10.1002/ejoc.201701299
European Journal of Organic Chemistry
FULL PAPER
(-)-(1R,2S,5S,6R,7S)-6-((Dibenzylamino)methyl)-2-
1.64 (m, 4H), 1.73 (s, 3H), 1.93 (d, J = 6.2 Hz, 3H), 2.08 (d, J = 17.8 Hz,
3H), 2.30 (br s, 2H), 2.67 (br s, 2H), 2.97 (q, 1H), 4.25 (br s, 1H), 4.65 (br
s, 1H), 5.13 (s, 1H), 7.37-7.45 (m, 3H), 7.65-7.67 (m, 2H), 8.64 (br s, 1H),
9.79 (br s, 1H); 13C-NMR (100 MHz, CDCl3) (ppm): 23.9 (CH3), 25.3
(CH3), 29.9 (CH2), 32.6 (CH2), 36.0 (CH), 43.7 (CH), 45.0 (CH), 47.2 (CH2),
58.8 (CH), 77.7 (CH), 118.4 (CH), 126.5 (CH), 127.3 (CH), 128.7 (CH),
139.8 (Cq), 144.9 (Cq). C18H25NO (271.40): calcd. C 79.66, H 9.28, N 5.16;
found C 79.60, H 9.12, N 5.03.
methylbicyclo[3.2.1]octane-2,7-diol ((-)-7) and (-)-(1S,5S,6R,7R)-7-
((Dibenzylamino)methyl)-4-methylbicyclo[3.2.1]oct-3-en-6-ol ((-)-8): A
mixture of acylation products (-)-5 and (-)-6 based on Method A (2.7 g)
was mixed with dibenzylamine (9.0 mL, 46.8 mmol) in neat. The mixture
was stirred for 20 h at room temperature. When completed (indicated by
TLC), the mixture was dissolved in the mixture of dry EtOH (40 mL) and
water (5 mL) and cooled to 0 °C. Solid NaBH4 (2.7 g, 71.4 mmol) was
added to the mixture in small portions followed by stirring overnight in ice
bath. The mixture was then quenched with water (100 mL) and extracted
with CH2Cl2 (3 x 100 mL). The organic phase was dried (Na2SO4) and
evaporated in vacuo. The crude product was purified by column
chromatography on silica gel (n-hexane/EtOAc = 19:1 to 2:1), resulting in
2.0 g (50 %) of compound (-)-7 and 0.58 g (30 %) of compound (-)-8.
(+)-(1R,5R,6S,7S)-4-Methyl-7-((((S)-1-
phenylethyl)amino)methyl)bicyclo[3.2.1]oct-3-en-6-ol
((+)-11)
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synthesized analogously to (-)-11; [α]D = + 76 (c 0.27 MeOH). All
spectroscopic data were similar to those of (-)-11. C18H25NO (271.40):
calcd. C 79.66, H 9.28, N 5.16; found C 79.73, H 9.38, N 4.91.
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Compound (-)-7: white crystals; m.p. 108-183 °C; [α]D = - 14 (c 0.25
MeOH); 1H-NMR (400 MHz, CDCl3) (ppm) 1.09 (dd, J = 6.6, 14.3 Hz, 1H),
1.16-1.22 (m, 2H), 1.26 (s, 3H), 1.28-1.36 (m, 1H), 1.57-1.62 (m, 1H), 1.91
(brs, 1H), 2.04-2.08 (m, 2H), 2.36-2.42 (m, 2H), 2.95 (t, 13.8 Hz, 1H), 3.21
(d, J = 13.1 Hz, 2H), 3.98 (d, J = 13.1 Hz, 2H), 4.47 (dd, J = 6.6, 9.4 Hz,
1H), 7.24-7.34 (m, 10H) ; 13C-NMR (100 MHz, CDCl3) (ppm): 24.2 (CH2),
31.0 (CH3), 31.9 (CH2), 32.5 (CH2), 36.3 (CH), 39.0 (CH), 50.7 (CH), 52.3
(CH2), 58.6 (CH2) 72.7 (Cq), 73.7 (Cq), 127.3 (CH), 128.6 (CH), 129.5 (CH),
138.0 (Cq). C24H31NO2 (365.51): calcd. C 78.86, H 8.55, N 3.83; found C
78.68, H 8.60, N 3.60. Compound (-)-8: white crystals; m.p. 165-169 °C;
[α]D20 = -63 (c 0.29 MeOH); 1H-NMR (400 MHz, CDCl3) (ppm) 1.51-1.56
(m, 1H), 1.61-1.64 (m, 4H), 1.79-1.83 (d, J = 17.8 Hz, 1H), 2.07-2.12 (m,
1H), 2.20 (q, J = 4.7, 6.0 Hz, 1H), 2.28 (t, J = 4.4 Hz, 1H), 2.36-2.42 (m,
1H), 2.48 (dd, J = 5.2, 11.9 Hz, 1H), 2.93 (t, J = 12.0 Hz, 1H), 3.42 (d, J =
13.6 Hz, 2H), 3.77 (d, J = 13.6 Hz, 2H), 4.31 (dd, J = 5.7, 9.3 Hz, 1H), 5.02
(s, 1H), 7.23-7.32 (m, 10H); 13C-NMR (100 MHz, CDCl3) (ppm): 25.1
(CH3), 29.8 (CH2), 32.5 (CH2), 36.2 (CH), 38.9 (CH), 45.4 (CH), 54.6 (CH2),
58.0 (CH2), 78.3 (CH), 117.8 (CH), 127.3 (CH), 128.4 (CH), 129.6 (CH),
137.8 (Cq), 140.3 (Cq). C24H29NO (347.49): calcd. C 82.95, H 8.41, N 4.03;
found C 82.75, H 8.22, N 4.05.
(-)-(1S,5S,6R,7R)-4-Methyl-7-((((S)-1-
phenylethyl)amino)methyl)bicyclo[3.2.1]oct-3-en-6-ol ((-)-12): 1.04 g
(21%); white crystals; m.p. 108-184 °C; [α]D = -131 (c 0.34 MeOH); 1H-
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NMR (400 MHz, CDCl3) (ppm) 1.50-1.55 (m, 1H), 1.61 (d, J = 13.9 Hz,
2H), 1.63 (s, 3H), 1.87 (d, J = 6.8 Hz, 3H), 2.07-2.12 (m, 1H), 2.24-2.31
(m, 2H), 2.69-2.79 (m, 2H), 2.98 (q, 1H), 4.27-4.30 (m, 1H), 4.57 (dd, J =
5.9, 9.2 Hz, 1H), 5.00 (s, 1H), 7.35-7.44 (m, 3H), 7.52-7.55 (m, 2H), 8.56
(br s, 1H), 9.79 (br s, 1H) ; 13C-NMR (100 MHz, CDCl3) (ppm): 20.1 (CH3),
24.9 (CH3), 29.5 (CH2), 32.5 (CH2), 36.2 (CH), 40.0 (CH), 44.8 (CH), 45.2
(CH2), 49.2 (CH), 75.0 (CH), 117.4 (CH), 127.9 (CH), 129.2 (CH), 129.3
(CH), 135.9 (Cq), 139.9 (Cq). C18H25NO (271.40): calcd C 79.66, H 9.28, N
5.16; found C 79.52, H 9.13, N 5.02.
(+)-(1R,5R,6S,7S)-4-Methyl-7-((((R)-1-
phenylethyl)amino)methyl)bicyclo[3.2.1]oct-3-en-6-ol
synthesized analogously to (-)-12; [α]D = + 141.7 (c 0.34 MeOH). All
spectroscopic data were similar to those of (-)-12. C18H25NO (271.40):
calcd. C 79.66, H 9.28, N 5.16; found C 79.73, H 9.31, N 4.93.
((+)-12):
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(-)-(1R,3S,4S,5S,6R,7R)-7-((Dibenzylamino)methyl)-4-
(+)-(1S,2R,5R,6S,7R)-6-((Dibenzylamino)methyl)-2-
methylbicyclo[3.2.1]octane-3,6-diol ((-)-13): To the cooled (0 °C)
solution of (-)-8 (1 g, 2.88 mmmol) in dry THF (30 mL) was added
(CH3)2S.BH3 (700 µL) under the argon atmosphere. The mixture was
stirred overnight at room temperature. The resulting solution then was
treated with 3M aqueous NaOH (3 mL) and 30% aqueous hydrogen
peroxide solution (3 mL) diluted in dry EtOH (10 mL). The mixture was
stirred for 1.5 h at room temperature and then it was diluted with EtOAc
(100 mL) and extracted with water (3 x 100 mL). The organic phase was
dried (Na2SO4), filtered and concentrated under reduce pressure. The
crude product obtained was purified by chromatography on silica gel (n-
hexane/EtOAc = 9:1 to 2: 1 as eluent), resulting in 0.45 g (43%) of (-)-13
methylbicyclo[3.2.1]octane-2,7-diol ((+)-7): synthesized analogously to
(-)-7 from the mixture of (+)-5 and (+)-6; [α]D = + 13 (c 0.25 MeOH). All
spectroscopic data were similar to those of (-)-7. C24H31NO2 (365.51):
calcd. C 78.86, H 8.55, N 3.83; found C 78.70, H 8.68, N 3.73.
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(+)-(1R,5R,6S,7S)-7-((Dibenzylamino)methyl)-4-
methylbicyclo[3.2.1]oct-3-en-6-ol ((+)-8): synthesized analogously to (-)-
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8 from the mixture of (+)-5 and (+)-6; [α]D = + 58 (c 0.29 MeOH). All
spectroscopic data were similar to those of (+)-8. C24H29NO (347.49): calcd.
C 82.95, H 8.41, N 4.03; found C 82.78, H 8.49, N 3.98.
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as white crystals; m.p. 191-193 °C; [α]D = -14 (c 0.26 MeOH); 1H-NMR
General procedure for preparation of conjugate addition with primary
amines: Compound (-)-6 obtained by method B (2.7 g, 18.2 mmol) was
stirred with (R)-methylbenzylamine or (S)-methylbenzylamine (6.0 mL,
46.8 mmol) in neat for 20 h at room temperature. When the reaction was
completed (indicated by TLC), the mixture was dissolved in the mixture of
dry EtOH (40 mL) and water (5 mL) and cooled to 0 °C. Solid NaBH4 (2.7
g, 71.4 mmol) was added to the mixture in small portions and stirred
overnight in an ice bath. The mixture was then quenched with water (100
mL) and extracted with CH2Cl2 (3 x 100 mL). The organic phases were
combined and washed with 5% aqueous HCl solution (100 mL), then dried
(Na2SO4) and evaporated in vacuo. The crude product was purified by
recrystallisation (n-hexane/CH2Cl2), resulting in compounds (-)-11 and (-)-
12, respectively.
(400 MHz, CDCl3) (ppm) 1.10 (d, J = 6.9 Hz, 3H), 1.26-1.46 (m, 5H),
1.76-1.83 (m, 1H), 2.00-2.05 (m, 1H), 2.20-2.23 (m, 1H), 2.30-2.37 (m, 1H),
2.41 (dd, J = 5.3, 12.4 Hz, 1H), 3.02 (t, J = 12.6 Hz, 1H), 3.28 (d, J = 12.8
Hz, 2H), 3.44-3.51 (m, 1H), 3.94 (d, J = 13.1 Hz, 2H), 4.47 (dd, J = 6.6, 9.5
Hz), 7.25-7.35 (m, 10H); 13C-NMR (100 MHz, CDCl3) (ppm) : 17.8 (CH3),
37.1 (CH2), 38.0 (CH), 38.5 (CH2), 40.2 (CH), 45.5 (Cq), 45.7 (CH), 51.1
(CH2), 58.5 (CH2), 70.9 (CH), 75.6 (CH), 127.6 (CH), 128.6 (CH), 129.6
(CH). C24H31NO2 (365.51): calcd. C 77.86, H 8.55, N 3.83; found C 77.70,
H 8.50, N 3.62.
(+)-(1S,3R,4R,5S,6S,7S)-7-((Dibenzylamino)methyl)-4-
methylbicyclo[3.2.1]octane-3,6-diol ((+)-13): synthesized analogously
to (-)-13; [α]D20 = + 16 (c 0.26 MeOH). All spectroscopic data were similar
to those of (-)-13. C24H31NO2 (365.51): calcd. C 77.86, H 8.55, N 3.83;
found C 77.93, H 8.62, N 3.87.
(-)-(1S,5S,6R,7R)-4-Methyl-7-((((R)-1-
phenylethyl)amino)methyl)bicyclo[3.2.1]oct-3-en-6-ol ((-)-11): 1.48 g
(30%); white crystals; m.p. 108-185 °C; [α]D20 = - 71 (c 0.27 MeOH); 1.48-
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