5364
B.J. van Lierop et al. / Tetrahedron 66 (2010) 5357e5366
solution, dried (MgSO4), filtered and concentrated under reduced
pressure to afford the acid fluoride 7d as an orange oil (0.25 g,100%).
nmax (KBr): 3419br s, 3334br s, 3066m, 3039m, 2951m, 2875m,
1852s, 1715s, 1515s, 1451s, 1405w, 1362w, 1337m, 1290m, 1250m,
1104m, 1080m, 1062m, 1040m, 939w, 916w, 759m, 740s, 689m,
896w, 858w, 820w, 759m, 738s, 700m, 665m, 621m cmꢁ1. 1H NMR
(400 MHz, MeOD): 1.57 (s, 3H, ]CCH3), 1.62 (s, 3H, ]CCH3), 2.45
d
(m, 1H, CHaHbCH]), 2.55 (m, 1H, CHaHbCH]), 3.72 (br s, 2H,
CHCHaHbO), 4.17 (t, J 6.4 Hz,1H, H90), 4.33 (d, J 6.4 Hz, 2H, CH2OCO),
4.39e4.49 (m, 2H, CHCH2O, CHCOOH), 4.51 (s, 2H, CH2Ph), 5.09 (t, J
5.4 Hz, 1H, CH]), 7.19e7.32 (m, 7H, H20, 70, 200, 300, 400, 500, 600), 7.35 (t,
J 7.5 Hz, H30, 60), 7.58e7.67 (m, 2H, H10, 80), 7.75 (d, J 7.5 Hz, 2H, H40,
666m, 621m cmꢁ1 1H NMR (200 MHz, CDCl3):
. d 3.73 (dd, J 9.2,
1.9 Hz, 1H, CHCHaHbO), 3.90 (dd, J 9.2, 1.8 Hz, 1H, CHCHaHbO), 4.24
(t, J 6.8, 1H, H90), 4.33e4.55 (m, 2H, CH2OCO), 4.57 (br s, 2H, CH2Ph),
4.72 (m, 1H, CHCOF), 5.69 (br d, J 8.5 Hz, 1H, NH), 7.20e7.50 (m, 9H,
H20, 30, 60, 70, 200, 300, 400, 500, 600), 7.61 (d, J 7.0 Hz, 2H, H10, 80), 7.70 (d, J
50) (NH and OH not observed). 13C NMR (50 MHz, MeOD):
d 18.0 (]
CCH3), 26.2 (]CCH3), 31.3 (CHCH2CH]), 48.3 (C90), 53.9
(CHCH2OCH2), 56.3 (CHCOOH), 68.2 (CH2OCO), 72.4 (CHCH2O), 74.2
(CH2Ph), 119.4 (CH]), 120.9 (C20, 70), 126.2 (C30, 60), 128.2 (C10, 80),
128.6 (200, 600), 128.7 (C400), 128.8 (C40, 50), 129.3 (C300, 500), 136.5 (]C),
139.2 (C100), 142.5 (C80a, 90a), 145.1, 145.2 (C40a, 40b), 158.3 (OCONH),
172.1 (CONH), 174.5 (COOH). HRMS (ESIþ, CH2Cl2eMeOH): m/z
calcd for C32H35N2O6 (MþH)þ 543.2495, found 543.2485.
The CM reaction was also conducted with 5 mol % second gen-
eration Grubbs’ catalyst. A 60% conversion to the required pre-
nylglycine derivative 9d was obtained.
7.3 Hz, 2H, H40, 50). 13C NMR (200 MHz, CDCl3):
d
47.2 (C90), 53.8 (d,
2JCF 61.5 Hz, CHCH2O), 67.6 (CH2OCO), 68.7 (CHCH2O), 73.8 (CH2Ph),
120.2 (C20, 70), 125.2 (C30, 60), 127.3 (C10, 80), 127.9 (C40, 50, 200, 600),
128.4 (C400), 128.8 (C300, 500), 136.8 (C100), 141.5 (C80a, 90a), 143.7, 143.8
(C40a, 40b), 156.0 (OCONH), 161.0 (d, 1JCF 370.2 Hz, COF). Mass spec-
trum (ESIþ, MeOH): The acid fluoride 7d readily converted to the
corresponding methyl ester during analysis: m/z calcd for
C26H25NNaO5 (MþNa)þ 454.2, found 454.2.
3.7.2. Fmoc-
L
-Ser(OBn)-
L
-Agl-OH, 8d. The dipeptide 8d was pre-
3.7.4. Fmoc-
9d was subjected to a modified procedure described by Hartwig
and Schlummer.20 Trifluoromethanesulfonic acid (3.6 mg, 24
mol)
L-Ser(OBn)-L-dmP-OH, 10d. Fmoc-L-Ser(OBn)-L-Pre-OH
pared according to a procedure described by Mutter et al.12 A so-
lution of Agl 5 (60 mg, 0.52 mmol) in 10% w/v Na2CO3 (4 mL) was
m
added to a stirred solution of Fmoc-
L
-Ser(OBn)-F 7d (0.20 g,
was added to a suspension of enamine 9d (65 mg, 0.12 mmol) in
toluene (10 mL). The reaction mixture was stirred at 100 ꢀC for 1 h,
cooled to room temperature and concentrated under reduced
pressure to give a dark brown oil. The crude reaction mixture was
purified via column chromatography (SiO2, light petroleum
eEtOAceMeOHeAcOH; 1:1:0.1:0.05, Rf 0.42) to afford the desired
dmP-containing dipeptide 10d as a colourless solid (31 mg, 48%),
mp 64e66 ꢀC. nmax (KBr): 3432br s, 3065m, 2965m, 2928m, 1709s,
1638s, 1543m, 1508w, 1500m, 1477w, 1451, 1380w, 1364w, 1320w,
1224m, 1215m, 1178w, 1106m, 1079w, 1044w, 909w, 758m, 739m,
0.48 mmol) in acetone (25 mL). The resultant white suspension was
stirred at room temperature and monitored by TLC (SiO2, light
petroleumeEtOAceMeOHeAcOH; 1:1:0.1:0.05). After 14 h, the
acetone was evaporated in vacuo and water (20 mL) was added. The
resultant aqueous phase was diluted with CH2Cl2 (30 mL), cooled in
an ice bath and carefully acidified to pH 2 with 1 M HCl. The phases
were separated and the aqueous layer further extracted with
CH2Cl2 (2ꢂ20 mL). The combined organic extract was washed with
saturated NaCl solution (1ꢂ30 mL), dried (MgSO4), filtered and
concentrated under reduced pressure to give a yellow oil (0.25 g,
97%). The crude reaction mixture was purified via column
chromatography (SiO2, light petroleumeEtOAceMeOHeAcOH;
1:1:0.1:0.05, Rf 0.48) and lyophilised to afford the desired dipeptide
8a as a colourless solid (0.21 g, 86%), mp 110e112 ꢀC. nmax (KBr):
3327br s, 3067m, 2926m, 2857m, 1719s, 1664s, 1528s, 1451m,
1409w, 1364w, 1330w, 1247m, 1105m, 924w, 759m, 740m, 698w,
698m, 666m cmꢁ1. 1H NMR (400 MHz, MeOD):
d 1.30 (s, 3H, CCH3),
1.54 (s, 3H, CCH3), 1.72 (m, 1H, CHCHaHbCH2), 1.82 (m, 1H,
CHCHaHbCH2), 1.98e2.11 (m, 2H, CH2C(CH3)2), 3.51e3.69 (m, 2H,
CHCH2O), 4.22 (t, J 7.5 Hz, 1H, H90), 4.27e3.39 (m, 2H, CH2O), 4.46
(m, 1H, CHCOOH), 4.51 (m, 1H, CHCH2O), 4.60 (s, 2H, CH2Ph), 7.21
(m, 7H, H20, 70, 200, 300, 400, 500, 600), 7.38 (t, J 7.5 Hz, H30, 60), 7.58e7.71
(m, 2H, H10, 80), 7.78 (d, J 7.5 Hz, 2H, H40, 50) (NH and OH not ob-
666m cmꢁ1
.
1H NMR (300 MHz, MeOD):
d
2.47 (m, 1H,
served). 13C NMR (75 MHz, MeOD):
d 25.0 (CCH3), 27.0 (CCH3), 28.4
CHaHbCH]), 2.62 (m, 1H, CHaHbCH]), 3.73 (d, J 4.9 Hz, 2H,
CH2OCO), 4.22 (t, J 6.8, 1H, H90), 4.37 (d, J 6.8 Hz, 2H, CH2OCO), 4.42
(m, 1H, CHCHaHbO), 4.49 (m, 1H, CHCOOH), 4.53 (s, 2H, CH2Ph),
5.02 (d, J 10.5 Hz, 1H, ]CHaHb), 5.09 (d, J 17.1 Hz, 1H, ]CHaHb),
5.75 (m, 1H, CH]), 7.21e7.34 (m, 7H, H20, 70, 200, 300, 400, 500, 600), 7.38
(tt, J 7.5, 0.6 Hz, H30, 60), 7.58e7.67 (m, 2H, H10, 80), 7.78 (d, J 7.5 Hz,
2H, H40, 50) (NH and OH not observed). 13C NMR (75 MHz, MeOD):
(CH2C(CH3)2), 40.7 (CH2CHCOOH), 48.3 (C90), 54.0 (CHCH2O), 56.3
(CHCOOH), 65.3 (C(CH2)3), 68.2 (CH2OCO), 72.4 (CHCH2O), 74.1
(CH2Ph), 120.9 (C20, 70), 126.3 (C30, 60), 128.2 (C10, 80), 128.7 (200, 600),
128.8 (C400), 129.3 (C40, 50), 129.4 (C300, 500), 139.3 (C100), 142.6 (C80a,
90a), 145.2, 145.4 (C40a, 40b), 158.4 (OCONH), 171.1 (CONH) (COOH
not observed). HRMS (ESIþ, CH2Cl2eMeOH): m/z calcd for
22
C32H35N2O6 (MþH)þ 543.2495, found 543.2490. [
a]
ꢁ8.2 (c 0.6,
D
d
37.0 (CH2CH]), 48.4 (C90), 53.5 (CHCH2O), 56.3 (CHCOOH), 68.2
MeOH).
(CH2OCO), 71.0 (CHCH2O), 74.2 (CH2Ph), 118.9 (]CH2), 120.9 (C20,
70), 126.2 (C30, 60), 128.1 (C10, 80), 128.7 (200, 600), 128.8 (C40, 50), 128.9
(C400), 129.4 (C300, 500), 134.1 (CH]), 139.2 (C100), 142.6 (C80a, 90a),
145.2, 145.3 (C40a, 40b),158.4 (OCONH), 172.2 (CONH),174.2 (COOH).
HRMS (ESIþ, CH2Cl2eMeOH): m/z calcd for C30H31N2O6 (MþH)þ
515.2182, found 515.2171.
3.8. (4S,9aS)-Hexahydro-4-((9H-fluoren-9-
ylmethoxycarbonyl)amino)-7,7-dimethyl-1H,5H-pyrrolo[2,1-
c][1,4]oxazepine-1,5-dione, 11
3.8.1. Fmoc-
-Ser(tBu)-F, 7e. The acid fluoride 7e was prepared
L
according to a modified procedure described by Carpino et al.19
3.7.3. Fmoc-
9d was subjected to the general CM procedure outlined previously:
Fmoc- -Ser(OBn)- -Agl-OH 9d (0.20 mg, 0.39 mmol), CH2Cl2
(5 mL), second generation HoveydaeGrubbs0 catalyst (12 mg,
19 mol), 2-methyl-2-butene (1 mL), , 40 h, 95%. The crude re-
action mixture was purified via column chromatography (SiO2,
light petroleumeEtOAceMeOHeAcOH; 1:1:0.1:0.05, Rf 0.46) to
afford the desired dipeptide 9d as a pale brown solid (0.15 g, 72%),
mp 55e57 ꢀC. nmax (KBr): 3410br s, 3344br s, 3065m, 2972m,
2931m, 2873m, 2617w, 1952w, 1715s, 1668s, 1519s, 1452s, 1415w,
1378w, 1361w, 1324w, 1266s, 1105s, 1044m, 968w, 951w, 910w,
L-Ser(OBn)-L-Pre-OH, 9d. Fmoc-L-Ser(OBn)-L-Agl-OH
Cyanuric fluoride (0.14 g, 1.04 mmol) and pyridine (0.04 g,
0.52 mmol) were added to a stirred solution of Fmoc-L
-Ser(tBu)-OH
L
L
6e (0.20 g, 0.52 mmol) in dry CH2Cl2 (15 mL). The pale yellow
solution was stirred at room temperature for 15 h, resulting in the
formation of a white precipitate. This suspension was dissolved by
addition of water (15 mL) and the phases were separated. The
aqueous layer was further extracted with CH2Cl2 (2ꢂ10 mL) and the
combined organic extract then washed with a saturated NaCl
solution, dried (MgSO4), filtered and concentrated under reduced
pressure to afford the acid fluoride 7e as a colourless oil (0.21 g, 98%).
nmax (film): 3440m, 3318m, 3067m, 2976s, 2886m, 1854s, 1782s,
m
D