Preparation of alpha-necrodyl isobutyrate from dienes

Abstract

Described herein is a method for preparing α-necrodyl isobutyrate, the method comprising: cyclizing a compound of formula (IX) to produce a mixture of compounds of formulas (Xa) and (Xb); and then reacting the mixture of compounds of formulas (Xa) and (Xb) with an isobutyryl donor to produce α-necrodyl isobutyrate. JPEG2024545946000117.jpg7279

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 282,459, filed November 23, 2021, the entire disclosure of which is incorporated herein by reference in its entirety.

[0002] Technical Field This disclosure relates generally to a process for preparing α-necrodyl isobutryate from a diene intermediate compound. [Background technology]

[0003] introduction

[0003] The grape mealybug (Pseudococcus maritimus) is a pest of grapes and pome fruits in the United States, Europe, and South America. The grape mealybug feeds on plant fluids, causing fruit damage, affecting long-term plant viability, and acting as a vector for disease. For these reasons, control of grape mealybugs is of great interest to commercial growers. Current methods for controlling grape mealybugs typically rely on broad spectrum insecticide sprays, which have problems with residues and long-term resistance, so the development of pheromone-based control products has attracted considerable commercial interest.

[0004] In 2007, Millar and coworkers (Figadere, BA et al., Tetrahedron Lett, 2007, 48, 8434-8437) identified the sex pheromone of the grape mealybug (Pleurotus gracilis) as trans-α-necrodyl isobutyrate. Subsequent follow-up studies by the same group in 2010 showed that a racemic mixture of trans-α-necrodyl isobutyrate was more effective than either enantiomer alone in attracting grape mealybugs in a field environment. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Figadere, B.A. et al., Tetrahedron Lett, 2007, 48, 8434-8437 Summary of the Invention

[0006] In some aspects, the present disclosure provides a method for preparing α-necrodyl isobutyrate, comprising: (i) A compound of formula (IX):

[0007] [ka]

[0008] (In the formula, R 2 teeth,

[0009] [ka]

[0010] and; Y is a halogen; PG is a hydroxyl protecting group; R 1 is C 1~10Alkyl, C 3~7 cycloalkyl, 6- to 12-membered aryl, or hydrogen, 1~10 Alkyl, the C 3~7 Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from the group consisting of C 1~4 Alkyl, C 1~2 Haloalkyl, halogen, cyano, -OC 1~4 Alkyl, and -OC 1~2 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of haloalkyl; R 2 but,

[0011] [ka]

[0012] where the reducing agent is added before or after cyclization; R 3 is hydrogen or C 1~10 Alkyl, halogen, -OR 4 , -N(R 4 )2, -CO2R 4 , -C(O)R 4 , -Si(R 4 )3, -B(OR 4 C substituted with 1 to 4 substituents independently selected from the group consisting of 1~10 alkyl or 1 to 4 R 4 a 3- to 12-membered heterocyclic ring optionally substituted with a substituent, or 1 to 4 R 4 a 3- to 12-membered carbocyclic ring optionally substituted with a substituent; R 4 is, for each occurrence, independently, hydrogen, halogen, C 1~4 Alkyl, -OH, -OC 1~4 Alkyl, -NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -C(O)C 1~4 Alkyl, -CO2C 1~4 Alkyl, -C(O)H, -COH, -C(O)NC 1~4alkyl, -CF3, -CHF2, or -NO2) by cyclization to give compounds of formula (Xa) and (Xb):

[0013] [ka]

[0014] producing a mixture of (ii) reacting the mixture of compounds of formula (Xa) and (Xb) with an isobutylyl donor to produce α-necrodyl isobutyrate; or alternatively, A compound of formula (IX) 2 teeth,

[0015] [ka]

[0016] ) to produce α-necrodyl isobutyrate. The method includes the steps of:

[0017] In some embodiments, the method comprises reacting a compound of formula (VII):

[0018] [ka]

[0019] and removing the hydroxyl protecting group (PG) to give a compound of formula (IX), 2 teeth,

[0020] [ka]

[0021] The method may further comprise producing

[0022] The method comprises reacting a compound of formula (VI):

[0023] [ka]

[0024] to produce a compound of formula (VII).

[0025] The method comprises reacting a compound of formula (V):

[0026] [ka]

[0027] to produce a compound of formula (VI).

[0028] The method comprises reacting a compound of formula (III):

[0029] [ka]

[0030] with a reducing agent to produce a compound of formula (V).

[0031] Alternatively, in another aspect, a method for preparing α-necrodyl isobutyrate comprises reacting a compound of formula (VIII):

[0032] [ka]

[0033] to obtain a compound of formula (IX), 2 teeth,

[0034] [ka]

[0035] The method may include producing a compound having a molecular weight of 100 or more, the compound being a

[0036] The method comprises reacting a compound of formula (IV):

[0037] [ka]

[0038] to produce a compound of formula (VIII).

[0039] The method comprises reacting a compound of formula (III):

[0040] [ka]

[0041] One of

[0042] [ka]

[0043] The method may further comprise selectively decarboxylating the moiety to produce a compound of formula (IV).

[0044] The method additionally comprises reacting a compound of formula (I) (wherein X is chlorine, bromine, or iodine) with a compound of formula (II):

[0045] [ka]

[0046] to produce a compound of formula (III). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] Before describing in detail all embodiments of the present disclosure, it is to be understood that the disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The disclosure is capable of other embodiments and of being practiced or carried out in various ways.

[0048] I. Definition

[0015] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, shall control. Although methods and materials are described below, methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. The materials, methods, and examples disclosed herein are merely illustrative and are not intended to be limiting.

[0049]

[0016] The terms "comprise(s)", "include(s)", "having", "having", "can", "can be", "containing", and their derivatives, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not exclude the possibility of additional acts or structures. The singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments that "comprise", "consist of", and "consist essentially of" the embodiments or elements set forth herein, whether expressly stated or not.

[0050]

[0017] As used herein, the term "about" is used to indicate that an exact value is not necessarily attainable. Therefore, the term "about" is used to indicate the limit of this uncertainty. The term "about" may refer to plus or minus 10% of the indicated number. For example, "about 10%" may indicate a range of 9% to 11%, and "about 1" may mean 0.9 to 1.1. Other meanings of "about" may be clear from the context, such as rounding, in which case, for example, "about 1" may mean 0.5 to 1.4. The modifier "about" shall also be considered as disclosing a range defined by the absolute values ​​of the two endpoints. For example, the expression "about 2 to about 4" also discloses the range "2 to 4".

[0051]

[0018] The definitions of specific functional groups and chemical terms are described in more detail below. For the purpose of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987, the entire contents of each of which are incorporated herein by reference.

[0052]

[0019] The term "alkoxy" as used herein refers to the group -O-alkyl. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0053] The term "alkyl" as used herein means a straight or branched saturated hydrocarbon chain. The terms "lower alkyl" or "C 1~6 "Alkyl" means a straight or branched chain hydrocarbon containing 1 to 6 carbon atoms. 1~4 "Alkyl" means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0054] The term "alkenyl," as used herein, means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond.

[0055] The term "alkoxyalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.

[0056] The term "alkylamino," as used herein, means at least one alkyl group, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein.

[0057] The term "amide" as used herein means -C(O)NR- or -NRC(O)-, where R can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0058] The term "aminoalkyl," as used herein, means at least one amino group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0059] The term "amino" as used herein means -NR x R y (In the formula, R x and R y (which can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl). In the case of an aminoalkyl group or any other moiety where an amino links two other moieties together, the amino is represented by -NR x -, where R x can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl).

[0060] The term "aryl" as used herein refers to phenyl or phenyl bonded to a parent molecular moiety, and phenyl fused to a cycloalkane group (e.g., aryl can be indan-4-yl), phenyl fused to a six-membered arene group (i.e., aryl is naphthyl), or phenyl fused to a non-aromatic heterocycle (e.g., aryl can be benzo[d][1,3]dioxol-5-yl). The term "phenyl" is used to refer to the substituent, and the term six-membered arene is used to refer to the fused ring. Six-membered arenes are monocyclic (e.g., benzene or benzo). Aryl can be monocyclic (phenyl) or bicyclic (e.g., 9-12 membered fused bicyclic systems).

[0061] The term "cyanoalkyl," as used herein, means at least one --CN group, attached to the parent molecular moiety through an alkylene group, as defined herein.

[0062] The term "cycloalkoxy," as used herein, refers to a cycloalkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom.

[0063]

[0030] The term "cycloalkyl" or "cycloalkane" as used herein refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term "cycloalkyl" is used herein to refer to a cycloalkane when present as a substituent. A cycloalkyl can be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthalenyl), or a bridged cycloalkyl (e.g., bicyclo[2.2.1]heptanyl) in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0064]

[0031] The term "cycloalkenyl" or "cycloalkene" as used herein means a non-aromatic monocyclic or polycyclic ring system containing all carbon atoms as ring members, containing at least one carbon-carbon double bond, and preferably having 5 to 10 carbon atoms per ring. The term "cycloalkenyl" is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl can be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl (e.g., bicyclo[2.2.1]heptenyl) in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0065] The term "carbocyclyl" means "cycloalkyl" or "cycloalkenyl." The term "carbocycle" means "cycloalkane" or "cycloalkene." The term "carbocyclyl," when present as a substituent, refers to a "carbon ring."

[0066] The terms cycloalkylene and heterocyclylene refer to divalent radicals derived from the base ring, i.e., cycloalkane, heterocycle. For illustrative purposes, examples of cycloalkylene and heterocyclylene include, respectively:

[0067] [ka]

[0068] and

[0069] [ka]

[0070] Cycloalkylene and heterocyclylene include geminal divalent groups, such as 1,1-C 3~6 Cycloalkylene (i.e.

[0071] [ka]

[0072] A further example is 1,1-cyclopropylene (i.e.

[0073] [ka]

[0074] ).

[0075] The term "halogen" or "halo" as used herein means Cl, Br, I, or F.

[0076] The term "haloalkyl" as used herein means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced by halogen.

[0077] The term "haloalkoxy," as used herein, means at least one haloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0078] The term "halocycloalkyl," as used herein, means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms have been replaced with halogen.

[0079] The term "heteroalkyl," as used herein, means an alkyl group, as defined herein, in which one or more of the carbon atoms are replaced with a heteroatom selected from S, O, P, and N. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides.

[0080] The term "heteroaryl" as used herein refers to an aromatic monocyclic heteroatom-containing ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). The term "heteroaryl" is used herein to refer to a heteroarene when present as a substituent. A monocyclic heteroaryl is a 5- or 6-membered ring containing at least one heteroatom independently selected from the group consisting of N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). A 5-membered aromatic monocyclic ring has two double bonds and a 6-membered aromatic monocyclic ring has three double bonds. Bicyclic heteroaryls are 8-12 membered ring systems, examples of which include fused bicyclic heteroaromatic ring systems (i.e., 10π electron systems), such as monocyclic heteroaryl rings fused to 6 membered arenes (e.g., quinolin-4-yl, indol-1-yl), monocyclic heteroaryl rings fused to monocyclic heteroarenes (e.g., naphthyridinyl), and phenyls fused to monocyclic heteroarenes (e.g., quinolin-5-yl, indol-4-yl). Bicyclic heteroaryl / heteroarene groups include 9 membered fused bicyclic heteroaromatic ring systems having four double bonds and at least one heteroatom that contributes a lone pair to a fully aromatic 10π electron system, such as ring systems with a nitrogen atom at the junction of the rings (e.g., imidazopyridine) or benzoxadiazolyl. Bicyclic heteroaryls also include fused bicyclic ring systems composed of one heteroaromatic ring and one non-aromatic ring, such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl) or a monocyclic heteroaryl ring fused to a monocyclic heterocyclic ring (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). A bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom.Other representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, etc.), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl ( For example, benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2-a]pyridinyl (e.g., imidazo[1,2-a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4-d]pyrimidin-2-yl.

[0081] The term "heterocycle" or "heterocyclic" as used herein means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The term "heterocyclyl" is used herein to refer to a heterocycle when it is present as a substituent. A monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains zero or one double bond and one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The 7- and 8-membered rings contain zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazoline, oxazolidinyl, oxetanyl, oxadiazoline, oxadiazolidin ... These include sepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl.A bicyclic heterocycle is a monocyclic heterocycle fused to a six-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiroheterocyclic group, or a bridged monocyclic heterocyclic ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms or an alkenylene bridge having 2, 3, or 4 carbon atoms. A bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-1-yl). Representative examples of bicyclic heterocyclyls include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzothien-2-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (e.g., 2-azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexanyl (e.g., 3-azabicyclo[3.1. 0]hexan-3-yl), 2,3-dihydro-1H-indol-1-yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2-oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octan-1-yl, and 3-oxabicyclo[3.1.0]hexan-6-yl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a 6-membered arene, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms or an alkenylene bridge having 2, 3, or 4 carbon atoms.Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxaadamantane (2-oxatricyclo[3.3.1.13,7]decane). Monocyclic, bicyclic, and tricyclic heterocyclyls are attached to the parent molecular moiety at a non-aromatic ring atom.

[0082]

[0041] The terms "hydroxyl" or "hydroxy" as used herein, refer to an --OH group.

[0083] The term "hydroxyalkyl," as used herein, means at least one --OH group, attached to the parent molecular moiety through an alkylene group, as defined herein.

[0084]

[0043] The terms "alkyl," "cycloalkyl," "alkylene," and the like, may, in certain instances, be preceded by a symbol indicating the number of atoms present in the group (e.g., "C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 These symbols are used as commonly understood by those of ordinary skill in the art. For example, the designation "C" followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, a "C alkyl" is an alkyl group having 3 carbon atoms (i.e., n-propyl, isopropyl). 1~4 When a range is stated, such as in "C", the members of the group that follow may have any number of carbon atoms included within the recited range. 1~4 "Alkyl" is an aligned (ie, straight or branched) alkyl group having from 1 to 4 carbon atoms.

[0085] The term "substituted" refers to a group that may be further substituted with one or more non-hydrogen substituents. The substituents include, but are not limited to, halogen, =O (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0086]

[0045] With respect to the compounds described herein, the groups and substituents thereof may be selected according to the permissible valences of the atoms and substituents such that the selection and substitution result in stable compounds, and do not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like.

[0087] II. Diene intermediate compounds In some aspects, the present disclosure provides a method for preparing diene intermediate compounds of formulas (III)-(IV), (VIII)-(IX), and (XI), 1 , R 2 , R 3 , R 4 , and R 5 is as defined herein.

[0088]

[0047] Diene intermediate compounds useful in the present disclosure are described in the following numbered embodiments, the first embodiment being designated E1, the second embodiment being designated E2, and so on.

[0089] E1. Compound of formula (IX):

[0090] [ka]

[0091] (In the formula, R 2 teeth,

[0092] [ka]

[0093] and; Y is a halogen; PG is a hydroxyl protecting group; R 1 is C 1~10 Alkyl, C 3~7 cycloalkyl, 6- to 12-membered aryl, or hydrogen, 1~10 Alkyl, the C 3~7 Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from the group consisting of C 1~4 Alkyl, C 1~2 Haloalkyl, halogen, cyano, -OC 1~4 Alkyl, and -OC 1~2 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of haloalkyl; R 3 is hydrogen or C 1~10 Alkyl or halogen, -OR 4 , -N(R 4 )2, -CO2R 4 , -C(O)R 4 , -Si(R 4 )3, -B(OR 4 C substituted with 1 to 4 substituents independently selected from the group consisting of 1~10 alkyl or 1 to 4 R 4 a 3- to 12-membered heterocyclic ring optionally substituted with a substituent, or 1 to 4 R 4 a 3- to 12-membered carbocyclic ring optionally substituted with a substituent; R 4 is, for each occurrence, independently, hydrogen, halogen, C 1~4 Alkyl, -OH, -OC 1~4 Alkyl, -NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -C(O)C 1~4 Alkyl, -CO2C 1~4 Alkyl, -C(O)H, -COH, -C(O)NC 1~4 alkyl, -CF3, -CHF2, or -NO2).

[0094] E2.R 3 but,

[0095] [ka]

[0096] wherein n is 0, 1, 2, 3, or 4.

[0097] E3.R 3 is hydrogen.

[0098] E4. Compound of formula (XI):

[0099] [ka]

[0100] (In the formula, R 2 teeth,

[0101] [ka]

[0102] and; Y is a halogen; PG is a hydroxyl protecting group).

[0103] E5. The compound according to embodiment 4, wherein the hydroxyl protecting group is a tert-butyl(dimethyl)silyl (TBS) group.

[0104] E6. Compound of formula (VIII):

[0105] [ka]

[0106] (In the formula, R 1 is C 1~10 Alkyl, C 3~7 cycloalkyl, 6- to 12-membered aryl, or hydrogen, 1~10 Alkyl, the C 3~7 Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from the group consisting of C 1~4 Alkyl, C 1~2 Haloalkyl, halogen, cyano, -OC 1~4 Alkyl, and -OC 1~2 haloalkyl).

[0107] E7. Compound of formula (IV):

[0108] [ka]

[0109] (In the formula, R 1 is C 1~10 Alkyl, C 3~7 cycloalkyl, 6- to 12-membered aryl, or hydrogen, 1~10 Alkyl, the C 3~7 Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from the group consisting of C 1~4 Alkyl, C 1~2 Haloalkyl, halogen, cyano, -OC 1~4 Alkyl, and -OC1~2 haloalkyl).

[0110] E8. Compound of formula (III):

[0111] [ka]

[0112] (In the formula, R 1 is C 1~10 Alkyl, C 3~7 cycloalkyl, 6- to 12-membered aryl, or hydrogen, 1~10 Alkyl, the C 3~7 Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from the group consisting of C 1~4 Alkyl, C 1~2 Haloalkyl, halogen, cyano, -OC 1~4 Alkyl, and -OC 1~2 haloalkyl).

[0113] E9.R 1 is methyl or ethyl.

[0114] III. Methods for Preparing α-Necrodyl Isobutyrate

[0048] α-Necrodyl isobutyrate can be prepared by the exemplary synthetic process shown in the following scheme:

[0115] Abbreviations used in the description of the schemes set forth below are as follows: Me is methyl; Et is ethyl; Cp is η 5 -cyclopentadienyl; Ph is phenyl; Ac is acetyl; Bn is benzyl; KO t Bu is potassium tert-butoxide; Ms is methanesulfonyl; Ts is toluenesulfonyl; Tf is trifluoromethanesulfonate; TMS is trimethylsilane; TBS is tert-butyl(dimethyl)silyl; TBDPS is tert-butyl(diphenyl)silyl; TIPS is triisopropylsilyl; NEt3 is triethylamine; n-BuLi is n-butyl lithium; LDA is lithium diisopropylamide; LiHMDS is lithium bis(trimethylsilyl)amide; KHMDS is potassium bis(trimethylsilyl)amide; NaHMDS is sodium bis(trimethylsilyl)amide; Δ is heat; MH x is a metal hydride; PG is a protecting group; DIBAL-H is diisobutylaluminum hydride; DMSO is dimethyl sulfoxide; PPh3 is triphenylphosphine; PhMe is toluene; THF is tetrahydrofuran; The Hoveyda-Grubbs catalyst is (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium.

[0116]

[0050] In some forms of the present disclosure, α-necrodyl isobutyrate may be synthesized according to the sequence shown in general Scheme A.

[0117] [ka]

[0118]

[0051] In another aspect of the present disclosure, α-necrodyl isobutyrate may be synthesized according to the sequence shown in general Scheme B.

[0119] [ka]

[0120] Each of the transformations presented in the above sequence is described in more detail below.

[0121] [ka]

[0122]

[0053] General Scheme 1 shows the first step in General Schemes A and B. As shown in General Scheme 1, a γ,γ-malonate of formula A can be reacted with an allylic Grignard reagent to form an intermediate diester compound of formula B.

[0123] [ka]

[0124] General Scheme 2 illustrates the second step in General Scheme A. As shown in General Scheme 2, the intermediate compound of formula B can be reacted with an inorganic salt under standard decarboxylation reaction conditions to form a monoester intermediate compound of formula C. In various cases, the inorganic salt can be LiCl. In various cases, the polar aprotic solvent can be DMSO. In various cases, the reaction can be heated to at least 150° C.

[0125] [ka]

[0126]

[0055] General Scheme 3 illustrates the third step in General Scheme A. As shown in General Scheme 3, the intermediate compound of formula C can be formylated under standard formylation conditions. In various cases, the compound of formula C is reacted with a base, followed by reaction with a formate or formic acid to form a compound of formula D. Suitable bases include, but are not limited to, organometallic bases (e.g., lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS), sodium bis(trimethylsilyl)amide (NaMDS), or lithium dialkylamide bases (e.g., lithium diisopropylamide (LDA)), or potassium tert-butoxide (KO t In various cases, the compound of formula C can be reacted with a base followed by reaction with ethyl formate (HC02Et) to form a compound of formula D. In various cases, the base can be an organolithium base. The organolithium base can be a lithium amide base (e.g., LiHMDS) or a lithium dialkylamide base (e.g., LDA). In various cases, the base can be LDA.

[0127] [ka]

[0128] General Scheme 4 illustrates the fourth step in General Scheme A. As shown in General Scheme 4, an intermediate compound of formula D can be prepared by reacting a compound of formula D with a titanium methylidene or phosphonium ylide (e.g., a compound of formula (CHR 3)PPh3) to form an intermediate compound of formula E. In various cases, the compound of formula D can be olefinated by reacting with a phosphonium ylide of formula (C5H5)2Ti(CHR 3 In various cases, the compound of formula D reacts with a titanium methylidene of formula (CHR 3 )PPh3. In various cases, the titanium methylidene can be (C5H5)2Ti(CH2). In various cases, the phosphonium ylide can be (CH2)PPh3. Titanium methylidene and phosphonium ylide reagents can be prepared using known procedures. For example, a titanium methylidene of the formula (C5H5)2Ti((CHR 3 ) titanium methylidene has the formula (C5H5)2Ti(CHR 3 )ClAl(CH3)2 (e.g., Tebbe's reagent) or the formula Cp2Ti(CH2R 3 The phosphonium ylides may be prepared by reacting a reagent (e.g., Petasis reagent) of formula 2 with a mild Lewis base (e.g., pyridine). The phosphonium ylides can be prepared by reacting a suitable base (e.g., KO t The phosphonium salts may be prepared from the phosphonium salts by deprotonation with an alkyl halide (e.g., of the formula CHR 3 It may be prepared by reacting Br (alkyl bromide) with triphenylphosphine (PPh3).

[0129] [ka]

[0130] General Scheme 5 illustrates the fifth step in General Scheme A. As shown in General Scheme 5, the intermediate compound of formula E may be cyclized via olefin cross-metathesis (also referred to as ring-closing metathesis (RCM)). The intermediate compound of formula E may be cyclized by reacting the compound of formula E with a transition metal catalyst (e.g., a transition metal carbene complex catalyst) to form an intermediate compound of formula F. Exemplary solvents for this reaction include aprotic organic solvents (e.g., toluene). In various cases, the transition metal catalyst is a ruthenium (II) carbene complex catalyst. In various cases, the ruthenium (II) carbene complex catalyst is (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium.

[0131] [ka]

[0132] General Scheme 6 illustrates the penultimate step in General Scheme A. As shown in General Scheme 6, a compound of formula F can be reacted with a metal hydride (MH x The intermediate compound of formula F can be reduced to produce a diastereomeric mixture of (R,R)-α-necrodol and (R,S)-α-necrodol by reaction with a metal hydride reducing agent. Table 1 lists examples of metal hydride reducing agents.

[0133] [Table 1]

[0134] In various instances, the reducing agent can be lithium aluminum hydride (LiAlH4), sodium borohydride (NaBH4), sodium bis(2-methoxyethoxy)aluminum hydride, or diisobutylaluminum hydride (DIBAL-H) ​​(Table 1). In various cases, the reducing agent is sodium bis(2-methoxyethoxy)aluminum hydride.

[0135] [ka]

[0136]

[0060] General scheme 7 shows the final step in general schemes A and B. The diastereomeric mixture of (R,R)-α-necrodol and (R,S)-α-necrodol can be reacted with an isobutyryl donor to form α-necrodyl isobutyrate. Suitable isobutyryl donors include, but are not limited to, isobutyryl chloride, isobutyric acid, isobutyric anhydride, and alkyl isobutyrate (e.g., methyl, ethyl, or propyl isobutyrate). The mixture of (R,R)-α-necrodol and (R,S)-α-necrodol can be reacted with an isobutyryl donor under suitable acylation conditions. For example, (R,R)-α-necrodol and (R,S)-α-necrodol can be reacted with an isobutyryl donor in the presence of 4-(dimethylamino)pyridine (DMAP) and triethylamine (NEt3) in an organic solvent. The organic solvent can be methyl tert-butyl ether. In various cases, the isobutyl donor is

[0137] [ka]

[0138] wherein X 1 are Cl, Br, I, -OH, -OC 1~4 Alkyl, -OPiv,

[0139] [ka]

[0140] ,or

[0141] [ka]

[0142] In various cases, the isobutyryl donor can be isobutyryl chloride.

[0143] [ka]

[0144] General Scheme 8 illustrates the second step in General Scheme B. General Scheme 8 illustrates the reduction of a diester intermediate compound of formula B to a diol intermediate compound of formula G. The compound of formula B is reduced to a diol intermediate compound of formula G using a metal hydride (MH x ) to produce a compound of formula G. Table 1 provides examples of metal hydride reducing agents. In various cases, the reducing agent can be lithium aluminum hydride (LiAlH4), sodium borohydride (NaBH4), sodium bis(2-methoxyethoxy)aluminum hydride, or diisobutylaluminum hydride (DIBAL-H) ​​(Table 1). In various cases, the reducing agent is sodium bis(2-methoxyethoxy)aluminum hydride.

[0145] [ka]

[0146] General scheme 9 shows the third step in general scheme B. General scheme 9 shows the monoprotection of the diol intermediate of formula G to form the mono-protected compounds of formula H. The protection of the hydroxyl group in the case of the compound of formula G can be done by any suitable method described in Greene and Wuts, or other methods known to those skilled in the art, depending on the desired protecting group (PG). For example, when the protecting group (PG) is a silyl ether, the protection of the hydroxyl group can include reacting the compound of formula G with a silylating agent, such as chlorotrimethylsilane (TMSCl), tert-butyldiphenylsilyl chloride tert-butyl(diphenyl)silyl (TBDPSCl), triisopropylsilyl chloride (TIPSCl), or tert-butyl(dimethyl)silyl chloride (TBSCl), in the presence of a base and an organic solvent to form the silylated compound of formula H. Exemplary organic solvents include aprotic solvents such as tetrahydrofuran (THF), dimethylsulfoxide (DMSO), and toluene (PhMe). Suitable bases include imidazole, triethylamine, pyridine, sodium hydride (NaH), and potassium tert-butoxide (KO t In various cases, the silylating agent may be TBSCl and the base may be potassium tert-butoxide (KO t In some cases, the solvent may include tetrahydrofuran (THF). In various cases, the solvent may further include toluene (PhMe). In various cases, the protecting group (PG) in the resulting compound of formula H may be trimethylsilyl (TMS), tert-butyl(diphenyl)silyl (TBDPS), triisopropylsilyl (TIPS), or tert-butyl(dimethyl)silyl (TBS). In various cases, the protecting group (PG) is tert-butyl(dimethyl)silyl (TBS).

[0147] [ka]

[0148] As shown in general scheme 10, intermediate alcohol compounds of formula H may be oxidized by reacting the compound of formula H with an oxidizing agent to form a compound of formula I. Suitable oxidizing agents include, but are not limited to, nitroxyl radicals, hypervalent iodine compounds, and activated DMSO (which may be formed by reacting DMSO with an activating agent, such as, but not limited to, oxalyl chloride, SO3, pyridine, or acetic anhydride). Table 2 provides examples of nitroxyl radicals that can be used to oxidize compounds of formula H.

[0149] [Table 2]

[0150] Table 3 shows examples of hypervalent iodine compounds that can be used to oxidize compounds of formula H.

[0151] [Table 3]

[0152] In various cases, the nitroxyl radical is formed by reacting a nitroxyl radical precursor with a stoichiometric oxidizing agent, where the nitroxyl radical precursor is (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), 4-hydroxy-(2,2,6,6-tetramethylpiperidin-1-yl)oxyl 4-acetamido (4-OH-TEMPO), 4-acetamido-(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (4-acetamido-TEMPO), 2-azaadamantane N-oxyl (AZADO), or 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO). In various cases, the nitroxyl radical precursor is TEMPO. In various cases, the stoichiometric oxidizing agent is sodium hypochlorite, oxygen, or (diacetoxyiodo)benzene.

[0153] [ka]

[0154] General Scheme 11 illustrates the fifth step in General Scheme B. As shown in General Scheme 11, intermediate compounds of formula I can be prepared by reacting compounds of formula I with titanium methylidene or phosphonium ylide (e.g., compounds of formula (CHR 3 )PPh3) to form an intermediate compound of formula J. In various cases, the compound of formula I can be olefinated by reacting with a phosphonium ylide of formula (C5H5)2Ti(CHR 3 In various cases, the compound of formula I reacts with a titanium methylidene of formula (CHR 3 )PPh3. In various cases, the titanium methylidene can be (C5H5)2Ti(CH2). In various cases, the phosphonium ylide can be (CH2)PPh3. Titanium methylidene and phosphonium ylide reagents can be prepared using known procedures. For example, a titanium methylidene of the formula (C5H5)2Ti((CHR 3) titanium methylidene has the formula (C5H5)2Ti(CHR 3 )ClAl(CH3)2 Tebbe reagent or the formula Cp2Ti(CH2R 3 The phosphonium ylide may be prepared by reacting the Petasis reagent of 2 with a mild Lewis base (e.g., pyridine). t The phosphonium salts may be prepared from the phosphonium salts by deprotonation with an alkyl halide (e.g., of the formula CHR 3 It may be prepared by reacting Br (alkyl bromide) with triphenylphosphine (PPh3).

[0155] [ka]

[0156]

[0067] As shown in general scheme 12, the protected alcohol intermediate compound of formula J may be deprotected to form an alcohol intermediate compound of formula K. The deprotection of the protected hydroxyl group in the compound of formula J may be done by any suitable method described in Greene and Wuts, or other methods known to those skilled in the art, depending on the particular protecting group. For example, when the protecting group (PG) is a silyl ether, it is expected that the preferred method is to react the protected hydroxyl group of formula J with an acid or a fluoride to convert the protected alcohol of formula J to an alcohol of formula K. Thus, in some implementations, the deprotection is done by reacting the protected alcohol with an acid (e.g., p-toluenesulfonic acid) or a fluoride (e.g., tetra-n-butylammonium fluoride (TBAF)). The particular deprotection method is selected according to the requirements of the particular protecting group and other functionalities present in the molecule.

[0157] [ka]

[0158]

[0068] General scheme 13 shows the penultimate step in general scheme B. As shown in general scheme 13, the intermediate compound of formula K may be cyclized via olefin cross-metathesis (also referred to as ring-closing metathesis (RCM)). The intermediate compound of formula K may be cyclized by reacting the compound of formula K with a transition metal catalyst (e.g., a transition metal carbene complex catalyst) to produce a diastereomeric mixture of (R,R)-α-necrodol and (R,S)-α-necrodol. Exemplary solvents for this reaction include aprotic organic solvents (e.g., toluene). In various cases, the transition metal catalyst is a ruthenium (II) carbene complex catalyst. In various cases, the ruthenium (II) carbene complex catalyst is (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium.

[0159] Olefination conditions suitable for use in the processes of General Scheme 4 and General Scheme 11 are well known in the art. Suitable conditions include those generally outlined in General Scheme 4 and General Scheme 11 and described in the Examples herein.

[0160]

[0070] Suitable reduction conditions for use in the processes of General Scheme 6 and General Scheme 8 are well known in the art. Suitable conditions include those outlined in General Scheme 6 and General Scheme 8, and as described in the Examples herein.

[0161]

[0071] Suitable cyclization conditions for use in the processes of General Scheme 7 and General Scheme 13 are well known in the art. Suitable conditions include those outlined in General Scheme 7 and General Scheme 13, and as described in the Examples herein.

[0162]

[0072] α-Necrodyl isobutyrate and intermediate compounds may be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, recrystallization at high or low temperatures, optionally with pretreatment with activated carbon, thin layer chromatography, distillation at various pressures, sublimation in vacuum, and trituration, as described, for example, in "Vogel's Textbook of Practical Organic Chemistry", 5th Edition (1989) by Furniss, Hannaford, Smith, and Tatchell, Longman Scientific & Technical Publishing, Essex CM20 2JE, England.

[0163]

[0073] The disclosed compounds may have at least one basic nitrogen, whereby the compounds can be treated with an acid to form the desired salt. For example, the compounds can be reacted with an acid at room temperature or above room temperature to provide the desired salt, which is deposited and collected by filtration after cooling. Examples of acids suitable for this reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic acid, atrolactic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carbonic acid, fumaric acid, maleic acid, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid.

[0164]

[0074] The optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and the substituents present in the reactants used. Specific procedures are provided in the Examples section. The reactants may be worked up in a conventional manner, for example by removing the solvent from the residue, and may be further purified according to techniques generally known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise stated, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. If the starting materials are not commercially available, they can be prepared by procedures selected from standard organic chemistry techniques, techniques analogous to the synthesis of known structurally similar compounds, or procedures analogous to those described in the Examples section of the above schemes or synthesis.

[0165]

[0075] Routine experimentation, including proper manipulation of reaction conditions, reagents and sequence of synthetic routes, protection of any chemical functional groups that are incompatible with the reaction conditions, and deprotection at suitable points in the reaction sequence of the method, is within the scope of the present invention. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art; examples can be found in Greene's book titled Protective Groups in Organic Synthesis (4th Edition), John Wiley & Sons, NY (2006), by PGM Wuts and TW Greene, which is incorporated herein by reference in its entirety. The synthesis of the compounds of the present invention can be achieved by methods similar to those described in the synthetic schemes and specific examples described above.

[0166]

[0076] If an optically active form of a disclosed compound is required, it may be obtained by carrying out one of the procedures described herein using optically active starting materials (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a stereoisomeric mixture of the compound or intermediate using standard procedures (e.g., chromatographic separation, recrystallization, or enzymatic resolution).

[0167]

[0077] Similarly, if a pure geometric isomer of a disclosed compound is required, it can be obtained by carrying out one of the procedures described above using a pure geometric isomer as a starting material, or by resolution of a mixture of geometric isomers of the compound or intermediate using standard procedures such as chromatographic separation.

[0168] It is understood that the synthetic schemes and specific examples described are illustrative and are not to be construed as limiting the scope of the invention as defined by the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims. EXAMPLES

[0169] IV. Working Examples

[0079] The foregoing can be better understood with reference to the following examples, which are presented for purposes of illustration and are not intended to limit the scope of the technology.

[0170] Abbreviation: aq. is aqueous; Me is methyl; Et is ethyl; g is grams; kg is kilogram; L is liters; mol or mol. is mole; M is moles / liter; N is the number of molar equivalents / liter; wt% or %(w / w) is weight percent; eq, eq., or equiv is equivalent; sat. is saturated; h or hr is hour; min or min. is minutes; s or sec is seconds; DMSO is dimethyl sulfoxide; THF is tetrahydrofuran; TBS is tert-butyl(dimethyl)silyl; GCMS is gas chromatography mass spectrometry; NMR is nuclear magnetic resonance; bp is the boiling point; CI is chemical ionization.

[0171] Example 1: Preparation of diethyl 2-(2,3,4-trimethylpent-4-en-2-yl)malonate

[0172] [ka]

[0173] A clean, dry reactor under N2 atmosphere was charged with magnesium turnings (875 g, 36.03 mol), 2-methyltetrahydrofuran (10.0 L) and toluene (10.0 L). 1-Bromopropane (4.387 kg, 135.67 mol) was then added to the reactor. The reaction was stirred until conversion to propylmagnesium bromide was complete. Titanocene dichloride (88.81 g, 0.36 mol) was then added to the reactor. The mixture was warmed to 40°C, then isoprene (3.038 kg, 44.59 mol) was added and the reaction was aged until conversion to the allyl Grignard reagent was complete. The mixture was cooled to -10°C and diethyl isopropylidenemalonate (5.00 kg, 24.97 mol) was added. The reaction was aged and then quenched with 20% (w / w) citric acid (17.5 L). The organic phase was then washed with saturated aqueous NaHCO3 and water. The organic phase was collected and concentrated in vacuo to give 7.151 kg (85% yield) of the desired product as an oil. 1 H NMR (600 MHz, CDCl3) δ ppm 0.97 - 1.05 (m, 6 H) 1.12 (s, 3 H) 1.20 - 1.26 (m, 6 H) 1.70 (s, 3 H) 2.61 (q, J=7.15 Hz, 1 H) 3.47 (s, 1 H) 4.10 - 4.18 (m, 4 H) 4.67 - 4.71 (m, 1 H) 4.81 (s, 1 H). GCMS (CI) m / z 271.0 (270.18 calcd. for C 17 H 34 O2 + [M] + ).

[0174] Example 2: Preparation of 2-(2,3,4-trimethylpent-4-en-2-yl)propane-1,3-diol

[0175] [ka]

[0176] A clean, dry reactor under N2 atmosphere was charged with toluene (27.7 L) and a 70% (w / w) solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (13.969 kg, 48.37 mol). Diethyl 2-(2,3,4-trimethylpent-4-en-2-yl)malonate (5.030 kg, 18.60 mol) was added and the reaction was aged at 20°C until deemed complete. The reaction was cooled to 10°C and then 20% (w / w) aqueous NaOH was added. Water was added after the caustic addition and the batch was then stirred until all solids were dissolved. The aqueous phase was removed and then the organic phase was washed three times with water. The solvent was removed in vacuo and the title compound was collected and purified by distillation in vacuo (bp 93° C. / 0.4 torr) to give 2.997 kg (86% yield) of the title compound as a waxy solid. 1 H NMR (600 MHz, CDCl3) δ ppm 0.85 (s, 3 H) 0.87 (s, 3 H) 1.03 (d, J=6.97 Hz, 3 H) 1.77 (s, 3 H) 1.90 (ddd, J=8.99, 5.69, 3.30 Hz, 1 H) 2.33 (q, GCMS (CI) m / z 186.9 (186.16 calcd. for C 11 H 22 O2 + [M] + ).

[0177] Example 3: Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl)-3,3,4,5-tetramethylhex-5-en-1-ol

[0178] [ka]

[0179] A clean, dry reactor under N2 atmosphere was charged with a 20% (w / w) solution of potassium tert-butoxide in THF (8.132 kg, 14.50 mol), then 2-(2,3,4-trimethylpent-4-en-2-yl)propane-1,3-diol (2.702 kg, 14.50 mol) and toluene (14.2 L) were added and stirred at room temperature for 30 minutes. The solution was then cooled to 15°C and a 50% (w / w) solution of tert-butyldimethylsilyl chloride in toluene (4.372 kg, 14.50 mol) was added in a metered manner. The reaction was aged for 30 minutes, then a saturated aqueous solution of NaHCO3 was added and stirred. The aqueous phase was removed and the organic residue was washed twice with water. The organic phase was collected and the solvent removed in vacuo to give 4.330 kg (99% yield) of the title compound as a 50 / 50 mixture of diastereomers. 1 H NMR (600 MHz, CDCl3) δ ppm 0.14 - 0.17 (range, 12 H) 0.86 (s, 3 H) 0.89 - 0.92 (m, 9 H) 0.96 - 0.98 (range, 18 H) 1.02 - 1.11 (range, 6 H) 1.81 (br d, J=6.24 Hz, 6 H) 1.86 - 1.95 (m, 2 H) 2.32 - 2.40 (m, 2 H) 3.29 (br s, 1 H) 3.42 (br s, 1 H) 3.74 - 3.88 (m, 4 H) 3.93 (br d, J = 10.27 Hz, 2 H) 4.00 - 4.06 (m, 1 H) 4.07 - 4.11 (m, 1 H) 4.75 - 4.97 (m, 5 H). GCMS (CI) m / z 301.0 (300.25 calcd. for C 17 H 32 O2Si + [M] + ).

[0180] Example 4: Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl)-3,3,4,5-tetramethylhex-5-enol

[0181] [ka]

[0182] A clean, dry reactor under air was charged with copper(I) bromide (353.9 g, 2.46 mol), 2,2'-bipyridyl (192.1 g, 1.23 mol), 2,2,6,6-tetramethylpiperidine-1-oxyl free radical (TEMPO) (192.2 g, 1.23 mol), 1-methylimidazole (101.0 g, 1.23 mol), -(((tert-butyldimethylsilyl)oxy)methyl)-3,3,4,5-tetramethylhex-5-en-1-ol (3.697 kg, 12.30 mol), and sulfolane (containing 3% water) (11.09 L). The mixture was warmed to 55°C and then air was bubbled in through a dip tube until the reaction was deemed complete. Heptane was added and the mixture was washed with 50% (w / w) aqueous citric acid, water and 25% (w / w) aqueous sodium thiosulfate. After removing the aqueous phase, the organic phase was washed with aqueous NaHCO3, followed by water and saturated aqueous sodium chloride. The organic phase was collected and the solvent removed in vacuo to give 3.329 kg (91% yield) of the title compound. The aldehyde was used in the next step without further purification. GCMS (CI) m / z 299.0 (298.23 calcd. for C 17 H 34 O2Si + [M] + ).

[0183] Example 5: Preparation of 3,3,4,5-tetramethyl-2-vinylhex-5-en-1-ol

[0184] [ka]

[0185] A clean, dry reactor was charged with methyltriphenylphosphonium bromide (4.057 kg, 11.36 mol), degassed, and backfilled with N2. THF (6.2 L) was added, followed by a 20 wt% solution of potassium tert-butoxide in THF (6.313 kg, 11.25 mol). The mixture was stirred at ambient temperature for 5 h. The mixture was cooled to -10°C, then 2-(((tert-butyldimethylsilyl)oxy)methyl)-3,3,4,5-tetramethylhex-5-enol (3.082 kg, 10.32 mol) was added. The reaction was stirred at 20°C until the target conversion was achieved. A saturated aqueous solution of NaHCO3 was added, followed by water. Agitation was stopped and the aqueous phase was removed. Heptane, water, and methanol were added and agitated. Agitation was stopped and the aqueous phase was removed. The organic phase was then washed twice with a mixture of water and methanol. Methanol (12.3 L) and a 15% aqueous solution of HCl (251 g, 1.03 mol) were then added and warmed to 35° C. The reaction was stirred until removal of the TBS ether was deemed complete. The mixture was washed with saturated aqueous NaHCO3, saturated aqueous sodium chloride, and water. The aqueous phase was removed and the organic phase was washed with water. The organic phase was collected and the solvent removed in vacuo. The crude product was purified by distillation (bp 51° C. / 0.4 torr) to give 1.335 kg (71% yield) of the title compound as a mixture of diastereomers. 1H NMR (600 MHz, CDCl3) δ ppm 0.76 - 0.84 (m, 9 H) 0.87 (s, 3 H) 0.92 - 0.99 (m, 6 H) 1.41 (br s, 2 H) 1.69 - 1.71 (s, 3 H) 1.71 - 1.72 (s, 3 H) 2.17 - 2.28 (m, 4 H) 3.34 (dt, J = 15.82, 10.34 Hz, 2 H) 3.69 - 3.83 (m, 2 H) 4.68 (br s, 2 H) 4.81 (br d, J=13.57 Hz, 2 H) 5.14 (dd, J=17.06, 1.65Hz, 2 H) 5.22 - 5.29 (m, 2 H) 5.67 - 5.75 (m, 2 H). GCMS (CI) m / z 182.9 (182.17 calcd. for C 12 H 22 O + [M] + ).

[0186] Example 6: Preparation of ((1S,4S)-3,4,5,5-tetramethylcyclopent-2-en-1-yl)methyl isobutyrate (α-necrodyl isobutyrate) from 3,3,4,5-tetramethyl-2-vinylhex-5-en-1-ol

[0187] [ka]

[0188] A clean, dry reactor under N2 atmosphere was charged with 3,3,4,5-tetramethyl-2-vinylhex-5-en-1-ol (1.185 kg, 6.50 mol) and ethyl acetate (3.6 L) and warmed to 60°C. Hoveyda-Grubbs catalyst (4.07 g, 0.0065 mol) was dissolved in dichloromethane (71 ml) and added to the reactor over 3 hours. The reaction was stirred until the reaction was deemed complete, then the reaction mixture was cooled to 25°C and 4-(dimethylamino)pyridine (7.94 g, 0.065 mol) was added followed by isobutyric anhydride (1.182 kg, 7.48 mol). The reaction was stirred until the reaction was deemed complete. Methanol (234 g, 7.31 mol) was added and stirred for 20 minutes. The reaction was then cooled to ambient temperature and aqueous HCl was added. The aqueous phase was removed and the organic phase was then washed twice with an 8% aqueous solution of NaHCO3 followed by water. The organic phase was collected and the solvent was removed in vacuo. The crude product was purified by distillation (bp 80°C / 2 torr) to give 1.367 kg (94% yield) of the title compound as a mixture of diastereomers. 1 H NMR (600 MHz, CDCl3) δ ppm 0.79 (s, 3 H) 0.88 - 0.93 (m, 6 H) 0.96 - 0.99 (m, 6 H) 1.11 (s, 3 H) 1.16 - 1.20 (m, 12 H) 1.67 (s, 6 H) 2.11 - 2.22 (m, 2 H) 2.48 - 2.58 (m, 4 H) 3.96 (ddd, J=15.22, 10.82, 7.15 Hz, 2 H) 4.04 - 4.14 (m, 2 H) 5.15 - 5.20 (m, 2 H). GCMS (CI) m / z 225.0 (224.18 calcd. for C 14 H 24 O2 + [M] + ).

[0189] Example 7: Preparation of methyl 3,3,4,5-tetramethylhex-5-enoate

[0190] [ka]

[0191] To dimethyl 2-(2,3,4-trimethylpent-4-en-2-yl)malonate (104.00 g, 429.1 mmol) in DMSO (624 mL) was added potassium acetate (210.557 g, 2145.5 mmol) and water (116 mL, 6436.5 mmol). The mixture was stirred at 20° C. until deemed complete. The mixture was cooled to ambient temperature and partitioned between methyl tert-butyl ether and water. The aqueous phase was removed and the organic phase was washed twice with water. The organic phase was filtered through Celite and then concentrated in vacuo to give 74.57 g (67% crude yield) of material as an oil. The crude product was purified by distillation (bp 78° C. / 7 torr) to give the title compound. GCMS(CI) m / z 184.9(184.15 calcd. for C 11 H 20 O2 + [M] + ).

[0192] Example 8: Preparation of methyl 2-formyl-3,3,4,5-tetramethylhex-5-enoate

[0193] [ka]

[0194] To a solution of diisopropylamine (36.428 g, 360 mmol) in THF (250 mL) at -70°C was added n-hexyllithium (2.3 M in hexanes, 150 mL, 345 mmol). The reaction was stirred for 20 min before adding methyl 3,3,4,5-tetramethylhex-5-enoate (51.680 g, 280.4 mmol). The reaction was aged for 90 min. Ethyl formate (41.544 g, 560.8 mmol) was added and stirred until the reaction was deemed complete. A solution of 2N HCl was added, the aqueous phase was removed, and the organic material was washed successively with saturated aqueous NaHCO3 and water. The organic residue was concentrated to give 65.54 g (72% yield) of the title compound as an oil. GCMS(CI) m / z 212.9(212.14 calcd. for C 12 H 20 O3 + [M] + ).

[0195] Example 9: Preparation of methyl 3,3,4,5-tetramethyl-2-vinylhex-5-enoate

[0196] [ka]

[0197] To a solution of methyltriphenylphosphonium bromide (115.028 g, 352 mmol) in THF (300 mL) at 20° C. was added n-butyllithium (2.5 M in hexanes, 123 mL, 308 mmol). The reaction was aged for 1 h. The mixture was cooled to −20° C., then methyl 2-formyl-3,3,4,5-tetramethylhex-5-enoate (59.441 g, 280 mmol) was added and stirred while warming to room temperature. Once the reaction was deemed complete, 2N HCl was added. The aqueous phase was removed, then the organic phase was washed with saturated aqueous NaHCO3 and water. The organic residue was concentrated in vacuo, then heptane was added, and the solution was filtered through silica gel and washed with heptane. The material was concentrated to give 47.33 g (65% yield) of the title compound as an oil. GCMS(CI) m / z 210.9(210.16 calcd. for C 13 H 22 O2 + [M] + ).

[0198] Example 10: Preparation of methyl 3,4,5,5-tetramethyl cyclopent-2-ene-1-carboxylate

[0199] [ka]

[0200] To a solution of methyl 3,3,4,5-tetramethyl-2-vinylhex-5-enoate (238 mg, 1.61 mmol) in toluene (4 mL) was added Hoveyda-Grubbs catalyst (20.2 mg, 0.032 mmol) and stirred at 20° C. until the reaction was deemed complete. The reaction mixture was filtered through a plug of silica gel and eluted with 10% methyl tert-butyl ether in hexane to give the title compound as an oil. GCMS (CI) m / z 182.9 (182.13 calcd. for C 11 H 18 O2).

[0201] Example 11: Preparation of 2-(hydroxymethyl)-3,3,4,5-tetramethylhex-5-en-1-yl isobutyrate

[0202] [ka]

[0203] To a 20 wt% solution of potassium tert-butoxide in THF (621 mL, 1.031 mol) was added 2-(2,3,4-trimethylpent-4-en-2-yl)propane-1,3-diol (192.14 g, 1.031 mol) and stirred at ambient temperature for 30 minutes. A separate clean reactor was charged with isobutyryl chloride (115.38 g, 1.083 mol) and THF (988 mL) and then cooled to below -20°C. The solution of deprotonated 2-(2,3,4-trimethylpent-4-en-2-yl)propane-1,3-diol was transferred onto the solution of isobutyryl chloride while maintaining the temperature below -20°C. The reaction was stirred while warming to room temperature. Water, 2N HCl and toluene were added. The aqueous phase was removed and the organic residue was then washed with saturated aqueous NaHCO3 and water. The solvent was removed in vacuo to give the title compound (262.22 g, 67% yield) as an oil. GCMS(CI) m / z 257.0(256.20 calcd. for C 15 H 28 O3 + [M] + ).

[0204] Example 12: Preparation of 3,3,4,5-tetramethyl-2-vinylhex-5-en-1-ol

[0205] [ka]

[0206] To a solution of methyl 3,3,4,5-tetramethyl-2-vinylhex-5-enoate in toluene at ambient temperature was slowly added a 70% solution of sodium bis(2-methoxyethoxy)aluminum dihydride in toluene (74.7 mL, 289.8 mmol). The reaction was stirred at ambient temperature until deemed complete, then a 20% w / w aqueous solution of sodium hydroxide was added and stirred until all solids had dissolved. The organic phase was washed three times with water. The organic residue was concentrated to give 32.82 g (74% yield) of the title compound as an oil. GCMS (CI) m / z 182.9 (182.17 calcd. for C 12 H 22 O + [M] + ).

[0207]

[0092] The description of the specific embodiments above sufficiently elucidates the general nature of the technology to allow others to easily modify and / or adapt such specific embodiments to various applications without undue experimentation by applying knowledge within the skill of the art, without departing from the general concept of the present disclosure. Therefore, such applications and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments based on the teachings and guidance set forth herein. It is understood that the expressions or terms in this specification are for the purpose of description and not for the purpose of limitation, and therefore the terms or terms in this specification are to be interpreted by those skilled in the art in the light of the teachings and guidance.

[0208]

[0093] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0209]

[0094] All publications, patents, patent applications, and / or other documents cited in this application are incorporated by reference in their entirety into this specification for all purposes to the same extent as if each individual publication, patent, patent application, and / or other document was individually indicated to be incorporated by reference for all purposes.

[0210] For completeness reasons, various forms of the process for preparing α-necrodyl isobutyrate are described in the following numbered embodiments, the first embodiment being designated E1, the second embodiment being designated E2, and so on.

[0211] E1. A method for preparing α-necrodyl isobutyrate, comprising the step of:

[0212] [ka]

[0213] (In the formula, R 2 teeth,

[0214] [ka]

[0215] and; Y is a halogen; PG is a hydroxyl protecting group; R 1 is C 1~10 Alkyl, C 3~7 cycloalkyl, 6- to 12-membered aryl, or hydrogen, 1~10 Alkyl, the C 3~7 Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from the group consisting of C 1~4 Alkyl, C 1~2 Haloalkyl, halogen, cyano, -OC 1~4 Alkyl, and -OC 1~2and optionally substituted with 1 to 5 substituents independently selected from the group consisting of haloalkyl; R 2 but,

[0216] [ka]

[0217] where the reducing agent is added before or after cyclization; R 3 is hydrogen or C 1~10 Alkyl or halogen, -OR 4 , -N(R 4 )2, -CO2R 4 , -C(O)R 4 , -Si(R 4 )3, -B(OR 4 C substituted with 1 to 4 substituents independently selected from the group consisting of 1~10 alkyl or 1 to 4 R 4 a 3- to 12-membered heterocyclic ring optionally substituted with a substituent, or 1 to 4 R 4 a 3- to 12-membered carbocyclic ring optionally substituted with a substituent; R 4 is, for each occurrence, independently, hydrogen, halogen, C 1~4 Alkyl, -OH, -OC 1~4 Alkyl, -NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -C(O)C 1~4 Alkyl, -CO2C 1~4 Alkyl, -C(O)H, -COH, -C(O)NC 1~4 alkyl, -CF3, -CHF2, or -NO2) by cyclization to give compounds of formula (Xa) and (Xb):

[0218] [ka]

[0219] producing a mixture of reacting the mixture of compounds of formula (Xa) and (Xb) with an isobutyryl donor to produce α-necrodyl isobutyrate; or alternatively, A compound of formula (IX) 2 teeth,

[0220] [ka]

[0221] ) to produce α-necrodyl isobutyrate. The above method.

[0222] E2. The process of embodiment 1, wherein cyclizing the compound of formula (IX) comprises reacting the compound of formula (IX) with a transition metal carbene complex catalyst.

[0223] E3. The process of embodiment 1 or 2, wherein cyclizing the compound of formula (IX) comprises reacting the compound of formula (IX) with a ruthenium(II) carbene complex catalyst.

[0224] E4. The method of embodiment 3, wherein the ruthenium(II) carbene complex catalyst is (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium.

[0225] E5.R 3 but,

[0226] [ka]

[0227] wherein n is 0, 1, 2, 3, or 4.

[0228] E6.R 3The method of any one of embodiments 1 to 4, wherein is hydrogen.

[0229] E7.R 2 but,

[0230] [ka]

[0231] and R 1 The method of any one of embodiments 1-6, wherein is methyl or ethyl.

[0232] E8. Compound of formula (VII):

[0233] [ka]

[0234] and removing the hydroxyl protecting group (PG) to give a compound of formula (IX), 2 teeth,

[0235] [ka]

[0236] 7. The method of any one of embodiments 1 to 6, further comprising producing a compound comprising the steps of:

[0237] E9. The method of any one of embodiments 1-6 or 8, wherein the hydroxyl protecting group is a tert-butyl(dimethyl)silyl (TBS) group.

[0238] E10. Olefining a compound of formula (VII) to obtain a compound of formula (VII) with a compound of formula (CHR 3 )PPh3 or a phosphonium ylide of the formula (C5H5)2Ti(CHR 3 10. The method of any one of embodiments 1-6 or 8-9, comprising reacting with titanium methylidene of formula (I).

[0239] E11. The method of any one of embodiments 1-6 or 8-10, wherein olefinating the compound of formula (VII) comprises reacting the compound of formula (VII) with a titanium methylidene of formula (C5H5)2Ti(CH2).

[0240] E12. The method of any one of embodiments 1-6 or 8-10, wherein olefinating a compound of formula (VIII) comprises reacting a compound of formula (VII) with a phosphonium ylide of formula (CH2)PPh3.

[0241] E13. Compound of formula (VI):

[0242] [ka]

[0243] to produce a compound of formula (VII).

[0244] E14. The method of any one of embodiments 1-6 or 8-13, wherein oxidizing the compound of formula (IV) comprises reacting the compound of formula (IV) with a nitroxyl radical, a hypervalent iodine compound, or activated DMSO.

[0245] E15. The method of any one of embodiments 1-6 or 8-14, wherein oxidizing the compound of formula (IV) comprises reacting the compound of formula (IV) with a nitroxyl radical.

[0246] E16. A nitroxyl radical is formed by reacting a nitroxyl radical precursor with a stoichiometric oxidant, where the nitroxyl radical precursor is The method of embodiment 15, wherein the compound is (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), 4-hydroxy-(2,2,6,6-tetramethylpiperidin-1-yl)oxyl 4-acetamide (4-OH-TEMPO), 4-acetamido-(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (4-acetamido-TEMPO), 2-azaadamantane N-oxyl (AZADO), or 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO).

[0247] E17. The method of embodiment 16, wherein the nitroxyl radical precursor is TEMPO.

[0248] E18. The method of embodiment 16 or 17, wherein the stoichiometric oxidant is sodium hypochlorite, oxygen, or (diacetoxyiodo)benzene.

[0249] E19. The method of any one of embodiments 16-18, wherein the stoichiometric oxidant is sodium hypochlorite.

[0250] E20. Compound of formula (V):

[0251] [ka]

[0252] The method of any one of embodiments 1-6 or 8-19, further comprising adding a hydroxyl protecting group to produce a compound of formula (VI).

[0253] E21. Compound of formula (III):

[0254] [ka]

[0255] with a reducing agent to produce a compound of formula (V).

[0256] E22. The method of any one of embodiments 1-21, wherein the reducing agent is a metal hydride.

[0257] E23. The method according to any one of the preceding embodiments, wherein the reducing agent is lithium aluminum hydride (LiAlH4), sodium borohydride (NaBH4), sodium bis(2-methoxyethoxy)aluminum hydride, or diisobutylaluminum hydride (DIBAL-H).

[0258] E24. The method of any one of embodiments 1-23, wherein the reducing agent is sodium bis(2-methoxyethoxy)aluminum hydride.

[0259] E25. Compound of formula (VIII):

[0260] [ka]

[0261] to obtain a compound of formula (IX), 2 teeth,

[0262] [ka]

[0263] The method of any one of embodiments 1 to 7, further comprising producing a compound comprising the steps of:

[0264] E26. Olefining a compound of formula (VIII) to give a compound of formula (VIII) 3 )PPh3 or a phosphonium ylide of the formula (C5H5)2Ti(CHR 3 26. The method of any one of embodiments 1-7 or 25, comprising reacting with titanium methylidene of formula (I).

[0265] E27. The method of any one of embodiments 1-7 or 25-26, wherein olefinating the compound of formula (VIII) comprises reacting the compound of formula (VIII) with a titanium methylidene of formula (C5H5)2Ti(CH2).

[0266] E28. The method of any one of embodiments 1-7 or 25-26, wherein olefinating the compound of formula (VIII) comprises reacting the compound of formula (VIII) with a phosphonium ylide of formula (CH2)PPh3.

[0267] E29. Compound of formula (IV):

[0268] [ka]

[0269] to produce a compound of formula (VIII).

[0270] E30. Compound of formula (III):

[0271] [ka]

[0272] One of

[0273] [ka]

[0274] The method of any one of embodiments 1-7 or 23-29, further comprising selectively decarboxylating a moiety to produce a compound of formula (IV).

[0275] E31. One of the compounds of formula (III)

[0276] [ka]

[0277] 30. The method of any one of embodiments 1-7 or 23-29, wherein decarboxylating the moiety comprises reacting a compound of formula (III) with LiCl.

[0278] E32. A compound of formula (I) (wherein X is chlorine, bromine or iodine) is reacted with a compound of formula (II):

[0279] [ka]

[0280] to produce a compound of formula (III).

[0281] E33. Compound of formula (IX):

[0282] [ka]

[0283] (In the formula, R 2 teeth,

[0284] [ka]

[0285] and; Y is a halogen; PG is a hydroxyl protecting group; R 1 is C 1~10 Alkyl, C 3~7 cycloalkyl, 6- to 12-membered aryl, or hydrogen, 1~10 Alkyl, the C 3~7Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from the group consisting of C 1~4 Alkyl, C 1~2 Haloalkyl, halogen, cyano, -OC 1~4 Alkyl, and -OC 1~2 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of haloalkyl; R 3 is hydrogen or C 1~10 Alkyl or halogen, -OR 4 , -N(R 4 )2, -CO2R 4 , -C(O)R 4 , -Si(R 4 )3, -B(OR 4 C substituted with 1 to 4 substituents independently selected from the group consisting of 1~10 alkyl or 1 to 4 R 4 a 3- to 12-membered heterocyclic ring optionally substituted with a substituent, or 1 to 4 R 4 a 3- to 12-membered carbocyclic ring optionally substituted with a substituent; R 4 is, for each occurrence, independently, hydrogen, halogen, C 1~4 Alkyl, -OH, -OC 1~4 Alkyl, -NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -C(O)C 1~4 Alkyl, -CO2C 1~4 Alkyl, -C(O)H, -COH, -C(O)NC 1~4 alkyl, -CF3, -CHF2, or -NO2).

[0286] E34.R 3 but,

[0287] [ka]

[0288] wherein n is 0, 1, 2, 3, or 4.

[0289] E35.R 3 is hydrogen.

[0290] E36. Compound of formula (XI):

[0291] [ka]

[0292] (In the formula, R 2 teeth,

[0293] [ka]

[0294] and; Y is a halogen; PG is a hydroxyl protecting group).

[0295] E37. The compound according to embodiment 36, wherein the hydroxyl protecting group is a tert-butyl(dimethyl)silyl (TBS) group.

[0296] E38. Compound of formula (VIII):

[0297] [ka]

[0298] (In the formula, R 1 is C 1~10 Alkyl, C 3~7 cycloalkyl, 6- to 12-membered aryl, or hydrogen, 1~10 Alkyl, the C 3~7Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from the group consisting of C 1~4 Alkyl, C 1~2 Haloalkyl, halogen, cyano, -OC 1~4 Alkyl, and -OC 1~2 haloalkyl).

[0299] E39. Compound of formula (IV):

[0300] [ka]

[0301] (In the formula, R 1 is C 1~10 Alkyl, C 3~7 cycloalkyl, 6- to 12-membered aryl, or hydrogen, 1~10 Alkyl, the C 3~7 Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from the group consisting of C 1~4 Alkyl, C 1~2 Haloalkyl, halogen, cyano, -OC 1~4 Alkyl, and -OC 1~2 haloalkyl).

[0302] E40. Compound of formula (III):

[0303] [ka]

[0304] (In the formula, R 1 is C 1~10 Alkyl, C 3~7 cycloalkyl, 6- to 12-membered aryl, or hydrogen, 1~10 Alkyl, the C 3~7 Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from the group consisting of C1~4 Alkyl, C 1~2 Haloalkyl, halogen, cyano, -OC 1~4 Alkyl, and -OC 1~2 haloalkyl).

[0305] E41.R 1 is methyl or ethyl.

Claims

1. 1. A method for preparing α-necrodyl isobutyrate, comprising: Compound of formula (IX): 【Chemistry 1】 (In the formula, R ２ teeth, 【Chemistry 2】 and Y is a halogen; PG is a hydroxyl protecting group; R １ is C １～１０ Alkyl, C ３～７ cycloalkyl, 6- to 12-membered aryl, or hydrogen, １～１０ Alkyl, the C ３～７ Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from C １～４ Alkyl, C １～２ Haloalkyl, halogen, cyano, -OC １～４ Alkyl, and —OC １～２ substituted with 1 to 5 substituents independently selected from the group consisting of haloalkyl; R ２ but, 【Transformation 3】 where the reducing agent is added before or after cyclization; R ３ is hydrogen or C １～１０ Alkyl or halogen, -OR ４ , -N(R ４ ) ２ , -CO ２ R ４ , -C(O)R ４ , -Si(R ４ ) ３ , -B(OR ４ ) ２ C substituted with 1 to 4 substituents independently selected from the group consisting of １～１０ alkyl or 1 to 4 R ４ a 3- to 12-membered heterocyclic ring optionally substituted with a substituent, or a heterocyclic ring having 1 to 4 R ４ a 3- to 12-membered carbocyclic ring optionally substituted with substituents; R ４ is, for each occurrence, independently hydrogen, halogen, C １～４ Alkyl, —OH, —OC １～４ Alkyl, —NH ２ , -NHC １～４ Alkyl, —N(C １～４ alkyl) ２ , -C(O)C １～４ Alkyl, —CO ２ C １～４ Alkyl, —C(O)H, —CO ２ H, —C(O)NC １～４ Alkyl, —CF ３ , -CHF ２ , or -NO ２ is) to form compounds of formula (Xa) and (Xb): 【Chemistry 4】 producing a mixture of; Next, reacting the mixture of compounds of formula (Xa) and (Xb) with an isobutylyl donor to produce α-necrodyl isobutyrate; or alternatively, A compound of formula (IX) ２ teeth, 【Transformation 5】 ) to produce α-necrodyl isobutyrate. The above method, comprising:

2. 10. The method of claim 1, wherein cyclizing the compound of formula (IX) comprises reacting the compound of formula (IX) with a transition metal carbene complex catalyst.

3. 3. The method of claim 1 or 2, wherein cyclizing the compound of formula (IX) comprises reacting the compound of formula (IX) with a ruthenium(II) carbene complex catalyst.

4. 4. The method of claim 3, wherein the ruthenium(II) carbene complex catalyst is (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium.

5. R ３ but, 【Transformation 6】 wherein n is 0, 1, 2, 3, or 4. C substituted with one substituent selected from the group consisting of １ 3. The method of claim 1 or 2, wherein the alkyl is alkyl.

6. R ３ The method of claim 1 or 2, wherein is hydrogen.

7. R ２ but, 【Transformation 7】 and R １ The method according to claim 1 or 2, wherein is methyl or ethyl.

8. Compound of formula (VII): 【Transformation 8】 and removing the hydroxyl protecting group (PG) to give a compound of formula (IX), ２ teeth, 【Chemistry 9】 3. The method of claim 1 or 2, further comprising producing a

9. 3. The method of claim 1, wherein the hydroxyl protecting group is a tert-butyl(dimethyl)silyl (TBS) group.

10. Olefinating a compound of formula (VII) to form a compound of formula (VII) ３ ) PPh ３ or a phosphonium ylide of formula (C ５ H ５ ) ２ Ti(CHR ３ 9. The method of claim 8, comprising reacting a titanium methylidene compound of formula (I) with a titanium methylidene compound of formula (II).

11. Olefinating the compound of formula (VII) converts the compound of formula (VII) to a compound of formula (C ５ H ５ ) ２ Ti(CH ２ 9. The method of claim 8, comprising reacting a titanium methylidene compound of formula (I) with a titanium methylidene compound of formula (II).

12. Olefinating the compound of formula (VII) converts the compound of formula (VII) to a compound of formula (CH ２ ) PPh ３ 9. The method of claim 8, comprising reacting with a phosphonium ylide of formula:

13. Compound of formula (VI): 【Chemistry 10】 to produce a compound of formula (VII).

14. 14. The method of claim 13, wherein oxidizing the compound of formula (VI) comprises reacting the compound of formula (VI) with a nitroxyl radical, a hypervalent iodine compound, or activated DMSO.

15. 15. The method of claim 14, wherein oxidizing the compound of formula (VI) comprises reacting the compound of formula (VI) with a nitroxyl radical.

16. 16. The method of claim 15, wherein the nitroxyl radical is formed by reacting a nitroxyl radical precursor with a stoichiometric oxidant, wherein the nitroxyl radical precursor is (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), 4-hydroxy-(2,2,6,6-tetramethylpiperidin-1-yl)oxyl 4-acetamide (4-OH-TEMPO), 4-acetamido-(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (4-acetamido-TEMPO), 2-azaadamantane N-oxyl (AZADO), or 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO).

17. 17. The method of claim 16, wherein the nitroxyl radical precursor is TEMPO.

18. 17. The method of claim 16, wherein the stoichiometric oxidizing agent is sodium hypochlorite, oxygen, or (diacetoxyiodo)benzene.

19. 17. The method of claim 16, wherein the stoichiometric oxidizing agent is sodium hypochlorite.

20. Compound of formula (V): 【Chemistry 11】 14. The method of claim 13, further comprising adding a hydroxyl protecting group to produce a compound of formula (VI).

21. Compounds of formula (III): 【Chemistry 12】 with a reducing agent to produce a compound of formula (V).

22. 22. The method of claim 21, wherein the reducing agent is a metal hydride.

23. The reducing agent is lithium aluminum hydride (LiAlH ４ ), sodium borohydride (NaBH ４ ), sodium bis(2-methoxyethoxy)aluminum hydride, or diisobutylaluminum hydride (DIBAL-H).

24. 24. The method of claim 23, wherein the reducing agent is sodium bis(2-methoxyethoxy)aluminum hydride.

25. Compound of formula (VIII): 【Chemistry 13】 is olefinated to give a compound of formula (IX), ２ teeth, 【Chemistry 14】 3. The method of claim 1 or 2, further comprising producing a

26. Olefinating the compound of formula (VIII) can be carried out by converting the compound of formula (VIII) to a compound of formula (CHR ３ ) PPh ３ or a phosphonium ylide of formula (C ５ H ５ ) ２ Ti(CHR ３ 26. The method of claim 25, comprising reacting a titanium methylidene of formula (I) with a titanium methylidene of formula (II).

27. Olefinating the compound of formula (VIII) converts the compound of formula (VIII) to a compound of formula (C ５ H ５ ) ２ Ti(CH ２ 27. The method of claim 26, comprising reacting a titanium methylidene of formula (I) with a titanium methylidene of formula (II).

28. Olefinating the compound of formula (VIII) converts the compound of formula (VIII) to a compound of formula (CH ２ ) PPh ３ 27. The method of claim 26, comprising reacting with a phosphonium ylide of formula:

29. Compound of formula (IV): 【Chemistry 15】 to produce a compound of formula (VIII).

30. Compounds of formula (III): 【Chemistry 16】 One of them 【Chemistry 17】 30. The method of claim 29, further comprising selectively decarboxylating the moiety to produce a compound of formula (IV).

31. One of the compounds of formula (III) [Chemistry 18] 31. The method of claim 30, wherein decarboxylating the moiety comprises reacting the compound of formula (III) with LiCl.

32. A compound of formula (I) (wherein X is chlorine, bromine, or iodine) is reacted with a compound of formula (II): 【Chemistry 19】 to produce a compound of formula (III).

33. Compound of formula (IX): 【Chemistry 20】 (In the formula, R ２ teeth, 【Chemistry 21】 and Y is a halogen; PG is a hydroxyl protecting group; R １ is C １～１０ Alkyl, C ３～７ cycloalkyl, 6- to 12-membered aryl, or hydrogen, １～１０ Alkyl, the C ３～７ Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from C １～４ Alkyl, C １～２ Haloalkyl, halogen, cyano, -OC １～４ Alkyl, and —OC １～２ substituted with 1 to 5 substituents independently selected from the group consisting of haloalkyl; R ３ is hydrogen or C １～１０ Alkyl or halogen, -OR ４ , -N(R ４ ) ２ , -CO ２ R ４ , -C(O)R ４ , -Si(R ４ ) ３ , -B(OR ４ ) ２ C substituted with 1 to 4 substituents independently selected from the group consisting of １～１０ alkyl or 1 to 4 R ４ a 3- to 12-membered heterocyclic ring optionally substituted with a substituent, or a heterocyclic ring having 1 to 4 R ４ a 3- to 12-membered carbocyclic ring optionally substituted with substituents; R ４ is, for each occurrence, independently hydrogen, halogen, C １～４ Alkyl, —OH, —OC １～４ Alkyl, —NH ２ , -NHC １～４ Alkyl, —N(C １～４ alkyl) ２ , -C(O)C １～４ Alkyl, —CO ２ C １～４ Alkyl, —C(O)H, —CO ２ H, —C(O)NC １～４ Alkyl, —CF ３ , -CHF ２ , or -NO ２ (It is).

34. R ３ but, 【Chemistry 22】 wherein n is 0, 1, 2, 3, or 4. C substituted with one substituent selected from the group consisting of １ 34. The compound of claim 33, which is alkyl.

35. R ３ 34. The compound of claim 33, wherein is hydrogen.

36. Compound of formula (XI): 【Chemistry 23】 (In the formula, R ２ teeth, 【Chemistry 24】 and Y is a halogen; PG is a hydroxyl protecting group).

37. 37. The compound of claim 36, wherein the hydroxyl protecting group is a tert-butyl(dimethyl)silyl (TBS) group.

38. Compound of formula (VIII): 【Chemistry 25】 (In the formula, R １ is C １～１０ Alkyl, C ３～７ cycloalkyl, 6- to 12-membered aryl, or hydrogen, １～１０ Alkyl, the C ３～７ Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from C １～４ Alkyl, C １～２ Haloalkyl, halogen, cyano, -OC １～４ Alkyl, and —OC １～２ and optionally substituted with 1 to 5 substituents independently selected from the group consisting of haloalkyl.

39. Compound of formula (IV): 【Chemistry 26】 (In the formula, R １ is C １～１０ Alkyl, C ３～７ cycloalkyl, 6- to 12-membered aryl, or hydrogen, １～１０ Alkyl, the C ３～７ Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from C １～４ Alkyl, C １～２ Haloalkyl, halogen, cyano, -OC １～４ Alkyl, and —OC １～２ and optionally substituted with 1 to 5 substituents independently selected from the group consisting of haloalkyl.

40. Compounds of formula (III): 【Chemistry 27】 (In the formula, R １ is C １～１０ Alkyl, C ３～７ cycloalkyl, 6- to 12-membered aryl, or hydrogen, １～１０ Alkyl, the C ３～７ Each of the cycloalkyl and the 6- to 12-membered aryl is optionally selected from C １～４ Alkyl, C １～２ Haloalkyl, halogen, cyano, -OC １～４ Alkyl, and —OC １～２ and optionally substituted with 1 to 5 substituents independently selected from the group consisting of haloalkyl.

41. R １ The compound of any one of claims 33-34 or 38-40, wherein is methyl or ethyl.

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