enantioselective total synthesis of the marine toxin ...ccc.chem.pitt.edu/wipf/current...
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Enantioselective Total Synthesis of the Marine Toxin (–)-Gymnodimine Employing a Barbier-Type Macrocyclization
Angew. Chem. Int. Ed. 2009, 48, 1–5
Current Literature Presentation12SEP2009Michael Yang
OH
Me
MeMe
N
Me
OO
Me
Michael Yang @ Wipf Group Page 1 of 17 10/3/2009
Gymnodimine Background
Isolated from dinoflagelate Karenia selliformis Sensitize neurons to the effects of Okadaic acid Binds to muscle nicotinic acetylcholine receptors Causes neurotoxic shellfish poisoning Spiroimine toxins: gymnodimine analogues B and
C, pinnatoxins, spirolides, pteriatoxins,prorocentrolide,
OH
Me
MeMe
N
Me
OO
Me
OH
MeMe
N
Me
OO
Me
R1
Gymnodimine A
Gymnodimine B: R1 = H, R2 = OHGymnodimine C: R1 = OH, R2 = H
R2
Michael Yang @ Wipf Group Page 2 of 17 10/3/2009
Formation of Spirocyclic Imines – The Diels-Alder Strategy - Kishi
McCauley, J. A.; Nagasawa, N.; Lander, P. A.; Mischke, S. G.; Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647-7648.Johannes, J. W.; Wenglowsky, S.; Kishi, Y. Org. Lett. 2005, 3997-4000.
R
N
H
Me
MeO
O
O O
OH
MeHO
MeOH
H
H
R
O
MeMe
O
O
O O
OH
MeHO
MeOH
H
H
Pinnatoxins Pteriatoxins
A: A:
B:
C: B/C:
O
OTES
Me
MeMe
O
Me
NH2
O
OH
Me
MeMe
N
Me OO
OO
Gymnodimine A
H2N
CO2HH2N
CO2H
O CO2H
SOH
CO2H
NH2
S
OH
H2N
OH
Michael Yang @ Wipf Group Page 3 of 17 10/3/2009
Synthesis of Diels Alder Precursor – Kishi
Johannes, J. W.; Wenglowsky, S.; Kishi, Y. Org. Lett. 2005, 3997-4000.
Me
HO
Me
O
Me
MeOAc
TESO
TBSO OH
p-TsOH.H2O86%
9:1
NiCl2, CrCl2, Ni(COD)2THF/DMF/t-BuPy
O
Me
Me
H
Swern oxidation80%
OTIPSMeBr
MeO
O
Me
Me
OH OTIPSMe
Me1) MnO2, 50%2) CBS reduction, 80%
O
Me
Me
OH OTIPSMe
Me
6:1 !:"
70%
1:1 !:"
O
TBSO
Me
OAcI
O
MeNMe OH
Ph
+
O
OTES
Me
MeMe
O
Me OTIPS
NHAlloc
OAcOAc
OAcOAc27% (5 steps)
Michael Yang @ Wipf Group Page 4 of 17 10/3/2009
Gymnodimine – Diels Alder Strategy – Kishi
O
OTES
Me
MeMe
O
Me OTIPS
O
OH
Me
MeMe
N
Me OH
NHAlloc
1) TBAF, AcOH, 78%2) (PPh3)4Pd, 0.1% AcOH O
OH
Me
MeMe
N
Me OH
1:1 Endo:Exo
185 °Cbenzene
60% (2:1 endo product only)
Johannes, J. W.; Wenglowsky, S.; Kishi, Y. Org. Lett. 2005, 3997-4000.
Michael Yang @ Wipf Group Page 5 of 17 10/3/2009
Murai THP and DA precursor
O
O
TBDPSO
HMe2CuLi
98%O
O
TBDPSO
HMeO
TBDPSO
HMe
OAc
1) DIBAL-H2) Ac2O, pyr
O
TBDPSO
Me
99% (3 steps)
TMS
BF3.OEt2 O
Me
Me CO2Me
O
P(OEt)2
Me
O
Me OO
O
HLiCl,DIEA90%
O
CO2MeMe
MeMe
Me OO
O
O
CO2MeMe
MeMe
Me OO
OTBDPS
1) CBS reduction, 85%2) TBDPSCl, imid., 90%
Ishihara, J.; Miyakawa, J.; Tsujimoto, T.; Murai, A. Synlett. 1997, 1417-1419.Ishihara, J.; Horie, M.; Tsujimoto, T.; Murai, A. Synlett. 2002, 399-402.
Retrosynthesis?
Michael Yang @ Wipf Group Page 6 of 17 10/3/2009
Murai
O
CO2MeMe
MeMe
Me OO
OTBDPS
CBZN
O
O
OH
CO2MeMe
MeMe
CBZN
Me OO
O(!)-siam.Cu(SbF6)2
58%
CBZN
Me OO
O
TBSO
30% (5 steps)OMe
Me CO2Me
O
P(OEt)2
Me
O
+Me O
O
TBSOCBZN
O
89%
94:6 exo:endo
Ishihara, J.; Horie, M.; Tsujimoto, T.; Murai, A. Synlett. 2002, 399-402.
Michael Yang @ Wipf Group Page 7 of 17 10/3/2009
THF fragment – Iodoetherification - White
White, J. D.; Wang, G.; Quaranta, L. Org. Lett. 2003, 4109-4112.
OO
Me Me
H
HO
OPMB
OH Me
O
1) Brown crotylation, 72%2) NaH, PMBCl, 88%3) p-TsOH, MeOH, 85%
R1O
OPMB
OR2 Me
O
I
Me
PMBO
OR1
O
I
Me
PMBO
OR1
I2, MeCN,-20 °C
+
see Table
O
Me
Me
OH
I
Michael Yang @ Wipf Group Page 8 of 17 10/3/2009
Diels Alder - White
O O
O O
N
Me Me
OPMB
MeOO
MeMe
O O
O O
Me Me
AcOH
MeOO
MeMe
O
O
O
OOPMB
MeMe
MeOO
MeMe
O
O
O
OOPMB
MeMe
1.2:1
85%
MeOO
MeMe
O
OHO
1) DDQ2) ClCO2Me, Et3N3) NaBH4, MeOH73% (3 steps)
1) Swern, 88%2) (EtO)2P(O)CH2CN, n-BuLi, 78%
MeOO
MeMe
O
O
CN
MeOO
MeMe
O
OH
CN
1) Mg, MeOH, 86%2) CH2=CHLi, 63%
MeOO
MeMe
CN
Et3SiCl, pyr, 68%
OTES
O
1) CH2=CHLi, (2-Th)Cu(CN)Li2) Me3SiCl
MeOO
MeMe
OTES
OTMS
1) LiAlH42) NaOH
29%
MeOO
MeMe
CN
N
OTES
White, J. D.; Wang, G.; Quaranta, L. Org. Lett. 2003, 4983-4986.
Michael Yang @ Wipf Group Page 9 of 17 10/3/2009
Retrosynthetic Analysis – Romo
O
OH
Me
MeMe
N
Me
OO
Me1) NHK reaction
2) Barbier Macrocyclization
3) Mukaiyama aldol
O
O
Me
Me
H
X
Me
TsN
Me
O
X O
O
Me
OTIPS
THF Fragment Spirolactam Fragment Siloxyfuran
H
O
MeOPMB
OTES
Me
MeMeOTBS
N
OPG
1013
1519
22
7 4
Michael Yang @ Wipf Group Page 10 of 17 10/3/2009
Synthesis of THF fragment – RomoO
O
Me
Me
H
Cl
Yang, J.; Cohn, S. T.; Romo, D. Org. Lett. 2000, 2, 763-766.
H OPMB
O
MeO
O
N
OMe
Ph Me
1) Bu2BOTf2)
O
O
N
O
MePh Me
OPMB
OH
Me
68%, major diastereomer
1) NaOMe, MeOH, 80%2) TESOTf, 2,6-lutidine, 90%3) DIBAL-H, 93%4) Swern, 99%
H
O
MeOPMB
OTES
Me
Ph3PCH2(OMe)Cl97%
cat. p-TsOH
86%
HMe
OPMB
OTES
Me
MeOO
Me
Me OPMB
OMe
TMS
BF3.OEt2
95%O
Me
Me OPMB
4:1 !:"
O
Me
Me Cl
1) Nao, NH3, 92%2) PPh3, CCl4, 85%3) 9-BBN; NaOH, H2O2, 98%4) Dess-Martin, 71%
H
O
Michael Yang @ Wipf Group Page 11 of 17 10/3/2009
Synthesis of the spirolactam fragment – Romo
Kong K.; Moussa, Z.; Romo, D. Org. Lett. 2005, 7, 5127-5130.
Me
TsN
Me
O
I O
Me Me SnBu3
MeMe
(Bu3Sn)2CuCNLi2
5:2 regioisomers
1) n-BuLi2) O
MeNMe
OMe
3) NaHMDS, TBSOTf MeMeOTBS
Me MeO
N N
O
CuCl2, AgSbF685%, dr >19:1, 95% ee
CbzN O
MeMeOTBS
CbzN O
45%
92%
1) [PdCl2(PPh3)2], n-Bu3SnH, 85%
2) I2, 76%Me
TsN
Me
O
I OMeMe
OTBS
TsN O 1) n-BuLi, 90%
2) KHMDS, TsCl, 80%
Michael Yang @ Wipf Group Page 12 of 17 10/3/2009
NHK reaction and Barbier Macrocyclization – Romo
Me
TsN
Me
O
I O
O
Me
Me Cl
H
O
CrCl2, NiCl2, 97%O
OH
Me
Me
1.3:1 !:"
Me
TsN
Me
O
O
Cl
t-BuLi
O
OH
Me
MeMe
O
MeO
NHTs
61%
O
Me
Me I
OTIPS
TsN
Me
O
OTBS
Me
t-BuLi
17%
O
Me
MeO
MeOTBS
NHTs
TIPSO
Me
O
OH
Me
MeMe
O
MeO
NHTs
NHKmacrocyclization
Michael Yang @ Wipf Group Page 13 of 17 10/3/2009
Vinylogous Mukaiyama Aldol – Romo
O
OH
Me
MeMe
O
MeO
NHTsO
Me
OTIPS
TiCl4
61%
1:1 d.r.
OO
Me
O
OH
Me
MeMe
O
MeOH
NHTs
Et3N, SOCl282%
OO
Me
O
OH
Me
MeMe
O
Me
NHTs
3:1 d.r.
Michael Yang @ Wipf Group Page 14 of 17 10/3/2009
Romo
OO
Me
O
OH
Me
MeMe
O
Me
NHTs
3:1 d.r.
1) (Boc)2O, Et3N, DMAP2) H2NNH2
99%
OO
Me
O
OH
Me
MeMe
O
Me
NHBoc
TFA,68%
O
OH
Me
MeMe
N
Me
OO
Me
Michael Yang @ Wipf Group Page 15 of 17 10/3/2009
Synthesis of THF Fragment via Anionic Condensation,Fragmentation and Elimination – Rainier
Rainier, J. D.; Xu, Q. Org. Lett. 1999, 27-29.
O
1) NaH, DMF;2) R3CHO3) MeI
CO2Et
EtO2C H
R3
R
R1
O
R1
R
O
CO2Et
O
R1
R
OCO2Et
R3O O
R1
R
OCO2Et
R3O
H
Michael Yang @ Wipf Group Page 16 of 17 10/3/2009
Summary
Michael Yang @ Wipf Group Page 17 of 17 10/3/2009