Full Paper
sulting mixture was stirred at room temperature for 30 min. The
solvents were removed under reduced pressure and the residue
was submitted to oxidation as follows. A suspension of NaIO4
(535 mg, 2.5 mmol) in water (1.25 mL) was added to a solution of
the obtained diol (0.5 mmol) in methanol (2.5 mL). The mixture
was stirred overnight at room temperature and then the solvent
was removed under reduced pressure. Water (4.5 mL) was added
to the crude product and the resulting mixture was extracted with
Et2O (36 mL) and CH2Cl2 (26 mL). The combined organic ex-
tracts were dried over MgSO4, filtered, and the solvent was evapo-
rated. The crude product was purified by flash column chromatog-
raphy on silica gel (eluent hexane/ethyl acetate 20:1) to afford 28
(5 days). Then the reaction mixture was submitted to flash column
chromatography (hexane/ethyl acetate 90:10). The residue was dis-
solved in dry EtOAc (40 mL) and 10% Pd/C was added (10.1 mg).
Air was evacuated under vacuum and H2 was introduced (this pro-
cess was carried out three times). The reaction mixture was stirred
under H2 atmosphere at room temperature for 2 h. Then, the mix-
ture was filtered through Celite and the filtrate was concentrated
under reduced pressure to afford 31 as an oil (70.6 mg, 70%).
1
[a]2D4 = +13.98 (c=0.5, CH2Cl2); H NMR (400 MHz, CDCl3): d=7.49–
7.05 (m, 15H), 5.49 (dd, J=11.2, 3.6 Hz, 1H), 5.02 (dd, J=14.0,
11.2 Hz, 1H), 4.88 (dd, J=14.0, 3.6 Hz, 1H), 3.93 (dd, J=11.2,
5.2 Hz, 1H), 3.84 (dt, J=10.8, 3.4 Hz, 1H), 3.71–3.67 (m, 1H), 3.00
(brs, 1H), 2.56–2.42 (m, 2H), 2.23–2.12 (m, 1H), 1.87–1.75 (m, 1H),
1.22 (s, 3H), 1.21 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=214.8,
141.0, 136.3, 135.1, 129.5, 129.4, 128.9, 128.7, 128.5, 128.4, 127.2,
126.2, 93.0, 73.5, 48.9, 47.8, 43.9, 33.3, 30.4, 28.1, 27.1 ppm; UPLC-
DAD-QTOF: m/z calcd for C29H36N3O6 [M+NH4]+: 522.2604; found:
522.2611.
1
as a colorless oil (110 mg, 74%). H NMR (400 MHz, (CDCl3): d=9.54
(d, J=2.8 Hz, 1H), 7.36–7.14 (m, 10H), 4.80 (dd, J=6.8, 13.2 Hz,
1H), 4.76 (dd, J=8.4, 13.2 Hz, 1H), 3.85 (dt, J=6.8, 8.4 Hz, 1H),
2.75–2.60 (m, 1H), 2.64–2.39 (m, 3H), 2.06 (m, 1H), 1.90 ppm (m,
1H); 13C NMR (100 MHz, CDCl3): d=202.9, 140.3, 136.0, 135.9,
129.2, 128.7, 128.3, 128.2, 126.5, 77.7, 52.7, 44.5, 33.2, 29.2 ppm;
UPLC-DAD-QTOF: m/z calcd for C18H19NO3Na [M+Na]+: 320.1263;
found: 320.1272.
Sequential reduction/oxidative cleavage of 31 to give 32:
BH3·THF complex (1m, 1.5 mL, 1.5 mmol) was added to a solution
of 31 (252 mg, 0.5 mmol) in dry THF (1.5 mL) at 08C, and the re-
sulting solution was stirred at room temperature for 24 h. Then
MeOH (2.5 mL) was added and the resulting mixture was stirred at
room temperature for 30 min. The solvents were removed under
reduced pressure and the resulting diol product was subjected to
oxidative scission by treatment with NaIO4. A suspension of NaIO4
(535 mg, 2.5 mmol) in water (1.25 mL) was added to a solution of
the diol (0.5 mmol) in methanol (2.5 mL). The mixture was stirred
overnight at room temperature. Then the solvent was removed
under reduced pressure. Water (4.5 mL) was added to the crude
product and the resulting mixture was extracted with Et2O (3
6 mL) and CH2Cl2 (26 mL). The combined organic extracts were
dried over MgSO4, filtered, and the solvent was evaporated. The
crude material was purified by flash column chromatography on
silica gel (eluent hexane/ethyl acetate 20:1) to afford 32 as a color-
less oil (179 mg, 80%). [a]2D3 = +16.48 (c=0.5, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=9.58 (dd, J=2.0, 0.8 Hz, 1H), 7.49–6.98 (m,
15H), 5.62 (dd, J=11.6, 3.6 Hz, 1H), 5.02 (dd, J=14.0, 11.0 Hz, 1H),
4.83 (dd, J=4.2 Hz, 1H), 2.74–2.60 (m, 2H), 2.47–2.42 (m, 1H),
2.01–1.92 (m, 1H), 1.75–1.66 ppm (m, 1H); 13C NMR (100 MHz,
CDCl3): d=203.0, 140.2, 134.9, 133.3, 129.9, 129.5, 129.3, 129.2,
129.0, 128.7, 128.4, 127.1, 126.5, 92.9, 73.6, 51.2, 49.3, 43.5, 33.5,
29.7 ppm; UPLC-DAD-QTOF: m/z calcd for C26H26N2NaO5 [M+Na]+:
469.1739; found: 469.1730.
Michael-aldol domino reaction involving 28 and acrolein to give
cycloadducts 29 and 30: DIPEA (10.2 mL, 0.06 mmol) was added to
a
solution of 28 (59.4 mg, 0.2 mmol) and acrolein (26.6 mL,
0.4 mmol) in CH2Cl2 (0.8 mL), and the solution was stirred overnight
at room temperature. CH2Cl2 (5 mL) was added and the mixture
was washed with 1m HCl (5 mL). The organic extract was dried
over MgSO4, filtered, and the solvent was evaporated to afford the
corresponding dialdehyde. 1H NMR (400 MHz, CDCl3): d=9.68 (s,
1H), 9.61 (d, J=2.4 Hz, 1H), 7.40–7.13 (m, 10H), 5.28 (m, 1H), 3.52
(dd, J=5.6, 10.4 Hz, 1H), 2.65 (m, 2H), 2.53 (m, 1H), 2.48 (t, J=
6.8 Hz, 2H), 1.94 (m, 1H), 1.90 (t, J=6.8 Hz, 2H), 1.74 ppm (m, 1H);
13C NMR (100 MHz, CDCl3): d=203.0, 199.3, 140.5, 134.4, 129.3,
129.2, 128.6, 128.5, 128.4, 126.4, 88.8, 51.6, 51.0, 39.5, 33.3, 29.6,
24.4 ppm.
l-Proline (2.1 mg, 0.02 mmol) was added to a solution of the
above-obtained dialdehyde in THF (0.4 mL) at 08C, and the mixture
was stirred at the same temperature for 8 h. CH2Cl2 (5 mL) was
added and the mixture was washed with water (25 mL). The or-
ganic extract was dried over MgSO4, filtered, and the solvent was
evaporated to afford a mixture of epimers 29 and 30 in a ratio of
90:10. Combined yield: 49.5 mg (70%, two steps). Each isomer was
separated by quick flash column chromatography on silica gel
(eluent hexane/ethyl acetate 1:1) and stored at À308C. Major
1
isomer (29): H NMR (400 MHz, CDCl3): d=10.04 (s, 1H), 7.35–6.98
(m, 10H), 4.91 (dt, J=6.0, 11.6 Hz, 1H), 4.50 (dd, J=6.0, 10.8 Hz,
1H), 4.00 (t, J=5.6 Hz, 1H), 3.36 (dt, J=4.4, 5.6 Hz, 1H), 2.67 (m,
1H), 2.60 (m, 2H), 2.50 (m, 1H), 2.15–2.00 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=204.5, 141.4, 134.3, 130.4, 128.8, 128.6, 128.4,
128.2, 126.0, 82.8, 70.1, 50.2, 47.7, 44.2, 33.0, 30.5, 23.1 ppm; UPLC-
DAD-QTOF: m/z calcd for C21H23NO4Na [M+Na]+: 376.1525; found:
Conversion of 32 into 33 and 34 (intramolecular Henry reaction
of 32): DIPEA (3.5 mL, 0.02 mmol) was added to a solution of 32
(44.6 mg, 0.1 mmol) in CH2Cl2 (2 mL) at 08C, and the resulting mix-
ture was stirred at room temperature for 20 h. CH2Cl2 (5 mL) was
added and the mixture was washed with 1m HCl (5 mL). The or-
ganic extract was dried over MgSO4, filtered, and the solvent was
evaporated to afford a mixture of epimeric 33 and 34 in a ratio of
92:8. Major isomer 33 was separated as a white solid by quick
flash column chromatography on silica gel (eluent hexane/ethyl
acetate 20:1). Yield: 37 mg (82%); m.p. 191–1938C; [a]2D5 =À38.38
1
376.1527. Minor isomer (30): H NMR (400 MHz, CDCl3): d=9.92 (s,
1H), 7.36–7.00 (m, 10H), 4.83 (ddd, J=4.4, 5.6, 12.0 Hz, 1H), 4.33 (t,
J=10.4 Hz, 1H), 4.06 (t, J=5.6 Hz, 1H), 2.70–2.66 (m, 1H), 2.57–
2.38 (m, 4H), 2.17 (m, 1H), 2.00 ppm (m, 1H); 13C NMR (100 MHz,
CDCl3): d=202.7, 141.4, 133.6, 130.6, 128.9, 128.4, 128.3, 128.2,
126.0, 85.6, 68.8, 54.2, 47.9, 45.5, 32.8, 30.2, 23.0 ppm; UPLC-DAD-
QTOF: m/z calcd for C21H23NO4Na [M+Na]+: 376.1525; found:
376.1527.
1
(c=0.65, CH2Cl2); H NMR (400 MHz, CDCl3): d=7.38–7.05 (m, 15H),
6.17 (dd, J=12.6, 2.2 Hz, 1H), 5.26 (t, J=5.2 Hz, 1H), 4.74 (t, J=
2.4 Hz, 1H), 4.42 (dd, J=12.4, 5.2 Hz, 1H), 4.03 (t, J=5.2 Hz, 1H),
2.81–2.74 (m, 1H), 2.56–2.48 (m, 1H), 2.47–2.42 (m, 1H), 2.22–
2.09 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=140.5, 136.3,
133.8, 129.3, 129.0, 128.8, 128.5, 128.4, 128.3, 127.9, 127.2, 126.2,
91.6, 83.5, 71.1, 45.4, 42.4, 42.1, 35.4, 27.6 ppm; UPLC-DAD-QTOF:
m/z calcd for C26H30N3O5 [M+NH4]+: 464.2185; found: 464.2190.
Synthesis of 31 (sequential double Michael/reduction of 18): cat-
alyst C6 (23.8 mg, 0.04 mmol, 20 mol%) was added at room tem-
perature to a solution of 18 (40.9 mg, 0.2 mmol, 1 equiv) and 5a
(89.5 mg, 0.6 mmol, 3 equiv) in dichloromethane (0.4 mL), and the
resulting mixture was stirred until completion of the reaction
Chem. Eur. J. 2018, 24, 1 – 10
7
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ