Macrolactamization Versus Macrolactonization
127.9, 127.2, 127.1, 125.1, 120.1, 67.6, 67.3, 63.4, 60.6, 58.0,
53.2, 47.3, 32.9, 31.3, 30.8, 19.4, 19.2, 18.3, 17.8, 17.6, 13.4,
-1.4; MS ESI m/z 968 (M + H+), 990 (M + Na+).
(eluent: EtOAc/Hexane ) 1/10-1/5) to give 14 (522 mg, 85%)
as a colorless oil: [R]25 15 (c, 0.69, CHCl3); IR 1712, 1219
D
cm-1; H NMR (400 MHz, CDCl3) δ 7.74 (d, 2 H, J ) 7.5 Hz),
1
(S)-2-((Z)-2-{(S)-2-[(R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-
3-methyl-butyrylamino]-3-tritylsulfanyl-propionylamino}-but-2-
enoylamino)-3-methyl-butyric Acid (12). At room temperature, to
a stirred solution of 11 (1.5 g, 1.55 mmol) in anhydrous THF (8
mL) was added 1 M TBAF in THF (4.65 mL). After stirring for
7.5 h, the solution was cooled in an ice bath, followed by the
addition of sat aq NaHCO3 (2 mL), Na2CO3 (164 mg, 1.55 mmol)
and Fmoc-Cl (481 mg, 1.86 mmol). After stirring for 2 h, the
solution was acidified to pH 4-5 with 1 M aq HCl. The phases
were separated, and the aqueous phase extracted with EtOAc
(20 mL × 5). The combined organic phases were dried (Na2SO4),
filtered and concentrated. The residue was purified by flash
chromatography (EtOAc/Hexane ) 1/5-1/1.5, then MeOH/
dichloromethane ) 1/20-1/10) to give 12 (0.94 g, 70%) as a
7.57 (m, 2 H), 7.20-7.38 (m, 19 H), 5.58-5.70 (m, 2 H), 5.34
(dd, 1 H, J ) 7.5, 15.5 Hz), 5.25 (d, 1 H, J ) 9.0 Hz), 4.30-4.42
(m, 2 H), 4.16 - 4.29 (m, 2 H), 4.05-4.15 (m, 2 H), 2.64 (dd,
1 H, J ) 8.0, 16.0 Hz), 2.53 (dd, 1 H, J ) 5.5, 12.0 Hz), 2.08
-2.20 (m, 3 H), 2.01 (m, 2 H), 0.90-0.98 (m, 2 H), 0.89 (d, 3
H, J ) 6.5 Hz), 0.78 (d, 3 H, J ) 7.0 Hz), 0.00 (s, 9 H); 13C
NMR (100 MHz, CDCl3) δ 171.0, 169.8, 156.3, 145.0, 144.8,
144.1, 144.0, 141.5, 134.2, 129.7, 128.0, 127.9, 127.2, 126.8,
125.3, 120.1, 72.0, 67.2, 66.8, 63.3, 58.9, 47.4, 39.8, 31.6, 31.5,
31.3, 19.1, 17.5, 17.5, -1.4; MS m/z 858 (M + NH+), 863 (M
+ Na+); HRMS m/z calcd for [M + Na]+ C51H57NNaO6SSi
862.3568, found 862.3546.
(2S,3R)-2-[(S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-tri-
tylsulfanyl-propionylamino]-3-hydroxy-butyric Acid Methyl Ester
(15). To a stirred solution of Fmoc-D-Cys(Tr)-OH (4.00 g, 6.83
mmol) in anhydrous dichloromethane (50 mL) cooled in an ice
bath was added PyBOP (4.00 g, 7.68 mmol), N,N-diisopropyl-
ethylamine (3.00 mL, 17.22 mmol), and then L-Thr-OMe.HCl
(1.27 g, 7.49 mmol). After stirring for 1.5 h, the reaction mixture
was worked up following the general procedure. The residue
was purified by flash chromatography (eluent: EtOAc/Hexane
white solid: [R]25 8.0 (c, 0.63, CHCl3); mp 118-120 °C; IR:
D
3277, 1651, 1504 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.90
(brs, 1 H), 7.70 (d, 2 H, J ) 7.7 Hz), 7.45 (d, 2 H, J ) 7.7 Hz),
7.05-7.36 (m, 20 H), 6.80-6.90 (m, 2 H), 6.67 (m, 1 H), 5.43
(d, 1 H, J ) 6.6 Hz), 4.28-4.40 (m, 2 H, 4.20 (m, 1 H),
4.00-4.12 (m, 2 H), 3.89 (brs, 1 H), 2.75 (m, 1 H), 2.60 (m, 1
H), 2.00-2.12 (m, 2 H), 1.58 (d, 3 H, J ) 6.9 Hz), 0.75-0.92
(m, 12 H); 13C NMR (75 MHz, CDCl3) δ 173.7, 172.0, 169.3,
164.7, 156.9, 144.2, 143.8, 143.5, 141.3, 133.1, 129.4, 128.1,
127.8, 127.1, 127.0, 125.0, 120.0, 67.4, 60.6, 58.9, 53.1, 47.1,
32.8, 30.8, 30.3, 19.1, 18.3, 13.5; MS m/z 866
(M-H+); HRMS m/z calcd for [M + Na]+ C51H54N4NaO7S
889.3605, found 889.3613.
) 1/2-2/1) to give 15 (4.62 g, 97%) as a white solid: [R]25
D
0.6 (c, 0.75, CHCl3); mp 90-95 °C; IR 3356 (brs), 1727, 1667,
1216 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.74 (t, 2 H, J ) 7.2
Hz), 7.56 (d, 2 H, J ) 7.5 Hz), 7.36-7.48 (m, 8 H), 7.16-7.30
(m, 11 H), 6.56 (d, 1 H, J ) 9.0 Hz), 5.08 (d, 1 H, J ) 7.5 Hz),
4.49 (dd, 1 H, J ) 2.5, 8.5 Hz), 4.37 (d, 2 H, J ) 7.0 Hz),
4.18-4.27 (m, 2 H), 3.88 (q, 1 H, J ) 6.5 Hz), 3.69 (s, 3 H),
2.67 (d, 2 H, J ) 6.5 Hz), 1.14 (d, 3 H, J ) 6.5 Hz); 13C NMR
(100 MHz, CDCl3) δ 170.9, 170.5, 144.4, 143.8, 143.7, 141.4,
129.6, 128.2, 127.8, 127.2, 127.0, 125.1, 120.1, 68.2, 67.5, 67.2,
57.3, 54.2, 52.7, 47.2, 34.0, 20.1; MS m/z 723 (M + Na+);
HRMS m/z calcd for [M + Na]+ C42H40N2NaO6S 723.2499,
found 723.2487.
(E)-(S)-3-((S)-2-{(Z)-2-[(S)-2-((R)-2-(9H-Fluoren-9-ylmethoxycar-
bonylamino)-3-methyl-butyrylamino)-3-tritylsulfanyl-propiony-
lamino]-but-2-enoylamino}-3-methyl-butyryloxy)-7-[(Z)-2-eth-(E)-
ylidene-1,1-diphenyl-hexa-3,5-dienylsulfanyl]-hept-4-enoic Acid
2-Trimethylsilanyl-ethyl Ester (13). To a stirred solution of 12
(100 mg, 0.12 mmol) and 6 (74 mg, 0.14 mmol) in anhydrous
dichloromethane (4 mL) cooled in an ice bath was added MSNT
(90 mg, 0.30 mmol) and 1-methylimidazole (28 uL, 35 mmol).
After stirring for 5 h, the solution was warmed to room
temperature and stirred for 100 min, followed by addition of
sat aq NH4Cl (5 mL). The phases were separated, and the
aqueous phase extracted with dichloromethane (10 mL × 3).
The combined organic phases were washed with brine (5 mL),
dried (Na2SO4), filtered, and concentrated. The residue was
purified by flash chromatography (eluent: EtOAc/Hexane ) 1/5
- 1/1.5) to give recovered 6 (30.6 mg, 42%) and 13 (53.6 mg,
(2S,3R)-2-{(S)-2-[(R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-
3-methyl-butyrylamino]-3-tritylsulfanyl-propionylamino}-3-hydroxy-
butyric Acid Methyl Ester (16). At room temperature, to a stirred
solution of 15 (4.62 g, 6.59 mmol) in anhydrous dichloromethane
(32 mL) was added piperidine (3.2 mL, 32.4 mmol). After
stirring for 70 min, the solution was concentrated, and the residue
purified by flash chromatography (eluent: EtOAc/Hexane )
1/4-1/2, then MeOH/dichloromethane ) 1/10) to give an amine
(2.95 g) which was used in the next step directly. To a stirred
solution of the above amine and Fmoc-D-Val-OH (2.23 g, 6.59
mmol) in anhydrous dichloromethane (50 mL) cooled in an ice
bath was added PyBOP (3.80 g, 7.30 mmol) and N,N-diisopro-
pylethylamine (1.72 mL, 9.87 mmol). After stirring overnight
at room temperature, the reaction mixture was worked up
following the general procedure. The residue was purified by
flash chromatography (eluent: EtOAc/Hexane ) 1/2-2/1) to give
34%) as a white solid: [R]25 -0.97 (c, 0.52, CHCl3); mp
D
95-100 °C; IR 3306, 1731, 1644, 1489 cm-1; H NMR (400
1
MHz, CDCl3) δ 7.74 (d, 2 H, J ) 7.5 Hz), 7.52 (d, 2 H, J ) 7.1
Hz), 7.12-7.40 (m, 35 H), 6.62 (m, 2 H), 6.29 (brs, 1 H),
5.52-5.65 (m, 2 H), 5.32 (dd, 1 H, J ) 7.1 Hz, 15.6 Hz), 5.24
(m, 1 H), 4.48 (dd, 1 H, J ) 5.5 Hz, 8.5 Hz), 4.40 (dd, 1 H, J
) 7.1, 10.8 Hz), 4.23 (m, 1 H), 4.00-4.13 (m, 4 H), 3.92 (m,
1 H), 2.89 (m, 1 H), 2.58-2.70 (m, 2 H), 2.50 (dd, 1 H, J )
6.2, 15.8 Hz), 1.94-2.18 (m, 6 H), 1.68 (d, 3 H, J ) 6.0 Hz),
0.75-0.95 (m, 14 H), 0.00 (s, 9 H); 13C NMR (100 MHz, CDCl3)
δ 171.7, 170.8, 169.8, 168.6, 163.9, 156.9, 145.0, 144.3, 141.4,
133.6, 129.7, 129.6, 128.3, 128.0, 127.9, 127.2, 127.1, 126.7,
125.1, 125.1, 120.1, 71.6, 67.6, 67.4, 66.7, 63.2, 60.6, 57.6, 53.1,
47.3, 39.8, 32.9, 31.5, 31.4, 31.2, 30.7, 19.4, 19.1, 18.0, 17.8,
17.4, 13.7, -1.4; MS m/z 1390 (M + Na+).
16 (4.30 g, 82%) as a white solid: [R]25 5.0 (c, 0.50, CHCl3);
D
mp 148-150 °C; IR 3357 (brs), 1727, 1667, 1216, 1032 cm-1
;
1H NMR (300 MHz, CDCl3:CD3OD ) 9:1) δ 7.76 (d, 2 H, J )
7.3 Hz), 7.60 (dd, 2 H, J ) 7.3, 11.7 Hz), 7.17-7.42 (m, 19 H),
4.22-4.45 (m, 5 H), 4.19 (t, 1 H, J ) 6.3 Hz), 3.90 (d, 1 H, J
) 5.5 Hz), 3.67 (s, 3 H), 2.67 (dd, 1 H, J ) 5.4, 12.6 Hz), 2.57
(dd, 1 H, J ) 8.4, 12.6 Hz), 2.05 (m, 1 H), 1.16 (d, 3 H, J ) 6.6
Hz), 0.95 (d, 3 H, J ) 6.9 Hz), 0.93 (d, 3 H, J ) 6.9 Hz); 13C
NMR (75 MHz, CDCl3:CD3OD ) 9:1) δ 171.9, 171.4, 170.6,
157.4, 144.3, 143.8, 143.5, 141.2, 129.4, 127.9, 127.7, 127.0,
126.7, 124.9, 119.9, 67.5, 67.1, 66.9, 61.0, 58.0, 52.3, 52.3, 47.0,
33.1, 30.5, 19.5, 19.0, 17.7; MS m/z 822 (M + Na+); HRMS
m/z calcd for [M + Na]+ C47H49N3NaO7S 822.3183, found
822.3167.
(E)-(S)-7-[(Z)-2-Eth-(E)-ylidene-1,1-diphenyl-hexa-3,5-dienylsul-
fanyl]-3-[(S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-
butyryloxy]-hept-4-enoic Acid 2-Trimethylsilanyl-ethyl Ester (14).
To a stirred solution of Fmoc-L-Val-OH (297 mg, 0.875 mmol)
and 2 (378 mg) in anhydrous dichloromethane (8 mL) cooled in
an ice bath was added DAMP (8 mg) and DCC (196 mg, 0.95
mmol). After stirring for 3 h, the solution was filtered and
concentrated. The residue was purified by flash chromatography
J. Org. Chem. Vol. 73, No. 23, 2008 9359