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Title:
CHIRAL LIGANDS FOR ASYMMETRIC CATALYSIS
Document Type and Number:
WIPO Patent Application WO/2006/002470
Kind Code:
A1
Abstract:
The present invention provides transition metal complexes of enantiomerically enriched compounds for use as catalysts in asymmetric transformations.

Inventors:
Perlmutter, Patrick (53 Munro Avenue, Ashburton, Victoria 3147, AU)
Thienthong, Neeranat (17 Plenty River Drive, Greensborough, Victoria 3088, AU)
Application Number:
PCT/AU2005/000963
Publication Date:
January 12, 2006
Filing Date:
June 30, 2005
Export Citation:
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Assignee:
MONASH UNIVERSITY (Wellington Road, Clayton, Victoria 3800, AU)
Perlmutter, Patrick (53 Munro Avenue, Ashburton, Victoria 3147, AU)
Thienthong, Neeranat (17 Plenty River Drive, Greensborough, Victoria 3088, AU)
International Classes:
B01J31/22; C07C53/134; C07C61/00; C07D413/04; (IPC1-7): C07D413/04; B01J31/22; C07C61/00; C07C53/134
Other References:
DATABASE CA [online] THIENTHONG N ET AL: "Anew class of nitrogen based chiral ligands: 2H-1,3 benzoxazines.Ligand synthesis X ray strutural studies and asymmetric catalysis", accession no. stn Database accession no. 143:26548
DATABASE CA [online] MIZUFUNE H ET AL: "Process development of potassium channel opener,TCV-295 based on convenient ring information of 2H-1,3 benzoxazine and selective N oxidation of the pyridyl moiety", accession no. stn Database accession no. 135:371695
DATABASE CA [online] SCHMIDT R R ET AL: "3-azapyrylium salts VI alkyliden-1,3 oxazines and alkylidenepyrimides", accession no. stn Database accession no. 73:109753
DATABASE WPI Week 199542, 1 August 1995 Derwent World Patents Index; Class B02, AN 1995-322961
DATABASE WPI Week 199410, 3 March 1994 Derwent World Patents Index; Class B02, AN 1994-083073
DATABASE WPI Week 199214, 1 April 1992 Derwent World Patents Index; Class B02, AN 1992-106200
DATABASE WPI Week 198238, 13 August 1982 Derwent World Patents Index; Class B02, AN 1982-80042
Attorney, Agent or Firm:
Caine, Michael J. (Davies Collison Cave, 1 Nicholson Street Melbourne, Victoria 3000, AU)
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Claims:
CLAIMS:
1. A transition metal complex of an enantiomerically enriched compound of the general formula (I) wherein R and R1, which cannot be the same, independently represent hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or R and R1 are linked together to form a substituted asymmetric cycloalkyl or cycloalkenyl group, R2, R3, R4 and R5 each independently represent hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted oxyacylamino, optionally substituted oxyacyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, nitro, cyano, trihalomethyl, hydroxyl, carboxyl, optionally substituted mono and dialkylamino, optionally substituted acylamino, optionally substituted aminoacyl, or an amino group, or one of R2, R3, R4 and R5 is a divalent linker group bound to a polymer solid support ; and R6 is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted oxyacylamino, optionally substituted oxyacyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted mono and di alkylamino; or one of R, R1, R2 and R6 is a group YZ, where Y is a direct bond or a divalent linker group having a length equivalent to 0 to 6 single CC bonds, and Z is a group of the formulae (II), (III), or (IV), where R, R1, R2, R3, R4 and R5 are independently selected and are as described above.
2. A complex according to claim 1 wherein the compound of general formula (I) is enantiomerically pure.
3. A complex according to claim 1 or claim 2 wherein the transition metal is selected from Ru, Ir, Rh, Zn, Re, Au, Ag, Ni, Pt, Cu, or Pd.
4. A complex according to claim 3 wherein the transition metal is selected from Zn, Pt, Rh, or Pd.
5. A complex according to any one of claims 1 to 4 wherein R and R1 are independently selected from a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl group, or together represent a substituted chiral cycloalkyl group.
6. A complex according to any one of claims 1 to 5 wherein one or more of the R2 to R5 substituents are either electron withdrawing or electron donating groups.
7. A complex according to any one of claims 1 to 4 wherein one of R, R1, R2, and R6 is the group YZ where Y represents a direct bond, an optionally substituted alkenylene, optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene or optionally substituted heteroarylene group, and Z is a group of formulae (II), (III), or (IV).
8. A complex according to claim 7 wherein YZ represents a group of formulae (a) to (f); where R7 and R8 are independently selected from, hydrogen, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkaryl, or together represent an optionally substituted cycloalkyl or cycloalkenyl group.
9. A complex according to any one of claims 1 to 6 wherein R is an optionally substituted aryl, optionally substituted alkyl or optionally substituted heteroaryl group.
10. A complex according to claim 9 wherein R6 represents a group of formulae (g), (h), (i) or Q): G) .
11. A complex according to any one of claims 1 to 10 wherein one of R2 to R5 is a divalent linker group bound to a polymer solid support.
12. A complex according to any one of claims 1 to 11 wherein the enantiomerically enriched compound of general formula (I) is capable of bi, tri, quaternary, or penta dentate metal coordination.
13. A method of preparing a complex according to any one of claims 1 to 12 comprising contacting an enantiomerically enriched compound of general formula (I): wherein R and R1, which cannot be the same, independently represent hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or R and R1 are linked together to form a substituted asymmetric cycloalkyl or cycloalkenyl group, R2, R3, R4 and R5 each independently represent hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted oxyacylamino, optionally substituted oxyacyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, nitro, cyano, trihalomethyl, hydroxyl, carboxyl, optionally substituted mono and dialkylamino, optionally substituted acylamino, optionally substituted aminoacyl, or an amino group, or one of R2, R3, R4 and R5 is a divalent linker group bound to a polymer solid support ; and R6 is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted oxyacylamino, optionally substituted oxyacyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted mono and di alkylamino; or one of R, R1, R2 and R6 is a group YZ, where Y is a direct bond or a divalent linker group having a length equivalent to 0 to 6 single CC bonds, and Z is a group of the formulae (II), (III), or (IV), where R, R1, R2, R3, R4 and R5 are independently selected and are as described above, with a reactive transition metal or transition metal complex for a time and under conditions sufficient to form a transition metal complex of an enantiomerically enriched compound of the general formula (I).
14. The method of claim 13 wherein the reactive transition metal complex is selected from one of the following: [Rh(COD)Cl]2, [Rh(COD)2]X, [Ir(COD)Cl]2, [Ir(COD)2]X, (where X=BF4, ClO4, SbF6, CF3SO3), Ru(COD)Cl2, Pd(CH3CN)4[BF4]2, Pd2(dba)3 and [Pd(C3H5)Cl]2, Pd2(dba)3, [Pd(C3H5)Cl]2, PtCl2, PtCl(Me)(SMe2)2, PtCl2(SMe2), [Pd(allyl)Cl]2, Rh(acac)(CO)2, Rh(ethylene)2(Acac), RIi(CO)2Cl2, Ru(RCOO)2(diphosphine), Ru(methylallyl)2 (diphosphine), RuCl2(=CHR)(PR'3)2, Cu(OTf), Cu(OTf)2, Cu(Ar)X1, CuX1, NiX'2, Ni(COD)2, MoO2(acac)2, Ti(OiPr)4, VO(acac)2, MeReO4, ZnCl2, ZnEt2, MnX'2 or Mn(acac), (where each X1 is independently selected from BF4, ClO4, SbF6, or CF3SO3, Ar is an aryl group and R and R' can independently represent an aryl or alkyl group).
15. A method of performing an asymmetric transformation comprising contacting the compound to be transformed with a catalytic amount of a transition metal complex of an enantiomerically enriched compound of the general formula (I) wherein R and R1, which cannot be the same, independently represent hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or R and R1 are linked together to form a substituted asymmetric cycloalkyl or cycloalkenyl group, R2, R3, R4 and R5 each independently represent hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted oxyacylamino, optionally substituted oxyacyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, nitro, cyano, trihalomethyl, hydroxyl, carboxyl, optionally substituted mono and dialkylamino, optionally substituted acylamino, optionally substituted aminoacyl, or an amino group, or one of R2, R3, R4 and R5 is a divalent linker group bound to a polymer solid support ; and R6 is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted oxyacylamino, optionally substituted oxyacyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted mono and di alkylamino; or one of R, R1, R2 and R6 is a group YZ, where Y is a direct bond or a divalent linker group having a length equivalent to 0 to 6 single CC bonds, and Z is a group of the formulae (II), (III), or (IV), where R, R1, R2, R3, R4 and R5 are independently selected and are as described above.
16. Use of a transition metal complex of an enantiomerically enriched compound of the general formula (I) according to any one of claims 1 to 12 to catalyse an asymmetric transfoπnation.
17. Use according to claim 16 wherein the asymmetric transformation is an asymmetric hydridetransfer reaction, hydrosilylation, alkene hydrogenation, allylic substitution, cycloaddition reaction, Heck reaction, hydroformylation, conjugate addition reaction, a nucleophilic addition to a carbonyl compound, an expoxidation, dihydroxlation, or an aminohydroxylation.
18. Use according to claim 16 or 17 wherein the transition metal complex is prepared immediately prior to use in the asymmetric transformation.
19. Use according to claim 16 or 17 wherein the transition metal complex is prepared in situ.
20. Use according to claim 16 or 17 wherein the asymmetric transformation is performed with 50.01 mol% of the transition metal complex.
21. Use according to claim 16 or 17 wherein the transition metal complex is defined according to claim 11 and the asymmetric transformation is performed under solidphase conditions.
22. An enantiomerically enriched compound of general formula (I): wherein R and R1, which cannot be the same, independently represent hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or R and R1 are linked together to form a substituted asymmetric cycloalkyl or cycloalkenyl group, R , R , R and R each independently represent hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted oxyacylamino, optionally substituted oxyacyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, nitro, cyano, trihalomethyl, hydroxyl, carboxyl, optionally substituted mono and dialkylamino, optionally substituted acylamino, optionally substituted aminoacyl, or an amino group, or one of R2, R3, R4 and R5 is a divalent linker group bound to a polymer solid support ; and R6 is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted oxyacylamino, optionally substituted oxyacyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted mono and di alkylamino; or one of R, R1, R2 and R6 is a group YZ, where Y is a direct bond or a divalent linker group having a length equivalent to 0 to 6 single CC bonds, and Z is a group of the formulae (II), (III), or (IV), where R, R1, R2, R3, R4 and R5 are independently selected and are as described above, for use in the preparation of catalysts for asymmetric transformations.
23. A compound according to claim 22 wherein R and R1 are independently a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl or together represent a substituted chiral cycloalkyl group.
24. A compound according to claim 22 or 23 wherein one or more of the R to R substituents are either electron withdrawing or electron donating groups.
25. A complex according to claim 22 wherein one of R, R1, R2, and R6 is the group Y Z where Y represents a direct bond, an optionally substituted alkenylene, optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and Z is a group of formulae (II), (III), or (IV).
26. A compound according to claim 25 wherein YZ represents a group of formulae (a) to (f); where R and R are independently selected from, hydrogen, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkaryl, or together represent an optionally substituted cycloalkyl or cycloalkenyl group.
27. A compound according to any one of claims 22 to 24 wherein R6 is an optionally substituted aryl, optionally substituted alkyl or optionally substituted heteroaryl group.
28. A compound according to claim 27 wherein R6 represents a group of formulae (g), (h), (i) or Q): G) .
29. A compound according to any one of claims 20 to 28 wherein one of R to R is a divalent linker group bound to a polymer solid support.
30. A compound according to any one of claims 22 to 29 capable of bi, tri, quaternary, or pentadentate metal coordination.
Description:
CHIRAL LIGANDS FOR ASYMMETRIC CATALYSIS

The invention relates to asymmetric organic synthesis, and in particular to chiral ligands and organometallic catalysts derived from these chiral ligands, and to synthetic processes which use such catalysts in asymmetric transformations.

In the last century, molecular chirality has grown as an increasingly important issue in many areas of science and technology. Chirotechnology has developed because of the need in many fields to produce single enantiomers of chiral molecules. For instance, the biological activities of many chiral pharmaceuticals and agrochemicals are dependent on their absolute molecular configuration, as the activity of one enantiomer may be markedly different from its opposite enantiomer or, for that matter, the racemate. Accordingly, there is a demand, especially in the pharmaceutical industry, for chiral compounds in enantiomerically pure form. In this regard, it has been estimated that the world wide sales of enantiomerically pure drugs was around $133 billion (US) in 2000 and may reach $200 billion by 2008.

Presently, there are many strategies available to prepare enantiomerically pure compounds. These range from optical resolution and structural modification of naturally occurring chiral compounds, to the use of chiral reagents or catalysts (including enzymes) to facilitate an asymmetric transformation of a pro-chiral substrate. Asymmetric catalysis has been found to be the most ideal way of producing enantiomerically pure compounds as it involves an integrated chemical approach where chiral efficiency can be obtained with a small amount of a chiral catalyst under the appropriate reaction conditions. The effectiveness of this approach is evident as it can generate a large quantity of the desired chiral compound while the catalyst can be recovered and reused in subsequent processes. The use of chiral organometallic molecular catalysts has proven to be most effective in such asymmetric synthetic strategies.

The asymmetric induction afforded by an organometallic catalyst is largely dependent on the chiral ligands that bind the intrinsically achiral metal atom. The properties of a chiral catalyst (structure and electronic nature) can induce discrimination between enantiotopic atoms, groups, or faces in prochiral and enantiomeric molecules.

Some of the most popular asymmetric catalysts currently available are the chiral bi and tri- dentate phosphines which form complexes with transition metals such as, for instance, Ruthenium (Ru), Rhodium (Rh), Palladium (Pd), Iridium (Ir) and Platinum (Pt). Some of the more well known phosphine ligands include DIPAMP (prepared using resolution techniques), BINAP (derived from binapthyl), DEGUPHOS (derived from tartaric acid), BPPM (derived from L-proline), SKEWPHOS (derived from R,R-pentane-2,4-diol) and DUPHOS (derived from enantiomerically pure phospholane). While high selectivities are observed in many reactions using these catalysts, there are many reactions where the ligands are not effective with respect to the activity and selectivity of the corresponding catalysts. There are further disadvantages associated with such ligands which limit their universal use. For example, for some of these ligands, their preparation is complex and tedious (eg, DIPAMP). Also, DIPAMP has only shown limited use in asymmetric hydrogenation reactions. The methylene group in SKEWPHOS and BPPM allows for conformational rearrangement/flexibility which is proposed to account for the moderate enantioselectivities observed in many reactions when using catalysts with these ligands. DEGUPHOS co-ordinates transition metals in a five membered ring. As a result, the created chiral environment is not close enough to the substrate and accordingly the observed enantioselectivity suffers. The binaphyl arrangement of BINAP means that this ligand is also quite flexible which limits its use. Also, the multitude of aryl groups makes the resultant BINAP based catalyst less electron donating than phosphines which bear less aryl substituents. This tends to slow reaction rates making the catalysts less efficient. Accordingly, phosphines attached to electron donating groups are generally preferred for hydrogenation reactions as they are observed to be more active.

Chiral nitrogen based ligands have also demonstrated utility in asymmetric transformations. For instance, catalysts incorporating chiral oxazolidines as a ligand framework have shown promise in various asymmetric reactions including the hydride- transfer reduction of ketones. The most popular representation of this class is the tridentate PYBOX ligand (bis(oxazolinylmethyl)pyridine) and its amine derivative, AMBOX. The two chiral groups which are positioned on the 4-carbon position of the oxazolidine rings enable better differentiation of the Re and Si faces of incoming substrates.

P,N-bidentate ligands from chiral oxazolidines and triphenyl phosphine are also known. For instance dihydro(phosphinophenyl)oxazole has been successfully applied to a range to enantioselective transition metal catalysed reactions. Pfaltz et ah, Helvetica Chimica Acta, Vol. 84 (2001) 3233, recently investigated the benzofused six-membered equivalents, particularly 1,3-benzoxazines. These ligands are similar to the PYBOX ligand framework wherein the stereogenic centre is positioned at the 4-carbon position of the benzoxazine moiety.

These ligands however are also not universally applicable and tend to suffer from the same problems already mentioned with respect to the diphosphine counterparts.

Accordingly, there is a need for alternate ligand frameworks, and catalysts derived therefrom, to assist in addressing some of the shortcomings of the currently available catalysts.

The present invention provides a transition metal complex of an enantiomerically enriched compound of the general formula (I)

wherein R and R1, which cannot be the same, independently represent hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or R and R1 are linked together to form a substituted asymmetric cycloalkyl or cycloalkenyl group,

R2, R3, R4 and R5 each independently represent hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted oxyacylamino, optionally substituted oxyacyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, nitro, cyano, trihalomethyl, hydroxyl, carboxyl, optionally substituted mono- and di-alkylamino, optionally substituted acylamino, optionally substituted aminoacyl, or an amino group, or one of R2, R3, R4 and R5 is a divalent linker group bound to a polymer solid support ; and

R6 is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted oxyacylamino, optionally substituted oxyacyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted mono- and di- alkylamino; or

one of R, R1, R2 and R6 is a group -Y-Z, where Y is a direct bond or a divalent linker group having a length equivalent to 0 to 6 single C-C bonds, and Z is a group of the formulae (II), (III), or (IV),

where R, R > 11, τ R> 55 are independently selected and are as described above.

These complexes are useful as catalysts to facilitate catalytic asymmetric transformations. Any reference to "catalyst" or "catalysts" or "metal catalyst" in the context of the present invention refers to the complexation product of a metal with the enantiomerically enriched compound of formula (I).

The present invention also provides the use of a transition metal complex of an enantiomerically enriched compound of formula (I) as a catalyst in a catalytic asymmetric transformation. When performing such an asymmetric transformation the transition metal complex should be present in a catalytically effect amount.

The present invention also provides a class of enantiomerically enriched (as well as enantiomerically pure) chiral ligands of the general formula (I), for use in the preparation of catalysts for asymmetric transformations.

One of the aims of the present invention is to provide a metal catalyst comprising an enantiomerically enriched compound of general formula (I) which provides high enantioselectivities and efficient substrate conversions. Accordingly, the phrase "a catalytically effective amount" refers to the amount of the transition metal complex of an enantiomerically enriched compound of general formula (I) which is required to generate desirable reactivity and selectivity in a method to which the catalyst is applied. Preferably, the amount is substantially less than the mole amount of the reactive substrate, for instance 20-0.001 mol %. The catalytic effect of the catalyst of the present invention is observed with an amount most preferably in the range of 5-0.01 mol%.

As used herein the term "enantiomerically enriched" means that the compound is in a form such that there is more of the enantiomer of general formula (I) than its enantiomeric pair. Such enantiomerically enriched chiral compounds display optical activity with respect to plane polarised light.

As used herein the term "enantiomerically pure" means that the enantiomer of formula (I) is substantially free of its enantiomeric pair. Enantiomeric purity is generally expressed in terms of enantiomeric excess or % e.e. For a pair of enantiomers [(+) and (-)] wherein the mixture of the two is given as the mole or weight fractions F(+) and FQ (wherein F(+) + F(.) =1) the enantiomeric excess is defined as F(+) - F(.). Accordingly, the percentage e.e is expressed by 100 x (F(+) - F(.)). As used herein the term "enantiomerically pure" refers to an enantiomer having a % e.e. of greater than 70%. Preferably the enantiomerically pure enantiomer has a % e.e. of greater than 85%, more preferably greater than 95%, and most preferably greater than 98%. Preferably, the compounds of formula (I) in respect of the present invention are utilised in enantiomerically pure form.

The benzoxazine compounds of general formula (I) are chiral by virtue of the non- equivalent substitution at the C-2 position (ie. R ≠ R1). Yet the present invention also includes such compounds which have more than one chiral or "asymmetric centre". In this regard, depending upon the substituents R-R6 the compounds of general formula (I) may possess multiple asymmetric centres. Where the compounds of the present invention possess asymmetric centres additional to that at C-2 it is preferred that these additional asymmetric centres are enantiomerically pure. It is also preferred that the compounds of general formula (I) are substantially free of diastereomers.

"Alkyl" refers to monovalent alkyl groups which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, π-propyl, /so-propyl, n-butyl, iso- butyl, «-hexyl, and the like.

"Alkylene" refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), and the propylene isomers (e.g., -CH2CH2CH2- and -CHCH3)CH2-), and the like.

"Aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), preferably having from 6 to 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl and the like.

"Arylene" refers to a divalent aryl group wherein the aryl group is as described above.

"Aryloxy" refers to the group aryl-O- wherein the aryl group is as described above.

"Alkaryl" refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.

"Alkaryloxy" refers to the group alkylaryl-O- wherein the alkylaryl group is as described above. Such alkaryloxy groups are exemplified by benzyloxy and the like.

"Alkoxy" refers to the group alkyl-O- where the alkyl group is as described above. Examples include, methoxy, ethoxy, π-propoxy, zsopropoxy, «-butoxy, tert-butoxy, sec- butoxy, n-pentoxy, w-hexoxy, 1,2-dimethylbutoxy, and the like.

"Alkenyl" refers to a monovalent alkenyl group which may be straight chained or branched and preferably have from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and have at least 1 and preferably from 1-2, carbon to carbon, double bonds. Examples include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), wo-propenyl (-C(CH3)=CH2), but-2-enyl (-CH2CH=CHCH3), and the like.

"Alkenyloxy" refers to the group alkenyl-O- wherein the alkenyl group is as described above.

"Alkenylene" refers to divalent alkenyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethenylene (-CH=CH-), and the propenylene isomers (e.g., -CH2CH=CH- and -C(CH3)=CH-), and the like.

"Alkynyl" refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1, and preferably from 1-2, carbon to carbon, triple bonds. Examples of alkynyl groups include ethynyl (-C≡CH), propargyl (-CH2C≡CH) and the like.

"Alkynyloxy" refers to the group alkynyl-O- wherein the alkynyl groups is as described above. "Alkynylene" refers to the divalent alkynyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethynylene (-C≡C-) , propynylene (-CH2-C≡C-) , and the like.

"Acyl" refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

"Oxyacyl" refers to groups alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl- OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

"Aminoacyl" refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

"Acylamino" refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.

"Acyloxy" refers to the groups -OC(O)-alkyl, -OC(O)-aryl, -C(O)O-heteroaryl, and -C(O)O-heterocyclyl where alkyl, aryl, heteroaryl and heterocyclyl are as described herein.

"Aminoacyloxy" refers to the groups -OC(O)NR-alkyl, -OC(O)NR-aryl, -OC(O)NR- heteroaryl, and -OC(O)NR-heterocyclyl where R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein. "Oxyacylamino" refers to the groups -NRC(O)O-alkyl, -NRC(O)O-aryl, -NRC(O)O- heteroaryl, and NRC(O)O-heterocyclyl where R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

"Cycloalkyl" refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 8 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.

"Cycloalkenyl" refers to cyclic alkenyl groups having a single cyclic ring and at least one point of internal unsaturation, preferably incorporating 4 to 8 carbon atoms. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclohex-4-enyl, cyclooct-3-enyl and the like.

"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

"Heteroaryl" refers to a monovalent aromatic carbocyclic group, preferably of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Preferably the heteroatom is nitrogen. Such heteroaryl groups can have a single ring (e.g., pyridyl, pyrrolyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).

"Heterocyclyl" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen.

Examples of heterocyclyl and heteroaryl groups include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7- tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.

"Heteroarylene" refers to a divalent heteroaryl group wherein the heteroaryl group is as described above.

"Heterocyclylene" refers to a divalent heterocyclyl group wherein the heterocyclyl group is as described above.

In this specification "optionally substituted" is taken to mean that a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, acylamino, cyano, halogen, nitro, sulphate, phosphate, phosphine, heteroaryl, heterocyclyl, oxyacyl, oxyacylamino, aminoacyloxy, trihalomethyl, mono- and di-alkylamino, mono-and di- (substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, aryl, heteroaryl and heterocyclyl, and the like. In the case of divalent groups, the term "optionally substituted" also indicates that one or more saturated carbon atoms may be substituted for a heteroatom or heterogroup, such as O, S, NH and the like. For example an optionally substituted alkylene group could be represented by a group such as -CH2CH2OCH2-, -CH2CH2NH-CH2-, -CH2NHCH2-, CH2CHOCH2 and the like.

NH2 "Divalent linker group" is taken to mean a divalent group capable of forming a stable bridge between the core structure of formula (I) and a group of formulae (II), (III), or (IV). Examples of divalent linker groups include alkylene, alkenylene, alkynylene, arylene, heteroarylene, heterocyclylene, alkylenearylene, alkylenearylenealkylene, alkyleneheteroarylenealkylene, alkyleneheterocyclylenealkylene, and the like.

In relation to the metal catalyst of the present invention, the substituents R and R1 to R6 are groups that may be selected for their chemical stability under the reaction conditions selected for either preparing the ligand framework, or catalyst thereof, or under the conditions for carrying out a catalytic asymmetric transformation.

R and R1 substituents are groups which enable chiral induction while at the same time do not interfere with co-ordination of a metal atom. Preferably R and R1 are independently a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl or together represent a substituted chiral cycloalkyl group. More • preferably R and R1 are independently selected from a hydrogen atom and an optionally substituted alkyl group or together represent a substituted asymmetric cycloalkyl group.

The benzoxazine nitrogen is capable of coordinating with a metal atom to form a metal complex with the ligand framework, and as such, the ligand framework of general formula (I) encompasses ligands capable of mono-, bi-, tri-, quaternary-, and penta-dentate metal coordination.

Any one of R, R1, R2, and R6 may be a group which provides extra ligand denticity and as such may be a group which contains suitably placed heteroatom(s) like nitrogen and/or phosphorus, which can co-ordinate with a metal atom. Such groups which provide sites for added co-ordination to a metal are referred to herein as "co-ordination groups". Such preferred groups include substituted alkyl, substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or the group -Y-Z, where Y is a direct bond or a divalent linker group having a length equivalent to 1 to 6 single C-C bonds, and may represent an optionally substituted alkenylene, optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, optionally substituted alkylenearylene, optionally substituted alkylenearylenealkylene, optionally substituted alkyleneheteroarylenealkylene, optionally substituted alkyleneheterocyclylenealkylene, and Z a group of formulae (II), (III), or (IV).

More preferably, one of R, R1, R2, and R6 is the group -Y-Z where Y represents a direct bond, an optionally substituted alkenylene, optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and Z is a group of formulae (II), (III), or (IV).

Examples of R, R1, R2, and R6 moieties which may be representative of the -Y-Z group include those of formulae (a) to (f);

where R7 and R8 are independently selected from, hydrogen, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkaryl, or together represent an optionally substituted cycloalkyl or cycloalkenyl group.

Preferably R6 is an optionally substituted aryl, optionally substituted alkyl or optionally substituted heteroaryl group. Examples of R substituents which are representative of optionally substituted aryl, optionally substituted alkyl, and optionally substituted heteroaryl groups are those of formulae (g), (h), (i), and (j).

C)

In relation to compounds of general formula (I) the benzoxazine nitrogen is capable of coordinating with a metal atom to form a metal complex with the ligand framework, and as such, the ligand framework of general formula (I) encompasses ligands capable of mono-, bi-, tri-, quaternary- and penta-dentate metal coordination. By way of example the below structures illustrate some of possible ligand frameworks which are encompassed by the present invention. The elements in the highlighted circles ( @ and @ ) are illu- strative of potential co-ordination groups, which provide for ligand denticity. Apart from the benzoxazine nitrogen Q preferred co-ordinating groups are those which are known in the art and accordingly, Q may represent -NH, -NH2, -N-, -NR2, -NR'-, -PR2, in which each R is an optionally substituted alkyl or optionally substituted aryl group, or a heterocyclic group, for example a pyridine, oxazole, pyrrole or the like. As also illustrated below, depending upon the substitution pattern it is possible to obtain symmetrical ligand frameworks and both C1 and C2 symmetrical ligand frameworks are encompassed by the present invention. Monodentate

Tridentate

Preferably one or more of R2 to R5 substituents are hydrogen. One or more of these substituents may be a substituent which affects the basicity of the co-ordinating groups through its ability to either donate or withdraw electron density from the benzoxazine nitrogen or other co-ordinating atoms which may be present on the ligand framework, for instance at C-2 (R or R1) or at C-4 (R6). Preferred electron withdrawing groups include halogen atoms, nitro, cyano, carboxylic acid or esters thereof, formyl, sulphate, acetyl, or quaternary ammonium salts. Preferred electron donating groups include alkyl, alkoxyl, amino, hydroxyl and amide groups. Accordingly, an advantage of the ligand framework of the general formula (I) is that it can be electronically "tuned" depending upon the electronic nature of the selected R2-R5 substituents. Varying the electronic nature of the ligand is extremely advantageous as it offers a convenient way to manipulate the affinity of a particular ligand to a particular metal. This tuning also offers an avenue to better control the kinetics and selectivities of the catalysed asymmetric transformations which utilise the metal catalysts of the present invention. Substituents R2-R5 may also be used as sites for attachment to solid polymeric supports for applications in many technologies, including solution phase, solid phase and microreactors. The attachment of the ligand and/or metal complexes to a solid support can significantly reduce the operational problems often associated with solution phase organic synthesis. Simple filtration of the solid supported catalyst at the end of a reaction obviates the need for special work up procedures to recover the catalysts. This accordingly has the advantage of enabling the catalysts to be truly recyclable. Typical polymeric solid supports include the commercially available resins, which are currently being used in solid phase organic synthesis. Examples include, alkenyl resins: eg. REM resins; BHA resins: eg. benzhydrylamine (polymer-bound hydrochloride, 2% crosslinked), benzhydryl chloride (polymer bound); Br- functionalised resins: eg. brominated PPOA resin, brominated Wang resin; Chloromethyl resins: eg. 4-methoxybenzhydryl chloride (polymer bound); CHO- functionalised resins: eg. indole resin, formylpolystyrene; Cl-functionalised resins: eg. Merrifields' resin, chloroacetyl (polymer bound); CO2H-functionalised resins: eg. carboxypolystyrene; I-functionalised resins: eg. 4-iodophenol (polymer bound); Janda Jels™; MBHA resins: eg. 4-methylbenzhydrylamine hydrochloride (polymer bound), 4- hydroxymethylbenzoic acid-4-methyl benzhydrylamine (polymer bound); Amine- functionalised resins: eg. (aminomethyl)polystyrene, PAL resin, Sieber amide resin; Nitrophenyl carbonate resins: eg. 4-nitrophenyl carbonate (polymer bound); OH- functionalised resins: eg. 4-benzyloxybenzyl alcohol (polymer bound); Hydroxy methyl resins: eg. benzyl alcohol (polymer bound); HMBA resin; Oxime resins; Rink acid resin; Triazine-based resin; Trityl amine resins; Trityl resins: eg. trityl-chloride (polymer bound), 2-chlorotrityl alcohol, 1,3-diaminepropane trityl.

Methods and reagents for coupling organic molecules with polymer support resins are known in the art, including polymer supported reagents for instance, polymer bound bases like piperidine, dimethylaminopyridine, morpholine, diethylamine as well polymer bound coupling reagents like l-(3-dimethylaminopropyl)-3-ethyl carbodiimide, diethylazodicarboxylate, and N-benzyl-N'-cyclohexylcarbodiimide.

Preferably, however, the compound of formula (I) is prepared bound to the polymer support resin prior to being used in an asymmetric reaction. Accordingly, another advantage of the present invention is that it enable asymmetric transformation to be conducted under solid-phase conditions.

A further advantage of the compounds of the general formula (I) is that benzofusion causes the ligand framework to be conformationally stable and relatively flat. It is proposed that such framework will enhance chiral recognition of the corresponding catalyst, and as such, aid the catalyst in chiral induction.

The preparation of ligands of general formula (I) can be achieved using modified strategies based upon existing methodologies for the synthesis of 2/f-l,3-benzoxazines.

For example Shiraishi et al, Chem. Pharm. Bull. 44(4) 734-745 (1996), describes various routes to racemic 1,3-benzoxazines, which can be adapted to prepare the compounds of general formula (I) (see schemes 1 to 3).

Scheme 1

Scheme 1 depicts a general protocol which involves reacting a salicylamide with an aldehyde or ketone (or equivalent, for example, a dimethyl acetal) in the presence of an acid catalyst to prepare the ring closed 2H-l,3-benzoxazine-4-one. The linking of the R6 group can be carried out by converting the benzoxazin-4-one to the corresponding imide where the L' group represents an appropriate leaving group. The R6 group can be introduced by an appropriate substitution reaction. For example, to facilitate a new carbon-carbon bond at C-4 of the 1,3-benzoxazine, it may be possible to subject an imino triflate (that is, where L' = OTf) to palladium catalysed cross coupling with an R6-halogen compound.

Scheme 2 depicts an alternate route which commences from a benzonitrile and essentially involves a one pot synthesis. Treatment of the benzonitrile with a lithiating agent (eg. 2- lithiopyridine) affords, in one step, the dilithiated intermediate, and also the addition of the R6 group, which can then be ring closed to form a 1,3-benzoxazine through treatment with a desired aldehyde or ketone (or equivalent thereof).

Scheme 3

Scheme 3 shows that the racemic compounds of formula (I) can also be obtained by cyclisation of the corresponding imine intermediate derived from salicylic acids (see also Mizufune, et al, Tetrahedron (2001) 7501-7506 and EP 0477 789 Al).

The versatility of the various synthetic strategies for preparing racemic compounds of formula (I) means that the R2 to R6 groups can be introduced either before or after the formation of the 1,3-benzoxazine ring.

Enantiomerically enriched and pure compounds of the general formula (I) can be prepared from their racemic counterparts through existing techniques available for resolving pairs of enantiomers, including chemical, kinetic, physical (eg. using chiral chromotography), or through enzymatic processes.

The enantiomers may be separated through initial conversation to diastereomers. In particular, the treatment of racemic mixtures of a compound of formula (I) with chiral auxiliaries, like (+)-O-Methylmandelyl chloride, affords chromatographically separable diastereomeric mixtures, for example, mixtures of diastereomeric mandelyl imides. Physical separation of each of the pure diastereomers and removal of the auxiliary (for example, by hydrolysis) provides enantiomerically pure compounds of formula (I). In a preferred embodiment, resolution is performed on the racemic 2H-l,3-benzoxazine-4-one (see scheme 1) prior to the addition of the R6 group.

It may be also possible to separate the two enantiomers using kinetic resolution techniques by treating the racemic mixture of a compound of formula (I) with a chiral reagent or an achiral reagent/chiral catalyst system. For example, the use of Sharpless's asymmetric epoxidation conditions and/or Kagan's asymmetric oxidation of sulfides may be employed for kinetically resolving racemic benzoxazines.

Enzymatic techniques may also be employed to resolve a racemic mixture of benzoxazines. For instance, the exocyclic carbonyl of a N-acylbenzoxazine can be hydrolysed selectively. Accordingly, hydrolases, amidases and esterases which have been reported to selectively hydrolyse acyl derivatives can be used to resolve the enantiomers after a racemic synthesis of the compounds of the present invention.

A convenient alternative to resolving racemic compounds of formula (I) is to employ enantiomerically pure ketones in the synthetic strategies already described. Preferred enantiomerically pure ketones are cyclic ketones. In such benzoxazines, R1 and R2 together form substituted asymmetric cycloalkyl or cycloalkenyl group. Preferred substituted cycloalkyl are enantiomerically pure cyclic ketones including [-] or [+]- menthone, 8-substituted [+] or [-]-menthone, [+] or [-] carvone and the like.

The ligand framework of compounds of formula (I) has been found to complex with reactive transition metals. Preferred metal complexes include those which contain Ru, Ir, Rh, Zn, Re, Au, Ag, Ni, Pt, Cu and Pd. As used herein, the term "transitional metal" or "metal" as referred to in the present invention includes either a metal in-isolation or a metal bound as a complex with stabilising ligands, eg. chloride, acetate, cyclooacta-1, 5-diene (COD), methylcyano, alkyl, benzonitrile, triaryl stibine, etc. Examples of available stabilised metal complexes include [Rh(COD)Cl]2, [Rh(COD)2]X, [Ir(COD)Cl]2, [Ir(COD)2]X, (where X=BF4, ClO4, SbF6, CF3SO3), Ru(COD)Cl2, Pd(CH3CN)4[BF4]2, Pd2(dba)3 and [Pd(C3H5)Cl]2, Pd2(dba)3, [Pd(C3H5)Cl]2, PtCl2, PtCl(Me)(SMe2)2, PtCl2(SMe2), [Pd(allyl)Cl]2, Rh(acac)(CO)2, Rh(ethylene)2(Acac), Rh(CO)2Cl2, Ru(RCOO)2(diphosphine), Ru(methylallyl)2-(diphosphine), RuCl2(=CHR)(PR'3)2, Cu(OTf), Cu(OTf)2, Cu(Ar)X1, CuX,1 NiX'2, Ni(COD)2, MoO2(acac)2, Ti(OiPr)4, VO(acac)2, MeReO4, ZnCl2, ZnEt2, MnX2 or Mn(acac), (where each X' is independently selected from BF4, ClO4, SbF6, or CF3SO3, Ar is an aryl group and R and R' can be independently an aryl or alkyl group). As such, the catalysts of the present invention are produced by complexing the ligands of formula (I) with a reactive transitional metal or transition metal complex. This is preferably achieved by an exchange reaction between the ligand of formula (I) and a stabilising complex of the metal wherein the bond between the metal and stabilising ligand is more labile than the bond that is formed between the metal and ligand of formula (I). Generally, the stabilised metal complex will be dissolved in a suitable solvent followed by the addition of the ligand of formula (I). The addition of the ligand of the present invention can be done either directly as a solid or as a solution in a suitable solvent which may or may not be the same solvent used to dissolve the metal complex. In the case where the sol-vents differ, the solvents are matched so as to avoid precipitation of the reactants from the reaction solvent mixture. Preferred solvents include polar solvents like alcohols, dimethylformamide, or chlorinated solvents like dichloromethane, chloroform, and carbontetrachloride, or aromatic hydrocarbons like benzene and toluene, or ethers like diethylether and tertrahydrofuran. The formation of the catalyst can usually be followed by observing colour changes in the reaction mixture or through spectroscopic means, such as for instance, 31P-NMR and/or G.C. The catalyst can be recovered by simply removing the reaction solvent in vacuo. The catalyst may be subjected to further purification according to known techniques or used without additional purification. Accordingly, the present invention also provides for transition metal complexes of the compounds of general formula (I) which are in an isolated form. The catalysts are preferably prepared immediately prior to their use in an asymmetric catalytic transformation. More preferably however, the catalysts of the present invention are prepared in situ. That is, the complexation of the metal or metal complex with the ligand (of formula I) is carried out in the presence of the reactants of the particular asymmetric reaction which requires the catalyst of the present invention.

The catalyst of the present invention may be used in any chemical reaction requiring an asymmetric catalyst. Examples of such reactions include asymmetric hydride-transfer reactions, hydrosilylations, alkene hydrogenation, allylic substitution, cycloaddition reactions, Heck reactions, hydroformylations, conjugate addition reactions, nucleophilic additions to carbonyl compounds, expoxidations, dihydroxlations, aminohydroxylations, etc.

In order to affect asymmetric induction in a prochiral substrate it is often not always necessary to have enantiomerically pure catalysts due to the phenomenon of "asymmetric amplification". Asymmetric amplification involves asymmetric catalysis where the product of the reaction being studied is itself acting as a catalyst. Thus the desired reaction is assisted or an undesired reaction suppressed by the product of the reaction. Such reactions are said to be "autocatalytic" and are generally observed in metal catalysed systems where the catalyst comprises 2 or more metal co-ordinating sites. Emperical models have been formulated by Kagan (Angew. Chem. Int. Ed., 1998, 37, 2922) which focuses on diastereomeric interactions between metal and chiral ligands in order to rationalise the observed amplification. Kagan has also reported that this phenomenon is not generally observed with monomeric chiral ligand-metal systems. Prediction of the efficiency of a particular transition metal catalyst of the present invention, in a particular reaction, can be assessed by simple well understood asymmetric transformations ("test systems") utilising standard test substrates.

Asymmetric hydrosilylation

In assessing the efficiency of a particular catalyst in an enantioselective hydrosilylation reaction, acetophenone is generally used as a standard test substrate. The reaction is often carried out with diphenylsilane in the presence of the catalyst at room temperature with a suitable aprotic solvent such as tetrahydrofuran. After hydrolysis the reaction affords (R) and/or (S)-l-phenylethanol. The determination of the chiral efficiency (% e.e) of a particular catalyst can be determined by gas chromatography through comparison with commercially available standard samples of (R) and (S)-l-phenylethanol. In this way, it is possible to quickly evaluate a large range of (R -R ) variables in the ligands of compounds of formula I as well as particular ligand/metal combinations. That is, factors like steric position and electronic influence of variables in the ligands can be quickly and systematically assessed allowing the catalyst can be suitably optimised. In the preferred test method a rhodium based metal complex is used to generate the catalyst in situ.

Asymmetric transfer hydro genation of ketones and imines

Acetophenone can also be used as a test substrate for studying the efficacy of a particular catalyst for the asymmetric hydrogenation of ketones. Until relatively recently catalytic asymmetric hydrogenations of ketones were carried out using rhodium complexes of phosphine-based ligands with unsatisfactory enantioselectivity. However, it has been shown that the use of chiral nitrogen-based ligands, like AMBOX in ruthenium based catalysts improves the efficiency of these processes. Accordingly, the present catalysts are also predicted to find utility in such transformations. Although acetophenone can be used as a test substrate in the determination of the chiral efficiency and reactivity of the catalysts of the present invention the reaction is amenable to a wide range of functionalised ketones. The reaction is also amenable to the reaction of selected imines to their corresponding amines. A typical test system for such a reaction is represent below:

Apart from the presence of a catalytic amount of the desired catalyst these reactions are performed in the presence of a hydrogen donor. Preferred hydrogen donors include alcohols, like iso-propanol and acids, such as formic acid. In the reduction of ketones using this procedure the typical test reaction medium is an iso-propanol/alkaline base system. A formic acid/triethylamine mixture also serves to effect reduction and is the preferred reaction medium for the test system illustrated for assessing the catalysts efficiency in reducing imines.

Asymmetric allylic substitutions

One of the current applications of dihydro(phosphinophenyl) oxazole ligands is in enantioselective allylic substitution transformations. Palladium catalysts based on these ligands is generally employed. The mechanism of such palladium catalysed transformations is well understood. Again in order to explore the efficacy of the catalysts of the present invention (with an aim to optimising the ligand variables) a standard test system can be employed. Such a system may involve the reaction of 1,3-diphenylallyl acetate with the nucleophile of dimethyl malonate. The reaction is usually performed at room temperature, in a suitable chlorinated solvent, preferably dichloromethane, in the presence of potassium acetate and bis(trimethylsilyl)acetamide. The palladium catalyst can be generated in situ, preferably prior to the generation of the malonate nucleophile. The reaction yields, time and enantioselectivities can be determined using standard methods.

Asymmetric alkene hydro genation

The literature is replete with examples of asymmetric hydrogenation of functionalised olefins such a dehydro-amino acids, unsaturated carboxylic acids and esters, unsaturated phosphate esters and allylic alcohols. These substrates are generally characterised with a heteroatom positioned close to the C=C bond. Such reactions are generally catalysed by ruthenium based BINAP catalysts. Recently, however it has been shown that [dihydro(phosphinophenyl)oxazole] iridium catalysts are effective in reducing alkenes which are tetra or tri-substituted by groups lacking heteroatoms in close proximity with the C=C bond. The catalysts of the present invention are predicted to show general applicability in these processes. A general procedure for a test system would involve mixing a catalytic amount of the desired catalyst with a substrate in a chlorinated solvent, for example dichloromethane. The reaction container is pressurised with hydrogen (~30~ 80 bar) at room temperature. The reaction products (alkanes) can be analysed and the reaction enantioselectivies assessed by conventional means, for instance by chiral GC and chiral HPLC/GC.

Asymmetric Heck Reactions

Palladium-catalysed asymmetric Heck reactions have been successfully performed under a variety of conditions to facilitate intra and intermolecular cross coupling of alkenes with aryl or alkyl triflates and halides. Dihydro(phosphinophenyl)oxazoles and the corresponding benzoxazines ligands have been shown to be effective chiral inductors in the intermolecular couplings of cycloalkenes with aryl or alkyl triflates. The catalysts of the present invention are also predicted to show similar chiral induction. Test systems for such reactions may involve the coupling of either cyclohex-1-en-lyl trifluoromethanesulfonate or phenyl trifluoromethanesulfonate with 2,3-dihydrofuran. The test alkyl triflate coupling can be performed at room temperature, with the catalyst, in the presence of a sterically hindered base like N,N-diisopropylethylamine (Hunigs base), in an aprotic solvent like, for instance benzene or toluene. The test aryl triflate coupling is preferably performed at elevated temperatures, (ie. ~ > 50°C) in an appropriate solvent, like, for instance, tetrahydrofuran. Substrate conversion and enantiomeric excess can be determined using known techniques as mentioned previously.

Asymmetric Diels-Alder reactions

There have been many reported methods for performing asymmetric Diels-Alder reactions using molecular organometallic catalysts as chiral Lewis acids. The most successful of these systems involve chiral ligands which are capable of bidentate chelation to the metal. Furthermore, dienophiles which are also able to exhibit two-point binding to the catalyst have resulted in better chiral induction in the resultant cycloadduct, presumably through the restriction of the number of accessible conformations of the dienophile-catalyst complex. A suitable test system to assess the present inventions ability to induce desirable reaction stereoselectivites (ie., enantioselectivity and diastereoselectivity of the resultant cycloadduct) is a reaction between cyclopentadiene and an acryloyl-oxazolidinone.

The reactions are preferably catalysed by Cu(II) catalysts and the test system can be performed at temperatures between 5O0C and -780C in a suitable solvent, for instance dichloromethane. Higher enantioselectivies are generally observed at lower reaction temperatures. Monitoring of the reaction progress, diastereoslectivities (ratio of endo:exo products) and enantioselectivities, can be carried out using known techniques. The diastereomeric cycloadducts can be separated via column chromatography.

Asymmetric conjugate addition reactions

Asymmetric conjugate addition reactions have been largely the domain of stoichiometric, diastereoselective processes. General methods for catalytic, asymmetric conjugate additions are still yet to be folly developed. It has been shown however that additions to unsaturated imides, which are particularly reactive conjugate acceptors, the use of Cu(II) complexes of C2-symmetrical ligands proceed with very high selectivity. Accordingly, Cu complexes of compounds of formula (I) show promise in such reactions.

Asymmetric nucleophilic additions to carbonyl compounds

A considerable amount of research has been done to control the stereochemical outcome of processes for adding alkyl groups to a carbonyl group with the use of orgnometallic reagents. The best results so far utilise dialkylzinc reagents which are complexed with chiral ligands. A test system for assessing the suitability of the ligands of the present invention in such processes is through monitoring ethyl addition from diethylzinc to benzaldehyde.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The following examples are provided to assist in the further understanding of the invention. Particular materials, and conditions employed are intended to be illustrative of the invention and not included to limit the scope thereof.

Examples l ffl. Preparation of a Zn-complex of (1"'S, 4"'R, 2SVM-4-(2- pyridyl)spirofmenthane-2,2'-benzo[e1fl,31-oxazine(2H)l, (9)

(a) Preparation of (1"1S, 4"'R, 2S)-(-)-2-Menthonyl-3 #-benzo[e][l,3]oxazin-4-one, (1) and (1"1S, 4"'R, 2S)-(+)-2-Methonyl-317-benzo[e] [l,3]oxazin-4-one, (2) 1 2 The reaction flask was fitted with Dean-Stark apparatus. A mixture of salicylamide (4.00 g, 29.16 mmol) and (-)-menthone (5.56 niL, 32.08 mmol) in chloroform (150 mL) with a catalytic amount of cone. H2SO4 (40 drops) was refluxed for 12Oh. Solvent was removed under reduced pressure to give a pale pink oil as a crude product. Two diastereomers were purified and separated by flash chromatography (EtOAc/hexane 1 :8) to give the title compound (-)-l (5.61 g, 70%) as a white foam and (+)-2 (1.87 g, 23%) as a white solid.

Treatment of a mixture of (-)-l/(+)-2 with a catalytic amount of DBU (388 μL, 2.6 mmol) in NMP (60 mL) at room temperature for 24 h. Then at -2O0C for 24 h yielded (-)-l in predominance over (+)-2 with 10:1 ratio.

Compound (-)-l

[α]26 (C=I, CHCl3) -76.3; 1H NMR (400 MHz, CDCl3) δ 0.78 (d, J = 6.6 Hz, 3H, H6"), 0.91 (d, J = 6.8 Hz, 3H, H8"), 0.94 (d, J= 7.0 Hz, 3H5 H8"), 0.96 (dd, J= 12.4 Hz, IH, H3"), 1.06 (dd, J= 12.4 and 14.0 Hz, IH, H5"), 1.36 (dd, J= 4.2 and 12.1 Hz5 IH, Hl"), 1.77 (m, 4H5 H2"&H3"&H4")5 2.38 (m, 2H, H5"&H7"), 6.90 (d, J= 0.9 and 8.2 Hz5 IH, Hl1), 7.03 (t, J= 1.0 and 7.5 Hz, IH, H31), 7.12 (bs, IH, NH), 7.42 (t, J= 1.7 and 7.8 Hz5 IH, H2')5 7.91 (d, J= 1.7 and 7.6 Hz, IH, H4'); 13C NMR (100 MHz, CDCl3) δ 17.93 (C9"), 21.17 (CT'), 21.53 (C6"), 23.35 (C8"), 26.04 (C7"), 28.72 (C4"), 34.20 (C3"), 45.78 (C5"), 49.85 (Cl"), 91.49 (C2), 116.97 (Cl'), 117.04 (C5), 121.48 (C31), 127.60 (C41), 134.39 (C2')5 155.38 (C6), 162.97 (C4); HRMS Calc'd for C17H24NO2 (M+H+): m/z 274.1807, Found 274.1805.

Recrystallisation (EtOAc/hexane) of (+)-2 yielded colourless crystals suitable for X-ray crystallography.

Compound (+)-2

m.p. 163-1650C; [α]26 (c=l, CHCl3) +57.1; 1H NMR (400 MHz, CDCl3) δ 0.84 (d, J = 6.5 Hz, 3H, H6"), 0.91 (d, J = 6.8 Hz, 3H5 H8"), 0.96 (dd, J= 12.4 Hz, H3"), 0.99 (m, J= 6.9 Hz, 3H, H3"), 1.06 (t, J= 12.7 Hz, IH, H5")5 1.36 (dd, J = 3.2 and 13.4 Hz, IH5 Hl"), 1.77 (m, 4H5 H3"5 H2"5 H4"), 2.38 (m, 2H, H5"&H7"), 6.90 {d, J = 0.9 and 8.2 Hz5 IH, Hl1), 7.03 (t, J = 1.0 and 7.5 Hz, IH5 H3'), 7.12 (bs, IH5 NH), 7.42 (t, IH, J= 1.7 and 7.8 Hz5 H2')5 7.90 (d, J = 1.7 and 7.6 Hz5 IH5 H4'); 13C NMR (100 MHz5 CDCl3) δ 18.76 (C8"), 21.67 (C6")5 22.79 (C2")5 23.68 (C8"), 25.96 (C7")5 28.84 (C4")5 34.12 (C3")5 46.07 (C5")5 49.71 (Cl"), 91.66 (C2)5 116.77 (Cl1), 116.97 (C5), 121.35 (C3')> 127.64 (C4')5 134.56 (C21), 156.01 (C6)5 162.48 (C4); HRMS Calc'd for C17H24NO2 (M+H+): m/z 274.1807, Found 274.1805; (b) Preparation of (I" 'S, 4" 'R, 2S)-(-)-4- (Trifluoromethanesulfonyloxy)spiro [menthane-2,2 '-benzo [e] - [1,3] oxazine(2H)] , (3) and (1"'S, 4"'R, 2R)-(+)-4-(TrifluoromethanesulfonyIoxy)spiro[menthane-2,2'- benzo[e]-[l,3]oxazine(2H)], (4)

Trifluoromethanesulfonic anhydride (185 μL, 1.1 mmol) was added dropwise to a solution of 1 (200 mg, 0.73 mmol) in dry dichloromethane (8 mL) under a nitrogen atmosphere at -780C and the mixture was stirred for 40 min. Then fresh distilled 2,6- lutidine (128 μL, 1.1 mmol) was added dropwise and stirred for 30 min. The reaction was quenched with saturated NaHCO3 solution (10 mL) and extracted with dichloromethane (20 mL). The extract was washed with saturated NaHCO3 (20 mL), KHSO4 (20 mL), and brine (20 mL), dried over anhydrous MgSO4 and evaporated in vacuum to give the title compound 3 as brown oils (94%). This was used in the next step without further purification. The NMR data of the title compound 3 is reported below. 1H NMR (300 MHz, CDCl3) 0.85 (d, J = 6.3 Hz, 3H, H6"), 0.85 (d, J = 6.9 Hz, 3H, H9"), 0.95 (d, J = 6.9 Hz, 3H, H8"), 1.02 (m, IH, H3"), 1.28 (t, J = Hz, IH, H5"), 1.60 (m, 3H, H4", H7", H2"), 1.80 (m, 2H, H2", H3"), 2.35 (m, 2H, Hl", H5"), 6.85 (d, J = 8.1 Hz, IH, Hl'), 6.95 (t, J = 7.8 Hz3 IH, H3'), 7.36 (d, J = 7.8 Hz, IH, H4'), 7.43 (dd, J = 1.5, 7.5 Hz, IH, H2'); 13C NMR (75 MHz, CDCl3) 18.25 (C9"), 22.25 (C6"), 23.38 (C2"), 23.91 (C8"), 26.49 (C7"), 28.72 (C4"), 35.09 (C3"), 47.73 (C5"), 51.70 (Cl"), 98.19 (C2), 109.51 (C5), 112.37 (CF3), 116.62 (CF3), 117.09 (Cl '), 120.87 (CF3), 121.24 (C3!), 124.55 (C45), 125.11 (CF3), 136.35 (C2'), 150.07 (C6), 157.30 (C4); HRMS CaIc. (found) for C18H21F3NO4S (M-H+): m/z 404.1143 (404.1170).

(1 ' "S, 4" % 2R)-(+)-4-(Trifluoromethanesulfonyloxy)spiro[menthane-2,2 '-benzofej- [l,3]oxazine(2H)], (4)

Compound 4 was prepared using the conditions described above for compound 3. [α]D26 (C=I, CHCl3) +140.7; 1H NMR (300 MHz, CDCl3) 0.83 (d, J = 6.3 Hz, 3H, H6"), 0.85 (d, J = 6.9 Hz, 3H, H9"), 0.95 (d, J = 6.9 Hz5 3H, H8"), 1.02 (m, IH, H3"), 1.28 (t, J = Hz, IH, H5"), 1-60 (m, 3H, H4", H7", H2"), 1.80 (m, 2H, H2", H3"), 2.35 (m, 2H, Hl", H5"), 6.85 (d, J = 8.1 Hz, IH, Hl'), 6.95 (t, J = 7.8 Hz, IH, H3'), 7.36 (d, J = 7.8 Hz, IH, H4'), 7.43 (dd, J = 1.5, 7.5 Hz, IH, H2'); 13C NMR (75 MHz, CDCl3) 18.25 (C9"), 22.27 (C6"), 23.38 (C2"), 23.92 (C8"), 26.50 (C7"), 28.72 (C4"), 35.09 (C3"), 47.75 (C5"), 51.71 (Cl"), 98.21(C2), 109.51 (C5), 116.62 (CF3), 117.09 (Cl'), 120.87 (CF3), 121.24 (C3')5 124.57 (C45), 136.35 (CT), 150.06 (C6), 157.30 (C4); HRMS CaIc. (found) for C18H23F3NO4S (M+H1"): m/z 406.1300 (406.1307).

(c) Preparation of (1"'S, 4"'R, 2S)-(-)-4-(2-Pyridyl)spiro[menthane-2,2'- benzo[e][l,3]oxazine(2H)], (5) and (1"'S, 4"'R, 2R)-(+)-4-(2- Pyridyl)spiro[menthane-2,2'-benzo[e] [l,3]oxazine(2H)], (6)

A 1.6M n-BuLi hexane solution (940 μL, 1.50 mmol) was added dropwise to a solution of 2-bromopyridine (136 μL, 1.43 mmol) in dry THF (12 mL) under a nitrogen atmosphere at -780C. The reaction mixture was stirred at this temperature for 40 min. To this mixture was added a solution of ZnCl2 (370 mg, 2.72 mmol) in dry THF (3 mL) at - 78°C and the reaction mixture was warmed 0°C and stirred at this temperature for 30 min. Dry LiCl (130 mg, 3.26 mmol) was added, followed by a solution of Pd(PPh3)4 (64 mg, 0.05 mmol) in dry THF (3 mL) and stirred for 10 min. A solution of 3 (380 mg, 0.93 mmoL) in dry THF (5 mL) was added dropwise to the mixture. The reaction was refluxed overnight (17 h). The reaction was quenched with saturated NaHCO3 (10 mL) and extracted with dichloromethane (3x10 mL). The combined extract was washed with brine (5 mL), dried over anhydrous MgSO4, and concentrated in a vacuum to give brown oils as a crude product. The crude product was purified by flash chromatography (EtO Ac/hexane 1:8) to give the title compound 5 (1.54 g, 75%, Rf = 0.53) as a white solid, together with another white solid, (I" 'S, 4 '"R, 2R)-(+)-2,2'-menthonyl-N-benzofl,3Jdioxin-4-ylidene- C,C,C-trifluoro-methanesulfonamide (7), (590mg, 23%, Rf = 0.6) and a colourless oil, (1"'S, 4"'R, 2S)-(-)-spiro[menthane-2,2'-benzo[e][l,3]oxazine(2H) (8) as by-products.

Compound (-)-5 m.p. 105-107°C; [α]D26 (C=I, CHCl3) -347.2; 1H NMR (400 MHz, CDCl3) 0.84 (d, J = 6.4 Hz, 3H, H6"), 0.89 (d, J = 6.9 Hz5 3H, H8"), 0.96 (d, J = 7.0 Hz, 3H, H8"), 1.03 (q, J = 4.0 Hz, IH, H3"), 1.25 (dd, J = 12.2, 13.7 Hz, IH, H5"), 1.76 (m, 5H, H4", H3", H2", Hl"), 2.18 (dd, J = 2.2, 13.8 Hz, IH, H5"), 2.23 (q, J = 2.0, 6.9 Hz5 IH, H7"), 6.86 (m, 2H, Hl ', H3'), 7.31 (dd, J = 1.6, 7.4 Hz, IH, H2'), 7.35 (t, J = 1.6, 7.1 Hz, IH, H5'")5 7.68 (dd, J = 1.6, 7.7 Hz5 IH, H4'), 7.78 (m, 2H, H3'", H4'"), 8.69 (dd, J = 1.6, 4.8 Hz, IH, H6'"); 13C NMR (100 MHz, CDCl3) 18.41 (C8"), 21.43 (C2"), 21.95 (C6")5 23.66 (C8"), 26.76 (C7"), 27.76 (C4"), 34.82 (C3")3 42.00 (C5")5 51.28 (Cl'), 94.17 (C2), 116.14 (C5), 116.84 (Cl'), 120.30 (C3'), 123.49 (C3'")5 123.84 (C5'"), 128.16 (C4'), 133.28 (C2')5 136.87 (C4'")3 148.42 (C6'"), 154.45 (C6), 156.33 (C2'")5 159.38 (C4); HRMS CaIc. (found) for C22H27N2O (M+H+): m/z 335.2045 (335.2118); IR (DCM) 3432bs, 2951m, 1620s, 1566m, 1452m, 1339m, 1233m, 1152m; Anal. CaIc. (found) for C22H26N2O: C 79.00 (79.21); H 7.84 (8.02), N 8.38 (8.58).

(V"S, 4"'R, 2R)-(+)-2,2>-Menthonyl-N-benzo[l,3]dioxin-4-ylidene-C,C,C -trifluro- methanesulfonamide

m.p. 146-1470C; [α]D26 (C=I, CHCl3) +17; 1H NMR (400 MHz, CDCl3) δ 0.83 (d, J = 6.6 Hz, 3H, H6"), 0.95 (d, J = 6.9 Hz, 3H, H8"), 1.03 (d, J = 7.0, 3H5 H8"), 1.08 (m, IH, H3"), 1.39 (t, J = 12.7 and 13.5 Hz, IH, H5"), 1.63 (m, 3H, H4"&H7"&H2"), 1.85 (m, 3H, H1"&H2"&H3"), 2.35 (m, IH5 H5"), 7.02 (d5 J = 8.0 Hz, IH, Hl'), 7.16 (t, J = 1.0 and 7.6 Hz, IH, H3')5 7.64 (t, J = 1.7 and 7.8 Hz5 IH5 H2'), 7.96 (d, J = 1.7 and 7.9 Hz5 IH5 H4'); 13C NMR (100 MHz, CDCl3) δ 18.64 (C8")5 21.28 (C6"), 22.80 (C2")5 23.08 (C8"), 25.80 (C7"), 29.60 (C4"), 33.64 (C3")5 40.98 (C5")5 49.11 (Cl"), 112.29 (C2), 112.56 (C5), 114.18 (CF3), 117.36 (CF3), 117.76 (Cl'), 120.54 (CF3), 123.39 (C3'), 123.72 (CF3), 129.40 (C4')s 138.30 (C25), 154.72 (C6), 163.33 (C4); HRMS CaIc. (found) for C18H22F3NO4SNa (M+Na+): m/z required 428.1119 (found) 28.1122; IR (DCM) 2952m, 1603s, 1576s, 1473s, 1348s, 1203s, 1111m;

Anal. CaIc. (found) for C18H22F3NO4S: C 53.32 (53.37); H 5.47 (5.61); N 3.45 (3.42). (1 '"S, 4"% 2S)-(-)-spiro[menthane-2,2'-benzo[e][l,3]oxazine(2H)]

8

1H NMR (300 MHz, CDCl3) 0.83 (t, J = 6.9 Hz, 6H, H), 0.96 (d, J = 6.9 Hz, 3H, H), 1.17 (dd, J = 12 Hz, IH, H, 1.74 (m, 5H, H), 2.07 (m, IH, H), 2.15 (t, J = 6.9 Hz, IH, H), 6.74 (d, J = 7.8 Hz, IH5 H), 6.88 (t, J = 7.3 Hz, IH), 7.11 (dd, J = 7.6 Hz, IH), 7.29 (m, 2H), 8.06 (s, IH); 13C NMR (75 MHz, CDCl3) 18.50 (C), 21.45 (C), 22.43 (C), 23.96 (C), 26.87 (C), 27.97 (C), 35.01 (C), 43.60 (C), 51.47 (C), 95.39 (C), 116.68 (C), 116.74 (C), 120.94 (C), 127.48 (C), 133.96 (C), 154.06 (C), 154.90 (C); HRMS CaIc. (found) for C17H23NO (H+): m/z required 258.18 (258.1854); IR (DCM) 2952s, 2870s, 1639s, 1607s, 1482m, 1457s, 1367m, 1235s, 938s, 756s.

(1"'S, 4"'R, 2R)-(+)-4-(2-Pyridyl)spiro[menthane-2,2'-benzo[e][l,3]oxazin e(2H)], (6) 6 A 1.6M n-BuLi hexane solution (1.42 niL, 2.28 mmol) was added dropwise to a solution of 2-bromopyridine (180 μL, 1.88 mmol) in dry Et2O (10 mL) under a nitrogen atmosphere at -78°C. The reaction mixture was stirred at this temperature for 2h. To this mixture was added a solution of ZnCl2 (517 mg, 3.8 mmol) in dry Et2O (3 mL) at -78°C and the reaction mixture was warmed O0C and stirred at this temperature for Ih. Then a solution of Pd(PPh3)4 (53 mg, 0.068 mmol) in dry Et2O (2 mL) and 4 (620 mg, 1.52 mmoL) in dry Et2O (3 mL) were added dropwise to the mixture. The reaction was refluxed overnight (18h). The reaction was quenched with saturated NaHCO3 (20 mL) and extracted with dichloromethane (3x50 mL). The combined extract was washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated in a vacuum to give a brown oil as a crude product. The crude product was purified by flash chromatography (EtOAc/hexane 1:8) to give the title compound (280 mg, 55%, Rf = 0.4) as a white solid; 1H NMR (400 MHz, CDCl3) 0.78 (d, J = 6.9 Hz5 3H, H6"), 0.82 (d, J = 6.3 Hz, 3H, H8")5 0.96 (d, J = 7.2 Hz, 3H, H8"), 0.99 (t, J = 4.0 Hz, IH, H3"), 1.20 (m, IH, H5"), 1.73 (m, 6H, H4", H3", H2", Hl"), 2.18 (dd, J = 2.2, 13.8 Hz, IH, H5" and H7'"), 2.26 (m, 2H, H7"), 6.86 (m, 2H, Hl', H3'), 7.31 (dd, J = 1.6, 7.4 Hz, IH, H2'), 7.35 (t, J = 1.6, 7.1 Hz, IH, H5'"), 7.68 (dd, J = 1.6, 7.7 Hz, IH, H4'), 7.78 (m, 2H, H3'", H4'"), 8.69 (dd, J = 1.6, 4.8 Hz, IH, H6'"); 13C NMR (100 MHz, CDCl3) 18.74 (C8"), 21.72 (C2"), 22.32 (C6"), 24.01 (C8"), 27.10 (C7"), 28.12 (C4"), 35.14 (C3"), 42.31 (C5"), 51.58 (Cl'), 94.51 (C2), 116.47 (C5), 117.26 (Cl'), 120.67 (C3'), 123.86 (C3'")5 124.23 (C5'")5 128.48 (C4'), 133.67 (C2')5 137.28 (C4'"), 148.81 (C6'")5 154.76 (C6), 156.63 (C2'"), 159.81 (C4); HRMS CaIc. (found) for C22H27N2O (M+H+): m/z 335.2045 (335.2118). (d) Preparation of a Zn-complex of (1"'S, 4"'R, 2S)-(-)-4-(2- pyridyl)spiro[menthane-2,2'-benzo[e] [l,3]-oxazine(2H)], (9)

A solution of 5 in dry THF (2 niL) was added to a solution of dry ZnCl2 (0.06 g, 0.45 mmol) in dry THF (5 niL). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the pale yellow solid was recrystallised in ethanol to give colourless crystal of the title compound (0.16 g, 75 %); m.p.: 2540C; 1H NMR (400 Hz, CDCl3) 0.80 (d, J= 6.6 Hz, 3H, H6"), 0.90 (d, J= 6.8 Hz, 3H, H8"), 1.10 (d, J = 6.8 Hz, 3H, H8"), 1.17 (dd, J = 3.8, 6.8 Hz, IH, H3"), 1.63 (m, IH, H4"), 1.81 (m, 3H, H2", H3"), 2.07 (m, 3H, Hl ", H5"), 2.32 (m, H7")5 7.13 (d, J = 8.7 Hz, IH, Hl'), 7.19 (t, J= 1.0, 7.6 Hz, IH, H3'), 7.64 (t, J= 1.5, 6.5 Hz, IH, H2'), 7.65 (d, J = 7.6 Hz, IH, H4'), 7.88 (dd, J = 5.0, 7.6 Hz, IH, H5'"), 8.16 (d, J = 7.9 Hz, IH, H3'"), 8.23 (t, J= 1.6, 7.9 Hz, IH, H4'"), 8.93 (d, J= 0.8, 5.0 Hz, IH, H6'"); 13C NMR (100 Hz, CDCl3): 17.82 (C8"), 21.58 (C6"), 21.15 (C2"), 23.51 (C8"), 27.14 (C7"), 28.15 (C4"), 33.79 (C3"), 38.68 (C5")5 50.67 (Cl"), 95.71 (C2), 115.29 (C5), 118.97 (Cl'), 122.43 (C2'), 127.83 (C4')5 127.17 (C3'"), 128.97 (C5'")5 136.91 (C3')5 140.77 (C4"!), 150.75 (C6'")5 146.74 (C2), 155.49 (C6), 161.37 (C4); HRMS CaIc. (found) for C22H26Cl2N2OZn (M-Cl"): m/z 433.1025 (433.1042); IR (DCM) 2954s, 1607s, 1598s, 1552m, 1472w, 1451m, 1348s, 1061m, 752s. Anal. CaIc. (found) for C22H26Cl2N2OZn: C, 56.13 (56.07); H, 5.57 (5.58); N, 5.95 (5.94). l(ii). Preparation of PtflMeVcomplex of (1'"S, 4"'R. 2SV(-V4-(2- pyridyI)spirofmenthane-2,2'-benzofel fl,31-oxazine(2H)l, (10)

10

To a solution Of K2PtCl4 (1.06 g, 2.56 mmol) in water (10 niL) in Schlenk flask, was added SMe2 (376 μL, 5.12 mmol) dropwise and stirred at room temperature for 3 Ii until the milky pink suspension is converted to yellow precipitate. The reaction mixture was extracted with DCM (30 mL). The extract was dried over anhydrous MgSO4 and solvent was removed under reduced pressure to give a crude cis/trans-[PtCl2(SMe2)2] as yellow solid (670 mg, m.p. = 157-158°C, 67%). The crude product was used in the next step without purification. Methyl lithium (1.5 M solution, as complex with lithium bromide, in Et2O, 4.6 mL, 6.9 mmol) was added to a solution of cis/trans- [PtCl2(SMe2)] (600 mg, 1.71 mmol) in dry Et2O (40 mL) at -78°C and stirred for 10 min. The reaction mixture was warmed to O0C and stirred for further 30 min. The reaction was quenched with water (10 mL) and extracted with Et2O (2x40 mL). The combined extract was dried over anhydrous MgSO4 and solvent was removed under reduced pressure to give crude [PtMe2(SMe2)]2 as brown solid. To solution a mixture of 5 (126 mg, 0.65 mmol) and [PtMe2(SMe2)J2 (110 mg, 0.33 mmol) in dry DCM under an argon atmosphere was stirred at room temperature for overnight. The solvent was removed under reduced pressure to give a crude of the title compound (188 mg, 50%); m.p.: 212-2130C; 1H NMR (300 Hz5 CDCl3) 0.83 (d, J = 6.6 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 0.92 (m, IH) 1.35 (m, IH), 1.70 (m, 3H), 1.90 (d, J =13.95 Hz, IH, H5"), 1.99 (m, 3H), 2.15 (m, IH), 2.88 (d, J = 11.85 Hz, IH), 7.04 (m, 2H, H1'&H3'), 7.54 (m, 3H, H2'&H4'&H5'"), 7.99 (d, J = 7.8 Hz, IH, H3"'), 8.12 (dt, J = 1.5, 7.5 Hz, IH, H4' ' '), 9.35 (d, J = 5.7 Hz, 3JPtH = 55 Hz, IH, H6' ' ').

l(iii). Preparation of PtflMeCIVcomplex of (T "S, 4"9R. 2SVM-4-(2- PVridvI)spiro[menthane-2,2'-benzofel fl,31-oxazine(2H)l, (11)

11 To a Schlenk flask contained a solution of [PtMe2(SMe2)J2 (149 mg, 0.23 mmol) and cis/trans-[PtCl2(SMe2)2] (179 mg, 0.46 mmol) in dry DCM (15 mL) was added SMe2 (34 μL) dropwise and stirred at room temperature overnight. The solvent was removed under reduced pressure to give a crude trans- [PtCl(Me)(SMe2)2] as creamy brown solid (g, %). A solution of trans-[PtCl(Me)(SMe2)2] (0.055 g, 0.13 mmol) and 5 (0.050 g, 0.15 mmol) in dry DCM (5 mL) was stirred at room temperature overnight. The volatiles were removed in a vacuum and the residues redissolved in dry dichloromethane, the solution was stirred under an argon atmosphere for 2 h, this procedure was repeated 3 times. The crude product was crystallized by diffusion of pentane into a solution of the Pt-complex in methanol to give a dark violet crystal of the title compound (40 mg, 52 %); m.p.: 233-2340C; 1H NMR (300 Hz, CDCl3) 0.83 (d, J = 6.6 Hz, 3H, H6"), 0.84 (d, J = 6.9 Hz, 3H, H8"), 1.04 (d, J = 6.9 Hz5 3H, H8"), 0.92 (m, IH) 1.35 (m, IH), 1.70 (m, 3H), 1.90 (d, J =13.95 Hz, IH, H5"), 2.11 (m, IH, H7"), 2.31 (m, IH, Hl"), 3.70 (d, J = 11.85 Hz, IH), 7.10 (m, 2H, H1'&H3'), 7.52 (m, 3H, H2'&H4'&H5'"), 8.00 (d, J = 7.2 Hz3 IH, H3'"), 8.18 (t, J = 1.5, 7.5 Hz, IH, H4"'), 9.26 (d, J = 6.0 Hz, 3Jp1H = 55.2 Hz, IH, H6'"); 13C NMR (75 Hz, CDCl3) 18.70 (C8"), 21.95 (C2"), 22.05 (C6"), 23.34 (C8"), 26.70 (C7"), 28.67 (C4"), 33.81 (C3"), 38.23 (C5"), 45.63 (Cl"), 98.97 (C2), 117.29 (C5), 119.10 (Cl'), 122.44 (CT), 126.48 (C4'), 128.56 (C3'")3 129.13 (C5"!), 135.07 (C3'), 136.63 (C4'"X 149.49 (C6'"), 154.34 (C2), 157.04 (C6), 164.10 (C4); Anal. CaIc. (found) for C23H29ClN2OPt: C 47.63 (46.33), H 5.04 (5.22), N 4.83 (4.50).

2. Preparation of Pd-complex of (1"'S, 4"'R, 2SW-V4-(r(6-MethvI)-2- pyridyllspirofmenthane^^'-benzorei [l,31-oxazine(2H))|, (13)

a) Preparation of (1"'S, 4"'R, 2S)-(-)-4-{[(6-MethyI)-2-pyridyl]spiro(menthane- 2,2'-benzo[e] [l,3]-oxazine(2H))},(12)

12 A 1.6M n-BuLi hexane solution (780 μL, 1.25 mmol) was added dropwise to a solution of 2-bromo-6-methylpyridine (118 μL, 1.00 mmol) in dry Et2O (5 niL) under an argon atmosphere at -78°C. The reaction mixture was stirred at this temperature for 0.5h. To this mixture was added a solution of ZnCl2 (285 mg, 2.10 mmol) in dry Et2O (5 mL) at -780C and the reaction mixture was warmed up O0C and stirred at this temperature for Ih. Then a solution of Pd(PPh3)4 (29 mg, 0.025 mmol) in dry Et2O (2 mL) and 3 (340 mg, 0.84 mmoL) in dry Et2O (5 mL) were added dropwise to the mixture. The reaction was refluxed overnight (17h). At room temperature, the reaction was quenched with saturated NaHCO3 (20 mL) and extracted with dichloromethane (2x20 mL). The combined extract was washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated in a vacuum to give brown oil as a crude product. The crude product was purified by flash chromatography (hexanes:EtOAc, 1:8) to give the title compound (106 mg, 35%, Rf = 0.54) as a white solid; m.p.: 89-9O0C; [α]26 (C=I, CHCl3) -316; 1U NMR (400 MHz, CDCl3) δ 0.84 (d, J = 6.4 Hz, 3H, H6"), 0.90 (d, J = 6.9 Hz, 3H, H8"), 0.98 (d, J = 7.0 Hz, 3H, H8"), 1.05 (m, IH, H3"), 1.24 (m, IH, H5"), 1.78 (m, 4H, H4", H3", H2", Hl"), 2.64 (s, 3H, Py-CH3), 6.84 (m, 2H, Hl', H3'), 7.21 (d, J = 7.7 Hz, IH, H2'), 7.30 (dd, J = 1.7, 7.4 Hz, IH, H5'"), 7.55 (d, J = 7.7 Hz, IH, H4'), 7.68 (t, J = 7.7 Hz, 2H, H3"\ H4'"), 7.73 (dd, J = 7.8 Hz, IH, H6'"); 13C NMR (100 MHz, CDCl3) δ 18. 80 (C8"), 21.79 (C2"), 22.30 (C6"), 24.05 (C8"), 27.08 (C7"), 28.12 (C4"), 35.18 (C3"), 42.51 (C5"), 51.63 (Cl'), 94.46 (C2), 116.62 (C5), 117.13 (Cl'), 120.59 (C3!), 123.74 (C3'"), 128.73 (C5'")3 133.55 (C45), 137.45 (C2'), 154.83 (C4'")5 156.26 (C6'"), 157.52 (C6), 156.33 (C2'"), 159.84 (C4); HRMS CaIc. (found) for C23H28N2O (M+H1"): m/z 349.2280 (349.2275); Anal. CaIc. (found) for C23H28N2O: C 79.27 (79.31); H 8.10 (8.19), N 8.04 (7.94).

b) Preparation of Pd-complex of (IS, 4R, 2S)-(-)-4-((6-methyl)-2- pyridyl)spiro[menthane-2,2'-benzo[e] [l,3]-oxazine(2H)], (13)

13 A solution of 12 (65 mg, 0.18 mmol) and allylpalladium chloride dimer (34 mg, 0.09 mmol) in dry DCM (5 mL) was heated at 50°C for 2 h. A solution Of AgBF4 (24 mg, 0.20 mmol) in 1 dry THF was added. The reaction mixture was stirred at 500C for Ih. The reaction mixture was filtered through a plug of Celite, the residue was washed with ethyl acetate and solvent was removed under reduced pressure to give yellow oil as a crude product. The crude product was crystallized from ethyl acetate/hexane to give very fine needles of the title compound (6Q mg, 65%); 1H NMR (400 Hz, CDCl3) 0.84 (d, J = 6.6 Hz, 3H, H6"), 0.88 (d, J = 6.8 Hz, 3H, H8"), 0.99 (d, J = 7.0 Hz, 3H, H8"), 1.01 (m, IH), 1.21 (bt, J = 13.1 Hz, IH), 1.66 (m, 3H)5 1.79 (m, 2H), 1.94 (m, 3H), 2.14 (m, IH, H7"), 3.48 (d, J = 12.4 Hz, IH, Hl"), 3.59 (d, J = 12.0 Hz, IH, Hl"), 4.56 (s, IH), 4.71 (s, IH), 5.85 (sep, J = 6.8 Hz, IH), 7.06 (dd, J = 0.8, 8.2 Hz, IH, H3"'), 7.24 (dt, J = 1.1, 7.7 Hz, IH, H4"'), 7.59 (dddd, J = 1.5, 7.5 Hz, IH, H6'"), 7.74 (m, 2H); 13C NMR (100 Hz, CDCl3) 18.66 (C8"), 22.16 (C2"), 22.42 (C6"), 24.40 (C8"), 27.00 (C7"), 28.28 (C4"), 29.86 (C3"), 34.78 (C5"), 36.94 (Cl"), 51.72 (C2), 66.39 (C2), 96.62 (C2), 117.09 (C5), 118.72 (Cl'), 123.54 (C2')> 127.21 (C4!), 128.80 (C3'")> 130.07 (C5'"), 136.37 (C3'). 140.72 (C4'")5 153.98 (C6"')> 154.58 (C2), 163.26 (C6), 167.74 (C4).

3(D. Preparation of Zn-complex of (T"S, 4'"R, 2S)-M-4-fBenzyr)spirormenthane- 2,2'-benzorel ri,31-oxazine(2EM, (15)

a) Preparation of (I" 'S, 4" 'R, 2S)-(-)-4-(Benzyl)spiro[menthane-2,2'- benzo[e][l,3]-oxazine(2H)], (14)

14 To a chilled (-3O0C) solution of 2-picoline (0.55 mL, 6 mmol) in dry THF (6 niL), n-BuLi (1.6 M in hexanes, 3.85 mL, 6.2 mmol) was added dropwise and stirred at -2O0C for 0.5 h. The orange solution mixture was transferred to an anhydrous ZnCl2 (0.840 g, 6.1 mmol) and stirred vigorously at -100C and allowed to warm to room temperature. The yellow reaction mixture was stirred until clear solution was obtained. The clear solution was transferred to a solution of 3 (1.13 g, 2.8 mmol) and Pd(PPh3)4 (0.97g, 3%) in dry THF (5 niL). The reaction mixture was refluxed overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM to give a crude product as brown oils. The crude product was purified by flash chromatography (hexanes:EtOAc, 8:1) to give the title compound (0.24g, 25%, Rf = 0.40) as yellow oils; 1H NMR (400 MHz, CDCl3) 0.75 (d, J = 6.6 Hz, 3H, CH3), 0.83 (d, J = 6.5 Hz, 3H, CH3), 0.87 (d, J = 6.9 Hz, 3H, CH3), 0.95 (d, J = 6.9 Hz, 3H, CH3), 0.99 (d, J = 7.0 Hz, 3H, CH3), 1.04 (d, J = 7.0 Hz, 3H, CH3), 1.23 (m, IH), 1.51 (dddd, J = 2.1, 3.9, 12.4 Hz, 3H), 1.73 (m, 10H), 2.07 (dddd, J = 2.1, 3.6, 14.0 Hz, 3H), 2.23 (m, J = 1.4, 6.9 Hz, IH), 2.31 (dddd, J = 2.1, 3.6, 14.0 Hz, 3H), 2.59 (m, J = 2.0, 6.9 Hz, IH), 4.19 (d, J = 1.7 Hz, 2H, H7), 5.76 (s, IH, H7), 6.74 (dd, J = 0.9, 8.1 Hz, IH), 6.79 (m, IH), 6.89 (dd, J = 1.1, 8.1 Hz, IH), 6.95 (dddd, J = 1.2, 7.6 Hz, IH), 7.02 (dt, J = 0.9, 8.1 Hz, IH), 7.12 (dddd, J = 1.1, 7.5 Hz, IH), 7.23 (m, 2H), 7.29 (d, J = 7.9 Hz, IH), 7.41 (dd, J = 1.5, 7.7 Hz5 IH), 7.46 (dddd, J = 1.9, 7.3 Hz, IH), 7.57 (dt, J = 1.8, 7.7 Hz, IH), 7.69 (dd, J = 1.5, 7.9 Hz, IH), 8.36 (d, J = 5.0 Hz, IH), 8.55 (d, J = 4.9 Hz, IH); 13C NMR (100 MHz, CDCl3) 21.25, 21.78, 21.79, 22.01, 23.69, 23.96, 26.04, 26.71, 27.84, 28.94, 34.80, 34.86, 43.06, 44.96, 45.69, 50.35, 51.18, 51.36, 87.83, 89.24, 94.11, 116.52, 116.71, 116.74, 118.25, 119.41, 120.40, 120.87, 121.87, 121.68, 122.13, 122.80, 123.54, 126.40, 130.33, 133.28, 135.44, 141.98, 147.23, 149.43, 152.31, 154.10, 157.94, 159.94, 160.10; MS CaIc. (found) for C12H9NO2 (M+H+): 349.4 (349.4, 100%); HRMS CaIc. (found) for C12H9NNaO2+ (M+Na+): m/z 371.2094 (371.2115).

b) Preparation of Zn-complex of (1"'S, 4"'R, 2S)-(-)-4-(Benzyl)spiro[menthane- 2,2'-benzo[e][l,3]-oxazine(2H)], (15)

15 To a solution of an anhydrous ZnCl2 (0.78 g5 0.57 mmol) in dry THF (6 mL), a solution of 14 (0.2 g, 0.57 mmol) in dry THF (3 mL) was added and stirred at room temperature overnight. The crude product was obtained after solvent was removed under reduced pressure. Crystallized in MeOH gave colourless crystals of the title compound (0.22 g, 80 % yield); 1H NMR (400 Hz, CDCl3) δ 0.73 (d, J = 6.4 Hz, 3H, H6"), 0.91 (d, J = 6.8 Hz, 3H, H8"), 1.13 (d, J = 6.8 Hz, 3H, H8"), 1.64 (m, 7H3 H2", H3", H4", H5"), 2.48 (q, J = 6.8 Hz, 3H, H7"), 2.63 (dddd, J = 1.2, 8.2, 15.9 Hz, IH, Hl"), 4.55 (d, J = 14.6 Hz, IH, CH2), 4.75 (d, J = 14.7 Hz, IH, CH2), 6.94 (d, J = 0.9, 8.2 Hz, IH, Hl'), 7.10 (t, J = 1.0, 7.6 Hz, IH, H3'), 7.53 (m, 2H, H4', H5'"), 7.66 (dd, J = 1.4, 7.9 Hz, IH, H2'), 7.67 (d, J = 7.7 Hz, IH, H3'"), 8.00 (d, J = 1.8, 7.7 Hz, IH, H4'"), 8.91 (dddd, J = 0.8, 1.7, 5.3 Hz, IH, H6'"); 13C NMR (100 Hz, CDCl3) δ 17.82 (C8"), 21.58 (C6"), 21.15 (C2"), 23.51 (C8"), 27.14 (C7"), 28.15 (C4"), 33.79 (C3"), 38.68 (C5"), 50.67 (Cl "), 95.71 (C2), 115.29 (C5), 118.97 (Cl'), 122.43 (C2'), 127.83 (C4'), 127.17 (C3'"), 128.97 (C5'"), 136.91 (C3'), 140.77 (C4'"), 150.75 (C6'"), 146.74 (C2), 155.49 (C6), 161.37 (C4); Anal. CaIc. (found) for C22H26Cl2N2OZn: C, 56.13 (56.07); H, 5.57 (5.58); N, 5.95 (5.94); HRMS CaIc. (found) for C23H28Cl2N2OZn (M+Na+): m/z 505.0768 (505.0753).

3(if). Preparation of Pd-complex of (I" 'S, 4'"R, 2SVM-4-(benzyr)spirormenthane- 2.2'-benzoM [l,31-oxazine(2HΗ. (16)

16 A solution of 14 (65 mg, 0.18 mmol) and allylpalladium chloride dimer (34 mg, 0.09 mmol) in dry DCM (5 mL) was heated at 40°C for 2 h. A solution Of AgBF4 (20 mg, 0.10 mmol) in 1 dry THF was added. The reaction mixture was stirred at 400C for Ih. The reaction mixture was filtered through a plug of Celite, the residue was washed with ethyl acetate and solvent was removed under reduced pressure to give yellow oil as a crude product of the title compound; 1H NMR (400 Hz, CDCl3) 0.72 (d, J = 6.5 Hz, 3H, H6"), 0.83 (d, J = 6.6 Hz, 3H, H8"), 1.03 (d, J = 7.0 Hz, 3H, H8"), 1.23 (m, 4H), 1.66 (m, 3H), 1.82 (m, 5H), 2.01 (m, IH), 2.19 (m, IH), 3.15 (s, IH), 4.13 (d, J = 5.9 Hz, IH), 4.48 (s, IH), 4.82 (s, IH), 5.66 (m, IH), 6.80 (dd, J = 8.9 Hz, IH), 7.05 (t, J = 8.4 Hz, IH), 7.30 (t, IH), 7.41 (t, IH), 7.64 (d, IH), 7.80 (t, IH), 8.53 (d, IH, J = 5.5 Hz, IH). ~

4. Preparation of (T"S, 4'"R, 2RV(+)-4-(N-Phenyl)spirormenthane-2,2'- benzorem,31-oxazin(2HYH, (17)

17 A mixture of (I " 'S, 4 '"R, 2R)-(+)-2,2'-methonyl-3H-benzo[e][l,3]oxazin-4-one (182 mg, 0.66 mmol) and PCl5 (30 mg, 0.13 mmol) and POCl3 (62 μL) was stirred at room temperature for 1 h. The reaction mixture was heated at 50°C for 2h. The excess of POCl3 was removed under reduced pressure to give pure (I " 'S, 4 " 'R, 2R)-(+)-4- (chloro)spiro[menthane-2,2 '-benzo[e]-[l,3]oxazine(2H)]. The crude product was analysed by 1H NMR spectroscopy and was used for next step without further purification. A mixture of crude (I " 'S, 4 '"R1 2R)-(+)-4-(chloro)spiro[menthane-2,2 '-benzo[eJ- [l,3Joxazine(2H)J and 1.2 eq aniline (72 μL, 0.79 mmol) was refluxed in CHCl3 for 2h (the reaction was followed by TLC). The solvent was removed under reduced pressure to give crude product as brown oil. The crude product was purified by flash chromatography (hexane:EtOAc, 4:1), the title compound was collected as yellow oils (80 mg, 53%, Rf = 0.46); 1H NMR (300 MHz, CDCl3) 0.76 (d, J = 6.6 Hz, 3H, CH3), 0.79 (d, J = 6.6 Hz, 3H, CH3), 0.85 (d, J = 6.9 Hz, 3H, CH3), 0.88 (d, J = 6.9 Hz, 3H, CH3), 0.92 (d, J = 6.9 Hz, 3H, CH3), 0.95 (d, J = 6.9 Hz, 3H, CH3), 1.13 (m, 2H), 1.25 (m, 3H), 1.69 (m, 7H), 2.05 (m, IH), 2.30 (m, 5H)5 4.83 (s, IH), 6.49 (s, IH), 6.96 (m, 8H), 7.33 (m, 6H), 7.69 (dd, J = 7.5 Hz, IH), 8.17 (dd, J = 1.5, 7.8 Hz, IH);

MS CaIc. (found) for C23H29N2O+(M+H+): 349.4 (349.4, 100%); HRMS CaIc. (found) for C23H29N2O+(M+H+): m/z 349.2274 (349.2281).

5. Asymmetric diethylzinc addition

To a chilled (O0C) solution of 5 (0.05 g, 0.15 mmol) in toluene (0.75 niL), IM (solution in hexanes) diethylzinc (1.30 niL, 1.30 mmol) was added dropwise and stirred at room temperature for 0.5h. At O0C, fresh distilled benzaldehyde (0.06 mL, 0.65 mmol) was added and stirred at O0C for 2 days. The reaction mixture was quenched with cold saturated NH4Cl (10 mL) and extracted with cold DCM (20 mL and 10 mL). The extracts were combined, dried over anhydrous MgSO4 and concentrated to give crude product (75 % conversion). The crude product was purified by flash chromatography using EtOAc/hexanes (1:9) to afford a pure adduct. The enantiomeric excess was determined by chiral HPLC (20%ee) : Daicel Chiracel OD-H, /-PrOH/Hexane 2/98, flow rate 1.0 ml/min, ^R 15.1 (iS)-isomer and 18.3 (i?)-isomer, 254 nm; 1H NMR (300 MHz, CDCl3) δ 0.90 (t, 3H), 1.80 (m, 2H), 4.60 (m, IH), 7.35 (m, 5H).

Note : racemic mixture, fa 14.8 and 18.4.

6. Asymmetric hydrosilylation

To a mixture of 5 (0.13 g, 0.4 mmol), [Rh(COD)Cl]2 (0.01 g, 0.04 mmol) and AgBF4 (0.03 g, 0.16 mmol) under argon atmosphere, dry acetophenone (0.93 mL, 8.00 mmol) was added at room temperature and stirred for 20 minute. The reaction mixture was cooled down to O0C and diphenylsilane (2.3 mL, 12.8 mmol) was added and stirred at O0C for 5 days. The reaction was quenched with cold methanol (5 mL) and cold IM HCl (10 mL) and stirred at O0C for Ih. The reaction mixture was extracted with diethylether (2x10 mL). The extracts were combined, dried over anhydrous MgSO4 and concentrated to give crude alcohol product with 60% conversion. The crude product was purified by flash chromatography using ethyl acetate/hexane (1:9) to afford (R)-I phenyl- 1-ethanol. The enantiomeric excess was determined by chiral HPLC (42%ee) : Daicel Chiracel OD-H, i- PrOH/Hexane 5/95, flow rate 0.5 ml/min, tκ 17.9 (i?)-isomer and 20.9 (5>isomer, 254 nm; 1H NMR (300 MHz, CDCl3) δ 1.49 (d, J=6.6Hz, 3H), 1.85 (s, IH), 4.90 (q, J=6.6Hz, IH), 7.38 (m, 5H)

Note : racemic mixture, fa 17.2 and 20.9.

7. General Procedure for Pd-Catalysed Allylic Alkylation of l,3-Diphenyl-2- propenyl Acetate with Dimethyl Malonate

Synthesis of (R)-Methyl 2-Carbomethoxy-3,5-diphenyIpent-4-enoate

A mixture of 5 (0.02 g, 0.06 mmol) and [(7/-C3H5)PdCl]2 (0.007 g, 0.02 mmol) in dry CH2Cl2 (2 ml) was degassed at -780C under argon atmosphere for 20 min. The reaction was sealed and refluxed for 2h. At -780C, a solution l,3-diphenyl-2-propenyl acetate (0.25 g, 1 mmol) in dry CH2Cl2 (2 ml) was added, followed by dimethyl malonate (0.29 g, 2.25 mmol), BSA (0.61 g, 3.00 mmol) and a few crystals of KOAc. The reaction was stirred at room temperature for 72h. The reaction was diluted with diethyl ether (20 ml) and washed with cold saturated aqueous NH4Cl (10 ml). The organic extract was dried over anhydrous magnesium sulfate and concentrate to give a crude product. For an analytically pure product the crude product was purified by chromatography on silica gel using ethyl acetate/hexane (1:6) to afford (jR)-isomer. The enantiomeric excess was determined by chiral HPLC (62%ee) : Daicel Chiracel OD-H, /-PrOH/Hexane 2/98, flow rate 0.2 ml/min, tR 59.30 (i?)-isomer and 64.46 (5)-isomer O. G. Mancheno, J. Prego, S. Cabrera, R. G. Arrayas, T. Llamas and J. C. Carretero, J. Org. Chem., 2003, 68, 3679-3686, 254 nm; 1H NMR (300 MHz, CDCl3) δ 3.52 (s, 3H), 3.70 (s, 3H), 3.95 (d, J=13.8Hz, IH), 4.26 (dd, J=8.4Hz, IH), 6.32 (dd, J=SAHz, IH), 6.47 (J, J=15.3Hz, IH), 7.30 (m, 10H); HRMS calc'd for C20H20O4 (M+Na+): m/z 347.1236, found 347.1251.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.