Synthesis of new chiral 1,4-morpholin-2,5-dione derivatives and evaluation as α-glucosidase inhibitors. Part 3

A series of chiral 1,4-morpholin-2,5-dione derivatives were synthesized starting from chiral synthons 1 and 2, monolactim ethers derived from l-valine, and the absolute configurations of the new stereocentres were assigned. The substrates investigation behave as noncompetitive inhibitors against α-glucosidases and are inactive towards β-glucosidase, α-mannosidase and α-galactosidase. Three of these substrates show very good and specific inhibition abilities towards α-glucosidase.

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(3R,6S)-3-(4′-Benzyloxy-(2′E)-butenyl)-6-methyl-4-[(S)-phenethyl]-morpholine-2,5-dioneC24H27NO4[α]D = −207 (c 0.4, CHCl3)Source of chirality: (S)-phenylethylamineAbsolute configuration: (3R,6S)

(3R,6S,2′S,3′S)-3-(4′-benzyloxy-2′,3′-dihydroxybutyl)-6-methyl-4-[(S)-phenethyl]-morpholine-2,5-dioneC24H29NO6[α]D = +13.5 (c 2, CHCl3)Source of chirality: (S)-phenylethylamineAbsolute configuration: (3R,6S,2′S,3′S)

(3R,6S,2′R,3′R)-3-(4′-benzyloxy-2′,3′-dihydroxybutyl)-6-methyl-4-[(S)-phenethyl]-morpholine-2,5-dioneC24H29NO6[α]D = −10.6 (c 0.5, CHCl3)Source of chirality: (S)-phenylethylamineAbsolute configuration: (3R,6S,2′R,3′R)

(3R,5R,1′R)-5-(2′-Benzyloxy-1′-hydroxyethyl)-3-[(S)-phenylethylamino]-dihydro-furan-2-oneC21H25NO4[α]D = −65.6 (c 0.7, CHCl3)Source of chirality: (S)-phenylethylamineAbsolute configuration: (3R,5R,1′R)

(3S,6R)-3-(4′-benzyloxy-(2′Z)-butenyl)-6-methyl-4-[(S)-phenethyl]-morpholine-2,5-dioneC24H27NO4[α]D = +84.8 (c 0.9, CHCl3)Source of chirality: (S)-phenylethylamineAbsolute configuration: (3S,6R)

(3S,5S,1′S)-5-(2′-benzyloxy-1′-hydroxyethyl)-3-[(S)-phenylethylamino]-dihydro-furan-2-oneC21H25NO4[α]D = −18.7(c 0.6 , CHCl3)Source of chirality: (S)-phenylethylamineAbsolute configuration: (3S,5S,1′S)

(3S,5R,1′R)-5-(2′-Benzyloxy-1′-hydroxyethyl)-3-[(S)-phenylethylamino]-dihydro-furan-2-oneC21H25NO4[α]D = −94.6 (c 0.5, CHCl3)Source of chirality: (S)-phenylethylamineAbsolute configuration: (3S,5R,1′R)

(3S,5S,1′R)-5-(2′-benzyloxy-1′-hydroxyethyl)-3-[(S)-phenylethylamino]-dihydro-furan-2-oneC21H25NO4[α]D = −63.7 (c 0.4, CHCl3)Source of chirality: (S)-phenylethylamineAbsolute configuration: (3S,5S,1′R)