Solution-Phase Synthesis of Oligopeptides
FULL PAPER
C17H17NO2: C 76.38, H 6.41, N 5.24; found: C 76.59, H 6.18, N 4.99. Ana-
lytical HPLC analysis: Chiralpack AD–H column (250ꢂ4 mm, Daicel),
eluent: iPrOH/hexane (0.8:99.2), flow rate: 0.5 mLminÀ1, UV detection
at 230 nm; tr (R enantiomer)=46.63 min: e.r.=94:6.
13C NMR (50 MHz, CDCl3, 258C, TMS): d=173.3, 166.8 (2C), 134.0
(2C), 131.7 (2C), 123.3 (2C), 101.1, 88.6, 51.5, 41.8, 33.0, 32.6, 21.6,
À0.23 ppm (3C); GC-MS: m/z (%): 357(24) [M+], 310 (36), 270 (22), 256
(100), 204(52), 130 (66), 102 (16), 73 (22); elemental analysis calcd (%)
for C19H23NO4Si: C 63.84, H 6.49, N 3.92; found: C 64.01, H 6.14, N 3.77.
Analytical HPLC: Chiracel OD-H column (250ꢂ4 mm, Daicel), eluent:
iPrOH/hexane (5:95), flow rate: 1 mLminÀ1, UV detection at 254 nm; tr
(R enantiomer)=10.58 min, e.r.=93:7.
The synthetic procedure illustrated above was also employed for the syn-
thesis of N-protected propargylic amines ent-2a, 2b, 2c, 2d, ent-2d, 2 f,
and 2g but in the case of 2d and ent-2d tributylphosphine was employed,
whereas for compounds 2e, ent-2e, 2h, 2i, ent-2i as well as for 2l di-tert-
butyl azodicarboxylate (DBAD) was utilized. For products 2b, 2c, 2e
and ent-2e a standard desilylative step was necessary before purification
by column chromatography. Yields, physical and spectral data of the new
compounds are reported below.
Methyl
(5S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)hept-6-ynoate
(ent-2e): Yield 56%; m.p. 58–618C; [a]2D1 =À5.09 (c=1.63 in Et2O). Ana-
lytical HPLC: Chiracel OD-H column (250ꢂ4 mm, Daicel), eluent:
iPrOH/hexane (5:95), flow rate: 1 mLminÀ1, UV detection at 254 nm; tr
(S enantiomer)=14.17 min, e.r.=94:6.
2-[(1S)-1-cyclohexylprop-2-yn-1-yl]-1H-isoindole-1,3ACTHUNRTGNEUNG(2H)-dione (ent-2a):
Yield 56%; oil; [a]2D3 =11.52 (c=1.50 in CHCl3); Analytical HPLC analy-
sis: Chiralpack AD–H column (250ꢂ4 mm, Daicel), eluent: iPrOH/
hexane (0.8:99.2), flow rate: 0.5 mLminÀ1, UV detection at 230 nm; tr (S
enantiomer)=53.06 min: e.r.=98:2.
2-{(1R)-1-[(1S)-1-(Benzyloxy)ethyl]prop-2-ynyl}-1H-isoindole-1,3ACHTUNGTRENNUNG(2H)-
dione (2 f): Yield 81%; oil; [a] 19 =À5.55 (c=1.33 in CHCl3); 1H NMR
D
(400 MHz, CDCl3, 258C, TMS): d= 7.92–7.60 (m, 4H; CH), 7.49–7.15
(m, 5H; CH), 5.13 (dd, 3J(H,H)=7.7 Hz, 4J
ACTHNUGTRENNUGN ACHTUNGTRENNNUG
4.79 (d, 2J
CH2O), 4.25 (dq, J
4J
N
ACHTUNGTRENNUNG
2-[(1S)-1-Isobutylprop-2-yn-1-yl]-1H-isoindole-1,3(2H)-dione (2b): Yield
85%; oil; [a] 2D2 =À10.52 (c=1.14 in dioxane); 1H NMR (200 MHz,
CDCl3, 258C, TMS): d=7.92–7.61 (m, 4H; CH), 5.21–5.05 (m, 1H;
CHN), 2.10–1.88 (m, 2H; CH2), 1.69–1.53 (m, 1H; CH), 0.94 (d, 3J-
3
3
ACHUTNGREN(NUG H,H)=7.7 Hz, JACHTNUGTRENNUNG
N
ACHTUNGTRENNUNG
13C NMR (100 MHz, CDCl3, 258C, TMS): d= 166.8 (2C), 137.2, 134.1
(2C), 131.5 (2C), 128.1 (2C), 127.5 (2C), 123.4 (3C), 78.6, 75.3, 73.4, 72.6,
45.5, 17.0 ppm; GC-MS: m/z (%): 274(4) [M+À45], 213(30), 185 (100),
128 (40), 91 (48), 76 (7); elemental analysis calcd (%) for C20H17NO3: C
75.22, H 5.37, N 4.39; found: C 75.53, H 5.11, N 4.65.
ACHTUNGTRENNUNG(H,H)=4.9 Hz, 3H; CH3), 0.91 (d, 3JACHTUNGTRNEN(GUN H,H)=4.9 Hz, 3H; CH3),
0.21 ppm (s, 9H; CH3); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=
166.9 (2C), 133.9 (2C), 131.4 (2C), 123.3 (2C), 101.9, 86.7, 41.9, 40.6, 27.7,
26.0, 25.1 (2C), 0.12 ppm (3C); GC–MS: m/z (%): 313(6) [M+], 298 (28),
270 (21), 256 (100), 204(70), 130 (55), 102 (19), 73 (24); elemental analy-
sis calcd (%) for C18H23NO2Si: C 68.97, H 7.40, N 4.47; found: C 69.49, H
7.65, N 4.19. Analytical HPLC: Chiracel OD-H column (250ꢂ4 mm,
Daicel), eluent: iPrOH/hexane (1:99), flow rate: 1 mLminÀ1, UV detec-
tion at 254 nm; tr (R enantiomer)=13.57 min, tR (S enantiomer)=
14.21 min: e.r.=1:99.
2-{(1S)-1-[(1S)-1-(Benzyloxy)ethyl]prop–2-ynyl}-1H-isoindole-1,3ACHTUNGTRENNUNG(2H)-
dione (2g): Yield 90%; m.p. 74–768C; [a]1D8 =43.94 (c=1.30 in CHCl3);
1H NMR (400 MHz, CDCl3, 258C, TMS): d=7.91–7.62 (m, 4H; CH),
3
4
7.48–7.19 (m, 5H; CH), 5.12 (dd, J
CHN), 4.69 (d, 2J(H,H)=11.5 Hz, 1H, CH2O), 4.67 (d, 2J
11.5 Hz, 1H, CH2O), 4.23 (dq, 3J(H,H)=7.7 Hz, 3J
(H,H)=6.3 Hz, 1H;
CHO), 2.42 (d, 4J(H,H)=2.5 Hz, 1H, CH), 1.24 ppm (d, 3J
(H,H)=
ACHUTGTNREN(NUG H,H)=7.7 Hz, JACHTNUGTRENNUNG
G
ACHTUNGTRENNUNG
E
ACHTUNGTRENNUNG
U
ACHTUNGTRENNUNG
2-[(1S)-1-Ethynylpent-4-en–1-yl]-1H--isoindole-1,3(2H)-dione (2c): Yield
67%; m.p. 50–558C; [a] D25 =10.26 (c=2.38 in CHCl3); 1H NMR
6.3 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=166.9
(2C), 137.8, 133.8 (2C), 131.7 (2C), 128.05 (2C), 127.4 (2C), 123.3 (3C),
86.3, 73.8, 73.4, 72.6, 46.8, 17.4 ppm;
3
(200 MHz, CDCl3, 258C, TMS): d=7.91–7.65 (m, 4H; CH), 5.76 (ddt, J-
ACHTUNGTRENNUNG(H,H)=16.8, 10.3 and 6.6 Hz, 1H; CH), 5.09–5.06 (m, 1H; CHN), 5.05–
5.01 (m, 1H; CH2), 4.99–4.97 (m, 1H; CH2), 2.30–2.08 (m, 2H; CH2),
2.20–2.01 (m, 2H; CH2), 0.97–0.15 ppm (s, 9H; CH3); 13C NMR (50 MHz,
CDCl3, 258C, TMS): d=166.8 (2C), 136.5, 133.9 (2C), 131.8, 123.3 (2C),
115.8, 101.4, 88.6, 41.7, 32.4, 30.4, 27.6, À0.18 ppm (3C); GC–MS: m/z
(%): 311(6) [M+], 296 (27), 256 (44), 220 (26), 204 (100), 149 (39), 130
(77), 102 (25), 73 (49); elemental analysis calcd (%) for C18H21NO4Si: C
69.41, H 6.80, N 4.50; found: C 69.66, H 6.59, N 4.86. Analytical HPLC:
Chiracel OD-H column (250ꢂ4 mm, Daicel), eluent: iPrOH/hexane
(1:99), flow rate: 1 mLminÀ1, UV detection at 254 nm; tr (R enantio-
mer)=5.10 min, tR (S enantiomer)=7.65 min: e.r.=4:96.
2-{(1R)-1-[3-(Benzyloxy)propyl]prop-2-ynyl}-1H-isoindole-1,3ACHTNUTGRNEUNG(2H)-dione
(2h): Yield 67%; oil; [a]D25 =5.76 (c=1.66 in dioxane); 1H NMR
(200 MHz, CDCl3, 258C, TMS): d=7.91–7.62 (m, 4H; CH), 7.40–7.19 (m,
5H, CH), 5,15–4,99 (m, 1H; CHN), 4,51 (s, 2H; CH2O), 3.43 (t, 3J-
AHCTUNGTRENG(NNU H,H)=6.2 Hz, 2H; CH2O), 2.39 (s, 1H, CH), 2.35–2.05 (m, 2H; CH2),
1.92–1.61 ppm (m, 2H; CH2); 13C NMR (50 MHz, CDCl3, 258C, TMS):
d=166.9 (2C), 138.2, 134.1 (2C), 131.6 (2C), 128.3 (2C), 127.5 (3C), 123.3
(2C), 80.0, 72.9, 72.0, 69.1, 41.2, 30.2, 26.5 ppm; GC-MS: m/z (%): 242
(12) [M+À91], 226 (10), 212 (13), 184 (76), 148 (50), 130 (57), 91 (100),
77 (21); elemental analysis calcd (%) for C21H19NO3: C 75.66, H 5.74, N
4.20; found: C 75.40, H 5.85, N 4.49. Analytical HPLC: Chiracel OD-H
column (250ꢂ4 mm, Daicel), eluent: iPrOH/hexane (4:96), flow rate:
1 mLminÀ1, UV detection at 254 nm; tr (S enantiomer)=28.80 min, tr (R
enantiomer)=31.35 min: e.r.=8:92.
2-[(1R)–1-(2-Phenylethyl)prop-2-yn-1-yl]-1H-isoindole-1,3ACTHUNRGTNE(NUG 2H)-dione
(2d): Yield 53%; oil; [a] 2D6 =À17.27 (c=1.72 in CHCl3); 1H NMR
(200 MHz, CDCl3, 258C, TMS): d=7.91–7.62 (m, 4H; CH), 7.30–7.01 (m,
5H, CH), 5.15–4.99 (m, 1H; CHN), 3.92–2.55 (m, 2H; CH2), 2.54–2.31
(m, 2H; CH2), 2,05 ppm (s, 1H; CH); 13C NMR (50 MHz, CDCl3, 258C,
TMS): d=166.8 (2C), 140.0, 134.0 (2C), 131.6 (2C), 128.3 (4C), 126.0,
123.4 (2C), 79.9, 72.2, 41.0, 34.4, 32.4 ppm; GC–MS: m/z (%): 288 (12)
[M+], 261 (34), 185 (100), 157 (28), 142 (62), 130 (29), 104 (24), 76 (22);
elemental analysis calcd (%) for C19H15NO2: C 78.87, H 5.23, N 4.84;
found: C 78.99, H 6.61, N 4.49. Analytical HPLC: Chiralpack AD-H
column (250ꢂ4 mm, Daicel), eluent: iPrOH/hexane (10:90), flow rate:
1 mLminÀ1, UV detection at 254 nm; tr (R enantiomer)=13.90 min: e.r.=
95:5.
2-{(1S)-1-[3-(Phenylseleno)propyl]prop-2-yn-1-yl}-1H-isoindole-1,3ACHTUNGTRENNUNG(2H)-
dione (2i): Yield 83%; oil; [a]2D4 =À12.50 (c=1.50 in CHCl3); 1H NMR
(200 MHz, CDCl3, 258C, TMS): d=7.91–7.62 (m, 4H; CH), 7.51–7.35 (m,
2H, CH), 7.25–7.05 (m, 3H, CH), 5.11–4.95 (m, 1H; CHN), 3.05–2.76
(m, 2H; CH2), 2.35 (s, 1H, CH), 2.31–2.09 (m, 2H; CH2), 2,99–2.69 ppm
(m, 2H; CH2); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=166.6 (2C),
133.9 (2C), 132.5 (2C), 131.3(2C), 129.5, 128.7(2C), 126.6, 123.2 (2C),
79.6, 72.6, 40.6, 32.9, 26.4 ppm (2C); GC-MS: m/z (%): 383 (16) [M+],
226 (43), 198(55), 184 (100), 160 (27), 130 (71), 77 (22); elemental analy-
sis calcd (%) for C20H17NO2Se: C 62.83, H 4.48, O 8.37, N 3.66; found: C
63.87, H 5.01, O 8.55, N 3.99. Analytical HPLC: Chiralpack AD-H
column (250ꢂ4 mm, Daicel), eluent: iPrOH/hexane (5:95), flow rate:
1 mLminÀ1, UV detection at 254 nm; tr (S enantiomer)=34.30 min:
e.r.=97:3.
2-[(1S)-1-(2-Phenylethyl)prop-2-yn-1-yl]-1H-isoindole-1,3ACTHUNRGTNE(NUG 2H)-dione
(ent-2d): Yield 60%; oil; [a]D26 =20.90 (c=2.97 in CHCl3). Analytical
HPLC: Chiralpack AD-H column (250ꢂ4 mm, Daicel), eluent: iPrOH/
hexane (10:90), flow rate: 1 mLminÀ1, UV detection at 254 nm; tr (S en-
antiomer)=15.30 min: e.r.=96:4.
2-{(1R)-1-[3-(Phenylseleno)propyl]prop-2-yn-1-yl}-1H-isoindole-1,3ACHTUNGTRENNUNG(2H)-
Methyl
(5R)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)hept-6-ynoate
(2e): Yield 67%; m.p. 59–608C; [a]2D5 =7.22 (c=1.79 in Et2O); 1H NMR
(200 MHz, CDCl3, 258C, TMS): d=7.82–7.62 (m, 4H; CH), 5.11–4.95 (m,
1H; CHN), 3.69 (s, 3H, CH3O), 2.45–2.29 (m, 2H; CH2), 2.20–2.01 (m,
2H; CH2), 1.82–1.65 (m, 2H; CH2), 0.97–0.19 ppm (s, 9H; CH3);
dione (ent-2i): Yield 91%; oil; [a]2D7 =13.31 (c=1.87 in CHCl3). Analyti-
cal HPLC: Chiralpack AD-H column (250ꢂ4 mm, Daicel), eluent:
iPrOH/hexane (5:95), flow rate: 1 mLminÀ1, UV detection at 254 nm; tr
(R enantiomer)=28.20 min: e.r.=93:7.
Chem. Eur. J. 2009, 15, 7883 – 7895
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7889