RESEARCH FRONT
674
M. A. Jones et al.
HCl (1 M) and EtOAc. The organic phase was separated, washed
successively with sat. aq. NaHCO3 (200 mL) and brine, dried
over MgSO4, and the solvent removed to give the title compound
as a glassy white solid (5.73 g, 87%). Mp 69–71◦C. (Found:
MH+ 572.2984. C30H42N3O8 requires 572.2972). δH (CD3OD)
7.24–7.37 (5H, m, Ph), 7.03 (2H, app d, J 8.5, HArO), 6.67
(2H, app d, J 8.5, HAr), 4.97–5.06 (2H, m, OCH2Ar), 4.41–4.46
(1H, m, CHCH2CH(CH3)2), 4.32–4.38 (2H, m, CHCH2ArO and
CHCO2Me), 3.69 (3H, s, OCH3), 3.50–3.55 (2H, m, CH2OH),
2.98–3.03 (1H, m, CHCHHAr), 2.73–2.77 (1H, m, CHCHHAr),
1.77–1.87 (1H, m, CHCH2CH(CH3)2), 1.66–1.75 (1H, m,
OCH2CHHCH2CH2), 1.60–1.64 (1H, m, OCH2CHHCH2CH2),
1.51–1.58 (4H, m, CHCH2CH(CH3)2 and OCH2CH2CH2CH2),
1.38–1.48(2H, m, OCH2CH2CH2CH2), 0.93(3H, d, J6.5, CH3),
0.90 (3H, d, J 6.5, CH3). δC (CD3OD) 173.5, 173.0, 157.1, 156.1,
137.0, 130.4, 128.4, 128.0, 127.8, 127.5, 115.2, 66.5, 62.4, 61.5,
56.7, 52.7, 40.9, 31.9, 31.1, 24.6, 22.4, 22.1, 21.3.
C30H41N3O7I requires 682.1989). δH (CD3OD) 7.22–7.31 (5H,
m, Ph), 7.03(2H, m, HArO), 6.67(2H, m, HArO), 4.96–5.05(2H,
m, OCH2Ar), 4.43–4.46 (1H, m, CHCH2CH(CH3)2), 4.36–4.38
(2H, m, CHCH2ArO and CHCO2Me), 3.70 (3H, s, OCH3), 3.16–
3.19 (2H, m, CH2I), 3.00–3.03 (1H, m CHCHHAr), 2.73–2.78
(1H, m CHCHHAr), 1.74–1.84 (3H, m, CHCH2CH(CH3)2 and
ICH2CH2CH2CH2), 1.64–1.67 (1H, m, OCH2CH2CHHCH2),
1.56–1.63 (3H, m, CHCH2CH(CH3)2 and ICH2CH2CHHCH2),
1.41–1.48 (2H, m, ICH2CH2CH2CH2), 0.90 (3H, d, J 6.5, CH3),
0.89 (3H, d, J 6.5, CH3). δC (CD3OD) 173.5, 173.0, 172.6, 157.2,
156.1, 137.0, 130.2, 128.3, 127.9, 127.8, 127.5, 115.1, 66.4, 56.8,
52.3, 51.9, 51.6, 40.8, 37.1, 33.0, 30.2, 26.6, 24.6, 22.3, 21.1.
Method B: To a solution of the alkyl bromide 9 (65 mg,
0.1 mmol) in acetone (1 mL) was added NaI (22 mg, 0.15 mmol).
The resulting yellow solution was stirred overnight, concentrated
under vacuum, and the residue partitioned between EtOAc and
H2O. The organic phase was separated, washed with H2O, dried
over MgSO4, and concentrated under vacuum to give a yellow
solid that had identical data to that reported above.
(S)-2-{(S)-2-[(S)-2-Benzyloxycarbonylamino-
3-(4-hydroxyphenyl)propionylamino]-4-
methylpentanoylamino}-6-bromohexanoic
Acid Methyl Ester 9
(7S,10S,13S)-13-Benzyloxycarbonylamino-10-isobutyl-
9,12-dioxo-2-oxa-8,11-diaza-bicyclo[13.2.2]nonadeca-
1(18),15(19),16-triene-7-carboxylic Acid Methyl Ester 11
DDQ (68 mg, 0.3 mmol) was added to a stirred solution of
triphenylphosphine (79 mg, 0.3 mmol) in dry DCM (2.5 mL)
under a nitrogen atmosphere. TBAB (97 mg, 0.3 mmol) was
added and the resulting mustard-brown suspension was stirred
for 5 min, at which time 8 (143 mg, 0.25 mmol) was added.
The reaction mixture was stirred overnight at room temper-
ature and then diluted with EtOAc. The organic phase was
separated, extracted with saturated NaHCO3 until the aque-
ous layer was no longer yellow, washed with H2O, dried over
MgSO4, and concentrated under vacuum. Recrystallization from
EtOAc and pentane gave the title compound as a white solid
(85 mg, 54%). (Found: MH+ 634.2139. C30H41BrN3O7 requires
634.2128). δH (CDCl3) 7.39–7.28 (5H, m, Ph), 7.02 (2H, m,
HArO), 6.72 (2H, m, HArO), 6.58 (1H, d, J 6.5, NH), 6.28 (1H,
d, J 8.5, NH), 5.20 (d, J 6.5, NH), 5.08 (2H, m, OCH2Ar),
4.53 (1H, dd, J 13.5 and 7.5, CHCH2CH(CH3)2), 4.39 (2H,
m, CHCH2ArO and CHCO2Me), 3.75 (3H, s, OCH3), 3.35–
3.45 (2H, m, CH2Br), 3.01 (m, 2H, CHCH2Ar), 1.80–1.90
(3H, m, CHCH2CH(CH3)2 and BrCH2CH2CH2CH2), 1.57–
1.75 (2H, m, BrCH2CH2CH2CH2), 1.57–1.40 (m, 4H, m,
CHCH2CH(CH3)2 and BrCH2CH2CH2CH2), 0.89 (m, 6H, m,
CH3).
Method A: The iodide 10 (7.0 g, 0.01 mol), K2CO3 (2.1 g,
0.015 mol) and Cs2CO3 (0.36 g, 1.0 mmol) were dissolved in
dry MeCN (30 mL) under a nitrogen atmosphere, and the solu-
tion was stirred overnight at reflux. After cooling to room
temperature, the solvent was removed under vacuum and the
yellow residue partitioned between EtOAc and aq. HCl (1 M).
The organic phase was separated, washed successively with
aq. HCl (1 M) and brine, dried over MgSO4 and the solvent
removed under vacuum to give a yellow solid. This was dis-
solved in EtOAc, activated charcoal (10 g) was added, and the
mixture stirred overnight at room temperature. The solvent was
removed under vacuum to give a white solid that was recrys-
tallized from EtOAc and pentane to give the title compound as
a white solid (3.87 g, 70%). Mp 274–276◦C. (Found: C 64.87,
H 7.07, N 7.71, MH+ 554.2859. C30H39N3O7 requires C 65.08,
H 7.10, N 7.59%, MH+ 554.2866). δH (C5D5N) 9.44 (1H,
d, J 9.0, NH), 8.88 (1H, d, J 8.0, NH), 8.52 (1H, d, J 8.0,
NH), 7.33 (2H, m, Ph), 7.18–7.23 (5H, m, Ph and HArO), 6.86
(2H, app d, J 8.5, HArO), 5.25 (2H, br s, PhCH2), 5.06–5.12
(1H, m, CHCH2ArO), 4.83–4.88 (1H, m, CHCH2CH(CH3)2),
3.95 (1H, dd, J 14.0 and 7.0, CHCO2CH3), 4.22–4.26 (1H, m,
ArOCHH), 3.41–3.99 (1H, m, ArOCHH), 3.54 (3H, s, OCH3),
3.22 (1H, dd, J 13.0 and 6.0, CHCHHArO), 3.14 (1H, t, m,
CHCHHArO, J 12.0 and 12.0, CHCHHArO), 1.76–1.82 (4H,
m, CHCH2CH(CH3)2, CHCHHCH(CH3)2, ArOCH2CHH and
CHHCHCO2CH3), 1.60–1.67 (2H, m, CH2CHCO2CH3 and
CHCH2CH(CH3)2), 1.41–1.52 (1H, m, CH2CHHCHCO2CH3),
1.21–1.32 (2H, m, ArOCH2CHH and CH2CHHCHCO2CH3),
0.72 (3H, d, J 6.5, CH3), 0.68 (3H, d, J 6.5, CH3). δC (CDCl3)
172.5, 170.8, 169.7, 157.1, 155.5, 136.3, 130.1, 128.5, 128.2,
128.1, 127.9, 115.7, 66.8, 66.7, 57.1, 52.5, 51.7, 51.2, 43.3, 39.0,
31.5, 28.0, 24.5, 22.9, 22.4, 21.2.
(S)-2-{(S)-2-[(S)-2-Benzyloxycarbonylamino-
3-(4-hydroxyphenyl)propionylamino]-4-
methylpentanoylamino}-6-iodohexanoic
Acid Methyl Ester 10
Method A: To a solution of triphenylphosphine (5.52 g,
0.021 mol) in dry DCM (40 mL) under a nitrogen atmosphere
was added DDQ (4.77 g, 0.021 mol). The resulting red solution
was treated with TBAI (7.76 g, 0.021 mol) to give a mustard-
brown suspension. Stirring was continued for 5 min at which
time 8 (8.0 g, 0.014 mol) was added. The reaction mixture was
stirred overnight at room temperature, diluted with EtOAc, and
the organic phase washed with sat. aq. NaHSO3 until the aque-
ous layer was no longer yellow in colour. The organic phase
was then washed with H2O, dried over MgSO4 and concen-
trated under vacuum to give a cream solid. Recrystallization
from EtOAc and pentane gave the title compound as a white
solid (7.15 g, 75%). Mp 108–110◦C. (Found: MH+ 682.1998.
Method B: Pseudo-tripeptide 14 (118 mg, 0.2 mmol) was
dissolved in DCM (5 mL) under a nitrogen atmosphere. Tri-
fluoroacetic acid (2 mL) was added and the solution was
stirred at room temperature for 3 h. The solvent was removed
under vacuum, the residue dissolved in toluene, and the
solution re-evaporated to give 15 (76 mg, 0.11 mmol) as