Job/Unit: O20323
/KAP1
Date: 21-06-12 11:22:22
Pages: 9
C. El-Nachef, K. Bajaj, J. Koblick, A. R. Katritzky
FULL PAPER
240–243 °C. 1H NMR ([D6]DMSO): δ = 8.03 (d, J = 8.1 Hz, 1 H),
14 H), 1.25–1.05 (m, 8 H), 1.04–0.86 (m, 12 H) ppm. 13C NMR
7.90 (d, J = 7.8 Hz, 1 H), 6.45 (s, 1 H), 6.38 (s, 1 H), 4.40–4.27 (m,
(CDCl3): δ = 170.81, 156.0, 149.8, 140.4, 136.3, 136.0, 129.5, 128.9,
2 H), 4.23–4.08 (m, 2 H), 3.12–3.04 (m, 1 H), 2.81 (dd, J = 12.6, 128.7, 128.3, 128.2, 127.4, 126.7, 125.0, 123.3, 117.6, 75.3, 67.2,
5.1 Hz, 1 H), 2.57 (d, J = 12.3 Hz, 1 H), 2.10 (t, J = 6.9 Hz, 2 H), 55.1, 39.6, 38.3, 37.6, 37.5, 33.0, 32.9, 31.2, 28.2, 25.0, 24.6, 22.9,
1.68–1.38 (m, 11 H), 1.35–1.24 (m, 2 H), 0.88 (d, J = 6.6 Hz, 3 H), 22.9, 21.2, 20.8, 20.0, 19.9, 13.2, 12.3, 12.0 ppm. HRMS: calcd. for
0.87 (d, J = 6.3 Hz, 3 H), 0.83 (d, J = 6.6 Hz, 3 H), 0.82 (d, J = C46H65NO5Na [M + Na]+ 734.4755; found 734.4775.
6.6 Hz, 3 H) ppm. 13C NMR ([D6]DMSO): δ = 174.0, 172.2, 171.9,
(2R)-2,5,7,8-Tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-
162.7, 61.1, 59.2, 55.5, 50.6, 50.2, 40.9, 35.0, 28.1, 25.4, 24.3, 24.2,
chroman-6-yl (S)-2-[(S)-2-{[(benzyloxy)carbonyl]amino}-3-methyl-
23.2, 22.9, 21.6, 21.4 ppm. C22H38N4O5S (470.63): calcd. C 56.15,
butanamido]-3-phenylpropanoate (Z-Val-Phe-O-Tocopherol) (9c):
H 8.14, N 11.90; found C 56.16, H 8.44, N 11.96.
Purified by column chromatography using hexanes/ethyl acetate in
(2S)-3-Methyl-2-[2-(2-{5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno-
a 8:2 ratio to yield the product as off-white microcrystals (44%);
[3,4-d]imidazol-4-yl]pentanamido}acetamido)acetamido]pentanoic m.p. 116–118 °C. 1H NMR (CDCl3): δ = 7.35–7.25 (m, 10 H), 6.38
Acid (Biotin-Gly-Gly-Ile-OH) (6g): This compound is water solu-
ble. For that reason, the mixture was not quenched with ice, but
instead 4 n HCl (0.5 mL) was added to neutralize the reaction mix-
ture, then diethyl ether. The aqueous phase was collected, then con-
centrated under reduced pressure. The resulting residue was washed
with ethanol, then acetone to yield the product as white microcrys-
tals (48%); m.p. 156–159 °C. 1H NMR ([D6]DMSO): δ = 12.60 (br.
s, 1 H), 8.10 (t, J = 5.9 Hz, 1 H), 8.04 (t, J = 6.3 Hz, 1 H), 7.96 (d,
J = 7.8 Hz, 1 H), 6.44 (s, 1 H), 6.37 (s, 1 H), 4.34–4.26 (m, 1 H),
(d, J = 7.8 Hz, 1 H), 6.27 (d, J = 7.8 Hz, 1 H), 5.28–5.12 (m, 2 H),
5.09–5.04 (m, 2 H), 4.05–3.93 (m, 1 H), 3.50–3.37 (m, 1 H), 3.20–
3.06 (m, 1 H), 2.56 (t, J = 6.5 Hz, 2 H), 2.07 (s, 3 H), 1.96–1.85
(m, 6 H), 1.82–1.70 (m, 2 H), 1.57–1.47 (m, 2 H), 1.45–1.04 (m, 22
H), 0.95–0.78 (m, 18 H) ppm. 13C NMR (CDCl3): δ = 171.2, 170.5,
156.4, 149.8, 140.4, 135.7, 129.5, 129.0, 128.7, 128.4, 128.3, 127.5,
125.0, 123.4, 117.7, 77.7, 77.2, 76.8, 75.3, 67.3, 60.5, 53.3, 39.6,
38.1, 37.7, 37.5, 33.0, 31.3, 28.2, 25.0, 24.7, 24.2, 23.0, 22.9, 21.3,
20.8, 20.0, 19.9, 19.3, 19.1, 13.2, 12.4, 12.1 ppm. HRMS: calcd. for
4.19–4.10 (m, 2 H), 3.76 (d, J = 6.0 Hz, 2 H), 3.68 (d, J = 5.7 Hz, C51H74N2O6Na [M + Na]+ 833.5439; found 833.5479.
2 H), 3.14–3.05 (m, 1 H), 2.82 (dd, J = 12.5, 5.3 Hz, 1 H), 2.57 (d,
(R)-2,5,7,8-Tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-
J = 12.3 Hz, 1 H), 2.13 (t, J = 7.1 Hz, 2 H), 1.85–1.72 (m, 1 H),
chroman-6-yl (5S,8S)-8-Benzyl-5-isopropyl-3,6,9-trioxo-1-phenyl-2-
1.66–1.10 (m, 8 H), 0.90–0.80 (m, 6 H) ppm. 13C NMR ([D6]-
oxa-4,7,10-triazadodecan-12-oate (Z-Val-Phe-Gly-O-Tocopherol)
DMSO): δ = 172.8, 172.6, 169.3, 168.8, 162.7, 61.0, 59.2, 56.2, 55.4,
(9d): Recrystallized from diethyl ether to yield the product as off-
42.1, 41.7, 36.4, 35.0, 28.2, 28.1, 25.1, 24.6, 15.6, 11.3 ppm.
1
white microcrystals (55%); m.p. 86–89 °C. H NMR (CDCl3): δ =
C20H33N5O6S (471.57): calcd. C 50.94, H 7.05, N 14.85; found C
7.44–7.28 (m, 5 H), 7.24–7.12 (m, 5 H), 6.85–6.75 (br. s, 1 H), 6.67
50.90, H 7.58, N 14.80.
(d, J = 8.4 Hz, 1 H), 5.24 (d, J = 6.9 Hz, 1 H), 5.11–4.98 (m, 3 H),
General Procedure for the Preparation of α-Tocopherol–Peptide Con-
jugates 9a–e: A dried heavy-walled Pyrex tube containing a small
stir bar was charged with a mixture of Z-protected acylbenzotri-
4.85–4.74 (m, 1 H), 4.40–4.26 (m, 1 H), 4.23–4.10 (m, 1 H), 3.97
(t, J = .5 Hz, 1 H), 3.23–3.12 (m, 1 H), 3.10–3.00 (m, 1 H), 2.62–
2.50 (m, 2 H), 2.07 (s, 3 H), 1.98 (s, 3 H), 1.94 (s, 3 H), 1.83–1.70
azole 8 (1 equiv.) and α-tocopherol (7) (1.1 equiv.) dissolved in an- (m, 3 H), 1.51–1.48 (m, 2 H), 1.45–1.02 (m, 21 H), 0.88–0.73 (m,
hydrous DMF (2 mL). K2CO3 (2 equiv.) was added, and the mix-
ture was exposed to microwave irradiation (20 W, 50 °C) for 20 min
until completion of the reaction (monitored by TLC). The mixture
was quenched with ice, then it was extracted with ethyl acetate
18 H) ppm. 13C NMR (CDCl3): δ = 171.4, 171.2, 168.6, 156.9,
149.8, 140.3, 136.6, 136.1, 129.4, 128.9, 128.8, 128.5, 128.4, 127.2,
126.7, 125.0, 123.4, 117.7, 75.3, 67.5, 61.1, 54.3, 41.3, 39.6, 38.1,
37.7, 37.5, 33.0, 31.2, 30.7, 28.2, 25.0, 24.7, 23.0, 22.9, 21.2, 20.8,
(2ϫ15 mL). The combined organic layers were concentrated under 20.0, 19.9, 19.4, 17.6, 13.2, 12.4, 12.0 ppm. HRMS: calcd. for
reduced pressure, then purified by column chromatography to yield
the corresponding product.
C53H77N3O7Na [M + Na]+ 890.5654; found 890.5667.
(R)-2,5,7,8-Tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-
chroman-6-yl (5S,8S)-8-Benzyl-5-methyl-3,6,9-trioxo-1-phenyl-2-
oxa-4,7,10-triazadodecan-12-oate (Z-Ala-Phe-Gly-O-Tocopherol)
(9e): Purified by column chromatography using hexanes/ethyl acet-
ate in a 8:2 ratio to yield the product as wax (51%). 1H NMR
(CDCl3): δ = 7.35–7.28 (m, 5 H), 7.20–7.16 (m, 5 H), 6.82–6.58 (m,
(2R)-2,5,7,8-Tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-
chroman-6-yl (S)-2-{[(Benzyloxy)carbonyl]amino}-3-methylbutano-
ate (Z-Val-O-Tocopherol) (9a): Purified by column chromatography
using hexanes/ethyl acetate in a 9.5:0.5 ratio to yield the product as
off-white microcrystals (68%); m.p. 63–64 °C. 1H NMR (CDCl3): δ
= 7.40–7.31 (m, 5 H), 5.32 (d, J = 9.3 Hz, 1 H), 5.17–5.10 (m, 2 2 H), 5.20 (d, J = 6.3 Hz, 1 H), 5.11–4.96 (m, 2 H), 4.81–4.72 (m,
H), 4.64 (dd, J = 9.3, 3.9 Hz, 1 H), 2.57 (t, J = 6.6 Hz, 2 H), 2.46–
2.42 (m, 1 H), 2.08 (s, 3 H), 2.00 (s, 3 H), 1.95 (s, 3 H), 1.84–1.70
(m, 2 H),1.56–1.00 (m, 30 H), 0.87–0.83 (m, 12 H) ppm. 13C NMR
1 H), 4.40–4.26 (m, 1 H), 4.20–4.10 (m, 2 H), 3.18 (dd, J = 13.5,
6.0 Hz, 1 H), 3.06 (dd, J = 13.8, 7.0 Hz, 1 H), 2.56 (t, J = 6.2 Hz,
2 H), 2.07 (s, 3 H), 1.99 (s, 3 H), 1.95 (s, 3 H), 1.81–1.70 (m, 3 H),
(CDCl3): δ = 171.1, 156.6, 149.8, 140.5, 136.4, 128.7, 128.4, 128.3, 1.59–1.48 (m, 3 H), 1.43–1.02 (m, 23 H), 0.92–0.80 (m, 12 H) ppm.
126.8, 125.0, 123.4, 117.7, 75.3, 67.3, 59.3, 39.6, 37.6, 37.5, 33.0,
32.9, 31.1, 28.2, 25.0, 24.7, 23.0, 22.9, 21.2, 20.8, 20.0, 19.9, 17.3,
13C NMR (CDCl3): δ = 172.4, 171.2, 168.6, 156.4, 149.8, 140.3,
136.6, 136.1, 129.4, 128.8, 128.5, 128.3, 127.2, 126.7, 125.0, 123.4,
13.3, 12.5, 12.1 ppm. HRMS: calcd. for C42H65NO5Na [M + Na]+ 117.7, 75.3, 67.5, 54.2, 51.2, 41.3, 39.6, 38.0, 37.7, 37.5, 33.0, 32.9,
686.4755; found 686.4786.
31.2, 29.9, 28.2, 25.0, 24.7, 23.0, 22.9, 21.2, 20.8, 20.0, 19.9, 18.3,
13.2, 12.4, 12.0 ppm. HRMS: calcd. for C51H73N3O7Na [M +
Na]+ 862.5357; found 862.5341.
(R)-2,5,7,8-Tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-
chroman-6-yl (S)-2-[(Benzyloxy)carbonyl]amino}-3-phenylpropano-
ate (Z-Phe-O-Tocopherol) (9b): Purified by column chromatog-
raphy using hexanes/ethyl acetate in a 9.5:0.5 ratio to yield the
General Procedure for the Preparation of Cholecalciferol–Peptide
Conjugates 11a–d: A dried heavy-walled Pyrex tube containing a
product as wax (60%).1H NMR (CDCl3): δ = 7.40–7.27 (m, 10 H), small stir bar was charged with a mixture of Z-protected acylbenzo-
5.33 (d, J = 8.4 Hz, 1 H), 5.11 (s, 1 H), 5.03–4.70 (m, 1 H), 3.50–
3.38 (m, 1 H), 2.60 (t, J = 6.5 Hz, 3 H), 2.11 (s, 3 H), 1.96 (s, 3 H),
1.93 (s, 3 H), 1.90–1.70 (m, 3 H), 1.62–1.52 (m, 2 H), 1.48–1.32 (m,
triazole 8 (1 equiv.), cholecalciferol (10) (1.2 equiv.) and DMAP
(0.2 equiv.) dissolved in freshly distilled THF (5 mL). The reaction
mixture was exposed to microwave irradiation (50 W, 70 °C) for
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