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Organic & Biomolecular Chemistry
Page 24 of 26
DOI: 10.1039/C8OB01756E
ARTICLE
Journal Name
(1 H, m, leu 2-H), 4.86 (1 H, m, 2-H), 4.93 (1 H, dd, J 8.5, 3.7,
thiopro 2-H), 5.02 (1 H, m, ser 2-H), 5.25 (1 H, d, J 8.0, NH), 7.03
(1 H, d, J 8.2, NH), 7.25–7.32 (4 H, m, ArH, NH), 7.67–7.69 (2 H,
m, ArH) and 8.73 (1 H, d, J 7.5, NH); δC (125 MHz, CDCl3) 17.9,
18.3, 22.2, 23.2, 24.5, 24.8, 25.0, 28.4, 29.2, 32.2, 40.3, 42.0,
46.9, 48.0, 49.3, 50.1, 52.3, 55.3, 59.2, 60.3, 61.6, 68.1, 80.7,
128.1, 129.2, 129.9, 135.7, 156.6, 167.8, 169.5, 172.2, 172.5,
173.4 and 203.1; m/z (ES+) 877.5 (M+ + 23, 95%), 875.5 (M+ + 23,
50), 855.5 (M+ + 1, 100) and 853.5 (M+ + 1, 50).
DCM (160 mL), and the reaction mixture stirred at rt for 2.5 d.
Saturated aqueous NH4Cl was added and the aqueous phase
was extracted with DCM. The organic extracts were washed
with brine, dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue (1:1 DCM:EtOAc to
DCM to 94:6 DCM:MeOH) gave the title compound 108 as pale
25
yellow solid (40 mg, 23%), mp 118-122 °C, [α]D −82 (c 1.0,
CHCl3) (Found: M+
+
Na, 1203.4698. C53H84N8O13SSeSiNa
max/cm-1 3293, 2957, 2929, 2880, 1747,
requires M, 1203.4705);
ν
1634, 1510, 1436, 1258, 1225, 1188, 1096, 837 and 732; δH (500
MHz, CDCl3) 0.08 (6 H, s, 2 × SiCH3), 0.88 [9 H, s, SiC(CH3)3], 0.88
(3 H, d, J 6.5, leu 4-CH3), 0.90-1.00 [9 H, m, leu 5-H3, val 4-H3, val
3-CH3), 1.10 (3 H, d, J 6.5, threo 4-H3), 1.28 (3 H, d, J 7.0, ala 3-
H3), 1.44 (3 H, d, J 6.5, 4′-H3), 1.30-1.60 (3 H, m, leu 3-H2, leu 4-
H), 1.85-2.01 (6 H, m, pro 4-H2, thiopro 4-H2, pro 3-H, thiopro 3-
H), 2.10 (3 H, s, CH3CO), 2.20-2.45 (3 H, m, pro 3-H′, thiopro 3-
H′, val 3-H), 2.68 (3 H, s, NCH3), 3.45-3.55 (2 H, m, pro 5-H,
thiopro 5-H), 3.71 (1 H, m, thiopro 5-H′), 3.78 (1 H, m, 3′-H), 3.88
(1 H, m, pro 5-H′), 4.07 (1 H, dd, J 9.0, 3.5, ser 3-H), 4.15 (1 H, m,
threo 3-H), 4.22 (1 H, d, J 13.5, 3-H), 4.30-4.35 (3 H, m, ser 3-H′,
ala 2-H, thiopro 2-H), 4.57 (1 H, d, J 8.0, val 2-H), 4.65-4.75 (3 H,
m, leu 2-H, threo 2-H, 2′-H), 4.78 (1 H, d, J 6.0, OH), 4.82 (2 H, m,
pro 2-H, ser 2-H), 4.99 (1 H, dd, J 13.5, 7.0, 3-H’), 5.18 (1 H, d, J
7.0, 2-H), 6.26 (1 H, d, J 6.0, NH), 6.59 (1 H, d, J 4.0, NH), 7.12 (1
H, d, J 10.1, NH), 7.25-7.30 (3 H, m, ArH), 7.60-7.65 (2 H, m,
ArH), 8.16 (1 H, d, J 8.0, NH) and 8.76 (1 H, d, J 4.0, NH); δC (125
MHz, DMSO) −5.2, 15.9, 18.3, 18.6, 18.9, 19.1, 20.2, 20.8, 21.6,
23.7, 24.0, 24.2, 25.0, 25.9, 27.2, 28.3, 29.5, 33.2, 38.8, 39.4,
39.7, 47.2, 47.8, 48.0, 51.0, 51.7, 55.9, 61.4, 61.6, 63.5, 64.0,
65.0, 67.2, 68.4, 74.0, 127.8, 128.2, 129.3, 134.5, 168.1, 168.9,
Methyl
N-[(2R,3R)-2-(N-tert-butoxycarbonyl-L-alaninyl-D-
leucinyl-L-thioprolinyl-L-serinyl)amino-3-
phenylselanylbutanoyl]-L-prolinate (110).
Following the procedure outlined for the preparation of the
alcohol 109, the TBS-protected peptide 68 (60 mg, 0.06 mmol)
in dry THF (0.9 mL) and TBAF (1 M in THF, 0.12 mL, 0.12 mmol),
after chromatography (1:2 light petroleum:EtOAc to 95:5
DCM:MeOH) gave the title compound 110 as a yellow oil (48 mg,
92%), Rf = 0.40 (95:5 DCM: MeOH) (Found: M+ + Na, 877.3046.
C38H58N6O9SSeNa requires M, 877.3043); δH (400 MHz, CDCl3)
0.93–0.96 (6 H, m, leu 4-CH3, leu 5-H3), 1.14 (3 H, d, J 7.1, ala 3-
H3), 1.41 [12 H, br. s, OC(CH3)3, 4-H3], 1.53–1.65 (3 H, m, leu 3-
H2, leu 4-H), 1.89–2.02 (5 H, m, pro 3-H, pro 4-H2, thiopro 4-H2),
2.21 (1 H, m, pro 3-H′), 2.31 and 2.42 (each 1 H, m, thiopro 3-H),
3.52–3.64 (2 H, m, pro 5-H, thiopro 5-H), 3.66 (3 H, s, OCH3),
3.81–3.95 (4 H, m, pro 5-H′, thiopro 5-H′, ser 3-H2), 4.11 (1 H,
pent, J 7.1, ala 2-H), 4.18-4.24 (2 H, m, 3-H, OH), 4.50 (1 H, dd, J
8.7, 4.6, pro 2-H), 4.75 (1 H, t, J 9.5, 2-H), 4.82 (1 H, m, leu 2-H),
4.87 (1 H, m, ser 2-H), 4.96 (1 H, dd, J 8.5, 3.6, thiopro 2-H), 5.21
(1 H, d, J 7.6, NH), 7.01 (1 H, d, J 7.5, NH), 7.27–7.33 (3 H, m,
ArH), 7.53 (1 H, d, J 8.8, NH), 7.60–7.63 (2 H, m, ArH) and 8.61 (1
169.3, 170.3, 171.0, 171.2, 171.4, 173.0, 173.1 and 203.9; m/z H, d, J 7.0, NH); δC (125 MHz, CDCl3) 18.1, 19.0, 22.1, 23.3, 24.5,
(ES+) 1205.8 (M+ + 23, 100%), 1203.8 (M+ + 23, 95), 1181.9 (M+ +
24.7, 25.0, 29.3, 32.3, 40.8(2), 47.5, 48.1, 49.3, 50.1, 52.2, 55.1,
1, 50) and 1179.8 (M+ + 1, 25).
59.1, 60.5, 61.5, 68.1, 80.6, 127.1, 128.3, 129.3, 135.7, 156.5,
168.4, 168.8, 172.3, 172.5, 173.4 and 202.7; m/z (ES+) 877.4 (M+
+ 23, 100%) and 875.4 (M+ + 23, 50).
Methyl
N-[(2R,3S)-2-(N-tert-butoxycarbonyl-L-alaninyl-D-
leucinyl-L-thioprolinyl-L-serinyl)amino-3-
Methyl
N-[2-(N-tert-butoxycarbonyl-L-alaninyl-D-leucinyl-L-
phenylselanylbutanoyl]-L-prolinate (109).
thioprolinyl-O-tert-butyldimethylsilyl-L-serinyl)amino-but-3-
Tetra-n-butylammonium fluoride (1 M in THF, 0.12 mL, 0.12
mmol) was added at 0 C to the TBS-protected peptide 80 (60
o
enoyl]-L-prolinate (111).
mg, 0.06 mmol) in dry THF (0.9 mL) and the solution was stirred tert-Butyl hydroperoxide in decane (5.5 M, 0.09 mL) was added
at 0 °C for 5 min then at rt for 2 h. Ethyl acetate (1 mL),
saturated aqueous NH4Cl (1 mL) and brine (1 mL) were added
and the aqueous phase was extracted with EtOAc (10 × 1 mL).
The organic extracts were dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue (1:2
light petroleum:EtOAc to 95:5 DCM:MeOH) gave the title
compound 109 as a yellow oil (48 mg, 92%), Rf = 0.43 (95:5
DCM:MeOH) (Found: M+ + Na, 877.3047. C38H58N6O9SSeNa
requires M, 877.3043); δH (500 MHz, CDCl3) 0.93 (6 H, d, J 5.8,
leu 4-CH3, leu 5-H3), 1.10 (3 H, d, J 7.1, ala 3-H3), 1.41 [9 H, s,
OC(CH3)3], 1.49 (3 H, d, J 7.1, 4-H3 ), 1.59–1.60 (3 H, m, leu 3-H2,
leu 4-H), 1.88–2.01 (5 H, m, pro 3-H, pro 4-H2, thiopro 4-H2),
2.17 (1 H, m, pro 3-H′), 2.28 and 2.40 (each 1 H, m, thiopro 3-H),
3.35 (1 H, m, pro 5-H), 3.53–3.63 (3 H, m, 3-H, pro 5-H′, thiopro
5-H), 3.68 (3 H, s, OCH3), 3.82 (1 H, m, ser 3-H), 3.91 (1 H, m,
thiopro 5-H′), 4.04 (1 H, pent, J 7.3, ala 2-H), 4.16 (1 H, m, ser 3-
H′), 4.37 (1 H, br. s, OH), 4.50 (1 H, dd, J 8.4, 3.9, pro 2-H), 4.80
to the peptide 68 (50 mg, 0.05 mmol) in DCM (0.5 mL) at 0 °C
and the mixture stirred at 0 oC for 5 min and at rt for 3 h.
Saturated aqueous Na2S2O3 (2 mL) was added and the mixture
stirred for 30 min then extracted with EtOAc (3 × 5 mL). The
organic extracts were dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue (1:1 light
petroleum:EtOAc to 1:1 EtOAc:CH3CN) gave the title compound
111 as a colourless oil (16 mg, 39%), some hindered rotation
was apparent (1H NMR), Rf = 0.48 (1:1 EtOAc:CH3CN) (Found: M+
+ Na, 833.4260. C38H66N6O9SSiNa requires M, 833.4273); δH (500
MHz, CDCl3) 0.07 and 0.09 (each 3 H, s, SiCH3), 0.86–0.95 [15 H,
m, SiC(CH3)3, leu 4-CH3, leu 5-H3], 1.30 (3 H, d, J 6.9, ala 3-H3),
1.44 [9 H, s, OC(CH3)3], 1.55–1.63 (3 H, m, leu 4-H, leu 3-H2),
1.91–2.00 (5 H, m, pro 4-H2, thiopro 4-H2, pro 3-H), 2.19-2.32 (3
H, m, pro 3-H′, thiopro 3-H2), 2.61–2.62 (3 H, m, pro 5-H2,
thiopro 5-H), 3.71 (3 H, s, OCH3), 3.85-3.90 (2 H, m, thiopro 5-H′,
ser 3-H), 4.18 (1 H, m, ser 3-H′), 4.28 (1 H, m, ala 2-H), 4.54 (1 H,
24 | J. Name., 2012, 00, 1-3
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