WO2003040083A1 - Enantioselective hydroxylation of beta-dicarbonyls catalyzed by cinchona alkaloid derivatives - Google Patents

Abstract

The present invention pertains to a process for preparing a compound of Formula I that is enantiomerically enriched at the chiral hydroxylation center indicated by Formula (I) comprising contacting a compound of Formula (II) with an oxidant in the presence of a chiral compound of Formula III or ent-III, wherein R?1, R2 and R3¿ are as defined in the disclosure.

Description

TITLE ENANTIOSELECTIVE HYDROXYLATION OF β-DICARBONYLS CATALYZED BY

CINCHONA ALKALOID DERIVATIVES

FIELD OF THE INVENTION The present invention pertains to a process for the hydroxylation of β-dicarbonyl compounds.

BACKGROUND OF THE INVENTION Certain β-dicarbonyl compounds (i.e. β-keto esters and their hydroxylated derivatives) are useful as intermediates for the preparation of fine chemicals, pharmaceuticals and plant protection products such as arthropodicidal oxadiazines. Arthropodicidal oxadiazines are disclosed in PCT Publications WO 92/11249 and WO 93/19045. Methods of preparing these compounds have also been reported in WO 95/29171, including a preparative step involving the hydroxylation of β-keto esters. However, improved preparative methods for these compounds are desirable for more economic commercial operation. Accordingly, the present invention provides an improved process to prepare hydroxylated β-dicarbonyl compounds, including those useful in preparing arthropodicidal oxadiazines.

SUMMARY OF THE INVENTION The present invention pertains to a process for preparing a compound of Formula I that is enantiomerically enriched at the chiral hydroxylation center indicated by *

* wherein

R¹ is H; or alkoxy, alkyl, cycloalkyl, cycloalkoxy, a phenyl ring, a phenoxy ring or a

5- or 6-membered heteroaromatic ring, each optionally substituted; R² is H; or alkyl, cycloalkyl, a phenyl ring, or a 5- or 6-membered heteroaromatic ring, each optionally substituted;

R³ is H; or alkoxy, alkyl, cycloalkyl, cycloalkoxy, a phenyl ring, a phenoxy ring or a

5- or 6-membered heteroaromatic ring, each optionally substituted; or R² and R³ are taken together to form an optionally substituted linking chain of 3 to 6 members including at least one carbon member, optionally including no more than two carbon members as C(=O), optionally including one member selected from nitrogen and oxygen, and optionally fused to a phenyl ring or a 5- or 6- membered heteroaromatic ring, each ring optionally substituted; or R¹ and R³ are taken together to form an optionally substituted linking chain of 2 to 5 members including at least one carbon member, optionally including no more than one carbon member as C(=O), and optionally fused to a phenyl ring or a 5- or 6-membered heteroaromatic ring, each ring optionally substituted; comprising: contacting a compound of Formula II

II wherein R¹, R² and R³ are as defined above with an oxidant in the presence of a chiral compound of Formula III or ent-III

HI ent-m wherein

R⁴ is H, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl; R⁵ is C1-C4 alkyl, C₁-C haloalkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl), aryl(C₁-C₄ haloalkyl), heteroaryl(Cι-C4 alkyl), C2-C4 alkenyl, C2-C4 haloalkenyl, aryl(C2-C4 alkenyl), heteroaryl(Cι-C4 alkenyl), C2-C4 alkynyl, aryl(C2-C4 alkynyl) or heteroaryl(C2-C4 alkynyl); and

R⁶ is H; or R⁵ and R⁶ are taken together to form C₂-C alkylidenyl, C₂-C haloalkylidenyl, or aryl(C₂-C4 alkylidenyl) or heteroaryl(C₂-C4 alkylidenyl); provided that when R⁴ is H or methoxy, then R⁵ is other than vinyl. This invention also involves a process for preparing a compound of Formula IV,

wherein

R¹ is C_J-C₃ alkoxy; and

R⁷ is F, CI or ^^₃ fluoroalkoxy; using a compound of Formula la

la wherein Formulae IV and la are enantiomerically enriched with the S isomer at the chiral center indicated by *; characterized by: preparing said compound of Formula la by the process indicated above.

DETAILED DESCRIPTION OF THE INVENTION In the recitations herein, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, -propyl, or the different butyl, pentyl or hexyl isomers. "Alkenyl" includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkylamino", "alkenylthio", "alkenylsulfinyl", "alkenylsulfonyl", "alkynylthio", "alkynylsulfmyl", "alkynylsulfonyl", and the like, are defined analogously to the above examples. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "cycloalkoxy" includes the same groups linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy. "Cycloalkenyl" includes groups such as cyclopentenyl and cyclohexenyl as well as groups with more than one double bond such as 1,3- and 1,4-cyclohexadienyl. Examples of "alkylcarbonyl" include C(O)CH₃, C(O)CH₂CH₂CH₃ and C(O)CH(CH₃)₂. Examples of "alkoxycarbonyl" include CH₃OC(=O),

CH₃CH₂OC(=O), CH₃CH₂CH₂OC(=O), (CH₃)₂CHOC(=O) and the different butoxy- or pentoxycarbonyl isomers. Other groups are defined analogously. The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" include F₃C, C1CH₂, CF₃CH₂ and CF₃CC1₂. The terms "haloalkenyl", "haloalkoxy" and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkenyl" include (C1)₂C=CHCH₂ and CF₃CH₂CH=CHCH₂. Examples of "haloalkoxy" include CF₃O, CCl₃CH₂O, HCF₂CH₂CH₂O and CF₃CH₂O. Substituents specified to contain a particular halogen are defined similarly. For example, fluoroalkoxy includes CHF₂O, CF₃O, CF₂HCF₂O, CH₂FCH₂O, CF₃CH₂O, CF₃(CH₂)₂O, CF₃(CF₂)₂O and the like.

The total number of carbon atoms in a substituent group can be indicated by the "Cj-C_j" prefix where i and j are numbers indicating the range of carbon atoms in the substituent group. For example, C1-C₃ alkyl designates methyl through propyl. When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, said substituents (when they exceed 1) are independently selected from the group of defined substituents.

The term "member" in the description of a chain or ring refers to an atom forming part of the backbone structure of said chain or ring. If said chain or ring is said to be optionally substituted, the atom members are optionally substituted with one or more substituent groups, consistent with the atom members' free valency remaining after bonding of the atom members to form the chain or ring.

The term "optionally substituted" refers to chain, ring or other group that is unsubstituted or substituted with at least one moiety other than hydrogen by replacement of said hydrogen.

The term "carbocyclic ring" denotes a ring wherein the atoms forming the ring backbone are selected only from carbon. The term "heterocyclic ring" denotes a ring wherein at least one atom forming the ring backbone is carbon and at least one other atom forming the ring backbone is other than carbon. The term "aryl" alone or in combination words, such as "arylalkyl" and the like, refers to phenyl rings or aromatic carbocyclic ring systems including polycyclic ring systems such as naphthalene, anthracene and the like, each ring or ring system optionally substituted. A "ring system" refers to two or more fused rings. The term "aromatic carbocyclic ring system" includes fully aromatic carbocycles and carbocycles in which at least one ring of a polycyclic ring system is aromatic. The term "heteroaryl" alone or in combination words, such as "heteroarylalkyl" and the like, refers to 5- or 6-membered heteroaromatic rings or aromatic heterocyclic ring systems. The terms "heteroaromatic ring" and "aromatic heterocyclic ring system" include fully aromatic heterocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic. Examples of heteroaromatic rings include thiophene, pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, triazine, triazole and furan. The heterocyclic ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen. The fragment "hetero" in these terms denotes a ring in which one at least one ring atom is not carbon and contains 1 to 4 heteroatoms independently selected from the group nitrogen, oxygen and sulfur, provided that each ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. Aromatic indicates that each of the ring atoms is essentially in the same plane and has ajo-orbital perpendicular to the ring plane, and in which (4n + 2) π electrons, where n is 0 or a positive integer, are associated with the ring to comply with Hϋckel's rule.

Molecular depictions drawn herein follow standard conventions for depicting stereochemistry. To indicate stereoconfiguration, bonds rising from the plane of the drawing and towards the viewer are denoted by solid wedges wherein the broad end of the wedge is attached to the atom rising from the plane of the drawing towards the viewer. Bonds going below the plane of the drawing and away from the viewer are denoted by dashed wedges wherein the narrow end of the wedge is attached to the atom further away from the viewer. Constant width lines indicate bonds with a direction opposite or neutral relative to bonds shown with solid or dashed wedges; constant width lines also depict bonds in molecules or parts of molecules in which no particular stereoconfiguration is intended to be specified. An asterisk (*) is used to indicate the Formula I chiral hydroxylation center comprising the hydroxy group introduced by a process of this invention. The hydroxylation center will not be chiral if at least two of the groups attached to the hydroxylation center are identical, causing a mirror plane of symmetry to exist through the hydroxylation center. Therefore all of the groups attached to the hydroxylation center must be different in order for the Formula I hydroxylation center to be chiral. If the hydroxylation center is a chiral center, two enantiomers are possible, corresponding to the two possible configurations at the chiral center. When the enantiomers are present in equal amounts the Formula I compound is racemic at the hydroxylation center; otherwise one enantiomer is present in excess and the Formula I compound is described as enantiomerically enriched at the hydroxylation center. An asterisk (*) is also used to indicate the chiral center originating from the chiral hydroxylation center through further synthetic transformation. The chiral hydroxylation center can be alternatively identified simply as a chiral center.

Furthermore, R¹, R² and R³ of Formulae I and II can optionally comprise one or more additional chiral centers. R⁴ and R⁵ of Formula III can also optionally comprise one or more chiral centers. A statement that Formula I is enantiomerically enriched at the chiral hydroxylation center indicated by * refers only to that center. A compound of Formula I that is enantiomerically enriched at the chiral hydroxylation center indicated by * can at the same time also be enantiomerically enriched at other chiral centers.

For a general reference regarding enantiomers and enantioselective processes, see E. L. Eliel, S. H. Wilen and L. N. Mander, Stereochemistry of Organic Compounds, Wiley- Interscience, New York, 1994.

In one embodiment of the present invention, an enantiomerically enriched compound of Formula I is prepared by an enantioselective procedure. By "enantiomerically enriched" it is meant that a bulk sample of the compound contains an excess of either the (+) or (-) enantiomer and includes anything greater than a 1-to-l (racemic) mixture of enantiomers up to and including 100% of a pure enantiomer. By definition, the enantiomeric excess (ee) of a sample is expressed as a percentage and is given by the equation Enantiomeric Excess = [(Enl - En2) • 100%] / (Enl + En2) where Enl and En2 are the amounts of the two enantiomers. Thus, for example, an enriched compound having 25% (-) enantiomer and 75% (+) enantiomer is referred to as having a 50% enantiomeric excess of the (+) enantiomer. Enantiomerically enriched compounds of Formula I can be produced, for example, by physically separating the enantiomers of a racemic mixture according to standard methods. However, such methods are difficult to operate on a large scale and are often wasteful, because the undesired enantiomer must be discarded if it cannot be racemized. By "enantioselective" it is meant that the desired enantiomer of the chiral product is formed preferentially, although not necessarily exclusively. "Enantiomeric purity" is calculated the same way as enantiomeric excess; a product of 100% enantiomeric purity has one enantiomer in 100% excess and none of the other enantiomer; a product of 0% enantiomeric purity has equal amounts of enantiomers such that neither is in excess, and therefore the product is racemic.

This embodiment of the present invention pertains to a process for preparing an enantiomerically enriched compound of Formula I by contacting a compound of Formula II with an oxidant and a chiral amine base, optionally in the presence of an inert solvent. More specifically, an enantiomerically enriched compound of Formula I is prepared by contacting a compound of Formula II with about 0.9 to 10.0 equivalents of an oxidant in the presence of about 0.001 to 1.5 equivalents of a chiral compound of Formula III or ent-III, and optionally an inert solvent. Typical reaction conditions include reaction temperatures in the range of about -5 to 100 °C and reaction times of about 2 hours to 8 days. Reaction temperatures of 20 to 75 °C are preferred. Suitable oxidants include oxygen (e.g., air), hydrogen peroxide, monoethers of hydrogen peroxide including t-butyl hydroperoxide, cumene hydroperoxide and combinations thereof, peracids such as peracetic acid or -chloroperbenzoic acid, hypochlorites such as sodium hypochlorite, monopersulfates such as potassium monopersulfate (e.g., Oxone®) and dioxiranes such as dimethyldioxirane. A preferred oxidant is *-butyl hydroperoxide. Suitable solvents include aliphatic hydrocarbons such as cyclohexane, aromatic hydrocarbons such as toluene, xylenes, ethylbenzene, mesitylene and cumene, halogenated hydrocarbons such as dichloromethane, dichloroethane and o /zo-dichlorobenzene, ketones such as methyl ethyl ketone, methyl isobutyl ketone and methyl isopropyl ketone, esters such as methyl acetate, ethyl acetate, isopropyl acetate, alcohols such as methanol and 2-methyl-2-propanol, and ethers such as diethyl ether or tetrahydrofuran. Aromatic hydrocarbon solvents are preferred. Chiral amine bases suitable for this process are compounds of Formulae III and ent-III as defined in the Summary of the Invention and described in further detail below. Preferred in the process of the invention are chiral amine bases of Formulae III and ent-III wherein R⁴ is H, methoxy or hydroxy; more preferably R⁴ is hydroxy. Also preferred in the process of the invention are chiral amine bases of Formula III and ent-III wherein R⁵ is haloalkyl; more preferably R⁵ is -CHBrCH₃ or -CHBrCH₂Br.

R¹, R² and R³ in Formulae I and II are appendages not directly involved in the hydroxylation reaction center. Because the reaction conditions of the hydroxylation process of the invention are so mild, a wide range of molecular structural features are possible for R¹, R² and R³, and only functionalities most reactive to oxidative conditions are susceptible to being affected. Therefore the substituent radicals listed for R¹, R² and R³ in the Summary of the Invention should be regarded as just describing a subgenus illustrative of the wide range of applicability of the process of this invention. Many of the radicals specified in the Summary of the Invention for R¹, R² and R³ in Formulae I and II are optionally substituted. A wide range of optional substituents are possible; illustrative optional substituents include alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, hydroxycarbonyl, formyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkoxycarbonyl, hydroxy, alkoxy, alkenyloxy, alkynyl- oxy, cycloalkoxy, aryloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, arylthio, alkylsulfϊnyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, amino, alkylamino, alkenylamino, alkynylamino, arylamino, aminocarbonyl, alkylaminocarbonyl, alkenyl- aminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylaminocarbonyl, alkenyl- aminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyloxy, alkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino and aryloxycarbonylamino, each further optionally substituted; and halogen, cyano and nitro. The optional further substituents are independently selected from groups like those illustrated above for the substituents themselves to give additional substituent groups such as haloalkyl, haloalkenyl and haloalkoxy. As a further example, alkylamino can be further substituted with alkyl, giving dialkylamino. The substituents can also be tied together by figuratively removing one or two hydrogen atoms from each of two substituents or a substituent and the supporting molecular structure and joining the radicals to produce cyclic and polycyclic structures fused or appended to the molecular structure supporting the substituents. For example, tying together adjacent hydroxy and methoxy groups attached to, for example, a phenyl ring gives a fused dioxolane structure containing the linking group -O-CH₂-O-. Tying together a hydroxy group and the molecular structure to which it is attached can give cyclic ethers, including epoxides. Illustrative substituents also include oxygen, which when attached to carbon forms a carbonyl function. Preferred processes of the invention are those wherein in Formulae I and II, the carbon atom of R² connected to the chiral hydroxylation center indicated by * is in the form of a methyl, methylene or carbonyl unit. When the connecting carbon of R² is in the form of a carbonyl unit, it forms a tricarbonyl system with the other two carbonyls of Formula II. The enhanced acidity of the tricarbonyl system can facilitate the hydroxylation of Formula II to give Formula I. Although there is no definite limit to the sizes of Formulae I and II suitable for the processes of the invention, typically Formula II comprises 5-100, more commonly 5-50, and most commonly 5-25 carbon atoms, and 2-25, more commonly 2-15, and most commonly 2-10 heteroatoms. The heteroatoms are commonly selected from halogen, oxygen, sulfur, nitrogen and phosphorus, and more commonly, halogen, oxygen and nitrogen. Two heteroatoms in Formula II are the β-dicarbonyl oxygen atoms. The numbers of atoms commonly in Formula I are similar to those described by Formula II, except that as result of hydroxylation, Formula I has one more heteroatom. Also, there is no definite limit to the size of the illustrative groups listed for R¹, R² and R³ including optional substituents, but alkyl, including derivatives such as alkoxy, is commonly C_j-Cg, alkenyl and alkynyl are commonly C₂~Cg and more commonly C₂-C₆, and cycloalkyl is commonly C₃~Cg.

One skilled in the art recognizes that sulfinyl and particularly thio moieties (in, for example, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, arylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl and arylsulfinyl substituents) are susceptible to oxidation. Thio- and sulfinyl-containing substituents in Formula II do not prevent the hydroxylation reaction of this invention, but thio can be converted to sulfinyl and sulfonyl, and sulfinyl converted to sulfonyl in the product of Formula I.

Of note are processes of this invention wherein, in Formulae I and II, R² is H, alkyl, cycloalkyl, a phenyl ring, or a 5- or 6-membered heteroaromatic ring, each ring optionally substituted; and R¹ and R³ are not taken together. Of note also are processes of the invention wherein, in Formulae I and II, R¹ is H; or alkoxy, alkyl, cycloalkyl, a phenyl ring, a phenoxy ring or a 5- or 6-membered heteroaromatic ring, each optionally substituted; and R³ is alkoxy, alkyl, cycloalkyl, a phenyl ring, or a 5- or 6-membered heteroaromatic ring, each optionally substituted.

Preferred processes of this invention are those wherein, in Formulae I and II, R¹ is alkyl or alkoxy, preferably alkoxy, more particularly C -Cg alkoxy, and more preferably C₁-C₃ alkoxy, R² is preferably alkyl or alkylcarbonyl (alkyl substituted with oxygen on the linking carbon), more preferably alkyl and more particularly C^Cg alkyl, R³ is optionally substituted phenyl, or R² and R³ are taken together to form an optionally substituted linking chain of 3 to 4 carbon members optionally fused to an optionally substituted phenyl ring. Preferably the optional substituents on phenyl are selected from halogen, cyano and nitro, and also alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, formyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkoxycarbonyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, aryloxy, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, amino, alkylamino, alkenylamino, alkynylamino, arylamino, aminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylaminocarbonyloxy, alkenylaminocarbonyloxy, alkynylaminocarbonyloxy, arylaminocarbonyloxy, alkoxy- carbonylamino, the aforementioned substituents optionally tied together, the aforementioned substitutents optionally substituted with halogen. Preferred processes of this invention include:

1. The process wherein the oxidant is -butyl hydroperoxide.

2. The process wherein in Formula III or ent-III, R⁴ is H, methoxy or hydroxy.

3. The process of Preferred 2 wherein R⁴ is hydroxy. 4. The process of Preferred 2 wherein in Formula III or ent-III, R⁵ is haloalkyl.

5. The process of Preferred 4 wherein in Formula III or ent-III, R⁵ is -CHBrCH₃ or -CHBrCH₂Br.

6. The process wherein, in Formulae I and II

R¹ is C^-Cg alkoxy; R² is alkyl;

R³ is optionally substituted phenyl, or

R² and R³ are taken together to form an optionally substituted linking chain of 3 to 4 carbon members optionally fused to an optionally substituted phenyl ring. Particularly preferred is a process of this invention wherein a compound of

Formula Ila

Ila wherein R¹ is ^-0₃ alkoxy and R⁷ is F, CI, or -C₃ fluoroalkoxy is contacted with an oxidant and a chiral compound of Formula III or ent-III to prepare a compound of Formula la

la that is enantiomerically enriched at the chiral hydroxylation center indicated by *.

Note that Formulae la and Ila are subsets of Formula I and II, respectively, in which R² and R³ are taken together to form a linking chain of 3 carbon members fused to a phenyl ring substituted with R⁷. Therefore the above described particularly preferred process is a process of the invention wherein the compound of Formula I is a compound of Formula la and the compound of Formula II is a compound of Formula Ila.

Preparation of compounds of Formula la from compounds of Formula Ila has been previously reported in PCT Publication WO 95/29171. The process of this invention affords improved enantioselectivity over the enantioselective process reported in WO 95/29171.

For the aforementioned particularly preferred process for preparing a compound of Formula la from a corresponding compound of Formula Ila, a chiral compound of Formula III or ent-III has been discovered to provide greater enantioselectivity in the process when R⁴ is H instead of methoxy and still greater enantioselectivity when R⁴ is hydroxy. Also in the process for preparing a compound of Formula la from Formula Ila, a chiral compound of Formula III or ent-III has been discovered to provide especially good enantioselectivity when R⁵ is haloalkyl, such as -CHBrCH₃ or -CHBrCH₂Br. Especially good enantioselectivity is also obtained when R⁵ and R⁶ are taken together to form =CH-CH₃ wherein the stereochemistry of the CH₃ group on the bicyclic ring component of Formula III or ent-III is syn to the quinolinylmethyl appendage. For the particular process of preparing a compound of Formula la from Formula Ila, better enantioselectivity is obtained in the presence of a chiral compound of Formula III or ent-III wherein when R⁵ is alkyl, alkenyl or alkynyl then R⁴ is other than H or alkoxy, and when R⁵ and R⁶ are taken together to form alkylidenyl then R⁴ is other than alkoxy. However, the compounds of Formula III or ent-III wherein R⁵ is alkyl, alkenyl or alkynyl and R⁴ is H or alkoxy, or wherein R⁵ and R⁶ are taken together to form alkylidenyl and R⁴ is alkoxy do provide significant enantioselectivity for the process of preparing a compound of Formula la from Formula Ila, and for the process of the invention involving other compounds within the more general Formulae I and II may provide better stereoselectivity than compounds of Formula III or ent-III with other radicals for R⁴, R⁵ and R⁶.

Preparation of chiral compounds of Formula III or their enantiomers of Formula ent-III are described below. Formulae Illa-k are subsets of Formula III. Note that only Formula III and its subsets are illustrated in Schemes 1^4. Preparation of compounds of Formula ent-III and its subsets can be accomplished by using the enantiomeric starting compounds in the syntheses illustrated. Thus, compounds of Formula ent-III can be prepared starting from cinchonidine in Schemes 1 and 2 or quinine in Scheme 3.

Convenient starting compounds for the synthesis of many of the chiral compounds of Formula III or ent-III are the natural cinchona alkaloids cinchonine (or its enantiomer cinchonidine) and quinidine (or its enantiomer quinine). The vinyl group of these alkaloids can be functionalized and elaborated by general methods well known to those skilled in the art, including but not limited to, halogenation, hydrohalogenation, dehydrohalogenation, hydrogenation, epoxidation, dihydroxylation and the like. Specific application of some of these methods to the alkaloid series is described in H. M. R. Hoffmann et al., Helv. Chim. Ada, 2000, 83, 777-792; P. Langer and H. M. R. Hoffmann, Tetrahedron, 1997, 53, 9145- 9148; H. M. R. Hoffmann et al., Chem. Eur. J, 1996, 673-679; C. von Riesen and H. M. R. Hoffmann, Chem. Eur. J., 1996, 680-684; and in L. Prajer and J. Suszko, Roczniki Chem., 1952, 26, 531-543 [Chem. Abstr., 49, 2448-2450 (1955)]. One skilled in the art will recognize that many of the derivatives obtained by the general methods, such as ketones, vinyl halides, acetylenes, and the like, can be further elaborated by well-known methods including alkylation and metal-catalyzed cross-coupling reactions to provide alkyl, aryl, arylalkyl and heteroarylalkyl derivatives. Specific application of some of these methods to the alkaloid series is described in H. M. R. Hoffmann et al., J. Chem. Soc, Perkin Trans. I, 2001, 47-65; and in J. Frackenpohl and H. M. R. Hoffinann, J. Org. Chem., 2000, 65, 3982- 3996.

One synthetic method (when R⁴ is H) involves dihalogenation or hydrohalogenation of the vinyl moiety of cinchonine (with its other functionality optionally protected) as shown in Scheme 1, to afford chiral compound of Formula Ilia. Alternatively, the vinyl moiety of cinchonine can be cleaved to an aldehyde, for example by ozonolysis, or by dihydroxylation with reagents such as osmium tetroxide and an appropriate re-oxidant followed by cleavage with a reagent such as sodium periodate. Reaction of the aldehyde with a Wittig-type reagent of Formula 1, or with an alkylmetal reagent of Formula 2 followed by dehydration of the intermediate alcohol, provides olefin an olefin of Formula lllb which can be dihalogenated, hydrohalogenated, or hydrogenated to provide additional chiral compounds of Formula IIIc.

Scheme 1

Alternatively, as shown in Scheme 2, the vinyl moiety of cinchonine can be isomerized, for example by treatment with mineral acid or the like, to produce an ethylidene group which can be cleaved to produce a ketone, for example by ozonolysis, or by dihydroxylation with reagents such as osmium tetroxide and an appropriate re-oxidant followed by cleavage with a reagent such as sodium periodate. This ketone can then be reacted with a Wittig-type reagent of Formula 3, or with an alkylmetal reagent of Formula 4 followed by dehydration of the intermediate alcohol, providing an olefin of Formula Hid, which can be dihalogenated, hydrohalogenated, or hydrogenated to provide additional chiral compounds of Formula Ille. Scheme 2

Hid ^ is ^l-^ ^a^ '> ^aryl ^or heteroaryl me

Wittig reactions and related reactions are well-known in the art and are extensively reported in the chemical literature. Although compounds of Formulae 1 and 3 are illustrated in Schemes 1 and 2 to represent Wittig-type reagents, one skilled in the art will realize that many variations of reagents and reaction conditions are available. One skilled in the art will also realize that the addition of alkylmetal reagents such as compounds of Formulae 2 and 4 to aldehydes and ketones is also well-known and extensively described in the chemical literature.

When R⁴ is alkoxy (e.g., methoxy), quinidine can be hydrohalogenated to afford chiral compounds of Formula Illf (Q is Q¹) as shown in Scheme 3. Also, the vinyl moiety of quinidine can be cleaved to an aldehyde, for example by ozonolysis, or by dihydroxylation with reagents such as osmium tetroxide and an appropriate re-oxidant followed by cleavage with a reagent such as sodium periodate. Reaction of the aldehyde with a Wittig-type reagent, or with an alkylmetal reagent followed by dehydration of the intermediate alcohol, provides olefins of Formula Illf (Q is Q²) which can be dihalogenated, hydrohalogenated, or hydrogenated to provide additional chiral compounds of Formula Illf (Q is Q³).

Scheme 3

Illf RisMe nig RisH lift Ris R¹⁰

Q¹ Q2 Q3 Q4 Q5 wherein X and Y are each independently H, CI, Br or I; R⁸ and R⁹ are C₁-C₂ alkyl, aryl or heteroaryl; and R¹⁰ is -C4 alkyl.

Alternatively, as also shown in Scheme 3, the vinyl moiety of quinidine can be isomerized, for example by treatment with mineral acid or the like, to produce an ethylidene group which can be cleaved to produce a ketone, for example by ozonolysis, or by dihydroxylation with reagents such as osmium tetroxide and an appropriate re-oxidant followed by cleavage with a reagent such as sodium periodate. This ketone can then be reacted with a Wittig-type reagent, or with an alkylmetal reagent followed by dehydration of the intermediate alcohol, providing an olefin of Formula Illf (Q is Q⁴), which can be dihalogenated, hydrohalogenated, or hydrogenated to provide additional chiral compounds of Formula Illf (Q is Q⁵).

Compounds of Formula III wherein R⁵ is a moiety other than those illustrated in Q¹ through Q⁵ can be prepared by the wide variety of general methodologies known in the art of organic synthesis. For example, compounds of Formula III wherein R⁵ is alkynyl, arylalkynyl or heteroarylalkynyl can be prepared by base-induced dehydrohalogenation of corresponding compounds wherein Q is Q³ and X and Y are each halogen.

The compounds of Formula Illf can be demethylated to provide additional chiral compounds of Formula Illg. This demethylation can be carried out under acidic conditions by contacting the methoxy compound with a mineral acid or a Lewis acid such as boron trihalide or the like. Alternatively, demethylation can be carried out under neutral to alkaline conditions by contacting the methoxy compound with a nucleophihc reagent such as a metal thioalkoxide or a cyanide or iodide salt, or the like, optionally in a suitable solvent. The resulting hydroxy compounds can be alkylated by treatment with an alkylating agent R¹⁰-Lg (wherein R¹⁰ is C₁-C₄ alkyl and Lg is a nucleophihc reaction leaving group) such as an alkyl halide (e.g., R¹⁰Br, R^I) or an alkyl sulfonate (e.g., R¹⁰OS(O)₂CH₃, R¹⁰OS(O)₂OR¹⁰) or the like, either thermally or in the presence of a suitable base, optionally in a suitable solvent, to provide chiral compounds of Formula Illh, as also shown in Scheme 3. Compounds of Formula III wherein R⁴ is alkyl can be prepared according to

Scheme 4. The hydroxyl function of compounds of Formula Illg can be converted to a displaceable group Lg such as a fluorosulfonate, trifluoromethanesulfonate, or the like. The resulting intermediate can be reacted with reagents such as acetylenes or vinylstannanes or the like (where Met is Sn, Zn, B(OH)₂, Mg, Li or Cu and additional counterions as necessary) in the presence of a palladium or nickel catalyst, optionally in a suitable solvent, to afford acetylenes Mi or olefins IIIj, respectively. Preferred catalysts for the synthesis of compounds of Formula Illi or IIIj include but are not limited to Pd(PPh₃)₄, PdCl₂(PPli₃)₂, PdCl₂(diphenylphosphinoferrocene), NiC^PPh^, and tetrakis(tri-2-furylphosphino)- palladium. The exact conditions for each reaction depend upon the catalyst used and the metal in the reagent. The additional presence of an external base (such as an alkali carbonate, tertiary amine or alkali fluoride) is necessary for reactions of compounds wherein Met is B(OH)₂. These unsaturated compounds can then be hydrogenated to provide chiral bases Illk, as shown in Scheme 4 (where Q is as defined in Scheme 3).

Scheme 4

Of note is the use of compounds of Formula III or ent-III in other enantioselective processes including oxidations of sulfides to chiral sulfoxides, oxidations of olefins to chiral epoxides, dihydroxy compounds or aminoalkoxy compounds, and oxidations of allylic alcohols to epoxyalcohols. Complexes comprising compounds of Formula III or ent-III may also be used in enantioselective hydrogenations or reductions.

One skilled in the art will also recognize that compounds of Formula HI and ent-III and the intermediates described herein can be subjected to various electrophilic, nucleophihc, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.

The hydroxylation method of the invention is useful for preparation of an arthropodicidal όxadiazine of Formula IV, involving as process intermediate the compound of Formula la prepared by said hydroxylation method

wherein Formulae IV and la are enantiomerically enriched with the S isomer at the chiral center indicated by *, R¹ is C₁-C₃ alkoxy, and R⁷ is F, CI or C₁-C₃ fluoroalkoxy. As the enantiomer of Formula IV having the S configuration has much greater arthropodicidal efficacy than does its antipode having the R configuration, oxadiazine products of Formula IV enantiomerically enriched with the S isomer and made from corresponding intermediates of Formula la prepared according to the process of this invention will have greater arthropodicidal efficacy than oxadiazine products of Formula IV that are racemic or less enantiomerically enriched. Preferred because of excellent arthropodicidal efficacy of the oxadiazine product of Formula IV is the aforementioned preparation wherein R¹ is OCH₃ and R⁷ is CI.

As already discussed, the compound of Formula la can be prepared from the corresponding compound of Formula Ila using the hydroxylation method of the invention. The further steps leading to the preparation of the compound of Formula IV from Formula la are disclosed by R. Shapiro et al. "Toward the Manufacture of Indoxacarb" Chapter 17 (pp. 178-185 in Synthesis and Chemistry of Agrochemicals VI (ACS Symposium Series 800), American Chemical Society, Washington, DC, 2002 and PCT Publications WO 92/11249, WO 95/29171, WO 96/31467 and WO 98/05656 and are depicted in Schemes 5 and 6. The reaction steps in these Schemes proceed substantially with retention of configuration at the chiral center indicated by * .

In the synthetic route shown in Scheme 5 the compound of Formula la is contacted with a protected hydrazine compound of Formula 7 to give the hydrazone of Formula 8. This hydrazone is then contacted with a formaldehyde equivalent (Formula 9) to form the cyclized compound of Formula 10. The protecting group is removed from the Formula 10 compound to give the compound of Formula 11, which is contacted with an acylating agent of Formula 12 to give the compound of Formula IV. Scheme 5

wherein R¹ and R⁷ are as previously defined, R¹⁴ is a protecting group, and X¹ is a leaving group. The hydrazine derivative of Formula 7 has one end protected with protecting group

R¹⁴. A variety of amino protecting groups are known (see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). A protecting group that is particularly convenient in this preparation is benzyloxycarbonyl (R¹⁴ is C(O)OCH₂Ph). Generally at least a molar equivalent of the hydrazine of Formula 7 is used in relation to the ketone of Formula la. The condensation of the hydrazine of Formula 7 with the ketone of Formula la is greatly facilitated by the presence of a catalyst. Useful catalysts for this condensation have acidic properties. Such catalysts include zeolites such as molecular sieves, as well as Lewis acids and, most commonly, protic acids. Useful protic acids include, for example, mixed toluenesulfonic acids, ^-toluenesulfonic acid, sulfuric acid or acetic acid. With strong protic acids such as the toluenesulfonic acids as little as about 10-12 mol % acid can provide high conversions. As strong acids can protonate the hydrazine derivative of Formula 7, generally the molar amount of Formula 7 should at least equal the sum of the molar amount of Formula la and the molar equivalents of acid catalyst. The condensation can be conducted without solvent or in the presence of an inert solvent such as methanol, isopropanol, tetrahydrofuran, dichloromethane, 1,2-dichloromethane, toluene and the like. Typical reaction conditions include temperatures of about 40 to 120 °C, preferably about 65 to 85 °C for about 0.5 to 25 hours. The hydrazone of Formula 8 can be recovered by standard methods such as filtration, optionally after dilution of the reaction mixture with water. Alternatively, the reaction mixture containing the hydrazone of Formula 8 can be used directly in the next reaction step, or the hydrazone of Formula 8 can be extracted with solvent and the solvent extract used in the next reaction step.

In the next step the hydrazone of Formula 8 is cyclized using a formaldehyde equivalent (9) to give the compound of Formula 10. Formaldehyde equivalents include formaldehyde itself, but it readily polymerizes and is inconvenient to use. Other formaldehyde equivalents include halomethyl alkyl ethers. Most convenient of formaldehyde equivalents are dialkoxymethanes, preferably di(Cι~C₃ alkoxy)methane, such as dimethoxymethane or diethoxymethane. The dialkoxymethane is preferably used in molar excess relative to Formula 8 and can also serve as the solvent. The reaction is optionally conducted using as co-solvent an inert solvent such as dichloromethane, trichloromethane, 1,2-dichloroethane, tetrahydrofuran, chlorobenzene, ,α,α- trifluorotoluene, toluene, heptane, xylenes, acetonitrile and the like. When the formaldehyde equivalent is a dialkoxymethane, the reaction is conducted in the presence of a Lewis or protic acid. Useful Lewis acids include phosphorus pentoxide, boron trifluoride or sulfur trioxide, of which 0.9 to 4.0 molar equivalents (relative to 8) is generally required for best results. Other useful Lewis acids include metal (especially scandium, ytterbium, yttrium and zinc) trifluoromethanesulfonates, which can be used in amounts of 0.1 to 0.5 molar equivalents relative to the compound of Formula 8. The most preferred Lewis acids for this step are phosphorus pentoxide and sulfur trioxide; the sulfur trioxide can be in the form of a complex such as SO₃ DMF (DMF is NN-dimethylformamide), and usually there is also present a protic acid scavenger such as an amine complex (e.g., Sθ₃-pyridine). A filter aid such as Celite® (diatomaceous earth) can be advantageously added to reactions employing phosphorus pentoxide. When a Lewis acid is used, halogenated solvents are most suitable. Useful protic acids include mineral acids such as sulfuric and sulfonic acids such as aromatic, aliphatic and polymeric sulfonic acids; preferred protic acids include -toluenesulfonic acid, mixtures of the isomeric sulfonic acids, benzenesulfonic acid, naphthalenesulfonic acids, xylenesulfonic acids, methanesulfonic acid, sulfuric acid, and camphorsulfonic acids; most preferred are ^-toluenesulfonic acid and mixtures of isomeric toluenesulfonic acids. While stoichiometric or greater amounts of a protic acid can be employed, no more than a catalytic amount is needed. Preferably the amount of protic acid is about 0.01 to 0.20, more preferably between about 0.05 and 0.10, molar equivalents relative to the compound of Formula 8.

For the cyclization step, typical reaction conditions include temperatures of about 0 to 150 °C, preferably about 40 to 70 °C, more preferably about 50 to 60 °C with Lewis acids, and with protic acids such as toluenesulfonic acid preferably about 100 to 130 °C, more preferably about 110 to 115 °C, and pressures of about ambient pressure to 600 kPa above ambient pressure, preferably ambient pressure to 200 kPa above ambient pressure, and most conveniently near ambient pressure, for about 0.5 to 48 h. The byproduct alcohol is preferably removed by distillation during the reaction when a non-sacrificial Lewis acid such as a rare-earth trifluoromethanesulfonate or a protic acid is employed. The cyclized product of Formula 10 can be recovered by standard methods such as concentration, optionally preceded by quenching with aqueous base and extraction of the organic material, and crystallization from a suitable solvent such as ethanol for the reactions involving protic acids or liquid or gaseous Lewis acids such as sulfur trioxide or alternatively filtration, washing with aqueous base, concentration and crystallization for the phosphorus pentoxide reactions. The reaction mixture can also be filtered and used without further purification in the next reaction step. When metal trifluoromethanesulfonates are employed as the Lewis acid, the cyclized product can be recovered by concentrating the reaction mass, optionally diluting with an inert, water-immiscible solvent such as ethyl acetate, washing with water to remove the metal trifluoromethanesulfonates, concentrating the organic phase and inducing the product of Formula 10 to crystallize, optionally by adding a suitable solvent such as aqueous methanol, ethanol, hexane and the like. In the next step, the protecting group R¹⁴ is removed from the compound of Formula

10 to give the compound of Formula 11. Conditions for cleaving amino protecting groups are well known (see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). The preferred benzyloxycarbonyl protecting group is most conveniently cleaved by hydrogenolysis. The reaction involves contacting a compound of Formula 11 wherein R¹⁴ is C(O)OCH₂Ph with hydrogen, from a hydrogen source or preferably molecular hydrogen itself, in the presence of a hydrogenolysis metal catalyst such as palladium, preferably supported on a substance such as charcoal, in an inert solvent such as methyl acetate, ethyl acetate, toluene or diethoxymethane. Typical reaction conditions include temperatures of about 0 °C to the boiling point of the solvent, preferably about 15 to 55 °C, more preferably about 20 to 40 °C, and pressures of close to ambient to about 350 kPa above ambient pressure, although higher pressures are also operable. The hydrogenolysis can be conveniently operated at near ambient pressure. Reaction time needed for complete conversion depends upon the usual parameters of temperature, hydrogen pressure, catalyst and reactant concentration, and typically requires 0.5 to 25 hours. The progress of the reaction can be monitored by analysis of the aliquots, or by consumption of hydrogen, as can be determined, for example, by pressure changes. The product of Formula 11 can be recovered from solution by standard methods such as filtering and collecting the metal catalyst for recycle to subsequent batches, separating the organic phase, concentrating by removing the solvent, and inducing crystallization of Formula 11, optionally by adding an aqueous Cχ-0₃ alcohol, acetonitrile or an aliphatic hydrocarbon such as hexane. Preferably the compound of Formula 11 is used in the next step without isolation from the organic phase solution. In the last step of Scheme 5, the compound of Formula 11 is contacted with about a molar equivalent of the acylating agent of Formula 12 to give the oxadiazine of Formula IV. The group X¹ is selected from groups useful as leaving groups in nucleophilic displacement reactions. Considering ease of synthesis and cost, X¹ is preferably halide, and most preferably CI. The reaction of the compound of Formula 11 with the acylating agent of Formula 12 is preferably conducted in the presence of about 1.0 to 1.5 molar equivalents (relative to Formula 11) of an acid scavenger such as a trialkylamine (e.g., triethylamine), NN-dimethylaniline, pyridine or, preferably, aqueous sodium carbonate or bicarbonate, in an inert solvent such as toluene, xylene, methyl acetate, ethyl acetate, dichloromethane, trichloromethane, 1,2-dichloroethane, diethoxymethane and the like. The reaction is facile and can be conducted over a wide range of temperatures, e.g., about -10 to 60 °C. Typical reaction conditions include temperatures of about 0 to 30 °C. For convenience, the reaction can be conducted at ambient temperature (e.g., about 15 to 35 °C). The reaction is usually complete within several hours, and 1 to 2 h is typical. The product of Formula IV can be recovered by standard methods such as washing the reaction mixture with aqueous acid or aqueous sodium chloride, concentrating the organic phase and inducing crystallization of IV, optionally by addition of a Cι~C₃ alcohol, water, alcohol-water mixtures or an aliphatic hydrocarbon such as hexane.

The last two steps of Scheme 5 can be combined in a single reaction pot by adding the acylating agent of Formula 12 and the optional acid scavenger during the hydrogenolysis of the compound of Formula 10. In this way, the compound of Formula 11 is acylated as soon as it is formed to give the product of Formula IV. Typical solvents for the combined steps are methyl acetate, ethyl acetate, toluene, xylene, dichloromethane, 1,2-dichloroethane and the like. Acid scavengers can be a tertiary amine, such as tripropylamine, tributylamine, diisopropylethylamine, NN-dimethylaniline, NN-diethylaniline, and the like, or a solid ionic compound such as sodium bicarbonate, calcium oxide, sodium pyrophosphate, citric acid trisodium salt and the like.

The sequence of condensation and acylation steps to convert the compound of Formula la to the compound of Formula IV can also be conducted in other orders, as is illustrated by Scheme 6 below. In this alternate route, the compound of Formula la is contacted with hydrazine (13) to give the hydrazone of Formula 14. This hydrazone is then contacted with an acylating agent of Formula 12 to give the compound of Formula 15, which is then contacted with a formaldehyde equivalent (9) to give the compound of Formula IV.

wherein the substituents are as defined for Scheme 5.

To prepare the hydrazone of Formula 14, the ketone of Formula la is contacted with preferably excess equivalents (e.g., 1.1 to 10 equivalents relative to la) of hydrazine, hydrazine monohydrate, hydrazine acetate, hydrazine hydrochloride and the like. The reaction is conducted in a solvent typically comprising methanol, ethanol, n-propanol, isopropanol and the like or acetic acid, and the reaction mixture is typically heated to the reflux temperature of the solvent. The reaction is generally complete within 24 hours. Step B of Example 2 of WO 92/11249 describes an example of this step.

The hydrazone of Formula 14 is then contacted with an acylating agent of Formula 12. This step is conducted using reaction conditions analogous to those already described for the conversion of the compound of Formula 11 to the compound of Formula IV in Scheme 5. The product of Formula 15 is isolated by standard methods, such as aqueous work up, concentration and crystallization from a suitable solvent. Example 1 of WO 96/31467 provides an example of this step.

In the final step of Scheme 6, the compound of Formula 15 is treated with a formaldehyde equivalent of Formula 9. This step is conducted using reaction conditions analogous to those already described for the conversion of the compound of Formula 8 to the compound of Formula 10 in Scheme 5. Example 2 of WO 96/31467 provides an example of this step.

Acylating agents of Formula 12 can be prepared by contacting methyl [4-(trifluoro- methoxy)phenyl]carbamate with a base such as sodium hydride, sodium methoxide and the like in a solvent comprising aromatic solvents such as benzene, toluene and the like and a ethereal solvent such as 1,2-dimethoxyethane to form the corresponding salt. The salt is then treated with the appropriate compound having formula X^^X¹ to form Formula 12. For the preferred acylating agent of Formula 12 wherein X¹ is CI, the appropriate compound is phosgene (ClC(O)Cl) or a phosgene substitute such as triphosgene (also named bis(trichloro- methyl) carbonate). Most conveniently an excess of phosgene is used. Suitable temperatures for this reaction are in the range of about -10 to 100 °C, preferably about -10 to 30 °C. The reaction is usually complete within several hours. Acylating agents of Formula 12 wherein X¹ is other than CI can be made from Formula 12 wherein X¹ is CI by nucleophihc displacement. For example, treatment with silver fluoride can give Formula 12 wherein X¹ is F, and treatment with sodium iodide can give Formula 12 wherein X¹ is I. Methyl [4-(trifluoromethoxy)phenyl]carbamate can be made from 4-(trifluoromethoxy)- benzenamine by standard methods, such as contacting 4-(trifluoromethoxy)benzenamine with methyl chloroformate in the presence of an acid scavenger such as NN-diethylaniline, triethylamine, aqueous potassium carbonate and the like, optionally in a solvent such as diethyl ether, dichloromethane and the like. Suitable temperatures for this reaction are typically in the range of about 0 to 100 °C, with temperatures of about 20 to 70 °C being preferred. The reaction is usually complete within several hours. Example 1 of WO 96/31467 provides an example of preparation of the preferred acylating agent of Formula 12 wherein X¹ is CI.

It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula III or ent-III may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula III or ent-III. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula III or ent-III. Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. *H NMR spectra are reported in ppm downfield from tetramethylsilane; "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet, "dd" means doublet of doublets, "dt" means doublet of triplets, and "br s" means broad singlet. Chemical selectivity (chemoselectivity) is the percentage of the consumed limiting reagent (i.e. Ila in Examples 2-9) that is converted into product.

In Examples 2-9, quantitative HPLC analysis was used to measure the amounts of methyl 5-chloro-2,3-dihydro-2-hydroxy-l-oxo-lH-indene-2-carboxylate and methyl 5-chloro-2,3-dihydro-l-oxo-lH-indene-2-carboxylate present in the reaction mixture, and a chiral ΗPLC method was used to determine the enantiomeric excess of methyl 5-chloro-

2,3 -dihydro-2-hydroxy- 1 -oxo- lH-indene-2-carboxylate.

The quantitative ΗPLC analyses were conducted using a Supelco (595 North Harrison Road, Bellefonte, PA 16823-0048 USA) Discovery C8 (octylsilane bonded to silica) column (25 cm x 4.6 mm, 5 μm) and a flow rate of 1.5 mL/min at 40 °C. The elution solvent was a mixture of water (pH 6.5) and acetonitrile, with the concentration of acetonitrile increased from 32% to 75% over 30 minutes to produce a solvent gradient. Detection utilized light absorption at 260 nm. The detector was calibrated using an external standard with 3 -point calibration curves for methyl 5-chloro-l,3-dihydro-2-hydroxy-l-oxo-2H-indene- 2-carboxylate and methyl 5-chloro- 1 -oxo-2,3-dihydroindene-2-carboxylate.

The chiral ΗPLC analyses were conducted using an Astec (Advanced Separation Technologies, Inc., 37 Leslie Court, Whippany, NJ 07981 USA) Chirobiotic T™ (teicoplanin glycopeptide covalently bound to 5 μm silica gel) column and a flow rate of 1.0 mL/min at 40 °C. The elution solvent was an isocratic 80:20 mixture of hexanes and ethanol. Detection utilized light absorption at 254 and 230 nm. Calibration was not necessary as the peak areas of the two enantiomers are directly compared and the detector sensitivity does not differ between enantiomers.

EXAMPLE 1 Synthesis of (9S)-10-bromo-10,l l-dihydrocinchonan-9-ol (alternatively named (aS,2R,4S,5R)-5-( 1 -bromoethyl)-α-4-quinolinyl- 1 -azabicyclo[2.2.2]octane-2-methanol;

Formula III where R⁴ and R⁶ are Η, and where R⁵ is CΗBrCΗ₃)

Fuming hydrobromic acid (50 mL, 85.1 g of a 63.7% solution, 1.05 mol) was cooled to 0 °C, and (+)-cinchonine (18.2 g, 61.8 mmol) was added in portions at this temperature. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was then diluted with water (50 mL) and a 25% potassium hydroxide solution (300 g) was added dropwise at 10-20 °C. The resulting mixture was extracted with chloroform (250 mL, 500 mL, 200 mL). The chloroform layers were combined, dried over magnesium sulfate, filtered, and evaporated to afford 11.16 g of the title compound as a white solid. The aqueous layer, which still contained solids, was filtered and the solids were washed with water and dried under nitrogen to afford a second crop of the title compound (13.9 g), as an off-white solid.

The crude product was purified via its acetate as described below: The second crop of crude title compound (13.9 g) was suspended in a mixture of acetic anhydride (40 mL) and pyridine (10 mL). NN-Dimethylaminopyridine (0.50 g) was added and the mixture was stirred for 18.5 hours at room temperature. After stripping off volatile components, the residue was diluted with dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate (200 mL). The aqueous layer was separated and extracted with dichloromethane (2 x 100 mL). All of the dichloromethane layers were combined, dried over magnesium sulfate, and evaporated to afford a dark red oil, 17.45 g. This oil was subjected to flash chromatography on a column of silica (200 g), eluting with 1:1 tetrahydrofuran/hexanes. Fractions containing the main component were combined and evaporated to afford a gold-colored oil, 9.31 g. This oil was triturated with hexanes, and the solids were filtered, washed with hexanes, and dried under nitrogen to afford the title compound acetate as pale yellow solids, 5.80 g, m.p. 131-136 °C. MS (AP+) 417, 419 (M⁺ + 1, l x Br).

The title compound acetate (0.83 g, 2.0 mmol) was dissolved in methanol (12 mL). Water (4 mL) was added, followed by potassium carbonate (0.69 g, 5.0 mmol), and the mixture was stirred at room temperature for 3 hours. Then water (8 mL) was added dropwise, and the mixture was stirred at room temperature for 5 minutes. The precipitated solids were filtered, washed with several portions of 1:1 methanol/water (total 10 mL), then with water, and dried under nitrogen to afford the title compound as fluffy white solids, 0.75 g (100%), m.p. 174-177 °C. *H ΝMR (CDC1₃) of major isomer: δ 8.89 (d, J= 4.2 Hz, IH), 8.13 (d, J= 8.4 Hz, IH), 7.99 (d, J= 8.4 Hz, IH), 7.70 (dd, J= 6.9, 8.4 Hz, IH), 7.60 (d, J= 4.5 Hz, IH), 7.53 (dd, IH), 5.76 (d, J= 3.3 Hz, IH), 4.48 (m, IH), 3.36 (m, IH), 2.7- 3.1 (m, 4H), 1.8-2.0 (m, 3H), 1.76 (d, J= 6.6 Hz, 3H), 1.4-1.7 (m, 3H).

EXAMPLE 2 Synthesis of (9S, 1 OR)- 10,11 -dibromo- 10, 11 -dihydro-6'-methoxycinchonan-9-ol

(alternatively named (ocR,2R,4S,5R)-5-(l,2-dibromoethyl)-α-4-(6-methoxyquinolinyl)-l- azabicyclo[2.2.2]octane-2-methanol; Formula III where R⁴ is OCH₃, R⁶ is H, and R⁵ is (R)-CHBrCH₂Br) and of (9S, 1 OS)- 10, 11 -dibromo- 10,1 l-dihydro-6*-methoxycinchonan-9-ol (alternatively named (oS,2R,4S,5R)-5-( 1 ,2-dibromoethyl)- -4-(6-methoxyquinolinyl)- 1 - azabicyclo[2.2.2]octane-2-methanol; Formula III where R⁴ is OCH₃, R⁶ is H, and R⁵ is (S)-

CHBrCH₂Br)

A solution of (+)-quinidine (5.00 g, 15.4 mmol) was dissolved in chloroform (100 mL), and the mixture cooled to 0 °C. Then bromine (7.80 g, 48.8 mmol) was added dropwise in three equal portions, each dissolved in chloroform (20 mL), followed by warming the thick orange reaction mixture to room temperature for 1 hour. The mixture was then cooled to 0 °C, and a 10% aqueous solution of sodium hydrogen sulfite was added dropwise at 0-10 °C, followed by warming to room temperature for 1 hour. Then the liquid was decanted off and the solid residue was dissolved in tetrahydrofuran (THF, 300 mL). The THF solution was washed with brine (50 mL), then with saturated aqueous sodium bicarbonate (2 x 50 mL), then it was dried over magnesium sulfate and filtered, and the solvent was evaporated to leave 5.75 g of brown glassy solids. These solids were chromatographed on silica gel (300 g), eluting with 3:1 THF-hexanes until the less polar product eluted, then with THF to elute the more polar product.

Fractions containing the less polar product were combined and evaporated, and the residue was triturated with hexanes-chlorobutane to afford (9S, 10R)- 10,11 -dibromo- 10,11 - dihydro-6'-methoxycinchonan-9-ol as a yellow powder, 2.07 g (27.8%), m.p. 120-130 °C (d). IH NMR (CDC1₃): δ 8.69 (d, J= 4.8 Hz, IH), 7.99 (d, J= 9.0 Hz, IH), 7.55 (d, J= 4.5 Hz, IH), 7.32 (dd, J= 9.0, 2.4 Hz, IH), 7.15 (d, J= 2.4 Hz, IH), 5.81 (m, IH), 4.68 (m, IH), 3.88 (s, 3H), 3.6 (m, IH), 2.8-3.2 (m, 4H), 2.2 (m, IH), 1.8-2.2 (m, 3H), 1.5-1.6 (m, 2H), 1.0-1.1 (m, IH).

Fractions containing the more polar product were combined and evaporated, and the residue was triturated with hexanes-chlorobutane to afford (9S,10S)- 10,11 -dibromo- 10,11 - dihydro-6'-methoxycinchonan-9-ol as yellow-tan solids, 2.09 g (28.0%), m.ρ. 207-215 °C (d). ^!H NMR (CDCI₃): δ 8.72 (d, J= 4.8 Hz, IH), 8.00 (d, J= 9.3 Hz, IH), 7.54 (d, J= 4.5 Hz, IH), 7.35 (dd, J= 9.0, 2.4 Hz, IH), 7.10 (d, J= 2.4 Hz, IH), 5.74 (m, IH), 4.59 (m, IH), 3.88 (s, 3H), 3.45 (m, IH), 2.7-3.1 (m, 4H), 2.28 (m, IH), 2.0-2.1 (m, 2H), 1.5-1.6 (m, 2H), 1.2-1.3 (m, 2H), 1.0-1.1 (m, IH). EXAMPLE 3

Synthesis of (9S, 1 OS)- 10, 11 -dibromo- 10, 11 -dihydrocinchonan-6',9-diol (alternatively named (θ(S,2R,4S,5R)-5-(l,2-dibromoethyl)-α-4-(6-hydroxy

2-methanol; Formula III where R⁴ is OH, R⁶ is H, and R⁵ is (S)-CHBrCH₂Br)

The more polar product of Example 2, (9S, 1 OS)- 10, 11 -dibromo- 10,11 -dihydro-6'- methoxycinchonan-9-ol (0.24 g, 0.50 mmol) was dissolved in 66% hydrobromic acid (5.0 mL, ~70 mmol), and the mixture was heated at 60-65 °C for 24 hours. The mixture was cooled to room temperature, water (20 mL) was added, and the mixture was stirred at room temperature for 2 hours. Then the mixture was filtered, and the solids were washed with water and dried to afford a tan powder, 0.18 g. The filtrate was evaporated and the residue was triturated with water to provide a second crop of solids as a tan powder, 0.06 g. The two crops of solids were combined and suspended in THF (5 mL), saturated aqueous sodium bicarbonate (3 mL) was added, and the mixture was stirred 5 minutes at room temperature. Then more THF (10 mL) and brine (20 mL) were added, the organic layer was separated, dried over magnesium sulfate, filtered, and evaporated to leave a tan solid residue, 0.15 g. The residue was triturated with diethyl ether and filtered, and the solids were washed with diethyl ether and dried to afford the title compound as a tan powder, 0.14 g (60%), m.p. 183— 189 °C. MS (AP+) 469, 471, 473 (M⁺ + 1, 2 x Br). ^lH NMR (DMSO-c?₆): δ 10.02 (br s, IH), 8.62 (d, J= 7.1 Hz, IH), 7.87 (d, J= 11.8 Hz, IH), 7.45 (d, J= 7.1 Hz, IH), 7.38 (m, IH), 7.28 (m, IH), 5.70 (br s, IH), 5.28 (m, IH), 4.77 (m, IH), 4.03 (m, 2H), 3.3-3.4 (m, 4H), 2.5-3.2 (m, 2H), 2.15 (m, IH), 1.8-2.0 (m, 2H), 1.4-1.6 (m, 2H), 1.2-1.3 (m, IH).

Table 1 provides physical property data for further chiral compounds of Formula III prepared using similar procedures.

Table 1 7.93 (d, IH), 6.19 (m, IH), Hz, 3H), 1.4- 389, 391

(d, J= 5.68 (br 4H), 2.98 (m, IH).

By the procedures described herein together with methods known in the art, the following chiral compounds of Formula III of Table 2 and Table 3 can be prepared. The following abbreviations are used in the Tables which follow: us iso, Me is methyl, Et is ethyl, Pr is propyl, z^'-Pr is isopropyl, Bu is butyl, Ϊ^'-BU is isobutyl Ph is phenyl, OMe is methoxy, OEt is ethoxy, OPr is normal propoxy, OPr-/ is isopropoxy, and OBu is normal butoxy. In table entries such as "CH=CH-naphthyl-l," "benzofuranyl-2" and the like, the number indicates the attachment point of the aryl or heteroaryl moiety to the remainder of the molecule.

Table 2

B⁴ E⁴ ! H Me OH Me El B£ El Bl

H Et OH Et

H Pr OH Pr

H z^'-Pr OH t-Pr

H t-Bu OH t-Bu

H CH=CHCH₃ OH CH=CH₂

H CH=CHCH₂CH₃ OH CH=CHCH₃

H C-≡CH OH CH=CHCH₂CH₃

H C≡CCH₃ OH G≡CH

H C≡CCH₂CH3 OH C≡CH₃

H CHCICH3 OH C≡CCH₂CH₃

H CHBrCH₃ OH CHCICH3

H CHICH3 OH CHBrCH₃

H CHBrCH₂Br OH CHICH3

H CHC1CH C1 OH CHBrCH₂Br

H CHBrCHBrCH₂CF₃ OH CHC1CH₂C1

H CHBrCHBrCH₂CCl₃ OH CHBrCHBrCH₂CF₃

H CH=CHBr OH CHBrCHBrCH₂CCl₃

H CH=CBrCH₂CH₃ OH CH=CHBr

H Ph OH CH=CBrCH₂CH₃

H CH₂Ph OH Ph

H CH₂CH₂Ph OH CH₂Ph

H CH₂CH₂CH₂Ph OH CH₂CH₂Ph

H CH₂CHBrPh OH CH₂CH₂CH₂Ph

H benzofiιranyl-2 OH CH₂CHBrPh

H CH=CHPh OH benzofuranyl-2

H CH=CHCH₂CH₂Ph OH CH=CHPh

H CH=CH-naphthyl-l OH CH=CHCH₂CH₂Ph

H CH=CH-naphthyl-2 OH CH=CH-naphthyl-l

H CH=CH-furanyl-2 OH CH=CH-naphthyl-2

H CH=CH-furanyl-3 OH CH=CH-furanyl-2

H CH=CH-thienyl-2 OH CH=CH-fiιranyl-3

H CH=CH-thienyl-3 OH CH=CH-thienyl-2

H CH=CH-pyridyl-3 OH CH=CH-thienyl-3

H CH=CH-quinolinyl-3 OH CH=CH-pyridyl-3

H CH=CH-thiazolyl-2 OH CH=CH-quinolinyl-3

H CH=CH-benzofuranyl-2 OH CH=CH-thiazolyl-2

H OCPh OH CH=CH-benzofuranyl-2

El E El R

OMe CH=CHCH₂CH₂Ph OPr CH=CH-quinolinyl-3

OMe CH=CH-naphthyl-l OPr CH=CH-thiazolyl-2

OMe CH=CH-naphthyl-2 OPr CH=CH-benzofuranyl-2

OMe CH=CH-furanyl-2 OPr C≡CPh

OMe CH=CH-furanyl-3 OPr C≡C-naphthyl-1

OMe CH=CH-thienyl-2 OPr C-≡C-furanyl-3

OMe CH=CH-thienyl-3 OPr C≡C-thienyl-3

OMe CH=CH-pyridyl-3 OPr CsC-ρyridyl-3

OMe CH=CH-quinolinyl-3 OPr C≡C-quinolinyl-3

OMe CH=CH-thiazolyl-2 OPr C≡C-thiazolyl-2

OMe CH=CH-benzofuranyl-2 OPr CfeC-benzofuranyl-3

OMe C≡CPh OBu Et

OMe C≡CCH₂CH₂Ph OBu t-Bu

OMe C≡C-naph%l-l OBu CH=CH₂

OMe CsC-naphthyl-2 OBu CH=CHCH₂CH₃

OMe C≡C-furanyl-2 OBu C-sCH

OMe C≡C-furanyl-3 OBu C≡CCH₃

OMe C≡C-thienyl-2 OBu C-sCCH₂CH₃

OMe CsC-thienyl-3 OBu CHCICH3

OMe C≡C-pyridyl-3 OBu CHBrCH₃

OMe C≡C-quinolinyl-3 OBu CHBrCH₂Br

OMe CsC-thiazolyl-2 OBu CHC1CH₂C1

OMe C≡C-benzofuranyl-3 OBu CHBrCHBrCH₂CF₃

OPr-t Et OBu CH=CHBr

OPr-t Pr OBu CH=CBrCH₂CH₃

OPr-t t-Bu OBu Ph

OPr-t CH=CH₂ OBu CH₂Ph

OPr-t CH=CHCH₂CH₃ OBu CH₂CHBrPh

OPr-t C≡CH OBu benzofuranyl-2

OPr-t C≡CCH₃ OBu CH=CHPh

OPr-t C--CCH₂CH₃ OBu CH=CH-naphthyl-l

OPr-t CHCICH3 OBu CH=CH-furanyl-3

OPr-t CHB1CH3 OBu CH=CH-benzofiιranyl-2

OPr-t CHBrCH₂Br OBu C≡CPh

OPr-t CHC1CH₂C1 OBu C≡C-naph l-l

OPr-t CHBrCHBrCH₂CF₃ OBu C≡C-furanyl-3

OPr-t CHBrCHBrCH₂CCl₃ Et Et

El R5 s! E

Pr CH=CH-naphthyl-l Bu CH=CHPh

Pr C≡CPh Bu C≡CPh

Bu Et Bu CHBrCH₂Br

Bu CH=CH₂ Bu CHC1CH₂C1

Bu C≡CH Bu CH=CHBr

Bu C≡CCH₂CH₃ Bu Ph

Bu CHCICH3 Bu CH₂Ph

Bu CHBrCH₃ CH=CHCH₂CH₃ CH=CH₂

CH=CH₂ Et CH=CHCH₂CH₃ CHBrCH₂Br

CH=CH₂ CH=CH₂ C≡CH CH=CH₂

CH=CH₂ CHBrCH₃ C≡CH CHBrCH₂Br

CH=CH₂ CHBrCH₂Br C≡CCH₂CH₃ CH=CH₂

C≡CCH₂CH₃ CHBrCH₂Br

Table 3

El R⁵. R⁶ El R⁵. R⁶

OMe =CH-naphthyl-3 OEt =CH-furanyl-2

OMe =CH-furanyl-2 OEt =CH-pyridyl-2

OMe =CH-pyridyl-2 OPr-t =CHCH₃

OPr =CHCH₃ OPr-t =CHCH₂CF₃

OPr =CHCH₂CF₃ OPr-t =CHPh

OPr =CHPh OPr-t =CHCH₂CH₂Ph

OPr =CHCH₂CH₂Ph OPr-t =CH-naρhthyl-2

OPr =CH-naphthyl-2 OPr-t =CH-furanyl-2

OPr =CH-furanyl-2 OPr-t =CH-pyridyl-2

OPr =CH-pyridyl-2 Et =CHCH₃

OBu =CHCH₃ Pr =CHCH₃

OBu =CHCH₂CF₃ t-Pr =CHCH₃

OBu =CHPh Bu =CHCH₃

OBu =CHCH₂CH₂Ph CH=CH₂ =CHCH₃

OBu =CH-naphthyl-2 CH=CHCH₂CH₃ =CHCH₃

OBu =CH-furanyl-2 C≡CH =CHCH₃

EXAMPLE 4 Formation of (+)-methyl 5-chloro- 1 ,3-dihydro-2-hydroxy- 1 -oxo-2H-indene-2-carboxylate

(Formula la wherein R¹ is OCΗ₃ and R⁴ is CI)

Methyl 5-chloro- l-oxo-2,3-dihydroindene-2-carboxylate (Formula Ila wherein R¹ is OCH₃ and R⁴ is CI, 2.50 g) was dissolved in toluene with gentle warming, and the solution was diluted with additional toluene to a final volume of 10 mL. An aliquot of this solution (400 μL, containing 100 mg, 0.445 mmol, of substrate) was added to (9S)-10-bromo- 10,l l-dihydrocinchonan-9-ol (i.e. product of Example 1, 16.7 mg, 0.0445 mmol), and the mixture was agitated at 30 °C. Then a 70% aqueous solution of f-butyl hydroperoxide (68 μL, 63 mg, 0.49 mmol) was added in a single portion, and the mixture was agitated at 30 °C for 20 hours. Then a known weight of biphenyl was added as HPLC standard, and the mixture was diluted with acetonitrile. Analysis by quantitative and chiral HPLC showed 90.8% consumption of methyl 5-chloro- l-oxo-2,3-dihydroindene-2-carboxylate, forming methyl 5-chloro- l,3-dihydro-2-hydroxy-l-oxo-2H-indene-2-carboxylate with 86.0% chemical selectivity and 62.0% enantiomeric excess of the S-enantiomer. Another run using similar reaction conditions gave 93.7% consumption of methyl 5-chloro- 1-oxo- 2,3-dihydroindene-2-carboxylate, forming methyl 5-chloro- l,3-dihydro-2-hydroxy-l -oxo- 2H-indene-2-carboxylate with 67.3% chemical selectivity and 57.8% enantiomeric excess of the S-enantiomer. EXAMPLES 5-21 AND REFERENCE EXAMPLES 1-2 Formation of (+)-methyl 5-chloro- 1 ,3 -dihydro-2-hydroxy- 1 -oxo-2H-indene-2-carboxylate

(Formula la wherein R¹ is OCΗ₃ and R⁴ is CI)

Examples 5-21 of the process of the invention were carried out using the procedure of Example 4, except that the chiral bases III listed in Table 4A (0.10 equivalent, relative to substrate) were used in place of (αS,2R,4S,5R)-5-(l-bromoethyl)- -4-quinolinyl- l-azabicyclo[2.2.2]octane-2-methanol. Reference Examples 1-2 were also carried out using the procedure of Example 4 with chiral bases outside the scope of the invention in place of (αS,2R,4S,5R)-5-(l-bromoethyl)-α-4-quinolinyl-l-azabicyclo[2.2.2]octane-2-methanol; results are listed in Table 4B.

Table 4A

Table 4B

Table 5 illustrates examples of hydroxylated compounds of Formula I preparable from the corresponding β-dicarbonyl compounds of Formula II according to the process of the invention. TABLE 5

Illustrative examples of hydroxylated compounds of Formula I preparable from the corresponding β-dicarbonyl compounds of Formula II according to the process of the invention. (* indicates a chiral hydroxylation center comprising the hydroxy group introduced by the process of the invention.)

Claims

CLAIMS What is claimed is:

1. A process for preparing a compound of Formula I that is enantiomerically enriched at the chiral hydroxylation center indicated by *

I

R¹ is H; or alkoxy, alkyl, cycloalkyl, cycloalkoxy, a phenyl ring, a phenoxy ring or a

5- or 6-membered heteroaromatic ring, each optionally substituted; R² is H; or alkyl, cycloalkyl, a phenyl ring, or a 5- or 6-membered heteroaromatic ring, each optionally substituted; R³ is H; or alkoxy, alkyl, cycloalkyl, cycloalkoxy, a phenyl ring, a phenoxy ring or a

5- or 6-membered heteroaromatic ring, each optionally substituted; or R² and R³ are taken together to form an optionally substituted linking chain of 3 to 6 members including at least one carbon member, optionally including no more than two carbon members as C(=O), optionally including one member selected from nitrogen and oxygen, and optionally fused to a phenyl ring or a 5- or

6-membered heteroaromatic ring, each ring optionally substituted; or R¹ and R³ are taken together to form an optionally substituted linking chain of 2 to 5 members including at least one carbon member, optionally including no more than one carbon member as C(=O), and optionally fused to a phenyl ring or a 5- or 6-membered heteroaromatic ring, each ring optionally substituted; comprising: contacting a compound of Formula II

II wherein R¹, R² and R³ are as defined above with an oxidant in the presence of a chiral compound of Formula III or ent-III

πi ent-m wherein

R⁴ is H, hydroxy, -C₄ alkoxy, C^- ^ alkyl, C₂-C alkenyl or C₂-C₄ alkynyl; R⁵ is Cj-C4 alkyl, C1-C₄ haloalkyl, aryl, heteroaryl, aryl(Cι-C₄ alkyl), aryl(C₁-C₄ haloalkyl), heteroaryl(Ci-C₄ alkyl), C₂-C₄ alkenyl, C₂-C₄ haloalkenyl, aryl(C₂-C₄ alkenyl), heteroaryl(C₁-C alkenyl), C₂-C alkynyl, aryl(C -C₄ alkynyl) or heteroaryl(C₂-C₄ alkynyl); and R⁶ is H; or R⁵ and R⁶ are taken together to form C₂-C₄ alkylidenyl, C₂-C₄ haloalkylidenyl, or aryl(C₂-C₄ alkylidenyl) or heteroaryl(C₂-C₄ alkylidenyl); provided that when R⁴ is H or methoxy, then R⁵ is other than vinyl.

2. The process of Claim 1 wherein the chiral compound is of Formula III.

3. The process of Claim 1 wherein the chiral compound is of Formula ent-III.

4. The process of Claim 1 wherein, in Formulae I and II, R¹ is C^-Cg alkoxy;

R² is alkyl;

R³ is optionally substituted phenyl, or

R² and R³ are taken together to form an optionally substituted linking chain of 3 to 4 carbon members optionally fused to an optionally substituted phenyl ring.

5. The process of Claim 1 wherein the oxidant is selected from the group consisting of oxygen, hydrogen peroxide, monoethers of hydrogen peroxide, peracids, hypochlorites, monopersulfates and dioxiranes.

6. The process of Claim 5 wherein the oxidant is ?-butyl hydroperoxide.

7. The process of Claim 1 wherein, in Formula III or ent-III, R⁴ is H, methoxy or hydroxy.

8. The process of Claim 7 wherein R⁴ is hydroxy.

The process of Claim 1 wherein, in Formula HI or ent-III, R⁵ is CHBrCH₃ or

CHBrCH₂Br.

10. The process of Claim 2 wherein the compound of Formula II is a compound of Formula Ila

Ila wherein R¹ is 0^₃ alkoxy and R⁷ is F, CI, or C₁-C₃ fluoroalkoxy and the compound of Formula I is a compound of Formula la

la

enantiomerically enriched at the chiral hydroxylation center indicated by *.

11. The process of Claim 10 wherein when R⁵ is alkyl, alkenyl or alkynyl then R⁴ is other than H or alkoxy, and when R⁵ and R⁶ are taken together to form alkylidenyl then R⁴ is other than alkoxy.

12. The process of Claim 10 wherein R⁴ is hydroxy.

13. The process of Claim 10 wherein R⁵ is haloalkyl.

14. The process of Claim 13 wherein R⁵ is CHBrCH₃ or CHBrCH₂Br.

15. A process for preparing a compound of Formula IV

wherein

R¹ is C1-C₃ alkoxy; and

R⁷ is F, CI or ^-0₃ fluoroalkoxy; using a compound of Formula la

la wherein Formulae IV and la are enantiomerically enriched with the S isomer at the chiral center indicated by *; characterized by: preparing said compound of Formula la by the process of Claim 10.

16. The process of Claim 15 wherein R¹ is OCH₃; and R⁷ is CI.

17. A process for preparing a compound of Formula IV

wherein

R¹ is C₁-C₃ alkoxy; R⁷ is F, CI or C₁-C₃ fluoroalkoxy; and

Formula IV is enantiomerically enriched with the S isomer at the chiral center indicated by *, comprising the steps of: (a) contacting a compound of Formula Ila

Ila wherein R¹ is C_j-C_β alkoxy, and R⁷ is F, CI, or C₁-C₃ fluoroalkoxy; with an oxidant in the presence of a chiral compound of Formula III

m wherein

R⁴ is H, hydroxy, -C₄ alkoxy, Cχ-0 alkyl, C₂-C₄ alkenyl or C₂-C4 alkynyl; R⁵ is Cι-C₄ alkyl, Cγ-C haloalkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl), aryl(C₁-C₄ haloalkyl), heteroary Ci-Cφ alkyl), C₂-C alkenyl, C₂-C haloalkenyl, aryl(C₂-C₄ alkenyl), heteroaryl(Cι-C₄ alkenyl), C₂-C alkynyl, aryl(C₂-C alkynyl) or heteroaryl(C₂-C₄ alkynyl); and R⁶ is H; or R⁵ and R⁶ are taken together to form C₂-C alkylidenyl, C₂-C haloalkylidenyl, or aryl(C₂-C₄ alkylidenyl) or heteroaryl(C₂-C₄ alkylidenyl); provided that when R⁴ is H or methoxy, then R⁵ is other than vinyl; to prepare a compound of Formula la

la that is enantiomerically enriched with the S isomer at the chiral center indicated by *; (b) contacting the compound of Formula la with H₂NNHR¹⁴, wherein R¹⁴ is a protecting group to form a compound of Formula 8

(c) contacting the compound of Formula 8 with a formaldehyde equivalent to form a compound of Formula 10;

(d) removing the protecting group from the compound of Formula 10 to form a compound of Formula 11; and

(e) contacting the compound of Formula 11 with a compound of Formula 12

wherein X¹ is a leaving group; to form the compound of Formula IV.

18. The process of Claim 17 wherein R¹ is OCH₃ and R⁷ is CI.

19. A process for preparing a compound of Formula IV

wherein

R¹ is C₁-C₃ alkoxy;

R⁷ is F, CI or C_!-C₃ fluoroalkoxy; and

Formula IV is enantiomerically enriched with the S isomer at the chiral center indicated by *, comprising the steps of: (a) contacting a compound of Formula Ila

Ila wherein R¹ is 0^₃ alkoxy, and R⁷ is F, CI, or C₁-C₃ fluoroalkoxy; with an oxidant in the presence of a chiral compound of Formula III

III wherein

R⁴ is H, hydroxy, C_j- ^ alkoxy, -C₄ alkyl, C₂-C alkenyl or C₂-C alkynyl; R⁵ is -C₄ alkyl, C_J-C₄ haloalkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl), aryl(C₁-C haloalkyl), heteroaryl(C₁-C alkyl), C₂-C alkenyl, C₂-C₄ haloalkenyl, aryl(C₂-C alkenyl), heteroaryl(C₁-C alkenyl), C₂-C alkynyl, aryl(C₂-C alkynyl) or heteroaryl(C₂-C₄ alkynyl); and

R⁶ is H; or R⁵ and R⁶ are taken together to form C₂-C alkylidenyl, C₂-C haloalkylidenyl, or aryl(C₂-C₄ alkylidenyl) or heteroaryl(C₂-C alkylidenyl); provided that when R⁴ is H or methoxy, then R⁵ is other than vinyl; to prepare a compound of Formula la

la that is enantiomerically enriched with S isomer at the chiral hydroxylation center indicated by *;

(b) contacting the compound of Formula la with H₂NNH₂ to form a compound of Formula 14;

(c) contacting the compound of Formula 14 with a compound of Formula 12

wherein X¹ is a leaving group to form a compound of Formula 15; and

(d) contacting the compound of Formula 15 with a formaldehyde equivalent to form the compound of Formula IV.

20. The process of Claim 19 wherein R¹ is OCH₃ and R⁷ is CI.