Stereocontrol with Rotationally Restricted Amides - Jonathan ...

August 1998 Stereocontrol with Rotationally Restricted Amides 815
helps ensure the configurational stability of 20, and our nonstereospecific
tin-lithium exchange is unusual in not having a
heteroatom at the Li-bearing centre). But at this point, we started to
move into uncharted waters where "precedent" had no real meaning. All
of what I have so far described could have been done using conventional
chiral centres – practically this may be difficult, since few chiral
substituents would have the stereodirecting power we have seen in
rotationally restricted amides. But what comes next could not be done
with central chirality – because the thermal instability inherent in axial
chirality is the key to some remarkable stereochemical effects.
groups would lie anti across the ring, and 25 would exist not only as a
single atropisomer but as a single conformer also.
Chirality due to rotational restriction can not only control
stereochemistry, but it can also respond to stereochemistry. We first
began to realise the power in this when we were making the stannanes
21a and 21b. 21a is the kinetic product of the reaction, and on heating
for 2 days at 65 °C it gives 21b in 97% yield: 21b is much more
thermodynamically stable than 21a. The amide group and the nearby
chiral centre must be interlocked, and the stereogenic centre has a
remarkably powerful influence on the preferred conformation of the
amide. The same is true of the silyl-substituted 14 (X = Me 3 Si): a
mixture of syn- and anti-14 (X = SiMe 3 ) equilibrates on heating almost
entirely to syn-14 (X = SiMe 3 ). (This provided further evidence that syn-
14 and 21b have the same relative stereochemistry). The ethylsubstituted
14 (X = Et) are different: their equilibrium mixture contains
a 60:40 ratio of syn and anti diastereoisomers.
We reasoned that if this is true of naphthamides, it ought to be true of
benzamides too: 22, for example, ought to sit largely as one conformer,
while we would expect 18 to exist as a conformational mixture. NMR
confirms that we are right: the NMR spectrum of 22 shows one main set
of peaks for the syn-conformer shown, with a smaller set accounting for
about 13% of the total, which we assign to the anti-conformer. The
NMR spectrum of 18 on the other hand clearly shows a 55:45 mixture of
two sets of peaks.
We decided to see whether we could exploit this assumed anti
arrangement of the amides by trapping with another substituent – and
adding another ethyl group gives a single atropisomer of 26 (Scheme
13). Finally, Samreen did a lateral lithiation–quench to get a single
diastereoisomer of 27. 27 (whose X-ray crystal structure is illustrated in
Figure 7) has two stereogenic centres related para across an aromatic
ring, and one has controlled the other by passing stereochemical
information firstly from centre to axis, then from axis to axis, then from
axis to centre. Axially chiral amides can not only control and respond to
stereochemistry, but they can relay stereochemical information across
space.
Tertiary amides aren't flat – and they're certainly not unreactive towards
lithiation chemistry (recently we have shown that some of them have a
remarkable reactivity towards anionic cyclisation reactions 35 ). While
their spectra may be complex, the information these spectra contain can
be extraordinarily useful. We can expect plenty more from them yet.
To be of any value to us, these conformers need trapping as
atropisomers. We did this using the trick we introduced above – adding a
second substitutent. So, for example, lithiating 22 (lithiation takes place
selectively at the ortho position) and adding ethyl iodide gives the
product 23 as a single diastereoisomer (Scheme 12): a conformationally
enriched mixture becomes a single atropisomer on the addition of a
second ortho substituent. It is also true of 24, which Samreen Yasin,
during a 6 month Master's project, lithiated and quenched with N,Ndiisopropyl
carbamoyl chloride to give one atropisomer of 25. The
NMR spectrum of 25 is in fact remarkably simple, and we assumed
(evidently, on the basis of later results, correctly – and partly inspired by
Snieckus' crystal structure 34 of a similar compound) that the amide