Andrew F. Parsons

Stereoselective radical reactions

For many years, the reputed lack of selectivity in some free-radical reactions has resulted in this class of reaction being overlooked in the stereoselective synthesis of important target molecules. More recently, however, the situation has changed as new and milder methods of radical generation have been developed, which have helped researchers to gain a better understanding of the key factors that influence selectivity in radical transformations. As a consequence, the use of radicals in stereoselective synthesis is increasing and there are a number of important intra- and intermolecular additions, where high levels of stereoselectivity have been achieved in the formation of carbon-carbon bonds.

A radical approach to N-desulfonylation

Abstract The deprotection of N-sulfonylated amides can be achieved under neutral conditions by reaction with tributylin hydride. Good yields are obtained using N-benzoyl and related amides while the corresponding N-acetyl derivatives are inert under the same reaction conditions. The mechanistic implications of this are discussed.

Manganese(III) acetate mediated radical reactions leading to araliopsine and related quinoline alkaloids

Tricyclic quinoline alkaloids, including araliopsine 2, can be prepared in ‘one-pot’ by reaction of 4-hydroxy-1-methyl-2(1H)-quinoline 5 or 2,4-quinolinediol 31 with manganese(III) acetate in the presence of a variety of electron-rich alkenes. The reaction mechanism involves an initial intermolecular radical addition reaction followed by radical oxidation and cyclisation steps. Both angular and linear tricyclic alkaloids can be formed and the regioselectivity of the cyclisation is shown to depend on whether alkyl or aryl groups are attached to the alkene.

Desulfonylation of Amides using Tributyltin Hydride, Samarium Diiodide or Zinc/Titanium Tetrachloride. A Comparison of Methods

Abstract Deprotection of N -sulfonylated amides can be achieved by reaction with Bu 3 SnH, SmI 2 or TiCl 4 /Zn. All three methods gave good yields (typically >60%) when using N -benzoyl or related amides while the corresponding N -acetyl derivatives proved to be inert to deprotection under the same reaction conditions. The mechanistic implications of this are discussed.

Preparation of N-Heterocycles by Radical Cyclisation of Enamides Mediated by Manganese(III) or Copper(I). A Comparison of Cyclisation Methods

Abstract Reaction of enamides with manganese(III) acetate or copper(I) chloride/bipyridine has been investigated. In both cases, an initial 5- endo - trig radical cyclisation reaction took place to produce functionalised pyrrolidinones. The copper(I)-mediated cyclisations were very efficient and bicyclic dienes could be isolated in >80% yield, while the corresponding manganese(III) reactions were generally more problematic, giving related dienes in lower yield (35–52%).

Cyclisation of dienes using phosphorus-centred radicals to form organophosphorus adducts

Abstract Reaction of various dienes with phosphites or related phosphorus hydrides, under free radical cyclisation conditions, affords cyclic organophosphorus adducts. This quick, mild and technically clean approach affords 5- and 6-ring carbocycles and heterocycles in good to excellent yield.

The influence of benzylic protection and allylic substituents on the CuCl-TMEDA catalyzed rearrangement of N-allyl-N-benzyl-2,2-dihaloamides to gamma-lactams. Application to the stereoselective synthesis of pilolactam.

Abstract A number of N-benzylic protecting groups and allylic substituents have been investigated for the rearrangement, promoted by CuCl-TMEDA, of N-allyl-2,2-dihaloamides to 3,4-disubstituted γ-lactams. An appreciable chiral induction was observed at the C-4 site when α-phenylethylamine was used as a chiral protecting group, while an unexpected Diels-Alder reaction occurred when using a 2-furyl-methyl protection. This rearrangement has been applied to the synthesis of pilolactam, a drug with muscarinic activity.

A radical approach to araliopsine and related quinoline alkaloids using manganese(III) acetate

Abstract Reaction of 4-hydroxy-1-methyl-2(1H)-quinolone 3 with electron-rich alkenes and manganese(III) acetate produces tricyclic quinoline alkaloids, including araliopsine 1, in one-pot reactions. This combined intermolecular addition–cyclisation reaction produces angular and/or linear tricycles and the regioselectivity of the cyclisation is shown to depend on whether alkyl or aryl substituents are attached to the alkene.

Metal-catalysed radical cyclisations leading to N-heterocycles: new approaches to gabapentin and pulchellalactam

The copper(I) or ruthenium(II)-mediated radical cyclisation of halo-amides has been utilised to afford functionalised pyrrolidinones via 5-endo-trig or 5-exo-trig radical cyclisation pathways. This methodology has been applied to novel and concise syntheses of the anti-epileptic drug gabapentin and the biologically active natural product pulchellalactam.

A radical cyclisation approach to pyroglutamates

Abstract Treatment of serine-derived N -( α -haloacetamido)dehydroalanine derivatives with tributyltin hydride in boiling benzene or toluene afforded pyroglutamates in 47–84% yield. The radical cyclisation reaction, which proceeded regioselectively in a disfavoured 5- endo-trig manner, was found to be most efficient when dichloro- and trichloroamides were employed as starting materials.