A molecular modelling explanation of the unexpected stereochemistry observed in the alkylation of oxazinone-derived glycine equivalents using 4-chloromethyl-1,3,2-dioxathiolane-2-oxide

The (R)- and (S)-enantiomers of 4-chloromethyl-1,3,2-dioxathiolane-2-oxide were used as ‘epoxide-like’ synthons in the asymmetric alkylation of the enantiomers of oxazinone-derived glycine equivalents. The configurations of the obtained spiro compounds were easily determined using 2D nuclear Overhauser effect nuclear magnetic resonance experiments. Additionally, the mechanisms of the reactions performed were explained using molecular modelling. The spiro derivatives obtained can also be modified and hydrolysed to their corresponding amino acids, which are derivatives of 1-aminocyclopropane-1-carboxylic acids.

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(R)-4-Chloromethyl-1,3,2-dioxathiolane 2-oxideC3H5ClO3S[α]D20 = −62.9 (c 1.470, MeOH), [α]D20 = −43.6 (c 1.108, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (R)

(R)-4-Chloromethyl-1,3,2-dioxathiolane 2,2-dioxideC3H5ClO4S[α]D20 = −26.4 (c 1.335, MeOH), [α]D20 = +2.6 (c 2.965, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (R)

(1R,3S,6S)-6-tert-Butyl-1-(chloromethyl)-5-methoxy-6-methyl-7-oxa-4-azaspiro[2.5]oct-4-en-8-oneC13H20ClNO3[α]D20 = +54.8 (c 2.338, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (1R,3S,6S)

(1S,3R,6S)-6-tert-Butyl-1-(chloromethyl)-5-methoxy-6-methyl-7-oxa-4-azaspiro[2.5]oct-4-en-8-oneC13H20ClNO3[α]D20 = −19.0 (c 2.570, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (1S,3R,6S)

(1R,3S,6R)-6-tert-Butyl-1-(chloromethyl)-5-methoxy-6-methyl-7-oxa-4-azaspiro[2.5]oct-4-en-8-oneC13H20ClNO3[α]D20 = +18.9 (c 2.530, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (1R,3S,6R)

(1S,3R,6R)-6-tert-Butyl-1-(chloromethyl)-5-methoxy-6-methyl-7-oxa-4-azaspiro[2.5]oct-4-en-8-oneC13H20ClNO3[α]D20 = −50.1 (c 2.365, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (1S,3R,6R)

(1S,3S,6R)-6-tert-Butyl-5-methoxy-6-methyl-1-((4-phenylpiperazin-1-yl)methyl)-7-oxa-4-azaspiro[2.5]oct-4-en-8-oneC23H33N3O3[α]D20 = −4.2 (c 1.140, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (1S,3S,6R)

C21H24N2O52-(((1S,3S,6R)-6-tert-Butyl-5-methoxy-6-methyl-8-oxo-7-oxa-4-azaspiro[2.5]oct-4-en-1-yl)methyl)isoindoline-1,3-dione[α]D20 = −24.9 (c 0.944, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (1S,3S,6R)