S.G. Davies et al. / Tetrahedron xxx (2018) 1e13
11
4.26. (2R,3S)-2-Amino-3-hydroxy-3-(40-fluorophenyl)propanoic
acid 45
CH2Cl2 (170 mL) at rt, and the resultant mixture was stirred at rt for
2 h. 5% aq NaHCO3 (1 mL) was added and the resultant mixture was
stirred at rt for 15 min, then extracted with CH2Cl2 (2 ꢃ 1 mL). The
combined organic extracts were dried, then filtered through a pad
of silica (eluent CH2Cl2) and concentrated in vacuo. Purification via
flash column chromatography (eluent 30e40 ꢁC petrol/Et2O, 50:1)
Step 1: Pd(OH)2/C (24 mg, 20% w/w) was added to a stirred,
degassed solution of 39 (121 mg, 0.27 mmol, >99:1 dr) in MeOH
(2 mL) at rt and the resultant mixture was placed under at atmo-
sphere of H2 (5 atm) and stirred at rt for 40 h. The reaction mixture
was then filtered through Celite® (eluent MeOH) and concentrated
in vacuo.
gave a 49 as a colourless oil (60 mg, 60%, >99:1 dr); ½a D25
ꢂ
e4.4 (c 1.0
in CHCl3); nmax (ATR) 1732 (C¼O); dH (400 MHz, CDCl3) 0.94 (3H, d, J
6.6, C(4)MeA), 0.95 (3H, d, J 6.6, C(4)MeB), 1.27 (3H, d, J 6.9, C(a)Me),
Step 2: The residue from the previous step was dissolved in
6.0 M aq HCl (2 mL) and the resultant mixture was stirred at rt for
3 h, then concentrated in vacuo. Purification via ion exchange
chromatography (Dowex 50WX8 resin hydrogen form, 100e200
1.52 (9H, s, CMe3), 1.94 (1H, septet, J 6.9, C(4)H) 3.09 (1H, ddd, J 26.4,
6.9, 3.8, C(3)H), 4.00 (1H, d, J 15.7, NCHAHBPh), 4.08e4.16 (2H, m,
C(a)H, NCHAHBPh), 4.82 (1H, dd, 47.7, 3.8, C(2)H), 7.17e7.46 (10H, m,
Ph); m/z (ESIþ) 400 ([MþH]þ, 100%); HRMS (ESIþ) C25H35FNOþ2
([MþH]þ) requires 400.2646; found 400.2642.
mesh, eluent 1.0 M aq NH4OH) gave 45 as a white solid (52 mg, 97%
44
from 39, >99:1 dr);
mp 232e234 ꢁC; {lit.44 mp 207e208 ꢁC
(dec.)}; ½a 2D5
ꢂ
þ17.9 (c 1.0 in H2O); {lit.44
½
a 2D5
ꢂ
þ20.5 (c 0.21 in H2O)};
4.29. tert-Butyl (2S,3S,
aR)-2-[N-benzyl-N-(a-methylbenzyl)
nmax (ATR) 3271 (OeH, NeH), 1611 (C¼O); dH (400 MHz, D2O) 3.88
(1H, d, J 4.6, C(2)H), 5.26 (1H, d, J 4.6, C(3)H), 7.18 (2H, app t, J 9.0,
C(30)H, C(50)H), 7.43e7.47 (2H, m, C(20)H, C(60)H); dC (100 MHz, D2O)
60.8 (C(2)), 70.8 (C(3)), 115.6 (d, J 21.4, C(30), C(50)), 127.8 (d, J 8.8,
C(20), C(60)), 135.0 (d, J 3.4, C(10)), 162.4 (d, J 244.7, C(40)), 171.9
(C(1)); dF (377 MHz, D2O) ꢀ114.5 (C(40)F); m/z (ESIe) 198 ([MeH]e,
100%); HRMS (ESIþ) C9H11FNO3þ ([MþH]þ) requires 200.0717; found
200.0718.
amino]-3-fluoro-3-phenylpropanoate 50
Et3N$3HF (304 mL, 1.85 mmol) was added to a stirred solution of
34 (400 mg, 0.93 mmol, >99:1 dr) and XtalFluor-E® (318 mg,
1.39 mmol) in CH2Cl2 (0.62 mL) at rt, and the resultant mixture was
stirred at rt for 2 h. 5% aq NaHCO3 (1 mL) was added and the
resultant mixture was stirred at rt for 15 min, then extracted with
CH2Cl2 (2 ꢃ 3 mL). The combined organic extracts were dried, then
filtered through a pad of silica (eluent CH2Cl2) and concentrated in
vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 40:1) gave 50 as a colourless oil (346 mg,
4.27. tert-Butyl (2S,3S,
amino]-3-fluorobutanoate 46 and tert-butyl (2S,3R,
[N-benzyl-N-( -methylbenzyl)amino]butanoate 48
a
R)-2-[N-benzyl-N-(
a
-methylbenzyl)
aR)-2-fluoro-3-
86%, >99:1 dr); ½a D25
ꢂ
þ51.5 (c 1.0 in CHCl3); nmax (ATR) 1720 (C¼O),
a
1146 (CeF); dH (500 MHz, CDCl3) 1.11 (9H, s, CMe3), 1.30 (3H, d, J 6.9,
Et3N$3HF (304 mL, 1.85 mmol) was added to a stirred solution of
C(
NCHAHBPh), 4.12 (1H, q, J 6.9, C(
5.62 (1H, dd, J 47.8, 8.7, C(3)H), 7.18e7.43 (15H, m, Ph); dC (125 MHz,
CDCl3) 20.4 (C( )Me), 28.1 (CMe3), 51.8 (NCH2Ph), 59.9 (C( )), 66.6
a)Me), 3.85 (1H, dd, J 15.5, 8.7, C(2)H), 4.00 (1H, d, J 15.8,
20 (400 mg, 1.08 mmol, >99:1 dr) and XtalFluor-E® (318 mg,
1.39 mmol) in CH2Cl2 (0.62 mL) at rt, and the resultant mixture was
stirred at rt for 2 h. 5% aq NaHCO3 (1 mL) was added and the
resultant mixture was stirred at rt for 15 min, then extracted with
CH2Cl2 (2 ꢃ 3 mL). The combined organic extracts were dried, then
filtered through a pad of silica (eluent CH2Cl2) and concentrated in
vacuo to give an 80:20 mixture of 46 and 48, respectively. Purifi-
cation via flash column chromatography (eluent 30e40 ꢁC petrol/
Et2O, 40:1) gave 46 as a colourless oil (261 mg, 65%, >99:1 dr);
a
)H), 4.45 (1H, d, J 15.8, NCHAHBPh),
a
a
(d, J 22.8, C(2)), 81.2 (CMe3)3, 92.9 (d, J 178.3, C(3)), 126.5, 127.0,
127.2 (p-Ph), 127.3, 127.9, 128.2, 128.3, 128.3, 128.4 (o,m-Ph), 137.0,
142.1, 144.0 (i-Ph), 169.3 (C(1)); dF (377 MHz, CDCl3) ꢀ178.7 (C(3)F);
m/z (ESIþ) 434 ([MþH]þ, 100%); HRMS (ESIþ) C28H33FNOþ2
([MþH]þ) requires 434.2490; found 434.2492.
½
a 2D5
CDCl3) 1.15 (3H, d, J 6.9, C(
1.28 (9H, s, CMe3), 3.29 (1H, dd, J 19.6, 6.8, C(2)H), 3.92 (1H, d, J 16.1,
NCHAHBPh), 3.98 (1H, q, J 6.9, C( )H), 4.19 (1H, d, J 16.1, NCHAHBPh),
4.79e4.85 (1H, m, C(3)H), 7.09e7.40 (10H, m, Ph); dC (125 MHz,
CDCl3) 18.4 (d, J 21.9, C(4)), 21.0 (C( )Me), 28.1 (CMe3), 52.7
(NCH2Ph), 60.4 (C( )), 66.1 (d, J 20.0, C(2)), 81.4 (CMe3), 89.7 (d, J
ꢂ
þ49.7 (c 1.0 in CHCl3); nmax (ATR) 1719 (C¼O), dH (500 MHz,
)Me), 1.22 (3H, dd, J 24.0, 6.3, C(4)H3),
4.30. tert-Butyl (2S,3S,aR)-2-[N-benzyl-N-(a-methylbenzyl)
amino]-3-fluoro-3-(30-fluorophenyl)propanoate 51
a
a
Et3N$3HF (0.15 mL, 0.89 mmol) was added to a stirred solution
of 35 (200 mg, 0.445 mmol, >99:1 dr) and Xtal-FluorE® (153 mg,
0.667 mmol) in CH2Cl2 (1.2 mL) at rt, and the resultant mixture was
stirred at rt for 2 h. 5% aq NaHCO3 (3 mL) was added and the
resultant mixture was stirred at rt for 15 min, then extracted with
CH2Cl2 (3 ꢃ 5 mL). The combined organic extracts were dried, then
filtered through a pad of silica (eluent CH2Cl2) and concentrated in
vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petroleum ether/Et2O, 30:1 to 10:1) gave 51 as a pale
a
a
172.6, C(3)), 126.4, 127.0, 127.8, 127.8, 128.2, 128.3 (o,m,p-Ph), 142.5,
144.1 (i-Ph), 170.4 (C(1)); dF (377 MHz, CDCl3) ꢀ180.1 (C(3)F); m/z
(ESIþ) 372 ([MþH]þ, 100%); HRMS (ESIþ) C23H31FNOþ2 ([MþH]þ)
requires 372.2333; found 372.2337. Further elution gave 48 as a
colourless oil (51 mg, 13%, >99:1 dr); 33
nmax (ATR) 1753 (C¼O), 1160 (CeF); dH (500 MHz, CDCl3) 1.10 (3H, J
6.8, C(4)H3), 1.26 (3H, d, J 6.8, C( )Me), 1.37 (9H, s, CMe3), 3.28e3.38
(1H, m, C(3)H), 3.70 (1H, d, J 14.7, NCHAHBPh), 3.84 (1H, d, J 14.7,
NCHAHBPh), 4.06 (1H, q, J 6.8, C( )H), 4.52 (1H, dd, J 49.2, 5.7, C(2)H)
½
a 2D5
ꢂ
ꢀ31.0 (c 0.1 in CHCl3);
yellow oil (142 mg, 70%, >99:1 dr); ½a D25
þ69.2 (c 1.0 in CHCl3); nmax
ꢂ
a
(ATR) 1720 (C¼O), 1147 (CeF); dH (500 MHz, CDCl3) 1.21 (9H, s,
CMe3), 1.31 (3H, d, J 6.9, C(
4.05 (1H, d, J 15.9, NCHAHBPh), 4.15 (1H, q, J 6.9, C(
a
)Me), 3.81 (1H, dd, J 16.6, 8.2, C(2)H),
)H), 4.43 (1H, d, J
a
a
7.11e7.34 (10H, m, Ph); dF (377 MHz, CDCl3) ꢀ192.1 (C(2)F); m/z
(ESIþ) 372 ([MþH]þ, 100%); HRMS (ESIþ) C23H31FNOþ2 ([MþH]þ)
requires 372.2333; found 372.2337.
15.9, NCHAHBPh), 5.66 (1H, dd, J 47.3, 8.2, C(3)H), 6.92 (1H, d, J 10.2,
C(20)H), 6.97e7.04 (2H, m, C(40)H, C(60)H), 7.22e7.29 (3H, m, C(50)H,
Ph), 7.31e7.37 (6H, m, Ph), 7.42 (2H, d, J 7.5, Ph); dC (125 MHz, CDCl3)
20.4 (C(a)Me), 27.8 (CMe3), 52.0 (NCH2Ph), 60.1 (C(a)), 66.5 (d, J
23.9, C(2)), 81.6 (CMe3), 92.3 (dd, J 178.9, 1.9, C(3)), 114.1 (dd, J 22.6,
6.7, C(20)), 115.5 (d, J 21.2, C(40)), 122.7 (dd, J 6.6, 2.9, C(60)), 126.6,
127.1, 127.9, 127.9, 128.2, 128.3 (o,m,p-Ph), 129.8 (d, J 7.6, C(50)), 139.7
(dd, J 20.3, 7.3, C(10)),162.6 (d, J 246.0, C(30)),169.2 (d, J 10.5, Cþ(1)); dF
(472 MHz, CDCl3) ꢀ181.2 (C(3)F), ꢀ113.0 (C(30)F); m/z (ESI ) 452
4.28. tert-Butyl (2S,3R,
methylbenzyl)amino]-4-methylpentanoate 49
aR)-2-fluoro-3-[N-benzyl-N-(a-
Et3N$3HF (82
mL, 503
mmol) was added to a stirred solution of 21
(100 mg, 251
m
mol, >99:1 dr) and XtalFluor-E® (86 mg, 38
mmol) in
Please cite this article in press as: Davies SG, et al., Trading N and O. Part 4: Asymmetric synthesis of syn-b-substituted-a-amino acids,