Dipolar Cycloaddition Reactions

Using 1,3-Dipoles for the Synthesis of Alkaloids

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.

A 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.


Route to manzamine A

Scheme 1


We have subsequently found that the corresponding dimethyl acetal rather than the dithiane is a better substrate for the cycloaddition process.

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).


Route to ABCE rings of manzamine A

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.


Analogues of manzamine A

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., with a backdrop of the 300-year-old cascade at Chatsworth House near Sheffield:

JOC cover page web site

Bridged alkaloid ring systems

We are currently investigating this efficient cyclization/cycloaddition cascade for the formation of bridged bicyclic rings. A good 1,3-dipole for this chemistry is a nitrone which can be prepared from the same aldehyde substrates by condensation (to an oxime) then cyclization (to a nitrone) then cycloaddition.

For example, heating the aldehyde shown in Scheme 5 with hydroxylamine hydrochloride gives an excellent yield of the tricyclic product shown. This product can be converted to the core of some daphniphyllum alkaloids such as daphnilactone B.



Scheme 5

For more details, see, for example:

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 α-benzenesulfonyl and α-phenylthio substituted aldehydes'
DOI: 10.3987/COM-11-S(P)29

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'
DOI: 10.3762/bjoc.8.11

M. J. Thompson, J. C. Louth, S. M. Little, M. P. Jackson, Y. Boursereau, B. Chen, I. Coldham, Chem. Med. Chem. 2012, 7, 578–586.
'Synthesis and Evaluation of 1-Amino-6-halo-β-carbolines as Antimalarial and Antiprion Agents'
DOI: 10.1002/cmdc.201200002

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'
DOI: 10.1039/C1OB06122D

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'
DOI: 10.1021/jo2000868

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'
DOI: 10.1021/ol102961x

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'
DOI: 10.1021/ol9001653

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'
DOI: 10.1039/B822743H

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'
DOI: 10.1021/jo-2008-019913.R1

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