A Stereoselective Synthesis of Five- and Six-Membered Cyclic β-Amino Acids
reaction mixture was warmed to room temperature and stirred (CHCH3), 66.1 (CH2Ph), 115.2 (C-6), 126.3, 126.8, 126.9 (Ph),
FULL PAPER
overnight. Following addition of sat. aqueous NaHCO3 (100 mL)
the entire mixture was filtered through CeliteTM. The organic phase
was separated, dried (Na2SO4), filtered, and concentrated under
reduced pressure, to give a mixture (2:1) of β-lactams (2.87 g, 63%).
Subjecting this material to flash chromatography (silica, hexane/
EtOAc, 5:1) afforded a major pure fraction containing isomer 7
(1.14 g, 25%) as an oil. [α]3D0.5 ϭ ϩ36.7 (c ϭ 1, CH3OH). IR
(CH2Cl2 film): ν˜max ϭ 2977 s, 2932 s, 1745 s, 1676 m, 1641 m, 1494
s, 1450 s, 1376 m, 967 s, 913 s, 747 s, 699 s cmϪ1. 1H NMR (CDCl3,
300 MHz): δ ϭ 1.64 (d, J ϭ 7.2 Hz, 3 H, CH3), 2.00Ϫ2.22 (br. m,
4 H, 3-H and 4-H), 2.84 (m, 1 H, 2-H), 3.68 (dd, J ϭ 9.0, 1.9 Hz,
1 H, 1Ј-H), 4.53 (q, J ϭ 7.2 Hz, 1 H, CHCH3), 4.80Ϫ5.00 (m, 2
H, 6-H), 5.68 (ddt, J ϭ 17.1, 10.2, 6.5 Hz, 1 H, 5-H), 5.84 (dd, J ϭ
15.8, 9.0 Hz, 1 H, 2Ј-H), 6.38 (d, J ϭ 15.8 Hz, 1 H, 3Ј-H),
7.00Ϫ7.30 (m, 10 H, 2 ϫ Ph) ppm. 13C NMR (CDCl3, 75 MHz):
δ ϭ 19.3 (CH3), 27.7 (C-3), 31.3 (C-4), 53.0 (C-2), 56.1 (C-1Ј), 59.6
(CHCH3), 115.5 (C-6), 126.4, 126.8, 127.4 (Ph), 127.8 (C-5), 128.0,
128.5, 128.5 (Ph), 133.3 (C-2Ј), 135.8 (Ph), 137.3 (C-3Ј), 141.6 (Ph),
169.3 (C-1) ppm. HRMS: calcd. for C23H25ONNaϩ 354.183;
found 354.183.
127.7 (C-5), 128.2, 128.3, 128.4, 128.5, 128.6, 130.0 (Ph), 133.0,
137.6 (C-2Ј and C-3Ј), 174.4 (CO) ppm. HRMS: calcd. for
C30H33NO2Naϩ 462.240; found 462.241.
Cyclic β-Amino Ester 16: The β-amino ester 8 (256 mg, 0.6 mmol)
was dissolved in degassed toluene (150 mL) and a solution of
Grubbs’ catalyst (97 mg, 0.1 mmol) in toluene (10 mL) was added
under Ar. The reaction mixture was kept under Ar and warmed at
55 °C for 48 h. The solvent was removed to give a dark brown
oil that was subjected to flash chromatography (alumina, hexane/
EtOAc, 6:1) to yield the title compound 16 (108 mg, 56%) as a dark
oil. Further chromatography gave a sample suitable for analysis. [α]
30.5 ϭ ϩ61.2 (c ϭ 1.0, CH3OH). IR (CH2Cl2): ν˜max ϭ 3030 w, 1730
D
s, 1494 s, 1452 s, 1351 m, 1263 m, 1158 m, 736 m, 699 s cmϪ1. H
1
NMR (CDCl3, 300 MHz): δ ϭ 1.30 (d, J ϭ 6.6 Hz, 3 H, CH3),
1.55 (br. s, 1 H, NH), 2.63 (m, 2 H, 5-H), 2.83 (m, 1 H, 1-H), 3.92
(q, J ϭ 6.6 Hz, 1 H, CHCH3), 4.02 (br. d, J ϭ 5.8 Hz, 1 H, 2-H),
5.08 (s, 2 H, CH2Ph), 5.70 (s, 2 H, 3-H and 4-H), 7.20Ϫ7.47 (m,
10 H, 2 ϫ Ph) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 24.4 (CH3),
35.05 (C-5), 50.4 (C-2), 56.2(CHCH3), 66.0 (C-1), 66.4 (CH2Ph),
126.5, 126.8, 128.1, 128.3, 128.4 (Ph), 130.3 (C-4), 131.4 (C-3),
135.8, 145.3 (Ph), 174.7 (CO) ppm. HRMS: calcd. for
C21H23NO2Naϩ 344.162; found 344.162.
β-Amino Ester 8: A mixture of the β-lactam 6 (412 mg, 1.3 mmol),
chlorotrimethylsilane (305 µL, 2.4 mmol) and a solution of benzyl
alcohol in CH2Cl2 (1 , 4 mL) was stirred at room temperature for
48 h. The reaction mixture was taken up in EtOAc (20 mL) and
washed with sat. aqueous NaHCO3 (20 mL). The organic phase
was separated, dried (Na2SO4), filtered, and concentrated under
reduced pressure. Subjection of this material to flash chromato-
graphy (silica, hexane/ethyl acetateEtOAc, 7:1) afforded the title
compound 8 (346 mg, 63%) as an oil. [α]3D0.5 ϭ ϩ20.8 (c ϭ 1,
CH3OH). IR (neat): ν˜max ϭ 3320 w, 1734 s, 1494 s, 1450 s, 1156 w,
969 s, 915 s, 750 m, 698 s cmϪ1. 1H NMR (CDCl3, 300 MHz): δ ϭ
1.22 (d, J ϭ 6.6 Hz, 3 H, CH3), 1.50 (br. s, 1 H, NH), 2.27 (t, J ϭ
6.9 Hz, 2 H, 3-H), 2.52 (t, J ϭ 8.1 Hz, 1 H, 2-H), 3.08 (t, J ϭ 8.8
Hz, 1 H, 1-H), 3.83 (q, J ϭ 6.6 Hz, 1 H, CHCH3), 4.90 (m, 2 H,
5-H), 5.05 and 5.29 (AB system, 2 H, J ϭ 12.3 Hz, CH2Ph), 5.64
(ddt, J ϭ 16.9, 10.1, 6.8 Hz, 1 H, 4-H), 5.82 (dd, J ϭ 15.8, 9.1 Hz,
1 H, 2Ј-H), 6.20 (d, J ϭ 15.8 Hz, 1 H, 3Ј-H), 7.10Ϫ7.40 (m, 15 H,
3 ϫ Ph) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 25.2 (CH3), 34.1
(C-3), 51.6 (C-2), 54.5 (C-1Ј), 59.7 (CHCH3), 66.2 (CH2Ph), 116.7
(C-5), 126.4, 126.8, 127.0 (Ph), 127.8 (C-3Ј), 128.2, 128.3, 128.4,
128.5, 128.6, 129.9 (Ph), 133.2, 135.3 (C-2Ј and C-3Ј), 173.8 (C-1)
ppm. HRMS: calcd. for C29H31NO2Naϩ 448.225; found 448.225.
Cyclic β-Amino Ester 17: The β-amino ester 9 (110 mg, 0.25 mmol)
was dissolved in degassed toluene (60 mL) and a solution of
Grubbs’ catalyst (40 mg, 0.05 mmol) in toluene (10 mL) was added
under Ar. The reaction mixture was kept under Ar and warmed at
55 °C for 48 h. The solvent was removed under reduced pressure
to give a dark brown oil. Subjection of this material to flash chro-
matography (alumina, hexane/EtOAc 4:1) afforded recovered start-
ing material (20 mg, 19%) and the title compound 17 (39 mg, 46%)
as a dark oil. Further chromatography gave a sample suitable for
analysis. [α]3D0.5 ϭ ϩ39.3 (c ϭ 1, CH3OH). IR (neat): ν˜max ϭ 3027
w, 1732 s, 1494 s, 1453 s, 1386 m, 1263 s, 1152 s, 736 m, 699 s cmϪ1
.
1H NMR (CDCl3, 300 MHz): δ ϭ 1.31 (d, J ϭ 6.5 Hz, 3 H, CH3),
1.52 (m, 1 H, 6-H), 1.90 (m, 1 H, 7-H), 2.05 (m, 2 H, 5-H), 2.43
(ddd, J ϭ 11.7, 8.8, 3.1 Hz, 1 H, 1-H), 3.32 (dt, J ϭ 8.8, 2.2 Hz, 1
H, 2-H), 4.01 (q, J ϭ 6.5 Hz, 1 H, CHCH3), 5.00 and 5.20 (AB
system, 2 H, J ϭ 12.4 Hz, CH2Ph), 5.72 (m, 1 H, 4-H), 5.85 (dq,
J ϭ 8.1, 2.2 Hz, 1 H, 3-H), 7.08Ϫ7.39 (m, 10 H, 2 ϫ Ph). 13C
NMR (CDCl3, 75 MHz): δ ϭ 24.3 (C-6), 24.6 (C-5), 25.3 (CH3),
47.6 (C-1), 52.6 (CHCH3), 54.8 (C-2), 66.0 (CH2Ph), 126.8, 126.9
(Ph), 127.3 (C-4), 127.9 (C-3), 127.9, 128.0, 128.2, 128.4, 136.2,
145.3 (Ph), 174.7 (CO) ppm. HRMS: calcd. for C22H25NO2Naϩ
358.178; found 358.177.
β-Amino Ester 9: A mixture of the β-lactam 7 (190 mg, 0.6 mmol),
chlorotrimethylsilane (140 µL, 1.1 mmol) and a solution of benzyl
alcohol in CH2Cl2 (1 , 2 mL) was stirred at room temperature for
48 h. The reaction mixture was taken up in EtOAc (10 mL) and
washed with sat. aqueous NaHCO3 (10 mL). The organic phase
was separated, dried (Na2SO4), filtered, and concentrated under
reduced pressure. Subjection of this material to flash chromato-
graphy (silica, hexane/EtOAc, 8:1) afforded the title compound 9
(203 mg, 84%) as an oil. [α]3D0.5 ϭ ϩ54.5 (c ϭ 1, CH3OH). IR (neat):
ν˜max ϭ 3030 w, 2931 s, 1735 s, 1640 s, 1601 s, 1495 m, 1451 m, 749
Cyclic β-Amino Acid 1: A stirred solution of 16 (60 mg, 0.18 mmol)
and palladium hydroxide on carbon (20%, 60 mg) in EtOH (7 mL)
was hydrogenated at 60 psi at room temperature for 48 h. The reac-
tion mixture was filtered through a short pad of CeliteTM, which
was then washed with EtOAc (2 ϫ 10 mL). The combined filtrates
were concentrated under reduced pressure, then taken up in EtOH
(1 mL) and treated with an ethereal solution of HCl. Concentration
of the solvent under reduced pressure gave the title compound
(19 mg, 79%) as a colourless solid. [α]3D0.5 ϭ ϩ62.0 (c ϭ 0.6, H2O)
{ref.[5a] [α]D ϭ ϩ51.8 (c ϭ 1, H2O)}. 1H NMR (CD3OD,
300 MHz,): δ ϭ 1.55Ϫ1.90 (br. m, 4 H, 2 ϫ CH2), 2.05Ϫ2.20 (br.
m, 2 H, CH2), 2.57 (q, J ϭ 8.5 Hz, 1 H, 1-H), 3.65 (q, J ϭ 7.8
Hz, 1 H, 2-H) ppm. HRMS: calcd. for C6H11NO2Naϩ 152.068;
found 152.068.
m, 696 m cmϪ1 1H NMR (CDCl3, 300 MHz): δ ϭ 1.23 (d, J ϭ
.
6.4 Hz, 3 H, CH3), 1.40Ϫ1.70 (br. m, 3 H, 3-H and NH), 1.95 (br.
m, 2 H, 4-H), 2.46 (dq, J ϭ 9.8, 4.9 Hz, 1 H, 2-H), 3.07 (t, J ϭ 8.8
Hz, 1 H, 1Ј-H), 3.84 (q, J ϭ 6.4 Hz, 1 H, CHCH3), 4.87 (m, 1 H,
6-H), 4.92 (m, 1 H, 5-H), 5.07 and 5.33 (AB system, 2 H, J ϭ 12.3
Hz, CH2Ph), 5.65 (ddt, J ϭ 17.1, 10.2, 6.5 Hz, 1 H, 5-H), 5.82 (dd,
J ϭ 15.8, 9.1 Hz, 1 H, 2Ј-H), 6.20 (d, J ϭ 15.8 Hz, 1 H, 3Ј-H),
7.30 (m, 15 H, 3 ϫ Ph) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ Cyclic β-Amino Acid 2: A stirred solution of compound 17 (22 mg,
25.5 (CH3), 29.0 (C-4), 31.6 (C-3), 51.2 (C-2), 54.1 (C-1), 59.9 0.07 mmol) and palladium hydroxide on carbon (20%, 25 mg) in
Eur. J. Org. Chem. 2003, 756Ϫ760
759