a
phase separator cartridge. An additional portion of
CH.sub.2Cl.sub.2 (2 mL) was passed through the separator and the
combined organics were concentrated to afford the title compound as
a colorless oil: IR (neat) 3445, 2942, 2866, 1747, 1706, 1512,
1464, 1367, 1247, 1175 cm.sup.-; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.00 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 5.05-4.45
(m, 3H), 4.23-4.03 (m, 1H), 3.72 (s, 4H), 3.68 (t, J=8.2 Hz, 1H),
3.23 (d, J=13.1 Hz, 3H), 3.09-2.97 (m, 2H), 2.23 (td, J=12.9, 5.4
Hz, 1H), 2.01-1.96 (m, 1H), 1.73 (d, J=9.8 Hz, 1H), 1.42-1.32 (m,
3H), 1.13-1.05 (m, 21H), 0.99 (d, J=0.8 Hz, 9H), 0.91-0.77 (m, 3H);
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 155.89, 127.66, 111.86,
53.32, 45.75, 43.84, 35.14, 34.42, 26.38, 26.30, 24.77, 22.70,
17.65, 16.86, 16.56, 16.46, 15.89, 15.76, 12.07, 10.72, 10.35,
6.69, 0.00, -1.94 (Note: Peaks missing, likely due to rotamers);
HRMS-ESI (m/z) ([M].sup.+) calcd for C.sub.33H.sub.57NO.sub.7Si,
607.3897; found, 607.3904.
Example 2
Step 1a-2: Preparation of tert-butyl
((3S,7R,8R,9S)-8-hydroxy-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)(m-
ethoxymethyl)carbamate
##STR00035##
[0115] To a round bottom flask were added tert-butyl
((3S,7R,8R,9S)-7-(4-methoxybenzyl)-9-methyl-2-oxo-8-((triisopropylsilyl)o-
xy)oxonan-3-yl)(methoxymethyl)carbamate (1.61 g, 2.65 mmol), THF
(26.5 ml) and TBAF (1.0 M, 5.30 ml, 5.30 mmol) at room temperature
and an exotherm noted. The reaction was stirred at room temperature
until thin layer chromatography (TLC) showed complete consumption
of starting material. After approximately 2 h, the reaction was
quenched by the addition of NaHCO.sub.3 and extracted with EtOAc
(3.times.). The combined organic extracts were washed with brine,
dried over MgSO4, concentrated, and purified by column
chromatography on SiO.sub.2 (0.fwdarw.10%, hold, 10.fwdarw.20%
hold, 20.fwdarw.50% hold EtOAc/hexanes gradient) to furnish the
title product as a colorless oil (703 mg, 59%): IR (neat) 3479,
2976, 2936, 1744, 1700, 1512, 1368, 1297, 1246, 1175 cm.sup.-1;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.15-7.06 (m, 2H),
6.87-6.79 (m, 2H), 4.96-4.87 (m, 1H), 4.85-4.73 (m, 2H), 4.61-4.49
(m, 1H), 4.23-4.18 (m, 1H), 3.79 (s, 3H), 3.51 (td, J=8.8, 5.8 Hz,
1H), 3.32 (d, J=12.9 Hz, 3H), 3.01 (dd, J=13.6, 4.9 Hz, 1H), 2.44
(dd, J=16.2, 7.3 Hz, 1H), 2.07 (d, J=16.5 Hz, 1H), 1.69 (s, 2H),
1.63-1.49 (m, 3H), 1.44 (d, J=5.9 Hz, 9H), 1.40 (d, J=6.3 Hz, 3H),
0.94 (s, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 173.45,
158.00, 129.72, 113.97, 76.28, 55.25, 37.08, 28.24, 27.29, 19.43,
18.18 (Note: Peaks missing, likely due to rotamers); HRMS-ESI (m/z)
([M].sup.+) calcd for C.sub.24H.sub.37NO.sub.7, 451.2558; found,
451.257.
Example 2
Step 1b: Preparation of tert-butyl
N-[(3S,7R,8R,9S)-8-benzyloxy-9-methyl-2-oxo-7-(p-tolylmethyl)oxonan-3-yl]-
-N-tert-butoxycarbonyl-carbamate (F230)
##STR00036##
[0117] A 25 mL screw top vial was charged with tert-butyl
((3S,7R,8R,9S)-8-(benzyloxy)-9-methyl-7-(4-methylbenzyl)-2-oxooxonan-3-yl-
)carbamate (720 mg, 1.50 mmol), DMAP (91.0 mg, 0.75 mmol), and
anhydrous CH.sub.3CN (7.5 mL). To the mixture was added
di-tert-butyl dicarbonate (1.30 g, 5.98 mmol) and the reaction was
stirred at room temperature for 17 h and then warmed to 50.degree.
C. and stirred for an additional 29 h. The reaction mixture was
concentrated under a gentle stream of N.sub.2 and the crude
concentrate was purified by column chromatography on
SiO.sub.2(gradient, 0.fwdarw.20% acetone in hexane) to give
tert-butyl
((3S,7R,8R,9S)-8-(benzyloxy)-9-methyl-7-(4-methylbenzyl)-2-oxooxonan-3-yl-
)carbamate as a white solid (167 mg, 19%): mp 164-166.degree. C.;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41-7.26 (m, 5H), 7.07
(d, J=8.1 Hz, 2H), 7.03 (d, J=8.0 Hz, 2H), 4.88-4.75 (m, 3H), 4.61
(d, J=10.8 Hz, 1H), 3.35 (t, J=9.1 Hz, 1H), 3.10 (dd, J=13.3, 3.3
Hz, 1H), 2.40-2.28 (m, 4H), 2.22 (tt, J=13.5, 7.2 Hz, 1H),
2.02-1.88 (m, 2H), 1.64-1.41 (m, 24H), 0.96-0.84 (m, 1H); .sup.13C
NMR (101 MHz, CDCl.sub.3) .delta. 171.13, 152.83 (2C), 137.98,
137.51, 135.31, 129.01, 128.77, 128.54, 127.89, 127.76, 84.14,
82.64 (2C), 75.44, 75.21, 57.57, 45.77, 36.43, 30.83, 27.97 (6C),
26.84, 21.04, 19.67, 18.49; ESIMS m/z 604 ([M+Na].sup.+).
Example 3
Step 1: Preparation of tert-butyl
((3S,7R,8R,9S)-8-(allyloxy)-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl-
)(methoxymethyl)carbamate
##STR00037##
[0119] A solution of tert-butyl
((3S,7R,8R,9S)-8-hydroxy-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)(m-
ethoxymethyl)carbamate (350 mg, 0.775 mmol), palladium
tetrakis(triphenylphosphine) (90 mg, 0.078 mmol), and allyl
tert-butyl carbonate (758 mg, 4.79 mmol) in degassed THF (3876
.mu.l) was heated to 60.degree. C. and stirred for 4 h. The
reaction mixture was cooled to room temperature and purified
directly by column chromatography on SiO.sub.2 (EtOAc/Hex gradient)
to afford the title product as a light yellow oil (200 mg, 52.5%):
IR (neat) 2977, 2934, 2836, 1746, 1702, 1511, 1367, 1297, 1246,
1175 cm.sup.-1; .sup.1H NMR (400 MHz, CDCl.sub.3) 6 7.07 (d, J=8.5
Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 6.02-5.88 (m, 1H), 5.33 (dd,
J=17.2, 1.6 Hz, 1H), 5.20 (dd, J=10.4, 1.5 Hz, 1H), 4.94-4.81 (m,
2H), 4.76 (t, J=10.3 Hz, 1H), 4.60-4.50 (m, 1H), 4.28 (dd, J=11.8,
5.6 Hz, 1H), 4.22-4.15 (m, 1H), 4.09 (dd, J=11.9, 5.3 Hz, 1H), 3.78
(s, 3H), 3.30 (d, J=14.5 Hz, 3H), 3.21 (t, J=9.0 Hz, 1H), 3.03 (dd,
J=13.5, 3.4 Hz, 1H), 2.34-2.22 (m, 1H), 2.15-1.98 (m, 1H), 1.80 (s,
1H), 1.65-1.59 (m, 2H), 1.50-1.39 (m, 13H), 0.90-0.76 (m, 1H);
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 173.53, 157.82, 134.40,
134.36, 132.63, 129.69, 117.12, 113.73, 84.28, 84.24, 81.09, 74.62,
58.57, 57.06, 55.24, 55.22, 46.01, 35.97, 28.32, 28.23, 26.57,
19.22, 18.26; HRMS-ESI (m/z) ([M].sup.+) calcd for
C.sub.27H.sub.41NO.sub.7, 491.2883; found, 491.2862.
Example 3
Step 2a: Preparation of tert-butyl
((3S,7R,8R,9S)-7-(4-methoxybenzyl)-9-methyl-2-oxo-8-propoxyoxonan-3-yl)(m-
ethoxymethyl)carbamate (F221)
##STR00038##
[0121] A vial was charged with 5 wt % Pd/C (26.0 mg, 0.012 mmol)
and a solution of tert-butyl
((3S,7R,8R,9S)-8-(allyloxy)-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl-
)(methoxymethyl)carbamate (200 mg, 0.407 mmol) in EtOAc (1 mL). The
vial was evacuated and backfilled with H.sub.2 (3.times.) and then
stirred vigorously under one atmosphere of H.sub.2 (balloon) at
room temperature for 15 h. The reaction mixture was filtered
through a plug of Celite.RTM. and concentrated to the title
compound as a colorless oil (168 mg, 84%) IR (neat) 3368, 2973,
2936, 2877, 1746, 1705, 1511, 1454, 1367, 1175 cm.sup.-1; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.12-7.03 (m, 2H), 6.87-6.77 (m,
2H), 5.04-4.67 (m, 2H), 4.21-4.09 (m, 1H), 3.78 (s, 3H), 3.71 (dtd,
J=8.6, 6.8, 1.9 Hz, 1H), 3.50 (dtd, J=8.4, 6.6, 1.7 Hz, 1H),
3.34-3.25 (m, 3H), 3.12 (td, J=9.3, 3.6 Hz, 1H), 3.07-2.98 (m, 1H),
2.27 (ddd, J=13.4, 11.7, 6.2 Hz, 1H), 2.07 (s, 2H), 1.76 (s, 1H),
1.71-1.54 (m, 4H), 1.55-1.33 (m, 14H), 0.97 (td, J=7.4, 1.0 Hz,
3H), 0.81 (s, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) .delta.
173.30, 157.80, 132.75, 129.69, 113.73, 99.98, 84.02, 83.99, 81.11,
75.59, 75.52, 55.25, 55.23, 46.20, 35.86, 35.82, 28.32, 26.56,
23.59, 19.21, 18.19, 18.12, 10.75; HRMS-ESI (m/z) ([M].sup.+) calcd
for C.sub.27H.sub.43NO.sub.7, 493.3040; found, 493.3018.
Example 3
Step 2b-1: Preparation of tert-butyl
((3S,7R,8R,9S)-7-(4-fluorobenzyl)-9-methyl-2-oxo-8-(2-oxoethoxy)oxonan-3--
yl)(methoxymethyl)carbamate
##STR00039##
[0123] A mixture of tert-butyl
((3S,7R,8R,9S)-8-(allyloxy)-7-(4-fluorobenzyl)-9-methyl-2-oxooxonan-3-yl)-
(methoxymethyl)carbamate (480 mg, 1.001 mmol), NaHCO.sub.3 (8.41
mg, 0.10 mmol) and anhydrous MeOH (0.31 mL) in anhydrous
CH.sub.2Cl.sub.2 (9.7 mL) was treated with ozone at -78.degree. C.
until the solution became light blue in color. The mixture was
purged with nitrogen until colorless and then quenched by addition
of dimethyl sulfide (0.148 mL, 2.00 mmol). The reaction mixture was
warmed to room temperature and stirred for 20 h, concentrated, and
purified by column chromatography on SiO.sub.2 (gradient,
hexanes/EtOAc) to provide the title compound as a mixture of
rotamers in the form of a white solid (461 mg, 96%): mp
51-53.degree. C.; IR (neat) 2935, 1740, 1701, 1509, 1367, 1297,
1173, 1081 cm.sup.-1; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
9.68 (s, 1H), 7.17-7.06 (m, 2H), 7.00-6.91 (m, 2H), 4.99-4.16 (m,
6H), 3.87-2.97 (m, 4H), 2.46-2.27 (m, 1H), 2.17-2.01 (m, 1H),
1.97-1.75 (m, 1H), 1.74-1.37 (m, 17H), 0.95-0.78 (m, 1H); HRMS-ESI
(m/z) ([M].sup.+) calcd for C.sub.25H.sub.36FNO.sub.7, 481.2476;
found, 481.2481.
Example 3
Step 2b-2: Preparation of tert-butyl
((3S,7R,8R,9S)-8-(2,2-difluoro-ethoxy)-7-(4-fluorobenzyl)-9-methyl-2-oxoo-
xonan-3-yl)(methoxymethyl)carbamate (F212)
##STR00040##
[0125] To a solution of tert-butyl
((3S,7R,8R,9S)-7-(4-fluorobenzyl)-9-methyl-2-oxo-8-(2-oxoethoxy)oxonan-3--
yl)(methoxymethyl)carbamate (461 mg, 0.957 mmol) in anhydrous
CH.sub.2Cl.sub.2 (6.0 mL) at 0.degree. C. was added a .about.50%
toluene solution of Deoxo-Fluor.RTM. (0.710 mL, 1.92 mmol) in
anhydrous CH.sub.2Cl.sub.2 (4 mL) dropwise at 0.degree. C. and the
reaction mixture was stirred at 0.degree. C. for 1 h. The reaction
mixture was concentrated and purified by column chromatography on
SiO.sub.2 (gradient, hexanes/EtOAc) to provide the title compound
as a mixture of rotamers in the form of a white solid (399 mg,
83%): IR (neat) 2978, 2938, 1747, 1700, 1509, 1368, 1297, 1080
cm.sup.-1; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.16-7.04 (m,
2H), 7.02-6.89 (m, 2H), 5.86 (tt, J=55.1, 4.0 Hz, 1H), 4.95-4.71
(m, 3H), 4.60-4.46 (m, 0.5H), 4.25-4.13 (m, 0.5H), 4.04-3.89 (m,
1H), 3.84-3.69 (m, 1H), 3.37-3.18 (m, 3H), 3.03 (dd, J=13.3, 3.5
Hz, 1H), 2.41-2.30 (m, 1H), 2.19-1.99 (m, 1H), 1.88-1.75 (m, 1H),
1.72-1.32 (m, 17H), 0.93-0.75 (m, 1H); .sup.19F NMR (376 MHz,
CDCl.sub.3) .delta. -117.16, -117.27, -125.28--125.61 (m, 2F);
HRMS-ESI (m/z) ([M].sup.+) calcd for
C.sub.25H.sub.36F.sub.3NO.sub.6, 503.2495; found, 503.2499.
Example 4
Step 1: tert-butyl
((3S,7R,8R,9S)-7-(4-methoxybenzyl)-9-methyl-2-oxo-8-((3-oxobut-1-en-1-yl)-
oxy)oxonan-3-yl)(methoxymethyl)carbamate
##STR00041##
[0127] A round bottomed flask was charged with tert-butyl
((3S,7R,8R,9S)-8-hydroxy-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)(m-
ethoxymethyl)carbamate (400 mg, 0.886 mmol) in CH.sub.2Cl.sub.2
(4429 .mu.l). To the solution was added DABCO (4.97 mg, 0.044 mmol)
and the reaction mixture was cooled to 0.degree. C. under N.sub.2.
Upon addition of but-3-yn-2-one (83 .mu.l, 1.063 mmol), the
colorless solution became dark brown-orange. After stirring for 2
h, the reaction mixture was concentrated and purified directly by
column chromatography on SiO.sub.2 (0.fwdarw.10%, hold,
10.fwdarw.20%, hold, 20.fwdarw.50% hold EtOAc/hexanes gradient) to
afford the title compound as a thick colorless oil (257 mg, 55.8%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.43 (d, J=12.2 Hz, 1H),
7.03 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 5.75 (d, J=12.4 Hz,
1H), 5.06-4.85 (m, 2H), 4.82-4.73 (m, 1H), 4.61-4.50 (m, 1H),
4.26-4.14 (m, 1H), 3.78 (s, 3H), 3.37-3.26 (m, 3H), 2.82 (dd,
J=13.6, 4.0 Hz, 1H), 2.41-2.28 (m, 1H), 2.24-2.01 (m, 1H), 2.18 (s,
3H), 1.62-1.39 (m, 12H), 1.34 (d, J=6.4 Hz, 3H), 1.26 (t, J=7.1 Hz,
2H), 0.92 (dt, J=13.6, 4.6 Hz, 1H); .sup.13C NMR (101 MHz,
CDCl.sub.3) .delta. 197.24, 173.18, 163.24, 158.03, 155.34, 131.19,
129.61, 113.83, 108.08, 88.73, 88.61, 81.19, 76.86, 76.23, 75.39,
72.61, 72.49, 58.42, 56.97, 55.41, 55.14, 44.87, 35.82, 30.38,
29.45, 28.43, 28.27, 28.16, 26.38, 26.18, 19.16, 18.24; ESIMS m/z
542.4 ([M+Na)].sup.+).
Example 4
Step 2: Preparation of
((3S,7R,8R,9S)-7-(4-methoxybenzyl)-9-methyl-2-oxo-8-(3-oxobutoxy)oxonan-3-
-yl)(methoxymethyl)carbamate
##STR00042##
[0129] A round bottomed flask was charged with tert-butyl
((3S,7R,8R,9S)-7-(4-methoxybenzyl)-9-methyl-2-oxo-8-((3oxobut-1-en-1-yl)o-
xy)oxonan-3-yl)(methoxymethyl)-carbamate (257 mg, 0.495 mmol), 5 wt
% Pd/C (35 mg, 0.033 mmol) and EtOAc (4 mL). The reaction flask was
briefly evacuated under vacuum and backfilled with H.sub.2
(3.times.) and then stirred vigorously under an H.sub.2 atmosphere
at room temperature overnight. The reaction mixture was filtered
through a plug of Celite.RTM. and concentrated to afford the title
compound as a colorless oil (256 mg, 99%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.14-7.01 (m, 2H), 6.87-6.77 (m, 2H), 4.94-4.73
(m, 3H), 4.08-3.95 (m, 1H), 3.88-3.71 (m, 1H), 3.78 (s, 3H),
3.39-3.25 (m, 3H), 3.21-3.09 (m, 1H), 3.07-2.88 (m, 1H), 2.70 (t,
J=6.2 Hz, 1H), 2.37-2.22 (m, 1H), 2.20 (s, 2H), 1.80-1.59 (m, 3H),
1.58-1.35 (m, 16H), 1.32-1.17 (m, 2H), 0.86-0.71 (m, 1H); .sup.13C
NMR (101 MHz, CDCl.sub.3) .delta. 206.65, 173.53, 157.82, 132.63,
129.72, 129.68, 113.81, 113.74, 84.56, 68.21, 55.23, 45.95, 43.90,
35.95, 30.73, 28.31, 28.21, 21.05, 19.42, 19.26, 18.17; ESIMS m/z
544.3 ([M+Na].sup.+).
Example 4
Step 3: Preparation of tert-butyl
((3S,7R,8R,9S)-8-(3,3-difluorobutoxy)-7-(4-methoxybenzyl)-9-methyl-2-oxoo-
xonan-3-yl)(methoxymethyl)carbamate (F218)
##STR00043##
[0131] A 20 mL vial was charged with tert-butyl
((3S,7R,8R,9S)-7-(4-methoxybenzyl)-9-methyl-2-oxo-8-(3-oxobutoxy)oxonan-3-
-yl)(methoxymethyl)carbamate (250 mg, 0.479 mol), CH.sub.2Cl.sub.2
(3 mL) and Deoxo-Fluor.RTM. (1.04 g, 2.35 mmol) and the mixture was
stirred vigorously at room temperature under N.sub.2 for 12 h. An
additional portion of Deoxo-Fluor.RTM. (900 mg, 4.07 mmol) was
added and reaction was stirred for an additional 48 h. Upon
complete consumption of starting material, the reaction mixture was
quenched (carefully) with saturated aqueous NaHCO.sub.3 solution
and extracted with CH.sub.2Cl.sub.2 (3.times.). The mixture was
passed through a phase separator and the organic phase was
concentrated, and purified by column chromatography on SiO.sub.2
(gradient, hexanes/EtOAc) to provide the title compound as a
colorless oil (106.6 mg, 40.9%): .sup.1H NMR (400 MHz, CDCl.sub.3)
d 7.10-7.00 (m, 2H), 6.88-6.76 (m, 2H), 4.97-4.82 (m, 2H),
4.81-4.71 (m, 1H), 4.55 (s, 1H), 4.19 (t, J=9.6 Hz, 1H), 3.97-3.84
(m, 1H), 3.78 (s, 3H), 3.72 (dt, J=9.1, 6.8 Hz, 1H), 3.37-3.26 (m,
3H), 3.14 (td, J=8.9, 3.2 Hz, 1H), 2.97 (dd, J=13.4, 3.5 Hz, 1H),
2.37-2.24 (m, 1H), 2.26-2.02 (m, 3H), 1.81-1.57 (m, 5H), 1.58-1.23
(m, 14H), 0.89-0.77 (m, 1H); .sup.19F NMR (376 MHz, CDCl.sub.3) d
-89.52, -89.56 (d, J=72.5 Hz); ESIMS m/z 566.3 ([M+Na].sup.+).
Example 5
Preparation of
(2S,3R,4R,8S)-8-((tert-butoxycarbonyl)-(methoxymethyl)-amino)-4-(4-methox-
ybenzyl)-2-methyl-9-oxooxonan-3-yl cyclopentanecarboxylate
(F217)
##STR00044##
[0133] A 20 mL vial was charged with tert-butyl
((3S,7R,8R,9S)-8-hydroxy-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)(m-
ethoxymethyl)carbamate (200 mg, 0.443 mmol), CH.sub.2Cl.sub.2 (2215
.mu.l), NEt.sub.3 (185 .mu.l, 1.329 mmol) and DMAP (5.41 mg, 0.044
mmol). The reaction mixture was cooled to 0.degree. C. in an ice
bath under N.sub.2 and cyclopentanecarbonyl chloride (76 mg, 0.576
mmol) was added in one portion. The reaction became dark
brownish-yellow. After stirring for 2 h, the reaction mixture was
quenched by the addition of saturated aqueous NaHCO.sub.3. The
mixture was extracted with CH.sub.2Cl.sub.2 (3.times.) and the
combined organic layers were washed with brine, dried over MgSO4,
concentrated, and and purified by column chromatography on
SiO.sub.2 (0.fwdarw.100% EtAOx/hexanes) to provide the title
compound as a yellow solid (85 mg, 35.0%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.01 (d, J=8.5 Hz, 4H), 6.81 (d, J=8.4 Hz, 4H),
5.06-4.85 (m, 3H), 4.77 (d, J=11.6 Hz, 1H), 4.57 (dd, J=10.7, 6.0
Hz, 0H), 4.29-4.17 (m, 1H), 3.78 (s, 3H), 3.38-3.26 (m, 3H), 2.74
(p, J=8.0 Hz, 1H), 2.61 (dd, J=13.7, 3.7 Hz, 1H), 2.31 (dd, J=13.7,
11.1 Hz, 1H), 2.20-2.07 (m, 1H), 1.99-1.52 (m, 8H), 1.51-1.40 (m,
9H), 1.27 (d, J=5.8 Hz, 3H), 1.15-0.96 (m, 1H), 0.97-0.87 (m, 1H);
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 176.26, 173.56, 157.94,
155.49, 131.94, 129.59, 113.80, 81.21, 75.54, 72.72, 58.52, 55.43,
55.22, 44.32, 44.04, 35.77, 30.09, 30.00, 29.58, 28.20, 26.48,
25.72, 25.70, 19.09, 17.56; ESIMS m/z 570.5 ([M+Na].sup.+).
Example 6
Preparation of tert-butyl
((3S,7R,8R,9S)-7-isopentyl-8-methoxy-9-methyl-2-oxooxonan-3-yl)(methoxyme-
thyl)carbamate (F205)
##STR00045##
[0135] To an oven-dried vial were added
N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (Proton Sponge.RTM.;
1.63 g, 7.60 mmol), tert-butyl
((3S,7R,8R,9S)-8-hydroxy-7-isopentyl-9-methyl-2-oxooxonan-3-yl)(methoxyme-
thyl)carbamate (436 mg, 1.086 mmol), anhydrous Na.sub.2SO.sub.4
(1.15 g, 8.10 mmol), and trimethyloxonium tetrafluoroborate (723
mg, 4.89 mmol) in anhydrous CH.sub.2Cl.sub.2 (11 mL) at 0.degree.
C. The reaction mixture was slowly warmed to room temperature and
stirred for 5 h. The reaction mixture was diluted with EtOAc,
filtered, and the filtrate was washed with water. The phases were
separated and the aqueous phase was extracted with additional
EtOAc, and the combined organic phases were washed with 1.0 M
aqueous sodium bisulfate (NaHSO.sub.4), washed with saturated
aqueous NaHCO.sub.3, dried over MgSO.sub.4, concentrated, and
purified by column chromatography on SiO.sub.2 (gradient,
hexanes/EtOAc) to provide the title compound as a mixture of
rotamers in the form of a white solid (320 mg, 71%): IR (neat)
2934, 1747, 1705, 1454, 1366, 1296, 1170, 1080 cm.sup.-1; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 4.97-4.70 (m, 3H), 4.60-4.47 (m,
0.5H), 4.25-4.11 (m, 0.5H), 3.49 (s, 3H), 3.40-3.28 (m, 3H),
2.97-2.86 (m, 1H), 2.17-2.01 (m, 1H), 1.79-1.42 (m, 16H), 1.42 (d,
J=6.4 Hz, 3H), 1.31-1.07 (m, 3H), 0.99-0.82 (m, 7H); .sup.13C NMR
(101 MHz, CDCl.sub.3) .delta. 173.54, 155.56, 155.39, 86.39, 81.02,
80.98, 76.34, 75.50, 74.70, 74.43, 61.04, 58.62, 57.11, 55.45,
55.36, 43.42, 36.40, 30.67, 29.62, 28.20, 28.15, 28.09, 27.31,
27.04, 23.05, 22.12, 19.19, 18.10; HRMS-ESI (m/z) ([M].sup.+) calcd
for C.sub.22H.sub.41O.sub.6, 415.2934; found, 415.2943.
Example 7
Step 1: Preparation of tert-butyl
((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)car-
bamate
##STR00046##
[0137] To a solution of tert-butyl
((3S,7R,8R,9S)-7-(2-((tert-butyldimethylsilyl)-oxy)ethyl)-9-methyl-2-oxo--
8-phenoxyoxonan-3-yl)carbamate (3.01 g, 5.77 mmol) in anhydrous THF
(58 mL) was added a 1M solution of TBAF in THF (8.65 ml, 8.65
mmol). The resulting yellow solution was stirred at room
temperature for 4 h, poured into 100 mL 1/2 saturated NaCl
solution, and extracted with EtOAc (3.times.50 mL). The organic
extracts were combined, dried over MgSO.sub.4, filtered, and
concentrated to provide a light yellow oil, which was purified by
column chromatography on SiO.sub.2 (5.fwdarw.25% acetone/hexanes)
to provide the title compound as a hard white foam (1.95 g, 83%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.44-7.17 (m, 2H), 6.95
(t, J=8.2 Hz, 3H), 5.17-4.98 (m, 2H), 4.29-4.11 (m, 2H), 3.75-3.53
(m, 2H), 2.28 (dt, J=13.4, 6.7 Hz, 1H), 2.03-1.88 (m, 1H),
1.88-1.74 (m, 2H), 1.74-1.62 (m, 1H), 1.62-1.48 (m, 2H), 1.44 (s,
10H), 1.28 (d, J=6.5 Hz, 3H), 1.26-1.19 (m, 1H), 1.14 (ddd, J=15.1,
7.5, 3.6 Hz, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) .delta.
173.30, 159.23, 154.90, 129.69, 121.20, 115.33, 80.99, 79.92,
74.68, 60.96, 52.99, 39.55, 34.07, 28.56, 28.33, 19.13, 18.36;
ESIMS m/z 408.3 ([M+H].sup.+), 430.3 ([M+Na].sup.+).
Example 7
Step 2a: Preparation of tert-butyl
((3S,7R,8R,9S)-9-methyl-2-oxo-8-phenoxy-7-(2-phenoxyethyl)oxonan-3-yl)car-
bamate (F240)
##STR00047##
[0139] To a solution of tert-butyl
((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)car-
bamate (215 mg, 0.528 mmol) in anhydrous toluene (5.3 mL) were
added Ph.sub.3Bi(OAc).sub.2 (354 mg, 0.633 mmol), diacetoxycopper
(19.17 mg, 0.106 mmol), and N-cyclohexyl-N-methylcyclohexanamine
(224 1.055 mmol). The resulting mixture was heated to 50.degree. C.
for 20 h, cooled to room temperature, filtered through a plug of
Celite.RTM., and rinsed the plug with toluene. The filtrate was
concentrated and purified by column chromatography on SiO.sub.2
(2.fwdarw.20% acetone/hexanes) to provide the title compound as a
sticky oil (253 mg). .sup.1H NMR gives the desired product, but it
is contaminated with Cy.sub.2NMe. The oil was dissolved in
CH.sub.2Cl.sub.2 (25 mL) and the solution was washed with 0.2 M HCl
(25 mL), dried over Na.sub.2SO.sub.4, decanted, and concentrated to
provide 234 mg of the desired product as a hard white foam. The
product was repurified by column chromatography on SiO.sub.2
(5.fwdarw.20% acetone/hexanes) to provide the title compound as a
hard white foam (199 mg, 78%): .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.33-7.20 (m, 4H), 6.93 (p, J=7.4 Hz, 4H), 6.86-6.75 (m,
2H), 5.21-4.97 (m, 2H), 4.32-4.11 (m, 2H), 3.94 (t, J=6.6 Hz, 2H),
2.34-2.22 (m, 1H), 2.06 (dd, J=16.4, 4.9 Hz, 2H), 1.93 (d, J=12.6
Hz, 1H), 1.89-1.78 (m, 1H), 1.78-1.65 (m, 2H), 1.44 (s, 9H), 1.31
(d, J=6.5 Hz, 3H), 1.19 (dd, J=25.8, 13.7 Hz, 2H); .sup.13C NMR
(101 MHz, CDCl.sub.3) .delta. 173.28, 159.34, 158.76, 154.89,
129.68, 129.39, 121.17, 120.61, 115.40, 114.42, 99.98, 81.14,
79.92, 74.68, 66.01, 53.01, 40.14, 34.11, 30.49, 19.20, 18.35;
ESIMS m/z 484.3 ([M+H].sup.+).
Example 7
Step 2b: Preparation of tert-butyl
((3S,7R,8R,9S)-7-(2-methoxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)car-
bamate (F242)
##STR00048##
[0141] To a solution of tert-butyl
((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)car-
bamate (400 mg, 0.982 mmol) and Proton Sponge.RTM. (841 mg, 3.93
mmol) in anhydrous CH.sub.2Cl.sub.2 (10 mL) at 0.degree. C.
(icewater bath) was added trimethyloxonium tetrafluoroborate (290
mg, 1.963 mmol; weighed under N.sub.2), and the resulting mixture
was stirred at 0.degree. C. for 3 h, quenched with 1N HCl (20 mL),
and extracted with CH.sub.2Cl.sub.2 (3.times.20 mL). The organic
extracts were combined, dried over Na.sub.2SO.sub.4, filtered, and
concentrated to provide an oily white solid, which was purified by
column chromatography on SiO.sub.2 (5.fwdarw.20% acetone/hexanes)
to provide the title compound as a white, crystalline solid (321
mg, 78%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.27 (t, J=8.0
Hz, 2H), 6.94 (dd, J=7.7, 3.3 Hz, 3H), 5.10 (d, J=8.1 Hz, 1H),
5.08-4.98 (m, 1H), 4.20 (q, J=7.9, 6.9 Hz, 2H), 3.36 (t, J=6.5 Hz,
2H), 3.25 (s, 3H), 2.27 (dt, J=13.3, 6.8 Hz, 1H), 1.88 (ddt,
J=10.8, 6.9, 3.9 Hz, 2H), 1.83-1.71 (m, 1H), 1.70-1.61 (m, 1H),
1.60-1.52 (m, 1H), 1.44 (s, 10H), 1.28 (d, J=6.5 Hz, 3H), 1.25-1.16
(m, 1H), 1.16-1.05 (m, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3)
.delta. 173.28, 159.46, 154.90, 129.61, 121.05, 115.38, 81.12,
79.86, 74.71, 70.79, 58.42, 52.99, 40.09, 34.12, 30.53, 28.33,
28.15, 19.07, 18.36; ESIMS m/z 422.3 ([M+H].sup.+), 444.3
([M+Na].sup.+).
Example 7
Step 2c-1: Preparation of tert-butyl
((3S,7R,8R,9S)-9-methyl-2-oxo-7-(2-oxoethyl)-8-phenoxyoxonan-3-yl)carbama-
te
##STR00049##
[0143] To a solution of tert-butyl
((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)car-
bamate (250 mg, 0.613 mmol) in CH.sub.2Cl.sub.2 (6.1 mL) at
0.degree. C. was added Dess-Martin periodinane (286 mg, 0.675
mmol). The resulting mixture was stirred at 0.degree. C. for 2 h,
quenched with sat. aqueous sodium thiosulfate
(Na.sub.2S.sub.2O.sub.3; 3 mL) and sat. aqueous NaHCO.sub.3 (3 mL)
solution, and then removed from the cold bath and stirred
vigorously for 10 min. The phases were separated and the aqueous
phase was extracted with CH.sub.2Cl.sub.2 (2.times.6 mL) and the
combined organic extracts were dried over Na.sub.2SO.sub.4,
filtered, and concentrated to provide the title compound as a
fluffy white foam (255.4 mg, 98%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.65 (t, J=1.7 Hz, 1H), 7.29 (dd, J=8.7, 7.4
Hz, 2H), 7.02-6.93 (m, 1H), 6.88 (d, J=7.9 Hz, 2H), 5.23-5.08 (m,
2H), 4.30-4.10 (m, 2H), 2.60 (dd, J=16.0, 5.4 Hz, 1H), 2.44 (d,
J=6.4 Hz, 1H), 2.38-2.21 (m, 2H), 1.73 (ddd, J=19.5, 13.8, 9.2 Hz,
3H), 1.44 (s, 9H), 1.37-1.22 (m, 5H); .sup.13C NMR (101 MHz,
CDCl.sub.3) .delta. 200.78, 173.29, 158.65, 154.90, 129.80, 129.73,
121.59, 115.23, 80.63, 79.98, 74.23, 53.28, 46.09, 36.71, 33.64,
31.78, 28.33, 19.72, 18.18; ESIMS m/z 428.2 ([M+Na].sup.+).
Example 7
Step 2c-2: Preparation of tert-butyl
((3S,7R,8R,9S)-7-(2,2-difluoroethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)-
carbamate
##STR00050##
[0145] To a solution of tert-butyl
((3S,7R,8R,9S)-9-methyl-2-oxo-7-(2-oxoethyl)-8-phenoxyoxonan-3-yl)carbama-
te (241 mg, 0.594 mmol) in anhydrous CH.sub.2Cl.sub.2 (6 mL) at
0.degree. C. (icewater bath) was added Deoxo-Fluor.RTM. (230 .mu.l,
1.248 mmol). The reaction was stirred for 2.5 h, concentrated, and
purified by column chromatography on SiO.sub.2 (2.fwdarw.20%
acetone/hexanes) to provide the title compound as a white
crystalline solid (153.2 mg, 60.3%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.29 (dtd, J=10.1, 4.8, 2.5 Hz, 2H), 7.01-6.95
(m, 1H), 6.93 (d, J=8.0 Hz, 2H), 5.83 (tt, J=57.0, 4.6 Hz, 1H),
5.18-5.00 (m, 2H), 4.21 (q, J=8.7 Hz, 2H), 2.29 (dt, J=13.4, 6.8
Hz, 1H), 2.12-1.94 (m, 2H), 1.91-1.77 (m, 2H), 1.77-1.70 (m, 1H),
1.66-1.54 (m, 1H), 1.44 (s, 9H), 1.30 (d, J=6.5 Hz, 3H), 1.27-1.16
(m, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 173.21, 158.93,
154.89, 129.83, 121.55, 116.74 (t, J=239.4 Hz), 115.25, 80.57,
79.97, 74.39, 53.02, 37.53, 35.74 (t, J=21.1 Hz), 33.86, 29.44,
28.32, 19.21, 18.27; ESIMS m/z 450.3 ([M+Na).sup.+]).
Example 7
Step 2d-1: Preparation of tert-butyl
((3S,7R,8R,9S)-7-(2-bromoethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carba-
mate (F249)
##STR00051##
[0147] To a solution of tert-butyl
((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)car-
bamate (700 mg, 1.718 mmol) in CH.sub.2Cl.sub.2 (17 mL) at
0.degree. C. (icewater bath) were added perbromomethane (627 mg,
1.890 mmol) and triphenylphosphine (541 mg, 2.061 mmol). After 70
min, TLC (2:1 hexanes:acetone) showed incomplete conversion so
additional CBr.sub.4 and Ph.sub.3P (64 mg and 54 mg, respectively)
were added and the reaction was stirred for an additional 20 min.
The reaction was concentrated and purified by column chromatography
on SiO.sub.2 (5.fwdarw.20% acetone/hexanes) to provide the title
compound as a hard white foam (712 mg, 88%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.39-7.27 (m, 2H), 7.03-6.82 (m, 3H), 5.18-4.99
(m, 2H), 4.21 (q, J=8.7 Hz, 2H), 3.44 (ddd, J=10.0, 7.4, 5.0 Hz,
1H), 3.33 (ddd, J=9.9, 8.4, 6.9 Hz, 1H), 2.28 (dt, J=13.0, 6.6 Hz,
1H), 2.10 (dtd, J=12.6, 7.9, 4.5 Hz, 1H), 2.05-1.96 (m, 1H),
1.85-1.73 (m, 2H), 1.73-1.61 (m, 1H), 1.44 (s, 10H), 1.30 (d, J=6.5
Hz, 3H), 1.28-1.20 (m, 1H), 1.20-1.09 (m, 1H); .sup.13C NMR (101
MHz, CDCl.sub.3) .delta. 173.20, 159.18, 154.89, 129.74, 121.33,
115.37, 80.94, 79.95, 74.57, 53.02, 41.18, 34.13, 33.95, 31.54,
28.33, 19.13, 18.29; HRMS-ESI (m/z) ([M+Na].sup.+) calcd for
C.sub.22H.sub.32BrNNaO.sub.5, 492.1356; found, 492.1352.
Example 7
Step 2d-2: Preparation of tert-butyl
((3S,7S,8R,9S)-7-ethyl-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carbamate
(F250)
##STR00052##
[0149] To a solution of tert-butyl
((3S,7R,8R,9S)-7-(2-bromoethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carba-
mate (408 mg, 0.867 mmol) and AIBN (14.24 mg, 0.087 mmol) in
anhydrous toluene (8.7 mL) was added Bu.sub.3SnH (257 .mu.l, 0.954
mmol), and the reaction was heated to 80.degree. C. After 1 h, TLC
(4:1 hexanes:acetone) still showed starting material. An additional
0.5 equivalents of Bu.sub.3SnH and 0.05 equiv AIBN were added and
the reaction was stirred for an additional 1 h at 80.degree. C. The
reaction was cooled to room temperature, stirred with 10% aqueous
potassium fluoride (KF) solution (7 mL) for 20 h, and partitioned
between Et.sub.2O (20 mL) and sat. NaCl solution (20 mL). The
phases were separated and the aqueous phase was extracted with
Et.sub.2O (2.times.20 mL). The organic extracts were combined,
dried over MgSO.sub.4, filtered and concentrated to provide a white
solid, which was purified by column chromatography on SiO.sub.2
(5.fwdarw.20% acetone/hexanes) to provide the title compound as a
white solid (295 mg, 87%): .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.38-7.16 (m, 2H), 7.00-6.87 (m, 3H), 5.19-4.97 (m, 2H),
4.18 (t, J=8.8 Hz, 2H), 2.27 (dt, J=13.1, 6.7 Hz, 1H), 1.91-1.77
(m, 1H), 1.70-1.58 (m, 3H), 1.58-1.48 (m, 1H), 1.44 (s, 9H), 1.28
(d, J=6.5 Hz, 3H), 1.25-1.14 (m, 2H), 1.12-1.01 (m, 1H), 0.86 (t,
J=7.3 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 173.34,
159.68, 154.91, 129.58, 120.95, 115.40, 81.44, 79.86, 74.74, 53.00,
44.96, 34.20, 28.34, 27.85, 27.03, 26.85, 23.50, 18.74, 18.40,
17.53, 13.61, 11.86; ESIMS m/z 392.3 ([M+H].sup.+), 414.3
([M+Na].sup.+).
Example 7
Step 2e: Preparation of
((3S,7R,8R,9S)-7-(2-fluoroethyl)-8-isobutoxy-9-methyl-2-oxooxonan-3-yl)ca-
rbamate (F235)
##STR00053##
[0151] To a solution of tert-butyl
((3S,7R,8R,9S)-7-(2-hydroxyethyl)-8-isobutoxy-9-methyl-2-oxooxonan-3-yl)c-
arbamate (200 mg, 0.516 mmol) in anhydrous chloroform (CHCl.sub.3;
5.1 mL) at 0.degree. C. (icewater bath) was added Deoxo-Fluor.RTM.
(114 .mu.l, 0.619 mmol). The resulting solution was stirred at
0.degree. C. for 4 h, poured into H.sub.2O (20 mL) and extracted
with CH.sub.2Cl.sub.2 (3.times.20 mL). The organic extracts were
combined, dried over Na.sub.2SO.sub.4, filtered, and concentrated
to provide a yellow solid, which was purified by column
chromatography on SiO.sub.2 (2.fwdarw.25% acetone/hexanes) to
provide the title compound as a white solid (177 mg, 88%) as a
white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.07 (d,
J=8.1 Hz, 1H), 4.92-4.78 (m, 1H), 4.55 (td, J=5.6, 3.2 Hz, 1H),
4.47-4.37 (m, 1H), 4.15 (dt, J=10.7, 7.8 Hz, 1H), 3.43 (dd, J=8.4,
6.6 Hz, 1H), 3.24 (dd, J=8.4, 6.4 Hz, 1H), 3.09-2.96 (m, 1H), 2.22
(dt, J=13.4, 6.7 Hz, 1H), 2.10-1.95 (m, 1H), 1.83 (dp, J=13.2, 6.6
Hz, 1H), 1.67 (d, J=7.9 Hz, 3H), 1.64-1.53 (m, 2H), 1.44 (s, 9H),
1.40 (d, J=6.4 Hz, 3H), 1.17 (q, J=11.6 Hz, 1H), 1.08-0.97 (m, 1H),
0.94-0.88 (m, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) .delta.
173.30, 154.91, 83.83, 83.78, 82.14, 80.21, 79.82, 75.14, 52.97,
39.75, 34.06, 31.57, 31.37, 29.15, 28.69, 28.32, 19.44, 19.40,
19.07, 18.14; ESIMS m/z 412.3 ([M+Na].sup.+).
Example 7
Step 2f-1: Preparation of tert-butyl
((3S,7R,8R,9S)-9-methyl-7-(2-((2-nitrophenyl)selanyl)ethyl)-2-oxo-8-pheno-
xyoxonan-3-yl)carbamate
##STR00054##
[0153] To a solution of tert-butyl
((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)car-
bamate (227 mg, 0.557 mmol) in anhydrous THF (5.6 mL) at 0.degree.
C. (ice water bath) were added 1-nitro-2-selenocyanatobenzene (177
mg, 0.780 mmol) and tributylphosphine (223 .mu.l, 0.891 mmol). The
resulting solution was stirred for 3 h and then treated with
additional 1-nitro-2-selenocyanatobenzene and tributylphospine (53
mg and 67 .mu.L, respectively). The reaction was stirred for an
additional 1 h, then poured into 20 mL sat. NaCl solution and
extracted with 3.times.20 mL EtOAc. The organic extracts were
combined, dried over MgSO.sub.4, filtered, and concentrated to
provide a brown oil, which was purified by column chromatography on
SiO.sub.2 (2.fwdarw.20% acetone/hexanes) to provide the title
compound as a bright yellow solid (294 mg, 89%): .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.24 (dt, J=8.2, 1.0 Hz, 1H), 7.36-7.19
(m, 5H), 7.00-6.92 (m, 1H), 6.92-6.84 (m, 2H), 5.16-4.98 (m, 2H),
4.21 (t, J=8.5 Hz, 2H), 3.05-2.76 (m, 2H), 2.30 (dt, J=13.2, 6.7
Hz, 1H), 1.94 (tdq, J=28.6, 14.1, 8.4, 6.4 Hz, 3H), 1.78-1.64 (m,
2H), 1.60 (d, J=4.5 Hz, 1H), 1.45 (s, 9H), 1.30 (d, J=6.5 Hz, 3H),
1.27-1.13 (m, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) .delta.
173.23, 159.12, 154.89, 146.86, 133.45, 133.21, 129.76, 128.95,
126.41, 125.29, 121.34, 115.33, 80.99, 79.97, 74.59, 52.99, 43.60,
34.00, 29.99, 28.58, 28.33, 24.24, 19.15, 18.29; ESIMS m/z 593.2
([M+Na].sup.+).
Example 7
Step 2f-2: Preparation of tert-butyl
((3S,7R,8R,9S)-9-methyl-2-oxo-8-phenoxy-7-vinyloxonan-3-yl)carbamate
(F259)
##STR00055##
[0155] To a solution of tert-butyl
((3S,7R,8R,9S)-9-methyl-7-(2-((2-nitrophenyl)-selanyl)ethyl)-2-oxo-8-phen-
oxyoxonan-3-yl)carbamate (284 mg, 0.480 mmol) in THF (4.8 mL) was
added 30% aqueous hydrogen peroxide (H.sub.2O.sub.2 392 .mu.l, 3.84
mmol), and the resulting bright yellow solution was stirred at room
temperature for 3 d. The reaction was cooled to 0.degree. C.
(icewater bath), quenched with sat. aqueous NaHSO.sub.3 solution (4
mL), diluted with H.sub.2O (20 mL), and extracted with EtOAc
(3.times.20 mL). The organic extracts were combined, dried over
MgSO.sub.4, filtered, and concentrated to the title compound as an
orange solid (134.9 mg, 72%): .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.34-7.19 (m, 2H), 7.02-6.86 (m, 3H), 5.76 (ddd, J=17.2,
10.3, 8.0 Hz, 1H), 5.17-5.06 (m, 2H), 5.03 (d, J=17.1 Hz, 1H), 4.94
(d, J=10.4 Hz, 1H), 4.28 (t, J=8.8 Hz, 1H), 4.25-4.17 (m, 1H),
2.56-2.41 (m, 1H), 2.27 (dt, J=13.5, 6.6 Hz, 1H), 1.85 (td, J=14.6,
7.1 Hz, 1H), 1.75 (dt, J=14.8, 7.3 Hz, 1H), 1.65 (s, 1H), 1.44 (s,
9H), 1.33 (d, J=6.4 Hz, 3H), 1.31-1.17 (m, 2H); .sup.13C NMR (101
MHz, CDCl.sub.3) .delta. 173.35, 159.33, 138.51, 129.49, 121.10,
116.18, 115.78, 99.98, 80.46, 74.39, 53.05, 47.47, 34.13, 31.07,
28.34, 19.66, 18.36; HRMS-ESI (m/z) ([M+Na].sup.+) calcd for
C.sub.22H.sub.31NO.sub.5Na, 412.2094, found 412.2106.
Example 8
Step 1: Preparation of
(3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl)-2-oxo-8-phenoxyoxonan-3-aminium
chloride (F244)
##STR00056##
[0157] A 25 mL screw top vial was charged with tert-butyl
((3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl)-2-oxo-8-phenoxyoxonan-3-yl)car-
bamate (300 mg, 0.642 mmol), anhydrous CH.sub.2Cl.sub.2 (4 mL), and
4.0 M HCl in dioxane (3.21 mL, 12.83 mmol). After stirring at room
temperature for 80 min, the reaction mixture was concentrated under
a stream of nitrogen and dried under high vacuum to provide the
title compound as a beige solid (259 mg, 100%): mp 200-210.degree.
C. (dec.); .sup.1H NMR (400 MHz, CDCl3) .delta. 7.46-6.81 (m, 9H),
5.14 (s, 1H), 3.78-3.52 (m, 3H), 2.86 (s, 1H), 2.60-1.12 (m, 12H),
0.96 (s, 1H); .sup.13C NMR (101 MHz, CD.sub.3OD) .delta. 171.05,
160.65, 137.89, 136.19, 130.75, 129.87, 129.75, 122.14, 117.03,
81.89, 76.55, 68.05, 46.67, 37.46, 32.38, 27.71, 21.05, 20.12,
18.85; ESIMS m/z 369 ([M+H].sup.+).
Example 8
Step 2: Preparation of
3-hydroxy-4-methoxy-N-((3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl)-2-oxo-8--
phenoxyoxonan-3-yl)picolinamide (F49)
##STR00057##
[0159] A 25 mL screw top vial was charged with
(3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl)-2-oxo-8-phenoxyoxonan-3-aminium
chloride (259 mg, 0.642 mmol), 3-hydroxy-4-methoxypicolinic acid
(122 mg, 0.721 mmol), anhydrous CH.sub.2Cl.sub.2 (6.5 mL), and
N,N-diisopropylethylamine (340 .mu.L, 1.95 mmol). To the mixture
was added PyBOP (376 mg, 0.723 mmol) and the reaction was stirred
at room temperature for 1.5 h and then directly purified by column
chromatography on SiO.sub.2 (2.fwdarw.30% acetone/hexanes) to
provide the title compound as a white solid (162 mg, 49%): mp
62-66.degree. C.; .sup.1H NMR (400 MHz, CDCl3) .delta. 12.09 (s,
1H), 8.48 (d, J=8.2 Hz, 1H), 7.98 (d, J=5.1 Hz, 1H), 7.37-7.28 (m,
2H), 7.12-6.93 (m, 7H), 6.86 (d, J=5.2 Hz, 1H), 5.14 (dq, J=9.2,
6.4 Hz, 1H), 4.62 (dt, J=10.9, 7.4 Hz, 1H), 4.35 (t, J=8.9 Hz, 1H),
3.93 (s, 3H), 2.99 (dd, J=13.3, 3.2 Hz, 1H), 2.42-2.26 (m, 5H),
2.16-2.04 (m, 1H), 1.79-1.52 (m, 3H), 1.41-1.23 (m, 4H), 1.08-0.98
(m, 1H); .sup.13C NMR (101 MHz, CDCl3) .delta. 172.06, 168.59,
159.58, 155.27, 148.66, 140.47, 136.92, 135.38, 130.28, 129.63,
128.98, 128.59, 121.16, 115.48, 109.43, 81.02, 74.89, 55.99, 51.43,
45.59, 36.34, 33.47, 26.57, 20.95, 18.78, 18.33; ESIMS: m/z 519
([M+H].sup.+).
Example 9
Preparation of
((2-(((3S,7R,8R,9S)-7-(2-fluoroethyl)-8-isobutoxy-9-methyl-2-oxooxonan-3--
yl)carbamoyl)-4-methoxypyridin-3-yl)oxy)methyl acetate (F128)
##STR00058##
[0161] To a solution of
N-((3S,7R,8R,9S)-7-(2-fluoroethyl)-8-isobutoxy-9-methyl-2-oxooxonan-3-yl)-
-3-hydroxy-4-methoxypicolinamide (97 mg, 0.220 mmol) in anhydrous
acetone (2.2 mL) were added powdered K.sub.2CO.sub.3 (60.9 mg,
0.440 mmol) and bromomethyl acetate (32.4 .mu.l, 0.330 mmol). The
resulting mixture was heated to 50.degree. C. and stirred
vigorously for 16 h, then filtered through a plug of Celite.RTM.,
concentrated, and purified by column chromatography on SiO.sub.2
(5.fwdarw.50% acetone/hexanes) to provide the title compound as a
sticky solid (87 mg, 77%): .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.34 (d, J=8.1 Hz, 1H), 8.28 (d, J=5.4 Hz, 1H), 6.95 (d,
J=5.4 Hz, 1H), 5.74 (s, 2H), 4.90 (dq, J=9.1, 6.4 Hz, 1H), 4.58
(ddt, J=9.4, 5.9, 4.6 Hz, 2H), 4.50-4.39 (m, 1H), 3.91 (s, 3H),
3.45 (dd, J=8.4, 6.6 Hz, 1H), 3.26 (dd, J=8.4, 6.4 Hz, 1H),
3.14-3.02 (m, 1H), 2.36 (dt, J=12.9, 6.7 Hz, 1H), 2.07 (s, 3H),
2.06-1.98 (m, 1H), 1.84 (dp, J=13.4, 6.7 Hz, 1H), 1.78-1.60 (m,
4H), 1.57 (s, 1H), 1.42 (d, J=6.4 Hz, 3H), 1.39-1.29 (m, 1H), 1.10
(dd, J=14.3, 5.7 Hz, 1H), 0.92 (d, J=6.8 Hz, 6H); .sup.13C NMR (101
MHz, CDCl.sub.3) .delta. 170.35, 167.84, 160.52, 157.81, 143.31,
141.51, 140.02, 107.14, 87.11, 81.42, 81.36, 79.73, 77.78, 72.81,
53.74, 49.43, 37.34, 37.30, 31.13, 29.17, 28.98, 26.73, 26.26,
18.44, 17.02, 16.98, 16.74, 15.69; HRMS-ESI (m/z) ([M+Na].sup.+)
calcd for C.sub.25H.sub.37FN.sub.2O.sub.8Na, 535.2426, found
535.2423.
Example 10
Preparation of
4-methoxy-2-(((3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl)-2-oxo-8-phenoxyox-
onan-3-yl)carbamoyl)pyridin-3-yl acetate (F79)
##STR00059##
[0163] A 25 mL screw top vial was charged with
3-hydroxy-4-methoxy-N-methoxy-N-((3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl-
)-2-oxo-8-phenoxyoxonan-3-yl)picolinamide (74.0 mg, 0.143 mmol),
DMAP (19.4 mg, 0.159 mmol), 1,2-dichloroethane (DCE; 1 mL), acetyl
chloride (20 .mu.L, 0.281 mmol), and NEt.sub.3 (70 .mu.L, 0.502
mmol). The resulting mixture was heated to 50.degree. C. for 7 h.
After cooling to room temperature, the crude reaction mixture was
directly purified by column chromatography on SiO.sub.2
(2.fwdarw.40% acetone/hexanes) to provide the title compound as a
white solid (56.0 mg, 70%): mp 96-100.degree. C.; .sup.1H NMR (400
MHz, CDCl3) .delta. 8.53 (d, J=8.4 Hz, 1H), 8.33 (d, J=5.5 Hz, 1H),
7.36-7.27 (m, 2H), 7.12-6.92 (m, 8H), 5.12 (dq, J=9.1, 6.4 Hz, 1H),
4.63 (dt, J=10.9, 7.5 Hz, 1H), 4.33 (t, J=8.9 Hz, 1H), 3.89 (s,
3H), 2.97 (dd, J=13.3, 3.2 Hz, 1H), 2.41 (s, 3H), 2.32 (d, J=9.3
Hz, 5H), 2.14-2.03 (m, 1H), 1.73-1.48 (m, 3H), 1.39-1.19 (m, 5H);
.sup.13C NMR (101 MHz, CDCl3) .delta. 172.55, 168.83, 162.34,
159.62, 159.36, 146.65, 141.31, 137.42, 137.01, 135.34, 129.62,
128.96, 128.61, 121.12, 115.50, 109.76, 81.10, 74.64, 56.22, 51.52,
45.62, 36.35, 33.75, 26.67, 20.95, 20.69, 18.83, 18.31; ESIMS: m/z
561 ([M+H].sup.+).
Example 11
Preparation of
2-(((3S,7R,8R,9S)-8-(cyclopropylmethoxy)-7-(4-methoxybenzyl)-9-methyl-2-o-
xooxonan-3-yl)carbamoyl)-4-methoxypyridin-3-yl 3-methoxypropanoate
(F195)
##STR00060##
[0165] To a 4 mL vial were added
N-((3S,7R,8R,9S)-8-(cyclopropylmethoxy)-7-(4-methoxybenzyl)-9-methyl-2-ox-
ooxonan-3-yl)-3-hydroxy-4- methoxypicolinamide (85 mg, 0.166 mmol),
CH.sub.2Cl.sub.2 (1 mL) and NEt.sub.3 (0.069 mL, 0.497 mmol),
3-methoxypropanoyl chloride (30.5 mg, 0.249 mmol), and DMAP (3 mg,
0.02 mmol), and the resulting light yellow solution was stirred at
room temperature overnight. The reaction mixture was concentrated
and purified by column chromatography on SiO.sub.2 (0.fwdarw.100%
EtOAc/hexanes) to provide the title compound as a colorless
semi-solid (77.8 mg, 78%): IR (neat) 3381, 2936, 1769, 1742, 1678,
1511, 1246, 1111 cm.sup.-1; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.47 (d, J=7.3 Hz, 1H), 8.31 (d, J=5.4 Hz, 1H), 7.09 (d,
J=8.6 Hz, 2H), 6.98 (d, J=5.5 Hz, 1H), 6.83 (d, J=8.6 Hz, 2H), 4.91
(dq, J=9.1, 6.4 Hz, 1H), 4.55 (ddd, J=10.9, 8.4, 7.0 Hz, 1H), 3.88
(s, 3H), 3.81 (t, J=6.6 Hz, 2H), 3.78 (s, 3H), 3.57 (dd, J=9.7, 7.0
Hz, 1H), 3.44 (dd, J=9.7, 6.8 Hz, 1H), 3.41 (s, 3H), 3.15 (t, J=9.0
Hz, 1H), 3.07 (dd, J=13.4, 3.3 Hz, 1H), 2.98 (t, J=6.6 Hz, 2H),
2.35-2.20 (m, 2H), 1.87-1.77 (m, 1H), 1.61-1.47 (m, 2H), 1.48-1.37
(m, 1H), 1.45 (d, J=6.4 Hz, 3H), 1.22-1.05 (m, 2H), 0.90-0.79 (m,
1H), 0.63-0.49 (m, 2H), 0.29-0.14 (m, 2H); .sup.13C NMR (101 MHz,
CDCl.sub.3) .delta. 172.61, 169.39, 162.32, 159.40, 157.82, 146.76,
141.45, 137.29, 132.66, 129.73, 113.77, 109.78, 83.79, 78.71,
75.22, 67.58, 58.78, 56.30, 55.22, 51.47, 46.17, 35.92, 34.62,
33.89, 26.55, 18.73, 18.08, 11.18, 3.16, 3.00; HRMS-ESI (m/z)
([M].sup.+) calcd for C.sub.32H.sub.42N.sub.2O.sub.9, 598.2890;
found, 598.2914.
Example 12
Preparation of
((2-(((3S,7R,8R,9S)-7-(cyclopentylmethyl)-8-(cyclopropylmethoxy)-9-methyl-
-2-oxooxonan-3-yl)carbamoyl)-4-methoxypyridin-3-yl)oxy)methyl
isobutyrate (F154)
##STR00061##
[0167] To a mixture of
N-((3S,7R,8R,9S)-7-(cyclopentylmethyl)-8-(cyclopropylmethoxy)-9-methyl-2--
oxooxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (60 mg, 0.126 mmol)
and K.sub.2CO.sub.3 (34.9 mg, 0.253 mmol) in acetone (1 mL) was
added chloromethyl isobutyrate (34.5 mg, 0.253 mmol) and the
reaction was heated to 60.degree. C. After TLC analysis indicated
full consumption of the picolinamide starting material, the mixture
was concentrated under a stream of N.sub.2 and the residue purified
by column chromatography on SiO.sub.2 (gradient, EtOAc/hexanes) to
yield the title compound as a colorless semi-solid (60.4 mg, 83%):
IR (thin film) 3381, 2942, 1745, 1678, 1506, 974 cm.sup.-1; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.38 (d, J=8.2 Hz, 1H), 8.27 (d,
J=5.3 Hz, 1H), 6.93 (d, J=5.4 Hz, 1H), 5.81-5.61 (m, 2H), 4.89 (dd,
J=9.2, 6.3 Hz, 1H), 4.57 (dt, J=11.0, 7.5 Hz, 1H), 3.89 (s, 3H),
3.50 (dd, J=9.6, 7.0 Hz, 1H), 3.36 (dd, J=9.6, 6.9 Hz, 1H), 3.01
(t, J=9.0 Hz, 1H), 2.54 (p, J=7.0 Hz, 1H), 2.36 (dd, J=13.1, 6.8
Hz, 1H), 1.92-1.43 (m, 15H), 1.42 (d, J=6.5 Hz, 2H), 1.35-1.19 (m,
2H), 1.14 (d, J=7.0 Hz, 3H), 1.17-0.92 (m, 5H), 0.62-0.48 (m, 2H),
0.29-0.17 (m, 2H); HRMS-ESI (m/z) ([M].sup.+) calcd for
C.sub.31H.sub.46N.sub.2O.sub.8, 574.3254; found, 574.3262.
Example 13
Preparation of
((4-methoxy-2-(((3S,7R,8R,9S)-9-methyl-7-(4-methyl-benzyl)-2-oxo-8-(4,4,4-
-trifluorobutoxy)oxonan-3-yl)carbamoyl)pyridin-3-yl)oxy)methyl
2-ethoxyacetate (F190)
##STR00062##
[0169] To a 25 mL screw top vial were added
3-hydroxy-4-methoxy-N-((3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl)-2-oxo-8--
(4,4,4-trifluorobutoxy)oxonan-3-yl)picolinamide (87.9 mg, 0.159
mmol), Na.sub.2CO.sub.3 (33.8 mg, 0.319 mmol), NaI (6.3 mg, 0.264
mmol), anhydrous acetone (2 mL), and chloromethyl 2-ethoxyacetate
(40.8 mg, 1.68 mmol), and the resulting mixture was warmed to
40.degree. C. and stirred for 17 h. The reaction was cooled to room
temperature, concentrated under a stream of nitrogen, and purified
by column chromatography on SiO.sub.2 (2.fwdarw.40%
acetone/hexanes) to provide the title compound as a colorless oil
(58.8 mg, 52%): .sup.1H NMR (400 MHz, CDCl3) .delta. 8.29 (d, J=8.1
Hz, 1H), 8.25 (d, J=5.4 Hz, 1H), 7.09 (d, J=7.9 Hz, 2H), 7.03 (d,
J=8.0 Hz, 2H), 6.93 (d, J=5.4 Hz, 1H), 5.80 (s, 2H), 4.89 (dq,
J=9.1, 6.4 Hz, 1H), 4.55 (dt, J=10.9, 7.4 Hz, 1H), 4.08 (s, 2H),
3.88 (s, 3H), 3.80 (dt, J=8.9, 6.1 Hz, 1H), 3.64-3.54 (m, 3H), 3.17
(t, J=9.0 Hz, 1H), 2.96 (dd, J=13.3, 3.4 Hz, 1H), 2.40-2.13 (m,
7H), 1.92-1.76 (m, 3H), 1.65 -1.37 (m, 6H), 1.30-1.14 (m, 4H),
0.93-0.80 (m, 1H); .sup.13C NMR (101 MHz, CDCl3) .delta. 172.62,
169.97, 162.83, 160.09, 145.73, 143.81, 142.18, 137.20, 135.41,
129.02, 128.58, 131.42-122.86 (m), 109.65, 89.44, 84.20, 74.83,
71.60, 67.71, 67.10, 56.15, 51.69, 45.80, 36.42, 33.56, 30.73 (q,
J=29.0 Hz), 26.62, 23.01 (q, J=3.1 Hz), 20.93, 18.75, 18.05, 14.94;
.sup.19F NMR (376 MHz, CDCl3) .delta. -66.35, ESIMS: m/z 669
([M+H].sup.+).
Example 14
Preparation of (S)-benzyl
5-((2R,3R)-2-((S)-1-(benzyloxy)ethyl)-tetrahydrofuran-3-yl)-2-((tert-buto-
xycarbonyl)amino)pentanoate
##STR00063##
[0171] To a solution of (2S,6R,7R,8S)-benzyl
8-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-7-(cyclopropylmethoxy)-6-(2--
hydroxyethyl)nonanoate (570 mg, 0.976 mmol) in anhydrous
CH.sub.2Cl.sub.2 (10 mL) at 0.degree. C. were added CBr.sub.4 (389
mg, 1.172 mmol) and triphenylphosphine (333 mg, 1.269 mmol). The
resulting solution was stirred for 6 h, at which time UPLC-MS
showed .about.50% conversion to the desired product. The reaction
was allowed to warm to room temperature and stirred for 3 d. The
mixture was concentrated and purified by column chromatography on
SiO.sub.2 (2.fwdarw.25% acetone/hexanes) to provide the title
compound as a clear, colorless oil (399.6 mg, 80%): .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.39-7.28 (m, 9H), 7.28-7.21 (m, 1H),
5.20 (d, J=12.3 Hz, 1H), 5.11 (d, J=12.3 Hz, 1H), 5.00 (d, J=8.1
Hz, 1H), 4.62 (d, J=11.9 Hz, 1H), 4.49 (d, J=11.9 Hz, 1H),
4.42-4.26 (m, 1H), 3.78 (dd, J=8.3, 4.8 Hz, 2H), 3.56-3.40 (m, 2H),
1.96 (ddd, J=14.2, 10.0, 7.2 Hz, 2H), 1.76 (dd, J=8.8, 4.7 Hz, 1H),
1.68-1.55 (m, 1H), 1.49 (dd, J=7.8, 3.6 Hz, 2H), 1.44 (s, 9H),
1.39-1.33 (m, 1H), 1.32-1.21 (m, 2H), 1.18 (d, J=6.1 Hz, 3H);
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 172.71, 155.37, 138.92,
135.43, 128.60, 128.43, 128.32, 128.29, 127.59, 127.41, 87.07,
79.88, 71.09, 67.77, 66.97, 53.39, 40.81, 33.92, 32.84, 32.66,
28.33, 24.04, 16.01; ESIMS m/z 412.3 ([M+H].sup.+) for M-BOC.
Example 15
Preparation of (phenylthio)methyl 2-ethoxyacetate
##STR00064##
[0173] To a mixture of Cs.sub.2CO.sub.3 (29.5 g, 91 mmol) in DMF
(150 mL) at 0.degree. C. was added 2-ethoxyacetic acid (18.0 mL,
191 mmol), and the resulting mixture was heated at 70.degree. C.
for 30 min. The reaction was cooled to 0.degree. C., chloromethyl
phenylsulfide (10.56 mL, 79 mmol) was added, and the reaction was
heated at 70.degree. C. for 90 min. The mixture was cooled to room
temperature, and then 0.degree. C., before diluting with H.sub.2O
(200 mL; an exotherm was observed). The reaction mixture was
divided into two equal portions and one portion was further diluted
with water (400 mL) and extracted with Et.sub.2O (200 mL.times.2,
100 mL.times.1). The combined organic extracts were diluted with
hexane (100 mL) and washed successively with 1.0 M aqueous NaOH
(100 mL) and brine (2.times.200 mL), dried over anhydrous
MgSO.sub.4, filtered, and concentrated. The second portion of the
reaction mixture from above was processed in an identical fashion
and the two lots were combined and concentrated in vacuo to afford
the title compound as a yellow oil (12.28 g, 97%): .sup.1H NMR (400
MHz, CDCl3) .delta. 7.48-7.41 (m, 2H), 7.31 (ddd, J=12.6, 7.9, 6.3
Hz, 3H), 5.51 (s, 2H), 4.11 (s, 2H), 3.59 (q, J=7.0 Hz, 2H), 1.24
(t, J=7.0 Hz, 3H); .sup.13C NMR (101 MHz, CDCl3) .delta. 170.00,
134.35, 130.53, 129.16, 127.55, 68.46, 68.10, 67.32, 14.99; ESIMS:
m/z 226 ([M].sup.+).
Example 15
Step 2: Preparation of chloromethyl 2-ethoxyacetate
##STR00065##
[0175] To a solution of (phenylthio)methyl 2-ethoxyacetate (17.28
g, 76 mmol) in CH.sub.2Cl.sub.2 (200 mL) at 0.degree. C. was added
a solution of sulfuryl chloride (7.36 mL, 92 mmol) in
CH.sub.2Cl.sub.2 (50 mL) over a period of 15 min, and the reaction
was stirred at room temperature for 90 min. The reaction was again
cooled to 0.degree. C. and treated with a second portion of
sulfuryl chloride (7.36 mL, 92 mmol) in CH.sub.2Cl.sub.2 (50 mL)
over a period of 15 min. The reaction was then warmed to 30.degree.
C., stirred for 1 hour, and then cooled back to 0.degree. C. A
solution of cyclohexene (24.5 mL, 242 mmol) in CH.sub.2Cl.sub.2 (50
mL) was added over a period of 10 min, during which gas evolution
was observed. The reaction was stirred at room temperature for 90
min, stored at -20.degree. C. overnight, and purified by vacuum
distillation to give the target compound as a slightly yellow oil
(11.33 g, 97%): bp 58.degree. C. at 6.8 mm Hg; .sup.1H NMR (400
MHz, CDCl3) .delta. 5.77 (s, 2H), 4.16 (s, 2H), 3.62 (q, J=7.0 Hz,
2H), 1.27 (t, J=7.0 Hz, 3H); .sup.13C NMR (101 MHz, CDCl3) .delta.
168.81, 68.59, 67.77, 67.48, 14.96.
Example 16
Preparation of
N-((3S,7R,8R,9S)-7-(cyclohexylmethyl)-8-(cyclopropyl-methoxy)-9-methyl-2--
oxooxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (F9)
##STR00066##
[0177] A high pressure reactor equipped with a stir bar was charged
with a solution of
N-((3S,7R,8R,9S)-8-(cyclopropylmethoxy)-7-(4-fluorobenzyl)-9-methyl-2-oxo-
oxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (230 mg, 0.459 mmol)
in THF (7 mL) and 5% rhodium on carbon (56.8 mg, 0.028 mmol). After
the reactor was sealed and purged with H.sub.2 (4.times.), the
reaction was charged to .about.600 psi of H.sub.2 at room
temperature. The reactor was warmed to 70.degree. C. and stirred
for 29 h, cooled to room temperature, and the reaction mixture was
filtered through a Celite.RTM. pad. The filtrate was concentrated
and purified by column chromatography on SiO.sub.2 (gradient,
hexanes/ethyl acetate) to furnish the title product as a white
solid (60.8 mg, 27%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
12.11 (d, J=0.6 Hz, 1H), 8.49 (d, J=8.2 Hz, 1H), 7.99 (d, J=5.2 Hz,
1H), 6.87 (d, J=5.2 Hz, 1H), 4.95-4.84 (m, 1H), 4.55 (ddd, J=10.7,
8.2, 7.0 Hz, 1H), 3.94 (s, 3H), 3.49 (dd, J=9.6, 7.0 Hz, 1H), 3.37
(dd, J=9.6, 6.8 Hz, 1H), 3.01 (t, J=8.8 Hz, 1H), 2.39-2.28 (m, 1H),
1.78-1.46 (m, 10H), 1.45 (d, J=7.0 Hz, 3H), 1.41-0.71 (m, 10H),
0.59-0.52 (m, 2H), 0.26-0.18 (m, 2H); .sup.13C NMR (101 MHz,
CDCl.sub.3) .delta. 172.21, 168.62, 155.31, 148.69, 140.51, 130.42,
109.44, 84.33, 78.51, 75.66, 56.05, 51.49, 40.09, 38.30, 35.05,
34.59, 33.63, 32.34, 27.44, 26.68, 26.48, 26.15, 18.77, 18.10,
11.14, 3.16, 2.94; ESIMS m/z 489.3 ([M+H].sup.+).
Example A
Evaluation of Fungicidal Activity: Leaf Blotch of Wheat
(Mycosphaerella Graminicola; Anamorph: Septoria Tritici; Bayer Code
SEPTTR)
[0178] Technical grades of materials were dissolved in acetone,
which were then mixed with nine volumes of water containing 110 ppm
Triton X-100. The fungicide solutions were applied onto wheat
seedlings using an automated booth sprayer to run-off. All sprayed
plants were allowed to air dry prior to further handling. All
fungicides were evaluated using the aforementioned method for their
activity vs. all target diseases. Wheat leaf blotch and brown rust
activity were also evaluated using track spray applications, in
which case the fungicides were formulated as EC formulations,
containing 0.1% Trycol 5941 in the spray solutions.
[0179] Wheat plants (variety Yuma) were grown from seed in a
greenhouse in 50% mineral soil/50% soil-less Metro mix until the
first leaf was fully emerged, with 7-10 seedlings per pot. These
plants were inoculated with an aqueous spore suspension of Septoria
tritici either prior to or after fungicide treatments. After
inoculation the plants were kept in 100% relative humidity (one day
in a dark dew chamber followed by two to three days in a lighted
dew chamber at 20.degree. C.) to permit spores to germinate and
infect the leaf. The plants were then transferred to a greenhouse
set at 20.degree. C. for disease to develop. When disease symptoms
were fully expressed on the 1.sup.st leaves of untreated plants,
infection levels were assessed on a scale of 0 to 100 percent
disease severity. Percent disease control was calculated using the
ratio of disease severity on treated plants relative to untreated
plants.
Example B
Evaluation of Fungicidal Activity: Wheat Brown Rust (Puccinia
Triticina; Synonym: Puccinia Recondita f. sp. Tritici; Bayer Code
PUCCRT)
[0180] Wheat plants (variety Yuma) were grown from seed in a
greenhouse in 50% mineral soil/50% soil-less Metro mix until the
first leaf was fully emerged, with 7-10 seedlings per pot. These
plants were inoculated with an aqueous spore suspension of Puccinia
triiticina either prior to or after fungicide treatments. After
inoculation the plants were kept in a dark dew room at 22.degree.
C. with 100% relative humidity overnight to permit spores to
germinate and infect the leaf. The plants were then transferred to
a greenhouse set at 24.degree. C. for disease to develop. Fungicide
formulation, application and disease assessment followed the
procedures as described in the Example A.
Example C
Evaluation of Fungicidal Activity: Wheat Glume Blotch
(Leptosphaeria Nodorum; Bayer Code LEPTNO)
[0181] Wheat plants (variety Yuma) were grown from seed in a
greenhouse in 50% mineral soil/50% soil-less Metro mix until the
first leaf was fully emerged, with 7-10 seedlings per pot. These
plants were inoculated with an aqueous spore suspension of
Leptosphaeria nodorum 24 hr after fungicide treatments. After
inoculation the plants were kept in 100% relative humidity (one day
in a dark dew chamber followed by two days in a lighted dew chamber
at 20.degree. C.) to permit spores to germinate and infect the leaf
The plants were then transferred to a greenhouse set at 20.degree.
C. for disease to develop. Fungicide formulation, application and
disease assessment followed the procedures as described in the
Example A.
Example D
Evaluation of Fungicidal Activity: Apple Scab (Venturia Inaequalis;
Bayer Code VENTIN)
[0182] Apple seedlings (variety McIntosh) were grown in soil-less
Metro mix, with one plant per pot. Seedlings with two expanding
young leaves at the top (older leaves at bottom of the plants were
trimmed) were used in the test. Plants were inoculated with a spore
suspension of Venturia inaequalis 24 hr after fungicide treatment
and kept in a 22.degree. C. dew chamber with 100% RH for 48 hr, and
then moved to a greenhouse set at 20.degree. C. for disease to
develop. Fungicide formulation, application and disease assessment
on the sprayed leaves followed the procedures as described in the
Example A.
Example E
Evaluation of Fungicidal Activity: Grape Powdery Mildew (Uncinula
Necator; Bayer Code UNCINE)
[0183] Grape seedlings (variety Carignane) were grown in soil-less
Metro mix, with one plant per pot, and used in the test when
approximately one month old. Plants were inoculated 24 hr after
fungicide treatment by shaking spores from infected leaves over
test plants. Plants were maintained in a greenhouse set at
20.degree. C. until disease was fully developed. Fungicide
formulation, application and disease assessment on the sprayed
leaves followed the procedures as described in the Example A.
Example F
Evaluation of Fungicidal Activity: Powdery Mildew of Cucumber
(Erysiphe Cichoracearum; Bayer Code ERYSCI)
[0184] Cucumber seedlings (variety Bush Pickle) were grown in
soil-less Metro mix, with one plant per pot, and used in the test
when 12 to 14 days old. Plants were inoculated with a spore
suspension 24 hr following fungicide treatments. After inoculation
the plants remained in the greenhouse set at 20.degree. C. until
disease was fully expressed. Fungicide formulation, application and
disease assessment on the sprayed leaves followed the procedures as
described in the Example A.
Example G
Evaluation of Fungicidal Activity: Leaf Spot of Sugar Beets
(Cercospora Beticola; Bayer Code CERCBE)
[0185] Sugar beet plants (variety HH88) were grown in soil-less
Metro mix and trimmed regularly to maintain a uniform plant size
prior to test. Plants were inoculated with a spore suspension 24 hr
after fungicide treatments. Inoculated plants were kept in a dew
chamber at 22.degree. C. for 48 hr then incubated in a greenhouse
set at 24.degree. C. under a clear plastic hood with bottom
ventilation until disease symptoms were fully expressed. Fungicide
formulation, application and disease assessment on the sprayed
leaves followed the procedures as described in the Example A.
Example H
Evaluation of Fungicidal Activity: Asian Soybean Rust (Phakopsora
Pachyrhizi; Bayer Code PHAKPA)
[0186] Technical grades of materials were dissolved in acetone,
which were then mixed with nine volumes of water containing 0.011%
Tween 20. The fungicide solutions were applied onto soybean
seedlings using an automated booth sprayer to run-off All sprayed
plants were allowed to air dry prior to further handling.
[0187] Soybean plants (variety Williams 82) were grown in soil-less
Metro mix, with one plant per pot. Two weeks old seedlings were
used for testing. Plants were inoculated either 3 days prior to or
1 day after fungicide treatments. Plants were incubated for 24 h in
a dark dew room at 22.degree. C. and 100% RH then transferred to a
growth room at 23.degree. C. for disease to develop. Disease
severity was assessed on the sprayed leaves.
Example I
Evaluation of Fungicidal Activity: Wheat Powdery Mildew (Blumeria
Graminis f. sp. Tritici; Synonym: Erysiphe Graminis f. sp. Tritici;
Bayer Code ERYSGT)
[0188] Wheat plants (variety Yuma) were grown from seed in a
greenhouse in 50% mineral soil/50% soil-less Metro mix until the
first leaf was fully emerged, with 7-10 seedlings per pot. These
plants were inoculated by dusting with infected stock plants 24 hr
after fungicide treatments. After inoculation the plants were kept
in a greenhouse set at 20.degree. C. for disease to develop.
Fungicide formulation, application and disease assessment on the
sprayed leaves followed the procedures as described in the Example
A.
Example J
Evaluation of Fungicidal Activity: Barley Powdery Mildew (Blumeria
Graminis f. sp. Hordei; Synonym: Erysiphe Graminis f. sp. Hordei;
Bayer Code ERYSGH)
[0189] Barley seedlings (variety Harrington) were propagated in
soil-less Metro mix, with each pot having 8 to 12 plants, and used
in the test when first leaf was fully emerged. Test plants were
inoculated by dusting with infected stock plants 24 hr after
fungicide treatments. After inoculation the plants were kept in a
greenhouse set at 20.degree. C. for disease to develop. Fungicide
formulation, application and disease assessment on the sprayed
leaves followed the procedures as described in the Example A.
Example K
Evaluation of Fungicidal Activity: Barley Scald (Rhyncosporium
Secahs; Bayer Code RHYNSE)
[0190] Barley seedlings (variety Harrington) were propagated in
soil-less Metro mix, with each pot having 8 to 12 plants, and used
in the test when first leaf was fully emerged. Test plants were
inoculated by an aqueous spore suspension of Rhyncosporium secalis
24 hr after fungicide treatments. After inoculation the plants were
kept in a dew room at 20.degree. C. with 100% relative humidity for
48 hr. The plants were then transferred to a greenhouse set at
20.degree. C. for disease to develop. Fungicide formulation,
application and disease assessment on the sprayed leaves followed
the procedures as described in the Example A.
Example L
Evaluation of Fungicidal Activity: Rice Blast (Magnaporthe Grisea;
Anamorph: Pyricularia Oryzae; Bayer Code PYRIOR)
[0191] Rice seedlings (variety Japonica) were propagated in
soil-less Metro mix, with each pot having 8 to 14 plants, and used
in the test when 12 to 14 days old. Test plants were inoculated
with an aqueous spore suspension of Pyricularia oryzae 24 hr after
fungicide treatments. After inoculation the plants were kept in a
dew room at 22.degree. C. with100% relative humidity for 48 hr to
permit spores to germinate and infect the leaf. The plants were
then transferred to a greenhouse set at 24.degree. C. for disease
to develop. Fungicide formulation, application and disease
assessment on the sprayed leaves followed the procedures as
described in the Example A.
Example M
Evaluation of Fungicidal Activity: Tomato Early Blight (Alternaria
Solani; Bayer Code ALTESO)
[0192] Tomato plants (variety Outdoor girl) were propagated in
soil-less Metro mix, with each pot having one plant, and used when
12 to 14 days old. Test plants were inoculated with an aqueous
spore suspension of Alternaria solani 24 hr after fungicide
treatments. After inoculation the plants were kept in 100% relative
humidity (one day in a dark dew chamber followed by two to three
days in a lighted dew chamber at 20.degree. C.). to permit spores
to germinate and infect the leaf. The plants were then transferred
to a growth room at 22.degree. C. for disease to develop. Fungicide
formulation, application and disease assessment on the sprayed
leaves followed the procedures as described in the Example A.
Example N
Evaluation of Fungicidal Activity: Cucumber Anthracnose (Glomerella
Lagenarium; Anamorph: Colletotrichum Lagenarium; Bayer Code
COLLLA)
[0193] Cucumber seedlings (variety Bush Pickle) were propagated in
soil-less Metro mix, with each pot having one plant, and used in
the test when 12 to 14 days old. Test plants were inoculated with
an aqueous spore suspension of Colletotrichum lagenarium 24 hr
after fungicide treatments. After inoculation the plants were kept
in a dew room at 22.degree. C. with 100% relative humidity for 48
hr to permit spores to germinate and infect the leaf. The plants
were then transferred to a growth room set at 22.degree. C. for
disease to develop. Fungicide formulation, application and disease
assessment on the sprayed leaves followed the procedures as
described in the Example A.
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* * * * *
References