Dipolar Cycloaddition Reactions

Total Synthesis of Biologically Active Compounds

We have developed expertise in the synthesis of alkaloid natural products and analogues. Such compounds form the basis of important medicinal drugs or agrochemicals. Our strategy is to construct the core ring systems of alkaloids using an intramolecular cycloaddition reaction as the key step. This is an efficient strategy to polycyclic compounds as it allows the formation of two new rings and a number of new chiral centres in one step, with control of regio- and stereochemistry.

The key reaction that we have focused on is the cycloaddition of an azomethine ylide and an alkene. There are various methods known for the formation of azomethine ylides, one of the simplest being to condense an aldehyde with a secondary amine. This gives an intermediate iminium ion that loses a proton to form the ylide. We are applying this methodology to the synthesis of several alkaloids including:

Manzamine A

Manzamine A is an alkaloid first isolated from the marine sponge haliclona sp. It was shown to have significant biological activity, inhibiting P388 mouse leukemia with IC₅₀ 0.07 µg/mL. Manzamine A has also been screened against human tumour cell lines by the NCI and has a broad spectrum of activity. In the last few years the interest in this compound has increased significantly and it is now known to be an effective anti-malarial, an anti-inflammatory agent, an insecticide and fungicide and to inhibit mycobacterium tuberculosis.

Our chemistry towards this natural product uses an intramolecular cycloaddition of an azomethine ylide as shown in Scheme 1. The product was isolated in about 45% yield and represents the tricyclic ABC ring system of manzamine A. Only one stereoisomer was formed and X-ray crystallography confirmed the relative stereochemistry.

 

Scheme 1

 

We have subsequently found that the corresponding dimethyl acetal rather than the dithiane is a better substrate for the cycloaddition process. Interestingly, use of glycine ethyl ester (a primary amine) rather than N-methyl or N-allyl-glycine ethyl ester (a secondary amine) gives a different stereoisomer of the product (epimeric ethyl ester group).

Conversion of the cycloadduct to the tetracyclic ABCE ring system of manzamine A has been achieved, with the 8-membered E ring being installed using a ring-closing metathesis strategy (Scheme 2). Investigations are continuing in our research group on the synthesis of manzamine A using this chemistry.

 

Scheme 2

 

In addition to these studies, we are preparing simpler analogues for biological tests. For example, heating 1-chloro-beta-carboline with a selection of amines provides various analogues such as those shown in Scheme 3. These have been tested for anti-cancer activity by the National Cancer Institute and for anti-malarial activity by the World Health Organisation.

 

Scheme 3

Aspidospermidine, aspidospermine and quebrachamine

Aspidospermidine is the simplest of a range of indole alkaloids containing a pentacyclic ring system. We have developed a short and efficient synthesis of several Aspidosperma alkaloids using a cyclization/cycloaddition cascade.

The key step in this chemistry is the addition of the simple amino-acid glycine to an aldehyde that contains two alkyl tethers, one with a halide leaving group and one with an alkene dipolarophile. Cyclization of the intermediate imine and decarboxylation provides the azomethine ylide that undergoes in situ intramolecular cycloaddition onto the alkene, as shown in Scheme 4. A single stereoisomer of the tricyclic product was isolated and its stereochemistry was confirmed by X-ray crystallography. Subsequent hydrolysis of the acetal gave the ketone that can be converted (using Fischer indole synthesis) to aspidospermidine, aspidospermine and quebrachamine.

 

Scheme 4

This work has been highlighted on the cover page of J. Org. Chem. 2009, issue 6, with a backdrop of the 300-year-old cascade at Chatsworth House near Sheffield:

JOC cover page web site

 

 

 

Selected Publications

 

I. Coldham, A. J. M. Burrell, H. D. S. Guerrand, L. Watson, N. G. Martin, N. Oram, Beilstein J. Org. Chem. 2012, 8, 107–111.

'Synthesis of fused tricyclic amines unsubstituted at the ring-junction positions by a cascade condensation, cyclization, cycloaddition then decarbonylation strategy'

I. Coldham, A. J. M. Burrell, L. Watson, N. Oram, N. G. Martin, Heterocycles 2012, 84, 597–613.

'Synthesis of fused tricyclic heterocycles by condensation, cyclization, dipolar cycloaddition cascade of alpha-benzenesulfonyl and alpha-phenylthio substituted aldehydes'

H. D. S. Guerrand, H. Adams, I. Coldham, Org. Biomol. Chem. 2011, 9, 7921–7928.

'Cascade Cyclization, Dipolar Cycloaddition of Azomethine Imines for the Synthesis of Pyrazolidines'

I. Coldham, L. Watson, H. Adams, N. G. Martin, J. Org. Chem. 2011, 76, 2360–2366.

'Synthesis of the Core Ring System of the Yuzurimine Type Daphniphyllum Alkaloids by Cascade Condensation, Cyclization, Cycloaddition Chemistry'

I. Coldham, A. J. M. Burrell, H. D. S. Guerrand, N. Oram, Org. Lett. 2011, 13, 1267–1269.

'Cascade Cyclization, Dipolar Cycloaddition to Bridged Tricyclic Amines Related to the Daphniphyllum Alkaloids'

A. I. Franklin, D. Bensa, H. Adams, I. Coldham, Org. Biomol. Chem. 2011, 9, 1901–1907.

'Transannular dipolar cycloaddition as an approach towards the synthesis of the core ring system of the sarain alkaloids'

A. J. M. Burrell, L. Watson, N. G. Martin, N. Oram, I. Coldham, Org. Biomol. Chem. 2010, 8, 4530–4532.

'Synthesis of the core ring system of the stemona alkaloids by cascade condensation, cyclization, intramolecular cycloaddition'

A. J. M. Burrell, I. Coldham, Curr. Org. Synth. 2010, 7, 312–331.

'Synthesis of Natural Products using Intramolecular Dipolar Cycloaddition Reactions'

A. J. M. Burrell, I. Coldham, N. Oram, Org. Lett. 2009, 11, 1515–1518.

'Synthesis of Fused Tricyclic Amines from Enolisable Acyclic Aldehydes by Cyclization then Dipolar Cycloaddition Cascade: Synthesis of Myrioxazine A'

I. Coldham, S. Jana, L. Watson, N. G. Martin, Org. Biomol. Chem. 2009, 7, 1674–1679.

'Cascade condensation, cyclization, intermolecular dipolar cycloaddition by multi-component coupling and application to a synthesis of (±)-crispine A'

A. J. M. Burrell, I. Coldham, L. Watson, N. Oram, C. D. Pilgram, N. G. Martin, J. Org. Chem. 2009, 74, 2290–2300.

'Stereoselective Formation of Fused Tricyclic Amines from Acyclic Aldehydes by a Cascade Process Involving Condensation, Cyclization and Dipolar Cycloaddition'

I. Coldham, S. Jana, L. Watson, C. D. Pilgram, Tetrahedron Lett. 2008, 49, 5408–5410.

'Cascade Cyclization Intermolecular Dipolar Cycloaddition by Multi-component Couplings - Synthesis of Indolizidines and Pyrrolizidines'

I. Coldham, A. J. M. Burrell, L. E. White, H. Adams, N. Oram, Angew. Chem. Int. Ed. 2007, 46, 6159–6162.

'Highly Efficient Synthesis of Tricyclic Amines by Cyclization/Cycloaddition Cascade: Total Syntheses of Aspidospermine, Aspidospermidine and Quebrachamine'

I. Coldham, B. C. Dobson, S. R. Fletcher, A. I. Franklin, Eur. J. Org. Chem. 2007, 2676–2686.

'Intramolecular Dipolar Cycloaddition Reactions to give Substituted Indoles - a Formal Synthesis of Deethylibophyllidine'

I. Coldham, B. C. Dobson, A. I. Franklin, S. R. Fletcher, Tetrahedron Lett. 2007, 48, 873–875.

'Synthesis of Tetracyclic Indole-containing Ring Systems by Intramolecular Cycloadditions of Azomethine Ylides'

I. Coldham, R. Hufton, Chem. Rev. 2005, 105, 2765–2810.

'Intramolecular Dipolar Cycloaddition Reactions of Azomethine Ylides'

I. Coldham, S. M. Pih, R. Rabot, Synlett 2005, 1743–1745.

'Dipolar Cycloaddition and Ring-Closing Metathesis in the Synthesis of the Tetracyclic ABCE Ring System of Manzamine A'

Y. Boursereau, I. Coldham, Bioorg. Med. Chem. Lett. 2004, 14, 5841–5844.

'Synthesis and Biological Studies of 1-Amino beta-Carbolines'

I. Coldham, K. M. Crapnell, J.-C. Fernandez, J. D. Moseley, R. Rabot, J. Org. Chem. 2002, 67, 6181–6187.

'Synthesis of the ABC Ring System of Manzamine A'

I. Coldham, K. M. Crapnell, J. D. Moseley, R. Rabot, J. Chem. Soc., Perkin Trans. 1 2001, 1758–1763.

'Intramolecular Azomethine Ylide Cycloaddition Reactions to give Octahydroindoles'

I. Coldham, S. J. Coles, K. M. Crapnell, J.-C. Fernandez, T. F. N. Haxell, M. B. Hursthouse, J. D. Moseley, A. B. Treacy, Chem. Commun. 1999, 1757–1758.

'A New, Stereoselective Approach to the Manzamine Alkaloids'

 

 

 

Further details are available from

Iain Coldham