TETRAHEDRON
LETTERS
Tetrahedron Letters 44 (2003) 3289–3292 Pergamon
The reaction of methyl isoferulate with FeCl
3
or
Ag
2
O—hypothesis on the biosynthesis of lithospermic acids and
related nor and neolignans
Philippe Cotelle* and Herve ´ Vezin
Laboratoire de Chimie Organique et Macromole ´culaire, UMR CNRS 8009, Universite ´ des Sciences et Technologies de Lille,
59655 Villeneuve d’Ascq, France
Received 25 February 2003; revised 27 February 2003; accepted 1 March 2003
Abstract—Methyl isoferulate reacts with FeCl
3
to give (2-6) dimer 3 (6-6) dimer 4 and (6-O-3) dimer 5 in low yields, whereas it
reacts with Ag
2
O leading to (2-O-3) dimer 6 and (6-O-3, 2-O-3) trimer 7. By comparison with literature data, we suggest that the
biosynthesis of lithospermic acids and related nor and neolignans that possess a -2 bond may be due to the cross dimerisation
of ferulate radical on isoferulate. © 2003 Elsevier Science Ltd. All rights reserved.
Lignans and neolignans have attracted much interest
over the years on account on their widespread occur-
rence in vegetal kingdom and their broad range of
biological activity including antitumoral, anti-inflam-
matory and antiviral activities. Of possibly even greater
importance is the isolation of lignans from animals
including human beings, which has led to the sugges-
tion that such compounds may be examples of a new
type of hormone controlling cell growth.
1
Lignans and neolignans are formed in nature by the
oxidative dimerisation of coniferyl alcohol
2
and can be
prepared from various C6C3 phenols 1 either by enzy-
matic oxidation or by using conventional oxidising
agents.
The most popular enzymatic system, i.e. horseradish
peroxidase/H
2
O
2
,
3
led to the obtention of neolignans as
main products, whereas the oxidative dimerisation of
ferulic alcohol with chloroperoxidase/H
2
O
2
4
or the oxi-
dation of caffeic acid by catechol oxidase
5
led to an
almost equimolar mixture of lignans and neolignans.
Chemically, the oxidative dimerisation of C6C3 phenols
1 may lead mainly to either lignans (FeCl
3
,
6
cathodic
reduction
7
or hepatic metabolism
8
) or neolignans
(Ag
2
O,
9
K
3
FeCN
6
,
10
, tri-t -butylphenoxyl radical,
11
proflavin,
12
anodic oxidation
13
or sodium periodate
14
)
or to a mixture of lignans and neolignans (alkaline
autoxidation
15
) (Scheme 1).
However, a new class of ‘neolignans’ has appeared
(lithospermic
16
, salvianolic,
17
przewalskinic
18
acids)
which cannot be biogenetically regarded as a product of
oxidative dimerisation of 1, since the C6C3 units are
linked by a -2 bond.
Scheme 1.
* Corresponding author. Tel.: 333 20 33 72 31; fax: 333 20 33 69 09; e-mail: philippe.cotelle@univ-lille1.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00584-7