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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
5.68 (d, br, J = 7.8 Hz, 1H), 5.47 (s, 1H), 4.30 (dd, J = 8.7, 4.9 Hz, (S,E)-Ethyl 2,5-dimethyl-4-(methylamino)hex-2-enoate 20 20
1H), 3.78 (s, 3 H), 3.69 (s, 3H), 3.26 (s, br, 3H), 1.97 (m, 1H), Prepared according to the literature. SpeDctOrIo: 1s0c.o10p3ic9/aCn5dOBo0p1t8i8c2aJl
1.61 (s, 3H), 1.41 (s, 3H), 0.74 (d, J = 6.8 Hz, 3H), 0.64 (d, J = 6.8 rotatory power data as in the literature.
Hz, 3H); 13C NMR (75 MHz, CDCl3)
171.6, 168.0, 158.9 (q, J = (S,E)-Ethyl
4-((S)-2-((S)-3-(4-methoxyphenyl)-3-methyl-2-
34.9 Hz), 158.5, 137.8, 127.5 (2C), 116.5 (q, J = 287.7 Hz), 113.8 (2,2,2-trifluoro-N-methylacetamido)butanamido)-N,3-
(2C), 65.0, 57.1, 55.2, 42.0, 41.7, 33.7, 30.5, 27.5, 25.5, 18.8, dimethylbutanamido)-2,5-dimethylhex-2-enoate, 21. LiOH
+
17.4; HRMS (ESI) calcd for C21H29F3N2O5 [MNa]+ 469.1921, (24 mg, 1.0 mmol) was added to a suspension of methyl ester
found 469.1919. 18b: white amorphous solid; Rf (9:1 n- 18a (88 mg, 0.2 mmol) in 50% aqueous methanol (v/v, 8 mL).
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1
hexane/ethyl acetate) 0.18; [a]D = + 26.3 (c = 0.1, CHCl3); H The resulting mixture was stirred for 18 h at 25 °C and then
NMR (300 MHz, CDCl3) 7.39 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 was diluted with water (10 mL) and extracted with diethyl
Hz, 2H), 5.82 (d, J = 8.1 Hz, 1H), 5.45 (s, 1H), 4.30 (dd, J = 8.4, ether (2 x 7 mL). The aqueous layer was acidified to pH 2 – 3
4.7 Hz, 1H), 3.77 (s, 3H), 3.65 (s, 3H), 3.22 (s, 3H) 1.96 (m, 1H), with a 5% aqueous solution of H3PO4 and extracted with EtOAc
1.61 (s, 3H), 1.41 (s, 3H), 0.70 (d, J = 6.8 Hz, 3H), 0.69 (d, J = 6.8 (3 x 5 mL). The combined organic layers were dried over
Hz, 3H); 13C NMR (75 MHz, CDCl3)
171.5, 167.7, 159.4 (q, J = Na2SO4 and concentrated in vacuo to afford the crude acid
34.9 Hz), 158.4, 137.5, 127.7 (2C), 116.4 (q, J = 287.7 Hz), 113.8 intermediate, which was used in the condensation step
(2C), 64.8, 57.2, 55.3, 52.2, 41.8, 33.5, 30.7, 27.2, 25.5, 18.7, without purification. HBTU (60 mg, 0.15 mmol) was added to a
+
17.7; HRMS (ESI) calcd for C21H29F3N2O5 [MNa]+ 469.1921, solution of the crude acid (60 mg, 0.14 mmol) in dry
found 469.1931.
(S)-methyl 3-methyl-2-((S)-3-methyl-3-(1-methyl-1H-indol-5- mmol) and DIPEA (30 mL, 0.17 mmol) in dry dichloromethane
yl)-2-(2,2,2-trifluoro-N- (3 mL) were added. The resulting reaction mixture was stirred
methylacetamido)butanamido)butanoate 19a and (S)-methyl for 24 h at 25 °C and then washed with a saturated aqueous
dichloromethane (3 mL). After 10 min, amine 20 (30 mg, 0.15
3-methyl-2-((R)-3-methyl-3-(1-methyl-1H-indol-5-yl)-2-(2,2,2-
trifluoro-N-methylacetamido)butanamido)butanoate 19b
solution of NaHCO3 (two times), water and finally with a 5%
aqueous solution of H3PO4. The resulting organic layer was
.
Aldehyde 14 (250 mg, 1.24 mmol) and methylamine (1 M in dried over Na2SO4 and concentrated in vacuo. The crude
MeOH, 1.37 mL, 1.37 mmol) were dissolved in dry MeOH (2.5 residue was purified by FC (4:1, n-hexane/ethyl acetate) to
mL), anhydrous MgSO4 (1.15 g) was added, and the mixture give 21 (48 mg, 58%). Pale yellow oil; Rf (4:1, n-hexane/ethyl
23
1
was stirred for 2 h at 25 °C. Trifluoroacetic acid (115 mL, 1.49 acetate) 0.25; [a]D = - 57.4 (c = 0.12, CHCl3); H NMR (400
mmol) and -isocyanoacetate 17 (210 mg, 1.49 mmol) were MHz, CDCl3) 7.39 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H),
added with a time gap of 20 min between the two additions. 6.61 (dq, br, J = 9.2 and 1.5 Hz, 1H), 6.09 (d, br, J = 8.6 Hz, 1H),
With all the reactants added, the mixture was stirred for 48 h. 5.44 (s, 1H), 5.01 (dd, J = 10.5 and 9.2 Hz, 1H), 4.52 (dd, J = 8.6
The reaction mixture was then concentrated in vacuo to give a and 6.8 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 3.77 (s, 3H), 3.15 (q,
residue that was purified by FC (4:1, n-hexane/ethyl acetate) br, J = 1.7 Hz, 3H), 2.88 (s, 3H), 1.93-1.75 (m, br, 2H), 1.85 (d, J
to give 19a (215 mg, 37%) and 19b (221 mg, 38%). 19a: white = 1.5 Hz, 3H), 1.54 (s, 3H), 1.40 (s, 3H), 1.28 (t, J = 7.0 Hz, 3 H),
21
amorphous solid; Rf (5.7:1 n-hexane/ethyl acetate) 0.17; [a]D
0.88 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H), 0.78 (d, J = 6.8
= + 53.0 (c = 0.1, CHCl3); 1H NMR (300 MHz, CDCl3)
7.77 (s, br, Hz, 3H), 0.65 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
1H), 7.43 (dd, J = 8.8 and 2.0 Hz, 1H), 7.33 (d, br, J = 8.8 Hz, 172.3, 167.9, 167.7, 158.4 (q, J = 34.9 Hz), 158.0, 138.2, 137.6,
1H), 7.04 (d, J = 2.9 Hz, 1H), 6.46 (d, br, J = 2.9 Hz, 1H), 5.75 (s, 132.9, 127.5 (2C), 116.6 (q, J = 287.7 Hz), 114.0 (2C), 65.0, 60.9,
1H), 5.65 (d, br, J = 7.8 Hz, 1 H), 4.22 (dd, J = 7.8 and 4.9 Hz, 56.4, 55.3, 54.0, 41.6, 33.5, 30.8, 30.3, 30.0, 27.3, 26.4, 19.4
1H), 3.77 (s, 3H), 3.60 (s, 3H), 3.31 (s, br, 3H), 1.83 (m, 1H), (2C), 18.8, 17.3, 14.2, 13.7; HRMS (ESI) calcd for
1.72 (s, 3H), 1.45 (s, 3H), 0.59 (d, J = 6.8 Hz, 3H), 0.37 (d, J = 7.0 C31H46F3N3NaO6+ [MNa]+ 636.3231, found 636.32423.
Hz, 3H); 13C NMR (75 MHz, CDCl3)
171.6, 168.4, 158.4 (q, J = (S,E)-4-((S)-2-((S)-3-(4-methoxyphenyl)-3-methyl-2-
34.9 Hz), 136.9, 135.5, 129.5, 128.7, 120.0, 119.6, 116.5 (q, J = (methylamino)butanamido)-N,3-dimethyl-butanamido-2,5-
287.7 Hz), 109.8, 101.0, 65.6, 57.2, 51.8, 42.2, 34.1, 32.8, 30.2, dimethylhex-2-enoic acid, 5. LiOH (16 mg, 0.64 mmol) was
+
28.3, 25.2, 18.7, 17.0; HRMS (ESI) calcd for C23H30F3N3NaO4 added to a suspension of ester 21 (50 mg, 0.08 mmol in 50%
[MNa]+ 492.2081, found 492.2071. 19b: white amorphous aqueous methanol (v/v, 3 mL). The resulting mixture was
solid; Rf (5.7:1 n-hexane/ethyl acetate) 0.18; [a]D21 = + 30.2 (c = stirred for 18 h at 60 °C, then diluted with water (10 mL) and
1
0.1, CHCl3); H NMR (300 MHz, CDCl3)
7.69 (s, br, 1H), 7.40 extracted with diethyl ether (2 x 10 mL). The aqueous layer
(dd, J = 8.7 and 2.0 Hz, 1H), 7.31 (d, br, J = 8.7 Hz, 1H), 7.03 (d, was acidified to pH 2 – 3 with a 5% aqueous solution of H3PO4
J = 2.9 Hz, 1H), 6.43 (d, J = 2.9 Hz, 1H), 5.67 (d, br, J = 7.8 Hz, and extracted with EtOAc (3 x 10 mL). The combined organic
1H), 5.58 (s, 1H), 4.25 (dd, J = 7.8 and 4.9 Hz, 1H), 3.77 (s, 3H), layers were dried over Na2SO4 and concentrated in vacuo to
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3.56 (s, 3H), 3.31 (s, 3H), 1.78 (m, 1H), 1.71 (s, 3H), 1.48 (s, 3H), afford pure
0.53 (d, J = 6.8 Hz, 3H), 0.51 (d, J = 6.8 Hz, 3H); 13C NMR (75 CHCl3); 1H NMR (400 MHz, CDCl3)
MHz, CDCl3) 171.3, 167.9, 158.4 (q, J = 34.9 Hz), 136.5, 135.6, (m, br, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.94-6.66 (m, br, 2H), 6.79
5
(30 mg, 76%). Foam; [a]D = - 47.1 (c = 0.58,
7.29 (d, J = 8.7 Hz, 2H), 7.28
129.4, 128.6, 120.1, 118.4, 116.5 (q, J = 287.7 Hz), 109.4, (dq, br, J = 9.9 and 1.5 Hz, 1H), 5.15 (dd, J = 9.9 and 5.3 Hz,
101.2, 65.2, 57.2, 51.9, 42.3, 33.6, 32.8, 30.6, 27.9, 25.5, 18.3, 1H), 4.48 (d, J = 10.9 Hz, 1H), 3.98 (s, 1H), 3.82 (s, 3H), 3.24
+
17.5; HRMS (ESI) calcd for C23H30F3N3NaO4 [MNa]+ 492.2081, (dhept, J = 10.9 and 6.7 Hz, 1H), 2.93 (s, 3H), 2.33 (s, 3H), 1.96
found 492.2066.
(s, br, 3H), 1.89 (m, 1H), 1.60 (s, 3H), 1.35 (s, 3H), 0.92-0.87 (m,
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