Stereocontrol with Rotationally Restricted Amides - Jonathan ...

810 J. Clayden SYNLETT 

Stereocontrol with Rotationally Restricted Amides 

Jonathan Clayden* 

Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK 

email j.p.clayden@man.ac.uk 

Received 5 May 1998 

Abstract: Rotational restriction in amides can be a blessing or a curse: 

this Account sets out highlight the former, in the light of our discovery 

that rotationally restricted amides have a remarkable ability to control 

stereochemistry. We start with an outline of the degree of steric 

hindrance to amide rotation required for a rotationally restricted amide 

group can give rise to stereoisomers, and move on to ways of using the 

amide group to control new stereogenic centres and to report the 

stereochemical details of substitution reactions. Amide stereochemistry 

can also respond to stereogenic centres within a molecule through 

"conformational interlocking", and we finish with an overview of the 

current state of affairs with regard to the use of amides to relay 

stereochemical information to remote stereogenic centres. 

by Mannschreck 9 using HPLC on a stationary phase – work followed up 

more recently by Pirkle 10 and by Pierini and Villani. 11 Mannschreck's 

work had also shown that, in general, for the axially chiral rotamers of 

tertiary aromatic amides to become atropisomers – that is, separable 

stereoisomers – the amide group must be flanked by two ortho 

substitutents. 

Most of us probably view tertiary amides as flat, hopelessly unreactive 

and really rather dull molecules. Those of us who have actually worked 

with them will also know that they have ghastly NMR spectra, ruined by 

slow rotation. The first tertiary aromatic amide I made, as a new postdoc 

in the group of Prof Marc Julia in 1993, was 1, and it seemed to 

confirm many of my expectations. But turning it into 2, a compound I 

needed as a sulfone precursor, 1 began a process of chipping away at 

those amide prejudices one by one. 

It turned out that these compounds had never been used for 

stereoselective reactions. 12 (We were only slightly put off our stride 

when Dennis Curran published 13 on the stereoselectivity of the reactions 

of axially chiral anilides – a topic that has now been followed up by two 

other research groups. 14,15 ) I asked one of the project students, Matthew 

Tomkinson, to make naphthamide 5, ortholithiate it, and add it to 

benzaldehyde. He did, and got two separable diastereoisomers syn- and 

anti-6 (Scheme 2), and we were able to prove their stereochemistry with 

a crystal structure (Figure 1). During the summer of 1995, I followed up 

his project with six weeks at the bench and found that most aldehydes 

show moderate selectivity in this reaction 16,17 – following Curran's lead, 

we called it "atroposelectivity" – for the syn diastereoisomer (syn 

because, as drawn, the hydroxyl group is on the same face of the ring as 

the amide carbonyl). 

Making 2 from 1 (Scheme 1) was my first ortholithiation – the one type 

of reaction which the "unreactivity" of tertiary amides suits very well: 

reactivity is diverted away from the carbonyl group and onto the 

aromatic ring. And the NMR spectrum of 2 was no longer a collection of 

broad hillocks but contained nice clean methyl doublets – four of them 

in fact. It was the realisation that the amide I was handling, with two 

pairs of diastereotopic methyl groups, was not flat, but twisted and 

therefore chiral, which started a train of thought that has led to a 

research programme that has been going on for four years and is still 

generating some fascinating chemistry. 

For the rest of my time as a post-doc, I mulled over the idea that the 

tertiary amides' axial chirality and their ability to direct lithiation might 

be made to work together in new stereoselective reactions, and when I 

started as a new lecturer in Manchester in 1994 I decided to invest my 

first research resources – three final year undergraduate research 

projects – in axially chiral amides. By this time I knew some of the 30- 

year history these compounds had, including the early 1970's debate 2-4 

about the reason for the geminal non-equivalence I had seen in my 

sulfide, an effect first noted in 1966. 5 1969 saw the resolution of 3 (and 

its separation from the meso diastereoisomer) by Ackerman and coworkers; 

6 1976 saw the resolution of the NMR debate by Jennings 7 and 

by Sandström; 8 and 1987 saw the resolution of tertiary 1-naphthamide 4 

We are still formulating a detailed explanation for the selectivity of this 

reaction, but coordination to the lithium atom must be the key. The 

simple attack of an aryllithium on a carbonyl group remains understood 

only in the crudest terms, but we realised that by introducing the 

question of stereochemistry to an otherwise "flat" reaction we could 

gain new insights into the mechanisms of organolithium reactions. The 

most significant success we have made in this vein is with laterally 

lithiated amides, of which more later. 

Our N,N-diisopropyl amides all had four diastereotopic methyl groups, 

as we had seen in the sulfide 2, and we were able to carry on the long 

tradition of using NMR to study conformational processes in amides 18

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.


now in a position to use conformationally anchored amides, with their 

ability to control the construction of a new chiral centre, to make new 

chiral auxiliaries. 

Chiral auxiliaries of course need to be made as single enantiomers, and 

we are only now just beginning to address this problem successfully. 

When Jennifer Pink, my first post-doctoral worker, joined the group in 

February 1996 we decided that she would start by applying the s-BuLi/ 

(–)-sparteine chemistry Peter Beak had used so successfully with 

benzamides 24 to our naphthamide systems. Jennifer set about lithiating 

2-substituted naphthamides 12 in the presence of (–)-sparteine 11, 

hoping for a kinetic resolution (Scheme 5). Disappointingly, neither the 

product 13 nor the remaining starting material displayed any useful 

enantiomeric excess, but remarkably the product was formed as only 

one single diastereoisomer. Shortly after we got this result, Peter Beak 

and Dennis Curran jointly published 25 on the limited success they had 

achieved in the asymmetric ortholithiation of naphthamides using s- 

BuLi/(–)-sparteine – the only time when I really did for a moment think 

we had been scooped! 

High levels of atroposelectivity turned out to be a general feature of the 

reactions of laterally lithiated amides with electrophiles, 26 and we were 

able to show that in general the favoured product was the one which had 

the new substitutent syn to the amide carbonyl group (Scheme 6): the 

ethyl-substituted syn-14 (X = Et) was crystalline, and its structure was 

proved by X-ray crystallography (Figure 5). Silyl-substituted syn-14 (X 

= PhMe 2 Si) could be converted to a known alcohol by a stereospecific 

Fleming oxidation – carried out at low temperature to avoid the 

possibility of epimerisation – and from this we deduced that the 

trimethylsilyl compound 13 had the same stereochemistry. Even 

deuterated syn-14 (X = D) was shown to have this same stereochemistry 

by NOE experiments. 

We surmised that this stereoselectivity would be a feature not only of 

naphthamide lateral lithiations, but also the lithiations of other 2-alkyl 

tertiary aromatic amides. Indeed, when Jennifer repeated the reactions 

on 2,6-disubstituted benzamide 15, she found she could do two 

successive stereoselective lateral lithiations, to make compounds such as 

16 with 1,5-related chiral centres (Scheme 7). 22 This raised the question 

of benzamide 17 (Scheme 8) – would its lithiation–quench reactions be 

diastereoselective The problem is of course that any stereoselectivity 

we might get in the reaction would be lost by the time we had warmed 

and worked the reaction up, because in benzamides like 18, with only 

one substituent ortho to the amide, the stereoisomers are merely rapidly


Ar–CO bond) stereochemical information could not survive from the 

lithiation step through to the final product 14. 

interconverting conformers. How could we observe an initial ratio of 

products obtained at low temperature A rough calculation suggested 

that the barrier to rotation 27 about the Ar–CO bond of 17 was such 

(about 60 kJ mol –1 ) that if we carried out the reaction at –78 °C the two 

stereoisomers might interconvert sufficiently slowly to be trappable as 

atropisomers by carrying out a second ortholithiation in situ. And indeed 

this worked: Jennifer laterally lithiated 17 (no ortholithiation was 

observed here) and added ethyl iodide, to give 18. Then – still keeping 

the reaction cold – she lithiated again, added methyl iodide, and got 19 

as a 90:10 ratio of products. At –78 °C, 17 behaves as a chiral 

compound! 

As it happened, these laterally lithiated naphthamides were about to 

inflict a series of blows to our confidence in making deductions from 

precedents – the first being that 20 is in fact configurationally stable 

even at –40 °C. 29 In the end, though, the experiments we designed to 

investigate the structure of 20 told us much more than we had originally 

expected, and we managed to get some important insights into the 

mechanisms of electrophilic substitution reactions of organolithiums 

and organostannanes. 

Our understanding of all of these reactions was complicated by the fact 

that there are two possible sources of stereoselectivity (Scheme 9): the 

first step (the lithiation) or the second (the electrophilic quench). The 

literature led us to expect the second, because Beak had shown that 

lithiated 17 is configurationally unstable at the lithium-bearing centre, 28 

and with a configurationally unstable organolithium 20 (that is, 

configurational stability at the lithium-bearing centre: we know that a 

2,6-disubstituted aromatic amide will be configurationally stable at the 

The experiments started with the atropisomeric stannane 21a, which, 

like its silyl analogues, was formed largely as a single atropisomeric 

diastereoisomer (though we could not at this stage be sure which one, so 

we must leave the stereochemistry of 21a undefined for the moment) on 

quenching laterally lithiated 12 with Bu 3 SnCl. 29 Stannane 21a could be 

transmetallated back to an organolithium and then quenched with an 

electrophile (ethyl iodide) and gave a 60:40 mixture of diastereoisomers 

of 14 (Scheme 10). Thanks to the thermal instability of atropisomeric 

diastereoisomers, Jennifer was able to epimerise 21a to its 

diastereoisomer 21b just heating it at 65 °C for a couple of days – 

indeed, it required considerable care to prevent the thermodynamically 

unstable 21a epimerising to 21b simply on work up. Unlike 21a, 21b 

gave a single diastereoisomer of 14 on transmetallation–electrophilic 

quench. The intermediate organolithium 20 clearly has some degree of 

configurational stability (or the two stannanes would have given 

identical results), but the results themselves raised yet more questions – 

for example, was the 60:40 ratio we got from 21a a consequence of slow 

equilibration between diastereoisomers of the intermediate 

organolithium 20, or did the transmetallation itself produce a mixture of 

organolithiums We spent some time designing and carrying out 

experiments to eliminate possibilities one by one, but in the end, we 

decided simply to run proton NMR spectra of the organolithiums we 

had obtained (a) just by lithiating the amide 12, (b) by transmetallating 

stannane 21a, and (c) by transmetallating stannane 21b. The aromatic 

regions of the spectra we got (shifted upfield as these are anions) are 

shown in Figures 6a, 6b and 6c, and remained the same after 1 hr at –40 

°C.


The mechanistic jigsaw was at this point nearly complete, but although 

we knew that the electrophilic substitution of lithium for tin went with 

inversion, we knew the stereochemistry of neither the organolithium 20 

nor of the stannane 21. We did know the stereochemistry of the products 

of alkylating, silylating and deuterating organolithium 20, but not the 

stereochemical course (retention or inversion) of the reaction (we were 

by now wary of precedents! 32 ). The key unknown was the 

stereochemistry of the organolithium we got by lithiating 12: was it syn- 

20 or anti-20 The way to find out was to re-deprotonate the deuterated 

compound syn-14 (X = D). If lithiation of 12 gives syn-20, lithiation of 

syn-14 (X = D) would involve breaking a C–D bond and would therefore 

be disrupted to some degree by the high values that primary kinetic 

isotope effects can take at –78 °C. 33 On the other hand, if lithiation of 12 

gives anti-20, lithiation of syn-14 (X = D) would not involve C–D bondbreakage 

and lithiation–electrophilic quench reactions of 12 and syn-14 

(X = D) should follow the same course. When we lithiated syn-14 (X = 

D), we got a mixture of diastereoisomers, and a mixture of protonated 

and deuterated products, all consistent with a primary kinetic isotope 

effect operating on the deprotonation, and indicating that the spectra in 

Figures 6a and 6c are those of syn-20, and hence that 21a is anti-21 (and 

21b is syn-21). 

So, the complete picture (Scheme 11) starts with a stereoselective 

deprotonation 12, presumably directed by coordination of s-BuLi to the 

amide carbonyl, to give syn-20, which reacts with retention with most 

electrophiles but with inversion with Bu 3 SnCl. The stannane 21a thus 

formed transmetallates non-stereospecifically to give a 65:35 mixture of 

stereoisomers of the organolithium syn- and anti-20. Just to confuse the 

issue still further, unlike syn-20, anti-20 does not react stereospecifically 

with electrophiles: a 65:35 ratio of syn:anti-20 converts, on reaction 

with ethyl iodide, to a 40:60 ratio of syn:anti-14! 

The spectra from 21a and 21b (Figures 6b and 6c) are different – and 

remain different – confirming the configurational stability of the 

organolithiums. Not only that, but while lithiation of 12 and 

transmetallation of 21b (Figures 6a and 6c) clearly give single 

organolithiums, the spectrum obtained by transmetallating 21a (Figure 

6b) shows a mixture of organolithium diastereoisomers – and this means 

that the transmetallation of the stannane was not stereospecific. This 

was even more of a surprise, since until this moment the 

stereospecificity of tin-lithium exchange had remained unquestioned 30 

since W. C. Still's seminal paper in 1980. 31 

The transmetallation of 21b, on the other hand, was stereospecific – and 

gave the same organolithium 20 as that obtained by lithiation of amide 

12. This means that the sequence of reactions from 12→20→21a→21b 

and back to 20 must contain two inversions of stereochemistry: one we 

know is the thermal epimerisation of 21a to 21b: is the other one the 

Li→Sn (20 to 21a) step or the Sn→Li (21b to 20) step It would have 

been remarkable if it had been the second – which would then be a 

stereospecific but invertive tin-lithium exchange – and indeed we now 

have plenty of evidence that it is the Li→Sn (20 to 21a) step which 

proceeds with inversion. 

All of this mechanistic reasoning was made possible by the fact that the 

amide not only controls the stereochemical course of some of the 

reactions, but acts as a stereochemical marker, telling us whether we are 

getting retention or inversion in the reactions, or a mixture. This was 

quite unexpected to us, and the idea of using a simple bystander group 

as a standard against which to judge the stereochemical course of the 

reaction really deserves revisiting in more detail. 

Although many of our conclusions seemed to go against literature 

precedents, we now believe we understand why our systems are 

different to those which have gone before (we think, for example, that 

the inability of the amide to lie anywhere near coplanar with the ring


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


Acknowledgements 

The work I have described was turned from ideas to substance by the 

dedicated researchers who have been part of my research group during 

the last four years. Some of their names are mentioned in the text, but I 

should also like to acknowledge the continuing contributions of Anjum 

Ahmed, Catherine McCarthy, Lai Wah Lai and Ryan Bragg in this area. 

Wide-ranging discussions with Dr Tim Donohoe helped keep up the 

flow of new ideas, and Dr Ian Watt has kept me on the rails with regard 

to interpreting kinetic data. Finally, I am grateful to the Leverhulme 

Trust, the Royal Society, Zeneca, Roche and GlaxoWellcome for 

funding this area of our research. 

References 

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Trans. 1 1995, 7. 

2. Bedford, G. R.; Greatbanks, D.; Rogers, D. B. J. Chem. Soc., 

Chem. Commun. 1966, 330. 

3. Lewin, A. H.; Frucht, M. Tetrahedron Lett. 1970, 1079. 

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Chem. Soc. 1992, 114, 6577. I am grateful to Prof Reich, and also 

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poor stereospecificity of our reaction. 

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