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M. Laars et al. / Tetrahedron: Asymmetry 19 (2008) 641–645
and stirred for 30 min and filtered. The solvent was
removed to give the crude aminal (1.26 g), which was
dissolved in MeOH (22 mL). NaBH4 (451 mg, 12.0 mmol)
was then added in portions followed by acetic acid
(1.36 mL, 23.8 mmol) at 0 °C. The mixture was stirred
overnight. The additional amount of NaBH4 (157 mg,
4.2 mmol) was required to complete the reaction. Et2O
(30 mL) and 10 M aq NaOH (7 mL) were added and the
organic layer was separated. The aqueous phase was ex-
tracted with EtOAc (4 ꢁ 25 mL). The combined organic
phase was dried over K2CO3, filtered and concentrated.
Purification by column chromatography on silica gel
4.4. (R,R)-N-iPr-2,20-Bipiperidine trifluoromethane-sulfonic
acid salt 3c
To a solution of iPr-bipiperidine 3a (92 mg, 0.44 mmol) in
Et2O (1.4 mL) trifluoromethanesulfonic acid (39 lL) was
added at 0 °C. The precipitate was collected and dried in
23
1
vacuum. Mp 143–147 °C. ½aꢃD ¼ ꢄ3:6 (c 5.2, MeOH). H
NMR (500 MHz, CDCl3): d substituted ring 3.15 (hp,
J = 6.4 Hz, 1H, iPr), 3.01 (ddd, J = 10.6, 5.0, 2.5 Hz, 1H,
H-2), 2.93 (m, 1H, H-6), 2.76 (ddd, J = 15.0, 12.2,
3.1 Hz, 1H, H-6), 1.76 (m, J = 14.4, 13.0, 5.0, 4.0 Hz, 1H,
H-3), 1.62 (m, J = 13.0, 3 ꢁ 4.0, 1.4 Hz, 1H, H-4), 1.57
(m, 1H, H-5), 1.55 (m, 1H, H-3), 1.44 (m, 1H, H-4), 1.38
(m, 1H, H-5), 1.18 and 1.15 (2d, J = 6.4 Hz, 6H, iPr), d
unsubstituted ring 3.56 (m, 1H, H-6), 3.27 (dt,
J = 2 ꢁ 10.6, 2.6 Hz, 1H, H-2), 2.93 (m, 1H, H-6), 1.94
(m, 2H, H-3,4), 1.90 (m, 1H, H-5), 1.83 (m, 1H, H-5),
1.58 (m, 1H, H-3). 13C NMR (125 MHz, CDCl3): d
120.40 (q, J = 319.9 Hz, CF3), d substituted ring 56.57
(C-2), 51.72 (iPr), 41.84 (C-6), 22.06 (iPr), 21.76 (C-5),
21.20 (iPr), 21.12 (C-3), 19.55 (C-4), d unsubstituted ring
55.83 (C-2), 45.81 (C-6), 25.39 (C-3), 22.44 (C-5), 22.30
(C4). IR: m = 3065, 2973, 2875, 1614, 1294, 1271, 1234,
1160 cmꢄ1. MS (EI): m/z (%) = 127 (10), 126 (100), 111
(6), 84 (30), 56 (12), 55 (5), 41 (6). Anal. Calcd for
C14H27F3N2O3S (360.44): C, 46.65; H, 7.55; N, 7.77.
Found: C, 46.70; H, 7.52; N, 7.84.
(30:1 mixture of CH2Cl2 and 17% solution of NH3 in
18
MeOH) afforded a yellow oil (0.95 g, 76%). ½aꢃD ¼ þ45 (c
1
7.0, MeOH). H NMR (800 MHz, CDCl3): d substituted
ring 3.08 (hp, J = 6.5 Hz, 1H, iPr CH), 2.82 (ddd,
J = 13.4, 9.0, 3.4 Hz, 1H, H-6), 2.51 (ddd, J = 13.4, 6.3,
3.4 Hz, 1H, H-6), 2.42 (m, 1H, H-2), 1.62 (m, 1H, H-3),
1.59 (m, 1H, H-4), 1.53 (m, 1H, H-5), 1.40 (m, 1H, H-3),
1.39 (m, 1H, H-4), 1.26 (m, 1H, H-5), 1.05 and 0.98 (2d,
J = 6.5 Hz; 6H, iPr), d unsubstituted ring 3.11 (dddd,
J = 11.9, 4.2, 2.3, 1.7 Hz, 1H, H-6eq), 2.78 (ddd,
J = 11.1, 7.6, 2.3 Hz, 1H, H-2ax), 2.61 (ddd, J = 12.3,
11.9, 2.8 Hz, 1H, H-6ax), 1.82 (m, J = 13.0, 4.0, 4.0, 2.8,
2.8, 1.7 Hz, 1H, H-4eq), 1.64 (m, 1H, H-3eq), 1.57 (m,
1H, H-5eq), 1.42 (m, J = 2 ꢁ 13.0, 12.3, 2 ꢁ 4.0 Hz, 1H,
H-5ax), 1.31 (m, J = 3 ꢁ 13.0, 2 ꢁ 4.0 Hz, 1H, H-4ax),
1.05 (m, 2 ꢁ 13.0, 11.1, 4.0 Hz, 1H, H-3ax); 13C NMR
(200 MHz, CDCl3): d substituted ring 60.46 (C-2), 48.68
(iPr), 42.49 (C-6), 23.53 (C-5), 22.64 (C-3), 22.50 (iPr),
22.08 (C-4), 18.44 (iPr), d unsubstituted ring 55.37 (C-2),
47.69 (C-6), 28.09 (C-3), 26.69 (C-5), 25.17 (C-4). IR:
m = 3327, 2931, 2855, 2795, 1381, 1360 cmꢄ1. MS (EI): m/
z (%) = 126 (100), 110 (3), 84(55), 56 (13), 41 (6). Anal.
Calcd for C13H26N2 (210.37): C, 74.23; H, 12.46; N,
13.32. Found: C, 74.16; H, 12.44; N, 13.42.
4.5. General procedure for the organocatalytic intramolec-
ular aldol reaction with catalysts 3a–c
Organocatalyst was added to the stirred solution of trike-
tone 4 or 5 (0.5 mmol) in MeCN (1 mL). The reaction mix-
ture was then refluxed for the indicated time (Table 1).
After the completion of the reaction, toluene was added,
the mixture concentrated and crude product purified by
column chromatography on silica gel (30% EtOAc in
petroleum ether). Ee was determined by HPLC (Chiralcel
OD-H column, hexane/iPrOH 96:4, flow rate 1 mL/min,
k = 254 nm).
4.3. (R,R)-N-iPr-2,20-Bipiperidine trifluoroacetic acid salt 3b
To a solution of iPr-bipiperidine 3a (330 mg, 1.57 mmol) in
Et2O (3 mL) trifluoroacetic acid (121 lL, 1.57 mmol) was
4.6. General procedure for the organocatalytic intermolec-
ular aldol reaction with catalysts 3a–c
added at 0 °C. The precipitate was collected and dried un-
20
der vacuum. Mp 165–167 °C. ½aꢃD ¼ ꢄ4:2 (c 5.6, MeOH).
1H NMR (500 MHz, CDCl3): d substituted ring 3.09 (hp,
J = 6.4 Hz, 1H, iPr), 3.04 (m, 1H, H-2), 2.77 (m, 2H,
H-6), 1.76 (m, 1H, H-3), 1.58 (m, 1H, H-4), 1.53 (m, 1H,
H-5), 1.52 (m, 1H, H-3), 1.48 (m, 1H, H-4), 1.36 (m, 1H,
H-5), 1.09 and 1.06 (2d, J = 6.4 Hz, 6H, iPr), d unsubstitut-
ed ring 3.54 (m, 1H, H-6), 3.28 (m, 1H, H-2), 2.86 (dt,
J = 2 ꢁ 12.0, 4.2 Hz, 1H, H-6), 1.94 (m, 1H, H-4), 1.91
(m, 1H, H-3), 1.82 (m, 2H, H-5), 1.70 (m, 1H, H-3), 13C
NMR (125 MHz, CDCl3): d 161.99 (q, J = 34.5 Hz,
COO), 116.81 (q, J = 293.7 Hz, CF3), d substituted ring
56.22 (C-2), 50.45 (iPr), 42.01 (C-6), 22.16 (C-5), 22.03
(iPr), 21.37 (C-3), 20.26 (2C, C-4 and iPr), d unsubstituted
ring 55.51 (C-2), 45.16 (C-6), 24.80 (C-3), 22.55 (C4), 22.36
(C-5). IR: m = 2974, 2868, 1674, 1456, 1422, 1203, 1167,
1128, 829, 797, 721 cmꢄ1. MS (EI): m/z (%) = 126 (100),
112 (5), 110 (5), 84 (52), 82 (5), 69 (13), 56 (14), 45 (16).
Anal. Calcd for C15H27F3N2O2 (324.38): C, 55.54; H,
8.39; N, 8.64. Found: C, 55.54; H, 8.64; N, 8.61.
The organocatalyst (0.09 mmol) was added to a solution of
p-nitrobenzaldehyde 8 (0.3 mmol) in acetone (0.6 mL), and
the mixture was stirred at rt for 6 days. The reaction mix-
ture was treated with water and extracted with EtOAc. The
extracts were dried, filtered and concentrated. The pure
aldol product was obtained by column chromatography
on silica gel (17–33% EtOAc in petroleum ether). The ee
of the product was determined by HPLC (Chiralpak
AS-H column, hexane/iPrOH 70:30, flow rate 0.75
mL/min, k = 254 nm).
Acknowledgements
The authors of the article thank Estonian Science Founda-
tion (Grants Nos. 6662, 5628 and 6778) and the Ministry of
Education and Research (Grant No. 0142725s06) for finan-
cial support.