Organocerium additions to proline-derived hydrazones: synthesis of enantiomerically enriched amines

The addition of organocerium reagents (from both organolithium and organomagnesium precursors) to chiral aldehyde hydrazones prepared from 1-aminoproline derivatives has been studied. The additions proceed in good yield and high diastereoselectivity and with good nucleophile (Me, n-Bu, i-Pr, t-Bu, Ph, etc.) and substrate scope (alkyl, alkenyl and aryl). The resulting hydrazines can be converted to amines by N–N bond cleavage through hydrogenolysis (Raney nickel) or by acylation and cleavage with Li/NH3. The influence of the side chain on the diastereoselectivity was investigated through variation of the substituents to include more coordinating atoms (oxygen and nitrogen) as well as the removal of coordinating atoms. The SAMEMP auxiliary bearing a 2-methoxyethoxymethyl group gave the highest diastereoselectivities. Remarkably, auxiliaries bearing simple methyl and isobutyl substituents gave high selectivities as well. Hypotheses for the origin of the selectivity are presented.

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(S)-1-(E-2-Butenylidenamino)-2-(methoxymethyl)pyrrolidineC10H18N2O[α]D = −138.5 (c 1.58 CHCl3)Source of chirality: (S)-prolinolAbsolute configuration: (2S)

(S)-2-[(2-Methoxyethoxymethoxymethyl)]-1-(3-phenylpropylidenamino)-pyrrolidineC18H28N2O3[α]D = −76.4 (c 0.72 CHCl3)Source of chirality: (S)-prolinolAbsolute configuration: (2S)

(S)-2-[(2-Methoxyethoxy)methyl]-1-(3-phenylpropylidenamino)pyrrolidineC17H26N2O2[α]D = −92.0 (c 1.0, CHCl3)Source of chirality: (S)-prolinolAbsolute configuration: (2S)

(2S,1′R)-2-(2-Methoxyethoxymethyl)-1-[N-(1-methyl-3-phenylpropyl)-N-methoxycarbonylamino]pyrrolidineC20H32N2O4dr = 97:3[α]D = −50.0 (c 1.42, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,1′R)

(S)-1-Formyl-2-(methoxymethoxymethyl)pyrrolidineC8H15NO3[α]D = −42.4 (c 1.55, CHCl3)Source of chirality: (S)-prolinolAbsolute configuration: (2S)

(S)-1-Formyl-2-((2-methoxyethoxy)methyl)pyrrolidineC9H17NO3[α]D = −45.8 (c 1.0, CHCl3)Source of chirality: (S)-prolinolAbsolute configuration: (2S)

(S)-2-((2-Methoxyethoxy)methyl)pyrrolidineC8H17NO2[α]D = +7.5 (c 1.0, CHCl3)Source of chirality: (S)-prolinolAbsolute configuration: (2S)

(S)-1-Carbamoyl-2-((2-methoxyethoxymethyl)pyrrolidineC9H18N2O3[α]D = −33.8 (c 1.0, CHCl3)Source of chirality: (S)-prolinolAbsolute configuration: (2S)

(S)-1-Amino-2-((2-methoxyethoxy)methyl)pyrrolidineC8H18N2O2[α]D = −6.7 (c 1.07, CHCl3)Source of chirality: (S)-prolinolAbsolute configuration: (2S)

(R)-(1-Methyl-3-phenyl)propylamineC10H15N[α]D = −3.6 (c 1.58, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R)

(R)-(1-Methyl-2-phenyl)ethylamineC9H13N[α]D = −35.8 (c 1.05, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R)