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General Procedure
for Immobilization
DHP-resin 9 (6
g, 0.99 mmol/g) was dried overnight at 100 ˚C,
then suspended in a mixture of DCE-toluene (42/18 mL)
under nitrogen. Then, 4- or 6-HSA (4.15 g, 30.0 mmol) and PPTS (2.26
g, 9.00 mmol) were added and the mixture agitated at 55 ˚C
overnight. Afterwards, the resin was filtered, washed (CH2Cl2,
2 ¥ H2O and DMF, 2 ¥ H2O
and THF, 3 ¥ MeOH and CH2Cl2,
4 ¥ CH2Cl2; with
20 mL/g resin each), and dried under vacuum.
9
General Procedure
for Cleavage
Resin (200 mg) were suspended in a 1:1
mixture of EtOH-DCE (4 mL). Then PPTS (100 mg, 0.40 mmol)
was added, and the mixture was agitated at 70 ˚C
overnight. The resin was separated by filtration, washed with EtOAc
(25 mL), and the filtrate concentrated. The crude product was diluted with
EtOAc (15 mL) and H2O (10 mL). The organic layer was
separated and the aqueous one extracted twice with EtOAc (15 mL).
The combined organic phases were dried (MgSO4) and concentrated
under reduced pressure. After Diels-Alder reactions the
crude product was additionally purified by flash chromatography
to separate endo- and exo-diastereomers.
10 For procedures see Supporting Information.
11a
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15
General Procedure
for DOMA Condensation
Resin (1.00 g) was suspended
in 1,4-dioxane (10 mL) in a 20 mL vial. Nitrogen was bubbled through
for a few minutes, before addition of K2CO3 (552
mg, 4.0 mmol) and the Michael acceptor (6.0 mmol). The vial was
closed and agitated at 80 ˚C for 4 d. After the
second day another portion of the Michael acceptor (1.0 mmol) was
added. At the end of the reaction, the resin was filtered, washed
(as described above), and dried under vacuum. The procedure was
repeated a second time if remaining starting material was detected
after cleavage.
16
General Procedure
for Wittig Reaction
Methyl triphenylphosphonium bromide
(1.79 g, 5.0 mmol) was suspended in anhydrous THF (14 mL) under
nitrogen and cooled to -25 ˚C. n-BuLi (3.1 mL, 5.0 mmol, 1.6 M solution
in hexanes) was added (yellow color) and the mixture stirred for
2 h (-25 ˚C up to r.t.). Afterwards,
it was cooled to -35 ˚C and added to
the resin (1.65 g), which was previously suspended in anhydrous
THF (12 mL), also cooled to -35 ˚C. The
reaction was allowed to warm up to r.t. and agitated overnight.
It was quenched with H2O (2 mL), washed (as described
above), and dried under vacuum.
17
General Procedure
for Diels-Alder Reaction
The resin (500 mg)
was dried overnight at 90 ˚C. It was suspended
in toluene (5 mL) in a vial and nitrogen was bubbled through for
10 min. The dienophile (5.0 mmol) was added, the vial closed, and
the reaction agitated at 80 ˚C for 2 d. The resin
was filtered, washed (as described above), and dried under vacuum
before being cleaved.
Analytical Data
for Compound 18bb
IR (ATR, platinum): 3329, 2978,
2937, 2248, 1622, 1589, 1506, 1456, 1310, 1296, 1160, 1139, 1121
cm-¹. ¹H NMR (250
MHz, acetone-d
6): δ = 1.39
(s, 3 H, CH3), 1.43 (s, 3 H, CH3), 1.84-2.01
(m, 1 H, CH2), 2.08-2.27 (m, 3 H, CH2), 3.00
(ddd, J = 11.5,
9.1, 3.1 Hz, 1 H, NCCH), 3.73 (br dd, J = 9.1,
2.2 Hz, 1 H, CH), 5.80-5.88 (m, 1 H, =CH), 6.28
(d, J = 2.5
Hz, 1 H, ArmH), 6.47 (dd, J = 8.5,
2.5 Hz, 1 H, ArmH), 7.51 (d, J = 8.5
Hz, 1 H, ArmH), 8.32 (s, 1 H, OH) ppm. ¹³C
NMR (125 MHz, acetone-d
6): δ = 25.0,
27.6, 28.28, 28.34, 32.4, 37.3, 79.2, 106.2, 110.3, 117.7, 121.7, 125.1,
128.2, 139.6, 156.6, 159.4 ppm. MS (EI, 70 eV): m/z (%) = 255
(43) [M+], 187 (100), 174
(27), 173 (29). HRMS (EI): [M+] calcd
for C16H17NO2: 255.1259; found:
255.1258. Structure verified by 2D NMR.
18
Minami T.
Matsumoto Y.
Nakamura S.
Koyanagi S.
Yamaguchi M.
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Org. Chem.
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167
