WO2011150205A2

WO2011150205A2 - Highly selective asymmetric hydroformylation of (1s,4r) or (1r,4s)-2-azabicyclo[2.2.1]hept-5-en-3- one (+) or (-)-lactam

Info

Publication number: WO2011150205A2
Application number: PCT/US2011/038134
Authority: WO
Inventors: Christopher James Cobley; Gary Noonan; Matthew Lee Clarke
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2010-05-27
Filing date: 2011-05-26
Publication date: 2011-12-01
Also published as: WO2011150205A3; EP2576553A2; EP2576553A4; IN2012CN10271A

Abstract

Methods of producing the compounds of formula (22) and (23) or enantiomers thereof comprising hydroformylation of compounds of the formula (21) or their enantiomers: using Kelliphite as chiral ligand wherein R is -H or an amine-protecting group.

Description

HIGHLY SELECTIVE ASYMMETRIC HYDROFORMYLATION OF (1S,4R) OR (1 R,4S)-2-AZABICYCLO[2.2.1]HEPT-5-EN-3-ONE (+) OR (-)-LACTAM

INTRODUCTION

The hydroformylation of lactam 1 has not been previously reported. Norbornene has been reported numerous times to give the exo product almost exclusively with a wide range Rh and Pt catalysts, but with this substrate there are not the same regioselectivity concerns as with the lactam substrate. In all cases except one, the enantioselectivities are low to moderate, (see Tetrahedron Letters, 46(45), 7831 -7834; 2005 for the best example). For other examples see Journal of Organic Chemistry, 51 (22), 4189-95; 1986; Journal of the American Chemical Society, 109(23), 7122-7; 1987; Organometallics, 10(6), 2046-51 ; 1991 ; Journal of Organometallic Chemistry, 447(1), 153-7; 1993; Catalysis Today, 63(2- 4), 531 -536; 2000; Tetrahedron Letters, 46(45), 7831 -7834; 2005; Chemistry-A European Journal, 14(24), 7144-7155; 2008.

Rh(acac)(CO)₂

(1) (2) (3)

The AstraZeneca platelet aggregation inhibiting compounds ( S,3R,4R)-3- hydroxy-4-[7-[(1 S^*,2R^*)-2-phenylcyclopropylamino]-5-(propylsulfanyl)-3H-[1 ,2,3] triazolo[4,5-d]pyrimidin-3-yl]cyclopentanecarboxylic acid (11 ) and (1 S,3R,4R)-3-[7- (hexylamino)-5-(propylsulfanyl)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl]-4-hydroxy cyclopentane carboxylic acid (12) taught in Pairaudeau (US Patent 6,166,022) and shown below, could be made by Baeyer-Villiger oxidation of aldehyde 8 with retention of configuration, followed by elaboration of the nitrogen atom on the cyclopentane ring of 10 to the 3H-[1 ,2,3]triazolo[4,5-d]pyrimidine ring.

Molecules that contain a functionalized cyclopentane, which could be derived from aldehyde 2 or its -Boc derivative 5 ma be found in Blumenkopf et al. WO 99/65908 A1 , Sharma et al, US 2010/0081713 A1 , Johansen et al. WO 2008/033466 A2, Chand et al. WO 2001/000558 A1 , Babu et al. WO 99/33781 A1 , and Babu et al. WO 97/47194 A1 . Molecules that contain a functionalized cyclopentane, which could be derived from aldehyde 3 or its -Boc derivative 6 may be found in Tibotec WO 2007/014924, Medivir WO 2008/1 19773, WO 1997/025316, Wishart et al. WO 2009/152133 A1 , Kvarnstroem et al. WO 2008/1 19773 A1 , Boehringer et al. WO 2006/048152 A2, and De Haen et al. WO 2001/064708 A1 . The beta-secretase 1 (BACE1) inhibitor, N1 -benzyl-N2-[6-(3,5- difluorophenoxy)-4(S)-hydroxy-2(R)-methoxy-5(S)-[(1 R,2R,4S)-4-[N-methyl-N- (methylsulfonyl)amino]-2-[N-[1 (S)-phenylethyl]carbamoyl]cyclopentylcarboxamido] hexanoyl]-L-valinamide, reported by Medivir for the treatment of Alzheimer's Dementia (see WO 2008/1 19773), is based on a core cyclopentyl fragment which is introduced using the orthogonally protected amino diacid shown below. This diacid could be readily accessible via oxidation of the correct stereoisomer of aldehyde 3 or its -Boc protected derivative 6, followed by t-butyl ester formation and ring opening via methanolysis.

In a similar fashion, the HCV NS3 NS4A protease inhibitor, N- [(2 R,3aR, 11 aS , 12aR, 14aR)-5-methyl-4 , 14-dioxo-2-(5-phenyl-2H-tetrazol-2-yl)- 1 ,2,3,3a, 4,5,6,7,8,9,1 1 a,12, 12a, 13,14, 14a-hexadecahydrocyclopenta[c]cyclo propa[g][1 ,6]diazacyclotetradecin-12a-ylcarbonyl]cyclopropanesulfonamide, reported by Tibotec in WO 2007/014924 for the treatment of Hepatitis C, is also based on a cyclopentyl fragment that could be accessed from the aldehydes described herein. Oxidation, ester formation, and methanolysis ring opening would once again provide an orthogonally protected synthon suitable for downstream chemistry.

The Neuraminidase (Sialidase) inhibitor, (1 R,3R,4R)-3-[1 (S)-acetamido-2- ethylbutyl]-4-guanidinocyclopentanecarboxylic acid, reported by Biocryst for the treatment of influenza (US 6,562,861 ) could be prepared from the regioisomeric - Boc protected aldehyde 5 also accessible via the route described herein. A Strecker reaction followed by ring opening could furnish the amino acid shown below, which would then allow access to the intermediate cyclopentyl derivative as described.

SUMMARY

In one aspect, the application provides a method of preparing (1 R,4R,6R)- 3-oxo-2-azabicyclo[2.2.1 ]heptane-6-carbaldehyde (2) and (1 S,4S,5S)-3-oxo-2- azabicyclo[2.2.1 ]heptane-5-carbaldehyde (3) :

from (1 R,4S)-2-azabicyclo[2.2.1 ]hept-5-en-3-one (1 ).

DETAILED DESCRIPTION

In one aspect, the application provides the compounds (1 R,4R,6R)-3-oxo- 2-azabicyclo[2.2.1 ]heptane-6-carbaldehyde (2) and (1 S,4S,5S)-3-oxo-2- azab icyclo[2.2.1 ]heptane-5-carbaldehyde (3) :

in optically active form.

In one aspect, the application provides the compounds (1 R,4R,6R)-ieAt- butyl 6-formyl-3-oxo-2-azabicyclo[2.2.1 ]heptane-2-carboxylate (5) and (1 S,4S,5S)- ie -butyl 5-formyl-3-oxo-2-azabicyclo[2.2.1 ]heptane-2-carboxylate (6):

5 6

in optically active form. In one aspect, the application provides the compound te/f-butyl ((1 R,2R,4R)-2,4-bis(hydroxymethyl)cyclopentyl)carbamate (7):

7

in optically active form.

In one aspect, the application provides the compound (1 R,3R,4R)-methyl 3-((feri-butoxycarbonyl)amino)-4-formylcyclopentanecarboxylate (8):

8

in optically active form.

In one aspect, the application provides the compound (1 R,4R,6S)-te/?-butyl 6-(((4 methoxyphenyl)amino)methyl)-3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate

(20):

in optically active form.

In one aspect, the application provides a method of preparing (1 R,4R,6R)- 3-oxo-2-azabicyclo[2.2.1]heptane-6-carbaldehyde (2) and (1 S,4S,5S)-3-oxo-2- azabicyclo[2.2.1 ]heptane-5-carbaldehyde (3):

2 3

from (1 R,4S)-2-azabicyclo[2.2.1 ]hept-5-en-3-one (1 ).

In one aspect, the application provides a method of preparing (1 R,4R,6R)- terf-butyl 6-formyl-3-oxo-2-azabicyclo[2.2.1 ]heptane-2-carboxylate (5) and (1 S,4S,5S)-ferf-butyl 5-formyl-3-oxo-2-azabicyclo[2.2.1 ]heptane-2-carboxylate (6):

5 6

from (1 R,4S)-tert-butyl 3-oxo-2-azabicyclo[2.2.1 ]hept-5-ene-2-carboxylate (4).

In one aspect, the application further comprises the step of reduction of (1 R,4R,6R)-tert-butyl 6-formyl-3-oxo-2-azabicyclo[2.2.1 ]heptane-2-carboxylate (5) to give terf-butyl ((1 R,2R,4R)-2,4-bis(hydroxymethyl)cyclopentyl)carbamate (7).

In one aspect, the application further comprises the step of methanolysis of (1 R,4R,6R)-tert-butyl 6-formyl-3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (5) to give (1 R,3R,4R)-methyl 3-((te/t-butoxycarbonyl)amino)-4-formylcyclopentane carboxylate (8).

In one aspect, the application further comprises the step of reductive amination of (1 R,4R,6R)-terf-butyl 6-formyl-3-oxo-2-azabicyclo[2.2.1 ]heptane-2- carboxylate (5) to give (1 R,4R,6S)-terf-butyl 6-(((4-methoxyphenyl)amino)methyl) - 3-oxo-2-azabicyclo[2.2.1 ]heptane-2-carboxylate (20).

In one aspect, the application provides a method of preparing protected (1 R,4R,6R)-6-formyl-3-oxo-2-azabicyclo[2.2.1]heptane (15) and protected (1 S,4S,5S)-butyl 5-formyl-3-oxo-2-azabicyclo[2.2.1 ]heptane (16):

from protected (1 R,4S)-3-oxo-2-azabicyclo[2.2.1 ]hept-5-ene-2-carboxylate (14), wherein protecting group is any amine-protecting group.

In one aspect, the application provides a method of preparing (1 R,4R,5R)- 3-oxo-2-azabicyclo[2.2.1 ]heptane-5-carbaldehyde (18) and (1 S,4S,6S)-3-oxo-2- azabicyclo[2.2.1 ]heptane-6-carbaldehyde (19):

solvent

17 18 19 from (1 S,4R)-2-azabicyclo[2.2.1 ]hept-5-en-3-one (17).

Highly selective asymmetric hydroformylation of (1 R,4S)-2- azabicyclo[2.2.1 ]hept-5-en-3-one (1 ) has been achieved using catalysts employing Kelliphite as chiral ligand. (R,R)-Kelliphite was by far the most effective ligand giving exo-aldehyde 2 in greater than 90% selectivity. (S,S)-Kelliphite gives the opposite regioisomer 3 in 86% selectivity and asymmetric hydroformylation of the N-Boc protected lactam gives higher selectivity in both cases.

Procedures used to synthesize the compounds of the present application are described in Schemes 1 -7 and are illustrated in the examples. Reasonable variations of the described procedures are intended to be within the scope of the present application: Scheme 1

As shown in Scheme 1 , highly selective asymmetric hydroformylation of (-)-lactam has been achieved using catalysts employing Kelliphite as chiral ligand. Having carried out a ligand screen of various chiral ligands, (fl,R)-Kelliphite was by far the most effective ligand giving exo-aldehyde 2 in greater than 90% selectivity. Use of (S,S)-Kelliphite gives the opposite regioisomer 3 in 86% selectivity and asymmetric hydroformylation of the Boc protected lactam 4 gives higher selectivity in both cases.

Scheme 2

As shown in Scheme 2, a larger scale run was carried out on 15 g of the N-Boc lactam 4 under constant pressure of 4.5 bar, temperature of 50°C, for 18 hours with a substrate to catalyst ratio of 5000:1. Crude ¹H NMR showed >99% conversion and a selectivity of >7:1 for 5:6. Upon crystallization from toluene 9.272g (55% yield from starting material) was isolated in >25:1 ratio of 5:6.

Scheme 3

Diol 7, formed by reaction of 5 with sodium borohydride, has been isolated in 49% yield as a single diastereomer after recrystallization is shown in Scheme 3.

Scheme 4

Aldehyde 8 has also been synthesized via basic methanolysis of 5 and has been crystallized to give the desired product in >30:1 yield as shown in Scheme 4. Scheme 5

Reductive amination of 5 is also possible without racemization using sodium tri- acetoxy borohydride to give amino functionalized 20 as shown in Scheme 5. Scheme 6

12

Baeyer-Villiger oxidation of aldehyde 8 with retention of configuration should give alcohol 9. Deprotection, followed by elaboration of the nitrogen atom on the cyclopentane ring of 10 will give the 3H-[1 ,2,3]triazolo[4,5-d]pyrimidine ring compounds 11 and 12 as shown in Scheme 6. Scheme 7

Alcohol 13, formed by reaction of 2 with sodium borohydride, has been isolated in 26 % yield as a single diastereomer after recrystallization as shown in Scheme 7.

DEFINITIONS

The following definitions are used in connection with the compounds of the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated "C_x-C_y", where x and y are the lower and upper limits, respectively. For example, a group designated as "Cr C₆" contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.

The following abbreviations are used herein and have the indicated definitions: acac is acetyl acetone or 2,4-pentanedione, Biphephos is 6,6'-[(3,3'-di- feri-butyl-S.S'-dimethoxy-I '-biphenyl^^'-diy bisioxy^bisidibenzotdflCl .a^] dioxaphosphepin), Boc is the tertiary-butyloxycarbonyl group, DiazaPhos-SPE is 2,2',2",2"'-(1 ,2-phenylenebis [tetrahydro-5,8-dioxo-1 H-[1 ,2,4]diazaphospholo[1 ,2- a]pyridazine-2,1 ,3(3H)-triyl])tetrakis(N-[1 -phenylethyl])benzamide, DIPPF is 1 ,1 '- bis(diisopropylphosphino)ferrocene, DPPE is 1 ,2-bis(diphenylphosphino) ethane, iPr-DuPHOS is 1 ,2-bis((2S,5S)-2,5-di-i-propylphospholano)benzene, Kelliphite is 6,6'-[(1 ,1 '-biphenyl-2,2'-diyl)bis(oxy)] bis[4,8-di-t-butyl-1 ,2,10,1 1 -tetramethyl]di benzo[d,f][1 ,3,2]dioxaphosphepin bisacetonitrile adduct, e-FerroTANE is 1 ,1 '- bis(2,4-dimethylphosphotano)ferrocene, FerroTANE™ is a trademark of Chirotech Technology Ltd., Nixantphos is 4,6-bis(diphenylphosphino)phenoxazine, P-Cage is 1 ,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane, PhanePHOS is 4,12-bis(diphenylphosphino)-[2.2]-paracyclophane, Ph-BPE is 1 ,2-bis(2,5- diphenylphospholano)ethane, r.t. is room temperature, Syn gas (or synthesis gas) is the name given to a gas mixture that contains varying amounts of carbon monoxide and hydrogen, THF is tetrahydrofuran, TLC is thin-layer chromatography, TMS₂-HMOB is 2,10-di-reri-butyl-6-((5,5'-di-te/ -butyl-2'-((8- methoxy-4H-benzo[d][1 ,3,2]dioxaphosphinin-2-yl)oxy)-3,3'-bis(trimethylsilyl)-[1 ,1 '- biphenyl]-2-yl)oxy)-4,8-bis(trimethylsilyl)dibenzo[d,f][1 ,3,2]dioxaphosphepine, and Tol-BINAP is 2,2'-bis(di-p-tolylphosphino)-1 ,1 '-binaphthyl.

"Amine-protecting group" refers to a radical when attached to a nitrogen atom in a target molecule is capable of surviving subsequent chemical reactions applied to the target molecule i.e. hydrogenation, reaction with acylating agents, alkylation etc. The amine-protecting group can later be removed. Amine protecting groups include, but are not limited to, fluorenylmethoxycarbonyl (FMOC), terf-butoxycarbonyl (t-BOC), benzyloxycarbonyl (Z), those of the acyl type {e.g., formyl, benzoyl, trifluoroacetyl, p-tosyl, aryl- and alkylphosphoryl, phenyl- and benzylsulfonyl, o-nitrophenylsulfenyl, o-nitrophenoxyacetyl), and of the urethane type (e.g. tosyloxyalkyloxy-, cyclopentyloxy-, cyclohexyloxy-, 1 ,1 - dimethylpropyloxy, 2-(p-biphenyl)-2-propyloxy- and benzylthiocarbonyl). Amine- protecting groups are made using a reactive agent capable of transferring an amine-protecting group to a nitrogen atom in the target molecule. Examples of an amine-protecting agent include, but are not limited to, C-i-C₆ aliphatic acid chlorides or anhydrides, C₆-Ci arylcarboxylic acid chlorides or anhydrides, t-butyl chloroformate, di-teri-butyl dicarbonate, butoxycarbonyloxyimino-2- phenylacetonitrile, t-butoxycarbonyl azide, t-butyl fluoroformate, fluorenylmethoxy carbonyl chloride, fluorenylmethoxycarbonyl azide, fluorenylmethoxycarbonyl benzotriazol-1 -yl, (9-fluorenylmethoxycarbonyl)succinimidyl carbonate, fluorenyl methoxycarbonyl pentafluorophexoxide, trichloroacetyl chloride, methyl-, ethyl-, trichloromethyl- chloroformate, and other amine protecting agents known in the art. Examples of such known amine-protecting agents are found in pages 385- 397 of T. W. Green, P. G. M. Wuts, "Protective Groups in Organic Synthesis, Second Edition", Wiley-lnterscience, New York, 1991.

"Borohydride" refers to a reagent containing a B-H group, which is capable of delivering the hydride group to a carbonyl functional group. Examples of such borohydride reagents include, but are not limited to, lithium borohydride, sodium borohydride, potassium borohydride, magnesium borohydride, calcium borohydride, zinc borohydride, triacetoxy sodium borohydride, or sodium cyano borohydride.

"Peracid" refers to a reagent containing a -C0₃H group. Examples of such peracid reagents include, but are not limited to, peracetic acid, propaneperoxoic acid, peroxybenzoic acid, m-chloroperbenzoic acid, peroxytrifluoroacetic acid, performic acid, peroxymaleic acid, or peroxydichloromaleic acid.

Procedures used to perform the processes of the present application are described in Schemes 1 through 7 and are illustrated in the examples. Reasonable variations of the described procedures are intended to be within the scope of the present application.

EXAMPLES

Table 1 : Results obtained in the (-)- lactam 1 using various ligands

^* Based on starting material remaining ^a reaction allowed to stir overnight insoluble solid formed, ^b no internal standard used, ⁰ percentage of desired aldehydes formed based on internal standard

Table 2: Results obtained in the hydroformylation of A-Boc-(-)-lactam 4 using various ligands

Based on starting ma^' erial remaining percentage of wanted aldehydes formed Example 1 (1 ?,4 ?,6fl)-3-oxo-2-azabicyclo[2.2.1]heptane-6- carbaldehyde (2). To a 50 ml_ autoclave (pre-purged with nitrogen) was added a catalyst solution containing (H.^-Kelliphite (4.8 mg, 0.5 mol%) and

Rh(acac)(CO)₂ (1 mg, 0.4 mol%) in toluene (1 ml_). Three pump-purge cycles were carried out using CO:H₂, the mixture placed under 5 bar of CO:H₂ (1 :1 ), heated to 50 °C in an oil bath and stirred at 1000 rpm with a magnetic cross stirrer bar for 1 hour. The autoclave was subsequently removed from the heating bath, depressurized and a solution containing the unsaturated 1 (109 mg, 1 mmol) and tetraethyl silane (30 μΙ_, 33 mol %) as internal standard in toluene (2 ml_) was injected into the autoclave. The autoclave was then pressurized to 4.5 bar CO:H₂ (1 :1 ) heated to 50 °C and stirred at 1000 rpm with a magnetic cross stirrer bar for 90 minutes. The autoclave was then removed from heating, allowed to cool to room temperature and depressurized. Solvent was removed from the crude reaction mixture and the product isolated by column chromatography with ethyl acetate as eluent, the product was isolated as (97% conversion to aldehydes by ¹H NMR spectroscopy based on internal standard, regio-isomeric ratio of 6.3:1 , the major product isomer being 2). Yield: 76 mg (colorless oil), 0.55 mmol (55%). a_D ²⁵= -278.4° (c= 2.85, CDCI₃); v_max/cm^"1= 3279, 2960, 2886, 1683, 1466, 1450, 1401 , 1329, 1290, 1229, 1209, 1 151 , 1 1 16, 1064; ¹H NMR (300 MHz, CDCI₃) δ_Η= 9.73 (d, 1 H, J= 1 .0 Hz, C8H), 6.33 (bs, 1 H, N2H), 4.1 1 (s, 1 H, C1 H), 2.86-2.94 (m, 1 H, C6H), 2.73-2.79 (m, 1 H, C4H), 2.13-2.22 (dt, 1 H, J= 12.9, 4.5 Hz, C5H), 1 .87- 1 .94 (m, 1 H, C7H), 1.74-1 .84 (ddd, 1 H, J= 2.9, 9.0, 2.4 Hz, C5H) .37- .44 (ddd, 1 H, J= 9.9, 3.5, 1 .5 Hz, C7H); ¹³C NMR (CDCI₃) 6_C= 200.6 (C8), 181 .7 (C3), 56.5 (C1 ), 56.3 (C6), 44.6 (C4), 39.6 (C7), 25.3 (C5); m/z (CI+) 140.0715 (M+Na)⁺ C7H10NO2 requires 140.0712. 2D-NMR spectroscopy used to determine identity of regioisomer (COSY, HMBC, and HSQC).

Example 2: (1 R,4R,6R)-tert-buty\ 6-formyl-3-oxo-2-azabicyclo[2.2.1 ] heptane-2-carboxylate (5). To an oven-dried glass liner of a 300 ml_ autoclave was added (fl,fl)-Kelliphite (17 mg, 0.025 mol%) and Rh(acac)(CO)₂ (3.7 mg, 0.02 mol%). Three pump-purge cycles were then carried out using CO:H₂ (1 :1 ), dry toluene (20 ml_) added and the solution placed under 5 bar CO:H₂ (1 : 1 ). The autoclave was then heated to 50 °C using an electric heating jacket and stirred at 1000 rpm with an overhead stirrer for 40 minutes. The autoclave was

subsequently removed from the heating jacket, depressurized and a solution containing (3) (15 g, 71 .6 mmol) in toluene (40 ml_) was injected into the autoclave. The autoclave was then pressurized with 4.5 bar CO:H₂ (1 :1) using apparatus to keep the pressure constant throughout the reaction, heated to 50 °C and stirred at 1000 rpm with an overhead stirrer for 15 hours. The autoclave was then removed from heating, allowed to cool to room temperature and

depressurized. Analysis by ¹H NMR showed >99% conversion to aldehydes in a diastereomeric ratio of 7.14:1 , with 5 being the major product. Crystallization from a minimum amount hot toluene gave 9.272 g of white solid (54% isolated yield, in a diastereomeric ratio of > 25:1 , 5 being the major product): H NMR(CDCI₃) 5H= 9.74 (s, 1 H, C1 1 H), 4.71 (s, 1 H, C1 H), 2.97-3.05 (m, 1 H, C6H), 2.81 -2.87 (m, 1 H, C4H), 2.19-2.19 (m, 1 H, C5H), 1 .79-1.92 (m, 2H, C5H and C7H), 1.46 (s, 9H, C10Hg) 1.33-1.39 (dt, 1 H, J= 10.5 1 .3Hz C7H); ¹³C NMR (CDCI₃) 5_C= 199.6 (C1 1 ), 175.0 (C3), 149.5 (C8) 83.4 (C9), 59.1 (C1 ), 54.0 (C6), 46.1 (C4), 25.2 (C5), 36.0 (C7);m/z (ES+) 294.1310 (M+MeOH+Na)⁺ Ci₃H₂iN0₅Na requires 294.1317.

NOESY and crystal structure confirm exo epimer formed exclusively 2D-NMR used to determine the identity of regioisomer (COSY, HMBC, HSQC).

Example 3: (1 /?,4/?,6fl)-ferf-Butyl 6-formyl-3-oxo-2-azabicyclo[2.2.1] heptane-2-carboxylate (5). The reaction was performed in a 300 ml Parr pressure vessel fitted with a glass liner, double impeller, injection port, bursting disk, pressure relief valve, and pressure gauge. The glass liner was charged with Rh(CO)₂(acac) (3.6 mg, 0.0142 mmol) and (f?,ft)-Kelliphite (16.8 mg, 0.0176 mmol), the vessel sealed and flushed three times with nitrogen (145 psi). Toluene (20 ml, anhydrous, and deoxygenated) was added to the vessel via the injection port and the system flushed three times with Syn gas (145 psi, 1 :1 ). The vessel was heated to 50 °C, charged to 90 psi with Syn gas (1 :1 ) and stirred (1 ,000 rpm) for 40 minutes. After this time, the stirring was stopped and the pressure released. A toluene solution (40 ml, anhydrous and deoxygenated) of /V-Boc-(-)- lactam (4, 15.0 g, 21 mmol) was then added via syringe and the vessel flushed a further three times with Syn gas (145 psi, 1 :1). The reaction was stirred (1000 rpm), heated to 50 °C, and charged to 65 psi with Syn gas (1 :1 ). The pressure was monitored and maintained at this pressure for 16 hours. The stirring was reduced to 500 rpm and the vessel allowed to cool to room temperature, vented to atmosphere, flushed once with nitrogen (145 psi) and opened. An aliquot of the reaction mixture was analyzed by ¹H NMR spectroscopy, showing the reaction had gone to completion with a ratio of 7.1 :1 in favor of the exo-aldehyde β to the NH. The reaction mixture was reduced to dryness and dissolved in toluene (20 mL). This was placed in the freezer for one week to aid crystallization, after which time filtration yielded 9.3 g of crystalline material (58 % yield, ββχο:γβχο 17.5:1 ).

Example 4: (1 S,4S,5S)-ferf-Butyl 5-formyl-3-oxo-2-azabicyclo[2.2.1 ] heptane-2-carboxylate (6). To a 50 mL autoclave pre-purged with nitrogen gas was added a catalyst solution containing (S,S)-Kelliphite (4.8 mg, 0.5 mol%) and Rh(acac)(CO)2 (1 mg, 0.4 mol%) in toluene (1 mL). Three pump-purge cycles were carried out using CO:H₂ and the mixture placed under 5 bar CO:H₂ (1 :1 ), heated to 50 °C in an oil bath and stirred at 1000 rpm with a magnetic cross stirrer bar for 40 minutes. The autoclave was subsequently removed from the heating bath, cooled to room temperature, depressurized and a solution containing 4 (209 mg, 1 mmol) and tetraethyl silane (30 μΙ_, 33 mol%) as internal standard in toluene (2 ml_) was injected into the autoclave. The autoclave was then pressurized with 4.5 bar CO:H₂ (1 :1 ) and stirred at 1000 rpm with a magnetic cross stirrer bar at room temperature for 15 hours. The autoclave was then removed from heating, allowed to cool to room temperature and depressurized. Analysis by ¹H NMR showed > 99% conversion to aldehydes in a diastereomeric ratio of 10.1 :1 , with 6 being the major product: ¹H NMR(CDCI₃) δ_Η= 9.72 (s, 1 H, C 1 H), 4.53 (t, 1 H, C1 H), 3.08-3.12 (m, 1 H, C4H), 2.90-2.98 (m, 1 H, C5H), 2.17-2.30 (m, 1 H, C6H), 1.82-1.97 (m, 2H, C6H and C7H), 1 .31 -1.39 (dt, 1 H, J= 10.5, 1.4 Hz, C7H); ¹³C NMR (CDCI₃) δ₀= 199.1 (C1 1), 173.9 (C3), n/o (C8 and C9), 59.0 (C1 ), 49.1 (C5), 47.9 (C4), 35.8 (C7), 30.0 (C6), 28.5 (C10). NOESY confirms exo epimer formed exclusively.

Example 5: (1 /?,4fl,6 ¾-6-(Hydroxymethyl)-2azabicyclo[2.2.1]heptan-3- one (13). Solvent was removed under reduced pressure from a crude asymmetric hydroformylation reaction (358 mg, 2.58 mmol of substrate) and the resulting residue dissolved in ethanol (15 ml_). To this solution was then added sodium borohydride (98 mg, 1 eq.) and the reaction mixture stirred for 4 hours, upon which time no starting material remained by TLC analysis. Acetone was then added and the reaction allowed to stir for 5 minutes. Hydrochloric acid (0.1 M) was then added to pH neutral and the water removed under reduced pressure. The resulting gum was stirred for 30 minutes in 25 ml_ dichloromethane, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to leave colorless oil (21 1 mg, 58%). This was then crystallized from a minimum amount of hot methyl ethyl ketone and filtered to leave a fluffy white solid (26% isolated yield, diastereomeric ratio > 100:1 ). H NMR(CD₃OD) δ_Η= 3.79-3.86 (m, 1 H, C1 H), 3.60 (dd, 1 H, J= 1 1.5, 5.8Hz, C8H), 3.42 (dd, 1 H, J=1 1 .5, 9.1 Hz, C8H), 2.58-2.66 (m, 1 H, C4H), 2.05-2.18 (m, 1 H, C6H), 1 .80-1.88 (m, 1 H, C7H), 1 .6-1.74 (m, 2H, C7H and C5H), 1 .43 (ddd, 1 H, J=12.7, 5.0, 4.1 Hz, C5H); ¹³C NMR (CD₃OD) 5c= 184.2 (C3), 64.0 (C8), 56.9 (C1 ), 46.3 (C6), 44.8 (C4), 38.1 (C7), 27.4 (C5); m/z (ES+) 164.0689 (M+Na)⁺ C_/HnNOaNa requires

164.0687; Anal. Calcd. for C₇HnN0₂: C 59.56, H 7.85, N 9.92. Found C 59.55, H 7.9, N 10.03. The crystal structure confirms relative stereochemistry and identity of regioisomer. 2D-NMR used to determine identity of regioisomer (COSY, HMBC, and HSQC .

Example 6 ferf-Butyl ((1 fl,2f?,4R)-2,4-bis(hydroxymethyl)

cyclopentyl)carbamate (7). Aldehyde (5) (1.000 g, 4.18 mmol) was dissolved in tetrahydrofuran:water 10:1 (20 mL) and to this solution was added sodium borohydride (318 mg, 8.36 mmol, 2 equivalents) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0 °C and 37% aqueous hydrochloric acid was added drop-wise to the solution (to pH about3). The resulting mixture was then extracted with dichloromethane (3 x 50 mL portions), the organics combined and washed with saturated sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to leave a colorless solid (744 mg). The solid was then purified by re-crystallization from a minimum amount of hot ethyl acetate. Yield: 498 mg (colorless crystals), 2.07 mmol, (49%), diastereomerically pure as a single regioisomer. oc_D ²⁵= -27.2° (c= 1.00, MeOH); ¹H NMR (300 MHz, CD3OD) δ_Η= 3.53-3.67 (m, 2H, C1 H and 01 OH), 3.40-3.52 (m, 3H, 01 1 H₂ and C10H'), 2.03-2.23 (m, 2H, C4H and C5H), 1.80-1.97 (m, 1 H, C2H), 1.54-1.73 (m, 2H, C3H₂), 1.45 (s, 9H, C9H₉), 1. -1 .29 (m, 1 H, C5H'); ¹³C NMR (CD₃OD) 5_C= 158.5 (C7), 80.0 (08), 66.1 (01 1 ) 63.6 (C10), 53.8(01), 47.4 (C2), 38.2 (C4), 36.3 (C5), 30.6 (C3), 28.8 (C9); HR S (ES⁺): 246.00 [M+1f, Ci₂H₂ N0₄ requires 246.17; Anal. Calcd. for Ci₂H₂₃N0₄: C 58.75, H 9.45, N 5.71 . Found C 58.63, H 9.39, N 5.71

Example 7: (1 ?,4 ?,6S)-ferf-Butyl 6-(((4-methoxyphenyl)amino)methyl)-

3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (20). Aldehyde (5) (355 mg, 1 .48 mmol) was dissolved in dichloromethane (10 mL) and to this solution was added sequentially, p-methoxyaniline (182 mg, 1 .48 mmol, 1 equivalent) and sodium tri-acetoxyborohydride (313 mg, 1.48 mmol, 1 eq.) and the mixture allowed to stir at room temperature for 16 hours. The initially insoluble sodium tri- acetoxyborohydride was seen to slowly dissolve in the reaction mixture with significant darkening of the solution. Upon completion the reaction was quenched with saturated sodium hydrogen carbonate (10 mL) extracted with

dichloromethane (3 x 20 mL), dried over magnesium sulfate and the solvent was removed under reduced pressure (47 % isolated yield). ¹H NMR (400 MHz,

CDCI₃) δ_Η= 6.69-6.74 (m, 2H, ArCH), 6.47-6.53 (m, 2H, ArCH), 4.37-4.40 (m, 1 H, C1 H), 3.67 (s, 3H, C15H₃), 3.49 (bs, 1 H, N12H), 3.01 (dd, 1 H, J= 12.0, 6.4 Hz, C1 1 H), 2.93 (dd, 1 H, J=12.0, 9.1 Hz, C1 1 H'), 2.75-2.79 (m, 1 H, C4H), 2.20-2.31 (m, 1 H, C6H), 1.92-2.00 (m, 1 H, C5H), 1.81 -1.89 (m, 1 H, C7H), 1.53 (dt, 1 H, J= 10.5, 1.4 Hz, C7H'), 1.41-1.49 (m, 1 H, C5H'); ¹³C NMR (75.5 MHz, CDCI₃)= 175.4 (C3), 152.4 (C14), 149.2 (C8), 142.0 (C13), 1 15.0 (ArCH), 1 13.9 (ArCH), 82.8 (C9), 60.6 (C1 ), 55.8 (C15), 48.4 (C1 1 ), 46.5 (C4), 42.1 (C6), 34.7 (C7), 29.5 (C5), 28.2 (C10); HRMS (ES⁺): 369.1792 [M+Na]⁺, Ci₉H₂₆N₂0₄Na requires 369.1790. Relative stereochemistry confirmed by NOESY.

Example 8 (1 /7,3/?,4fl)-Methyl 3-((fert-butoxycarbonyl)amino)-4-formyl cyclopentane carboxylate (8). Aldehyde 5 (880 mg, 3.68 mmol, > 28:1 regio- isomeric ratio) was dissolved in methanol (10 mL) and placed under a nitrogen atmosphere. The reaction mixture was then cooled to 0 °C, sodium methoxide (219 mg, 4.06 mmol, 1.1 eq.) was added, and the reaction allowed to stir for 10 minutes at 0°C. The reaction vessel was then allowed to warm to room

temperature and stirred for a further 16 hours, under a nitrogen atmosphere.

Water was then added (10 mL) and the mixture was extracted with

dichloromethane (3 x 20 mL portions), dried over magnesium sulfate and the solvent removed under reduced pressure to give 777 mg of colorless oil. The product was initially purified by column chromatography with hexane: ethyl acetate 3:1 as eluent. This yielded 51 1 mg of a colorless solid, with partial epimerization of the aldehyde centre apparent. Three products were present in a 91 :7:2 ratio by ¹H NMR spectroscopy (91 % (8), 7% 3-epi-(8) tentatively assigned as most likely side product, the final 2% being the regioisomeric aldehyde which was present in the starting material for the reaction. The product was further purified by re- crystallization from warm ether. Yield: 280 mg, 1.03 mmol, (28%), 30:1 ratio of (8) to 3-epi-(8). a_D ²⁵= -8.3° (c= 0.58, CDCI₃), v_max/cm^"1= 3366, 2976, 2952, 1727, 1682, 1522, 1434, 1368, 1288, 1254, 1 172, 1 102, 1075, 1046; ¹H NMR (300 MHz, CDCI₃) δ_Η= 9.73 (d, 1 H, J= 2.0 Hz, C12H), 5.00-5.37 (bm, 1 H, N6H), 4.18-4.38 (m, 1 H, C4H), 3.70 (s, 3H, C1 1 H₃), 2.76-3.00 (m, 2H, C3H and C1 H), 1.98-2.37 (m, 3H, C2H₂ and C5H), 1.76-1 .92 (m, 1 H, C5H), 1 .44 (s, 9H, C9H₉); ¹³C NMR (75.5 MHz, CDCI₃)= 201.5 (C12), 176.8 (C10), 155.7 (C7), 80.2 (C8), 59.2 (C3), 52.7 (C4), 52.5 (C1 1 ), 41 .7 (C1 ), 35.8 (C5), 28.7 (C9), 28.4 (C2); HRMS (ES⁺): 272.1493 [M+H]⁺, C₁₃H₂₂N0₅ requires 272.1498; Anal. Calcd. for Ci₃H₂₁N0₅: C 57.55, H 7.80, N 5.16. Found: C 57.48, H 7.73, N 5.22.

Example 9 (1 S,4S,5S)-3-Oxo-2-azabicyclo[2.2.1]heptane-5-carb aldehyde (3). When the asymmetric hydroformylation was carried out, according to the procedure for compound 2, using (S,S)-Kelliphite as modifying ligand the other regio-isomer, 3 was formed in excess (up to 7.15:1 ). ¹H NMR (300 MHz, CDCI₃) δ_Η= 9.74 (s, 1 H, C8H), 7.08 (bs, 1 H, N2H), 3.92 (s, 1 H, C1 H), 2.96 (s, 1 H, C4H), 2.78-2.86 (m, 1 H, C5H), 2.1 1 -2.23 (m, 1 H, C6H), 1 .80-1.91 (m, 1 H, C7H), 1.73-1.81 (m, 1 H, C6H), 1 .32-1.40 (m, 1 H, C7H); ¹³C NMR (75.5 Hz, CDCI₃) δ₀=199.9 (C8), 179.7 (C3), 55.1 (C1 ), 49.1 (C5), 46.3 (C4), 39.5 (C7), 31.9 (C6). NOESY confirms exo-epimer formed exclusively. 2D-NMR spectroscopy used to determine identity of regioisomer (COSY, HMBC, and HSQC). Example 10 (1 /?,4S)-ferf-Butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2- carboxylate (4). The product was purified by recrystallization from boiling hexane to leave a pale orange solid. a_D ²⁵= -194.4° (c= 1.93, CDCI₃); ¹H NMR (400 MHz, CDCIs) δ_Η= 6.91 (dd, 1 H, J= 5.4, 2.3Hz, C5H, based on most intense olefinic cross peak in HMBC with C=0 of lactam), 6.68 (ddd, 1 H, J=5.4, 3.2, 1.5Hz, C6H), 4.95-5.00 (m, 1 H, C1 H), 3.37-3.44 (m, 1 H, C4H), 2.37 (dt, 1 H, J=8.5, 1.7Hz, C7H), 2.17 (dt, 1 H, J= 8.5, 1.6Hz, C7H), 1.52 (s, 9H, C10H₉); ¹³C NMR (75.5 MHz, CDCI₃) δο= 176.3 (C3), 150.4 (C8), 140.0 (C5), 138.2 (C6), 82.6 (C9), 62.4 (C1 ), 54.9 (C7), 54.5 (C4), 28.1 (C10); MS (ES⁺): 232.00 (M+Na)⁺, CnH₁₅N0₃Na requires 232.10.

Example 11 (1 H,4/?,6 ?)-iert-Butyl 6-formyl-3-oxo-2-azabicyclo[2.2.1] heptane-2-carboxylate (5). To an oven-dried glass liner of a 300 ml_ autoclave was added (/?,f?)-Kelliphite (17 mg, 0.025 mol%) and [Rh(acac)(CO)₂] (3.7 mg, 0.02 mol%). Three pump-purge cycles were then carried out using CO:H₂ (1 :1 ), dry toluene (20 ml_) added and the solution placed under 5 bar CO: H2 (1 :1). The autoclave was then heated to 50 °C using an electric heating jacket and stirred at 1000 rpm with an overhead stirrer for 40 minutes. The autoclave was

subsequently removed from the heating jacket, depressurized and a solution containing olefin (4) (15 g, 71.60 mmol) in toluene (40 ml_) was injected into the autoclave. The autoclave was then pressurized with 4.5 bar CO:H₂ (1 :1) (using apparatus to keep the pressure constant throughout the reaction), heated to 50 °C and stirred at 1000 rpm with an overhead stirrer for 15 hours. The autoclave was then removed from heating, allowed to cool to room temperature, and

depressurized. Analysis by ¹H NMR showed > 99% conversion to aldehydes, regioisomeric ratio = 7.1 :1 , with (5) being the major product. The solvent was removed under reduced pressure and the colorless oil which remained dissolved in a minimum amount of hot toluene, allowed to cool to room temperature and placed in the fridge for one week. Yield: 9.272 g (colorless crystalline solid), 38.66 mmol, (54%), regio-isomeric ratio (5):(6) > 25:1 . a_D ²⁵= -99.7° (c= 2.30, CHCI₃); v_max/cm^'1=2976, 1778, 1723, 1449, 1391 , 1342, 1291 , 1252, 1 142, 1123, 1075, 1038; ¹H NMR (300 MHz, CDCI₃) δ_Η= 9.74 (s, 1 H, C1 1 H), 4.71 (s, 1 H, C1 H), 2.97- 3.05 (m, 1 H, C6H), 2.81 -2.87 (m, 1 H, C4H), 2.19-2.27 (m, 1 H, C5H), 1 .79-1.92 (m, 2H, C5H and C7H), 1.46 (s, 9H, C10H₉) 1 .33-1.39 (dt, 1 H, J= 10.5 1.3Hz C7H); ¹³C NMR (CDCI₃) 6_C= 199.6 (C1 1 ), 175.0 (C3), 149.5 (C8) 83.4 (C9), 59.1 (C1 ), 54.0 (C6), 46.1 (C4), 36.0 (C7), 28.3 (C10), 25.2 (C5); HRMS (ES)⁺

294.1310 [M+MeOH+Na]⁺, Ci₃H₂iN0₅Na requires 294.1317. Note: MS (Cl⁺): 184.06 observed [M-^fBu+H] requires 184.06. NOESY confirms exo-epimer formed exclusively. 2D-NMR spectroscopy used to determine identity of regioisomer (COSY, HMBC, and HSQC).

Example 12 (1 S,4S,5S)-fert-Butyl 5-formyl-3-oxo-2-azabicyclo[2.2.1] heptane-2-carboxylate (6). To a 50 mL autoclave (pre-purged with nitrogen gas) was added a catalyst solution containing (S,S)-Kelliphite (4.8 mg, 0.5 mol%) and [Rh(acac)(CO)₂] (1 mg, 0.4 mol%) in toluene (1 mL). Three pump-purge cycles were carried out using CO:H₂ and the mixture placed under 5 bar CO:H₂ (1 :1), heated to 50 °C in an oil bath and stirred at 1000 rpm with a magnetic cross stirrer bar for 40 minutes. The autoclave was subsequently removed from the heating bath, cooled to room temperature, depressurized and a solution containing (4) (209 mg, 1 mmol) and tetraethyl silane (30 μί, 33 mol%) as internal standard in toluene (2 mL) was injected into the autoclave. The autoclave was then pressurized with 4.5 bar CO:H₂ (1 :1 ) and stirred at 1000 rpm with a magnetic cross stirrer bar at room temperature for 15 hours. The autoclave was then depressurized and the solvent removed under reduced pressure. Analysis by ¹ H NMR spectroscopy showed > 99% conversion to aldehydes, based on internal standard, regio-isomeric ratio (5):(6) =1 :10.1 . ¹H NMR (CDCI₃) δ_Η= 9.72 (s, 1 H, C1 1 H), 4.53 (t, 1 H, J= 1 .7, C1 H), 3.08-3.12 (m, 1 H, C4H), 2.90-2.98 (m, 1 H, C5H), 2.17-2.30 (m, 1 H, C6H), 1 .82-1.97 (m, 2H, C6H and C7H), 1.45 (s, 9H, C10H₉), 1.31 -1.39 (dt, 1 H, J= 10.5, 1.4 Hz, C7H) ¹³C NMR (CDCI₃) 5_C= 199.1 (C1 1), 173.9 (C3), 149.4 (C8), 83.3 (C9), 59.0 (C1 ), 48.9 (C5), 48.0 (C4), 35.8 (C7), 30.0 (C6), 28.4 (C10). 2D-NMR used to determine identity of regioisomer (COSY, HMBC, and HSQC).

Example 13 (1 H,4H,6/?)-6-(Hydroxymethyl)-2-azabicyclo[2.2.1]heptan- 3-one (13). The solvent was removed under reduced pressure from a crude asymmetric hydroformylation reaction (358 mg, 2.58 mmol of substrate) and the resulting residue dissolved in ethanol (15 mL). To this solution was then added sodium borohydride (98 mg, 2.58 mmol, 1 eq.) and the reaction mixture stirred for 4 hours, upon which time no starting material remained by TLC analysis. Acetone was then added and the reaction allowed to stir for 5 minutes. Hydrochloric acid (0.1 M) was added to pH neutral and the water was removed under reduced pressure. The resulting gum was stirred for 30 minutes in dichloromethane (30 ml_), the solution was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to leave colorless oil (21 1 mg, 58%). This product was then purified by crystallization from a minimum amount of hot methyl ethyl ketone. Yield: 95 mg (colorless crystalline solid), 0.67 mmol (26%), diastereomeric ratio > 100:1 . a_D ²⁵= -100.4° (c= 2.00, MeOH); v_max/cm^"1= 3355, 2936, 2933, 1727, 1682, 1476, 1422, 1377, 1330, 1300, 1243, 1224, 1 176, 1 1 19, 1083, 1037; ¹H NMR (300 MHz, CD₃OD) δ_Η= 3.79-3.86 (m, 1 H, C1 H), 3.60 (dd, 1 H, J= 1 1.5, 5.8 Hz, C8H), 3.42 (dd, 1 H, J= 1 1.5, 9.1 Hz, C8H'), 2.58-2.66 (m, 1 H, C4H), 2.05-2.18 (m, 1 H, C6H), 1 .80-1.88 (m, 1 H, C7H), 1.60-1.74 (m, 2H, C7H' and C5H), 1 .43 (ddd, 1 H, J=12.7, 5.0, 4.1 Hz, C5H'); ¹³C NMR (75.5 MHz,

CD₃OD) 6_C= 184.2 (C3), 64.0 (C8), 56.9 (C1 ), 46.3 (C6), 44.8 (C4), 38.1 (C7), 27.4 (C5); HRMS (ES⁺): 164.0689 [M+Na]⁺, C₇HnNO₂Na requires 164.0687;

Anal. Calcd. for C₇H N0₂: C 59.56, H 7.85, N 9.92. Found: C 59.55, H 7.9, N 10.03. Crystal structure and NOESY confirm relative stereochemistry and identity of regioisomer. 2D-NMR also used to determine identity of regioisomer (COSY, HMBC, and HSQC).

The structure depicted for the compounds within the present application are also meant to include all isomeric (e.g., enantiomeric or conformational) forms of the structures. For example, both the R and the S configurations at the stereogenic carbon are included in this application. Therefore, single stereochemical isomers as well as enantiomeric and conformational mixtures of the present compound are within the scope of the application. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹ C-enriched carbon are within the scope of this application. Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the application described and claimed herein.

While particular embodiments of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims

CLAIMS:

1 . A process for producing the compounds of formula (22) and (23) or enantiomers thereof comprising hydroformylation of compounds of the formula (21 ) or their enantiomers:

using a chiral ligand, wherein R is -H or an amine-protecting group.

2. The process of claim 1 , wherein R is -H and the chiral ligand is (R,R)- Kelliphite.

3. The process of claim 1 , wherein R is -H and the chiral ligand is (S,S)- Kelliphite.

4. The process of claim 1 , wherein R is the amine-protecting group -Boc and the chiral ligand is (R,R)-Kelliphite.

5. The process of claim 1 , wherein R is -the amine-protecting group Boc and the chiral ligand is (S,S)-Kelliphite.

6. The process of claim 4, further comprising production of compound of formula (7):

from the compound of formula (22), wherein R is the amine-protecting group -Boc by reacting with a borohydride.

7. The process of claim 6, wherein the borohydride is sodium borohydride or sodium triacetoxy borohydride.

8. The process of claim 4, further comprising production of compound of formula (8):

from the compound of formula (22), wherein R is the amine-protecting group -Boc by reacting with methanol.

9. The process of claim 4, further comprising production of compound of formula (20):

from the compound of formula (22), wherein R is the amine-protecting group - Boc, by reacting with 4-methoxy aniline in presence of a borohydride.

10. The process of claim 9, wherein the borohydride is sodium borohydride or sodium triacetoxy borohydride.

1 1 . The process of claim 2, further comprising production of compound of formula (13):

(13) from the compound of formula (22), wherein R is -H by reacting with borohydride.

12. The process of claim 1 1 , wherein the borohydride is sodium borohydride sodium triacetoxy borohydride.

A compound of formula (8):