+
+
502 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4
Ksander et al.
1,2,3,4,5,6,7,8,9,10-Decah ydr o-3-oxo-4-ben zazacyclodode-
cin e-2,5(S)-d ica r boxylic Acid 2-Meth yl Ester (18). The
macrocyclic lactam alcohol 17 (322 mg, 1.0 mmol) in 15 mL of
acetonitrile and 15 mL of water was oxidized with sodium
periodate (864 mg, 4.0 mmol) and ruthenium trichloride
hydrate (5 mg, 0.022 mmol). The mixture was stirred for 15
min at room temperature and left to stand for 2 h. The
reaction mixture was diluted with methylene chloride, and the
organic layer was washed with water, dried (MgSO4), filtered,
and evaporated to dryness to give 280 mg (84%) of 18 as a
crude mixture of diastereomers. The compound was used
without further purification in the next step.
7.1 (m, 2H), 5.86 (d, 1H), 4.63 (m, 1H), 3.70 (s, 3H), 3.2 (m,
3H), 2.7 (m, 3H), 2.4 (m, 1H), 2.31 (s, 3H), 1.9 (m, 1H), 1.5-
1.2 (m, 9H).
Ben zyl 2(S)-[(a cet ylt h io)m et h yl]-2,3,4,5,6,7,8,9,10,11-
d eca h yd r o-3-oxo-1H -4-b en za za cyclot r id ecin e-5(S)-ca r -
boxyla te (44a ): 1H NMR (CDCl3) δ 7.4 (m, 1H), 7.25 (m, 1H),
7.1 (m, 2H), 6.11 (d, 1H), 5.14 (AB q, 2H), 4.45 (m, 1H), 3.22
(d, 2H), 3.13 (m, 1H), 2.9 (m, 2H), 2.6 (m, 3H), 2.35 (s, 3H),
1.8 (m, 1H), 1.6-1.2 (m, 9H).
Ben zyl 2(R)-[(a cetylth io)m eth yl]-2,3,4,5,6,7,8,9,10,11-
d eca h yd r o-3-oxo-1H -4-b en za za cyclot r id ecin e-5(S)-ca r -
boxyla te (44b): 1H NMR (DMSO-d6) δ 7.3 (m, 5H), 7.15 (m,
4H), 5.88 (d, 1H), 5.1 (AB q, 2H), 4.69 (m, 1H), 3.2 (m, 3H),
2.65 (m, 2H), 2.3 (s, 3H), 2.4 (m, 1H), 1.9 (m, 1H), 1.6-1.0 (m,
10H); MS m/ e 468 (M + 1). Anal. (C27H33NO4S) C, H, N.
1,2,3,4,5,6,7,8,9,10-Deca h yd r o-2(S)-m er ca p t o-3-oxo-4-
ben za za cyclod od ecin e-5(S)-ca r boxylic Acid (23a ). To a
deoxygenated solution of the S-acetyl ester 22a (56 mg, 0.15
mmol) in 5 mL of THF and 1.5 mL of water was added 3 equiv
of lithium hydroxide. The mixture was stirred 4 h at room
1,2,3,4,5,6,7,8,9,10-Decah ydr o-3-oxo-4-ben zazacyclodode-
cin e-2,5(S)-d ica r boxylic Acid (19). To a solution of 18 (280
mg, 0.84 mmol) in 2 mL of methanol was added 1 N NaOH
(2.1 mL, 2.5 equiv). The reaction mixture was stirred at room
temperature for 4 h and acidified with 1 N HCl. The
precipitate was collected, washed with water, and dried under
high vacuum to give 200 mg (75%) of 19 as a mixture of
diastereomers.
temperature, concentrated, then taken up in
a minimal
1,2,3,4,5,6,7,8,9,10-Deca h yd r o-2-m eth ylen e-3-oxo-4-ben -
za za cyclod od ecin e-5(S)-ca r boxylic Acid (20). A mixture
of 19 (200 mg, 0.62 mmol), piperidine (10.6 mg, 0.125 mmol),
and paraformaldehyde (28.2 mg, 0.94 mmol) in 1 mL of
pyridine was heated for 3 h at 60 °C. The reaction mixture
was concentrated, taken up in ethyl acetate, washed with 1 N
HCl and brine, dried (MgSO4), filtered, and concentrated to
give 158 mg (88%) of 20: 1H NMR (CDCl3) δ 7.14 (m, 4H), 5.8
(d, 1H), 5.79 (s, 1H), 5.6 (s, 1H), 4.6 (m, 1H), 3.84 and 3.52
(dd, 2H), 2.9 (m, 1H), 2.65 (m, 1H), 2.0-1.0 (m, 8H).
2-[(Acetylth io)m eth yl]-1,2,3,4,5,6,7,8,9,10-d eca h yd r o-3-
oxo-4-ben za za cyclod od ecin e-5(S)-ca r boxylic Acid (21). A
mixture of thiol acetic acid (3 mL) and 20 (158 mg, 0.55 mmol)
was stirred for 24 h at room temperature. The solution was
concentrated to give 21. The material was used crude in the
next reaction.
amount of water, and acidified with 1 N HCl. The precipitate
was collected and washed with a small amount of water and
then hexanes to give 41 mg (84%) of 23a melting at 222-225
°C: 1H NMR (DMSO-d6) δ 12.45 (br, 1H), 8.1 (d, 1H), 7.1 (m,
4H), 4.04 (m, 1H), 3.5-2.2 (m, 7H), 1.8-1.0 (m, 8H); MS m/ e
322 (M + 1). Anal. (C17H23NO3S) C, H, N.
1,2,3,4,5,6,7,8,9,10-Deca h yd r o-2(R)-m er ca p t o-3-oxo-4-
ben za za cyclod od ecin e-5(S)-ca r boxylic Acid (23b): pre-
pared similarly from 22b was the thiol acid 23b melting at
127-131 °C; 1H NMR (DMSO-d6) δ 12.4 (br, 1H), 8.04 (d, 1H),
7.2 (m, 4H), 4.42 (m, 1H), 3.0-2.0 (m, 7H), 1.8-1.0 (m, 8H):
MS m/ e 322 (M + 1). Anal. (C17H23NO3S) C, H, N.
2,3,4,5,6,7,8,9-Octah ydr o-2(S)-m er capto-3-oxo-1H-4-ben -
za za cyclou n d ecin e-5(S)-ca r boxylic Acid (25a ): 1H NMR
(DMSO-d6) δ 12.5 (s, 1H), 8.24 (d, 1H), 7.1 (m, 4H), 4.0 (t, 1H),
3.15 (t, 1H), 3.0-2.6 (m, 3H), 2.3 (m, 3H), 2.0 (m, 1H), 2.85
(m, 1H), 1.5 (m, 3H), 1.3 (m, 1H): MS m/ e 308 (M + 1). Anal.
(C16H21NO3S) C, H, N.
Met h yl 2(S)-[(Acet ylt h io)m et h yl]-1,2,3,4,5,6,7,8,9,10-
d eca h yd r o-3-oxo-4-ben za za cyclod od ecin e-5(S)-ca r boxy-
la te (22a ) a n d Meth yl 2(R)-[(Acetylth io)m eth yl]-1,2,3,4,
5,6,7,8,9,10-d eca h yd r o-3-oxo-4-b en za za cyclod od ecin e-
5(S)-ca r boxyla te (22b). To a suspension of S-acetyl acid 21
(200 mg, 0.578 mmol) and cesium carbonate (188 mg, 0.578
mmol) in 3 mL of DMF was added methyl iodide (0.5 mL, 1.16
mmol). The reaction mixture was stirred for 1 h, concentrated,
and taken up in ethyl acetate. The organic layer was washed
with water and brine, dried (MgSO4), concentrated, and flash
chromatographed on silica gel, eluting with ethyl acetate/
hexanes (1:4) to give 68 mg (34%) of 22b followed by 56 mg
(28%) of 22a .
2,3,4,5,6,7,8,9-Octah ydr o-2(R)-m er capto-3-oxo-1H-4-ben -
1
za za cyclou n d ecin e-5(S)-ca r boxylic Acid (25b): H NMR
(DMSO-d6) δ 12.7 (br, 1H), 7.85 (br, 1H), 7.14 (m, 4H), 4.3 (m,
1H), 3.07 (m, 1H), 2.9-2.5 (m, 3H), 2.3 (m, 3H), 2.0 (m, 1H),
2.8 (m, 1H), 1.4 (m, 3H), 1.25 (m, 1H); MS m/ e 308 (M + 1).
Anal. (C16H21NO3S) C, H, N.
2,3,4,5,6,7,8,9,10,11-Deca h yd r o-2(S)-m er ca p t o-3-oxo-
1H-4-ben za za cyclotr id ecin e-5(S)-ca r boxylic Acid (27a ):
1H NMR (DMSO-d6) δ 12.4 (br, 1H), 8.24 (d, 1H), 7.2 (m, 1H),
7.1 (m, 3H), 4.17 (m, 1H), 3.3-3.05 (m, 3H), 2.7 (m, 2H), 2.4
(m, 1H), 1.8-1.11 (m, 11H); MS m/ e 336 (M + 1). Anal.
(C18H25NO3S) C, H, N.
2,3,4,5,6,7,8,9,10,11-Deca h yd r o-2(R)-m er ca p t o-3-oxo-
1H-4-ben za za cyclotr id ecin e-5(S)-ca r boxylic Acid (27b):
1H NMR (DMSO-d6) δ 12.3 (br, 1H), 8.24 (m, 1H), 7.2 (m, 1H),
7.1 (m, 3H), 4.40 (m, 1H), 3.1 (d, 1H), 2.87 (m, 3H), 2.3 (m,
1H), 1.8 (m, 1H), 1.7-1.1 (m, 11H); MS m/ e 336 (M + 1). Anal.
(C18H25NO3S) C, H, N.
22a (S,S): 1H NMR (CDCl3) δ 7.14 (m, 4H), 5.84 (d, 1H),
4.08 (q, 1H), 3.68 (s, 3H), 3.27 (d, 2H), 2.95 (m, 5H), 2.37 (s,
3H), 1.95 (q, 2H), 1.7-1.0 (6H).
1
22b (R,S): H NMR (CDCl3) δ 7.25 (m, 4H), 5.55 (d, 1H),
4.65 (m, 1H), 3.68 (s, 3H), 3.27 (d, 2H), 3.1 (m, 1H), 2.9 (m,
1H), 2.8 (d, 2H), 2.5 (m, 1H), 2.36 (s, 3H), 2.1 (m, 1H), 1.7-1.0
(m, 7H).
4-[(2-Br om op h en yl)m eth yl]-3-t-Boc-2,2-d im eth yloxa zo-
lid in e (28). To a solution of 2-N-Boc-3-(2-bromophenyl)-
propanol (27.2 g, 82.4 mmol) in 200 mL of methylene chloride
were added p-toluenesulfonic acid hydrate (1.56 g, 8.2 mmol)
and 2,2-dimethoxypropane (100 mL). The solution was stirred
at room temperature for 2 days. The reaction mixture was
washed with NaHCO3 and brine, dried over MgSO4, filtered,
and evaporated to dryness to give 30.1 g (98%) of 28 as an oil:
1H NMR (CDCl3) δ 7.55 (d, 1H), 7.23 (m, 2H), 7.07 (m, 1H),
4.23 (m, 1H), 3.7 (m, 2H), 3.2 (m, 1H), 2.9 (m, 1H), 1.7, 1.57
(two s, 6H), 1.45 and 1.40 (two s, 9H).
2-[(3-t -Boc-2,2-d im e t h yloxa zolid in yl)m e t h yl]b e n z-
a ld eh yd e (29). The aryl bromide 28 (28.0 g, 75.6 mmol) in
1000 mL of THF was cooled to -78 °C. A solution of 2.5 N
nBuLi (48 mL, 0.12 mol) was added dropwise. After comple-
tion of nBuLi addition, DMF (11 mL) was added, and the
mixture was warmed to 0 °C over a 1 h period. The reaction
solution was poured into ice water and extracted with ether
two times. The ethereal layer was washed with water (2×)
and brine (2×
), dried over MgSO4, filtered, and evaporated to
Meth yl 2(S)-[(a cetylth io)m eth yl]-2,3,4,5,6,7,8,9-octa h y-
d r o-3-oxo-1H -4-b e n za za cyclou n d e cin e -5(S )-ca r b oxy-
la te (24a ): H NMR (CDCl3) δ 7.1 (m, 4H), 5.61 (d, 1H), 3.9
(m, 1H), 3.62 (s, 3H), 3.1 (m, 2H), 2.9 (d, 1H), 2.6 (m, 2H),
1
2.45 (m, 1H), 2.3 (s, 3H), 2.1-1.0 (m, 7H).
Meth yl 2(R)-[(a cetylth io)m eth yl]-2,3,4,5,6,7,8,9-octa h y-
d r o-3-oxo-1H -4-b e n za za cyclou n d e cin e -5(S )-ca r b oxy-
1
la te (24b): H NMR (CDCl3) δ 7.16 (m, 4H), 5.60 (d, 1H), 4.5
(m, 1H), 3.63 (s, 3H), 3.20 (d, 2H), 3.0 (m, 1H), 2.7 (m, 1H),
2.5 (m, 2H), 2.32 (s, 3H), 2.0 (m, 4H), 1.45 (m, 3H).
Meth yl 2(S)-[(a cetylth io)m eth yl]-2,3,4,5,6,7,8,9,10,11-
d eca h yd r o-3-oxo-1H -4-b en za za cyclot r id ecin e-5(S)-ca r -
1
boxyla te (26a ): H NMR (CDCl3) δ 7.2 (m, 1H), 7.1 (m, 3H),
6.1 (d, 1H), 4.4 (m, 1H), 3.71 (s, 3H), 3.27 (d, 2H), 3.15 and
3.10 (dd, 2H), 2.85 (m, 1H), 2.55 (m, 2H), 2.37 (s, 3H), 1.75
(m, 1H), 1.5-1.1 (m, 9H); MS m/ e 392 (M + 1).
Met h yl 2(R)-[(a cet ylt h io)m et h yl]-2,3,4,5,6,7,8,9,10,11-
d eca h yd r o-3-oxo-1H -4-b en za za cyclot r id ecin e-5(S)-ca r -
1
boxyla te (26b): H NMR (CDCl3) δ 7.3 (d, 1H), 7.2 (m, 1H),