Microwave promoted amination of 3-bromoisoxazoles

This Letter describes the amination of 3-bromoisoxazoles by a nucleophilic aromatic substitution reaction. We have found 3-bromoisoxazoles to be inert to substitution under thermal conditions, however, the employment of phosphazene bases under microwave irradiation facilitates the amination process and allows the corresponding 3-aminoisoxazoles to be isolated in moderate yield.     

Investigation of a stereoselective co-mediated rearrangement reaction

A stereocontrolled approach to alpha-alkyl beta-alkynyl cyclohexanones is reported through a Lewis acid mediated rearrangement reaction of enol ethers bearing an Co-alkyne moiety. The reaction proceeds with high levels of stereoselectivity in the presence of Ti- and B-Lewis acids to provide a range of alpha,beta-disubstituted cyclohexanones in high yield although the products are prone to epimerization at the alpha-position in the presence of the B-promoter system. The potential for an enantioselective variant of this process is outlined, and a rationale for the observed stereochemical trends and detailed structural analyses of the ketone products are described.     

Development of a flexible approach to Nuphar alkaloids via two enantiospecific piperidine-forming reactions

In this paper we describe the stereoselective synthesis of functionalized lactam 7 via two enantiospecific piperidine-forming techniques and its employment in a general synthetic approach to Nuphar alkaloids. Specifically, the formation of piperidine 18 by formal [3 + 3] cycloaddition and stepwise annelation processes is described; the latter technique was found to be significantly more efficient than the Pd-catalyzed TMM addition process. Finally, exploitation of the exocyclic alkene installed in the piperidine-forming reaction in the transformation of 18 to (-)-deoxynupharidine ((-)-2), (-)-castoramine ((-)-3), and (-)-nupharolutine ((-)-4) via intermediate lactam 7 is delineated.     

5‐Butyl‐4‐(4,4,5,5‐tetra­methyl‐1,3,2‐dioxaborolan‐2‐yl)‐3‐(2,4,6‐tri­methyl­phenyl)­isoxazole

A novel [3+2]‐cyclo­addition reaction of alkynyl­boronates and nitrile oxides gave the title compound, C₂₂H₃₂BNO₃, as a single regioisomer. The X‐ray crystal structure analysis of this compound shows two independent mol­ecules in the asymmetric unit, each with approximately coplanar isoxazole and boronate rings.     

Synthesis of an azabicyclic framework towards (±)-actinophyllic acid

Lewis acid mediated intramolecular Mannich reaction between an azocinone and a 3-formylindole was investigated as part of a study towards the synthesis of actinophyllic acid. The intramolecular Mannich reaction resulted in a single diastereomer of the 1-azabicyclo[4.2.1]nonan-5-one core framework, although single crystal X-ray structure analysis revealed that this had the undesired stereochemistry in comparison with the natural product.     

Development of an Enantioselective Allylic Alkylation of Acyclic α-Fluoro-β-ketoesters for Asymmetric Synthesis of 3-Fluoropiperidines

The first useful enantioselective Pd-catalyzed asymmetric allylic alkylation of α-fluoro-β-ketoesters has been achieved using the Trost family of chiral ligands yielding products in up to 92 % ee. This work provides new insights regarding the typically modest selectivities associated with acyclic α-fluoroenolates and shows experimental evidence that the typically poor levels of enantiocontrol associated with these systems are not necessarily due to the presence of E/Z enolate mixtures. Finally, this methodology allows the easy preparation of useful 3-fluoropiperidine intermediates, and it is demonstrated that these systems are applicable to a range of functionalization reactions leading to new building blocks for the discovery of bioactive products.     

Development of a Mild and Versatile Directed Cycloaddition Approach to Pyridines

The aza‐Diels–Alder cycloaddition of 1,2,4‐triazines with alkynes offers a rapid and convenient method for the synthesis of highly substituted pyridines, but often requires harsh conditions and long reaction times. The present study offers a solution to these limitations by use of a temporary tether established by a Lewis acid–base complexation of in situ generated alkynylboranes and triazines bearing a Lewis basic donor. The cycloaddition reactions take place within 20 min at 40 °C and provide direct access to a broad range of pyridines with complete and predictable regiocontrol. The carbon?boron bond can be further functionalised by cross‐coupling allowing further functionality to be introduced after cycloaddition.     

A [3 + 3] annelation approach to tetrahydropyridines

[reaction: see text] A stepwise [3+3] annelation sequence to tetrahydropyridines via addition of the Büchi Grignard to aziridines has been developed. These intermediates can be further functionalized with good regio- and stereocontrol and this methodology has been employed in the stereoselective formal synthesis of (-)-dihydropinidine.     

Investigation of an organomagnesium-based [3 + 3] annelation to pyrans and its application in the synthesis of rhopaloic acid A

A stepwise [3 + 3] annelation reaction has been developed that allows access to pyrans from epoxides. This process involves the addition of an allylmagnesium reagent, itself readily prepared from methallyl alcohol, and a Pd-catalyzed cyclodehydration reaction. The potential of this process to be employed in natural product synthesis has been exemplified by its use in the preparation of rhopaloic acid A.