Synthesis of conjugated unsaturated Amino Acids

131 Pages·2016·3.97 MB·English

by  Vanja Buvik

Synthesis of conjugated unsaturated
Amino Acids
Vanja Buvik
Chemistry
Submission date: May 2016
Supervisor: Vassilia Partali, IKJ
Co-supervisor: Hans-Richard Sliwka, IKJ
Norwegian University of Science and Technology
Department of Chemistry

Abstract

Of the three main groups of biomolecules - lipids, carbohydrates and proteins - lipids and
carbohydrates containing polyene functionalities have already been investigated. This thesis
describes a first approach to the synthesis of polyene amino acids. Conjugated unsaturated
amino acids could be interesting building blocks for the making of novel peptides and proteins
with rigid structural elements and chromophoric properties. The first L-polyene amino acid was
synthesized by a Wittig reaction between a protected glutamic acid aldehyde and a
triphenylphosphonium salt of a C15:3-polyene compound.

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Sammendrag

Av de tre hovedgruppene av biomolekyler – lipider, karbohydrater og proteiner – har både
polyen-karbohydrater og polyen-lipider allerede blitt undersøkt. Denne oppgaven beskriver en
første tilnærming til syntese av en konjugert, polyenisk aminosyre. Konjugerte umettede
aminosyrer er interessante med tanke på framstilling av nye peptider og proteiner med rigide
strukturelementer og kromoforiske egenskaper. Den første L-polyen-aminosyren ble framstilt
ved en Wittig-reaksjon mellom et beskyttet glutaminsyrealdehyd og et trifenylfosfoniumsalt av
et C15:3-polyen.

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Acknowledgements
First of all I want to thank my supervisor Vassilia Partali, for giving me the opportunity to work
on this thesis, but also for always having time for me, for all that she has taught me and for all
the interesting conversations we had during the two years. I am equally grateful for the help
from my co-supervisor, Hans-Richard Sliwka. His ability to always find solutions to problems
that occur along the way has been a great help during the work for, and the writing of this thesis.
For all good advice, for teaching me techniques both regarding NMR, IR and laboratory work,
I thank Melanie Siah, the best colleague and friend I could wish for. Thank you to Susana Villa
Gonzales and Julie Asmussen for running my MS-samples and always patiently answering my
emails and many questions. I want to thank Torun Margareta Melø for all good advice and
instructions about running NMR. Thanks also to Claire Katja Peterson, for helping me in the
writing process and to Josip Zecevic for helping me in the lab on long afternoons and evenings.
Thank you to all the great people in my life who support me and who make Trondheim the
greatest place in the world. My family: my parents and my brother, being an inspiration in so
many ways, and Mormor, who has taught me and still teaches me so much about life. Torunn
who maybe knows me better than I know myself and always cheers me on. Julie, with whom I
can always have a rewarding conversation or a good laugh, and all the rest of the amazing
people I know here.

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Table of contents
Abstract ..................................................................................................................................... iii
Sammendrag ............................................................................................................................... v
Acknowledgements .................................................................................................................. vii
Table of contents ....................................................................................................................... ix
List of figures ............................................................................................................................ xi
Abbreviations .......................................................................................................................... xiii
1 Introduction ......................................................................................................................... 1
1.1 Amino acids ................................................................................................................. 5
1.2 Unsaturated amino acids .............................................................................................. 5
1.3 Carotenoids .................................................................................................................. 6
1.4 Key biological compounds, polyene modified ............................................................ 7
2 Results and discussion ........................................................................................................ 9
2.1 Strategies ..................................................................................................................... 9
2.2 Addition of amino acid function to a polyene ............................................................. 9
2.3 Addition of the polyene to an amino acid .................................................................. 11
2.3.1 Synthesis of L-glutamic acid aldehyde .............................................................. 12
2.3.2 Synthesis of polyene Wittig salt ......................................................................... 16
2.3.3 Wittig reaction with a triene phosphonium salt ................................................. 18
3 Molecular models of L-20N:4 .......................................................................................... 21
4 Future aspects .................................................................................................................... 23
4.1 Triphenyl phosphonium salt of glutamic acid ........................................................... 23
4.2 Deprotection of glutamic acid before Wittig reaction ............................................... 24
5 Experimental ..................................................................................................................... 27
5.1 Synthesis of 5-undecylimidazolidine-2,4-dione (2) .................................................. 27
5.2 Synthesis of 2-aminotridecanoic acid (3) .................................................................. 28
5.3 Attempted synthesis of β-apo-8’-carotene-5-imidazolidine-2,4-dione (5) ................ 29
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5.4 Synthesis of dibenzyl N,N-dibenzyl-L-glutamate (10) ............................................. 30
5.5 Attempted synthesis of benzyl (S)-2-(dibenzylamino)-5-hydroxypentanoate (12) ... 31
5.6 Synthesis of dimethyl (tert-butoxycarbonyl)-L-glutamate (13) ................................ 32
5.7 Synthesis of dimethyl di(tert-butoxycarbonyl)-L-glutamate (14) ............................. 33
5.8 Synthesis of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-hydroxypentanoate
(16) ................................................................................................................................... 34
5.9 Synthesis of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxopentanoate (15) 35
5.10 Synthesis of 8'-apo-β-caroten-8'-ol (17) .................................................................... 36
5.11 Attempted synthesis of β-apo-8’-bromocarotene (18) and 8’-apo-β-caroten-8’-
triphenylphosphine bromide (19) ......................................................................................... 37
5.11.1 Reaction a) .......................................................................................................... 37
5.11.2 Reaction b) ......................................................................................................... 38
5.11.3 Reaction c) .......................................................................................................... 38
5.12 Synthesis of L-C20N:4-diBoc-methylester (23) ........................................................ 39
5.12.1 Reaction a) .......................................................................................................... 39
5.12.2 Reaction b) ......................................................................................................... 39
5.13 Synthesis of L-C20N:4 (25) ...................................................................................... 41
5.14 General procedures and apparature ........................................................................... 43
5.14.1 Chromatography ................................................................................................. 43
5.14.2 Molecular models ............................................................................................... 43
5.14.3 Apparature .......................................................................................................... 43
6 References ......................................................................................................................... 45
Appendix A: Reaction mechanisms
Appendix B: Protective groups
Appendix C: Spectra and data

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