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SYNTHETIC STUDIES IN TERPENOIDS

By

HARISH RANJAN CHEMISTRY DEPARTMENT

SUBMITTED

IN FULFILMENT OF THE REQUIREMENTS OF THE DEGREE OF

DOCTOR OF PHILOSOPHY

TO THE

INDIAN INSTITUTE OF TECHNOLOGY, DELHI

JULY, 1983

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CERTIFICATE

This is to certify that the thesis entitled "Synthetic Studies in Terpenoids", being submitted by Mr. Harish Ranjan to the Indian Institute of Technology, Delhi, for the award of the degree of Doctor of Philosophy in Chemistry, is a record of bonafide research work carried out by him. Mr. Ranjan has worked under my guidance and supervision and has fulfilled the requirements for the submission of this thesisr which to my knowledge, has reached the requisite standard.

The results contained in this thesis have not been submitted, in part or in full, to any other university or institute for the award of any degree or diploma.

(R.C. ANAND) Thesis Supervisor,.

Oepartment of Chemistry, Indian Institute'of.Technology,

New Delhi-110016.

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ACKNDWLEDGEMENTS

I wish to record my deep sense of gratitude to

Dr. R.C. Anand, Assistant Professor, Department of Chemistry, Indian Institute of Technology, Delhi, for his guidance,

interest and encouragement which made this work possible.

I am grateful to Professor N.K. Jha, Head, Depart- ment of Chemistry, for providing laboratory facilities.

The fruitful discussions and cooperations of all friends are thankfully acknowledged.

Ply thanks are also due to Mr. Krishan K. Rehani for his help and encouragement at various stages of this work and to Mr. U.N. Sharma for typing the dissertation.

6(91.4Ak..1 (HARISH. RANJAN)

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ABSTRACT

The thesis embodies results of investigations towards the syntheses. of following terpenoids.

(a) 4-Nerolidylcatechol dimethyl ether

(b) 2,2-Dimethy1-5-hydroxy-3-(3-oxo-butyl)-7-n-pentyl-4-chromanone (c) 0C-cuparenone

(d) Dihydrojtsmone

(e) ar-trans-Atlantone.

Synthesis of 4-nerolidylcatechol dimethyl ether has been accomplished for the first time. Wittig reaction has been

utilized for the introduction of vinylic substituent at the quaternary carbon. Attempts to synthesize 4-berolidylcatechol dimethyl ether through [3,3] sigmatropic.rearrangement or using 1-(3', 41-dimethoxy-phenyl)-5,9-dimethyl-418-decadienone as the key intermediate were not successful.

A synthesis of 2,2-dimethy1-5-hydroxy-3-(3-oxo-butyl)- 7-n-pentyl-4-chromanone, a cannabinoid, has been carried out starting from olivetol and thus corroborated .its structure.

An interesting. observation in this synthesis is that alkylation and deformylation of 2,2-dimethyl-3-hydroxymethylene-5-hydroxy- 7-n-penty1-4-chromanone have taken place in the same step.

A practical synthesis of olivetol has also been developed.

The advantages of the present synthesis are (i) an overall yield of 55 percent (ii) the intermediates isolated are solid crystalline compounds and are easier to purify (iii) deprotection of the

masked hydroxyl groups under mild reaction conditions.

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An attempt to prepare olivetol, by coupling of n-butyl magnesium bromide with 3,5-dimethoxy-benzyl bromide, resulted in the formation of 3,5-dimethoxy-toluene.. The proposed pathway for this unusual observation (hydrogenolysis of 3,5-dirnethoxy- benzyl bromide with n-butyl magnesium bromide) has been supported experimentally.

In view of potential of tetrahydrocannabinol derivatives as therapeutic agents, an isoxazole analogue of THC has been

synthesized utilizing an intermediate of 2,2-dimethy1-5-hydroxy-3- (3-oxo-butyl)-77n-penty1-4-chromanonels synthesis.

During the synthesis of QC-cuparenone, the present studies have resulted in the development of a new synthetic route for

substituted 2-cyclopentenone (a moiety present in several biolo-

gically important compounds) through the cyclisation of 1,4-diketone.

The approach involves elaboration of easily accessible conjugated ketone into 1,4-diketone through the sequence of following reactions.

(i) Methylene transfer to the double bond (ii) nucleophilic ring opening by thjophenoxide anion (iii) chlorination-dehydro- chlorination of thioether (iv) generation of carbonyl group from enol thioether.

oC-cuparenone has also been synthesized through an extension of the route, established earlier in our laboratory, for substituted 2-cyclopentenone.

An attempt to synthesize OC -cuparenone, through [3,3 ]

sigmatropic rearrangement as the key reaction, did not materialize.

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Dihydrojasmone, an important perfume constituent, has been synthesized to illustrate the generality of the new

approach for substituted 2-cyclopentenone, developed during the synthesis of OC-cuparenone.

ar-tran2-Atlantone has been synthesized through two approaches. The first pathway makes use of 6-methyl-6-E-toly1-

4-

ethoxy-5,6-dihydro-pyran-2-one as an important intermediate and the second route involves copper catalysed conjugate addition of an alkyl group to cci p-unsaturated ketone.

During the synthesis of ar-trans-atlantone following unprecedent experimental results were also observed.

(i) Acid catalysed hydrolysis of enol ether of p-keto-&- lactone (6-methyl-6-2.-toly1-4-ethoxy-5,6-dihydro-pyran-2-one) resulted in the formation of only an unsaturated ketone (472- toly1-3-penten-2-one) instead of expected 13 -keto- S -lactone.

The structure of the isolated product has been confirmed through its unambiguous synthesis. The mode for the present acid

catalysed decarboxylative-elimination of 6-methyl-6-p-toly1-4- ethoxy-5,6-dihydro-pyran-2-one has been proposed. (ii) Allylic rearrangement-oxidation reaction with 6-p-toly1-4-hepten-2,6-diol using Jones reagent or, pyridinium chlorochromate-sodium acetate resulted in carbon-carbon bond cleavage to afford p-methyl

acetophenone as the only reaction product.

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CONTENTS

Page

CHAPTER - 1 Introduction 1

CHAPTER

-

2 Discussion 17

Section - I

Synthesis of 4-Nerolidylcatechol

dimethyl ether 17

Section - II

(i) Synthesis of 21 2-Dimethy1-5-hydroxy-

-

3-(3-oxo-buty1)-7-n-pentyl-4-

-chromanone 29

(ii) Synthesis of 51 5-Dimethy1-10-hydroxy- -8-n-penty1-5H-C13-benzo-pyrano

C4,3-0 isoxazole (an isoxazole

analogue of tetrahydrocannabinol) 38 Section - III

Syntheses ofo< -Cuparenone 40 Section - IV

Synthesis of Dihydrojasmone 53

Section - U

Syntheses of ar-trans-Atlantone .. 59

CHAPTER - 3 Experimental 70

REFERENCES .. 161

SUMMARY .. 166

IR SPECTRA NMR SPECTRA

References

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