Synthesis of new enantiopure proton-ionizable crown ethers containing a dialkylhydrogenphosphate moiety

Seven new enantiopure proton-ionizable crown ethers containing a dialkylhydrogenphosphate moiety were prepared starting from optically active dialkyl-substituted oligoethylene glycols and phosphorus oxychloride followed by mild hydrolysis of the resulting macrocyclic chlorophosphates. Pentaethylene glycols having primary hydroxyl groups gave good yields of 17-crown-6 type ethers. Pentaethylene glycols with secondary hydroxyl groups rendered about the same amount of 17-crown-6 ethers and open chain dihydrogenphosphates in low yields. Tetraethylene glycols are reluctant to undergo macrocyclization with phosphorus oxychloride, especially the ones which contain secondary hydroxyl groups.

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(4S,12S)-1-Hydroxy-4,12-diisobutyl-2,5,8,11,14-pentaoxa-1-phosphacyclotetradecane 1-oxideC16H33O7PEe >97%[α]D23=-8.5 (c 1.52, CH2Cl2)Source of chirality: (S)-(+)-leucineAbsolute configuration: 4S,12S

(4S,15S)-1-Hydroxy-4,15-dimethyl-2,5,8,11,14,17-hexaoxa-1-phosphacycloheptadecane 1-oxideC12H25O8PEe >97%[α]D24=+26.8 (c 1.77, CH2Cl2)Source of chirality: (S)-(−)-ethyl lactateAbsolute configuration: 4S,15S

(3S,16S)-1-Hydroxy-3,16-dimethyl-2,5,8,11,14,17-hexaoxa-1-phosphacycloheptadecane 1-oxideC12H25O8PEe >97%[α]D23=+20.1 (c 2.85, CH2Cl2)Source of chirality: (S)-(−)-ethyl lactateAbsolute configuration: 3S,16S

(4S,15S)-1-Hydroxy-4,15-diisobutyl-2,5,8,11,14,17-hexaoxa-1-phosphacycloheptadecane 1-oxideC18H37O8PEe >97%[α]D26=+10.2 (c 1.49, CH2Cl2)Source of chirality: (S)-(+)-leucineAbsolute configuration: 4S,15S

(3S,16S)-1-Hydroxy-3,16-diisobutyl-2,5,8,11,14,17-hexaoxa-1-phosphacycloheptadecane 1-oxideC18H37O8PEe >97%[α]D26=+7.95 (c 1.59, CH2Cl2)Source of chirality: (S)-(+)-leucineAbsolute configuration: 3S,16S

(4S,15S)-1-Hydroxy-4,15-dioctyl-2,5,8,11,14,17-hexaoxa-1-phosphacycloheptadecane 1-oxideC26H53O8PEe >97%[α]D26=+7.0 (c 2.50, CH2Cl2)Source of chirality: (S)-(+)-2-hydroxydecanoic acidAbsolute configuration: 4S,15S

(3S,16S)-1-Hydroxy-3,16-dioctyl-2,5,8,11,14,17-hexaoxa-1-phosphacycloheptadecane 1-oxideC26H53O8PEe >97%[α]D24=+12.1 (c 1.93, CH2Cl2)Source of chirality: (S)-(+)-2-hydroxydecanoic acidAbsolute configuration: 3S,16S

(2S)-2-(2-{2-[(2S)-1-Hydroxypropan-2-yloxy]ethoxy}ethoxy)propyl dihydrogenphosphateC10H23O8PEe >97%[α]D28=+24.2 (c 2.91, CH2Cl2)Source of chirality: (S)-(−)-ethyl lactateAbsolute configuration: S,S

(2S)-3-(2-{2-[(2S)-2-Hydroxypropoxy]ethoxy}ethoxy)propan-2-yl dihydrogenphosphateC10H23O8PEe >97%[α]D27=+11.1 (c 1.41, CH2Cl2)Source of chirality: (S)-(−)-ethyl lactateAbsolute configuration: S,S

(2S)-2-(2-{2-[(2S)-1-Hydroxy-4-methylpentan-2-yloxy]ethoxy}ethoxy)-4-methylpentyl dihydrogenphosphateC16H35O8PEe >97%[α]D23=-7.3 (c 2.05, CH2Cl2)Source of chirality: (S)-(+)-leucineAbsolute configuration: S,S

(2S)-1-(2-{2-[(2S)-2-Hydroxy-4-methylpentyloxy]ethoxy}ethoxy)-4-methylpentan-2-yl dihydrogenphosphateC16H35O8PEe >97%[α]D20=-9.8 (c 1.85, CH2Cl2)Source of chirality: (S)-(+)-leucineAbsolute configuration: S,S

(2R)-2-(2-{2-[(2R)-1-Hydroxydecan-2-yloxy]ethoxy}ethoxy)decyl dihydrogenphosphateC24H51O8PEe >97%[α]D27=-5.2 (c 1.74, CH2Cl2)Source of chirality: (R)-(+)-2-hydroxydecanoic acidAbsolute configuration: R,R

(2S)-1-(2-{2-[(2S)-2-Hydroxydecyloxy]ethoxy}ethoxy)decan-2-yl dihydrogenphosphateC24H51O8PEe >97%[α]D27=+9.8 (c 2.29, CH2Cl2)Source of chirality: (S)-(+)-2-hydroxydecanoic acidAbsolute configuration: S,S

(2S,15S)-15-Hydroxy-4,7,10,13-tetraoxahexadecan-2-yl dihydrogenphosphateC12H27O9PEe >97%[α]D23=+8.75 (c 4.16, CH2Cl2)Source of chirality: (S)-(−)-ethyl lactateAbsolute configuration: S,S

(4S,17S)-17-Hydroxy-2,19-dimethyl-6,9,12,15-tetraoxaeicosan-4-yl dihydrogenphosphateC18H39O9PEe >97%[α]D23=-11.4 (c 2.47, CH2Cl2)Source of chirality: (S)-(+)-leucineAbsolute configuration: S,S

(9S,22S)-22-Hydroxy-11,14,17,20-tetraoxatriacontan-9-yl dihydrogenphosphateC26H55O9PEe >97%[α]D24=+8.1 (1.46, CH2Cl2)Source of chirality: (S)-(+)-2-hydroxydecanoic acidAbsolute configuration: S,S