Table Of ContentAU APPROACH TO THE SYNTHESIS
OP ASPERGILLIC ACID.
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A THESIS
submitted to
THE UNIVERSITY OE GLASGOW
in fulfilment of the
requirements for the
DEGREE OE DOCTOR OF PHILOSOPHY
■by
DAVID V. C. RAMSAY
May, 1951.
AR APPROACH TO THE SYNTHESIS OF ASPERGILLIC ACID
SUHMARY
Aspergillic acid, the antibiotic isolated from
cultures of the mould Aspergillus flavus, was shown
by hut cher end Vint erst einer to have structure (I) or
(IA) . Later, Bunn, Rewbold and Spring identified the
side-chains and showed that aspergillic acid must be
either (i; R a Bus, R! = Bu^-) or (I; R = Bu^, R1 ■= Bus) .
>1/ I
O OH
(i) (IA) (II)
The investigations described in this Thesis were
directed towards establishing methods for the synthesis
of pyrazine cyclic hydroxamic acids with the synthesis
of aspergillic acid as the ultimate objective.
Reduction of aspergillic acid gives deoxyaspergillic
acid (II), a 2-hydroxy-3:6-disubstituted pyrazine.
Thus it appeared possible that oxidation of a suitably
substituted pyrazine would lead to a synthesis of
aspergillic acid. This route was shown to be
'impracticable by Baxter, Newbold and Spring who found
that when a 2-ethoxy-3 :6-disubstituted pyrazine was
oxidised, oxidation occurred at the nitrogen remote
from the ethoxy group and hence hydrolysis to give a
hydroxyl group in the 2-position gave a compound which
was not a hydroxamic acid.
Although the direct oxidation method had proved
unsuccessful for a synthesis of aspergillic acid there
was a possibility that it could be used to prepare a
pyrazine cyclic hydroxamic acid by the following route
NH,
e/v-e- h CHO -C.A/ ^ ~CN OH
I I •
cisf-e% CHO % N -C N -QN OH
MH
I
O
(III) (IV)
The oxide (IV) was obtained in low yield. The scheme
however, had to be abandoned when difficulty was experienced
in hydrolysing the nitrile groups of the oxide as a
preliminary to the formation of the required hydroxyl
groups. An account is given of the experiments with
aminoiminosuecinonitrile (ill) which extend its
application as a synthetic intermediate.
An entirely different approach, namely the formation
of the pyrazine ring by ring-closure of an acyclic
hydroxsmic acid proved more successful. The following
general method for the synthesis of 3:6-disubstituted
pyrazine cyclic hydroxsmic acids has been developed:-
,NH1
R—
K-C<H CHO
-R
CO C&r-CH R' co NHC6r=c HR' 0=
OH OH OH
This method was applied successfully to three cases
including that of a homologue of aspergillic acid
(R ■ R1 1 = Et) which was isolated in very low yield.
The synthesis of one of the possible structures of
aspergillic acid (I; R = Bu^, R1 = Bus) was attempted
by this route. After a number of methods for the
synthesis of -unsaturated aldehydes had been
,
investigated the required Schiff.1 s base was prepared
as follows?-
Me-CO* C H = C H C f ---> ^ ) C ~ C H = C H C I
OH I
|H'OH
^ e>C=CfivCHO et = CH' CHO
^
AVe^CH- CH 'e^/ CHO M c CH CH-Cu ^ ch
| H- I /* ---£ I I /*
CO Cftr" CO C13r=C
cv
X NH E*" £f~
I I
OH OH
A satisfactory cyclisation of the SchiffTs base to
give (I; R = Bu^, R' = Bus) was not achieved.
An ultra-violet absorption spectrum showed that
the cyclic a,cid had been formed but only to thee xtent
of 30$? of a resinous reaction product isolated in
low yield. The difficulties encountered at this
ring-closure stage are discussed.
An alternative route to 3:6-disubstituted pyrazine
cyclic hydroxamic acids has been developed. An •C-.keto
hydroxsmic acid is condensed with an aminohetone to form
the cyclic acid in one step thus:-
NHt. AVc
R-CO < «- CH' CO
I
+ I >
C0\ CO-*' 0=\ ai/ “^ C4ff
NH x N
(V) 0H (VI) OH (VII) (VIII) CH
In the first instance pyruvchydroxamyl chloride
was converted into the bisulphite compound of
pyruvohydroxamic acid (V; R = Me). This was
condensed with aminoacetone (VI; Rf = Me) to give
an aspergillic acid homologue (VII; R = R* s Me)
in good yield. The structure of the cyclic acid was
completely defined when ' reduct ion gave 2-hydroxy-3:6-
dimethylpyrazine, a known compound.
Application of the above method to the aspergillic
acid case (VII; R = Bus, R1 = Bui) proved less successful.
A cyclic acid was not formed when the bisulphite
compound of the Jt-keto■*hydroxsmic acid (V; R = Bus)
was treated with the aminoketone (VI; R* = Bui). ^n
experiment in which the /.-keto-hydroxamic acid was
formed by hydrolysis of the hy dr ox amyl chloride (VIII)
with sodium acetate in acetic acid showed more promise.
The acid was not isolated but treated directly with, the
aminoketone. A non-crystalline reaction product had
an ultra-violet absorption spectrum from which it was
evident that it contained a small proportion of the
cyclic acid (VII; R = Bus, R1 = Bui).
The author wishes to record his indebtedness
to Professor P.S. Spring for his invaluable guidance
and constant encouragement. To Dr. J.A. Elvidge
the author is indebted for advice, especially on
practical techniques.
The author also wishes to thank Dr. G.T. Bewbold
for his continued interest and in particular for his
co-operation on some aspects of this investigation.
C 0 H T 1 I T S
Page
Historical ............... 1
Theoretical 14
Experimental ......... 78
Bibliography ....... 156
