Chemistry Reference
In-Depth Information
A principal structural difference between ergosterol and cholesterol that affects binding to polyene drugs is the
extra methyl group on the side-chain in ergosterol. This extra methyl is known to be introduced in nature by an
electrophilic alkylation of a double-bond system, and it employs
S
-adenosylmethionine (SAM) as the electrophilic
agent. We have already met SAM as a biochemical alkylating agent through S
N
2 reactions (see Box 6.5). The
role of SAM in these electrophilic reactions is similar. It possesses a good leaving group in the neutral molecule
S
-adenosylhomocysteine, and the methyl group can be donated to the alkene nucleophile in an electrophilic
addition.
Ad = adenosine
electrophilic addition;
C-methylation using SAM
Ad
S
-adenosyl-
homocysteine
second electrophilic
addition involving SAM
S
CO
2
H
NH
2
Ad
Ad
SAM
S
CO
2
H
H
3
C
S
CO
2
H
H
3
C
H
NH
2
1,2-hydride shift followed
by loss of proton
NH
2
H
e.g. lanosterol
NADPH
NADPH
H
e.g. cholesterol
NADPH
dehydrogenation
dehydrogenation
e.g. sitosterol
e.g. stigmasterol
e.g. ergosterol
Cholesterol and ergosterol share a common biosynthetic pathway from squalene oxide as far as lanosterol
(see Box 6.12), but then subsequent modifications vary. Part of the route to cholesterol involves reduction of
the side-chain double bond, an enzymic process utilizing the hydride donor NADPH as reducing agent (see
Box 7.6). During ergosterol biosynthesis, the side-chain double bond is involved in an electrophilic reaction with
SAM, addition yielding the anticipated tertiary carbocation. This carbocation then undergoes a Wagner - Meerwein
1,2-hydride shift (see Section 6.4.2), an unexpected change, and subsequently loses a proton from the SAM-derived
methyl group to generate a new alkene. NADPH reduction of this double bond leads to the
C
-methylated side-
chain, as found in ergosterol, though further unsaturation needs to be introduced via an enzymic dehydrogenation
reaction.
Plant sterols such as
stigmasterol
typically contain an extra ethyl group when compared with cholesterol. Now
this is not introduced by an electrophilic ethylation process; instead, two successive electrophilic methylation
processes occur, both involving SAM as methyl donor. Indeed, it is a methylene derivative like that just seen in
ergosterol formation that can act as the alkene for further electrophilic alkylation. After proton loss, the product
has a side-chain with an ethylidene substituent; the side-chains of the common plant sterols stigmasterol and
sitosterol
are then related by repeats of the reduction and dehydrogenation processes already seen in ergosterol
formation.
