Convergent Total Synthesis of (+)-Ophiobolin Accc.chem.pitt.edu/wipf/Current...
Transcript of Convergent Total Synthesis of (+)-Ophiobolin Accc.chem.pitt.edu/wipf/Current...
Eric E. Buck Current Literature October 8, 2011
Convergent Total Synthesis of (+)-Ophiobolin A Tsuna, K.; Noguchi, N.; Nakada, M. Angew. Chem. Int. Ed. 2011, 50, ASAP
OHC
O H
HOH
HO
(+)-ophiobolin A
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Background and Bioactivity of (+)-Ophiobolin A!
Shen, X.; Krasnoff, S. B.; Lu, S.; Dunbar, C. D.; O’Neal, J.; Turgeon, B. G.; Yoder, O. C.; Gibson, D. M.; Hamann, M. T. J. Nat. Prod. 1999, 62, 895-897 Leung, P. C.; Taylor, W. A.; Wang, J. H.; Tipton, C. L. J. Bio. Chem. 1984, 259, 2742-2747 Au, T. K.; Chick, W. S. H.; Leung, P. C. Life Sci. 2000, 67, 733-742 Fujiwara, H.; Matsunaga, K.; Kumagai, H.; Ishizuka, M.; Ohizumo, Y. Pharm. Pharmacol. Commun. 2000, 6, 427-431
• Isolated from the culture broth of the pathogenic plant fungus Ophiobolus miyabeanus (among others) in 1958. The picture right is the effect of this fungus on rice plants.
• The absolute structure was elucidated through X-ray analysis of a derivative.
• Induces apoptotic cell death in the L1210 cell line.
• Inhibits calmodulin-activated cyclic nucleotide phosphodiesterase through interaction with the ε-amino lysine group of calmodulin and the aldehyde function of ophiobolin A.
• Shows potent (IC50 62.5 to 125 nM) cytotoxicity against several cancer cell lines.
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Biosynthesis of (+)-Ophiobolin A and Related Family Members!
Canonica, L.; Fiecchi, A.; M. Galli Kienle; Ranzi, B. M.; Scala, A.; Salvatori, T.; Pella, E. Tetrahedron Lett. 1967, 35, 3371-3376
OHC
O H
HOH
HO
(+)-ophiobolin A
H
HCO2HH
albolic acid
H
HH
H
OH
(+)-ceroplastol I
HOAc
CH2OMe
fusicoccin A
HO O
OH
OHO
AcOOH
O
OPP
geranylfarnesyl pyrophosphate
H
HO HO
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Recent Efforts Towards the 5,8,5 Ring System!
Ruprah, P. K.; Cros, J-P.; Pease, J. E.; Whittingham, W. G.; Williams*, M. J. Eur. J. Org. Chem. 2002, 3145-3152
OGrubbs I, 103 oC
toluene
O
97:3 (Pdt:SM), 49%
McGee, Jr., K. F; Al-Tel, T. H.; Sieburth*, S. M. Synthesis 2001, 8, 1185-1191
NO
N
O
OTBS
O
OTBS
NH
HNO
O
hv
OO
84%
toluene, 0 oCHN
O
HN
OOTBS
0 oC
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Recent Efforts Towards the 5,8,5 Ring System!
Br
HOTMS
HO
EE
Bu3Sn
Pd(PPh3)4, PhH, 85 oC
HOHO TMS
EE
TMS
EE
O
H
OH
20%
Salem, B.; Suffert*, J. Angew. Chem. Int. Ed. 2004, 43, 2826-2830 Bour, C.; Blond, G.; Salem, B.; Suffert*, J. Tetrahedron. 2006, 62, 10567-10581
O
tBuS
TMSO
1) TMSOTf, CH2Cl2, -78 oC2) A, Pd(OAc)2, dppb, THF
+
OBoc
A
O
HO StBu
2) Grubb's II
1) MeOK
O
HCO2Me
86% yield over 2 steps
Michalak, K.; Michalak, M.; Wicha, J. Molecules. 2005, 10, 1084-1100
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Total Synthesis of Albolic Acid!
Kato, N.; Kataoka, H.; Ohbuchi, S.; Tanaka, S.; Takeshita, H. J. Chem. Soc., Chem. Commun. 1988, 354-356 Kato, N.; Takeshita, H. J. Chem. Soc. Perkin. Trans. I. 1989, 165-174
H
HCO2HH
Albolic acid
H
H OHHHO OH
H
H OHHO O
H
BnO OH
OTMSO
H
OTMS
McMurray coupling
OBnH
Hboat TS
Cope
H
OBnH
H
OH
CH2ClOBnH
OH
+
CrCl2-mediated condensation
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Total Synthesis of (+)-Ceroplastol I!
Paquette, L. A.; Wang, T-Z.; Vo, N. J. Am. Chem. Soc. 1993, 115, 1676-1683
H
HH
H
OH
(+)-ceroplastol I
O
OO
O
OO
HO
OO
OH
[3,3]sigmatropic
rearrangement
OO
HO
Cl
OO
H
H
H
OH
H
H O
Wittig olefinationalkylation
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Total Synthesis of (±)-Ceroplastol I!
Boeckman, Jr., R. K.; Arvanitis, A.; Voss, M. E. J. Am. Chem. Soc. 1989, 111, 2737-2739
H
HH
H
OH
(±)-ceroplastol I
CO2Me
H
H
H
H
H
H O
CO2Me
H
HOMs
CO2Me
O
H
MsO H
MeO2C
O
Dieckmann condensation
HMOMO
O CO2Me
OEE OO
O O
OOH
H
GrobFragmentation
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Total synthesis of (+)-Ophiobolin C!
H
HOHC H
H (+)-Ophiobolin C
O
HO
O
THPOH
OPivH+
TMS
Li
OTBS
TBDPSO
TMS H
TBDPSO
OTBSOH
OPiv
OTHP
I H
TBDPSO
O
OPiv
O
H
HOPivH
H
TBDPSO
HO
O
NHK coupling
Rowley, M.; Tsukamoto, M.; Kishi, Y. J. Am. Chem. Soc. 1989, 111, 2735-2737
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Title Paper: Retrosynthesis!
Noguchi, N.; Nakada, M. Org. Lett. 2006, 8, 2039-2042 Tsuna, K.; Noguchi, N.; Nakada, M. Angew. Chem. Int. Ed. 2011, ASAP
OHC
O H
HOH
HO
(+)-ophiobolin A
BnOH
HOH
HOTBSO
HO
RCM
Couplingstereo selective hydrogenation
OHC
HO
PivO
OTBDPS + TBDPSO
O
Br
TBSO
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Title Paper: The Prelude!
MeO2C CO2Me
Ph 1) PLE, KPB8, 30 oC, 9 h
2) PLE, KPB8, 30 oC, 7 d MeO2C CO2H
Ph
100%, 89% ee to 88%, 96% ee
step-wise oxidation state changes and FG protection
6 steps, 80% yield OMOMOAc
OH 1) protection2) Hydrolysis3) Swern [O]
6 steps, 81% yield
4) HWE5) Reduction6) MsCl, LiCl
OMOM
OEE
Cl1) Me3SiSiMe3, MeLi
HMPA / Et2O
2) PPTs
3) PPh3, I2, imidazole
OMOM
I
TMS
3 steps, 81% yield
Noguchi, N.; Nakada, M. Org. Lett. 2006, 8, 2039-2042
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Title Paper: The Prelude!
Noguchi, N.; Nakada, M. Org. Lett. 2006, 8, 2039-2042
N O
O
i-Pr
O
1) NCS, NaI, NaHCO3
EtOAc / H2O OOOTBDPS
2) CF3CO2Na; Et2NH
3)TBDPSCl A, 3 steps, 56% yield
OMOM
I
TMSt-BuLi, Et2O, -78 oC, 15 min;
A, 1.5 h O OTBDPS
TMS
MOMO
HO
84 %
HO OTBDPS
MOMO
BF3•OEt2 (3.0 equiv)
CH2Cl2, -78 oC, 4 h
2006: 45%
2011: 68%
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Title Paper: Coupling the Two Pieces!
HO OTBDPS
MOMO
1) Hydroboration2) PivCl
3) BF3•OEt24) DMP [O] OHC
HO OTBDPS
PivO
Ph3SnH, Et3B, benzene, rt
TBDPSO
O
Br
TBSO
TBSO
TBDPSOH
HOTBDPSO
OH OH
PivO
wrong epimer Non-required functionality
4 steps, 86% yield
90% (83% from other Br-isomer)Tsuna, K.; Noguchi, N.; Nakada, M. Angew. Chem. Int. Ed. 2011, ASAP
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Title Paper: Middle Game and Oxidation State Changes!
Tsuna, K.; Noguchi, N.; Nakada, M. Angew. Chem. Int. Ed. 2011, ASAP
TBSO
TBDPSO H
HO
OH OH
PivO1) Burgess reagent
2) H2, Raney Ni, MeOH / THF
TBSO
TBDPSO H
HO
O
PivO
H
1) MeLi2) Swern [O]3) Wittig4) PPTs
5) IBX [O]6) MeLi7) DMP [O]8) TMSCl
TBDPSO H
HOTBDPSO
OTMSH
O
TBDPSOH
HOTBDPSO
OTMSH
1) Comin's reagent, KHMDS2) Pd(PPh3)4. Et3N, CO (1 atm)
3) DIBAL-H
OH
2 steps, 75% yield
8 steps, 75% yield
3 steps, 47% yield
OTBDPSOTBDPS
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Title Paper: Formation of B Ring and End Game!
Tsuna, K.; Noguchi, N.; Nakada, M. Angew. Chem. Int. Ed. 2011, ASAP
TBDPSO H
HOTBDPSO
OTMSH
OH 1) PivCl2) TBAF
3) TBSCl4) BnBr5) DIBAL-H
BnO H
HOTBSO
OHH
OH
(Note: RCM did not work on this substrate)
1) Hoveyda-Grubbs II
BQ, toluene, 110 oCBnO H
HOH
HO
OBnOH
1) Swern [O]2) Wittig
3) Li, Naphthalene4) Swern [O]
OHC
O H
HOH
HO
(+)-ophiobolin A
5 steps, 76% yield
2) BnBr3) PPTS
3 steps, 68% yield
4 steps, 49% yield
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Summary!
• The Nakada group finished the synthesis of (+)-Ophiobolin A in 57 steps (0.77 % overall yield) utilizing a key Reformatsky type reaction to couple the two 5-membered rings together and a RCM reaction to form the central B-ring.
• Other methods to construct the 5,8,5 core of this family of compounds included various RCM strategies, [4+4] photocycloaddition of pyridones, and a 4-exo-dig cyclocarbopalladation/ 8π electrocyclization strategy.
• The Takeshita group assembled albolic acid utilizing a key Cr (II) mediated coupling, cope rearrangement, and a McMurray coupling was used to for the B-ring.
• Boeckman Jr’s group assembled the core of (+)-ceroplastol I with a key [3,3]-sigmatropic rearrangement to establish the B-ring and a simple alkylation installed the A-ring.
• Through the use of a grob fragmentation to set the 8-membered B-ring and late stage Dieckmann condensationo install the C-ring, the Paquette group completed the total synthesis of (±)-seroplastol I.
• A vinyl lithium addition into a complex aldehyde brought rings A and C together in Kishi’s synthesis of (+)-ophiobolin C. An NHK coupling finished the assembly of the B-ring.
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