PAPER
Synthesis of Constrained a-Amino Acid Derivatives
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the crude amino ester (100 mg, 0.43 mmol) in anhyd CH2Cl2 (20
mL) were added DMAP (52.4 mg, 0.43 mmol) and freshly distilled
Ac2O (0.04 mL) at r.t., and the resulting mixture stirred for 12 h. Af-
ter completion of the reaction, the mixture was worked up according
to the general procedure. The crude residue was purified by column
chromatography (eluent: 30% EtOAc–PE) to afford protected ami-
no ester 5 as a white solid (25 mg, 35% over three steps).
1H NMR (400 MHz, CDCl3): d = 1.25 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 1.78 (s, 3 H, NHCOCH3), 1.92–1.96 (m, 4 H, CH2),
2.74 (s, 4 H, CH2), 3.16 (ABq, J = 16.8 Hz, 2 H, CH2), 3.56 (ABq,
J = 16.8 Hz, 2 H, CH2), 4.23 (q, J = 7.0 Hz, 2 H, OCH2CH3), 5.99
(s, 1 H, NHCOCH3), 6.91 (s, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): d = 14.3, 23.2, 23.4, 29.6, 43.3,
61.7, 66.2, 125.2, 136.1, 137.2, 170.4, 173.1.
Mp 144–146 °C; Rf = 0.31 (30% EtOAc–PE).
IR (thin film): 3437, 1735, 1676, 1265 cm–1.
HRMS (Q-Tof): m/z [M + H]+ calcd for C18H24NO3: 302.1756;
found: 302.1756.
1H NMR (400 MHz, CDCl3): d = 1.25 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 1.94 (s, 3 H, NHCOCH3), 2.08 (s, 2 H, CH2CH2), 3.10
(s, 2 H, CH2CH2), 3.19 (ABq, J = 16.4 Hz, 2 H, CH2), 3.59 (ABq,
J = 16.4 Hz, 2 H, CH2), 4.12 (q, J = 7.1 Hz, 2 H, OCH2CH3), 6.06
(s, 1 H, NHCOCH3), 6.91 (s, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): d = 14.2, 23.2, 28.9, 43.7, 61.7,
65.8, 119.4, 137.8, 144.5, 170.3, 173.0.
Ethyl 2-Acetamido-1,2,3,5,6,7,8,9-octahydrocyclohepta[f]in-
dene-2-carboxylate (38)
To a soln of isonitrile derivative 31 (crude reaction mixture) (78 mg,
0.27 mmol) in absolute EtOH (10 mL) was added dil. HCl (6 drops).
After completion of the hydrolysis (ca. 12 h), the mixture was
worked up according to the general procedure. The amino ester ob-
tained was used in the next step without purification. To a soln of
the crude amino ester (46 mg, 0.17 mmol) in anhyd CH2Cl2 (20 mL)
were added DMAP (20 mg, 0.17 mmol) and freshly distilled Ac2O
(0.02 mL) at r.t., and the resulting mixture stirred for 12 h. After
completion of the reaction, the mixture was worked up according to
the general procedure. The crude residue was purified by column
chromatography (eluent: 40% EtOAc–PE) to afford the protected
amino ester 38 as a thick liquid (30 mg, 42% over three steps).
HRMS (Q-Tof): m/z [M + H]+ calcd for C16H20NO3: 274.1443;
found: 274.1431.
Ethyl 2-Acetamido-1,2,3,5,6,7-hexahydro-s-indacene-2-carbox-
ylate (36)
To a soln of isonitrile derivative 29 (100 mg, 0.39 mmol) in absolute
EtOH (10 mL) was added dil. HCl (5–6 drops). After completion of
the hydrolysis (ca. 12 h), the mixture was worked up according to
the general procedure. The amino ester obtained was used in the
next step without purification. To a soln of the crude amino ester (90
mg, 0.36 mmol) in anhyd CH2Cl2 (20 mL) were added DMAP (44
mg, 0.36 mmol) and freshly distilled Ac2O (0.5 mL) at r.t. After
completion of the reaction (24 h, TLC monitoring), the mixture was
worked up according to the general procedure. The crude residue
was purified by column chromatography (eluent: 20% EtOAc–PE)
to afford N-acetyl derivative 36 as a colorless liquid (28 mg, 25%
over two steps).
Rf = 0.46 (20% EtOAc–PE).
IR (neat): 3439, 1735, 1654, 1265 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.25 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 1.60–1.63 (m, 4 H, CH2), 1.80–1.82 (m, 2 H, CH2), 1.92
(s, 3 H, NHCOCH3), 2.75 (t, J = 5.4 Hz, 4 H, CH2), 3.12 (ABq,
J = 16.4 Hz, 2 H, CH2), 3.57 (ABq, J = 16.4 Hz, 2 H, CH2), 4.21 (q,
J = 7.3 Hz, 2 H, OCH2CH3), 6.07 (s, 1 H, NHCOCH3), 6.94 (s, 2 H,
ArH).
13C NMR (100.6 MHz, CDCl3): d = 14.2, 23.2, 28.5, 32.8, 36.7,
43.5, 61.6, 66.2, 125.3, 137.4, 142.6, 170.2, 173.0.
Rf = 0.24 (30% EtOAc–PE).
IR (neat): 3430, 2964, 1742, 1652, 1260, 1023 cm–1.
HRMS (Q-Tof): m/z [M + H]+ calcd for C19H26NO3: 316.1912;
found: 316.1921.
1H NMR (400 MHz, CDCl3): d = 1.26 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 1.94 (s, 3 H, NHCOCH3), 2.07 (t, J = 7.3 Hz, 4 H,
CH2), 2.84–2.89 (m, 2 H, CH2), 3.14 ( ABq, J = 16.5 Hz, 2 H, CH2),
3.59 ( ABq, J = 16.5 Hz, 2 H, CH2), 4.22 (q, J = 7.0 Hz, 2 H,
OCH2CH3), 6.04 (s, 1 H, NHCOCH3), 7.06 (s, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): d = 14.3, 23.3, 25.9, 32.7, 43.3,
61.7, 66.5, 120.7, 137.8, 143.6, 170.4, 173.0.
Ethyl 2-Acetamido-2,3-dihydro-1H-cyclopenta[a]naphthalene-
2-carboxylate (12)
To a soln of isonitrile derivative 40 (150 mg, 0.57 mmol) in absolute
EtOH (10 mL) was added dil. HCl (5 drops). After completion of
the hydrolysis (ca. 12 h), the mixture was worked up according to
the general procedure. The amino ester obtained was used in the
next step without purification. To a soln of the crude amino ester
(136 mg, 0.53 mmol) in anhyd CH2Cl2 (20 mL) were added DMAP
(65 mg, 0.53 mmol) and freshly distilled Ac2O (0.5 mL) at r.t. After
completion of the reaction (24 h, TLC monitoring), the mixture was
worked up according to the general procedure. The crude residue
was purified by column chromatography (eluent: 20% EtOAc–PE)
to afford protected amino ester derivative 12 as a colorless liquid
(45 mg, 30% over two steps).
HRMS (Q-Tof): m/z [M + H]+ calcd for C17H22NO3: 288.1600;
found: 288.1608.
Ethyl 2-Acetamido-2,3,5,6,7,8-hexahydro-1H-cyclopen-
ta[b]naphthalene-2-carboxylate (37)
To a soln of isonitrile derivative 30 (120 mg, 0.45 mmol) in absolute
EtOH (10 mL) was added dil. HCl (5–6 drops). After completion of
the hydrolysis (ca. 12 h), the mixture was worked up according to
the general procedure. The amino ester obtained was used in the
next step without purification. To a soln of the crude amino ester
(106 mg, 0.41 mmol) in anhyd CH2Cl2 (20 mL) were added DMAP
(50.1 mg, 0.41 mmol) and freshly distilled Ac2O (0.5 mL) at r.t. Af-
ter completion of the reaction (24 h, TLC monitoring), the mixture
was worked up according to the general procedure. The crude resi-
due was purified by column chromatography (eluent: 20% EtOAc–
PE) to afford N-acetyl derivative 37 as a colorless liquid (48 mg,
36% over two steps).
Rf = 0.32 (30% EtOAc–PE).
IR (neat):3437, 1736, 1647, 1265, 740 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.25 (t, J = 7.0 Hz, 3 H, CH2CH3),
1.94 (s, 3 H, NHCOCH3), 3.39 (dd, J1 = J2 = 16.8 Hz, 1 H, CHa),
3.62 (dd, J1 = J2 = 17.1 Hz, 1 H, CHb), 3.82 (dd, J1 = J2 = 16.8 Hz,
1 H, CHa), 3.95 (dd, J1 = J2 = 17.1 Hz, 1 H, CHb), 4.25 (q, J = 7.0
Hz, 2 H, CH2CH3), 6.25 (s, 1 H, NHCOCH3), 7.34 (d, J = 8.6 Hz, 1
H, ArH), 7.43–7.48 (m, 2 H, ArH), 7.72 (t, J = 7.0 Hz, 2 H, ArH),
7.85 (d, J = 8.6 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): d = 14.3, 23.3, 42.6, 44.9, 61.9,
65.8, 122.9, 124.1, 125.5, 126.6, 127.9, 128.7, 130.3, 132.9, 135.5,
136.9, 170.4, 173.3.
Rf = 0.24 (30% EtOAc–PE).
IR (neat): 3436, 2925, 1738, 1649, 1265, 739 cm–1.
Synthesis 2011, No. 18, 2945–2950 © Thieme Stuttgart · New York