total synthesis of (+)-discodermolide chem635 kelsey roberts group b february 19, 2013 patterson,...
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![Page 1: Total Synthesis of (+)-Discodermolide CHEM635 Kelsey Roberts Group B February 19, 2013 Patterson, I*; Florence, G. J.; Gerlach, K.; Scott, J. P. Agnew](https://reader036.vdocument.in/reader036/viewer/2022062422/56649f045503460f94c1861d/html5/thumbnails/1.jpg)
Total Synthesis of (+)-Discodermolide
CHEM635
Kelsey RobertsGroup B
February 19, 2013
Patterson, I*; Florence, G. J.; Gerlach, K.; Scott, J. P. Agnew. Chem. Int. Ed. 2000, 39, 377-380.
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Ian Paterson
• Born in 1954 in Dundee, Scottland• B.S. in Chemistry from U of Saint Andrews, 1976• PhD from Cambridge under Ian Flemming, 1979• NATO post-doctoral fellow with Gilbert Stork at Columbia• Lectureship at University College London• 1983-present Cambridge University Professor of Organic
Chemistry and Fellow of Jesus College• 237 Publications to date.• Research focuses on synthetic methods, synthesis and
structure determination of biologically active materials2
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History of (+) Discodermolide
• First isolated in 1990 by Gunasekera in Florida from the Caribbean sponge Discodermia dissoluta.
• 13 Stereogenic centers, tetrasubstituted δ-lactone, on di and one tri-substituted Z-alkene, a carbamate, and a terminal Z-diene
• Acts as a antimitotic agent by stabilizing microtubules and promotes polymerization of tubulin
• Inhibits growth of breast cancer cells in vitro, resistant ovarian and colon cancer cells.
• Before Ian Paterson, 2 total synthesis of (+)-Discodermolide (Schreiber et al) and 3 of (-)-Discodermolide (Kobayashi, Myles, Johns)
• Schreiber et al determined absolute stereochemistry
3
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Retrosynthesis
4
OO
OH
HO
OH O
OH H2N
O
O
OTBS
O
OH OTBSO
OTBS H2N
O
O
PMBO
OArO
TBSO O
H
OPMB
(+)-Discodermolide
+
2: C1-C6 5
+
3: C9-C16 4: C17-C24
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Synthesis of 2
5
BnO
O
BnO
TBSO OTBS
HO
TBSO OH
HO
TBSO OO
BnO
TBSO OH
O
TBSO O
MeO
TBSO OO
BnO
OH OH
BnO
TBSO OTBS
HO
TBSO OH
HO
TBSO OO
1) (cy)2BCl, Et3N, Et2O,0°C, 3h; MeCHO,
-78°C to -27°C2) LiBH4, -78°C, 3h
3) H2O2/MeOH, NaOH, 0°CTBSOTf, 2,6-lutidine
CH2Cl2, -78°C, 2h
CSA, MeOH/CH2Cl20°C, 8h
20% Pd(OH)2/C, H2, EtOH
20°C, 20h
1) DMSO, (COCl)2CH2Cl2, -78°C, 1.5 h
2) Et3N-78°C to -20°C
20 min
NaClO2, NaH2PO4,2-methyl-2-butene
tBuOH, H2O, 20°C, 2h
CH2N2, Et2O,20°C, 5 min
2
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Synthesis of 3
6
PMBO
O
PMBO
OH OCOEt
PMBO
O OH
PMBO
O O
PhSe
PMBO
OH OCOEt
OO
PMBO
MeMe
Me
1) (cy)2BCl, Et3N, Et2O,0°C, 3h
2) LiBH4, -78°C, 3h
3) H2O2/MeOH, NaOH, 0°CSmI2, EtCHO
THF, -10°C,2.5h
1)K2CO3, MeOH20°C, 3h
2) PhSeCH2CH(OEt)2toluene, cat PPTS,
reflux, 4.5h
NaIO4, NaHCO3
MeOH/H2O
20°C, 2h
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Synthesis of 3 Continued
7
OO
PMBO
MeMe
Me
O
PMBO
O
PMBO
CO2Me
OTBS
OO
PMBO
MeMe
Me
PMBO
CO2Ar
OTBS
PMBO
CO2Me
OTBS
O
PMBO
O
1)NaOMe, MeOH0°C, 1h
2) TBSOTf, CH2Cl2,2,6-lutidine, -78°C,
1.5h
1)KOH (1M), MeOH,reflux, 1h
2) 2,6-dimethylphenol,DCC, 4-DMAP,CH2Cl2,
20°C, 16h
3
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Synthesis of 4
8
O
OBzTSBO
CHO
TSBOOBz
OH O
TSBOOBz
PMBO O
TSBOOBz
PMBO O
TSBOOH
PMBO OH
TSBO
PMBO O
HSiMe3
Br
TSBO
PMBO
H
OPMBO
TSBO
PMBO
TSBOOBz
OH O
TSBO
PMBO O
H
+
1) (cy)2BCl, Et3N, Et2O,0°C, 3h
2) LiBH4, -78°C, 3h
3) H2O2/MeOH, NaOH, 0°C
PMBTCA, cat.
TfOH, THF, 20°C, 9h
LiAlH4, THF-78 to -27°C,
3h
NaIO4, MeOH,20°C, 30 min
+
1)CrCl2, THF,20°C, 16h
2) KH, THF,0°C, 1.5h
1) CSA, MeOH,20°C, 30 min
2) DMP, CH2Cl220°C, 15 min
4
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Synthesis of 5
9
PMBO
CO2Ar
OTBS
PMBO
OTBS
OPMBOH
PMBO
ArO2C
OTBS
OPMBOH
H
OPMBO
PMBO
OTBS
OPMBOH
PMBOArO2C
OTBS
OPMBOH
HO
OTBS
OHOTBS
3
LiTMP, LiBr, THF, -100°C+
1) LiAlH4, THF, -30°C, 3h2) 2,4,6-Me3(C6H2)SO2Cl,Et3N, CH2Cl2, 20°C, 24 h
3) LiAlH4, THF, -30°C, 3h
1) TBSOTf, Et3N, CH2Cl2,20°C, 24h
2) DDQ, CH2Cl2/ pH 7buffer, 20°C, 16h
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Synthesis of 5 Continued
10
HO
OTBS
OHOTBS
OTBS
OHOTBSMeO2C
OTBS
OHOTBSMeO2C
OTBS
OOTBS
O
H
H2N
O
1) cat. TEMPO, BAIB, CH2Cl220°C, 4h
2) (CF3CH2O)2P(O)CH2CO2Me,[18]c-6, K2CO3, PhMe,
-20 to 0°C, 2h
1)Cl3CC(O)NCO, CH2Cl2,20°C, 1 h
2) K3PO4, MeOH, 20°C, 1h3)DIBAL-H, CH2Cl2, -78°C, 1.5h
4) DMP, CH2Cl2, 20°C, 1H
5
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Final Steps to (+)-Discodermolide
11
O
OTBS
O
O
H OTBSO
OTBS H2N
O
O
OTBSO
OTBS H2N
O
HO
O
OTBS
MeO2C
OTBSO
OTBS H2N
O
HO
O
OTBS
OOTBSO
OTBS H2N
O
HO
HO
OTBS
MeO2C
OO
OH
HO
OH O
OH H2N
O
(+)-Discodermolide
52
+
1) (+)-Ipc2BCl, Et3N, Et2O, 1.5h
2)H2O2/MeOH pH 7 buffer, 0°C, 1h
Me4NBH(OAc)3, MeCN/AcOH-25 to 20°C, 16h
+
HF pyr, THF, 20°C, 16h
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Conclusion
• (+) Discodermolide synthesized in overall 7.7% yield
• 27 steps for longest linear sequence
12