total synthesis of antascomincin bccc.chem.pitt.edu/wipf/current literature/ruth_3.pdf · 2005. 5....
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04/30/05Ruth Nunes @ Wipf Group 1
Total Synthesis of Antascomincin BDominic E. A. Brittain, Dr., Charlotte M. Griffiths-Jones, Dr.,
Michael R. Linder, Dr., Martin D. Smith, Dr., Catherine McCusker,Dr., Jaqueline S. Barlow, Dr., Ryo Akiyama, Dr., Kosuke Yasuda,
Dr., Steven V. Ley, Professor Dr. *Angewandte Chemie International Edition
Volume 44, Issue 18, Pages 2732-2737Published Online: 1 Apr 2005
HO
HO
HO
O
N
O
OO
O
HO
O
26
30
61
11
16
1
N
Fmoc
61CO2H
fragment IO
O
MOMO
O
26
30
MeO
MeO
fragment II
TBSO OPMB
OTBS OTBS10 24
fragment III
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04/30/05Ruth Nunes @ Wipf Group 2
Antascomincin A - E and the FKBP12
• Isolated from a strain of Micromonospora (China), 1996;J. Antibiot. 1996, 49, 230.
• Immunophilin FKBP12, main target of rapamycin andFK506, used as binding to evaluate more than 12000 strainsof Actinomycetes;
• FKBP’s known as peptydil prolyl cis-trans isomerases;• Ligand-FKBP12 complex determines the
immunosuppressant effect;Science, 1990, 250, 556.JACS, 1991, 113, 8045.
• The new family presented same degree of bindingto the FKBP12 as rapamycin and FK506, but noimmunosuppressive property;
• Antascomincins antagonize bothimmunosuppressants;
• FKBP12 found in high quantities in the brain;Nature,1992, 358, 584.
R2O
HO
R1
On(H2C)
N
O
OO
O
HO
O
R3
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Immunosuppressive mechanismrapamycin, FK506, ascomycin andmeridamycin.
Calcineriunand RAFT
FKBP
12
Drug Calcineriun
and RAFTFKBP
12
FKBP
12
Drug
Drug
The Immunosuppressive Drug Action:
The Non-Immunosuppressive Ligand:
FKBP
12
FKBP ligands
FKBP
12 FKBP ligands
• Ligand-FKBP neurotropic non-immunosuppressant complexes: clinical use.• Independent mechanisms.• Attention returned to the strong FKBP’s ligands with no immunosuppression activity.
Ruth Nunes @ Wipf Group 3 5/2/2005
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First Synthesis of an Antascomincin Member
HO
HO
HO
O
N
O
OO
O
HO
O
26
30
61
11
16
1
N
Fmoc
61CO2H
fragment IO
O
MOMO
O
26
30
MeO
MeO
fragment II
TBSO OPMB
OTBS OTBS10 24
fragment III
Ruth Nunes @ Wipf Group 4 5/2/2005
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Fragment II
O
O
MOMO
O
26
30
MeO
MeO
fragment II
O
O
MOMO
BnO
MeO
MeO
OBn2
O
O
O
MeO
MeOOTBS
H3
BnO
BnO
SnBu3
4
HO
H
HO
H
CO2MeCO2Me
5
OO
OMe
CO2MeCO2Me
OMe
6
MeCOCOMe, CSA
CH(OMe)3, MeOH,68%
OO
OMe
OMe
7
OH
OTBSa. LAH, THF, 99%
b. NaH, TBSCl, 87%
OO
OMe
OMe
O
OTBS(COCl)2, DMSO,
DCM, TEA3
J. Chem. Soc. Perkin Trans. 1, 1999, 1627, 1631Chem Rev. 2001, 101, 53.
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O
O
MOMO
O
26
30
MeO
MeO
fragment II
OBn
OBnBu3Sn
4
HOBn
O
8
1) a. (E)-butene, KOtBu,
n-BuLi, THF -78°C; b. (+)-(Ipc)2BOMe, Et2O, BF3.OEt, -78°C;2) BnBr, NaH, DMF, 62%
OBn
OBn
9
a. O3, DCM, -78°C
then PPh3;b. NaBH4, MeOH, 90%
OBn
OBn
10
HO
OBn
OBn
11
I
I2, im., PPh3,
DCM, 90%
allylpyridylsulfide, tBuLi
THF, -78°C, 95%
OBn
OBn
12SPy
Bu3SnLi, CuBr, THF
-78°C, 98%
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O
O
O
MeO
MeOOTBS
H3
BnO
BnO
SnBu3
4
+
ZnI2, DCM, -78°C to rt, 85%O
O
HO
BnO
MeO
MeO
OBn
OTBS
13
O
O
MOMO
BnO
MeO
MeO
OBn
OH
a. MOMCl, DIPEA
DCM;b. TBAF, THF, 89%
O
O
MOMO
BnO
MeO
MeO
OBn
14
2
1) (COCl)2, DMSO, TEA, DCM;2) MePPh3Br, BuLi THF, -78°C to rt 87%
1) Grubbs 2nd gener.
toluene, reflux, 75%;
2) H2, Pd/C, EtOH, 96%
O
O
MOMO
HO
MeO
MeO
OH
syn/anti 6:1 at C29-C30
30 29
NaH, THF, 88% O
O
MOMO
O
26
30
MeO
MeO
fragment II
2-(2,4,6-triisopropylbenzenesulfonyl)imidazole
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Fragment III
TBSO OPMB
TBSO OTBS10 24
fragment III
TBSO
TBSO O10
16
OPMB
2417
16
17
asymmetric Aldol
8 steps
10 steps
hydrozirconation
1) [Zr(Cp)2(H)(Cl)] DCM, -78°C to 0°C2) 16, AgClO4, DCM 96%
TBSO OPMB
TBSO OH
28
1) separation;
2) TBSCl, im., 93%
separated diastereomersof fragment III
Ruth Nunes @ Wipf Group 8 5/2/2005
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Fragment III + Fragment II
TBSO OPMB
TBSO OTBS
fragment III
1) DDQ, DCM, H2O;
2) PhSSPh, PBu3, py, 95%3) PhSeSePh, H2O2, Et2O 88%
TBSO SO2Ph
TBSO OTBS
O
O
MOMO
O
MeO
MeO
1) BuLi, HMPA, THF, -78°C, then fragment II at -20°C, 70%2) lithium 4,4-di-t-butylbiphenol 78%
fragment II
O
O
MOMO
HO
MeO
MeO
24
25
OTBSTBSO
TBSO
24
25
29
30
Ruth Nunes @ Wipf Group 9 5/2/2005
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24
25
30
O
MOMO
O
MeO
MeO
OH
OTBSTBSO
TBSO
31
O
MOMO
O
MeO
MeO
O
OTBSTBSO
HO
N
FmocO
32
O
MOMO
O
MeO
MeO
O
OTBSTBSO
HO
N
HO
O
33
O
MOMO
O
MeO
MeO
O
OTBSTBSO
HO
NO
O
O
OH
O
34
O
MOMO
O
MeO
MeO
O
OTBS
NO
O
OO
OTBSO
1) EDCI, frg I, 95%
2) CSA, MeOH, 62%
1) a. TPAP, NMO
b. NaClO2, NaH2PO4 2-methlbut-2-ene, 75%2) piperidine, DMF;
benzo[1,4]dioxin-2-one DMAP, 87%
EDCI, DCM, 71%
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04/30/05Ruth Nunes @ Wipf Group 11
34
O
MOMO
O
MeO
MeO
O
OTBS
NO
O
OO
OTBSO
LHMDS, THF, 68%
35
O
MOMO
O
MeO
MeO
O
OTBS
NO
O
OO
OTBS
36
O
MOMO
O
MeO
MeO
O
OTBS
NO
O
OO
OTBS
OH
HO
HO
HO
O
O
NO
O
OO
HO
Antascomicin B
Dess-Martin, H2O, DCMpy, 80%
1) HF.py, py, THF, 4 days;
2) Dess-Martin, DCM, py;3) TFA, H2O, 10 min 13%
Ruth Nunes @ Wipf Group 11 5/2/2005
04/30/05Ruth Nunes @ Wipf Group 12
Conclusion• First total synthesis of antascomicin family member;• Butanediacetal as protecting stereodirecting group;• Transannular Dieckmann condensation - oxidation;• Related approach used by Ohtsuka in 1983, in 1999 for a taxane skeleton;• Vicinal tricarbonyls;• 52 total steps from commercially available materials;• Longest linear sequence of 23 steps;
Ruth Nunes @ Wipf Group 12 5/2/2005