The Journal of Organic Chemistry
Note
column chromatography on silica gel (heptane/EtOAc 70:30 to
6.87−6.81 (m, 2H), 5.37−5.31 (m, 1H), 4.69 (d, 1H, J = 15 Hz),
4.31−4.25 (m, 1H), 4.22−4.15 (m, 1H), 3.96 (d, 1H, J = 15 Hz),
3.95−3.89 (m, 1H), 3.78 (s, 3H), 3.59−3.56 (m, 1H), 3.15−3.12 (m,
1H), 2.03−1.95 (m, 1H), 1.90−1.84 (m, 1H), 1.75−1.71 (m, 3H),
1.71−1.67 (m, 3H), 1.47−1.37 (m, 2H). 13C NMR (CDCl3, 125
MHz) δ 174.2, 159.1, 137.2, 129.5 (2C), 129.4, 121.0, 114.0 (2C),
77.6, 65.8, 57.5, 55.4, 49.9, 43.8, 39.5, 35.3, 25.9, 18.2. IR λ 1700, 1514
cm−1. HRMS (ES) calcd [M + H]+ for C19H25NO3 316.1913; obsd
316.1926.
(1S,4R,5S)-5-(Benzyloxy)-2-(4-methoxybenzyl)-2-azabicyclo-
[2.2.1]heptan-3-one (9d). Compound 9d was synthesized according
to general procedure C. The crude material was purified by column
chromatography on silica gel (heptane/EtOAc 80:20 to 50:50) to give
9d as a colorless oil (65 mg, 64%). [α]2D0 −48 (c 1.0, CHCl3). 1H NMR
(CDCl3, 500 MHz) δ 7.41−7.25 (m, 5H), 7.23−7.18 (m, 2H), 6.85−
6.80 (m, 2H), 4.75 (d, 1H, J = 10 Hz), 4.65 (d, 1H, J = 15 Hz), 4.44
(d, 1H, J = 10 Hz), 4.35−4.29 (m, 1H), 4.08 (d, 1H, J = 15 Hz), 3.78
(s, 3H), 3.63−3.59 (m, 1H), 3.24−3.20 (m, 1H), 2.01−1.94 (m, 1H),
1.94−1.88 (m, 1H), 1.48−1.38 (m, 2H). 13C NMR (CDCl3, 125
MHz) δ 174.2, 159.1, 138.0, 129.6 (2C), 129.4, 128.5 (2C), 128.2
(2C), 127.7, 114.0 (2C), 77.5, 71.2, 57.7, 55.4, 49.9, 44.0, 39.5, 35.2.
IR λ 1700, 1518 cm−1. HRMS (ES) calcd [M + H]+ for C21H23NO3
338.1756; obsd 338.1752.
30:70) to give 8e as a colorless oil (30 mg, 30%). [α]2D0 +7 (c 1.0,
1
CHCl3). H NMR (CDCl3, 500 MHz) δ 7.17−7.11 (m, 2H), 6.88−
6.82 (m, 2H), 4.52 (d, 1H, J = 15 Hz), 4.19 (q, 2H, J = 5 Hz), 4.13−
4.04 (m, 2H), 3.95−3.91 (m, 1H), 3.85 (d, 1H, J = 15 Hz), 3.79 (s,
3H), 3.67−3.64 (m, 1H), 3.01−2.98 (m, 1H), 2.04−1.97 (m, 1H),
1.92−1.88 (m, 2H), 1.68−1.62 (m, 1H), 1.27 (t, 3H, J = 5 Hz). 13C
NMR (CDCl3, 125 MHz) δ 175.1, 170.2, 159.3, 129.4 (2C), 128.8,
114.2 (2C), 79.3, 67.2, 61.2, 58.0, 55.4, 51.0, 44.4, 37.6, 37.5, 14.3. IR λ
1756, 1693, 1521 cm−1. HRMS (ES) calcd [M + H]+ for C18H23NO5
334.1654; obsd 334.1667.
(1S,4R,5R)-5-Methoxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]-
heptan-3-one (8f). Compound 8f was synthesized according to
general procedure B. The crude material was purified by column
chromatography on silica gel (heptane/EtOAc 70:30 to 35:65) to give
8f as a colorless oil (69 mg, 87%). [α]2D0 +8 (c 1.0, CHCl3). 1H NMR
(CDCl3, 500 MHz) δ 7.17−7.11 (m, 2H), 6.87−6.82 (m, 2H), 4.52
(d, 1H, J = 15 Hz), 3.86 (d, 1H, J = 15 Hz), 3.78 (s, 3H), 3.75−3.71
(m, 1H), 3.65−3.61 (m, 1H), 3.32 (s, 3H), 3.03−2.99 (m, 1H), 1.97−
1.89 (m, 1H), 1.89−1.75 (m, 2H), 1.52−1.45 (m, 1H). 13C NMR
(CDCl3, 125 MHz) δ 175.6, 159.2, 129.4 (2C), 128.9, 114.2 (2C),
79.7, 58.0, 57.3, 55.4, 50.5, 44.3, 37.4, 37.3. IR λ 1693, 1518 cm−1.
HRMS (ES) calcd [M + H]+ for C15H19NO3 262.1443; obsd
262.1433.
General Procedure C: Alkylation of (1S,4R,5R)-5-Hydroxy-2-(4-
methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (4b) with Selec-
tive Inversion (9a−f). A slurry of NaH (24 mg, 0.61 mmol) in dry
THF (2 mL) was cooled to 0 °C with an icebath, and (1S,4R,5R)-5-
hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (4b)
(75 mg, 0.30 mmol) dissolved in dry THF/DMF 2:1 (1 mL) was
added. The reaction was stirred at 0 °C for 1 h. The electrophile (see
Table 3) (0.61 mmol) was added, and the reaction was stirred for 15 h
(0 °C to rt). The reaction mixture was diluted with brine and extracted
by EtOAc, and the organic phase was dried (Na2SO4), filtered, and
concentrated. The crude material was purified by column chromatog-
raphy.
(1S,4R,5S)-5-(Allyloxy)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]-
heptan-3-one (9a). Compound 9a was synthesized according to
general procedure C. The crude material was purified by column
chromatography on silica gel (heptane/EtOAc 80:20 to 50:50) to give
9a as a colorless oil (54 mg, 62%). [α]2D0 −32 (c 1.0, CHCl3). 1H NMR
(CDCl3, 500 MHz) δ 7.22−7.16 (m, 2H), 6.87−6.81 (m, 2H), 5.97−
5.86 (m, 1H), 5.32−5.25 (m, 1H), 5.20−5.14 (m, 1H), 4.63 (d, 1H, J
= 15 Hz), 4.32−4.26 (m, 1H), 4.20−4.13 (m, 1H), 4.05 (d, 1H, J = 15
Hz), 3.97−3.91 (m, 1H), 3.78 (s, 3H), 3.61−3.57 (m, 1H), 3.14−3.10
(m, 1H), 2.01−1.94 (m, 1H), 1.91−1.84 (m, 1H), 1.43−1.37 (m, 2H).
13C NMR (CDCl3, 125 MHz) δ 174.1, 159.1, 134.7, 129.6 (2C),
Ethyl 2-(((1S,4R,5S)-2-(4-Methoxybenzyl)-3-oxo-2-azabicyclo-
[2.2.1]heptan-5-yl)oxy)-acetate (9e). Compound 9e was synthesized
according to general procedure C. The crude material was purified by
column chromatography on silica gel (heptane/EtOAc 70:30 to
35:65) to give 9e as a colorless oil (62 mg, 61%). [α]2D0 −46 (c 1.0,
1
CHCl3). H NMR (CDCl3, 500 MHz) δ 7.21−7.16 (m, 1H), 6.87−
6.81 (m, 2H), 4.63 (d, 1H, J = 15 Hz), 4.49−4.44 (m, 1H), 4.25 (d,
1H, J = 15 Hz), 4.19 (q, 2H, J = 5 Hz), 4.09 (d, 1H, J = 15 Hz), 4.02
(d, 1H, J = 15 Hz), 3.78 (s, 3H), 3.62−3.58 (m, 1H), 3.15−3.11 (m,
1H), 2.08−2.00 (m, 1H), 1.92−1.85 (m, 1H), 1.55−1.48 (m, 1H),
1.42−1.38 (m, 1H), 1.27 (t, 3H, J = 5 Hz). 13C NMR (CDCl3, 125
MHz) δ 173.8, 170.2, 159.1, 129.6 (2C), 129.1, 114.1 (2C), 78.6, 66.3,
60.9, 57.6, 55.4, 49.6, 43.9, 39.5, 35.3, 14.3. IR λ 1753, 1700, 1518
cm−1. HRMS (ES) calcd [M + H]+ for C18H23NO5 334.1654; obsd
334.1654.
(1S,4R,5S)-5-Methoxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]-
heptan-3-one (9f). Compound 9f was synthesized according to
general procedure C. The crude material was purified by column
chromatography on silica gel (heptane/EtOAc 80:20 to 50:50) to give
9f as a colorless oil (48 mg, 61%). [α]2D0 −19 (c 1.0, CHCl3). 1H NMR
(CDCl3, 500 MHz) δ 7.21−7.16 (m, 2H), 6.87−6.81 (m, 2H), 4.68
(d, 1H, J = 15 Hz), 4.17−4.12 (m, 1H), 3.97 (d, 1H, J = 15 Hz), 3.79
(s, 3H), 3.61−3.57 (m, 1H), 3.38 (s, 3H), 3.18−3.14 (m, 1H), 2.02−
1.94 (m, 1H), 1.91−1.85 (m, 1H), 1.43−1.36 (m, 2H). 13C NMR
(CDCl3, 125 MHz) δ 174.1, 159.1, 129.6 (2C), 129.3, 114.1 (2C),
80.2, 57.5, 57.3, 55.4, 49.7, 43.8, 39.4, 34.9. IR λ 1697, 1514 cm−1.
HRMS (ES) calcd [M + H]+ for C15H19NO3 262.1443; obsd
262.1452.
129.3, 117.3, 114.0 (2C), 77.6, 70.3, 57.6, 55.4, 49.9, 43.9, 39.5, 35.2.
IR λ 1697, 1518 cm−1. HRMS (ES) calcd [M + H]+ for C17H21NO3
288.1599; obsd 288.1608.
(1S,4R,5S)-2-(4-Methoxybenzyl)-5-((2-methylallyl)oxy)-2-aza-
bicyclo[2.2.1]heptan-3-one (9b). Compound 9b was synthesized
according to general procedure C. The crude material was purified by
column chromatography on silica gel (heptane/EtOAc 80:20 to
50:50) to give 9b as a colorless oil (59 mg, 65%). [α]2D0 −30 (c 1.0,
(S)-2-(1-(4-Methoxybenxyl)-5-oxopyrrolidin-2-yl)acetaldehyde
(14).16 A solution of (1S,4R,5R)-5-hydroxy-2-(4-methoxybenzyl)-2-
azabicyclo[2.2.1]heptan-3-one (4b) (18.0 mg, 0.073 mmol) in dry
DMSO (0.5 mL) was treated with NaOtBu (20.0 mg, 0.208 mmol) at
room temperature. After 20 min, trifluoroacetic acid (0.1 mL) was
added and the solution was stirred for further 15 min. The mixture was
diluted with water (5.0 mL), and the crude product was extracted with
DCM (2 × 5.0 mL). The combined organic phases were washed with
brine, dried over MgSO4, and concentrated. Purification by column
chromatography (TBME/MeOH 12:1) gave 14 as a colorless oil (14.8
1
CHCl3). H NMR (CDCl3, 500 MHz) δ 7.22−7.17 (m, 2H), 6.86−
6.81 (m, 2H), 4.98−4.95 (m, 1H), 4.89−4.85 (m, 1H), 4.61 (d, 1H, J
= 15 Hz), 4.28−4.22 (m, 1H), 4.06 (d, 1H, J = 15 Hz), 4.05 (d, 1H, J
= 10 Hz), 3.84 (d, 1H, J = 10 Hz), 3.78 (s, 3H), 3.61−3.57 (m, 1H),
3.13−3.10 (m, 1H), 2.00−1.93 (m, 1H), 1.91−1.84 (m, 1H), 1.75−
1.72 (m, 3H), 1.43−1.36 (m, 2H). 13C NMR (CDCl3, 125 MHz) δ
174.2, 159.1, 142.1, 129.6 (2C), 129.4, 114.0 (2C), 112.4, 77.4, 73.1,
57.7, 55.4, 49.9, 43.9, 39.5, 35.1, 19.7. IR λ 1700, 1518 cm−1. HRMS
(ES) calcd [M + H]+ for C18H23NO3 302.1756; obsd 302.1757.
(1S,4R,5S)-2-(4-Methoxybenzyl)-5-((3-methylbut-2-en-1-yl)oxy)-
2-azabicyclo[2.2.1]-heptan-3-one (9c). Compound 9c was synthe-
sized according to general procedure C. The crude material was
purified by column chromatography on silica gel (heptane/EtOAc
80:20 to 50:50) to give 9c as a colorless oil (68 mg, 71%). [α]2D0 −37
mg, 82%). [α]2D0 +2 (c 1.0, CH3CN). H NMR (CDCl3, 500 MHz) δ
1
9.80 (t, 1H, J = 1.3 Hz), 7.27 (m, 2H), 6.98 (m, 2H), 4.88 (d, 1H, J =
15.1 Hz), 4.18 (d, 1H, J = 15.1 Hz), 4.07 (m, 1H), 3.92 (s, 3H), 2.89
(m, 1H), 2.65 (m, 2H), 2.55 (m, 1H), 2.39 (m, 1H), 1.80 (m, 1H).
13C NMR (CDCl3, 100.6 MHz) δ 199.3, 174.9, 159.1, 129.1, 128.3,
114.1, 55.2, 52.3, 47.5, 44.0, 29.8, 24.9. HRMS (FI) calcd [M]+ for
C14H17NO3 247.1208; obsd 247.1227.
1
(c 1.0, CHCl3). H NMR (CDCl3, 500 MHz) δ 7.21−7.16 (m, 2H),
F
J. Org. Chem. XXXX, XXX, XXX−XXX