The Journal of Organic Chemistry
Article
1.11 (s, 5H), 0.93 (m, 6H), 0.86 (m, 3H); 13C NMR (101 MHz,
CDCl3) δ 172.1, 172.0, 170.0, 169.8, 154.0, 153.6, 151.9, 150.5, 144.1,
142.6, 128.9, 128.7, 128.6, 128.5, 127.3, 127.1, 125.1, 124.8, 107.4,
106.9, 82.1, 81.8, 81.0, 80.3, 66.9, 66.6, 65.1, 64.0, 51.6, 51.3, 51.3,
47.9, 43.9, 43.7, 43.4, 42.8, 42.2, 42.0, 32.3, 32.2, 28.4, 28.2, 28.1, 28.0,
26.9, 26.5, 26.2, 24.9, 24.8, 22.9, 22.7, 22.6, 22.5, 22.2, 14.2; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C32H52ClN2O5 579.35593, found
579.35436; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C32H51ClN2O5Na 601.33787, found 601.33641.
by 10% aq Na2CO3. The organic layer was dried over Na2SO4 and
evaporated. Purification by flash column chromatography over silica
gel (10−20% EtOAc/hexanes) afforded 25 as a white foam (268 mg,
1
77%): [α]24 −10.3 (c 2.00, CHCl3); H NMR (400 MHz, CDCl3) δ
D
7.79−7.62 (m, 4H), 7.49−7.32 (m, 6H), 6.32 (d, J = 8.3 Hz, 1H),
5.38−5.14 (m, 2H), 4.49 (m, 1H), 4.35 (d, J = 12.4 Hz, 1H), 4.21 (d,
J = 12.4 Hz, 1H), 3.08 (m, 1H), 1.68−1.50 (m, 2H), 1.44 (m, 10H),
1.38 (m, 12H), 1.11−1.03 (m, 12H), 0.95−0.86 (m, 6H); 13C NMR
(101 MHz, CDCl3) δ 172.0, 171.2, 155.7, 139.2, 135.8, 135.7, 133.5,
133.4, 129.8, 129.8, 127.9, 127.8, 127.7, 122.8, 81.8, 60.8, 57.5, 51.2,
41.9, 39.3, 28.4, 28.1, 27.1, 24.9, 22.9, 22.0, 19.4, 13.3; HRMS (ESI-
TOF) m/z [MH]+ calcd for C39H61N2O6Si 681.42989, found
681.43066.
(R)-tert-Butyl 4-Methyl-2-[(2R,3S,5S)-4-methylene-3-pentyl-
5-phenylpyrrolidine-2-carboxamido]pentanoate (21). Prepared
from 20 following the same deprotection/cyclization procedure
described for the 14 → 16 reaction (60%): [α]26 +7.3 (c 2.08,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 9.0 Hz, 1H), 7.34
(m, 2H), 7.26 (m, 3H), 4.98 (m, 1H), 4.86 (s, 1H), 4.55 (m, 2H), 4.19
(d, J = 6.7 Hz, 1H), 2.95 (dd, J = 13.4, 6.8 Hz, 1H), 1.93 (bs, 1H), 1.61
(m, 2H), 1.51 (m, 1H), 1.43 (m, 12H), 1.28 (m, 5H), 0.93 (m, 6H),
0.86 (t, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.2, 172.1,
155.0, 144.6, 128.9, 127.7, 109.1, 81.7, 64.7, 64.4, 50.7, 48.0, 42.2, 31.9,
28.5, 28.1, 27.2, 25.1, 23.0, 22.7, 22.2, 14.2; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C27H43N2O3 443.32682, found 443.32668.
(R)-tert-Butyl 2-[(2S,3R)-2-(tert-Butoxycarbonylamino)-3-(3-
chloro-3-phenylprop-1-en-2-yl)octanamido]-4-methylpenta-
noate (22). Prepared from 19 following the same desilylation/
chlorination sequence described for the 14 → 16 reaction.
(S)-tert-Butyl 2-[(2R,3S,Z)-2-(tert-Butoxycarbonylamino)-4-
(hydroxymethyl)-3-methylhex-4-enamido]-4-methylpenta-
noate (26). Prepared from 25 following the same three-step
procedure described for the 14 → 16 reaction.
Data for the allylic alcohol intermediate (90%): [α]24 −12.3 (c
D
1
1.50, CHCl3); H NMR (400 MHz, CDCl3) δ 6.90 (d, J = 7.8 Hz,
1H), 5.44 (q, J = 6.8 Hz, 1H), 5.34 (d, J = 8.4 Hz, 1H), 4.48−4.29 (m,
3H), 4.11 (d, J = 11.3 Hz, 1H), 3.55 (bs, 1H), 2.63 (m, 1H), 2.10 (bs,
1H), 1.66 (d, J = 6.8 Hz, 3H), 1.63−1.46 (m, 2H), 1.44 (m, 10H),
1.41 (s, 9H), 1.03 (d, J = 6.7 Hz, 3H), 0.92 (dd, J = 6.3, 5.3 Hz, 6H);
13C NMR (101 MHz, CDCl3) δ 172.2, 171.3, 156.2, 139.3, 125.6, 82.0,
80.2, 77.5, 76.8, 59.9, 57.6, 51.5, 43.1, 42.0, 28.4, 28.1, 25.0, 22.9, 22.1,
15.2, 13.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C23H43N2O6
443.31156, found 443.31136.
Data for the primary alcohol intermediate (93%): [α]24 +4.1 (c
D
1.17, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 5H), 7.21 (m,
1H), 6.83 (d, J = 8.4 Hz, 1H), 6.46 (s, 1H), 5.26 (d, J = 9.0 Hz, 1H),
4.44 (m, 2H), 4.26 (m, 2H), 3.98 (s, 1H), 2.63 (t, J = 8.0 Hz, 1H),
2.03 (s, 1H), 1.71−1.47 (m, 3H), 1.43 (m, 11H), 1.35 (s, 9H), 1.32−
1.09 (m, 6H), 0.94−0.80 (m, 9H); 13C NMR (101 MHz, CDCl3) δ
172.3, 171.7, 156.1, 139.0, 136.7, 132.7, 129.1, 128.2, 127.1, 82.2, 80.2,
60.2, 58.4, 51.4, 49.7, 42.0, 34.8, 31.9, 29.3, 28.4, 28.1, 28.0, 27.1, 25.4,
24.9, 22.9, 22.7, 22.1, 14.2; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C32H53N2O6 561.39037, found 561.38930.
Data for the intermediate allylic chloride (97%): [α]24 −27.9 (c
D
1
1.25, CHCl3); H NMR (400 MHz, CDCl3) δ 6.43−6.32 (m, 1H),
5.58 (q, J = 6.8 Hz, 1H), 4.99 (bs, 1H), 4.52−4.40 (m, 1H), 4.31−4.21
(m, 2H), 4.12 (d, J = 11.5 Hz, 1H), 2.93−2.81 (m, 1H), 1.71 (d, J =
6.8 Hz, 3H), 1.68−1.46 (m, 3H), 1.44 (s, 9H), 1.40 (s, 9H), 1.05 (d,
J = 7.1 Hz, 3H), 0.92 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 171.9,
170.8, 155.8, 137.0, 127.9, 82.1, 80.0, 57.1, 51.4, 42.0, 41.4, 41.2, 28.4,
28.1, 25.0, 22.9, 22.1, 14.3, 13.7; HRMS (ESI-TOF) m/z [M + H]+
Data for the diastereomeric mixture of allylic chlorides 22 (84%):
calcd for C23H42ClN2O5 461.27768, found 461.27780.
1H NMR (400 MHz, CDCl3) δ 7.41−7.18 (m, 6H), 6.23 (d, J = 8.6
1
Data for 26 (70%, two steps): [α]24 −22.0 (c 0.75, CHCl3); H
D
Hz, 0.5H), 6.02 (d, J = 8.2 Hz, 0.5H), 5.50 (s, 0.5H), 5.38 (s, 0.5H),
5.18 (m, 0.5H), 5.05 (s, 0.5H), 4.85 (m, 1H), 4.63−4.45 (m, 2H), 2.99
(m, 1H), 1.73 (m, 0.5H), 1.63−1.48 (m, 3H), 1.46 (m, 9.5H), 1.40
(m, 6H), 1.34−1.18 (m, 4H), 1.12 (m, 5H), 0.94 (m, 6H), 0.85 (m,
3H); 13C NMR (101 MHz, CDCl3) δ 172.2, 172.0, 169.8, 169.6,
154.3, 152.6, 151.0, 144.5, 142.7, 128.91, 128.88, 128.7, 128.6, 128.4,
127.3, 127.0, 125.2, 124.9, 106.7, 106.2, 82.2, 81.9, 80.9, 80.3, 67.0,
66.5, 65.2, 64.1, 51.3, 51.2, 44.0, 43.7, 42.9, 42.7, 32.3, 32.2, 28.4, 28.3,
28.2, 28.1, 28.04, 28.00, 26.6, 26.3, 25.0, 24.7, 23.1, 22.8, 22.6, 22.5,
22.3, 22.2, 14.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C32H52ClN2O5 579.35593, found 579.35374; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C32H51ClN2O5Na 601.33787, found 601.33532.
(R)-tert-Butyl 4-Methyl-2-[(2S,3R,5R)-4-methylene-3-pentyl-
5-phenylpyrrolidine-2-carboxamido]pentanoate (23). Prepared
from 22 following the same deprotection/cyclization procedure
NMR (400 MHz, CDCl3) δ 7.80 (bs, 1H), 5.31 (m, 1H), 4.59 (bs,
1H), 4.42 (dd, J = 14.9, 7.5 Hz, 1H), 4.08 (d, J = 6.6 Hz, 1H), 3.87 (d,
J = 14.5 Hz, 1H), 3.65 (d, J = 14.4 Hz, 1H), 2.92 (m, 1H), 1.72−1.59
(m, 1H), 1.55 (m, 5H), 1.42 (m, 9H), 1.02 (d, J = 7.1 Hz, 3H), 0.91
(m, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4, 169.4, 139.9, 116.7,
82.5, 64.0, 51.5, 47.2, 41.0, 40.0, 28.0, 25.9, 22.9, 21.7, 14.7, 14.5;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H33N2O3 325.24857,
found 325.25005.
(S)-2-{(2R,3S,Z)-1-[(S)-2-Benzamido-6-guanidinohexanoyl]-4-
ethylidene-3-methylpyrrolidine-2-carboxamido}-4-methyl-
pentanoic Acid (27). To a solution of 26 (70.0 mg, 0.215 mmol)
and Fmoc-Har(Boc)2-OH (158 mg, 0.259 mmol) in 3 mL of THF at 0
°C were added DEPBT (96.5 mg, 0.322 mmol) and NEt3 (60.0 μL,
0.431 mol). The mixture was stirred at 0 °C for 6 h, the reaction
quenched with saturated aq NH4Cl, and the THF removed under
reduced pressure. The crude residue was taken up in EtOAc and
washed with 1 M HCl and saturated aq NaHCO3. The organic layer
was dried over Na2SO4 and concentrated under reduced pressure.
Purification by flash chromatography over slica gel (30% EtOAc/
described for the 14 → 16 reaction (59%): [α]26 −7.4 (c 1.42,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 9.0 Hz, 1H), 7.33
(m, 2H), 7.26 (m, 3H), 4.98 (d, J = 1.3 Hz, 1H), 4.82 (s, 1H), 4.56
(m, 2H), 4.21 (d, J = 6.8 Hz, 1H), 2.95 (m, 1H), 1.70 (m, 1H), 1.65−
1.50 (m, 2H), 1.43 (m, 12H), 1.37−1.20 (m, 5H), 0.93 (m, 6H), 0.87
(t, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.5, 172.1,
154.8, 144.5, 128.9, 127.7, 127.6, 109.4, 81.9, 64.7, 64.5, 50.8, 47.7,
42.0, 32.0, 29.0, 28.1, 27.1, 25.1, 23.1, 22.7, 22.0, 14.3; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C27H43N2O3 443.32682, found
443.32647.
hexanes) gave the desired tripeptide as a sticky white foam (148 mg,
1
75%): [α]24 +2.8 (c 0.92, CHCl3); H NMR (400 MHz, CDCl3) δ
D
11.49 (d, J = 5.9 Hz, 1H), 8.30 (m, 1H), 7.75 (d, J = 7.5 Hz, 2H), 7.59
(dd, J = 7.0, 4.5 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.4 Hz,
2H), 6.35 − 6.27 (m, 1H), 5.67 (d, J = 7.6 Hz, 1H), 5.39−5.26 (m,
1H), 4.62−4.32 (m, 5H), 4.31−4.02 (m, 3H), 3.45−3.33 (m, 2H),
3.03−2.83 (m, 1H), 1.89−1.75 (m, 1H), 1.75−1.54 (m, 5H), 1.52−
1.37 (m, 33H), 1.18−1.06 (m, 3H), 0.96−0.83 (m, 6H). 13C NMR
(101 MHz, CDCl3, mixture of rotomers) δ 171.8, 170.9, 168.7, 163.7,
156.3, 156.2, 153.4, 144.0, 143.9, 141.4, 138.3, 127.8, 127.22, 127.18,
125.3, 120.1, 116.6, 83.2, 81.8, 79.4, 79.2, 67.3, 64.1, 52.4, 51.4, 49.1,
47.3, 41.8, 40.7, 38.8, 32.5, 29.0, 28.44, 28.42, 28.2, 28.09, 28.05, 25.2,
24.9, 22.7, 22.3, 14.7, 12.2, 11.9; HRMS (ESI-TOF) m/z [M + H]+
calcd for C50H73N6O10 917.53882, found 917.53804.
(S)-tert-Butyl 2-{(2R,3S,Z)-2-(tert-Butoxycarbonylamino)-4-
[(tert-butyldiphenylsilyloxy)methyl]-3-methylhex-4-enamido)-
4-methylpentanoate (25). A solution of 24 (260 mg, 0.508 mmol)
in 3.5 mL of MeCN was treated with HBTU (250 mg, 0.661 mmol),
HOBt (13.7 mg, 0.102 mmol), NEt3 (354 μL, 2.54 mmol), and
H-Leu-OtBu-HCl (136 mg, 0.609 mmol). After being stirred at rt for
20 h, the mixture was concentrated under reduced pressure. The
residue was diluted with EtOAc and washed with 1 M aq HCl followed
8973
dx.doi.org/10.1021/jo201727g|J. Org. Chem. 2011, 76, 8962−8976