1 H
H
OH OMe OH
O
OH OMe
O
H OMe
O
2
Total Synthesis of the Antibiotic Branimycin
S. Marchart, A. Gromow, J. Mulzer, Angew. Chem. Int. Ed. 2009, 49, 2050-2053.
(A. Gromov, V. Enev, J. Mulzer, Org. Lett. 2009, 11, 2884-2886.) Building Block 1a
(W. Felzmann, D. Castagnolo, D. Rosenbeiger, J. Mulzer, J. Org. Chem. 2007, 72, 2182-2186.) Buildingblock 1b
2
6 eq. 3
1 eq.
EtAlCl
2DCM, 0 °C, 4 h O O H
CO
2Me 4
52% from NMR 5
14% from NMR
O O
H
CO
2Me 0 °C 23 h 49 °C - name:
- why does 5 isomerize to 4 after 27 h?
1)
2)
3)
HPT = 1-hydroxypyridine-2(1 H )-thione N
OH S
O O
H
O O
N S
4)
- name:
4 6
8
O O
H
H
7
O O H
H 7
O H
H rac-12
OPMB OMe
H
H 15
OPMB OMe PhMe2SiCH2MgCl
CuCl (10 mol%) Ph3P (10 mol%) toluene, rt, 48 h 75% (82% brsm)
(+)-9, 50% (-)-9, 50% rac-10
PMBCl, NaBr DMF, rt, 2 h;
then rac-9, NaH THF, 0 °C to rt, 8 h 85% (96% brsm)
KH, tBuOOH TBAF, NMP THF, rt, 3 h, 82%
name:
hint: "silicon seminar"
14, er = 93:7, 45%
Ni(COD)2 (20 mol%) (R)-BINAP (30 mol%) DIBAL, toluene, rt, 6h 13, er = 94:6, 46%
- 13 and 14 are regioisomers,
separation possible, omly 14 is reacted further - 14 sensitive to air even at -20 °C - Why?
1)
O
1) DDQ, pH-7-buffer DCM, 0 °C, 30 min ultrasound
2) TBSOTf, 2,6-di-tert-butylpyridine THF, -78 °C, 1h
89% over 2 steps
16 2) DBU, DCM,
reflux, 45 min, 82%
(for isomerization)
("H ")
16
mCPBA, DCM, 0 °C, 2 h
Building Block 1a - which side rxt can occur?
84% brsm, dr = 10:1
1) MeI, Ag2O, DCM reflux, 24 h, 60%
2) Me3S I , nBuLi
toluene, reflux, 30 min, 76%
18 19
1)
2)
MeO H
O
OTIPS
TMS H3C
H CH3 20 TiCl4, DCM, -78 °C, 2h, then -78 °C to -20 °C, 77%
21 OMe
CH3
TIPS
HO CH3
17
MeO OH
22 1) MOMCl, Hünig base DCM, rt, 12 h, 95%
2) CpZrCl2, DIBAL THF, rt, 12 h, then I2, 0 °C, 5 min, 83%
Building Block 1b
Building Block 1b
tBuLi, THF, -78 °C, 2.5 h, then building block 1a, -78 °C, 5 min, then -78 °C to rt over night, 82%
23 24
25
H H
OH OMe OTBS MOMO
OTBS OMe
O
H H
OTBS OMe OTBS MOMO
OTBS OMe
O O 1)
2)
26 H
H OTBS
OMe OTBS MOMO
OTBS OMe
O
name:
OH
1 H
H OH
OMe OH O
OH OMe
O
name:
O H MeO
DMF, mw, 220 °C, 2 min, 64%
dr = 10:1
OMe NMe2
OMe
steps
27
25 H
H OTBS
OMe OTBS MOMO
OTBS OMe
O O
28 H
H OTBS
OMe OTBS MOMO
OTBS OMe 1) O
2)
3)
MeO2C MeO2C
name of 1):
29 H
H OTBS
OMe OTBS HO
OTBS OMe 1) O
2)
3)
H OMe
HO
1) TEMPO, PhI(OAc)2 DCM, rt, 2 h, 92%
2) NaClO2, NaH2POH4, tBuOH, H2O, 15 °C, 30 min, 90%
30 - 2) epimers are fomed
- after 3) separation of epimers possible
name of 2):
1)
2) 1
H H
OH OMe OH O
OH OMe
O
H OMe O
name of 1):
step2:
hint: Macrolactonization under Yamaguchi conditions preceeded with loss of 2-CH2OMe
neutral condions needed
2
