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. Crucial to the chemistry is the need to provide not only high yields but also high selectivities in the new reactions. Especially important for synthesis is the discovery of new carbon–carbon bond-forming reactions. Therefore, our research group is studying the use of organometallic compounds for the formation of nitrogen-containing compounds and their application to the synthesis of biologically active molecules.

The main focus of this work is on the use of chiral organolithium compounds in asymmetric synthesis using dynamic resolution. We are probing in depth the formation, properties, reactivity and reactions of chiral α-amino-organolithium compounds.

• For their formation, we are studying a variety of methods, including proton abstractions with a base and transmetallations of α-amino-organostannanes.
• For their properties, we are carrying out structural and kinetic studies to determine the aggregate structure and stability of the organolithium species. The rate of racemization of different substituted chiral organolithium compounds is being determined. This research is providing vital information on the role that different functional groups play on the configurational stability of chiral organolithium 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 inter- and intramolecular quenches of these organometallic compounds.

 

Intermolecular:

We have recently developed asymmetric methodology that is highly enantioselective using intermolecular reactions of chiral organometallic compounds. In particular, excellent results have been obtained with 2-lithiopyrrolidines (Scheme 1). 

 

Scheme 1

 

Addition of a chiral ligand L*, such as (-)-sparteine or the deprotonated prolinol derivative 1, to a chiral, racemic organolithium species, followed by quenching with different electrophiles gave enantiomerically enriched products. By this approach we have prepared 2-substituted pyrrolidines with very high levels of asymmetric induction.

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.

High yields and selectivities have recently been achieved in our chemistry and we have determined that the process occurs by a dynamic thermodynamic resolution. So, 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 (and other compounds).

 

In addition to these studies, we have determined, in collaboration with Professor Bob Gawley (University of Arkansas), the kinetics of racemization of various chiral organolithium compounds.

Scheme 2 shows the compounds that we have studied and their barriers to inversion. These values were determined by measuring the enantiomer ratios of the products after quenching over different time periods at 3 or 4 different temperatures. The enantiomerizations show first order kinetics and Eyring plots provide the enthalpies and entropies. In collaboration with Professor Fredrik Haeffner we have also calculated (DFT) the barriers to inversion and these support inversion through a monomer.

 

Scheme 2

 

Intramolecular:

Intramolecular carbolithiation (anionic cyclization) provides cyclic amine products with excellent levels of stereocontrol. We have determined that cyclization reactions proceed with retention of configuration at the carbanion (lithium-bearing) centre, during cyclization to a five-membered ring. This chemistry provides an extremely short, asymmetric synthesis of pyrrolizidine and indolizidine alkaloids such as pseudoheliotridane.

Current work in this area involves the use of proton abstraction methodology to prepare the desired organolithium compounds for cyclization.

 

 

Selected Publications

 

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'

Kh. M. Shakhidoyatov, I. Coldham, T. F. Ibragimov, Chem. Nat. Compds. 2011, 46, 929–931.

'Lithiation of deoxypeganinine and chiral synthesis of deoxypeganine derivatives'

O. Garcia-Calvo, N. Sotomayor, E. Lete, I. Coldham, Arkivoc 2011, v, 57–66.

'Organolithium or Heck-type cyclization of N-ortho-iodobenzyl-2-alkenylpyrrolidines to give indolizidines'

I. Coldham, D. Leonori, J. Org. Chem. 2010, 75, 4069–4077.

'Regioselective and Stereoselective Copper(I)-Promoted Allylation and Conjugate Addition of N-Boc-2-lithiopyrrolidine and N-Boc-2-lithiopiperidine'

S. P. Robinson, N. S. Sheikh, C. A. Baxter, I. Coldham, Tetrahedron Lett. 2010, 51, 3642–3644.

'Dynamic thermodynamic resolution of lithiated N-Boc-N'-alkylpiperazines'

I. Coldham, H. Adams, N. J. Ashweek, T. A. Barker, A. T. Reeder, M. C. Skilbeck, Tetrahedron Lett. 2010, 51, 2457–2460.

'Synthesis of 2-hydroxy-3-indolinones and 3-hydroxy-2-indolinones by anionic cyclization, in situ oxidation and rearrangement'

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'

I. Coldham, N. S. Sheikh, Top. Stereochem. 2010, 26, 253–293.

'Dynamic Resolutions of Chiral Organolithiums'

D. Leonori, I. Coldham, Adv. Synth. Cat. 2009, 351, 2619–2623.

'Direct Preparation of 7-Allyl- and 7-Arylindolines'

I. Coldham, D. Leonori, T. K. Beng, R. E. Gawley, Chem. Commun. 2009, 5239–5241.

'The Barrier to Enantiomerization and Dynamic Resolution of N-Boc-2-lithiopiperidine and the Effect of TMEDA'

T. K. Beng, T. I. Yousaf, I. Coldham, R. E. Gawley, J. Am. Chem. Soc. 2009, 131, 6908–6909.

'Enantiomerization Dynamics and a Catalytic Dynamic Resolution of N-Trimethylallyl-2-lithiopyrrolidine'

I. Coldham, S. Raimbault, P. T. Chovatia, J. J. Patel, D. Leonori, N. S. Sheikh, D. T. E. Whittaker, Chem. Commun. 2008, 4174–4176.

'Dynamic Resolution of N-Boc-2-lithiopiperidine'

I. Coldham, D. Leonori, Org. Lett. 2008, 10, 3923–3925.

'Synthesis of 2-Arylpiperidines by Palladium Couplings of Aryl Bromides with Organozinc Species Derived from Deprotonation of N-Boc-piperidine'

I. Coldham, J. J. Patel, S. Raimbault, D. T. E. Whittaker, H. Adams, G. Y. Fang, V. K. Aggarwal, Org. Lett. 2008, 10, 141–143.

'Asymmetric Lithiation–Substitution of Amines Involving Rearrangement of Borates'

T. I. Yousaf, R. L. Williams, I. Coldham, R. E. Gawley, Chem. Commun. 2008, 97–98.

'The Barrier to Enantiomerization of N-Boc-2-lithiopyrrolidine: The Effect of Chiral and Achiral Diamines'

I. Coldham, J. J. Patel, S. Raimbault, D. T. E. Whittaker, Chem. Commun. 2007, 4534–4536.

'Dynamic Kinetic and Kinetic Resolution of N-Boc-2-lithiopiperidine'

I. Coldham, P. O'Brien, J. J. Patel, S. Raimbault, A. J. Sanderson, D. Stead, D. T. E. Whittaker, Tetrahedron: Asymmetry 2007, 18, 2113–2119.

'Asymmetric deprotonation of N-Boc-piperidines'

I. Coldham, S. Dufour, T. F. N. Haxell, J. J. Patel, G. Sanchez-Jimenez, J. Am. Chem. Soc. 2006, 128, 10943–10951.

'Dynamic Thermodynamic and Dynamic Kinetic Resolution of 2-Lithiopyrrolidines'

C. Stratmann, G. Christoph, I. Coldham, D. Hoppe, Org. Lett. 2006, 8, 4469–4471.

'Asymmetric Synthesis of 3-Hydroxy-pyrrolidines via Tin–Lithium Exchange and Cyclization'

I. Coldham, J. J. Patel, G. Sanchez-Jimenez, Chem. Commun. 2005, 3083–3085.

'Dynamic Kinetic Resolution of N-Boc-2-lithiopyrrolidine'

N. J. Ashweek, P. Brandt, I. Coldham, S. Dufour, R. E. Gawley, F. Haeffner, R. Klein, G. Sanchez-Jimenez, J. Am. Chem. Soc. 2005, 127, 449–457.

'The Barrier to Enantiomerization of Unstabilized, Chelated, and Dipole-Stabilized 2-Lithiopyrrolidines'

I. Coldham, S. Dufour, T. F. N. Haxell, G. P. Vennall, Tetrahedron 2005, 61, 3205–3220.

'Dynamic Resolution of N-Alkyl-2-lithiopyrrolidines with the Chiral Ligand (-)-Sparteine'

R. E. Gawley, R. Klein, N. J. Ashweek, I. Coldham, Tetrahedron 2005, 61, 3271–3280.

'NMR Structural Studies of {⁶Li} 2-Lithiopyrrolidines'

R. E. Gawley, I. Coldham, in 'The Chemistry of Organolithium Compounds', eds. Z. Rappoport, I. Marek, Wiley, 2004, Ch. 16, p. 997–1053.

'α-Amino-organolithium Compounds'

I. Coldham, K. N. Price, R. E. Rathmell,Org. Biomol. Chem. 2003, 1, 2111–2119.

'Intramolecular Carbolithiation Reactions for the Preparation of 3-Alkenylpyrrolidines'

N. J. Ashweek, I. Coldham, T. F. N. Haxell, S. Howard, Org. Biomol. Chem. 2003, 1, 1532–1544.

'Preparation of Diamines by LithiationÐSubstitution of Imidazolidines and Pyrimidines'

I. Coldham, S. Dufour, T. F. N. Haxell, S. Howard, G. P. Vennall, Angew. Chem. Int. Ed. 2002, 41, 3887–3889.

'Enantioselective Synthesis of Substituted Pyrrolidines by Dynamic Resolution'

N. J. Ashweek, I. Coldham, D. J. Snowden, G. P. Vennall, Chem. Eur. J. 2002, 8, 195–207.

'Intramolecular Carbolithiation Reactions of Chiral α-Amino-organolithium Species'

I. Coldham, R. C. B. Copley, T. F. N. Haxell, S. Howard, Org. Lett. 2001, 3, 3799–3801.

'Synthesis of Chiral 1,2-Diamines by Asymmetric Lithiation-Substitution'

I. Coldham, R. Hufton, K. N. Price, R. E. Rathmell, D. J. Snowden and G. P. Vennall, Synthesis 2001, 1523–1531.

'Stereoselective Synthesis of Pyrrolidines and Pyrrolizidines by Intramolecular Carbolithiation'

I. Coldham, J.-C. Fernandez, K. N. Price, D. J. Snowden, J. Org. Chem. 2000, 65, 3788–3795.

'Intramolecular Carbolithiation Reactions for the Preparation of Azabicyclo[2.2.1]heptanes'

 

 

 

Further details are available from

Iain Coldham