M. Achmatowicz et al. / Tetrahedron 61 (2005) 9031–9041
9039
31.7, 31.1, 30.6, 29.6, 29.4, 24.1, 23.2, 19.2, 18.4; IR
(CHCl3): nZ3454, 3330, 2963, 2816, 1722, 1657, 1516,
1456 cmK1; MS (HR ESI, MeOH): m/z calcd for
C28H45N4O5 [MCHC] 517.3384; found: 517.3406.
2.52 (dt, 1H, J1Z4.4 Hz, J2Z11.5 Hz; NCHH), 2.41–2.33
(m, 1H; NCHH), 2.33–2.26 (m, 2H; 2!NCHH), 2.19–2.05
(m, 2H; 2!CHH), 1.94–1.51 (m, 12H; 2!CHH, 4!CH2,
2!CH), 0.91–0.85 (m, 12H, 4!CH3); 13C NMR
(125 MHz, CDCl3, 30 8C): dZ174.8, 174.4, 156.3, 136.6,
128.5, 128.1, 128.0, 67.8, 66.6, 66.2, 54.9, 54.4, 53.9, 53.5,
52.4, 52.2, 51.8, 32.2, 32.1, 31.9, 31.2, 30.8, 29.5, 24.3,
23.2, 19.2, 18.9, 18.3, 17.6; IR (KBr): nZ3276, 2960, 2811,
1741, 1724, 1636, 1523, 1455 cmK1; MS (HR ESI, MeOH):
m/z calcd for C31H51N4O5 [MCHC] 559.3854; found:
559.3858; elemental analysis calcd (%): C 66.55, H 8.96, N
10.04; found: C 66.56, H 9.05, N 9.98.
4.4.4. (2S,9R,12S,19R)-2,6-Cyclo-12,16-cyclo-6,10,16-
triaza-19-(benzyloxycarbonylamino)-9-metylo-11-okso-
icosanoic acid methyl ester (15d). Prepared from acid 14a
and amine 13a in 87% yield; [a]2D0 K64.9 (c 1.0 in CHCl3);
1H NMR (500 MHz, CDCl3, 30 8C): dZ7.64 (d, 1H, JZ
8.1 Hz; NH), 7.37–7.29 (m, 5H; C6H5), 5.07 (br s, 2H;
CH2Ph), 4.92 (br s, 1H; NH), 4.11–4.04 (m, 1H; CHCH3),
3.76–3.65 (m, 4H; CHCH3, OCH3), 3.21–3.16 (m, 1H),
3.13–3.07 (m, 2H), 2.99–2.92 (m, 1H), 2.89–2.81 (m, 1H),
2.64–2.54 (m, 1H), 2.53–2.46 (m, 1H), 2.38–2.22 (m, 3H),
2.20–2.06 (m, 2H), 1.92–1.54 (m, 10H), 1.16 (d, 3H, JZ
6.5 Hz; CH3), 1.12 (d, 3H, JZ6.7 Hz; CH3); 13C NMR
(125 MHz, CDCl3, 30 8C): dZ174.6, 174.2, 155.8, 136.6,
128.5, 128.0, 67.7, 66.4, 66.3, 54.4, 53.4, 52.9, 51.8, 51.5,
45.7, 43.2, 36.2, 34.4, 30.8, 29.4, 24.1, 23.0, 21.5, 20.1; IR
(CHCl3): nZ3439, 3323, 2974, 2815, 1718, 1655, 1514,
1455 cmK1; MS (HR ESI, MeOH): m/z calcd for
C27H43N4O5 [MCHC] 503.3228; found: 503.3236;
elemental analysis calcd (%): C 64.54, H 8.37, N 11.16;
found: C 64.24, H 8.48, N 11.17.
4.5. Macrocyclization procedures
N-Cbz-protected aminoesters 15a–f were subjected to
catalytic hydrogenation (H2 over Pd-C in methanol) prior
to cyclization reactions. The aminoester (1.90 mmol),
obtained from 15a–f, was dissolved in 0.5 M NaOH solution
in methanol (0.20 L), and allowed to stand at room
temperature for 1 day. The reaction mixture was neutralized
with aq HCl and evaporated to dryness. The solid residue
was dissolved in water (20 mL) and extracted with CHCl3
(4!20 mL). The combined chloroform extracts were dried
(Na2SO4) and the solvent was evaporated. The crude
product was purified by column chromatographic
(CH2Cl2/methanolZ19:1) followed by a recrystallization.
Details of other macrocyclization procedures were
described in our previous work.13b
4.4.5. (2S,9R,12S,19R)-2,6-Cyclo-12,16-cyclo-6,10,16-
triaza-9-benzylo-19-benzyloxycarbonyl-amino)-20-phe-
nylo-11-oksoicosanoic acid methyl ester (15e). Prepared
form acid 14b and amine 13b in 75% yield; [a]2D0 K49.1 (c
1
0.85 in CHCl3); H NMR (500 MHz, CDCl3, 30 8C): 7.64
4.5.1.
(4R,7S,17S)-1,5,11,15-Tetraaza-4-methyltri-
(d, 1H, JZ9.7 Hz; CONH), 7.35–7.11 (m, 15H; 3!C6H5),
5.04 (dAB, 2H, JABZ12.3 Hz, dABZ30.5 Hz; OCH2Ph),
4.84 (d, 1H, JZ8.4 Hz; CO2NH), 4.28–4.21 (m, 1H;
CHCH2Ph), 3.88–3.81 (m, 1H; CHCH2Ph), 3.66 (s, 3H;
OCH3), 3.17–3.11 (m, 1H; NCHH), 3.06 (dd, 1H, J1Z
6.1 Hz, J2Z8.5 Hz; CHCO2), 3.02–2.97 (m, 1H; NCHH),
2.92 (dd, 1H, J1Z4.2 Hz, J2Z9.7 Hz; CHCO), 2.86–2.70
(m, 5H; 2!CH2Ph, NCHH), 2.57–2.48 (m, 1H; NCHH),
2.47–2.40 (m, 1H; NCHH), 2.37–2.31 (m, 1H; NCHH),
2.34–2.17 (m, 2H; 2!NCHH), 2.14–2.03 (m, 2H; 2!
CHH), 1.91–1.47 (m, 10H; 4!CH2, 2!CHH); 13C NMR
(125 MHz, CDCl3, 30 8C): dZ174.7, 174.3, 155.9, 138.5,
137.7, 136.6, 129.4, 129.2, 128.5, 128.4, 128.3, 128.1,
128.0, 126.5, 126.3, 67.6, 66.5, 66.3, 54.3, 53.5, 52.9, 51.8,
51.7, 50.9, 48.5, 41.6, 40.4, 33.2, 31.6, 30.8, 29.4, 24.2,
23.1; IR (CHCl3): nZ3434, 3322, 2956, 2816, 1736, 1720,
1656, 1512, 1456, 1404, 1347 cmK1; MS (HR ESI, MeOH):
m/z calcd for C39H51N4O5 [MCHC] 655.3854; found:
655.3860.
cyclo[15.3.0.0.7,11]icosan-6,16-dion (2a) Recrystallization
from CH2Cl2/hexane yielded 2a as colourless crystals; mp
140–141 8C; [a]D20 K53.4 (c 0.50 in CHCl3); 1H NMR
(500 MHz, CDCl3, 30 8C): dZ8.45 (br s, 1H; NH), 8.36 (br
s, 1H; NH), 4.09–4.01 (m, 1H; CHCH3), 3.74–3.67 (m, 1H),
3.31–3.24 (m, 2H), 3.14–3.03 (m, 2H), 3.00 (dd, 1H,
J1Z9.8 Hz, J2Z5.4 Hz; CHCO), 2.91 (dd, 1H, J1Z9.3 Hz,
J2Z5.8 Hz; CHCO), 2.86–2.80 (m, 1H), 2.55 (dt, 1H, J1Z
12.4 Hz, J2Z3.5 Hz), (ddd, 1H, J1Z12.8 Hz, J2Z5.0 Hz,
J3Z2.3 Hz), 2.28–2.17 (m, 4H), 1.93–1.71 (m, 9H), 1.58
(ddt, 1H, J1Z15.2 Hz, J2Z5.0 Hz, J3Z1.6 Hz), 1.20 (d,
3H, JZ6.6 Hz; CH3); 13C NMR (125 MHz, CDCl3, 30 8C):
dZ174.8, 173.9, 70.5, 70.0, 56.3, 53.6, 53.4, 52.0, 44.9,
40.4, 31.2, 30.6, 30.5, 25.2, 24.2, 23.8, 19.2; IR (CHCl3):
nZ3678, 3325, 2822, 1654, 1530, 1471 cmK1; MS (HR
ESI, MeOH): m/z calcd for C17H30N4O2Na [MCNaC]
345.2261; found: 345.2283.
4.5.2. (4R,7S,17S)-1,5,11,15-Tetraaza-4-benzylotri-
cyclo[15.3.0.0.7,11]icosan-6,16-dion (2b) Recrystallization
from CH2Cl2/ether yielded 2b as colourless crystals; mp
184–188 8C; [a]D20 K71.5 (c 0.50 in CHCl3); 1H NMR
(500 MHz, CDCl3, 30 8C): dZ8.13 (br s, 1H; NH), 8.08 (br
s, 1H; NH), 7.30–7.18 (m, 5H; C6H5), 4.01–3.93 (m, 1H;
NHCH), 3.55–3.47 (m, 1H; NHCHH), 3.26–3.16 (m, 4H;
NHCHH, 2!NCHH, CHHPh), 3.07–2.97 (m, 2H; CHCO,
NCHH), 2.91 (dd, 1H, J1Z6.3 Hz, J2Z9.6 Hz; CHCO),
2.82 (dt, 1H, J1Z2.5 Hz, J2Z12.3 Hz; NCHH), 2.67 (dd,
1H, J1Z8.6 Hz, J2Z13.3 Hz; CHHPh), 2.46 (dt, 1H, J1Z
3.2 Hz, J2Z12.5 Hz; NCHH), 2.40–2.34 (m, 1H; NCHH),
2.26–2.15 (m, 4H; 2!NCHH, 2!CHCHH), 1.89–1.63 (m,
10H; 2!CHCHH, 4!CH2); 13C NMR (125 MHz, CDCl3,
4.4.6. (2S,9S,12S,19S)-2,6-Cyclo-12,16-cyclo–6,10,16-
triaza-19-(benzyloxycarbonylamino)-20-metylo-11-
okso-9-(20-propylo)henicosanoic acid methyl ester (15f).
Prepared from acid 14c and amine 13c in 93% yield; mp 64–
66 8C; [a]2D0 K69.3 (c 0.70 in CHCl3); 1H NMR (500 MHz,
CDCl3, 30 8C): dZ7.41 (d, 1H, JZ10.1 Hz; NH), 7.37–7.29
(m, 5H; C6H5), 5.08 (br s, 2H; CH2Ph), 4.68 (d, 1H, JZ
9.7 Hz; NH), 3.77–3.71 (m, 1H; NHCH), 3.70 (s, 3H;
OCH3), 3.52–3.46 (m, 1H; NHCH), 3.20–3.15 (m, 1H;
NCHH), 3.15–3.09 (m, 2H; NCHH, CHCO), 3.04 (dd, 1H,
J1Z4.5 Hz, J2Z10.1 Hz; CHCO), 2.74–2.67 (m, 1H;
NCHH), 2.65 (dt, 1H, J1Z5.6 Hz, J2Z11.5 Hz; NCHH),