WO2008027740A2

WO2008027740A2 - Catalytic asymmetric synthesis of primary amines via borane reduction of oxime ethers using spiroborate esters

Info

Publication number: WO2008027740A2
Application number: PCT/US2007/076195
Authority: WO
Inventors: Melvin De Jesus; Margarita Ortiz-Marciales; Viatcheslav Stepanenko; Xiaogen Huang; Kun Huang; Merced Francisco
Original assignee: OFFICE OF INTELLECTUAL PROPERTY AND TECHNOLOGY
Current assignee: OFFICE OF INTELLECTUAL PROPERTY AND TECHNOLOGY
Priority date: 2006-08-29
Filing date: 2007-08-17
Publication date: 2008-03-06
Anticipated expiration: 2009-02-28
Also published as: WO2008027740A3; CN101547890A; WO2008027740B1; JP2010502632A; EP2061748A2

Abstract

Asymmetric reduction of arylalkyl and pyridylalkyl ketoxime ether with borane catalyzed by several chiral spiroborates derived from non-racemic 1,2-amino alcohols are presented. Complete conversion of oxime to primary amine is highly dependant of the catalyst, source and amount of borane and temperature. The conversion and enantioselectivity is determined by the benzylic substitution of the oxime. After optimization, a catalyst derived from diphenyl valinol could, successfully, afford primary amines with good yield and enantioselectivity up to 99% ee. Using the developed methodology, other related non-racemic primary pyridyl alkyl methanamines were also prepared in high chemical yield and excellent enantioselectivity.

Description

Catalytic Asymmetric Synthesis of Primary Amines via Borane Reduction of Oxime Ethers using Spiroborate Esters

GOVERNMENT INTEREST

The claimed invention was made with U.S. Government support under grant numbers MBRS GM 08216 and NIH-IMBRE NC P20 RR-016470 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention.

TECHNICAL FIELD:

The present invention relates to a method for the reduction of oxime ethers using stable spiroborate esters to prepare enantiopure primary amines in a truly catalytic process with excellent enantioselectivity.

BACKGROUND ART:

The asymmetric reduction of oxime ethers with boranes in the presence of chiral catalysts, viz., 1 ,3,2-oxazaborolidines, has been an important synthetic strategy in the preparation of enantiopure amines and has received much attention over the past two decades, in both: academic and industrial research. High efficiency of the reaction with high enantioselectivity, usually, requires an application of higher than stoichiometric amounts of chiral 1 ,2-aminoalcohols to prepare in situ the chiral reducing agent, 1 ,3,2- oxazaborolidines-borane complex. One method in the prior art considered necessary 2.5 equiv of (S)-diphenylvalinol to achieve high selectivity and complete conversion to α- methylbenzylamine. There are few instances in which a catalytic amount of catalysts were used. Another method of the prior art for example, reported that the reduction could be achieved in catalytic mode; however, the enantio-selectivity was modest (See Fig. 1). When O-benzylacetophenone oxime (1 a) is reduced with borane in the presence of 10% of (S)-diphenylvalinol as a catalyst, α-methyl benzylamine is obtained with only 52% ee. In general, O-benzyloxy amine 2a can also, be obtained due to incomplete reduction. Recently, O-methylarylalkyl oxime ethers have been reduced with spiroborate esters derived from (S) proline and [R)- or (S)-1 ,1 '-bi-2-naphthol. Reduction of acetophenone O-methyloxime, as a model compound, with 2 equiv of borane and 10% of catalyst produced only 58% yield and 42% ee. Therefore, one equiv of catalyst was required to increase the yield and enantioselectivity of the reaction.

The enantioselective reduction of oxime ethers to prepare chiral amines has been previously achieved with moderate to excellent enantiomeric excess (ee) using at least one equivalent of expensive chiral borane catalysts, like oxazaborolidines. Previously, we have developed a new type of practical catalytic system for the reduction of prochiral ketones. This is described in U.S. Patent Application No. 1 1/512,599 titled "High Enantioselective Carbonyl Reduction with Borane Catalyzed by Chiral Spiroborate Esters derived from Chiral 1 ,2-Aminoalcohols," by M. Ortiz-Marciales et ai, filed August 30, 2006, which is incorporated herein by reference in its entirety. This invention relates to a method for the reduction of oxime ethers using these stable spiroborate esters to prepare enantiopure primary arylalkyl amines in a truly catalytic process with excellent enantioselectivity. More specifically, we developed and synthesized stable chiral spiroborate esters derived from enantiopure 1 ,2-aminoalcohols, 5 - 10, shown in Figure 2, as a new type of catalysts for asymmetric reduction of ketones. Based on the high reactivity and outstanding enantioselectivity of these reagents, we apply these catalysts for the reduction of oxime ethers. Herein, we report the first successful catalytic, highly enantio-selective process for the reduction of oxime ethers.

Additional background is provided by the following references, each of which is incorporated by reference in their entirety:

(1 a) Fontaine, E.; Namane, C; Meneyrol, J.; Geslin, M.; Serva, L.; Roussey E.;

Tissandie S.; Maftouh, M.; Roger, P. Tetrahedron: Asymmetry 2001 , 12, 2185-

2189.

(1 b) Demir, A. S.; Pure & Appl. Chem. 1997, 69, 105-108. (1 c) Sakito, Y.; Yoneyoshi, Y.; Suzukamo, G. Tetrahedron Lett. 1988, 29, 223-224. (1d) Krzeminski, M. P.; Zaidlewicz, M. Tetrahedron: Asymmetry 2003, 14, 1463-

1466. (1 e) Itsuno, S.; Matsumoto, T.; Sato, D.; Inoue, T. J. Org. Chem. 2000, 65, 5879-

5881. (1f) Lantos, I.; Flisak J.; Liu, L; Matsunoka, R.; Mendelson, W.; Stevenson, D.;

Tubman, K.; Tucker L.; Zhang, W. -Y.; Adams, J.; Sorenson, M.; Garigipati, R.;

Erhardt K.; Ross, S. J. Org. Chem. 1997, 62, 5358-5391. (1 g) lnoue T.; Sato, D.; Komura, K.; ltsuno S. Tetrahedron Lett. 1999, 40, 5379-

5382.

(1 h) BoIm, C; Felder, M. Synlett 1994, 655-666. (1 i) Sailes, H. E.; Watts, J. P.; Whiting; A. J. Chem. Soc. Perkin Trans. 1 2000,

3362-3374. (1j) ltsuno, S.; Nakano, M.; Miyazaki, K.; Masuda H.; lto K. J. Chem Soc. Perkin

Trans 1 1985, 2039-2044.

(1 k) Cho, B. T.; Ryu, M. H. Bull. Korean Chem. Soc. 1994, 15, 191 -192. (11) ltsuno S.; Sakurai, Y.; Shimizu, K.; lto K. J. Chem. Soc. Perkins Trans 1 1990,

1859-1863. (2) Glushkov, V. A.; Tolstikov, A. G. Russ. Chem. Rev. (Engl. Transl.) 2004, 73,

581 -608, and references cited therein. (3a) Tillyer, R. D.; Boudreau, C; Tschaen, D.; Dolling, U. H.; Reider, P. J.

Tetrahedron Lett. 1995, 36, 4337-4340.

(3b) Shimizu, M.; Kamei, M.; Fujisawa, T. Tetrahedron Lett. 1995, 36, 8607-8610. (3c) Shimizu, M.; Tsukamoto, K.; Matsutani, T.; Fujisawa, T. Tetrahedron 1998, 54,

10265-10274. (3d) Masui, M.; Shioiri, T. Tetrahedron Lett, 1998, 39, 5195-5198.

(4) ltsuno, S.; Sakurai,Y.; lto, K.; Hirao, A.; Nakahama, S. Bull. Chem. Soc. Jpn. 1987, 60, 395-396.

(5) Chu, Y.; Shan, Z.; Liu, D.; Sun, N. J. Org. Chem. 2006, 71, 3998-4001.

(6) Stepanenko, V.; Ortiz-Marciales, M.; Correa, W.; De-Jesύs, M.; Espinosa, S.; Ortiz, L Tetrahedron: Asymmetry 2006, 17, 112-115. SUMMARY OF THE INVENTION

Details related to this invention were published in Stepanenko, V.; Ortiz-Marciales, M.; Correa, W.; De-Jesύs, M.; Espinosa, S; Ortiz, L. Tetrahedron Asymmetry, 2006, 17, 112-115; and in Xiaogen Huang, Kun Huang, Margarita Ortiz-Marciales,^* Viatcheslav Stepanenko, Francisco G. Merced, Angel M. Ayala Wildeliz Correa and Melvin De Jesύs, Organic Letters 2007, 9, 1793-1795, each of which is incorporated by reference in its entirety.

Enantiopure spiroborate esters (5 - 10) are demonstrated as chirality transfer catalysts for the borane reduction of acetophenone oxime ethers (R = Me, 4-MeOBn, 4-CF₃Bn; 2-NO₂Bn) under different reaction condition, to optimize the conversion and enantioselectivity for the synthesis of the corresponding primary amine, which were applied to other prochiral oximes. Initially, catalyst 5 (derived from (S)-diphenylvalinol) was found to be the best reagent for the reduction of the model compound, acetophenone benzyloxime ether, using 50% of catalyst and two equivalents of borane- DMS in toluene at 50 ⁰C for 12 hours. To achieve full conversion to methylbenzyl amine, the reaction mixture was then heated at 110 ⁰C for 3 hours. Modification of the reduction process for acetophenone benzyl oxime ether using lower catalytic loads, different borane sources or reagents, and a higher number of borane equivalents, lead to full conversion of the oxime ether to (S)-α-methylbenzylamine at room temperature, with good enantioselectivity (87% ee), using only 10% of catalyst 5. Further optimization was achieved by changing temperature, solvents and oxime ethers with different electronegative effects of the benzylic group and the possible π stacking interactions with the phenyl groups of the catalyst. Therefore, the 4-MeOBn, 4-CF₃Bn; 2-NO₂Bn substituents were investigated, obtaining 99% ee for 4-CF₃Bn substituted oxime with Borane-THF in dioxane at 0 ° C.

Because similar high enantioselectivities were observed with all of the O-benzylated acetophenone oximes, representative (£)-benzyloxime of aryl alkyl ketones and pyridyl alkyl ketones were prepared by standard methods and submitted to the optimized reductive conditions (0.1 - 0.3 equiv of 5, dioxane, 25 ⁰C - 0 ⁰C). The product amines were isolated as their Λ/-acetyl derivatives. In general, the process gives excellent enantioselectivity (83-99%) at 0 ⁰C.

In summary, a highly efficient new borane-based process for the first truly catalytically asymmetric synthesis of amines from oxime ethers, as indicated in Figure 3, is disclosed. The new process employs the easily prepared and stable spiroborate ester derived from (S)-diphenylvalinol (5) with only 10% of catalyst as the chiral transfer agent. The spiroborate ester does not need to be prepared in situ for subsequent reactions and is sufficiently stable to be stored for up to 1 year under inert atmospheric conditions. Employing simple procedures, this methodology provides a convenient entry to highly versatile and important non-racemic amines for the synthesis of intermediaries and catalysts in the preparation pharmaceutical compounds. It is important to point out that instant invention can be implemented in the preparation and synthesis of many compounds commonly prepared and/or used in the pharmaceutical industries.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1 is a schematic diagram showing a catalytic reduction according to the prior art.

Fig. 2 is a schematic diagram showing spiroborate esters derived from chiral aminoalcohols according to an embodiment of the invention.

Fig. 3 is a schematic diagram showing the enantioselective reduction of oxime ethers according to an embodiment of the invention.

Fig. 4 is a schematic diagram showing the enantioselective reduction of O-benzyl acetophenone oxime with the catalysts according to one embodiment of the invention. Fig. 5 is a schematic diagram showing the synthesis of oximes and corresponding O- benzylated arylketoximes according to an embodiment of the invention.

Fig. 6 is a schematic diagram showing the synthesis and enantioselective reduction of O-benzyl pyridyl ketoximes 13 with a catalyst according to a preferred embodiment of the invention. DISCLOSURE OF THE INVENTION

The synthesis and use of oxazaborolidines for the enantioselective reduction of ketones, oximes and imino derivatives in the preparation of pharmaceutical intermediaries are widely known. The present invention is industrially advantageous since it offers a new process for a more efficient and facile preparation of enantiopure amines by reduction with borane in the presence of our recent developed spiroborate esters, which are highly efficient chiral transfer catalysts, analogous to the well-known oxazaborolidines catalysts. This process can be used to carry out the preparation of enantiopure drugs with equal or better stereoselectivity in a practical catalytic way. The disclosed invention can be applied to the synthesis of (S)-dolaphenine (as disclosed in U.S. Patent No. 6,020,495), a precursor for the preparation of the antineoplastic peptide chain Dolastatin 10, by the borane reduction of 4-CF₃Bn oxime ether using as reagent the spiroborate ester derived from valinol and ethylene glycol. The above-mentioned patent mentions other examples of important chiral amines with pharmaceutical properties that can be prepared by the proposed process using the discovered catalysts, such as the 3-phenyl-1 -indanamines that have antidepressant activity (as disclosed by Bogeso, K. P. et al, "Potential Antidepressant Activity and Potent Inhibition of Dopamine, Norepinephrine, and Serotonin Uptake, " J. Med. Chem., 1985, 28,1817- 1828), as well as the antidepressant agents, 1-amino-4-aryltetralins (as disclosed by Welch, W. M. et al., " Nontricyclic Antidepressant Agents Derived from cis and trans 1 - amino-4-aryltetralins," J. Med. Chem., 1984, 1984, 27, 1508-1515).

A) Asymmetric synthesis of alpha-methylbenzylamine by the reduction of acetophenone O-benzyloximes

We developed and synthesized pure and relatively stable chiral spiroborate esters derived from enantiopure 1 ,2-aminoalcohols, 5 - 10, (Figure 2) as a new type of catalysts for asymmetric reduction of ketones. These reagents exhibit high reactivity and outstanding enantioselectivity. Hence, they were applied as catalysts for the reduction of oxime ethers. Initially, we studied the reduction of pure (£)-benzyl oxime ether 1 a, as a model reaction, in toluene with 0.5 equiv. of catalyst 5 - 10 and 2 equiv. of BH₃-DMS at 50 ⁰C for 12 hours and then at 110 ⁰C for 3 hours, as shown in Fig. 4. Under these conditions, catalysts 5 - 10 provided quantitatively primary amine 3, which by GC analysis of the ethoxycarbonyl derivative 4 on a chiral column exhibited moderate to high enantioselectivity, catalyst 5 being the most efficient, since it provided 93% ee of α-methylbenzylamine 3, as illustrated in Table 1.

Table 1 : Enantioselective reduction of O-benzyl acetophenone oxime with spiroborates 5 - 10 in Toluene

Conditions ee

Entry Cat equiv BH₃-DMS (equiv), Toluene (%)

1 5 0.15 2, 1 10 ⁰C, 5h 49

2 5 0.30 2, 110 ⁰C, 5h 67

3 5 0.50 2, 1 10 ⁰C, 5h 83

4 5 0.50 2, 50 ⁰C, 12 h, then 110 ⁰C 3h 88

5 6 0.50 1 , 50 ⁰C, 12 h, then 110 ⁰C 3h —

6 5 0.50 2, 50 ⁰C, 12 h, then 110 ⁰C, 3h 93

7 5 0.50 2, 50 ⁰C, 12 h, then 110 ⁰C, 3h 70

8 10 0.50 2, 50 ⁰C 12 h and 110 ⁰C, 3 h 77

9 7 0.50 2, 50 ⁰C 12 h and 110 ⁰C, 3 h 80

10 9 0.50 2, 50 ⁰C 12 h and 110 ⁰C, 3 h 88

If not otherwise specified in Table 1 , all the reactions were 100% conversions according to GC analysis. The ee was determined by chiral GC analysis of the benzylamine ethoxycarbonyl derivative 4. For entry 7, the catalytic system was preheated to 50 ⁰C, the oxime ether in Toluene was added during 5 h, and then heated to 110 ⁰C. For entry 5, no reaction was observed. For entries 9 and 10, the [R) enantiomer of 3 was obtained.

According to another aspect of the invention, the reaction was performed at room temperature in THF using different equivalents of catalyst 5 and borane, and different borane sources like, borane-DMS and borane-THF, with NaBH₄ or Λ/-isopropyl Λ/-methyl te/t-butyl amine, as additives. The results are listed in Table 2.

Table 2. Optimization conditions for the Reduction of O-benzyl Acetophenone Oxime Ether using different catalytic Loads of 5 and different Borane Sources

Cat. equiv, borane Time products ee

Entry

(%) reagents (h) 2 3 (%)

1 50 1 , BH₃-DMS 48 0 60 94

2 50 2, BH₃-DMS 36 15 85 96

3 50 4, BH₃-DMS 12 0 100 93

4 25 2, BH₃-DMS 48 17 58 93

5 25 6, BH₃-DMS 12 0 85 89

6 20 2.4, BH₃-THF 36 9 91 89

7 10 2.4, BH₃- DIEA 36 16 44 86

8 10 4, BH₃-THF 36 0 100(75) 87

For the reactions listed in Table 2, the ratio of products was determined by GC analysis. The ee of compound 3 was determined by chiral GC analysis of the ethoxy carbamide derivative. For entry 2, oxime in THF was added in 10 hours, then 24 hours stirring at room temperature. For entries 6, 7 and 8, the borane reagent was stabilized with <0.005 M Λ/-isopropyl Λ/-methyl te/t-butyl amine. For entry 8, the yield in parenthesis was obtained after purification of ethoxy carbamide.

As shown in Table 2, when the amount of BH₃-DMS was increased from 1 equiv to 4 equiv, the reduction with 50 mol% of 5, occurred faster with complete conversion to primary amine 3 (entry 3). However, there was only a slight decrease in the enantioselectivity. With 25 mol% of catalyst, and using 6 equiv of BH₃-DMS the conversion was partial (85%, entry 5). The more reactive BH₃-THF reagent, with 20% catalyst and using 2.4 equiv BH₃-THF provided almost full conversion to 3 (91 %, entry 6). On the contrary, BH₃-DIEA was ineffective. Interestingly, complete reduction of oxime ether 1 was achieved with 10% of catalyst and 4 equiv BH₃-THF, affording the primary amine 3 in a 75% yield with a minor decrease in ee (87%, entry 10). According to a further aspect of the invention, different solvents were assessed and, in general, ethereal solvents, gave higher ee, while the conversion in toluene was excellent but the ee decreased, and the reaction was not promoted in CHCI₃, as indicated in Table 3. The best solvent for the reduction at room temperature (rt) is dioxane, which afforded 90% ee (entry 4). Moreover, that selectivity did not change with the time of the oxime ether addition in the chosen solvent (entry 4 vs. entry 5).

Table 3. Reduction of Oxime Ether 1 a with 10% cat 5 in different Solvents

Entry Conditions conv. (%), ee (%)

1 THF 100, 3 87

2 Toluene 100, 3 71

3 TBME 100, 3 82

4 Dioxane 100, 3 90

5 Dioxane 100, 3 90

6 CHCI₃ 40, 3; 14, 2 6

7 Glyme 100, 3 86

8 Diglyme 100, 3 87

For the entries in Table 3, BH₃-THF reagent is stabilized with 0.005 M Λ/-isopropyl N- methyl te/t-butylamine. The amount of borane was 4 equiv to 1 equiv of oxime ether and the reactions were made at room temperature for 36 hours. For entries 1 - 4, the oxime in the chosen solvent was added during the 1 1^th hour. For entries 5 - 8 the oxime in the chosen solvent was added during 1^st hour.

According to further aspects of the invention, the reduction efficiency and selectivity in dioxane were optimized using different temperatures and reagents. The results are shown in Table 4, below. Table 4. Further Modification in the Reduction of 1 a using 10% Cat 5

conv. ee Entry Conditions

(%) (%)

1 BH₃-THF (4 equiv), Dioxane, 0 ⁰C, 48 hr 100, 3 97

2 BH₃-THF (4 equiv), Dioxane, -20 ⁰C, 60 hr 15, 2 -

3 BH₃-THF (4 equiv), Dioxane, RT, 36 hr 100, 3 95

4 BH₃-THF (4 equiv), Dioxane, 0 ⁰C, 36 hr 100, 3 97

5 BH₃-THF (4 equiv), THF, 0 ⁰C, 48 hr 100, 3 94

6 BH₃-DMS (4 equiv), Dioxane, RT, 36 hr 85, 3 37

7 BH₃-DMS (4 equiv), THF, RT, 36 hr 85, 3 82

For entries 1 - 2, BH₃-THF reagent is stabilized with 0.005 M Λ/-isopropyl Λ/-methyl tert- butyl amine. For entries 3 - 5, BH₃-THF reagent is stabilized with 0.005 M NaBH₄.

As also shown in Table 4, at 0 ⁰C the reaction needs a longer reduction time (entry 1 ), but the conversion was complete (100%) and the enantioselectivity was higher, 97%. However at -20 ⁰C, primary amine 3 was no detected by GC analysis after 60 hours. BH₃-THF stabilized with NaBH₄ afforded 95% ee at room temperature in dioxane (entry 3), and at 0 ⁰C, the ee of amine 3 was slightly increased to 97%. In THF at 0 ⁰C the ee was 94% (entry 5), lower than in dioxane. For BH₃-DMS the ee decreased dramatically to 37% (entry 6) in dioxane. When the solvent was changed to THF, the ee of the product was 82%. The highly enantioselective catalytic process shown in Table 4, entry 1 , was extended to the other spiroborates in Fig. 2, as shown in Table 5.

Table 5. Reduction of Oxime Ether 1 a with 10% Chiral Spiroborates 6 - 10 at RT in Dioxane.

Entry Catalyst config. conv. ( %) ee (%)

1 6 S 100 59

2 7 R 100 65

3 8 S 100 54

4 9 R 100 88

5 10 S 100 (0 ⁰C) 77

For the reductions of Table 5, the reactivity of catalysts 6 - 10 was rather low at 0 ⁰C. Therefore, the reaction temperature was changed to room temperature except for catalyst 10 (entry 5). It is clear that the stereochemistry outcome of the primary amine depends on the chirality of the amino group in the catalyst. All the catalysts showed lower selectivity comparing with catalyst 5. But catalyst 9 derived from amino indanol (entry 4) afforded the (/^-enantiomer in 88% ee at room temperature.

A further aspect of the invention involves the effect of aromatic substitution of acetophenone oximes 1 b-e in the enantioselectivity of the reduction shown in Fig. 5. As indicated in Table 6, steric and electronic factors did not change significantly the ee, except for 4-CF₃ benzyl oxime that readily afforded 99% ee.

Table 6. Chiral Spiroborate Ester 5 catalyzed Reduction of different O-substituted oximes ethers ee

Oxime Yield of 3

Entry R (%) Ether (%)

1 1 b Me 85 95

2 1 c 4-MeOBn 70 97

3 1d 4-CF₃Bn 60 99

4 1 e 2-NO₂Bn 95 97 These studies demonstrate that careful modifications enable us to discover an asymmetric reduction of oximes ethers in good to excellent yields with outstanding enantioselectivity.

B) Enantioselective reduction of representative aromatic ketones O- benzyloximes

According to a further aspect of the invention, the optimized synthetic method was extended to other substrates using unsubstituted O-benzyl oxime ethers since the benzyl bromide not only is less expensive, but also affords pure (£)-benzylated products. Representative aromatic benzyl oximes 11 were prepared by the general method, shown in Fig 5, and reduced using 0.1 equiv of catalyst 5 in dioxane at room temperature and 0 ⁰C. The results are indicated in Table 7. After an acidic work up, the corresponding crude (S) primary amines were acetylated with acetic anhydride in the presence of triethylamine and DMAP in dichloromethane.

The reactions in Table 7 were carried out using 1 equiv of oxime ethers 11 a -1 11, 0.1 equiv of catalyst 5 and 4 equiv of borane stabilized with NaBH₄ in dioxane for 36 h or until the conversion was 100%. All of the products 12 were purified by column chromatography and the ee's were determined using a Crompack Chirasil-Dex-CB GC column.

As indicated in Table 7, the yield of pure acetamides 12a -12i, purified by column chromatography, were good to high and, in general, the enantioselectivity of the reaction was higher at 0 ⁰C, in up to 99% ee.

Table 7. Asymmetric Reduction of Representative Oxime Benzyl Ethers 11 with 0.1 equiv of Catalyst 5

Temp Yield Ee

1 1 12 (⁰C) (%)

C) Asymmetric reduction of O-benzyl pyridyl alkyl ketoximes 13 with chiral spiroborate 5.

According to a further aspect of the invention, 2-, 3- or 4-pyridyl alkyl oxime ethers were prepared and reduced in the presence of catalyst 5 at different reaction conditions, as indicated in Fig 6 and Table 8. The 4-acetylpyridine O-benzyloxime, 13a, afforded the N-(1 -pyridyl-4yl-ethyl)-acetamides, 14a, in 99% ee at 0 ^QC in dioxane with 5 equiv of BH₃-THF, but the chemical yield was low, as indicated in entries 4. Although the mixture was stirred for four days in an ice-bath, TLC indicated remaining starting material. THF and te/t-butyl methyl ether were screened for the reduction of 4-pyridyl oxime ether (entries 1 -3). However, dioxane was the optimal solvent. To improve the conversion, the reduction was carried out at room temperature in THF. After two days the reaction was complete, but the ee's value decreased (entries 2). The reduction of 3-pyridyl-oxime ether was also investigated at different temperatures and different catalytic loads. We discovered that the reaction was complete at 10 ^QC with 30% catalyst in dioxane after the reaction was stirred over 48 h. The isolated product was 84% and the ee value was > 98%, as shown in entry 8.

Similar optimization studies were carried out for the reduction of 13c. In the presence of 1.0 equiv catalyst, 2.0 equiv of borane, 60% ee was obtained (entry 10) with modest yield. With 0.3 equiv of catalyst 5 at 10 ^QC in dioxane and protecting the pyridine nitrogen with BEt₃ (entry 11 ) the reaction was unsatisfactory. Addition of BF₃ resulted in higher yield but lower enantioselectivity (entry 12). Stoichiometric amount of catalyst 5 was required to accomplish the reduction of 2-pyridyl oxime benzyl ethers, but with moderate ee's value (entry 10).

Table 8 Asymmetric reduction of 13a - 13c under different reduction conditions

Entry Sub. Cat. 5 BH₃-THF Temp. SoIv. Time Yield ee

(equiv) (equiv) (^SC) (h) (%) (%)

1 13a 0.1 5 0 THF 72 46 92

2 13a 0.1 5 25 THF 48 53 89

3 13a 0.1 5 0 ^ 72 42 93

4 13a 0.1 5 0 Dioxane 72 50 99

5 13b 0.1 5 0 THF 72 38 99

6 13b 0.1 5 25 THF 48 63 90

7 13b 0.2 5 10 Dioxane 72 64 94

8 13b 0.3 5 10 Dioxane 48 84 98

9 13b 0.5 5 10 Dioxane 48 79 98

10 13c 1.0 2 10 Dioxane 72 57 60

11 13c 0.3 5 (1 BEt₃) 10 Dioxane 72 34 4

12 13c 1.0 2 (1 BF₃) 10 Dioxane 48 73 54

For the reactions listed in Table 8, the products were isolated by column chromatography. The ee was determined by GC analysis of the acetyl derivative using a chiral column (CP-Chirasil-DexCB).

According to a further aspect of the invention, we applied the optimized conditions (0.3 equiv of 5, 5 equiv of BH₃-THF, dioxane, 10 ^QC) in Table 8, to the reduction of representative O-benzyl oxime derivatives 13 of pyridyl alkyl ketones in Fig 6. As indicated in Table 9, excellent enantioselectivities were obtained for the 3- and 4-pyridyl derivatives with 30% of spiroborate ester of 5 and in high chemical yield. Table 9. Asymmetric reduction of representative pyridyl alkyl oxime ethers with 30% 5 at 1 O ⁰C

Time Yield Ee

Entry 13 15 (h) (%) (%)

The reactions in Table 9 were carried out using 1 equiv of oxime ether 13, 0.3 equiv of catalyst 5 and 5 equiv of borane stabilized with NaBH₄ in dioxane. All of the products 15 were purified by column chromatography and the ee's were determined using a Crompack Chirasil-Dex-CB GC column.

A general procedure for reduction according to the invention will be explained.

PROCEDURE (F?)-2-amino-1 ,1 ,2-triphenylethanol¹, (S)-2-amino-1 ,1 ,2-triphenylethanol¹, (S)-2-amino-3- methyl-1 ,1 -diphenylbutan-1 -ol² were synthesized according to literature procedures. These include: (1 ) Bach, J.; Berenger, R.; Garcia, J.; Loscertales, T.; Vilarrasa, J. J. Org. Chem. 1996, 61, 9021 -9025; and (2) Itsuno, S.; Ito, K. J. Org. Chem. 1984, 49, 555-557. Acetophenone oxime, (S)-methyl 2-amino-3-methylbutanoate, (S)-methyl 2- amino-2-phenylacetate, (/^-methyl 2-amino-2-phenylacetate, (i ft^S^-amino-i - phenylpropan-1 -ol, (1 /=?,2S)-1 -amino-2,3-dihydro-1 H-inden-2-ol, (S)-diphenyl(pyrrolidin- 2-yl)methanol, 4-trifluoromethyl benzyl bromide, 2-nitrobenzyl bromide, 4- methoxybenzyl chloride, triisopropyl borate, BH₃-DMS (2M solution in THF), BH₃-THF (1 M solution in THF, stabilized with <0.005 M NaBH₄), BH₃-THF (1 M solution in THF, stabilized with <0.005 M Λ/-isopropyl Λ/-methyl te/t-butyl amine), 4-dimethylamino pyridine, ethyl chloroformate were purchased and used directly without purification.

All reactions were carried out in dried glassware under N₂ atmosphere. Air and moisture sensitive liquids and solutions were transferred via syringe. All reagents were obtained commercially unless otherwise noted. Common solvents were dried and distilled by standard procedures. Anhydrous glyme and diglyme were purchased from Aldrich and used directly from the sealed bottle. Chromatographic purification of products was accomplished using flash chromatography on a Merck silica gel Si 60^® (200-400 mesh).

¹H, ¹³C and ¹¹B spectra were recorded on a Bruker Avance 400 MHz spectrometer with standard pulse sequences operating at 400.152 MHz, 100.627 MHz, and 128.384 MHz for ¹H, ¹³C and ¹¹B respectively. Chiral gas chromatography analysis was processed on a Hewlett Packard GC 5890 equipped with a Chrompack Chiralsil-Dex-CB column (30 m x 0.25 mm χθ.25μm). GC-MS analysis was processed on a Finnigan Trace GC/Polaris Q Mass detector using a Restek RTX-5MS column.

General procedures for the preparation of chiral spiroborates 5 - 10

To a 50 ml_ round flask equipped with a septum and N₂ flow, dry ethylene glycol (0.31 g, 5.0 mmol, 1 equiv.) was added. Then, dry toluene (10 ml_) was added followed by triisopropyl borate (1.17 ml_, 5.1 mmol, 1.02 equiv.). The reaction mixture was heated to reflux until a homogeneous colorless solution was formed. A solution of non-racemic amino alcohol (5 mmol, 1 equiv.) in dry toluene (10 ml_) was added to the reaction mixture while a white precipitate was observed during the process. The mixture was concentrated in the rotor-evaporator and then dried overnight under high vacuum. The resulting white solid was used directly for our reaction without further purification.

General procedure for the preparation of O-methyl and O-benzyloximes ethers 1 a-e, 1 1 and 13

To a suspension of NaH (1.1 equiv.) in DMF, a solution of oxime (1 equiv.) at 0 ⁰C was added drop-wise. After the addition, the reaction mixture was stirred for 1 h. Then, RBr(CI) or MeI (1.05 equiv.) in DMF at 0 ⁰C was added drop-wise. The resulting mixture was stirred overnight at RT. It was then quenched with a saturate aqueous NH₄CI solution and extracted with ether. The organic phase was combined and dried over anhydrous Na₂SO₄. The solvent was evaporated under vacuum and the residue was purified by silicon gel column chromatography. In the case where the (£)-oxime was not pure, it was recrystallized from PE/CH₂CI₂.

The data for compound 1 c is as follows: H NMR (400MHz) δ (ppm) 7.77 (d, J = 8.0 Hz, 2H), 7.44 (m, 2H), 7.23 (m, 3H), 6.90 (d, J = 8.0 Hz, 2H), 5.36 (s, 2H), 3.39 (s, 3H), 2.16 (s, 3H).

The data for compound 1d is as follows: H NMR (400MHz) δ (ppm) 7.66 (m, 2H), 7.55 (m, 1 H), 7.39 (m, 2H), 5.32 (s, 2H), 2.32 (s, 3H).

The data for compound 1 e is as follows: H NMR (400MHz) δ (ppm) 8.11 (m, 1 H), 7.66 (m, 2H), 7.42 (m, 2H), 5.68 (s, 2H), 2.37 (s, 3H).

The data for (£)-1-phenyl-propan-1 -one O-benzyloxime (11 a) is as follows: ¹H-NMR (C₆D₆) δ (ppm) 1.14 (t, 3H, CH₃), 2.76 ( q, 2H, CH₂) 5.33 (s, 2H, CH₂), 7.2 (m, 6H, Ar), 7.45 (d, 2H, Ar), 7.75 (dd, 2H, Ar); ¹³C-NMR (C₆D₆) δ 1 1.0, 19.9, 76.3, 126.4, 127.5, 127.8, 127.9, 128.0, 128.3, 128.6, 135.8, 138.6, 159.3; GC/MS RT(min) 14.8, m/z 239.2 (M⁺), 132.1 (M⁺- OBn), 222.3, 91.1.

The data for (£)-1 -phenyl-butan-1 -one O-benzyloxime (11 b) is as follows: ¹H-NMR (C₆D₆) δ (ppm) 0.90 (t, 3H, CH₃), 1 .57(m, 2H, CH₂), 2.78 (t, 2H, CH₂), 5.27 (s, 2H,CH₂),7.19 (dd, 2H, Ar), 7.25(d-d, 3H, Ar), 7.42 (dd,3H, Ar), 7.70 (d-d, 2H,Ar); ¹³C- NMR (C₆D₆) δ 14.0, 20.0, 28.1 , 76.1 , 127.8, 127.9,128.1 ,128.6,129.0, 135.9,138.6, 158.2; MS m/z: 253.1 (M⁺), 146.1 (M⁺ - OBn), 91 .1 , 77.1 .

The data for compound (£)-1 -(4-methoxy-phenyl)ethanone O-benzyl oxime (1 1 c) is as follows: ¹ H-NMR (C₆D₆) δ (ppm) 2.18 (s, 3H, CH₃), 3.37 (s, 3H, CH₃O), 5.34 ( q, 2H, CH₂), 6.8 (dd, J = 6.8 Hz), 2H, Ar), 7.29 (dd J = 8.2 Hz, 2H, Ar), 7.27 (m, 3H, Ar), 7.70 (dd, J = 6.8 Hz, 2H, Ar); ¹³C-NMR (C₆D₆) δ 12.4, 21 .3, 30.2, 76.4, 1 13.9, 127.74, 127.79, 127.9, 128.0, 128.3, 128.5, 128.6, 138.9, 154.1 , 160,8; MS m/z: 255.3 (M⁺); HRMS calcd. for Ci₆H₁₈NO₂ [M + H]⁺ 256.13375, found 256.13279.

The data for compound (£)-1 -(4-methylphenyl)ethanone O-benzyl oxime (1 1 d) is as follows: ¹ H-NMR (C₆D₆) δ (ppm) 2.17 (s, 3H, CH₃), 2.51 (s, 3H, CH₂), 5.32 (s, 2H,CH₂), 7.05 (dd, 2H, Ar), 7.19(m, 1 H, Ar), 7.26 (m, 2H, Ar), 7.44 (dd, 2H,Ar), 7.65 (dd, 2H, Ar); ¹³C-NMR (C₆D₆) δ 12.2, 20.9, 76.2, 126.1 , 127.4, 128.1 , 128.0, 129.0, 134.0, 138.6, 138.7 154.2, 161 .6; MS m/z: 239.31 (M⁺); HRMS calcd. for Ci₆H₁₈NO [M + H]⁺ 240.13884, found 240.13782.

The data for compound (£)-1 -(4-methylphenyl)propanone O-benzyl oxime (1 1 e) is as follows: ¹ H-NMR (C₆D₆) δ (ppm) 1 .16 (t, J = 7.6 Hz, 3H, CH₃), 2.17 (s, 3H, CH₃), 2.74 ( q, J = 7.6 Hz, 2H, CH₂), 5.26 (s, 2H, CH₂), 7.06 (dd, J = 8.4 Hz, 2H, Ar), 7.18 (m, 1 H, Ar), 7.27 (m, 3H, Ar), 7.46 (d, J = 7.6 Hz, 2H, Ar), 7.72 (d, J = 8.0 Hz, 2H, Ar); ¹³C- NMR (C₆D₆) δ 1 1 .1 , 19.9, 20.9, 76.2, 126.3, 127.6, 127.8, 128.0, 128.2, 129.1 , 133.0, 138.6, 159.2; MS m/z: 253.2 (M⁺), 146.1 (M⁺- OBn), 91 .1 ; HRMS calcd. for Ci₇H₂₀NO [M + H]⁺ 254.15449, found 254.15348.

The data for compound (£)-1 -(4-chloro-phenyl)ethanone O-benzyl oxime (1 1f) is as follows: ¹ H-NMR (400 MHz, C₆D₆) δ 1 .99 (s, 3H, CH₃), 5.31 (s, 2H, CH₂), 7.14 (m, 2H, Ar), 7.19 (m, 3H, Ar), 7.29 (m, 2H, Ar), 7.45 (m, 2H, Ar); ¹³C-NMR (100MHz, C₆D₆): δ 12.2, 76.6, 127.6, 127.9, 128.2, 128.6, 135.1 , 135.3, 138.5, 153.4; IR (KBr, cm^"1): v 3039, 2868, 1610, 1455, 1397, 1308, 1093, 1039, 693. MS m/z 258.9 (M⁺), 168.1 (M⁺ - OBn), 91.1 . Anal. Calcd. for Ci₅Hi₄CINO; C, 69.36; H, 5.43; N, 5.39. Found: C, 69.90; H, 5.83; N, 5.44.

The data for compound (£)-indanone O-4-trifluoromethylbenzyl oxime (11 g) is as follows: ¹H-NMR (C₆D₆): δ (ppm) 2.90 (t, 2H, CH₂), 3.0(t, 2H, CH₂), 5.29 (s, 2H,CH₂),

7.2 -7.0 (m, 8H, Ar); ¹³C-NMR (C₆D₆) δ 22.7, 26.6, 28.6, 75.2, 121.7, 125.9, 125.6, 127.6, 129.6, 130.4, 135.9, 142.5, 148.3, 163.6.

The data for compound (£)-tetralone-0-benzyl oxime (11 h) is as follows: ¹H-NMR (C₆D₆) δ (ppm) 0.90 (t, 3H, CH₃), 1.5(m, 2H, CH₂), 2.42 (t, 2H, CH₂), 2.75 (t, 2H, CH₂), 5.27 (s, 2H₅CH₂O), 7.1 (m, 5H, Ar), 7.48 (d, 2H, Ar), 8.3(dd, 1 H, Ar); ¹³C-NMR (C₆D₆) δ 21.6, 24.8, 29.9, 76.6, 124.8, 126.6, 127.8, 128.5, 128.6, 128.8, 129.1 , 131.2, 138.9, 139.6, 154.1 ; HRMS calcd. for Ci₇Hi₈NO [M + H]⁺ 252.13884, found 254.13794.

The data for compound (£)-6-Methoxy-3,4-dihydro-2H-naphthalen-1 -one O-benzyl- oxime (11 i) is as follows: Purified by column chromatography on silicon gel/hexane: ethylacetate (95:5 V/V) as a white solid; yield 84% (1.8 g); Melting Point: 64-65 ^QC; ¹HNMR (400 MHz, CDCI3): δ 1.89 (m, 2H, CH₂), 2.75 (m, 2H, CH₂), 2.85 (m, 2H, CH₂), 3.85 (s, 3H, OCH₃), 5.26 (s, 2H, OCH₂), 6.69 (m, 1 H, Ar), 6.81 (m, 1 H, Ar), 7.31-7.49 (m, 5H, Ph), 7.99 (m, 1 H, Ar); ¹³CNMR (100 MHz, CDCI₃) δ (ppm) 21.6, 24.5, 30.1 , 55.3, 76.1 , 112.8, 112.9, 123.6, 126.0, 127.7, 128.1 , 128.3, 138.4, 141.3, 154.2, 160.2; MS m/z 281.2 (M⁺).

The data for compound (£)-chroman-4-one O-benzyl-oxime (11j) is as follows: Purified by column chromatography on silicon gel/hexane: ethylacetate gradient, as colorless oil, 2.10 g, yield (88%); ¹ H-NMR (CDCI₃) δ (ppm) 3.03 (t, 2H), 4.27 (t, 2H), 5.31 (s, 2H),

7.03 (dd, 2H), 7.31 (d, 1 H), 7.37 (d, 1 H), 7.41 (d, 2H), 7.46 (d, 1 H), 7.51 (d, 1 H), 8.01 (d,1 H); ¹³C-NMR (CDCI₃) δ (ppm) 24.3, 65.0, 76.5, 117.7, 118.6, 121.4, 124.4, 127.9, 128.3, 128.4, 130.9, 137.9, 148.8,156.6; GC/MS RT(min): 18.17 min, m/z 253.1 (M⁺), 91.1 (PhCH₂ ⁺).

The data for (£)-6-chlorochroman-4-one O-benzyl oxime (11 k) is as follows: Purified by column chromatography on silicon gel with hexane: ethylacetate gradient, as a slight yellow oil, 1.62 g, yield (84 %); ¹H-NMR (CDCI₃) δ (ppm) 2.99 (t, 2H), 4.24 (t, 2H), 5.31 (s, 2H), 7.23 (dd, 2H), 7.25 (dd, 2H), 7.41 (s, 1 H), 7.44 (d, 1 H), 7.50 (d, 1 H), 7.97 (s, 1 H) ; ¹³C-NMR (CDCI₃) δ (ppm) 24.0, 65.1 , 76.7, 118.8, 119.8, 123.8, 126.6, 128.0, 128.3, 128.5, 130.7, 137.7, 147.7, 155.1 GC/MS RT(min): 20.64 min, m/z 287.0 (M⁺), 91.1 (PhCH₂ ⁺).

The data for (£)-thiochroman-4-one O-benzyl oxime (111) is as follows: Purified by column chromatography on silicon gel/hexane: ethylacetate gradient as a slight yellow oil; 1.89 g, yield: 84%; ¹H-NMR (CDCI₃) δ (ppm) 2.99 (t, 2H), 3.21 (t, 2H), 5.32 (s, 2H), 7.17 (dd,1 H), 7.26 (dd, 2H), 7.31 (dd, 2H), 7.39 (dd, 1 H), 7.49 (dd, 2H), 8.06 (d,1 H) ; ¹³C-NMR (CDCI₃) δ (ppm) 26.0, 26.9, 76.6, 125.4, 126.2, 127.1 , 127.8, 127.9, 128.1 , 130.7, 131.0, 136.0, 137.9, 152.3; GC/MS RT(min): 20.95 min, m/z 269.0 (M⁺), 91.1 (PhCH₂ ⁺).

Pyridylalkyl O-benzyloxime ethers:

The data for compound (£)-1 -pyridin-4-yl-ethanone O-benzyl oxime (13a) is as follows: Purified by column chromatography on silicon gel/hexane: ethylacetate (5:1 ) as a white solid; yield 89% (5.75 g); Melting Point: 41 -42 ³C¹HNMR (400 MHz, CDCI₃) δ (ppm)2.30 (s, 3H, CH₃), 5.32 (s, 2H, OCH₂), 7.37-7.47 (m, 5H, Ph), 7.58 (m, 2H, Ar), 8.66 (m, 2H, Ar); ¹³CNMR (100 MHz, CDCI₃) δ (ppm) 12.1 , 76.7, 120.2, 128.0, 128.3, 128.5, 137.6, 143.8, 150.1 , 152.7; MS m/z 226.2 (M⁺).

The data for compound (£)-1 -pyridin-3-yl-ethanone O-benzyl oxime (13b) is as follows: Purified by column chromatography on silicon gel/hexane: ethylacetate (5:1) as a colorless oil; yield 92% (6.21 g); ¹HNMR (400 MHz, CDCI₃): δ (ppm) 2.37 (s, 3H, CH₃), 5.31 (s, 2H, OCH₂), 7.30-7.49 (m, 6H, Ar), 7.99 (m, 1 H, Ar), 8.63 (m, 1 H, Ar), 8.92 (m, 1 H, Ar); ¹³CNMR (100 MHz, CDCI₃): δ 12.5, 76.5, 123.2, 127.9, 128.3, 128.4, 132.3, 133.3, 137.8, 147.5, 150.0, 152.5; MS m/z 226.2 (M⁺).

The data for compound (£)-1 -pyridin-2-yl-ethanone O-benzyl oxime (13c) is as follows: Purified by column chromatography on silicon gel/hexane: ethylacetate (5:1) as a colorless oil; yield 88% (6.21 g); ¹HNMR (400 MHz, CDCI₃) δ (ppm) 2.43 (s, 3H, CH₃), 5.33 (s, 2H, OCH₂), 7.28-7.49 (m, 6H, Ar), 7.69 (m, 1 H, Ar), 7.96 (m, 1 H, Ar), 8.64 (m, 1 H, Ar); ¹³CNMR (100 MHz, CDCI₃) δ (ppm)11.4, 76.5, 120.7, 123.5, 127.8, 128.1 , 128.4, 136.1 , 138.0, 148.8, 154.4, 156.2; MS m/z 226.2 (M⁺).

The data for compound (E)-1 -(6-methoxypyridin-3-yl)ethanone O-benzyl oxime (13d) is as follows: Purified by column chromatography on silicon gel/hexane: ethylacetate (5:1 ) as a colorless oil; yield 90% (1.41 g); ¹HNMR (400 MHz, CDCI₃): δ 2.29 (s, 3H, CH₃), 4.00 (s, 3H, OCH₃), 5.27 (s, 2H, OCH₂), 6.76 (m, 1 H, Ar), 7.36-7.48 (m, 5H, Ph), 7.98 (m, 1 H, Ar), 8.42 (m, 1 H, Ar); ¹³CNMR (100 MHz, CDCI₃): δ 12.4, 53.6, 76.3, 1 10.7, 125.9, 127.8, 128.2, 1284, 136.2, 138.0, 144.8, 152.4, 164.6; MS m/z 256.1 (M⁺).

The data for (£)-pyridin-3-yl-propan-1 -one O-benzyl oxime (13e) is as follows: Purified by column chromatography on silicon gel/hexane: ethylacetate (5:1) as a colorless oil; yield 80% (0.96 g); ¹HNMR (400 MHz, CDCI₃): δ 1.19 (t, 3H, J = 7.6 Hz, CH₃), 2.86 (q, 2H, J = 7.6, CH2), 5.29 (s, 2H, OCH₂), 7.31-7.48 (m, 6H, Ar), 7.98 (m, 1 H, Ar), 8.64 (m, 1 H, Ar), 8.89 (m, 1 H, Ar); ¹³CNMR (100 MHz, CDCI₃): δ 10.9, 19.9, 76.5, 123.3, 127.9, 128.2, 128.4, 131.3, 133.5, 137.9, 147.7, 150.0, 157.6; MS m/z 240.2 (M⁺).

The data for compound [E)- 1 -Pyridin-4-yl-propan-1 -one O-benzyl-oxime (13f) is as follows: Purified by column chromatography on silicon gel/hexane: ethylacetate (5:1 ) as a white solid; yield 89% (5.75 g); ¹HNMR (400 MHz, CDCI₃): δ (ppm) 1.19 (t, 3H, J = CH₃), 2.82 (q, 2H, J =, CH₂), 5.31 (s, 2H, OCH₂), 7.37-7.47 (m, 5H, Ph), 7.58 (m, 2H, Ar), 8.66 (m, 2H, Ar); ¹³CNMR (100 MHz, CDCI₃): δ 10.9, 19.5, 76.7, 120.4, 128.0, 128.2, 128.4, 137.7, 142.9, 150.2, 157.7; MS m/z 240.2 (M⁺).

General procedures for asymmetric reduction of aromatic O-benzyl oximes ethers

To a 25 ml two-necked flask was added catalyst 5 - 10 (0.1 mmol, 0.1 equiv) under N₂. Then from about 4 to about 10 ml of anhydrous dioxane was introduced and 4 ml_ of BH₃-THF (1 M in THF) was added in one portion. The resulting mixture was stirred at RT from about 30 min to about 1 h until the transparent solution formed. Then oxime ether (1 mmol, 1 equiv) in 5 ml of THF or dioxane was added drop-wise by a syringe pump. The resulting mixture was stirred until the conversion to amine was complete. The reaction was quenched with 6N HCI and then 6 N NaOH until the solution was strongly basic. The aqueous solution was extracted with diethylether to obtain the primary amine and the combined organic phase was washed with saturated NaCI solution and dried over anhydrous Na₂SO₄. The solvent was removed under vacuum and the residue acetylated to prepare the amide derivative. In the case of pyridyl compounds, the reaction mixture was quenched with methanol (5 ml_) and then refluxed for 6 h. The solvent was evaporated under vacuum and the residue was directly acetylated.

The conversion ratio was determined by GC analysis (Hewlett Packard GC 5890); for compound 1 a: 13.3 min, compound 2a: 12.6 min, and compound 3: 3.9 min. The ratio was calculated from the area accumulation.

Data for compound 2a is as follow: ¹H NMR (400MHz) δ (ppm) 7.2-7.6 (m, 10H), 5.64 (s, 1 H), 4.65 (dd, ²J = 11.48 Hz, 2H), 4.20 (q, ³J = 6.64 Hz, 1 H), 1.40 (d, ³J = 6.64 Hz, 3H).

General procedures for determination of enantio-selectivitv of primary amine

To a solution of crude amine 3 in anhydrous CH₂CI₂ was added DMAP (25 mg, 10%), Et₃N (0.30 ml, 1.1 mmol, 1.1 eq.) and ethyl chloroformate (0.2 ml, 1.1 mmol, 1.1 eq.). The resulting mixture was stirred for 3 hrs. It was then quenched with water and extracted with CH₂CI₂ (3χ30 ml_). The organic phase was collected and dried over anhydrous Na₂SO₄. Solvent was evaporated under vacuum and the residue was purified by silica gel column chromatography with PE/EA (6/1 ) giving the corresponding product to be analyzed by chiral GC.

The ethoxycarbonyl derivatives of (±)-σ-methyl benzyl amine and enantiopure (S)-cr- methyl benzyl amine purchased from Aldrich were prepared as standard samples for chiral GC analysis: (S)-enantiomer: 24.6 min, (/^-enantiomer: 25.5 min.

Data for ethoxycarbonyl derivative of compound 3 is as follows: ¹H NMR (400MHz) δ (ppm) 7.2-7.5 (m, 5H), 4.85 (m, 1 H), 4.1 (m, 2H), 1.5 (d, 3H), 1.2(m, 3H).

For the synthesis of acetamide derivatives, acetic anhydride (0.11 ml_, 1.0 mmol, 2.0 equiv) was added to a solution of the crude amine in anhydrous CH₂CI₂ (1 OmL) with DMAP (13mg, 10%), Et₃N (0.2 ml_, 1 mmol, 2.0 equiv). The resulting mixture was stirred for 3 h. The solvent was removed under vacuum. The residue was purified directly by column chromatography on silica gel, eluted with PE/EA (1v/1v) giving the corresponding amides. The pyridyl compounds (15a-15h) were purified by column chromatography by elution first with ether, and then with CH₂CI₂/CH₃OH (10v/1 v). The pure amides were analyzed by GC using the chiral column.

Examples of Acetamide Characterization

Aryl alkylacetamides:

Data for (S)-Λ/-(1 -phenyl-propyl) acetamide (12a) is as follows: Purified by column chromatography on silica gel/hexane: ethylacetate (1 :1 ) as a white solid; yield 89% (0.16g); ¹H-NMR (400 MHz, C₆D₆) δ (pm) 0.96 (t, 3H, CH₃), 1.55 (m, 2H, CH₂), 1.89 (s, 3H, CH₃), 5.12 (dd, 1 H, CH), 8.27 (s, 1 H, NH), 7.26(dd, 3H, Ar), 7.32 (dd, 2H, Ar); ¹³C- NMR (C₆D₆) δ (ppm): 8.6, 23.6, 27.6, 55.4, 126.1 , 128.1 , 128.9, 139.9, 170.7; MS m/z: 177.2 (M⁺), 148.0 (M⁺-Ac), 91.1 (M⁺-C₅H₁₂NO); Chiral GC: RT.10.05 min (83% ee).

Data for (S)-Λ/-(1-phenylbutyl) acetamide (12b) is as follows: Purified by column chromatography on silica gel/hexane: ethylacetate (1 :1 ) as a white solid; yield 71 % (0.07g); m.p. 80-82 ⁰C. ¹H-NMR (400 MHz, CDCI₃) δ (pm): 0.93 (t, J = 7.6 Hz, 3H, CH₃), 1.36 (m, 2H, CH₂), 1.7 (m, 2H, CH₂), 1.99 (s, 3H, CH₃), 4.98 (dd, 1 H, CH), 5.77 (s, 1 H, NH), 7.2 (dd, 3H, Ar), 7.30 (dd, 2H, Ar); ¹³C-NMR (C₆D₆) δ (ppm): 13.8, 19.5, 23.5, 38.3, 53.3, 126.6, 127.3, 128.6, 142.5, 169.1 ; MS m/z: 191.1 (M⁺), 148.0 (M⁺-Ac), 91.1 (M⁺-C₅Hi₂NO); Chiral GC: RT.35.26 min (99% ee).

Data for [S)-N- [1-(4-Methoxy-phenyl)-ethyl]-acetamide (12c) is as follows: Purified by column chromatography on silica gel/hexane: ethylacetate (1 :1 ) as a white solid; yield 90% (0.174g); ¹H-NMR (C₆D₆) δ (ppm) 1.44 (t, 3H, CH₃), 2.02 (s, 3H, CH₃), 3.72 (s, 3H, CH₃), 4.94(q, 1 H, CH), 8.27(s, 1 H, NH), 6.88 (dd, 2H,Ar), 7.22 (dd, 2H, Ar); MS m/z 150.2 (M⁺), 136.1 (M⁺-NH₂), 107.2 (M⁺-C₇H₇O); Chiral GC: RT. 27.49 min (85% ee).

Data for (S)-Λ/-[1 -(4-Methyl-phenyl)-ethyl]-acetamide (12d) is as follows: Purified by column chromatography on silica gel/hexane: ethylacetate (1 :1 ) as a white solid; yield 92% (0.103g); ¹H-NMR (CDCI₃) δ (ppm) 1.49 (d, ³J = 7.2 Hz, 3H, CH₃), 1.99 (s, 3H, CH₃), 2.35(s, 3H, CH₃), 5.12 (m, 1 H, CH), 5.64 (s, 1 H, NH), 7.17 (d, ³J = 7.9 Hz, 2H, Ar), 7.28 (d, ³J= 8.0 Hz, 2H, Ar); Chiral GC: RT.11.99 min (98% ee).

Data for (S)-Λ/-[1-(4-methylphenyl)-propyl]-acetamide (12e) is as follows: Purified by column chromatography on silica gel/hexane: ethylacetate (1 :1 ) as a white solid; yield 91 % (0.098g); ¹H-NMR (CDCI₃) δ (ppm) 0.92 (t, J = 7.6 Hz, 3H, CH₃), 1.83 (m, 2H₅CH₂), 1.91 (s, 3H, CH₃), 2.35(s, 3H,CH₃), 4.86 (q, ³J = 7.6 Hz, 1 H,CH), 5.68 (s, 1 H, NH), 7.15 (dd, 2H, Ar), 7.28 (dd, 2H, Ar); MS m/z 149.2 (M⁺), 148.1 (M⁺-H), 132.1 (M⁺- NH₂), 91.1 (M⁺-CHCH₂CH₃NH₂); Chiral GC: RT.15.47 min (93% ee).

Data for (S)-Λ/-[1-(4-chloro-phenyl-ethyl]-acetamide (12f) is as follows: Purified by column chromatography on silica gel/hexane: ethylacetate (1 :1 ) as a white solid; yield 77% (0.153g); ¹H NMR (400 MHz) δ 1.2 (³J = 6.8 Hz, d, 3H), 2.05 (s, 3H), 5.1 (m, 1 H), 5.7 (s, 1 H, NH), 7.2-7.5 (m, 4H). Chiral GC: RT.23.6 min (94% ee).

Data for (S)-Λ/-indan-1 -yl-acetamide (12g) is as follows: Purified by column chromatography on silica gel/hexane: ethylacetate (1 :1 ) as a white solid; yield 77% (66mg). ¹HNMR (CDCI₃): δ (ppm) 1.75 (DDm, 1 H, CH), 1.96(s, 3H, CH₃), 2.54(m, 1 H, CH), 2.81 (m, 1 H, CH), 1.91 (m, 1 H, CH), 5.40(m, 1 H, CH), 5.58 (s, 1 H, NH), 7.19 (m, 4H, Ph). ¹³CNMR (100MHz, CDCI₃): δ 168.7, 142.5, 142.1 , 127.0, 125.8, 123.0, 53.8, 33.1 , 29.2, 28.7, 22.5. Chiral GC: (97% ee).

Data (S)-Λ/-(1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-acetamide (12h) is as follows : Purified by column chromatography on silica gel/hexane: ethyl acetate (1 :1 ) as a white solid; yield 85% (0.16Og). ¹H-NMR (CDCI₃) δ (ppm) 1.6 (m, 2H, CH₂), 1.86 (m, 2H, CH₂), 2.1 (m, 3H, CH₃), 2.8 (s, 2H, CH₂), 5.2 (m, 1 H, CH), 5.7(s, 1 H, NH), 7.1 (m, 1 H, Ar), 7.2 (m, 1 H, Ar), 7.28 (m, 2H, Ar). Chiral GC: (84% ee).

Data for (S)-Λ/-(6-methoxy-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-acetamide (12i) is as follows: Purified by column chromatography on silicon gel/Hexane: Ethyl acetate (1 :1 ) as a white solid; Melting Point: 133-135 ⁰C yield 24% (26 mg); ¹HNMR (400 MHz, CDCI₃): δ (ppm) 1.84-1.89 (m, 3H, CH2), 2.05 (m, 2H, CH2), 3.83 (s, 3H, CH₃), 5.12 (m, 1 H, CH), 5.67 (s, 1 H, NH), 6.66 (m, 1 H, Ar), 6.79 (m, 1 H, Ar), 7.24 (m, 1 H, Ar); ¹³CNMR (100 MHz, CDCI3): δ 19.8, 23.6, 29.6, 30.2, 47.0, 55.3, 112.7, 1135, 128.9, 130.1 , 139.0, 158.7, 169.; MS m/z 219.1 (M⁺). Chiral GC analysis at 150 ⁰C, (5 min), then 5 °C/min increasing to 195 ⁰C: (S)-enantiomer, 31.249 min; (/^-enantiomer, 32.540 min (96% ee).

Data for (S)-Λ/-chroman-4-yl-acetamide (12j) is as follows: Purified by column chromatography on silicon gel/Hexane: Ethyl acetate gradient as a white solid, 0.145 g, yield 76 %; mp 186-187⁰C; ¹H-NMR (CDCI₃) δ (ppm) 2.08 (s, 3H), 2.26 (m, 2H), 4.21 (t, 2H), 5.18 (q, 1 H), 5.60 (s, 1 H), 6.87 (dd, 1 H), 6.96 (dd, 1 H), 7.23 (dd, 1 H), 7.25 (dd, 1 H); ¹³C-NMR (CDCI₃) δ (ppm) 23.5, 29.0, 43.7, 63.2, 117.2, 120.8, 121.9, 129.3, 129.4 155.2, 169.4; GC/MS RT(min): 14.35 min, m/z 191.1 (M⁺), 132.0 (M⁺-NHAc). Chiral GC: 94% ee.

Data for (S)-Λ/-6-chlorochroman-4-yl-acetamide (12k) is as follows: Purified by column chromatography on silicon gel/Hexane: Ethyl acetate gradient as a white solid, mp 188- 19O ⁰C; 0.16 g, yield: 73%; GC/MS RT(min): 12.67 min, m/z 183.1 (M⁺), 167.1 (M⁺- NHAc). Chiral GC: 76% ee.

Data for (S)-Λ/-thiochroman-4-yl-acetamide (121) is as follows: Purified by column chromatography on silicon gel/Hexane: Ethyl acetate as a white, white solid, mp 186- 188 ⁰C , 0.150 g, yield: 71 %; ¹H-NMR (CDCI₃) δ (ppm) 2.04 (s, 3H), 2.44 (q, 2H), 2.98 (t, 2H), 5.22 (t, 1 H), 5.91 , (s, 1 H), 7.08 (dd, 1 H), 7.10 (dd, 1 H), 7.25 (dd, 1 H), 7.13 (dd, 1 H) ; ¹³C-NMR (CDCI₃) δ (ppm) 22.7, 23.4, 28.1 , 46.8, 124.5, 125.5, 126.8, 130.5, 132.6, 133.5, 169.1 ; GC/MS RT(min): 16.28 min, m/z 207.0 (M⁺), 149.0 (M⁺-NHAc). Chiral GC: 99% ee.

Pyridyalkyl acetamides:

Data for (S)-Λ/-(1-pyridin-4-yl-ethyl)-acetamide (15a) is as follows: Purified by column chromatography on silicon gel/CH₂CI₂: CH₃OH (10:1 ) as a colorless oil; yield 75% (61 mg); N²⁰D = -74.0 (c 1.40, CHCI₃); ¹HNMR (400 MHz, CDCI₃) δ 1.35 (d, 3H, J = 7.2 Hz, CH3), 1.92 (s, 3H, CH3), 4.98 (m, 1 H, J = 7.2 Hz, CH), 6.7 (s, 1 H, NH), 7.15 (d, 2H, J = 6.0 Hz, Ar), 8.43 (d, 2H, J = 4.4 Hz, Ar); ¹³CNMR (100 MHz, CDCI3): δ 21.4, 23.1 , 47.9, 121.3, 149.8, 152.7, 169.7; MS m/z 164.2 (M⁺). Chiral GC analysis: 98% ee at 150 ⁰C (remaining 5 min), then 5 °C/min increasing to 170 ⁰C: (S)-enantiomer, 17.514 min; (R)- enantiomer, 18.208 min; at 170 ⁰C: (S)-enantiomer, 14.033 min; (F?)-enantiomer, 14.649 min; at 140 ⁰C: (S)-enantiomer, 63.084 min; (/=?)-enantiomer, 69.534 min.

Data for (S)-N-(I -pyridin-3-yl-ethyl)-acetamide (15b) is as follows: Purified by column chromatography on silicon gel/CH₂CI₂: CH₃OH (10:1 ) as a colorless oil; yield 84% (69 mg); [(X]²⁰ _D = -28.3 (c 1.30, CHCI₃); ¹HNMR (400 MHz, CDCI3) δ (ppm) 1.35 (d, 3H, J = 7.2 Hz, CH3), 1.88 (s, 3H, CH3), 5.00 (m, 1 H, J = 7.2 Hz, CH), 7.16 (m, 1 H, Ar), 7.58 (m, 1 H, Ar), 7.87 (m, 1 H, Ar), 8.36 (m, 1 H, Ar), 8.48 (s, 1 H, NH); ¹³CNMR (100 MHz, CDCI3): δ 21.6, 22.8, 46.5, 123.3, 133.9, 139.5, 147.8, 147.9, 169.7; MS m/z 164.1 (M⁺). Chiral GC analysis at 170 ⁰C: (S)-enantiomer, 13.628 min; (F?)-enantiomer, 14.073 min; at 150 ⁰C, (remaining 15 min), then 2 °C/min increasing to 160 ⁰C: (S)-enantiomer, 27.035 min; (F?)-enantiomer, 28.076 min. (99% ee).

Data for (S)-N-(I -pyridin-2-yl-ethyl)-acetamide (15c) is as follows: Purified by column chromatography on silicon gel/CH₂CI₂: CH₃OH (10:1) as a white solid; yield 72% (60 mg); Melting Point: 100-101 ⁰C. ¹HNMR (400 MHz, CDCI₃): δ 1.40 (d, 3H, J = 6.8 Hz, CH₃), 1.96 (s, 3H, CH₃), 5.07 (m, 1 H, J = 6.8 Hz, CH), 6.89 (s, 1 H, NH), 7.14-7.20 (m, 2H, Ar), 7.62 (m, 1 H, Ar), 8.47 (m, 1 H, Ar); ¹³CNMR (100 MHz, CDCI3): δ 22.7, 23.5, 49.7, 121.8, 122.5, 137.2, 148.8, 161.0, 169.4; MS m/z 164.2 (M⁺). Chiral GC analysis at 170 ⁰C: (S)-enantiomer, 7.634 min; (F?)-enantiomer, 7.860 min; at 160 ⁰C: (S)- enantiomer, 10.067 min; (/=?)-enantiomer, 10.502 min; at 150 ⁰C: (S)-enantiomer, 14.864 min; (/^-enantiomer, 15.458 min (60% ee).

Data for (S)-N-[I -(6-Methoxy-pyridin-3-yl)-ethyl]-acetamide (15d) is as follows: Purified by column chromatography on silicon gel /CH₂CI₂: CH₃OH (10:1 ) as a white solid; yield 88% (85 mg); Melting Point: 47-48 ⁰C; ¹HNMR (400 MHz, CDCI₃): δ ¹³CNMR (100 MHz, CDCI₃): δ 21.3, 23.4, 46.3, 53.5, 110.9, 131.4, 137.2, 144.6, 163.6, 169.2; MS m/z 194.1 (M⁺). Chiral GC analysis at 100 ⁰C for 10 min, then 5 °C/min increasing to 170 ⁰C: (S)-enantiomer, 39.331 min; (F?)-enantiomer, 39.827 min; (98% ee). [α]²⁰ _D = -63.5 (c 1.85, CHCI₃).

Data for (S)-N-(I -pyridin-3-yl-propyl)-acetamide (15e) is as follows: Purified by column chromatography on silicon gel/CH₂CI₂: CH₃OH (10:1 ) as a colorless oil; yield 89% (80 mg); [α]²⁰ _D = -109.7 (c 1.30, CHCI₃); ¹HNMR (400 MHz, CDCI₃): δ 0.96 (t, 3H, J = 7.6 Hz, CH₃), 1.88 (m, 2H, J = 7.6 Hz, CH2), 4.95 (m, 1 H, J = 7.6 Hz, CH), 6.10 (s, 1 H, NH), 7.29 (m, 1 H, Ar), 7.64 (m, 1 H, Ar), 8.54 (m, 1 H, Ar), 8.60 (m, 1 H, Ar); ¹³CNMR (100 MHz, CDCI₃): δ 10.7, 23.3, 28.8, 53.0, 123.5, 134.5, 137.8, 148.4, 148.7, 169.5; MS m/z 178.1 (M⁺). Chiral GC analysis at 120 ⁰C for 15 min, then 2 °C/min increasing to 150 ⁰C: (S)-enantiomer, 61.44 min; (R)-enantiomer, 62.77 min (99% ee).

Data for (S)-N-(I -pyridin-4-yl-propyl)-acetamide (15e) is as follows: Purified by column chromatography on silicon gel/CH₂CI₂: CH₃OH (10:1 ) as a colorless oil; yield 85% ( 76 mg); [(X]²⁰D = -114 (c 1.15, CHCI₃); ¹HNMR (400 MHz, CDCI3): δ 0.97 (t, 3H, J = 7.6 Hz, CH₃), 1.84 (m, 2H, J = 7.6 Hz CH2), 4.93 (m, 1 H, J = 7.6 Hz, CH), 5.87 (s, 1 H, NH), 7.23 (dd, 2H, J = 1.6, 6.0 Hz, Ar), 8.60 (dd, 2H, J = 1.6, 6.0 Hz, Ar); ¹³CNMR (100 MHz, CDCI₃): δ10.5, 23.3, 28.6, 54.0, 121.7, 150.1 , 169.8; MS m/z 178.1 (M⁺). Chiral GC analysis at 120 ⁰C for 15 min), then 2 °C/min increasing to 150 ⁰C: (S)-enantiomer, 62.43 min; (/=?)-enantiomer, 65.87 min (96% ee).

Although the invention has been described in conjunction with specific embodiments, it is evident that many alternatives and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, the invention is intended to embrace all of the alternatives and variations that fall within the spirit and scope of the appended claims.

Claims

1. A process for asymmetrically reducing a prochiral ketoxime ether having the formula IV:

where, R⁵, R_L and R_s are different, and each are an unsubstituted or substituted, aryl, alkyl, aralkyl or heteroaryl group, the process comprising reacting the prochiral ketoxime ether having the formula IV with borane derived from a borane reagent in the presence of a chiral accessory having the formula II:

where, the R and R¹ groups are equal or different; a hydrogen atom or a substituted or unsubstituted, aryl, alkyl, cycloalkyl or aralkyl;

R² and R ³ groups are different; a hydrogen atom or a substituted or unsubstituted, alkyl, aryl, aralkyl group; and the R⁴ group is a H or a cycloalkyl or aralkyl group; wherein the substituents R, R¹, R², R³, and R⁴ groups are substantially non- reactive, to form a chiral primary amine having the formula I:

(R) or (S) where, R_L and R_s are the same as defined above for the prochiral ketoximes ether having the formula IV.

2. The process according to claim 1 , where the R and R¹ groups are each a H, phenyl or aralkyl group.

3. The process according to claim 1 , wherein R² and R³ are different; a H, a methyl, substituted alkyl, phenyl or aralkyl groups, and the R⁴ group is a H or a cyclopentyl group.

4. The process according to claim 1 , where R_L is the unsubstituted or substituted, aryl, aralkyl, heteroaryl, unsubstituted or substituted pyridyl groups and R_s is the unsubstituted or substituted alkyl, cycloalkyl, pyridyl or heteroaryl group and the R⁵ is a methyl a unsubstituted or substituted benzyl with nitro, trifluoromethy, methoxy groups.

5. The process of claim 1 , wherein the reduction requires between about 0.1 to about 0.3 equivalent of said chiral accessory.

6. The process of claim 1 , wherein said chiral accessory comprises:

7. The process of claim 1 , wherein said chiral accessory comprises:

8. The process of claim 1 , wherein said chiral accessory comprises:

9. The process of claim 1 , wherein said chiral accessory comprises:

10. The process of claim 1 , wherein said chiral accessory comprises:

11. The process of claim 1 , wherein said chiral accessory comprises:

12. The process of claim 1 , wherein said chiral accessory is prepared at least one month prior to the reduction of said prochiral ketoxime ether.

13. The process of claim 1 , wherein said chiral accessory is added under a substantially humidity-free environment.

14. The process of claim 13, wherein a solvent and said borane reagent are added to said mixing element to create a mixture.

15. The process of claim 14, wherein a resulting solution is formed by stirring said mixture at room temperature for a predetermined period of time.

16. The process of claim 15, wherein said prochiral ketoxime ether in the presence of an effective amount of solvent is selectively added to said resulting solution.

17. The process of claim 16, wherein said resulting solution and said prochiral ketoxime ether are stirred until an amine is formed.

18. The process of claim 17, wherein the reaction is quenched with an effective amount of at least one acidic compound and at least one basic compound to produce a basic solution.

19. The process of claim 18, wherein an aqueous solution is extracted with a solvent to produce a primary amine.

20. The process of claim 19, wherein a combined organic phase is washed with a saturated compound solution and further dried with a drying agent.

21. The process of claim 20, wherein any remaining solvent is removed under vacuum conditions.

22. The process of claim 21 , wherein a resulting residue is acetylated to produce a amine derivative.

23. The process of claim 17, wherein the reaction is quenched with an effective amount of at methanol and then refluxed for a predetermined amount of time.

24. The process of claim 14, wherein the solvent comprises from about 4 to about 10 ml of dioxane.

25. The process of claim 14, wherein the borane reagent comprises from about 4 to about 5 equivalents of BH₃-THF.

26. The process of claim 15, wherein said predetermined period of time comprises between about 30 to about 60 minutes.

27. The process of claim 16, wherein said selective addition is performed on a drop- by-drop basis.

28. The process of claim 23, wherein the reaction is quenched with about 5 ml_ of methanol and then refluxed for about 6 hours.

29. The process of claim 1 , wherein said chiral accessory is able to reduce said prochiral ketoxime ether to obtain an enantiomeric excess of up to 99%.

30. A pharmaceutical compound comprising an amine synthesized by the process of claim 1.