Synthesis of 2-amino alcohols and unnatural amino acids from serine

An efficient route for the synthesis of enantiopure unnatural α -amino acids and 2-amino alcohols was developed. The synthesis is based on the Wittig-type olefination of 3-benzyloxy-2-( tert - butoxycarbonylamino)propanal with various ylides


Introduction
The synthesis of unnatural amino acids has attracted special attention in recent years. 1,24][5] Aldehydes obtained from natural amino acids constitute a class of chiral synthons useful in the synthesis of optically active bioactive compounds and, in particular, in the synthesis of unnatural amino acids.Aldehyde 1, known as Garner's aldehyde, 6 is prepared from serine and has been used extensively in asymmetric synthesis.N,N-Dibenzylamino aldehydes 2 have been proven particularly useful in C-C bond forming processes. 7More recently, N,N-bisBoc-glutamate and aspartate aldehydes 3 have been proposed as chiral intermediates for the synthesis of unnatural amino acids 8,9 and have found many applications. 10

Results and Discussion
O-Benzyl-N-(tert-butoxycarbonyl)-L-serinol (4), prepared as described in literature, 12,13 was oxidized to aldehyde 5 [14][15][16] (Scheme 1) with NaOCl in the presence of a catalytic amount of 4acetamido-2,2,6,6-tetramethylpiperidin-1-yloxy radical (AcNH-TEMPO). 17,18N-Protected αaminoaldehydes may be prepared either by reduction of a carboxy derivative of an amino acid or by oxidation of 2-aminoalcohols, and it is known that they have a high tendency for racemization. 19The NaOCl/TEMPO method was chosen because it appears superior to reductive methods in terms of preservation of the enantiomeric purity. 20ur strategy to synthesize unnatural α-amino acids was based on a Wittig-type olefination reaction of aldehyde 5.This useful chiral synthon should be used immediately after its preparation without any purification.Thus, compound 5 reacted with ylides that were generated by treatment of tridecyltriphenylphosphonium bromide and benzyltriphenylphosphonium bromide with potassium bis(trimethylsilyl)amide (KHMDS) in toluene at 0° C (Scheme 1).Under these reaction conditions, compound 6 was obtained as Z/E mixture, whereas compound 7 mainly as E isomer (>95%), as shown by 1 H NMR spectroscopic analysis.The Horner-Wadsworth-Emmons olefination reaction of this aldehyde with the phosphonate anion, generated from ethyl (2E)-4-(diethoxyphosphoryl)but-2-enoate by treatment with LiOH 21 afforded compound 8.

H
Catalytic hydrogenation of the double bonds of compounds 6-8 with simultaneous removal of benzyl group produced Boc-protected 2-amino alcohols 9-11, respectively (Scheme 2).The Bocprotected α-amino acids 12 and 13 were obtained by oxidation of 9 and 10, respectively, using 2.5 equivalents of NaOCl in the presence of AcNH-TEMPO, and tetrabutylammonium hydrogensulfate as a phase transfer catalyst.The enantiomeric purity of the final products, 2-amino alcohols and α-amino acids, depends on the conditions used for both the preparation of aldehyde 5 and the Wittig-type reaction.Compounds 9-11 were converted with (S)-(-) and (R)-(+)-α-methoxy-(αtrifluoromethyl)phenylacetic acid 22 almost quantitatively into esters. 1H and 19 F NMR analysis of these Mosher esters indicated an enantiomeric excess >95%.The proposed method produced optically pure amino acids 12 and 13 as indicated by comparison of their specific rotation values with those reported in the literature. 23,24n conclusion, a general method for the synthesis of enantiopure unnatural α-amino acids and 2-amino alcohols has been developed using 3-benzyloxy-2-(tert-butoxycarbonylamino)propanal 6 as the key intermediate.The strengths of the method are (1) simplicity and efficiency, and (2) flexibility with respect to the side chains that can be introduced through the olefination reaction.

Experimental Section
General Procedures.Specific rotations were measured on polarimeter using a 10 cm cell.NMR spectra were recorded on a 200 MHz ( 1 H NMR) spectrometer.For analytical TLC plates silica gel 60 F 254 and for column chromatography silica gel 60 (70-230 or 230-400 mesh) were used (Merck).Dry solvents (THF, toluene, Et 2 O) were were used.N-Methylmorpholine was distilled from ninhydrin.All other solvents and chemicals were of reagent grade and used without further purification.The phosphonium salts were prepared by refluxing PPh 3 and the corresponding alkyl halide in MeCN and were used for the Wittig reactions without purification.

Wittig reaction. General procedure
To a stirred suspension of the appropriate phosphonium salt (1.20 mmol) in dry toluene (5.0 mL) was added dropwise over a period of 5 min at 0 °C under N 2 a solution of KHMDS in toluene (0.5 M, 2.4 mL).The bright red solution was stirred for another 10 min, and a solution of the aldehyde 5 (279 mg, 1.00 mmol) in dry toluene (5 mL) was added in one portion.The light yellow mixture was stirred at room temperature for 20 h.Then, the reaction mixture was quenched with a saturated aqueous solution of NH 4 Cl (50 mL) and extracted with Et 2 O (3 × 30 mL).The combined organic phases were washed with brine and dried (Na 2 SO 4 ).The solvent was removed, and the residue was purified by column chromatography using a mixture of EtOAc/petroleum ether as eluent.

Catalytic hydrogenation. General procedure
To a solution of 6, 7 or 8 (1.00 mmol) in MeOH (10 mL) was added Pd/C (10%, 60 mg).The reaction mixture was stirred under H 2 (1 atm) at room temperature for 16 h.After filtration through a pad of Celite, the solvent was removed, and the product was purified by column chromatography using petroleum ether/EtOAc (7:3, v/v) as eluent.