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Md. S. Islam et al.
to yield Z-L-Phe-D-Pro-OtBu (7.52 g, 92%, HPLC, rt
6.55 min) as a colorless oil. The protected dipeptide
(7.52 g, 16.6 mmol) was dissolved in acetic acid (85 mL).
Pd–C (0.85 g) was added, and the mixture was stirred
under hydrogen atmosphere for 12 h. The reaction was
monitored by TLC and HPLC. After completion of the
reaction, Pd–C was filtered off, and the acetic acid was
evaporated. The residue was dissolved in ethyl acetate, and
the organic phase was washed with saturated sodium car-
bonate solution and dried over anhydrous Na2CO3. Evap-
oration of ethyl acetate gave H-L-Phe-D-Pro-OtBu (5.53 g,
83%, HPLC, rt 5.43 min) which was coupled with Z-Aib-
OH (3.25 g, 13.7 mmol) following the same procedure
described above to get Z-Aib-L-Phe-D-Pro-OtBu (7.01 g,
95%, HPLC, rt 8.03 min) as a white foam. The tripeptide
Z-Aib-L-Phe-D-Pro-OtBu (1.06 g, 2.0 mmol) was subjected
to hydrogenation in a similar manner as described for H-L-
Phe-D-Pro-OtBu to obtain H-Aib-L-Phe-D-Pro-OtBu
(0.880 g, 100%, HPLC, rt 4.56 min).
Cyclo(-L-Asu(2-aminoanilinyl)-Aib-L-Phe-D-Pro-)(6) Com-
pound 12 (5.35 g, 9.0 mmol) was dissolved in methanol
(45 mL) and Pd–C (0.45 g) was added. The solution was
stirred under hydrogen overnight. After filtration of Pd–C,
methanol was evaporated to yield cyclo(-L-Asu-Aib-L-
Phe-D-Pro-) (4.5 g, 100%). HPLC, rt 4.68 min. To a
cooled solution of cyclo(-L-Asu-Aib-L-Phe-D-Pro-) (0.20 g,
0.40 mmol) and o-phenylenediamine (0.21 g, 2.0 mmol) in
DMF (2 mL), triethylamine (0.084 mL, 0.6 mmol) and BOP
(0.265 g, 0.6 mmol) were added, and the mixture was stirred
at room temperature for 12 h. After completion of the reac-
tion, the compound was purified according to the procedure
reported for 12 to yield compound 6 as solid crystal (0.05 g,
21%). HPLC, rt 6.03 min, HRMS (FAB) calcd for
C32H43N6O5 [(M ? H)?] 591.3295, found 591.3278.
Cyclo(-L-Ae7-Aib-L-Phe-D-Pro-) (13) This compound
was synthesized according to the procedure reported for
compound 12 using Boc-L-Ae7-OH instead of Boc-L-
Asu(OBzl)-OH. The product is white foam (0.768 g, 82%).
HPLC, rt 7.91 min, LC–MS calcd for C25H34N4NaO4
[(M ? Na)?] 477.3, found 477.5.
Synthesis of cyclic tetrapeptides
Cyclo(-L-7-(pinacolboranyl)-Ahp-Aib-L-Phe-D-Pro-) (14)
A
Cyclo(-L-Asu(OBzl)-Aib-L-Phe-D-Pro-) (12) The N-ter-
minal free tripeptide H-Aib-L-Phe-D-Pro-OtBu (8.1 g,
20 mmol) was coupled with Boc-L-Asu(OBzl)-OH (7.56 g,
20 mmol) according to the method described above, and
the fully protected crude linear tetrapeptide was purified by
silica gel chromatography using a mixture of chloroform
and methanol (99:1) to yield Boc-L-Asu(OBzl)-Aib-L-Phe-
D-Pro-OtBu (9.7 g, 12.7 mmol, 64%). Boc-L-Asu(OBzl)-
Aib-L-Phe-D-Pro-OtBu (9.6 g, 12.5 mmol) was dissolved in
TFA (50 mL) at 0°C and kept for 3 h. After evaporation of
TFA, the residue was solidified by precipitating with ether
to yield H-L-Asu(OBzl)-Aib-L-Phe-D-Pro-OH as TFA salt
(9.0 g, 12.5 mmol, 100%). To a volume of DMF
(1,200 mL) solvent TFA salt (9.0 g, 12.5 mmol), HATU
(7.13 g, 18.7 mmol) and N,N-diisopropylethylamine
(DIEA) (7.61 mL, 43.7 mmol) were added in five aliquots
with 30 min time interval while the solution was stirred
vigorously. After the final addition, the reaction mixture
was allowed to stir for an additional hour. Completion of
the cyclization reaction was monitored by HPLC, and then
DMF was evaporated under vacuo. The crude cyclic tet-
rapeptide was dissolved in ethyl acetate, and the solution
was washed successively by 10% citric acid, 4% sodium
bicarbonate, and brine. Finally, the ethyl acetate solution
was dried over anhydrous MgSO4 and filtered. After
evaporation of ethyl acetate, the residue was purified by
silica gel chromatography using a mixture of chloroform
and methanol (99:1) to yield compound 12 (5.35 g,
9.0 mmol, 72%). HPLC, rt 7.98 min.
solution of [Ir(cod)Cl]2 (0.034 g, 0.05 mmol) and DPPM
(0.038 g, 0.10 mmol) in anhydrous and degassed dichloro-
methane (DCM) (5.0 mL) was flashed with Ar for 5 min
and stirred for 10 min at room temperature. After that,
to the solution, cyclo(-L-Ae7-Aib-L-Phe-D-Pro-) (0.227 g,
0.50 mmol) and pinacolborane (113 lL, 0.75 mmol) were
added, and the mixture was flashed with Ar for 5 min, then
stirred at room temperature for 2 days. The reaction mixture
was concentrated and purified according to the procedure
reported for 12 to give compound 14 (0.260 g, 90%) as a
white solid. HPLC, rt 8.94 min, LC–MS calcd for
C31H48BN4O6 [(M ? H)?] 583.4, found 583.5.
Cyclo(-L-7-(boronyl)-Ahp-Aib-L-Phe-D-Pro-) (7) To
a
solution of cyclo(-L-7-(pinacolboranyl)-Ahp-Aib-L-Phe-D-
Pro-) (0.200 g, 0.34 mmol) in acetone/H2O (4 mL/2 mL),
NaIO4 (0.215 g, 1.0 mmol) and NH4OAc (0.770 g,
1.0 mmol) were added, and the suspension was stirred at
room temperature for 20 h. Then acetone was evaporated,
and the reaction mixture was poured into water and
extracted with ethyl acetate. Finally, the ethyl acetate
solution was dried over anhydrous MgSO4 and filtered.
After evaporation of ethyl acetate, the residue was purified
by silica gel chromatography using a mixture of chloro-
form and methanol (98:2) to yield compound 7 (0.070 g,
42%) as a white solid. HPLC, rt 6.10 min, LC–MS calcd
for C25H37BN4NaO6 [(M ? Na)?] 523.3, found 523.5.
HRMS (FAB) calcd for C39H48O10N6B [(M ? 2NBA
2H2O ? H)? 771.3525, found 771.3587.
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