10.1002/ejoc.201801690
European Journal of Organic Chemistry
FULL PAPER
4.16-4.01 (m, 2H), 3.24-2.99 (m, 2H), 2.33 (s, 3H), 1.23-1.08 (m, 3H);
(11) δ:8.13 (d, J=16.2 Hz, 1H), 7.58-6.97 (m, 7H), 6.91 (d, J=8.4 Hz, 1H),
6.59 (d, J=16.2 Hz, 1H), 5.21 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.36 (s, 3H),
1.40 (t, J=7.1 Hz, 3H).
2.36-2.32 (m, 2H), 2.27 (s, 3H), 2.17-2.10 (m, 2H), 0.91 (d, J = 6.5 Hz,
12H). 13C NMR (100 MHz, CDCl3) δ: 154.0, 145.1, 137.5, 133.6, 129.8,
128.5, 128.4, 128.3, 128.0, 127.6, 127.4, 127.2, 125.6, 111.8, 70.2, 48.9,
25
44.2, 41.6, 37.0, 20.8, 20.6, 20.5. [α]D = -2.9 (c=0.89, CHCl3) for 96%
ee.
(R)-3-(2’-benzyloxy-5’-methyl)phenylpropanoic acid (13)[3a, 17]
(R)-N,N-diisopropyl-3-(2’-benzyloxy-5’-methyl)phenylpropanammine
-
(R)-Tolterodine (1)[2b]
10mL of 10% NaOH solution were added to the mixture (1.01 g) of 11
and 12 and the suspension was stirred under reflux for 3 hours. 1M HCl
solution was added until pH 1-2. The mixture was extracted with ethyl
acetate (3 x 30mL) and the combined organic extracts were dried over
anhydrous Na2SO4, filtered and evaporated to give the crude product as
waxy solid. The crude product was a mixture (983.1mg) of 13 (71%) and
(E)-3-(2’-benzyloxy, 5’-methylphenyl)-2-propenoic acid (29%), as showed
by 1H NMR analysis.
Under a nitrogen atmosphere, Pd/C (10%, 90.4mg) was added to a
solution of 15 (357.1mg, 0.86mmol) in disareated MeOH (6mL). The
mixture was saturated with H2 and was stirred for 24h under 1.5bar
hydrogen pressure. The solid was filtered off and the solvent was
removed under reduced pressure to give 1 as white glue-foam (257.4mg,
0.79mmol, 94% yield).
1H NMR (200 MHz, CDCl3) δ (13): 11.10-9.70 (bs, 1H), 7.45-6.95 (m,
12H), 6.80 (d, J=8.1 Hz, 1H), 5.03-4.95 (m, 3H), 3.23-3.01 (m, 2H), 2.29
(s, 3H); (E)-3-(2’-benzyloxy, 5’-methylphenyl)-2-propenoic acid δ:
11.10-9.70 (bs, 1H), 8.15 (d, J=16.1 Hz, 1H), 7.45-6.95 (m, 7H), 6.88 (d,
J=8.5 Hz, 1H), 6.54 (d, J=16.1 Hz, 1H), 5.18 (s, 2H), 2.33 (s, 3H).
1H NMR: (400 MHz, CDCl3) δ: 7.34–7.28 (m, 4H), 7.28–7.19 (m, 2H),
6.87–6.78 (m, 2H), 6.57 (s, 1H), 4.48 (dd, J = 11.1, 4.0 Hz, 1H), 3.26 (qui,
J = 6.7 Hz, 2H), 2.80–2.67 (m, 1H), 2.48–2.33 (m, 2H), 2.21–2.06 (m,
4H), 1.13 (dd, J = 19.5, 6.7 Hz, 12H). 13C NMR (100 MHz, CDCl3) δ:
153.1, 144.6, 132.2, 129.4, 128.6, 128.5, 128.3, 128.10, 127.8, 126.2,
29
120.0, 118.1, 48.5, 42.5, 39.6, 33.1, 20.8, 19.8, 19.4. [α]D = +28.8
(c=1.67, MeOH) for 96% ee. [α]D20 = +24.9 (c=1.50, MeOH) for 96% ee.
(R)-N,N-diisopropyl-3-(2’-benzyloxy-5’-methyl)-phenylpropanammide
(14)[3a]
[Lit. value:[2b] [α] D 20 = –23.0 (c 1.5, MeOH) for (S)-Tolterodine].
Under
nitrogen
atmosphere,
1-Ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl, 697.8mg,
3.6mmol), 4-(dimethylamino)pyridine (DMAP, 96.3mg, 0.79mmol) and
diisopropylamine (1.5mL, 10.5mmol) were added to a solution of the
mixture of 13 and (E)-3-(2’-benzyloxy, 5’-methylphenyl)-2-propenoic acid
(983.1mg) in dry CH2Cl2 (6mL). The yellow-green mixture was stirred at
room temperature and the reaction was monitored by TLC analysis (n-
Hexane:Ethyl Acetate 85:15). After 24h the mixture was diluted with
CH2Cl2 (90mL) and washed with 1M HCl solution (2 x 90mL), saturated
NaHCO3 solution (2 x 45mL) and H2O (2 x 45mL). The organic phase
was dried over anhydrous Na2SO4 and the solvent was removed under
vacuum to give the crude product as a white-yellow glue (1.02g), which
was purified by Biotage IsoleraTM Chromatograph (n-Hexane:Ethyl
Acetate 85:15) to give 14 as a yellow glue (494.1mg, 1.2mmol, 40% yield
calculated on 11).
Acknowledgments
Financial support from Università di Pisa is gratefully
acknowledged. We thank Mr. Vincenzo Rositano for helping with
the synthesis of ligand 4 and ethyl-3-arylpropenoates 6b-d..
Keywords: Asymmetric catalysis; P-ligands; Steroids; Chiral
pool; Chiral auxiliaries; (R)-Tolterodine
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1H NMR (400 MHz, CDCl3) δ: 7.34-7.13 (m, 10H), 7.04 (d, J=2.1 Hz, 1H),
6.97 (dd, J= 8.2, 2.2 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 5.02-4.90 (m, 3H),
4.00 (qui, J=6.7 Hz 1H), 3.35 (bs, 1H), 3.07-2.97 (m, 2H), 2.29 (s, 3H),
1.28 (dd, J=15.5 6.8 Hz, 6H), 1.07 (d, J=6.7 Hz, 3H), 0.98 (d, J = 6.7 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ: 170.2, 154.0, 144.2, 137.3, 132.6,
129.6, 129.1, 128.3 (2 peaks), 128.0, 127.6, 127.4, 125.8, 111.9, 70.0,
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28
45.7, 41.9, 39.6, 21.0, 20.8, 20.7, 20.6, 20.5. [α]D = -2.7 (c=0.70,
CH2Cl2) for 96% ee.
(R)-N,N-diisopropyl-3-(2’-benzyloxy-5’-methyl)phenylpropanammine
(15)[3g]
Under nitrogen atmosphere a solution of BH3∙Me2S (10.0-10.2M, 0.5mL)
was added dropwise to a solution of 14 (494.1mg, 1.2mmol) in dry THF
(6mL). The clear solution was heated under reflux and the reaction was
monitored by TLC analysis (n-Hexane:Ethyl Acetate 85:15). After 20h the
reaction was quenched with MeOH (10mL) at 0°C, the mixture was
stirred under reflux for one hour, then was concentrated under vacuum
and water (15mL) was added. The mixture was extracted with Et2O (3 x
15mL) and the combined organic extracts were dried over anhydrous
Na2SO4. After removing the solvent under reduced pressure, 15 was
obtained as withe glue (448.5 mg, 1.08 mmol, 90% yield).
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1H NMR (400 MHz, CDCl3) δ: 7.37–7.28 (m, 5H), 7.25–7.19 (m, 4H),
7.18–7.10 (m, 2H), 6.92 (dd, J=8.3, 2.2 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H),
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