Lecture 27

Special Topics - Drug Discovery:Synthetic Research: Natural Product Isolation Molecular ModificationAnesthetics

This Week in Lab:Spec Unknown (Ch 12) Final Report

Next Week in Lab:Synthetic #2 Final Report; Lab Clean-up & Check-out!Bring in your graded PreLabs!

Synthesis Research

Nakadomarin A

Why an attractive target?

• Unusual ring system• Anticancer, antibacterial and antifungal properties

N

N

O

H

H

Nakadomarin A

Isolated in 1997 by Kobayashi and co-workers from an Okinawan marine sponge:N

N

O

H

H1. Extracted sponge (1 kg) with methanol

2. Extracted methanol layer with ethyl acetate

3. Purified 51.1 g by column chromatography 3X:(a) chloroform/methanol mobile phase(b) cyclohexane/acetone/diethyl amine mobile phase(c) chloroform/methanol mobile phase

Only 6.0 mg of Nakadomarin A was isolated! Other relatedcompounds were also isolated from this procedure.

Nakadomarin A

Structure Determination:N

N

O

H

H 1. Molecular formula was established as C26H36N2O bymass spectrometry

2. 1H and 13C NMR data

3. Advanced two-dimensional NMR studies to confirm structure and determine stereochemistry of stereocenters

Nakadomarin AOnly 6.0 mg of Nakadomarin A was isolated from 1 kg of sponge!Therefore, synthesis is needed to produce mass quantities.

N

N

O

H

H

1

Retrosynthetic Analysis:

NP

N

O

SO2Ar

P'H

3

NP

N P'

SnBu3

O

4

N

HN

O

2

NH

O

N P'

O2N

+

5 6

SiMe3

Taxol®

Treatment of:• Lung, ovarian, and breast cancers• Prevention of restenosis

Marketed by Bristol-Myers Squibb in 19932000 annual sales - $1.6 billion

O

NHPh

Ph

OH

O

OOH

AcOO OH

H

OCOPh

OAc

O

Taxol®

• Discovered in 1967• Isolated from the bark of the Pacific yew tree• Need six 100-year old trees to treat one patient! Thus, aneed for synthesis!

• Can be made from 10-deacetylbaccatin (an extract fromvarious yew-related species) in several steps (semisynthesis)OR• Can be made from plant cell fermentation technology: (1) propagation ofa specific taxus cell line (2) taxol is isolated via extraction, purified bychromatography and crystallization

O

NHPh

Ph

OH

O

OOH

AcOO OH

H

OCOPh

OAc

O

A Taxol Derivative1H NMR Spectrum:

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are needed to see this picture.

Molecular Modification

1. A compound is isolated from nature2. Its basic structure serves as a prototype (a.k.a. a lead compound) in search for other biologically active compounds3. Analogs of the lead compound are synthesized and tested for biological activity

Process:

Classic example: cocaine

Cocaine

• Isolated from the leaves of Erythroxylon coca (South American Andes)• Effective local anesthetic• Produces disturbing effects on the central nervous system (CNS); initial euphoria to severe depression• Goal: identify the portion of cocaine that serves as the local anesthetic; make an anesthetic with no CNS effects

ester

methyl ester

7-memberedring

NH3C CO2CH3

O

O

Amine (tertiary)

Molecular Modification of Cocaine

NH3C CO2CH3

O

O

Identify the beneficial portion:Degrade the cocaine moleculestep by step by:1. Removing the CO2CH3 group2. Cleaving the 7-membered ring

Result:An improved lead compound:1. Aromatic ester2. Terminal tertiary amine

O

O

NH3C

CH3

Molecular Modification of Cocaine

Hundreds of esters synthesized:• Putting groups on aromatic ring• Changing the alkyl groups bonded to nitrogen• Changing the length of the alkyl chain

O

O

NH3C

CH3

New lead compound

Successful Anesthetics

O

O

N

NH2

H3CH2C

CH2CH3

Procaine(Novocain)

• Contains an ester that is easily hydrolyzed, thus a short lifetime.• First synthesized in 1905• Used primarily in dentistry• Primary ingredient in the preparation of Gerovital H3 (remedy aging effects), but this claim was studied and discredited in the 1960’s

Successful Anesthetics

H3C

H3C

HNC

O

NH3CH2C

H3CH2C

Lidocaine(Xylocaine)

• Contains amide that is not so easily hydrolyzed - faster acting and longer lasting than Novocain• Popular local anesthetic used in dentistry or topically• Developed in 1943