Two Essential Building Blocks for the Signal Metabolite Hormaomycin
dried, filtered and concentrated under reduced pressure. The resi-
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510:508 (1:3) [Mϩ Ϫ CH3O], 191 (10), 178 (100) [C14H10ϩ], 165
due was crystallized from hexane, taken up with Et2O (4 mL), and (12), 130:128 (3:10) [C5H3ClNOϩ], 45 (36) [C2H5Oϩ]. HRMS (EI):
the solution was filtered through a silica gel pad (1.5 cm) to give,
after concentration of the filtrate under reduced pressure, 31
calcd. for C27H26ClN3O7: 539.1459; correct mass. Elemental analy-
sis calcd. (%) for C27H26ClN3O7 (540.0): calcd. C 60.06, H 4.85, N
(0.26 g, 74%) as a colorless solid. Rf ϭ 0.30 (EtOAc/hexane, 1:4), 7.78; found C 60.10, H 5.00, N 7.71.
m.p. 79Ϫ81 °C, [α]2D0 ϭ Ϫ27.0 (c ϭ 0.3, CHCl3). IR (KBr): ν˜ ϭ
3420 cmϪ1, 3067, 2980, 2934, 1738, 1715, 1684, 1545, 1521, 1451,
1369, 1208, 1163. 1H NMR (250 MHz, CDCl3): δ ϭ 1.14 (ddd, J ϭ
6.8, 6.8, 5.3 Hz, 1 H, 3Ј-Ha), 1.43 [s, 9 H, C(CH3)3], 1.43Ϫ1.60 (m,
1 H, 3Ј-Hb), 1.58Ϫ1.71 (m, 1 H, 1Ј-H), 1.72Ϫ1.92 (m, 2 H, 3-H),
3.90 (ddd, J ϭ 6.9, 3.5, 3.5 Hz, 1 H, 2-H), 4.23 (t, J ϭ 6.0 Hz, 1 H,
9ЈЈЈ-H), 4.35 (ddd, J ϭ 6.8, 6.8, 6.8 Hz, 1 H, 1Ј-H), 4.55 (dd, J ϭ
10.8, 6.0 Hz, 1 H, 1ЈЈ-Ha), 4.66 (dd, J ϭ 10.8, 6.0 Hz, 1 H, 1ЈЈ-Hb),
5.13 (d, J ϭ 8 Hz, 1 H, NH), 7.26Ϫ7.48 (m, 4 H, Ar-H), 7.57 (d,
J ϭ 7.4 Hz, 2 H, Ar-H), 7.77 (d, J ϭ 7.5 Hz, 2 H, Ar-H). 13C NMR
(62.9 MHz, CDCl3): δ ϭ 17.5 (Ϫ, C-3Ј), 21.8 (ϩ, C-1Ј), 28.1 [ϩ,
C(CH3)3], 33.6 (Ϫ, C-3), 46.6 (ϩ, C-1ЈЈ), 52.6 (ϩ, C-2), 59.0 (ϩ,
C-2Ј), 66.9 (Ϫ,C-2ЈЈ), 80.2 [Cquat, C(CH3)3], 119.9, 120.0 (ϩ, Ar-
C), 124.6, 124.7 (ϩ, Ar-C), 127.1 (ϩ, Ar-C), 127.9 (ϩ, Ar-C),
Chpca-(2S)-(3-Ncp)Ala-OFm
(33):
MgBr2·Et2O
(0.239 g,
0.93 mmol) and EtSH (0.07 mL, 0.95 mmol) were added to a vigor-
ously stirred solution of the acylamino ester 32 (50 mg, 92.6 µmol)
in CH2Cl2 (15 mL), and stirring was continued for another 3 h.
The reaction mixture was then taken up with EtOAc (40 mL), and
washed with 1 NaHSO4 solution (3 ϫ 10 mL), water (3 ϫ 5 mL),
brine (2 ϫ 5 mL), dried, filtered and concentrated under reduced
pressure. The residue was purified by preparative TLC (200 ϫ
200 mm, EtOAc/hexane, 1:4, 2 runs) and gave 33 (36 mg, 78%) as
an extremely viscous oil which was unlimitedly stable upon storage
under argon at Ϫ28 °C. Rf ϭ 0.20 (EtOAc/hexane, 1:3). IR (KBr):
ν˜ ϭ 3750Ϫ1800 cmϪ1, 3067, 1740, 1542, 1451, 1426, 1368, 1198.
1H NMR (250 MHz, CDCl3): δ ϭ 0.83Ϫ0.96 [m, 1 H, 3Ј-Ha, (3-
Ncp)Ala], 1.42Ϫ1.56 [m, 1 H, 3Ј-Hb, (3-Ncp)Ala], 1.67Ϫ1.82 [m,
3 H, 1Ј-H, 3-H, (3-Ncp)Ala], 3.89 [ddd, J ϭ 7.0, 3.1, 3.1 Hz, 1 H,
2-H, (3-Ncp)Ala], 4.25 (t, J ϭ 5.1 Hz, 1 H, 9ЈЈ-H, Fm), 4.67 (dd,
J ϭ 10.7, 5.1 Hz, 1 H, 1Ј-Ha, Fm), 4.82 (dd, J ϭ 10.7, 5.1 Hz, 1 H,
1Ј-Hb, Fm), 5.96 (d, J ϭ 5.0 Hz, 1 H, 4-H, Chpca), 6.37 (d, J ϭ
7.0 Hz, 1 H, NH), 6.40 (d, J ϭ 5.0 Hz, 1 H, 3-H, Chpca), 7.26Ϫ7.37
(m, 2 H, Ar-H, Fm), 7.42 (dd, J ϭ 7.3, 7.3 Hz, 2 H, Ar-H, Fm),
7.56 (d, J ϭ 7.3 Hz, 2 H, Ar-H, Fm), 7.76 (dd, J ϭ 7.1, 5.3 Hz,
2 H, Ar-H, Fm), 13.0Ϫ13.3 (br, 1 H, OH); the signal of 1Ј-Ha of
the Fm group overlapped with the signal of 1Ј-H of the (3-Ncp)Ala
moiety. 13C NMR (62.9 MHz, CDCl3): δ ϭ 17.4 [Ϫ, C-3Ј, (3-
Ncp)Ala], 21.6 [ϩ, C-1Ј, (3-Ncp)Ala], 33.4 [Ϫ, C-3, (3-Ncp)Ala],
46.7 (ϩ, C-9ЈЈ, Fm), 51.2 [ϩ, C-2, (3-Ncp)Ala], 58.9 [ϩ, C-2Ј, (3-
Ncp)Ala], 66.9 (Ϫ, C-1Ј, Fm), 102.8 (ϩ, C-4, Chpca), 106.1 (ϩ, C-
3, Chpca), 114.4 (Cquat, C-2, Chpca), 116.0 (Cquat, C-5, Chpca),
120.0, 120.1 (ϩ, Ar-C, Fm), 124.4, 124.5 (ϩ, Ar-C, Fm), 127.2,
127.3 (ϩ, Ar-C, Fm), 128.0 (ϩ, Ar-C, Fm), 141.3, 141.4 (Cquat, Ar-
C, Fm), 142.9, 143.0 (Cquat, Ar-C, Fm), 162.2 (Cquat, C-1, Chpca),
170.9 [Cquat, C-1, (3-Ncp)Ala]. MS (EI, 70 eV), m/z (%) ϭ 497:495
(2:7) [Mϩ], 319:317 (1:4) [Mϩ Ϫ C14H10], 178 (100) [C14H10ϩ],
146:144 (3:10) [C5H2ClNO2ϩ]. HRMS (EI): calcd. for
C25H22ClN3O7: 495.1197; correct mass.
141.2, 141.3 (Cquat, Ar-C), 143.0, 143.2 (Cquat, Ar-C), 155.0 (Cquat
,
NCO2), 175.4 (Cquat, C-1). MS (EI, 70 eV), m/z (%) ϭ 452 (3) [Mϩ],
178 (100) [C14H10ϩ], 129 (2) [C5H9N2O2ϩ], 91 (3) [C7H7ϩ], 57 (16)
[C4H9ϩ], 41 (5) [C3H5ϩ]. HRMS (EI): calcd. for C25H28N2O6:
452.1947; correct mass. Elemental analysis calcd. (%) for
C25H28N2O6 (452.5): calcd. C 66.36, H 6.24, N 6.19; found C 66.11,
H 5.99, N 6.02.
Chpca(MOM)-(2S)-(3-Ncp)Ala-OFm (32): The ester 31 (0.223 g,
0.49 mmol) was deprotected by treatment with 4 HCl in EtOAc
(5 mL) for 90 min to give HCl·H-(3-Ncp)Ala-OFm (0.182 g, 95%)
as a colorless solid. EDC (93 mg, 0.49 mmol) and HOAt (64 mg,
0.47 mmol) were added to a cooled (4 °C) solution of 29 (96 mg,
0.47 mmol) in anhydrous CH2Cl2 (5 mL). After 5 min, to the solu-
tion of the amino ester were added DIEA (61 mg, 0.47 mmol) and
TMP (0.114 g, 0.94 mmol) in anhydrous CH2Cl2 (1 mL). After 3 h,
the reaction mixture was diluted with Et2O (50 mL) and subjected
to the usual aqueous workup. The organic layer was dried, filtered
and concentrated under reduced pressure. The residue was crys-
tallized from Et2O/pentane to give 32 (0.202 g, 76% on two steps)
as a colorless solid. Rf ϭ 0.20 (EtOAc/hexane, 1:3), m.p. 94Ϫ95
°C, [α]2D0 ϭ Ϫ33.3 (c ϭ 0.3, CHCl3). IR (KBr): ν˜ ϭ 3370 cmϪ1
,
3038, 2962, 2935, 2836, 1729, 1638, 1538, 1428, 1374, 1339, 1239,
1164. 1H NMR (250 MHz, CDCl3): δ ϭ 1.14 [ddd, J ϭ 6.8, 6.8,
5.5 Hz, 1 H, 3Ј-Ha, (3-Ncp)Ala], 1.47Ϫ1.60 [m, 1 H, 3Ј-Hb, (3-
Ncp)Ala], 1.69Ϫ1.90 [m, 3 H, 1Ј-H, 3-H, (3-Ncp)Ala], 3.57 (s, 3 H, Chpca-(2S)-(3-Ncp)Ala-OH (34): The ester 33 (35 mg, 70.6 µmol)
OMe), 3.89 [ddd, J ϭ 7.0, 3.3, 3.3 Hz, 1 H, 2-H, (3-Ncp)Ala], 4.25 was deprotected by treatment with 10% tris(2-aminoethyl)amine
(t, J ϭ 5.8 Hz, 1 H, 9ЈЈ-H, Fm), 4.63 (dd, J ϭ 10.6, 5.8 Hz, 1 H, (TAEA) in CH2Cl2 (1 mL) for 20 min and the mixture was then
1Ј-Ha, Fm), 4.73 (dd, J ϭ 10.6, 5.8 Hz, 1 H, 1Ј-Hb, Fm), 5.17 (d, taken up with EtOAc (30 mL). The organic layer was briefly
J ϭ 6.8 Hz, 1 H, OCH2O), 5.25 (d, J ϭ 6.8 Hz, 1 H, OCH2O), 6.04 washed with 1 NaHSO4 solution (3 ϫ 10 mL), water (3 ϫ 5 mL),
(d, J ϭ 4.7 Hz, 1 H, 4-H, Chpca), 6.68 (d, J ϭ 4.7 Hz, 1 H, 3-H,
brine (2 ϫ 5 mL), dried, filtered and concentrated to give 34 as a
Chpca), 7.17 (d, J ϭ 7.0 Hz, 1 H, NH), 7.26Ϫ7.37 (m, 2 H, Ar-H, turbid oil which completely polymerized into a colorless insoluble
Fm), 7.42 (dd, J ϭ 7.0, 7.0 Hz, 2 H, Ar-H, Fm), 7.57 (d, J ϭ 7.3 Hz, solid at 20 °C within ca. 2 h. In solution 34 was even less stable.
2 H, Ar-H, Fm), 7.77 (dd, J ϭ 7.5, 3.6 Hz, 2 H, Ar-H, Fm); the 1H NMR (250 MHz, [D6]acetone): δ ϭ 1.30 [ddd, J ϭ 7.0, 7.0,
signal of 1Ј-Hb of the Fm group overlapped with the signal of 1Ј-
7.0 Hz, 1 H, 3Ј-Ha, (3-Ncp)Ala], 1.71Ϫ1.87 [m, 1 H, 3Ј-Hb, (3-
H of the (3-Ncp)Ala moiety. 13C NMR (62.9 MHz, CDCl3): δ ϭ Ncp)Ala], 1.90Ϫ2.21 [m, 3 H, 1Ј-H, 3-H, (3-Ncp)Ala], 4.42 [ddd,
17.5 [Ϫ, C-3Ј, (3-Ncp)Ala], 21.7 [ϩ, C-1Ј, (3-Ncp)Ala], 33.3 [Ϫ, J ϭ 6.3, 3.5, 3.5 Hz, 1 H, 2-H, (3-Ncp)Ala], 4.71Ϫ4.84 [m, 1 H,
C-3, (3-Ncp)Ala], 46.6 (ϩ, C-9ЈЈ, Fm), 51.3 [ϩ, C-2, (3-Ncp)Ala], 2Ј-H, (3-Ncp)Ala], 6.03 (d, J ϭ 5.0 Hz, 1 H, 4-H, Chpca), 6.82 (d,
58.9 [ϩ, C-2Ј, (3-Ncp)Ala], 59.4 (ϩ, OMe), 66.9 (Ϫ, C-1Ј, Fm), J ϭ 5.0 Hz, 1 H, 3-H, Chpca), 7.0Ϫ8.0 (br, 2 H, OH, CO2H), 8.17
104.2 (ϩ, C-4, Chpca), 104.8 (Ϫ, OCH2O), 111.1 (ϩ, C-3, Chpca),
118.7 (Cquat, C-2, Chpca), 119.9, 120.0 (ϩ, Ar-C, Fm), 121.7 (Cquat
C-5, Chpca), 124.5, 124.6 (ϩ, Ar-C, Fm), 127.1, 127.2 (ϩ, Ar-C,
(d, J ϭ 7.5 Hz, 1 H, NH). It was impossible to obtain a 13C NMR
spectrum because 34 underwent complete decomposition during
the measurement. MS (EI, 70 eV), m/z (%) ϭ 319:317 (12:40) [Mϩ],
,
Fm), 127.9 (ϩ, Ar-C, Fm), 141.2, 141.3 (Cquat, Ar-C, Fm), 143.0, 283 (6), 144 (100), 130:128 (15:46) [C5H3ClNOϩ], 112 (6), 91:89
143.1 (Cquat, Ar-C, Fm), 158.0 (Cquat, C-1, Chpca), 171.1 [Cquat, C-
(4:12), 80 (18) [C5H6Nϩ], 64 (12), 45 (10) [CO2Hϩ]. HRMS (EI):
1, (3-Ncp)Ala]. MS (EI, 70 eV), m/z (%) ϭ 541:539 (1:2) [Mϩ], calcd. for C11H12ClN3O6: 317.0414; correct mass.
Eur. J. Org. Chem. 2004, 4492Ϫ4502
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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