Timothy Gallagher

Palladium(II)-mediated routes to functionalised heterocycles

Abstract A series of allenic amines/amides 3 have been prepared and shown to undergo a palladium(II)-catalysed cyclisation, in the presence of carbon monoxide and methanol, to give α-(heterocyclic) acrylates 4 .

Asymmetric synthesis via electrophile-mediated cyclisations

Abstract The electrophile-mediated cyclisation of a series of allenic amines (8a-e), carrying a chiral benzylic residue on nitrogen, has been examined using Ag(I) and Pd(II). The cyclised products, (9/10)(using Ag(I)) and (12/13)(using Pd(II), CO, MeOH), are formed diastereoselectively. With Ag(I) up to 81% d.e. has been observed and the stereochemical course of this reaction has been established. The Pd(II)-mediated cyclisation is less selective (up to 43% d.e.) and the factors controlling the selectivities of both of these reactions are discussed.

A new approach to cyclic nitrones: Application to the synthesis of α,α′-disubstituted piperidines and pyrrolidines

Abstract A new synthesis of nitrones is described. This involves the Ag(I)-catalysed cyclisation of allenic oximes, the resulting nitrones being trapped by various 1,3-dipolarophiles.

Electrophile-mediated cyclisations involving the allene π-system. Stereoselectivity and synthetic utility of PdII-catalysed heteroatom cyclisation reactions. X-Ray molecular structure of methyl 2-[trans-3-phenyl-N-(p-tolylsulfonyl)pyrrolidin-2-yl]acrylate

PdII-Mediated cyclisation and methoxycarbonylation of the phenyl-substituted allenic sulfonamides 4,5 and 6 gave the corresponding N-sulfonyl 2,3-, 2,4- and 2,5-disubstituted pyrrolidines 9, 10 and 11, respectively. With the exception of compound 4, cyclisations were not highly selective and similar trends were observed with the α-amino allenic esters 7 and 8. Some improvement, both in yield and diastereoselectivity, was apparent when cyclisations were carried out in the presence of an excess of Et3N. The isolation of acyclic by-products 14 and 15 from α-amino allenic ester 7 suggests that chloropalladiation may play a key role in the mechanism of this cyclisation sequence and similar byproducts were obtained from cyclisation of the unsubstituted allenic sulfonamides 16 and 20 leading to 6- and 7-membered rings, respectively. Other synthetic aspects of this palladium-based chemistry, including efforts directed towards coupling of the cyclisation step with a Heck-type olefination, are also described.

β-Substituted ketene thioacetals as β-lithioacrylate equivalents. The synthesis of (±)-eldanolide

Abstract Lithiation of 1,1-bis(phenylthio)-3-phenylthio-1-propene 3 and reaction with a range of electrophiles gave exclusively the γ-substituted product 4 . This reagent has been used in a short synthesis of the pheromone, (±)-eldanolide.

Ketene-S,S-acetals as 1,3-dipolarophiles reactivity towards electron-deficient azides

Abstract The reactivity of a series of ketene-S,S-acetals (2a-e) towards p-toluenesulphonyl azide and ethoxycarbonyl azide is determined by the nature of the substituents on both the dipolarophile and the 1,3-dipole. With p-toluenesulphonyl azide rearrangement of the 1,3-dithianyl ring is observed to give (4), but with ethoxycarbonyl azide a different pathway is followed leading to β-amino ketene-S,S-acetals (6), albeit in low yield.

Regiospecific tetrahydropyran-3-one enolates. Synthesis and reactivity of silyl enol ether derivatives

Abstract The synthesis and reactivity of the silyl enol ether ( 3 ) is reported. This reagent complements the reactivity of the lithiated enol ether ( 2 ) previously used as a synthetic equivalent of the regiospecific tetrahydropyran-3-one enolate ( 1 ).

Conformational studies on (+)-anatoxin-a and derivatives.

SummaryAnatoxin-a (AnTX) is a highly potent agonist acting at the nicotinic acetylcholine receptor (nAChR) and represents a valuable tool in the study of this receptor. Molecular mechanics, semi-empirical and ab initio molecular orbital energy minimization procedures were conducted to investigate the conformation of AnTX. For each minimization procedure, the s-trans enone isomer of protonated AnTX was the energetically favoured conformer due to intramolecular electrostatic interactions. Our studies are discussed in the light of previous experimental observations and conformational studies, in addition to their importance in the development of future pharmacophore models for nAChR agonist binding.

Ketene-S,S-acetals as 1,3-dipolarophiles towards azides. A new synthetic entry into cyclic amino acids

Abstract Intramolecular azide cycloaddition reactions of ketene-S,S-acetals proceed to give a reactive imine as the initially-formed intermediate and this mechanism is supported by thermolysis of (18) which gave the stable imine (22). N-Acylation of this intermediate leads to cyclic variants of 2-amino ketene-S,S-acetals (20, 24, 27), which can be viewed as masked α-amino acids, and reduction leads to the corresponding dithiane (21, 25, 29a). Both systems have been converted to cyclic α-amino acids and the scope, in terms of the ring sizes available, and the limitations of this intramolecular cycloaddition process are discussed.

Synthetic and stereochemical studies directed towards anatoxin-a

The synthesis and stereocontrolled AgI-catalysed cyclisation of a series of allenic amino esters 8a–e is described. For compounds 8a–d the cis-2,5-disubstituted pyrrolidine 9 is formed exclusively but the primary amine 8e undergoes cyclisation nonselectively to give a mixture of cis- and trans-pyrrolidines 9e and 10e. The synthetic potential of this allene-based methodology has been illustrated by the conversion of compound 8avia9a into (±)-anatoxin-a 1 and the methoxy phosphine oxides 18 and 19 have been studied as ketone homologating agents within this context. The enzymatic resolution of (±)-8a using chymotrypsin is also described.