Deprotection of 7 with DDQ
22.8 mmol), (S)-N-benzyl-N-α-methylbenzylamine (5.0 g, 23.5
mmol) in THF (20 ml) and tert-butyl cinnamate (3.0 g, 14.7
mmol) in THF (10 ml) gave, after purification by column
chromatography on silica gel (hexane–Et2O 20:1) 14 as a
colourless oil (5.45 g, 89%). [α]D23 Ϫ4.0 (c 1.0, CHCl3), lit.35 (ent)
[α]D20 ϩ3.9 (c 0.7, CHCl3); δH (400 MHz, CDCl3) 1.22 (9H, s,
OC(Me)3), 1.27 (3H, d, J 6.8, C(α)Me), 2.45–2.60 (2H, m,
C(2)H2), 3.68 (2H, ABq, NCH2), 4.00 (1H, q, J 6.8, C(α)H),
4.41 (1H, dd, J3,2A 9.5, J3,2B 5.6, C(3)H), 7.20–7.49 (15H, m,
Ph).
DDQ (131 mg, 0.58 mmol, 1.2 eq.) was added to a solution of 7
(200 mg, 0.48 mmol, 1.0 eq.) in DCM–H2O (5:1) (3 ml) and
stirred overnight at RT. The solution was poured onto saturated
aqueous sodium bicarbonate solution (20 ml), extracted with
1
DCM (3 × 60 ml), dried and concentrated in vacuo. H NMR
spectroscopic analysis of the crude reaction mixture and
comparison with authentic 1H NMR spectra of tert-butyl
3-(N-benzylamino)-3-phenylpropanoate
8
and tert-butyl
3-(N-4-methoxybenzylamino)-3-phenylpropanoate 9 indicated
the selective cleavage of the 4-OMe substituted benzyl group to
give 8 and 4-methoxybenzaldehyde.
Preparation of (3R,ꢀS)-tert-butyl 3-(N-ꢁ-methylbenzylamino)-
3-phenylpropanoate26 15
Deprotection of 7 with CAN
Following representative procedure 2, CAN (1.10 g, 2 mmol)
was added to 14 (346 mg, 0.83 mmol) in MeCN–H2O (5:1)
(6 ml). Following work-up, the residue was purified by column
chromatography on silica gel (hexane–Et2O 5:1) to give 15 as a
yellow oil (234 mg, 86%). Rf 0.25; [α]D23 Ϫ15.8 (c 1.0, CHCl3);
lit.26 [α]D23 Ϫ16.3 (c 1.45, CHCl3); δH (400 MHz, CDCl3) 1.39
(3H, d, J 6.5, C(α)Me), 1.42 (9H, s, CO2C(Me)3), 1.91 (1H, br s,
NH), 2.59 (1H, dd, J2A,2B 14.7, J2A,3 6.2, C(2)HA), 2.68 (1H, dd,
J2B,2A 14.7, J2B,3 7.9, C(2)HB), 3.70 (1H, q, J 6.5, C(α)H), 4.21
(1H, dd, J3,2B 7.9, J3,2A 6.2, C(3)H), 7.22–7.36 (10H, m, Ph).
Following representative procedure 2, CAN (536 mg, 0.98
mmol, 2.1 eq.) was added to 7 (200 mg, 0.47 mmol, 1.0 eq.) in
MeCN–H2O (5:1) (6 ml) at RT. Following work-up, H NMR
spectroscopic analysis of the crude reaction mixture and com-
parison with authentic 1H NMR spectra of 8 and 9 indicated a
50:50 mixture of secondary amines 8 and 9.
1
Preparation of tert-butyl 3-(N-4-methoxybenzylamino)-3-phenyl-
propanoate 9
Following representative procedure 1, n-butyllithium (1.6 M,
2.38 ml, 3.8 mmol), 4-methoxybenzylamine 5 (538 mg, 3.92
mmol) in THF (10 ml) and tert-butyl cinnamate (0.5 g, 2.45
mmol) in THF (5 ml) gave, after purification by column
chromatography on silica gel (hexane–Et2O 2:1) 9 as a colour-
less oil (673 mg, 81%). Rf 0.3; C21H27NO3 requires C 73.9; H 8.0;
N 4.1; found C 73.5; H 7.75; N 4.0%; νmax/cmϪ1 (film) 3330
Preparation of (3S,ꢁS)-isopropyl 3-(N-benzyl-N-ꢁ-methyl-
benzylamino)butanoate 16
Following representative procedure 1, n-butyllithium (2.5 M,
1.26 mmol, 0.5 ml), (S)-N-benzyl-N-α-methylbenzylamine (250
mg, 1.30 mmol) in THF (3 ml) and isopropyl crotonate (104
mg, 0.81 mmol) in THF gave, after purification by column
chromatography on silica gel (hexane–Et2O 15:1) 16 as a col-
ourless oil (234 mg, 85%). C22H29NO2 requires C 77.8; H 8.6; N
4.1%; found C 77.6; H 8.5; N 4.1%; [α]D24 ϩ4.4 (c 1.0, CHCl3);
(NH), 2924, 2839 (C–H), 1726 (C᎐O), 1514, 1458 (OMe bend),
᎐
1245 (Ph–O), 1151 (C–O); δH (400 MHz, CDCl3) 1.38 (9H, s,
CO2C(Me)3), 1.91 (1H, br s, NH), 2.53 (1H, dd, J2A,2B 15.2,
J2A,3 5.3, C(2)HA), 2.64 (1H, dd, J2B,2A 15.2, J2B,3 8.7, C(2)HB),
3.56 (2H, ABq, NCH2), 3.80 (3H, s, OMe), 4.06 (1H, dd, J3,2B
8.7, J3,2A 5.3, C(3)H), 6.84 (2H, m, Ph(3)H and Ph(5)H
C6H4OMe), 7.25–7.38 (7H, m, Ph); δC (50 MHz, CDCl3) 28.0,
44.2, 50.7, 55.2, 59.0, 80.6, 113.7, 127.3, 128.5, 129.3, 132.4,
142.7, 158.5, 171.1; m/z APCIϩ 342.2 (MHϩ, 60%), 364.2
(MNaϩ, 10%), 286.2 (MHϩ Ϫ C4H8, 100%).
νmax/cmϪ1 (film) 1727 (C᎐O), 1151 (C–O); δ (300 MHz, CDCl )
᎐
H
3
1.12, 1.16 (2 × 3H, d, J 6.2, OCH(Me)2), 1.34 (3H, d, J 6.9,
C(α)Me), 2.07 (1H, dd, J2A,2B 14.2, J2A,3 8.6, C(2)HA), 2.31 (1H,
dd, J2B,2A 14.2, J2B,3 5.1, C(2)HB), 3.39–3.50 (1H, m, C(3)H),
3.63 (1H, d, J 14.9, NCHA), 3.76 (1H, d, J 14.9, NCHB), 3.89
(1H, q, J 6.9, C(α)H), 4.89 (1H, septet, J 6.2, OCH(Me)2), 7.18–
7.43 (10H, m, Ph); δC (100 MHz, CDCl3) 18.7, 21.8, 39.8, 49.7,
50.3, 53.8, 67.4, 126.6, 126.7, 127.8, 128.1, 128.2, 128.3, 142.0,
144.3, 172.1; m/z APCIϩ 340.2 (MHϩ, 100%), 362.1 (MNaϩ,
10%).
Preparation of tert-butyl 3-(N,N-dibenzylamino)-3-phenyl-
propanoate33 13
Following representative procedure 1, n-butyllithium (2.5 M,
3.0 ml, 7.6 mmol), dibenzylamine (1.54 g, 7.8 mmol) in THF
(10 ml) and tert-butyl cinnamate (1.0 g, 4.9 mmol) in THF
(5 ml) gave, after purification by column chromatography on
silica gel (hexane–Et2O 20:1) 13 as a white solid (1.90 g, 96%).
Rf 0.3; δH (200 MHz, CDCl3) 1.34 (9H, s, CO2C(Me)3), 2.72
(1H, dd, J2A,2B 14.4, J2A,3 8.5, C(2)HA), 3.00 (1H, dd, J2B,2A 14.4,
J2B,3 7.1, C(2)HB), 3.27 and 3.72 (2 × 2H, ABq, NCH2 × 2), 4.28
(1H, dd, J3,2A 8.5, J3,2B 7.1, C(3)H), 7.19–7.41 (15H, m, Ph).
Preparation of (3S,ꢀS)-isopropyl 3-(N-ꢁ-methylbenzylamino)-
butanoate 17
Following representative procedure 2, CAN (1.38 g, 2.1 mmol)
was added to 17 (340 mg, 1.0 mmol) in MeCN–H2O (5:1)
(6 ml). Following work-up, the residue was purified by column
chromatography on silica gel (hexane–Et2O 3:1) to give 17 as a
colourless oil (212 mg, 85%). Rf 0.3; [α]D24 Ϫ46.4 (c 1.0, CHCl3);
νmax/cmϪ1 (film) 3339 (NH), 2978, 2932 (C–H), 1728 (C᎐O),
᎐
1109 (C–O); δH (400 MHz, CDCl3) 1.05, 1.24, 1.33 (4 × 3H, d,
C(α)Me, OCH(Me)2 and C(4)H3), 1.53 (1H, br s, NH), 2.32–
2.42 (2H, C(2)H2), 2.98 (1H, app sextet, J 6.2, C(3)H), 3.89
(1H, q, J 6.5, C(α)H), 5.02 (1H, septet, J 6.4, OCH(Me)2), 7.21–
7.33 (5H, m, Ph); δC (50 MHz, CDCl3) 21.4, 21.8, 24.5, 41.0,
47.9, 55.1, 67.5, 126.5, 126.8, 128.3, 146.0, 171.8; m/z APCIϩ
250.2 (MHϩ, 100%), 272.2 (MNaϩ, 20%), 145.9 (MHϩ Ϫ C4H8,
70%); HRMS (CIϩ) C15H24NO2 requires 250.1807; found
250.1808.
Preparation of tert-butyl 3-(N-benzylamino)-3-phenyl-
propanoate23
8
Following representative procedure 2, CAN (1.15 g, 2.1 mmol)
was added to 13 (400 mg, 1.0 mmol) in MeCN–H2O (5:1)
(6 ml). Following work-up, the residue was purified by column
chromatography on silica gel (hexane–Et2O 2:1) to give 8 as a
colourless oil (246 mg, 79%). δH (400 MHz, CDCl3) 1.42 (9H, s,
CO2C(Me)3), 2.14 (1H, br s, NH), 2.58 (1H, dd, J2A,2B 15.2,
J2A,3 5.3, C(2)HA), 2.69 (1H, dd, J2B,2A 15.2, J2B,3 8.7, C(2)HB),
3.64 (2H, ABq, NCH2), 4.13 (1H, dd, J3,2B 8.7, J3,2A 5.3, C(3)H),
7.24–7.43 (10H, m, Ph).
Preparation of N-benzyl-N-propylamine36 20
Based upon a literature procedure,32 benzaldehyde (11.1 g, 105
mmol) and propylamine (5.91 g, 100 mmol) were heated at
reflux in EtOH (50 ml) before addition of NaBH4 (6.05 g, 160
mmol) at 0 ЊC and allowed to warm to RT. After work-up,
concentration in vacuo gave 20 as a colourless oil (13.7 g,
Preparation of (3R,ꢁS)-tert-butyl 3-(N-benzyl-N-ꢁ-methyl-
benzylamino)-3-phenylpropanoate34 14
Following representative procedure 1, n-butyllithium (1.6 M,
3770
J. Chem. Soc., Perkin Trans. 1, 2000, 3765–3774