(Aminomethano)proline, Synthesis and Incorporation into Small Oligopeptides
FULL PAPER
112–114 °C, [α]2D0 = +42.9 (c = 0.85, CHCl ). IR (KBr): ν =
2934 (C–H), 2882 (C–H), 1696 (C=O), 1676 (C=O), 1403. 1H
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3485 cm–1 (O–H), 3022 (C–H), 2997 (C–H), 2978 (C–H), 2943 (C– NMR (300 MHz, C2D2Cl4, 100 °C): δ = 1.48–1.72 (m, 2 H, 3,4-H),
H), 2931 (C–H), 2912 (C–H), 2877 (C–H), 2843 (C–H), 2813 (C– 1.50 [s, 9 H, C(CH3)3], 2.24–2.32 (m, 1 H, 1Ј-H), 3.41 (dd, 2J = 8.0,
H), 1670 (C=O), 1493, 1479, 1454, 1433, 1416, 1366 (tBu), 1168,
1123, 1088, 1076. 1H NMR (300 MHz, C2D2Cl4, 100 °C): δ = 1.14–
1.25 (m, 1 H, 3-H*), 1.35–1.42 (m, 1 H, 4-H*), 1.48 [s, 9 H,
3J = 5.0 Hz, 1 H, 5-H), 3.62–3.74 (m, 3 H, 1,5-H), 4.01–4.09 (m, 1
H, 2-H), 4.24 (t, 3J = 8.0 Hz, 1 H, 9-H, Fmoc), 4.50 (d, 3J = 8.0 Hz,
2 H, 1Ј-H, Fmoc), 4.80 (br. s, 1 H, NH), 7.30–7.48 (m, 4 H, Ph-H),
C(CH3)3], 1.54–1.58 (m, 1 H, 1Ј-H), 3.28 (dd, 2J = 12.0 Hz, 3J = 7.57–7.64 (m, 2 H, Ph-H), 7.76–7.84 (m, 2 H, Ph-H) ppm. The
6.0 Hz, 1 H, 5-H), 3.43–3.56 (m, 3 H, 1,5-H), 3.71 (s, 2 H, signal of the OH proton could not be assigned. 13C NMR
NCH2Ph), 3.73 (s, 2 H, NCH2Ph), 3.78–3.87 (m, 1 H, 2-H), 7.24–
7.38 (m, 10 H, Ph-H) ppm. The signal of the OH proton could not
be assigned. 13C NMR (75.5 MHz, C2D2Cl4, 100 °C): δ = 24.5 (+,
C-3*), 28.1 (+, C-4*), 28.3 [+, C(CH3)3], 46.9 (+, C-1Ј), 47.7 (–, C-
5), 59.1 (–, NCH2Ph), 61.1 (+, C-2), 65.3 (–, C-1), 79.7 [–, OC-
(CH3)3], 126.8, 127.9, 129.1 (+, Ph-C), 138.4 (–, Ph-C) ppm. The
signal of the NCO carbon could not be detected. MS (EI): m/z (%)
= 408 (5) [M+], 317 (10) [M+ –Bn], 261 (25) [M+ –Bn–C4H8], 217
(26) [M+ –Bn–CO2 –C4H8], 91 (100) [Bn+], 57 (56) [tBu+], 43 (50).
C25H32N2O3 (408.54): calcd. C 73.50, H 7.89, N 6.86; found C
73.24, H 8.06, N 6.90.
(75.5 MHz, C2D2Cl4, 100 °C): δ = 24.0 (+, C-3*), 27.1 (+, C-4*),
28.2 [+, C(CH3)3], 32.8 (+, C-1Ј), 47.3 (+, C-9, Fmoc), 47.5 (–, C-
5), 60.7 (+, C-2), 64.9 (–, C-1*), 66.5 (–, C-1Ј*, Fmoc), 79.9 [–,
C(CH3)3], 119.7, 124.6, 126.8, 127.5 (+, Ph-C), 141.1, 143.7 (–, Ph-
C), 156.2 (–, NCO) ppm. MS (ESI): positive, m/z (%) = 1374 (15)
[3M+Na+], 923 (100) [2M+Na+], 473 (89) [M+Na+].
(2R,1ЈS,3S,4S)-Nα-Boc-3,4-(Fmoc-Aminomethano)proline
[(2R,1ЈS,3S,4S)-21]: Jones reagent (1.2 mL, 3.20 mmol, 2.67 soln.
in H2O) was added dropwise at 0 °C to a solution of the diamino
alcohol (2R,1ЈS,3S,4S)-20 (1.08 g, 2.40 mmol) in acetone (24 mL),
until the solution stayed orange for Ͼ5 min. The reaction mixture
was stirred at 0 °C for 30 min, the cooling bath was removed, and
stirring was continued for an additional 1 h. iPrOH (0.5 mL) and
H2O (20 mL) were added, and the solution was concentrated to a
volume of ca. 25 mL. The reaction mixture was extracted with Et2O
(3×20 mL). The combined organic extracts were washed with brine
(20 mL), dried and concentrated under reduced pressure. Column
chromatography of the residue (40 g of silica gel, 2×25 cm column,
hexane/EtOAc/HOAc, 25:25:1, Rf = 0.38) gave 901 mg (1.94 mmol,
81%) of (2R,1ЈS,3S,4S)-21 as a colorless, voluminous solid, m.p.
(2R,1ЈS,3S,4S)-Nα-Boc-3,4-(Dibenzylaminomethano)proline
[(2R,1ЈS,3S,4S)-19]: Jones reagent (0.32 mL, 854 µmol, 2.67 solu-
tion in H2O) was added dropwise at 0 °C to a solution of the di-
amino alcohol (2R,1ЈS,3S,4S)-18 (204 mg, 500 µmol) in acetone
(5 mL) until the reaction mixture stayed orange for Ͼ5 min. It was
then stirred at 0 °C for 30 min, the cooling bath was removed, and
stirring was continued for an additional 45 min. iPrOH (0.1 mL)
and H2O (5 mL) were added, and 1 aq. NaOH soln. was added
until the pH value was adjusted to 6. The mixture was extracted
with EtOAc (5×10 mL). The combined organic extracts were dried
and concentrated under reduced pressure. Column chromatography
of the residue (10 g of silica gel, 1×5 cm column, hexane/EtOAc,
1:1, Rf = 0.06) yielded 104 mg (246 mmol, 49%) of (2R,1ЈS,3S,4S)-
19 as a pale beige, voluminous solid. 1H NMR (300 MHz,
C2D2Cl4, 100 °C): δ = 1.40–1.58 (m, 1 H, 3-H*), 1.46 [s, 9 H,
C(CH3)3], 2.23–2.34 (m, 2 H, 1Ј,4-H*), 3.36–3.52 (m, 2 H, 5-H),
3.52 (s, 2 H, NCH2Ph), 3.54 (s, 2 H, NCH2Ph), 4.18–4.25 (m, 1 H,
2-H), 6.16 (br. s, 1 H, COOH), 7.24–7.42 (m, 10 H, Ph-H) ppm.
13C NMR (75.5 MHz, C2D2Cl4, 100 °C): δ = 25.0 (+, C-3*), 28.2,
28.3 [+, C-4*, C(CH3)3,], 46.8 (+, C-1Ј), 47.7 (–, C-5), 59.8 (–,
NCH2Ph), 60.9 (+, C-2), 80.4 [–, OC(CH3)3], 126.9, 127.9, 129.0
(+, Ph-C), 138.2 (–, Ph-C), 154.5 (–, NCO) ppm. The signal of the
COOH carbon could not be detected. MS (EI): m/z (%) = 422 (4)
[M+], 331 (8) [M+ –Bn], 275 (18) [M+ –Bn–C4H8], 231 (11), 106
(34), 91 (100) [Bn+], 57 (17) [tBu+].
97–104 °C, [α]2D0 = +48.1 (c = 0.47, CHCl ). IR (KBr): ν =
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3322 cm–1 (O–H, N–H), 3067 (C–H), 2977 (C–H), 2937 (C–H),
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2888 (C–H), 1704 (C=O), 1397, 1368, 1338, 1253, 1175. H NMR
(300 MHz, C2D2Cl4, 100 °C): δ = 1.50 [s, 9 H, C(CH3)3], 1.66–1.76
(m, 1 H, 3-H*), 1.92–2.02 (m, 1 H, 4-H*), 2.33–2.44 (m, 1 H, 1Ј-
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H), 3.52 (dd, J = 8.0, J = 5.0 Hz, 1 H, 5-H), 3.60–3.72 (m, 1 H,
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5-H), 4.24 (t, J = 8.0 Hz, 1 H, 9-H, Fmoc), 4.40–4.50 (m, 1 H, 2-
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H), 4.52 (d, J = 8.0 Hz, 2 H, 1Ј-H, Fmoc), 4.92 (br. s, 1 H, NH),
5.40 (br. s, 1 H, COOH), 7.30–7.47 (m, 4 H, Ph-H), 7.55–7.64 (m,
2 H, Ph-H), 7.74–7.82 (m, 2 H, Ph-H) ppm. 13C NMR (75.5 MHz,
C2D2Cl4, 100 °C): δ = 24.1 (+, C-3*), 27.3 (+, C-4*), 28.1 [+,
C(CH3)3], 32.8 (+, C-1Ј), 47.3 (+, C-9, Fmoc), 47.7 (–, C-5), 60.4
(+, C-2), 66.6 (–, C-1Ј, Fmoc), 81.1 [–, C(CH3)3], 119.7, 124.5,
126.8, 127.5 (+, Ph-C), 141.1, 143.6 (–, Ph-C), 156.2 (–, 2 C, NCO),
171.8 (–, COOH) ppm. MS (ESI, positive): m/z (%) = 951 (71)
[2M+Na+], 487 (100) [M+Na+]; MS (ESI, negative): m/z (%) =
927 (100) [2M– H+], 463 (14) [M – H+]. HRMS (ESI) calcd. for
C26H28N2O6Na [M+Na+] 487.18396, found 487.18393.
(2R,1ЈS,3S,4S)-Nα-Boc-3,4-(Fmoc-Aminomethano)prolinol
[(2R,1ЈS,3S,4S)-20]: A suspension of Pd (86 mg, 81.0 µmol, 3 mol-
%, 10% on charcoal) in MeOH (5 mL) was shaken under an atmo-
sphere of H2 for 5 min. A solution of the diamino alcohol
(2R,1ЈS,3S,4S)-Nα-Boc-3,4-(Z-Aminomethano)prolinol
[(2R,1ЈS,3S,4S)-22]: A suspension of Pd (86 mg, 81.0 µmol, 3 mol-
%, 10% on charcoal) in MeOH (5 mL) was shaken under H2 for
(2R,1ЈS,3S,4S)-18 (1.10 g, 2.70 mmol) in MeOH (25 mL) was 5 min. A solution of the diamino alcohol (2R,1ЈS,3S,4S)-18 (1.10 g,
added, and the mixture was shaken under an atmosphere of H2 for
17 h. The reaction mixture was filtered through Celite and concen-
trated in vacuo. The residue was dissolved in acetone/H2O (10 mL/
2.70 mmol) in MeOH (25 mL) was added, and the mixture was
shaken under H2 for 17 h. The reaction mixture was filtered
through celite and concentrated in vacuo. The residue was dissolved
5 mL), the solution treated with NaHCO3 (250 mg, 2.97 mmol) and in acetone/H2O (10 mL/5 mL), treated with NaHCO3 (250 mg,
FmocOSu (1.00 g, 2.97 mmol), and then stirred for 4 h. After con-
centration to a volume of ca. 5 mL, H2O (10 mL) was added, and
the mixture was extracted with Et2O (3×10 mL). The combined
organic extracts were washed with brine (10 mL), dried and evapo-
rated under reduced pressure. Column chromatography of the resi-
due (40 g of silica gel, 2×25 cm column, hexane/EtOAc, 2:1, Rf =
2.97 mmol) and ZOSu (740 mg, 2.97 mmol) and stirred for 3 h. Af-
ter concentration to a volume of ca. 5 mL, H2O (10 mL), was
added and the mixture was extracted with Et2O (3×10 mL). The
combined organic extracts were washed with brine (10 mL), dried
and evaporated under reduced pressure. Column chromatography
of the residue (40 g of silica gel, 2×25 cm column, hexane/EtOAc,
0.25) furnished 1.22 g (2.70 mmol, 100%) of (2R,1ЈS,3S,4S)-20 as 2:1, Rf = 0.25) furnished 980 mg (2.70 mmol, 100 %) of
a colorless, voluminous solid, m.p. 77–82 °C, [α]2D0 = +30.5 (c = (2R,1ЈS,3S,4S)-22 as a colorless, highly viscous oil, [α]2D0 = +41.2 (c
0.57, CHCl ). IR (KBr): ν = 3424 cm–1 (O–H, N–H), 2974 (C–H), = 0.49, CHCl ). IR (KBr): ν = 3316 cm–1 (O–H, N–H), 2975 (C–
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Eur. J. Org. Chem. 2006, 4440–4450
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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