Photoenolization Diels-Alder Reactions Application to the ... · Examples of PEDA and Applications...
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Photoenolization Diels-Alder ReactionsPhotoenolization Diels-Alder ReactionsApplication to the Total Synthesis of Application to the Total Synthesis of HybocarponeHybocarpone
and and HamigeransHamigerans
Group Meeting01/08/04
VijayReferences
Hybocarpone⇒ Nicolaou,K.C.; Gray, D. L.F.J.Am,Chem,Soc.2004,126 ASAP
Nicolaou,K.C.; Gray, D. L.F.Angew.Chem.Int.Ed.2001,40,761Hamigerans ⇒ Nicolaou,K.C.; Gray, D. L.F.; Tae, Jinsung.
J.Am,Chem,Soc.2004,126 ASAP
Photoenolization Diels-Alder Reaction: Introduction
Yang, N.; Rivas, C. J.Am.Chem.Soc.1961,83, 2213
Benzophenone to Benzopinacol
Dienol(α-Hydroxy o-Quninodimethane) Formation via Intramolecular hydrogen transfer
Other methods for Dienol Formation
CHO
CH3
hνOH
OH
SO2
OH
1 2
3
4
hν
CO2R
CO2R
+
CO2R
RO2COH
CO2R
CO2RYields NR
CO2R
CO2R+
OHCO2R
CO2R
OHCO2R
CO2R+
1 2
5A
5B
5A
6
2
7 8
3TsOH CO2R
CO2R
CO2R
CO2R+
70 : 30
91 % Yield
R =O
H CO2MeCH3
Charlton, J.; Koh, K.; Plourde, G. Tet.Lett.1989, 30, 3279
Mechanism
Sammes,P. Tetrahedron 1976, 32, 405Charlton, J.; Alauddin, M. Tetrahedron 1987, 43, 2873
H
O
H
Hhν
H
H
HO
H
H
HO
H
H
OH
Diels-Alder TrapEWG
EWG
OH
H H H
OH
endo adduct shown
Examples of PEDA and ApplicationsPhotochemical Synthesis of Estrone
Quinkert, G.; Stark, H.Angew Chem.Int.Ed.1983, 22,637-655
OMe
MeO
O
O
CHO hν1.
2. 170 oC O
O
H
H
HOH
OMe
MeOAgO
HNO3
THF OO
H HH
HOHHO
O50 %
Pleurotin Analog
Kraus,G.A.; Chen,Li. Synth.Commun.23, 2041, 1993
O
H3CO
O
H
Z / exo /
β
favored
O CH3
O
OH
HH
E / endo / disfavored
E / exo /
β α
OCH3
OH
O
H
Z / endo / α
(or)
Pleurotin
H3CO
O
O
H
hν
λ 340 nmH3CO
O
H
O
H
H
OH+
O
H
H
OH
Me-Cyclohexane95 oC
2,6-dimethyl phenolPyridine
2,6- Dimethyl phenol prevents light induced decomposition of dienolPyridine increases the life time of (Z)-Dienol
trans-anti-trans cis-anti-trans
Major Minor
OH
Hybocarpone
Isolated from lichen species Lecanora Hybocarpa in Lousiana woodlandCytotoxic against murine mastocytoma P815 transplantable tumor cell line IC50 of 150 ng/mLPossible DNA intercalation/DNA damage pathway as viable mode of actionNovel molecular architecture containing dinaphtho furantetraone skeleton possessing element of C2 symmetryClosely structurally related to the naphthazarins
Synthesis of Protected hybocarpone 21
Low yields for dimerization 36 % combined yield of 25&21 afterthree iterations using recovered starting material.Longer reaction times and other reactionvariables did not affect conversion and chemical yields
Synthesis of Hybocarpone Analogs
Two isomeric compoundsfor 46 were isolated in 1:1ratio. The other isomerdoesn’t interconvert in acidicconditions. More proneto decomposition
Hamigerans
Isolated from Hamigera Tarangaensis in NewzealandCytotoxic against P-388 leukemia cells[4-bromo-hamigeran B, IC50 = 13.5µMStrong antiviral activity against herpes andpolio viruses Substituted benzenoid nucleus fused to [4.3.0] or [5.3.0] bicyclic system
Synthesis of 80 via Jacobsen’s Hydrolytic kinetic resolution
Tokunga, M.; Larrow, J.F.; Kakiuchi, F.; Jacobsen, E.N.Science 1997, 277, 936-938
Conclusions Inter and Intramolecular PEDA reactions have been developed as versatile
synthetic methodologies for construction of polycyclic natural products such asHybocarpone and Hamigerans.
Norrish Type I fragmentation pathway led to isomerization of 88 and ringcontraction leading to [3.3.0] bicyclic system 123
Barium hydroxide mediated cascade pathway was developed to facilitateinterconversion to other members of Hamigerans
Our Approach Alternative approach
OMe
Cr(CO)5
X
OMe
O
X X
OOMe
Me
OR Cr(CO)5
OMe
OR Cr(CO)5OMe
Cr(CO)5
OMe
ORa) Nucleophile
O
OMe
OR
oxidationMe
b)
Hamigeran Analogs
HH