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Synthetic Investigations In Terpenoids And Steroids

Electronic Theses of Indian Institute of Science

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Title Synthetic Investigations In Terpenoids And Steroids
 
Creator Bijoy, P
 
Subject Organic Chemistry
Pfaffic Acid
1-Hydroxymethylindanes
1-Hydroxymethyltetralins
Indan-1-Ones
Teral-1-Ones
Cinnamic Acid
ACE Synthon
Cyclopentaphenanthrene
4-Methoxybenzyl Alcohol
Estratetraenes
19-Nortestosterone
 
Description The thesis entitled "SYNTHETIC INVESTIGATIONS IN TERPENOIDS AND STEROIDS" consists of 3 Chapters

Chapter-I deals with the synthetic studies on the hexacyclic nortriterpene Pfaffic acid 1, and is divided into two sections.

Section-I begins with a brief introduction to Pfaffic acid 1, a naturally occurring hexacyclic nortriterpene, in particular to its isolation, structural elucidation and antitumor activity. The antitumor activities of the Pfafosides A, B, C, D, E and F, the glycosides of pfaffic acid 1, isolated from the same plant is also described. The discussion presents the synthetic strategy developed to construct the AB ring system along with the results of the attempted synthesis of DEF ring of Pfaffic acid 1.

The retrosynthetic analysis of 1 identified the key intermediates as AB synthon 2, and the DEF synthon 3, Regioselective hydride reduction of Wieland-Mischer ketone, followed by hydroxyl protection and Woodward methylation gave the dimethylated compound 4 Deprotection of the hydroxyl group and reduction of the carbonyl followed by acetylation resulted in the diacetate 5 Oxidation of the diacetate 5 with PDC-/BuOOH-celite system followed by lithium-liquid ammonia reduction yielded the saturated keto diol 6, which on dehydration and subsequent acetylation afforded the enone acetate 2, which formed the AB ring of Pfaffic acid 1

The synthetic studies towards the construction of DEF rings of Pfaffic acid commenced with the preparation of the indane methanol 7 The alcohol 7 was synthesized starting from 5-methoxyindan-l-one Thus 5-methoxyindanone was converted into the hydroxymethyl compound 8 by Wittig reaction and subsequent hydroboration Swern oxidation of 7, followed by methylation and reduction resulted in the indane methanol 7

Lithium-ammonia reduction of 7 gave a dihydrocompound, which on hydrolysis with oxalic acid gave the isomeric enones 9 and 10 in 1 1 ratio On the other hand, hydrolysis of the dihydrocompound with 5N HC1 in methanol afforded the isomers 9 and 10 in 85 15 ratio Addition of KCN to the isomeric enone mixture (85 15) resulted in the lactone 11 in 60% yield.The formation of the lactone 11 clearly established that the major isomer of the mixture has the angular hydrogen and hydroxymethyl group in as orientation as represented in 9, but unfortunately this geometry is unfavorable for the construction of the DEF ring of Pfaffic acid

Similar Birch reduction of the alcohol 8 gave the corresponding dihydrocompound, which on hydrolysis with 5N HC1 in methanol afforded the isomeric alcohols 12 and 13 in 92 8 ratio Hydrogenation of the mixture followed by tosylation yielded the tosylates 14 and 15 in the same ratio Attempted intramolecular cyclisation of the tosylate mixture with different bases failed to yield any tricyclic compound, indicating that the major isomer has the unfavorable geometry for intramolecular alkylation. The origin of stereoselectivity during the hydrolysis of the enol-ether leading to the formation of the isomers 9 and 12 in major amount, was found to be due to a novel hydroxyl directed protonataon as represented in 16

Section-ll describes a novel oxidative C-C bond cleavage reaction with chromium reagents The alcohol 8 when oxidized with a variety of chromium reagents gave 5-methoxyindan-1-one in good yields. The mechanism of this reaction seems to go via the enol 17, which undergoes C-C bond cleavage to afford 5-methoxyindan-l-one. A number of 1-hydroxymethyl indanes 18 and 1-hydroxymethyl tetralins 19 were synthesized and their oxidation with PCC and PDC was examined In all these cases a smooth C-C cleavage was observed resulting in the respective aryl ketones

Chapter-II deals with the synthetic investigations on the construction of the tricyclic ACE synthon 20, a potential intermediate for the synthesis of A-ring aromatic steroids, and is divided into two sections.

Section-] describes the literature pertaining to the synthetic approaches towards A-ring aromatic steroids, with the emphasis being a critical analysis of the methodologies developed for estrone.

Section-ll is divided into two parts Part-I presents the results of the synthetic studies on the construction of the tricyclic ACE synthon 20 The section starts with a need to develop a convenient methodology for the synthesis of aryltetralin 21 The new process developed for the synthesis of 21 involved a one pot Friedel-Crafts arylation of the 7-methoxy-l-tetralol 22 with the phenol to afford the aryltetralin 21 in high yield This methodology was extended to the synthesis of a number of aryl tetralins 22 to show the generality of this reaction

Benzylic oxidation of the acetate of 21, afforded the aryl ketone, which on hydrolysis followed by benzylation with yielded the tetralone 24 Wittig olefination of the tetralone 24, followed by hydroboration afforded the hydroxymethyl compound 25 Swern oxidation of the hydroxymethyl compound 25 and subsequent methylation and sodium borohydride reduction gave the aryltetralin 26 along with its isomer 27 Both these isomers were separated by column chromatography over silica gel and subjected to hydrogenation to afford isomeric diols 28 and 29 Birch reduction of 28 afforded the dihydrocompound, which on acid hydrolysis resulted in a mixture of compounds consisting of 30, 31, 32, and 33 The diastereomeric isomers 30 and 31 were separated together from the other set of diastereomeric isomers 32 and 33 by column chromatography over silicagel, but the individual diastereomers could not be separated On the other hand hydrolysis of the dihydrocompound for a longer period (24 h) yielded the compound 32 as a single isomer along with the mixture 30 and 31

Part-II describes a new synthetic methodology for the construction of bicyclo[3 2 2]nonanes, During the preparation of the aryltetralin derivative 28, a hitherto unknown double Friedel-Crafts reaction, leading to the formation of bicyclo[3.2 2]nonane derivative was observed The diol 35 on treatment with phenol and A1C1, unexpectedly underwent a novel double Friedel-Crafts reaction to afford the bicyclo[3 2 2]nonane derivative 36 The mechanism of this reaction was found to go via the aryl tetralin 28 and the generality of this reaction was demonstrated by the synthesis of different aryltetralin derivatives 37, by reacting the diol with various arylating agents

Chapter-III deals with the direct conversion of 130-alkylgona tetraenes into 19-nortestosterone derivatives Birch reduction of 8-dehydroestradiol-3-methyl ether 38 and 9(11)-dehydroestradiol-3-methyl ether 39 followed by acid hydrolysis results in a mixture of 19-nortestosterone 40 and retro-19- nortestosterone 41 in varying amounts However, reduction of the acetates of 38 and 39 with sodium or lithium, in the presence of aniline affords exclusively 19-nortestosterone 40 Similarly the acetate of 42 was converted to 18-homo-19-nortestosterone 43
 
Publisher Indian Institute of Science
 
Contributor Subba Rao, G S R
 
Date 2005-11-17T06:26:31Z
2005-11-17T06:26:31Z
2005-11-17T06:26:31Z
1994-07
 
Type Electronic Thesis and Dissertation
 
Format 8467501 bytes
application/pdf
 
Identifier http://etd.iisc.ernet.in/handle/2005/163
null
 
Language en
 
Rights I grant Indian Institute of Science the right to archive and to make available my thesis or dissertation in whole or in part in all forms of media, now hereafter known. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation.