Thermodynamic equilibration of dihydropyridone enolates: application to the total synthesis of (+/−)-epiuleine

Following 1,4-reduction of 2-substituted dihydropyridones (1), the requisite ‘kinetic’ enolate can be isomerized upon warming to allow the isolation of the thermodynamic enolate as its vinyl triflate (3). This enolate interconversion is dependent on the dihydropyridone C-2 substituent and can be interpreted in terms of conformational analysis. This novel scaffold (3) opens another avenue for the strategic deployment of dihydropyridones into both natural product synthesis and drug discovery. To this end, this method is highlighted by its use as a key step in a total synthesis of (+/−) epiuleine (14).     

Total synthesis of (+/−)-diospongin A via Prins reaction

A straightforward synthesis of (+/−)-diospongin A starting from benzaldehyde is described. A Prins cyclization reaction to control the relative configuration of the three stereogenic centers and a Mitsunobu inversion represent the key steps of the approach.     

A concise and stereoselective synthesis of (+/−)-erythro-methylphenidate

A concise and stereoselective synthesis of racemic erythro-methylphenidate (1) is described. The coupling reaction between piperidine-2-thione (3) and 2-bromo-2-phenylmethylacetate (4) afforded the β-enaminocarbonyl compound 2 in 60% yield by a modified Eschenmoser sulfide contraction reaction. In most cases the bicyclic thiazolidinone 5 was produced. Diastereoselective reduction of 2 in the presence of borohydrydes furnished the (+/−)-erythro-methylphenidate in good yields with dr >95%.     

A short and efficient asymmetric synthesis of (−)-frontalin, (−)-exo-isobrevicomin and a volatile contributor of beer-aroma

The natural products, (−)-frontalin and (+)-exo-isobrevicomin were synthesized employing Sharpless asymmetric epoxidation and ZrCl₄-catalyzed intramolecular acetalization as the key steps. (−)-Frontalin was synthesized in three steps with a 61.4% overall yield and 89.9% ee and (−)-exo-isobrevicomin also obtained in an overall satisfactory yield of 10.1% and 97% ee. We have also synthesized the volatile contributor of beer aroma in a 96% ee.     

Sequential cross-metathesis/cyclopropanation: short syntheses of (+/−)-cascarillic acid and (+/−)-grenadamide

The total synthesis of (+/−)-cascarillic acid has been achieved by a sequential cross-metathesis/Simmons-Smith cyclopropanation between, respectively, 1-octene with an appropriate unsaturated carboxylic acid. In parallel, a direct access to grenadamide was developed from 1-nonene with a readily available unsaturated amide. In both cases, the chemical yields were high (up to 98%) and the E/Z ratio was near 80/20. The synthesis of a dibromocyclopropane analogue has also been considered.     

Dibromomethane as one-carbon source in organic synthesis: total synthesis of (±)- and (−)-methylenolactocin

A general method was developed to construct monocyclic α-methylene-γ-butyrolactone moiety. The key step is to introduce the α-methylene group by the ozonolysis of mono-substituted alkenes followed by reacting with a preheated mixture of CH₂Br₂-Et₂NH. Application of this key step in the total synthesis of the (±)- and (−)-methylenolactocin was described.     

The Pauson-Khand reaction as a new entry to the synthesis of bridged bicyclic heterocycles: application to the enantioselective total synthesis of (−)-alstonerine

The first application of the Pauson-Khand reaction (PKR) to the synthesis of azabridged bicyclic structures is described. Compounds containing azabicyclo[3.3.1]nonane and azabicyclo[3.2.1]octane rings fused to cyclopentenones were efficiently constructed via the PKR of cis-2,6-disubstituted N-acyl piperidine enyne substrates, many of which can be readily prepared from 4-methoxypyridine in a few steps. Moreover, the PKR of cis-2,6-disubstituted piperazine enynes allowed the preparation of diazabicyclo[3.3.1]nonanes fused to cyclopentenones. This new strategy for the synthesis of azabridged bicyclic frameworks was exploited as a key step in a concise, enantioselective total synthesis of the macroline alkaloid (−)-alstonerine.     

Silenes in organic synthesis: a concise synthesis of (+/-) -epi-picropodophyllin

A concise, seven step synthesis of the aryl tetralin lignan lactone epi-picropodophyllin from piperonal is described. The key steps are a silene diene Diels-Alder reaction and the Hosomi-Sakurai reaction of the resultant silacyclohexene.     

First total synthesis of (+/-)-taxifolial a and (+/-)-iso-caulerpenyne

The first synthesis of (+/-)-taxifolial A and iso-caulerpenyne was accomplished. The key steps in the sequence are (1) the stereoselective assembly of a vinyltin derived from butynediol and a functionalized aldehyde and (2) the construction of the dienyne moiety via a Stille cross-coupling.     

Thermal elimination of diethyldithiocarbamates and application in the synthesis of (+/-)-ferrugine

Dithiocarbamate-substituted lactams, prepared through group-transfer cyclization reactions of carbamoyl radicals, undergo a Chugaev-like thermal elimination of the dithiocarbamate group in refluxing diphenyl ether to form alpha,beta- and/or beta,gamma-unsaturated amides, depending on the structure of the starting material. This reaction sequence was used to prepare an unsaturated [3.2.2] bridged bicyclic amide, which was converted in a one-pot procedure to the 8-azabicyclo[3.2.1]octane ring system of the tropane alkaloid ferrugine by treatment with phenyllithium followed by aqueous sodium hydroxide.     

A new synthesis of (−)-epipyriculol: a phytotoxic metabolite

A convenient synthesis of the phytotoxic natural product epipyriculol has been accomplished in 17 steps from methyl l-tartrate. The synthetic strategy is based upon the use of a butanediacetal-protected scaffold as central core from which the alkenyl side chains were assembled.     

Dibromomethane as one-carbon source in organic synthesis: total synthesis of (±)-canadensolide

A diastereoselective total synthesis of (±)-canadensolide is described. The key step is to introduce the α-methylene group by the ozonolysis of mono-substituted alkenes followed by reaction with a preheated mixture of CH₂Br₂-Et₂NH.     

A practical route to enantiopure 3-hydroxy-pyrrolidines: application to a straightforward synthesis of (−)-bulgecinine

A practical synthesis of enantiopure substituted 3-hydroxy-pyrrolidines is reported. In four steps, starting from commercially available amino acids as chiral educts, this method allows for an efficient preparation of a variety of 3-hydroxy-pyrrolidines, as well as 3-hydroxy-piperidines and azepanes. Application of this methodology for a straightforward asymmetric synthesis of (−)-bulgecinine is also described.     

Synthesis of isoquinuclidinones via a tandem amination/imination sequence: application to the synthesis of (−)-mearsine

The facile synthesis of a range of novel isoquinuclidinones from 6-acyl-cyclohex-2-enones is described, employing aqueous ammonia in a one-pot procedure involving initial conjugate addition of ammonia followed by cyclisation via intramolecular imine formation. The scope and limitations of the methodology are described as is an efficient synthesis of the Elaeocarpus alkaloid (−)-mearsine.     

Asymmetric synthesis of (−)-tetrahydrolipstatin

Attempts toward the asymmetric synthesis of (−)-tetrahydrolipstatin are described. A palladium catalyzed Wacker-type reaction to convert an alkene to a ketone, highly diastereoselective reduction of a β-hydroxy ketone, selective oxidation of a diol, and modular synthesis are the key features of the successful approach.     

Stereoselective synthesis of (−)-jimenezin

Total synthesis of jimenezin was achieved via radical cyclization of β-alkoxyacrylate and β-alkoxyvinyl sulfoxide intermediates and intramolecular olefin metathesis reaction.     

Total synthesis of (−)-incarvilline

An enantioselective synthesis of (−)-incarvilline is presented, employing a three-component coupling reaction and an intramolecular enone-olefin [2+2] photocycloaddition followed by a SmI₂-induced cyclobutane ring-opening reaction.