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

2.4 – Mechanistic discussion
Gringard derived from norbornane, which was found to have an innate stereochemical
bias in its reaction. However, Hoffmann and co-workers succeeded in generating the
chiral secondary Grignard 154 in 90% e.e. from sulfoxide 153. In their reaction with
achiral substrates any isomerisation of the nucleophilic centre would due to a radical
intermediate; with a barrier to rotation estimated at only 0.5 kcal mol -1 this probe
should identify even the most short-lived radicals.
Ph
Cl
S Ar
O
153
EtMgCl (5 eq)
−78 to −30 °C
Ph
O
MgCl
E =
R H
< −30 °C
154 90% e.e.
R
OH
155
Ph
Entry E Product Yield / % e.e. / %
a R = Ph 155 84 84 & 88
b R = p-OMe C 6 H 4 155 82 84 & 89
c R = C 6 F 6 155 90 43 & 47
d CO 2 HO 2 C-CH(Et)Bn 80 92
e Ph 2 CO Ph 2 CO- CH(Et)Bn 85 12
Table 2.11 – addition of Hoffmann’s chiral Grignard to electrophiles 108
These results show a surprising preference for polar addition, with even addition to
benzophenone apparently exhibiting some polar nature. 108
Confirmation of absolute
configuration showed that the polar reaction proceeded with retention. Intriguingly,
the diastereomers resulting from addition to aldehydes were of different optical purities
(entries a-c, Table 2.11), even though they were isolated from the same reaction; no
explanation is offered for this outcome.
Instead of identifying partial radical nature, it is of course possible that all or some of
these reactions are entirely radical in nature, and that any apparent polar nature is
because the rate of radical combination is greater that bond rotation of 154•. However
this seems unlikely, and with the uncertainty of how to interpret data from other kinetic
methods, radical clocks such as 154 appears to offer the best measure of SET
behaviour, and the use of an organolithium equivalent would almost certainly offer
illumination about the mechanism of the dearomatising addition. Indeed, the 3:1
diastereomeric ratio of the exocyclic centre observed upon addition of s-BuLi could be
88