An approach to an asymmetric synthesis of stemofoline

A stereoselective Mannich reaction between an (S)-tert-butylsulfinimine and methyl (S)-4-benzyloxy-3-methylbutanoate followed by treatment with acid and N-protection was used to prepare methyl (2R,3S)-2-[(S)-2-benzyloxy-1-methylethyl]-3-tert-butoxycarbonylamino-6-methylenedecanoate. This was taken through to methyl (4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-5-tert-butoxycarbonylamino-3,8-dioxododecanoate which on treatment with trifluoroacetic acid cyclised stereoselectively to give (1R,2S,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-tert-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane, a potential precursor of stemofoline. Reduction and N-deprotection of this ketone gave (1R,2S,3R,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-azabicyclo[3.2.1]octan-3-ol the structure of which was confirmed by X-ray diffraction.

A stereoselective Mannich reaction between a chiral ester and a chiral sulfinimine is used to prepare precursors of tropinones which may be useful in an asymmetric synthesis of stemofoline.Figure optionsDownload as PowerPoint slide

Methyl (2R,3S)-2-[(S)-2-benzyloxy-1-methylethyl]-3-[(SS)-tert-butylsulfinylamino]-6-oxodecanoate ethylene acetalC27H45NO6SEe ca. 100%[α]D26=+7.2 (c 8.3, CHCl3)Source of chirality: synthesis from (S)-tert-butylsulfinimine and methyl (R)-3-benzyloxy-2-methylpropanoate

Methyl (2R,3S)-2-[(S)-2-benzyloxy-1-methylethyl]- 3-[(SS)-tert-butylsulfinylamino]-6-methylenedecanoateC26H43NO4SEe ca. 100%[α]D23=+6.8 (c 4.7, CHCl3)Source of chirality: synthesis from (S)-tert-butylsulfinimine and methyl (R)-3-benzyloxy-2-methylpropanoate

(1R,2S,4R,5S)-4-[(S)-2-Benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]octan-3-oneC28H41NO6Ee ca. 100%[α]D22=-16.5 (c 17, CHCl3)Source of chirality: synthesis from (S)-tert-butylsulfinimine and methyl (R)-3-benzyloxy-2-methylpropanoate

(1R,2S,3R,4R,5S)-4-[(S)-2-Benzyloxy-1-methyl-ethyl]-1-butyl-2-methoxycarbonyl-8-tert-butoxycarbon-yl-8-azabicyclo[3.2.1]octan-3-olC28H43NO6Ee ca. 100%[α]D22=-48.05 (c 35.3, CHCl3)Source of chirality: synthesis from (S)-tert-butylsulfinimine and methyl (R)-3-benzyloxy-2-methylpropanoate

(1R,2S,3R,4R,5S)-4-[(S)-2-Benzyloxy-1-methyl-ethyl]-1-butyl-2-methoxycarbonyl-8-azabicyclo[3.2.1]-octan-3-olC23H35O4NEe ca. 100%[α]D26=-48 (c 0.5, CHCl3)Source of chirality: synthesis from (S)-tert-butylsulfinimine and methyl (R)-3-benzyloxy-2-methylpropanoate

(1R,2R,4R,5S)-4-[(S)-2-Benzyloxy-1-methylethyl]-1-butyl-2,8-dimethoxycarbonyl-8-azabicyclo[3.2.1]octan-3-oneC25H35NO6Ee ca. 100%[α]D29=-37.7 (c 5.1, CHCl3)Source of chirality: synthesis from (S)-tert-butylsulfinimine and methyl (R)-3-benzyloxy-2-methylpropanoate

(1R,2S,4R,5S)-4-[(S)-2-Benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-tert-butoxycarbonyl-2-prop-2-enyl-8-azabicyclo[3.2.1]octan-3-oneC31H45NO6Ee ca. 100%[α]D26=-56 (c 75.1, CHCl3)Source of chirality: synthesis from (S)-tert-butylsulfinimine and methyl (R)-3-benzyloxy-2-methylpropanoate