Synthesis of unsaturated α-amino acid derivatives by palladium catalysed modification of the α

207 Pages·2016·11.02 MB·English

by  Peter Thomas Glink

\.qÌ
ß.
Synthesis of
unsaturated o(-amino acid derivatives
by palladium catalysed modification
g-side
of the chain
A thesis submitted for the degree of
Doctor of Philosophy
by
Peter Thomas Glink
The Department of Organic Chemistry
The University of Adelaide
Se.ptember 1993
A little knowledge is a dangerous thing.
Table of Contents
Abstract
Statement u
Acknowledgements üi
List of abbreviations iv
1.
Chapter Introduction.
1
Chapter 2. Heck reactions of vinylglycine derivatives. l7
2.I Introduction. Heck reactions. t7
2.2 Synthesis of vinylglycine derivatives. 2I
2.3 Synthesis of vinyl triflates and a halide. 26
2.4 Heck reactions of N-CBz-l-vinylglycine. 31
2.4.L Attempted coupling with vinyl triflates and halides. 31
2.4.2 Attempted coupling with aryl triflates and halides. 39
2.5 Heck reaction s of 2- (CBz-amino)-Z-but- 3 -enyl ac etate. 42
2.5.1 Attempted coupling with vinyl triflates and a halide. 42
2.5.2 Attempted coupling with aryl triflates and iodides. 44
Chapter 3. (Tributylstannyl)allylglycine derivatives. Synthesis and
reactivity. 47
3.1 Propargylglycine derivatives. Synthesis and enzymatic resolution. 47
3.2 Hydrostannation reactions. An overview. 50
3.3 Hydrostannation of ethyl N-acetylpropargylglycinate. 58
3.4 Stille coupling reactions. An overview. 6s
3.5 Stille coupling reactions of ethyl N-acetyl-1-tributylstannylallylglycinate. 68
3.5.1 Coupling with aryl halides. 68
3.5.2 Coupling with aryl triflates. 77
3.5.3 Coupling with vinyl halides. 80
3.5.4 Coupling with vinyl riflates. 84
3.5.5 Coupling with miscellaneous halides. 85
3.6 Stille coupling reactions of ethyl N-acetyl-ô-tributylstannylallylhglycinate. 88
3.6.1 Coupling with aryl halides and an aryl halide. 88
3.6.2 Coupling with vinyl halides and triflates. 89
3.6.3 Coupling with miscellaneous halides. 91
3.7 Copper(Il) nitrate mediated dimerisation of stannylallyl glycin ate s. 92
3.8 An attempted route to stannylated vinylglycine derivatives. 96
Chapter 4. Iodoallylglycinates. Synthesis and reactivity. 99
4.1 Formation of iodoallyglycinates by iododestannylation of
tributylstannylallylglycinates. r02
4.2 An attempted route to a trifloxyallylglycine derivative. 103
4.3 Heck reactions of ethyl N-aceryl-y-iodoallylglycinate. t07
4.4 Heck reactions of E-ethyl N-acetyl-ô-iodoatlylgtycinate. 111
4.5 Stille coupling reactions of ethyl N-acetyl-y-iodoallytglycinate. 114
4.6 Stille coupling reactions of E-ethyl N-acetyl-&iodoallylglycinate. tt7
4.7 Coupling of the iodoallylglycine derivatives with terminal alkynes. 119
4.8 Carboethoxylation reactions of the iodoallylglycine derivatives. r23
Chapter 5. Ethyl N-ac:etylbis(trimethylstannyl)allylglycinate. Synthesis
and reactivity. 127
5.1 Hexamethylditin addition to ethyl N-acetylpropargylglycinate. r21
5.2 Stitle coupling of cis-ethyl N-acetylbis(trimethylstannyl)allylglycinate. r29
5.3 Iododestannylation of c¡"s-ethyl N-acetylbis(trimethylstannyl)allylglycinate. t33
Experimental. r35
Bibliography. 188
I
Abstract
A number of routes to unsaturated cr-amino acid derivatives by modif,rcation of the side
chain of suitably protected amino acid precursors ¿re discussed, particularly palladium catalysed
processes.
Two L-vinylglycine derivatives were prepared from optically pure L-methionine. These
compounds were investigated as the olefinic moiety in palladium catalysed Heck reactions with
a variety of vinyl and aryl halides and trifluoromethanesulphonates. A number of
Þ,y-
unsaturated cr,-amino acid derivatives were prepared without racemisation of the chiral c[-centre.
A protected propargylglycine was prepared in racemic and chiral forms and was
converted to y and E-ô-tributylstannylallylglycine derivatives by palladium catalysed
hydrostannantion. These two vinylstannanes were investigated as partners in Stille coupling
with halides and triflates and a number of y,ô-unsaturated cr-amino acid derivatives were
prepared. Some interesting phenomena were observed, including cin¿-substituted products
formed from reaction of the y-stannane, phenyl substituted products arising from migration of a
phenyl group from a triphenylarsine ligand, and the propensity for aryl triflates to couple in the
absence of lithium chloride. Symmetrical 1,3-dienes were prepared stereospecifically from the
vinylstannanes by copper(Il) mediated dimerisation. No racemisation of the G-centre was
observed for these reactions.
The two vinylstannanes were converted to l and E-õ-iodoallylglycine derivatives by
electrophilic substitution with iodine. These vinyliodides were investigated in Heck coupling
with olefins and Stille coupling with organostannanes, with moderate success. Coupling with
terminal alkynes in the presence of palladium(O) and copper(I) cocatalysts yietded a number of
enynes. Carboethoxylation of the iodides by a palladium catalysed reaction wirh ethanol under
a ca¡bon monoxide atmosphere was also undertaken. No racemisation occurred at the ü-centre
for any of these reactions.
Addition of hexamethylditin to the triple bond of the propargylglycine derivative yielded
a crs-bis(trimethylstannyl)allylglycine derivative. This compound was investigated in a number
of Stille and iododestannylation reactions.
11
Statement
This thesis contains no material which has been accepted for the award of any other
degree or diploma in any university or other tertiary institution and, to the best of my
knowledge and belief, contains no material previously published or written by another person,
except where due reference has been made in the text.
I give consent to this copy of my thesis, when deposited in the University Library,
being made available for loan and photocopying.
20 7
Signed: Date
lu
Acknowled gements
When looking back over the last three and a half years of study, there a¡e a number of
people who must be thanked for their contribution towards the completion of this work.
Foremost amongst these people is my supervisor, Geoff Crisp, whose ideas, encouragement
and enthusiasm never waned, his ability to find references in the twinkling of an eye never
ceased to amazþ and whose cheap sarcasm never raised a laugh!
I have been fortunate to share lab space wittr a group of people who have made coming
in to uni enjoyable. To these people, the past and present members of 'Ye Olde Lab 5' and
now lab seven, and particularly (chronologically) George 'Skurry' Skouroumounis, Mick Pitt,
Bernard 'Bernie'Flynn, Adam 'The Big A' Meyer and Martin 'Skatole Max' Merrett,I send a
heartfelt thanþou for friendship, advice, chemicals and occasionally clean glassware. I would
particularly like to thank George and Bernie for their major contributions, practically and
theoretically, towards turning this inept into (I hope) a slightly less inept chemist.
_c_hemist
Thanks to Adam and Martin for proofraedt'ng this thesis. Thanks for all the triflates, too,
Adam.
I would like to acknowledge the past and present members of the Crisp group ("the
packet of Crisp's") for their good humour, helpful advice and stimulating discussion.
To other members of the research school, academic and technical staff I would also like
to extend my gratitude and best wishes for the future.
Thanks also to the tax payers of Australia for allowing me to ride the gravy train
throughout my Ph.D. years with an Australian Postgraduate Research Award.
My family deserve a big thankyou for constant encouragement to pursue my academic
career this far and for the comfortable and loving envi¡onment at home.
I salute you all!
lv
List of abbreviations.
AIBN Azobi sisobutyronitrile
CBz Carbobenzyloxy (PhCHzCOz-)
dba Dibenrytidineacetone
d.e. Diastereomeric excess
DEAD Diethyl azodicarboxylate
DMAP N, N-4- (dimethylamino)pyridine
DMF Dimethylformamide
DMFDMA Dimeûrylformamide dimethylacetal
DMSO Dimethylsulphoxide
e.e. . Enantiomeric excess
HMPA Hexamethylphosphoramide
IR Infra red
L Ligand
LDA Lithium dü sopropylamide
LHMDS Lithium hexamethyldisilizide
LICA Lithium cyclohexylisopropylamide
M Transition metal
NBS N-Bromosuccinimide
NMP N-Methylpyrollidinone
NMR Nuclear magnetic resonance
MS Mass spectromebry
o-Tol o-Tolyl (o-CH¡C¿H¿-)
PDC Pyridinium dichromate
PTC Phase transfer catalyst
TBDMS r-Butyldimethylsilyl
Tf (Trifl uoromethyl) sulphonyl
THF Tetrahydrofuran
- Clnpter I -
Introduction
cr-Amino acids in the form of peptides, proteins and enzymes are amongst the most
important biological compounds because of their vital role in sustaining life.l'2 To date, the
number of known naturally occurring amino acids is approaching one thousand,3 with
unnatural amino acids becoming increasingly important in areas such as pharmaceuticals,4
agrochemicalss and food products.6 This is because unnatural amino acids can, in some cases,
mimic the biological roles or enzymatic functions of their natural analogues. For instance, a
number of drugs a¡e derived from the non-natural D-amino acid series, such as the anticancer
agent, buseralin (1).4 fhis nonapeptide is believed to be active partly because of its resistance
to proteases invivo, that is, the inability of enzymes to hydrolyse the peptide bond of D-amino
acids. D-Alanine is an unnatural amino acid which is produced annually in bulk quantities
because of its utility in the synthesis of the artificial sweetener, alitame (2).7 Unnatural amino
acid derivatives are also used in the synthesis of novel peptides and proteins in an attempt to
furnish information about the mode of action of particular enzymes.S In addition to their
biological properties, amino acids are extremely important from a chemist's viewpoint as
synthetic intermediates and chiral auxiliaries.9'I0 161r is especially true for the proteinogenic
amino acids because they are readily available, optically pure, multifunctional molecules.l0
This is sometimes referred to as the synthetic approach via the chiral pool. Another very
common approach to 0-amino acids has, in recent years, been the asymmetric construction of
one of the four bonds which comprise the chiral c¿-centre.9 Although this approach has
produced excellent results, it is often plagued by problems associated with the separation of
enantiomers and the removal and recovery of chiral auxiliaries. The use of enantiomeric
separation techniques, such as enzymatic resolution, and chiral catalysts can overcome these
problems to some extent.
NH2
H
N
PyroGlu-His-Tr¡S er-Tyr-D-S er@u) -t eu -Arg-Pro-NHEt N
H
o Me
Buseralin, 1 Alihme,2
An important class of non-proteinogenic cr-amino acids a¡e those which possess olehnic
or acetylenic groups in the a-side chain. Many of these compounds, some of which are found
-Chapterl-
2
naturally, have been shown to act as irreversible mechanism based inhibitors of a number of
pyridoxal phosphate dependent and, to a lesser extent, flavin dependent enzyme5.ll These
unsaturated amino acids include olefinic compounds [e.g. vinylglycine (3),12 rhizobitoxin
(4),13 4-methoxyvinylglycine (5),14 3-methyleneaspartic acid (6),15 3,4-didehydroglutamic
acid (7),16 3-halovinylglycines (8),17 allylglycine (9),1lb'18 4-¡¿oallylglycines (10¡l9l and
acetylenic compounds [¿.g. propargytglycine (11),20 ethynylglycine (12)21]. Mechanism
based inhibitors (also known as kat inhibitors or suicide substrates) are a class of i¡reversible
inactivators of specific target enzymes where the target enzyme pafticipates in its own
destruction by catalytic unmasking of a latent functional group at some stage of the catalytic
cycle of the enzyme.ll
co2H co2H co2H
M"/
NHz NH2 NH2
3 4 5
co2H co2H co2H co2H
NH2 NH2 NH2 NH2
6 7 8 9
co2H co2H co2H
NH2 NHz NH2
10 11 L2
Pyridoxal phosphate dependant enzymes generally catalyse chemical changes at the a, p
and y-positions of proteinogenic amino acids.ll The types of enzymes which react at the cr-
cabon include transaminases (e.9. ¿-aspartate and L-alanine transaminases) and decarboxylases
(¿.g. glutamate deca¡boxylase); those which react at the p-carbon include decarboxylases
(aspartate decarboxylase) and p-eliminators (e.g. tryptophanase); and those which catalyse
chemical changes at the y-carbon include y-cystathionase (elimination) and y-cystathionine
synthetase (replacement). These enzymes are vital to biosynthesis and metabolism of the
relevant amino acids and inhibition can result in the disruption to the growth of cells, tissues
and even whole organisms. As examples of the biological roles of pyridoxal phosphate
dependant enzymes and the effects unsaturated o-amino acids can have on such enzymes,