3598
C. Peggion et al. / Tetrahedron 56 (2000) 3589±3601
CH2Cl2 (15 mL) and NMM (0.29 mL, 2.68 mmol),
EDC´HCl (291 mg, 1.52 mmol) and HOAt (207 mg, 1.52
mmol) were added at 08C. The two solutions were combined
and the reaction mixture was stirred at room temperature for
3 d. Then, EtOAc was added and the mixture was washed
with 0.5 M citric acid, water, 5% NaHCO3 and water, dried
over anhydrous Na2SO4, and concentrated. Addition of light
petroleum gave the title compound (379 mg, 70%) as a
solid, mp 240±2418C; RfI 0.65, RfII 0.85, RfIII 0.20;
[a]2D026.3 (c 0.5, MeOH); nmax (KBr) 3310, 1727, 1661,
1530 cm21; dH (250 MHz, CDCl3) 7.72(1H, s, NH),
7.41(1H, s, NH), 7.10 (1H, s, NH), 6.47 (1H, s, NH), 5.74
(2H, m, 2 Mag 2 gCH), 5.06 (4H, m, 2 Mag 2 dCH2), 4.87
(1H, s, Mag NH), 3.69 (3H, s, OMe CH3), 3.052.51 (4H, m,
2Mag 2 bCH2), 1.551.39 (24H, m, 2 Mag 2 bCH3 and 3 Aib
6 bCH3), 1.46 (9H, s, Boc 3 CH3); HRMS (EI): M1, found
609.3739. C30H51N5O8 requires 609.3738.
1.41 (3H, d, J7.3 Hz, Ala bCH3), 1.36 (3H, d, J7.0 Hz,
Ala bCH3); HRMS (EI): M1, found 385.2227. C18H31N3O6
requires 385.2213.
N-tert-Butyloxycarbonyl-l-alanyl-l-alanyl-Ca-methyl-l-
allylglycyl-l-alanine methylester, Boc-l-Ala-l-Ala-l-
Mag-l-Ala-OMe. To a solution of Boc-l-Ala-OH (666
mg, 3.52 mmol) in CH2Cl2 (10 mL) and NMM (0.64 mL,
6.21 mmol) cooled to 08C, HOAt (479 mg, 3.52 mmol) and
EDC´HCl (675 mg, 3.52 mmol) were added. After 15 min
TFA´H-l-Ala-l-Mag-l-Ala-OMe [obtained by treatment of
the corresponding Boc-protected tripeptide methylester
(800 mg, 2.07 mmol) with a 30% solution of TFA in
CH2Cl2)] in CH2Cl2 (10 mL) and NMM (0.64 mL, 6.21
mmol) were added and the reaction was stirred at room
temperature for 2 d. Then, EtOAc was added and the
mixture was washed with 0.5 M citric acid, water, 5%
NaHCO3 and water, dried over anhydrous Na2SO4, and
evaporated to dryness. The title compound (680 mg, 72%)
was recrystallized from Et2O/light petroleum, mp 164±
1658C; RfI 0.90, RfII 0.90, RfIII 0.30; [a]2D0269.6 (c 0.5,
MeOH); nmax (KBr)3369, 3284, 1745, 1705, 1657,
1539 cm21; dH (250 MHz, CDCl3) 7.00 (1H, d, J7.0 Hz,
Ala NH), 6.61 (1H, d, J6.2 Hz, Ala NH), 6.60 (1H, s, Mag
NH), 5.64 (1H, m, Mag gCH), 5.14 (2H, m, Mag dCH2),
4.91 (1H, br d, J6.5 Hz, Ala NH), 4.52 (1H, dq, J7.0,
7.3 Hz, Ala aCH), 4.28 (1H, dq, J6.2, 7.3 Hz, Ala aCH),
4.13 (1H, dq, J6.5, 6.6 Hz, Ala aCH), 3.74 (3H, s, OMe
CH3), 2.772.66 (2H, m, Mag bCH2), 1.54 (3H, s, Mag
bCH3), 1.44 (9H, s, Boc 3 CH3), 1.40 (3H, d, J7.3 Hz,
Ala 3 bCH3), 1.39 (3H, d, J7.3 Hz, Ala 3 bCH3), 1.36 (3H,
d, J6.6 Hz, Ala 3 bCH3); HRMS (EI): MH1, found
457.2665. C21H37N4O7 requires 457.2662.
N-tert-Butyloxycarbonyl-Ca-methyl-l-allylglycyl-l-ala-
nine methylester, Boc-l-Mag-l-Ala-OMe. To a solution
of Boc-l-Mag-OH (750 mg, 3.27 mmol) in CH2Cl2 (10 mL)
and NMM (1.1 mL, 9.6 mmol) cooled to 08C, HOAt
(899 mg, 6.60 mmol) and EDC´HCl (1.26 g, 6.60 mmol)
were added. After 15 min HCl´H-l-Ala-OMe (1.0 g,
7.0 mmol) was added and the reaction was stirred at room
temperature for 20 h. Then, the solvent was removed and the
residue redissolved in EtOAc. The solution was extracted
with 0.5 M citric acid, water, 5% NaHCO3 and water, dried
over anhydrous Na2SO4, and concentrated. Addition of light
petroleum gave the title compound (0.98 g, 96%) as a solid,
mp 90±918C; RfI 0.95, RfII 0.95, RfIII 0.50; [a]2D0240.8 (c
1, MeOH); nmax (KBr) 3314, 1751, 1712, 1684, 1653,
1524 cm21; dH (250 MHz, CDCl3) 6.95 (1H, d, J7.0 Hz,
Ala NH), 5.72 (1H, m, Mag gCH), 5.15 (2H, m, Mag dCH2),
4.91 (1H, s, Mag NH), 4.57 (1H, dq, J7.0, 7.3 Hz, Ala
aCH), 3.74 (3H, s, OMe CH3), 2.762.53 (2H, m, Mag
bCH2), 1.48 (3H, s, Mag bCH3), 1.44 (9H, s, Boc 3 CH3),
1.40 (3H, d, J7.3 Hz, Ala bCH3); HRMS (EI): M1, found
314.1857. C15H26N2O5 requires 314.1842.
N-tert-Butyloxycarbonyl-Ca-methyl-l-allylglycyl-l-alanyl-
l-alanyl-Ca-methyl-l-allylglycyl-l-alanine methylester,
Boc-l-Mag-l-Ala-l-Ala-l-Mag-l-Ala-OMe. To a solu-
tion of Boc-l-Mag-OH (392 mg, 1.71 mmol) in CH2Cl2
(5 mL) and NMM (0.33 mL, 3.0 mmol) cooled to 08C,
HOAt (233 mg, 1.71 mmol) and EDC´HCl (328 mg, 1.71
mmol) were added. After 15 min TFA´H-l-Ala-l-Ala-l-
Mag-l-Ala-OMe [obtained by treatment of the correspond-
ing Boc-protected tetrapeptide methylester (520 mg,
1.14 mmol) with a 30% solution of TFA in CH2Cl2)] in
CH2Cl2 (5 mL) and NMM (0.33 mL, 3.0 mmol) were
added and the reaction was stirred at room temperature for
24 h. Then, EtOAc was added and the mixture was washed
with 0.5 M citric acid, water, 5% NaHCO3 and water, dried
over anhydrous Na2SO4, and concentrated. Addition of light
petroleum gave the title compound(582 mg, 90%) as a solid,
mp 132±1348C; RfI 0.90, RfII 0.90, RfIII 0.25; [a]2D0246.6
(c0.5, MeOH); nmax (KBr) 3314, 1742, 1665, 1526 cm21; dH
(200 MHz, CDCl3) 7.71 (1H, d, J7.0 Hz, Ala NH), 7.10
(1H, d, J7.3 Hz, Ala NH), 6.90 (1H, s, Mag NH), 6.42
(1H, d, J5.5 Hz, Ala NH), 5.78 (2H, m, 2Mag 2 gCH),
5.315.11 (4H, m, 2 Mag 2 dCH2), 5.03 (s, 1H, Mag NH),
4.51 (1H,dq, J7.3, 6.3 Hz, Ala aCH), 4.32 (1H, dq, J7.0,
7.0 Hz, Ala aCH), 4.24 (1H, dq, J5.5, 7.0 Hz, Ala aCH),
3.70 (s, 3H, OMe CH3), 2.812.42 (4H, m, 2 Mag 2 bCH2),
1.52 (6H, s, 2 Mag 2 bCH3), 1.45 (9H, s, Boc 3 CH3), 1.44
(6H, d, J7.0 Hz, 2 Ala 2 bCH3), 1.39 (3H, d, J6.3 Hz,
Ala bCH3); HRMS (EI): M1, found 567.3260. C27H45N5O8
requires 567.3268.
N-tert-Butyloxycarbonyl-l-alanyl-Ca-methyl-l-allylglycyl-
l-alanine methylester, Boc-l-Ala-l-Mag-l-Ala-OMe. To
a solution of Boc-l-Ala-OH (1.07 g, 5.4 mmol) in CH2Cl2
(10 mL) and NMM (0.89 mL, 8.1 mmol) cooled to 08C,
HOAt (734 mg, 5.4 mmol) and EDC´HCl (1.05 g, 5.4
mmol) were added. After 15 min TFA´H-l-Mag-l-Ala-
OMe [obtained by treatment of the corresponding Boc-
protected dipeptide methylester (850 mg, 2.70 mmol) with
a 30% solution of TFA in CH2Cl2)] in CH2Cl2 (10 mL) and
NMM (0.89 mL, 8.1 mmol) were added and the reaction
was stirred at room temperature for 24 h. Then, EtOAc
was added and the mixture was washed with 0.5 M citric
acid, water, 5% NaHCO3 and water, dried over anhydrous
Na2SO4, and concentrated. Addition of light petroleum gave
the title compound (1.00 g, 97%) as a solid, mp 154±1568C;
RfI 0.95, RfII 0.95, RfIII 0.35; [a]2D0264.8 (c 0.5, MeOH);
nmax (KBr) 3390, 3294, 1746, 1683, 1644, 1529 cm21; dH
(250 MHz, CDCl3) 7.11 (1H, d, J6.3 Hz, Ala NH), 6.60
(1H, s, Mag NH), 5.69 (1H, m, Mag gCH), 5.17 (2H, m,
Mag dCH2), 4.90 (1H, br d, J6.0 Hz, Ala NH), 4.52 (1H,
dq, J6.3, 7.3 Hz, Ala aCH), 4.05 (1H, dq, J6.0, 7.0 Hz,
Ala aCH), 3.73 (3H, s, OMe CH3), 2.822.62 (2H, m, Mag
bCH2), 1.57 (3H, s, Mag bCH3), 1.45 (9H, s, Boc 3 CH3),