Enantioselective Synthesis of 9’-Desmethylgarugamblin I

Andrew WillefordDr. Christopher M. BeaudryDepartment of Chemistry

HHMI 2009

Natural Products

Opium Poppy

Morphine Penicillin

Penicillum Fungi Chromodoris macfarlandi

Macfarlandin E

Diaryl Ether Heptanoids

• Exhibit useful biological activities1) Anti-inflammatory2) Anticancer3) Antibacterial

• General structure1) Seven carbon chain tethered together by a diaryl ether linkage2) Cyclophanes

Optical Activity

• 17 diaryl ether heptanoids do not possess stereocenters1) Six of these 17 compounds are chiral by virtue of their

tethered-ring structure and have been isolated as optically active compounds.

• Planar chirality 1) Mobius Strip

This work is licensed under a Creative Commons Attribution-Share Alike 3.0 Unported License.

Question

• These compounds are almost identical to each other1) Minimal difference in substituents2) Why such a difference in optical rotation?

Isolation

• All 17 compounds were isolated from plant sources1) 9’-desmethylgarugamblin I is a bark extract of Garuga

pinnataa) A frankencense b) Found in Asiac) Used in folk medicine

• Typical isolation 1) Includes extraction in a Soxhlet apparatus at high temperatures

Hypothesis

• Isolation of these compounds have led to racemization1) Enantioselective synthesis of 9’-desmethylgarugamblin I

would allow verification of our hypothesis2) Will offer proof of concept to enantioselectively

synthesize the compounds with non-reported optical rotations

O

OMeO

H

OMe

O

MeO

O

OMeH

> 60 °C

Enantioselectivity

• Selective synthesis of one enantiomer• Pathway

1) Cu catalyst on non-racemic, chiral ligands promotes the enantioselective synthesis of 9’-desmethylgarugamblin I

Chiral Catalysts

• A catalyst with enantiomeric forms1) Holds substrate in specific conformation2) Lowers energy barrier for formation of one enantiomer

• Examples1) Walphos2) Naud3) Josiphos4) Enzymes

Mechanistic Considerations

NCu

NX

ROH

base

base-H+

NCu

NOR

R' X

NCu

N

OR

R'

X

RO R'

NCu

NHOR

X

Cu(III) Intermediate

N CuN

MeMe

H

H

O

OOH

MeO

Cu(III) Intermediate

Progress

O

OH OTBS

O

A

TBSCl, THF,

O

OTBS

THF, r.t.Imidazole r.t.Ph3P

COMe

O

OH

O

OMeBr

1. Br2, MeOH

OMeBr

O O

BrOMe

O

B

1. DIBAL, CH2Cl2H2O, 20°C 2. DMSO, (COCl)2,

Et3N, CH2Cl22. MeI, K2CO3

Ph3PCO2Me

O

TBSOA 1. LDA, THF

1. Dess-Martin2. H2, Pd/CHO

2. B 3. TBAF, THF, r.t.

OMeBr

O

TBSO

OMeBr

HO

O

MeO

OH

BrHO

OO

MeO

OH

Chiral Cu cat.NaOH, THF

9'-desmethylgarugamblin I

Future Research

• Enantioselective synthesis of other aryl ethers

O

OH

O

O

O

Me

ClCl

OMe

Cl

Cl

HOOH

Cl

Cl

HOO

HO

O

OMe

OH

O OCl

Cl OH

Cl

Cl

HO

Cl

Cl

MeOrussuphelol []

OMe

OP

O OCl

Cl OP

Cl

Cl

PO

Cl

Cl

MeO

OH

Br

+ Chiral cat.NaOH, THF

O

HO

HO

cavicularin []PO

POOH

Br

Chiral cat.NaOH, THF

Acknowledgements

• Howard Hughes Medical Institute

• Undergraduate Research, Innovation, Scholarship, & Creativity (URISC) Program

• Dr. Christopher M. Beaudry

• Dr. Kevin Ahern