total synthesis of (+)-discodermolide chem635 kelsey roberts group b february 19, 2013 patterson,...
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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.
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
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
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
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
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
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
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
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
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
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
Conclusion
• (+) Discodermolide synthesized in overall 7.7% yield
• 27 steps for longest linear sequence
12
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