N. Kutsumura et al.
Bull. Chem. Soc. Jpn., 75, No. 4 (2002) 849
gradually added TFA (19 mL); the mixture was stirred at the same
temperature for 3 h. Evaporation of the mixture provided the cor-
responding TFA salt (1.5 g, quant.).
m), and 5.40 (1H, m); 13C NMR δ 14.2, 21.1, 24.7, 27.8, 28.3,
31.0, 39.2, 47.1, 47.5, 52.3, 58.1, 59.6, 60.4, 79.8, 124.0, 126.8,
127.1, 128.3, 128.6, 128.7, 129.3, 129.5, 135.4, 135.9, 148.3,
160.5, 171.2, 171.7, and 172.4.
To a mixture of the salt (349 mg, 1.1 mmol) and Boc-L-Phe-OH
(384 mg, 1.5 mmol) in DMF (20 mL) were added the BOP reagent
(710 mg, 1.6 mmol) and Et3N (0.3 mL, 2.1 mmol) at 0 °C; the re-
action mixture was stirred at the same temperature for 2 h, and
then at ambient temperature overnight. The resulting mixture was
diluted with EtOAc, washed successively with sat. aq NaHCO3,
5% aq KHSO4, then brine. After being dried (Na2SO4), evapora-
tion of the mixture afforded a crude product, which upon purifica-
tion by silica-gel column chromatography (hexane/EtOAc = 5/1)
gave 3 (381 mg, 78%): [α]1D8 −64.8° (c 1.00, CHCl3); IR (film)
3316, 1710, and 1646 cm−1; 1H NMR δ 1.38 (9H, complex), 2.00
(2H, complex), 2.25 (1H, m), 2.41 (1H, m), 2.91 (1H, m), 3.04
(1H, m), 3.35 (1H, m), 3.73 (1H, m), 3.94 (3H, s), 4.42 (1H, m),
4.75 (1H, dd, J = 16, 7 Hz), 7.23 (5H, complex), and 8.06 (1H, m)
13C NMR δ 24.6, 28.4, 31.5, 39.4, 47.2, 52.4, 53.1, 58.6, 59.5,
79.8, 126.8, 127.0, 128.4, 129.2, 136.0, 146.3, 171.0, and 172.4.
Found (FAB): m/z 459.1799. Calcd for C23H29N3O5S: M,
459.1826.
To a mixture of the carboxylic acid (719 mg, 1.0 mmol) and the
triflate salt of 5 (727 mg, 1.8 mmol) in DMF (30 mL) were added
the BOP reagent (553 mg, 1.3 mmol) and Et3N (0.58 ml, 4.2
mmol). After being stirred at 0 °C for 2.5 h, the reaction mixture
was diluted with EtOAc, washed successively with sat. aq
NaHCO3, 5% aq KHSO4, and brine, then dried (Na2SO4). Remov-
al of the solvent under reduced pressure provided a crude product,
which upon purification by preparative TLC (CHCl3/MeOH = 20/
1) gave 8 as an oil (512 mg, 54%): [α]1D8 −52.8° (c 1.00, CHCl3);
IR (film) 3397, 1740, and 1644 cm−1; 1H NMR δ 0.82–0.95 (6H,
complex), 1.40 (9H, s), 3.78 (3H, s), 5.05 (1H, m), 5.28 (1H, d, J
= 9.3 Hz), 5.43 (1H, dd, J = 2.4, 7.8 Hz), 7.2 (10H, complex),
and 7.9 (2H, complex). Found (FAB): m/z 940.4244. Calcd for
C47H63N7O10SNa: M + Na, 940.4251.
14-[(S)-1-Methylpropyl]-11-[(S)-1-hydroxyethyl]-(2S,8S,
14S,17S,23S)-6,9,12,15,21,24,29-heptaaza-8,23-dibenzyl-28-
thiatetracyclo[24.2.1.02,6.016,20]nonacosa-1(29),26-diene-7,10,
12,15,21,24-hexone (9). A triflate salt (470 mg, 0.51 mmol), ob-
tained by a treatment of 8 with 1 M aq NaOH (20 mL)–MeOH (20
mL), followed by TMSOTf, was dissolved in DMF (500 mL). Af-
ter the addition of DPPA (0.33 mL, 1.5 mmol) and DIPEA (0.53
mL, 3.0 mmol), the resulting mixture was stirred at ambient tem-
perature for 3 d. The mixture was diluted with EtOAc, washed
successively with 5% KHSO4, sat. aq NaHCO3, and brine, dried
(Na2SO4), then evaporated. The residue was purified by prepara-
tive TLC (CHCl3/MeOH = 20/1) to give 9 as a mixture of the cor-
responding diastereomers (71 mg, 18% yield in three steps).
Found (FAB): m/z 786.3612. Calcd for C41H52N7O7S: M + H,
786.3646.
Methyl
amino-3-phenylpropanoyl]pyrrolodin-2-yl}thiazol-4-ylcarbon-
ylamino)-3-phenylpropanoyl]pyrrolidine-3-carboxylate (7).
(S)-1-[(S)-2-(2-{(S)-1-[(S)-2-tert-butoxycarbonyl-
A solution of 3 (781 mg, 1.7 mmol) in 1 M (= 1 mol dm−3) aq
NaOH (14 mL, 14 mmol) and MeOH (10 mL) was stirred at 0 °C
for 2 h. After the addition of 5% aq KHSO4, the mixture was par-
titioned between EtOAc and brine. The organic extracts were
combined, dried (Na2SO4), then evaporated to give the corre-
sponding carboxylic acid (758 mg, quant.): IR (film) 2977, 1708,
1
and 1645 cm−1; H NMR δ 1.38 (9H, complex), 2.98 (2H, com-
plex), 3.28 (1H, m), 7.19 (5H, complex), and 8.15 (1H, m).
To a mixture of the carboxylic acid (0.758 g, 1.7 mmol) and 4
(1.17 g, 3.0 mmol) in DMF (30 mL) were added the BOP reagent
(1.13 mg, 2.6 mmol) and Et3N (1.65 mL, 12 mmol). After being
stirred at 0 °C for 2 h and at ambient temperature overnight, the
reaction mixture was diluted with EtOAc, washed successively
with sat. aq NaHCO3, 5% aq KHSO4, and brine. After being dried
(Na2SO4), evaporation of the solution gave a crude product, which
upon purification by silica-gel column chromatography (hexane/
EtOAc = 1/3) afforded 7 as an oil (1.17 g, 97%): [α]1D8 −74.7°(c
Dehydrocyclization of 9 to 1a and 1c. To an ice-cooled
mixture of the diastereomer (9, 63 mg, 0.081 mmol) in CH2Cl2 (10
mL) was added the Deoxo-Fluoro reagent (89 µL, 0.48 mmol); the
reaction mixture was stirred at the same temperature for 2 h. After
the addition of sat. aq NaHCO3, the mixture was diluted with
CHCl3, washed with brine, dried (Na2SO4), then evaporated. The
residue was purified by preparative TLC (CHCl3/MeOH = 20/1)
to give 1a (7.3 mg, 12%) and 1c (29 mg, 46%). 1c: [α]2D4 −99.6°
1
1
1.00, CHCl3); IR (film) 3404, 1743, 1703, and 1644 cm−1; H
(c 1.00, CHCl3); IR (film) 3385 and 1647 cm−1; H NMR δ 0.62
NMR δ 1.38 (9H, complex), 2.38 (1H, m), 2.91–3.26 (8H, com-
plex), 4.42 (1H, m), 4.70 (1H, m), 5.10 (1H, m), 5.25 (1H, m),
5.40 (1H, m), 7.20 (10H, complex), and 7.95 (1H, m); 13C NMR δ
14.2, 21.0, 22.2, 24.9, 28.3, 29.0, 30.7, 39.1, 47.0, 52.1, 52.4,
58.0, 58.9, 79.6, 123.6, 126.8, 127.1, 128.2, 128.3, 128.5, 128.7,
129.2, 129.3, 129.6, 136.0, 148.6, 150.3, 155.0, 160.2, 169.8,
170.9, and 172.0. Found (FAB): m/z 704.3102. Calcd for
C37H46N5O7S: M + H, 704.3115.
Methyl (2S,3S)-2-[(2S,3S)-{(S)-1-[(S)-2-(2-{(S)-1-[(S)-tert-
butoxycarbonylamino-3-phenylpropanoyl]pyrrolidin-2-yl}thi-
azol-4-ylcarbonylamino)-3-phenylpropanoyl]pyrrolidin-2-yl-
carbonylamino}-3-methylpentanoylamino]-3-hydroxybutano-
ate (8). A solution of 7 (1.17 g, 1.7 mmol) in 1M aq NaOH (10
mL)–MeOH (12 mL) was stirred at 0 °C for 90 min. After the re-
action was quenched by the addition of 5% aq KHSO4, the mix-
ture was partitioned between EtOAc and brine. The organic ex-
tracts were dried (Na2SO4), then evaporated to give a carboxylic
acid (1.07 g, 94%): [α]2D4 –60.4° (c 1.00, CHCl3); IR (film) 3390,
3062, 1709, and 1644 cm−1; 1H NMR (CD3OD) δ 1.38 (9H, com-
plex), 2.22 (2H, complex), 4.40 (1H, m), 4.50 (1H, m), 5.05 (1H,
(3H, d, J = 6.4 Hz), 0.80 (3H, t, J = 7.3 Hz), 0.81 (1H, m), 0.86
(3H, d, J = 6.4 Hz), 1.00 (1H, m), 1.41 (1H, m), 1.53 (1H, m),
1.66 (1H, m), 1.70 (1H, m), 1.70 (2H, complex), 1.78 (1H, m),
1.84 (1H, m), 2.01 (1H, m), 2.71 (1H, dd, J = 10.3, 12.7 Hz), 2.78
(1H, dd, J = 11.7, 12.7 Hz), 3.11 (1H, dd, J = 4.4, 12.7 Hz), 3.32
(1H, m), 3.41 (1H, m), 3.52 (1H, br d, J = 9.8 Hz), 3.58 (1H, dd, J
= 4.4, 12.7 Hz), 3.65 (1H, d, J = 7.8 Hz), 3.82 (1H, ddd, J = 2.4,
8.8, 11.2 Hz), 4.00 (1H, d, J = 5.9 Hz), 4.30 (1H, ddd, J = 4.4,
7.3, 11.7 Hz), 4.44 (1H, t, J = 9.3 Hz ), 4.48 (1H, J = d, 8.8 Hz),
4.61 (1H, ddd, J = 4.0, 4.4, 10.3 Hz), 4.74 (1H, dq, J = 8.8, 6.4
Hz), 7.05 (1H, d, J = 9.3 Hz), 7.18 (2H, complex), 7.21 (1H, m),
7.23 (2H, complex), 7.24 (1H, d, J = 7.3 Hz), 7.26 (2H, complex),
7.28 (2H, complex), 7.88 (1H, d, J = 4.0 Hz), and 7.89 (1H, s);
13C NMR δ 10.5, 15.0, 16.0, 21.3, 21.5, 24.7, 30.8, 34.2, 35.5,
39.8, 40.8, 46.1, 46.4, 50.5, 53.6, 53.7, 58.8, 61.4, 71.2, 77.2,
77.8, 123.6, 127.1, 127.3, 128.5, 128.9, 129.3, 129.4, 135.8,
136.7, 149.0, 159.7, 167.9, 168.1, 170.2, 170.5, and 171.2. Found
(FAB): m/z 768.3564. Calcd for C41H50N7O6S: M + H, 768.3543.
Isomerization of 1c to 1a. To a solution of 1c (15 mg, 0.019
mmol) in MeOH (3 mL) was added NaOMe in MeOH (33 µL,