Stereocontrol with Rotationally Restricted Amides - Jonathan ...

August 1998 Stereocontrol with Rotationally Restricted Amides 811
by raising the temperature of 5 in the NMR machine. What happens to
the methyl doublets in its spectrum is shown in Figure 2: lineshape
simulation of the coalescences that take place at 72 °C and 97 °C
allowed us to estimate the barrier to rotation about both the Ar–CO bond
(which gives rise to axial chirality) and the C–N bond. 19 Both turned out
to be about 75 kJ mol –1 , so the enantiomers of 5 have a half-life of the
order of seconds at 20 °C. With 2-substituted naphthamides, barrier to
rotation is some 30 kJ mol –1 higher, 20 and almost all 2-substituted N,Ndiisopropyl
naphthamides we have made have been separable into
atropisomers. 21
We found that the rate of rotation about the Ar–CO bond in N,Ndiisopropyl
amides is usually at least two or three times slower than
N,N-diethyl or N,N-dimethyl amides – they are more stable as
atropisomers. They are also usually crystalline, and are more resistant to
nucleophilic attack by butyllithium during ortholithiation reactions.
Looking at models showed us another important feature: they are
superbly lopsided: one face of the naphthalene ring sees just one little
oxygen atom, while the other shelters under the leafy shade of the
nitrogen's isopropyl foliage (Figure 3). Surely any reagent we use to
attack the ring, or groups closely attached to the ring, will prefer to float
in from the oxygen's side, avoiding these entangling branches
If the group is a carbonyl group in the 2-position, this certainly is the
case. The bulkier the attacking reagent the better: Neil Westlund, my
first PhD student, found that Grignard reagents attack ketones to give
just the isomer resulting from approach alongside O rather than N
(Scheme 3), 22 and bulky reducing agents give excellent selectivity
towards the isomer arising from this same trajectory. 23 The X-ray crystal
structure of the compound obtained by adding EtMgBr to 7 is shown in
Figure 4 – Neil was able to make both diastereoisomers and show that
they were completely stable to interconversion on heating.
Rotational freedom elsewhere in the molecule complicates things, and
when Neil tried reactions using the aldehydes 10 he found that the
outcome depended on how well the nucleophile's metal counterion was
able to chelate both aldehyde and amide carbonyls (Scheme 4). 23 We are
Biographical Sketch
Jonathan Clayden was born in Kampala, Uganda in 1968 and grew up on the east coast of Essex.
After gaining a degree in Natural Sciences from the University of Cambridge he remained in
Cambridge to conduct research on enantioselective synthesis phosphine oxides under the
supervision of Dr Stuart Warren. In 1993 he received his PhD and moved to the École Normale
Supérieure in Paris as a Royal Society Western European Research Fellow, where he joined the
research group of Prof. Marc Julia. In September 1994 he moved to his current post as a
Lecturer in Organic Chemistry at the University of Manchester, where he began a research
programme investigating the application of rotational restriction to stereocontrolled synthesis,
and the application of lithiated amides to synthesis.