Synthesis of phthalideisoquinoline alkaloids and of other antagonists of γ-aminobutyric acid

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SYNTHESIS OF PHTHALIDEISOQUINOI.INE ALKALOIDS AND 0F OTHER ANTAG0NISTS 0F Y-AMINOBUTYRIC ACID.

A

^THESIS

PßESENTED FOR THE DEGREE OF

DOCTOR OF ^PHILOSOPHY

IN

THE UNIVERSITY OF ADELAIDE

BY

JAMES MORTON TIPPETT, B.Sc. ^(HONS)

DEPARTMENT OF ORGANIC CHEMISTRY (1977)

CONTENTS

SUMMARY

STATEtl|ENT

ACKNOl¡JLEDGEMENTS

CHAPTER I Synthesi s

of

Phthalideisoquinoli ^ne

A'lkal oi ^{ds .}

Introducti ^on

Resu'lts and Discussion

CHAPTER

II

^Synthesis

^of

^{Aminoaì kylphthal i des}

Introducti ^on

Results and Discussion

CHAPTER

III

^Synthesis

of

Caprolactams

Introducti ^on

Resuìts and Discussion

EXPERIMENTAL

General Topics

CHAPTER I

CHAPTER

II

CHAPTER

III

Appendix Structural Determination

of

3- ^and

7-Aryl caprol actams ^.

Page

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t

17

133 137 157

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204 54 63

92 99

I

I

I

I

REFERENCES 205

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SUMMARY

The syntheses of several classes of ^{compounds wj'Ch known cenÈral}

nervous system activity ^are described, with partícular ^{regard Èo those}

which were thought to acÈ as antagonísts of '1-aminobutyric acid'

Variousne\^ImethodsforthesynthesisofthephtlralídeÍsoguinolí.ne alkaloids are ^described i.n chapter I. ^{The most} successful route involved thecouplíngofanelecÈrophilicisoquíno1-ínemoietywiÈhthe

nucleophilic phthalide anion. ^{This procedure provides a quick and} efficÍent synthesis of ^the naturally occurring alkaloíd corcirastine ^and

also the synthesis of ^seve-ra1 other previously unreported phthalideisoquinolines' Another method which led to ^Èhe phÈhalídeisoquinoline skeleton ^involved

the electrophilic substiËution of ^the ReÍssert ^anion by Lhe 3-substituted phthalide. ^{The use} of an electrophilic ^{phthalÍde has not} previously ^been successfully ^enployed for phthalídeisoquinoline ^synËhesis.

In chapter II the synthesís of 3-arninoalkylphthalides is considered'

of ^Ëhe five potential ^synthetic approaches three !'/eÏe tesÈed in the

laboratory. ^The most succ:essful involved a reaction of the electrophilÍc phthalaldehydic acid with ^the aryl-propan-2-one and subsequent elaboratÍon

to the desired amine. ^{This method enables} the preparation of substituLed analogues, excepË Ëhose conËaining a strongly electron-donating ^group in the para positíon of ^Èhe non-phthalidyl ^aromatic ring'

Chapterl'IldescribesËhesynthesisof3-,6-and7-substítuted caprolactams.}fostofthesecompoundswerePreParedbytheSchmidt

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rearfangement of the correspondíng ketone. A detaíled investigaÈion of the rearrangement of these ketones ^and of arylpropan-2-ones has ^shown Ëhat the ratio of ^{the two possíble a¡ride products} Ín each case can vary when any one of the fol-lowíng factors: ^soLvent, temperaLure ^and

subsËiËution Pattern, is ^changed'

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STATEMENT

This thesís contaíns no material- prevlously submftted for a ^degree or ^dJ-ploma in any university, ^and to the best of ^aty

knowledge and be1Íef, conEains no material prevíously written ^or published except where due reference is ^made in the text.

J,M. ^TIPPETT

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ACKNOÌ^ILEDG 14ENTS

I- ¡.rj-sh to express my since-re Ëhanks to Dr. ^R.lI . Prager for his enthusÍastic help and encoulagcment throughout t.he- course of this ^r¿ork.

In addition I would like to thank the following ^people.

Dr. A.D. trfard for his supervisíon during the absence of Dr. Prager'

Dr. T.M. Spotswood, Mr. E.H. I,üillams and Mr. R.L. Paltridge for theír help wíth nuclear ma¡lnetic resonance work, Mr. T. ^Blumenthal for runnÍng nass specÈra, Mr. P. Moulder for the bÍologícal

testíng of compounds, Mr. P. Babídge for help with hígh pressure

IÍquid chromatographic techniques, and other members of staff and my colleagues for ^ttumerous helpful discussions.

This research was carrÍed out during the tenure of ^a

Commonv¡ealth Postgraduate Award, whích I gratefully acknowledge.

Finally, I ^{t-hank my fíancee, Ms} Iren Baranyaí, for her help and ^paÈi.ence throughout the preparaËion of this thesis.