Organic & Biomolecular Chemistry
Paper
(2S,4R)-Methyl 4-(2-((1R,3R)-1-methoxymethyloxy-4-methyl- 2.28–2.21 (m, 1H), 2.14 (s, 3H), 2.13–2.07 (m, 1H), 2.02–1.96
3-((2S,3S)-3-methyl-2-((R)-1-methylpiperidine-2-carboxamido)- (m, 1H), 1.93–1.84 (m, 2H), 1.83–1.76 (m, 2H), 1.71–1.53 (m,
pentanamido)pentyl)thiazole-4-carboxamido)-2-methyl-5-phe- 5H), 1.45–1.35 (m, 1H), 1.23–1.12 (m, 1H), 1.14 (d, J = 7.0 Hz,
nylpentanoate, 24f. (White foam, 74%); Rf = 0.71 (8 : 92 3H), 0.97 (d, J = 6.8 Hz, 3H), 0.94–0.87 (m, 9H); 13C NMR
MeOH–CHCl3); [α]D23 = −11.2 (c = 0.6, CHCl3); 1H NMR (100.5 MHz, CD3OD) δ: 181.9, 173.7, 173.3, 171.7, 162.7, 151.1,
(400 MHz, CDCl3) δ: 7.99 (s, 1H), 7.25–7.14 (m, 5H), 7.02 139.6, 130.5, 129.3, 127.3, 125.0, 71.3, 69.6, 59.6, 56.3, 52.0,
(d, J = 8.7 Hz, 1H), 6.20 (d, J = 9.6 Hz, 1H), 4.80 (dd, J = 9.9, 51.0, 44.0, 41.9, 39.2, 38.9, 38.1, 37.6, 33.7, 31.0, 25.9, 25.4,
2.6 Hz, 1H), 4.74 (d, J = 6.7 Hz, 1H), 4.69 (d, J = 6.7 Hz, 1H), 23.5, 20.7, 19.5, 18.8, 18.6, 16.2, 11.1; LC/MS (ESI Ion Trap):
4.43–4.36 (m, 1H), 4.16–4.10 (m, 2H), 3.61 (s, 3H), 3.37 (s, 3H), m/z 720.3 [M + H]+.
2.95–2.80 (m, 3H), 2.63–2.57 (m, 1H), 2.49 (dd, J = 11.2, 3.2 Hz,
(2S,4R)-4-(2-((1R,3R)-1-Acetoxy-3-((2S,3S)-3-methyl-2-((R)-1-
1H), 2.20 (s, 3H), 2.04–1.95 (m, 4H), 1.88–1.74 (m, 3H), methylpiperidine-2-carboxamido)pentanamido)-3-phenylpro-
1.70–1.35 (m, 5H), 1.28–1.17 (m, 2H), 1.14 (d, J = 7.0 Hz, 3H,), pyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoic acid,
0.96 (d, J = 6.7 Hz, 3H), 0.92–0.84 (m, 9H); 13C NMR 1b. (White foam, 80% yield); Rf = 0.28 (1 : 9 MeOH–CH2Cl2);
1
(100.5 MHz, CDCl3) δ: 176.8, 175.4, 174.1, 171.3, 160.9, 150.5, [α]2D3 = −14.05 (c = 0.19, CHCl3); H NMR (400 MHz, CD3OD) δ
138.1, 129.8, 128.4, 126.8, 123.5, 97.4, 74.6, 70.0, 58.2, 57.0, 8.16 (s, 1H), 7.45–7.16 (m, 10H), 6.11 (dd, J = 9.6, 3.9 Hz, 1H),
55.7, 52.0, 51.0, 48.9, 45.3, 41.7, 40.5, 38.2, 36.8, 35.6, 32.6, 5.22 (dd, J = 9.8, 4.6 Hz, 1H), 4.50–4.38 (m, 1H), 4.32 (dd, J =
31.1, 25.5, 23.6, 19.2, 18.1, 16.3, 14.4, 11.1; LC/MS (ESI) m/z 14.3, 8.6 Hz, 1H), 3.22–3.10 (m, 1H), 3.05–2.89 (m, 2H), 2.70
752.2 [M + Na]+.
(ddd, J = 14.2, 10.3, 3.8 Hz, 1H), 2.62–2.40 (m, 3H), 2.35 (s,
(2S,4R)-Methyl-4-(2-((1R,3R)-1-benzoyloxy-4-methyl-3-((2S,3S)- 3H), 2.21 (s, 3H), 2.16–1.31 (m, 12H), 1.20 (d, J = 6.9 Hz, 3H),
3-methyl-2-((R)-1-methylpiperidine-2-carboxamido)pentana- 1.02 (d, J = 6.7 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR
mido)pentyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentano- (100.5 MHz, CD3OD) δ: 182.5, 173.2, 171.8, 170.9, 163.0, 151.1,
ate, 32. (White foam, 82%); Rf = 0.41 (1 : 9 MeOH–CHCl3); 143.1, 143.1, 139.7, 130.7, 129.9, 129.5, 128.8, 127.9, 127.6,
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[α]2D3 = −20.5 (c = 0.39, CHCl3); H NMR (400 MHz, CDCl3) δ: 125.6, 72.5, 71.6, 70.9, 60.9, 57.8, 52.8, 52.1, 45.2, 44.0, 43.2,
8.08 (d, J = 8.1 Hz, 2H), 8.01 (s, 1H), 7.59 (t, J = 7.3 Hz, 1H), 40.6, 39.1, 32.2, 27.5, 26.6, 24.8, 22.2, 19.3, 17.7, 12.6; LC/MS
7.46 (t, J = 7.7 Hz, 2H), 7.30–7.16 (m, 5H), 6.90 (br s, 1H), 6.21 (ESI) m/z 748.3 [M + H]+, 770.3 [M + Na]+.
(br s, 1H), 6.15 (dd, J = 10.6, 3.1 Hz, 1H), 4.45–4.38 (m, 1H),
(2S,4R)-4-(2-((1R,3R)-1-Acetoxy-3-((2S,3S)-3-methyl-2-((R)-1-
4.20–4.14 (m, 1H), 4.11–4.05 (m, 1H), 3.62 (s, 3H), 2.96 (dd, J = methylpiperidine-2-carboxamido)pentanamido)-3-(4-methoxy-
13.6, 6.2 Hz, 1H), 2.87 (dd, J = 13.6, 6.9 Hz, 1H), 2.65–2.57 (m, phenyl)propyl)thiazole-4-carboxamido)-2-methyl-5-phenylpen-
1H), 2.52–2.44 (m, 1H), 2.37–2.29 (m, 1H), 2.12 (s, 3H), tanoic acid, 1c. (White foam, 95% yield); Rf = 0.37 (1 : 9
2.05–1.93 (m, 6H), 1.88–1.85 (m, 2H), 1.70–1.60 (m, 5H), MeOH–CH2Cl2); [α]2D3 = +21.63 (c = 0.59, CHCl3); 1H NMR
1.55–1.47 (m, 3H), 1.17 (d, J = 6.9 Hz, 3H), 0.95–0.86 (m, 12H); (400 MHz, CD3OD) δ: 8.13 (s, 1H), 7.29–7.03 (m, 7H), 6.85 (d,
13C NMR (63 MHz, CDCl3) δ: 176.6, 175.1, 170.8, 169.9, 165.4, J = 8.6 Hz, 2H), 6.04 (dd, J = 9.7, 3.8 Hz, 1H), 5.12 (dd, J = 10.0,
160.3, 150.1, 137.7, 133.5, 129.8, 129.4, 128.5, 128.3, 126.4, 4.8 Hz, 1H), 4.44–4.41 (m, 1H), 4.30–4.22 (m, 1H), 3.74 (s, 3H),
123.4, 70.4, 69.7, 57.8, 51.7, 50.4, 48.5, 44.9, 41.2, 39.9, 37.8, 3.23 (t, J = 12.8 Hz, 1H), 2.86 (d, J = 6.1 Hz, 2H), 2.72–2.42
35.6, 35.5, 34.9, 31.8, 29.7, 25.2, 24.8, 23.2, 18.8, 17.7, 15.8, (m, 3H), 2.41 (s, 3H), 2.11 (s, 3H), 2.05–1.14 (m, 13H), 1.11
10.7; LC/MS (ESI) m/z 790.3 [M + H]+, 812.3 [M + Na]+.
(d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 0.89 (t, J = 7.1 Hz,
General procedure for the hydrolysis of methyl ester 24a–f 3H); 13C NMR (100.5 MHz, CD3OD) δ: 180.5, 179.3, 173.7,
and acetylation of 25a–d. To a solution of compound 24a 172.4, 171.8, 164.0, 161.4, 151.4, 140.3, 135.8, 131.3, 130.1,
(120 mg, 0.17 mmol) in THF (5 mL), a 1 N aqueous solution of 129.7, 128.3, 120.6, 115.9, 71.9, 69.8, 61.5, 57.1, 56.7, 51.7,
LiOH (510 μL, 0.51 mmol) was added. After stirring for 3 days, 51.4, 44.4, 43.1, 42.6, 41.4, 40.7, 39.4, 31.3, 26.8, 25.6, 23.8,
TFA (53 μL, 0.68 mmol) was then added and the solvent was 21.6, 20.0, 17.0, 12.0; LC/MS (ESI) m/z 778.2 [M + H]+, 800.2
removed in vacuo to give 25a, which was used in the next step [M + Na]+.
without further purification. To a solution of 25a (126 mg,
(2S,4R)-4-(2-((1R,3R)-1-Acetoxy-3-((2S,3S)-3-methyl-2-((R)-1-
0.16 mmol) in pyridine (3 mL), Ac2O (1 mL) was added. The methylpiperidine-2-carboxamido)pentanamido)-3-cyclohexyl-
resulting mixture was stirred overnight. The mixture was propyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoic
concentrated under reduced pressure and the crude purified acid, 1d. (White foam, 75% yield); Rf = 0.38 (1 : 9 MeOH–
by FC.
CH2Cl2); [α]2D3 = +13.6 (c = 0.32, CHCl3); 1H NMR (400 MHz,
(2S,4R)-4-(2-((1R,3R)-1-Acetoxy-4-methyl-3-((2S,3S)-3-methyl- CD3OD) δ: 7.99 (s, 1H), 7.26–7.09 (m, 5H), 6.00 (dd, J = 9.5,
2-((R)-1-methylpiperidine-2-carboxamido)pentanamido)pentyl)- 4.9 Hz, 1H), 4.38 (d, J = 6.9 Hz, 1H), 4.24 (d, J = 8.2 Hz, 1H),
thiazole-4-carboxamido)-2-methyl-5-phenylpentanoic
acid, 4.09–3.95 (m, 1H), 3.23–3.12 (m, 1H), 3.02–2.86 (m, 2H),
1a. (White foam, 89% yield); Rf = 0.28 (1 : 9 MeOH–CH2Cl2); 2.77–2.54 (m, 1H), 2.53–2.41 (m, 1H), 2.48 (s, 3H), 2.12 (s, 3H),
[α]2D3 = −1.42 (c 1.55, MeOH); 1H NMR (400 MHz, CD3OD) δ: 2.08–0.87 (m, 25H), 1.19 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 6.9 Hz,
8.07 (s, 1H), 7.21 (d, J = 4.2 Hz, 4H), 7.17–7.11 (m, 1H), 5.90 3H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (100.5 MHz, CD3OD) δ:
(dd, J = 10.8, 3.0 Hz, 1H), 4.39–4.32 (m, 1H), 4.21 (d, J = 8.2 Hz, 173.9, 173.6, 172.2, 171.6, 163.9, 163.7, 151.9, 140.9, 131.5,
1H), 3.99–3.94 (m, 1H), 3.13–3.05 (m, 2H), 2.91(d, J = 6.8 Hz, 130.1, 128.1, 125.5, 73.3, 70.6, 61.8, 57.3, 52.4, 52.0, 45.0, 44.9,
2H), 2.57–2.49 (m, 1H), 2.48–2.42 (m, 1H), 2.40 (s, 3H), 43.5, 42.6, 40.0, 39.1, 38.7, 31.8, 31.6, 30.8, 29.7, 28.4, 28.2,
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2273–2287 | 2285