One-pot synthesis of enantiomerically pure N-protected allylic amines from N-protected α-amino esters

An improved protocol for the synthesis of enantiomerically pure allylic amines is reported. N-Protected α-amino esters derived from natural amino acids were submitted to a one-pot tandem reduction–olefination process. The sequential reduction with DIBAL-H at −78 °C and subsequent in situ addition of organophosphorus reagents yielded the corresponding allylic amines without the need to isolate the intermediate aldehyde. This circumvents the problem of instability of the aldehydes. The method tolerates well both Wittig and Horner–Wadsworth–Emmons organophosphorus reagents. A better Z-(dia)stereoselectivity was observed when compared to the previous one-pot method. The (dia)stereoselectivity of the process was affected neither by the reaction solvent nor by the amount of DIBAL-H employed. The method is compatible with the presence of free hydroxy groups as shown with serine and threonine derivatives.


General procedure A: preparation of N-protected allylic amines
To a solution of (S)-methyl 2-(dibenzylamino)propanoate (1, 1 mmol) in dry toluene (3 mL) was added dropwise DIBAL-H (1.0 M solution in hexanes, 1 mmol) at −78 °C. After stirring for 2 h at −78 °C, the appropriate organophosphorus reagent was added in small portions (or dropwise) at −78 °C (some of them required to be prepared separately, see below). The mixture was allowed to warm gradually to 0 °C. Then, the mixture was quenched with saturated Rochelle's salt solution (10 mL). The reaction mixture was vigorously stirred for 2 h at rt. After dilution with water (10 mL), the biphasic mixture was separated and extracted with Et 2 O (3 × 10 mL). The combined organic phases were washed with brine, dried over MgSO 4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent EtOAc/hexanes) to give the corresponding N-protected allylic amine.

General procedure B: preparation of N-protected β-hydroxy allylic amines
To a solution of (S)-benzyl 2-(dibenzylamino)-3-hydroxypropanoate (3) or (2S,3R)-ethyl 2-(dibenzylamino)-3-hydroxybutanoate (5) (0.27 mmol) in dry toluene (3 mL) was added DIBAL-H in two portions, first dropwise at −78 °C (0.41 mL, 1.0 M solution in hexanes, 0.41 mmol) and the rest 1 h later (0.14 mL, 1.0 M solution in hexanes, 0.14 mmol). After stirring for 2 h at −78 °C, the appropriate organophosphorus reagent was carefully added at -78 °C (some of them were prepared separately, see below). The mixture was allowed to warm gradually to 0 °C. Then, the mixture was quenched with saturated Rochelle's salt solution (10 mL). The reaction mixture was vigorously stirred for 2 h at rt. After dilution with water (10 mL), the biphasic mixture was separated and extracted with Et 2 O (3 × 10 mL). The combined organic phases were washed with brine, dried over MgSO 4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (eluent EtOAc/hexanes) to give the corresponding N-protected β-hydroxy allylic amine.

General procedure C: preparation of Wittig organophosphorus reagents
To a stirred suspension of the appropriate phosphonium bromide (1.0 mmol) in dry toluene (10 mL) was added dropwise KN(TMS) 2 (1 mL, 0.5 M solution in toluene, 1.0 mmol) at 0 °C. After 30 min the flask was cooled to -78 °C.

General procedure D: preparation of HWE organophosphorus reagents
To a solution of the appropriate phosphonate (0.5 mmol) in dry toluene (2 mL) at 0 °C, was added carefully NaH (60% in mineral oil, 0.5 mmol). The mixture was stirred for 4 h at 0 °C.

General procedure E: preparation of Still-Gennari organophosphorus reagents
To freshly distilled THF (20 mL) was added KN(TMS) 2 (2 mL, 0.5 M in THF, 1 mmol) and 18-crown-6 (280 mg, 1.1 mmol). The reaction mixture was cooled to −78 °C and a solution of the appropriate phosphonate (1.0 mmol) in 10 mL of dry THF was added via cannula. The reaction was stirred 30 min at −78 °C and then 1 h at 0 °C. Then, the mixture was cooled to −78 °C.
The general procedure A was applied to 1 on a 0.35 mmol (100 mg) scale using the ylide of benzyltriphenylphosphonium bromide (303.3 g, 0.7 mmol) prepared according to the general procedure C, to give after purification (eluent Et 2 O/hexanes 1/99) 2b (68 mg, 60%, E/Z = 1/1.3) as a colorless oil inseparable mixture of E/Z isomers.

(S,Z)-N,N-dibenzyloctadec-3-en-2-amine (2c)
The general procedure A was applied to 1 on a 0.35 mmol (100 mg) scale using the ylide of tetradecyltriphenylphosphonium bromide (387.5 mg, 0.7 mmol) prepared according to the general procedure C, to give after purification (eluent