Stereoselective synthesis and conformational analysis of unnatural tetrapeptides. Part 2

Stereoselective synthesis of unnatural tetrapeptides 20a and 20b, 21a and 21b and 30 and 31, containing two l-valine units and two unnatural α-amino acids (ornithine and modified aspartic acid), has been accomplished starting from the l-valine derived chiral synthon 1. Structural investigations of these non-proteinogenic peptides have been carried out on the acetamido derivatives using 1H NMR, IR spectroscopic techniques and a conformational analysis based on molecular dynamics (MD) and cluster analysis.

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(3R,6S)-1-Benzyl-3-(3-dibenzylaminobutyl)-5-ethoxy-1,6-dihydro-6-isopropylpyrazin-2-(3H)-oneC33H41N3O2[α]D = +41 (c 0.9, CHCl3)Source of chirality: l-valineAbsolute configuration: (2R,5S)

2-[(2R,5S)-4-Benzyl-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl]-N-[2-((2R,5S)-4-benzyl-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-3-oxopyrazin-2-yl)ethyl]acetamideC37H51N5O5[α]D = +28.4 (c 0.9, CHCl3)Source of chirality: l-valineAbsolute configuration: (2R,5S)

2-[(2R,5S)-4-Benzyl-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl]-N-[2-((2R,5S)-4-benzyl-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl)ethyl]acetamideC38H53N5O5[α]D = +7.1 (c 0.7, CHCl3)Source of chirality: l-valineAbsolute configuration: (2R,5S)

2-[(2R,5S)-4-Benzyl-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl]-N-[2-((2R,5S)-benzyl-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-3-oxopyrazin-2-yl)propyl]acetamideC38H53N5O5[α]D = +31.2 (c 2.2, CHCl3)Source of chirality: l-valineAbsolute configuration: (2R,5S)

2-[(2R,5S)-4-Benzyl-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl]-N-[2-((2R,5S)-4-benzyl-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl)propyl]acetamideC39H55N5O5[α]D = +9.7 (c 1.2, CHCl3)Source of chirality: l-valineAbsolute configuration: (2R,5S)

2-[(2R,5S)-6-Ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl]-N-[2-((2R,5S)-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-3-oxopyrazin-2-yl)ethyl]acetamideC23H39N5O5[α]D = +9.2 (c 0.2, CHCl3)Source of chirality: l-valineAbsolute configuration: (2R,5S)

2-[(2R,5S)-6-Ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl]-N-[2-((2R,5S)-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl)ethyl]acetamideC24H41N5O5[α]D = +12 (c 0.9, CHCl3)Source of chirality: l-valineAbsolute configuration: (2R,5S)

2-[(2R,5S)-6-Ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl]-N-[2-((2R,5S)-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-3-oxopyrazin-2-yl)propyl]acetamideC24H41N5O5[α]D = +33.8 (c 0.9,CHCl3)Source of chirality: l-valineAbsolute configuration: (2R,5S)

2-[(2R,5S)-6-Ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl]-N-[2-((2R,5S)-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-2-methyl-3-oxopyrazin-2-yl)propyl]acetamideC25H43N5O5[α]D = +5.5 (c 0.9, CHCl3)Source of chirality: l-valineAbsolute configuration: (2R,5S)

(2S,5R,11R,l4S)-5,11-Diacetyldiamino-3,8,13-triazo-2,14-diisopropyl-5-methyl-4,7,12-trioxo-pentadecan-1,15-dioic acid diethylesterC27H47N5O9[α]D = +38.5 (c 0.7, CHCl3)Source of chirality: l-valineAbsolute configuration: (2S,5R,11R,14S)

(2S,5R,11R,14S)-5,11-Diacetyldiamino-3,8,13-triazo-2,14-diisopropyl-5,11-dimethyl-4,7,12-trioxo-pentadecan-1,15-dioic acid diethylesterC28H49N5O9[α]D = +53.3 (c 0.4, CHCl3)Source of chirality: l-valineAbsolute configuration: (2S,5R,11R,14S)

(2S,5R,12R,15S)-5,12-Diacetyldiamino-3,8,14-triazo-2,15-diisopropyl-5-methyl-4,7,13-trioxo-hexadecan-1,16-dioic acid diethylesterC28H49N5O9[α]D = +34.1 (c 0.6, CHCl3)Source of chirality: l-valineAbsolute configuration: (2S,5R,11R,14S)

(2S,5R,12R,15S)-5,12-Diacetyldiamino-3,8,14-triazo-2,15-diisopropyl-5,12-dimethyl-4,7,13-trioxo-hexadecan-1,16-dioic acid diethylesterC29H51N5O9[α]D = +28.3 (c 0.9, CHCl3)Source of chirality: l-valineAbsolute configuration: (2S,5R,12R,15S)

(3S,6S)-1-Benzyl-3-methyl-3-(3-dibenzylaminobutyl)-5-ethoxy-1,6-dihydro-6-isopropylpyrazin-2-(3H)-oneC34H43N3O2[α]D = +5.3 (c 1.2, CHCl3)Source of chirality: l-valineAbsolute configuration: (3S,6S)

(3S,6S)-1-Benzyl-3-methyl-3-(3-aminopropyl)-5-ethoxy-1,6-dihydro-6-isopropylpyrazin-2-(3H)-oneC19H29N3O2[α]D = +13.2 (c 1.2, CHCl3)Source of chirality: l-valineAbsolute configuration: (3S,6S)

2-[(2R,5S)-4-Benzyl-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl]-N-[2-((2S,5S)-4-benzyl-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl)propyl]acetamideC39H55N5O5[α]D = +5.4 (c 0.8, CHCl3)Source of chirality: l-valineAbsolute configuration: (2R,5S,2S,5S)

2-[(2R,5S)-6-Ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-3-oxopyrazin-2-yl]-N-[2-((2S,5S)-6-ethoxy-2,3,4,5-tetrahydro-5-isopropyl-2-methyl-2-methyl-3-oxopyrazin-2-yl)propyl]acetamideC25H43N5O5[α]D = −19.9 (c 0.7, CHCl3)Source of chirality: l-valineAbsolute configuration: (2R,5S,2S,5S)

(2S,5R,12S,15S)-5,12-Diacetyldiamino-3,8,14-triazo-2,15-diisopropyl-5,12-dimethyl-4,7,13-trioxo-hexadecan-1,16-dioic acid diethylesterC29H51N5O9[α]D = +26.1 (c 0.5, CHCl3)Source of chirality: l-valineAbsolute configuration: (2S,5R,12S,15S)

(3R,6S)-(1-Benzyl-5-ethoxy-6-isopropyl-3-methyl-1,6-dihydro-pyrazin-2-yl)-acetic acid pentafluorophenyl esterC25H25F5N2O4[α]D = −31.5 (c 1, CHCl3)Source of chirality: l-valineAbsolute configuration: (3R,6S)

(3R,6S)-(1-Benzyl-5-ethoxy-6-isopropyl-3-methyl-1,6-dihydro-pyrazin-2-yl)-acetic acidC19H26N2O4[α]D = −14.8 (c 0.5, CHCl3)Source of chirality: l-valineAbsolute configuration: (3R,6S)

(3R,6S)-l-Benzyl-3-(2-dibenzylaminoethyl)-5-ethoxy-1,6-dihydro-6-isopropylpyrazin-2-(3H)-oneC32H39N3O2[α]D = +39.8 (c 1, CHCl3)Source of chirality: l-valineAbsolute configuration: (3R,6S)