An Efficient Synthesis of Conformationally Restricted Peptides Containing β-Aminocyclopropanecarboxylic Acids

Synlett

Volumn 1997, Issue 2, 1997, Pages 202-204

  Voigt, Johannes ^a   Noltemeyer, Mathias ^a   Reiser, Oliver ^a,b  

^a UNIVERSITY OF GÖTTINGEN   (Germany)

^b UNIVERSITY OF STUTTGART   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0002483946     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-1997-733     Document Type: Article

References (15)

1. Seebach, D.; Overhand, M.; Kühnle, F. N. M.; Martinoni, B.; Oberer, L.; Hommel, U.; Widmer, H. Helvetica Chim. Acta 1996, 79, 913-41 and cited references.
2. Lombardi, A.; Saviano, M.; Nastri, F.; Maglio, O.; Mazzeo, M.; Isernia, C.; Paolillo, L.; Pavone, V. Biopolymers 1996, 38, 693, (a) Blasio, B. D.; Lombardi, A.; Yang, X.; Redone, C.; Pavone, V. Biopolymers 1991, 31, 1181-1188. (b) Pavone, V.; Lombardi, A.; Yang, X.; Pedone, C.; Blasio, B. D. Biopolymers 1990, 30, 189-196.
3. Lombardi, A.; Saviano, M.; Nastri, F.; Maglio, O.; Mazzeo, M.; Isernia, C.; Paolillo, L.; Pavone, V. Biopolymers 1996, 38, 693, (a) Blasio, B. D.; Lombardi, A.; Yang, X.; Redone, C.; Pavone, V. Biopolymers 1991, 31, 1181-1188. (b) Pavone, V.; Lombardi, A.; Yang, X.; Pedone, C.; Blasio, B. D. Biopolymers 1990, 30, 189-196.
4. Lombardi, A.; Saviano, M.; Nastri, F.; Maglio, O.; Mazzeo, M.; Isernia, C.; Paolillo, L.; Pavone, V. Biopolymers 1996, 38, 693, (a) Blasio, B. D.; Lombardi, A.; Yang, X.; Redone, C.; Pavone, V. Biopolymers 1991, 31, 1181-1188. (b) Pavone, V.; Lombardi, A.; Yang, X.; Pedone, C.; Blasio, B. D. Biopolymers 1990, 30, 189-196.
5. Pavone, V.; Lombardi, A.; D'Auria, G.; Saviano, M.; Nastri, F.; Paolillo, L.; Blasio, B. D.; Pedone, C. Biopolymers 1992, 32, 173-183.
6. (a) Cannon, J. G.; Garst, J. E. J. Org. Chem. 1975, 40, 182-184.
7. (b) Shroff, C. C.; Stewart, W. S.; Uhm, S. J.; Wheeler, J. W. J. Org. Chem. 1971, 22, 3356-3361.
8. Paulini, K.; Reißig, H.-U. Liebigs Ann. Chem. 1991, 455-461.
9. (a) J. Voigt, J. Evanseck, O. Reiser, unpublished.
10. (b) C. Cabrele, A. Beck-Sickinger, O. Reiser, unpublished.
11. Paulini, K.; Reißig, H.-U. Liebigs Ann. Chem. 1994, 549-554.
12. 2).
13. Selected spectroscopical data, (+ ≅ positive, - ≅ negative signal in DEPT-135):9c: 1H NMR (250 MHz, CDCl3) O = 0.91 (d, 7 = 6.8 Hz, 3H1CH3), 1.11 (d, / = 6.5 Hz, 3H, CH3), 3.01-3.13 (m, IH. Ctf(CH3)2), 5.01 (d, J= 9.9 Hz, IH, NC//CH(CH3)2), 6.21-6.23 (m, 2H, pyrrole-H), 7.32-7.33 (m, 2H, pyrrole), 7.71-7.88 (m, 4H, phthalyl-H); 13C NMR (62.9 MHz, CDCl3) 8= 18.60(+,CH3), 20.41 (+, CH3), 27.30 (+, CH(CHj)2), 57.33 (+, NCHCH(CH3),), 113.53(+,C-pyrrole), 119.27 (+,C-pyrrole), 123.76 (+,C-phenyl), 131.18 (Cquat), 134.47 (+,C-phenyl), 165.08 (Cquai). 167.28 (Cquai); [ot|28 -185.0° (c = 0.65, CHCl3). 1Oc (signal doubling due to rotamers): 1H-NMR (25OMHz, CDCl3) 8 = 0.63 / 1.00(m, IH, 5-H), 0.84 /1.06 (m, 6H, 2 CH3), 2.66-3.13 (m, 2H, CMCH3I2 + 6-H), 3.23 / 3.64 (2s, 3H, OCH3), 4.01-4.12 (m, IH, 1-H), 4.55 / 4.59 (2d, 9H, NC//CH(CH3)2), 5.44-5.48 (m, 1H, 4-H), 6.48 / 6.90 (m, IH, 3-H), 7.71-7.86 (m, 4H, phthalyl-H); 13C-NMR (62.9 MHz, CDCI3) 8= 18.45 /18.66 (+), 20.42 / 20.84 (+), 23.92 / 24.21 (+), 27.16/ 27.87 (+), 29.69 (+), 33.34 (+), 43.11 /43.60 (+),51.74 /51.86 (+(,56.86/57.11 (+), 112.01 / 114.101+, C-pyrrole). 123.57/123.65 (+,C-pyrrole), 127.23/129.74(+), 130.96/131.07 (Cquai), 134.30/ 134.38 (+), 163.70/164.22 (Cquai), 166.98/ 167.43 (Cquai), 171.41 / 172.52 (Cquat); [«128 -243.0° (c = 0.2, CHCl3). lie (signal doubling due to rotamers): 1H NMR (250 MHz, CDCl3) 8 = 0.84-1.05 (m, 7H, 2 CH3 + 5-H), 2.74 / 2.91 (m. IH, 6-H), 3.06-3.31 (m, IH, C//(CH3)2), 3.61 / 3.74 (2s, 3H, OCH3), 4.57 /4.78 (2d, J= 10.3, 10.9 Hz, IH, NCWCH(CH3I2), 4.61-4.71 (m, IH, I-H), 5.51-5.59 (m, IH, 4-H), 6.61 /6.84 (2d, / = 4.1, 4.0 Hz, IH, 3-H), 7.70-7.86 (m, 4H, phthalyl-H); 11C NMR (62.9MHz, CDCl3)S= 18.75/ 19.37 (+), 19.99/20.29 (+), 24.27 / 24.89 (+), 26.89/27.28 (+), 29.75 (+), 32.69 (+), 43.54 (+), 51.83 / 52.14 (+), 57.27 / 58.92 (+), 113.63 /114.14 (+, C-pyrrole), 123.53 /123.62 (+, C-pyrrole), 127.64 /129.23 (+), 131.10/131.37 (Cquai), 134.24/ 134.38 (+), 164.76/165.78 (Cquai), 167.44/ 167.78 (Cquai), 172.13 / 172.51 (Cquai); [a]2g +73.1° (c = 1.3, CHCl3). 12 (signal doubling due to rotamers): 1H NMR (250 MHz, CDCl3) 8 = 0.84-1.22 (m, 7H, 5-H + 2 CH3). 1.38 (s, 9H, /Bu). 1.75-2.12(m, IH, CW(CH3J2), 2.76/2.85 (m, IH,6-H), 3.64/3.67 (2s, 3H, OCH3), 4.25 / 4.34 (m, !H, 1 -H), 4.53 / 4.64 (2d, JH. NCHCH(CH3J2), 5.56 (m, IH,4-H), 6.57/6.82 (m, IH, 3-H); 13C NMR (62.9 MHz, CDCl3) 8 = 16.89 /17.31 (+, CH3), 19.32 /19.76 (+, CH3), 24.25 / 24.38 (+), 28.18 (+, C(CH3J3), 29.70 / 30.84 (+), 31.57/ 32.45 (+), 43.23 / 43.42 (+), 51.90 / 52.02 (+, OCH3), 56.26 / 56.93 (+), 79.54 / 79.69 (Cquat), 113.20/113.95 (+), 128.01 / I29.I6(+), 155.56 (Cquat), 169.15/169.37 (Cquai), 172.48 (Cquat); MS (DCI-NH3) m/e 694 (3, 2M+NH3+H), 356 (100, M+NH,+H), 339 (60); 1«128 -114.7° (c = 0.7, CHCl3). 14 (signal doubling due to rotamers): 1H NMR (250 MHz, CDCl3) S = 0.79-1.20 ( m, 7H, 5-H+ 2CH3), 1.83-2.16 (m, IH. CH(CH3J2), 2.78/2.91 (m, IH, 6-H), 3.68 / 3.69 (2s, 3H, OCH3), 3.91 (m, 2H. glycyl-H). 4.29 /4.65 (m, IH, 1-H), 4.72/4.84 (m, IH, NCHCH(CH3J2), 5.10 (s, 2H, benzyl-H), 5.56 (m, IH, 4-H), 5.70 (m, IH, N-H), 6.66/6.81 (m, IH, 3-H), 6.89/7.01 (2bs, IH, N-H), 7.35 (m, 5H, phenyl-H); 13C NMR (62.9 MHz, CDCI3) ô= 17.37 /17.62 (+, CH3), 19.28 /19.62 (+,CH3), 24.27/24.81 (+), 29.72 / 30.61 (+), 31.61 / 32.42 (+). 43.20 / 43.65 (+), 44.28 (-), 52.02 / 52.20 (+, OCH3), 54.90 / 55.73 (+), 67.07 (-), 113.66/ 114.44(+), 128.03 (+), 128.12 (+), 128.45 (+), 129.06 (+), 136.09 (Cquat), 156.47 (Cquat), 168.23 (Cquat), 168.75 / 168.99 (Cquat), 172.44 (Cquat); MS (DCI-NH3) m/e 479 (100. M+NH3+H). 461 (9); I«|2B-97.1° (c = 0.4, CHCl3). 15: 1H NMR (250MHz, CDCl3) S = 0.82-1.01 (m, 12H, 4 CH3), 2.04-2.18 (m, 2H, 2 C//(CH3)2), 2.57-2.64 (m, 2H, cyclopropyl-H), 3.19-3.24 (m, IH, cyclopropyl-H), 3.75 (s, 3H, OCH3), 3.80-4.07 (m, 2H, Glycyl-H), 4.37-4.42 (m, IH, NCHCH(CH3)2), 4.98-5.04 (m, IH, NCHCH(CH3),), 5.08-5.22 (m.4H, benzyl-H), 5.74 (m, IH, N-H),6.71 (m, IH, N-H).6.93 (m, IH, N-H), 7.31 /7.36(2bs, IOH, phenyl-H), 9.00 (bs, IH, formyl-H); 11C NMR (62.9 MHz, CDCl3) 5 = 16.99 (+. CH3), 17.70 (+, CH3), 18.89 i-t-, CH3), 19.67 (+. CH3), 27.70 (+), 29.62 (+), 30.34 (+), 30.86 (+), 35.80 ( + ), 44.50 (-, C-glycine), 52.69 (+, OCH3), 55.72 (+), 57.73 <+). 67.15 (-). 67.22 (-), 128.05 (+), 128.16 (+), 128.49 (+), 128.61 (+, not all C-phenyl were resolved), 135.12 (Cquat), 136.09 (Cquai), 156.49 (Cquat), 162.03 (-*->. 166.50 (Cquat), 169.16 (Cquat), 170.84 (Cquat), 171.29 (Cquai). 173.65 (Cquat); MS (DCI-NH3) m/e 684 (36, M+NH3+H), 656 (I I. M-CHO+H), 576(23), 253 (100); -61.3° (c = 1.3, CHCl3).
14. 1H-NMR). The mixture was separated repeatedly by column chromatography (18×4 cm silica gel, hexanes / EtOAc 3:1, Rf(11c): 0.26, Rf(10c): 0.21), a typical run of 720 mg of the mixture afforded 126 mg of pure 11, 156 mg of pure 10 and 370 mg of a mixture of both isomers.
15. Atomic coordinates, bond lengths and angels, and thermal parameters can be obtained at the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ(UK), on quoting the full literalure citation and the reference number CSD 100073. The absolute configuration was assigned according to the known stereocenter at the α-amino acid part of the molecule.