I= CHIRAL BUILDING BLOCKS FOR CEPHALOSTATIN ANALOGUES FROM THE HAJOS WIECHERT KETONE
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Title of Thesis
CHIRAL BUILDING BLOCKS FOR CEPHALOSTATIN ANALOGUES FROM THE HAJOS WIECHERT KETONE

Author(s)
Uzma Yunus
Institute/University/Department Details
Department of Chemistry/ Qauid-i-Azam University Islamabad
Session
2001
Subject
Chemistry
Number of Pages
146
Keywords (Extracted from title, table of contents and abstract of thesis)
chiral building blocks, cephalostatin, hajos wiechert ketone, bissteroidal pyrazine, hecogenin, cancer therapy, rittrazine, aminoketone, azidoketones

Abstract
Since the initial characterization of cephalostatins in 1988, the bissteroidal pyrazine structure has attracted many synthetic chemists . Because access to these highly potent and structurally complex cytostatics from natural sources is extremely limited. The search for simple biologically active analogues has been the priority. The present work is a part of the project which aimed to prepare analogues of cephalostatins in order to study the features essential in cephalostatin for being potent against cancer of various kinds. Till to date , many researchers have chosen the abundant steroid, hecogenin as the starting material for the purpose of both analogues and total synthesis. In the present work , multi-step synthesis of various non-steroidal chiral building blocks for cephalostatin analogues possessing functionalities capable of yielding pyrazines , analogous to cephalostatins with a basic hydrindane nucleus is under taken In this regard Hajos Wiechert ketone (31) was chosen as starting material . Hajos Wiechert ketone (31) possess two carbonyl functionalities which can be transformed into a number of other functionalities by known series of reactions . Moreover, a preformed chiral center in (31) is thought to be useful in bringing functional groups in stereo-selective manner. Thus starting from ketone (31), The bromoketones (48 and 55) , enaminoketone (49), azidoketones (62 and 63), acetoxyketoe (64) and hydroxyketone (65) were prepared in acceptable yields.

A prerequisite for cephalostatin analogues is the presence of double bond in five membered ring which is known to be associated with the biological activity of the cephalostatins. This was achieved in ketone (31) by migrating the double bond in ketone (31) from six member ring to five member ring by ketalization. Moreover , to check the potential of synthesized synthones to yield pyrazine , enaminoketone (49) was coupled reductively to pyrazine (50) . Similarly, the hydroxyketone (65) in presence of ammonium acetate afforded pyrazine (67).Vinyl azide is an equivalent of azirine, which on reaction with enaminoketone is known to yield unsymmetrical pyrazines. Thus efforts were made to prepare vinyl azide (71) in hydrindane series starting from ketone (31). These attempts ,however remained unsuccessful. A brief account of these efforts is also included in the present work. As cephalostatins have shown remarkable cytostatic activities against various kinds of cancers , The preliminary tests to compare cytostatic activity of the pyrazine (38) were also carried out. A discussion of the comparison of activity of (38) with some potent cytostatic compounds is also included here.

Thus the thesis describes a comprehensive account of the results of all efforts and attempts to synthesize the above mentioned compounds. All the synthesized compounds were characterized by various spectroscopic techniques. These spectroscopic data are also included in the thesis.

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3728.91 KB
S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
300.19 KB
2 1 Introduction 1-31
612.14 KB
  1.0 Natural Products In Cancer Therapy 02
  1.1 Cephalostatin And Rittrazine 04
  1.2 Cyntones For Pyrazine Ring Formation 10
  1.3 Aim Of The Present Work 21
  1.4 Plan Of Work 22
3 2 Results And Discussion 32-98
1808.74 KB
  2.1 Preparation Of Pyrazines( 37 And 38) 33
  2.2 Transformation Of ” 3a-4 To ” 3a-3 In ‘ ,’ - Unsturated Ketone Into Ketone(32) 39
  2.3 Characterization Of Alcholos ( 40a And 40 B) Pivalates (41a And 41b), And Ketoens (42a And 42b) 47
  2.4 Role Of Protecting Groups In Present Work 52
  2.5 Regeneration Of ” 3a-3 Bond In (40) 54
  2.6 Preparation Of Aminoketone And Its Equivalents 56
  2.7 Preparation €“ Azidoketones (62 And 63) 69
  2.8 Aza-Witting Reaction To Prepare Pyrazine 82
  2.9 Preparation Of Hydroxyketone( 65) 84
  2.10 Preparation Of Pyrazine( 67) 93
4 3 Experimental 99-138
1033.47 KB
  3.1 General Remarks 100
  3.2 Methods Of Preparation Of All New Compounds 99-138
  3.3 Scheme Wise
5 4 References 139-146
157.85 KB