7922
S. D. Bull et al. / Tetrahedron 62 (2006) 7911–7925
to afford (S)-30 (23 mg, 16%); [a]2D3 ꢀ11.1 (c 1.1 in CHCl3);
{lit.13 for enantiomer [a]D23 +37.0 (c 1.0 in CHCl3)}.
4.1.3.21. (3R,6S,20R)-N,N0-Bis-(p-methoxybenzyl)-3-
iso-propyl-6-(20-ethylbutanoate)piperazine-2,5-dione 39.
Compound 1 (200 mg, 0.5 mmol) in THF (10 mL),
LiHMDS (1.0 M in THF, 0.55 mL, 0.55 mmol) and (RS)-
35 (975 mg, 5.0 mmol) were reacted together according to
Section 4.1.1 to give a crude oil. Chromatography (silica,
ether/hexane 1:1) gave 39 as a colourless solid (212 mg,
82%); [a]2D3 ꢀ28.3 (c 1.0 in CHCl3); nmax (film) 2960,
1731, 1657; dH (400 MHz, CDCl3) 0.79 (3H, d, J 7.0,
CH3CHCH3), 0.86 (3H, t, J 7.4, CHCH2CH3), 1.07 (3H, d,
J 7.0, CH3CHCH3), 1.14 (3H, t, J 7.2, OCH2CH3), 1.49
(1H, m, CHCH2CH3), 1.90 (1H, m, CHCH2CH3), 2.30
(1H, m, CH3CHCH3), 3.12 (1H, m, (EtO2C)CHCH2CH3),
3.73 (1H, d, J 3.0, 6-H), 3.77 (3H, s, OCH3), 3.77 (3H, s,
OCH3), 3.80 (1H, d, J 14.4, NCH2ArOMe), 3.92 (1H, d, J
14.9, NCH2ArOMe), 3.96 (1H, m, OCH2CH3), 4.11 (1H,
m, OCH2CH3), 4.34 (1H, d, J 2.1, 3-H), 5.28 (1H, d, J
14.4, NCH2ArOMe), 5.31 (1H, d, J 14.9, NCH2ArOMe),
6.82–6.85 (4H, m, Ar), 7.14–7.20 (4H, m, Ar); dC
(100 MHz, CDCl3) 12.7, 14.0, 16.2, 19.9, 21.3, 31.0, 46.0,
47.0, 49.1, 55.2, 58.9, 61.0, 62.8, 114.0, 127.4, 127.4,
129.7, 130.0, 159.2, 159.2, 165.4, 165.6, 172.9; m/z (ESI+)
533 ([M+Na]+, 100%); HRMS (ESI+) C29H38N2NaO+6
([M+Na]+) requires 533.2628, found 533.2622.
4.1.3.18. Epimerisation of 31 and 32. LiHMDS
(1.6 mL, 1 M in THF, 1.60 mmol) was added to a 94.5:5.5
mixture of 31:32 (787 mg, 1.60 mmol) and methyl iodide
(100 mL, 1.60 mmol) in anhydrous ethanol (50 mL), and
the mixture stirred for 12 h at rt. NH4Cl (satd aq) was then
added and the mixture was partitioned between EtOAc and
H2O. The aqueous phase was extracted with EtOAc and
the combined organic layers were dried and concentrated
in vacuo to yield a crude solid 20:80 mixture of 31:32. Crys-
tallisation from EtOAc/hexane gave 32 (522 mg, 66%).
4.1.3.19. (3R,6S,20R)-N,N0-Bis(p-methoxybenzyl)-3-
iso-propyl-6-(20-methylpropanoate)piperazine-2,5-dione
37. Compound 1 (200 mg, 0.5 mmol) in THF (10 mL),
LiHMDS (0.55 mL, 1 M in THF, 0.55 mmol) and (RS)-33
(835 mg, 5.0 mmol) were reacted together according to Sec-
tion 4.1.1 to give a crude oil from which excess of (RS)-33
was removed under vacuum (1 mmHg, ambient tempera-
ture). Chromatography (silica, ether/hexane 1:1) gave 37
as a colourless solid (212 mg, 87%); [a]2D3 ꢀ10.4 (c 1.0 in
CHCl3); nmax (KBr) 2958, 1730, 1644; dH (400 MHz,
CDCl3) 0.79 (3H, d, J 7.0, CH3CHCH3), 1.08 (3H, d,
J 7.0, CH3CHCH3), 1.15 (3H, d, J 7.2, (EtO2C)CHCH3),
2.31 (1H, m, CH3CHCH3), 3.49 (1H, dq, J 1.6, 7.2,
(EtO2C)CHCH3), 3.59 (3H, s, CO2CH3), 3.68 (1H, d,
J 15.2, NCH2ArOMe), 3.77 (1H, d, J 3.4, 6-H), 3.79
(3H, s, OCH3), 3.80 (3H, s, OCH3), 3.88 (1H, d, J 14.7,
NCH2ArOMe), 4.52 (1H, d, J 1.6, 3-H), 5.31 (1H, d, J
15.2, NCH2ArOMe), 5.36 (1H, d, J 14.7, NCH2ArOMe),
6.82–6.87 (4H, m, Ar), 7.13–7.21 (4H, m, Ar); dC
(100 MHz, CDCl3) 12.0, 16.4, 19.8, 26.9, 31.3, 42.1, 45.9,
47.1, 52.1, 55.2, 55.3, 60.2, 62.8, 113.9, 114.2, 127.3,
127.5, 129.6, 129.9, 159.1, 159.3, 165.7, 165.7, 174.1; m/z
(CI+) 483 ([M+H]+, 40%), 378 (10), 121 (100); HRMS
(CI+) C27H35N2O6+ ([M+H]+) requires 483.2495, found
483.2496.
4.1.3.22. (3S,6R,20R)-N,N0-Bis-(p-methoxybenzyl)-3-
iso-propyl-6-(20-ethylhexanoate)piperazine-2,5-dione 40.
Compound 1 (200 mg, 0.5 mmol) in THF (10 mL),
LiHMDS (0.55 mL, 1 M in THF, 0.55 mmol) and (RS)-36
(1.11 g, 5.0 mmol) were reacted together according to
Section 4.1.1 to give a crude oil. Chromatography (silica,
ether/hexane 1:1) gave 40 as a colourless oil (233 mg,
86%); [a]2D3 ꢀ30.1 (c 1.0 in CHCl3); nmax (film) 1731,
1658, 1513, 1248; dH (400 MHz, CDCl3) 0.78 (3H, d,
J 7.0, CH3CHCH3), 0.84 (3H, t, J 7.4, CH2CH2CH3), 1.07
(3H, d, J 7.0, CH3CHCH3), 1.14 (3H, t, J 7.2, OCH2CH3),
1.10–1.42 (3H, m, CH2CH2CH3 and CH2CH2CH3), 1.82
(1H, m, CH2CH2CH3), 2.30 (1H, m, CH3CHCH3), 3.21
(1H, m, (EtO2C)CH(CH2)2CH3), 3.74 (1H, d, J 3.2, 6-H),
3.77 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.79 (1H, d,
J 14.6, NCH2ArOMe), 3.91 (1H, d, J 14.6), 3.94 (1H, m,
OCH2CH3), 4.13 (1H, m, OCH2CH3), 4.38 (1H, d, J 1.6,
3-H), 5.30 (1H, d, J 14.6, NCH2ArOMe), 5.33 (1H, d,
J 14.6, NCH2ArOMe), 6.81–6.86 (4H, m, Ar), 7.13–7.21
(4H, m, Ar); dC (100 MHz, CDCl3) 13.9, 14.0, 16.3, 19.9,
22.6, 27.5, 30.5, 31.1, 46.0, 47.1, 47.7, 55.2, 59.3, 61.0,
62.8, 114.0, 114.1, 127.4, 127.4, 129.7, 130.0, 159.2,
159.3, 165.5, 165.6, 173.2; m/z (CI+) 539 ([M+H]+, 20%)
121 (100); HRMS (CI+) C31H43N2O6+ ([M+H]+) requires
538.3121, found 539.3114.
4.1.3.20. (3R,6S,20R)-N,N0-Bis-(p-methoxybenzyl)-3-
iso-propyl-6-(20-tert-butylpropanoate)piperazine-2,5-
dione 38. Compound 1 (200 mg, 0.5 mmol) in THF (10 mL),
LiHMDS (1.0 M in THF, 0.55 mL, 0.55 mmol) and (RS)-34
(1.04 g, 5.0 mmol) were reacted together according to
Section 4.1.1 to give a crude oil. Chromatography (silica,
ether/hexane 1:1) gave 38 as a colourless solid (220 mg,
83%); C30H40N2O6 requires C, 68.7; H, 7.7; N, 5.3%. Found
C, 68.2; H, 7.6; N, 5.1%; [a]2D3 ꢀ10.3 (c 1.0 in CHCl3); nmax
(KBr) 2965, 1716, 1648; dH (400 MHz, CDCl3) 0.65 (3H, d, J
7.0, CH3CHCH3), 1.01 (3H, d, J 7.0, CH3CHCH3), 1.10 (3H,
d, J 7.3, (tBuO2C)CHCH3), 1.42 (9H, s, C(CH3)3), 2.24 (1H,
m, CH3CHCH3), 3.41 (1H, dq, J 1.8, 7.3, (tBuO2C)CHCH3),
3.69 (1H, d, J 14.8, NCH2ArOMe), 3.72 (1H, d, J 3.3, 6-H),
3.77 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.92 (1H, d, J 14.8,
NCH2ArOMe), 4.61 (1H, d, J 1.2, 3-H), 5.18 (1H, d, J 14.8,
NCH2ArOMe), 5.28 (1H, d, J 14.8, NCH2ArOMe), 6.81–
6.86 (4H, m, Ar), 7.17–7.28 (4H, m, Ar); dC (100 MHz,
CDCl3) 12.3, 16.2, 19.8, 27.9, 31.3, 43.4, 46.2, 47.2,
55.2, 55.2, 60.5, 62.9, 81.6, 113.8, 114.1, 127.5, 128.3,
129.8, 130.0, 159.1, 159.2, 165.4, 166.0, 172.8; m/z (ESI+)
547 ([M+Na]+, 100%); HRMS (ESI+) C30H40N2NaO+6
([M+Na]+) requires 547.2784, found 547.2779.
4.1.3.23. (3R,6S,10S)-1,4-N,N0-Bis-(p-methoxybenzyl)-
6-iso-propyl-3-(1-phenylethylethanoate)piperazine-2,5-
dione 46. Compound 1 (200 mg, 0.5 mmol) in THF (10 mL),
LiHMDS (1.0 M in THF, 0.62 mL, 0.6 mmol) and (RS)-45
(0.14 mL, 1.1 mmol) were reacted together according to
Section 4.1.1 to give a brown oil. Chromatography (silica,
ether/hexane 1:9) gave 46 as a colourless crystalline solid
(210 mg, 75%); C33H38N2O6 requires C, 70.9; H, 6.9; N,
5.0%. Found C, 70.6; H, 6.9; N, 5.0%; mp 115–118 ꢁC
(EtOAc/hexane); [a]2D3 +81.2 (c 1.0 in CHCl3); nmax (film)
1744, 1645, 1513; dH (400 MHz, CDCl3) 0.63 (3H, d,
J 7.0, CH3CHCH3), 0.95 (3H, d, J 7.0, CH3CHCH3), 1.27