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_{Asymmetric Synthesis IV.}
Preparation of Chiral α-Aminonitriles from a new N-Cyanomethyl-1,3-Oxazolidine Synthon
José L. Marco, Jacques Royer and Henri-Philippe Husson
Tetrahedron Letters 26(30), 3567-3570 (1985) (../rhodium/pdf /cyanomethyl-4-phenyl-13-oxazolidine.pdf)

Abstract: The synthesis of (-)-N-cyanomethyl-4-phenyl-1,3-oxazolidine 1 is reported. Good yields and moderate diastereomeric excesses of mono- and di-substituted α-aminonitriles were obtained from this simple chiral template.

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Preparation of (-)-N-cyanomethyl-4-phenyl-1,3-oxazolidine 1

To a stirred solution of (-)-phenylglycinol (23.62g, 0.16 mol), KCN (10.4g, 0.16 mol) in water (650 mL) at pH ~3 (citric acid) was added over 30 min at room temp a solution of formaldehyde (40%, 260 mL). The reaction mixture was stirred for ar additionnal 30 min, then basified (Na₂CO₃) and extracted (CH₂Cl₂). The combined organic fractions were washed with water, dried (Na₂SO₄) and concentrated to give a yellow oil which was purified by flash chromatography (SiO₂, hexane-AcOEt, 80:20). 1 was obtained as a colorless oil (31.15g, 94% yield, [α]²⁰_D -173°(CHCl₃, c=1.4)).

Alkylation of 1 with Methyl Iodide

To a stirred solution of LDA/HMPA (1:1, 1.1 eq. 0.48 M in THF) at -78°C, was added 1 (1 eq., 0.66M in THF) via syringe over 5 min; after 15 min 1.1 eq. of MeI was added. The reaction mixture was stirred for 1 h, quenched by NH₄Cl then extracted with ether, dried and concentrated to dryness. Flash chromatography of the residual oil (SiO₂, hexane-EtOAc, 85:15) separated the isomers to give 2 as the major product, yield 55% (38% d.e.) [α]²⁰_D -282° (c=2.4, CDCl₃)

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_{Asymmetric Synthesis IX:}
Preparation of Chiral α-Substituted Phenethylamines
J.L. Marco, J. Royer & H.-P. Husson
Synth. Commun. 17(6), 669-676 (1987) (../rhodium /meth.n-cyanomethyloxazolidine.html)

Abstract: (S)-N-methyl-α-methyl-phenethylamines 5a-d were obtained in 56-62% e.e. from the chiral synthon (-)-N-cyanomethyl-4-phenyl-1,3-oxazolidine-1.

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Alkylation of 2 with Benzyl Bromide
To a stirred solution of LDA/HMPA (1:1; 5 mmol, prepared from 3.12 mL of BuLi 1.6 M and 0.75 mL of diisopropylamine at -10°C/-30°C under a nitrogen atmosphere) in THF (20 mL) was added 2 (0.909g, 4.5 mmol, THF, -78°C) via syringe over 5 min. After 20 min, the resultant anion solution was added benzyl bromide (2 equiv.) and the mixture was stirred at -78°C for 1 h, quenched by NH₄Cl then extracted with ether dried and concentrated to dryness. Flash chromatography of the residual oil (SiO₂, hexane-AcOEt, 80:20) yielded compound 3, which was used in the next step without further purification.

Reductive Decyanation/Ring-Opening of 3
NaBH₄ (1.1 eq.) was added portionwise to a solution of 3 in EtOH (~0.4 M); stirring was continued at room temp overnight. The solvent was removed and the residue taken up in DCM, washed with H₂O and brine, dried over Na₂SO₄ and evaporated to dryness. The oily residue was purified by flash-chromatography (DCM-MeOH, 95:5) to give 4. The diastereomeric excess of the RS isomer was 66% and the overall yield from 1 was 30%.

Hydrogenolysis of 4 to give (S)-5 (d-Methamphetamine)
A methanolic solution (~0.2 M) of 4 was hydrogenolysed overnight at room temp, using 1 atm. H₂ in the presence of 10% Pd/C. The reaction mixture was then filtered through a celite bed and the filtrate  evaporated in vacuo to yield an oily residue which was purified by flash chromatography on silica (DCM-MeOH) to give (S)-5 (d-Methamphetamine) in 90% yield (66% e.e.).