Vol. 30, No. 4 (2018)
Enantioselective Synthesis of All Stereoisomers of Cordiarimide B and Their Antioxidant Study 929
mixture was filtered through suction filtration. The filtrate is,
diluted with DCM (20 mL) and washed with 1 M HCl (3 × 10
mL) followed by 5 % NaHCO3 (3 × 10 mL) and brine (1 × 15
mL), dried over anhydrous MgSO4 and concentrated in vacuo.
The crude residues were purified by column chromatography
to afford compound17 (6.5 g, 85 %) as a white solid.
tert-Butyl (S)-1-[(S)-2-(tert-butyldimethylsilyloxy)-2-
phenylethanamine]-2,6-dioxopiperidine-3yl-carbamate
(17): A white solid (6.2 g, 81 %), [α]D25 = 9.54 (c 0.1, DCM);
IR (KBr, νmax, cm-1): 3445, 1617; 1H NMR (300 MHz CDCl3):
δ 0.13 (s, 6H, TBDMS), 0.98 (s, 9H, TBDMS), 1.31 (s, 9H,
Boc) 2.12 (q, 2H, CH2) 2.25 (t, 2H, CH2), 4.01 (t, 1H CH),
4.16 (d, 2H, CH2) 5.6 (t, 1H CH2) 7.58 (m, 5H, Ar-H); 8.04 (s,
1H, NH); 13C NMR (100 MHz): δ -0.21, 24.3, 25.8, 27.2, 28.4,
31.3, 58.4, 76.7, 79.4, 127.4, 139.8, 155.2, 169.7, 171.8. HRMS
m/z calcd. for C24H38N2O5Si [M +1]+: 463.25, Found: 462.2032.
tert-Butyl (R)-1-[(S)-2-(tert-butyldimethylsilyloxy)-2-
phenylethanamine]-2,6-dioxopiperidine-3yl-carbamate
(19):A white solid (6.0 g, 78 %), [α]D25 = -15.28 (c 0.1, DCM);
IR (KBr, νmax, cm-1): 3445, 1617; 1H NMR (300 MHz CDCl3):
δ 0.12 (s, 6H, TBDMS), 0.96 (s, 9H, TBDMS), 1.33 (s, 9H,
Boc) 2.21 (q, 2H, CH2) 2.34 (t, 2H, CH2), 4.21 (t, 1H CH), 4.21
(d, 2H, CH2) 5.63 (t, 1H CH2) 7.52 (m, 5H, Ar-H); 8.06 (s, 1H,
NH); 13C NMR (100 MHz): δ -0.23, 24.6, 26.1, 27.8, 28.2, 32.3,
58.9, 77.1, 79.5, 127.9, 140.1, 155.6, 170.7, 172.3. HRMS m/z
calcd. for C24H38N2O5Si [M +1]+: 463.25, Found: 462.2035.
tert-Butyl (S)-1-[(R)-2-(tert-butyldimethylsilyloxy)-2-
phenylethanamine]-2,6-dioxopiperidine-3yl-carbamate
(21): A white solid (6.1 g, 79 %), [α]D25 = 7.54 (c 0.1, DCM);
IR (KBr, νmax, cm-1): 3445, 1617; 1H NMR (300 MHz CDCl3):
δ 0.11 (s, 6H, TBDMS), 0.93 (s, 9H, TBDMS), 1.36 (s, 9H,
Boc) 2.19 (q, 2H, CH2) 2.41 (t, 2H, CH2), 4.19 (t, 1H CH),
4.25 (d, 2H, CH2) 5.67 (t, 1H CH2) 7.58 (m, 5H, Ar-H); 8.07
(s, 1H, NH); 13C NMR (100 MHz): δ -0.21, 23.6, 25.7, 28.1,
28.8, 32.6, 59.2, 77.6, 78.3, 128.4, 141.2, 156.1, 171.2, 173.1.
HRMS m/z calcd. for C24H38N2O5Si [M +1]+: 463.25, Found:
462.2034.
tert-Butyl (R)-1-[(R)-2-(tert-butyldimethylsilyloxy)-2-
phenylethanamine]-2,6-dioxopiperidine-3yl-carbamate
(23): A white solid (5.8 g, 75 %), [α]D25 = 11.30 (c 0.1, DCM);
IR (KBr, νmax, cm-1): 3445, 1617; 1H NMR (300 MHz CDCl3):
δ 0.19 (s, 6H, TBDMS), 0.12 (s, 9H, TBDMS), 3.32 (d, 1H,
CH2) 3.57 (d, 1H, CH2), 4.81 (t, 1H, CH) 5.4 (s, 2H NH2) 7.35
(m, 5H,Ar-H); 8.17 (s, 1H, NH); 13C NMR (100 MHz): δ -0.20,
24.9, 32.3, 47.9, 72.98, 123.4, 138.1, 140.2, 157.1, 170.9,
172.6.HRMS m/z calcd. for C24H38N2O5Si [M +1]+: 463.25,
Found: 462.2035.
General procedure forTBDMS deprotection: To a solu-
tion of 17 (1g, 2.1 mmol) in THF (6 mL) was added TBAF (7
mL, 1.0 M in THF, 0.69 mmol). The solution was stirred at 0
°C for 2 h and poured into saturated NH4Cl. The mixture was
extracted with EtOAc followed by drying with Na2SO4 and
concentration of combined organic layers under reduced pressure.
Residue was purified by silica gel column chromatography
(hexanes/EtOAc, 7:3) to obtain 18.
δ 2.27 (t 2H CH2) 4.31 (t 2H CH2) 5.37 (t 1H CH) 7.25 (m 5H
Ar-H) 8.0 (s 1H NH); 13C NMR (100 MHz): δ 23.91, 25.41,
30.48, 58.80, 77.05, 127.45, 155.4, 175.422. HRMS m/z calcd.
for C18H24N2O5[M +1]+: 349.17 found: 349.314.
tert-Butyl (3R)-1[(S)-2-hydoxy-2-phenylethanamine]-
2,6-dioxopiperidine-3yl-carbamate (20):White solid (0.72g,
97 %), [α]D25 = -7.542 (c 0.1, DCM); H NMR (300 MHz
1
CDCl3): δ 2.47 (t 2H CH2) 3.31 (t 2H CH2) 5.12 (t 1H CH)
13
7.25 (m 5H Ar-H) 8.12 (s 1H NH), C NMR (100 MHz): δ
24.5, 25.42, 29.59, 30.75, 36.2, 67.84, 77.36, 128.5, 155.52,
HRMS m/z calcd. for C18H24N2O5[M +1] +:349.17 found:
349.312.
tert-Butyl (3S)-1[(R)-2-hydoxy-2-phenylethanamine]-
2,6-dioxopiperidine-3yl-carbamate (22): White solid (0.68
g, 90 %), [α]D25 = 8.23 (c 0.1, DCM); H NMR (300 MHz
1
CDCl3): δ 2.15 (t 2H CH2) 4.05 (t 2H CH2) 5.07 (t 1H CH) 7.3
(m 5H Ar-H) 8. (s 1H NH); 13C NMR (100 MHz): δ 24.4,
28.75, 30.3, 34.6, 42.0, 50.1, 51.6, 53.7, 77.4, 173.2, HRMS
m/z calcd. for C18H24N2O5[M +1] +: 349.17 found: 349.313.
tert-Butyl (3R)-1[(R)-2-hydoxy-2-phenylethanamine]-
2,6-dioxopiperidine-3yl-carbamate (24): White solid (0.71
g, 94 %), [α]D25 = 9.45 (c 0.1, DCM); H NMR (300 MHz
1
CDCl3): δ 2.20 (t 2H CH2) 4.05 (t 2H CH2) 5.71 (t 1H CH) 7.3
13
(m 5H Ar-H) 8. (s 1H NH); C NMR (100 MHz): δ 24.69,
27.84, 34.77, 65.53, 76.84, 125.7, 151.5, 170.9, 174.5, HRMS
m/z calcd. for C18H24N2O5[M +1] +: 349.17 found: 349.315.
RESULTS AND DISCUSSION
Teng et al. [9] reported the synthesis of cordiarimide B
(Scheme-I). This is the only methodology available in literature
so far and which is not suitable for large-scale synthesis.
Epimerization at C-3 carbon during alkylation of diamide
nitrogen is a major drawback of the reported method to access
pure isomers. Also, in reported method moderate diastereo
selectivity was achieved during reduction of the keto group by
using expensive Zhou’s catalyst [10].
Retro synthetic analyses: The present retro synthetic
analysis of cordiarimide B is outlined in Scheme-II. The two
stereogenic centers of cordiarimide B can be easily introduced
by N-Boc (L)-glutamic acid and (S)-mandelic acid as starting
materials. These two compounds are commercially available
in enantiomerically pure form. In this synthetic plan no center
of inversion/stereo selective reduction and no harsh reaction
conditions were required. Therefore, the enantiopurity of both
chiral molecules is retained.
Synthesis of chiral 2-amino-1-phenylethanol: Our first
focus is on the preparation of chiral 2-amino-1-phenylethanol
16 and 21. Commercially available (S)-mandelic acid 13 was
activated with ethylychloroformate in dichloromethane solvent
at 0 °C, then the activated ester was stirred with excess of ammonia
solution in methanol to form amide compound 14.
The alcohol group of amide 14 was protected in order to
reduce side reaction by treating with TBDMS-chloride, in
presence of immidzole in dichloromethane solvent at 0 °C. The
amide group of compound 15 was reduced using 2 M solution
of borandimethyl sulphide (BMS) in THF under reflux condi-
tion to form (S)-aminoalcohol 16 in 83 % yield (Scheme-III).
tert-Butyl (3S)-1[(S)-2-hydoxy-2-phenylethanamine]-
2,6-dioxopiperidine-3yl-carbamate (18): White solid (0.7 g,
93 %), [α]D25 = 11.30 (c 0.1, DCM); 1H NMR (300 MHz CDCl3):