Versatile Synthesis of New Substituted Cyclic -Lysines
extracted with Et2O (3ϫ100 mL). The combined organic layers
were washed with brine (2ϫ40 mL), dried with MgSO4 and con-
centrated in vacuo. The crude compound 10 (1.25 g) was dissolved
in trifluoroacetic acid (8 mL), triethylsilane (3.56 mL, 22.4 mmol)
was added, and the mixture was stirred overnight at room tempera-
the mixture was stirred overnight at room temperature. The reac-
tion mixture was concentrated in vacuo and the crude residue was
purified by silica gel column chromatography (EtOAc/cyclohexane,
15:85) to afford the pure compound 14 (170 mg, 92%) as a white
solid. Rf(EtOAc/cyclohexane, 15:85) = 0.3. [α]2D0 = +15 (c = 0.785,
ture. The reaction mixture was concentrated in vacuo, and the CH Cl ); m.p. 125–127 °C. IR (neat): ν = 3349, 2920, 2853, 1718,
˜
2
2
crude residue was purified by silica gel column chromatography
(EtOAc/cyclohexane, 8:2) to afford pure compound 11 (605 mg,
53% over 2 steps) as a white solid. Rf(EtOAc/cyclohexane, 8:2) =
1649, 1483, 1437, 1204, 1161, 902, 729, 696 cm–1 1H NMR
.
(250 MHz, CDCl3): δ = 8.03 (br. s, 1 H), 7.36–7.18 (m, 5 H), 5.62
and 3.97 (qAB, JAB = 15.0 Hz, 2 H, PhCH2), 4.53–4.45 (m, 2 H),
3.73 (d, J = 16.0 Hz, 1 H), 3.51 (dd, J = 16.0, 5.1 Hz, 1 H), 2.35–
2.33 (m, 2 H), 2.07–2.02 (m, 2 H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 171.1, 155.5 (q, J = 38 Hz), 136.3, 129.1 (2 C), 128.4
0.3. [α]2D0 = +8 (c = 1.00, CH Cl ); m.p. 115–117 °C. IR (neat): ν =
˜
2
2
3271, 2925, 2098, 1716, 1638, 1184, 727 cm–1. 1H NMR (250 MHz,
CDCl3): δ = 8.04 (br. s, 1 H), 7.33–7.19 (m, 5 H), 5.50 and 3.96
(qAB, JAB = 14.9 Hz, 2 H, PhCH2), 4.56 (dd, J = 8.5, 5.6 Hz, 1 H), (2 C), 128.2, 115.9 (q, J = 287 Hz), 53.9, 52.8, 52.1, 49.4, 37.2,
3.96–3.90 (m, 1 H), 3.49 (d, J = 15.7 Hz, 1 H), 3.33 (dd, J = 15.7,
4.7 Hz, 1 H), 1.69–2.29 (m, 4 H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 170.9, 156.4 (q, J = 38 Hz), 136.3, 129.0 (2 C), 128.6
(2 C), 128.0, 115.9 (q, J = 286 Hz), 56.9, 53.2, 52.5, 49.1, 31.4,
25.8 ppm. HRMS (ESI): m/z calcd. for C15H16F3N5NaO2 [M +
Na]+ 378.1154, found 378.1163.
26.0 ppm. MS (ESI): m/z (%) = 415.0 (50), 417.0 (50) [M + Na]+.
(S)-1-Benzyl-3-(trifluoroacetamido)azepan-2one (15): Triethylsilane
(356 µL, 2.24 mmol) was added to a solution of compound 9
(150 mg, 0.32 mmol) in trifluoroacetic acid (3 mL), and the mixture
was stirred overnight at room temperature. The reaction mixture
was concentrated in vacuo, and the crude residue was purified by
silica gel column chromatography (EtOAc/cyclohexane, 2:8) to af-
ford pure compound 15 (91 mg, 91 %) as a colourless oil.
Rf(EtOAc/cyclohexane, 2:8) = 0.35. [α]2D0 = +1 (c = 1.00, CH2Cl2).
(3S,7S)-1-Benzyl-7-methoxy-3-(trifluoroacetamido)-2,3,4,7-tetra-
hydro-1H-azepin-2-one (12): DBU (300 µL, 2 mmol) was added to
a solution of compound 8 (84.6 mg, 0.2 mmol) in DMF (2 mL),
and the mixture was stirred for 3 h at 80 °C. The reaction mixture
was concentrated in vacuo and the crude residue was purified by
silica gel column chromatography (EtOAc/cyclohexane, 7:3) to af-
ford pure compound 12 (40 mg, 59%) as a pale yellow solid and
compound 13 (6 mg, 9%) as pale yellow oil. For 12: Rf(EtOAc/
cyclohexane, 7:3) = 0.25. [α]2D0 = –8 (c = 1.00, CH2Cl2); m.p. 91–
IR (neat): ν = 3245, 2925, 1711, 1636, 1181, 1153, 716 cm–1. 1H
˜
NMR (250 MHz, CDCl3): δ = 7.95 (br. s, 1 H), 7.25–7.11 (m, 5
H), 4.64, 4.39 (qAB, JAB = 14.7 Hz, 2 H, PhCH2), 4.51 (dd, J =
10.6, 5.8 Hz, 1 H), 3.37–3.12 (m, 2 H), 2.03–1.98 (m, 1 H), 1.87–
1.60 (m, 3 H), 1.52–1.30 (m, 1 H), 1.14–1.07 (m, 1 H) ppm. 13C
NMR (62.5 MHz, CDCl3): δ = 171.9, 156.5 (q, J = 38 Hz), 136.9,
129.2 (2 C), 128.8 (2 C), 128.6, 116.2 (q, J = 286 Hz), 53.2, 52.2,
48.5, 31.3, 27.9, 27.3 ppm. MS (ESI): m/z (%) = 337.3 (100) [M +
Na]+.
93 °C. IR (neat): ν = 3276, 1718, 1649, 1210, 1184, 1145, 1070, 729,
˜
1
696 cm–1. H NMR (250 MHz, CDCl3): δ = 8.09 (d, J = 4.0 Hz, 1
H), 7.74–7.37 (m, 5 H), 6.07–5.94 (m, 2 H), 5.67 (ddd, J = 12.1,
6.2, 4.0 Hz, 1 H), 5.26 and 4.57 (qAB, JAB = 15.0 Hz, 2 H, PhCH2),
4.90–4.83 (m, 1 H), 3.41 (s, 3 H), 2.97 (ddd, J = 18.3, 4.2, 4.2 Hz,
1 H), 2.45–2.19 (m, 1 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
171.3, 156.5 (q, J = 37 Hz), 137.0, 131.3, 129.2 (2 C), 128.5 (2 C),
128.3, 126.0, 116.2 (q, J = 286 Hz), 87.8, 56.9, 53.3, 50.7, 31.3 ppm.
HRMS (ESI): m/z calcd. for C16H17F3N2NaO3 [M + Na]+
365.1089, found 365.1097.
(3S,5R,6R,7S)-1-Benzyl-5,6-diacetoxy-7-methoxy-3-(trifluoroacet-
amido)azepan-2-one (16): To a stirred solution of compound 12
(50 mg, 0.15 mmol) in CH3CN/H2O/acetone (1:1:1, 3 mL) were
added NMO·H2O (40 mg, 0.29 mmol) and a solution of osmium
tetroxide (1 wt.-% in H2O, 0.19 mL), dropwise. After 16 h at room
temperature, the reaction mixture was diluted with EtOAc (5 mL),
and Na2S2O3 (300 mg) was added. After 30 min of stirring, the
suspension was filtered through a Celite® pad, the solid residue was
thoroughly washed with EtOAc, and the organic layer was concen-
trated in vacuo to give the corresponding crude diol as a colorless
oil (44 mg). Rf(EtOAc/cyclohexane, 7:3) = 0.3. 1H NMR
(250 MHz, CDCl3): δ = 8.15 (d, J = 5.5 Hz, 1 H), 7.32–7.27 (m, 5
H), 5.40 and 3.93 (qAB, JAB = 14.6 Hz, 2 H, PhCH2), 4.72–4.63 (m,
2 H), 4.29 (m, 1 H), 4.14 (br. s, 1 H), 3.02–3.34 (m, 2 H), 2.77 (s,
3 H), 2.15–1.85 (m, 2 H) ppm. The crude diol (44 mg, 0.12 mmol)
was then dissolved in CH2Cl2 (2 mL), and DMAP (86 mg,
0.7 mmol) was added. Acetic anhydride (66 µL, 0.7 mmol) was
added dropwise, and the mixture was stirred overnight at room
temperature. The reaction mixture was washed with an aqueous
saturated solution of NH4Cl (5 mL), and the aqueous layer was
extracted with CH2Cl2 (3ϫ30 mL). The combined organic layers
were dried with MgSO4 and concentrated in vacuo. Column
chromatography on silica gel (EtOAc/cyclohexane, 4:6) gave pure
compound 16 (52 mg, 78 % over 2 steps) as a white solid.
Rf(EtOAc/cyclohexane, 4:6) = 0.3. [α]2D0 = +25 (c = 1.00, CH2Cl2);
(1S,4R,5R)-3-Benzyl-4-methoxy-8-(trifluoroacetyl)-3,8-diazabicy-
1
clo[3.2.1]octan-2-one (13): Rf(EtOAc/cyclohexane, 7:3) = 0.2. H
NMR (500 MHz, CDCl3) (major/minor rotamers ratio 7:3, H num-
bers are those of the corresponding position according to IUPAC
nomenclature): δ = 7.34–7.27 (m, 3 H), 7.19–7.17 (m, 2 H), 5.33
and 3.80 (qAB, JAB = 15 Hz, 0.6 H, PhCH2, minor rotamer), 5.29
and 3.87 (qAB, JAB = 15.0 Hz, 1.4 H, PhCH2, major rotamer), 4.95–
5.15 (br. d, J = 3.5 Hz, 0.3 H1 and 0.7 H5), 4.76 (br. s, 0.7 H1),
4.63 (br. d, J = 7.5 Hz, 0.3 H5), 3.96 (br. d, J = 1.5 Hz, 0.7 H4),
3.86 (br. d, J = 1.5 Hz, 0.3 H4), 3.36 (s, 2.1 H, OMe, major rot-
amer), 3.33 (s, 0.9 H, OMe, minor rotamer), 2.20–2.14 (m, 1.4 H7,7Ј
,
major rotamer and 0.3 H6, minor rotamer), 2.11–2.02 (m, 0.7 H6,
major rotamer and 0.6 H7,7Ј, minor rotamer), 1.55–1.49 (m, 0.3
H6Ј), 1.44–1.40 (m, 0.7 H6Ј) ppm. 13C NMR (126 MHz, CDCl3) for
major conformer: δ = 166.8, 153.5 (q, J = 19 Hz), 136.0, 129.0 (2
C), 128.2 (2 C), 128.0, 115.9 (q, J = 284 Hz), 88.1, 59.9, 55.2, 51.4,
45.2, 30.4, 22.0 ppm; for minor conformer: δ = 167.5, 154.8 (q, J
= 17 Hz), 136.0, 129.0 (2 C), 128.2 (2 C), 128.0, 116.1 (q, J =
287 Hz), 88.1, 58.0, 56.1, 54.8, 44.9, 28.1, 24.4 ppm. HRMS (ESI):
m/z calcd. for C16H17F3N2NaO3 [M + Na]+ 365.1089, found
365.1075.
m.p. 174–176 °C. IR (neat): ν = 2925, 1742, 1716, 1654, 1367,
˜
1
1225 cm–1. H NMR (250 MHz, CDCl3): δ = 7.98 (d, J = 5.2 Hz,
1 H), 7.34–7.27 (m, 5 H), 5.55 (ddd, J = 11.9, 2.6, 2.6 Hz, 1 H),
5.44 (dd, J = 5.6, 2.6 Hz, 1 H), 4.98 and 4.19 (qAB, JAB = 14.5 Hz,
2 H, PhCH2), 4.79 (ddd, J = 9.8, 5.7, 5.2 Hz, 1 H), 4.70 (d, J =
5.6 Hz, 1 H), 3.00 (s, 3 H), 2.25–2.03 (m, 2 H), 1.95 (s, 3 H), 1.84
(s, 3 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 171.1, 170.4,
(3S,6R)-1-Benzyl-6-bromo-3-(trifluoroacetamido)azepan-2-one (14):
Triethylsilane (526 µL, 3.31 mmol) was added to a solution of com-
pound 8 (200 mg, 0.472 mmol) in trifluoroacetic acid (5 mL), and
Eur. J. Org. Chem. 2008, 1901–1909
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1907