Lipase-catalyzed kinetic resolutions of racemic 1-(10-ethyl-10H-phenothiazin-1,2, and 4-yl)ethanols and their acetates

The synthesis of both enantiomers of 1-(10-ethyl-10H-phenothiazin-1,2, and 4-yl)ethanols 1a–c and their acetates via enantioselective methanolysis of the corresponding racemic esters rac2a–c with lipase B from Candida antarctica (CaL-B) or/and by acylation of the racemic alcohols with the lipase A or lipase B from C. antarctica (CaL-A and CaL-B) is described. The absolute configuration of enantiopure 1-(10-ethyl-10H-phenothiazin-1-yl)ethyl acetate 2a was assigned as (R) by using QM/MM(hf/3–21g:uff) calculations within the CaL-B (1LBT crystal structure) enzymic environment.

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(R)-1-(10-ethyl-10H-phenothiazin-1-yl)ethanolC16H17NOSEe >99% on LiChroCART (R,R)-Whelk-O1 column HPLC column[α]D25=+14.8 (c 1.0, CHCl3)Source of chirality: enzymatic reactionAbsolute configuration: (R)

(R)-1-(10-ethyl-10H-phenothiazin-2-yl)ethanolC16H17NOSEe >99% on Chiralpak IB HPLC column[α]D25=+46.4 (c 1.0, CHCl3)Source of chirality: enzymatic reactionAbsolute configuration: (R)

(R)-1-(10-ethyl-10H-phenothiazin-4-yl)ethanolC16H17NOSEe >99% on Chiralpak IC HPLC column[α]D25=+145.3 (c 1.0, CHCl3)Source of chirality: enzymatic reactionAbsolute configuration: (R)

(S)-1-(10-ethyl-10H-phenothiazin-1-yl)ethyl acetateC18H19NO2SEe >99% on LiChroCART (R,R)-Welk-O1 HPLC column[α]D25=-13.0 (c 1.0, CHCl3)Source of chirality: enzymatic reactionAbsolute configuration: (S)

(S)-1-(10-ethyl-10H-phenothiazin-2-yl)ethyl acetateC18H19NO2SEe >99% on Chiralpak IB HPLC column[α]D25=-80 (c 1.0, CHCl3)Source of chirality: enzymatic reactionAbsolute configuration: (S)

(S)-1-(10-ethyl-10H-phenothiazin-4-yl)ethyl acetateC18H19NO2SEe >99% on Chiralpak IC HPLC column[α]D25=-3.5 (c 1.0, CHCl3)Source of chirality: enzymatic reactionAbsolute configuration: (S)