Asymmetric synthesis of pent-3-yl (R)-6-methyl-cyclohex-1-ene carboxylate

An expeditious asymmetric synthesis of pent-3-yl (R)-6-methyl-cyclohex-1-enecarboxylate has been achieved in four steps in 42% overall yield employing as the key step a domino reaction initiated by a highly diastereoselective lithium amide 1,4-conjugate addition to a nona-2,7-diendioic diester followed by a 6-exo-trig cyclisation of the thus formed enolate. Cope elimination protocol of the cyclic adduct affords, depending on the lithium amide used, the corresponding nitro-compound or the expected cyclohexene derivative. The methyl group attached to the cyclohexane ring is achieved by selective ester hydrolysis and subsequent Barton decarboxylation.     

Asymmetric synthesis of d-fagomine and its diastereoisomers

A divergent strategy for the asymmetric syntheses of d-fagomine and three of its diastereoisomers has been developed. The diastereoselective conjugate addition of an enantiopure lithium amide to an α,β-unsaturated ester was used as the key step to install the correct configuration required for the C(5)-stereogenic centre within the targets. In situ enolate oxidation generated the corresponding anti-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d-fagomine and d-3-epi-fagomine. Subsequent epimerisation of this key anti-α-hydroxy-β-amino ester upon oxidation and diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d-4-epi-fagomine and d-5-epi-fagomine. Elaboration of both α-hydroxy-β-amino esters upon reduction to the corresponding aldehydes followed by aldol reaction generated the requisite C(3)-stereogenic centres within the target compounds, then cyclisation and deprotection gave the enantiopure iminosugars in good overall yields, as single diastereoisomers (>99:1 dr).     

Free radical cyclisation of enamides leading to biologically important γ-lactams

This review describes the free radical cyclisation of enamides using tributyltin hydride, manganese(III) acetate, copper(I) complexes or dichlorotris(triphenylphosphine)ruthenium(II). These cyclisations can proceed via either 4-exo or 5-endo pathways, to produce β- or γ-lactam products, respectively. In general, the reactions produce γ-lactams derived from an unusual (disfavoured) 5-endo-trig radical cyclisation. These results can be explained on the basis of a reversible cyclisation mechanism; the 4-exo cyclisation produces the kinetically favoured β-lactam while the 5-endo cyclisation produces the thermodynamically more stable γ-lactam.     

Asymmetric synthesis of (−)-(1R,7aS)-absouline

The most efficient and concise asymmetric synthesis of (?)-(1R,7aS)-absouline to date, which was accomplished in eight steps and 20% overall yield from commercially available starting materials, is described. The doubly diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)-amide to an enantiopure α,β-unsaturated ester derived from l-proline was employed as the key step. Subsequent hydrogenolytic N-debenzylation and acid-promoted cyclisation of the resultant β-amino ester produced the 1-aminopyrrolizidin-3-one scaffold, then reduction with DIBAL-H was followed by DCC-mediated coupling with (E)-p-methoxycinnamic acid to complete the synthesis of (?)-(1R,7aS)-absouline.     

Design and Synthesis of a Potential Dopamine D-1 Antagonist

The diastereoselective synthesis of (±)-trans-transoid-7-bromo-8-hydroxy-1-methyl-1,2,3,4,4a,5,10,10a-octahydro-10-phenylbenzo[g]quinoline ( 8 ) is described, using an intramolecular Diels-Alder reaction and a reductive cyclisation for piperidine ring-formation as key steps. Compound 8 was prepared as a putative D-1 receptor antagonist which contains (2,2-diphenylethyl)amine as a partial structure.     

A comparative study on the synthesis of pyrazolo-[4,3-c]quinoline oxides by reductive cyclisations

Alternate routes for the reductive cyclisation of 4-acetyl-3-methyl-5-(2-nitrophenyl)-1-phenylpyrazole under different conditions are described. Whereas 3,4-dimethyl-1-phenylpyrazolo[4,3-c]quinoline 5-oxide is formed by mild noncatalytic reductions, catalytic and transfer hydrogenation processes cause the diastereoselective formation of cis-4,11-dihydro-3,5-dimethyl-1-phenylpyrazolo[4,3-c]quinoline 6-oxide.     

Tandem intermolecular-intramolecular carbolithiation: application to the synthesis of silacyclopentanes

Silacyclopentanes have been prepared from vinyl(homoallyl)silanes or vinyl(homopropargyl)silanes and organolithium reagents by a tandem intermolecular-intramolecular sequence involving a 5-exo cyclisation process. The unexpected stereochemical outcome of the sequence involving a 5-exo-dig cyclisation is rationalised.     

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.     

C-O and C-C bond formation in the cyclisation of gem-(dialkoxymethyl)-1,6-dienes catalysed by tin(IV) triflimidate at room temperature

We described herein a Sn(NTf₂)₄-catalysed cyclisation of gem-(dialkoxymethyl)-1,6-dienes and derivatives where cyclohexane or tetrahydrofuran rings are formed following either a 6-enexo-endo-trig process or a 5-exo-trig process, respectively, depending on substitution patterns. The latter process features an unusual dealkylative ether cyclisation, triggered by the strong Lewis acid character of the tin(IV) triflimidate catalyst.     

Tributyltin hydride-mediated cyclisations of cinnamic enamides to piperidin-2-ones or pyrrolidin-2-ones. Indolizidinone ring formation by tandem radical cyclisation

Efficient 6-endo-trig free radical cyclisations of various 3-phenyl-acryl enamides to piperidin-2-ones, by using Bu₃SnH and AIBN in boiling toluene, are reported. A different result has been observed for related enamide system without phenyl substituent at the 3-position of an acrylic moiety, as such a reaction of 3-methyl-butenoic acid cyclohex-1-enyl-methyl-amide afforded only the 5-exo-trig product. The difference in the cyclisation mode has been explained in terms of a reversible process leading to the thermodynamically more stable product. An application of this method for the tandem cyclisation permits to obtain idolizidine derivatives.     

A synthesis of 2-epi-fagomine using gold(I)-catalysed allene cyclisation

A synthesis of 2-epi-fagomine via a highly stereoselective gold(I)-catalysed allene cyclisation is described. The stereochemical outcome of the cyclisation is opposite to that observed in previous studies. In contrast, gold(III)-catalysed cyclisation is inefficient and gives rise to double cyclisation by-products.     

Annulated 1,2,3,4-tetrahydro-β-carbolines by intramolecular Mannich-type amino- and amidoalkylations of N(9)-(ω-nitroalkyl)-3,4-dihydro-β-carbolines

2-[1-(ω-Nitroalkyl)-1H-indol-3-yl]ethylformamides 11 were transformed to the corresponding 9-(ω-nitroalkyl)-4,9-dihydro-3H-β-carbolines 5 and through a diastereoselective intramolecular aminoalkylation to the annulated tetrahydro-β-carbolines 13, in high yields. Intramolecular N-acyliminium cyclisation of compounds 5 afforded the tetracyclic diazacycloalkano[jk]fluorenes in two diastereoisomeric forms 18 and 19 with moderate selectivity. Conjugate addition reactions performed on compounds 18 and 19 led to pentacyclic indolo[3,2,1-de]pyrido[3,2,1-jk]naphthyridinone 26a or diazabenzo[a]naphtho[2,1,8-cde]azulenone 26b.     

Preparation of novel pyridine-fused tris-heterocycles; pyrido[4,3-e]pyrrolo-/pyrido[4,3-e]furano[2,3-c]pyridazines and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole

Three novel pyrido-fused tris-heterocycles have been prepared based on a Suzuki coupling and subsequent cyclisation approach. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b, 77%) and pyrido[4,3-e]furano[2,3-c]pyridazine (5b, 76%) were obtained by intramolecular diazocoupling. Successful diazocoupling of furan (5b) is thus reported for the first time by NOBF₄ generation of the diazonium intermediate. N-TIPS-pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (TIPS-4b) was synthesised by thermal cyclisation of pyridyl nitrene in considerably higher yield (71%) than previously experienced from similar cyclisations, due to TIPS-activation.     

Highly stereoselective synthesis of perhydropyrano[2,3-b]pyrans from the new 3-methylidenepentane-1,5-dianion synthon

4-Phenylsulfanyl-2-(2-phenylsulfanylethyl)but-1-ene (2) is a new 3-methylidenepentane-1,5-dianion synthon which on reaction with an excess of lithium powder and a catalytic amount of DTBB (2.5%) in the presence of a carbonyl compound in THF at 0 °C, leads, after hydrolysis, to the expected methylidenic diols 3. These diols when subjected to successive hydroboration-oxidation and final oxidation, undergo spontaneous cyclisation to furnish a series of cis-perhydropyrano[2,3-b]pyrans (4) in a highly diastereoselective manner (>99% de). Acid-catalysed isomerisation of the cis-perhydropyrano[2,3-b]pyrans (4) leads, also stereoselectively, to the corresponding trans-perhydropyrano[2,3-b]pyrans (5). A discussion about the stability of 4 and 5 is also included.     

Cyclisation of α-chiral aminyl radicals

α-Chiral aminyl radicals have been generated from sulfenamides of α-amino acid esters and α-phenylethylamine using Bu₃SnH. The aminyl radicals of α-amino acid esters undergo 5-exo-trig cyclisation reactions onto side chain alkenes to yield proline analogues with reasonable diastereoselectivity. Preliminary studies show urethanyl radicals generated from sulfenamides of alkenyl urethane derivatives of α-amino acid esters and α-phenylethylamine undergo 5-exo-rig cyclisations to providing a protocol for the radical amination of unactivated alkenes. The α-ester of the amino acid or the urethane groups impart electrophilic behaviour to the aminyl radicals and facilitates cyclisation onto alkenes.     

Sulfur-mediated radical cyclisation reactions on solid support

Two methods for effecting radical cyclisation reactions of solid-supported 1,6-dienes are described. Additions of thiophenol and p-tolyl benzeneselenosulfonate have each been achieved with a concomitant 5-exo-trig radical cyclisation leading to the formation of highly functionalised cyclopentanes.     

A new synthetic approach towards isoquinobenzazepinone and isoindolinobenzazepinone using acid-mediated cyclisation and Heck reaction

Six-membered ring cyclisation of N-ethylbenzazepinone, prepared from the condensation of benzazepinone with phenethyl iodide under basic conditions, smoothly provided the corresponding product, isoquino[1,2-b][3]benzazepinone, under acid-mediated conditions. On the other hand, the attempted direct five-membered ring cyclisation using the acid-mediated conditions failed to give the 7,5 fused ring isoindolinobenzazepinone from N-benzylbenzazepinone, but the 7,6 fused ring product was instead obtained. However, five-membered ring cyclisation of N-benzylbenzazepinone could be effected efficiently by employing the Heck reaction followed by catalytic hydrogenation to furnish the desired isoindolinobenzazepinone.     

Spiro cyclisations of N-acyliminium ions involving an aromatic π-nucleophile

Spiro 2-pyrrolidin-5-ones were obtained from N-substituted succinimides by a two-step procedure, involving 5- or 6-endo-trig cyclisation of N-acyliminium ion intermediates with a tethered aromatic π-nucleophile.     

Synthesis of 5-methylfuro[3,2-c]quinolin-4(5H)-one via palladium-catalysed cyclisation of N-(2-iodophenyl)-N-methyl-3-furamide

A new synthesis of the furo[3,2-c]quinolin-4(5H)-one heterocycle has been developed using a palladium-catalysed cyclisation of N-(2-iodophenyl)-N-methyl-3-furamide. By varying the catalyst, base and solvent, the yield of the cyclisation was optimised. It was found that the use of palladium oxide with potassium acetate in N,N-dimethylacetamide (DMA) with a small amount of tetrabutylammonium chloride gave the highest yield of 5-methylfuro[3,2-c]quinolin-4(5H)-one (9).     

An iodoacetamide-based free radical cyclisation approach to the 7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one (paullone) system

A potentially versatile route to 2-(2-aminoaryl)indoles is described based on a palladium-mediated cyclisation of N-substituted indoles, together with free radical cyclisation of their N-benzyliodoacetamide derivatives to the 7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one system.