Chemoenzymatic synthesis of (3R,4S)- and (3S,4R)-3-methoxy-4-methylaminopyrrolidine

An efficient and a convenient enantioselective synthesis of (3R,4S)-3-methoxy-4-methylaminopyrrolidine has been carried out by a lipase-mediated resolution protocol. This method describes the preparation of (±)-1-Cbz-cis-3-azido-4-hydroxypyrrolidine starting from commercially available diallylamine followed by ring-closing metathesis (RCM) via SN2 displacement reactions. Pseudomonas cepacia lipase immobilized on diatomaceous earth (Amano PS-D) provides (3R,4S)-11 and (3S,4R)-12 in an excellent enantiomeric excess.

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(3S,4R)-1-Cbz-3-Azido-4-hydroxypyrrolidineC12H14N4O3Ee = 92% [by chiral HPLC][α]D25=-9.5 (c 1.01, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3S,4R)

(3R,4S)-1-Cbz-3-Acetyloxy-4-azidopyrrolidineC14H16N4O4Ee = 97% [by chiral HPLC][α]D25=-29.3 (c 1.04, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3R,4S)

(3R,4S)-1-Cbz-3-Azido-4-methoxypyrrolidineC13H16N4O3Ee = 97% [by chiral HPLC][α]D25=-48.4 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3R,4S)

(3R,4S)-1-Cbz-3-[(tert-Butoxycarbonyl)amino]-4-methoxypyrrolidineC18H26N2O5Ee = 97% [by chiral HPLC][α]D25=-7.3 (c 1.07, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3R,4S)

(3R,4S)-1-Cbz-3-[(tert-Butoxycarbonyl)methylamino]-4-methoxypyrrolidineC19H28N2O5Ee = 97% [by chiral HPLC][α]D25=-42.6 (c 1.05, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3R,4S)

(3R,4S)-1-tert-Butoxycarbonyl-3-methoxy-4{[tert-butoxycarbonyl]methylamino}pyrrolidineC16H30N2O5Ee = 97% [by chiral HPLC][α]D25=-53.2 (c 1.05, MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: (3R,4S)

(3S,4R)-1-tert-Butoxycarbonyl-3-methoxy-4{[tert-butoxycarbonyl]methylamino}pyrrolidineC16H30N2O5Ee = 92% [by chiral HPLC][α]D25=+50.9 (c 1.01, MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: (3S,4R)