G. Chaume, N. Lensen, C. Caupène, T. Brigaud
FULL PAPER
the resulting mixture was stirred at room temperature for 48 h. Pu-
rification on silica gel (cyclohexane/AcOEt, 80:20) gave pure (S,S)-
5 (80 mg, 76%) as a white solid; m.p. 88 °C, Rf = 0.38 (cyclohexane/
CH2-Ha), 5.19 (d, J = 12.4 Hz, 1 H, Bn CH2-Hb), 7.22–7.42 (m, 5
H, Bn arom.), 7.87 (d, J = 6.9 Hz, 1 H, NH Ala) ppm. 13C NMR
(100.5 MHz, CDCl3): δ = 17.8 (CH3, Cβ Ala), 20.7 (CH3, Cβ Tfm-
AcOEt, 80:20). [α]D = +0.7 (c = 1.4, CHCl3). 1H NMR (400 MHz, Ala), 47.9 (CH, Cα Ala), 60.5 (C, q, J = 27.8 Hz, Cα Tfm-Ala), 67.0
CDCl3): δ = 1.36 (s, 9 H, tBu 3ϫCH3-H), 1.36–1.52 (m, 1 H, Hγ
(CH2, Bn CH2), 125.5 (C, q, J = 284.7 Hz, CF3), 128.0 (2ϫCH, Bn
Pro-Ha), 1.66–1.76 (m, 1 H, Hγ Pro-Hb), 1.96 (ddd, J = 13.8, 7.8, arom.), 128.3 (CH, Bn arom.), 128.5 (2ϫCH, Bn arom.), 135.1
4.4 Hz, 1 H, Hβ Pro-Ha), 2.07 (ddd, J = 13.8, 9.2, 7.8 Hz, 1 H, Hβ
Pro-Hb), 2.33 (br. s, 1 H, NH Pro), 2.84–2.94 (m, 2 H, Hδ Pro-H),
2.97 (dd, J = 14.0, 6.9 Hz, 1 H, Hβ Phe-Ha), 3.11 (dd, J = 14.0,
(C, Bn arom.), 168.9 (C, C=O), 172.2 (C, C=O) ppm. 19F NMR
(376.2 MHz, CDCl ): δ = –81.2 (s, CF ) ppm. IR (neat): ν = 3373,
˜
3
3
1738, 1678, 1148 cm–1. MS (EI): m/z (%) = 318 [M]+, 298, 275
6.0 Hz, 1 H, Hβ Phe-Hb), 4.63 (ddd, J = 7.8, 6.9, 6.0 Hz, 1 H, Hα (100), 206. HRMS (EI): calcd. for C14H17F3N2O3: 318.1191; found
Phe-H), 7.04–7.09 (m, 2 H, arom. Phe-H), 7.12–7.22 (m, 3 H, arom.
Phe-H); 7.81 (d, J = 7.8 Hz, 1 H, NH Phe) ppm. 13C NMR
(100.5 MHz, CDCl3): δ = 25.5 (CH2, Cγ Pro), 27.8 (3ϫCH3, tBu
CH3), 32.2 (CH2, Cβ Pro), 37.7 (CH2, Cβ Phe), 47.4 (CH2, Cδ Pro),
53.4 (CH, Cα Phe), 70.5 (q, J = 26.8 Hz, CH2, Cα Pro, C), 82.3 (C,
tBu C), 125.9 (q, J = 283.7 Hz, CF3, C), 126.9 (CH, Phe arom.),
128.2 (2ϫCH, Phe arom.), 129.3 (2ϫCH, Phe arom.), 136.0 (C,
Phe arom.), 168.7 (C, C=O), 170.1 (C, C=O) ppm. 19F NMR
386.1181.
(R)-α-Tfm-Ala-L-Val-OtBu [(R,S)-11]: The dipeptide (R,S)-11 was
prepared by the General Procedure, with -valine tert-butyl ester
hydrochloride (266 mg, 1.27 mmol, 2 equiv.), triethylamine
(363 µL, 2.54 mmol, 4.1 equiv.), HOBt (129 mg, 0.95 mmol,
1.5 equiv.), EDCI (183 mg, 0.95 mmol, 1.5 equiv.), and (R)-α-Tfm
alanine (100 mg, 0.64 mmol) in DMF (3 mL). After 20 min at 0 °C,
the resulting mixture was stirred at room temperature for 24 h. Pu-
rification on silica gel (cyclohexane/AcOEt, 90:10) gave pure (R,S)-
11 (159 mg, 80%) as a white solid; m.p. 68 °C, Rf = 0.39 (cyclohex-
ane/AcOEt, 80:20). [α]D = +12.5 (c = 1.37, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 0.87 (d, J = 6.9 Hz, 3 H, Hγ Val-H), 0.91
(d, J = 6.9 Hz, 3 H, Hγ Val-H), 1.45 (s, 9 H, tBu 3ϫCH3-H), 1.50
(s, 3 H, Hβ Ala-H), 1.81 (br. s, 2 H, NH2 Ala), 2.20 (septd, J =
6.9, 4.1 Hz, 1 H, Hβ Val-H), 4.37 (dd, J = 9.2, 4.1 Hz, 1 H, Hα Val-
H), 7.81 (d, J = 9.2 Hz, 1 H, NH Val) ppm. 13C NMR (100.5 MHz,
CDCl3): δ = 17.3 (CH3, Cγ Val), 18.9 (CH3, Cγ Val), 21.0 (CH3, Cβ
Ala), 27.9 (3ϫCH3, tBu CH3), 31.3 (CH, Cβ Val), 57.3 (CH, Cα
Val), 60.8 (C, q, J = 27.8 Hz, Cα Ala), 82.0 (C, tBu C), 125.7 (C,
q, J = 283.7 Hz, CF3), 168.8 (C, C=O), 170.6 (C, C=O) ppm. 19F
(376.2 MHz, CDCl ): δ = –77.6 (s, CF ) ppm. IR (neat): ν = 3343,
˜
3
3
1712, 1672, 1604, 1164 cm–1. MS (EI): m/z (%) = 386 [M]+, 138
(100). C19H25F3N2O3 (386.18): C 59.06, H 6.52, N 7.25; found C
59.08, H 6.52, N 7.15.
(S)-α-Tfm-Pro-L-Leu-OBn [(S,S)-6]: The dipeptide (S,S)-6 was pre-
pared by the General Procedure with -leucine tert-butyl ester hy-
drochloride (215 mg, 0.55 mmol, 2 equiv.), triethylamine (156 µL,
1.12 mmol, 4.1 equiv.), HOBt (55 mg, 0.41 mmol, 1.5 equiv.),
EDCI (79 mg, 0.41 mmol, 1.5 equiv.), and (S)-α-Tfm proline
(50 mg, 0.27 mmol) in DMF (1 mL). After 20 min at 0 °C, the re-
sulting mixture was stirred at room temperature for 30 h. Purifica-
tion on silica gel (cyclohexane/AcOEt, 80:20) gave pure (S,S)-6
(87 mg, 80%) as a colorless oil, Rf = 0.34 (cyclohexane/AcOEt,
80:20). [α]D = –46.6 (c = 2.2, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 0.91 (d, J = 6.4 Hz, 3 H, Hδ Leu-H), 0.92 (d, J = 6.4 Hz, 3 H,
Hδ Leu-H), 1.52–1.62 (m, 2 H, Hβ Leu-Ha, Hγ Leu-H), 1.65–1.76
(m, 2 H, Hγ Pro-Ha, Hβ Leu-Hb), 1.84–1.93 (m, 1 H, Hγ Pro-Hb),
2.13–2.28 (m, 2 H, Hβ Pro-H), 2.53 (br. s, 1 H, NH Pro), 3.09 (dd,
J = 7.0, 5.7 Hz, 2 H, Hδ Pro-H), 4.64 (td, J = 8.7, 5.2 Hz, 1 H, Hα
Leu-H), 5.13 (d, J = 12.2 Hz, 1 H, Bn CH2-Ha), 5.19 (d, J =
12.2 Hz, 1 H, Bn CH2-Hb), 7.30–7.40 (m, 5 H, Bn arom.), 7.74 (d,
J = 8.7 Hz, 1 H, NH Leu) ppm. 13C NMR (100.5 MHz, CDCl3):
δ = 21.7 (CH3, Cδ Leu), 22.8 (CH3, Cδ Leu), 25.0 (CH, Cγ Leu),
25.4 (CH2, Cγ Pro), 32.4 (CH2, Cβ Pro), 41.1 (CH2, Cβ Leu), 47.6
(CH2, Cδ Pro), 50.9 (CH, Cα Leu), 67.1 (CH2, Bn CH2), 70.7 (C,
q, J = 25.9 Hz), 126.0 (C, q, J = 284.7 Hz, CF3), 128.2 (2ϫCH,
Bn arom.), 128.4 (CH, Bn arom.), 128.5 (2ϫCH, Bn arom.), 135.2
(C, Bn arom.), 169.1 (C, C=O), 172.2 (C, C=O) ppm. 19F NMR
NMR (376.2 MHz, CDCl ): δ = –81.4 (s, CF ) ppm. IR (neat): ν
˜
3
3
= 3368, 3354, 3308, 1723, 1686, 1158 cm–1. MS (EI): m/z (%) = 312
[M]+, 211 (100), 112. C13H23F3N2O3 (312.17): C 49.99, H 7.42, N
8.97; found C 49.70, H 7.40, N 8.76.
(R)-α-Tfm-Ala-L-Phe-OtBu [(R,S)-12]: The dipeptide (R,S)-12 was
prepared by the General Procedure, with -phenylalanine tert-butyl
ester hydrochloride (326 mg, 1.27 mmol, 2 equiv.), triethylamine
(363 µL, 2.54 mmol, 4.1 equiv.), HOBt (129 mg, 0.95 mmol,
1.5 equiv.), EDCI (183 mg, 0.95 mmol, 1.5 equiv.), and (R)-α-Tfm
alanine (100 mg, 0.64 mmol) in DMF (3 mL). After 20 min at 0 °C,
the resulting mixture was stirred at room temperature for 24 h. Pu-
rification on silica gel (cyclohexane/AcOEt, 90:10) gave pure (R,S)-
12 (177 mg, 77%) as a white solid; m.p. 68 °C, Rf = 0.36 (cyclohex-
ane/AcOEt, 80:20). [α]D = +53 (c = 3.31, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.36 (s, 3 H, Hβ Ala-H), 1.40 (s, 9 H, tBu
3ϫCH3-H), 1.60 (br. s, 2 H, NH2 Ala), 3.04 (dd, J = 14.2, 6.0 Hz,
1 H, Hβ Phe-Ha), 3.09 (dd, J = 14.2, 6.0 Hz, 1 H, Hβ Phe-Hb),
4.62 (dt, J = 7.8, 6.0 Hz, 1 H, Hα Phe-H), 7.04–7.09 (m, 2 H, arom.
Phe-H), 7.12–7.25 (m, 3 H, arom. Phe-H); 7.63 (d, J = 7.8 Hz, 1
H, NH Phe) ppm. 13C NMR (100.5 MHz, CDCl3): δ = 20.9 (CH3,
Cβ Ala), 27.9 (3ϫCH3, tBu CH3), 37.6 (CH2, Cβ Phe), 53.4 (CH,
Cα Phe), 60.6 (C, q, J = 26.8 Hz, Cα Ala), 82.5 (C, tBu C), 125.7
(C, q, J = 284.7 Hz, CF3), 127.0 (CH, Phe arom.), 128.3 (2ϫCH,
Phe arom.), 129.4 (2ϫCH, Phe arom.), 135.9 (C, Phe arom.), 168.5
(C, C=O), 170.1 (C, C=O) ppm. 19F NMR (376.2 MHz, CDCl3): δ
(376.2 MHz, CDCl ): δ = –77.7 (s, CF ) ppm. IR (neat): ν = 3338,
˜
3
3
1740, 1677, 1509, 1147 cm–1. MS (EI): m/z (%) = 386 [M]+, 138
(100). C19H25F3N2O3 (386.18): C 59.06, H 6.52, N 7.25; found C
59.31, H 6.52, N 7.01.
(R)-α-Tfm-Ala-L-Ala-OBn [(R,S)-10]: The dipeptide (R,S)-10 was
prepared by the General Procedure, with -alanine benzyl ester hy-
drogen tosylate (447 mg, 1.27 mmol, 2 equiv.), triethylamine
(363 µL, 2.54 mmol, 4.1 equiv.), HOBt (129 mg, 0.95 mmol,
1.5 equiv.), EDCI (183 mg, 0.95 mmol, 1.5 equiv.), and (R)-α-Tfm
alanine (100 mg, 0.64 mmol) in DMF (3 mL). After 20 min at 0 °C,
the resulting mixture was stirred at room temperature for 24 h. Pu-
rification on silica gel (dichloromethane/AcOEt, 90:10) gave pure
(R,S)-10 (166 mg, 82%) as a colorless oil, Rf = 0.15 (cyclohexane/
AcOEt, 80:20). [α]D = –12.7 (c = 0.86, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.42 (d, J = 7.3 Hz, 3 H, Hβ Ala-H), 1.46
= –81.3 (s, CF ) ppm. IR (neat): ν = 3407, 3370, 3338, 1708, 1673,
˜
3
1147 cm–1. MS (EI): m/z (%) = 360 [M]+, 304 (100), 259, 193, 148,
120. C17H23F3N2O3 (360.17): calcd. C 56.66, H 6.43, N 7.77; found
C 56.68, H 6.63.
(s, 3 H, Hβ Tfm-Ala-H), 1.85 (br. s, 2 H, NH2 Tfm-Ala), 4.57 (qd, (R)-α-Tfm-Ala-L-Leu-OBn [(R,S)-13]: The dipeptide (R,S)-13 was
J = 7.3, 6.9 Hz, 1 H, Hα Ala-H), 5.12 (d, J = 12.4 Hz, 1 H, Bn prepared by the General Procedure, with -leucine benzyl ester hy-
5722
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5717–5724