Proline-DeriVed Peptide Mimetics
MHz, protons located at the same side of the ring plane as H-3a
are designated as â-protons) δ 1.43 (s, 4.5H, t-Bu, conf.), 1.45 (s,
4.5H, t-Bu, conf.), 1.49-1.57 (m, 2H, H-4â, H-3), 1.59-1.67 (m,
1H, H-4R), 2.12-2.24 (m, 2H, H-3′, H-5â), 2.45 (ddddd, J ) 11.0,
11.0, 4.4, 2.1, 2.1 Hz, 0.5H, H-3a, conf.), 2.56 (ddddd, J ) 11.0,
11.0, 4.4, 2.1, 2.1 Hz, 0.5H, H-3a, conf.), 2.66 and 2.68 (2 × dddd,
each: J ) 16.4, 12.1, 10.8, 4.9, 1H, H-5R, 2 conf.), 3.37 (dd, J )
16.5, 6.2 Hz, 0.5H, H-8â, conf.), 3.37 (dd, J ) 9.0, 8.9 Hz, 0.5H,
H-2, conf.), 3.42 (dd, J ) 9.0, 8.9 Hz, 0.5H, H-2, conf.), 3.43 (dd,
J ) 16.5, 6.2 Hz, 0.5H, H-8â, conf.), 3.64 (ddd, J ) 10.5, 9.0, 3.6
Hz, 0.5H, H-2′, conf.), 3.66 (d, J ) 17.4 Hz, 0.5H, NCH2, conf.),
3.71 (s, 1.5H, OCH3, conf.), 3.72 (ddd, J ) 10.5, 9.0, 3.6 Hz, 0.5H,
H-2′, conf.), 3.73 (s, 1.5H, OCH3, conf.), 3.99 (d, J ) 17.0 Hz,
0.5H, NCH2, conf.), 4.31 (d, J ) 17.0 Hz, 0.5H, NCH2, conf.),
4.64 (d, J ) 17.4 Hz, 0.5H, NCH2, conf.), 4.64 (dd, J ) 16.5, 10.8
Hz, 0.5H, H-8R), 4.67 (d, J ) 2.1 Hz, 0.5H, H-10a, conf.), 4.77
(d, J ) 2.1 Hz, 0.5H, H-10a, conf.), 4.78 (dd, J ) 16.5, 10.8 Hz,
0.5H, H-8R), 5.70 (2 × ddd, each: J ) 10.8, 10.8, 4.9 Hz, 1H,
H-6), 5.80 (2 × ddd, J ) 10.8, 10.8, 6.2 Hz, 1H, H-7); 13C NMR
δ 23.8, 23.9 (C-5, conf.), 28.2, 28.4 (C(CH3)3, conf.), 29.7, 30.2
(C-3), 31.5, 31.7 (C-4, conf.), 39.3, 40.7 (C-3a, conf.), 45.2, 45.7
(C-8), 46.0, 46.5 (C-2, conf.), 49.2, 50.8 (NCH2, conf.), 52.0
(OCH3), 58.4, 58.5 (C-10a, conf.), 79.6, 79.7 (C(CH3)3, conf.),
125.2, 126.0 (C-6, conf.), 130.1, 130.7 (C-7, conf.), 154.1, 154.8
(COOtBu, conf.), 169.8, 170.1 (COOCH3, conf.), 172.6, 173.0 (C-
10, conf.); EIMS 352 [M+]. Anal. Calcd for C18H28N2O5 × 0.5
H2O (352.43): C, 59.82; H, 8.09; N, 7.75. Found: C, 59.72; H,
8.06; N, 7.88.
tert-Butyl (3aR,8aS)-7-[2-(Methylamino)-2-oxoethyl)]-8-oxo-
3,3a,6,7,8,8a-hexahydropyrrolo[2,3-c]azepine-1(2H)-carboxy-
late (3a). Compounf 11a (4.4 mg, 0.0136 mmol, see Supporting
Information) was dissolved at room temperature in a solution of
methyl amine in EtOH (1 mL, 8.03 M). The reaction mixture was
stirred for 1 h and evaporated. The residue was purified by flash
chromatography (CH2Cl2-MeOH 95:5) to give 3a (2.9 mg, 66%)
as a colorless oil: [R]2D0 -108.6° (c ) 0.158, CHCl3); IR (film)
3317, 1694, 1681, 1675 cm-1; 1H NMR δ 1.42 (s, 4.5H, t-Bu, first
conf.), 1.48 (s, 4.5H, t-Bu, second conf.), 1.60-1.76 (m, 1H, H-3),
2.10 (ddd, J ) 11.7, 5.9, 5.9 Hz, 1H, H-3′), 2.77 (d, J ) 5.0 Hz,
3H, HNCH3), 2.78-2.90 (m, 1H, H-3a), 3.36-3.48 (m, 1H, H-2),
3.60-3.74 (m, 1.5 H, H-2′/H-6), 3.79 (dd, J ) 10.6, 8.5 Hz, 0.5H,
H-2′), 4.01 (d, J ) 15.3 Hz, 1H, NCH2, conf.), 4.12 (d, J ) 15.3
Hz, 0.5H, NCH2, conf.), 4.21 (d, J ) 15.3 Hz, 0.5H, NCH2, conf.),
4.49-4.66 (m, H-6′/H-8a), 5.67-5.75 (m, 1H, H-5), 5.88 (ddd, J
) 11.4, 2.1, 2.1 Hz, 1H, H-4), 6.22 (brs, 0.4H, HNCH3, first conf.),
6.33 (brs, 0.6H, HNCH3, second conf.); 13C NMR δ 26.1, 26.2
(HNCH3, conf.), 28.2, 28.4 (C(CH3)3, conf.), 30.6, 31.2 (C-3, conf.),
42.0, 42.8 (C-3a, conf.), 46.5, 47.1 (C-2, conf.), 48.7, 48.8 (C-6,
conf.), 53.4, 53.5 (NCH2, conf.), 61.2, 61.3 (C-8a, conf.), 79.9, 80.1
(C(CH3)3, conf.), 125.1, 125.4 (C-5 or C-4, conf.), 130.6, 131.0
(C-4 or C-5, conf.), 154.1, 154.8 (COOtBu, conf.), 169.5 (CON-
HCH3), 172.0, 172.5 (C-8, conf.); APCI-MS 324 [M + 1]+. Anal.
Calcd for C16H25N3O4 (323.40): C, 59.43; H, 7.79; N, 12.99.
Found: C, 59.53; H, 7.83; N, 12.83.
6.8, 2.2 Hz, 0.7H, H-7, first conf.), 3.37 (ddd, J ) 12.4, 10.6, 6.9
Hz, 1H, H-2), 3.49 (ddd, J ) 16.3, 6.8, 2.2 Hz, 0.3H, H-7, second
conf.), 3.64 (d, J ) 16.0 Hz, 0.7H, NCH2, first conf.), 3.69 (dd, J
) 10.6, 7.6 Hz, 0.7H, H-2′, first conf.), 3.72 (ddd, J ) 16.2, 8.8,
2.2 Hz, 0.3H, H-7′, second conf.), 3.72 (d, J ) 14.5 Hz, 0.3H,
NCH2, second conf.), 3.81 (dd, J ) 10.6, 7.6 Hz, 0.3H, H-2′, second
conf.), 4.29 (d, J ) 14.5 Hz, 0.3 H, NCH2, second conf.), 4.49 (d,
J ) 7.8 Hz, 0.3 H, H-9a, second conf.), 4.55 (d, J ) 8.2 Hz, 0.7
H, H-9a, first conf.), 4.57 (d, J ) 16.0 Hz, 0.7 H, NCH2, first conf.),
5.69-5.84 (m, 1H, H-4/H-5), 6.59 (brs, 0.3H, HNCH3, second
conf.), 6.74 (brs, 0.7H, HNCH3, first conf.); 13C NMR δ 26.1, 26.2
(HNCH3, conf.), 28.2, 28.4 (C(CH3)3, conf.), 29.5, 30.3 (C-6, conf.),
33.3, 33.5 (C-3, conf.), 43.6, 44.9 (C-3a, conf.), 45.8, 46.3 (C-2,
conf.), 49.2, 49.3 (C-7, conf.), 52.7, 53.0 (NCH2, conf.), 62.4, 63.4
(C-9a, conf.), 79.5, 80.0 (C(CH3)3, conf.), 130.5, 131.1 (C-5, conf.),
133.3, 134.4 (C-4, conf.), 154.6 (COOtBu), 169.3 (COOCH3),
173.6, 174.6 (C-9, conf.); EIMS 337 [M+]. Anal. Calcd for
C17H27N3O4 (337.42): C, 60.51; H, 8.07; N, 12.45. Found: C,
60.48; H, 7.98; N, 12.36.
tert-Butyl (3aR,10aS)-9-[2-(Methylamino)-2-oxoethyl)]-10-
oxo-3,3a,6,7,8,9,10,10a-octahydropyrrolo[2,3-c]azonine-1(2H)-
carboxylate (3c). Aminolysis of 11c (3.0 mg, 0.0085 mmol) was
analogously performed with methyl amine in EtOH (1 mL, 8.03
M) as described for 11a. Reaction time: 1 h. Flash chromatography
(CH2Cl2-MeOH 95:5) gave 3c (3.0 mg, 100%) as a colorless oil:
[R]2D0 -73.7° (c ) 0.45, CHCl3); IR (film) 3361, 1678, 1657 cm-1
;
1H NMR (600 MHz, protons located at the same side of the ring
plane as H-3a are designated as â-protons) δ 1.35-1.43 (m, 1H,
H-7R), 1.38 (s, 1.3H, t-Bu), 1.46 (s, 7.7H, t-Bu), 1.85 (dddd, J )
12.0, 12.0, 12.0, 7.8 Hz, 1H, H-3R), 1.88-1.96 (m, 1H, H-6â),
1.91-2.00 (m, 1H, H-7â), 1.88-2.05 (m, 1H, H-6R), 2.19 (ddd, J
) 12.0, 7.1, 5.6 Hz, 1H, H-3â), 2.78 (d, J ) 4.6 Hz, 3 H, HNCH3),
3.07 (dddd, J ) 12.0, 8.3, 7.1, 6.6 Hz, 1H, H-3R), 3.12 (ddd, J )
14.5, 2.8. 2.8 Hz, 1H, H-8â), 3.44 (ddd, J ) 12.0, 10.6, 5.6 Hz,
1H, H-2), 3.48 (d, J ) 16.3 Hz, 1H, NCH2), 3.69 (dd, J ) 14.5,
14.5 Hz, 1H, H-8R), 3.72 (dd, J ) 10.6, 7.8 Hz, 1H, H-2′), 4.26
(d, J ) 8.3 Hz, 1H, H-10a), 4.66 (d, J ) 16.3 Hz, 1H, NCH2),
5.60 (dddd, J ) 10.9, 10.9, 5.7, 1.2 Hz, 1H, H-5), 5.69 (dd, J )
10.9, 6.6 Hz, 1H, H-4), 6.96 (brs, 0.15H, HNCH3), 7.22 (brs, 0.85H,
HNCH3); 13C NMR δ 23.6 (C-6), 26.4 (HNCH3), 28.0 (C-7), 28.4
(C(CH3)3), 33.6 (C-3), 40.7 (C-3a), 45.0 (C-8), 47.0 (C-2), 49.0
(NCH2), 62.4 (C-10a), 80.3 (C(CH3)3), 131.7 (C-5, conf.), 133.4
(C-4), 154.9 (COOtBu), 169.0 (COONHCH3), 174.0 (C-10, conf.);
EIMS 351 [M+]. Anal. Calcd for C18H29N3O4 (351.45): C, 61.52;
H, 8.32; N, 11.96. Found: C, 61.32; H, 8.29; N, 11.88.
tert-Butyl (3aS,9aS)-8-[2-(Methylamino)-2-oxoethyl)]-9-oxo-
2,3,3a,4,7,8,9,9a-octahydro-1H-pyrrolo[2,3-c]azocine-1-carboxy-
late (3d). Aminolysis of 11d (4.0 mg, 0.0118 mmol) was
analogously performed with methyl amine in EtOH (1 mL, 8.03
M) as described for 11a. Reaction time: 1 h. Column chromatog-
raphy (CH2Cl2-MeOH 97:3) gave 3d (3.7 mg, 93%) as a colorless
oil: [R]2D0 -200.9° (c ) 0.492, CHCl3); IR (film) 3366, 1690,
1
1667 cm-1; H NMR δ 1.39 (s, 1.8H, t-Bu, first conf.), 1.46 (s,
7.2H, t-Bu, second conf.), 1.61-1.75 (m, 1H, H-3), 1.90-2.05 (m,
2H, H-3′/H-3a), 2.33-2.45 (m, 2H, H-4/H-4′.), 2.75 and 2.77 (2×
d, J ) 4.9 and 4.7 Hz, 3H, HNCH3, conf.), 3.38 (ddd, J ) 11.7,
10.6, 5.3 Hz, 1H, H-2), 3.42 and 3.59 (2× dd, J ) 15.0, 7.3 Hz
and 15.7, 6.6 Hz, 1H, H-7, 2 conf.), 3.62 (d, J ) 16.2 Hz, 0.8 H,
NCH2, second conf.), 3.66 and 3.79 (2× dd, each J ) 10.7, 7.9
Hz, 1H, H-2′, 2 conf.), 3.97 (d, J ) 14.5 Hz, 0.2 H, NCH2, first
conf.), 4.03 (d, J ) 14.5 Hz, 0.2 H, NCH2, first conf.), 4.39 and
4.48 (2× dd, J ) 15.0, 9.1 Hz and 15.7, 9.2 Hz, 1, H-7′, 2 conf.),
4.52 (d, J ) 16.2 Hz, 0.8 H, NCH2, second conf.), 4.52 (d, J ) 9.1
Hz, 1 H, H-9a), 5.87-6.02 (m, 2H, H-5/H-6), 6.64 (s, 0.2H,
HNCH3, first conf.), 6.92 (s, 0.8H, HNCH3, second conf.); 13C NMR
δ 26.0, 26.1 (HNCH3, conf.), 28.3, 28.4 (C(CH3)3, conf.), 31.2,
31.6, (C-4, conf.) 33.1, 33.4 (C-3, conf.), 41.4 (C-3a), 45.2, 45.6
(C-7, conf.), 46.1, 46.6 (C-2, conf.), 51.9, 52.6 (NCH2, conf.), 64.4,
tert-Butyl (3aR,9aS)-8-[2-(Methylamino)-2-oxoethyl)]-9-oxo-
2,3,3a,6,7,8,9,9a-octahydro-1H-pyrrolo[2,3-c]azocine-1-carboxy-
late (3b). Aminolysis of 11b (8.4 mg, 0.0248 mmol) was
analogously performed with methyl amine in EtOH (2 mL, 8.03
M) as described for 11a. Reaction time: 4 h. Column chromatog-
raphy (CH2Cl2-MeOH 97:3) furnished 3b (6.9 mg, 82%) as a
colorless oil: [R]2D0 -79.3° (c ) 0.442, CHCl3); IR (film) 3329,
1
1695, 1668 cm-1; H NMR δ 1.39 (s, 2.7H, t-Bu, second conf.),
1.46 (s, 6.3H, t-Bu, first conf.), 1.79 (dddd, J ) 12.4, 12.4, 12.4,
7.6 Hz, 0.3H, H-3, second conf.), 1.83 (dddd, J ) 12.4, 12.4, 12.4,
7.6 Hz, 0.7H, H-3, first conf.), 2.16 (ddd, J ) 12.4, 6.9, 6.3 Hz,
0.3H, H-3′, second conf.), 2.18 (ddd, J ) 12.4, 6.9, 6.3 Hz, 0.7H,
H-3′, first conf.), 2.29-2.50 (m, 2H, H-6/H-6′), 2.78 (d, J ) 4.6
Hz, 3H, HNCH3), 2.86-2.97 (m, 1H, H-3a), 3.29 (ddd, J ) 15.9,
J. Org. Chem, Vol. 72, No. 24, 2007 9111