V. Harish, M. Periasamy / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
4.4.1. (20S,40R)-Methyl 10-((S)-2-tert-butoxycarbonyl)amino)-2-
1H). 13C NMR (100 MHz, ppm, DMSO-d6):170.2, 165.4, 137.2,
129.3, 128.4, 128.3, 67.3, 60.2, 57.6, 54.6, 37.8.; HRMS (ESI): m/z
[M+H]+ calcd for C13H14N2O3: 247.1082; found 247.1083.
phenylacetyl)-40-hydroxypyrrolidine-20-carboxylate 19a
Yield: 2.401 g (44%); colorless liquid; ½a D25
ꢂ
= +52.6 (c 0.16,
EtOH); IR (neat): 3416, 2977, 1753, 1711, 1644, 1438, 1365,
1169, 709 cmꢃ1
;
1H NMR (500 MHz, ppm, CDCl3): 7.43–7.34 (m,
4.5.2. (3S,7R,8aS)-7-Hydroxy-3-methylhexahydropyrrolo[1,2-a]
pyrazine-1,4-dione 15b
5H), 5.86 (d, J = 7.7, 1H), 5.42 (d, J = 7.6, 1H), 4.67 (t, J = 8.1, 1H),
4.40 (s, 1H), 3.73 (s, 3H), 3.64–3.62 (m, 1H), 3.17–3.13 (m, 1H),
2.32–2.27 (m, 1H), 1.95–1.89 (m, 1H), 1.40 (s, 9H). 13C NMR
(100 MHz, ppm, CDCl3): 172.3, 169.1, 155.4, 136.4, 128.9, 128.4,
128.3, 80.0, 70.2, 58.1, 56.6, 55.1, 52.2, 37.4, 28.3.
Yield: 0.717 g (78%); White solid; mp 198–201 °C;
½
a 2D5
ꢂ
= ꢃ130.2 (c 0.09, EtOH); IR (KBr): 3380, 3235, 1675, 1639,
1422, 1283, 1097, 957, 756 cmꢃ1 1H NMR (400 MHz, ppm,
;
MeOH-d4): 4.56–4.48 (m, 1H), 4.27–4.25 (m, 1H), 3.70–3.68 (m,
1H), 3.47–3.44 (m, 1H), 3.33 (s, 1H), 2.32–2.28 (m, 1H) 2.13–2.07
(m, 1H), 1.41 (d, J = 6, 3H). 13C NMR (125 MHz, ppm, MeOH-d4):
171.4, 167.7, 67.7, 57.5, 53.8, 50.6, 36.8, 14.3; HRMS (ESI): m/z
[M+H]+ calcd for C8H12N2O3: 185.0926; found 185.0925.
4.4.2. (20S,40R)-Methyl 10-((S)-2-tert-butoxycarbonyl)amino)
propanoyl)-40-hydroxypyrrolidine-20-carboxylate 19b
Yield: 2.476 g (38%); colorless liquid; ½a D25
= ꢃ84.2 (c 0.28,
ꢂ
EtOH); IR (neat): 3369, 2977, 2930, 1742, 1686, 1634, 1531,
1458, 1371, 1159 cmꢃ1
;
1H NMR (500 MHz, ppm, CDCl3): 5.53–
4.5.3. (3S,7R,8aS)-7-Hydroxy-3-isopropylhexahydropyrrolo[1,2-
a]pyrazine-1,4-dione 15c
5.49 (m, 1H), 4.59–4.55 (m, 1H), 4.48 (s, 1H), 4.39–4.36 (m, 1H),
4.13–4.12 (m, 1H), 3.75–3.72 (m, 1H), 3.67 (s, 3H), 3.64–3.60 (m,
1H), 2.30–2.25 (m, 1H), 1.99 (s, 1H), 1.36 (s, 9H), 1.27 (d, J = 6.8,
3H). 13C NMR (100 MHz, ppm, CDCl3): 172.5, 172.0, 155.4, 79.8,
70.0, 57.7, 54.9, 52.2, 47.8, 37.3, 28.9, 17.8.
Yield: 0.669 g (75%); White solid, mp 196–198 °C;
½
a 2D5
ꢂ
= ꢃ136.7 (c 0.08, EtOH); IR (KBr): 3369, 3271, 2967, 2879,
1675, 1644, 1422, 1092, 740, 601 cmꢃ1 1H NMR (400 MHz, ppm,
;
MeOH-d4): 4.52–4.48 (m, 2H), 4.10 (s, 1H), 3.76–3.72 (dd, J = 4.5,
J = 12.9, 1H), 3.44 (d, J = 13, 1H), 2.53–2.50 (m, 1H), 2.33–2.28
(dd, J = 6.1, J = 13.1, 1H) 2.10–2.02 (m, 1H), 1.12 (d, J = 7.2, 3H),
0.96 (d, J = 6.9, 3H). 13C NMR (125 MHz, ppm, MeOH-d4):171.5,
166.2, 67.5, 60.0, 56.9, 53.8, 37.2, 28.3, 17.5, 15.3; HRMS (ESI):
m/z [M+H]+ calcd for C10H16N2O3: 213.1239; found 213.1237.
4.4.3. (20S,40R)-Methyl 10-((S)-2-tert-butoxycarbonyl)amino)-3-
methylbutanoyl)-40-hydroxypyrrolidine-20-carboxylate 19c
Yield: 2.470 g (36%); colorless liquid; ½a D25
= ꢃ79.5 (c 0.28,
ꢂ
EtOH); IR (neat): 3390, 2961, 1737, 1691, 1629, 1520, 1443,
1365, 1169, 1004, 875 cmꢃ1 1H NMR (400 MHz, ppm, CDCl3):
;
5.37 (d, J = 8.7, 1H), 4.61 (t, J = 8.3, 1H), 4.48 (s, 1H), 4.19–4.15
(m, 1H), 3.93–3.86 (m, 2H), 3.68 (s, 3H), 2.33–2.27 (m, 3H), 2.00–
1.95 (m, 2H), 1.38 (s, 9H), 1.24–1.22 (m, 1H), 0.98 (d, J = 6.7, 3H),
0.89 (d, J = 6.7, 3H). 13C NMR (100 MHz, ppm, CDCl3): 172.6,
171.5, 156.2, 79.8, 69.9, 57.7, 57.0, 55.4, 52.1, 37.4, 30.9, 28.3,
19.2, 17.3.
4.5.4. (3S,7R,8aS)-7-Hydroxy-3-isobutylhexahydropyrrolo[1,2-a]
pyrazine-1,4-dione 15d
Yield: 0.847 g (91%); White solid, mp 176–178 °C;
½
a 2D5
ꢂ
= ꢃ141.8 (c 0.07, EtOH); IR (KBr): 3447, 3276, 2941, 1686,
1670, 1618, 1433, 1097 cmꢃ1 1H NMR (400 MHz, ppm, MeOH-
;
d4): 4.56–4.48 (m, 2H), 4.19–4.18 (m, 1H), 3.70–3.66 (m, 1H),
3.47–3.44 (m, 1H), 3.33 (s, 1H), 2.32–2.27 (m, 1H) 2.14–2.07 (m,
1H), 1.95–1.92 (m, 2H), 1.55–1.51 (m, 1H), 0.99–0.98 (m, 6H). 13C
NMR (125 MHz, ppm, MeOH-d4): 171.6, 167.6, 67.7, 57.3, 53.7,
53.2, 37.9, 36.7, 24.4, 21.9, 20.8; HRMS (ESI): m/z [M+H]+ calcd
for C11H18N2O3: 227.1395; found 227.1395.
4.4.4. (20S,40R)-Methyl 10-((S)-2-tert-butoxycarbonyl)amino)-4-
methylpentanoyl)-40-hydroxypyrrolidine-20-carboxylate 19d
Yield: 3.22 g (45%); colorless liquid; ½a D25
= ꢃ58.3 (c 0.27, EtOH);
ꢂ
IR (neat): 3344, 2961, 2868, 1753, 1701, 1649, 1520, 1427, 1365,
;
1179, 1092 cmꢃ1 1H NMR (400 MHz, ppm, CDCl3): 5.17 (d,
J = 8.4, 1H), 4.72–4.68 (m, 1H), 4.56 (s, 1H), 4.45–4.39 (m, 1H),
4.09 (d, J = 11.2, 1H), 3.75 (s, 3H), 3.69–3.67 (m, 1H), 3.07 (s, 1H),
2.41–2.36 (m, 1H), 2.05–1.98 (m, 1H), 1.812 (s, 3H), 1.43 (s, 9H),
1.00–0.96 (m, 6H). 13C NMR (100 MHz, ppm, CDCl3): 172.6,
172.1, 156.0, 79.8, 70.1, 57.6, 54.9, 52.2, 50.4, 41.5, 37.4, 28.3,
24.5, 23.2, 21.9.
4.6. General procedure for the reduction of diketopiperazine
derivatives
An oven dried three necked reaction flask was cooled under
nitrogen atmosphere with a stirring bar. Diketopiperazine 15
(3 mmol) was dissolved in freshly distilled THF (10 mL) and NaBH4
(15 mmol) added at 0 °C. A solution of iodine (7 mmol) in freshly
distilled THF (5 mL) was added dropwise over 30 min via the side
neck of the reaction flask and allowed to stir for 2 h and then
refluxed for 24 h. The reaction was brought to room temperature
and quenched with methanol (the residue was carefully poured
into the methanol containing ice cold beaker slowly) and the sol-
vents were evaporated. The residue obtained after evaporation,
was refluxed with 5 M KOH (10 mL) for 6 h and the resultant chiral
piperazine 16 was extracted with DCM (2 ꢁ 30 mL) dried over
anhydrous Na2SO4. The combined organic extract was evaporated
and chromatographed on basic Al2O3 column using 50:50 hexane
and ethyl acetate as the eluent.
4.5. General procedure for the preparation of diketopiperazine
derivatives
A solution of amide 19 (5 mmol) in dry CH2Cl2 (20 mL) was
treated with trifluoroacetic acid (0.4 mL) at rt for 3 h. The solvent
was then evaporated and the reaction mixture was dissolved in
2-butanol:toluene (1:2 mL) followed by addition of triethylamine
(5 mmol). The mixture was allowed to reflux for 16 h. After evap-
oration of the solvent, diketopiperazine 15 precipitated as a white
solid, which was further purified by column chromatography on
silica gel (100–200 mesh) using 90:10 ethyl acetate and methanol.
4.5.1. (3S,7R,8aS)-7-Hydroxy-3-phenylhexahydropyrrolo[1,2-a]
4.6.1. (3S,7R,8aS)-3-Phenyloctahydropyrrolo[1,2-a]pyrazine-7-
pyrazine-1,4-dione 15a
ol 16a
Yield: 1.00 g (82%); White solid, mp 228–230 °C; ½a D25
ꢂ
= ꢃ57.9 (c
Yield: 0.516 g (79%); light brown liquid,; ½a D25
ꢂ
= +6.9 (c 0.19,
0.1, EtOH); IR (KBr): 3321, 3240, 2925, 1665, 1634, 1433, 973,
EtOH); IR (neat): 3282, 2925, 2843, 1453, 1309, 1092 cmꢃ1 1H
;
720 cmꢃ1
;
1H NMR (500 MHz, ppm, DMSO-d6): 8.41 (s, 1H),
NMR (400 MHz, ppm, CDCl3): 7.50 (d, J = 7.36, 2H), 7.36–7.27 (m,
3H), 4.57–4.53 (m, 1H), 4.02–3.99 (m, 1H), 3.65 (s, 1H), 3.33–
3.29 (dd, J = 6.6, J = 11.2, 1H), 3.19–3.15 (dd, J = 3.3, J = 12.0, 1H),
3.06–3.02 (m, 1H), 2.93–2.88 (m, 2H), 2.84–2.80 (m, 1H), 2.63–
7.37–7.32 (m, 2H), 7.25 (d, J = 7.2, 2H), 5.24 (s, 1H), 5.15 (s, 1H),
4.51–4.47 (m, 1H), 4.33 (s, 1H), 3.59–3.56 (m, 1H), 3.23 (d,
J = 12.5, 1H), 2.50–2.49 (m, 1H), 2.14–2.10 (m, 1H), 2.02–1.97 (m,