Chemistry Reference
In-Depth Information
reaction (see Section 6.4.1). Bromination of the alkene under aqueous alkaline conditions then leads to formation
of the bromohydrin. Interestingly, this reaction is quite stereospecific. Only one bromonium cation is formed,
because the upper face of the steroid is sterically hindered by the methyl groups and approach of the large bromine
molecule occurs from the lower less-hindered
α
-face. Ring opening by nucleophilic attack of hydroxide occurs
from the upper
-face, and at C-11, since the methyl groups, particularly that at C-10, again hinder attack at C-9.
The natural glucocorticoid is
hydrocortisone
(
cortisol
). Semi-synthetic 9
β
-bromohydrocortisone 21-acetate
was found to be less active as an anti-inflammatory agent than hydrocortisone 21-acetate by a factor of three,
and 9
α
-fluorohydrocortisone
21-acetate (
fludrocortisone acetate
) was discovered to be about 11 times more active than hydrocortisone
acetate. Although the bromination sequence shown is equally applicable to chlorine and iodine compounds,
fluorine must be introduced indirectly by the
α
-iodohydrocortisone 21-acetate was also less active by a factor of 10. However, 9
α
β
-epoxide formed by base treatment of the 9
α
-bromo-11
β
-hydroxy
analogue.
OAc
OH
OAc
OH
21
O
OH
O
OH
O
OH
O
OH
HO
HO
HO
HO
11
H
H
H
H
1
9
16
2
10
F
H
H
H
Br
H
F
H
O
O
O
O
9
α
-bromohydrocortisone
acetate
fludrocortisone acetate
(9α-fluorohydrocortisone
acetate)
hydrocortisone
(cortisol)
betamethasone
-fluoro substituent increases anti-inflammatory activity, but it increases mineralocor-
ticoid activity even more (300
The introduction of a 9
α
). Fludrocortisone acetate is of little value as an anti-inflammatory, but it is
employed as a mineralocorticoid. On the other hand, additional modifications may be employed. Introduction
of a 1,2-double bond increases glucocorticoid activity over mineralocorticoid activity, and a 16-methyl group
reduces mineralocorticoid activity without affecting glucocorticoid activity. A combination of these three struc-
tural modifications gives valuable anti-inflammatory drugs, e.g.
betamethasone
, with hardly any mineralocorticoid
activity.
×
8.1.3 Electrophilic additions to alkynes
the less-substituted carbon, a secondary vinyl cation
being preferred over a primary vinyl cation. Thus,
electrophilic addition of HX follows Markovnikov
orientation.
The vinyl halide product is then able to react
with a further mole of HX, and the halide atom
already present influences the orientation of addition
in this step. The second halide adds to the carbon that
already carries a halide. In the case of the second
addition of HX to RC
≡
CH, we can see that we
are now considering the relative stabilities of tertiary
and primary carbocations. The halide's inductive
effect actually destabilizes the tertiary carbocation.
Nevertheless, this is outweighed by a favourable
stabilization from the halide by overlap of lone pair
electrons, helping to disperse the positive charge.
Electrophilic reactions of
alkynes
can readily be
predicted, based on the mechanisms outlined above
for alkenes. Of course, the main extension is that
addition will initially produce an alkene, which will
then undergo further addition.
Protonation of the alkyne is actually less favourable
than protonation of an alkene, because the result-
ing vinyl cation is
sp
hybridized, having
σ
bonds
π
to just two substituents, a
bond, and a vacant
p
orbital. A vinyl cation is thus less stable than
a comparable trigonal
sp
2
-hybridized carbocation,
since
sp
-hybridization brings bonding electrons closer
to carbon; it thus becomes less tolerant of posi-
tive charge. Protonation, when it occurs, will be on
