WO2013007371A2

WO2013007371A2 - Kinetic resolution of chiral amines

Info

Publication number: WO2013007371A2
Application number: PCT/EP2012/002884
Authority: WO
Inventors: Jeffrey Bode; Michael BINANZER
Original assignee: Eth Zurich
Priority date: 2011-07-13
Filing date: 2012-07-09
Publication date: 2013-01-17
Also published as: WO2013007371A3

Abstract

The present invention refers to a method for the kinetic resolution of a chiral primary or secondary amine by treating the amine with a chiral, hydroxamic acid derived reagent of the formula (I). These chiral reagents are particularly useful for the kinetic resolution of cyclic amines and may be generated in situ in the presence of an N-heterocyclic carbene, thus allowing for a catalytic reaction.

Description

Kinetic Resolution of Chiral Amines

The present invention refers to the kinetic resolution of chiral amines .

Kinetic resolutions offer an important approach to the preparation of enant iomerically enriched organic compounds by selective reaction of one enantiomer of a racemic mixture. They are often the method of choice for the preparation of enant iomerically pure building blocks, such as secondary alcohols, carboxylic acids, and epoxides, for instance.

The kinetic resolution of amines, however, has so far been a long-standing synthetic problem that is not adequately met by either small molecule catalysis or biotechnological approaches. This is particularly true for the resolution of chiral secondary amines . Despite the fact that enantiomerically pure cyclic amines are among the most important building blocks for modern pharmaceuticals and agricultural chemicals, there are few methods for the catalytic kinetic resolution of their racemic mixtures . The state of the art for the resolution of secondary amines remains classical resolution by diastereomeric salt or derivative formation or by chromatography on chiral supports .

The difficultly in achieving kinetic resolution of chiral amines is ascribed to the high nucleophilicity of these substrates, which leads to fast background reactions with standard acylating agents, and to the large number of conformations involved in their acylation reactions.

For this reason, the most promising chemical methods reported to date require stoichiometric amounts of chiral reagents: Mioskowski et al . , for instance, have described the non-enzymatic kinetic resolution of primary amines through enantioselective N-acetylation using chiral 1,2- disulfonamide derivatives (S. Arseniyadis, A. Valleix, A. Wagner, C. Mioskowski, Angew. Chem. 2004, 116, 3376-3379; Angew. Chem. Int. Ed. 2004, 43, 3314-3317; C. Sabot, P.V. Subhash, A. Valleix, S. Arseniyadis, C. Mioskowski, Synlett 2008, 268-272; and S. Arseniyadis, P.V. Subhash; A. Valleix, A. Wagner, C. Mioskowski, Chem. Comm. 2005, 3310-3312) .

Given that chiral secondary amines are among the most important and prevalent structural motifs in modern pharmaceuticals, the lack of effective catalytic methods for kinetic resolution is noteworthy. The few examples of catalytic resolutions with small molecule catalysts use protected amines, such as 0- acyloxazolines , or N-formyl amines - a strategy that precludes resolutions of secondary amines - or the combination of poorly reactive substrates, such as indolines, and bulky acylation reagents. Fu et al . , for example, have disclosed the kinetic resolution of indolines by a 4-(l- pyrrolidinyl ) pyridine derivative (F.O. Arp, G.C. Fu, J. Am. Chem. Soc. 2006, 128, 14264-14265; and S. Arai, S. Bellemin-Laponnaz, G.C. Fu, Angew. Chem. Int. Ed. 2001, 40, 234-236) .

Alternatively, low reaction temperatures and concentrations can suppress background acylation, a strategy employed in a promising kinetic resolution of primary amines using standard acylating reagents and chiral co- catalysts. Seidel et al., for instance, have described the kinetic resolution of primary benzylic amines (C.K. De, E.G. Klauber, D. Seidel, J. Am. Chem. Soc. 2009, 131, 17060-17061) and of primary propargylic amines (E.G. Klabuer, C.K. De, T.K. Shah, D. Seidel, J. Am. Chem. Soc. 2010, 132, 13624-13626) using a DMAP-derived acyl pyridinium salt.

Biocatalytic approaches including carbamate formation (B. Orsat, P.B. Alper, W. oree, C.-P. Mak, C . -H . Wong, J. Am. Chem. Soc, 118, 1996, 712), amide formation (A.J. Blacker, M.J. Stirling, M.I. Page, Org. Process Res. Dev. 2007, 11, 642; G.F. Breen, Tetrahedron: Asymmetry 2004, 15, 1427), hydrolysis (N.J. Turner, Nat. Chem. Biol. 2009, 5, 567), and transamidation (M. Hohne, U.T. Bornscheuer, Chem. Cat. Chem. 2009, 1, 42) are among the most important emerging methods, but not presently successful for the resolution of simple cyclic amines including piperidines, morpholines, and piperazines.

In a different approach, Rovis et al. have described the catalytic amidation of a-chloro, a-epoxy, a-aziridino and α,β-unsaturated aldehydes with both primary and secondary amines in the presence of a nucleophilic carbene (H.U. Vora, T. Rovis, J. Am. Chem. Soc. 2007, 129, 13796-13797) . However, the use of a chiral carbene did not provide any selectivity for the kinetic resolution of a chiral secondary amine. Thus, the kinetic resolution of chiral secondary amines, and in particular of cyclic amines, still remains a challenging problem in organic synthesis, and especially a non-enzymatic catalytic process would be highly desirable.

It is therefore a problem of the present invention to provide an efficient and highly selective method for the kinetic resolution of chiral amines, and in particular for the kinetic resolution of secondary and cyclic amines.

This problem is solved by the method according to claim 1, the chiral reagent according to claim 14, and its precursor according to claim 22. Preferred embodiments are subject of the dependent claims.

It has been found that the kinetic resolution of a chiral primary or secondary amine can be accomplished in a highly selective and efficient manner by treating the amine with a chiral reagent of the formula (I)

Rl is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkoxycarbonyl , alkylamino, alkylamido, alkylthio, aryl, heteroaryl, halogen, and heterocyclyl. is selected from the group consisting of 0, NH, NR, and S, wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl, and m is 0 or 1.

R2 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkoxycarbonyl, alkylamino, alkylamido, alkylthio, aryl, heteroaryl, halogen, and heterocyclyl.

Rl and R2 are optionally forming a four-, five-, six- or seven-membered ring, which is substituted. Such a ring may comprise - apart from the nitrogen atom shown in formula (I) - one or more further hetero atoms, such as oxygen, nitrogen and/or sulphur.

X is selected from the group consisting of O, NH, NR, and S, wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl .

R3 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkyl- amino, and alkylthio.

Y is selected from the group consisting of O, NH, NR, and S, wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl, and n is 0 or 1.

Rl and/or R2 comprise (s) at least one stereogenic center.

Throughout this application, the following definitions apply : - The term "alkyl" refers to a saturated hydrocarbon group, which may be linear, branched or cyclic. The alkyl group may further be substituted as specified at the relevant passages. In the context of this application, alkyl groups in general comprise one to eighteen carbon atoms, preferably one to eight carbon atoms, and more preferably one to four carbon atoms.

- A "substituted alkyl group", as used in this application, also includes, e.g. a -CH₂-CH₂-0-CH₃ group, which would be referred to as "an ethyl (i.e. alkyl) group with a methoxy (i.e. alkoxy) substi- tuent" .

The same applies, in analogous manner, to all other substituted groups.

The term "alkenyl" refers to a hydrocarbon group, which may be linear, branched or cyclic and comprises at least one carbon-carbon double bond. The alkenyl group may further be substituted as specified at the relevant passages. In the context of this application, alkenyl groups in general comprise one to eighteen carbon atoms, preferably one to eight carbon atoms, and more preferably one to four carbon atoms.

The term "aryl" refers to an aromatic hydrocarbon group, which may further be substituted and/or fused. In the context of this application, an aryl group is usually a phenyl group, which may optionally be substituted .

The term "heteroaryl" refers to an aromatic hydrocarbon group, which comprises at least one heteroatom, such as oxygen, nitrogen or sulphur. The heteroaryl group may further be substituted and/or fused. In the context of this application, a heteroaryl group is preferably a pyridyl, pyrrolyl indolyl or thiophenyl, group, which may optionally be substituted.

The term "alkoxy" refers to an ether group, i.e. an oxygen atom carrying an alkyl or alkenyl group, which may be linear, branched or cyclic. The alkyl or alkenyl group may further be substituted and in general comprises one to eighteen carbon atoms, preferably one to eight carbon atoms, and more preferably one to four carbon atoms.

The term "alkoxycarbonyl" refers to an ester group carrying an alkyl or alkenyl group, which may be linear, branched or cyclic. The alkyl or alkenyl group may further be substituted and in general comprises one to eighteen carbon atoms, preferably one to eight carbon atoms, and more preferably one to four carbon atoms.

The term "alkylcarbonyl" refers to a carbonyl group carrying an alkyl or alkenyl group, which may be linear, branched or cyclic. The alkyl or alkenyl group may further be substituted and in general comprises one to eighteen carbon atoms, preferably one to eight carbon atoms, and more preferably one to four carbon atoms .

The term "alkylamino" refers to an amino group, i.e. a nitrogen atom carrying one or two alkyl and/or alkenyl groups, which may be linear, branched or cyclic. The alkyl and/or alkenyl group (s) may further be substituted and in general each comprise one to eighteen carbon atoms, preferably one to eight carbon atoms, and more preferably one to four carbon atoms.

The term "alkylamido" refers to an amide group carrying an alkyl or alkenyl group, which may be linear, branched or cyclic. The alkyl or alkenyl group may further be substituted and in general comprises one to eighteen carbon atoms, preferably one to eight carbon atoms, and more preferably one to four carbon atoms. - The term "alkylthio" refers to a thioether group, i.e. a sulphur atom carrying an alkyl or alkenyl group, which may be linear, branched or cyclic. The alkyl or alkenyl group may further be substituted and in general comprises one to eighteen carbon atoms, preferably one to eight carbon atoms, and more preferably one to four carbon atoms.

The term "heterocyclyl" refers to a cyclic group comprising at least one hetero atom, such as oxygen, nitrogen or sulphur. In the context of this application, heterocyclyl groups in general refer to three- to seven-membered rings, preferably five- or six-membered rings. These heterocyclic groups may be saturated or partially unsaturated. Examples of such heterocyclyl groups are, for instance, tetrahydro- furyl, dihydrofuranyl , tetrahydropyranyl , dihydro- pyranyl, dioxanyl, piperidinyl, piperazinyl, pyrroli- dinyl, imidazolidinyl , triazolidinyl , oxazolidinyl , thiazolidinyl, morpholinyl, and tetrahydroiso- quinolinyl .

- The term "substituted" includes branched, fused and spiro structures. It also includes one or several substituents on the respective group. For instance, a substituted aryl group includes aryl groups with one or several (additional) substituents.

The method of the present invention allows for the kinetic resolution of both primary and secondary amines in high selectivity. The chiral reagents of formula (I), which are derived from a chiral hydroxamic acid, are very easily prepared from inexpensive precursors. The resolution reaction is in general very clean and affords the enantiomerically pure amine in high yield. It works well for both primary and secondary amines, and in particular also for cyclic amines.

The reaction generally proceeds at a temperature of about -20 °C to 60 °C and is preferably carried out at about 0 °C to room temperature, i.e. to about 25 °C.

Typically, the kinetic resolution is completed within a few hours to a couple of days, depending on the substrate, chiral reagent, and reaction temperature. The reaction is preferably carried out in a chlorinated solvent, such as methylene chloride, chloroform or carbon tetrachloride, or an ester solvent, such as ethyl acetate or propyl acetate. Alternatively, it is also possible to use toluene, tetrahydrofuran or acetonitrile . Usually, the reaction is carried out at a concentration of about 0.1 M to 1.0 M of the chiral amine.

Depending on the chiral reagent used, one enantiomer of the chiral amine is converted to an amide, carbamate, urea, thiourea, thiocarbamate or thioamide, while the other enantiomer does not react:

- If n is 0, R3 is an alkyl, alkenyl, heterocyclyl , aryl or heteroaryl group, which is optionally substituted, and X is 0, an amide is obtained.

- If n is 1, Y is 0, R3 is an alkyl, alkenyl, heterocyclyl, aryl or heteroaryl group, which is optionally substituted, and X is 0, a carbamate is obtained . - If n is 1, Y is NH or NR, R3 is an alkyl, alkenyl, heterocyclyl, aryl or heteroaryl group, which is optionally substituted, and X is 0, a urea is obtained . - If n is 1, Y is S, R3 is an alkyl, alkenyl, heterocyclyl, aryl or heteroaryl group, which is optionally substituted, and X is 0, a thiocarbamate is obtained.

- If n is 0, R3 is an alkyl, alkenyl, heterocyclyl, aryl or heteroaryl group, which is optionally substituted, and X is sulphur, a thioamide is obtained .

- If n is 1, Y is NH or NR, R3 is an alkyl, alkenyl, heterocyclyl, aryl or heteroaryl group, which is optionally substituted, and X is sulphur, a thiourea is obtained.

After completion of the resolution reaction, the unreacted amine enantiomer is very easily isolated by simple aqueous extraction. Alternatively, it may in certain cases also be isolated by chromatography, crystallization, distillation or sublimation.

Furthermore, the other amine enantiomer can be obtained from the amide, carbamate, urea, thiourea, thiocarbamate or thioamide by standard isolation and hydrolysis techniques. This applies, in particular, to certain amides and carbamates, which can especially easily be removed to afford the amine.

A further advantage of the method of the present invention is that it is even possible to form the chiral reagent (I) in situ, thus allowing for a catalytic version of the reaction, wherein a suitable, achiral co-catalyst is used for the preparation of the chiral reagent of formula (I) . Such a catalytic system will be described further down.

In general, preferred chiral reagents (I) are derived from natural or non-natural amino acids, in particular from a- or β-amino acids. This allows for a relatively simply preparation of the chiral reagents.

In a preferred embodiment, R2 comprises a stereogenic center in a-position. More preferably, this stereogenic center is a tertiary carbon atom.

In a preferred embodiment, Rl and R2 of the chiral reagent of formula (I) are forming a five- or six-membered ring. It has been found that these cyclic reagents lead to an even better selectivity in the resolution reaction, possibly thanks to the relatively rigid ring structure. Furthermore, these reagents are very easily prepared from commercially available starting materials, in particular from the corresponding chiral amino alcohols.

In an even more preferred embodiment, Rl and R2 are forming a five- or six-membered ring bearing at least two stereogenic centers. This allows not only for the choice between two enantiomeric reagents, but also between a syn and an anti arrangement of the substituents on the ring, and hence for a fine tuning of the reagent used for the resolution of a particular chiral amine substrate.

In a preferred embodiment, X is 0. In this case, the kinetic resolution leads to the formation of an amide, carbamate, urea or thiocarbamate, depending on n and Y. In a preferred embodiment, m is 1 and W is 0, NH or NR, more preferably O.

In a preferred embodiment, n is 1 and Y is 0, NH or NR, more preferably O. This allows for recovery of the reacted amine by hydrolysis.

In a preferred embodiment, n is 0 and R3 is an alkyl group, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, hetero- cyclyl, alkoxy, alkylamino, and alkylthio. In this case, the kinetic resolution leads to the formation of an amide or thioamide, depending on X. Both the amide and thioamide can very easily be hydrolyzed after separation from the unreacted amine, thus also providing access to the second enantiomer of the chiral amine. Preferably, X is 0, so that one amine enantiomer is converted to the corresponding amide. More preferably, R3 is not methyl, as for most cases, the selectivities are better for larger substituents .

In a preferred embodiment, X is 0, n is 1, Y is 0, and R3 is a benzyl or tert-butyl group. In this case, the reacting enantiomer of the chiral amine is converted to a carbamate, namely a carbobenzyloxy- (Cbz-) or tert-butyl- oxycarbonyl- (B0C-) protected amine. These protecting groups are well known in chemical synthesis and can be very easily removed under standard conditions. Thus, after separation from the unreacted amine enantiomer, the reacted amine enantiomer can also be accessed in a highly efficient manner by simple deprotection.

In a preferred embodiment, the chiral reagent is linked to a peptide. By linking the chiral reagent of formula (I) to a peptide, it is possible to achieve an even better selectivity in the kinetic resolution of the chiral amine, especially for particularly difficult substrates. Examples of peptides, which can be linked to the chiral reagent (I), can be found, for instance, in S.J. Miller, G.T. Copeland, N. Papaioannou, T.E. Horstmann, E.M. Ruel, <J. Am. Chem. Soc. 1998, 120, 1629-1630; E.R. Jarvo, G.T. Copeland, N. Papaioannou, P.J. Bonitatebus, Jr., S.J. Miller, J. Am. Chem. Soc. 1999, 121, 11638-11643; G.T. Copeland, S.J. Miller, J. Am. Chem. Soc. 2001, 123, 6496- 6502; M.B. Fierman, D.J. 0' Leary, W.E. Steinmetz, S.J. Miller, J. Am. Chem. Soc. 2004, 126, 6967-6971; C.A. Lewis, A. Chiu, M. Kubryk, J. Balsells, D. Pollard, C.K. Esser, J. Murry, R.A. Reamer, K.B. Handsen, S.J. Miller, J. Am. Chem. Soc. 2006, 128, 16454-16455; C.A. Lewis, J.L. Gustafson, A. Chiu, J-Balsells, D. Pollard, J. Murry. R.A. Reamer, K.B. Hansen, S.J. Miller, J. Am. Chem. Soc. 2008, 130, 16358-16365; and B.S. Fowler, P.J. Mikochik, S.J. Miller, J. Am. Chem. Soc. 2010, 132, 2870-2871.

In a preferred embodiment, the chiral reagent is linked to a solid support. By linking the chiral reagent to a solid support, such as a resin, the chiral reagent is easily recovered after completion of the resolution reaction by simple filtration. Thus, the reagent can be very easily regenerated and reused. The chiral reagent may be linked, for instance, to functionalized crosslinked polystyrene or a derivative thereof (e.g. Merrifield resin and its derivatives), a polyethylenglycol (PEG) based resin, a polyacrylamide crosslinked resin or the magnetic beads, which may be derived from similar resin materials, by means of a standard linker group, which is well known to a person skilled in the art. It has been found that some of the cyclic reagents are particularly preferred for the kinetic resolution reaction of the present invention. These preferred reagents include the following chiral reagents:

)

(VI)

In the above preferred reagents (II) to (VIII), the following substitution patterns apply:

X is selected from the group consisting of 0, NH, NR, and S, wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl.

Y is selected from the group consisting of 0, NH, NR, and S, wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl, and n is 0 or 1. R4 and R5 are, independently, selected from the group consisting of hydrogen, alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkyl- amino, alkylthio, aryl, heteroaryl, halogen, and hetero- cyclyl, and/or linked to a peptide or solid support.

R6 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, alkoxy, alkylamino, alkylthio, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, alkoxy, and halogen, and/or linked to a peptide or solid support .

R6 is optionally forming a five-, six- or seven-membered ring with R4 or R5, which may be substituted.

R7 is selected from the group consisting of alkyl, alkoxy, alkenyl, heterocyclyl, halogen, nitro, alkoxy, alkylamino, alkylthio, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, aryl, heteroaryl, and alkoxy, and/or linked to a peptide or solid support.

Furthermore, * denotes a stereogenic center.

The above preferred reagents are all derived from a cyclic chiral hydroxamic acid and are easily prepared in only a few steps from commercially available starting materials. By using these preferred reagents in the kinetic resolution, the desired chiral amine is obtained in very high enantiomeric purity.

Particularly preferred is the use of a chiral reagent having formula (II) or (V), since these reagents may be prepared from aspartic acid derivatives.

The above preferred reagents may be linked to a peptide or solid support via any of the substituents R4, R5, R6 or R7, preferably via R7 , if present. In a particularly preferred embodiment, the chiral reagent used for the kinetic resolution is

or its enantiomer (IX' ). R3 is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkyl- amino, and alkylthio. Y is selected from the group consisting of 0, NH, NR, and S, wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl , and n is 0 or 1.

The chiral reagent (IX), (IX' ) may optionally be linked to a peptide or solid support, preferably via a substituent on the phenyl group (not shown) .

Preferably, n is 0 and R3 is a propyl group or a -(CH₂)₂Mes group ("Mes" refers to a mesityl group, i.e. a 2,4,6- trimethyl phenyl group) . It has been found that a chiral reagent of formula (IX), (IX' ), which is derived from a cyclic hydroxamic acid, is particularly preferred for the kinetic resolution of secondary amines, and especially for cyclic amines. Furthermore, the chiral reagent (IX) is very easily prepared from the commercially available chiral amino alcohol (X)

in three steps and high yield (see below) .

In a preferred embodiment, the chiral reagent (I) is formed in situ by reaction of

in the presence of an N-heterocyclic carbene. This affords the chiral reagent of formula (I), wherein n is 0 and R3 is -(CH₂)₂R8. The only by-product of this reaction is acetone .

Furthermore, an achiral N-heterocyclic carbene can be used, which further facilitates the reaction and lowers the costs of the reagents.

As an alternative to the alcohol (XII), it is also possible to prepare the chiral reagent (I) in the presence of an W-heterocyclic carbene by using the following reagents: - an aldehyde in combination with an external oxidant, such as 0₂, the Kharasch oxidant (PhC=00₂tBu and cat. CuBr₂), Mn0₂, TEMPO ( ( 2 , 2 , 6, 6-tet ramethyl-piperidin-1- yl)oxyl) or napthoquinone; - an α-functionalized aldehyde, such as an a-halo aldehyde (bromo, chloro, fluoro or iodo) , an α, β- epoxy aldehyde, a formyl aziridine, a formyl cyclopropane, an a-oxo aldehyde, or basically any other aldehyde with an a-heteroatom substituent;

- an a-ketoacid or an acyl silane with an a-heteroatom or in combination with an oxidant.

As an alternative to the use of an N-heterocyclic carbene, it is also possible to prepare the chiral reagent (I) by reacting a stoichiometric amount of an acylating reagent, such as an acid chloride, acid anhydride, chloroformate or acyl cyanide, for instance, with the chiral precursor (XI) under standard reaction conditions. In this case, the chiral reagent (I) is preferably formed prior to the addition of the chiral amine to be resolved, more preferably in situ prior to the addition of the amine,

In an even more preferred embodiment of the above reaction, only catalytic amounts of the chiral precursor (XI), which is used to form the chiral reagent (I) in situ, are used. Thus, only catalytic amounts of the chiral precursor (XI) are necessary, whereas the achiral precursor (XII) is used in stoichiometric amounts. Typically, about 0.5 mol% to 30 mol%, preferably about 5 mol% to 20 mol%, e.g. 10 mol%, of the chiral precursor (XI) are used.

Preferably, the N-heterocyclic carbene (XIII)

Mes (xiii) is used for the generation of the chiral reagent (I) .

Alternatively, it would also be possible to use other N- heterocyclic carbenes for the generation of the chiral reagent (I), in particular triazolium, imidazolium or thiazoliura derived N-heterocyclic carbenes, with triazolium derived N-heterocyclic carbenes being preferred.

This N-heterocyclic carbene (XIII) has been described by Bode et al . for the redox amidation of a-functionalized aldehydes with amines (J.W. Bode, S.S. Sohn, J. Am. Chem. Soc. 2007, 129, 13798-13799) and for the catalytic amide formation with a' -hydroxyenones as acylating reagents (P.- C. Chiang, Y. Kim, J.W. Bode, Chem. Comm. 2009, 4566- 4568) . The disclosure of these two papers with respect to the N-heterocyclic carbene is herewith incorporated by reference .

It is believed that the kinetic resolution proceeds via the following synergistic catalytic cycles:

The above proposed reaction mechanism has been depicted for the kinetic resolution of 2-methyl piperidine using the preferred chiral reagent (IX), which is formed in situ in the presence of the ZV-heterocyclic carbene (XIII) . The same mechanism should, of course, also apply to all other chiral amines, chiral reagents and N-heterocyclic carbenes .

In another particularly preferred embodiment, the chiral reagent used for the kinetic resolution is derived from hydroxylamine (XXIV)

or its enantiomer (XXIV ) . It has been found that a chiral reagent, which is derived from (XXIV) , (XXIV ) is particularly preferred for the kinetic resolution of secondary amines, and especially for cyclic amines . The method of the present invention is particularly well suited for the kinetic resolution of secondary amines, and especially of cyclic amines, which have otherwise proven to be difficult substrates. Therefore, in a preferred embodiment, the chiral amine is a secondary amine, preferably a cyclic amine.

More preferably, the chiral amine is a substituted morpholine, piperidine, piperazine, azepane, diazapine, oxazapine, thiazapine, pyrrolidine, imidazolidine , oxazolidine, thiazolidine , tetrahydroisoquinoline or a bicyclic diamine. Examples of chiral bicyclic diamines have been described, e.g., by 0.0. Grygorenko, D.S. Radchenko, D.M. Volochyuk, A. A. Tolmachev and I.V. Komarov in Chemical Reviews (Web publication date: 28 June 2011), the contents of which is herewith incorporated by reference with respect to the bicyclic diamines.

The best results are achieved for the kinetic resolution of chiral amines having at least one stereogenic center in a-position. Therefore, in a preferred embodiment, the chiral amine has at least one stereogenic center in a- position.

Even more preferred is the use of the method of the present invention for the kinetic resolution of cyclic amines having at least one stereogenic center in el- position, and in particular of a-substituted morpholines, piperidines, piperazines, azepanes, diazapines, oxaza- pines, thiazapines, pyrrolidines, iraidazolidines, oxazoli- dines, thiazolidines or tetrahydroisoquinolines .

In a preferred embodiment, the chiral amine comprises a stereogenic center in a-position, which carries a removable group, such as an alkoxy, alkylthio, amide, sulfo- nylamide, cyano or nitro group, and a further stereogenic center in a different position. These removable groups improve the selectivity of the kinetic resolution reaction and can afterwards very easily be removed under standard reaction conditions, i.e. under reductive conditions, such as hydrogenation, dissolving metal or with a hydride reagent, if desired.

In a further aspect, the present invention also refers to chiral reagents suitable for use in the kinetic resolution of primary and secondary amines as specified above.

It has been found that a chiral reagent of the formula (I)

is particularly well suited for the method of the present invention. This hydroxamic acid derived reagent has the following substitution pattern:

Rl is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkoxycarbonyl, alkylamino, alkylamido^', alkylthio, aryl, heteroaryl, halogen, and heterocyclyl. W is selected from the group consisting of 0, NH, NR, and S, wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl, and m is 0 or 1. R2 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkoxycarbonyl, alkylamino, alkylamido, alkylthio, aryl, heteroaryl, halogen, and heterocyclyl. Rl and R2 are optionally forming a four-, five-, six- or seven-membered ring, which is optionally substituted. Such a ring may comprise - apart from the nitrogen atom shown in formula (I) - one or more further hetero atoms, such as oxygen, nitrogen and/or sulphur. X is selected from the group consisting of 0 , NH, NR, and S, wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl.

R3 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkylamino, and alkylthio.

Y is selected from the group consisting of 0, NH, NR, and S, wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl, and n is 0 or 1.

Rl and/or R2 comprise (s) at least one stereogenic center. The chiral reagent of the present invention allows for the kinetic resolution of both primary and secondary amines in high selectivity. Furthermore, chiral reagents of formula (I) are very easily prepared from inexpensive precursors. In general, preferred chiral reagents (I) are derived from natural or non-natural amino acids, in particular from a- or β-amino acids. This allows for a relatively simply preparation of the chiral reagents.

In a preferred embodiment, Rl and R2 are forming a substituted five- or six-membered ring. It has been found that cyclic reagents lead to an especially high selectivity in the kinetic resolution reaction of the present invention. This might be due to the relatively rigid ring structure. Furthermore, these chiral reagents are very easily prepared from commercially available starting materials in only a few reaction steps. In an even more preferred embodiment, Rl and R2 are forming a five- or six-membered ring bearing at least two stereogenic centers. This allows not only for the choice between two enantiomeric reagents, but also between a syn and an anti arrangement of the substituents on the ring, and hence for a fine tuning of the reagent used for the resolution of a particular chiral amine substrate.

In a preferred embodiment, X is 0. In this case, the kinetic resolution leads to the formation of an amide, carbamate, urea or thiocarbamate , depending on n and Y. In a preferred embodiment, m is 1 and is O, NH or NR, more preferably 0.

In a preferred embodiment, X is O, n is 1, Y is O, and R3 is a benzyl or tert-butyl group. In this case, the reacting enantiomer of the chiral amine is converted to a carbamate, namely a carbobenzyloxy- (Cbz-) or tert- butyloxycarbonyl- (BOC-) protected amine. These protecting groups are well known in chemical synthesis and can be very easily removed under standard conditions. Thus, after separation from the unreacted amine enantiomer, the reacted amine enantiomer can also be accessed in a highly efficient manner by simple deprotection.

In a preferred embodiment, the chiral reagent is linked to a peptide. By linking the chiral reagent of formula (I) to a peptide, it is possible to achieve an even better selectivity in the kinetic resolution of the chiral amine, especially for particularly difficult substrates.

In a preferred embodiment, the chiral reagent is linked to a solid support. By linking the chiral reagent to a solid support, such as a resin, the chiral reagent is easily recovered after completion of the resolution reaction by simple filtration. Thus, the reagent can very easily be regenerated and reused. The chiral reagent may be linked, for instance, to functxonalized crosslinked polystyrene or a derivative thereof (e.g. Merrifield resin and its derivatives), a polyethylenglycol (PEG) based resin, a polyacrylamide crosslinked resin or the magnetic beads, which may be derived from similar resin materials, by means of a standard linker group, which is well known to a person skilled in the art.

In a preferred embodiment, the chiral reagent of the present invention is selected from the group consisting of

(III)

In the above preferred reagents (II) to (VIII), the following substitution patterns apply: X is selected from the group consisting of 0, NH, NR, and S, wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl . R3 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkyl- amino, and alkylthio. Y is selected from the group consisting of 0, NH, NR, and S, wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl, and n is 0 or 1.

R4 and R5 are, independently, selected from the group consisting of hydrogen, alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkyl- amino, alkylthio, aryl, heteroaryl, halogen, and heterocyclyl, and/or linked to a peptide or solid support. R6 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, alkoxy, alkylamino, alkylthio, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, alkoxy, and halogen, and/or linked to a peptide or solid support .

Furthermore, * denotes a stereogenic center.

The above preferred reagents are very easily prepared in only a few steps from commercially available starting materials and afford the chiral amine in very high enantiomeric purity.

Particularly preferred are the chiral reagents having formula (II) or (V), since these reagents may be prepared from aspartic acid derivatives.

The above preferred reagents may be linked to a peptide or solid support via any of the substituents R4, R5, R6 or R7 ; preferably via R7 , if present.

In a particularly preferred embodiment, the chiral reagent used for the kinetic resolution has the formula (IX)

or is its enantiomer (IX' )

R3 is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkyl- amino, and alkylthio. Y is selected from the group consisting of 0, NH, NR, and S, wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl , and n is 0 or 1. The chiral reagent (IX), (IX') may optionally be linked to a peptide or solid support, preferably via a substituent on the phenyl group (not shown) .

Preferably, n is 0 and R3 is a propyl group or a -(CH₂)₂Mes group ("Mes" refers to a mesityl group, i.e. a 2,4,6- trimethyl phenyl group) .

It has been found that a chiral reagent of formula (IX), (IX' ), which is derived from a chiral hydroxamic acid, is particularly preferred for the kinetic resolution of secondary amines, and especially for cyclic amines. In a preferred embodiment of the chiral reagent (IX), (ΙΧ'), n is 0 and R3 is -(CH₂)₂Mes, i.e. a 2-(2,4,6- trimethyl phenyl) ethyl group. It has been found that the use of this reagent in the kinetic resolution of the present invention leads to a particularly clean reaction.

In a further aspect, the present invention also refers to the precursors of the chiral reagents of formula (I), having the formula (XIV)

In these hydroxamic acid precursors, Rl is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkoxycarbonyl, alkylamino, alkylamido, alkylthio, aryl, heteroaryl, halogen, and heterocyclyl . W is selected from the group consisting of O, NH, NR, and S wherein R is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl, and m is 0 or 1.

Rl and/or R2 comprise (s) at least one stereogenic center. From the precursor (XIV), the chiral reagent (I) of the present invention may be prepared, for instance, by reaction with alcohol (XI)

in the presence of an ZV-heterocyclic carbene, to afford reagent of formula (I), wherein n is 0 and R3 is -(CH₂)2R8 In a preferred embodiment, R2 comprises a stereogenic center in a-position. More preferably, this stereogenic center is a tertiary carbon atom.

In a preferred embodiment, Rl and R2 are forming a substituted five- or six-membered ring. This allows for the preparation of a cyclic chiral reagent of formula (I), which has been found to lead to an especially high selectivity in the kinetic resolution reaction of the present invention. In an even more preferred embodiment, Rl and R2 are forming a five- or six-membered ring bearing at least two stereogenic centers. This allows not only for the choice between two enantiomeric reagents, but also between a syn and an anti arrangement of the substituents on the ring, and hence for a fine tuning of the reagent used for the resolution of a particular chiral amine substrate.

In a preferred embodiment, the precursor is linked to a peptide or solid support. This allows for the preparation of a chiral reagent of formula (I), which is linked to a peptide or solid support, respectively, having the advantages specified above.

In a preferred embodiment, the precursor of the present invention is selected from the group consisting of

(XV)

In the above precursors (XV) to (XXI), the following substitution patterns apply:

R4 and R5 are, independently, selected from the group consisting of hydrogen, alkyl, alkenyl, heterocyclyl , aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkyl- amino, alkylthio, aryl, heteroaryl, halogen, and heterocyclyl, and/or linked to a peptide or solid support.

R6 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, alkoxy, alkylamino, alkylthio, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, alkoxy, and halogen, and/or linked to a peptide or solid support . R6 is optionally forming a five-, six- or seven-membered ring with R4 or R5, which may be substituted.

Furthermore, * denotes a stereogenic center.

These precursors (XV) to (XXI) allow for the preparation of the preferred chiral reagents (II) to (VIII), respectively .

In a particularly preferred embodiment, the precursor of the present invention has the formula (XXII)

or is the enantiomer (XXII' ) of (XXII) .

This precursor may optionally be linked to a peptide or solid support, for instance via a substituent on the phenyl group (not shown) and allows for the preparation of the preferred chiral reagent of formula (IX) or (IX' ), respectively .

The precursor (XXII) is easily prepared from commercially available chiral amino alcohol (X) in two steps and almost 60% overall yield:

(X) (XXIII) (XXII)

In the first step, the amino alcohol (X) is converted to the corresponding oxazinone (XXIII), which is in the second step treated with N, O-bis ( trimethylsilyl ) acetamide (BSA) and oxodiperoxymolybdenum (MoOPH) to afford the chiral hydroxamic acid (XXII). This allows for a short and very straight forward preparation of the precursor (XXII) and thus the chiral reagent (IX) .

or its enantiomer (XXIV )

The present invention is further illustrated by means of the following, non-limiting examples:

EXAMPLES

General Information

All reactions were carried out in oven dried glassware under nitrogen using standard manifold techniques (J. Leonard, B. Lygo, G. Procter, Advanced Practical Organic Chemistry, Taylor & Francis, Boca Raton, 1998) . All chemicals were purchased from Acros, Aldrich or BioBlocks Inc. and used without further purification unless otherwise stated.

Dichloromethane was distilled from CaH₂ and stored over 4 A molecular sieves. DBU ( 1 , 8-diazabicyclo [ 5.4.0 ] undec-7-ene ) and other amines were distilled from KOH under reduced pressure. 2- (2, 4, 6-trimethyl-phenyl ) -2, 5, 6, 7-tetrahydro- pyrrolo [2, 1-c] [ 1 , 2 , 4 ] triazol-4-ylium perchlorate (also abbreviated as RMesC10₄) was obtained from BioBlocks Inc. (BioBlocks Catalogue Number: BC003-13) .

Flash column chromatography was performed on silica gel (Silicycle SiliaFlash F60, 230-400 mesh) . Thin layer chromatography was performed on aluminium backed plates pre-coated with silica gel (Merck, Silica Gel 60 F254) .

NMR spectra were recorded on Bruker Avance 400 MHz, and Varian Mercury 300 MHz spectrometers using deuturated chloroform as the solvent unless indicated otherwise. The residual signal of the undeuturated solvent was used as the internal standard. Infrared (IR) data was obtained on a JASCO FT-IR-4100 spectrometer with only major peaks being reported. Optical rotations were measured on a JASCO P-1010 operating at the sodium D line with a 100 mm path length cell.

Chiral HPLC (High-Performance Liquid Chromatography) and SFC (Supercritical Fluid Chromatography) was performed on Jasco liquid chromatography units. Daicel Chiralcel or Chiralpak columns (0.46 ^χ 25 cm) were used. Details of chromatographic conditions are indicated under each compound .

Melting points were measured on an Electrothermal Mel-Temp melting point apparatus and are uncorrected.

Example 1: Preparation of (4aR, 9aS) -4-Hydroxy-4 , 4a, 9 , 9a- tetrahydroindeno [2 , 1-Jb] [1,4] oxazin-3 (2H) -one

(4aR, 9aS) -4, 4a, 9, 9a-Tetrahydroindeno [ 2 , 1-b] [1, 4]oxazin- 3(2tf)-one (H.U. Vora, S.P. Lathrop, N.T. Reynolds, M.S. Kerr, J.R. de Alaniz, T. Rovis, Org. Synth. 2010, 87, 350) (1.89 g, 10.0 mmol) was dissolved in acetonitrile (15 ml) and N, O-bis (trimethylsilyl) acetamide (BSA, 2.69 ml, 11.0 mmol) was added dropwise. The reaction mixture was heated to 80 °C for one hour, cooled to room temperature and concentrated in vacuo under Schlenk-conditions . To this residue, oxodiperoxymolybdenum* (pyridine) · (hexamethyl- phosphoric triamide) (Mo0₅ · Py · HMPA = MoOPH, 5.28 g, 12.0 mmol) (E. Vedejs, S. Larsen, Sorg. Synth. 1985, 64, 127) in dichloromethane (20 ml) was added dropwise and the reaction mixture was stirred for 3 days at room temperature before Na₄EDTA (50 ml of a saturated solution in water) was added. HC1 (1 M solution in water) was added to adjust the pH to 7-8 and the aqueous phase was extracted with ethyl acetate (8 * 80 ml) . The combined organic layers were washed (brine), dried (sodium sulfate), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (silica gel, 100% ethyl acetate) to give the hydroxamic acid as a fine off-white solid (1.09 g, 53%) which was recrystallized from methanol to give colourless needles.

R_f = 0.2 (100% ethyl acetate) ;

[a]²³ _D (c = 0.5, ethyl acetate) = -33.9;

¹³C NMR (100 MHz, DMSO-d₆) : δ [ppm] = 162.6, 140.2, 140.1, 128.0, 126.8, 124.9, 124.8, 77.6, 66.5, 66.4, 36.9; ^XH NMR (400 MHz, DMSO-d₆) : δ [ppm] = 10.3 (s, 1 H) , 7.65- 7.60 (m, 1 H), 7.29-7.19 (m, 3 H) , 4.98 (d, J = 4.3 Hz, 1 H), 4.65 (apparent t, J = 4.3 Hz, 1 H) , 4.17 (d, J = 15.8 Hz, 1 H), 4.03 (d, J = 15.8 Hz, 1 H) , 3.18 (dd, J = 16.8, 4.3 Hz, 1 H), 2.89 (d, J = 16.8 Hz, 1 H) ; HRMS (ESI) : calculated for [CuHi₂N0₃] ⁺ : m/z = 206.0812, found: m/z = 206.0816;

MS (ESI) : 206.1 (100), 228.1 (54);

IR (v/cnf¹, neat) : 3073, 2909, 1655, 1603, 1332, 1118, 749, 736; mp : compound decomposes at T > 210 °C;

Elementary analysis: calculated for CiiHi₂N0₃: [C] 64.38%, [H] 5.40%, [N] 6.83%, [O] 23.39%; found: [C] 64.27%, [H] 5.35%, [N] 6.77%, [0] 23.45%.

Example 2: Preparation of (4aS, 9aR) -4-Hydroxy-4 , 4a , 9 , 9a- tetrahydroindeno [2 , 1-b] [1,4] oxazin-3 (2H) -one

The enantiomer of the hydroxamic acid from example 1 was prepared by substituting ( 4a.R, 9aS) -4 , 4a , 9 , 9a- tetrahydroindeno [ 2 , 1-b] [ 1 , 4 ] oxazin-3 ( 2H) -one with its enantiomer (4aS, 9aR) -4, 4a, 9, 9a-tetrahydroindeno [ 2 , 1-b]

[ 1 , 4 ] oxazin-3 ( 2H) -one under otherwise identical reaction conditions .

[a]²⁷ _D (c = 0.5, ethyl acetate) = +49.1.

Example 3: Preparation of (IE) -4-Hydroxy-l-mesityl-4- methylpent-1-en-3-one

Mesityl aldehyde (4.5 ml, 30.0 mmol), 3-hydroxy-3-methyl- 2-butanone (3.5 ml, 30.0 mmol) and LiOH^»H₂0 (0.84 g, 20.0 mmol) were dissolved in a mixture of methanol (60 ml) and water (20 ml) and the reaction mixture was heated to 80 °C for 18 hours. Methanol was removed under reduced pressure and the remaining aqueous phase was extracted with dichloromethane (3 * 50 ml) . The combined organic layers were dried (sodium sulfate), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) and finally recrystallized from hexane to give the ' -hydroxyenone (3.54 g, 51%) as a colourless solid.

R_f = 0.6 (30% ethyl acetate in hexane);

¹³C NMR (100 MHz, CDC1₃) : δ [ppm] = 202.4, 143.8, 138.9, 137.2, 130.9, 129.3, 123.7, 75.3, 26.3, 21.1;

^XH NMR (400 MHz, CDC1₃) : δ [ppm] = 8.02 (d, J = 16.0 Hz, 1 H), 6.91 (s, 2 H), 6.67 (d, J = 16.0 Hz, 1 H) , 4.07 (s, 1 H), 2.35 (s, 6 H), 2.29 (s, 3 H), 1.44 (s, 6 H) ;

HRMS (ESI): calculated for [Ci₅H₂₀O2+H⁺] : m/z = 233.1536, found: m/z = 233.1539;

IR (v/cnf¹, neat): 3489, 2971, 2945, 2370, 2350, 1673, 1600, 1464, 1441, 1154; mp : 75-77 °C (hexane);

Elementary analysis: calculated for Ci₅H₂o0₂ : [C] 77.55%, [H] 8.68%, [0] 13.77%; found: [C] 77.51%, [H] 8.65%, [O] 13.67%. Preparation of (4ai¾, 9aS) -4- [ (3-Mesitylpro panoyl) oxy] -4 , 4a, 9 , 9a-tetrahydroindeno [2 , l-i]

[1 ,4] oxazin-3 (2H) -one

RMesC10₄ (8.2 mg, 0.025 mmol), hydroxamic acid (51.3 mg, 0.250 mmol; from example 1) and a'-hydroxyenone (58.1 mg, 0.250 mmol; from example 3) were dissolved in CH₂CI2 (5 ml) and DBU (7.5 μΐ, 0.050 mmol) was added. After 8 hours at 23 °C, the reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography (silica gel, 30% ethyl acetate in hexane) to give the ester (84 mg, 88%) as a colourless oil.

R_f = 0.2 (30% ethyl acetate); [a]²⁶ _D (c = 1.8, CHCI₃) = -43.3; ¹³C NMR (75 MHz, CDC1₃) : δ [ppm] = 169.5, 162.5, 139.4, 138.2, 135.9, 132.9, 129.0, 128.8, 127.3, 125.2, 124.7, 78.4, 67.4, 37.3, 31.1, 24.6, 20.9, 19.8;

*H NMR (300 MHz, CDCI₃) : δ [ppm] = 7.48-7.43 (m, 1 H) , 7.36-7.23 (m, 3 H) , 6.85 (s, 2 H) , 5.00 (d, J = 4.4 Hz, 1 H), 4.79 (apparent td, J = 4.4, 1.6 Hz, 1 H) , 4.39 (d, J = 16.3 Hz, 1 H), 4.32 (d, J = 16.3 Hz, 1 H) , 3.28-3.06 (m, 4 H), 2.84-2.63 (m, 2 H), 2.35 (s, 6 H) , 2.23 (s, 3 H) ;

HRMS (ESI): calculated for [C^HzeNOd ⁺ : m/z = 380.1856, found: m/z = 380.1852. Example 5 : General Procedure for the Preparation of Racemic Amides

Imidazole (0.9 mg, 12.5 μπιοΐ, 0.1 equiv) , R esC10₄ (4.1 mg, 12.5 μπιοΐ, 0.1 equiv), " -hydroxyenone (29.0 mg, 125 μπιοΐ, 1.0 equiv) and amine (125 μιηοΐ, 1.0 equiv) were dissolved in CH₂C1₂ (1.25 ml, 0.1 M) . DBU (3.8 μΐ, 25.0 μmol, 0.2 equiv) was added and the reaction mixture was heated to 40 °C for 18 h before being placed directly on a silica gel column for purification.

Example 6 : General Procedure for the Preparation

Racemic Carbamates

The amine (0.2 mmol) and DIPEA (34.6 μΐ, 0.2 mmol) were dissolved in CH₂C1₂ (2 ml, 0.10 M) and benzyl chloroformate (28.4 μΐ, 0.2 mmol) was added at 23 °C. After 30 minutes, saturated aqueous NaHC0₃-solution (5 ml) was added and the aqueous phase was extracted with EtOAc (3 ^χ 10 ml) . The combined organic layers were washed with brine, dried (MgS0₄) , filtered, and concentrated in vacuo. The crude products were purified by column chromatography (silica gel) .

Example 7 : General Procedure for -the Kinetic Resolution of Secondary Amines

The Reaction

Hydroxamic acid co-catalyst (5.1 mg, 0.025 mmol, 0.10 equiv) , pre-catalyst RMesC10₄ (8.2 mg, 0.025 mmol, 0.10 equiv), a -hydroxyenone (40.7 mg, 0.175 mmol, 0.70 equiv) and the respective amine (0.250 mmol, 1.00 equiv) were dissolved in dichloromethane (2.5 ml, 0.10 M) . DBU (7.5 μΐ, 0.050 mmol, 0.20 equiv) was added and the reaction mixture was stirred for 18 hours at room temperature.

Workup Procedures

Workup A: DBU (37.4 μΐ, 0.250 mmol) and CbzCl (37.6 μΐ, 0.250 mmol) were added and the mixture was stirred for 2 hours at room temperature before saturated aqueous NaHC0₃- solution (10 ml) was added. The aqueous phase was extracted with CH₂C1₂ (3 * 10 ml) and the combined organic layers were dried (Na₂S0₄) and concentrated in vacuo. The crude product mixture was purified by column chromatography (silica gel) . Workup B: The reaction mixture was concentrated in vacuo and the crude product mixture was purified by column chromatography (silica gel) .

Workup C: CH₂C1₂ (2.5 ml) and 1 M HC1 (5 ml) were added and the aqueous solution was extracted with CH₂CI₂ (3 * 10 ml) . The combined organic layers were washed with 1 HC1 (5 ml) , dried (Na₂S0₄) , and concentrated in vacuo to give the crude amide product, which was purified by column chromatography . The combined acidic aqueous phases were basified with solid K₂CO₃, extracted with CH₂C1₂ (3 * 10 ml), dried (Na₂S0₄) , and concentrated in vacuo. The crude amine was purified by column chromatography (silica gel) .

Workup D: CH₂C1₂ (2.5 ml) and 1 M HC1 (5 ml) were added and the aqueous solution was extracted with CH₂C1₂ (3 ^χ 10 ml) . The combined organic layers were washed with 1 M HC1 (5 ml) dried (Na₂S0₄) , and concentrated in vacuo to give the crude amide product, which was purified by column chromatography . The combined acidic aqueous phases were basified with solid K₂C0₃, extracted with CH₂C12 (3 * 20 ml), dried (Na₂S0₄) , and concentrated in vacuo. The residue was redissolved in CH₂C1₂ (2.5 ml) and DBU (37.4 μΐ, 0.250 mmol) and CbzCl (37.6 μΐ, 0.250 mmol) were added. The mixture was stirred for 2 h at 23 °C before saturated aqueous NaHC0₃-solution (10 ml) was added. The aqueous phase was extracted with CH₂C1₂ (3 ^χ 10 ml) and the combined organic layers were dried (Na₂S0₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) . Selectivity

The s-factor (selectivity) was calculated using the following equations (1. H.B. Kagan, J.C. Fiaud, in Topics in Stereohemistry, Editors: E. Eliel, S.H. Wilen, Eds. Wiley, 1988, 18, 249-330; 2. J. M. Goodman, A.-K. Kohler, S.C.M. Alderton, Tetrahedron Lett. 1999, 40, 8715-8718; 3. http : //www . jmg . ch . cam. ac . uk/tools/magnus/KinRes . html ) : ln[(l-C)(l-eQ]

s =

\n[(\ - C)(\ + ee^SM)] where ee is the enantiomeric excess of the (acylated) recovered starting material amine or ln[l-C(l + ee PRODUCT

)]

s =^■

\n[(\ - C(\ - ee^PR0DUCT)] where _ee ^PR°DucT ^_{s the} enantiomeric excess of the amide product.

The conversion C was calculated using this equation: l 00 ee^SM

" ee^SM + _ee ^PRODUCT

The er values were determined by HPLC- or SCF-separations , which were performed on Jasco liquid chromatography units. Daicel Chiralcel /Chiralpak columns (0.46 * 25 cm) were used. Details of chromatographic conditions are indicated under each compound. Further Notes

The hydroxamic acid co-catalyst can be recovered. The absolute stereochemistry was assigned by comparison with compounds reported in the literature or by analogy as indicated under each compound.

All amides obtained revealed hindered rotation on the NMR timescale or were conformational isomers at room temperature .

Example 8: Kinetic Resolution of Racemic 2-Methyl piperidine

According to the General Procedure (Example 7, Workup A), 24.8 mg (0.25 mmol) of racemic 2-methyl piperidine were resolved .

Recovered (Cbz-protected) amine: 23 mg (39% yield, er = 94:6); acylated product: 38 mg (55%, er = 86:14).

Calculated conversion: 55%; s = 17.

Acylated Product: (S) -1- (3-Mesitylpropanoyl) -2-methyl piperidine

J?_f = 0.2 (30% ethyl acetate);

[a] D (c = 6.3, CHC1₃) : +18.6

¹³C NMR (100 MHz, CDC1₃) : δ [ppm] = 170.7, 136.1, 135.3, 135.0, 128.9, 48.1, 43.6, 40.5, 36.2, 32.8, 32.3, 30.5, 29.8, 26.2, 25.4, 25.1, 20.7, 19.7, 18.7, 16.5, 15.5;

¹H NMR (400 MHz, CDC1₃) : δ [ppm] = 6.84 (s, 2 H) , 4.96 (br s, 0.5 H), 4.55 (d, J = 12.4 Hz, 0.5 H) , 4.06 (br s, 0.5 H), 4.54 (d, J = 12.0 Hz, 0.5 H) , 3.05 (apparent t, J = 13.3 Hz, 0.5 H), 3.00 (m, 2 H) , 2.67 (apparent t, J = 13.1 Hz, 0.5 H), 2.55-2.35 (m, 2 H) , 2.30 (s, 6 H) , 2.25 (s, 3 H), 1.73-1.25 (m, 5 H) , 1.21-1.13 (m, 3 H) ;

HRMS (ESI) : calculated for [ Ci₈H₂₇NO+H⁺] : m/z = 274.2165, found: m/z = 274.2166; IR (v/cnf¹, neat) : 2936, 2862, 17256, 1638, 1424, 1270, 1180;

SFC: column: Daicel Chiralpak ASH (4.6 χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml /min; detection: 254 nm.

Recovered Amine : (R) -Benzyl 2-methylpiperidine-l - carboxylate

H N R (300 MHz, CDC1₃) : δ [ppm] = 7.42-7.26 (m, 5 H) , 5.15 (d, J = 12.9 Hz, 1 H), 5.10 (d, J = 12.9 Hz, 1 H) , 4.55- 4.40 (m, 1 H), 4.01 (dd, J = 13.3, 3.0 Hz, 1 H) , 2.89 (td, J - 13.3, 2.0 Hz, 1 H), 1.75-1.30 (m, 6 H) , 1.16 (d, J = 7.0 Hz, 3 H) ;

HPLC: column: Daicel Chiralcel ADH (4.6 * 250 mm); eluent: 1% iPrOH in hexane, flow: 1.0 ml/min; detection: 254 nm.

All data corresponded to that reported (F.E. Michael, B.M. Cochran, J. Am. Chem. Soc, 2006, 128, 4246-4247).

Assignment of the absolute stereochemistry:

In one · kinetic resolution, after the consumption of the hydroxyenone , benzoylchloride (29.0 μΐ, 0.25 mmol) was added to the recovered amine (instead of CbzCl) to get this known compound:

(2R) -1 -Benzoyl-2-methylpiperidine

¹³C NMR (100 MHz, CDC1₃) : δ [ppm] = 170.4, 137.0, 129.0, 128.3, 126.3, 30.2, 26.0, 18.8, 16.1; There is a very broad signal around 43 ppm corresponding to the missing two carbons. ^XH NMR (400 MHz , CDC1₃) : δ [ppm] = 7.38-7.30 (m, 5 H) , 3.10-2.80 (m, 1 H) , 5.50-3.20 (m, 2 H) , 3.15-2.80 (m, 1 H), 1.78-1.33 (m, 6 H) , 1.21 (d, J = 6.9 Hz, 3 H) ;

[a]²⁸ _D (c = 0.35, CHCI₃) = -22.4 ( er = 90:10);

Lit.: [a]_D (c = 0.8, CHC1₃) = -31.4 (95% ee) ; [a]_D (c =

0.7, CHCI₃) = -26.7 (81% ee) ; [a]²¹ _D (c = 1.95, CHC1₃) = -8.7 (26% ee) ;

SFC: column: Daicel Chiralpak ADH (4.6 ^χ 250 mm) gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min flow: 3.0 ml/min; detection: 254 nm.

Example 9: Kinetic Resolution of Racemic 2-Ethyl piperidine

According to the General Procedure (Example 7, Workup A), 28.3 mg (0.25 mmol) of racemic 2-ethyl piperidine were resolved .

Recovered (Cbz-protected) amine: 27 mg (44% yield, er = 88:12); acylated product: 38 mg (53%, er = 84:16). Calculated conversion: 53%; s = 12.

Acylated product: (S) -1- (3-Mesitylpropanoyl) -2-ethyl piperidine

R_f = 0.2 (30% ethyl acetate in hexane) ; [a]²⁸ _D (c = 1.5, CHC1₃) = +10.1;

¹³C NMR (100 MHz, CDCI₃) : δ [ppm] = 171.1, 171.0, 136.1, 135.0, 128.9, 54.2, 49.4, 40.9, 36.4, 32.8, 32.5, 28.6, 27.5, 26.2, 25.4, 25.2, 25.1, 22.9, 22.2, 20.7, 19.7, 19.0, 10.73, 10.71; H NMR (400 MHz, CDCI₃) : δ [ppm] = 6.82 (s, 2 H) , 4.78-4.69 (m, 0.5 H), 4.59 (dd, J = 13.6, 3.1 Hz, 0.5 H) , 3.74 (q, J = 6.7 Hz, 0.5 H) , 3.57 (dd, J = 13.3, 2.8 Hz, 0.5 H) , 3.06-2.89 (m, 2.5 H) , 2.58 (dt, J = 13.3, 2.1 Hz, 0.5 Hz), 2.52-2.35 (m, 2 H) , 2.30 (s, 6 H) , 2.24 (s, 3 H) , 1.79- 1.24 (m, 8 H), 0.86 (t, J = 7.5 Hz, 1.5 H) , 0.84 (t, J = 7.5 Hz, 1.5 H) ; HRMS (ESI): calculated for [Ci₉H₃₀NO] ⁺ : m/z = 288.2322, found: m/z = 288.2317;

IR (v/cnf¹, neat) : 2961, 2934, 2866, 1729, 1638, 1446, 1425, 1377, 1272, 1235, 1147, 1044;

SFC: column: Daicel Chiralpak ASH (4.6 * 250 mm) ; gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm.

Recovered Amine: (R) -Benzyl 2-ethylpiperidine-l- carboxyla te

[a] D (c = 0.9, chloroform) = -11.8;

^:H NMR (400 MHz, CDCl₃) : δ [ppm] = 7.38-7.26 (m, 5 H) , 5.14 (d, J = 12.5 Hz, 1 H), 5.10 (d, J = 12.5 Hz, 1 H) , 4.23- 4.15 (m, 1 H), 4.04 (dd, J = 12.9, 1 H) , 2.81 (td, J = 13.5, 2.6 Hz, 1 H), 1.76-1.33 (m, 8 H) , 0.84 (t, J = 7.4 Hz, 3 H) ;

HRMS (ESI) : calculated for [C15H22NO2] ⁺ : m/z = 248.1645, found: m/z = 248.1641; SFC: column: Daicel Chiralpak ADH (4.6 ^χ 250 mm) ; gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm.

All data corresponded to that reported (S.J. Aitken, G. Grogan, C.S.-Y. Chow, N.J. Turner, S.L. Flitsch, J. Chem. Soc, Perkin Trans. 1 1998, 3365-3370).

The absolute stereochemistry was assigned by analogy to 2- methyl piperidine. It is likely that the sense of stereoinduction for 2-ethyl piperidine and for 2-methyl piperidine is the same.

Example 10: Kinetic Resolution of Racemic l-Benzyl-3- methyl piperazine

According to the General Procedure (Example 7, Workup -B), 47.6 mg (0.25 mmol) of racemic l-benzyl-3-methyl piperazine were resolved. Recovered (Cbz-protected) amine: 37 mg (46% yield, er = 82:18); acylated product: 41 mg (45%, er = 89:11) .

Calculated conversion: 45%; s = 16.

Acylated Product: (S) -4-Benzyl-l- (3-mesitylpropanoyl) methyl piperazine

R_f = 0.2 (30% ethyl acetate in hexane) ;

¹³C NMR (100 MHz, CDC1₃) : δ [ppm] = 170.9, 170.7, 138.2, 136.1, 135.4, 134.8, 129.0, 128.7, 128.3, 127.1, 62.6, 57.4, 57.3, 53.2, 49.0, 44.8, 41.0, 36.9, 32.7, 32.1, 25.0, 20.8, 19.7, 16.9, 15.8;

^XH NMR (400 MHz, CDC1₃) : 7.35-7.22 (m, 5 H) , 6.83 (s, 2 H) , 4.77 (br s, 0.5 H) , 4.43 (d, J = 13.4 Hz, 0.5 H) , 3.86 (br s, 1 H), 3.60-3.25 (m, 3 H) , 3.05-2.88 (m, 2 H) , 2.84 (d, J = 10.5 Hz, 0.5 H) , 2.72 (d, J = 9.9 Hz, 0.5 H) , 2.65 (d, J = 11.1 Hz, 0.5 H), 2.57 (d, J = 10.8 Hz, 0.5 H) , 2.53- 2.30 (m, 2 H) , 2.28 (s, 6 H) , 2.24 (s, 3 H) , 2.15-1.83 (m, 2 H) , 1.32-1.24 (m, 3 H) ; HR S (ESI): calculated for [C₂₄H3₃N₂0] ⁺ : m/z = 356.2587, found: m/z = 356.2583;

SFC: column: Daicel Chiralpak ASH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm.

Recovered amine: (R) -Benzyl 4-benzyl-2-methyl piperazine- 1-carboxylate

R_f = 0.6 (30% ethyl acetate in hexane) ;

¹³C NMR (100 MHz, CDC1₃) : δ [ppm] = 155.0, 138.2, 136.8, 128.6, 128.3, 128.1, 127.8, 127.6, 126.9, 66.9, 62.8, 57.4, 53.2, 47.4, 39.5, 16.2;

¹ NMR (400 MHz, CDC1₃) : δ [ppm] = 7.38-7.21 (m, 10 H) , 5.16 (d, J = 12.6 Hz, 1 H) , 5.11 (d, J = 12.5 Hz, 1 H) , 4.34-4.22 (m, 1 H) , 3.90 (d, J = 13.1 Hz, 1 H) , 3.53 (d, J = 13.3 Hz, 1 H), 3.40 (d, J = 13.3 Hz, 1 H) , 3.20 (apparent td, J = 12.6, 3.4 Hz, 1 H) , 2.77 (d, J = 11.2 Hz, 1 H), 2.61 (apparent dt, J = 11.2, 1.7 Hz, 1 H) , 2.15 (dd, J = 11.2, 3.9 Hz, 1 H) , 2.03 (ddd, J = 12.1, 11.3, 3.5 Hz, 1 H), 1.28 (d, J = 6.6 Hz, 3 H) ;

HRMS (ESI): calculated for [C₂oH24 ₂0₂+Na⁺] : m/z = 347.1730, found: m/z = 347.1728; SFC: column: Daicel Chiralpak OJH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm.

Assignment of the absolute stereochemistry:

In one kinetic resolution, after the consumption of the hydroxyenone, the reaction mixture was concentrated in vacuo and the unreacted amine was isolated by column chromatography . [a]²⁶ _D (c = 1.1, CHC1₃) = +4.3;

Lit.: [a]²⁰ _D (c = 0.68, CHC1₃) = +7; [a]²⁰ _D (c = 0.68, CHC1₃) = +7.38;

This indicates that the amine and the Cbz-protected recovered amine, respectively, have the (R) -configuration, while the configuration of the amide product is (S) . The analytical data of the amine was consistent with that reported .

Example 11: Kinetic Resolution of Racemic 3-Methyl morpholine

According to the General Procedure (Example 7, Workup A), 25.3 mg (0.25 mmol) of racemic 3-methyl morpholine were resolved . Recovered (Cbz-protected) amine: 13 mg (22% yield, er = 90:10); acylated product: 15 mg (22%, er = 79:21).

Calculated conversion: 58%; s = 9.

Acylated Product: (3S) -4- (3-Mesitylpropanoyl) -3-methyl morpholine

R_f = 0.1 (40% ethyl acetate in hexane) ;

¹³C NMR (100 MHz, CDC1₃) : δ [ppm] = 171.1, 136.1, 135.5, 134.6, 129.0, 71.1, 70.5, 67.1, 66.6, 49.0, 44.6, 41.0, 36.7, 32.4, 31.8, 24.9, 20.8, 19.7, 15.8, 14.6;

*H NMR (400 MHz, CDC1₃) : δ [ppm] = 6.84 (s, 2 H) , 4.61 (br s, 0.5 H), 4.30 (d, J = 13.2, Hz, 0.5 H) , 3.91 (d, J = 9.3 Hz, 0.5 H) , 3.77 (dd, J = 9.7 Hz, 0.5 H) , 3.74-3.48 (m, 2 H), 3.47-3.20 (m, 2.5 H) , 3.07-2.88 (m, 2.5 H) , 2.58-2.33 (m, 2 H) , 2.29 (s, 6 H) , 2.24 (s, 3 H) , 1.32- 1.22 (m, 3 H) ;

HRMS (ESI): calculated for [C17H26NO2] ⁺ : m/z = 276.1958, found: m/z = 276.1962; IR

neat) : 2968, 2917, 2857, 1644, 1421, 1303, 1138, 854;

SFC: column: Daicel Chiralpak ODH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Recovered Amine: Benzyl (3R) -3-methyl morpholine-4- carboxylate

R_f = 0.5 (40% ethyl acetate in hexane) ;

¹³C N R (100 MHz, CDCl₃) : δ [ppm] = 155.1, 136.6, 128.5, 128.0, 127.9, 70.8, 67.1, 66.8, 47.1, 39.2, 14.9;

^XH NMR (400 MHz, CDC1₃) : δ [ppm] = 7.39-7.27 (m, 5 H) , 5.16 (d, J = 12.4 Hz, 1 H), 5.12 (d, J = 12.4 Hz, 1 H) , 4.18- 4.09 (m, 1 H), 3.84 (dd, J = 11.4, 3.5 Hz, 1 H) , 3.77 (dd, J = 12.9, 2.4 Hz, 1 H), 3.64 (d, J = 11.4 Hz, 1 H) , 3.58 (dd, J = 11.4, 3.1 Hz, 1 H) , 3.44 (td, J = 11.9, 3.0 Hz, 1 H), 3.23 (td, J = 12.9, 3.7 Hz, 1 H) , 1.27 (t, J = 6.9 Hz, 3 H) ; SFC: column: Daicel Chiralpak ODH (4.6 250 ram); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm.

The absolute stereochemistry was assigned by analogy to 2- methyl piperidine. It is likely that the sense of stereoinduction for 3-methyl morpholine and for 2-methyl piperidine is the same.

Example 12 : Kinetic Resolution of Racemic 1-Methyl- 1,2,3, 4-tetrahydroisoquinoline

According to the General Procedure (Example 7, Workup B) , 36.8 mg (0.25 mmol) of racemic 1-methyl-l , 2 , 3 , 4 - tetrahydroiso-quinoline were resolved.

Recovered amine: 20 mg (28% yield, er = 93:7); acylated product: 38 mg (47%, er = 83:17).

Calculated conversion: 56%; s = 13.

Acylated Product: (IS) -2- (3-Mesitylpropanoyl) -1-methyl- 1,2,3, 4-tetrahydroisoquinoline

R_£ = 0.2 (20% ethyl acetate in hexane) ;

At room temperature, the ratio of rotamers is 56:44, as determined by NMR . This makes the interpretation and the integration rather challenging.

¹³C NMR (100 MHz, CDC1₃) : δ [ppm] = 170.6, 138.8, 137.5, 136.1, 136.0, 135.5, 135.4, 134.9, 134.8, 134.2, 133.2,

129.1, 129.0, 128.5, 127.1, 126.7, 126.6, 126.5, 126.3,

126.2, 51.6, 48.6, 39.5, 34.9, 32.9, 32.6, 29.3, 28.5, 24.9, 24.8, 22.7, 21.7, 20.8, 19.73, 19.70;

^XH NMR (400 MHz, CDC1₃) : δ [ppm] = 7.24-7.07 (m, 4.6 H) , 7.02-6.96 (m, 0.4 H) , 6.86 (s, 1.1 H) , 6.84 (s, 0.9 H) , 5.70 (q, J = 6.8 Hz, 0.6 H) , 5.90 (q, J = 6.8 Hz, 0.4 H) , 4.74 (dddd, J = 13.0, 5.7, 2.9, 0.6 Hz, 0.4 H) , 3.76 (apparent td, J = 8.9, 4.5 Hz, 0.6 H) , 3.46 (ddd, J = 13.4, 10.2, 4.7 Hz, 0.6 H) , 3.11-2.73 (m, 3 H) , 2.65-2.40 (m, 2 H), 2.32 (s, 3.4 H) , 2.31 (s, 2.6 H) , 2.27 (s, 1.7 H), 2.24 (s, 1.3 H) , 1.49 (d, J = 6.8 Hz, 1.3 H) , 1.48 (d, J = 6.8 Hz, 1.7 H) ;

HRMS (ESI) : calculated for [C₂₂H₂₈NO] ⁺ : m/z = 322.2165, found: m/z = 322.2161; SFC: column: Daicel Chiralpak ASH (4.6 * 250 ram) ; gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm.

Recovered amine: Benzyl (1R) -l-methyl-3, 4- dihydroisoquinol ine-2 (IE) -carboxylate

R_f = 0.6 (20% ethyl acetate in hexane);

¹³C N R (100 MHz, CDC1₃) : δ [ppm] = 155.2, 155.0, 138.6, 138.1, 136.9, 134.0, 133.7, 128.9, 128.7, 128.5, 127.94, 127.87, 126.9, 126.8, 126.4, 126.2, 67.1, 67.0, 50.53, 50.50, 38.0, 37.5, 29.0, 28.8, 22.4, 21.9;

^XH NMR (400 MHz, CDC1₃) : δ [ppm] = 7.42-7.29 (m, 5 H) , 7.22-7.06 (m, 4 H) , 5.35-5.12 (m, 3 H) , 4.32-4.18 (m, 0.5 H), 4.16-4.04 (m, 0.5 H) , 3.43-3.20 (m, 1 H) , 3.02- 2.85 (m, 1 H), 2.80-2.70 (m, 1 H) , 1.52-1.43 (m, 3 H) ; HRMS (ESI): calculated for [Ci₈H₂oN0₂] ⁺ : m/z = 282.1489, found: m/z = 282.1484;

SFC: column: Daicel Chiralpak ASH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml /min; detection: 254 nm.

Example 13: Kinetic Resolution of Racemic 1-Phenyl-

1,2,3, 4-tetrahydroisoquinoline

According to the General Procedure (Example 7, Workup B) , 52.3 mg (0.25 mmol) of racemic 1-phenyl-l, 2, 3, 4- tetrahydroisoquinoline were resolved.

Recovered amine: 25 mg (48% yield, er = 93:7); acylated product: 45 mg (49%, er = 95:5) . Calculated conversion: 49%; s = 53.

Acylated product: (IS) -2- (3-Mesitylpropanoyl) -1 -phenyl - 1,2,3, 4-tetrahydroisoquinoline

R_f = 0.4 (30% ethyl acetate in hexane) ;

At room temperature, the ratio of rotamers is 76:24, as determined by NMR. This makes the interpretation and the integration rather challenging. ¹³C NMR (100 MHz, CDC1₃) : δ [ppm] = 171.8 (minor), 170.9, 142.4, 141.1 (minor), 136.1, 135.44, 135.43, 134.8, 134.6 (minor), 134.3, 129.0, 128.9, 128.7, 128.6, 128.5, 128.2, 127.8, 127.6, 127.4, 127.3, 127.0, 126.9, 126.3, 126.1, 59.7 (minor), 55.2, 39.6, 38.4 (minor), 32.9 (minor), 32.7, 28.9, 27.6 (minor), 25.0 (minor), 24.8, 20.7, 19.7, 19.6 (minor) ;

^XH NMR (400 MHz, CDC1₃) : δ [ppm] = 7.58-7.32 (m, 9 H) , 7.10 (s, 1.5 H, major), 7.07 (s, 0.5 H, minor), 4.52-4.42 (m, 0.25 H, minor), 3.95 (ddd, J = 13.4, 4.6, 3.9, 0.75 H, major), 3.78-3.64 (m, 1 H) , 3.38-2.65 (m, 6 H) , 2.58-2.46 (m, 9 H) ;

HRMS (ESI): calculated for [C₂7H₃₀NO] ⁺ : m/z = 384.2322, found: m/z = 384.2317;

Recovered Amine: (R) -1 -Phenyl-1 ,2,3, 4-tetrahydroiso- quinoline

¹H NMR (400 MHz , DMSO-d₆) : δ [ ppm] = 7.32-7.21 (m, 5 H) , 7.13-7.05 (m, 2 H) , 7.01-6.95 (m, 1 H) , 6.61 (d, J = 7.5 Hz, 1 H), 4.96 (s, 1 H) , 3.13-3.02 (m, 1 H) , 2.96-2.84 (m, 1 H) , 2.75-2.65 (m, 1H) ;

[a]²⁵ _D (c = 0.7, CHC1₃) = -16.7;

lit.: [a]²⁵ _D (c = 1.1, CHC1₃) = -10.9; [a]²⁵ _D (c = 1.55, CHCI₃) = -12.3; [a]²⁵ _D (c = 0.6, CHC1₃) = -10.12;

Chiral HPLC: column: Daicel Chiralcel ODH (4.6 ^χ 250 mm); eluent : 10% iPrOH in hexane, flow: 1.0 ml/min; detection: 254 nm.

Example 14: Kinetic Resolution of Racemic 6 , 7-Dimethoxy- 1-phenyl-l ,2,3, 4-tetrahydroisoquinoline

According to the General Procedure (Example 7, Workup B) , 67.3 mg (0.25 mmol) of racemic 6, 7-dimethoxy-l-phenyl- 1, 2, 3, 4-tetrahydroisoquinoline were resolved. 5 ml of CH₂C1₂ was used in order to dissolve the amine starting material . Recovered amine: 39 mg (49% yield, er = 95:5); acylated product: 52 mg (50%, er = 96:4) .

Calculated conversion: 50%; s = Acylated Product: 2- (3-Mesitylpropanoyl) -6, 7-dimethoxy-l- phenyl-1 ,2,3, 4-tetrahydro-isoquinoline

Rf = 0.6 (50% ethyl acetate in hexane) ; At room temperature, the ratio of rotamers is 77:23, as determined by NMR. This makes the interpretation and the integration rather challenging.

¹³C NMR (100 MHz, CDC1₃) : δ [ppm] = 171.3 (minor), 170.7, 148.4 (minor), 148.0, 147.6, 147.2, 142.5, 141.4 (minor), 136.1, 135.4, 134.8, 134.7 (minor), 129.0, 128.8, 128.5,

128.2, 127.6, 127.3, 127.2, 127.0, 126.3, 111.4 (minor),

111.3, 111.0, 110.8 (minor), 59.1 (minor), 55.9, 55.8, 54.7, 39.2, 37.2 (minor), 32.9 (minor), 32.6, 28.5, 27.3 (minor), 25.0 (minor), 24.8, 20.7, 19.7; ^XH NMR (400 MHz, CDC1₃) : δ [ppm] = 7.33-7.23 (m, 4 H) , 7.15-7.10 (m, 0.2 H) , 6.93 (s, 0.8 H) , 6.84 (s, 1.6 H) , 6.81 (s, 0.4 H) , 6.68 (s, 0.2 H) , 6.65 (s, 0.8 H) , 6.55 (s, 0.8 H), 6.50 (0.2 H) , 5.85 (s, 0.2 H) , 4.41-4.32 (m, 0.2 H), 3.88 (s, 3 H) , 3.79 (s, 2.4 H) , 3.76 (s, 0.6 H) , 3.72-3.62 (m, 0.8 H) , 3.34 (ddd, J = 13.7, 11.6, 4.4 Hz, 0.8 H), 3.25-3.15 (m, 0.2 H) , 3.11-2.77 (m, 3 H) , 2.75- 2.40 (m, 3 H), 2.29 (s, 4.8 H) , 2.27 (s, 1.2 H) , 2.25 (2.4 H) , 2.22 (s, 0.6 H) ;

HRMS (ESI) : calculated for [C₂₉H₃₄NO₃] ⁺ : m/z = 444.2533, found: m/z = 444.2543; SFC: column: Daicel Chiralpak ASH (4.6 ^χ 250 mm) gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min flow: 3.0 ml/min; detection: 254 nm.

Recovered Amine: (1R) -6,7-Dimethoxy-l-phenyl-1 , 2, 3, 4 tetrahydroisoquinoline

^XH NMR (400 MHz , CDC1₃) : δ [ppm] = 7.45-7.33 (m, 5 H) , 6.62 (s, 1 H), 6.18 (s, 1 H), 5.39 (s, 1 H) , 3.86 (s, 3H) , 3.62 (s, 3H), 3.26-3.11 (m, 2 H) , 3.08-2.88 (m, 2 H) ;

[ a] ²² _D (c = 1.0, CHC1₃) = +20.4

lit.: [ a] ²³ _D (c = 0.5, CHC1₃) = +23.8; [ a] ²² _D (c = 1.0,

Chiral HPLC: column: Daicel Chiralpak OJH (4.6 * 250 mm); eluent: 60% iPrOH in hexane + 0.1% Et₃N, flow: 0.5 ml/min; detection: 254 nm.

Further Examples for the Kinetic Resolution of Cyclic Secondary Amines

Further examples for the kinetic resolution of cyclic secondary amines using the general reaction procedure of Example 7 can be found in: M. Binanzer, S . -Y . Hsieh, J. W. Bode, J. Am. Chem. Soc . 2011, 133, pages 19698-19701.

The contents of this publication are herewith incorporated by reference.

Example 15: Kinetic Resolution of Racemic 2-Methyl

Piperidine Using the Pre-Formed Reagent of Example 4

(4a£, 9aS) -4- [ (3-Mesitylpropanoyl) oxy] -4, 4a, 9, 9a-tetrahy- droindeno [ 2 , 1-b] [ 1 , 4 ] oxazin-3 ( 2H ) -one (example 4; 47.4 mg, 125 μπιοΐ) and 2-methylpiperidine (29.5 μΐ, 250 pmol) were dissolved in CH₂CI₂ (2.5 ml) and the reaction mixture was stirred for 18 h at 23 °C. DBU (37.4 μΐ, 0.250 mmol) and CbzCl (37.6 μΐ, 0.250 mmol) were added and the mixture was stirred for 2 hours at room temperature before saturated aqueous NaHC0₃-solution (10 ml) was added. The aqueous phase was extracted with CH₂C1₂ (3 ^χ 10 ml) and the combined organic layers were dried (Na₂S0₄) and concentrated in vacuo. The crude product mixture was purified by column chromatography (silica gel).

Recovered (Cbz-protected) amine: er = 75:25; acylated product: er = 91.5:8.5.

Calculated conversion: 38%; s = 18. Example 16: NMR Investigation of the Kinetic Resolution of Racemic 2-Ethyl Piperidine

The kinetic resolution of racemic 2-ethyl piperidine, as described in example 9 (see above), was monitored by in situ ^XH and ¹³C NMR. The respective spectra are shown in figures 1 (^XH) and 2 (¹³C) . The reaction was carried out according to the procedure of example 9 with the exception of the solvent, which was CDC1₃ instead of CH₂C1₂ to allow for the NMR monitoring. As can be clearly seen from these NMR spectra, (4aR,9aS)- 4- [ ( 3-Mesitylpropanoyl ) oxyl ] -4 , 4a , 9 , 9a-tetrahydroindeno

[ 2 , 1-b] [ 1 , 4 ] oxazin-3 ( 2H) -one is indeed formed in situ during this reaction.

Example 17: Preparation of (4ai , 9aS) -6-Bromo-4 , 4a , 9 , 9a- tetrahydroindeno [2 , 1-b] [1 , 4] oxazin-3 (2H) - one

A mixture of CF₃COOH (15 ml) and concentrated H₂S0₄ (4.5 ml) was cooled to 0 °C and ( AaR, 9aS) -4 , 4a , 9 , 9a- tetrahydroindeno [2, 1-b] [1, 4] oxazin-3 (2H) -one (see: H. U. Vora, S. P. Lathrop, N. T. Reynolds, M. S. Kerr, J. Read de Alaniz and T. Rovis, Org. Synth., 2010, 87, 350-361; 3.00 g, 1.60 mmol) was added in one portion. N- Bromosuccinimide (2.90 g, 1.62 mmol) was added portion- wise via powder funnel, while keeping the temperature below 5 °C. After 1.5 h, the yellow reaction mixture was slowly poured into ice-cold water (50 ml) . CH₂C1₂ (30 ml) was added and the phases were separated. The aqueous phase was extracted with CH₂C1₂ (2 * 30 ml) and combined organic layers were washed with saturated aqueous sodium bicarbonate (20 ml), dried (Na₂S0₄) , filtered and concentrated under reduced pressure to give the bromolactam as a yellow solid (3.30 g, 80%) .

[a]²⁷ _D (c = 1.4, CHC1₃) : +21.3; ¹³C NMR (100 MHz, CDCI₃) : δ [ppm] = 169.4, 143.0, 138.2, 131.4, 127.3, 126.7, 121.0, 76.2, 66.4, 58.4, 37.2;

^XH NMR (400 MHz, CDC1₃): δ [ppm] = 8.30 (broad s, 1H) , 7.48 (apparent s, 1 H) , 7.45 (dd, J = 8.0, 1.2 Hz, 1 H) , 7.15 (d, J = 8.0 Hz, 1 H) , 4.75 (apparent t , J = 4.0 Hz, 1 H) , 4.55 (apparent t, J = 4.0 Hz, 1 H) , 4.15 (2d, J = 16.7 Hz,

2 H), 3.15 (dd, J = 16.8, 5.0 Hz, 1 H) , 3.04 (d, J = 16.8

Hz, 1 H) ;

HRMS (ESI) : calculated for [CiiH_xlBrN0₂] ⁺: m/z = 267.9968, found: m/z = 267.9971; IR /cm^"1, neat) : 3217, 1742, 1686, 1479, 1552, 1405, 1068, 769; mp: decomposes at 165 °C.

Example 18: Preparation of (4aJ¾, 9aS) -6-Bromo-4-hydroxy- 4 , 4a, 9 , 9a-tetrahydroindeno [2 , 1-b] [1,4] oxazin-3 (2H) -one

The bromolactam of example 17 (2.70 g, 10.00 mmol) was dissolved in CH₃CN and bis (trimethylsilyl) acetamide (2.25 g, 11.00 mmol) was added dropwise. The resulting solution was heated at 80 °C for 1 h, followed by cooling to 23 °C and removal of the solvent in vacuo under Schlenk conditions. The resulting colorless oil was re-dissolved in CH₂C1₂ (10 ml) and a solution of MoOPH (see: E. Vedejs and S. Larsen, Org. Synth., 1986, 64, 127-132; 4.86 g, 12.0 mmol) in CH₂C1₂ (10 ml) was added dropwise over 5 min . The reaction was protected from light and left stirring for 3 days at 23 °C. The solvent was removed under reduced pressure and the resulting yellow solid was suspended in saturated aqueous tetrasodium ethylenediaminetetraacetate (Na₄EDTA) solution (200 ml) and stirred for 1 h after which pH of the solution was adjusted to 4-5 with 1 M HCl . The aqueous phase was extracted with EtOAc (6 ^χ 70 ml) and the combined organic layers were washed with brine (50 ml), dried (Na2S0₄) , filtered and concentrated under reduced pressure. Purification by flash chromatography (100% EtOAc) afforded the desired hydroxamic acid (2.10 g, 73%) as colorless solid.

[a] D (c = 1.3, DMF) : -5.8;

¹³C NMR (100 MHz, CDCI₃) : δ [ppm] = 162.5, 140.8, 138.4, 131.9, 128.9, 126.5, 121.1, 78.1, 66.3, 65.5, 37.2;

^XE NMR (400 MHz, CDCI₃) : δ [ppm] = 7.98 (s, 1 H) , 7.45 (dd, J = 8.0, 1.5 Hz, 1 H), 7.15 (d, J = 8.0, 1 H) , 5.10 (d, J = 4.3 Hz, 1 H) , 4.70 (t, J = 4.3 Hz, 1 H) , 4.95 (m, 2 H) , 3.19 (dd, J = 16.8, 4.7 Hz, 1 H) , 3.07 (d, _L

H) ;

HRMS (ESI) : calculated for [CuHuBrN0₃] ⁺ : m/

found m/z = 283.9912;

IR (v /cm^"1, neat): 2749, 1742, 1650, 1478,

1123, 1048, 948; decomposes at 175

Example 19: Improved General Procedure for the Kinetic

Resolution of Secondary Amines

The hydroxamic acid co-catalyst of example 18 (7.1 mg, 25 pmol, 0.05 equiv) , triazolium salt (16.4 mg, 50 μιηοΐ, 0.10 equiv), ^' -hydroxyenone (81.4 mg, 0.35 mmol, 0.70 equiv), K₂C0₃ (13.8 mg, 0.1 mmol, 0.20 equiv) and the respective amine (0.50 mmol, 1.00 equiv) were dissolved in iPrOAc (2.5 ml, 0.20 M) and the reaction mixture was stirred at 23 °C for 24 hours.

EtOAc (25 ml) was added, the mixture was filtered through Celite and concentrated in vacuo. The crude products were purified by column chromatography. Example 20: Kinetic Resolution of Racemic 3-Methylpip zin-2-one

Racemic 3-methylpiperazin-2-one (57.1 mg, 0.50 mmol) was resolved according to the improved general procedure (Example 19) .

Recovered amine: 24 mg (42%, er = 90:10); acylated product: 80 mg (56%, er = 79:21).

Calculated conversion: 58%; s = 9.

Recovered amine: (3R) -3-methylpiperazin-2-one

The amine was protected with benzyl chloroformate to determine the er:

[a] ²⁸ _D (c = 0.2, CHC1₃) : +/- 0.0;

SFC : column: Daicel Chiralpak ASH (4.6 ^χ 250 mm) ; gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 6.8 min (major) and 7.3 min (minor) .

Amide product: (3S) -4- (3-Mesitylpropanoyl) -3-methylpipera- zin-2-one Me O Me [a] D (c = 4.0, CHC1₃) : +59.6; at room temperature the ratio of rotamers was 50:50 as determined by ^XH NMR;

¹³C NMR (100 MHz, CDC1₃) : δ [ppm] = 171.9, 170.8, 170.5, 170.3, 136.0, 135.9, 135.7, 134.2, 134.1, 129.0, 53.9, 51.2, 41.3, 41.2, 38.9, 34.4, 32.4, 31.8, 24.7, 24.6, 20.7, 19.7, 17.8, 16.4;

^XH NMR (400 MHz, CDCI₃) : δ [ppm] = 6.83 (s, 2 H) , 5.05 (q, J = 7.1 Hz, 0.5 H), 4.70 (dd, J = 13.6, 2.4 Hz, 0.5 H) , 4.28 (q, J = 7.1 Hz, 0.5 H), 3.69 (br d, J = 12.6 Hz, 0.5 H) , 3.46-3.21 (m, 2.5 H) , 3.05-2.90 (m, 2.5 H) , 2.58-2.32 (m, 2 H), 2.28 (s, 6 H) , 2.23 (s, 3 H) ; 1.44 (t, J = 6.5 Hz, 3 H) ;

HRMS (ESI): calculated for [C17H25N2O2] ⁺ : m/z = 289.1911, found: m/z = 289.1914;

IR (v /cm^-1, neat) : 3244, 2998, 2944, 2921, 1668, 1648, 1457, 1427, 1332, 1208, 1091, 1062;

SFC: column: Daicel Chiralpak ODH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 7.8 min (minor) and 9.4 min (major).

Example 21: Kinetic Resolution of Racemic 7-Methyl-l , 4- diazepan-5-one

Racemic (64.1

mg, 0.50 mmol) was resolved according to the improved general procedure (Example 19) .

Recovered amine: 27 mg (43%, er = 95:5); acylated product: 81 mg (54%, er = 88:12). Calculated conversion: 54%; s = 22.

Recovered amine: (7R) -7-methyl-l , 4-diazepan-5-one

XH NMR (400 MHz, CDC1₃) : δ [ppm] = 7.25 (br, 1H) , 3.28 (ddd, J = 14.1, 9.8, 4.1 Hz, 1 H) , 3.15-2.98 (m, 2 H) , 2.94 (dq, J = 13.1, 6.4 Hz, 1 H) , 2.77 (dd, J = 13.1, 9.7 Hz, 1 H), 2.50 (dd, J = 14.2, 9.7 Hz, 1H) , 2.35 (apparent d, J = 14.2 Hz, 1 H), 2.07 (br, 1 H) , 1.09 (d, J = 6.4 Hz, 3H) . The amine was protected with benzyl chloroformate to determine the er:

[ ot] ²⁶ _D (c = 1.0, CHCI₃) : -20.8;

SFC : column: Daicel Chiralpak ADH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 6.9 min (minor) and 7.4 min (major) .

Amide product: (7S) -1- (3-Mesitylpropanoyl) -7-methyl-l , 4- diazepan-5-one

[ a] ²⁶ _D (c = 1.0, CHC1₃) : +20.1; at room temperature the ratio of rotamers was 55:45 as determined by ¹H NMR; ¹³C NMR (100 MHz, CDCI₃) : δ [ppm] = 175.9, 174.7, 171.4, 171.2, 136.1, 136.0, 135.7, 134.5, 134.4, 129.1, 47.0, 43.8, 43.5, 42.8, 41.9, 39.1, 33.2, 32.6, 25.0, 25.0, 21.1, 20.8, 19.8, 16.6, 15.5;

^XH NMR (400 MHz, CDC1₃) : δ [ppm] = 7.42 (br, 0.45 H) , 7.16 (br, 0.55 H) , 6.84 (s, 2 H) , 5.26 (apparent dd, J = 6.0

Hz, 4.5 Hz, 0.45 H) , 4.77 (apparent d, <J = 15.3 Hz, 0.55

H), 4.18 (apparent dd, J = 6.3 Hz, 4.1 Hz, 0.55 H) , 3.69 (apparent d, J = 15.4 Hz, 0.45 H) , 3.36-3.30 (m, 0.55 H) ,

3.30-3.21 (m, 1 H) , 3.18-3.08 (m, 1 H) , 3.04-2.87 (m, 2.55 H), 2.75 (apparent dd, J = 14.7 Hz, 2.2 Hz, 0.45 H) , 2.64 (apparent dd, J = 14.3 Hz, 2.2 Hz, 0.45 H) , 2.58-2.37 (m,

3 H), 2.29 (s, 6 H), 2.24 (s, 3 H) , 1.23 (overlapping d, J

= 7.0 Hz, 3 H) ;

HRMS (ESI): calculated for [Ci₈H₂ N₂0₂] ⁺ : m/z = 303.2067, found: m/z = 303.2070;

IR (v/cnf¹, neat): 3272, 2970, 2919, 1670, 1638, 1427, 1212, 1126, 754;

SFC : column: Daicel Chiralpak ADH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml /min; detection: 254 nm. Retention time: t_R = 6.7 min (major) and 7.1 min (minor) . Example 22: Kinetic Resolution of Racemic 7-Ethyl-l, 4- diazepan-5-one

Racemic 7-ethyl-l, 4 -diazepan-5-one (71.1 mg, 0.50 mmol) was resolved according to the improved general procedure (Example 19) .

Recovered amine: 25 mg (34%, er > 99:1); acylated product: 76 mg (48%, er = 78:22) . Calculated conversion: 64%; s > 20.

.Recovered amine: (7R) - 7-Ethyl-l , 4-diazepan-5- one

Me

[a] D (c = 1.0, CHC1₃) : +1.11;

¹H NMR (400 MHz, CDCI₃) : δ [ppm] = δ 7.25 (br, 1 H) , 3.34-

3.22 (m, 1 H) , 3.09 (ddd, J = 20.3, 13.0, 5.5 Hz, 2 H) ,

2.76 (t, J = 11.4 Hz, 1 H) , 2.66 (dd, J = 13.9, 7.2 Hz, 1 H), 2.55-2.35 (m, 2 H) , 2.05 (br, 1 H) , 1.49-1.34 (m, 2 H) , 0.88 (t, J = 7.4 Hz, 3 H) .

The amine was protected with benzyl chloroformate to determine the er: SFC: column: Daicel Chiralpak OJH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 5.3 min (minor) and 5.8 min (major).

product: (7S) -7-Ethyl-l- (3-mesitylpropanoyl) diazepan-5-one

[a] D (c = 1.0, CHC1₃) : +7.9; at room temperature the ratio of rotamers was 60:40 as determined by ¹H NMR;

¹³C NMR (100 MHz , CDC1₃) : δ [ppm] = 176.1, 174.9, 172.0, 171.7, 136.1, 136.1, 135.7, 134.5, 134.5, 129.2, 129.1, 52.8, 47.6, 43.7, 43.5, 43.0, 42.6, 42.1, 39.2, 33.2, 32.8, 25.1, 25.0, 23.3, 22.5, 20.8, 19.8, 19.8, 10.5;

^XH NMR (400 MHz, CDC1₃) : δ [ppm] = 7.40 (br, 0.4 H) , 7.14 (br, 0.6 H), 6.85 (s, 2 H) , 5.09-4.92 (m, 0.4 H) , 4.81 (dd, J = 13.3 Hz, 1.7 Hz, 0.6 H) , 4.00-3.81 (m, 0.6 H) , 3.72 (apparent d, J = 15.0 Hz, 0.4 H) , 3.39-3.18 (m, 1.6 H) , 3.18-3.08 (m, 0.8 H) , 3.08-2.87 (m, 2H) , 2.80 (dd, J = 13.2 Hz, 10.5 Hz, 0.6 H) , 2.73 (dd, J = 14.8 Hz, 2.7 Hz, 0.4 H), 2.65-2.55 (m, 1H) , 2.55-2.35 (m, 2.6 H) , 2.29 (s,. 6H), 2.24 (s, 3H), 1.86-1.45 (m, 2H) , 1.04-0.73 (m, 3H) ;

HRMS (ESI) : calculated for [C₁₉H₂₉N2O2] ⁺ : m/z = 317.2224, found: m/z = 317.2217; IR (v/cnf¹, neat): 3272, 2965, 2921, 1671, 1640, 1429, 1211, 1127, 961, 754; SFC: column: Daicel Chiralpak OJH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 5.2 min (major) and 5.7 min (minor).

Example 23: Kinetic Resolution of Racemic 7-Benzyl-l , 4- diazepan-5-one

Racemic 7-benzyl-l, 4-diazepan-5-one (102.1 mg, 0.50 mmol) was resolved according to the improved general procedure (Example 19) .

Recovered amine: 40 mg (39%, er = 81:19); acylated product: 75 mg (40%, er = 94:6) . Calculated conversion: 41%; s = 30.

Recovered amine: (7R) - 7-benzyl-l , 4-diazepan-

5-one

[ ot] ²⁶ _D (c = 1.0, CHC1₃) : -12.0; H NMR (400 MHz, CDC1₃) : δ [ppm] = 7.44-7.10 (m, 6 H) , 3.43-3.32 (m, 1 H) , 3.16 (dt, J = 13.9, 6.4 Hz, 1 H) , 3.12-3.01 (m, 2H) , 2.85 (dd, J = 13.5, 4.5 Hz, 1 H) , 2.75 - 2.54 (m, 4 H) , 2.09 (br, 1 H) ;

The amine was protected with benzyl chloroformate to determine the er:

SFC: column: Daicel Chiralpak ADH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 8.4 min (minor) and 8.9 min (major).

Amide product: (7S) -7-benzyl-l- (3-mesitylpropanoyl) -1 , 4- diazepan-5-one

[a] D (c = 1.0, CHCI₃) : +7.9; at room temperature the ratio of rotamers was 65:35 as determined by H NMR;

¹³C NMR (100 MHz, CDCI₃) : δ [ppm] = 175.5, 174.4, 172.2, 171.6, 137.4, 137.2, 136.2, 136.2, 135.8, 135.7, 134.6, 134.5, 129.2, 129.1, 129.0, 129.0, 128.6, 127.2, 126.8, 53.6, 47.5, 44.3, 43.6, 42.9, 42.9, 41.6, 39.7, 36.5, 33.1, 32.4, 24.9, 24.9, 20.9, 19.8, 19.7;

^XH NMR (400 MHz, CDCI₃) : δ [ppm] = 7.37-7.20 (m, 4 H) , 7.17-7.07 (m, 1.35 H) , 6.85 (overlapping s, J = 9.5 Hz, 2 H), 6.72 - 6.61 (m, 0.65 H) , 5.48 (td, J = 8.5 Hz, 3.0 Hz, 0.35 H) , 5.03-4.88 (m, 0.65 H) , 4.19 (td, J = 9.3 Hz, 5.4 Hz, 0.65 H) , 3.72 (apparent d, J = 15.7 Hz, 0.35 H) , 3.48- 3.30 (m, 1.65 H) , 3.26-3.20 (m, 0.7 H) , 3.12 (ddd, J = 14.5 Hz, 9.4 Hz, 2.6 Hz, 0.65 H) , 3.03 (ddd, J = 15.8 Hz, 9.7 Hz, 6.1 Hz, 1H), 2.95-2.83 (m, 2 H) , 2.83-2.75 (m, 0.65 H), 2.74-2.59 (m, 2.35 H) , 2.42-2.29 (m, 0.65 H) , 2.27-2.25 (m, 6 H) , 2.21 (dd, J = 11.4 Hz, 5.2 Hz, 0.65 H), 2.15 (s, 3 H), 1.97 (ddd, J = 16.2 Hz, 11.6 Hz, 4.9 Hz, 0.7 H) ;

HRMS (ESI): calculated for [C24H31N2O2] ⁺ : m/z = 379.2380, found: m/z = 379.2372; IR (v/crn^-1, neat) : 3264, 3004, 2920, 1671, 1643, 1203, 1123, 753, 701;

SFC: column: Daicel Chiralpak OJH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 6.2 min (major) and 6.7 min (minor) .

Example 24: Kinetic Resolution of Racemic 1-Benzyl 3- methyl piperazine-1 , 3-dicarboxylate

Racemic 1-benzyl 3-methyl piperazine-1 , 3-dicarboxylate (139.2 mg, 0.5 mmol) was resolved according to the improved general procedure (Example 19) . Recovered amine: 77 mg (55%, er = 84:16); acylated product: 99 mg (44%, er = 92:8) Calculated conversion: 45%; s = 23.

Recovered amine: 1-Benzyl 3-methyl (2S) -piperazine-1 , 3- dicarboxylate

The amine was protected with benzyl chloroformate to determine the er:

[a]²⁵ _D (c = 1.3, CHC1₃) : -7.1; SFC: column: Daicel Chiralpak OJH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 6.4 min (major) and 6.9 min (minor) .

Acylated product: 1-Benzyl 3-methyl (3R) -4- (3- mesitylpropanoyl)piperazine-1 , 3-dicarboxylate

[a] D (c = 3.8, CHCI3) : +2.9;

¹³C NMR (100 MHz , CDCI3) : δ [ppm] = 172.9, 172.6, 154.8, 136.2, 136.1, 136.0, 135.7, 135.6, 134.33, 134.27, 129.0, 128.5, 128.2, 127.94, 127.91, 67.5, 55.7, 52.7, 52.5, 51.9, 44.6, 44.4, 42.9, 42.4, 32.5, 32.1, 24.6, 24.5, 20.8, 19.7, 19.64, 19.57; Η NMR (400 MHz, CDC1₃) : δ [ppm] = 7.40-7.28 (m, 5 H) , 6.84 (br s, 2 H), 5.25 (dd, J = 4.5, 1.7 Hz, 1 H) , 5.21-5.12 (ra, 1 H), 5.11-5.04 (m, 1 H) , 4.66 (dt, J = 13.6 Hz, 1.8 Hz, 0.5 H) , 4.59 (d, J = 13.6 Hz, 0.5 H) , 4.50-4.20 (m, 0.5 H), 4.18-3.90 (m, 1 H) , 3.80-3.40 (m, 4.5 H) , 3.11 (dd, J = 13.7, 4.2 Hz, 1 H) , 3.02-2.70 (m, 4 H) , 2.57-2.37 (m, 2 H), 2.30-2.23 (m, 9 H) ; HRMS (ESI): calculated for [C26H33N2O5] ⁺ : m/z = 453.2384, found: m/z = 453.2371;

IR (v /cnf¹, neat) : 3002, 2948, 2918, 1743, 1704, 1657, 1427, 1226, 1119;

SFC: column: Daicel Chiralpak OJH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 6.1 min (major) and 6.5 min (minor) .

Example 25 : Kinetic Resolution of Racemic tert-Butyl methylpiperazine-l-carboxylate

Racemic tert-butyl 3-methylpiperazine-l-carboxylate

(100.1 mg, 0.50 mmol) was resolved according to the improved general procedure (Example 19) . Recovered (Bz-protected) amine: 60 mg (35%, er = 97:3); acylated product: 40 mg (21%, er = 86:14).

Calculated conversion: 57%; s = 21.

Recovered amine: (3R) -tert-Butyl 3-methylpiperazine-1 - carboxylate

The amine was protected with benzoyl chloride to determine the er:

[OC]²⁶D (c = 1.0, CHC1₃) : -21.3;

SFC: column: Daicel Chiralpak ADH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 5.5 min (minor) and 5.7 min (major) .

Amide product: tert-Butyl (3S) -4- (3-mesitylpropanoyl) -3-

methylpiperazine-l-carboxylate [a] D (c = 1.0, CHC1₃) : +14.5; at room temperature, the ratio of rotamers was 50:50 as determined by ^XH NMR; ¹³C NMR (100 MHz, CDC1₃) : δ [ppm] = 171.2, 155.1, 136.2, 135.7, 134.7, 129.2, 80.2, 48.9, 48.5, 47.1, 44.7, 44.1,

43.0, 40.4, 36.2, 32.9, 32.3, 28.5, 25.0, 20.9, 19.9,

16.1, 15.1; H NMR (400 MHz, CDC1₃) : δ [ppm] = 6.84 (s, 2 H) , 4.81 (br, 0.5 H), 4.42 (apparent d, J = 11.7 Hz, 0.5 H) , 4.01 (br, 0.5 H), 3.86 (br, 2 H) , 3.42 (apparent d, J = 12.4 Hz, 0.5 H), 3.22 (apparent t , J = 11.4 Hz, 0.5 H) , 3.04-2.61 (m, 4.5 H) , 2.60-2.34 (m, 2 H) , 2.29 (s, 6 H) , 2.25 (s, 3 H) , 1.46 (s, 9H), 1.16 (br, 3H) ; HRMS (ESI) : calculated for [C22H35N2O3] ⁺ : m/z = 375.2642, found: m/z = 375.2634;

IR (v/crtf¹, neat): 2973, 2921, 1698, 1646, 1421, 1365, 1267, 1172, 1134, 1038, 852;

SFC: column: Daicel Chiralpak ODH (4.6 ^χ 250 mm) ; gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 5.7 min (minor) and 6.1 min (major) .

Example 26: Kinetic Resolution of Racemic N- Heterocycles with a Recyclable , Polymer- Supported Reagent This refers to the synthesis of a robust and recyclable polystyrene supported reagent and its use for the facile resolution of chiral amines. The resolutions are conducted simply by mixing the racemic amine and this reagent (~0.6 equiv) followed by aqueous extraction or column chromatography to separate the acylated product from the enantioenriched recovered amine. The reagent can be recycled dozens of times without loss of efficiency or selectivity. This approach is useful for obtaining enantiopure amines from their racemates, as well as preparing enantioenriched amides with groups that can be cleaved under mild conditions.

Preparation of solid-supported amine resolving agent 9. Reagents and conditions: a) TFA:H₂S0„ (3:1) 0 °C, then NBS (1.01 equiv), 80%; b) N, O-bis ( trimethylsilyl ) acetamide (1.1 equiv), CH₃CN, 23 °C to 75 °C , then Mo0₅*PyHMPA (MoOPH) (1.2 equiv), CH₂C1₂, 23 °C, 73%; c) benzylacrylate (1.50 equiv), Pd(OAc)₂ (0.10 equiv), P(o-tolyl)₃ (0.21 equiv) , Et₃N (5.00 equiv) , CH₃CN, 23 °C to 75 °C, 65%; d) Ac₂0 (1.10 equiv), EtOAc, 23 °C to 45 °C, then Pd/C (10 wt%), H₂; then 1 M LiOH, 73%; e) 7(0.50 equiv), HATU (0.95 equiv), DMAP (1.00 equiv), Hiinig' s base (3.00 equiv), DMF; f) 3-phenylpropanoic anhydride, DMF, 45 °C.

Example 27: Preparation of (£) -Benzyl-3- ( (4ai¾, 9aS) -4- hydroxy-3-oxo-2 , 3 , 4 , 4a, 9 , 9a-hexahydroindeno

Pd(OAc)₂ (39.0 mg, 0.17 mmol, 0.10 equiv), P(o-tolyl)₃ (113 mg, 0.37 mmol, 0.21 equiv) and ( 4aR, 9aS) -6-Bromo-4- hydroxy-4 , 4a, 9 , 9a-tetrahydroindeno [ 2 , 1-b] [ 1 , 4 ] oxazin- 3(2H)-one (Example 18; 500 mg, 1.76 mmol, 1.00 equiv) were dissolved in degassed CH₃CN (15 ml) . Et₃N (890 mg, 8.80 mmol, 5.00 equiv) and benzyl acrylate (430 mg, 2.65 mmol, 1.50 equiv) were added and the reaction vessel was sealed and heated to 90 °C. After 18 h, the solvent was removed under reduced pressure, purification by column chromatography on silica (EtOAc) afforded 5 (415 mg, 65%) as a light brown amorphous solid.

[o]²⁷ _D (c = 1.0, CHC1₃) : +196.3; [a]^2SD (c = 1.5, CHC1₃) : -152.2 (for the opposite S,R enantiomer synthesized from the S,R enantiomer of the starting material) ^XH NMR (400 MHz, CDC1₃) δ 10.20 (broad 1H) , 8.05 (apparent s, 1H), 7.75 (d, J = 16.0, 1H) , 7.45 - 7.30 (m, 7H) , 6.60 (d, J = 16.0, 1H), 5.30 (apparent s, 2H) , 5.10 (d, J = 4.3, 1H), 4.67 (apparent t, J = 4.3, 1H) , 4.20 (m, 2H) , 3.25 (dd, J = 17.3, 4.3, 1H) , 3.10 (d, J = 17.3, 1H) ;

¹³C NMR (100 MHz, CDC1₃) δ 166.8, 162.9, 144.8, 142.0, 140.0, 136.1, 134.1, 129.5, 128.6, 128.3, 128.2, 125.5, 124.6, 118.0, 78.3, 66.4, 65.8, 37.6;

HRMS (ESI) calculated for [C₂iHi₉N0₅Na] ⁺ m/z = 388.1155, found m/z = 388.1165;

IR (u/cnf¹, neat) 2833, 1708, 1654, 1492, 1375, 1332, 1263, 1164, 1118.

Example 28: Preparation of 3- ( (4ai , 9aS) -4-Hydroxy-3- oxo-2 , 3 , 4 , 4a , 9 , 9a-hexahydroindeno [2 , 1-b]

[1,4] oxazin-6-yl) propanoic acid (6)

To a solution of 5 (Example 27; 2.00 g, 5.50 mmol, 1.00 equiv) in EtOAc (20 ml), acetic anhydride (615 mg, 6.00 mmol, 1.10 equiv) was added dropwise. The resulting mixture was heated for 4 h at 45 °C. After completion (as judged by TLC and LCMS), 10% Pd/C (230 mg) was added in one portion. H₂ was bubbled through the 'reaction mixture for 5 min . A balloon with H₂ gas was connected to the reactions vessel and the mixture was stirred vigorously under H₂ atmosphere. After 24 h, the mixture was filtered through a short pad of celite and the solvent was removed under reduced pressure. The resulting colorless oil was dissolved in THF (20 ml), followed by the addition of aqueous 1 M LiOH (30 ml) . The emulsion was vigorously stirred for 2 h. THF was removed under reduced pressure and pH of the aqueous layer was adjusted to 4-5 with aqueous 1 HC1 solution. Upon acidification, compound 6 precipitated as a colorless solid, which was collected on the filter, washed with cold MeOH (15 ml) and dried under high vacuum (0.2 mm Hg) . The remaining aqueous layer was extracted with EtOAc (4 ^χ 50 ml), combined organic layers were washed with brine (15 ml), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica ( CH₂CI₂ : eOH : AcOH 93:7:0.1) afforded compound 6. Both batches of product were combined to yield 6 (1.1 g, 73%) as a colorless solid.

[a]²⁶ _D (c = 1.0, DMF) : -20.9;

[O]²⁵ _D (c = 0.35, DMF): +19.8 (for the opposite S,R enantiomer synthesized from the S,R enantiomer of the starting material);

^XH NMR (400 MHz, d₆-DMSO) δ 12.10 (broad, 1H) , 10.30 (broad, 1H) , 7.50 (s, 1H) , 7.15 (m, 2H) , 4.95 (d, J = 4.5, 1H), 4.63 (apparent t , J = 4.5, 1H) , 4.15 (d, J = 15.9, 1H), 4.05 (d, J = 15.9, 1H) , 3.10 (dd, J = 16.7, 4.5, 1H), 2.80 (m, 3H), 2.50 (m, 2H) ;

¹³C NMR (100 MHz, d₆-DMSO) δ 174.2, 163.1, 140.9, 140.1, 138.3, 128.6, 125.3, 125.1, 78.4, 67.0, 66.9, 37.1, 35.9, 30.9; HRMS ( E S I ) calculated for [ Ci ₄H₁₆N0₅]⁺ m/z = 278.1023, found m/z = 278.1024; IR (u/cm^"1, neat) 3013, 1739, 1686, 1539, 1479, 1363, 1218, 1131, 1062, 783; mp decomposes at 200 °C.

Example 29 : Preparation of the Polymer Supported

Reagent (R,S)-8

Hydroxamic acid 6 (Example 28; 1.1 g, 4.0 mmol, 2.0 equiv) and Hunig' s base (0.7 g, 6.0 mmol, 3.0 equiv) were added to the solution of 2- ( lH-7-Azabenzotriazol-l-yl ) -1 , 1 , 3 , 3- tetramethyluronium hexafluorophosphate (HATU) (1.4 g, 3.8 mmol, 1.9 equiv) and 4 -dimethylamino pyridine (D AP) (0.5 g, 4.0 mmol, 2.0 equiv) in DMF (6 ml). The resulting mixture was left shaking for 15 min to generate the activated ester. The aminomethyl polystyrene resin (7) {Acros Organics, CAS 78578-28-6, 2.0-2.2 mmol/g loading) (1.0 g, 2.0-2.2 mmol, 1.0 equiv) was swollen in DMF (10 ml) for 1.5 h and washed with DMF (3 * three volume-beds) . The solution of the activated ester was added to the beads and left shaking. After 24 h the beads were washed with DMF (4 x three volume-beds), CH₂C1₂ : n-PrNH₂ solution (2:1) (2 x three volume-beds) , DMF, CH₂C1₂, iPrOH and hexanes (all 3 x three volume beds) and dried under high vacuum (0.2 mm Hg) for 18 h. Example 30: Preparation of the Polymer Supported Reagent (R,S)-9

Polymer reagent 8 (Example 29) was swollen in DMF (two volume-beds) for 1 h and washed with DM F (3 ^x three volume-beds) . An excess of benzylacetic acid anhydride (2.82 g, 10.0 mmol, ~10.0 equiv) as a solution in DM F was added to the resin beads, and the reaction mixture was left shaking at 45 °C for 4 h. The beads were washed with DMF , CH₂C1₂ and hexanes (all 3 ^χ three volume-beds) and dried under high vacuum (0.2 mm Hg) for 18 h.

Example 31: General Procedure for the Kinetic

Resolution of N-Heterocyclic Amines with the Polymer Supported Reagent (R,S)-9

Resin beads with the polymer bound reagent 9 (Example 30; 0.6-0.7 equiv) were swollen in CH₂C1₂ for 1 h and washed with CH₂C1₂ (3 x three volume beds) . A solution of the N- heterocyclic amine (1.0 equiv) in CH₂C1₂ (0.3-0.5 M) was added to the beads and left shaking for 48 h. The polymer support was washed with CH₂C1₂ (7 ^χ three volume-beds) to afford a CH₂C1₂ solution of the amide product and the unreacted amine. Workup procedures are described separately for each compound. Regeneration of the Polymer Supported Reagent (R,S)-9

After the kinetic resolution, resin beads were washed with CH₂C1₂ and DMF (4 three volume beds) and reacylated by treatment with excess of benzylacetic acid anhydride solution in DMF at 45 °C for 4 h. Washing of the resin was performed as described above (Example 30).

Quantification of the Resin Loading

A 4 ml vial was charged with the resin beads containing active acylating agent 9 (Example 30; 10.0 mg) and n-PrNH₂ (700 mg, 12.0 mmol, 1.00 ml) solution in CH₂C1₂ (2 ml) and shaken for 4 h at 23 °C. The reaction mixture was filtered, washed with CH₂C1₂ (5 * 3 mL) , concentrated under reduced pressure and dried under high vacuum (0.2 mm Hg) , to afford 3-phenyl-N-propylpropanamide . Resin loading in mmol was calculated according to the amount of amide 3-phenyl-N- propylpropanamide in mmol (equation 1) : n amide (mmol) x m resin (mg) resin (mmol)

10 (mg)

The amount of the amide was determined either via ¹H-NMR using N, N-dimethylacetamide as an internal standard or by weighing of the amide product.

Example 32: Kinetic Resolution of Racemic 2-Ethyl-piperi- dine

Racemic 2-ethyl piperidine (25 mg, 0.22 mmol, 1.00 equiv) in CH₂C1₂ (5 ml) was resolved according to the general procedure of Example 31 with the polymer supported reagent 9 (Example 30; 1.24 g, -0.12 mmol/g, -0.65 -0.70 equiv) . {Novabiochem 0.36 mmol/g CAS 01-64-0447 resin was used) . The CH₂C1₂ solution from the resin wash was extracted with aqueous 1 M HC1 solution (3 ^χ 10 ml) . The organic phase was washed with brine (1 ^χ 10 ml), dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to afford the amide product. The pH of the aqueous phase was adjusted to 9-10 with solid K₂C0₃ and extracted with CH₂C1₂ (5 x 4 ml) . The combined organic phases were dried over anhydrous Na₂S0₄ and filtered. Et₃N (24.4 mg, 0.24 mmol, 1.10 equiv) and 3-phenylpropanoyl chloride (37.0 mg, 0.22 mmol, 1.00 equiv) were added to this solution and the reaction mixture was allowed to stir overnight. The solvent was removed under reduced pressure and the crude product purified by column chromatography ( hexanes : EtOAc 1:1) . Recovered (N-3-phenylpropanoyl protected amine) 10 mg (19% yield, er = 98:2); acylated product 30 mg (56% yield, er = 80:20) .

Calculated conversion c = 62%, s = 15.

(S) -1- (2-Ethylpiperidin-l-yl) -3-phenylpropan-l-one (amide product)

[a] D (c = 0.75, CHCI₃) : +9.8 (er = 80:20); ^lH NMR (400 MHz , CDC1₃) δ 7.30-7.05 (m, 5H) , 4.80 (m, 0.5H), 4.60 (m, 0.5H), 3.79 (m, 0.5H), 3.61 (m, 0.5H), 3.10 (m, 2.5H), 2.75 (m, 2.5H), 1.80-1.50 (m, 8H) , 0.95 (t, J = 7.4, 3H) ; ¹³C NMR (100 MHz, CDCI₃) δ 170.9, 170.8, 141.6, 128.5, 128.5 126.1, 54.4, 49.4, 41.0, 36.5, 35.6, 35.3, 31.8, 31.7, 28.7, 27.6, 26.3, 25.5, 23.0, 22.2, 19.0, 10.8, 10.7;

HRMS (ESI) calculated for [Ci₆H₂₄NO]⁺ m/z = 246.1852, found m/z = 246.1843;

IR (u/cm^-1, neat) 2962, 2935, 2868, 1638, 1431, 1235, 1135, 994;

SFC column: Daicel Chiralpak ASH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 3.6 min (minor), 4.0 min (major) .

(R) -1- (2-Ethylpiperidin-l-yl) -3-phenylpropan-l-one

(recovered amine)

[a]²⁷ _D (c = 0.1, CHCI₃) : -37.5 (er = 98:2);

SFC column: Daicel Chiralpak ASH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 3.6 min (major), 4.0 min (minor). Example 33: Kinetic Resolution of Racemic 2-Propylpiperi- dine

Racemic 2-propylpiperidine (57.0 mg, 0.45 mmol, 1.00 equiv) in CH₂C1₂ (2 ml) was resolved according to the general procedure of Example 31 with the polymer supported reagent 9 (Example 30; 300 mg, ~1.00 mmol/g, ~0.65 0.70 equiv) . To the CH₂CI₂ solution from the resin wash was added Et₃N (91.0 mg, 0.90 mmol, 2.00 equiv) and benzylchloroformate (115 mg, 0.67 mmol, 1.50 equiv) and the reaction mixture stirred for 10 h. The solvent was removed under reduced pressure and the reaction products separated by column chromatography (hexanes : EtOAc 5:1 for the carbamate) (hexanes : EtOAc 1:1 for the amide) .

Recovered ( Cbz-protected) amine 25 mg (21% yield, er = 93:7); acylated product 60 mg (51% yield, er = 86:14).

Calculated conversion c = 54%, s = 17.

(S) -3-Phenyl-l- (2-propylpiperidin-l-yl)propan-l-one (amide product)

[<x] D (c = 3.0, CHCI₃) : +19.2 (er = 86:14) ;

^XH N R (400 MHz, CDCI₃) δ 7.35-7.15 (m, 5H) , 4.90 (m, 0.5H), 4.60 (m, 0.5H), 3.90 (m, 0.5H), 3.60 (m, 0.5H), 3.10 (m, 2.5H), 2.70 (m, 2.5H), 1.70-1.20 (m, 10H) , 0.94 (t, J = 7.3, 3H) ; ^l3C NMR (100 MHz, CDC1₃) δ 170.8, 170.6, 141.6, 128.5, 128.5, 126.1, 52.9, 47.8, 41.0, 36.5, 35.6, 35.2, 32.4, 31.8, 31.7, 31.6, 29.0, 28.0, 26.3, 25.5, 19.7, 19.5, 19.1, 14.1;

HRMS (ESI) calculated for [Ci₇H₂₆NO]⁺ m/z = 260.2009, found m/z = 260.2013; IR (u/citf¹, neat) 2931, 2864, 2868, 1741, 1534, 11433, 1365, 1227, 888;

SFC column: Daicel Chiralpak ASH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 3.6 min (minor), 4.0 min (major) .

-Benzyl 2-propylpiperidine-l-carboxylate (recovered amine)

[oc]^Z _D (c = 0.6, CHC1₃) : -18.2 ( er = 93:7);

^XH NMR (400 MHz, CDC1₃) δ 7.39-7.26 (m, 5H) , 5.13 (d, J = 12.5, 1H), 5.10 (d, J =12.5, 1H) , 4.29 (s, 1H) , 4.03 (d, J = 12.3, 1H), 2.83 (apparent t, J = 13.6, 1H) , 1.73-1.15 (m, 10H), 0.88 (t, J = 7.3, 3H) ;

SFC column: Daicel Chiralpak ADH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 5.0 min (major), 5.3 min (minor) . Example 34 : Kinetic Resolution of Racemic Ethyl piperi- dine-2-carboxylate

Racemic ethyl piperidine-2-carboxylate (228 mg, 1.45 mmol, 1.00 equiv) , in CH₂C1₂ (7 ml) was resolved according to the general procedure of Example 31 with the polymer supported reagent 9 (Example 30; 1.00 g, -1.00 mmol/g, -0.65 - 0.70 equiv) . The solution from the polymer support wash was extracted with aqueous 1 M HC1 (3 *10 ml), washed with sat. NaHC0₃ (20 ml), dried over anhydrous Na₂S0₄ and concentrated under reduced pressure, to afford the amide product. The aqueous layer was neutralized with solid K₂C0₃, the pH was adjusted to 8-9 and extracted with CH₂C1₂ (3 x 8 ml) . The organic layer was dried over anhydrous Na₂S0₄ and filtered. Benzylchloroformate (256 mg, 1.45 mmol, 1.00 equiv) and Et₃N (152 mg, 1.50 mmol) were added and the mixture was stirred for 3 h at 23°C before saturated aqueous NaHC0₃ (10 ml) was added. Layers were separated and the aqueous phase was extracted with CH₂C1₂ (3 x 10 ml), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (hexanes : EtOAc 4:1).

Recovered (Cbz- protected) amine 135 mg (32% yield, er = 96:4); acylated product 200 mg (48% yield, er = 84:16).

Calculated conversion, c = 58%, s —

-Ethyl 1- (3-phenylpropanoyl)piperidine-2-carboxylate (amide product)

[ ] D (c = 3.75, CHC1₃) : +32.6 (er = 84:16);

^XH NMR (400 MHz, CDC1₃) δ 7.35-7.15 (m, 5H) , 5.41 (d, J = 5.3, 0.8H), 4.65 (m, 0.2H), 4.52 (d, J = 5.3, 0.2H), 4.25 (m, 2H) , 3.75 (m, 0.8H), 3.25 (m, 0.8H), 3.00 (m, 2H) , 2.70-2.50 (m, 2.2H), 2.25 (m, 1H) 1.75-1.55 (m, 3H) , 1.45- 1.25 (m, 5H);

¹³C NMR (100 MHz, CDC1₃) δ 172.3, 171.9, 171.5, 170.8, 141.4, 128.5, 128.4, 126.1, 61.5, 61.1, 56.1, 52.0, 43.3, 39.4, 35.4, 35.0, 31.4, 31.2, 27.2, 26.7, 25.3, 20.9, 20.8, 1 4 . 3 ;

HRMS (ESI) calculated for [Ci₇H₂₄N0₃]⁺ m/z = 290.1751, found m/z = 290.1752; IR (u/cnf¹, neat) 2977, 2938, 2865, 1736, 1633, 1430, 1366, 1199, 1029, 831, 748;

SFC column: Daicel Chiralpak ASH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t R — 3.3 mm (minor), 3.7 min (major) .

(S) -1-Benzyl 2-ethyl piperidine-1 , 2-dicarboxylate

(recovered amine)

[a]^Z7D (c = 4.0, CHCI₃) : 39.9 (er = 96 ^XH NMR (400 MHz, CDC1₃) δ 7.40-7.29 (m, 5H) , 5.26-5.02 (m, 2H), 4.93 (d, J = 3.8, 0.5H), 4.83 (broad, 0.5H), 4.39- 3.99 (m, 3H), 3.08 (apparent t, J = 12.9, 0.5H), 2.97 (apparent t , J = 12.6, 0.5H), 2.23 (t, J = 14.3, 1H) , 1.70-1.67 (m, 3H) , 1.51-1.34 (m, 1H) , 1.34-1.15 (m, 4H) ;

SFC column: Daicel Chiralpak ODH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: tR — 4.1 m n (major), 4.5 min (minor) .

Example 35: Kinetic Resolution of Racemic l-Benzyl-3- methylpiperazine

Racemic l-benzyl-3-methylpiperazine (85.0 mg, 0.45 mmol, 1.00 equiv) in CH₂C1₂ (2 ml), was resolved according to the general procedure of Example 31 with the polymer supported reagent 9 (Example 30; 300 mg, ~1.00 mmol/g, -0.65 - 0.70 equiv). The solution from the polymer support wash was concentrated under reduced pressure and the crude product mixture was purified by column chromatography (CH₂C1₂ : MeOH 7:3). The recovered amine was dissolved in CH₂C1₂ (5 ml) and benzylchloroformate (77.0 mg, 0.45 mmol, 1.00 equiv), Et₃N (51.0 mg, 0.50 mmol, 1.10 equiv) were added and the mixture was stirred for 3 h at room temperature before saturated aqueous NaHC0₃ (10 ml) was added. The layers were separated and the aqueous phase was extracted with CH₂C1₂ (3 ^χ 10 ml), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (CH₂Cl₂:MeOH 7:3) . Recovered amine 20 mg, (23% yield, er > 99:1); acylated product 75 mg, (52% yield, er = 75:25) .

Calculated conversion c = 66%, s >14.

(S) -1- (4-Benzyl-2-methylpiperazin-l-yl) -3-phenylpropan one (amide product)

[a] D (c=1.25, CHCI3) : +20.2 (er = 75:25);

^XH NMR (400 MHz, CDC1₃) δ 7.40-7.10 (m, 10H) , 4.75 (m, 0.5H), 4.45 (d, J = 13.2, 0.5H), 3.95 (broad, 0.5H), 3.60- 3.25 (m, 3H), 3.10-2.90 (m, 2.5H), 2.80-2.50 (m, 4H) , 2.10-1.80 (m, 2H) , 1.30 (m, 3H) ;

¹³C NMR (100 MHz, CDC1₃) δ 170.6, 170.5, 141.4, 138.2, 128.8, 128.5, 128.5, 128.3, 127.2, 126.2, 62.6, 57.4, 57.3, 53.3, 53.2, 49.1, 44.7, 41.1, 36.9, 35.4, 34.9, 31.6, 17.0, 15.8;

HRMS (ESI) calculated for [C₂iH₂₇N₂0]⁺ m/z = 323.2118, found m/z = 323.2120;

IR (u/cm^"1, neat) 2807, 1742, 1364, 1218, 1083, 1132, 1063, 910; SFC column: Daicel Chiralpak ASH (4.6 x 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 7.8 min (minor), 8.2 min (major).

(R) -Benzyl 4-benzyl-2-methylpiperazine-l-carboxylate (recovered amine)

[<x] ^b _D (c = 0.75, CHC1₃) : -44.5 ( er > 99:1);

^XH NMR (400 MHz, CDC1₃) δ 7.38-7.21 (m, 10H) , 5.16 (d, J = 12.6, 1H), 5.11 (d, J = 12.5, 1H) , 4.34-4.22 (m, 1H) , 3.90 (d, J = 13.1, 1H), 3.53 (d, J = 13.3, 1H) , 3.40 (d, J = 13.3, 1H) , 3.20 (apparent td, J = 12.6, 3.4, 1H) , 2.77 (d, J = 11.2, 1H), 2.61 (apparent dt, J = 11.2, 1.7, 1H) , 2.15 (dd, J = 11.2, 3.9, 1H) , 2.03 (ddd, J = 12.1, 11.3, 3.5, 1H) , 1.28 (d, J = 6.6, 3H) ;

SFC: column: Daicel Chiralpak OJH (4.6 * 250 mm) ; gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R - 5.0 min (major), 5.2 min (minor) .

Example 36: Kinetic Resolution of Racemic l-Methyl-3- phenylpiperazine

Racemic l-methyl-3phenylpiperazine (44.0 mg, 0.25 mmol, 1.00 equiv) , in CH₂C1₂ (2 ml) was resolved according to the general procedure of Example 31 with the polymer supported reagent 9 (Example 30; 200 mg, -1.00 mmol/g, -0.70 - 0.80 equiv) . The solution from the polymer support wash was concentrated under reduced pressure and the amide product and unreacted amine were separated by column chromatography (CH₂Cl₂:MeOH 9:1 for the amide) (CH₂Cl₂:MeOH 1:1 for the amine) .

Recovered amine 15 mg (34% yield, er = 96:4); acylated product 40 mg (52% yield, er = 81:19).

Calculated conversion c = 60%, s = 13.

(S) -1- (4-Methyl-2-phenylpiperazin-l-yl) -3-phenylpropan-l- one (amide product)

[<x]^Z5 _D (c = 2.0, CHC1₃) : +58.2 (er = 81:19); ^XH NMR (400 MHz , CDC1₃) δ 7.50-7.15 (m, 10H) , 5.90 (broad, 0.5H), 4.90 (broad, 0.4H), 4.50 (broad, 0.4H), 3.60 (broad, 0.5H), 3.35 (apparent d, J = 12.0, 1H) , 3.18 (broad, 0.6H), 3.0 (apparent t, J = 7.9, 2.4H), 2.70 (broad, 3H) , 2.30 (broad, 4H) , 1.95 (broad, 1.2H); ¹³C NMR (100 MHz, CDC1₃) δ 141.2, 129.7, 128.5, 128.5, 127.9, 127.0, 126.2, 57.0, 56.8, 55.3, 50.5, 46.4, 41.8, 38.1, 35.1, 31.6; HRMS (ESI) calculated for [C₂oH25 ₂0]⁺ m/z = 309.1961, found m/z = 309.1957;

IR (u/crrf¹, neat) 3026, 2937, 1643, 1451, 1426, 1211, 1022, 749, 700;

SFC column: Daicel Chiralpak ODH (4.6 x 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 7.4 min (major), 7.9 min (minor) .

(R) -l-methyl-3- phenylpiperazme (recovered amine)

Me

[ocr _D (c = 2.0, CHC1₃) C HI 28.3 (er = 96:4)

¹H MR (400 MHz, CDC1₃) δ 7.41-7.20 (m, 5 H) , 3.87 (dd, J = 10.5, 3.6, 1 H), 3.15-3.08 (m, 1 H) , 3.12 (apparent td, J = 10.9, 2.8, 1 H), 2.90-2.78 (m, 2 H) , 2.31 (s, 3 H) , 2.13 (apparent td, J = 10.9, 3.9, 1 H) , 2.00 (apparent t, J = 10.5, 1 H), 1.88 (broad, 1 H) ;

HPLC column: Daicel Chiralcel ODH (4.6 ^χ 250 mm); eluent: 1% iPrOH in hexanes, flow:1.0 ml/min; detection: 254 nm. Retention time: t_R = 15 min (minor), 18 min (major) .

Example 37 : Kinetic Resolution of Racemic 3-Benzylmorpho- line

Racemic 3-benzylmorpholine (52.0 mg, 0.30 mmol, 1.00 equiv) , in CH₂C1₂ (2 ml) was resolved according to the general procedure of Example 31 with the resin supported reagent 9 (Example 30; 200 mg, -1.00 mmol/g, -0.6-0.7 equiv) . The solution from the polymer support wash was extracted with aqueous 1 M HCl solution (3 * 10 ml), washed with sat. NaHC0₃ solution (10 ml) dried over anhydrous Na₂S0₄ and concentrated under reduced pressure, to afford the amide product. The pH of the aqueous layer was adjusted to 8-9 with solid K₂C0₃, saturated with solid NaCl and extracted with CH₂C1₂ (3 >< 7 ml) . The organic layer was dried over anhydrous Na₂S0₄ and filtered. Benzylchloro- formate (52 mg, 0.30 mmol, 1.00 equiv) and Et₃N (35.0 mg, 0.35 mmol, 1.10 equiv) were added and the mixture was stirred for 3 h at 23 °C before saturated aqueous NaHC0₃ solution (10 ml) was added. The layers were separated and the aqueous phase was extracted with CH₂C1₂ (3 * 10 ml), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (hexanes : EtOAc 2:1) .

Recovered amine (Cbz-protected) 20 mg (21% yield, er = 93:7); acylated product 45 mg (49% yield, er = 88:12).

Calculated conversion c = 53%, s = 20.

(S)-l-(3- Benzylmorpholino) -3- phenylpropan-1 -one (amide product)

[<x]^Z6 _D (c = 2.5, CHC1₃) : -15.2 (er = 88:12) ; ^lH NMR (400 MHz, CDC1₃) δ 7.40-7.10 (m, 10H) , 4.70 (m, 0.5H), 4.45 (m, 0.5H), 3.99 (dd, J = 11.3, 4.0, 0.5H), 3.88 (d, J = 11.3, 0.5H), 3.75 (m, 1.5H), 3.45-3.30 (m, 3H), 3.25-3.05 (m, 1.5H), 3.00-2.85 (m, 2.5H), 2.75-2.60 (m, 1H), 2.55 (m, 0.5H), 2.37 (m, 0.5H), 2.00 (m, 0.5H);

¹³C NMR (100 MHz, CDC1₃) δ 171.3, 171.0, 141.2, 141.1, 138.2, 137.9, 129.6, 129.3, 128.9, 128.6, 128.5, 128.5, 128.4, 126.9, 126.5, 126.3, 126.1, 68.8, 67.3, 67.2, 66.6, 55.6, 50.5, 41.8, 37.1, 35.9, 35.1, 34.7, 34.2, 31.4;

HRMS (ESI) calculated for [C₂oH₂₄ 0₂]⁺ m/z = 310.1802, found m/z = 310.1802;

IR (u/crrf¹, neat) 2856, 1741, 1643, 1417, 1364, 1219, 1129, 1064, 892; SFC column: Daicel Chxralpak OJH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 5.8 min (minor), 6.4 min (major) .

(R) -Benzyl 3-benzylmorpholine-4-carboxylate (recovered amine)

[a] D (c = 0.4, CHCI3) : +14.5 (er = 93:7) ;

^XH NMR (400 MHz, CDC1₃) δ 7.40-7.08 (m, 10H) , 5.20-4.85 ( 2H), 4.13 (broad, 1H) , 3.98 (m, 2H) , 3.71 (s, 0.5H), 3. (s, 0.5H), 3.50 (dd, J = 11.8, 2.3, 1H) , 3.45 (dd, J 11.8, 3.1, 1H) , 3.33 (apparent td, J = 12.8, 3.7, 1H) , 3.05 (broad, 1H) , 2.91 (dd, J= 13.2, 6.3, 1H) ;

SFC column: Daicel Chiralpak OJH (4.6 x 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 nal/min; detection: 254 nm. Retention time: tR — 4.9 min (major), 5.6 min (minor).

Example 38: Kinetic Resolution of Racemic 6 , 7-Dimethoxy- l-phenyl-l ,2,3, 4-tetrahydroisoquinoline

6, 7-Dimethoxy-l-phenyl-l, 2,3, 4-tetrahydro isoquinoline (380 mg, 1.40 mmol, 1.00 equiv) , in CH₂C1₂ (5 ml) was resolved according to the general procedure of Example 31 with the polymer supported reagent 9 (Example 30; 1.00 g, -1.00 mmol/g, ~0.65-0.70 equiv). The solution from the polymer support wash was concentrated under reduced pressure and the amide product and unreacted amine were separated by column chromatography (hexanes : EtOAc 1:1 for the amide) (EtOAc:Et₃N 99.9:0.1 for the amine).

Recovered amine 140 mg (37% yield, er = 99:1); acylated product 340 mg (58% yield, er = 84:16).

Calculated conversion c = 59%, s = 23.

(R) -1- (6, 7-Dimethoxy-l -phenyl-3, 4-dihydroisoquinolin-2 (IE) -yl) -3-phenylpropan-l-one (amide product)

[a]^Z6 _D (c = 5.5, CHC1₃) : +133.9 (er = 84:16); ^lH NMR (400 MHz, CDC1₃) δ 7.30-7.10 (m, 10H) , 6.95 (s, 0.8H), 6.70 (s, 0.2H), 6.65 (s, 0.8H), 6.55 (s, 0.8H), 6.50 (s, 0.2H), 5.80 (s, 0.2H), 4.40 (m, 0.2H), 3.95 (s, 3H), 3.85 (s, 0.6H), 3.80 (s, 2.4H), 3.70 (m, 0.8H), 3.35 (m, 0.8H), 3.15 (m, 0.2H), 3.05 (m, 2H) , 3.00-2.75 (m, 1.5H), 2.75-2.60 (m, 2.5H); ¹³C NMR (100 MHz, CDC1₃) δ 170.6, 148.1, 147.7, 142.6, 141.3, 128.8, 128.5, 128.4, 128.2, 127.4, 126.4, 126.1, 111.5, 111.3, 111.1, 111.0, 59.3, 56.0, 55.9, 54.7, 39.3, 37.1, 35.7, 35.4, 31.7, 31.5, 28.6, 27.4;

HRMS (ESI) calculated for [C₂6H₂₈ 0₃]⁺ m/z = 402.2064, found m/z = 402.2066;

IR ( u/cm^"1, neat) 2936, 2834, 1638, 1515, 1439, 1249, 1232, 1116, 913;

SFC column: Daicel Chiralpak ASH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 7.3 min (major), 9.2 (minor) .

(R) -6, 7-Dimethoxy-l -phenyl-1 ,2,3, 4-tetrahydroisoquinoline (recovered amine)

Ph

[cc]²⁶ _D (c = 2.25, CHCI₃) : +22.0 ( er = 99:1); *H NMR (400 MHz , CDC1₃) δ 7.45-7.33 (m, 5H) , 6.62 (s, 1H) ,

6.18 (s, 1H), 5.39 (s, 1H) , 3.86 (s, 3H) , 3.62 (s, 3H) , 3.26-3.11 (m, 2H) , 3.08-2.88 (m, 2H) ;

HPLC column: Daicel Chiralpak OJH (4.6 ^χ 250 mm); eluent: 60% iPrOH in hexanes + 0.1% Et₃N, flow: 0.5 ml /min; detection: 254 nm. Retention time: t_R = 10.5 min (minor), 15.5 min (major) .

Example 39: Kinetic Resolution of Racemic Ethyl 2- (6,7- dimethoxy-1 ,2,3, 4-tetrahydroisoquinolin-l-yl)

Racemic ethyl 2- ( 6 , 7-dimethoxy-l , 2 , 3 , 4-tetrahydroisoquinolin-l-yl ) acetate (273 mg, 0.98 mmol, 1.00 equiv) was resolved according to the general procedure of Example 31 with polymer supported reagent 9 (Example 30; 1.00 g, ~1.00 mmol/g, -0.97 - 1.00 equiv) . The reaction time was increased to 96 h to increase the enantiopurity of the amine. The solution from the polymer support wash was concentrated under reduced pressure. The amide product and unreacted amine were separated by column chromatography (CH₂Cl₂:MeOH 9:1 for the amide) (CH₂Cl_2:MeOH 8:2 for the amine) .

Recovered amine 90 mg (33% yield, er = 90:10); acylated product 260 mg (64% yield, er not determined) . (R) -Ethyl-2- (6, 7'-dimethoxy-2- (3-phenylpropanoyl) -1,2,3, 4-

hydroisoquinolin-l-yl) acetate (amide product)

[cc] D (c = 1.4, CHC1₃) : +40.7 (er not determined);

^XH NMR (400 MHz, CDC1₃) δ 7.30-7.10 (m, 5H) , 6.75 (s, 0.5H), 6.60 (s, 1H) , 6.50 (s, 0.5H), 6.00 (m, 0.5H) 5.30 (m, 0.5H), 4.73 (m, 0.5H), 4.15 (m, 2H) , 3.90-3.80 (m, 6H) , 3.60 (m, 0.5H), 3.10-2.55 (m, 9H) , 1.25 (m, 3H) ; ¹³C NMR (100 MHz, CDCI₃) δ 171.5, 171.0, 170.8, 170.7,

148.3, 148.1, 147.8, 147.5, 141.4, 141.2, 128.5, 128.4,

128.4, 128.4, 126.2, 126.0, 125.6, 111.7, 111.2, 110.1, 109.1, 61.1, 60.8, 56.0, 56.0, 55.9, 52.9, 49.6, 42.3, 41.5, 40.2, 35.6, 35.5, 34.9, 31.6, 31.3, 28.5, 27.4, 14.2, 14.2;

HRMS (ESI) calculated for [C₂₄H₃o 0₅]⁺ m/z = 412.2118, found m/z = 412.2113; IR (u/cm^"1, neat) 2977, 2935, 1729, 1644, 1516, 1453, 1438, 1256, 1115, 1030.

(R) -Ethyl 2- (6, 7-dimethoxy-l , 2, 3, 4-tetrahydroisoquinolin- 1-yl) acetate (recovered amine)

Et0₂C

[O]²⁶D (c = 4.5, EtOH) : +30.2 (er = 90:10) ;

^XH NMR (400 MHz, CDC1₃) δ 6.55 (s, 2H) , 4.39 (dd, J = 9.5, 3.7, 1H), 4.18 (q, J = 7.1, 2H) , 3.85 (s, 3H) , 3.83 (s, 3H), 3.20 (m, 1H) , 3.00 (m, 1H) , 2.90-2.55 (m, 4H) , 1.25 (t, J = 7.1, 3H) ;

HPLC column: Daicel Chiralpak IB (4.6 ^χ 250 mm); eluent: 60 % iPrOH in hexanes + 0.1 % Et₃N, flow: 0.5 mL/min; detection: 286 nm. Retention time: t_R = 12.0 min (minor), 14.0 min (major) .

Example 40: Kinetic Resolution of Racemic 7-Benzyl-l , 4- diazepan-5-one

Racemic 7-benzyl-l , 4- diazepan-5-one

(92.0 mg, 0.45 mmol, 1.00 equiv) in CH₂C1₂ (2 ml) was resolved according to the general procedure of Example 31 using resin supported reagent 9 (Example 30; 300 mg, ~1.00 mmol/g, ~0.65 - 0.70 equiv). The solution from the polymer support wash was concentrated under reduced pressure and the amide product and unreacted amine were separated by column chromatography (CH₂Cl₂:MeOH 9:1 for the amide) (CH₂Cl_2:MeOH 1:1 for the amine) . Recovered amine 70 mg (76% yield, er = 62:38); acylated product 30 mg (19% yield, er = 94:6). Calculated conversion c = 20% s = 19.

(S) -7-Benzyl-l - (3-phenylpropanoyl) -1 , 4-diazepa

(amide product)

[ot] D (c = 0.75, CHC1₃) : +2.7 (er = 94:6);

^XH NMR (400 MHz, CDC1₃) δ 7.40-7.10 (m, 10H) , 6.55 (broad, 0.4H), 6.40 (broad, 0.6H), 5.45 (m, 0.4H), 4.90 (apparent dt, J = 14.6, 3.3, 0.6H), 4.25 (m, 0.6H), 3.70 (m, 0.4H), 3.35 (m, 1.6H), 3.20 (m, 0.6H), 3.15-3.05 (m, 0.6H), 3.00- 2.80 (m, 3.5H), 2.75-2.50 (m, 3.3H), 2.50-2.40 (m, 0.7H), 2.05 (m, 0.7H);

¹³C NMR (100 MHz, CDCl₃) δ 175.3, 174.1, 171.9, 171.3, 141.0, 141.0, 137.3, 137.0, 129.0, 128.9, 128.6, 128.5, 128.5, 128.4, 128.4, 128.3, 127.1, 126.7, 126.3, 126.3, 126.2, 53.9, 47.4, 44.2, 43.6, 42.7, 42.5, 41.5, 39.4, 36.8, 36.4, 35.7, 34.7, 31.5, 31.3;

HRMS (ESI) calculated for [C21H25 2O2] ⁺ m/z = 337.1911 found m/z = 337.1908;

IR (u/cnf¹, neat) 3272, 2925, 1669, 1494, 1453, 1429, 1207;

SFC column: Daicel Chiralpak OJH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 7.0 min (major), 7.7 min (minor). (R) -7-benzyl-l , 4-diazepan-5-one (recovered amine)

[<x]^Z6 _D (c = 0.75, CHC1₃) : - 0.5 (er = 62:38) ^lH NMR (400 MHz, CDCI₃) : δ 7.44-7.10 (m, 6H) , 3.43-3.32 (m, 1H), 3.16 (dt, J = 13.9, 6.4, 1H) , 3.12-3.01 (m, 2H) , 2.85 (dd, J = 13.5, 4.5, 1H) , 2.75-2.54 (m, 4 H) , 2.09 (broad, 1H) . The amine was Cbz protected to determine the er with SFC. SFC column: Daicel Chiralpak ADH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3..0 ml/min; detection: 254 nm. Retention time: t_R = 8.5 min (minor), 9.0 min (major) .

Example 41:

Preparation of the Polymer Supported Reagent {R,S) -10 To the carboxylic acid (1.0 equiv) solution in dry CH₂CI₂ was added Hunig's base (2.0 equiv) and the reaction mixture was cooled to 0 °C. N,N'-Diisopropylcarbodiimide (DIC) (1.0 equiv) solution in CH₂C1₂ was added dropwise, the reaction mixture was warmed to 23 °C and stirred for 30 min . The resulting precipitate was filtered and washed with CH₂C1₂. The filtrate was concentrated under reduced pressure, redissolved in D F and added to the pre-swollen polymer supported reagent 10. The reaction mixture was left to shake at 45 °C for 4 h. The beads were washed with DMF, CH₂C1₂ and hexanes (all 3 * three volume-beds) and dried under high vacuum (0.2 mm Hg) for 18 h.

Example 42: Preparation of the Polymer Supported Reagent

(J¾,S)-11

To the carboxylic acid (1.0 equiv) solution in dry CH₂C1₂ was added Hunig's base (2.0 equiv) and the reaction mixture was cooled to 0 °C. N, N' -Diisopropylcarbodiimide (DIC) (1.0 equiv) solution in CH₂C1₂ was added dropwise, the reaction mixture was warmed to 23 °C and stirred for 30 min. The resulting precipitate was filtered and washed with CH₂C1₂. The filtrate was concentrated under reduced pressure, redissolved in DMF and added to the pre-swollen - Ill -

polymer supported reagent 11. The reaction mixture was left to shake at 45 °C for 4 h. The beads were washed with DMF, CH₂C1₂ and hexanes (all 3 * three volume-beds) and dried under high vacuum (0.2 mm Hg) for 18 h.

Example 43: Kinetic Resolution of Racemic 3-Benzyl- morpholine with Polymer Supported Reagent (R,S) -10

Racemic 3-benzylmorpholine (79.0 mg, 0.45 mmol, 1.00 equiv) , in CH₂C1₂ (2 ml) was resolved according to the general procedure of Example 31 by treatment with the resin supported reagent 10 (Example 41; 300 mg, ~1.00 mmol/g, -0.65 - 0.70 equiv) for 48 h. The solution from the polymer support wash was concentrated under reduced pressure and the amide product and unreacted amine were separated by column chromatography (CH₂Cl₂: eOH 95:5 for amide) ( CH₂C1₂ : MeOH 1:1 for amine) .

Recovered amine 40 mg (50% yield, er = 87:13); acylated product 68 mg (43% yield, er = 92:8) .

Calculated conversion c = 47%, s = 25.

(S)-l-(3- Benzylmorpholino) -3- (2- nitrophenyl)propan-

1 -one (amide product)

[a] ²³ _D (c = 0.75, CHC1₃) -14.4 ( er = 92:8); H NMR (400 MHz, CDCl₃) δ 7.90 (m, 1H) , 7.55 (m, 1H) , 7.45- 7.30 (m, 2H), 7.30-7.10 (m, 5H) , 6.75 (m, 0.1H), 4.65 (m, 0.4H), 4.42 (apparent dd, J = 13.8, 2.6, 0.5H), 3.95 (m, 1H), 3.75 (m, 1.5H), 3.60-3.30 (m, 2.4H), 3.20-3.00 (m, 2.8H), 3.00-2.90 (m, 1H) , 2.85-2.65 (m, 1.5H), 2.60-2.50 (m, 1H), 2.0 (m, 0.6H), 1.80 (m, 0.2H);

¹³C NMR (100 MHz, CDC1₃) δ 175.6, 170.8, 170.5, 149.3, 133.1, 132.8, 129.6, 129.3, 128.8, 128.5, 127.4, 126.9, 124.8, 124.7, 114.3, 68.9, 67.4, 67.2, 66.7, 55.5, 50.5, 41.8, 37.2, 35.8, 34.7, 34.4, 34.2, 33.2, 29.1, 28.8, 28.2;

HRMS (ESI) calculated for [C₂₀H₂₂N₂O,jNa ] ⁺ m/z = 377.1472; found m/z = 377.1465;

IR (u/cnf¹, neat) 2923, 2858, 1643, 1523, 1495, 1426, 1348, 1119;

SFC column: Daicel Chiralpak ADH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 7.3 min (minor), 7.6 min (major) .

(R) -3-Benzylmophol ine (recovered amine)

[ aj D (c = 0.75, CHCI₃) : +11.7 (er = 92:8); Amine was converted into an amide by using 3 phenylpropanoyl chloride and Et₃N to determine er by SFC;

SFC: column: Daicel Chiralpak OJH (4.6 ^χ 250 mm) gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min flow: 3.0 ml/min; detection: 254 nm. Retention time t_R = 5.8 min (major), 6.4 min (minor) .

Example 44: Kinetic Resolution of Racemic 3-Benzyl- morpholine with Polymer Supported Reagent

Racemic 3-benzylmorpholine (53.0 mg, 0.30 mmol, 1.00 equiv) , in CH₂CI₂ (2 ml) was resolved according to the general procedure of Example 31 by treatment with the polymer supported reagent 11 (Example 42; 300 mg, -1.00 mmol/g, 1.00 equiv) for 15 h. Solution from the polymer support wash was concentrated under reduced pressure and the amide product and unreacted amine were separated by column chromatography (CH₂Cl₂:MeOH 95:5 for amide) (CH₂C1₂ : MeOH 1:1 for amine) .

Recovered amine 30 mg (57% yield, er = 65:35); acylated product 17 mg (21% yield, er = 93:7).

Calculated conversion c = 26%, s = 18.

The amine was converted into corresponding amide treatment with 3-phenylpropionic chloride and Et₃N determine the er. (S) -1- (3-Benzylmorpholino)pent-4-en-l-one (amide product)

[a] a (c = 1.0 CHC1₃) : - 1.2 ( er = 93:7) ; ^XH NMR (400 MHz, CDC1₃) δ 7.40-7.15 (m, 5H) , 5.90-5.70 (m, 1H) , 5.10-4.95 (m, 2H) , 4.70 (m, 0.5H), 4.45 (dd, J = 13.8, 2.3, 0.5H), 4.00 (m, 1H) , 3.85 (m, 1H) , 3.75 (d, J = 11.8, 0.5H), 3.60-3.35 (m, 3H) , 3.20-3.00 (m, 2H) , 2.85 (m, 0.5H), 2.45-2.00 (m, 3.5H), 1.85 (m, 0.5H); ¹³C NMR (100 MHz, CDC1₃) δ 171.4, 171.1, 138.1, 137.9, 137.4, 137.3, 129.6, 129.3, 128.9, 128.5, 126.9, 126.5, 115.3, 115.1, 68.7, 67.4, 67.3, 66.7, 55.6, 50.4, 41.8, 37.1, 35.9, 34.7, 32.6, 31.7, 29.1, 29.1;

HRMS (ESI ) calculated for [C₁₆H₂₂ O₂] ⁺m/z = 260.1645 found m/z = 260.1643;

IR (u/cnf¹, neat) 2966, 2921, 1643, 1454, 1422, 1222, 1119,

913;

SFC column: Daicel Chiralpak ADH (4.6 x 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in CO₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 5.0 min (minor), 5.5 min . (major).

(R) -1- (3-Benzylmorpholino) -3-phenylpropan-l-one (recovered amine)

[a] D (c = 3.5, CHC1₃) : +5.7 (er = 65:35);

SFC column: Daicel Chiralpak OJH (4.6 x 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 5.8 min (major), 6.4 min (minor).

Example 45: Kinetic Resolution of Racemic 6 , 7-Dimethoxy- 1-phenyl-l ,2,3, 4-tetrahydroisoquinoline with Polymer Supported Reagent (j ,S)-10

6, 7-Dimethoxy-l-phenyl-l , 2, 3, 4-tetrahydroisoquinoline

(94.0 mg, 0.35 mmol, 1.00 equiv) , in CH₂C1₂ (2 ml) was resolved according to the general procedure of Example 31 by treatment with the resin supported reagent 10 (Example 41; 300 mg, -1.00 mmol/g, -080 - 0.85 equiv) for 48 h. The solution from the polymer support wash was concentrated under reduced pressure and the amide product and unreacted amine were separated by column chromatography (CH₂Cl2:MeOH 95:5 for the amide) ( CH₂C1₂ : MeOH 70:30 for the amine) .

Recovered amine 30 mg (32% yield, er > 99:1); acylated product 95 mg (61% yield, er = 80:20) .

Calculated conversion c = 62%, s > 23. (S) -1- (6, 7-Dimethoxy-l-phenyl-3, 4-dihydroisoquinolin-2 (1H) -yl) -3- (2-nitrophenyl)propan-l-one (amide product)

[a] _D (c = 5.0, CHC1₃) : +91.3 (er = 80:20);

^XH NMR (400 MHz, CDC1₃) δ 7.92 (d, J = 8.0, 0.8H), 7.85 (d, J = 8.0, 0.2H), 7.50-7.40 (m, 2H) , 7.38-7.20 (m, 6H) , 7.10 (d, J = 6.6, 0.5H), 6.90 (s, 0.8H), 6.65 (s, 1H) , 6.55 (s, 0.2H), 6.52 (s, 0.8H), 5.95 (s, 0.2H), 4.30 (m, 0.5H), 3.88 (s, 2.6H), 3.80 (s, 0.6H), 3.75-3.70 (m, 2.8H), 3.35- 3.25 (m, 2.5H), 3.20-3.00 (m, 0.5H), 2.95-2.55 (m, 4H) ;

¹³C NMR (100 MHz, CDC1₃) δ 170.0, 149.3, 148.1, 147.7, 142.5, 136.4, 133.2, 132.8, 128.8, 128.6, 128.3, 127.7, 127.5, 127.4, 126.9, 126.4, 124.8, 111.3, 111.1, 110.9, 59.2, 56.0, 55.9, 54.8, 39.3, 37.0, 34.6, 34.3, 29.2, 28.6, 27.4;

HRMS (ESI) calculated for [ C26H27 2O5] ⁺ m/z = 447.1914, found m/z = 447.1909;

IR (u/crrf¹, neat) 2935, 1638, 1520, 1492, 1440, 1347, 1251, 1117;

SFC column: Daicel Chiralpak ASH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 7.3 min (major), 8.7 min (minor). (R) -6, 7-Dimethoxy-l-phenyl-l ,2,3, 4-tetrahydroisoquinoline (recovered amine)

(c = 5.0, CHC1₃) : +14.1 (er > 99:1); HPLC column: Daicel Chiralpak OJH (4.6 ^χ 250 mm); eluent:

60% iPrOH in hexanes + 0.1% Et₃N, flow: 0.5 ml /min; detection: 254 nm. Retention time: t_R = 10.5 min (minor), 15.5 min (maj or ) .

Example 46: Kinetic Resolution of Racemic 6 , 7-Dimethoxy- l-phenyl-l ,2,3, 4-tetrahydroisoquinoline with Polymer Supported Reagent (R,S) -11

6, 7-dimethoxy-l-phenyl-l , 2, 3, 4-tetrahydroisoquinoline

(121 mg, 0.45 mmol, 1.00 equiv) , in CH₂C1₂ (2 ml) was resolved according to the general procedure of Example 31 by treatment with the polymer supported reagent 11 (Example 42; 300 mg, -1.00 mmol/g, -0.65-0.70 equiv) for 48 h. The solution from the polymer support wash was concentrated under reduced pressure. The amide product and unreacted amine were separated by column chromatography (CH₂Cl₂:MeOH 95:5 for the amide) (CH₂Cl₂:MeOH 7:3 for the amine) . Recovered amine 50 mg (41% yield, er = 88:12); acylated product 70 mg (44% yield, er = 90:10). Calculated conversion c = 49%, s = 20.

(S) -1- (6, 7-Dimethoxy-l -phenyl-3, 4-dihydroisoquinolin-2 (1H)

-yl)pent-4-en-l- one (amide product)

[a] D (c = 3.5 CHC1₃) : +149.0 (er = 90:10) ;

¹H NMR (400 MHz, CDC1₃) δ 7.30-7.20 (m, 5H) , 6.90 (s, 0.8H), 6.72 (s, 0.2H), 6.70 (s, 0.8H), 6.60 (s, 0.2H), 6.55 (s, 0.8H), 5.90 (m, 1H) , 5.00 (m, 2H) , 3.90 (s, 2.7H), 3.80 (s, 0.5H), 3.75 (s, 3H) , 3.40 (m, 1H) , 2.95 (m, 1.5H), 2.75 (m, 1.5H), 2.60-2.40 (m, 4H) ;

¹³C NMR (100 MHz, CDC1₃) δ 170.7, 148.1, 147.7, 142.6, 137.5, 128.8, 128.2, 127.4, 127.0, 126.3, 115.3, 111.4, 111.1, 56.0, 55.9, 54.6, 39.4, 32.8, 29.3, 28.7;

HRMS (ESI) calculated for [C22H₂₆ 0₃]⁺ m/z = 352.1907 found m/z = 352.1899;

IR (u/cirf¹, neat) 2934, 1638, 1515, 1493, 1437, 1251, 1234, 1190, 1119;

SFC column: Daicel Chiralpak OJH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 5.5 min (major), 5.8 min (minor). (R) -6, 7-Dimethoxy-l -phenyl-1 ,2,3, 4-tetrahydroisoquinoline (recovered amine)

[a]²⁵ _D (c = 2.5, CHC1₃) : +14.8 (er = 88:12); HPLC column: Daicel Chiralpak OJH (4.6 ^χ 250 mm); eluent: 60% iPrOH in hexanes + 0.1% Et₃N, flow: 0.5 ml /min; detection: 254 nm. Retention time: t_R = 10.5 min (minor), 15.5 min (maj or ) .

Example 47: Kinetic Resolution of Racemic Ethyl piperi- dine-2-carboxylate with Polymer Supported Reagent (R,S) -10

Racemic ethyl piperidine-2-carboxylate (71.0 mg, 0.45 mmol, 1.00 equiv) , in CH₂C1₂ (2 ml) was resolved according to the general procedure of Example 31 by treatment with the polymer supported reagent 10 (Example 41; 300 mg, -1.00 mmol/g, -0.65 - 0.70 equiv) for 48 h. To the CH₂C1₂ solution from the resin wash was added Et₃N (25.0 mg, 0.25 mmol, 0.55 equiv) and benzylchloroformate (34.2 mg, 0.20 mmol, 0.45 equiv) and the reaction mixture was stirred for 8 h. The solvent was removed under reduced pressure and the reaction products were separated by column chromatography (hexanes : EtOAc 3:1 for the carbamate) (hexanes : EtOAc 1:1 for the amide). Recovered (Cbz protected) amine 55 mg (42% yield, er = 80:20); acylated product 60 mg (40% yield, er = 90:10).

Calculated conversion c = 43%, s = 17.

(R) -Ethyl 1- (3- (2-nitrophenyl)propanoyl)piperidine-2- carboxylate (amide product)

[ct] D (c = 3.0 CHC1₃) : +40.1 (er = 90:10);

^XH NMR (400 MHz, CDC1₃) δ 7.90 (m, 1H) , 7.52 (m, 1H) , 7.45 (m, 1H), 7.35 (m, 1H) , 5.35 (d, J = 5.4, 0.8H), 4.5 (m,

0.4H), 4.15 (m, 2H) , 3.75 (m, 0.8H), 3.25(m, 2.8H), 2.80 (m, 1.8H), 2.6 (m, 0.4H), 2.25 (m, 1H) , 1.80 (broad, 0.2H), 1.70-1.50 (m, 3H) , 1.40-1.30 (m, 1.8H), 1.30-1.20 (m, 3H);

¹³C NMR (100 MHz, CDC1₃) δ 171.7, 171.4, 171.3, 170.7, 149.3, 136.5, 136.5, 133.2, 132.7, 127.4, 124.7, 61.6, 61.1, 56.0, 52.1, 43.3, 39.6, 34.3, 34.0, 29.0, 28.9, 27.2, 26.6, 25.3, 24.6, 20.9, 20.8, 14.2, 14.2;

HRMS (ESI) calculated for [C17H23N2O5] ⁺ m/z = 335.1601 found m/z = 335.1595;

IR (u/cnf¹, neat) 2940, 2861, 1735, 1650, 1525, 1427, 1349, 1200, 1160, 1024; SFC column: Daicel Chiralpak ADH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 6.1 min (major), 6.4 min (minor) .

(S)-l-Benzyl 2-ethyl piperidine-1 , 2-dicarboxyla te

(recovered amine)

[a]^Z3D (c = 2.75 CHC1₃) : -26.5 (er = 80:20); SFC column: Daicel Chiralpak ODH (4.6 ^χ 250 mm); gradient: 5% IPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t R — 4. Z min (major), 4.6 min (minor) .

Example 48: Kinetic Resolution of Racemic 2-

Ethylpiperidine with Polymer Supported Reagent (R,S) -11

Resin beads 11 (Example 42; 300 mg, -1.00 mmol/g, 1.00 equiv) were treated with racemic 2-ethylpiperidine (170 mg, 1.50 mmol, -5.00 equiv) as a solution in CH₂C1₂ (3 ml) for 15 h. The CH₂C1₂ solution from the resin was washed with a 1 M HC1 solution (3 * 10 ml) and brine (1 ^χ 10 ml), dried over anhydrous Na₂S0₄ and concentrated under reduced pressure, to afford the amide product (60 mg; er = 92:8) . (S) -1- (2-Ethylpiperidin-l-yl)pent-4-en-l-one (amide product)

[a]² D (c = 3.0 CHC1₃) : +17.3 (er = 92:8) ;

^XH NMR (400 MHz, CDC1₃) δ 5.90 (m, 1H) , 5.05-4.95 (m, 2H) , 4.70 (m, 0.5H), 4.53 (m, 0.5H), 3.80 (m, 0.5H), 3.60 (apparent d, J = 12.8, 0.5H), 3.05 (m, 0.5H), 2.55 (m, 0.5H), 2.50 - 2.30 (m, 4H) , 1.80-1.20 (m, 8H) , 0.90-0.80 (m, 3H);

¹³C NMR (100 MHz, CDC1₃) δ 171.0, 170.8, 137.9, 137.8, 115.0, 54.3, 49.3, 41.0, 36.4, 29.6, 28.9, 27.6, 26.4, 25.5, 23.0, 22.3, 19.1, 10.9, 10.7;

HRMS (ESI) calculated for [C₁₂H₂iNONa] ⁺ : m/z = 218.1515 found m/z = 218.1518;

IR (u/cnf¹, neat) 2934, 1637, 1430, 1267, 1232, 1149, 1136,

1046;

SFC column: Daicel Chiralpak ADH (4.6 * 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R - 3.7 min (minor), 4.1 min (major) .

Example 49: General Procedure of the Synthesis of

Hydroxamic Acids NEt₃

*HCI

DIPEA

CH2CI2 O rt

R2^H

DIPEA

6

Preparation of 2

Amino acid 1 (1 equiv.) was added to a round bottom flask and suspended in dry THF (0.3 M) under N₂ atmosphere. The suspension was cooled to 0 °C and triethylamine (2.2 equiv.) was added. After 15 min Ethyl chloroformate (1.1 equiv.) was added dropwise and the solution was stirred for an additional hour. H₂NOBn*HCl (1.3 equiv.) was in one portion to yield a suspension which was stirred for 30 min at 0 °C and then 24 hours at room temperature. The reaction was stopped with saturated NH₄C1 solution and extracted three times with CH₂C1₂. The combined organic layers were washed with saturated NaHC0₃ solution and brine and dried over anhydrous Na₂S0₄. The solvent was removed in vacuo to yield the product as a colorless solid in 70-90% yield. Preparation of 3

2 was dissolved in CH₂C1₂ (0.15 M) and 1.5% H₂0 was added. Then 50% TFA was added slowly and the mixture stirred for one hour. The solvent was removed in vacuo and the oily residue purified by column chromatography (CH₂C1₂ : eOH = 10:1) to yield the product as a colorless solid in 80-90% yield .

Preparation of 4

3 (1 equiv.) was dissolved in CH₂C1₂ (0.1 ) under N₂ atmosphere, followed by the addition of DIPEA (2 equiv.) and an aldehyde (1.2 equiv.) . The solution was stirred at 45 °C until TLC showed completion of the reaction (~1-10 hours) . The solvent was removed in vacuo and the residue purified by column chromatography (Hex:EtOAc 9:1 - 2:1 gradient) to yield the two diastereomers as colorless oil or solid in 80-95% yield.

Preparation of 5

The two diastereomers 4 (1 equiv) were dissolved in dry CH₂C1₂ under N₂ atmosphere, followed by the addition of DIPEA (2.1 equiv.) and the acyl donor (2 equiv.) . The solution was stirred at room temperature for 5-24 hours until the reaction was complete. The solvent was removed in vacuo and the residue purified via column chromatography ( Hex : EtOAc = 9:1 -> 2:1 gradient) to yield the two separated diastereomers as colorless oils or solids in 20- 40% each.

Preparation of 6

5 was dissolved in EtOH (0.05 M) and a spatula tip of Pd(OH)₂/C was added. The solution was stirred under H₂ atmosphere for 1-10 hours until completion of the reaction. The solution was filtered over Celite and the solvent removed in vacuo. The oily residue was purified by column chromatography (CH₂Cl₂:MeOH = 50:1) to yield the product as a pale reddish oil in 70-95% yield.

Example 50: Cleavage of the Amide Group

I₂ (152 mg, 0.60 mmol, 3.00 equiv) was added to a 1:1 THF/H₂0 solution (4 ml) of the amide ( er = 90:10) (70 mg, 0.20 mmol, 1.00 equiv), the resulting dark mixture was stirred at 23 °C for 4 h. After completion, the excess I₂ was quenched with saturated Na₂S₂0₃ aqueous solution (3 ml) and solid K₂C0₃ was added to adjust the pH to 8-9. The aqueous layer was extracted with CH₂C1₂ (4 * 5 ml) and the combined organic phases were dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. Purification by column chromatography provided the amine (40 mg, 74 %) . Racemization was not observed judging from the SFC analysis. The amine was converted into an amide by treatment with 3- phenylpropanoyl chloride and Et₃N to determine er.

SFC column: Daicel Chiralpak ASH (4.6 ^χ 250 mm); gradient: 5% iPrOH in C0₂ to 50% iPrOH in C0₂ over 10 min; flow: 3.0 ml/min; detection: 254 nm. Retention time: t_R = 7.3 min (major), 9.2 (minor).

Example 51: Preparation of (4£7, 6E) -2-Hydroxy-2-methyl-7- phenylhepta-4 , 6-dien-3-one

trans-Cinnamaldehyde (2.5 ml, 20.0 mmol), 3-hydroxy-3- methyl-2-butanone (2.1 ml, 20.0 mmol) and LiOH^«H₂0 (0.84 g, 20.0 mmol) were dissolved in a mixture of MeOH and water (3:1, 50 ml) and the reaction mixture was stirred at 23 °C for 3 days. MeOH was removed under reduced pressure and the remaining aqueous phase was extracted with CH₂C1₂ (3 ^χ 50 ml). The combined organic layers were dried (Na₂S0₄) , filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) and the resulting product was washed with ethyl acetate and hexane to give the a ' -hydroxydienone (1.57 g, 36%) as a fine yellow powder.

¹³C MR (75 MHz, CDCI₃) : δ [ppm] = 202.7, 145.6, 143.2,

136.0, 129.6, 129.0, 127.5, 126.5, 121.9, 75.5, 26.7;

^XH NMR (300 MHz, CDCI₃) : δ [ppm] = 7.63 (ddd, J = 14.9,

10.4, 0.6 Hz, 1H), 7.53-7.45 (m, 2H) , 7.42-7.29 (m, 3H) , 7.07—.6.87 (m, 2H) , 6.59 (d, J = 14.7 Hz, 1H) , 4.03 (s, 1H) , 1.43 (s, 6H) .

Example 52: Procedure for Kinetic Resolution with α'- Hydroxydienone

Hydroxamic acid co-catalyst 1 (Example 18; 7.1 mg, 25 pmol, 0.05 equiv) , triazolium salt (16.4 mg, 50 μιηοΐ, 0.10 equiv) , a ' -hydroxydienone (75.6 mg, 0.35 mmol, 0.70 equiv), K₂C0₃ (13.8 mg, 0.1 mmol, 0.20 equiv) and 3- benzylmorpholine (88.6 mg, 0.50 mmol, 1.00 equiv) were dissolved in THF (2.5 ml, 0.20 M) and the reaction mixture was stirred at 23 °C for 36 hours.

Ethyl acetate (2.5 ml) was added and the organic phase was washed with 1 M HC1 (3 > 2 ml) and the organic layer was dried (Na₂S0₄) and concentrated in vacuo to give the crude amide product, which was purified by column chromatography. The combined acidic aqueous phases were basified with solid K₂C0₃, extracted with CH₂C1₂ (3 * 5 ml) , dried (Na₂S04) and concentrated in vacuo to give the recovered amine.

Recovered amine: 59 mg (66%, er = 70:30); acylated product: 52 mg (31%, er = 93:7) .

Calculated conversion: 32%; s = 20. Example 53 : Procedure to Remove the Acylating Group

The amide of example 52 (20 mg, 60 μιτιοΐ, 1 equiv) was dissolved in THF (0.5 ml). Water (0.5 ml) and I₂ (45 mg, 0.18 mmol, 3 equiv) were added and the resulting mixture was stirred at 23 °C for 3 hours. The reaction was quenched by saturated aqueous Na₂S₂0₃ solution, basified by solid K₂C0₃, and extracted with CH₂C1₂ (3 ^χ 3 ml) . The combined organic phases were washed with 1 M HC1 (3 ^x 2 ml) and the resulting combined acidic aqueous phases were basified with solid K₂C0₃, extracted with CH2CI2 (3 ^χ 5 ml), dried (Na₂S0₄) and concentrated in vacuo to give the recovered amine. The recovered amine and K₂C0₃ (8.3 mg, 60 μπιοΐ, 1 equiv) were dissolved in CH₂C1₂ (1 ml) and benzyl chloroformate (8.6 μΐ, 60 pmol, 1 equiv) was added at 23 °C. After 3 hour saturated aqueous NaHC0₃ (5 ml) was added and the aqueous phase was extracted with CH₂C1₂ (3 * 3 ml) . The combined organic layers were washed with brine, dried (Na₂S0₄) , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (10 mg, 51%, er = 93:7).

Claims

Method for the kinetic resolution of a chiral primary or secondary amine by treating the amine with a chiral reagent of the formula (I)

wherein

Rl is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkoxycarbonyl, alkyl- amino, alkylamido, alkylthio, aryl, heteroaryl, halogen, and heterocyclyl;

W is selected from the group consisting of 0, NH, NR, and S;

R is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl; m is 0 or 1;

R2 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkoxycarbonyl, alkyl- amino, alkylamido, alkylthio, aryl, heteroaryl, halogen, and heterocyclyl; Rl and R2 are optionally forming a four-, five-, six- or seven-membered ring, which is substituted;

X is selected from the group consisting of 0, NH, NR, and S;

Y is selected from the group consisting of 0, NH, NR, and S ; n is 0 or 1; and

R3 is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkylamino, and alkylthio; wherein Rl and/or R2 comprises at least one stereogenic center.

Method according to claim 1, characterized in that R2 comprises a stereogenic center in a-position.

Method according to claim 1 or 2, characterized in that Rl and R2 are forming a five- or six-membered ring .

Method according to one of claims 1 to 3, characterized in that X is O.

Method according to one of claims 1 to 4, characterized in that n is 1 and Y is O.

6. Method according to one of claims 1 to 4, characterized in that n is 0 and R3 is an alkyl group, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkylamino, and alkylthio.

Method according to one of claims 1 to 6, characterized in that the chiral reagent is linked to a peptide.

Method according to one of claims 1 to 7, characterized in that the chiral reagent is linked to a solid support.

Method according to one of claims 1 to 8, characterized in that the chiral reagent is selected from the group consisting of

(IV)

and

wherein

X is selected from the group consisting of 0, NH, NR, and S;

R is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl;

Y is selected from the group consisting of O, NH, NR, and S; n is 0 or 1; R3 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkylamino, and alkylthio;

R4 and R5 are, independently, selected from the group consisting of hydrogen, alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkylamino, alkylthio, aryl, heteroaryl, halogen, and heterocyclyl, and/or linked to a peptide or solid support;

R6 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, alkoxy, and halogen, and/or linked to a peptide or solid support;

R6 is optionally forming a five-, six- or seven- membered ring with R4 or R5, which is optionally substituted;

R7 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, halogen, nitro, alkoxy, alkylamino, alkylthio, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, aryl, heteroaryl, and alkoxy, and/or linked to a peptide or solid support; and

* denotes a stereogenic center.

10. Method according to claim 9, characterized in that the chiral reagent is

or its enantiomer (IX')_/ wherein

Y is selected from the group consisting of O, NH, NR, and S;

R is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl; n is 0 or 1 ;

R3 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkylamino, and alkylthio; and wherein the chiral reagent is optionally linked to a peptide or solid support.

11. Method according to one of claims 1 to 10, characterized in that the chiral reagent is formed in situ by reaction of

R2 (XI) with X (XII) in the presence of an N-heterocyclic carbene, to afford the chiral reagent (I), wherein n is 0 and R3 is -(CH₂)₂R8.

12. Method according to claim 11, characterized in that the W-heterocyclic carbene is

13. Method according to one of claims 1 to 12, characterized in that the chiral reagent (I) is derived from hydroxylamine (XXIV)

or its enantiomer (XXIV ) .

Method according to one of claims 1 to 13, characterized in that the chiral amine is a secondary amine, preferably a cyclic amine.

Method according to claim 14, characterized in that the chiral amine is a substituted morpholine, piperidine, piperazine, azepane, diazapine, oxazapine, thiazapine, pyrrolidine, imidazolidine , oxazolidine, thiazolidine, tetrahydroisoquinoline or a bicyclic diamine.

Method according to one of claims 1 to 15, characterized in that the chiral amine has at least one stereogenic center in a-position. Chiral reagent of the formula

wherein

W is selected from the group consisting of 0, NH, NR, and S;

R2 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, alkenyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkoxycarbonyl, alkylamino, alkylamido, alkylthio, aryl, heteroaryl, halogen, and heterocyclyl;

Rl and R2 are optionally forming a four-, five-, six- or seven-membered ring, which is substituted;

X is selected from the group consisting of 0, NH, NR, and S; Y is selected from the group consisting of 0, NH, NR, and S; n is 0 or 1; and

18. Chiral reagent according to claim 17, characterized in that R2 comprises a stereogenic center in opposition .

19. Chiral reagent according to claim 17 or 18, characterized in that Rl and R2 are forming a five- or six-membered ring.

20. Chiral reagent according to one of claims 17 to 19, characterized in that X is 0.

21. Chiral reagent according to one of claims 17 to 19, characterized in that n is 1 and Y is 0.

22. Chiral reagent according to one of claims 17 to 19, characterized in that n is 0 and R3 is an alkyl group, which may optionally be substituted by a group selected from alkyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkylamino, and alkylthio.

23. Chiral reagent according to one of claims 17 to 22, characterized in that the chiral reagent is linked to a peptide or a solid support.

24. Chiral reagent according to one of claims 17 to 23, being^' selected from the group consisting of

X is selected from the group consisting of 0, NH, NR, and S;

R is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl; Y is selected from the group consisting of 0, NH, NR, and S; n is 0 or 1;

R3 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkylamino, and alkylthio;

R6 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, alkoxy, alkylamino, alkylthio, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, aryl, heteroaryl, alkoxy, and halogen, and/or linked to a peptide or solid support;

R7 is selected from the group consisting of alkyl, alkoxy, alkenyl, heterocyclyl, halogen, nitro, alkoxy, alkylamino, alkylthio, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, aryl, heteroaryl, and alkoxy, and/or linked to a peptide or solid support; and

* denotes a stereogenic center.

25. Chiral reagent according to claim 24, having the formula (IX)

or its enantiomer (IX' ), wherein Y is selected from the group consisting of 0, NH, NR, and S;

R is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl; n is 0 or 1;

Chiral reagent according to claim 25, characterized in that n is 0 and R3 is -(CH₂)₂Mes.

Precursor of the formula (XIV)

(XIV) wherein

Rl is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkoxycarbonyl, alkylamino, alkylamido, alkylthio, aryl, heteroaryl, halogen, and heterocyclyl; is selected from the group consisting of 0, NH, NR, and S ;

R is selected from the group consisting of alkyl, alkenyl, heterocyclyl , aryl, heteroaryl, alkyl- carbonyl, and alkoxycarbonyl; m is 0 or 1;

R2 is selected from the group consisting of alkyl, alkenyl, heterocyclyl, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, alkenyl, alkoxy, alkoxycarbonyl, alkylamino, alkylamido, alkylthio, aryl, heteroaryl, halogen, and heterocyclyl; and

Rl and R2 are optionally forming a four-, five-, six- or seven-membered ring, which is substituted; wherein Rl and/or R2 comprises at least one stereogenic center.

Precursor according to claim 27, characterized in that R2 comprises a stereogenic center in a-position.

Precursor according to claim 27 or 28, characterized in that Rl and R2 are forming a five- or six-membered ring .

Precursor according to one of claims 27 to 29, characterized in that the precursor is linked to a peptide or a solid support.

Precursor according to one of claims 27 to 30, being selected from the group consisting of

and

wherein

R7 is selected from the group consisting of alkyl, alkoxy, alkenyl, heterocyclyl, halogen, nitro, alkoxy, alkylamino, alkylthio, aryl, and heteroaryl, which may optionally be substituted by a group selected from alkyl, aryl, heteroaryl, and alkoxy, and/or linked to a peptide or solid support; and * denotes a stereogenic center.

32. Precursor according to claim 31, having the formula (XXII)

or being the enantiomer (XXII' ) of (XXII), wherein the precursor is optionally linked to a peptide or solid support.

33. Precursor according to claim 31, having the formula (XXIV)

or being the enantiomer (XXIV ) of (XXIV) .