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

Tetralones as precursors to Hybocarpone andAnalogs

PEDA Approach to Tetralones

Oxidative Dimerization of Ketone Enolate 15

Ireland Claisen Rearrangement Approach -A Simple ModelSystem

Biomimetic Approach

Possible diastereomers formed upon hydration/cyclizationevent

Synthesis of Napthazarins 3,4

Naphthazarins (Cont’d)41,42

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

Completion of synthesis

Synthesis of Hybocarpone Analogs

Two isomeric compoundsfor 46 were isolated in 1:1ratio. The other isomerdoesn’t interconvert in acidicconditions. More proneto decomposition

Substrate Scope For Intermolecular PEDA

Asymmetric Induction in PEDA

Intramolecular PEDA Approach to Hamigerans

Substrate scope of IMPEDA

Proposed Model to account for Stereoselectivity in (Z)-Olefin

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

Retrosynthesis of Hamigerans

Synthesis of 80 via Jacobsen’s Hydrolytic kinetic resolution

Tokunga, M.; Larrow, J.F.; Kakiuchi, F.; Jacobsen, E.N.Science 1997, 277, 936-938

Photocyclization of 71

5-epi Hamigeran A&B

Photoisomerization of Tricyle 88

Strain Energies of Hamigerans

Photocyclization of 72

Advanced intermediate 109

Unexpected Endo Attack Upon Hydrogenation

Hydrogenation Studies

6-epi-Hamigerans

Hydroboration to set C-6 in 121

Construction of Hamigerans A and B

Ring Contraction of Tricycle 96

Mechanism for Ring Contraction

Synthesis of Hamigeran E

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