A Straightforward Synthesis of Enantiopure (1S,2R)-Ephenamine

Chiral amino alcohols are very versatile compounds used in organic chemistry as chiral auxiliaries, chiral ligands and synthetic intermediates. They also present high biological activity, and take part in the structure of valuable drugs. Syn and anti 1,2-diphenyl2-aminoethanol, 1 and 2 (Figure 1), have been used widely as part of designed ligands for asymmetric transformations including α-arylation of α-aminoacids, synthesis of enantiomerically enriched 1,2-diaryl carbonyl compounds, asymmetric Baeyer-Villiger oxidation, asymmetric epoxidation of alkylidenemalononitriles, among others. (1S,2S)-Pseudoephenamine 3 and (1S,2R)-ephenamine 4 (Figure 1) are known chiral auxiliaries used in diastereoselective alkylations which provide alcohols, ketones and carboxylic acids with high enantiomeric purity. Several synthetic methods have been reported for the synthesis of (1S,2R)-ephenamine 4, as well as the respective (1S,2R)-1,2-aminoalcohol 2, however, to the best of our knowledge, none of these methods starts from readily available chiral amino acid. Zhou et al. has described the synthesis of enantiopure syn N-Boc-protected-1,2-amino alcohols in good yields from readily available L-amino acids in four reaction steps (Scheme 1). Ghorai et al. has described the synthesis of anti N-Boc-protected-1,2-amino alcohols starting from N-Boc-(S)-phenylglycine on a similar approach, nevertheless none chiral ephenamine 4 precursor had been synthesized (Scheme 2).

Zhou et al. 28,29 has described the synthesis of enantiopure syn N-Boc-protected-1,2-amino alcohols in good yields from readily available L-amino acids in four reaction steps (Scheme 1).
The acidic α-carbonyl/benzylic stereogenic center on the starting materials (Scheme 3) demands highly mild conditions in each step in order to avoid racemization as previously observed by Hultin and co-workers. 31 In order to overcome this obstacle we developed a new approach for the synthesis of such important chiral auxiliary starting from commercially available chiral glycine derivative which is less suitable for racemization.
The high hindrance provided by the Boc group combined with the sodium poor chelation ability makes a chelation control unlikely in this case. 40 Inspired by these results, we decided to investigate the stereoselective reduction of ketone 10, which presents slightly structural resemblance with (S)-7, 34 over several conditions ( Table 1).
As illustrated on Table 1, the use of NaBH 4 presented slightly better selectivity for the alcohol anti-11 (Table 1, entry 1). Even when using highly chelating reagent as Zn(BH 4 ) 2 (entry 4) or very bulky ones (entries 5 to 7) it was not observed any considerable diastereoselectivity. The results on Table 1 (entry 1) suggest the Felkin-Anh model for the stereoselective reduction of ketone 10 (Scheme 7a) is similar to that suggested for reduction of ketone (S)-7 (Scheme 6). The 1,4-cyclohexadienyl group on 10 has slightly higher priority (bulkier) over the NHBoc group providing the alcohol anti-11 as the major stereoisomer (Scheme 7a).
In contrast, when using L-selectride as reducing agent (Table 1, entry 5) a modest shift in diastereoselectivity was observed providing a slight excess of alcohol syn-11. In this case, the bulkiness of both L-selectride and NHBoc group may contribute to elevate the energy of transition state that leads to alcohol anti-11 (Scheme 7a) slightly favoring the synthesis of syn stereoisomer (Scheme 7b).
The protection of crude alcohol 11 41 (3:1 anti/syn ratio) followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) mediated aromatization afforded the aromatic  ester 13 (3:1 anti/syn ratio) which upon chromatographic column afforded the pure anti-13 stereoisomer in 61% yield (Scheme 8). The nuclear magnetic resonance (NMR) spectra of all NHBoc-derivatives corroborate the respective structures despite presenting a complex pattern due to the presence of Boc group rotamers. 42,43 The (1S,2R)-ephenamine 4 was obtained by the reduction of anti-13 using a large excess of lithium aluminium hydride (LAH) in 75% yield (Scheme 8). 19 The physical and spectroscopic data of compound 4 were in full agreement with those reported in the literature. 19,21 Conclusions In this work we described a simple and efficient sixstep synthesis of (1S,2R)-ephenamine 4, an important chiral auxiliary, from commercially available chiral glycine derivative through straightforward procedures with 26% overall yield and high optical purity. The use of chiral phenylglycine as starting material was not satisfactory due to the presence of a very sensitive α-carbonyl/benzylic stereogenic center which, in our hands, led to partial racemization. When starting from (R)-2-(2,5-dihydrophenyl)-glycine instead this problem was suppressed consisting in an excellent strategy for the synthesis of similar chiral molecules in high optical purity.

Experimental
Unless indicated otherwise, all reagents and solvents were purchased from commercial suppliers (Sigma-Aldrich Corp., St. Louis, USA) and used without further purification. Melting points were measured on a Stuart Scientific melting point apparatus. NMR spectra were measured with a VARIAN 400.1 MHz in CDCl 3 or CD 3 OD solutions (Sigma-Aldrich Corp., St. Louis, USA). Chemical shifts are expressed as d (ppm) relative to tetramethylsilane (TMS) as an internal standard and the J values are given in hertz. Infrared spectra (IR) (neat) were recorded with a Bruker Alpha ATR (attenuated total reflection) spectrometer. Optical rotations were measured with a Jasco P-2000 Polarimeter. High resolution mass spectra (HRMS) were recorded with a Bruker Impact II UHPLC-QTOF (ultra-high performance liquid chromatography-quadrupole time-of-flight) mass spectrometer. HPLC analysis was performed on a Shimadzu LC-20AT chromatograph. Column chromatography was performed by using silica gel (230-400 mesh) according to the methods described by Still et al. 44 Thin layer chromatography (TLC) was performed by using silica gel 60 with fluorescent indicator UV 254 (0.20 mm thickness). For visualization, TLC plates were either placed under ultraviolet light, iodine cell or treated with vanillin or ninhydrin followed by heating. Air and moisture sensitive reactions were conducted in flame or oven dried glassware equipped with tightly fitted rubber septa and under a positive pressure of dry nitrogen. Solvents were purified when necessary using standard procedures. 45 (R)-2-(tert-Butoxycarbonylamino)-2-(cyclohexa-1,4-dienyl) acetic acid (8) Adapted from literature. 32 To a solution of (R)-2-(2,5-dihydrophenyl)-glycine (1.0 equiv., 2.0 g, 13.0 mmol) in 1 M aqueous NaOH (2.0 equiv., 26 mL, 26.0 mmol) at 0 °C was added a solution of (Boc) 2 O (1.1 equiv., 3.1 g, 14.3 mmol) in dioxane (15 mL) dropwise over 30 min. The resulting mixture was stirred at 0 °C for another 30 min, then allowed to warm to room temperature and stirred overnight. The organic solvent was removed under reduced pressure. The remaining aqueous solution was acidified to pH ca. 4 with 1 M KHSO 4 and the aqueous solution was extracted with CHCl 3 (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous K 2 CO 3 , and concentrated by rotary evaporation to afford carbamate 8 ( (R)-tert-Butyl 1-(cyclohexa-1,4-dienyl)-2-(methoxy(methyl) amino)-2-oxoethylcarbamate (9) Adapted from literature. 33 To an ice cold solution of carbamate 8 (1.0 equiv., 1.2 g, 4.7 mmol), in dry dichloromethane (DCM, 50 mL) was added DIPEA (1.1 equiv., 0.9 mL, 5.1 mmol). After stirring for 15 min, pivaloyl chloride was added (1.1 equiv., 0.6 mL, 5.1 mmol). The solution was stirred at room temperature for two hours and then N,O-dimethylhydroxylamine hydrochloride (1.1 equiv., 0.5 g, 5.1 mmol) and DIPEA (2.0 equiv., 1.6 mL, 9.6 mmol) were added. The reaction mixture was stirred overnight, washed with 5% HCl solution (20 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous K 2 CO 3 , and concentrated by rotary evaporation. Flash chromatography on a short pad silica gel (0 → 30% v/v ethyl acetate/hexane) afforded Weinreb amide 9 (1.  2978, 1672, 1486, 1448, 1364, 1247, 1155, 1055 tert-Butyl (1R,2S)-1-(cyclohexa-1,4-dienyl)-2-hydroxy-2-phenyl ethylcarbamate (11) A solution of ketone 10 (1.0 equiv., 0.64 g, 2.0 mmol) in dry MeOH (30 mL) was cooled to −40 °C and stirred for 10 min. NaBH 4 (3.0 equiv., 0.23 g, 6.1 mmol) was added in one portion and the mixture was stirred at −40 °C for seven hours under N 2 atmosphere. The methanol was removed under reduced pressure and a 3% HCl solution (30 mL) was added to the crude solid. The aqueous phase was extracted with DCM (3 × 40 mL) and the organic layers were combined, washed with brine, dried over anhydrous K 2 CO 3 and concentrated under reduced pressure affording the alcohol 11 (3:1 anti/syn ratio) as white solid that was used in the next step without further purification (0.5 g, 86%). IR (ATR) ν / cm − To a stirred solution of diastereomeric mixture (3:1 anti/syn ratio) of 11 (1.0 equiv., 0.49 g, 1.55 mmol) in DCM (35 mL) were added acetic anhydride (1.1 equiv., 0.17 mL, 1.8 mmol), triethylamine (1.1 equiv., 0.26 mL, 1.8 mmol) and catalytic 4-dimethyl-aminopyridine (DMAP). The solution was stirred for 16 h at room temperature and then a 5% HCl solution was added. The organic phase was separated, and the aqueous layer was extracted with DCM (3 × 30 mL). The organic extracts were washed with water (20 mL), dried over anhydrous K 2 CO 3 and concentrated under reduced pressure providing a light yellow oil that was immediately dissolved in dry DCM (25 mL) and treated with DDQ (2.0 equiv., 0.7 g, 3.2 mmol). The system was stirred at room temperature for 18 h under N 2 atmosphere and then the solution was filtered through a short pad of celite. The solvent was evaporated affording a crude yellow solid that was purified by silica gel flash chromatography (0 → 20% v/v ethyl acetate/hexane) affording pure compound anti-13 (0.33 g, 61%) as a pale yellow solid (mixture of rotamers).

Supplementary Information
Supplementary information (NMR, infrared and HRMS spectra from all the compounds) is available free of charge at http://jbcs.sbq.org.br as PDF file.