The Journal of Organic Chemistry
Page 6 of 8
For characterization of rac-6c: white solid; m.p. 74.9-76.6 °C; 1H
brine (x 1), dried over MgSO4, concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel
(hexanes:EtOAc 2:1) to afford azaspirene analogue (–)-(5S, 8R,
9R)-6a (1.6 mg, 5.1 µmol) in 92% yield as a white solid which
was analyzed by HPLC using a chiral stationary phase for
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NMR (400 MHz, CDCl3) δ 1.33 (t, J = 7.6 Hz, 3H), 1.70 (s, 3H),
2.60 (d, J = 2.4 Hz, 1H), 2.28-2.80 (m, 2H), 3.20 (d, J = 1.2 Hz,
2H), 4.14 (m, 1H), 6.08 (t, J = 1.2 Hz, 1H), 6.26 (brs, 1H), 7.27-
7.44 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ 5.7, 10.6, 22.8,
40.0, 75.4, 87.6, 91.0, 110.8, 127.3, 128.5, 131.1, 134.8, 165.6,
192.9, 200.7; HRMS (FAB) m/z: [M+H]+ Calcd for C17H20NO5
318.1336; Found 318.1337.
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enantiomeric ratio determination (>99% ee); []D –106 (с 0.22,
MeOH).
Alcohol 20a and 20b. To a solution of aldehyde 18 (1.22 g, 3.56
mmol) in THF (71 mL) was added HCl (1 M in H2O, 35.6 mL),
and the reaction mixture was stirred at room temperature for 20
min. After the addition of saturated aqueous NH4Cl, the resulting
solution was extracted with EtOAc (x 3). The combined organic
layers were washed with brine (x 1), dried over MgSO4,
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexanes:EtOAc 6:1 to 2:1) to afford
alcohol rac-20a (787 mg, 2.63 mmol) in 74% yield as a white
solid and alcohol rac-20b (99.0 mg, 0.331 µmol) in 9.3% yield as
a white solid. Each enantiomer of rac-20b was separated by chiral
HPLC to afford (5S, 9S)-20b (95% ee) and (5R, 9R)-20b (95% ee).
HPLC conditions: CHIRALPAK AD-H (Daicel Chemical
Industries Ltd.), 0.46 x 25 cm, i-PrOH:hexanes 1:5, 1.0 mL/min,
room temperature, 10.2 min for (5R, 9R)-20b and 12.7 min for (5S,
9S)-20b.
Ester 19a and 19b. To a solution of N-Boc-O-benzyl-l-serine A
(27.9 mg, 94.5 µmol) in CH2Cl2 (1.0 mL) was added MNBA
(32.5 mg, 94.5 µmol), DMAP (1.2 mg, 9.5 µmol), and
triethylamine (26 µL, 180 µmol). After stirring for 30 min, a
solution of azaspirene analogue rac-6a (10.0 mg, 31.5 µmol) in
CH2Cl2 (1.0 mL) was added to the reaction mixture. After stirring
for another 1 h at room temperature, the mixture was quenched by
saturated aqueous NH4Cl, and biphasic solution was extracted
with CH2Cl2 (x 3). The combined organic layers were washed
with brine (x 1), dried over anhydrous MgSO4, filtered and
concentrated in vacuo. The residue was purified by preparative-
TLC (CHCl3:CH3CN 5:1) to give ester 19a (8.3 mg, 14.0 µmol) in
44% yield as colorless oil, and ester 19b (7.5 mg, 12.6 µmol) in
40% yield as colorless oil.
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Ester 19a: TLC (CHCl3:CH3CN 4:1): Rf = 0.64; H NMR (400
MHz, CDCl3) δ 1.27 (t, J = 7.6 Hz, 3H), 1.45 (s, 9H), 1.69 (s, 3H),
2.55-2.73 (m, 2H), 2.89 (d, J = 14.0 Hz, 1H), 3.20 (d, J = 14.0 Hz,
1H), 3.71 (dd, J = 9.2, 2.8 Hz, 1H), 4.00 (dd, J = 9.2, 2.4 Hz, 1H),
4.46-4.52 (m, 1H), 4.52 (d, J = 12.0 Hz, 1H), 4.67 (d, J = 11.6 Hz,
1H), 5.43 (d, J = 9.2 Hz, 1H), 5.74 (s, 1H), 6.03 (s, 1H), 6.43-6.51
(m, 1H), 7.17-7.36 (m, 10H); 13C{1H} NMR (125 MHz, CDCl3) δ
5.7, 10.3, 22.9, 28.4, 43.9, 54.0, 70.4, 73.6, 74.0, 80.4, 84.8, 90.9,
110.3, 127.7, 127.7, 128.0, 128.6, 128.8, 130.6, 134.2, 137.5,
rac-20a: TLC (hexanes:EtOAc 1:1): Rf = 0.26; white solid, m.p.
137.9-139.0 °C; 1H NMR (400 MHz, CDCl3) δ 1.30 (t, J = 7.6 Hz,
3H), 1.73 (s, 3H), 2.46-2.75 (m, 3H), 5.02 (dd, J = 8.8, 1.6 Hz,
1H), 6.02 (s, 1H), 7.23-7.29 (m, 3H), 7.38 (t, J = 7.6 Hz, 2H),
8.01 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 5.7, 10.7, 22.6,
72.2, 86.8, 106.1, 111.3, 127.4, 127.7, 129.2, 134.7, 135.9, 167.2,
191.0, 199.7; HRMS (FAB) m/z: [M+H]+ Calcd for C17H18NO4
300.1230; Found 300.1237.
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155.6, 163.3, 170.1, 194.9, 198.8; []D +6.8 (с 0.15, CHCl3);
rac-20b: TLC (hexanes:EtOAc 1:1): Rf = 0.38; white solid, m.p.
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CD (CH3CN): λext = 302.7 (Δε = –0.8), 270.7 (+0.6), 220.8 (–
1.2); HRMS (ESI) m/z: [M+Na]+ Calcd for C32H38N2O9Na
617.2470; Found 617.2468.
175.5 °C (decomp.); H NMR (400 MHz, CDCl3) δ 1.33 (t, J =
7.6 Hz, 3H), 1.70 (s, 3H), 2.61-2.77 (m, 2H), 2.92 (d, J = 12.4 Hz,
1H), 5.20 (dd, J = 12.4, 2.4 Hz, 1H), 5.98 (d, J = 2.0 Hz, 1H),
7.23-7.30 (m, 3H), 7.38 (t, J = 7.6 Hz, 2H), 7.88 (s, 1H); 13C{1H}
NMR (150 MHz, CDCl3) δ 5.6, 10.5, 22.7, 73.8, 91.5, 104.6,
110.3, 127.4, 127.7, 129.3, 134.8, 135.4, 165.3, 193.4, 198.0;
HRMS (FAB) m/z: [M+H]+ Calcd for C17H18NO4 300.1230;
Found 300.1243.
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Ester 19b: TLC (CHCl3:CH3CN 4:1): Rf = 0.59; H NMR (400
MHz, CDCl3) δ 1.15 (t, J = 7.6 Hz, 3H), 1.45 (s, 9H), 1.57 (s, 3H),
2.32-2.54 (m, 2H), 2.98 (d, J = 14.0 Hz, 1H), 3.22 (d, J = 14.0 Hz,
1H), 3.64 (dd, J = 9.6, 3.2 Hz, 1H), 3.78 (dd, J = 9.6, 2.8 Hz, 1H),
4.40 (d, J = 12.0 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.43-4.49 (m,
1H), 5.31 (d, J = 8.4 Hz, 1H), 5.74 (s, 1H), 6.08 (s, 1H), 6.45-6.52
(m, 1H), 7.20-7.40 (m, 10H); 13C{1H} NMR (125 MHz, CDCl3):
5.6, 10.2, 22.6, 28.5, 43.9, 54.0, 70.3, 73.5, 73.8, 80.3, 84.5, 91.2,
109.9, 127.3, 127.8, 128.0, 128.6, 128.8, 130.7, 134.1, 137.5,
155.3, 163.4, 169.6, 194.7, 198.5; []D29 –19 (c 0.19, CHCl3); CD
(CH3CN): λext = 282.4 (Δε = –1.3), 254.8 (+0.1), 223.9 (–1.8);
HRMS (ESI) m/z: [M+Na]+ Calcd for C32H38N2O9Na 617.2470;
Found 617.2468.
MTPA ester (S)-21. To a solution of (5S, 9S)-20b (1.8 mg, 6.0
μmol) in CH2Cl2 (600 μL) was added (S)-(–)--methoxy--
(trifluoromethyl)phenylacetic acid (7.0 mg, 30 μmol), EDC·HCl
(5.8 mg, 30 μmol), and DMAP (<1 mg). After stirring for 1 h, the
mixture was quenched by saturated aqueous NH4Cl, and biphasic
solution was extracted with CH2Cl2 (x 3). The combined organic
layers were dried over anhydrous MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexanes:EtOAc 3:1) to afford
MTPA ester (S)-21 (2.6 mg, 5.0 μmol) in 84% yield as a yellow
solid: TLC (hexanes:EtOAc 1:1): Rf = 0.53; m.p. 107.6-108.8 °C;
1H NMR (400 MHz, CDCl3) δ 1.29 (t, J = 7.6 Hz, 3H), 1.62 (s,
3H), 2.64 (q, J = 7.6 Hz, 2H), 3.50 (s, 3H), 5.39 (s, 1H), 6.40 (s,
1H), 7.15 (d, J = 7.2 Hz, 2H), 7.20-7.28 (m, 1H), 7.34 (t, J = 7.2
Hz, 2H), 7.39-7.48 (m, 3H), 7.49-7.59 (m, 2H), 7.95 (s, 1H);
HRMS (FAB) m/z: [M]+ Calcd for C27H24F3NO6 515.1550; Found
Azaspirene analogue (+)-6a. To a solution of 19a (4.3 mg, 7.2
µmol) in THF (0.8 mL) was added HCl (3 M in H2O, 0.4 mL),
and the reaction mixture was stirred at 50 ºC for 14 h. After the
addition of NaHCO3, the resulting solution was extracted with
EtOAc (x 3). The combined organic layers were washed with
brine (x 1), dried over MgSO4, concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel
(hexanes:EtOAc 2:1) to afford azaspirene analogue (+)-(5R, 8S,
9S)-6a (2.2 mg, 6.9 µmol) in 96% yield as a white solid which
was analyzed by HPLC using a chiral stationary phase for
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515.1543; []D +107 (c 0.06, MeOH); CD (CH3CN): λext =
299.1 (Δε = +5.4), 283.8 (+2.1), 262.8 (+5.9), 226.4 (–7.8), 208.0
(+4.0).
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enantiomeric ratio determination (>99% ee); []D +106 (с 0.15,
MeOH), HPLC conditions: CHIRALPAK AD-H (Daicel
Chemical Industries Ltd.), 0.46 x 25 cm, i-PrOH:hexanes 1:3, 1.0
mL/min, room temperature, 13.1 min for (+)-6a and 19.1 min for
(–)-6a.
MTPA ester (R)-22. To a solution of (5S, 9S)-20b (1.8 mg, 6.0
μmol) in CH2Cl2 (600 μL) was added (R)-(+)--methoxy--
(trifluoromethyl)phenylacetic acid (7.0 mg, 30 μmol), EDC·HCl
(5.8 mg, 30 μmol), and DMAP (<1 mg). After stirring for 4 h, the
mixture was quenched by saturated aqueous NH4Cl, and biphasic
solution was extracted with CH2Cl2 (x 3). The combined organic
layers were dried over anhydrous MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexanes:EtOAc 2:1) to afford
Azaspirene analogue (–)-6a. To a solution of 19b (3.3 mg, 5.6
µmol) in THF (0.6 mL) was added HCl (3 M in H2O, 0.3 mL),
and the reaction mixture was stirred at 50 ºC for 14 h. After the
addition of NaHCO3, the resulting solution was extracted with
EtOAc (x 3). The combined organic layers were washed with
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