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Enantioselective Organocatalysis

Catalysis of reactions using an organic molecule as the catalytic species has been a significantly overlooked area in recent years. However, organocatalysis often has notable advantages over conventional transition metal catalysis. For example, organocatalytic reactions seldom suffer from the requirement for inert conditions frequently necessary in metal chemistry. Furthermore, environmental factors favour the use of non-toxic small organic molecules and they are often less expensive than the rare metal species commonly used in synthesis.

Organic Catalysts

We are developing new enantioselective organocatalytic processes that generate highly functionalised molecules from simple starting materials in a single step. Some of our early results are shown below.

1. Enantioselective Organocatalytic Cyclopropanation via Ammonium Ylides

The cyclopropane motif is a common feature in complex molecule synthesis and in medicinal chemistry due to a unique combination of reactivity and structural properties. These properties have made the preparation of cyclopropanes an attractive target for new methodology development. Despite the many processes for the synthesis of functionalized cyclopropanes there are surprisingly few general catalytic enantioselective methods. Of the methods available the carbenoid mediated reactions are most often utilized (eqns. 1 and 2) however, there are isolated examples of catalytic ylide based enantioselective cyclopropanations.

Recently, we described a new cyclopropanation process using a reaction that was mediated by a stoichiometric quantity of a nucleophilic tertiary amine through the formation of an ammonium ylide. Here, we report the development of a new enantioselective organocatalytic cyclopropanation reaction via ammonium ylides that produces a range of functionalized molecules with excellent diastereo- and enantioselectivity (eqn. 3).

Methods of Enantioselective Cyclopropanation

An organocatalytic cyclopropanation process via ammonium ylides has a number of advantages over its metal counterparts. There are no toxic transition metals involved in the reaction and the starting materials are readily available and conveniently handled. Furthermore, the number of known chiral amines represents a significant pool from which potential catalysts can be selected.

In this system an Α-bromo carbonyl compound 1 undergoes SN2 displacement with the tertiary amine catalyst 3 to form a quaternary ammonium salt I. Deprotonation with mild base forms the ylide II that undergoes conjugate addition to alkene 2, forming III. Finally, 3-exo-tet cyclization generates the cyclopropane 4 and reforms the catalyst.

Proposed Catalytic Cycle

The scope of this process is broad with more than 10 examples giving ee > 90% as either enantiomer. We are currently exploring applications in natural product synthesis and chemical biology using cyclopropanes as the key component. In summary, we have developed a new enantioselective organocatalytic cyclopropanation reaction. Importantly the cyclopropanes can be produced as either enantiomer using the quinine or quinidine series of cinchona alkaloid catalysts. The reaction is applicable to a range of substrates with a variety of versatile functional groups.


  1. Angew. Chem. Int. Ed. 2003, 42, 828.

  2. Angew. Chem. Int. Ed. 2004, 43, 4641.

2. Organocatalytic Intramolecular Cyclopropanation

Catalytic processes that form functionalized cyclic molecules represent a key transformation for synthetic organic chemistry. Recently, a number of organocatalytic processes have emerged that often provide excellent levels of both enantio- and diastereocontrol for the synthesis of cyclic molecules.

We have developed a new organocatalytic intramolecular cyclopropanation reaction that forms synthetically versatile [n.1.0]-bicycloalkanes using a nucleophilic tertiary amine catalyst.

The synthesis of these bicycloalkanes is most commonly carried out by inter- or intramolecular metal catalyzed carbene transfer of diazo-compounds to electron rich alkenes (eqn. 1). Other than these methods there are few general alternatives to form [n.1.0]-bicycloalkenes. [n.1.0]-Bicycloalkanes offer many exciting applications in complex molecule synthesis due to the high levels of stereochemistry and latent reactivity inherent within their structure. Therefore, new complementary methods for their catalytic enantioselective synthesis are very important. We have identified an interesting organocatalytic intramolecular cyclopropanation process that is stereoselective and produces highly functionalized bicycloalkanes containing three stereocentres, two rings and three levels of orthogonal functionality in a single step from linear building blocks (Scheme 1, eqn. 2).

Methods for Catalytic Intramolecular Cylcopropanation

In this approach an α-chloroketone with a tethered electron deficient alkene reacts through a catalytically generated ammonium ylide to form the bicyclic structure 2(Scheme 1, eqn. 2). This organocatalytic strategy precludes the use of highly sensitive diazo compounds. It should also offer a wider substrate scope due to compatibility with the metal-free catalyst, and produce bicycloalkanes with higher levels of functionality. Furthermore, there are many readily available chiral tertiary amines from which an enantioselective process can be developed.

Proposed Catalytic Cycle

A proposed catalytic cycle is shown in Scheme 2. The amine catalyst I displaces the chloride in 1 giving the quaternary ammonium salt II. Deprotonation forms the ammonium ylide III and intramolecular conjugate addition forms IV and finally the bicycloalkane 2 is generated through displacement of the ammonium group, concurrently re-generating catalyst I.

The scope of this new reaction was broad when DABCO was used as the catalyst with excellent yields and diastereoselectivity for a variety of substrates. However, DABCO was selected as the catalyst because of structural similarity to the cinchona alkaloids making it a racemic model for an enantioselective reaction. On replacement of DABCO with chiral cinchona alkaloid catalyst the reaction produced the bicycloalkanes in good yield and excellent enantioselectivity (95%). Importantly both enantiomers are accessible using the pseudoenantiomeric quinine/quinidine catalysts. To the best of our knowledge this excellent result represents the first enantioselective organocatalytic intramolecular cyclopropantion reaction.

Enantioselective Organocatalytic Intramolecular Cyclopropanation

In summary, we have developed an organocatalytic intramolecular cyclopropanation reaction for the formation of synthetically versatile [n.1.0]-bicycloalkanes as single diastereoisomers. This powerful catalytic process effects the controlled formation of three stereocenters, two carbon-carbon bonds and two rings in a single transformation. The reaction is enantioselective with a catalytic amount of chiral amine and can form either enantiomer. We are currently exploring the scope of the catalytic enantioselective process and applications towards the synthesis of complex molecules.


  1. Angew. Chem., Int. Ed. 2004, 43, 2681.
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