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T. Coursindel et al. / Bioorganic Chemistry 38 (2010) 210–217
4.6.1. (3R,5R)-3-(tert-butoxycarbonylamino)-3-((E)-4-ethoxy-4-
oxobut-2-enyl)-5-isopropyl-2,4-dioxopyrrolidine-1-carboxylic acid
tert-butyl ester (7c)
171.0 (CCOlactam), 204.2 (CCOketone); m/z (ESI+) 487.2 (HRMS-ESI+)
487.2448 ([M + H]+ C26H35N2O7 calculated 487.2444).
Following the general procedure, compound 7c was isolated as
a yellowish oil (42%), tr = 2.824 min, dH (300 MHz, CDCl3; Me4Si) d
0.95 (d, 3H, J = 6.9 Hz, H(CH3)2CH), 1.21 (d, 3H, J = 6.9 Hz, H(CH3)2CH),
1.30 (t, 3H, J = 7.2 Hz, HCH3ACH2), 1.37 (s, 9H, HC(CH3)3), 1.56 (s, 9H,
4.6.5. (3R,5R)-4-(3-tert-Butoxycarbonylamino-5-isopropyl-2,4-dioxo-
pyrrolidin-3-yl)-but-2-enoic acid ethyl ester 9c
To
a solution of (3R,5R)-3-(tert-butoxycarbonylamino)-3-
((E)-4-ethoxy-4-oxobut-2-enyl)-5-isopropyl-2,4-dioxopyrrolidine-
1-carboxylic acid tert-butyl ester 7c (100 mg, 0.21 mmol) in
dichloromethane (5 mL) was added dropwise trifluoroacetic acid
(0.15 mL) at 0 °C. The reaction mixture was stirred during 2.5 h
at 0 °C. The reaction media was then evaporated to dryness, and
the remaining TFA was coevaporated with toluene to afford 9c
(71 mg, 90%) as a yellowish oil, tr = 2.068 min. dH (300 MHz, CDCl3;
Me4Si) d 0.91 (d, 3H, J = 6.7 Hz, H(CH3)2CH), 1.02 (d, 3H, J = 6.7 Hz,
HC(CH3)3), 2.42 (m, 1H, HCH(CH3)2), 2.58 (m, 2H, HCH2ACH@CHACO2Et),
4.21 (q, 2H, J = 7.2 Hz,
HCH2ACH3), 4.53 (d, 1H, J = 4.2 Hz,
HCHÃCH(CH3)2), 5.20 (sl, 1H, HNHBoc), 5.96 (d, 1H, J = 15.6 Hz,
HCHCO2Et), 6.95 (m, 1H, HCH@CHACO2Et); dC (75 MHz, CDCl3; Me4Si)
d 14.2 (CCH3ACH2), 18.0 (CCH(CH3)2), 19.2 (CCH(CH3)2), 27.9 (CC(CH3)3),
28.1 (CC(CH3)3), 30.2 (CCH(CH3)2), 34.1 (CCH2ACH), 60.8 (CCH2ACH3),
69.9 (CCHÃ), 77.2 (CquatÃ), 81.8 (CC(CH3)3), 84.4 (CC(CH3)3), 127.3
(CCHACO2Et), 138.2 (CCH
@
CHACO2Et), 149.5 (CCOBoc), 154.8 (CCOBoc),
H
(CH3)2CH), 1.23 (t, 3H, J = 7.1 Hz, HCH3ACH2), 1.32 (s, 9H, HC(CH3)3),
165.1 (CCOester), 171.0 (CCOlactam), 204.9 (CCOketone); m/z (ESI+)
469.3 (HRMS-ESI+) 469.2541 ([M + H]+ C23H37N2O8 calculated
469.2550).
2.07 (m, 1H, HCH(CH3)2), 2.49 (m, 2H, HCH2ACH CHACO2Et), 4.01 (d,
1H, HCHÃ), 4.14 (q, 2H, J = 7.1 Hz, HCH2ACH3), 5.10 (sl, 1H, HNHBoc),
5.89 (d, 1H, J = 15.6 Hz, HCHACO2Et), 6.47 (sl, 1H, HNH), 6.88 (m,
@
1H, HCH
18.4 (CCH(CH3)2), 19.3 (CCH(CH3)2), 28.1 (CC(CH3)3), 30.4 (CCH(CH3)2),
35.2 (CCH2ACH CHACO2Et), 59.6 (CCH2ACH3), 60.7 (CCHÃ), 67.5 (CquatÃ),
@CHACO2Et); dC (75 MHz, CDCl3; Me4Si) d 14.2 (CCH3ACH2),
4.6.2. (3R,5R)-3-(tert-butoxycarbonylamino)-5-isopropyl-3-((E)-3-
methoxycarbonyl-allyl)-2,4-dioxo-pyrrolidine-1-carboxylic acid tert-
butyl ester (7d)
Following the general procedure, compound 7d was isolated as
a yellowish oil (49%), tr = 2.696 min, dH (300 MHz, CDCl3; Me4Si) d
0.97 (d, 3H, J = 6.9 Hz, H(CH3)2CH), 1.23 (d, 3H, J = 6.9 Hz, H(CH3)2CH),
1.38 (s, 9H, HC(CH3)3), 1.58 (s, 9H, HC(CH3)3), 2.44 (m, 1H, HCH(CH3)2),
@
81.7 (CC(CH3)3), 127.2 (CCH@CHACO2Et), 138.6 (CCHACO2Et), 154.8 (CCOBoc),
165.2 (CCOester), 173.0 (CCOlactam), 207.1 (CCOketone); m/z (ESI+) 369.2
(HRMS-ESI+) 369.2024 ([M + H]+ C18H29N2O6 calculated 369.2026).
4.6.6. TFA salt of (3R,5R)-4-(3-Amino-5-isopropyl-2,4-dioxo-
pyrrolidin-3-yl)-but-2-enoic acid ethyl ester 10c
2.60 (m, 2H, HCH2ACH
J = 4.1 Hz, HCHÃCH(CH3)2), 5.14 (s, 1H, HNHBoc), 5.98 (d, 1H, J = 15.7 Hz,
CHCO2Me), 6.96 (m, 1H, HCH CHACO2Me); dC (75 MHz, CDCl3; Me4Si)
@CHACO2Me), 3.77 (s, 3H, HCO2CH3), 4.55 (d, 1H,
To
a solution of (3R,5R)-3-(tert-butoxycarbonylamino)-3-
((E)-4-ethoxy-4-oxobut-2-enyl)-5-isopropyl-2,4-dioxopyrrolidine-
1-carboxylic acid tert-butyl ester 7c (100 mg, 0.21 mmol) in
dichloromethane (5 mL) was added dropwise trifluoroacetic acid
(0.5 mL) at room temperature. The reaction mixture was stirred
during 2 h at room temperature. Then, the reaction media was
evaporated to dryness, and the remaining TFA was coevaporated
with toluene to afford 10c (82 mg, 100%) as a brownish oil,
H
@
d 18.0 (CCH(CH3)2), 19.2 (CCH(CH3)2), 28.0 (CC(CH3)3), 28.1 (CC(CH3)3),
30.2 (CCH(CH3)2), 34.1 (CCH2ACH), 51.8 (CCO2CH3), 69.9 (CCHÃ), 77.2
(CquatÃ), 81.9 (CC(CH3)3), 84.4 (CC(CH3)3), 126.9 (CCHACO2Me), 138.5
(CCH@CHACO2Me), 149.5 (CCOBoc), 154.7 (CCOBoc), 165.5 (CCOester),
170.9 (CCOlactam), 204.9 (CCOketone); m/z (ESI+) 455.2 (HRMS-ESI+)
455.2392 ([M + H]+ C22H35N2O8 calculated 455.2393).
tr = 1.284 min. dH (300 MHz, CDCl3; Me4Si)
d 0.89 (d, 3H,
J = 6.7 Hz, HCH(CH3)2), 1.00 (d, 3H, J = 6.7 Hz, HCH(CH3)2), 1.21 (t, 3H,
J = 7.1 Hz, HCH3ACH2), 1.65 (sl, 2H,, HNH2), 2.04 (m, 1H, HCH(CH3)2),
4.6.3. 5-Allyl-3-tert-butoxycarbonylamino-3-(3-methoxycarbonyl-
allyl)-2,4-dioxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7j)
Following the general procedure, compound 7j was isolated as a
yellowish oil (35%), tr = 2.591 min, dH (300 MHz, CDCl3; Me4Si) d
2.51 (m, 2H, HCH2ACH
4.11 (q, 2H, J = 7.1 Hz,
CHACO2Et), 6.82 (m, 1H, HCH
(75 MHz, CDCl3; Me4Si) d 13.6 (CCH3ACH2), 17.5 (CCH(CH3)2), 18.5
(CCH(CH3)2), 30.0 (CCH(CH3)2), 37.8 (CCH2ACH CHACO2Et), 59.2
(CCH2ACH3), 59.9 (CCHÃ), 65.9 (Cquat), 125.9 (CCH CHACO2Et), 139.3
@
CHACO2Et), 3.82 (d, 1H, J = 5.4 Hz, HCHÃ),
CH2ACH3), 5.85 (d, 1H, J = 15.6 Hz,
CHACO2Et), 7.47 (sl, 1H, HNH); dC
H
H
@
1.23 (s, 9H, HC(CH3)3), 1.35 (s, 9H, HC(CH3)3), 2.55 (m, 2H, HCH2CH
2.69–2.90 (m, 2H, HCHÃCH2), 3.74 (s, 3H, HCO2CH3), 4.65 (dd, 1H,
J = 3.1 Hz, J = 6.6 Hz, HCHÃ), 5.10–5.22 (m, 3H, HCH CH2 + HNHBoc),
5.65 (m, 1H, HCH CH2), 5.93 (d, 1H, J = 15.6 Hz, HCH2CH CHCO2Me),
6.88 (m, 1H, HCH2CH CHCO2Me); dC (75 MHz, CDCl3; Me4Si) d 28.0
(CC(CH3)3), 28.1 (CC(CH3)3), 34.2 & 34.3 (CCHÃCH2& CCH2CH CH), 51.9
(CCO2CH3), 60.7 (Cquat), 65.1 (CCHÃ), 82.0 (CC(CH3)3), 84.5 (CC(CH3)3),
120.8 (CCH CH2), 127.0 (CCHCO2Me), 131.5 (CCH2 CH), 138.4
(CCH
@CH),
@
@
@
@
@
(CCHACO2Et), 164.9 (CCOester), 174.1 (CCOlactam), 208.9 (CCOketone);
m/z (ESI+) 269.1 (HRMS-ESI+) 269.1497 ([M + H]+ C13H21N2O4 cal-
culated 269.1501).
@
@
@
@
4.6.7. (3R,5R)-3-Isopropyl-2,6-diaza-spiro[4.5]decane-1,4,7-trione 11
The TFA salt of (3R,5R)-4-(3-Amino-5-isopropyl-2,4-dioxo-pyrr-
olidin-3-yl)-but-2-enoic acid ethyl ester 10c (200 mg, 0.52 mmol)
was dissolved in ethanol and reduced via catalytic hydrogenation
with 10% Pd/C at room temperature for 46 h. The catalyst was fil-
tered off trough Celite, and the solvent was removed in vacuo to
give a tan oil. This material was then redissolved in EtOH and
heated with a microwave oven (Biotage Initiator Microwave Syn-
thesizer Producing controlled radiation at 2450 MHz and using
fixed hold-time) at 150 °C for 1 h. After evaporation, the crude res-
idue was purified on a RP-18 column (H2O/EtOH 100:0 ꢁ 65:35 in
35 min) to afford 11 (95 mg, 81%), as a yellow oil, tr = 1.163 min. dH
(300 MHz, DMSO-d6; Me4Si) d 0.90 (d, 3H, J = 6.7 Hz, HCH(CH3)2),
@
CHCO2Me), 149.1 (CCOBoc), 154.8 (CCOBoc), 165.5 (CCOester),
170.7 (CCOlactam), 204.6 (CCOketone); m/z (ESI+) 453.2 (HRMS-ESI+)
453.2240 ([M + H]+ C22H33N2O8 calculated 453.2237).
4.6.4. 5-(1-Benzyloxy-ethyl)-3-tert-butoxycarbonylamino-2,4-dioxo-
3-prop-2-ynyl-pyrrolidine-1-carboxylic acid tert-butyl ester (7n)
Following the general procedure, compound 7n was isolated as
a colorless oil (30%), tr = 2.840 min, dH (300 MHz, CDCl3; Me4Si) d
1.29 (d, 3H, J = 6.6 Hz, HCHCH3), 1.34 (s, 9H, HC(CH3)3), 1.54 (s, 9H,
H
C(CH3)3), 2.17 (t, 1H, J = 2.6 Hz, HC„CH), 2.51 (dd, 1H, J = 2.6 Hz,
J = 17.5 Hz, HCH2C CH), 2.62 (dd, 1H, J = 2.6 Hz, J = 17.5 Hz,
HCH2C CH), 4.10 (m, 1H, HCHCH3), 4.27 (d, 1H, J = 11.0 Hz, HCH2C6H5),
„
„
4.52 (d, 1H, J = 11.0 Hz, HCH2C6H5), 4.72 (d, 1H, J = 2.7 Hz, HCHÃ), 5.52
(br s, 1H, HNHBoc), 7.21–7.34 (m, 5H, HC6H5); dC (75 MHz, CDCl3;
0.96 (d, 3H, J = 6.7 Hz, HCH(CH3)2), 1.18–2.22 (m, 7H, HCH2CH2CH2CO +
HCH2CH2CH2CO + HCH2CH2CH2CO + HCH(CH3)2), 3.67 (d, 1H, J = 6.2 Hz,
CHÃ), 7.50 (br s, 1H, HNH), 8.81 (br s, 1H, HNH); dC (75 MHz,
Me4Si)
d 16.7 (CCHCH3), 22.0 (CCH2AC„CH), 27.9 (CC(CH3)3),
H
28.1 (CC(CH3)3), 69.2, 71.2, 73.6, 75.0, 77.2, 81.7 (CC(CH3)3), 84.3
(CC(CH3)3), 128.2–136.7 (CC6H5), 150.3 (CCOBoc), 155.1 (CCOBoc),
DMSO-d6; Me4Si) d 16.4 (CCH2CH2CH2CO), 18.5 (CCH(CH3)2), 18.8
(CCH(CH3)2), 27.9/30.7/30.9 (CCH2CH2CH2CO + CCH2CH2CH2CO + CCH(CH3)2),