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

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.

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

References

1 Giannis A. Kolter T. Angew. Chem., Int. Ed. Engl.  1993,  32:  1244 ; Angew. Chem. 1993, 105, 1303

2 Gante J. Angew. Chem. Int. Ed.  1994,  33:  1699 ; Angew. Chem. Engl. 1994, 106, 1780

3 Freidinger RM. J. Org. Chem.  1985,  50:  3631 

4 Wolfe MS. Dutta D. Aubé J. J. Org. Chem.  1997,  62:  654 

5a Schuster M. Blechert S. Angew. Chem. Int. Ed.  1997,  36:  2036 ; Angew. Chem. 1997, 109, 2124

5b Fürstner A. Angew. Chem. Int. Ed.  2000,  39:  3012 ; Angew. Chem. 2000, 112, 3140

6a Miller SJ. Blackwell HE. Grubbs RH. J. Am. Chem. Soc.  1996,  118:  9606 

6b Piscopio AD. Miller JF. Koch K. Tetrahedron Lett.  1999,  55:  8189 

6c For a review on RCM and peptide mimics see: Philipps AJ. Abell AD. Aldrichimica Acta  1999,  32:  75 

6d Creighton CJ. Reitz AB. Org. Lett.  2001,  3:  893 

6e Vo-Thanh G. Boucard V. Sauriat-Dorizon H. Guibé F. Synlett  2001,  1:  37 

6f Reichwein JF. Wels B. Kruijtzer JAW. Versluis C. Liskamp RMJ. Angew. Chem. Int. Ed.  1999,  38:  3684 ; Angew. Chem. 1999, 111, 3906

6g Reichwein JF. Versluis C. Liskamp RMJ. J. Org. Chem.  2000,  65:  6187 

For examples see:

7a Seebach D. Matthews JL. Chem Commun.  1997,  2015 

7b Apella DH. Christianson LA. Klein DA. Klein DR. Powell DR. Huang X. Barchi JJ. Gellmann SH. Nature (London)  1997,  387:  381 

8a Ede NJ. Rae JD. Hearn MTW. Tetrahedron Lett.  1990,  31:  6071 

8b Weber K. Gmeiner P. Synlett  1998,  885 

8c Michel D. Waibel R. Gmeiner P. Heterocycles  1999,  51:  365 

8d Lehmann T. Michel D. Glänzel M. Waibel R. Gmeiner P. Heterocycles  1999,  51:  1389 

9 Thomas C. Ohnmacht U. Niger M. Gmeiner P. Bioorg. Med. Chem. Lett.  1998,  8:  2885 

10 Chiu S. Paulose CS. Mishra RK. Science (Washington D.C.)  1981,  214:  1261 

11 Weber K. Ohnmacht U. Gmeiner P. J. Org. Chem.  2000,  65:  7406 

12 Hoffmann T. Lanig H. Waibel R. Gmeiner P. Angew. Chem. Int. Ed.  2001,  40:  3361 ; Angew. Chem. 2001, 113, 3465

13

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

14 Fukuyama T. Jow C.-K. Cheung M. Tetrahedron Lett.  1995,  36:  6373 

15a Reichwein JF. Liskamp RMJ. Eur. J. Org. Chem.  2000,  2335 

15b Reichwein JF. Liskamp RMJ. Tetrahedron Lett.  1998,  39:  1243 

16a Schwab P. Grubbs RH. Ziller JW. J. Am. Chem. Soc.  1996,  118:  100 

16b Scholl M. Ding S. Lee CW. Grubbs RH. Org. Lett.  1999,  1:  953 

17 Alkene Metathesis in Organic Synthesis: Fürstner A. Top. Organomet. Chem.  1998,  1:  37 

18

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: R_f 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: R_f 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: R_f 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: R_f 0.13 (ligroin/EtOAc 6:4).

19 Trnka TM. Grubbs RH. Acc. Chem. Res.  2001,  34:  18