Catalytic Enantioselective Alkylative Dearomatization-Annulation: Total Synthesis and Absolute Configuration Assignment of Hyperibone K Ji Qi, Aaron B. Beeler, Qiang Zhang, and John A. Porco, Jr.* Total Synthesis of Plukenetione A Qiang Zhang, Branko Mitasev, Ji Qi, and John, A. Porco, Jr.* Ph O O O O H O O O H Hyperibone K 10.1021/ja1057828 Plukenetione A 10.1021/ja105784s Ph O Xueling Mi 09/25/2010 Wipf Group Current Literature
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Catalytic Enantioselective Alkylative Dearomatization-Annulation: Total Synthesis and Absolute Configuration Assignment of Hyperibone K
Ji Qi, Aaron B. Beeler, Qiang Zhang, and John A. Porco, Jr.*
Total Synthesis of Plukenetione A Qiang Zhang, Branko Mitasev, Ji Qi, and John, A. Porco, Jr.*
Ciochina, R.; Grossman, R. B. Chem. Rev. 2006, 106, 3963.
• isolated from Hypericum perforatum (St. John’s wort) • highly oxygenated and densely substituted bicyclic or tricyclic trione core • over 100 biologically active PPAPs isolated • biosynthetically derived from MPAPs • biological activity: antifungal, anti-HIV, antifeedant, antioxidant, antiderpressant • 3 classes of PPAPs type A: C(1) acyl group and C(8) quaternary center type B: C(3) acyl group and C(8) quaternary center type C: C(1) acyl group and C(6) quaternary center
Plukenetione A
• isolated by Jacobs in 1996 from Clusia plukenetii (Lesser Antilles/Barbados) • the structrue was elucidated by NMR spectroscopic methods • the first natural product bearing an adamantane framework isolated from plant source • biologically derived from oxidation of 7-epi-nemorosone • antitumoral effect: inhibit the enzymatic activities of both topoisomerase I and DNA polymerase (LNCap ETO: IC50 = 1.72 µM; LNCap WT: IC50 = 1.98 µM; Jurkat WT: IC50 = 5.28 µM; M51 WT: IC50 = 6.53 µM; M51 DDP: IC50 = 7.60 µM)
Isolation and Biological Activity of PPAP Plukenetione A and Hyperibone K
Hyperibone K
• isolated by Takaishi in 2004 from Hypericum scabrum (Uzbekistan) • its structure was elucidated by NMR spectroscopy • the only example of a type B PPAP bearing an adamantane core • moderately inhibit breast and lung tumor cell replication (IC50 = 10.0 and 13.7 µM) • no anti-HIV activity
Tanaka, N., Takaishi, Y., Shikishima, Y., Nakanishi, Y., Bastow, K., Lee, K. –H., Honda, G., Ito, M., Takeda, Y., Kodzhimatov, O. K., Ashurmetov, O. J. Nat. Prod. 2004, 67, 1870.
Henry, G. E., Jacobs, H., Carrington, C. M. S. McLean, S., Reynolds W. F. Tetrahedron Lett. 1996, 37, 8663; Diaz-Carballo, D., Malak, S., Bardenheuer, W., Freistuehler, M., Reusch, H. P. Bioorg. Med. Chem. 2008, 16, 9635.
Biosynthesis of Type A and Tpye B PPAP
R SCoA
OHO
O
SCoA
O3!
(malonyl-CoA) O
O O
R
SCoAO
Dieckmanncondensation
OH
HO OH
R
O
prenylpyrophosphate
O
R
O
OHHO
O
R
O
OHHO
HO O
R
OO
HO O
OO
RO
C(1) attack C(5) attack
type A PPAPexo 7-prenyl
1
5
type B PPAPedo 7-prenyl
O
O O
H
Hyperibone K
Ph
O[O][O]
Ph
O
O
O O
H
Plukenetione A
Synthesis of Representative PPAPs
Construction of the Adamantane Core of Plukenetione-Type PPAP
Takagi, R., Miwa, Y., Matsumura, S., Ohkata, K. J. Org. Chem. 2005, 70, 8587. Takagi, R., Inoue, Y., Ohkata, K. J. Org. Chem. 2008, 73, 9320.
CO2EtOAc +
O
OEt
LDA
THF, -78 oC92%
O
OEt
EtO2C K2CO3 (3 eq.)
TBAB (1 eq.)Tol., 110 oC, 3 h
55%
EtO2C
OEtO
THF, 0 oC100%
LiBH4
EtO2C
OEtHO H
single diastereomer
MeLi, CeCl3
THF, -78 oC74%
OEtHO H
HO
Pd(OH)2/CtBuOOH, O2
Cs2CO3
CH2Cl2, 0 oC58%
OEtHO H
HO
O
CrO3•3,5-DMP
CH2Cl2, 0 oC
OEt
HO
O
O
TMSCl, Im
DMF, r.t.85% over 2 steps
OEt
TMSO
O
O
LTMP, BzCl
THF, -78 oC88%
OEt
HO
O
O
O
Ph
O
HO
O
Ph
O
O
HEtO
O
Ph
O
H
HO
TfOH, CH2Cl2
reflux, 5.5 h59%
plukenetione adamantane core
CO2ROAc
O
rt, 1 d, reflux, 1 d63%
O
EtO2C
CO2Et
O
+Et3N
OCO2R
O
OCO2EtRO2C
O
ORO2C
O
CO2EtCO2R
ORO2C
O
RO2CCO2Et
+
O
CO2R
O
RO2C CO2Et
Total Synthesis of (±)-Clusianone via Alkylative Dearomatization-Annulation
OH
HO OH
Ph
O
clusiaphenone B
Br
aq. KOH, 0 oC40%
OH
HO OH
Ph
O CHOAcO1)
KHMDS, THF, 65 oC
2) TMSCHN2, DIPEA CH3CN/CH3OH
54%
O
O OMe
Ph
O
OHC
1) MgBrTHF, -78 oC
2) Ac2O, DIPEA DMAP, DCM 0 oC to rt, 74%
O
O OMe
Ph
O
AcO
1) Pd(PPh3)4, HCO2NH4 Toluene, 105 oC, 90%
2) Grubbs 2nd Gen. cat. 2-methyl-2-butene, 89%
O
O OMe
Ph
OLiOH, dioxane
, 77%
or LiOH, DMSO , 69%
O
O OH
Ph
O
O
O OH
Ph
O
OHC
OAc
1) Michael Addition
2) Elimination
O
OH
Ph
O
intramolecular
Michael additionO
OHC
O
O OH
Ph
O
OHC
• Proposed Mechanism of Alkylative Dearomatization-Annulation
Qi, J., Porco, J. A. J. Am. Chem. Soc. 20057 129, 12682.
Synthesis of Type B Adamantane Core
O
O O
H
Ph
OO
O OHPh
OOH O
O O
OHH
Ph
OOH
HO OH
Ph
O
clusiaphenone B
OH
HO OH
Ph
OCHO
AcO
1.5 eq.
KHMDS (3 eq.), THF0 oC, 4 h
O
O OPh
O
H CHO
O
O O
OHH
Ph
O
65%
KHMDS (1 eq.)THF, 65 oC
retro-aldol
O
O OPh
O
H CHO
baseO
O OPh
O
OHC H
H3O+
OH
O O
Ph
O
OHC
O
OH
Ph
O
O
OHC
Retrosynthetic Analysis for Hyperibone K
Dearomatization-alkylation using Cinchona alkaloid-derived catalysts
OH
HO OH
Ph
O
O
O O
OHH
Ph
OO
O
CHOn
chiral PTC, 4A MSCsOH•H2O (5 eq.)
CH2Cl2, -50 oC9: n = 0 10: n = 5
27R
Mechanism and Mode of Action for the Phase-Transfer Catalyst
OH
O O
Ph
O OH
O O
Ph
O OH
HO
Ph
O
O
OH
HO
Ph
O
O
A B C D
Binding element: hydrophobic interaction of prenyl group in a hydrophobic cleft of the catalyst formed by the vinyl and O-benzyl groups