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A. Banerjee et al. / Bioorg. Med. Chem. 18 (2010) 7855–7867
° = index for the major diastereomer (S,S)-15c; x = index for the
minor diastereomer (R,S)-15a. 13C NMR (CDCl3): d (ppm) = 36.7
(C-3o), 37.3 (C-3x), 55.2 (C-2o), 56.1 (C-2x), 58.2 (OCoH3, OCxH3),
58.7 (PhCoH2), 59.4 (PhCxH2), 66.7 (OCoH2), 66.8 (OCxH2), 74.1
(OCoH, OCxH), 96.8 (C5x), 98.5 (C5°), 109.4 (OC°O), 110.5 (OCxO),
114.2/114.3/125.6/125.8/125.9/126.0/128.0/128.1/128.2/128.3/
128.5/128.7/128.9/141.6/141.8/141.9 (PhC), 152.6 (C-6x), 153.2 (C-
6°), 159.4/159.5 (PhC), 188.7 (C-4x), 189.5 (C-4o). HRMS: calcd for
15 min. Then, Danishefsky’s diene 14 (0.10 mL, 0.53 mmol) was
added and the mixture was stirred for another 4 h at ꢁ78 °C before
the reaction mixture was allowed to warm to rt overnight. A satu-
rated solution of NaHCO3 and EtOAc were added, the organic layer
was separated, the aqueous layer was extracted twice with EtOAc,
the organic layer was dried (K2CO3), filtered and concentrated in
vacuo. The residue was purified by fc (2 cm, 12 cm, petroleum
ether/EtOAc = 1:1, 20 mL).
C
28H27NO4H 442.2018, found 442.2013. HPLC (method A): purity
Compound (S,R,S)-19a (Rf = 0.15): pale yellow oil, yield 0.106 g
40% (R,S)-15a, tR = 22.0 min, 53%, (S,S)-15c, tR = 21.5 min, together
93%.
(69%). IR (neat): m
(cmꢁ1) = 1637 (m, C@O), 1575 (s, C@C), 1204/
1084 (m, C–O–C). 1H NMR (CDCl3): d (ppm) = 1.53 (d, J = 6.9 Hz,
3H, CH3), 1.98 (d broad, J = 16.9 Hz, 1H, 3-H), 2.78 (dd, J = 16.9/
7.3 Hz, 1H, 3-H), 3.66–3.74 (m, 2H, 2-H + OCH2), 4.06 (dd, J = 8.3/
6.7 Hz, 1H, OCH2), 4.69 (dt, J = 9.4/6.8 Hz, 1H, OCH), 4.74 (d,
J = 7.6 Hz, 1H, 5-H), 4.84 (q, J = 6.9 Hz, 1H, CHPh), 6.66 (d,
J = 7.5 Hz, 1H, 6-H), 7.17–7.35 (m, 9H, Ph), 7.40–7.45 (m, 6H, Ph).
6.6. (2R)-2-[(4S)-2,2-Diphenyl-1,3-dioxolan-4-yl]-1-[(1R)-1-
phenylethyl]-2,3-dihydropyridin-4(1H)-one ((R,R,S)-18a) and
(2S)-2-[(4S)-2,2-diphenyl-1,3-dioxolan-4-yl]-1-[(1R)-1-
phenylethyl]-2,3-dihydropyridin-4(1H)-one ((R,S,S)-18c)
HRMS: calcd for
589 = +49.3 (23.0 °C, c 1.61, CH2Cl2). HPLC (Method A): purity
98%, tR = 21.7 min.
Compound (S,S,S)-19c (Rf = 0.20): pale yellow oil, yield 17.0 mg
(10%). IR (neat):
(cmꢁ1) = 1638 (m, C@O), 1576 (s, C@C), 1206/
C28H27NO3Na 448.1883, found 448.1887.
The aldehyde (R)-11 (0.143 g, 0.56 mmol) was dissolved in tri-
methyl orthoformate (5 mL), (R)-1-phenylethylamine (0.1 mL,
0.56 mmol) was added and the solution was stirred overnight at
rt. The mixture was concentrated in vacuo, the obtained yellow
residue ((R,S)-17) was dissolved in CH2Cl2 (2 mL) and the resulting
solution was cooled down to ꢁ78 °C. Then BF3ꢀOEt2 (0.10 mL,
0.84 mmol) was added and the mixture was stirred at ꢁ78 °C for
15 min. Then, Danishefsky’s diene 14 (0.16 mL, 0.84 mmol) was
added and the mixture was stirred for another 4 h at ꢁ78 °C before
the reaction mixture was allowed to warm to rt overnight. A satu-
rated solution of NaHCO3 and EtOAc were added, the organic layer
was separated, the aqueous layer was extracted twice with EtOAc,
the organic layer was dried (K2CO3), filtered and concentrated in
vacuo. The residue was purified by fc (2 cm, 12 cm, petroleum
ether/EtOAc = 1:1, 20 mL).
[a]
m
1087 (m, C–O–C). 1H NMR (CDCl3): d (ppm) = 1.24 (d, J = 7.0 Hz,
3H, CH3), 2.27 (d broad, J = 16.9 Hz, 1H, 3-H), 2.56 (dd, J = 16.8/
8.3 Hz, 1H, 3-H), 3.69 (dd, J = 7.1/5.5 Hz, 1H, 2-H), 3.90 (dd,
J = 8.3/7.1 Hz, 1H, OCH2), 4.00 (dd, J = 8.3/6.3 Hz, 1H, OCH2), 4.21
(q, J = 6.5 Hz, 1H, OCH), 4.57 (q, J = 7.0 Hz, 1H, CHPh), 4.96 (d,
J = 7.6 Hz, 1H, 5-H), 7.09–7.11 (m, 2H, 6-H + Ph), 7.18–7.30 (m,
10H, Ph), 7.40–7.45 (m, 4H, Ph). HRMS: calcd for C28H27NO3Na
448.1883, found 448.1882. [
HPLC (Method A): purity 93%, tR = 22.6 min.
a
]
589 = ꢁ192 (22.5 °C, c 0.85, CH2Cl2).
6.8. (2R)-1-(4-Methoxybenzyl)-2-[(4S)-2,2-diphenyl-1,3-
dioxolan-4-yl]piperidin-4-one ((R,S)-22a) and (2S)-1-(4-
methoxybenzyl)-2-[(4S)-2,2-diphenyl-1,3-dioxolan-4-
yl]piperidin-4-one ((S,S)-22c)
Compound (R,R,S)-18a (Rf = 0.18): pale yellow oil, yield 0.126 g
(53%). IR (neat):
m
(cmꢁ1) = 1637 (m, C@O), 1572 (s, C@C), 1207/
1072 (m, C–O–C). 1H NMR (CDCl3): d (ppm) = 1.56 (d, J = 6.9 Hz,
3H, CH3), 1.92 (d broad, J = 17.0 Hz, 1H, 3-H), 2.71 (dd, J = 17.0/
7.1 Hz, 1H, 3-H), 3.36–3.41 (m, 1H, 2-H), 3.72 (dd, J = 8.7/5.3 Hz,
1H, OCH2), 4.01 (dd, J = 8.7/6.6 Hz, 1H, OCH2), 4.70 (q, J = 6.9 Hz,
1H, CHPh), 4.81 (ddd, J = 9.9/6.5/5.4 Hz, 1H, OCH), 5.04 (d,
J = 7.5 Hz, 1H, 5-H), 7.02 (d, J = 7.5 Hz, 1H, 6-H), 7.27–7.53 (m,
Under N2 a mixture of (R,S)-15a and (S,S)-15c (43:57, 1.16 g,
2.6 mmol) was dissolved in THF (10 mL) and the solution was
cooled down to ꢁ78 °C, BF3ꢀOEt2 (0.67 mL, 5.3 mmol) was added
slowly and the solution was stirred for 30 min at ꢁ78 °C. Then a
1 M solution of LiEt3BH in THF (5.30 mL, 5.3 mmol) was added
slowly and the reaction mixture was stirred for 2 h at ꢁ78 °C.
Afterwards a saturated solution of NaHCO3 and EtOAc were added
and the reaction mixture was warmed to rt. Then further EtOAc
was added, the organic layer was separated, the aqueous layer
was extracted twice with EtOAc, the organic layer was dried
(K2CO3) filtered and concentrated in vacuo. The residue was puri-
fied by fc (4 cm, 20 cm, petroleum ether/EtOAc = 85:15, 20 mL).
Compound (R,S)-22a (Rf = 0.16): pale yellow oil, yield 0.433 g
15H, Ph). HRMS: calcd for
C28H27NO3Na 448.1883, found
448.1880. [ 589 = +197 (22 °C, c 0.37, CH2Cl2). HPLC (Method A):
a]
purity 87%, tR = 22.3 min.
Compound (R,S,S)-18c (Rf = 0.11): pale yellow oil, yield 33.0 mg
(14%). IR (neat):
m
(cmꢁ1) = 1637 (m, C@O), 1572 (s, C@C), 1207/
1072 (m, C–O–C). 1H NMR (CDCl3): d (ppm) = 1.62 (d, J = 6.8 Hz,
3H, CH3), 2.60 (dd, J = 16.7/1.6 Hz, 1H, 3-H), 2.77 (dd, J = 16.7/
7.5 Hz, 1H, 3-H), 3.92–3.98 (m, 2H, 2-H + OCH2), 4.05 (dd, J = 8.7/
6.5 Hz, 1H, OCH2), 4.37 (q, J = 6.5 Hz, 1H, CHPh), 4.68 (q,
J = 6.8 Hz, 1H, OCH), 4.90 (d, J = 7.6 Hz, 1H, 5-H), 6.75 (d,
J = 7.7 Hz, 1H, 6-H), 7.15–7.54 (m, 15H, Ph). HRMS: calcd for
(37%). IR (neat):
m
(cmꢁ1) = 1714 (s, C@O), 1205(s)/1070 (s, –C–
O–C–). 1H NMR (CDCl3): d (ppm) = 2.21 (ddd, J = 14.7/5.0/1.3 Hz,
1H, 5-H), 2.26–2.33 (m, 1H, 5-H), 2.40–2.47 (m, 1H, 3-H), 2.66
(ddd, J = 14.8/5.9/0.9 Hz, 1H, 3-H), 2.78–2.84 (m, 1H, 6-H), 3.17
(ddd, J = 12.9/8.3/4.7 Hz, 1H, 6-H), 3.31 (q, J = 5.6 Hz, 1H, 2-H),
3.82 (s, 3H, OCH3), 3.85 (d, J = 13.4 Hz, 1H, PhCH2), 3.94 (t,
J = 7.6 Hz, 1H, OCH2), 4.05 (d, J = 13.4 Hz, 1H, CH2Ph), 4.07 (dd,
J = 7.8/7.0 Hz, 1H, OCH2), 4.37 (q, J = 7.2 Hz, 1H, OCH), 6.87–6.89
(m, 2H, Ph), 7.25–7.37 (m, 8H, Ph), 7.48–7.55 (m, 4H, Ph). HRMS:
calcd for C28H29NO4H 444.2169, found 444.2164. EI (70 eV): m/z
(rel. int.) = 443 (M+, 2), 366 (M-Ph, 2), 218 (M-diphenyldioxolanyl,
C
28H27NO3Na 448.1883, found 448.1891. [
a
]
589 = ꢁ18 (21 °C, c
0.24, CH2Cl2). HPLC (Method A): purity 92%, tR = 21.4 min.
6.7. (2R)-2-[(4S)-2,2-Diphenyl-1,3-dioxolan-4-yl]-1-[(1S)-1-
phenylethyl]-2,3-dihydropyridin-4(1H)-one ((S,R,S)-19a) and
(2S)-2-[(4S)-2,2-diphenyl-1,3-dioxolan-4-yl]-1-[(1S)-1-
phenylethyl)]-2,3-dihydropyridin-4(1H)-one ((S,S,S)-19c)
The aldehyde (R)-11 (91.4 mg, 0.36 mmol) was dissolved in tri-
methyl orthoformate (5 mL), (S)-1-phenylethylamine (0.06 mL,
0.36 mmol) was added and the solution was stirred overnight at
rt. The mixture was concentrated in vacuo, the obtained yellow
oil ((S,S)-17) was dissolved in CH2Cl2 (2 mL) and the resulting solu-
tion was cooled down to ꢁ78 °C. Then BF3ꢀOEt2 (0.07 mL,
0.53 mmol) was added and the mixture was stirred at ꢁ78 °C for
10), 121 (CH2C6H4OCH3, 100), 77 (Ph, 18). [
a]
(82% ee) = +6.4
589
(24 °C, c 0.44, CH2Cl2). HPLC (method A): purity 95%, tR = 18.0 min.
Compound (S,S)-22c (Rf = 0.11): pale yellow oil, yield 0.632 g
(54%). IR (neat):
m
(cmꢁ1) = 1709 (s, C@O), 1450 (m, C–H), 1205
(s)/1069 (s, C–O–C). 1H NMR (CDCl3): d (ppm) = 2.30 (dt, J = 15.1/
3.8 Hz, 1H, 5-H), 2.51 (ddd, J = 15.4/9.5/6.1 Hz, 1H, 5-H), 2.64 (dd,