Chiral Organometallic Chemistry

New Methodology in Organic Synthesis

The development of new methods for the construction of novel compounds plays a crucial role in the field of synthetic chemistry. The importance and prevalence of nitrogen-containing compounds in natural products and medicinal drugs has led us to develop new chemistry for their formation. The chemistry needs to provide high yields and high selectivities if it is to be useful. Especially important for synthesis is the discovery of new carbon–carbon bond-forming reactions. There are many ways to form C–C bonds and our research group is studying the use of organometallic compounds, especially organolithium and organomagnesium compounds for stereoselective synthesis.

A focus of our work is on the formation, properties, reactivity and reactions of chiral α-amino-organolithium compounds. We have also started studying chiral α-nitrile-organomagnesium compounds.

  • For their formation, we are studying a variety of methods, particularly proton abstractions with a base.
  • For their properties, we are carrying out structural and kinetic studies to determine the aggregate structure and stability of the organometallic species. The rate of enantiomerization of different substituted chiral organometallic compounds is being determined. This research is providing valuable information on the role that different functional groups play on the configurational stability of chiral organometallic compounds.
  • We are determining the reactivity of these compounds and their mode of reaction with electrophiles, be it with retention, inversion or racemization of configuration.
  • For their reactions, we are investigating intermolecular quenches with a range of electrophiles and we have studied intramolecular carbolithiation reactions.

Preparation of 2-substituted pyrrolidines and piperidines

We have developed asymmetric methodology that is highly enantioselective using reactions of chiral organometallic compounds. Excellent results have been obtained for the dynamic resolution of 2-lithiopyrrolidines and 2-lithiopiperidines. The theory behind the chemistry is shown in Scheme 1.  

Dynamic Resolution Scheme

Scheme 1

Addition of a chiral ligand L*, such as (–)-sparteine or a diaminoalkoxide to a chiral, racemic organolithium species, followed by quenching with different electrophiles gives enantiomerically enriched products.

The key issues are the configurational stability of the organolithium compound (relative to its rate of reaction) and the steric course of the reaction (retention or inversion). Asymmetric induction can typically be achieved either by the formation of an enantiomerically enriched organolithium compound that maintains its optical purity (no racemization) or by asymmetric substitution of an organolithium compound that is complexed to a chiral ligand. In the latter case, the chiral ligand renders the organolithium complexes diastereomeric. One of these complexes may be present to a greater extent (thermodynamic resolution) and/or one may react with the electrophile faster than the other (kinetic resolution). If the organolithium complexes can interconvert then there is a dynamic resolution and it is possible to start with racemic organolithium species and prepare, in high yield, enantiomerically enriched products.

With N-alkyl-2-lithiopyrrolidines and N-Boc-2-lithiopiperidine, good selectivities have been achieved by a dynamic thermodynamic resolution. The enantiomer ratio of the products is a reflection of the greater proportion of one diastereomeric complex of the organolithium species over the other. There is however, some kinetic component (minor complex reacts faster) that can be observed when the reaction is quenched with less than one equivalent of the electrophile or when it is quenched slowly at temperatures in which dynamic equilibration is taking place. This chemistry has significant potential for the asymmetric synthesis of many different chiral amines.


Recently, we have been studying the lithiations of N-Boc-2-phenylpiperidine and N-Boc-tetrahydroisoquinoline. NMR and in situ IR spectroscopy have been helpful to monitor the rate of rotation of the Boc group. This rotation is important, as only one rotamer, with the carbonyl oxygen atom pointing towards the benzylic position, undergoes lithiation with n-BuLi.

For example, with N-Boc-tetrahydroisoquinoline we found that using a temperature of –50 oC was preferable to –78 oC as the rotation of the Boc group otherwise slows the lithiation at the 1-position. Addition of electrophiles (E+) then provides 1-substituted tetrahydroisoquinoline products. Removal or reduction of the Boc group leads to alkaloids, such as laudanosine (Scheme 2).



Scheme 2


For more details, see, for example:

R. A. Talk, A. Duperray, X. Li, I. Coldham, Org. Biomol. Chem. 2016, 14, 49084917.
'Synthesis of substituted tetrahydroisoquinolines by lithiation then electrophilic quench'
DOI: 10.1039/C6OB00577B

E. J. Cochrane, D. Leonori, L. A. Hassall, I. Coldham, Chem. Commun. 2014, 50, 99109913.
'Synthesis and kinetic resolution of N-Boc-2-arylpiperidines'
DOI: 10.1039/c4cc04576a

X. Li, I. Coldham, J. Am. Chem. Soc. 2014, 136, 55515554.
'Synthesis of 1,1-Disubstituted Tetrahydroisoquinolines by Lithiation and Substitution, with in Situ IR Spectroscopy and Configurational Stability Studies'
DOI: 10.1021/ja500485f

X. Li, D. Leonori, N. S. Sheikh, I. Coldham, Chem. Eur. J. 2013, 19, 7724–7730.
'Synthesis of 1-substituted tetrahydroisoquinolines by lithiation and electrophilic quench guided by in situ IR and NMR spectroscopy and application to the synthesis of salsolidine, carnegine and laudanosine'
DOI: 10.1002/chem.201301096

N. S. Sheikh, D. Leonori, G. Barker, J. D. Firth, K. R. Campos, A. J. H. M. Meijer, P. O'Brien, I. Coldham, J. Am. Chem. Soc. 2012, 134, 5300–5308.
'An Experimental and In Situ IR Spectroscopic Study of the Lithiation-Substitution of N-Boc 2-phenylpyrrolidine and piperidine: Controlling the Formation of Quaternary Stereocenters'
DOI: 10.1021/ja211398b

I. Coldham, S. Raimbault, D. T. E. Whittaker, P. T. Chovatia, D. Leonori, J. J. Patel, N. S. Sheikh, Chem. Eur. J. 2010, 16, 4082–4090.
'Asymmetric Substitutions of 2-Lithiated N-Boc-piperidine and N-Boc-azepine by Dynamic Resolution'
DOI: 10.1002/chem.200903059

Metallation and electrophilic quench of chiral nitriles

We have recently started a project on the configurational stability of metallated nitriles. These intermediates might be expected to be achiral (ketenimine structure), whereas in fact addition of an electrophile can provide enantioenriched products, indicating a C-metallated intermediate or possibly an ion pair (Scheme 3).

High selectivities are possible with a reactive electrophile, particularly if this is present in situ.


Metallated nitriles

Scheme 3


Information on nitriles in chemistry »

For more details, see, for example:

D. Nath, M. C. Skilbeck, I. Coldham, F. F. Fleming, Org. Lett. 2014, 16, 6265.
'Arylthio-Metal Exchange of alpha-Arylthioalkanenitriles'
DOI: 10.1021/ol403020s

G. Barker, M. R. Alshawish, M. C. Skilbeck, I. Coldham, Angew. Chem. Int. Ed. 2013, 52, 7700–7703.
'Remarkable Configurational Stability of Magnesiated Nitriles'
DOI: 10.1002/anie.201303442

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