HAVING AN UN ACTIVATED SP3 C-H BOND

FIELD OF THE INVENTION

[0001] The application relates to a process for fluorination of organic compounds. More specifically, the application relates to a photochemical process for fluorination of organic compounds including an unactivated sp3 C-H bond.

BACKGROUND OF THE INVENTION

[0002] Fluorinated organic compounds, including fluorinated amino acids and their derived peptides, have a number of useful properties, which can include metabolic stability, thermal stability, enhanced lipophilicity, and high target-affinity. Additionally, ¹⁸ F-labeled organic compounds are useful as PET imaging agents, ¹ and a number of ¹⁸ F-fluorinating agents have

18 18 2 18

been developed, including F-N-fluorobenzenesulfonimide ( F-NFSI) and F-l- chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) ( ¹⁸ F-

Selectfluor™). ³ ' ⁴ While significant effort has focused on preparation of various fluorinated analogues of organic compounds, including analogues of natural and non-proteinogenic amino acids, it remains a challenge to develop chemoselective methods for direct conversion of unactivated C-H bonds into C-F bonds. ⁵ For example, synthesis of fluorinated amino acids via direct fluorination currently requires lengthy synthetic sequences to prepare such

compounds. ⁶ ' ⁷ Similarly, synthetic methods for selective introduction of ¹⁸ F into organic molecules are limited, for example, for formation of sp3 C- ¹⁸ F bonds. ¹ ' ⁸

[0003] Synthetic methods that have been explored to prepare fluorinated organic compounds containing an sp3 C-F bond include decarboxylative radical fluorination, ⁹ ' ¹⁰ oxidative aliphatic C-H fluorination, ¹¹ iron(II)-catalyzed benzylic fluorination, ¹² palladium-catalyzed benzylic fluorination, ¹³ palladium-based electrophilic fluorination, ¹⁴ electrophilic fluorination using CF ₃ OF, ^15"17 CsS0 ₄ F, ¹⁸ XeF ₂ , ¹⁹ or F ₂ , ¹⁶ and free radical approaches. ²⁰ ' ²¹ ' ²² However, these and related techniques can suffer from several problems, including low yield, poor selectivity, use of expensive or unstable reagents, lack of compatibility with typical substituents and functional groups, lack of suitability for large-scale preparation and, in many cases, difficulty in fiuorination of unactivated sp3 C-H bonds.

[0004] A photochemical method for fluorination of easily oxidized organic compounds, containing activated sp3 C-H bonds that form stable carbocations upon oxidation (e.g., diphenyl-, or triphenylmethyl), using superstoichiometric quantities of an illuminated semiconductor (Ti0 ₂ ) and AgF as a fluoride source has been reported. ²³ For this reaction, the only reported substrates containing an sp3 C-H bond are, to date, triphenylmethane, diphenylmethane, and 2-nitropropane. ²³

SUMMARY OF THE INVENTION

[0005] The present disclosure provides, in part, a photochemical process for chemoselective fluorination of organic compounds containing an unactivated sp3 C-H bond.

[0006] In one aspect, there is provided a process for fluorinating a carbon-containing compound comprising combining a carbon-containing compound of Formula (II):

^{R R3}

R ¹ ^H

(II)

with a fluorinating agent, and a catalyst, in the presence of a light source, whereby the C-H bond is replaced by a C-F bond, resulting in a fluorinated carbon-containing compound of Formula (I): 1^F

(I)

where R ¹ , R ² , and R ³ are independently non-activating substituents.

[0007] In alternative embodiments, R ¹ may be alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted, and R ² and R ³ may be independently H, alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which excluding H may be optionally substituted; or R ¹ and R ² may be joined together with the carbon to which they are attached to form a ring, and R ³ may be H, alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which excluding H may be optionally substituted; or R ¹ may be alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted, and R ² and R ³ may be joined together with the carbon to which they are attached to form a ring.

[0008] In alternative embodiments, the fluorinated carbon-containing compound of Formula (I) may be:

(la)

or a suitable salt thereof; and the carbon-containing compound of Formula (II) may be:

(Ila)

or a suitable salt thereof; where R ⁴ may be Ci-io alkyl. In alternative embodiments of this embodiment, the fluorinating agent may be N-fluorobenzenesulfonimide (NFSI); the catalyst may be tetrabutylammonium decatungstate (TBADT); and the light source may be a 365 nm UV lamp.

[0009] In alternative embodiments, the fluorinated carbon-containing compound of Formula (I) may be: (<S)-4-fiuoroleucine methyl ester, (5)-4-fluoroleucine ethyl ester, (S)-4- fluoroleucine propyl ester, (5)-4-fluoroleucine isopropyl ester, (5)-4-fluoroleucine butyl ester, (5)-4-fluoroleucine isobutyl ester, (5)-4-fluoroleucine sec-butyl ester, (5)-4-fluoroleucine pentyl ester, (5)-4-fluoroleucine hexyl ester, (5)-4-fluoroleucine heptyl ester, (S)-4- fluoroleucine octyl ester, (5)-4-fluoroleucine nonyl ester, (5)-4-fluoroleucine decyl ester, (S)- valine methyl ester, N-acetyl-(5)-leucine ethyl ester, N-Boc-(5)-leucine methyl ester, N-CBZ- (<S)-leucine methyl ester, (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldecahydronaphtho[2,l - b]furan-2(3aH)-one ((3ai?)-(+)-Sclareolide), (2R,4S)-l ,7,7-trimethylbicyclo[2.2. l]heptan-2-yl acetate ((-)-Bornyl acetate), (lR,2S,5R)-2-isopropyl-5-methylcyclohexyl acetate (L-Menthyl acetate), (l S,5R)-l ,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one, (S)-ethyl 2-(((S)-l -(4- bromophenyl)-2,2,2-trifluoroethyl)amino)-4-methylpentanoate, (S)-ethyl 4-methyl-2-(((S)- 2,2,2-trifluoro- 1 -(4'-(methylsulfonyl)-[ 1 , 1 '-biphenyl] -4-yl)ethyl)amino)pentanoate, (S)-4- methyl-2-(((S)-2,2,2-trifluoro- 1 -(4'-(methylsulfonyl)- [1, 1 '-biphenyl] -4- yl)ethyl)amino)pentanoic acid, (S)-N-(l -cyanocyclopropyl)-4-methyl-2-(((S)-2,2,2-trifluoro- l-(4'-(methylsulfonyl)-[l, -biphenyl]-4-yl)ethyl)amino)pentanamide, or a suitable salt of any of the foregoing compounds, and the corresponding carbon-containing compound compound of Formula (II) may be: (<S)-leucine methyl ester, (^-leucine ethyl ester, (^-leucine propyl ester, (5)-leucine isopropyl ester, (5)-leucine butyl ester, (5)-leucine isobutyl ester, (S)- leucine sec -butyl ester, (5)-leucine pentyl ester, (5)-leucine hexyl ester, (^-leucine heptyl ester, (5)-leucine octyl ester, (^-leucine nonyl ester, (5)-leucine decyl ester, (S)-3- fluorovaline methyl ester, N-acetyl-(5)-4-fluoroleucine ethyl ester, N-Boc-(5)-4-fluoroleucine methyl ester, N-CBZ-(S)-4-fluoroleucine methyl ester, (3aR,5aS,8S,9aS,9bR)-8-fluoro- 3a,6,6,9a-tetramethyldecahydronaphtho[2,l-b]furan-2(3aH)-one , (2R,4S,5S)-5-fluoro- 1,7,7- trimethylbicyclo[2.2. l]heptan-2-yl acetate, (lR,2S)-5-fluoro-2-isopropyl-5-methylcyclohexyl acetate, (l S,3R,6S)-2-fluoro-6-isopropyl-3-methylcyclohexyl acetate, (lR,4R,5S)-5-fluoro- l,7,7-trimethylbicyclo[2.2.1]heptan-2-one, (lR,4R)-4-fluoro-l,7,7- trimethylbicyclo[2.2.1]heptan-2-one, (lS,5R,6R)-6-fluoro-l,8,8-trimethyl-2- oxabicyclo[3.2.1]octan-3-one, (S)-ethyl 2-(((S)-l-(4-bromophenyl)-2,2,2- trifluoroethyl)amino)-4-fluoro-4-methylpentanoate, (S)-ethyl 4-fluoro-4-methyl-2-(((S)- 2,2,2-trifluoro- 1 -(4'-(methylsulfonyl)-[ 1 , 1 '-biphenyl] -4-yl)ethyl)amino)pentanoate, (S)-4- fluoro-4-methyl-2-(((S)-2,2,2-trifluoro- 1 -(4'-(methylsulfonyl)- [ 1 , 1 '-biphenyl] -4- yl)ethyl)amino)pentanoic acid, (S)-N-(l -cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2- trifluoro-l-(4'-(methylsulfonyl)-[l, -biphenyl]-4-yl)ethyl)amino)pentanamide (Odanacatib), or a suitable salt of any of the foregoing compounds.

[0010] In alternative embodiments, the compound of Formula (I) may be (<S)-4-fiuoroleucine ethyl ester or a suitable salt thereof and the compound of Formula (II) may be (<S)-leucine ethyl ester or a suitable salt thereof.

[0011] In alternative embodiments, the fluorinating agent may be N- fluorobenzenesulfonimide (NFSI) or l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™).

[0012] In alternative embodiments, the process may be carried out at room temperature.

[0013] In alternative embodiments, the process may be carried out for about 16 to about 18 hours.

[0014] In alternative embodiments, the fluorinated carbon-containing compound may be a compound of Formula (III): ^R y ^R3

_R 1 ^18 _F

(III)

and the carbon-containing compound may be a compound of Formula (II):

(II)

where R ¹ , R ² , and R ³ may be independently non- activating substituents and where the fluorinating agent may be an ¹⁸ F-fluorinating agent. In alternative embodiments of this embodiment, R ¹ may be alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted, and R ² and R ³ may be independently H, alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which excluding H may be optionally substituted; or R ¹ and R ² may be joined together with the carbon to which they are attached to form a ring, and R ³ may be H, alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which excluding H may be optionally substituted; or R ¹ may be alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted, and R ² and R ³ may be joined together with the carbon to which they are attached to form a ring. In alternative embodiments of this embodiment, the

18 F-fluorinating agent may be 18 F-N-fluorobenzenesulfonimide ( 18 F -NFSI) or 18 F-l- chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) ( ¹⁸ F- Selectfluor™). In alternative embodiments of this embodiment, the compound of Formula (III) may be ¹⁸ F-(5)-4-fluoroleucine ethyl ester, ¹⁸ F-(5)-3-fluorovaline methyl ester, or a suitable salt of either of these compounds, and the corresponding compound of Formula (II) may be (<S)-leucine ethyl ester, (5)-valine methyl ester, or a suitable salt of any of these compounds.

[0015] In alternative embodiments, the catalyst may be tetrabutyl ammonium decatungstate (TBADT).

[0016] In alternative embodiments, the light source may be a mercury lamp, a xenon lamp, a deuterium lamp, a tungsten halogen lamp (also known as a quartz iodine lamp), a light- emitting diode (LED), a 365 nm UV lamp, a UV-Vis lamp emitting light in the wavelength range 200-500 nm, or sunlight. [0017] This summary of the invention does not necessarily describe all features of the invention.

DETAILED DESCRIPTION

[0018] The present disclosure provides, in part, a photochemical process for chemoselective fluorination of organic compounds containing an unactivated sp3 C-H bond. Fluorinated compounds prepared as described herein may have a number of useful properties, such as increased metabolic stability, increased thermal stability, enhanced lipophilicity, or high target-affinity. Fluorinated compounds prepared as described herein may be useful as precursors. The present disclosure also provides methods for preparation of fluorinated amino acids, 4-fluoroleucine alkyl esters, and/or ¹⁸ F-labeled compounds suitable, for example, for use as PET imaging agents.

[0019] More specifically, the disclosure provides, in part, a process for fluorinating a carbon- containing compound by combining a carbon-containing compound including an unactivated sp3 C-H bond, a fluorinating agent, and a catalyst, in the presence of a light source, such that the C-H bond is replaced by a C-F bond, resulting in a fluorinated carbon-containing compound. In some embodiments, a carbon-containing compound can include multiple unactivated sp3 C-H bonds. In alternative embodiments, a fluorinated carbon-containing compound prepared as described herein may include one or more fluorine groups, up to a maximum of the number of unactivated sp3 C-H bonds present in the starting carbon- containing compound. It is to be understood that not all the unactivated sp3 C-H bonds present in the starting carbon-containing compound would necessarily be replaced with a C-F bond, when subjected to a process as discussed herein. Accordingly, in some embodiments, fewer than the maximum number of unactivated sp3 C-H bonds present in the starting carbon-containing compound may be replaced with a C-F bond, when subjected to a process as discussed herein. In alternative embodiments, a single unactivated sp3 C-H bond in a carbon-containing compound including multiple unactivated sp3 C-H bonds may be replaced with a C-F bond, when subjected to a process as discussed herein.

[0020] By an "sp3 C-H bond" is meant a carbon-hydrogen single bond in which the orbital hybridization of the carbon atom is sp3. In an sp3 hybridized carbon, one of the s-orbitals and three of the p-orbitals of the carbon atom combine to form four equivalent sp3 hybrid orbitals, each of which forms a single bond to one of four substituents attached to the carbon atom in a tetrahedral geometry.

[0021] In general, sp3 C-H bonds are considered unreactive. However, several classes of compounds contain functional groups (e.g. , ketone, aldehyde, ester, amide, nitro, nitrile, aryl, heteroaryl, etc.) that stabilize an anion on the adjacent carbon (where "adjacent carbon" means the sp3 carbon atom directly attached to such a functional group). As a result, the sp3 C-H bond on the adjacent carbon can be sufficiently acidic for proton removal with common organic bases (e.g. LDA, n-BuLi) and the resulting carbanion can be reacted selectively; such sp3 C-H bonds are considered "activated". The relationship between an activating functional group and the adjacent sp3 C-H is shown below:

R = Activating functional — R^^H — Adjacent activated sp3 C-H group

1

Adjacent sp3 carbon

The anion-stabilizing effect of the functional groups described above is reflected in the reduced pKa values of activated sp3 C-H bonds. In general, an sp3 C-H bond with a pKa value of less than 40 may be considered activated. By an "unactivated sp3 C-H bond" is meant an sp3 C-H bond with a pKa value of greater than 40. In some embodiments, an "unactivated sp3 C-H bond" has a pKa value of about 40 to about 60, or any value in between, such as 40, 45, 50, 55, or 60. In general, the skilled person is readily able to determine whether or not an sp3 C-H bond is activated or unactivated, or to determine pKa values of an sp3 C-H bond. The skilled person would also recognize that a single molecule may include one or more unactivated sp3 C-H bonds. Examples of activated and unactivated sp3 C-H bonds are shown below, with corresponding pKa values:

pKa = 20 pKa = 25 pKa = 8 pKa pKa = 31

Activated sp3 C-H Bonds

pKa ~ 50 pKa ~ 50 pKa - 50

Unactivated sp3 C-H Bonds

[0022] The fluorinated carbon-containing compound can be a compound of Formula (I):

^{R R3}

(I)

and the carbon-containing compound can be a compound of Formula (II):

R ¹ ^H

(II)

where R ¹ , R ² , and R ³ may be independently non- activating substituents.

[0023] As will be appreciated by a person skilled in the art, the process as described herein may also be represented as follows in Scheme A:

Fluorinating agent

^{R2 R3 R} y ^R3

Catalyst

Light (hv)

(Π) (I)

Scheme A

where R ¹ , R ² , and R ³ may be independently non-activating substituents.

[0024] In general, a "non-activating substituent" is a group that provides a low degree of stabilization to an anion on an adjacent carbon atom. As described herein, substituents that result in the adjacent sp3 C-H group being unactivated, i.e., that result in an adjacent "unactivated sp3 C-H bond," are non-activating substituents. Examples of non-activating substituents may include, without limitation: alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted. In some embodiments, the non-activating substituents may include, without limitation, alkyl and cycloalkyl. Non-limiting examples of non-activating substituents are shown below:

Non-activating Substituents (C-H group not activated)

[0025] In some embodiments, R ¹ as described herein may be alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted.

[0026] In some embodiments, R ¹ may be:

where R ⁴ may be Ci-io alkyl, such as C _1; C ₂ , C ₃ , C ₄ , C5, Ce, C ₇ , C ₈ , C9, or C ₁₀ alkyl.

[0027] In some embodiments, R ² as described herein may be H, alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted. In some embodiments, R ² may be CH ₃ . [0028] In some embodiments, R ³ as described herein may be H, alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which may be optionally substituted. In some embodiments, R ³ may be CH ₃ .

[0029] In some embodiments, R ¹ and R ² may be optionally joined together with the carbon to which they are attached to form a ring. For example, R ¹ and R ² may be joined together with the carbon to which they are attached to form an optionally substituted cyclopentane, cyclohexane, cycloheptane, decalin, or bridged ring system, as indicated below:

[0030] In some embodiments, R ² and R ³ may be optionally joined together with the carbon to which they are attached to form a ring. For example, R ² and R ³ may be joined together with the carbon to which they are attached to form an optionally substituted cyclopentane, cyclohexane, cycloheptane, decalin, or bridged ring system, as indicated below:

[0031] In some embodiments, the carbon-containing compound or the compound of Formula (II), or the corresponding fluorinated compound thereof, may be a "suitable salt," which may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like, or organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or the like. In some embodiments, the carbon-containing compound or the compound of Formula (II), or the corresponding fluorinated compound thereof, may be a hydrochloride salt.

[0032] In some embodiments, the carbon-containing compound or the compound of Formula (II), or the corresponding fluorinated compound thereof, may be an ester of an optionally N- protected naturally-occurring or unnatural amino acid. Examples of esters of N-protected and unprotected amino acids are shown below:

Unprotected W-Protected where R may be alkyl, cycloalkyl, or aryl and R' may be alkyl, cycloalkyl, aryl, or heteroaryl, and P may be an amino acid N-protecting group such as Boc, CBZ, Fmoc, Acyl, etc. A discussion of amino acid protecting groups may be found, for example, in "Protective Groups In Organic Synthesis" P.G.M. Wuts and T.W. Green, Fourth Edition (John Wiley & Sons, Inc., 2007).

[0033] In some embodiments, the carbon-containing compound or the compound of Formula (II), or the corresponding fluorinated compound thereof, may be an ester of a naturally- occurring amino acid (such as alanine, valine, leucine, isoleucine, etc.), optionally N- protected with a suitable amino acid N-protecting group (Boc, CBZ, Fmoc, Acyl, etc.), or a suitable salt thereof.

[0034] In some embodiments, the carbon-containing compound or the compound of Formula (II), or the corresponding fluorinated compound thereof, may be an ester of an unnatural amino acid, optionally N-protected with a suitable amino acid N-protecting group (Boc, CBZ, Fmoc, Acyl, etc.), or a suitable salt thereof.

[0035] In some embodiments, the carbon-containing compound or the compound of Formula (II), or the corresponding fluorinated compound thereof, may be a peptide or an amino acid derivative, or a suitable salt thereof.

[0036] In some embodiments, the carbon-containing compound or the compound of Formula (II) may be an ester of (<S)-leucine, optionally N-protected with a suitable amino acid N- protecting group (Boc, CBZ, Fmoc, Acyl, etc.), or a suitable salt thereof. In some embodiments, the carbon-containing compound or the compound of Formula (II) may be (S)- leucine ethyl ester hydrochloride.

[0037] In some embodiments, the fluorinated carbon-containing compound or the compound of Formula (I) may be an ester of (<S)-4-fiuoroleucine, optionally N-protected with a suitable amino acid N-protecting group (Boc, CBZ, Fmoc, Acyl, etc.), or a suitable salt thereof. In some embodiments, the fluorinated carbon-containing compound or the compound of Formula (I) may be (<S)-4-fiuoroleucine ethyl ester. In some embodiments, the fluorinated carbon-containing compound or the compound of Formula (I) may be (<S)-4-fluoroleucine ethyl ester hydrochloride.

[0038] In some embodiments, a compound of Formula (I), or a suitable salt thereof, may be prepared by combining a fluorinating agent and a catalyst with a compound of Formula (II), or a suitable salt thereof, in the presence of a light source, as described in Table 1.

Table 1.

Scheme A

(Odanacatib)

[0039] In alternative embodiments, a compound of Formula (III), or suitable salt thereof, may be prepared by combining an ¹⁸ F-fluorinating agent and a catalyst with a compound of Formula (II), in the presence of a light source, as described in Table 2.

Table 2.

Scheme B

[0040] In alternative embodiments, a compound of Formula (lb), or suitable salt thereof, may be prepared by combining a fluorinating agent and a catalyst with a compound of Formula (lib), or a suitable salt thereof, in the presence of a light source as indicated in Scheme C:

(lib) Ob)

Scheme C

where X may be O, S, or NR ⁷ ; R ⁵ and R ⁶ may be independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, acyl, arylacyl, heteroarylacyl, arylalkylacyl, heteroarylalkylacyl, alkoxycarbonyl, or carbamoyl, each of which may be optionally substituted; and each R ⁷ may be independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, acyl, arylacyl, heteroarylacyl, arylalkylacyl, heteroarylalkylacyl, alkoxycarbonyl, or carbamoyl, each of which may be optionally substituted.

[0041] Carbon-containing compounds as described in, for example, Formula (I), Formula (la), Formula (lb), Formula (II), Formula (Ila), Formula (lib), or Formula (III) may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Any formulas, structures or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion. When stereochemistry is specified, the invention is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion.

[0042] In some embodiments, non-activating substituents may be optionally substituted. Suitable substituents include, without limitation: H, alkyl (Ci-io), alkenyl (C _2-1 o), alkynyl (C _2- io), aryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which may optionally contain one or more heteroatoms selected from O, S, P, N, F, CI, Br, I, or B , and each of which may be further substituted, for example, by =0; or optionally substituted forms of acyl, arylacyl, alkyl- alkenyl-, alkynyl- or arylsulfonyl and forms thereof which contain heteroatoms in the alkyl, alkenyl, alkynyl or aryl moieties. Other substituents include =0, =NR, halo, CN, CF ₃ , CHF ₂ , N0 ₂ , OR, SR, NR ₂ , N ₃ , COOR, and CONR ₂ , where R is H or alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or heteroaryl. Where the substituted atom is C, the substituents may include, in addition to the substituents listed above, halo, OOCR, NROCR, where R is H or a substituent set forth above.

[0043] "Alkyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation and including, for example, from one to ten carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and which is attached to the rest of the molecule by a single bond. In altemative embodiments, the alkyl group may contain from one to eight carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In alternative embodiments, the alkyl group may contain from one to six carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms. Unless stated otherwise specifically in the specification, the alkyl group may be optionally substituted by one or more substituents as described herein. Unless stated otherwise specifically herein, it is understood that the substitution can occur on any carbon of the alkyl group.

[0044] "Alkenyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond and including, for example, from two to ten carbon atoms, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond. In altemative embodiments, the alkenyl group may contain from two to eight carbon atoms, such as 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In alternative embodiments, the alkenyl group may contain from three to six carbon atoms, such as 3, 4, 5, or 6 carbon atoms. Unless stated otherwise specifically in the specification, the alkenyl group may be optionally substituted by one or more substituents as described herein. Unless stated otherwise specifically herein, it is understood that the substitution can occur on any carbon of the alkenyl group. [0045] "Alkynyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond and including, for example, from two to ten carbon atoms. In alternative embodiments, the alkynyl group may contain from two to eight carbon atoms, such as 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In alternative embodiments, the alkynyl group may contain from three to six carbon atoms, such as 3, 4, 5, or 6 carbon atoms. Unless stated otherwise specifically in the specification, the alkynyl group may be optionally substituted by one or more substituents as described herein.

[0046] "Aryl" refers to a mono- or bicyclic aromatic ring containing only carbon atoms, including for example, 6-14 members, such as 6, 7, 8, 9, 10, 11, 12, 13, or 14 members. Examples of aryl groups include phenyl, biphenyl, naphthyl, indanyl, indenyl,

tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like. Unless stated otherwise specifically herein, the term "aryl" is meant to include aryl groups optionally substituted by one or more substituents as described herein.

[0047] "Heteroaryl" refers to a single or fused aromatic ring group containing one or more heteroatoms in the ring, for example N, O, S, including for example, 5-14 members, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 members. Examples of heteroaryl groups include furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, 1,2,3- oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, imidazole, benzimidazole, benzoxazole, benzothiazole, indolizine, indole, isoindole, benzofuran, benzothiophene, lH-indazole, purine, 4H- quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8- naphthyridine, pteridine, and the like. Unless stated otherwise specifically herein, the term "heteroaryl" is meant to include heteroaryl groups optionally substituted by one or more substituents as described herein.

[0048] "Cycloalkyl" refers to a stable monovalent monocyclic, bicyclic or tricyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having for example from 3 to 15 carbon atoms, and which is saturated and attached to the rest of the molecule by a single bond. In alternative embodiments, the cycloalkyl group may contain from three to six carbon atoms, such as 3, 4, 5, or 6 carbon atoms. Unless otherwise stated specifically herein, the term "cycloalkyl" is meant to include cycloalkyl groups which are optionally substituted as described herein. [0049] "Cycloalkenyl" refers to a stable monovalent monocyclic, bicyclic or tricyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having for example from 3 to 15 carbon atoms, and which is attached to the rest of the molecule by a single bond. In alternative embodiments, the cycloalkyl group may contain from five to seven carbon atoms, such as 5, 6, or 7 carbon atoms. Unless otherwise stated specifically herein, the term "cycloalkenyl" is meant to include cycloalkenyl groups which are optionally substituted as described herein.

[0050] "Arylalkyl" refers to a group of the formula -R _a Rb where R _a is a C _MO alkyl group as described herein and R, is one or more aryl moieties as described herein. The aryl group(s) may be optionally substituted as described herein.

[0051] "Heteroarylalkyl" refers to a group of the formula -R _a R _e where R _a is a C _MO alkyl group as described herein and R _e is one or more heteroaryl moieties as described herein. The aryl group(s) may be optionally substituted as described herein.

[0052] "Acyl" refers to a group of the formula -C(0)Rf, where Rf is H or a C _MO alkyl group or a Ci_ ₆ alkyl group or a C3- ₁₅ cycloalkyl group as described herein. The alkyl or cycloalkyl group(s) may be optionally substituted as described herein.

[0053] "Arylacyl" refers to a group of the formula -C(0)Rb, where R, is one or more aryl moieties as described herein. The aryl group(s) may be optionally substituted as described herein.

[0054] "Heteroarylacyl" refers to a group of the formula -C(0)R _e , where R _e is one or more heteroaryl moieties as described herein. The heteroaryl group(s) may be optionally substituted as described herein.

[0055] "Arylalkylacyl" refers to a group of the formula -C(0)R _g Rb, where R _g is a Ci- ₁₀ alkyl or a Ci- ₆ alkyl group as described herein and R, is one or more aryl moieties as described herein. The alkyl or aryl group(s) may be optionally substituted as described herein.

[0056] "Heteroarylalkylacyl" refers to a group of the formula -C(0)R _g R _e , where R _g is a Ci- ₁₀ alkyl or a Ci- ₆ alkyl group as described herein and R _e is one or more heteroaryl moieties as described herein. The alkyl or heteroaryl group(s) may be optionally substituted as described herein. [0057] "Alkoxy" refers to a group of the formula -OR _a , where R _a is a Ci-io alkyl or a C e alkyl group as described herein. The alkyl group(s) may be optionally substituted as described herein.

[0058] "Alkoxy carbonyl" refers to a group of the formula -(C=0)OR _a , where R _a is a Ci-io alkyl group or a Ci_6 alkyl group or a C3-15 cycloalkyl group as described herein. The alkyl or cycloalkyl group(s) may be optionally substituted as described herein.

[0059] "Carbamoyl" refers to a group of the formula -(C=0)N(R _a )2, where each R _a is independently H or a Ci-10 alkyl group or a Ci-6 alkyl group or a C3-15 cycloalkyl group as described herein. The alkyl or cycloalkyl group(s) may be optionally substituted as described herein.

[0060] "Halo" refers to bromo, chloro, fluoro, iodo, etc. In some embodiments, suitable halogens include fluorine or chlorine.

[0061] "Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs one or more times and instances in which it does not. For example, "optionally substituted alkyl" means that the alkyl group may or may not be substituted and that the description includes both substituted alkyl groups and alkyl groups having no substitution, and that said alkyl groups may be substituted one or more times. Examples of optionally substituted alkyl groups include, without limitation, methyl, ethyl, propyl, etc. and including cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.; examples of optionally substituted alkenyl groups include allyl, crotyl, 2-pentenyl, 3-hexenyl, 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc. In some embodiments, optionally substituted alkyl and alkenyl groups include Ci-6 alkyls or alkenyls.

[0062] In some embodiments, the fluorinating agent may be N-fluorobenzenesulfonimide (NFSI), l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™), 2-fluoro-3,3-dimethyl-2,3-dihydro-l,2-benzisothiazole 1,1 -dioxide,

(3aS ^, ,6i?,7a/?)-l-fluorohexahydro-8,8-dimethyl-3H-3a,6-meth ano-2,l-benzisothiazole 2,2- dioxide, N-fluoropyridinium triflate (NFPY), N-fluoro-2,6-bis(methoxymethyl)-pyridinium trifluoromethanesulfonate, any other N-fluoropyridinium salt, l-fluoro-4-hydroxy-l,4- diazoniabicyclo[2,2,2] octane bis(tetrafluoroborate) (Accufluor), l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane hexefluorophosphate (Selectfluor™ PF ₆ ), l-fluoro-4-methyl- l,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectfluor™ II), CsS0 ₄ F, HgF ₂ , RbS0 ₄ F, PbF ₂ (OAc) ₂ , PhIF ₂ , F ₂ , N-fluoroperfluoropiperidine, N-fluoropyridone, an N-fluoro- N-alkylarenesulfonamide, an N-fluoro-N-alkylsulfonamide, an N-fluorosulfonamide, (CF ₃ S0 ₂ ) ₂ NF, N-fluoro-o-benzenedisulfonimide (NFOBS), a sulfonyl derivative of formula RS0 ₂ N(F)R' where R and R' may be independently alkyl, cycloalkyl, aryl, or heteroaryl, a N-fluoroquinuclidinium salt, a N-fluoroperfluoroalkylsulfonamide, a N-fluorosultam, CF ₃ OF, FOCIO ₃ , hypofluorous acid, an alkylhypofluorite (e.g., methylhypofluorite), an

acylhypofluorite (e.g. CH ₃ COOF, CF ₃ COOF), perchloryl fluoride, xenon difluoride (XeF ₂ ), bis(trifluoromethane)sulfonimide, 2,6-dichloro-l-fluoropyridinium triflate, l-fluoro-2,4,6- trimethylpyridinium tetrafluoroborate, C0F ₃ , Et ₃ N.HF (TREAT-HF), HFx.Pyr (Olah's reagent, PPHF), BF ₃ , BrF ₃ , SF ₄ , SF ₄ /Et ₃ N, SF ₄ /Py, N0 ₂ BF ₄ /HF.Pyr, SbF ₅ -HF, Et ₂ NSF ₃ (DAST), (dimethylamino)sulfur trifluoride, (diethylamino)difluorosulfonium

tetrafluoroborate (XtalFluor-E), difluoro(morpholino)sulfonium tetrafluoroborate (XtalFluor- M), (Me ₂ N) ₃ S(Me) ₃ SiF ₂ (TASF), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor), a dialkylaminosulfurtrifluoride reagent, tetrabutylammonium fluoride (TBAF),

difluoromethyl phenyl sulfone, sodium fluoride, potassium fluoride, cesium fluoride, tetra alkyl ammonium fluoride, trialkyl amine trihydrofluoride designated as R ₃ N(HF) ₃ or as the ammonium salt [R ₃ NH] [H ₂ F ₃ ], potassium crown ether fluoride, and any agent capable of being a fluorine donor. In some embodiments, the fluorinating agent may be aN- fluorosulfonamide. In some embodiments, the fluorinating agent may be N- fluorobenzenesulfonimide (NFSI). In some embodiments, the fluorinating agent may be N- fluoropyridinium triflate (NFPY). In some embodiments, the fluorinating agent may 1- chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)

(Selectfluor™).

[0063] In some embodiments, the fluorinating agent may be an ¹⁸ F-fluorinating agent. For

18 18 18 18 example, the F-fluorinating agent may be F-N-fluorobenzenesulfonimide ( F-NFSI), F- l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) ( ¹⁸ F-

18 18 18 18

Selectfluor™), F-perchloryl fluoride, F-acetyl hypofluorite, F-xenon difluoride, an F- N-fluoro-N-alkylsulfonamide, or any other suitable ¹⁸ F-labelled fluorinating agent, including ¹⁸ F-labelled analo gues of the fluorinating agents described herein or known in the art.

[0064] The amount of fluorinating agent used in the process described herein may be 0.5-10 equivalents, or 1-5 equivalents, or 1-2 equivalents, or any specific amount of equivalents within any of these ranges, such as 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5.

[0065] In some embodiments, the catalyst may be tetrabutylammonium decatungstate (TBADT), sodium tungstate dihydrate (Na ₂ WC)4 2H ₂ 0), tetraethyl ammonium decatungstate, tetra-n-propylammonium decatungstate, tetrabenzyl ammonium decatungstate, any suitable tetraalkylammonium salt of decatungstate, any suitable ammonium salt of decatungstate, any suitable pyridinium salt of decatungstate, any suitable salt of decatungstate with an organic counterion, any suitable salt of decatungstate with an inorganic counterion, or any suitable polyoxometallate (POM) or suitable salt thereof including polyoxometallates of Group 5 and Group 6 metals such as vanadium, niobium, tantalum, molybdenum, and tungsten. In some embodiments, the catalyst may be a tetraalkylammonium salt of decatungstate. In some embodiments, the catalyst may be tetrabutylammonium decatungstate (TBADT). In some embodiments, mixtures of catalysts may be used.

[0066] The amount of catalyst may be 0.01-200 mol%, or 0.1-20 mol%, or 0.5-5 mol%, or any specific mol% within any of these ranges, such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In some embodiments, the amount of catalyst may be 0.0001-2 equivalents, or 0.001-0.2 equivalents, or 0.005-0.05 equivalents, or any specific number of equivalents within any of these ranges, such as 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 equivalents.

[0067] In some embodiments, the light source may be a mercury lamp, a xenon lamp, a deuterium lamp, a tungsten halogen lamp (also known as a quartz iodine lamp), a light- emitting diode (LED), a 365 nm UV lamp, a UV-Vis lamp or UV lamp or Vis lamp, or sunlight, or any light source capable of emitting UV and/or Visible light in the wavelength range between 200-500 nm including any or all wavelengths in this range, such as 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 310 nm, 320 nm, 330 nm, 340 nm, 350 nm, 360 nm, 365 nm, 370 nm, 380 nm, 390 nm, 400 nm, 410 nm, 420 nm, 430 nm, 440 nm, 450 nm, 460 nm, 470 nm, 480 nm, 490 nm, or 500 nm. In some embodiments, the light source may be a 365 nm UV lamp.

[0068] In some embodiments, temperatures between and including 0°C and 150°C may be used. The temperature may be in a range between any two values selected from 0°C to 150°C. The temperature may be in a range between and including 0°C and 10°C, or 10°C and 20°C, or 20°C and 30°C, or 30°C and 40°C, or 40°C and 50°C, or 50°C and 60°C, or 60°C and 70°C, or 70°C and 80°C, or 80°C and 90°C, or 90°C and 100°C, or 100°C and 110°C, or 110°C and 120°C, or 120°C and 130°C, or 130°C and 140°C, or 140°C and 150°C. The temperature may be any value temperature selected from those including and between 0°C and 150°C. In some embodiments, temperatures between room temperature (about 20°C to about 25°C) and 70°C may be used.

[0069] In some embodiments, a suitable solvent may be used. Examples of a suitable solvent include but are not limited to: dichloromethane, dichlorobenzene, acetonitrile, 1,2- dichloroethane, water, MTBE, DMF, DMSO, acetone, ethyl acetate, isopropylacetate, N- methylpyrrolidinone, and mixtures thereof. A solvent mixture of acetonitrile/water may be used.

[0070] In some embodiments, the reaction concentration may be in the range 1 mM-10 M, or 0.1 M-1.0 M, or any specific concentration within these ranges, such as 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, 0.7 M, 0.8 M, 0.9 M, 1.0 M, 1.1 M, 1.2 M, 1.3 M, 1.4 M, 1.5 M, 2.0 M, or 2.5 M.

[0071] In some embodiments of the invention, the reaction time may be in the range 1 min- 48 h, or 30 min-24 h, or 1-15 h, or 2-8 h, or any specific time within these ranges, including 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, or 24 h.

General Procedure for Photochemical Fluorination of Unactivated C-H Bonds

Fluorinating agent

(1-2 equiv)

Catalyst (1-5 mol%)

Light source

(Π) (I)

[0072] A clear glass reaction vessel equipped with a magnetic stir bar is charged with the substrate (1.0 equivalents) in a suitable solvent (e.g. acetonitrile/water 2: 1) (10 mL solvent/mmol substrate). The catalyst (0.01-0.05 equivalents) and fluorinating agent (1-2 equivalents) are then added. The catalyst may be, for example, tetrabutylammonium decatungstate (TBADT) or another suitable tetraalkylammonium decatungstate salt. The fluorinating agent may be, for example, N-fluorobenzenesulfonimide (NFSI) or 1- chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)

(Selectfluor™). The resulting mixture is purged for 5-30 minutes by bubbling with inert gas (e.g. N ₂ or Ar gas). The reaction vessel is then quickly capped and sealed, and allowed to stir under irradiation with a light source for 2-18 hours. The resulting mixture is quenched with water or saturated sodium bicarbonate solution (10 mL/mmol substrate), and extracted with a suitable organic solvent (for example, EtOAc, MTBE, CHCI ₃ , or CH ₂ C1 ₂ ). The organic layer is dried using a drying agent (e.g. MgSC^) and then concentrated to give the crude mixture, which is further purified using appropriate techniques (e.g., column chromatography, crystallization, etc.).

[0073] Various alternative embodiments and examples of the invention are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the invention.

EXAMPLES

[0074] The following examples are intended to illustrate embodiments of the invention and are not intended to be construed in a limiting manner.

Abbreviations

EtOAc = ethyl acetate

MeCN = acetonitrile

MTBE = methyl tert-butyl ether

NFSI = N-fluorobenzenesulfonimide

TBADT = tetrabutylammonium decatungstate ²⁴

General Procedures and Methods

[0075] Exemplary processes and methods of the invention are outlined in, for example, Schemes 1 to 8 below, and in Examples 1 to 28. Scheme 1

Scheme 3

Scheme 4

Scheme 5

Scheme 7

Scheme 8 General Procedure A for Photochemical Fluorination of Unactivated C-H Bonds

[0076] A 2 mL glass vial equipped with a magnetic stir bar was charged with the aliphatic substrate (0.300 mmol) in acetonitrile (0.15 mL). Solid sodium bicarbonate (2.5 mg, 0.030 mmol), TBADT ²⁴ (20 mg, 0.006 mmol), and NFSI (142 mg, 0.450 mmol) were then added. This resulting suspension was purged for 5 minutes by bubbling with N ₂ through a 3.5" septic needle. The vial was then quickly capped and sealed, and was allowed to stir under irradiation with a 365 nm UV lamp at room temperature for 16-18 hours. The resulting dark blue mixture was quenched with 1 mL of saturated sodium bicarbonate solution, and extracted with CH ₂ C1 ₂ . The organic layer was dried with MgSC>4 and concentrated to give the crude mixture, which was further purified by column chromatography.

Example 1

Conversion of (iS)-leucine ethyl ester hydrochloride to (iS)-4-fluoroleucine ethyl ester

[0077] A solution of (L)-leucine ethyl ester hydrochloride salt (18 mg, 0.1 mmol), TBADT (7 mg, 2%), NFSI (38 mg, 0.12 mmol), CD ₃ CN/D ₂ 0 (2: 1, 1 mL) was purged with nitrogen (10 minutes) and then added to a nitrogen gas-filled NMR tube. This was then placed between two 15 watt UVB lamps and irradiated for 18 hours. A conversion of >90% was observed by H NMR using CD ₃ CN as internal standard. The blue solution was then diluted with CHCI ₃ and water/NaHC03 was added to pH >10. The solvent was removed and the resulting white solid was suspended in CHCI ₃ and dried over MgS0 ₄ . The resulting solution was cooled in a freezer and then filtered over celite, washing with cold CHCI ₃ . Concentration of the filtrate yielded pure (5)-4-fluoroleucine ethyl ester. ^X H (600 MHz, CDC1 ₃ ): δ 4.18 (q, J =

7 Hz, 2H), 3.69 (m, 1H), 2.14 (ddd, J= 23.6, 14.8, 4.8 Hz, 1H), 1.85 (ddd, J = 25.5, 14.8, 7.9 Hz, 1H), 1.44 (d, J= 21.5 Hz, 3H), 1.43 (d, J= 21.4 H, 3H), 1.28 (t, J= 7.1 Hz, 3H); ¹³ C (150 MHz, CDCI ₃ ): δ 175.8, 95.2 (d, J= 165.8 Hz), 61.2, 51.7, 45.9 (d, J= 21.3 Hz), 27.3 (d, J = 90.5 Hz) 27.2 (d, J = 90.8 Hz), 14.3; HRMS m/z [M+H] calcd for C ₈ Hi ₇ FN0 ₂ : 178.1238; found: 178.1222.

[0078] On a larger scale, a solution of (L)-leucine ethyl ester hydrochloride salt (100 mg, 0.51 mmol), TBADT (37 mg, 2%) and NFSI (193 mg, 0.61 mmol) in CH ₃ CN/H ₂ 0 (2: 1, 6.0 mL) was purged with nitrogen (10 minutes) then sealed. The resulting solution was then placed between two 15 watt UVB (365 nm) lamps and irradiated for 18 hours. At this time, another aliquot of solid NFSI (75 mg) was added to the solution and it was purged with nitrogen for another 10 minutes. The resulting solution was irradiated between two 15 watt UVB (365 nm) lamps for another 24 hours. At this time more solid NFSI (50 mg) was added to the solution and it was purged with nitrogen for another 10 min, and irradiated for a further 24 hours, and then worked up as follows: The blue solution was diluted with CHC1 ₃ and water/potassium carbonate was added to pH >10. The solvent was removed via rotary evaporator and the resulting white solid was suspended in CHCI ₃ and dried over MgSC>4. The solution was cooled in a freezer and then filtered over celite, washing with cold CHCI ₃ .

Concentration of the filtrate yielded an orange oil (68 mg) that was -75% pure based on H NMR analysis. The approximate isolated yield of (<S)-4-fluoroleucine ethyl ester was 58%. ^X H (600 MHz, CDCI ₃ ): δ = 4.18 (q, J = 7 Hz, 2H), 3.69 (m, 1H), 2.14 (ddd, J= 23.6, 14.8, 4.8 Hz, 1H), 1.85 (ddd, J= 25.5, 14.8, 7.9 Hz, 1H), 1.44 (d, J = 21.5 Hz, 3H), 1.43 (d, J= 21.4 H, 3H), 1.28 (t, J = 7.1 Hz, 3H); ¹³ C (150 MHz, CDC1 ₃ ): δ = 175.8, 95.2 (d, J = 165.8 Hz), 61.2, 51.7, 45.9 (d, J = 21.3 Hz), 27.3 (d, J= 90.5 Hz) 27.2 (d, J= 90.8 Hz), 14.3; HRMS m/z [M+H] ⁺ calcd for C ₈ Hi ₇ FN0 ₂ : 178.1238; found: 178.1222; enantiomeric excess (ee) determined by chiral GC (CDX cyclodextrin chiral column, 100°C isothermal, retention time (major): 23.04 min, retention time (minor): 22.32 min): 97% ee. The ee of the product establishes that the reaction does not effect racemization or epimerization of the amino acid starting material or product - that is, the stereochemistry of the starting material is carried over to the product without loss of enantiomeric purity.

[0079] On a smaller scale, the progress of the reaction was monitored by H NMR. A solution of (L)-leucine ethyl ester hydrochloride salt (18 mg, 0.2 mmol), TBADT (7 mg, 2%), and NFSI (76 mg, 0.24 mmol) in CD ₃ CN/D ₂ 0 (2: 1, 1.0 mL) was purged with nitrogen gas for 10 minutes, then added to a nitrogen-filled NMR tube, which was sealed and irradiated between two 15 watt UVB (365 nm) lamps. H NMR spectra were taken at 1 h, 2.5 h, and 18 h to give the following ratios of product ((<S)-4-fluoroleucine ethyl ester) to starting material ((S)-leucine ethyl ester): 1 h: 1 :3 P:SM; 2.5 h: 1 : 1 P: SM; 18 h: >20: 1 P: SM. Based on this analysis, the reaction was approximately 25% complete after 1 h, 50% complete after 2.5 h, and had progressed to completion (full conversion) at 18 h.

[0080] The reaction was also carried out using a flow setup, consisting of a 3.0 m length of fluorinated ethylene propylene (FEP) tubing (0.79 mm ID), coiled around a 15 watt blacklight blue UV lamp (365 nm), and attached to a syringe pump. A reagent solution of (L)-leucine methyl ester hydrochloride salt (36 mg, 0.2 mmol), NFSI (76 mg, 0.24 mmol), and TBADT (7 mg, 2%) in CH ₃ CN/H ₂ 0 (4: 1, 1.5 mL) was purged with N ₂ gas to remove oxygen. Degassed CH ₃ CN was passed through the flow setup at a flow rate of 3.0 mL/min, then the reagent solution described above was passed through the flow setup at a flow rate of either 0.25 mL/min or 1.0 mL/min, and then the tubing was purged by passing through additional degassed CH ₃ CN at a flow rate of 2.0 mL/min. The reagent solution was collected after passing through the flow setup, and a small aliquot (0.1 mL) was concentrated then dissolved in CDCI ₃ and filtered through a celite/cotton plug for Η NMR analysis. Using a flow rate of 1.0 mL/min (1.5 h UV exposure time), Η NMR analysis indicated a ratio of product ((<S)-4-fluoroleucine methyl ester) to starting material ((<S)-leucine methyl ester) of 1.2: 1, roughly 55% conversion. Using a flow rate of 0.25 mL/min (4 h UV exposure time), Η NMR analysis indicated a ratio of product ((<S)-4-fluoroleucine methyl ester) to starting material ((<S)-leucine methyl ester) of 1.7: 1 , roughly 63% conversion.

Example 2

Conversion of (iS)-valine methyl ester hydrochloride to (iS)-3-fluorovaline methyl ester

365 nm UV lamp

[0081] A solution of (<S)-valine methyl ester hydrochloride salt (33 mg, 0.2 mmol), TBADT (15 mg, 2%), and NFSI (75 mg, 0.24 mmol) in CH ₃ CN/H ₂ 0 (2: 1 , 1.5 ml) was purged with nitrogen (10 minutes) then sealed. This solution was then placed between two 15 watt UVB (365 nm) lamps and irradiated for 18 hours. At this time, another aliquot of solid NFSI (75 mg) was added to the solution and it was purged with nitrogen for another 10 minutes. The resulting solution was irradiated between two 15 watt UVB (365 nm) lamps for another 24 hours then worked up as follows: The blue solution was diluted with CHCI ₃ and

water/sodium bicarbonate was added to pH >10. The solvent was removed via rotary evaporator and the resulting white solid was suspended in CHCI ₃ and dried over MgSC>4. The solution was cooled in a freezer and then filtered over celite, washing with cold CHCI ₃ . Concentration of the filtrate yielded a white/yellow solid (142 mg) that, based on H NMR analysis, was a mixture of NFSI, (<S)-3-fluorovaline methyl ester, and the starting material (<S)-valine methyl ester in a 6.5: 1 :0.5 ratio. The approximate isolated yield of (S)-3- fluorovaline methyl ester was 59%. ^X H (600 MHz, CDC1 ₃ ): δ

Hz, 1H), 1.43 (d, J = 22 Hz, 3H), 1.40 (d, J = 22 Hz, 3H).

Example 3

Conversion of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldecahydronaphtho[2,l- b]furan- 2(3aH)-one ((3afl)-(+)-Sclareolide) to (3aR,5aS,8S,9aS,9bR)-8-fluoro-3a,6,6,9a- tetramethyldecahydronaphtho[2,l-b]furan-2(3aH)-one

[0082] The reaction was performed according to General Procedure A above using

(3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldecahydronaphtho[2 , 1 -b]furan-2(3aH)-one ((3ai?)- (+)-Sclareolide) (75 mg, 0.30 mmol) as substrate. Purification by column chromatography (hexanes to 10% EtOAc/hexanes to 20% EtOAc/hexanes) afforded the maj or 2 -fluoro isomer (3aR,5aS,8S,9aS,9bR)-8-fluoro-3a,6,6,9a-tetramethyldecahydro naphtho[2, l -b]furan- 2(3aH)-one as a white solid (47 mg, 58% yield). ^X H NMR (500 MHz, CDC1 ₃ ) δ 4.84 (dtt, J=48.0, 1 1.3, 4.6 Hz, 1H), 2.46 (dd. J=16.2, 14.7 Hz, 1H), 2.28 (dd, J=15.8, 6.5 Hz, 1H), 2.13-1.86 (m, 6H), 1.71 (td, J=12.6, 4.1 Hz, 1H), 1.44-1.31 (m, 6H), 1.00 (s, 3H), 0.96 (s, 3H), 0.90 (s, 3H); ¹⁹ F NMR δ -179.9 ppm; MS (EI) m/z calc'd for CigHzjFNaOz [M+Na] ⁺ : 291.17, found 291.17.

Example 4

Conversion of (2R,4S)-l,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate ((-)-Bornyl acetate) to (2R,4S,5S)-5-fluoro-l,7,7-trimethylbicyclo[2.2.1]heptan-2-yl acetate

[0083] The reaction was performed according to General Procedure A above using (-)-bomyl acetate (59 mg, 0.30 mmol) as substrate. Purification by column chromatography (4% EtOAc/pentane) afforded the 5-exo-fluoro isomer (2R,4S,5S)-5-fiuoro-l ,7,7- trimethylbicyclo[2.2.1]heptan-2-yl acetate as a colourless oil (20 mg, 31% yield). H NMR (500 MHz, CDC1 ₃ ) δ 4.79 (d, J=9.7 Hz, 1H), 4.63 (ddd, J=60.0, 7.6, 2.3 Hz, 1H), 2.40 (m, 2H), 2.06-1.99 (m, 1H), 2.04 (s, 3H), 1.69 (dd, J=35.3, 15.4 Hz, 1H), 1.04 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H), 0.74 (dd, J=14.5, 3.4 Hz, 1H); ¹⁹ F NMR δ -157.8 ppm; MS (EI) m/z calc'd for Ci ₂ Hi ₉ FNa0 ₂ [M+Na] ⁺ : 237.13, found 237.13.

Example 5

Conversion of (lR,2S,5R)-2-isopropyl-5-methylcyclohexyl acetate (L-Menthyl acetate) to (lR,2S)-5-fluoro-2-isopropyl-5-methylcyclohexyl acetate and (lS,3R,6S)-2-fluoro-6- isopropyl-3-methylcyclohexyl acetate

[0084] The reaction was performed according to General Procedure A above using L- menthyl acetate (59 mg, 0.30 mmol) as substrate. Purification by column chromatography (6% EtOAc/hexane) afforded a mixture of the fluorination products (lR,2S)-5-fluoro-2- isopropyl-5-methylcyclohexyl acetate and (l S,3R,6S)-2-fluoro-6-isopropyl-3- methylcyclohexyl acetate as a colourless oil (combined yield: 28% yield), with the 5-fluoro isomers as the major products. ^X H NMR (500 MHz, CDC1 ₃ ) δ 4.98 (ddd, J=10.8, 10.8, 4.7

Hz, 1H), 2.30 (m, 1H), 1.93-1.79 (m, 4H), 1.46 (dd, J=13.3, 3.8 Hz, 2H), 1.44-1.30 (m, 4H), 1.35 (d, J=21.1 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H), 0.80 (d, J=6.8 Hz, 3H); ¹⁹ F NMR δ -133.1 ppm, -150.0 ppm, -178.1 ppm, -199.5 ppm.

Example 6

Conversion of (lR,4R)-l,7,7-trimethylbicyclo[2.2.1]heptan-2-one (D-Camphor) to (lR,4R,5S)-5-fluoro-l,7,7-trimethylbicyclo[2.2.1]heptan-2-on e and (lR,4R)-4-fluoro- l,7,7-trimethylbicyclo[2.2.1]heptan-2-one

[0085] The reaction was performed according to General Procedure A above using D- camphor (46 mg, 0.30 mmol) as substrate. Purification by column chromatography (8% EtOAc/hexane) afforded a mixture of the fluorination products (lR,4R,5S)-5-fiuoro-l,7,7- trimethylbicyclo[2.2.1]heptan-2-one and (lR,4R)-4-fluoro-l,7,7- trimethylbicyclo[2.2.1]heptan-2-one as a white solid (combined yield: 4.5 mg, 9% yield). H

NMR (500 MHz, CDC1 ₃ ) δ 5.35 (dm, J=56.6 Hz, IH), 2.68 (d, J=7.1 Hz, IH), 2.56 (d, J=18.8 Hz, IH), 2.45-2.31 (m, IH), 2.30-2.15 (m, IH), 1.55 (ddd, J=27.7, 15.1, 3.0 Hz, IH), 1.26 (d, J=24.3 Hz, 3H), 1.16 (d, J=6.7 Hz, 3H), 0.98 (s, 3H); ¹⁹ F NMR δ -139.1 ppm, -190.3 ppm.

Example 7

Conversion of (lS,5R)-l,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one to (lS,5R,6R)-6- fluoro- l,8,8-trimethyl-2-oxabicyclo [3.2.1] octan-3-one

[0086] The reaction was performed according to General Procedure A above using (1S,5R)- l,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one (50 mg, 0.30 mmol) as substrate.

Purification by column chromatography (16% EtOAc/hexane) afforded the fluorination product (lS,5R,6R)-6-fluoro-l,8,8-trimethyl-2-oxabicyclo[3.2.1]octan -3-one as a white solid (6.5 mg, 12% yield). 'H NMR (500 MHz, CDC1 ₃ ) δ 4.91(ddd, J=54.3, 7.4, 2.3 Hz, IH), 2.87 (dt, J=19.3, 6.2 Hz, IH), 2.70 (ddd, J=16.2, 16.2, 7.4 Hz, IH), 2.42 (d, J=19.3 Hz, IH), 2.30 (dd, J=39.2, 16.8 Hz, IH), 2.27 (d, J=16.2 Hz, IH), 1.34 (s, 3H), 1.18 (s, 3H), 1.07 (s, 3H); ¹⁹ F NMR δ -160.2 ppm.

[0087] The following examples may be carried out according to procedures analogous to the schemes and examples outlined above.

Table 3.

Scheme A

(Odanacatib)

[0088] The following examples may be carried out according to procedures analogous to the schemes and examples outlined above.

Table 4.

F-Fluorinating agent

Light (hv)

(II) (III)

Scheme B

[0089] The present invention has been described with regard to one or more embodiments. However, it will be apparent to persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the claims. REFERENCES

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