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Durham E-Theses
The Synthesis of homochiral ligandsand their
application to asymmetric (cid:29)uorinating reagents
Bailey, David John
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2
The Synthesis of Homochiral Ligands
and their Application
to Asymmetric Fluorinating Reagents
by
David John Bailey
A Thesis submitted in partial fulfilment of the requirements for
the degree of doctor of Philosophy
Department of Chemistry
University of Durham
The copyright of this thesis rests with the author.
No quotation from it should be pubhshed without
his prior written consent and information derived
from it should be acknowledged.
" With men this is impossible; but with god all things are possible"
New Testament 26
" Blessed are they that have not seen and yet have believed "
New Testament 29
II
Abstract
This thesis is concerned with the synthesis of homochiral Ugands and their apphcation to
asymmetric fluorinations. Initial work focused on the synthesis of homochiral pyridine
based Ugands and the determination of their optical purity. 2-Acetylpyridine was
reduced using bakers' yeast m the presence of an enzyme inhibitor to give a homochiral
pyridyl alcohol. A double asymmetric reduction of 2,6-diacetylpyridine was also
achieved using bakers' yeast and the resulting diol was also found to be homochiral.
Derivatives of the above pyridyl alcohols were then reacted with 10% F2/N2 in the
presence of a suitable counterion to form N-fluoropyridinium salts. These reagents were
then used to fluorinate a range of silyl ketene acetals and metal enolates to assess their
abUity as asymmetric electrophihc fluorinating reagents. Although the reagents achieved
fluorination, they were found to be poor asymmetric fluorinating reagents.
A new synthetic route into the pyrrohdine based amine (2S>-(diphenyl)methylpyrroUdine
was developed and its use in a nimiber of asyrmnetric transformations was mvestigated.
Both DAST and Ishikawa's reagent have proved successful in achieving the replacement
of alcohol hydroxyl groups by fluorine. Development of a nucleophilic asymmetric
fluorinating reagent based on DAST and Ishikawa's reagent was atteiiq)ted using
(2S)-(diphenyl)methylpyrrohdine as the precursor amine. The homochiral derivatives of
DAST and Ishikawa's reagent which were developed, only achieved limited success as
fluorinating reagents and the fluorinated products were found to be racemic.
(2S)-(Diphenyl)methyIpyrrolidine was also found to act as a chiral solvating reagent with
certain carboxylic acids and alcohols, these showing chemical non-equivalence by
NMR. Two (2S)-(diphenyl)methylpyrrolidine imits were also coupled together by a two
and three carbon bridge forming two novel diamines. Initial studies on the ability of
these amines to act as asymmetric catalysts in dihydroxylation reactions usmg osmium
tetroxide and asymmetric addition reactions of Grignard reagents to aldehydes are also
described.
Ill
Memorandum
The research described in this thesis has been carried out at the Department of Chemistry, University
of Durham between October 1991 and 1994. It is the original work of the author unless otherwised
stated.
A three month period of research was spent at Glaxo Group Research, the industrial case sponsors of
this project. Chiral HPLC and X-ray crystal data shown is this thesis were supphed by Glaxo Group
Research on my behalf
The copyright of this thesis rests with the author. No quotation from it may be pubUshed with out his
consent, and information derived from it has to be acknowledged.
IV
Acknowledgements
I would like to express my thanks to the following for their contribution to the
completion of this thesis:-
Dr David O' Hagan for his encouragement and support throughout the last three years.
Also for his support in conquering Mount Fuji.
Glaxo Group Research and ERSRC for their ftmding of this project and their
contribution towards the 19th International Conference on Fluorine Chemistry, which
was held in Yokohama Japan.
Bob Boughtflower and Steven Jackson Glaxo Group Research for chiral HPLC and
chiral GC analysis. This project would have been impossible without their time and
effort and I am eternally gratefiil to both of them
Brian Lamont for the X-ray crystal data which gave valuable information on the
structures of the homochiral molecules produced during this thesis.
My two industrial supervisors Uldrich Dyer and Michael Montief who both left Glaxo
Group Research in my final year, hopefiilly not because of me.
All technicians and support services at the University of Durham for their support in
obtainiog experimental data for this thesis.
Elke for her loving support and patience during my studies at Durham
My parents for then beUef m me over the last six years and also their financial support.
Maggie and Billy my two dogs who have suppUed a good excuse to escape from the
rigours of Organic Chemistry
Last but not least Organic Chemistry for proving to be an extremely hard mistress to
please.
V
Publications
D. Bailey, D. O' Hagan, U. Dyer and R. B. Lamont,
Tetrahedron Asymmetry, 1993, 4, 1255.
Conferences Attended
a) " Stereochemistry at Sheffield "
University of Sheffield
Sheffield
December 1991.
b) " Stereochemistry at Sheffield "
University of Sheffield
Sheffield
December 1992.
c) The Royal Society of Chemistry
" Asymmetric Synthesis"
University of Manchester
Manchester
February 1994.
d) " 19th International Conference on Fluorine Chemistry " (Poster)
Yokohama
Japan
July 1994
Presentations
a) " 19th International Conference on Fluorine Chemistry " (Poster)
Yokohama
Japan
July 1994
b) " Towards an Asymmetric Fluorinating Reagent" (Lecture)
University of Durham
Durham
1994
VI
Abbreviations
AD-mix. Asymmetric dihydroxylation mixture.
BINAL-H. Binapthol aluminium hydride.
BPPM. (2S,4S)-N-?er^butoxycarbonyl-l,4-diphenylphosphiao-2-diphenyl
phosphinomethylpyrrohdine.
CBS. Corey, Bakshia, Shilata reduction procedure.
Cp2TiCl2. Dicyclopentadienyltitanium dichloride.
DAST. Diethylamino sulphur trifluoride.
DCC. 1,3-Dicyclohexylcarbodiimide.
(DHQD)2-Phal (Dihydroquinidine)2-Phthalazme.
DMAP 4-Dimethylammopyridine.
[Eu(tfc)3]. Tris[3-(trifluoromethylhydroxymethylene)-(+)-camphorato].
GC. Gas chromatography.
GC-MS. Gas chromatography coupled vvdth mass spectroscopy.
HCLA. Homochiral hthium amide.
HFP. Hexafluoropropene.
HMPA. Hexamethylphosphoramide.
HPLC High pressure Uquid chromatography.
IpC. Isopinocamphenylborane.
LDA. Lithium Diisopropylamine.
LHMDS. Lithium hexamethyldisilazane.
MTPA. a-Methoxy-a-trifluoromethylphenylacetic acid.
NAD(P) H. Nicotinamide adenine dinucleotide phosphate.
NFQNF. N-Fluoroquinuchdinium fluoride.
NMR. Nuclear magnetic resonance.
PET. Positron emission tomography.
PPM. (2S,4S)-4-diphenylphosphino-2-diphenylphosphinomethylpyrroUdme.
RAMP. (R)- l-Amino-2-methoxymethylpyrroUdine.
SAMP. (Sy l-Ammo-2-methoxymethylpyTrolidine.
TAE. (R)-(-)-2,2,2-Trifluoro-1-(9 anthryl)ethanol.
TBAF. Tetrabutylarmnonium fluoride.
TBDMSCl. ^er^-Butyldknethylsilyl chloride.
TMSCl. Chlorotrimethylsilane.
p-TsOH. /?-Toluenesulfonyl chloride.
VII
CONTENTS
CHAPTER 1 1
1. Introduction I
1.1 Historical viewpoint 1
1.2 Effects of fluorine substitution on organic molecules 1
1.3 Prerequisite for practical fluorinating reagents 5
1.4 Electophihc Fluorinating Reagents 5
1.4.1 Acetyl hypofluorite 5
1.4.2 N-Fluorosulphonamides 6
1.4.3 N-Fluorosultams 7
1.4.4 N-FluoroquinucUdinium fluoride 10
1.4.5 N-Fluoropyridinium triflates 13
1.5 Nucleophihc Fluorinatmg Reagents 16
1.5.1 F-Propene-dialkylamine fluorinating reagents 16
1.5.2 Diethylaminosulphur trifluoride (DAST) and related reagents 17
1.5.2.1 (2S)-(Methoxymethyl)pyrrohdin-l-ylsulphur trifluoride 22
1.6 Towards new asymmetric fluorinating reagents 23
1.6.1 Electrophilic fluorinating reagents 23
1.6.2 Nucleophihc fluorinating reagents 24
1.6.2.1 Homochiral DAST reagents 24
1.6.2.2 Homochiral Ishikawa's reagents 24
CHAPTER! 25
2. Asymmetric Synthesis of homochiral pyridine systems 25
2.1 Introduction. 25
2.2 Objectives 26
2.3 Resolution of homochiral pyridines using lipase enzymes 27
2.3.1 Attempted resolution of 8-acetoxy-5,6,7,8-tetrahydroqumoline &
(R,R),(S,S)-l,8-diacetoxy-I,2,3,4,5,6,7,8-octahydroacridine 30
2.4 Synthesis of homochiral pyridines using asymmetric reductions 31
2.4.1 Corey Bakshia and Shilata, CBS reduction 32
2.4.2 Binapthol aluminium hydride BENAL-H 33
2.4.3 Diisopinocamphenylchloroborane reductions 34
2.4.4 Bakers' yeast reductions 37
2.4.4.1 Introduction 37
2.4.4.2 Bakers' yeast reductions of mono-ketones 38
VIII