Step 2 Epoxidation. A nitrogen-flushed solution of alkene
diester (1.0 eq.) in dry THF was cooled to 0 ◦C in an ice bath
before tert-butyl hydroperoxide (TBHP) (1.2 eq. of a 1.14 M
toluene solution) was added by syringe. Following rapid stirring
for 10 min, potassium tertbutoxide (KOtBu) (0.25 eq.) was added
and the reaction stirred for another 10 min. The ice bath was
removed and the solution stirred at RT overnight whereupon
aqueous sodium thiosulfate solution (10%) was added and the
mixture stirred for a further 30 min. The resultant two-phase
mixture was concentrated to 1/3 of its volume, transferred to a
separatory funnel and extracted with CHCl3 (¥3), the organics
combined, dried (MgSO4), filtered and evaporated to dryness
under reduced pressure. The crude solid was purified by column
chromatography and/or recrystallisation resulting in the requisite
cyclobutane epoxide as a white solid.
Dimethyl (2b,3a,4a,8a,9a,10b,12b,13a,16a,17b) 6-tertbutoxy-
carbonylaminoethyl-14,15-di[(tertbutoxycarbonylamino)ethyl
carboximido]-6-aza-19-oxa-5,7-dioxoheptacyclo [9.6.1.13,9.113,16
02,10.04,8.012,17] icosa-14-ene-1,11-dicarboxylate 14
.
Equimolar amounts of epoxide 88a (902 mg, 1.94 mmol) and
norbornene 912 (901 mg, 1.94 mmol) were heated (150 ◦C) in
THF (4 ml) for 70 h. Column chromatography (EtOAc, Rf =
0.37) gave 14 (1.601 g, 1.72 mmol, 89%) as an off-white powder;
◦
mp 147.2–150.7 C; dH(270 MHz; d6-DMSO; Me4Si) 1.02 (1 H,
d, J = 7.8 Hz, H20), 1.18 (1 H, d, J = 9.8 Hz, H18), 1.34 (9
H, s, 1 ¥ C(CH3)3), 1.36 (18 H, s, 2 ¥ C(CH3)3), 2.02 (2 H, s,
H2,10), 2.24 (1 H, d, J = 8.2 Hz, H20), 2.31 (2 H, s, H13,16),
2.33 (1 H, d, J = 8.2 Hz, H18), 2.43 (2 H, s, H3,9), 3.02 (4
H, s, 2 ¥ CH2NHCO), 3.04 (4 H, s, H4,8,12,17), 3.11 (4 H, s,
2 ¥ CH2NHCOO), 3.14 (2 H, s, 1 ¥ CH2NHCOO), 3.41 (2 H, s,
1 ¥ CH2N), 3.84 (6 H, s, 2 ¥ COOCH3), 6.78 (1 H, s, 1 ¥ NHCOO),
6.84 (2 H, t, J = 5.1 Hz, 2 ¥ NHCOO) and 8.89 (2 H, s, 2 ¥ NHCO);
dC(270 MHz; CDCl3; Me4Si) 28.3, 28.4, 38.1, 39.0, 40.0, 41.0, 48.4,
48.5, 50.9, 52.8, 53.8, 79.7, 89.1, 148.4, 156.1, 156.7, 164.3, 168.2,
176.9; HRMS: m/z = 929.45020 [M + H]+, C45H65N6O15 requires
929.45024.
Dimethyl (1a,2a,6a,7a,8b,12b)-4-(2¢-tertbutoxycarbonylamino
ethyl)-4-aza-10-oxapentacyclo [5.5.1.02,6.08,12.09,11]trideca-3,5-
dione-9,11-dicarboxylate 88a
Prepared according to a standard two step protocol; Step
1: (1a,2a,6a,7a)-4-(2¢-tert-Butoxycarbonylaminoethyl)-4-azatri-
cyclo[5.2.1.02,6]deca-8-ene-3,5-dione 78a (5.002 g, 16.34 mmol),
DMAD (2.5 ml, 20 mmol) and RuH2(CO)(PPh3)3 (401 mg,
See ESI for the synthesis of [n]polynorbornenes 15, 16, 17
and 18.
◦
0.436 mmol) in THF (20 ml) at 70 C for 48 h to give (1.823 g,
3.005 mmol, 94%) the cyclobutene diester as a white powder
following chromatographic purification (50% EtOAc/Pet Sp, Rf =
0.26); mp 153.8–154.7 ◦C; dH(400 MHz; CDCl3; Me4Si) 1.37
(9H, s, C(CH3)3), 1.47 (1 H, d, J = 11.6 Hz, H12), 1.74 (1 H,
d, J = 11.6 Hz, H12), 2.79 (2 H, s, H8,11), 2.83 (2 H, s, H1,7),
3.22 (2 H, s, H2,6), 3.33 (2 H, m, NHCH2), 3.61 (2 H, m, NCH2),
3.76 (6 H, s, 2 ¥ COOCH3) and 4.70 (1 H, br s, NH); dC(400 MHz;
CDCl3; Me4Si) 27.9, 33.7, 35.5, 37.8, 38.4, 42.0, 47.0, 51.5, 79.0,
140.7, 155.8, 160.1 and 176.5; HRMS: m/z = 449.19030 [M + H]+,
C22H29N2O8 requires 449.19240.
General hydrogenation procedure
A
round-bottomed flask was charged with the required
[n]polynorbornene scaffold, catalytic Pd(OH)2/C, EtOH and
equipped with a reflux condenser. This reaction mixture was stirred
at 45 ◦C under a H2 atmosphere for up to 48 h. After cooling to
RT the solution was diluted with EtOH, filtered through celite and
solvent removed under reduced pressure. The product was purified
using column chromatography.
Dimethyl (2b,3a,4a,8a,9a,10b,12b,13a,14a,15a,16a,17b)
6-tertbutoxycarbonylaminoethyl-14b,15b-di[(tertbutoxy-
carbonylamino)ethylcarboximido]-6-aza-19-oxa-5,7-dioxo-
heptacyclo [9.6.1.13,9.113,16.02,10.04,8.012,17] icosa-1,11-dicarboxylate
Step 2. The above diester (1.197 g, 2.670 mmol) was epoxidised
with TBHP (1.14M, 3.0 ml, 3.4 mmol) and KOtBu (81 mg,
0.72 mmol) in dry THF (150 ml) for 28 h. Column chromatography
(50% EtOAc/Pet Sp, Rf = 0.22) afforded 88a (854 mg, 1.84 mmol,
69%) as a white solid; mp 190.8–192.2 ◦C; dH(270 MHz; CDCl3;
Me4Si) 1.39 (9 H, s, C(CH3)3), 1.72 (1 H, d, J = 11.5 Hz, H13), 2.12
(1 H, d, J = 11.5 Hz, H13), 2.37 (2 H, s, H8,12), 3.17 (2 H, s, H1,7),
3.27 (2 H, m, NHCH2), 3.29 (2 H, s, H2,6), 3.55 (2 H, m, NCH2),
3.79 (6 H, s, 2 ¥ COOCH3) and 4.68 (1 H, br s, NH); dC(400 MHz;
CDCl3; Me4Si) 27.9, 34.2, 36.4, 38.6, 38.7, 45.6, 47.1, 52.5, 79.1,
141.2, 155.5, 163.3 and 176.2; HRMS: m/z = 465.18621 [M + H]+,
C22H29N2O9 requires 465.18732.
The [3]polynorbornene 14 (0.891 mg, 0.959 mmol) was subject
to hydrogenation conditions in EtOH (30 ml) for 48 h, column
chromatography (10% EtOH/EtOAc, Rf = 0.42) gave the 3-
armed [3]polynorbornane scaffold (0.879 mg, 0.944 mmol, 98%)
as a white powder; mp 152.1–154.2 ◦C; dH(270 MHz; d6-DMSO;
Me4Si) 0.81 (1 H, d, J = 9.2 Hz, H20), 1.17 (1 H, d, J = 6.7 Hz,
H18), 1.35 (9 H, s, 1 ¥ C(CH3)3), 1.37 (18 H, s, 2 ¥ C(CH3)3),
1.81 (2 H, s, H13,16), 2.10 (2 H, s, H2,10), 2.18 (1 H, d, J =
9.4 Hz, H20), 2.33 (1 H, d, J = 8.2 Hz, H18), 2.38 (2 H, s,
H3,9), 2.59 (2 H, s, H14,15), 2.72 (2 H, s, H12,17), 2.94 (6 H, s,
2 ¥ CH2NHCO, H4,8), 3.01 (6 H, br s, 3 ¥ CH2NHCOO), 3.47
(2 H, br s, 1 ¥ CH2N), 3.77 (6 H, s, 2 ¥ COOCH3), 6.59 (2
H, s, 2 ¥ NHCOO), 6.85 (1 H, t, J = 5.4 Hz, 1 ¥ NHCOO)
and 7.56 (2 H, s, 2 ¥ NHCO); dC(270 MHz; d6-DMSO; Me4Si)
28.8, 29.6, 29.9, 34.8, 37.5, 37.8, 38.8, 39.4, 40.8, 43.1, 46.8, 48.3,
49.7, 50.7, 52.7, 78.2, 78.3, 90.4, 156.1, 156.3, 169.0, 171.6 and
177.4; HRMS: m/z = 931.46566 [M + H]+, C45H67N6O15 requires
931.46589.
See ESI for the syntheis of epoxides 10, 12 and 13.
General ACE coupling reaction
A pressure vessel was charged with equimolar amounts of the
desired epoxide and norbornene unit (two eq. in the case of bis
epoxides), the minimum amount of tetrahydrofuran (THF) added
for dissolution then the vessel sealed and heated at 140–150 ◦C
for up to 72 h. The vessel was then cooled, opened, the solvent
removed under reduced pressure, and the crude purified using flash
chromatography.
See ESI for the hydrogenation of compounds 16, 17 and 18.
4238 | Org. Biomol. Chem., 2009, 7, 4233–4240
This journal is
The Royal Society of Chemistry 2009
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