832
T. Gorewoda et al. / Tetrahedron: Asymmetry 22 (2011) 823–833
d, J 6.6, CH3), 1.06 (3H, d, J 7.2, CH3), 2.49–2.52 (1H, m, CH(CH3)2),
3.75 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.96 (1H, m, CH-i-Pr),
4.25 (1H, d, J 4.8, COCHCO), 4.59 (1H, m, C(3)H), 6.24 (1H, s, NH),
6.74 (1H, s, NH); 13C NMR (151 MHz, CDCl3): d 16.11, 18.71,
30.93, 53.21, 53.60, 53.78, 59.96, 164.99, 166.36, 166.54,
168.03. HRMS m/z (EI) calcd for C12H18N2O6 286.11649; found:
286.11648.
54.19,b 54.53,a 56.75,a 56.97,b 58.29,a 58.41,b 113.64,a 113.65,b
160.53,b 160.74,a 163.47,b 164.15,a 168.10,a 168.11.b HRMS m/z
(ESI) calcd for C11H13N3O4Na 274.07983; found: 274.07915.aMajor
diastereomer and bminor diastereomer.
4.14.5. 3-[Acetyl(ethoxycarbonyl)methyl]-1,6-trimethylene-2,5-
piperazinedione (3R,6S,10RS)-17b
Column chromatography (silica gel, 1:4 CH3CN/CH2Cl2) yielded
a mixture of two diastereomers of the product as a thick oil
4.14.2. 3-[Di(methoxycarbonyl)methyl]-1,6-trimethylene-2,5-
piperazinedione (3RS,6S)-14b
(0.118 g, 70%, de = 13%), ½a D23
ꢅ
¼ ꢀ99:0 (c 3.0, CH2Cl2); IR (KBr,
CHCl3) 3380, 1736, 1688, 1672 cmꢀ1
;
1H NMR (600 MHz, CDCl3):
Column chromatography (silica gel, 1:1 CH3CN/CH2Cl2) yielded
an oily mixture of two diastereomers of the pure product (0.144 g,
d 1.29 (3H, t, J 6.6, CH3)a, 1.33 (3H, t, J 6.6, CH3)b, 1.86–1.94
(2 ꢄ 1H, m, CH2), 2.00–2.06 (2 ꢄ 2H, m, CH2), 2.30 (3H, s, CH3)a,
2.38 (3H, s, CH3)a, 2.41 (2 ꢄ 1H, m, CH2), 3.49–3.55 (2 ꢄ 1H, m,
CH2), 3.67–3.74 (2 ꢄ 1H, m, CH2), 4.09 (1H, d, J 4.8, COCHCO)b,
84%, de = 64%), ½a D23
¼ ꢀ66:3 (c 0.9, CHCl3), IR (KBr, CHCl3) 3384,
ꢅ
3008, 2960, 1752, 1744, 1692, 1680, 1668 cmꢀ1. (3R,6S)-14b: 1H
NMR (600 MHz, CDCl3) d 1.80–2.07 (3H, m, CH2), 2.38–2.43 (1H,
m, CH2), 3.52–3.59 (1H, m, CH2), 3.55–3.67 (1H, m, CH2), 3.76
(3H, s, OCH3), 3.81 (3H, s, OCH3), 4.09 (1H, d, J 4.2, COCHCO),
4.18 (1H, dd, J 9.9, J 6.3, CHpro), 4.53 (1H, dd, J 3.0, J 3.0,
C(3)H), 6.92 (1H, s, NH); 13C NMR (151 MHz, CDCl3): d 21.43,
28.97, 45.36, 53.07, 53.64, 56.23, 58.12, 162.14, 166.71, 167.64,
168.20. (3S,6S)-14b: 1H NMR (600 MHz, CDCl3): d 1.94–2.13 (3H,
m, CH2), 2.42–2.47 (1H, m, CH2), 3.50–3.61 (1H, m, CH2), 3.71–
3.82 (1H, m, CH2), 3.81 (3H, s, OCH3), 3.88 (3H, s, OCH3), 4.16–
4.19 (1H, m, CHpro), 4.32 (1H, d, J 5.4, COCHCO), 4.65 (1H, d, J 5.4,
C(3)H), 6.76 (1H, s, NH); 13C NMR (151 MHz, CDCl3): d 22.25,
28.64, 45.68, 51.75, 53.18, 54.58, 58.92, 162.79, 166.75, 168.11,
168.38. HRMS m/z (ESI) calcd for C12H16N2O6Na 307.08896; found:
307.09006.
4.14/9.6/6.6 (1H, dd, J 9.6, J 6.6, CHpro),a 4.20–4.32 (6H, m, 2xOCH2,
b
CHpro
,
COCHCOa), 4.49 (1H, dd, J 2.9, J 2.9, C(3)H),a 4.50 (1H, dd, J
3.3, J 3.3, C(3)H),b 6.63 (1H, s, NH),a 6.80 (1H, s, NH)b; 13C NMR
(151 MHz, CDCl3) d 13.89,a 13.92,b 21.45,b 21.46,a 28.98,b 29.09,a
30.03,a 30.19,b 45.35,b 45.37,a 55.97,a 56.01,b 58.21,a 58.37,b
60.24,a 60.64,b 62.39,a 62.48,b 162.70,a 162.88,b 166.54,b 167.53,a
167.85,a 168.28,b 200.41,a 202.35.b HRMS m/z (ESI) calcd for
C
13H18N2O5Na 305.10940; found: 305.11079.aMajor diastereomer
and bminor diastereomer.
4.15. Synthesis of 3-dimethoxyphosphoryl-1,6-trimethylene-
2,5-piperazinedione (3R,6S)-18b
The piperazinedione 7b (1.00 g; 2.0 mmol), methyltriphenyl-
phosphonium iodide (0.198 g; 0.50 mmol), CH2Cl2 (3.2 mL), CH3CN
(1.0 mL) and a solution of trimethyl phosphite (0.280 mL; 0.296 g;
2.4 mmol) in CH2Cl2 (0.8 mL) were added to a glass vial with a
screw-cap. The sealed vial was heated at 60 °C for 3 h. The solvent
was evaporated under reduced pressure. The oily residue obtained
contained a single diastereomer of the expected product (3R,6S)-
18b (0.424 g, 81%). Further purification of (3R,6S)-18b was
achieved by chromatography (silica gel, 1:5 MeOH/CH2Cl2). The
spectroscopic properties of the thick oil obtained were consistent
4.14.3. 3-(Diacetylmethyl)-1,6-trimethylene-2,5-
piperazinedione (3R,6S)-15b
Column chromatography (silica gel, 1:4 CH3CN/CH2Cl2) yielded
a single diastereomer of the product (0.104 g, 69%) as a colourless
oil, ½a 2D3
ꢅ
¼ ꢀ54:4 (c 1.0, CH2Cl2); IR (KBr, CHCl3) 3388, 1692, 1708,
1668 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d 1.86–1.98 (2H, m, CH2),
2.00–2.60 (1H, m, CH2), 2.27 (3H, s, CH3), 2.39–2.42 (1H, m, CH2),
2.30 (3H, s, CH3), 3.48–3.52 (1H, m, CH2), 3.65–3.70 (1H, m, CH2),
4.15 (1H, dd, J 10.2, J 6.6, CHpro), 4.23 (1H, d, J 6.0, COCHCO), 4.59
(1H, dd, J 5.9, J 3.5, C(3)H), 7.08 (1H, s, NH); 13C NMR (151 MHz,
CDCl3): d 21.54, 28.90, 29.67, 30.62, 45.43, 55.75, 58.09, 69.19,
162.88, 168.38, 201.51, 201.75. HRMS m/z (ESI) calcd for
with the literature data.35
½
a 2D3
ꢅ
¼ ꢀ31:7 (c 0.5, MeOH); IR (NaBr,
CH3CN) 3312, 1692, 1672 cmꢀ1
;
1H NMR (600 MHz, CH3CN): d
1.82–1.94 (3H, m, CH2CH2), 2.25 (1H, m, CH2), 3.44–3.47 (2H, m,
CH2), 3.78 (3H, d, J 10.8, OCH3), 3.79 (3H, d, J 11.4, OCH3), 4.28–
4.32 (1H, m, CH), 4.35 (1H, dd, J 17.7, J 3.7, CH(3)P), 7.19 (1H, s,
NH); 13C NMR (151 MHz, CH3CN): d 22.85, 29.43, 46.67, 49.88,
54.79 (d, J 26.5, OCH3), 54.83 (d, J 26.5, OCH3), 56.20 (d, J 142.5,
CH–P), 160.70, 170.30.
C12H16N2O4Na 275.10051; found: 275.10023.
4.14.4. 3-(Methoxycarbonylcyanomethyl)-1,6-trimethylene-2,5-
piperazinedione (3R,6S,10RS)-16b
A different synthesis procedure was applied. The piperazinedi-
one 7b (2.0 g, 3.98 mmol) was dissolved in CH3CN (100 mL) and
cooled to 0 °C. A solution of methyl cyanoacetate (1.40 mL;
1.576 g; 15.92 mmol) and DBU (0.90 mL; 0.92 g; 5.96 mmol) in
CH3CN (10 mL) was added dropwise. The mixture was stirred at
0 °C for 1 h and then at room temperature for 23 h. Evaporation
of the solvent in vacuo (15 mmHg) yielded a colorless oil. Column
chromatography (silica, 1:2 CH3CN/CH2Cl2) gave a mixture of two
diastereomers of the product (0.670 g, 71%, de = 12%). Crystalliza-
tion of the product from CH3CN yielded a pure mixture of two
diastereomers as colorless crystals (0.184 g, de = 56%),
4.16. Hydrolysis of 3-substituted-2,5-piperazinediones: general
procedure
A piperazinedione derivative (1.4 mmol) and hydrochloric acid
(40 mL, 36%) were added to a glass vial with a screw-cap, and the
sealed vial was heated at 100 °C for 24 h. The hydrochloric acid
was evaporated in vacuo (0.1 mmHg), and the residue was sepa-
rated on a column filled with Amberlyst 15 resin (70 mL) in
acidic form. Eluting initial fractions with water provided pure
aspartic acid hydrochloride. Subsequent fractions were eluted
with a solution of ammonia in water (0.2 mol/L) and provided
½
a 2D3
ꢅ
¼ ꢀ31:0 (c 0.4, CHCl3); IR (KBr, CH3CN) 3304, 1756, 1700,
1672 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d 1.91–2.00 (2 ꢄ 2H, m,
CH2), 2.05–2.10 (2 ꢄ 1H, m, CH2), 2.43–2.47 (2 ꢄ 1H, m, CH2),
3.56–3.64 (2 ꢄ 1H, m, CH2), 3.69–3.77 (2 ꢄ 1H, m, CH2), 3.87 (3H,
s, OCH3),b 3.92 (3H, s, OCH3),a 4.24 (1H, d, J 3.6, COCHCO),b 4.25
(1H, d, J 2.4, COCHCO),a 6.63 (1H, d, J 2.4, NH),b 4.23 (1H, dd, J
10.2, J 2.6, CHpro),b 4.46 (1H, dd, J 9.6, J 6.0, CHpro),a 4.53 (1H, dd,
either L-valine or L-proline. After evaporation of the water or
ammonia solution under reduced pressure, the residue was dried
in vacuo (0.1 mmHg). The spectroscopic properties of the ob-
tained amino acids were in accordance with spectroscopic prop-
erties of pure, commercially available reagents. The following
amino acids, characterized by their specific optical rotations,
were obtained:
J 2.7, J 2.7, C(3)H),a 4.63 (1H, dd, J 3.5, J 3.5, C(3)H),b 6.63 (1H, d, J
2.4, NH),b 6.77 (1H, s, NH)a;
C NMR (151 MHz, CDCl3): d
13
21.47,b 21.57,a 29.04,b 29.20,a 41.56,b 41.67,a 45.63,b 45.99,a