Synthesis of very long chain fatty acid methyl esters

201 Pages·2016·9.12 MB·English

by  Marcel Robert Kling

2\-'ì',9
Syrthesis of
Very Long Chain Fatty Acid
Methyl
Esters
A thesis presented for the
Degree of
Doctor of Philosophy
in
the
Department of Organic Chemistry
by
Marcel Robert Kling B.Sc. (Hons.)
The University Of Adelaide
7997
CoNTENTS
STATEMENT lll
ABSTRACT lv
INTRODUCTION
1
RESULTS AND DISCUSSION
1
Chapter Synthesis of Methylene-Interrupted Polyalkynes 27
2
Chapter Synthesis of ro-Iodoesters and or-Oxoesters 50
3
Chapter Synthesis of VLCFA viø Cuprate Methodology 78
4
Chapter Synthesis of VLCFA aíøWíttigMethodology 111
CONCLUSION 724
EXPERIMENTAL 726
REFERENCES 186
AcTNowLEDGEMENTS
I would like to thank Drs. Chris Easton and Alf Poulos for their supervisic-rn and help
throughout the length of my Ph.D. I am especially grateful to Dr. Easton for his help,
encouragement, enthusiasium and guidance which brought me througl'r the lnore
difficult periods.
I am forever indebted to my parents, Rosemarie and Nicholaas Kling, for their love and
support over all my years as a student. I am also grateful to the help and support
provided by rny brothers, Lawrence, Peter and Anthony. I would particularly like to
thank my mother, Rosemarie, for always being there when I needed encouragement or
help of any kind. Thanks Mum! I'm also very appreciative of the help of Omi.
Throughout tny post-graduate studies I was fortunate to have a srnall bunch of good
friends who rnade the tough times more bearable. Thanks Craig Francis, Pasquale
Razzino and Terry Badran for being the great guys you are. AIso thanks to Kevin
Downard and Caroline Ward for their comradeship over the years.
I would also like to thank the members of Lab.7, past and present, who created a great
working environment and put up with my many idiosyncrases. I particularly rvould
like to thank Peter Roselt for showing an interest in my work, helping me when titne
was running short and for his many morning jokes.
Thanks to all the technical staff for their help, often at short notice, over the rnany years.
Special thanks to Marelle Smith for always being very helpful. I am also very
appreciative of the interest and help I have received from the acacìemic staff, in
particular Dr. G. E. Grearn, Dr. A. D. Ward and Dr. L Van Altena.
I
I would also like to thank my typist, Hélène Thomas, for typing this thesis, mainly after
work, and doing a great job. I also thank her and Joseph Terek for their friendship over
the years.
Lastly, I acknowledge, with gratitude, the scholarship provided by tl're Adelaide
Childrens Hospital, which made this work possible.
Marcel R. Kling
II
SrarEn¿ENT
This thesis contains no material previously submitted for a degree or diplorna in any
University and to the best of my knowledge and belief, contains no material previously
published or written by another person, except where due reference is made in the text.
I give consent to this copy of my thesis, when deposited in the University Library, being
available for loan and photocopying.
/KtJ*g
M. R. Kling
lu
ArsrnACT
Several methods for the total synthesis of very long chain fatty acids were investigated.
The synthesis of methylene-interrupted polyalkynes by reiterative coupling of 1-
heptyne with propargyl bromide under copper(I) catalysis was studied, with the aim of
coupling the products with rrl-haloacids. The first homologue of the reiterative
coupling sequence, 1,4-decadiyrìe, was formed readily ína53"/o isolated yield. The next
homologue, 7,4,7-triclecatriyne, was formed in a 36% unisolated yield. Due to the
unstable nature of these polyalkynes and the difficulties encountered in tl"reir isolation
and purification, together with a literature report indicating greater difficulties in the
purification of higher homologues, this approach was not taken further.
The synthesis of polyalkynes in the form of substituted propargyl brornides was also
studied. Initial copper(I) catalyzed coupling of 1-heptyne with 1,4-dibrornobutyne
gave 1-bromo-2,5-undecadiyne ín a 437o yield. Coupling of this diyne, under copper(I)
catalysis, with propargyl alcohol, followed by treatment with phosphorous tribromicle,
Save 1-bromo-2,5,8-tridecatriyne. Similarly, 1-bromo-4,7,70-hexa-decatriyne and
1-brorno-3,6,9-pentadecatriyne were formed by the copper(I) catalyzed coupling of
1-bromo-2,5-undecadiyne with 4-pentyn-l-ol and 3-butyn-1-ol, respectively, followed
by treatment with triphenylphosphine and carbon tetrabromide. Tl'rese results
inclicated that substituted propargyl bromides were readily available from this roube.
The utility of 1-bromo-2,5-undecadiyne and 1-bromo-2,5,8-tridecatriyne as substrates in
tlre copper(I) catalyzed reaction with S-hexynoic acid or 1-(4-pentynyt)-4-t.nethyl-2,6,7-
trioxabicyclo-Í2.2.2)octane was investigated. The yields of the coupled products were
generally poor and the results inconsistent, therefore this method was founcì to be
unsuitable for the synthesis of polyunsaturated very long chain fatty acids.
1V
Cuprate methodology was shown to be effective in coupling alkyl and alkenyl
brornides with ro-iodoesters to produce a range of very long chain fatty acid methyl
esters. Grignard derivatives of alkyl and alkenyl bromides were reacted with
metlrylcopper(I) (formed in situ), at low temperature, to form mixed dialkyl cuprate
species, which were subsequently reacted with co-iodoesters to produce a range of
saturated, monounsaturated and polyunsaturated very long chain fatty acid methyl
esters. A byproduct, due to competing methylation of the co-iodoesters, was observed
in all cases. Separation of the product esters from the methylatecl material was not
achieved in some cases. To overcome this problem, alternative cuprate species were
studied. Dialkyl cuprate species with two identical copper ligands were successfully
ernployed to form pure samples of very long chain fatty acid methyl esters for the cases
which could not be purified originally.
A study of the Wittig method as a means to form unsaturated very long chain fatty acid
methyl esters was also undertaken. 1-Bromononane and 1-bromooctadecalle were
treated with triphenylphosphine in acetonitrile to produce the corresponcling salts,
1-nonyl-triphenylphosphonium bromide and 1-octadecyltriphenyl-phosphonium
bromide, respectively. These saturated phosphonium salts were coupled with
o-oxoesters under cls-Wittig conditions to produce a range of monoenoic very long
t3ç-*tO
chain fatty acid methyl esters with high cis*tereoselectivity, as shown by
spectroscopy. In a similar fashion, 1-(cis-3-nonenyl)-triphenylphospl-ronium brornide,
formed by treating commercial c¡s-3-nonen-1-ol with phosphorous tribromide followed
by triphenylphosphine in acetonitrile, and l-(cis,cis,cis-3,6,9-pentadecatrienyl)-
triphenylphosphonium bromide, formed by reduction of 1-bromo-3,6,9-penta-
decatriyne with dicyclohexylborane followed by treatment with tripl-renylphosphine in
acetonitrile, were coupled to co-oxoesters to produce polyunsaturated very long chain
fatty acid methyl esters. In these cases, 13C-NVÍR spectroscopic analysis indicated a
significant amount of double bond isomerization.
V
The r¡-oxoesters and o-iodoesters used in this work were synthesized in a variety of
ways, keeping the methods as general as possible. o>Iodoesters were produced in good
yield and in few steps from a range of different starting materials. rrl-Hydroxyacids
were treated with hydrobromic acid in acetic acid and the co-bromoacids obtained were
trans-haloqenated with sodium iodide in acetone followed by esterification witl'r acidic
methanol to produce the required co-iodoesters. Alternatively, co-unsaturated acids and
esters, obtained commercially or synthetically, were treated with hydrobrornic acid in
hexane under radical conditions, followed by trøns-halogenation with socliurn iodide in
acetone and esterification of the acids with acidic methanol to provide another source
of ro-iodoesters. In a different approach, 4-chlorobutyryl chloride was treated with
metlranol followed by trans-halogenation with sodium iodide in acetone to produce
methyl 4-iodobutyrate.
co-Oxoesters were formed in good yield by the ozonolysis of a number of crr-unsaturated
esters
VI
INrnopucrroN
Interest in the area of fatty acids (FA) began as early as the beginning of the 1800s, due
to the industrial uses of oils, fats and waxes, where the FA are present as triglycerides.
çH2OCOR1
B2699-- ç -<H
eHtOCOR3
Rl, R2, R3 = alkyl
TRIGLYCERIDES
In the late 1800's, Lieben et a1.7,2 prepared all of the straight-chain saturated FA from
acetic to heptanoic acid. A few years later, Krafft3'A prepared a series of FA, starting
with stearic acid and, by systematic degradation, produced all of the homologous
saturated acids down to nonanoic acid. Previous to these syntheses, individual acids
had been prepared.5,6
Since the beginning of organic chemistry, FA have been one of the rnost intensely
studied class of compounds, with hundreds of FA being identified over the years.T The
continued interest in FA over rnore than a century, stems from the increasingly diverse
role of FA in a vast range of biological systems. A lot is known about the rnetabolism of
FA but still more remains unclear.
1
Introduction
The different types of FA include straight-chain saturated and unsaturated acids,
branched acids, acids with oxygen in the molecule (mostly 2-hydroxyacids) and acids
containing the cyclopropane ring.7 The work in this thesis only concerns the
straight-chain acids and it is these acids only that will be discussed.
Almost all of the FA content of living organisms is lipid bound. Only a very small
percentage of free FA exist in living cells. The function due to FA is either associated
with lipid bound FA or to enzymatically released FA where the liberation of the free FA
from the lipid is possibly the rate determining step.8 The three major types of lipids
associated with FA are the phospholipids, glycolipids and cholesterol esters, with the
cH2ocoRl
HH
R2coor- c H tr ans- CH3(CH2 CH=cHð-òcH2 ox
) 12 llL
HO NH
I
COR
cHzoPo3x
X = Serine, Ethanolamine, Choline, Inositol X = Sugar Unit
R1, R2 = alkyl R = alkyl
PHOSPHOLIPID GLYCOLIPID
CH. H
nðcä
2c}j2crj2
CH
R
R alkyl
CHOLESTEROL ESTER
2