Synthesis of Unnatural Amino Acids and Peptides
J . Org. Chem., Vol. 64, No. 23, 1999 8473
(CH3), 21.81 (CH3), 22.61 (CH3), 22.84 (CH3), 24,67 (CH), 28.21
(CH3), 37.91 (CH2), 41.21 (CH2), 50.81 (CH), 52.06 (CH3), 53.57
(CH), 53.98 (CH), 80.09 (C), 126.82 (CH), 128.45 (CH), 129.32
(CH), 136.39 (C), 155.50 (C), 170.40 (C), 172.42 (C), 172.59 (C);
[R]D ) -48.0° (c 1.0, CHCl3); MS(EI) 505 (M+, 22). Anal. Calcd
for C27H43N3O6: C, 64.13; H, 8.57; N, 8.31. Found: C, 64.35;
H, 8.51; N, 8.27.
Boc-Phe-Leu-Leu-OMe (29) was prepared by coupling of Boc-
Phe-Leu-OH, obtained by methanolic alkaline hydrolysis of
dipeptide Boc-Phe-Leu-OM,32 and HCl‚H-Leu-OMe by the
mixed anhydride method with isobutyl chloroformate.
Boc-P h e-Leu -Leu -OMe (29): mp 155-156 °C; 1H NMR
(CDCl3, 200 MHz) 0.83-1.04 (m, 12H), 1.39 (s, 9H), 1.40-1.76
(m, 6H), 3.06 (m, 2H), 3.73 (s, 3H), 4.32-4.64 (m, 3H), 5.09
(d, 1H, J ) 7.8 Hz), 6.60 (d, 1H, J ) 8.2 Hz), 6.68 (d, 1H, J )
8.1 Hz), 7.13-7.37 (m, 5H); 13C NMR (CDCl3, 50 MHz) 21.84
(CH3), 22.05 (CH3), 22.69 (CH3), 22.74 (CH3), 24.44 (CH), 28.13
(CH3), 37.89 (CH2), 40.96 (CH2), 41.14 (CH2), 50.70 (CH), 51.64
(CH3), 52.15 (CH), 55.64 (CH), 80.25 (C), 126.87 (CH), 128.56
(CH), 129.24 (CH), 136.44 (C), 155.40 (C), 171.38 (C), 173.00
(C); [R]D ) -64° (c 2.5, CHCl3). MS(EI) 505 (M+, 20). Anal.
Calcd for C27H43N3O6: C, 64.13; H, 8.57; N, 8.31. Found: C,
64.43; H, 8.51; N, 8.52.
6b: 92% substrate conversion; 140.0 mg; 45.6%; mp 154-
156 °C; 1H NMR (CDCl3, 200 MHz) 1.42 (s, 9H), 2.57-2.64
(m, 2H), 3.64 (s, 3H), 4.58-4.78 (m, 1H), 5.30-5.45 (m, 1H),
6.88-7.05 (m, 2H), 7.12-7.32 (m, 2H); 13C NMR (CDCl3, 50
MHz) 28.16 (CH3), 42.05 (CH2), 52.21 (CH3), 61.76 (CH), 81.64
(C), 98.63 (CH), 115.14 (CH), 121.89 (CH), 123.15 (CH), 130.20
(CH), 149.09 (C), 154.52 (C), 172.37 (C), 173.90 (C); [R]D
+83.6° (c 1.0, CHCl3). MS(EI) 334 (M+, 16). Anal. Calcd for
17H22N2O5: C, 61.06; H, 6.63; N, 8.38. Found: C, 61.10; H,
)
C
6.63; N, 8.19.
Boc-(s)-r-a cetylglycin e m eth yl ester (8): 66% substrate
1
conversion; 140.9 mg; 92.4%; mp 63-65 °C; H NMR (CDCl3,
200 MHz) 1.41 (s, 9H), 2.23 (s, 3H), 3.80 (s, 3H), 5.15-5.25
(br s, 1H), 6.35-6.48 (br s, 1H); 13C NMR (CDCl3, 50 MHz)
23.12 (CH3), 28.08 (CH3), 53.98 (CH3), 81.12 (CH), 84.02 (C),
156.0 (C), 168.13 (C), 198.56 (C); [R]D ) -4.3° (c 2.8, CHCl3);
MS(EI) 231 (M+, 11). Anal. Calcd for C10H17NO5: C, 51.95; H,
7.40; N, 6.06. Found: C, 52.11; H, 7.36; N, 6.18.
Boc-5-h yd r oxyp r olin e m eth yl ester (11): 70% substrate
1
conversion; 151.9 mg; 88.6%; oil; H NMR (CDCl3, 200 MHz)
1.36 (s, 9H), 1.78-2.65 (m, 4H), 3.69 (s, 3H), 4.14-4.41 (m,
1H), 5.36-5.65 (m, 1H); 13C NMR (CDCl3, 50 MHz) 26.87
(CH2), 28.17 (CH3), 31.01 (CH2), 52.01 (CH3), 58.94 (CH), 80.69
(C), 82.19 (CH), 153.37 (C), 172.87 (C); [R]D ) -205.3° (c 1.5,
CHCl3); MS(EI) 245 (M+, 15). Anal. Calcd for C11H19NO5: C,
53.88; H, 7.80; N, 5.71. Found: C, 53.75; H, 7.78; N, 5.90.
Cbz-5-h yd r oxyp r olin e eth yl ester (14): 65% substrate
Boc-Phe-Leu-Phe-OMe (23) and Boc-Leu-Leu-Leu-OMe (31)
were synthesized as reported in refs 34 and 35, respectively.
Oxid a tion of Boc-a m in o Ester s a n d Boc-p ep tid e Es-
ter s. Gen er a l P r oced u r e. The oxidations were carried out
by adding a freshly prepared solution of 6 equiv of 3,3-
dimethyldioxirane (0,1 N acetone solution) (2.5 equiv for Boc-
His-OMe 3 and Boc-Trp-OMe 5; 4 equiv for Boc-Pro-OMe 10,
Cbz- Pro-OEt 12, Boc-Pro-OH 13, Boc-Ala-Leu-OMe 16, and
Boc-Leu-Ala-OEt 17), to the appropriate substrate (1 mmol)
in 5 mL of CH2Cl2 (Boc-amino acid and Boc-dipeptide esters)
or acetone (Boc-tripeptide esters) at 25 °C (10 °C for Boc-His-
OMe 3 and Boc-Trp-OMe 5) for 3 days (2 days for 3 and 5).
The DMD excess and the reaction solvent were evaporated
under reduced pressure and the crude purified by flash
chromatography on silica gel usinga gradient petroleum ether/
ethyl acetate as the elution solvent.
(2S)-2-(ter t-Bu toxyca r bon yla m in o)-4,4-d im eth yl-4-bu -
ta n olid e (2): 45% substrate conversion; 96.2 mg; 93.4%); oil;
1H NMR (CDCl3, 200 MHz) 1.41 (s, 3H), 1.43 (s, 9H), 1.47 (s,
3H), 1.88-2.80 (m, 2H), 4.42-4.62 (m, 1H), 4.95-5.09 (br s,
1H); 13C NMR (CDCl3, 50 MHz) 26.26 (CH3), 28.87 (CH3), 28.98
(CH3), 42.68 (CH2), 51.35 (CH), 80.02 (C), 82.51 (C), 156.03
(C), 173.25 (C); [R]D ) +13.0° (c 1.0, CHCl3); MS(EI) 229 (M+,
15). Anal. Calcd for C11H19NO4: C, 57.63; H, 8.35; N, 6.11.
Found: C, 57.83; H, 8.40; N, 6.32.
1
conversion; 170.2 mg; 89.4%; oil; H NMR (CDCl3, 200 MHz)
1.12 (t, 3H, J ) 8.0 Hz), 1.82-2.59 (m, 4H), 3.94-4.52 (m, 3H),
5.13 (m, 2H), 5.51-5.76 (m, 1H), 7.12-7.41 (m, 5H); 13C NMR
(CDCl3, 50 MHz) 14.04 (CH3), 27.95 (CH2), 30.93 (CH2), 59.12
(CH), 61.16 (CH2), 67.21 (CH2), 82.69 (CH), 127.91 (CH), 128.07
(CH), 128.44 (CH), 128.56 (CH), 128.67 (CH), 136.96 (C),
153.94 (C), 172.03 (C); [R]D ) -82° (c 2.0, CHCl3); MS(EI) 293
(M+, 27). Anal. Calcd for C15H19NO5: C, 61.43; H, 6.53; N, 4.77.
Found: C, 61.38; H, 6.50; N, 4.92.
Boc-5-h yd r oxyp r olin e (15): 53% substrate conversion;
113.2 mg; 92.5%; oil; 1H NMR (CDCl3, 200 MHz) 1.42 (s, 9H),
1.74-2.38 (m, 4H), 4.10-4.24 (m, 1H), 5.05-5.24 (m, 1H),
6.54-6.88 (br s, 1H); 13C NMR (CDCl3, 50 MHz) 27.93 (CH3),
29.86 (CH2), 30.81 (CH2), 55.85 (CH), 80.75 (C), 89.17 (CH),
154.19 (C), 154.28 (C); [R]D ) +13.5° (c 2.5, CHCl3). MS(EI)
231 (M+, 21). Anal. Calcd for C10H17NO5: C, 51.94; H, 7.40;
N, 6.06. Found: C, 52.13; H, 7.41; N, 6.10.
(2S)-2-(Boc-alan ylam in o)-4,4-dim eth yl-4-bu tan olide (18):
40% substrate conversion; 105 mg; 87.5%; mp 170-172 °C;
1H NMR (CDCl3, 200 MHz) 1.23 (s, 3H), 1.33-1.37 (m, 3H),
1.41 (s, 9H), 1.48 (s, 3H), 1.88-2.00 (m, 1H), 2.58-2.68 (m,
1H), 4.09-4.20 (m, 1H), 4.65-4.79 (m, 1H), 4.94-4.97 (br s,
1H), 6.77-6.80 (br s, 1H); 13C NMR (CDCl3, 50 MHz) 18.06
(CH3), 27.05 (CH3), 28.28 (CH3), 28.92 (CH3), 41.91 (CH2), 50.28
(CH), 51.30 (CH), 80.0 (C), 82.50 (C), 156.03 (C), 173.18 (C),
174.08 (C); [R]D ) +15.7° (c 1.3, CHCl3). MS(EI) 300 (M+, 15).
Anal. Calcd for C14H24N2O5: C, 56.0; H, 8.0; N, 9.33. Found:
C, 56.22; H, 8.12; N, 9.24.
Boc-Leu (γ-OH)-Ala -OEt (19): 47% substrate conversion;
131.9 mg; 81%; oil; 1H NMR (CDCl3, 200 MHz) 1.15-1.30 (m,
12H), 1.42 (s, 9H), 1.51-1.85 (m, 2H), 4.06-4.30 (m, 2H), 4.35
(m, 1H), 4.48-4.60 (m, 1H), 5.59-5.62 (br s, 1H), 6.99-7.02
(br s, 1H); 13C NMR (CDCl3, 50 MHz) 14.12 (CH3), 18.19 (CH3),
18.26 (CH3), 28.32 (CH3), 45.28 (CH2), 48.20 (CH), 50.10 (CH),
61.53 (CH2), 70.35 (C), 81.66 (C), 156.20 (C), 172.15 (C), 172.84
(C); [R]D ) -4.2° (c 1.1, CHCl3). MS(EI) 346 (M+, 37). Anal.
Calcd for C16H30N2O6: C, 55.5; H, 8.7; N, 8.0. Found: C, 55.4;
H, 8.7; N, 8.22.
Boc-â-(2,3-d ih yd r o-2-oxo-im id a zol-4-yl)-a la n in e m eth -
yl ester (4): 59% substrate conversion; 156.7 mg; 93.2%; oil;
1H NMR (CDCl3, 200 MHz) 1.39 (s, 9H), 2.95-3.05 (m, 2H),
3.71 (s, 3H), 4.55-4.85 (m, 1H), 5.32-5.49 (br s, 1H), 7.20
(m, 1H), 8.98 (br s, 1H); 13C NMR (CDCl3, 50 MHz) 28.00
(CH3), 31.05 (CH2), 50.70 (CH), 52.47 (CH3), 80.39 (C), 85.46
(C), 158.15 (CH), 162.51 (C), 163.50 (C), 171.27 (C); [R]D
+13.6° (c 1.8, CHCl3). MS(EI) 285 (M+, 21). Anal. Calcd for
12H19N3O5: C, 50.52; H, 6.71; N, 14.73. Found: C, 50.34; H,
)
C
6.92; N, 14.79.
Boc-â-(2,3-d ih yd r o-2-oxo-in d ol-3-yl)-a la n in e m eth yl es-
ter (6). 6a : 92% substrate conversion; 140.0 mg; 45.6%; mp
1
180-182 °C; H NMR (CDCl3, 200 MHz) 1.38 (s, 9H), 2.39-
2.57 (m, 2H), 3.76 (s, 3H), 4.19-4.32 (m, 1H), 5.44 (s, 1H),
6.59-6.62 (m, 1H), 6.63-6.84 (m, 1H), 7.09-7.20 (m, 1H),
7.21-7.31 (m, 2H); 13C NMR (CDCl3, 50 MHz) 28.16 (CH3),
41.36 (CH2), 52.34 (CH3), 59.77 (CH), 81.15 (C), 84.33 (CH),
110.52 (CH), 119.44 (CH), 123.15 (CH), 130.27 (CH), 148.32
(C), 154.12 (C), 173.90 (C), 175.21 (C); [R]D ) -221.4° (c 1.0,
CHCl3). MS(EI) 334 (M+, 18). Anal. Calcd for C17H22N2O5: C,
61.06; H, 6.63; N, 8.38. Found: C, 61.0; H, 6.59; N, 8.15.
(2S)-2-(Boc-leu cyla m in o)-4,4-d im et h yl-4-b u t a n olid e
(21): 42% substrate conversion; 112.9 mg; 78.6%; oil; 1H NMR
(CDCl3, 200 MHz) 0.91-0.94 (m, 6H), 1.23 (s, 3H), 1.41 (s, 9H),
1.48 (s, 3H), 1.48-1.80 (m, 3H), 1.88-2.02 (m, 1H), 2.62-2.76
(m, 1H), 4.07-4.18 (m, 1H), 4.63-4.77 (m, 1H), 4.88-4.91 (d,
1H, J ) 6.0 Hz), 6.73-6.76 (br s, 1H); 13C NMR (CDCl3, 50
MHz) 18.06 (CH3), 22.97 (CH3), 24.69 (CH), 27.03 (CH3),
28.27 (CH3), 41.06 (CH2), 41.94 (CH2), 50.24 (CH), 51.10 (CH),
(34) Toniolo, C.; Crisma, M.; Moretto, V.; Freer, R. J .; Becker, E. L.
Biochem. Biophys. Acta 1990, 1034, 67-72.
(35) Shields, J . E.; McDowell, S. T.; Pavlos, J .; Gray, G. R. J . Am.
Chem. Soc. 1968, 90, 3549-3556.
81.10 (C), 82.55 (C), 155.53 (C), 173.15 (C), 174.05 (C); [R]D
)
+7.8° (c 1.9, CHCl3); MS(EI) 342 (M+, 15). Anal. Calcd for