Peptidic Aldehydes Based on α- and β-Amino Acids
881
residue by chromatography (as described above) gave 7b (0.14 g, 94%)
as a white solid (Found: C 54.6, H 7.4, N 6.7. C19H29FN2O5S requires
C 54.8, H 7.0, N 6.7%). δH (CDCl3) 0.78 (3H, d, J 5.9, CH3), 0.80 (3H,
d, J 5.9, CH3), 0.81 (3H, d, J 6.3, CH3), 0.92 (3H, d, J 6.3, CH3), 1.11
(2H, m, CH2), 1.22 (1H, m, CH), 1.98 (1H, m, CH), 2.44 (2H, m, CH2),
3.43 (1H, dd, J 3.9 and 8.3, Val α-CH), 3.66 (3H, s, CO2Me), 4.12 (1H,
m, β-Leu-CH), 5.44 (1H, d, J 8.3, Val-NH), 6.15 (1H, d, J 9.3, β-Leu-
NH), 7.13 (2H, m, 2 ArH), 7.83 (2H, m, 2 ArH). δC (CDCl3) 16.9, 19.2,
21.9, 22.7, 24.7, 31.9, 38.2, 42.9, 44.3, 51.8, 61.6, 116.2 (d, J 22.8),
130.0 (d, J 9.3), 135.5, 165.0 (d, J 253), 169.1, 172.2. m/z (EI) 230,
159 (100%).
(1ꢀS,2S)-2-(4-Fluorobenzenesulfonylamino)-3-methyl-
N-[3-methyl-(1-oxoethyl)butyl]butyramide 8b
The ester 7b (49 mg, 0.1 mmol) was reduced in the manner described
above with DIBAL-H (0.11 mL, 0.6 mmol). Workup and purification of
the resultant residue by chromatography (as described above) gave 8b
(26 mg, 58%) as a white solid (Found: C 54.8, H 7.4, N 6.9%, 387.1759.
•
C18H27FN2O4S·0.5H2O requires C 54.5, H 7.4, N 7.1%, [M + H]+
387.1754). vmax/cm−1 (KBr) 1715, 1668. δH (CDCl3) 0.78 (3H, d, J
6.3, CH3), 0.79 (3H, d, J 5.4, CH3), 0.83 (3H, d, J 5.9, CH3), 0.86 (3H,
d, J 6.8, CH3), 1.18–1.36 (3H, m, CH2 and CH), 1.96 (1H, m, CHMe2),
2.58 (2H, m, CH2), 3.41 (1H, dd, J 4.4 and 7.8, Val α-CH), 4.19 (1H,
m, Leu α-CH), 5.30 (1H, d, J 7.8, Val-NH), 5.97 (1H, d, J 8.8, Leu-
NH), 7.15 (2H, m, 2 ArH), 7.84 (2H, m, 2 ArH), 9.69 (1H, s, CHO). δC
(CDCl3) 16.8, 19.2, 21.7, 22.8, 24.8, 31.7, 43.1, 43.7, 48.3, 61.7, 116.2
(d, J 22.8), 130.1 (d, J 9.3), 169.4, 200.9.
Methyl (2S,3ꢀS)-2-[3-(4-Fluorobenzenesulfonylamino)-
4-methylpentanoylamino]-4-methylpentanoate 7c
The acid 6b (51 mg, 0.2 mmol) was allowed to react as described above
with l-leucine methyl ester (35 mg, 0.2 mmol). Workup and purifica-
tion of the resultant residue by chromatography (as described above)
gave 7c (59 mg, 81%) as a white solid (Found: C 55.1, H 7.5, N 6.5.
C19H29FN2O5S requires C 54.8, H 7.0, N 6.7%). δH (CDCl3) 0.82 (6H,
d, J 6.8, 2 CH3), 0.91 (3H, d, J 6.3, CH3), 0.92 (3H, d, J 6.4, CH3),
1.24–1.62 (3H, m, CH2 and CH), 1.84 (1H, m, CH), 2.27 (2H, m, CH2),
3.23 (1H, m, β-Val-CH), 3.73 (3H, s, CO2Me), 4.51 (1H, m, Leu α-
CH), 5.84 (1H, d, J 8.3, NH), 5.84 (1H, d, J 5.8, NH), 7.14 (2H, m, 2
ArH), 7.88 (2H, m, 2 ArH). δC (CDCl3) 19.00, 19.04, 21.9, 22.6, 24.8,
31.5, 36.8, 41.4, 50.6, 52.3, 57.1, 116.1 (d, J 22.8), 129.7 (d, J 9.3),
137.1 (d, J 3.2), 164.8 (d, J 254.7), 170.6, 173.2. m/z (EI) 373, 202, 159,
146 (100%).
(1ꢀS,3S)-3-(4-Fluorobenzenesulfonylamino)-
N-(1-formyl-3-methylbutyl)-4-methylpentamide 8c
The ester 7c (45 mg, 0.1 mmol) was reduced in the manner described
above with DIBAL-H (0.096 mL, 0.5 mmol). Workup and purification
of the resultant residue by chromatography (as described above) gave 8c
(28 mg, 67%) as a white solid (Found: C 54.6, H 7.3, N 6.9%, 387.1751.
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C18H27FN2O4S·0.5H2O requires C 54.5, H 7.4, N 7.1%, [M + H]+
387.1754). vmax/cm−1 (KBr) 1734, 1659. δH (CDCl3) 0.82 (3H, d, J
6.8, CH3), 0.83 (3H, d, J 6.3, CH3), 0.96 (6H, d, J 6.3, 2 CH3), 1.40
(1H, m, CH), 1.68 (2H, m, CH2), 1.83 (1H, m, CHMe2), 2.34 (2H, m,
CH2), 3.23 (1H, m, Val α-CH), 4.52 (1H, m, Leu α-CH), 5.73 (1H, d, J
7.8, NH), 5.93 (1H, m, NH), 7.16 (2H, m, 2 ArH), 7.88 (2H, m, 2 ArH),
9.53 (1H, s, CHO). δC (CDCl3) 18.6, 18.7, 21.8, 22.9, 24.7, 31.6, 37.2,
37.4, 56.9, 57.2, 116.1 (d, J 22.3), 129.7 (d, J 9.3), 136.9 (d, J 3.7), 164.8
(d, J 254.7), 171.3, 199.8.
Methyl (3S,3ꢀS)-3-[3-(4-Fluorobenzenesulfonylamino)-
4-methylpentanoylamino]-5-methylhexanoate 7d
The acid 6b (60 mg, 0.2 mmol) was allowed to react as described above
with 4 (52 mg, 0.2 mmol). Workup and purification of the resultant
residue bychromatography (as describedabove)gave 7d (64.5 mg, 78%)
as a white solid. δH (CDCl3) 0.78 (3H, d, J 6.8, CH3), 0.82 (3H, d, J 6.8,
CH3), 0.87 (3H, d, J 7.8, CH3), 0.87 (3H, d, J 6.4, CH3), 1.23 (1H, m,
CHH), 1.42 (1H, m, CHH), 1.48 (1H, m, CH), 1.79 (1H, m, CH), 2.15
(2H, m, CH2), 2.46 (2H, m, CH2), 3.22 (1H, m, β-Val-CH), 3.65 (3H, s,
CO2Me), 4.23 (1H, m, β-Leu-CH), 6.07 (1H, d, J 8.8, NH), 6.11 (1H, d,
J 6.8, NH), 7.14 (2H, m, 2 ArH), 7.88 (2H, m, 2 ArH). δC (CDCl3) 19.0
(2C), 22.1, 22.7, 25.0, 31.5, 36.8, 38.3, 42.9, 44.1, 51.7, 57.2, 116.1 (d,
J 22.8), 129.7 (d, J 9.3), 137.2, 164.8 (d, J 254.2), 170.2, 172.3. m/z (EI)
387 (100%), 355, 202, 159.
(1ꢀS,3S)-3-(4-Fluorobenzenesulfonylamino)-4-methyl-
N-[3-methyl-1-(2-oxoethyl)butyl]pentamide 8d
The ester 7d (59 mg, 0.1 mmol) was reduced in the manner described
above with DIBAL-H (0.122 mL, 0.7 mmol). Workup and purification
of the resultant residue by chromatography (as described above) gave 8d
(35 mg, 64%) as a white solid (Found: C 56.1, H 7.9, N 6.6%, 401.1909.
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C19H29FN2O4S·0.5H2O requires C 55.9, H 7.6, N 6.8%, [M + H]+
401.1910). vmax/cm−1 (KBr) 1715, 1649. δH (CDCl3) 0.77 (3H, d, J
6.8, CH3), 0.81 (3H, d, J 6.8, CH3), 0.90 (6H, d, J 6.3, 2 CH3), 1.30
(1H, m, CHH), 1.53 (2H, m, CH and CHH), 1.76 (1H, m, CH), 2.20
(2H, m, CH2), 2.63 (2H, m, CH2), 3.20 (1H, m, β-Val-CH), 4.32 (1H,
m, β-Leu-CH), 5.82 (1H, d, J 8.3, NH), 5.94 (1H, d, J 8.8, NH), 7.15
(2H, m, 2 ArH), 7.91 (2H, m, 2 ArH), 9.73 (1H, s, CHO).
(1ꢀS,2S)-2-(4-Fluorobenzenesulfonylamino)-N-(1-formyl-
3-methylbutyl)-3-methylbutyramide 8a (SJA6017)
Methyl (2ꢀS,3S)-3-(2-Benzyloxycarbonylamino-
3-methylbutanoylamino)-5-methylhexanoate 10b
A
solution of ester 7a (40 mg, 0.1 mmol) in freshly distilled
dichloromethane (10 mL) under an atmosphere of argon was cooled
to −78◦C. Diisobutyl aluminium hydride (0.09 mL, 0.5 mmol) was
added dropwise and the mixture was stirred at −78◦C for 3 h. Super-
dry methanol (10 mL), which had been precooled to −78◦C, was added
dropwise and the mixture was stirred for a further 25 min at −78◦C.
The cooling bath was removed and 10% aqueous HCl (10 mL) was
added. The organic layer was separated from the resultant white precip-
itate, diluted with ethyl acetate (20 mL), washed with 10% aqueous HCl
(10 mL), saturated aqueous NaHCO3 (10 mL), and saturated aqueous
NaCl (10 mL), dried over MgSO4, and concentrated under vacuum to
give a cream oil which was purified by column chromatography (ethyl
acetate/light petroleum, 2 : 3) to give 8a (27 mg, 73%) as a white solid[28]
(Found: C 54.3, H 7.0, N 7.3%, 373.1603. C17H25FN2O4S requires C
To a mixture of Cbz-l-valine (200 mg, 0.8 mmol) and 4 (248 mg,
0.9 mmol) was added BOP (387 mg, 0.9 mmol) in the manner described
above for 7a. Workup and purification of the resultant residue through
a small plug of silica (ethyl acetate) gave 10b (276 mg, 88%) as a white
•
solid (Found: 415.2208. C21H32N2O5 requires [M + Na]+ 415.2209).
δH (CDCl3) 0.88 (6H, d, J 6.8, 2 CH3), 0.93 (6H, d, J 6.8, 2 CH3), 1.26
(1H, m, CH), 1.51 (2H, m, CH2), 2.10 (1H, m, CH), 2.49 (2H, m, CH2),
3.65 (3H, s, CO2Me), 3.93 (1H, m, Val α-CH), 4.32 (1H, m, β-Leu-CH),
5.09 (2H, s, CH2), 5.36 (1H, d, J 8.3, NH), 6.36 (1H, d, J 8.3, NH), 7.32
(5H, m, ArH). δC (CDCl3) 17.7, 19.2, 22.0, 22.8, 24.9, 30.9, 38.6, 43.0,
44.4, 51.7, 60.5, 67.0, 128.0, 128.1, 128.5, 136.3, 156.3, 170.6, 172.1.
•
54.7, H 7.0, N 7.5%, [M + H]+ 373.1597). vmax/cm−1 (KBr) 1725,
Methyl (2S,3ꢀS)-(3-Benzyloxycarbonylamino-
4-methylpentanoylamino)-4-methylpentanoate 10c
1638. δH (CDCl3) 0.84 (3H, d, J 7.3, CH3), 0.86 (3H, d, J 6.8, CH3),
0.89 (3H, d, J 6.8, CH3), 0.94 (3H, d, J 6.8, CH3), 1.22–1.27 (2H, m,
CH2), 1.55 (1H, m, CH), 2.06 (1H, m, CHMe2), 3.56 (1H, dd, J 4.8 and
8.3, Val α-CH), 4.42 (1H, m, Leu α-CH), 5.31 (1H, d, J 8.8, Val NH),
5.97 (1H, d, J 7.3 Hz, Leu-NH), 7.15 (2H, m, 2 ArH), 7.86 (2H, m, 2
ArH), 9.49 (1H, s, CHO). δC (CDCl3) 16.9, 19.2, 21.7, 22.9, 24.6, 31.9,
37.9, 57.4, 61.6, 116.2 (d, J 22.3), 130.1 (d, J 9.3), 170.2, 198.5.
To a solution of ester 1 (600 mg, 2.2 mmol) in THF/water (1 : 1 v/v,
50 mL) was added KOH (482 mg, 8.6 mmol), and the resultant mix-
ture was heated at 40◦C for 3 h. The reaction mixture was allowed
to cool to room temperature, ethyl acetate (30 mL) was added, and
the aqueous phase was acidified to pH 1 by the dropwise addition of