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Synlett 2002(6): 1014-1016
DOI: 10.1055/s-2002-31916
LETTER
© Georg Thieme Verlag Stuttgart · New York

Short and Efficient Synthesis of Homo-Freidinger Lactams: An Olefin
Metathesis Approach Towards Conformationally Restricted β-Amino Acid Analogues

Tobias Hoffmann, Peter Gmeiner*
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstr. 19, 91052 Erlangen, Germany
Fax: +49(9131)8522585; e-Mail: gmeiner@pharmazie.uni-erlangen.de;
Further Information

Publication History

Received 27 March 2002
Publication Date:
07 February 2007 (online)

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Abstract

Peptide coupling of the N-allyl or N-homoallyl α-amino acid esters 6a-d with enantiomerically pure β-C-allylglycine gave access to the dienes 7a-d which were subjected to an olefin metathesis reaction. Thus, the novel lactam bridged peptide mimics 8a-d were obtained in good overall yield. Modifications in ring size and substitution pattern of the Homo-Freidinger lactams were demonstrated.

Key words

β-amino-acids - lactams - metathesis - peptide mimics - ruthenium

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Obtained from PepTechCorp, Cambridge, 02140 MA and used without further purification.

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General Procedure for the Ring-Closing Olefin Metathesis Reaction: Catalyst 9a (10 mol%) or 9b (5 mol%), was added to a 2 mM solution of the diene 8 in degassed 1,2-dichloro ethane under an atmosphere of dry nitrogen employing flame-dried glass ware. Subsequently, the mixture was heated to reflux until TLC indicated completion of the reaction. After evaporation of the solution the resulting residue was purified by column chromatography on Merck silica gel (230-400 mesh, ASTM) using freshly distilled solvents. All RCM-products were fully characterized by spectroscopic methods and microanalysis:
8a: colorless oil, [α]D 21 +5.3 (0.19, CHCl3). 1H NMR (360 MHz, CDCl3): δ 1.28 (t, J = 7.1 Hz, 3 H, CH 3 ), 1.43 (s, 9 H, tert-Bu), 2.35-2.46 (m, 3 H, H-5a,b/H-3a), 3.01 (dd, J = 12.4, 5.3 Hz, 1 H, H-3b), 3.78-3.89 (m, 1 H, H-8a), 4.00-4.10 (m, 1 H, H-4), 4.16 (d, J = 17.4 Hz, 1 H, α-CH 2 ), 4.20 (q, J = 7.2 Hz, 2 H, OCH 2 ), 4.24 (d, J = 17.4 Hz, 1 H, α-CH 2 ), 4.31-4.45 (m, 1 H, H-8b), 5.30 (d, J = 8.2 Hz, 1 H, NH), 5.48-5.66 (m, 1 H, CH=), 5.72-5.83 (m, 1 H, CH=). 13C NMR (CDCl3, 91 MHz): δ 14.1, 28.3, 29.8, 36.8, 48.9, 49.8, 52.6, 61.3, 79.2, 126.3, 128.5, 154.8, 169.2, 171.0. IR(film): 3324, 2977, 2931, 1747, 1712, 1700, 1643 cm-1. MS (EI):
m/z 326 [M+]. Anal. Calcd for C16H26N2O5: C, 58.88; H, 8.03; N, 8.58. Found: C, 59.05; H, 8.21; N, 8.43. TLC: Rf 0.12 (ligroin-EtOAc, 6:4).
8b: colorless oil, [α]D 22 -25.7 (0.07, CHCl3). 1H NMR (360 MHz, CDCl3): δ 1.39 (d, J = 7.1 Hz, 3 H, CH 3 ), 1.44 (s, 9 H, tert-Bu), 2.35-2.47 (m, 3 H, H-5a,b/H-3a), 2.95 (dd, J = 12.2, 5.5 Hz, 1 H, H-3b), 3.69 (s, 3 H, OCH 3 ), 3.82-3.95 (m, 1 H, H-8a), 4.05-4.15 (m, 2 H, H-8b/H-4), 5.30 (d, J = 8.5 Hz, 1 H, NH), 5.36 (q, J = 7.1 Hz, 1 H, α-CH), 5.45-5.55 (m, 1 H, CH=), 5.70-5.80 (m, 1H, CH=). 13C NMR (CDCl3, 91 MHz): δ = 14.8, 28.6, 29.4, 36.9, 47.7, 49.4, 52.1, 60.4, 79.3, 126.1, 128.9, 154.9, 160.4, 172.0. IR(film): 3318, 2978, 1741, 1708, 1641, 1502, 1475 cm-1. MS (EI): m/z 326 [M+]. Anal. Calcd for C16H26N2O5: C, 58.88; H, 8.03; N, 8.58. Found: C, 58.73; H, 8.11; N, 8.31. TLC: Rf 0.11 (ligroin-EtOAc 6:4).
8c: colorless oil, [α]D 20 +31.6 (0.19, CHCl3). 1H NMR (CDCl3, 360 MHz): δ 1.28 (t, J = 7.1 Hz, 3 H, CH 3 ), 1.42 (s, 9 H, tert-Bu), 1.67 (s, 3 H, CH 3 ), 2.35-2.40 (m, 3 H, H-5a,b/H-3a), 2.98 (dd, J = 12.4, 5.3 Hz, 1 H, H-3b), 3.64 (d, J = 17.8 Hz, 1 H, α-CH 2 ), 4.20 (q, J = 7.2 Hz, 2 H, OCH 2 ), 4.28 (d, J = 17.5 Hz, 1 H, α-CH 2 ), 4.75-4.95 (m, 2 H, H-8a,b), 5.24 (d, J = 8.5 Hz, 1 H, NH), 5.48-5.55 (m, 1 H, H-4), 5.55-5.60 (m, 1 H, CH=). 13C NMR (CDCl3, 91 MHz): δ 14.1, 19.9, 23.3, 28.4, 29.7, 36.9, 50.0, 56.3, 61.3, 79.2, 121.9, 135.2, 154.9, 169.3, 173.1. IR(film): 3340, 2978, 2935, 1745, 1708, 1646, 1504 cm-1. MS (EI): m/z 340 [M+]. Anal. Calcd for C17H28N2O5 × 1/4 H2O: C, 58.94; H, 8.14; N, 8.09. Found: C 58.87; H, 8.56; N, 7.57. TLC: Rf 0.18 (ligroin-EtOAc 1:1).
8d: colorless oil, [α]D 22 +9.2 (0.13, CHCl3). 1H NMR (DMSO-d 6, 360 MHz, 353 K): δ 1.20 (t, J = 7.1 Hz, 3 H, CH 3 ), 1.40 (s, 9 H, tert-Bu), 2.15-2.25 (m, 2 H, CH 2 ), 2.28-2.39 (m, 2 H, CH 2 ), 2.40-2.50 (m, 2 H, CH 2 ), 3.45-3.60 (m, 2 H, H-9a,b), 3.70-3.85 (m, 1 H, H-4), 3.97 (d, J = 17.0 Hz, 1 H, α-CH 2 ), 4.07 (d, J = 17.0 Hz, 1 H, α-CH 2 ), 4.11 (q, J = 7.1 Hz, 2 H, OCH 2 ), 5.62 (ddd, J = 8.5, 10.6, 8.5 Hz, 1 H, CH=), 5.76 (ddd, J = 8.1, 10.6, 8.1 Hz, 1 H, CH=), 6.28 (br s, 1 H, NH). 13C NMR (DMSO-d 6, 91 MHz): δ = 13.9, 26.0, 28.1, 31.3, 40.8, 49.6, 49.9, 50.3, 60.3, 79.1, 128.4, 130.2, 154.3, 169.3, 171.7. IR(film): 3385, 2979, 2933, 1747, 1706, 1630, 1487 cm-1. MS (EI): m/z 340 [M+]. Anal. Calcd for C17H28N2O5: C, 59.98; H, 8.29; N, 8.23. Found: C, 59.61; H, 8.48; N, 7.93. TLC: Rf 0.13 (ligroin/EtOAc 6:4).