Diastereoselective Route to Novel Fused or Bridged Tricyclic β-Lactams
Major Isomer (+)-13d: White solid. M.p. 106–107 °C (hexanes/ethyl
FULL PAPER
Tricyclic 2-Azetidinone (+)-18: White solid. M.p. 123–124 °C (hex-
anes/AcOEt). [α]2D5 = +105.4 (c = 1.0, CHCl3). 1H NMR (300 MHz,
acetate). [α]2D5 = +62.7 (c = 1.0, CHCl3). 1H NMR (300 MHz,
2
2
CDCl3, 25 °C): δ = 1.66 (m, 2 H, 3-H, 3Ј-H), 2.18 (d, J5,5Ј
=
CDCl3, 25 °C): δ = 1.71 (d, J4,4Ј = 12.5 Hz, 1H, 4-H), 2.35 (m,
2
13.3 Hz, 1 H, 5-H), 2.60 (s, 3 H, NMe), 2.67 (m, 1 H, 5Ј-H), 3.00
1H, 4Ј-H), 2.63 (s, 3H, NMe), 3.06 (d, J2,2Ј = 14.1 Hz, 1H, 2-H),
3.63 (d, J2,2Ј = 14.1, J2Ј,3 = 3.6 Hz, 1H, 2Ј-H), 3.65 (d, J4Ј,5
4.6 Hz, 1H, 5-H), 3.94 (s, 1H, 6-H), 4.56 (dd, J3,4Ј = 5.8, J2Ј,3
2
3
3
3
2
3
3
(ddd, J2,2Ј = 14.6, J = 11.7, J = 5.4 Hz, 1 H, 2-H), 3.42 (d, J5,6
=
=
3
3
3
3
= 6.4 Hz, 1 H, 6-H), 3.80 (ddd, 2J2,2Ј = 14.6, J = 4.9, J = 1.3 Hz,
1 H, 2Ј-H), 4.03 (d, 3J7,8 = 4.7 Hz, 1 H, 7-H), 4.64 (dd, 3J4,5Ј = 9.6,
3J = 4.9 Hz, 1 H, 4-H), 5.21 (d, 3J7,8 = 4.7 Hz, 1 H, 8-H), 6.96 (m,
3 H, Ar), 7.23 (m, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 165.7 (C9), 157.4, 129.7, 122.4, 115.4, 80.6, 74.9, 65.0,
3
3.6 Hz, 1H, 3-H), 4.92 (d, J6,7 = 1.4 Hz, 1H, 7-H), 6.99 (m, 2H,
Ar), 7.24 (m, 3H, Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 168.4 (C8), 157.2, 129.7, 122.5, 115.9, 82.2, 73.9, 63.7, 63.2, 48.9,
46.3(NMe), 27.3 (C4) ppm. IR (KBr): ν = 1751 cm–1. MS (CI):
˜
63.2, 46.3 (NMe), 35.7, 33.6 (C5), 31.0 ppm. IR (KBr): ν =
m/z (%) = 261 (8) [M + H]+, 260 (49) [M]+, 167 (53), 84 (100).
C14H16N2O3 (260.29): C 64.60, H 6.20, N 10.76; found C 64.62, H
6.15, N 10.79.
˜
1751 cm–1. MS (CI): m/z (%) = 275 (2) [M + H]+, 274 (100) [M]+,
181 (58), 84 (93). C15H18N2O3 (274.32): C 65.68, H 6.61, N 10.21;
found C 65.66, H 6.60, N 10.18.
Tricyclic 2-Azetidinone (+)-19: Colorless oil. [α]2D5 = +59.3 (c = 1.0,
1
2
Minor Isomer: Colorless oil. [α]2D5 = +19.6 (c = 0.5, CHCl3). 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 1.62 (m, 1 H, 3-H), 1.97 (d,
2J5,5Ј = 12.9 Hz, 1 H, 5-H), 2.14 (m, 1 H, 3Ј-H), 2.52 (s, 3 H, NMe),
CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 1.94 (d, J4,4Ј
=
12.5 Hz, 1H, 4-H), 2.46 (m, 1H, 4Ј-H), 2.65 (s, 3H, NMe), 2.69 (d,
2J2,2Ј = 13.1 Hz, 1H, 2-H), 3.39 (d, J4Ј,5 = 5.5 Hz, 1H, 5-H), 3.54
3
2
3
2
2.70 (ddd as dt, J5,5Ј = 12.9, 3J = 7.8 Hz, 1 H, 5Ј-H), 2.95 (dt,
(s, 1H, 6-H), 3.69 (d, J2,2Ј = 13.1, J2Ј,3 = 3.0 Hz, 1H, 2Ј-H), 4.47
3
3
3
3
3
2J2,2Ј = 13.9, J = 6.6 Hz, 1 H, 2-H), 3.25 (d, J5Ј,6 = 7.8 Hz, 1 H,
(dd, J3,4Ј = 6.4, J2Ј,3 = 3.0 Hz, 1H, 3-H), 5.32 (d, J6,7 = 1.2 Hz,
1H, 7-H), 7.03 (m, 2H, Ar), 7.22 (m, 3H, Ar) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 167.0 (C8), 157.5, 129.6, 122.0, 115.4,
82.6, 72.3, 61.0, 60.5, 47.3, 47.0 (NMe), 32.7 (C4) ppm. IR
3
3
6-H), 3.70 (dd, J7,8 = 4.4, J6,7 = 0.9 Hz, 7-H), 1 H, 3.94 (ddd as
dt, J2,2Ј = 13.9, J = 6.6 Hz, 1 H, 2Ј-H), 4.62 (ddd as dt, J = 7.8,
2
3
3
3
5
3J = 4.9 Hz, 1 H, 4-H), 5.11 (dd, J7,8 = 4.4, J = 1.2 Hz, 1 H, 8-
H), 6.90 (m, 3 H, Ar), 7.25 (m, 2 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 165.8 (C9), 157.4, 129.7, 121.9, 115.0, 78.9,
74.8, 63.0, 61.7, 46.5 (NMe), 36.6, 32.8, 29.7 (C5) ppm.
(CHCl ): ν = 1750 cm–1. MS (CI): m/z (%) = 261 (9) [M + H]+,
˜
3
260 (46) [M]+, 84 (100). C14H16N2O3 (260.29): C 64.60, H 6.20, N
10.76; found C 64.57, H 6.23, N 10.73.
Tricyclic 2-Azetidinone (+)-25: Compound (+)-3 (100 mg,
0.38 mmol), yielded (+)-28 (72 mg, 65%) after purification by flash
chromatography (hexanes/AcOEt 1:1). White solid. M.p. 132–
133 °C (hexanes/AcOEt). [α]2D5 = +55.5 (c = 2.0, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 2.74 (s, 3 H, NMe), 2.79 (m, 1 H,
Tricyclic 2-Azetidinone (+)-13e: Compound (+)-1e (100 mg,
0.38 mmol) yielded (+)-9e (77 mg, 70%) after 3 h, after purification
by flash chromatography (hexanes/AcOEt 1/2). White solid. M.p.
1
104–106 °C (hexanes/AcOEt). [α]2D5 = +104.0 (c = 1.0, CHCl3). H
NMR (300 MHz, CDCl3, 25 °C): δ = 1.85 (m, 4 H, 3-H, 3Ј-H, 4-
3
2
3
7-H), 3.28 (d, J3,7 = 9.6 Hz, 1 H, 3-H), 3.74 (s, 3 H, OMe), 3.74
H, 4Ј-H), 2.16 (dd, J6,6Ј = 13.3, J5,6 = 4.7 Hz, 1 H, 6-H), 2.43
3
(dd, 2J = 12.8, J = 1.8 Hz, 1 H, OCH2), 3.83 (dd as t, J = 7.9 Hz,
(ddd, 2J6,6Ј = 13.3, 3J5,6Ј = 10.0, 3J6Ј,7 = 7.6 Hz, 1 H, 6Ј-H), 2.57 (s,
3 H, NMe), 2.94 (ddd, J2,2Ј = 13.9, J = 9.7, J = 2.0 Hz, 1 H, 2-
H), 3.46 (d, J6Ј,7 = 7.6 Hz, 1 H, 7-H), 3.69 (dd, J2,2Ј = 13.9, J =
2
1 H, OCH2), 3.94 (dd, J = 12.8, 3J = 3.1 Hz, 1 H, OCH2), 3.97
2
3
3
3
2
3
(d, J2,10 = 5.1 Hz, 1 H, 2-H), 4.14 (dd as t, J = 8.5 Hz, 1 H,
3
3
OCH2), 5.02 (d, J2,10 = 5.1 Hz, 1 H, 10-H), 6.85 (d, J = 8.9 Hz, 2
6.0 Hz, 1 H, 2Ј-H), 4.18 (d, J8,9 = 4.9 Hz, 1 H, 8-H), 4.54 (m, 1
H, Ar), 7.31 (d, J = 8.9 Hz, 2 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 163.7 (C11), 156.7, 129.8, 118.4, 114.7, 78.9,
H, 5-H), 5.15 (d, 3J8,9 = 4.9 Hz, 1 H, 9-H), 6.98 (m, 3 H, Ar), 7.23
(m, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 165.6
(C10), 157.5, 129.6, 122.3, 115.5, 80.4, 74.5, 66.3, 65.7, 43.4 (NMe),
68.6, 61.9, 60.8, 55.5, 51.9, 43.8 (NMe), 37.8 ppm. IR (KBr): ν =
˜
1739 cm–1. MS (CI): m/z (%) = 291 (13) [M + H]+, 290 (58) [M]+,
98 (100). C15H18N2O4 (290.32): C 62.06, H 6.25, N 9.65; found C
62.05, H 6.24, N 9.69.
40.1, 29.1 (C6), 28.7, 24.2 ppm. IR (KBr): ν = 1757 cm–1. MS (CI):
˜
m/z (%) = 289 (7) [M + H]+, 288 (35) [M]+, 84 (100), 99 (51).
C16H20N2O3 (288.34): C 66.65, H 6.99, N 9.72; found C 66.66, H
7.00, N 9.67.
General Procedure for the Preparation of INAC Cycloadducts 22,
23, ( )-29, and ( )-30: The appropriate N-alkylhydroxylamine hy-
drochloride (0.75 mmol) and Na2CO3 (0.75 mmol) were added to
Tricyclic 2-Azetidinone (+)-13f: Compound (+)-1a (100 mg,
0.43 mmol), yielded (+)-9f (90 mg, 62%) after purification by flash
chromatography (hexanes/AcOEt 1:1). White solid. M.p. 51–52 °C
(hexanes/AcOEt). [α]2D5 = +18.2 (c = 1.0, CHCl3). 1H NMR
a
well-stirred solution of the corresponding alkenylaldehyde
(0.50 mmol) in MeOH (30 mL). The reaction mixture was heated
at reflux until complete disappearance of the starting aldehyde
(TLC). The mixture was allowed to cool to room temp., and the
solvent was then removed under reduced pressure. The residue was
partitioned between dichloromethane and water. The organic ex-
tract was washed with brine, dried (MgSO4), and concentrated un-
der reduced pressure. Chromatography of the residue gave analyti-
cally pure compounds. Spectroscopic and analytical data for some
representative pure forms of cycloadducts follow.[42]
2
(300 MHz, CDCl3, 25 °C): δ = 1.91 (d, J4,4Ј = 12.8 Hz, 1 H, 4-H),
2
2.38 (m, 1 H, 4Ј-H), 3.07 (d, J2,2Ј = 13.5 Hz, 1 H, 2-H), 3.64 (d,
3
2J = 12.8 Hz, 1 H, PhCHH), 3.68 (d, J4Ј,5 = 4.4 Hz, 1 H, 5-H),
2
3
3.71 (dd, J2,2Ј = 13.5, J2Ј,3 = 3.4 Hz, 1 H, 2Ј-H), 3.94 (d, 2J =
12.8 Hz, 1 H, PhCHH), 3.97 (d, 3J6,7 = 4.3 Hz, 1 H, 6-H), 4.56 (dd,
3J3,4Ј = 6.1, J2Ј,3 = 3.4 Hz, 1 H, 3-H), 5.25 (dd, J6,7 = 4.3, J2,7
=
3
3
5
1.3 Hz, 1 H, 7-H), 6.91 (m, 3 H, Ar), 7.20 (m, 7 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 170.8 (C8), 157.2, 136.7, 129.6,
129.0, 128.5, 127.5, 122.4, 115.3, 81.0, 73.6, 62.4, 60.3, 59.7, 49.7,
Bicyclic Cycloadducts (+)-22a and (+)-23a: Compound (+)-1a
(465 mg, 1.97 mmol) yielded the less polar pyrrolidyl ester (+)-22a
(288 mg, 50%) and the more polar piperidyl ester (+)-23a (57 mg,
8%) after column chromatography (AcOEt/MeOH, 4:1).
28.9 (C4) ppm. IR (KBr): ν = 1762 cm–1. MS (CI): m/z (%) = 336
˜
(27) [M]+, 91 (100). C20H20N2O3 (336.39): C 71.41, H 5.99, N 8.33;
found C 71.49, H 5.89, N 5.91.
Tricyclic 2-Azetidinones (+)-18 and (+)-19: Compound (+)-2a Pyrrolidyl Ester (+)-22a: Colorless oil. [α]2D5 = +23.4 (c = 1.6,
(62 mg, 0.27 mmol) yielded the less polar compound (+)-18 (36 mg,
52%) and the more polar compound (+)-19 (12 mg, 18%) after
column chromatography (hexanes/AcOEt, 2:1).
CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 2.62 (s, 3 H,
3
NMe), 2.81 (dd, 2J8,8Ј = 10.6, J7,8 = 5.9 Hz, 1 H, 8-H), 3.29 (m, 1
3
3
H, 7-H), 3.42 (m, 2 H, 8Ј-H, 2-H), 3.53 (dd, J = 8.5, J = 5.5 Hz,
Eur. J. Org. Chem. 2005, 1680–1693
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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