Synthesis of Easily Functionalizable Azabicycloalkane Scaffolds
(d, J = 14.2 Hz, 1 H), 3.64 (s, 3 H), 4.13 (m, 1 H), 4.58 (app t, J =
6.3 Hz, 1 H), 4.99–5.10 (m, 2 H), 5.04 (d, J = 12.5 Hz, 1 H), 5.10
(d, J = 12.5 Hz, 1 H), 5.78 (dddd, J = 6.4, 7.6, 10.3, 17.2 Hz, 1 H),
7.05–7.15 (m, 3 H), 7.19–7.28 (m, 3 H), 7.29–7.41 (m, 5 H), 9.80
(s, 1 H) ppm. 13C NMR ([D6]DMSO, 120 °C, 100 MHz): δ = 28.8
(t, 2 C), 38.9 (t), 39.1 (t), 52.5, 59.9, 60.9, 67.3 (t), 70.9 (s), 117.4
(t), 127.8, 128.7 (2 C), 128.9, 129.1, 131.2, 135.2 (s), 136.0, 137.3
(s), 155.6 (s), 166.9 (s), 172.9 (s), 197.8 ppm. MS (ESI): m/z = 501.3
[M + Na]+. C27H30N2O6 (478.54): calcd. C 67.77, H 6.32, N 5.85;
found C 67.93, H 6.42, N 5.85.
128.3, 128.6, 128.7 (2 C), 128.9 (2 C), 129.1, 129.5, 131.2, 135.1 (s),
137.3 (s), 155.6 (s, 2 C), 166.7 (s), 167.0 (s), 172.9 (s, 2 C), 198.0,
198.1 ppm. C31H40N2O6Si (564.75): calcd. C 65.93, H 7.14, N 4.96;
found C 66.08, H 7.23, N 5.01.
Synthesis of Methyl (3S,6S,9aR)-6-Benzyl-6-(benzyloxycarbonyl-
amino)-7-hydroxy-5-oxo-8-vinyloctahydro-1H-pyrrolo[1,2-a]azepine-
3-carboxylate (2): Compound 3 [mixture of (E)/(Z) isomers, 1.01 g,
1.79 mmol] was solubilized in dry CH2Cl2 (17.9 mL) under nitro-
gen and cooled to –10 °C. Sc(OTf)3 (2.15 mmol) was added; after
30 min, the reaction mixture was warmed to room temperature.
Synthesis of Methyl (2S,5R)-1-[(S)-2-Benzyl-2-(benzyloxycarbonyl- After 5 h, the reaction mixture was filtered through a pad of Celite.
amino)-3-oxopropanoyl]-5-[4-(trimethylsilyl)but-2-enyl]pyrrolidine- CH2Cl2 was removed under reduced pressure. The crude mixture
2-carboxylate [3, (E) + (Z) Mixture). Starting from Compound 19: was purified by flash chromatography (hexane/EtOAc, 65:35) to
Oxalyl chloride (2 m) in CH2Cl2 (0.32 mL, 0.64 mmol) was cooled
to –60 °C under nitrogen, and a solution of freshly distilled DMSO
obtain compounds 2a (49%), 2b (16%), and 2c (21%) as foamy
solids. Compound 2a: Rf = 0.36 (hexane/EtOAc, 65:35). [α]2D2 –34.9
(0.06 mL, 0.85 mmol) in dry CH2Cl2 (0.25 mL) was added drop- (c = 0.5, CDCl ). IR (neat): ν = 3364, 3361 (br.), 1745, 1700,
˜
3
wise. After 30 min, a solution of 19 (121 mg, 0.21 mmol) in dry
CH2Cl2 (1.27 mL) was added, and the reaction mixture was stirred
for a further 30 min. Then, a solution of Et3N (0.23 mL,
1.71 mmol) in dry CH2Cl2 (0.51 mL) was added, and the reaction
mixture was slowly warmed to 0 °C. After the reaction was com-
plete (TLC analysis, hexane/EtOAc, 6:4), phosphate buffer (pH =
7) was added to quench the reaction, and the aqueous phase was
extracted with CH2Cl2. The organic phases were collected, dried
with anhydrous Na2SO4, filtered, and the solvents evaporated in
vacuo. The crude mixture was purified by flash chromatography
(hexane/EtOAc, 85:15) to obtain 3 (pale yellow oil) as a 7:3 mixture
of (E)/(Z) isomers (90%). Starting from Compound 20: HG2 cata-
lyst (0.04 mmol) was loaded in a dry round-bottomed flask under
1637 cm–1. 1H NMR ([D6]DMSO, 400 MHz): δ = 1.57 (m, 1 H,
H6), 1.69 (m, 1 H, H6), 1.79 (m, 1 H, H8), 1.91 (m, 1 H, H9), 2.22–
2.38 (m, 3 H, H5, H8, H9), 2.99 (d, J = 14.0 Hz, 1 H, Hb), 3.51 (d,
J = 14.0 Hz, 1 H, Hb), 3.57 (s, 3 H, CO2CH3), 4.18 (t, J = 7.6 Hz,
1 H, H10), 4.28 (d, J = 5.7 Hz, 1 H, H4, singlet after exchange with
D2O), 4.59 (m, 1 H, H7), 4.92–5.06 (m, 3 H, OCH2Ph, HC, HT),
5.21 (d, J = 12.5 Hz, 1 H, OCH2Ph), 5.90 (ddd, J = 7.8, 10.2,
17.7 Hz, 1 H, HV), 5.98 (d, J = 5.7 Hz, 1 H, OH, exchanges with
D2O), 6.19 (s, 1 H, NH), 6.73 (app d, J = 6.7 Hz, 2 H, ArH), 7.04–
7.16 (m, 3 H, ArH), 7.32–7.46 (m, 5 H, ArH) ppm. 13C NMR ([D6]
DMSO, 75 MHz): δ = 26.5 (t), 30.7 (t), 33.3 (t), 34.7 (t), 42.9, 51.8,
53.9, 60.8, 65.4 (t), 68.4 (s), 73.7, 114.0 (t), 126.2, 127.7, 128.0 (2
C), 128.4, 129.9, 136.4 (s), 136.9 (s), 141.6, 153.8 (s), 168.3 (s), 172.3
argon. Compound 20 (200 mg, 0.42 mmol), solubilized in dry (s) ppm. MS (ESI): m/z = 493.6 [M + H]+, 515.6 [M + Na]+. MS
CH2Cl2 (4.2 mL), 2,6-dichloro-1,4-benzoquinone (0.042 mmol),
and allyltrimethylsilane (2.09 mmol) were then sequentially added,
and the reaction mixture was heated to reflux. After 3 h, a second
portion of HG2 (0.021 mmol) was added, and the reaction mixture
was heated to reflux for a further 8 h. After the reaction was com-
(ESI): m/z = 501.3 [M + Na]+. C28H32N2O6 (492.57): calcd. C
68.28, H 6.55, N 5.69; found C 68.41, H 6.49, N 5.57. Compound
2b: Rf = 0.30 (hexane/EtOAc, 65:35). [α]2D2 –55.8 (c = 0.6, CDCl3).
IR (neat): ν = 3415, 3296 (br.), 1735, 1687, 1625 cm–1. 1H NMR
˜
([D6]DMSO, 400 MHz): δ = 1.57–1.76 (m, 2 H, H6, H8), 1.82–1.96
plete (TLC analysis), CH2Cl2 was removed under reduced pressure. (m, 2 H, H6, H9), 2.07 (m, 1 H, H9), 2.24 (m, 1 H, H8), 2.76 (m, 1
The crude mixture was purified by flash chromatography (hexane/ H, H5), 3.34 (d, J = 14.1 Hz, 1 H, Hb), 3.41 (d, J = 14.1 Hz, 1 H,
EtOAc, 85:15) to obtain compound 3 as a 7:3 mixture of (E)/(Z) Hb) 3.59 (s, 3 H, CO2CH3), 4.06 (dd, J = 5.7, 10.1 Hz, 1 H, H4,
isomers (84%). Compound 3a: Rf = 0.33 (hexane/EtOAc, 85:15). 1H doublet after exchange with D2O), 4.16 (d, J = 8.7 Hz, 1 H, H10),
NMR ([D6]DMSO, 120 °C, 400 MHz): δ = 0.02 (s, 9 H), 1.51 (app
d, J = 8.5 Hz, 2 H), 1.59 (m, 1 H), 1.80 (m, 1 H), 1.87–1.99 (m, 2
H), 2.20 (m, 1 H), 2.55 (m, 1 H), 3.38 (AB system, 2 H), 3.63 (s, 3
4.32 (m, 1 H, H7), 4.93 (d, J = 12.5 Hz, 1 H, OCH2Ph), 4.97–5.18
(m, 4 H, OH, OCH2Ph, HC, HT, 1 H exchanges with D2O), 5.86–
6.09 (m, 2 H, HV, NH), 6.94–7.08 (m, 2 H, ArH), 7.15–7.26 (m, 3
H), 4.08 (m, 1 H), 4.58 (app t, J = 6.2 Hz, 1 H), 5.04 (d, J = H, ArH), 7.28–7.41 (m, 5 H, ArH) ppm. 13C NMR ([D6]DMSO,
12.6 Hz, 1 H), 5.08 (d, J = 12.6 Hz, 1 H), 5.24 (ddddd, J1 = J2 =
100 MHz): δ = 27.5 (t), 32.9 (t), 34.3 (t), 39.2 (t), 46.3, 52.7, 57.4,
1.5, J3 = 6.3 Hz, J4 = 7.9 Hz, J5 = 10.2 Hz, 1 H), 5.49 (ddddd, J1 63.4, 66.2 (t), 70.2 (s), 74.3, 114.9 (t), 127.6, 128.6 (2 C), 129.1 (2
= J2 = 1.7, J3 = J4 = 8.5 Hz, J5 = 10.2 Hz, 1 H), 7.04–7.14 (m, 3 C), 130.7, 136.5 (s), 137.8 (s), 143.3, 156.1 (s), 168.9 (s), 173.0 (s)
H), 7.19–7.27 (m, 3 H), 7.30–7.41 (m, 5 H), 9.79 (s, 1 H) ppm. MS
(ESI): m/z = 565.7 [M + H]+, 587.7 [M + Na]+. Compound 3b: Rf
= 0.31 (hexane/EtOAc, 85:15). [α]2D2 –12.4 (c = 1.0, CDCl3). IR
ppm. MS (ESI): m/z = 493.6 [M + H]+, 515.6 [M + Na]+.
C28H32N2O6 (492.57): calcd. C 68.28, H 6.55, N 5.69; found C
68.34, H 6.43, N 5.61. Compound 2c: Rf = 0.27 (hexane/EtOAc,
(neat): ν = 3380, 2840, 2720, 1736, 1716, 1635 cm–1. 1H NMR ([D ]- 65:35). [α]2D2 –81.9 (c = 1.4, CDCl ). IR (neat): ν = 3349 (br.), 1738,
˜
˜
6
3
DMSO, 120 °C, 400 MHz): δ = 0.18 (m, 9 H), 1.44 (app d, J = 1700, 1623 cm–1. 1H NMR ([D6]DMSO, 400 MHz): δ = 1.62 (br.
7.9 Hz, 2 H), 1.57–1.69 (m, 1 H), 1.70–1.82 (m, 1 H), 1.85–2.00 (m, d, J = 13.0 Hz, 1 H, H6), 1.78 (m, 1 H, H8), 1.90 (m, 1 H, H9),
2 H), 2.02–2.14 (m, 1 H), 2.50–2.58 (m, 1 H), 3.36 (d, J = 14.3 Hz, 2.05–2.21 (m, 2 H, H6, H9), 2.26 (m, 1 H, H8), 2.82 (br. t, J =
1 H), 3.41 (d, J = 14.3 Hz, 1 H), 3.63 (s, 3 H), 4.00–4.09 (m, 1 H),
4.54 (app t, J = 6.6 Hz, 1 H), 5.04 (d, J = 12.5 Hz, 1 H), 5.09 (d,
9.6 Hz, 1 H, H5), 3.35 (d, J = 13.6 Hz, 1 H, Hb), 3.40 (d, J =
13.6 Hz, 1 H, Hb), 3.58 (s, 3 H, CO2CH3), 4.28 (d, J = 8.9 Hz, 1
J = 12.5 Hz, 1 H), 5.16–5.26 (ddddd, J1 = J2 = 1.3 Hz, J3 = 7.6 Hz, H, H10), 4.38 (m, 1 H, H7), 4.48 (d, J = 5.3 Hz, 1 H, H4, singlet
J4 = 9.0 Hz, J5 = 15.4 Hz, 1 H), 5.41–5.51 (ddddd, J1 = J2 = 1.3, after exchange with D2O), 4.90 (d, J = 12.6 Hz, 1 H, OCH2Ph),
J3 = J4 = 7.9 Hz, J5 = 15.4 Hz, 1 H), 7.01–7.12 (m, 3 H), 7.17–7.27 5.05 (dd, J = 1.5, 10.3 Hz, 1 H, HC), 5.11–5.23 (m, 2 H, OCH2Ph,
(m, 3 H), 7.29–7.41 (m, 5 H), 9.77 (s, 1 H) ppm. MS (ESI): m/z = HT), 5.30 (d, J = 5.3 Hz, 1 H, OH, exchanges with D2O), 5.94 (ddd,
565.7 [M + H]+, 587.7 [M + Na]+. 13C NMR ([D6]DMSO, 120 °C, J = 7.5, 10.3, 17.5 Hz, 1 H, HV), 6.31 (s, 1 H, NH), 6.73–6.83 (m,
100 MHz mixture of diastereoisomers): δ = –1.1, –0.9, –0.3, 19.2
(t), 23.3 (t), 28.8 (t), 32.2 (t), 37.8 (t), 39.0 (t), 39.1 (t) 52.6 (3 C), ppm. 13C NMR ([D6]DMSO, 100 MHz): δ = 27.5 (t), 33.6 (t), 33.8
60.5, 60.8, 67.2 (t, 2 C), 70.7 (s, 2 C), 124.2, 125.6, 127.8 (2 C), (t), 34.5 (t), 43.9, 52.6, 58.6, 63.5, 65.8 (t), 69.6 (s), 70.6, 115.1 (t),
2 H, ArH), 7.07–7.19 (m, 3 H, ArH), 7.30–7.44 (m, 5 H, ArH)
Eur. J. Org. Chem. 2015, 7557–7570
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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