DARWIN Digitale Dissertationen German Version Strich

FU Berlin
Digitale Dissertation

Thomas Speck :
Axial Chiral Olefins & Development of Syntheses to Carbacyclin- and Isocarbacyclin-Precursors
Axial chirale Olefine & Entwicklung von Synthesen zu Carbacyclin- und Isocarbacyclin-Vorstufen

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Abstract

In this work it was shown that the use of Evans auxiliaries in aldol addition reactions is limited by ringopening reactions. The structures of the ringopening products were proved by X-ray analysis.

Imidazolidinone 1 ( and it?s hydrogenated variation 3 ) was found to be an auxiliary that combines the useful characteristics of Evans auxiliaries with greater stability especially against nucleophilic attack at the carbonyl group. The hydrogenated auxiliary 3 showed excellent selectivity in the aldol addition reaction at 4-tbutylcyclohexanone but not in the case of the carbacyclin precursor. However it has the disadvantages of lower yields, difficult removal of auxiliary and higher price.

Using the new auxiliary 1 and following way I chiral olefin 8 was prepared from 4-tbutylcyclohexanone in very good yield. Contrary to expectation the optical purity of 8 was only 82 % ee. Racemization of aldol addition product 5A under the basic conditions of auxiliary cleavage appeared to be the reason. The usage of other techniques of cleavage ( lower temperature, LiOOH instead of LiOH, Ti(OEt)4 etc. ) could probably prevent racemization.

Application of the olefination sequence to a carbacyclin precursor was very successful. The optical purity of olefin 13A reached 97.6 % de. Due to this result almost no racemization occured during auxiliary removal.

Extension of the sequence was very promising until the auxiliary removal step ( good yields, only one diastereomer ). But even with only the ethyl group instead of methyl it is impossible to remove the auxiliary ( usually retroaldol is observed ). The most probable reason for this behaviour seems to be steric hindrance. The possibility to adapt this sequence to larger substituents should be a good reason for further studies on the auxiliary removal. In addition it could be examined whether larger substituents are possible with other molecules like for example the carbacyclin precursor.

Also starting from 4-tbutylcyclohexanone a synthesis of endocyclic olefins 37A and 37B was developed. It leads to an isocarbacyclin precursor in good yield. The elimination reaction produces more (Z)-olefin than (E)-olefin but this can be changed by using the auxiliary?s enantiomer.

Though for carbacyclins as well as for isocarbacyclins Gais and coworkers recently published some good syntheses with high yields and high optical purities ( up to 98% de ).

As a solution to the problems observed on way I ( racemization, larger substituents ) the alternative way II was examined. Because of the different structure racemisation is almost impossible and the synthesis of larger substituents seems to be possible. Following way II axial chiral olefin (R)-8 was produced in very high optical purity ( 98 % ee ) for the first time. A synthesis of the (S)-enantiomer with the same optical purity would be possible in the same way using auxiliary 1?s enantiomer.

No racemization and the probable possibility to introduce larger substituents are the main arguments for using way II in a synthesis of carbacyclin precursors.

Table of Contents

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I. Allgemeiner Teil 2

1. Einleitung 2

1.1. Carbonylolefinierung - einfache Olefine 2

1.2. Carbonylolefinierung - schwer zugängliche Olefine 5

2. Axial chirale Olefine - das Testsystem 4-tButylcyclohexanon 13

2.1. Axiale Chiralität 14

2.2. Literatursynthesen: Alkyliden-4-tbutylcyclohexane 17

3. Aufgabenstellung 22

4. Ausgangssituation 23

4.1. Bisherige Ergebnisse 23

II. Spezieller Teil 30

1. Allgemeines 30

1.1. Retrosynthese 30

1.2. Vorgehensweise 31

2. Weg I - Synthesen ausgehend von 4-tButylcyclohexanon 32

2.1. Ergebnis der Röntgenstrukturanalysen früherer Aldoladdukte 32

2.2. Evans-Auxiliar-Ringöffnung 33

2.3. Imidazolidinon-Auxiliar 35

2.4. Stereoselektive Synthese mit dem Imidazolidinon-Auxiliar 37

3. Anwendung der Olefinierungssequenz auf eine Carbacyclin-Vorstufe 43

3.1. Stereoselektive Synthese einer Carbacyclin-Vorstufe 43

4. Erweiterung der Olefinierungssequenz auf größere Substituenten 50

4.1. Stereoselektive Synthese einer geschützten Säure (ausgehend von 4-tButylcyclohexanon) 50

4.2. Stereoselektive Synthese eines geschützten Alkohols (ausgehend von 4-tButylcyclohexanon) 52

4.3. Testfall: Stereoselektive Synthese der Ethyl- u. Propyl-substituierten Verbindungen (ausgehend von 4-tButylcyclohexanon) 56

5. Isocarbacyclin - Entwicklung einer Olefinsynthese 60

5.1. Stereoselektive Synthese am Testsystem 4-tButylcyclohexanon 60

6. Weg II - Synthesen ausgehend von 4-tButylcyclohexancarbonsäure 64

6.1. Racemische Synthese 64

6.2. Stereoselektive Synthese mit dem Evans-Auxiliar 66

6.3. Stereoselektive Synthese mit dem Imidazolidinon-Auxiliar 69

7. Zusammenfassung und Ausblick 74

7. Summary E 74

III. Experimenteller Teil 77

1. Allgemeines 77

1.1. Präparative Methodik 77

1.2. Lösungsmittel 77

1.3. Chemikalien 78

1.4. Chromatographische Verfahren 79

1.5. Analytik 81

1.6. Nomenklatur 83

2. Reagenzien 84

2.1. Lithiumdiisopropylamid 84

3. Synthetisierte Verbindungen 85

IV. Anhang 179

1. Röntgenstrukturanalysen (Tabellen) 179

1.1. Diastereomer A (Diplomarbeit) 179

1.2. Diastereomer B (Diplomarbeit) 186

1.3. Aldoladdukt 5A 193

1.4. Aldoladdukt 13A 200

1.5. Aldoladdukt 13B 212

1.6. Olefin (E)-17 224

1.7. Aldoladdukt 27 230

1.8. Aldoladdukt 32A 239

1.9. Trifluoressigsäurester 35 247

1.10. endocyclisches Olefin 36A 255

1.11. Aldoladdukt 45 262

1.12. Aldoladdukt 48 269

2. Abkürzungen 278

V. Lebenslauf 280

VI. Literatur

More Information:

Online available: http://www.diss.fu-berlin.de/1999/51/indexe.html
Language of PhDThesis: german
Keywords: axial chiral olefins; chiral auxiliary; carbacyclin; isocarbacyclin; aldol
DNB-Sachgruppe: 30 Chemie
Date of disputation: 14-Jun-99
PhDThesis from: Department Biologie, Chemie, Pharmazie, Freie Universität Berlin
First Referee: Prof. Dr. Dieter Rewicki
Second Referee: Prof. Dr. Johann Mulzer
Contact (Author): thomassp.@t-online.de
Contact (Advisor): mulzer@felix.orc.univie.ac.at
Date created:18-Aug-99
Date available:18-Aug-99

 

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