Analogues of insulin secretagogue (2S,3R,4S)-4-hydroxyisoleucine: synthesis by 1,3-dipolar cycloaddition reactions of chiral nitrones to alkenes

(2S,3R,4S)-4-Hydroxyisoleucine, found in fenugreek, is an insulin secretagogue molecule. Non-natural analogues of (2S,3R,4R)- and (2R,3S,4S)-4-hydroxyisoleucine were efficiently prepared by 1,3-dipolar cycloaddition reactions of chiral nitrones derived from either (−)- or (+)-menthone to alkenes. The cycloadducts, obtained via the exo-approach of the alkenes to the nitrone’s less hindered face, led after a reductive step and cleavage of the chiral auxiliary, to enantiopure non-natural amino acids in good overall yield.

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(1S,2S,2′S,3′R,3′aS,5R)-3′-Ethyl-2′-(hydroxymethyl)-2-isopropyl-5,5′-dimethyl-3′,3′a-dihydro-2′H-spiro[cyclohexane-1,6′-imidazo[1,5-b]isoxazol]-4′(5′H)-oneC18H32N2O3[α]D = +62 (c 1.0, CH2Cl2)Source of chirality: (−)-menthoneAbsolute configuration: (1S,2S,2′S,3′R,3′aS,5R)

(1S,2S,2′R,3′S,3′aS,5R)-2′-Ethyl-3′-(hydroxymethyl)-2-isopropyl-5,5′-dimethyl-3′,3′a-dihydro-2′H-spiro[cyclohexane-1,6′-imidazo[1,5-b]isoxazol]-4′(5′H)-oneC18H32N2O3[α]D = +29 (c 1.0, CH2Cl2)Source of chirality: (−)-menthoneAbsolute configuration: (1S,2S,2′R,3′S,3′aS,5R)

(1S,2S,2′S,3′S,3′aS,5R)-2′,3′-Bis(methoxymethyl)-2-isopropyl-5,5′-dimethyl-3′,3′a-dihydro-2′H-spiro[cyclohexane-1,6′-imidazo[1,5-b]isoxazol]-4′(5′H)-oneC19H34N2O4[α]D = +26 (c 1.0, CH2Cl2)Source of chirality: (−)-menthoneAbsolute configuration: (1S,2S,2′S,3′S,3′aS,5R)

(3S,5R,6S,9R)-3-[(1R,2S)-1-Ethyl-2,3-dihydroxypropyl]-6-isopropyl-1,9-dimethyl-1,4-diazaspiro[4.5]decan-2-oneC18H34N2O3[α]D = +8 (c 1.0, CH2Cl2)Source of chirality: (−)-menthoneAbsolute configuration: (3S,5R,6S,9R)-3-(1R,2S)

(3S,5R,6S,9R)-3-[(1S,2R)-2-Hydroxy-1-(hydroxymethyl)butyl]-6-isopropyl-1,9-dimethyl-1,4-diazaspiro[4.5]decan-2-oneC18H34N2O3[α]D = +10 (c 1.0, CH2Cl2)Source of chirality: (−)-menthoneAbsolute configuration: (3S,5R,6S,9R)-3-(1S,2R)

(3S,5R,6S,9R)-3-[(1S,2S)-2-Hydroxy-3-methoxy-1-(methoxmethyl)propyl]-6-isopropy-1,9-dimethyl-1,4-diazaspiro[4,5]decan-2-oneC19H36N2O4[α]D = +4 (c 1.0, CH2Cl2)Source of chirality: (−)-menthoneAbsolute configuration: (3S,5R,6S,9R)-3-(1S,2S)

(2S,3R,4S)-2-Amino-3-ethyl-4,5-dihydroxy-pentanoic acidC7H15NO4[α]D = −7 (c 1.0, H2O)Source of chirality: (−)-menthoneAbsolute configuration: (2S,3R,4S)

(2S,3S,4R)-2-Amino-4-hydroxy-3-(hydroxymethyl)-hexanoic acidC7H15NO4[α]D = −31 (c 0.4, H2O)Source of chirality: (−)-menthoneAbsolute configuration: (2S,3S,4R)

(2S,3S,4S)-2-Amino-4-hydroxy-5-methoxy-3-(methoxymethyl)-pentanoic acidC8H17NO5[α]D = +5 (c 1.0, CH2Cl2)Source of chirality: (−)-menthoneAbsolute configuration: (2S,3S,4S)

(1R,2R,2′R,3′S,3′aR,5S)-3′-Ethyl-2′-(hydroxymethyl)-2-isopropyl-5,5′dimethyl-3′,3′a-dihydro-2′H-spiro[cyclohexane-1,6′-imidazo[1,5-b]isoxazol]-4′(5′H)-oneC18H32N2O3[α]D = −61 (c 1.0, CH2Cl2)Source of chirality: (+)-menthoneAbsolute configuration: (1R,2R,2′R,3′S,3′aR,5S)

(1R,2R,2′S,3′R,3′aR,5S)-2′- Ethyl-3′-(hydroxymethyl)-2-isopropyl-5,5′-dimethyl-3′,3′a-dihydro-2′H-spiro[cyclohexane-1,6′-imidazo[1,5-b]isoxazol]-4′(5′H)-oneC18H32N2O3[α]D = −27 (c 1.0, CH2Cl2)Source of chirality: (+)-menthoneAbsolute configuration: (1R,2R,2′S,3′R,3′aR,5S)

(1R,2R,2′R,3′R,3′aR,5S)-2′,3′-Bis(methoxymethyl)-2-isopropyl-5,5′-dimethyl-3′,3′a-dihydro-2′H-spiro[cyclohexane-1,6′-imidazo[1,5-b]isoxazol]-4′(5′H)-oneC19H34N2O4[α]D = −26 (c 1.0, CH2Cl2)Source of chirality: (+)-menthoneAbsolute configuration: (1R,2R,2′R,3′R,3′aR,5S)

(3R,5S,6R,9S)-3-[(1S,2R)-1-Ethyl-2,3-dihydroxypropyl]-6-isopropyl-1,9-dimethyl-1,4-diazaspiro[4.5]decan-2-oneC18H34N2O3[α]D = −9 (c 1.0, CH2Cl2)Source of chirality: (+)-menthoneAbsolute configuration: (3R,5S,6R,9S)-3-(1S,2R)

(3R,5S,6R,9S)-3-[(1R,2S)-2-Hydroxy-1-(hydroxymethyl)butyl]-6-isopropyl-1,9-dimethyl-1,4-diazaspiro[4.5]decan-2-oneC18H34N2O3[α]D = −10 (c 1.0, CH2Cl2)Source of chirality: (+)-menthoneAbsolute configuration: (3R,5S,6R,9S)-3-(1R,2S)

(3R,5S,6R,9S)-3-[(1R,2R)-2-Hydroxy-3-methoxy-1-(methoxymethyl)propyl]-6-isopropyl-1,9-dimethyl-1,4-diazaspiro[4.5]decan-2-oneC19H36N2O4[α]D = −4 (c 1.0, CH2Cl2)Source of chirality: (+)-menthoneAbsolute configuration: (3R,5S,6R,9S)-3-(1R,2R)

(2R,3S,4R)-2-Amino-3-ethyl-4,5-dihydroxy-pentanoic acidC7H15NO4[α]D = +7 (c 1.0, H2O)Source of chirality: (+)-menthoneAbsolute configuration: (2R,3S,4R)

(2R,3R,4S)-2-Amino-4-hydroxy-3-(hydroxymethyl)-hexanoic acidC7H15NO4[α]D = +28 (c 1.0, H2O)Source of chirality: (+)-menthoneAbsolute configuration: (2R,3R,4S)

(2R,3R,4R)-2-Amino-4-hydroxy-5-methoxy-3-(methoxymethyl)-pentanoic acidC8H17NO5[α]D = −5 (c 1.0, H2O)Source of chirality: (+)-menthoneAbsolute configuration: (2R,3R,4R)