Andrew Regan: Current Research Areas
Synthesis of Biologically Active Phosphinic Acids

There is increasing interest in the chemistry of phosphinic acids as non-hydrolysable isosteres of biologically important phosphate diesters. We have developed new methods for the synthesis of phosphinic acids (3) based on silyl esters of phosphonous acid, e.g. (1) and (2), which are highly nucleophilic, and react with a wide range of electrophiles under very mild conditions. The mildness of the conditions allows smooth reactions which have been previously reported to be unsuccessful.

This methodology is being applied to the synthesis of analogues of important hormones, e.g. platelet activating factor (4), and cyclic AMP (5). The tris-methylene analogue (6) of tripolyphosphate is also a current target, which would be of interest as a novel non-hydrolysable dysprosium-based shift reagent for binding alkali metal cations in aqueous solution.

It is planned to utilise the phosphinic acid synthesis shown above in the preparation of dinucleotide analogues, e.g. (7), which is a potential antisense oligonucleotide, or the 2,5-A core dimer (8). Use of b ,b -difluoroacrylates as electrophiles will be investigated in order to give bis(difluoromethylene)phosphinic acids, e.g. (9), which will be closer analogues of phosphate diesters in an electronic as well as an isosteric sense.

We also plan to use our synthetic methodology to synthesise phosphinic acid analogues of the anti-cancer compounds mitelfosine and edelfosine:

 
Synthesis of Macrolides
We plan to synthesise analogues of erythromycin, e.g. (10), which will have simplified substitution patterns around the macrolide ring, but which will require the presence of the sugars for activity. N.m.r. studies of binding with ribosomes, in collaboration with the Department of Pharmacy, will be used to define the minimal structural requirements for recognition. Similarly, synthetic studies on analogues of the macrolide drug rhizoxin (11) will be pursued. Studies on binding and recognition by microtubules will be carried out in collaboration with the School of Biological Sciences.
[2,3]-Wittig Rearrangements

Various aspects of the stereoselectivity of the [2,3]-Wittig rearrangement are being investigated, with the aim of increasing its utility as a synthetic method:

The influence of chiral centres adjacent to the cyclic transition state is being studied: both the detailed structure of the chiral centre and the geometry of the double bond appear to be important:

We have rearranged symmetrical acetals to enol ethers: discrimination by a suitable chiral reagent could lead to an enantioselective version. These substrates are also among the very few examples that do not rearrange with complete E-selectivity for the newly formed double bond. Variation in the nature of the anion-stabilising group could give reversal to a Z-selective reaction:

Cyclic versions of the acetal rearangement will also be attempted as a novel ring expansion:

 
Synthesis of Biologically Active Alkaloids
We have recently synthesised the alkaloid epibatidine, isolated from the Ecuadoran poison frog Epipedobates tricolor, which has excited a great deal of interest both because of its unusual structure, and also because of its very potent analgesic activity. Our approach is distinctly different from other syntheses of epibatidine, is highly convergent and is currently being extended to an asymmetric synthesis and also the preparation of analogues. This approach has also been extended to incorporate an asymmetric palladium-catalysed coupling reaction.

 
Use of Enzymes in Organic Synthesis: Synthesis of Chiral Tetronic Acids

The enzyme oxynitrilase (from almonds) is being used for the enantioselective synthesis of cyanohydrins. These are then used for the synthesis of chiral tetronic acids using a Blaise reaction:

This method is currently being applied to the asymmetric synthesis of some biologically active tetronic acids, and the synthesis of the antibiotic sesquiterpene shown below has recently been completed.

 

Recent Publications:

"A Versatile Route to Substituted Phosphinic Acids", E. A. Boyd, M. Corless, K. James and A. C. Regan, Tetrahedron Letters, 1990, 31, 2933-2936.

"Nazarov Cyclisation of Dienone-Esters and Tetrahydropyrones using Trimethylsilyltriflate", J. F. P. Andrews and A. C. Regan, Tetrahedron Letters, 1991, 32, 7731-7734.

"Synthesis of g-Keto-substituted Phosphinic Acids from Bis(trimethylsilyl)phosphonite and a,b-Unsaturated Ketones", A. C. Regan, E. A. Boyd, and K. James, Tetrahedron Letters, 1992, 33, 813-816.

"A Total Synthesis of (±)-Epibatidine" Clayton, S.C.; Regan, A.C.; Tetrahedron Lett., 1993, 34, 7493-7496.

"Synthesis of Alkyl Phosphinic Acids from Silyl Phosphonites and Alkyl Halides", A. C. Regan, E. A. Boyd, and K. James Tetrahedron Lett., 35, 1994, 4223-4226.

"Conformational Analysis of the Erythromycin Analogues Azithromycin and Clarithromycin in Aqueous Solution and bound to Bacterial Ribosomes", A C Regan, A Awan, R J Brennan and J Barber, J. Chem. Soc., Chem. Commun., 1995, 1653-1654.

"Asymmetric Synthesis of Tetronic Acids by Blaise Reaction of Protected Optically Active Cyanohydrins", J J Duffield and A C Regan,Tetrahdron Asymmetry. 1996, 7, (3) 663-666.

"Synthesis of a C1-C9 fragment of rhizoxin", R J Davenport and A C Regan, Tetrahedron Lett., 2000, 41, 7619-7622.

"Synthesis of a phosphinic acid analogue of cyclic AMP", A C Regan, N Sciammetta and P I Tattersall, Tetrahedron Lett., 2000, 41, 8211-8215.