Synthesis of Cyclic Biphenyl Ether Peptides K-13 and OF4949-III
J. Am. Chem. Soc., Vol. 119, No. 28, 1997 6493
(s, 9H), 0.75-0.95 (m, 6H). LSIMSHRMS: calcd for C35H45N3O7-
ClRu+ 756.1986 (M)+, found 756.1979.
pump to the above solution over 4 h and allowed to stir for an additional
20 h. The solution was filtered through a plug of neutral alumina and
concentrated in Vacuo to give the title compound as a brown solid (65
mg, 78%). LSIMSHRMS: calcd for C38H42N3O7Ru+ 754.2077 (M)+,
found 754.2093.
[N-(tert-Butoxycarbonyl)-p-phenylalanyl-isoleucyl-m-tyrosyline
methyl ester]cyclopentadienylruthenium Hexafluorophosphate Di-
phenyl Ether (11). A stock solution (1.5 mL, 0.092 mmol) was diluted
with 30 mL of THF, and a solution of 8 (75 mg, 0.083 mmol) dissolved
in 10 mL of THF was added via syringe pump to the above solution
over 4 h and allowed to stir for an additional 20 h. The solution was
concentrated in Vacuo, dissolved in CH3CN, and filtered. The filtrate
was concentrated in Vacuo to give 11 as a brown solid (56.0 mg, 78%)
which was used in the next step without further purification.
[N-(tert-Butoxycarbonyl)-p-phenylalanyl-isoleucyl-m-tyrosine Meth-
yl ester Diphenyl Ether (14). 11 (91.2 mg, 0.105 mmol) was dissolved
in 25 mL of CH3CN, irradiated at 350 nm for 24 h and worked up as
in the general procedure. The filtrate and washings were concentrated
in Vacuo, and the crude solid was purified by column chromatography
(SiO2, 20% EtOAc/CH2Cl2) to give the title compound as a white solid
(40 mg, 83%) (mp 225-226 °C) (Rf 0.52, 30% EtOAc/CH2Cl2). 1H
NMR: δ 7.30 (d, 1H, J ) 8.9 Hz), 7.23 (t, 1H, J ) 7.8 Hz), 7.03-
7.14 (dq, 3H, J ) 2.3, 11.0 Hz), 6.76 (dd, 1H, J ) 2.5, 8.3 Hz), 6.70
(d, 1H, J ) 7.7 Hz), 6.33 (d, 1H, J ) 8.0), 6.24 (s, 1H), 5.88 (d, 1H,
J ) 6.3 Hz), 5.23 (d, 1H, J ) 11.0 Hz), 4.70-4.82 (dt, 1H, J ) 3.6,
7.0 Hz), 4.10-4.25 (m, 1H), 3.85-3.92 (dd, 1H, 4.7, 6.7 Hz), 3.80 (s,
3H), 3.40 (dd, 1H, J ) 15.4, 3.6 Hz), 3.12 (dd, 1H, J ) 5.0, 12.3 Hz),
3.01 (dd, 1H, J ) 7.0, 15.3 Hz), 2.81 (t, 1H, J ) 12.0 Hz), 1.90-2.08
(m, 1H), 1.47 (s, 9H), 1.56-1.45 (m, 1H), 1.05-1.20 (m, 1H), 0.91
(dd, 3H, J ) 6.9, 7.4 Hz), 0.79 (d, 3H, J ) 6.9 Hz). LSIMSHRMS:
calcd for C30H39N3O7 584.2866 (M + H)+, found 554.2866.
[p-Chlorophenylalanine methyl ester]cyclopentadienylruthenium
Hexafluorophosphate (18). To a solution of H2N-p-Cl-Phe-OMe (17)-
(0.27 g, 1.26 mmol) in 34 mL of degassed 1,2-DCE at 60 °C was added
RuCp(CH3CN)3PF6 (0.55 g, 1.26 mmol). The resulting solution was
heated to reflux for 2 h, allowed to cool to room temperature and then
filtered. The reaction mixture was concentrated in Vacuo, redissolved
in CH3CN, and added to Et2O. The light brown precipitate was filtered,
rinsed with ether, redissolved in DCM/MeOH, concentrated in Vacuo,
and dried under vacuum overnight to give the title compound as a brown
foam (0.61 g, 92%). 1H NMR: δ 6.50-6.58 (d, 2H, J ) 6.2 Hz),
6.32-6.42 (dd, 2H, J ) 12.6, 5.7 Hz), 5.48 (s, 5H), 3.80 (s, 3H), 3.70-
3.80 (m, 1H), 2.89-2.98 (dd, 1H, J ) 13.6, 5.3 Hz), 2.70-2.81 (dd,
1H, J ) 13.6, 7.7 Hz). LSIMSHRMS: calcd for C15H17NO2ClRu+
379.9992 (M)+, found 379.9997.
[N-(Carbobenzyloxy)-m-tyrosyl-isoleucyl-p-chlorophenylala-
nine methyl ester]cyclopentadienylruthenium Hexafluorophosphate
(22). To a solution of Cbz-m-Tyr-Ile-OH (19) (0.120 g, 0.28 mmol)
and HOBt (57 mg, 0.42 mmol) in 1.4 mL of DMF at 0 °C was added
EDCI (59 mg, 0.31 mmol). The mixture was stirred for 15 min at 0
°C followed by the addition of a solution of 18 (0.150 g, 0.28 mmol)
dissolved in 1.4 mL of DMF and 2 h of stirring at 0 °C and then at
ambient temperature for an additional 10 h. The mixture was diluted
with H2O (10 mL) and then extracted with CH2Cl2 (3 × 20 mL). The
organic layers were pooled, washed successively with saturated
NaHCO3 (2 × 10 mL), 1 N KHSO4 (10 mL), and saturated NaCl (10
mL), dried over Na2SO4, and concentrated in Vacuo. The brown oil
was redissolved in CH3CN, filtered through a plug of alumina,
concentrated to about 2 mL which was added to 50 mL of Et2O, filtered,
and dried to give the title compound as a brown solid (0.180 g, 69%).
1H NMR: δ 7.25-7.40 (m, 7H), 7.07-7.17 (dd, 1H, J ) 7.9, 7.5 Hz),
6.72 (d, 1H, J ) 7.4 Hz), 6.65 (d, 2H, J ) 7.9 Hz), 6.40-6.45 (dd,
1H, J ) 6.2, 1.3 Hz), 6.32-6.36 (dd, 1H, J ) 6.1, 1.3 Hz), 6.28 (d,
1H, J ) 6.8 Hz), 6.16 (d, 1H, J ) 5.9 Hz), 6.00 (d, 1H, J ) 6.8 Hz),
5.39 (s, 5H), 5.08 (s, 2H), 4.62-4.72 (dd, 1H, J ) 7.0, 5.3 Hz), 4.38-
4.48 (m, 1H), 4.05-4.13 (dd, 1H, J ) 7.6, 7.9 Hz), 3.78 (s, 3H), 2.84-
3.12 (m, 4H), 1.70-1.86 (m, 1H), 1.35-1.50 (m, 1H), 1.00-1.16 (m,
1H), 0.90 (d, 3H, J ) 6.8 Hz), 0.85 (t, 3H, J ) 7.3 Hz). LSIMSMS:
calcd for C38H43N3O7ClRu+ 790.184 (M)+, found 756.1 (C38H44N3O7-
Ru+, 756.223).
Method B (Nondilution). A stock solution (1.6 mL, 0.098 mmol)
was added slowly to a solution of 22 (83 mg, 0.089 mmol) dissolved
in 4 mL of THF, and the resultant mixture was stirred for 20-24 h.
The solution was filtered through a plug of neutral alumina and
concentrated in Vacuo to give the title compound as a brown solid (73
mg, 88%). 1H NMR: δ 7.32-7.40 (m, 6H), 7.18-7.25 (dd, 1H, J )
7.8, 8.2 Hz), 6.92-7.00 (dd, 1H, J ) 8.2, 1.9 Hz), 6.72-6.80 (d, 1H,
J ) 7.6 Hz), 6.23-6.30 (d, 1H, J ) 6.2 Hz), 6.13-6.19 (dd, 1H, J )
6.2, 1.0 Hz), 6.05-6.14 (m, 5H), 5.41 (s, 5H), 5.17 (d, 1H, J ) 12.2
Hz), 5.07 (d, 1H, J ) 12.2 Hz), 4.80-4.90 (dd, 1H, J ) 12.3, 3.0 Hz),
4.49-4.56 (dd, 1H, J ) 6.8, 1.5 Hz), 4.33-4.40 (d, 1H, J ) 5.0 Hz),
3.82 (s, 3H), 3.15-3.26 (m, 2H), 2.90-3.00 (d, 1H, J ) 12.8 Hz),
2.57-2.70 (t, 1H, J ) 12.7 Hz), 1.77-1.92 (m, 1H), 1.30-1.45 (m,
1H), 1.05-1.20 (m, 1H), 0.92 (d, 3H, J ) 6.8 Hz), 0.88 (t, 3H, J )
7.4 Hz). LSIMSHRMS: calcd for C38H42N3O7Ru+ 754.2077 (M)+,
found 754.2088.
N-(Carbobenzyloxy)-m-tyrosyl-isoleucyl-p-phenylalanine Methyl
Ester Diphenyl Ether (28). Ruthenium complex 25 (66 mg, 0.073
mmol) was dissolved in 30 mL of CH3CN, irradiated at 350 nm for 24
h, and worked up according to the general procedure. The filtrate and
washings were concentrated in Vacuo, and the crude solid was purified
by column chromatography (SiO2, 20% EtOAc/CH2Cl2) to give the
title compound as a white solid (30 mg, 70%) (Rf 0.29, 20% EtOAc/
CH2Cl2). 1H NMR: δ 7.30-7.40 (s, 5H), 7.08-7.18 (t, 1H, J ) 7.8
Hz), 6.93-7.06 (m, 2H), 6.82-6.92 (dd, 1H, J ) 8.1, 2.4 Hz), 6.50-
6.59 (d, 1H, J ) 7.4 Hz), 6.42-6.48 (d, 1H, J ) 8.8 Hz), 6.04-6.13
(d, 1H, J ) 9.9 Hz), 5.84 (s, 1H), 5.42 (d, 1H, J ) 7.0 Hz), 5.03-5.22
(dd, 2H, J ) 40 Hz, 9.9 Hz), 4.85-4.98 (m, 1H), 4.47-4.54 (m, 1H),
4.30-4.36 (m, 1H), 3.85 (s, 3H), 3.38-3.46 (dd, 1H, J ) 3.9, 13.4
Hz), 3.18-3.26 (dd, 1H, J ) 6.8, 14.1 Hz), 2.72-2.80 (d, 1H, J )
12.9 Hz), 2.49-2.61 (t, 1H, J ) 12.9 Hz), 1.61-1.75 (br s, 1H), 1.23-
1.40 (br s, 1H), 0.94-1.11 (br s, 1H), 0.89 (d, 3H, J ) 7.1 Hz), 0.85
(t, 3H, J ) 6.9 Hz). LSIMSHRMS: calcd for C33H37N3O7 588.2710
(M + H)+, found 588.2706.
[3-Chloro-4-O-methyltyrosine methyl ester]cyclopentadienyl-
ruthenium Hexafluorophosphate (36). To a solution of H2N-Tyr-
(3-Cl)(OMe)-OMe (34) (80.0 mg, 0.33 mmol) in 1,2-DCE (10 mL) at
60 °C was added RuCp(CH3CN)3PF6 (173 mg, 0.40 mmol). The
resulting solution was heated to reflux for 2 h, allowed to cool to room
temperature and then filtered through a plug of alumina. The reaction
mixture was concentrated in Vacuo, redissolved in CH3CN, and added
to Et2O. The light brown precipitate was filtered, redissolved in DCM/
MeOH, concentrated in Vacuo, and dried under vacuum overnight to
give the title compound as a foam (183 mg, 89%). 1H NMR: δ 6.58-
6.62 (d, 2H, J ) 13.7 Hz), 6.39-6.46 (d, 1H, J ) 7.7 Hz), 6.07-6.18
(dd, 1H, J ) 13.7, 7.7 Hz), 5.39 (s, 5H), 3.95 (s, 3H), 3.78 (s, 3H),
3.70-3.83 (m, 1H), 2.84-2.95 (dd, 1H, J ) 16.3, 6.9 Hz), 2.70-2.81
(dd, 1H, J ) 16.3, 8.6 Hz). LSIMSHRMS: calcd for C16H19NO3ClRu+
410.0098 (M)+, found 410.0101.
[N-(tert-Butoxycarbonyl)-3-chlorotyrosine methyl ester]cyclo-
pentadienylruthenium Hexafluorophosphate (37). To a solution of
Boc-Tyr-(3-Cl)(OMe)-OH (35) (158 mg, 0.46 mmol) in 1,2-DCE (12
mL) at 60 °C was added RuCp(CH3CN)3PF6 (200 mg, 0.46 mmol).
The resulting solution was heated to reflux for 2 h, allowed to cool to
room temperature and then filtered through a plug of neutral alumina.
The reaction mixture was concentrated in Vacuo, redissolved in CH3-
CN, and added to Et2O. The light brown precipitate was filtered,
washed, redissolved in DCM/MeOH, concentrated in Vacuo, and dried
under vacuum overnight to give the title compound (236 mg, 80%).
1H NMR: δ 6.40-6.60 (m, 3H), 6.08-6.13 (t, 2H, J ) 7.7 Hz), 5.39
(s, 5H), 4.31-4.43 (m, 1H), 3.97 (s, 3H), 2.92-3.12 (m, 1H), 2.71-
2.82 (m, 1H), 1.42 (s, 9H). LSIMSHRMS: calcd for C20H25NO5ClRu+
496.0467 (M)+, found 496.0464.
[N-(Carbobenzyloxy)-m-tyrosyl-isoleucyl-p-phenylalanine methyl
ester]cyclopentadienylruthenium Hexafluorophosphate Diphenyl
Ether (25). Method A (Slow Addition). A stock solution (1.6 mL,
0.098 mmol) was diluted with 30 mL of THF, and a solution of 22 (83
mg, 0.089 mmol) dissolved in 10 mL of THF was added Via syringe
N-Acetyltyrosyl-4-O-methyltyrosine-OBn (41). To a solution of
Ac-Tyr-OH (40) (0.31 g, 1.4 mmol) and HOBt (0.29 g, 2.1 mmol) in
10 mL of DMF at 0 °C were added Tyr(4-OMe)-OBn-TsOH (39) (0.60
g, 1.3 mmol) and EDCI (0.32 g, 1.6 mmol), followed by NMM (0.14