A Route to Carbasugar Analogues - Jonathan Clayden - The ...

Chapter 1: Introduction
controlled protonation of cyclohexadienyl anion 7, arguments for which mostly
resemble the principle of least motion analysis. 6 Relatively recent MO calculations of
7 by Zimmerman show that electron density is highest at the centre of the conjugated
H
H
system. 7 Li, NH 3
ROH
ROH, −33 °C
7 8
~70%
Scheme 1.3 – the Birch reduction
The regioselectivity of the reaction of substituted benzenes is highly dependent upon
the substituent, but often follows the Birch rule, 7 in which the product is the
“regioisomer with the maximum number of alkyl and/or alkoxy groups on the residual
double bonds.” The reason for this empirical rule becomes clear when considering the
most stable radical anion resulting from the first reduction, allowing the above
statement to be generalised; electron donating groups result in vinylogous products
(9), 8 whilst electron withdrawing groups give allylic products (11). 9
OMe
OMe
Li, NH 3 , THF
t-BuOH, −33 °C
9
75%
O
NMe 2
K (2.2 eq), NH 3
t-BuOH (1 eq)
THF, −78 °C
OK
NMe 2
NH 4 Cl
O
NMe 2
10 11
92%
Scheme 1.4 – regiomeric products of the Birch reduction
As expected, more electron deficient arenes are reduced more rapidly, and a
conjugated electron withdrawing group, such as an ester, gives stable enolates (10)
which may be quenched with a range of electrophiles. If there is a source of
asymmetry in the enolate, then preferential attack may occur on one of the
diastereotopic faces. This source of diastereoselectivity may be inherent in the
substrate (Scheme 1.5) or by means of a chiral auxiliary (Scheme 1.6, next section).
The former was demonstrated in House’s study of the synthesis of gibberellins, when
the stereochemistry of the quench was shown to be determined solely by the bulk of
17