Chemistry Reference
In-Depth Information
Box 9.4 (continued)
Coupling
ortho
to the phenol group in the tetrahydroisoquinoline and
para
to the phenol in the benzyl substituent
then yields the dienone salutaridine, found as a minor alkaloid constituent in the opium poppy. Only the original
benzyl aromatic ring can be restored to aromaticity, since the tetrahydroisoquinoline fragment becomes coupled
para
to the phenol function, a position that is already substituted.
The alkaloid thebaine is obtained by way of salutaridinol, formed from salutaridine by stereospecific reduction
of the carbonyl group involving NADPH as reducing agent (see Box 7.6). Ring closure to form the ether linkage
in thebaine would be the result of nucleophilic attack of the phenol group on to the dienol system and subsequent
displacement of the hydroxyl (termed an S
N
2
reaction). This cyclization step can be demonstrated chemically
by treatment of salutaridinol with acid.
In vivo
, however, an additional reaction is used to improve the nature of
the leaving group, and this is achieved by acetylation with acetyl-CoA. The cyclization then occurs readily, and
without any enzyme participation.
Subsequent reactions involve conversion of thebaine into morphine by way of codeine, a process that most
significantly removes two
O
-methyl groups. The involvement of these
O
-demethylation reactions is rather unusual;
metabolic pathways tend to increase the complexity of the product by adding methyls rather than removing them.
In this pathway, it is convenient to view the methyl groups in reticuline as protecting groups, which reduce the
possible coupling modes available during the oxidative coupling process; these groups are then removed towards
the end of the synthetic sequence.
Box 9.5
Phenolic oxidative coupling: the biosynthesis of thyroxine
The thyroid hormone
thyroxine
is necessary for the development and function of cells throughout the body. It
increases protein synthesis and oxygen consumption in almost all types of body tissue. Excess thyroxine causes
hyperthyroidism, with increased heart rate, blood pressure, overactivity, muscular weakness, and loss of weight.
hydrogen abstractions to
give resonance-stabilized
radicals
I
I
I
O
O
oxidative
coupling
O
HN
HN
HN
HO
O
O
I
I
I
I
I
O
I
O
O
HN
H
HN
HO
HN
O
O
H
I
I
I
iodinated tyrosine
residues in protein
thyroglobulin
aromaticity restored by E2
elimination reaction; phenolate
anion is good leaving group
CO
2
H
I
NH
2
HO
I
CO
2
H
I
HO
O
tyrosine
NH
2
HN
I
O
O
hydrolysis of peptide
(amide) bonds in
protein
I
I
thyroxine
I
O
HN
HO
I
