10.1002/chem.201802390
Chemistry - A European Journal
FULL PAPER
Hz), 6.37 (dd, 1H, J = 8.8, 3.1 Hz), 5.12-5.03 (m, 2.9H, major rotamer),
4.86-4.73 (m, 0.1H, minor rotamer), 4.26-4.17 (m, 0.9H, major rotamer),
4.12-4.01 (m, 0.1H, minor rotamer), 3.32 (q, 4H, J = 7.1 Hz), 2.55-2.38 (m,
2H), 2.24-2.14 (m, 1H), 2.01-1.90 (m, 1H), 1.45 (9H, s), 1.43 (9H, s), 1.14
(t, 6H, J = 7.1 Hz) ppm. 13C NMR (125 MHz, CDCl3): δ 172.6, 171.5, 155.5,
148.0, 139.8, 138.4, 113.8, 113.8, 82.3, 79.9, 79.8, 70.9, 53.5, 44.5, 30.5,
28.5, 28.3, 28.1, 12.5 ppm. HRMS (MALDI) m/z: [M]·+ Calcd for
C25H39IN2O6 590.18473; Found 590.18292.
14.0 mmol, 2.9 eq) was added. The mixture was stirred overnight (18 h),
then diluted with water and extracted three times with ethyl acetate. The
combined organic phase washed with water, saturated NaHCO3 and brine,
dried over Na2SO4 and filtrated. The solvent was removed under reduced
pressure to give light brown powder. This was crystalized from ethyl
acetate and cyclohexane to give 658 mg (61%) of a slightly brown solid.
1H NMR (400 MHz, CDCl3): δ 7.59-7.55 (m, 1H), 7.51-7.47 (m, 2H), 7.34-
7.29 (m, 1H), 7.18 (td, 1H, J = 7.4, 1.0 Hz), 7.04 (d, 1H, J = 2.4 Hz), 6.73
(dd, 1H, J = 8.4, 2.4 Hz), 5.51 (s, 1H), 3.02 (s, 6H) ppm. 13C NMR (100
MHz, CDCl3): δ 151.1, 147.5, 145.0, 141.0, 129.1, 128.7, 125.9, 125.0,
120.8, 118.7, 113.1, 109.4, 75.6, 41.0 ppm. HRMS (MALDI-LTQ Orbitrap)
m/z: [M·] + Calcd for C15H15N1O1 225.11482; Found: 225.11492.
General procedure
B
–
Suzuki coupling: Synthesis of
5-(diethylamino)-2-(para-cyanophenyl) methanol Boc-OtBu-Glu ester
P3. The reaction conditions were adopted from the literature.[58] The 5-
(diethylamino)-2-iodophenyl methanol Boc-OtBu-Glu ester (para-iodo P2)
(400 mg, 0.68 mmol, 1.0 eq) was dissolved in toluene (10 mL). Then 2M
Na2CO3 (1.2 mL) was added and solution degassed by passing through
argon stream for 10 min. Then Pd(PPh3)4 (47mg, 0.04 mmol, 0.06eq) was
added and degassing with argon stream was repeated. In a separate flask
4-cyanobenzeneboronic acid (208 mg, 1.42 mmol, 2.1 eq) was dissolved
in EtOH and degassed with argon stream before adding it to the toluene
solution. The reaction mixture was then refluxed under argon atmosphere
until TLC analysis showed full conversion (5 h). Upon completion the
mixture was diluted with ethyl acetate and H2O, organic phase separated,
aqueous phase washed twice with ethyl acetate. The combined organic
phase was washed with brine, dried over Na2SO4 and after filtration
concentrated in reduced pressure to give slightly yellow oil. Purification
was done by column chromatography (SiO2, cyclohexane : ethyl acetate
9:1 to 3:1). However, it was not possible to separate side products (boronic
acid homocoupling) in direct phase chromatography. To obtain analytically
pure sample also reverse phase (C18) column chromatography was
performed (MeCN : H2O 70:30 to 100%). However, it is important to note
that for next synthetic step (deprotection of tert-butyl and Boc esters) this
impurity does not disturb and can be easily removed by filtration afterward.
The product was obtained as oil (230 mg, 60%). 1H NMR (500 MHz,
CDCl3): δ 7.68-7.64 (m, 2H), 7.45-7.42 (m, 2H), 7.13 (d, 1H, J = 8.6 Hz),
6.76 (d, 1H, J = 2.5 Hz), 6.70 (dd, 1H, J = 8.6, 2.5 Hz), 5.10-5.04 (m, 0.9H,
major rotamer), 4.99 (s, 2H), 4.84-4.73 (m, 0.1H, minor rotamer), 4.23-4.15
(m, 0.9H, major rotamer), 4.08-3.99 (m, 0.1H, minor rotamer), 3.40 (q, 4H,
J = 7.1 Hz), 2.47-2.30 (m, 2H), 2.18-2.08 (m, 1H), 1.92-1.83 (m, 1H), 1.45
(9H, s), 1.42 (9H, s), 1.19 (t, 6H, J = 7.1 Hz) ppm. 13C NMR (125 MHz,
CDCl3): δ 172.6, 171.4, 155.5, 147.9, 145.9, 133.8, 132.1, 131.3, 130.1,
127.3, 119.2, 113.1, 111.8, 110.1, 82.4, 79.9, 65.2, 53.4, 44.5, 30.5, 28.4,
28.3, 28.1, 12.7 ppm. HRMS (MALDI) m/z: [M·]+ Calcd for C32H43N3O6
565.31464; Found 565.31301.
Synthesis of 2-(dimethylamino)-9H-fluoren-9-yl Boc-OtBu-Glu ester
(8): The synthesis was done according to general procedure A with small
variations. Compound 7 (388 mg, 1.72 mmol, 1.0 eq) was dissolved in
CH2Cl2 (10 mL). To the solution EDC-HCl (658 mg, 3.44 mmol, 2 eq),
DMAP (21 mg, 0.17 mmol, 0.1 eq) and N-(tert-butoxycarbonyl)-L-glutamic
acid 1-tert-butyl ester (522 mg, 1.72 mmol, 1 eq) was added. The reaction
mixture was stirred until TLC analysis showed full conversion (20 h). Upon
completion the mixture was diluted with CH2Cl2 and washed with water.
The water layer was extracted two times with CH2Cl2. Combined organic
phase was washed with brine and dried over Na2SO4, concentrated in
reduced pressure to give slightly brown oil. After column chromatography
(SiO2, cyclohexane : ethyl acetate 9:1 to 1:1) product 9 (570 mg, 65%) was
obtained as light brown oil (mixture of diastereomers). 1H NMR (500 MHz,
CDCl3): δ 7.53-7.44 (m, 3H), 7.36-7.30 (m, 1H), 7.18-7.12 (m, 1H), 6.92 (s,
1H), 6.78-6.70 (m, 2H), 5.18-5.04 (0.9H, major rotamer), 4.90-4.75 (0.1H,
minor rotamer), 4.30-4.20 (0.9H, major rotamer), 4.15-4.02 (0.1H, minor
rotamer), 3.01 (s, 6H), 2.60-2.44 (m, 2H), 2.30-2.18 (m, 1H), 2.05-1.92 (m,
1H), 1.46-1.44 (m, 9H), 1.44-1.42 (m, 9H) ppm. 13C NMR (125 MHz,
CDCl3): δ 173.9, 173.8, 171.5, 155.5, 151.0, 143.7, 143.6, 142.0, 141.3,
141.2, 129.6, 125.9, 125.8, 125.8, 120.8, 118.7, 113.3, 110.1, 82.4, 80.0,
75.7, 53.6, 53.5, 41.0, 30.7, 28.5, 28.3, 28.1 ppm. HRMS (MALDI-LTQ
Orbitrap) m/z: [M·]+ Calcd for C29H38N2O6 510.27244; Found: 510.27131.
Synthesis of 2-(dimethylamino)-9H-fluoren-9-yl glutamic acid
ammonium trifluoroacetate (9): The synthesis was done according to
general procedure C. From compound 8 (510 mg, 1.0 mmol, 1 eq), the
product (209 mg, 45%) was obtained as white powder (mixture of
diastereomers). 1H NMR (400 MHz, CD3OD-d4 + D2O): δ 7.53-7.49 (m, 2H),
7.44 (d, 1H, J = 7.5 Hz), 7.34-7.29 (m, 1H), 7.15-7.09 (m, 1H), 6.97-6.94
(m, 1H), 6.79 (dd, 1H, J = 8.4, 2.5 Hz), 6.68 (s, 1H), 3.64 (dt, 1H, J = 6.3,
2.9 Hz), 2.97 (s, 6H), 2.72-2.64 (m, 2H), 2.28-2.14 (m, 2H) ppm. 13C NMR
(100 MHz, CD3OD+D2O): δ 175.0, 173.8, 152.5, 144.8, 144.7, 143.3,
143.2, 142.5, 142.5, 131.0, 130.9, 130.5, 126.8, 126.6, 121.6, 119.5, 114.7,
111.2, 76.9, 55.4, 55.4, 41.1, 31.5, 31.4, 27.7, 27.6 ppm. HRMS (MALDI-
LTQ Orbitrap) m/z: [M]+ Calcd for C20H22N2O4 354.15796; Found:
354.15730.
General procedure
C – protecting group cleavage with TFA:
Synthesis of 2e. The 5-(diethylamino)-2-(para-cyanophenyl) methanol
Boc-OtBu-Glu ester P3 (70 mg, 0.12 mmol) was dissolved in dry CH2Cl2 (4
mL). To the solution TFA (4 mL) was added. Resulting mixture was stirred
overnight (20 h), then evaporated. Additional co-evaporation with MeCN
and toluene was done to ensure that all the TFA is removed. The oily
product was purified using reverse phase (C18) column chromatography
(MeCN : H2O 20:80 to 100%). After removal of the solvent, product 2e was
obtained as solid (46 mg, 73%). 1H NMR (300 MHz, D2O): δ 7.89-7.81 (m,
2H), 7.66 (d, 1H, J = 1.8 Hz), 7.60-7.50 (m, 4H), 5.11 (d, 2H, J = 2.3 Hz),
3.90 (t, 1H, J = 6.7 Hz), 3.67 (q, 4H, J = 7.2 Hz), 2.52-2.43 (m, 2H), 2.10-
1.99 (m, 2H), 1.11 (t, 6H, J = 7.2 Hz) ppm. 13C NMR (75 MHz, D2O): δ
173.4, 171.9, 143.6, 142.6, 136.5, 135.5, 132.6, 132.2, 129.6, 123.4, 122.6,
119.3, 110.8, 64.4, 53.8, 52.3, 29.3, 24.8, 9.6 ppm. HRMS (MALDI) m/z:
[M]+ Calcd for C23H28N3O4 410.20743; Found 410.20692.
General procedure
E – acylation with Ac2O: Synthesis of 2-
(dimethylamino)-9H-fluoren-9-yl acetate (10): 2-Dimethylamino-9-
fluorenol 7 (63 mg, 0.28 mmol, 1 eq) was dissolved in pyridine (6 mL). To
the solution Ac2O (1.08 g, 10.5 mmol, 38 eq) was added and mixture was
stirred overnight. Upon completion the solution was evaporated until
dryness, then purified via column chromatography (SiO2, cyclohexane :
ethyl acetate 9:1) to give 49 mg (65%) product as off white foam.
1H NMR (500 MHz, CDCl3): δ 7.53-7.49 (m, 2H), 7.47 (d, 1H, J = 7.4 Hz),
7.36-7.31 (m, 1H), 7.18-7.13 (m, 1H), 7.0-6.9 (br s, 1H), 6.81-6.69 (m, 2H),
3.01 (s, 6H), 2.19 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 172.1, 151.0,
143.8, 142.0, 141.3, 129.8, 129.6, 125.9, 125.7, 120.9, 118.8, 113.4, 110.1,
75.5, 41.0, 21.5 ppm. HRMS (MALDI-LTQ Orbitrap) m/z: [M·]+ Calcd for
C17H17NO2 267.12538; Found: 267.12552.
General procedure
D – reductive amination: Synthesis of 2-
(dimethylamino)-9H-fluoren-9-ol (7). 2-Amino-fluoren-9-one 6 (932 mg,
4.78 mmol, 1 eq) was dissolved in AcOH (20 mL). To this mixture
paraformaldehyde (890 mg, 29.6 mmol, 6.2 eq) and NaCNBH3 (879 mg,
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