CDCl3) d 201.96, 166.86, 155.18, 136.04, 129.24, 128.67, 127.00,
80.21, 61.45, 60.43, 46.86, 36.89, 28.20, 14.02; HR-MS m/z Calcd.
for C18H25NO5 [M + Na]+ 358.1630, observed 358.1633.
Experimental section
All amino acids, ethyl diazoacetate, LAH, DiPEA, tin(II) chloride,
TFA, DMP, Cs2CO3, Cbz-Cl were purchased from Aldrich. THF,
DCM, DMF, were purchased from Merck. Isobutyl chlorofor-
mate, NaBH4, HBTU, HOBt, methanesulfonic acid, di-tert-butyl
dicarbonate, Fmoc-OSu, 3-methoxyphenol, benzyl bromide were
obtained from Spectrochem and used without further purification.
THF and DiPEA were dried over sodium and distilled immediately
prior to use. Column chromatography was performed on Merck
(S)-Ethyl-4-(tert-butoxycarbonylamino)-5-(4-methoxyphenyl)-
25
3-oxopentanoate (2c). Semi solid (0.586 g, 80%); [a]D = -56.32
(c = 1, MeOH); 1H NMR (400 MHz, CDCl3): d 12.15 (s, 1H, enolic
10%), 7.07–7.05 (d, J = 8.68, 2H, aromatic), 6.82–7.80 (d, J = 8.65,
2H, aromatic), 5.01–4.99 (d, J = 7.6 Hz, 1H, NH), 4.53–4.48 (q,
J = 7 Hz, 1H, CH), 4.17–4.12(q, J = 7.2 Hz, 2H, -OCH2), 3.76
(s, 3H, -OCH3), 3.49–3.38 (dd, J = 16 Hz, J = 11.4 Hz, 2H, CH2,
AB coupling), 3.07–2.88 (m, 2H, CH2Ph), 1.38 (s, 9H, C(CH3)3),
1.25–1.22 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d 202.11, 166.85, 158.60, 155.18, 130.26, 127.82, 114.07, 80.17,
61.45, 60.55, 46.93, 36.12, 28.22, 14.04; MALDI TOF/TOF m/z
Calcd. for C19H27NO6 [M + Na]+ 388.1736, observed 388.1783.
1
silica gel (120–200 mesh). The H spectra were recorded on Jeol
400 MHz (or 100 MHz for 13C) and 500 MHz (or 125 MHz for 13C)
Bruker spectrometers using residual solvent signals as an internal
reference (CDCl3 dH, 7.24 ppm, dC 77.0 ppm or [D6] DMSO dH
=
2.50 ppm, dC = 39.5 ppm). The chemical shifts (d) are reported in
ppm and coupling constants in (J) in Hz. Specific rotations were
recorded using MeOH as a solvent (Rudolph Analytical Research).
UV and fluorescence data were obtained on Thermo Scientific and
Fluorolog (Horiba Jobin Yvin) spectrophotometers, respectively.
Mass spectra were obtained from MALDI TOF/TOF (Applied
Biosciences) and HRMS-ESI (Waters). X-Ray data were collected
by using a Bruker APEX DUO.
(S)-Ethyl-4-(tert-butoxycarbonylamino)-6-methyl-3-oxohepta-
noate (2d). Light yellowish liquid (0.476 g, 79%); [a]2D5 -53.70
1
(c = 1, MeOH); H NMR (500 MHz, CDCl3) d 12.10 (s, 1H,
enolic 5.5%), 4.96– 4.94 (d, J = 9.5 Hz, 1H, NH), 4.40–4.36 (m,
1H, CH), 4.24–4.20 (q, J = 7 Hz, 2H, -OCH2), 3.63–3.53 (dd, J =
16.0 Hz, J = 18.5 Hz, 2H, CH2, AB coupling), 1.74–1.67 (m, 3H,
CH2, CH), 1.46 (s, 9H, C(CH3)3, Boc-), 1.32–1.29 (t, J = 7 Hz, 3H,
CH3), 0.979 (b, s, 6H, C(CH3)2); 13C-NMR (125 MHz, CDCl3):d
203.02, 167.07, 155.55, 80.15, 61.51, 58.19, 46.35, 39.90, 28.31,
24.83, 23.28, 21.59, 14.12; HR-MS m/z Calcd. for C15H27NO5
[M + Na]+ 324.1786 observed 324.1784.
General procedure for the synthesis of N-protected
c-amino-b-keto-esters
All ethyl esters of N-protected b-keto-g-amino acids were syn-
thesized using a previously reported procedure.10a In general, the
N-protected amino aldehyde (10.0 mmol) was dissolved in 15 mL
of DCM at room temperature (20–25 ◦C) and then anhydrous
tin(II) chloride (0.796 g, 20 mol%) was added to the reaction
followed by ethyl diazoacetate (1.19 g, 10.5 mmol). Immediate
gas evolution was observed and it ceased within 30 min. The
progress of the reaction was monitored by TLC. After completion
(~30 min) of the reaction, it was quenched with 60 mL of 0.5 N
HCl and immediately extracted with DCM (80 mL ¥ 3). The
combined organic layer was washed with brine (100 mL), dried
over anhydrous sodium sulfate and concentrated under reduced
pressure to give a greenish oily crude product which was further
purified by silica gel column chromatography.
(S)-Ethyl-4-(tert-butoxycarbonylamino)-5-methyl-3-oxohexan-
oate (2e). Colorless liquid (0.48 g, 84%);[a]2D5 -32.64 (c = 1,
MeOH); 1H NMR (500 MHz, CDCl3) d 12.11 (s, 1H enolic form
6.5%), 5.06 (s, b, 1H, NH), 4.35–4.32 (m, 1H, CH), 4.22– 4.18
(q, J = 7 Hz, 2H, -OCH2), 3.57–3.50 (dd, J = 15.5 Hz, J = 3 Hz,
2H, CH2, AB coupling), 2.27–2.23 (m, 1H, CH(CH3)2), 1.44 (s,
9H, C(CH3)3, Boc-), 1.29–1.26 (t, J = 7 Hz, 3H, CH3), 1.029–0.822
(m, 6H, C(CH3)2); 13C NMR (125 MHz, CDCl3): d 202.23, 166.75,
155.86, 80.03, 64.38, 61.55, 47.14, 29.56, 28.31, 19.84, 16.67, 14.10;
HR-MS m/z Calcd. for C14H25NO5 [M + Na]+ 310.1630, observed
310.1620.
(S)-tert-Butyl-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carbo-
xylate (2f). Colorless liquid (0.445 g, 78%); [a]2D5 -64.34 (c = 0.6,
MeOH); H NMR (400 MHz, DMSO d6): d 4.31–4.26 (m, 1H,
(S)-Ethyl-4-(tert-butoxycarbonylamino)-3-oxopentaanoate (2a).
1
Colorless liquid (0.398 g, 76%); [a]2D5 -35.69 (c = 1, MeOH); H
1
NMR (500 MHz, CDCl3): d 12.13 (s, 1H enolic 3.5%), 5.17 (b,
s, 1H, NH), 4.43–4.37 (m, 1H, CH), 4.24–4.20 (q, J = 7 Hz,
2H,-OCH2), 3.62–3.54 (dd, J = 14.5 Hz, J = 10.5 Hz 2H, CH2,
AB coupling), 1.46 (s, 9H, C(CH3)3, Boc), 1.38–1.36 (d, J = 6.5
Hz, 3H, CH3), 1.31–1.28 (t, J = 7 Hz, 3H, CH3); 13C NMR (125
MHz, CDCl3) d 202.50, 166.96, 155.19, 80.14, 61.57, 55.42, 45.91,
28.32, 17.11, 14.11; HR-MS m/z Calcd. for C12H21NO5 [M + Na]+
282.1317, observed 282.1317.
CH), 4.1265–4.06 (m, 2H, -OCH2), 3.66–3.53 (dd, J = 13.64 Hz,
J = 22.4 Hz, 2H, CH2, AB coupling), 3.34–3.31 (m, 2H, dCH2),
2.07–2.05 (m, 1H, one proton of bCH2), 1.91–1.68 (m, 3H, g CH2,
and one proton of bCH2), 1.40, 1.33 (s, 9H, C(CH3)3), 1.20–
1.17 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d 203.49, 167.41, 154.31, 153.31, 79.71, 65.34, 61.14, 47.11, 46.99,
46.07, 45.84, 29.45, 28.51, 28.31, 24.45, 23.60, 14.53; MALDI
TOF/TOF m/z Calcd. for C14H23NO5 [M + Na]+ 308.1474,
observed 308.1439.
(S)-Ethyl-4-(tert-butoxycarbonylamino)-3-oxo-5-phenylpen-
tanoate (2b). White crystal (0.521 g, 78%); [a]2D5 -54.5 (c = 0.6,
MeOH); Melting Point = 61.4 ◦C; 1H NMR (400 MHz, CDCl3): d
12.16 (s, 1H, enolic 17%), 7.24 –7.15 (m, 5H, C6H5), 5.03–5.01 (d,
J = 7.3 Hz, 1H, NH), 4.57–4.52 (q, J = 6.4 Hz, 1H, CH), 4.18–4.12
(q, J = 7.2 Hz, 2H, -OCH2), 3.51–3.40 (dd, J = 16 Hz, J = 11.4 Hz,
2H, CH2, AB coupling), 3.15–2.95 (m, 2H, CH2Ph), 1.38(s, 9H,
C(CH3)3), 1.26–1.22 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz,
(S)-1-Benzyl-6-ethyl 2-(benzylcarbonylamino)-4-oxohexanedio-
ate (2g). White solid (0.589 g, 69%); Melting Point = 68.3 ◦C;
1
[a]2D5 -16.30 (c = 0.3, MeOH); H NMR (400 MHz, CDCl3) d
12.06 (s, 1H, enolic), 7.33–7.28 (m, 10H, aromatic), 5.75–5.72
(d, J = 8.2 Hz, 1H, NH), 5.63–5.59 (m, 1H, CH), 5.14 (s, 2H,
-OCH2Ph), 5.08 (s, 2H, -OCH2Ph), 4.17–4.11 (q, J = 7 Hz, 2H,
-OCH2Me), 3.39 (s, 2H, CH2, AB coupling), 3.33–3.10 (m, 2H,
8092 | Org. Biomol. Chem., 2011, 9, 8089–8095
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The Royal Society of Chemistry 2011
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