An improved synthesis of the scyphostatin side-chain

A formal synthesis of the lipophilic side-chain of scyphostatin has been achieved using a convergent synthesis, in 16% yield over six steps. This synthesis involves enzymatic desymmetrisation of a meso-diol, resolution of 2-methylbutan-1-ol, stereoselective hydrozirconation of a volatile acetylene and a Negishi-style cross coupling.     

Desymmetrisation of a diallyl system by intramolecular Heck reaction

The development of a desymmetrising cyclisation of a benzylic diallyl iodide is reported. The final procedure generates a new quaternary chiral centre in greater than 80% yield giving a highly functionalised methylene indan product suitable for further application in synthesis.     

Lipase-catalysed synthesis of homotartaric acid enantiomers

The investigation of lipase-catalysed kinetic resolution of diol anti-2 and desymmetrisation of diol meso syn-2 allowed the development of a new procedure to synthesise optically active (R,R)-homotartaric acid.     

Efficient synthesis of an α-trifluoromethyl-α-tosyloxymethyl epoxide enabling stepwise double functionalisation to afford CF3-substituted tertiary alcohols

The efficient synthesis of an α-trifluoromethyl-α-tosyloxymethyl epoxide is reported. This highly versatile building block may be reacted sequentially with two different nucleophiles to furnish α-trifluoromethyl tertiary alcohols. Furthermore, the two enantiomers of this key intermediate have been separated using chiral HPLC and the stereochemistry shown to be conserved during subsequent chemical manipulations. Finally, an enzyme-driven desymmetrisation approach has been successfully employed to confer chirality on an intermediate in the sequence.     

Enantioselective Total Synthesis of (+)-Incargranine A Enabled by Bifunctional Iminophosphorane and Iridium Catalysis

Herein we report the first enantioselective total synthesis of (+)-incargranine A, in nine steps. The total synthesis was enabled by an enantioselective intramolecular organocatalysed desymmetrising Michael addition of a malonamate ester to a linked dienone substrate that established pivotal stereocentres with excellent enantio- and complete diastereoselectivity. Furthermore, a key hemiaminal intermediate was accessed by developing an iridium-catalysed reductive cyclisation, and the scope of this transformation was explored to produce a range of bicyclic hemiaminal motifs. Once installed, the hemiaminal motif was used to initiate a biomimetic cascade to access the natural product directly in a single step.     

Desymmetrisation of bicyclo[4.4.0]decadienes: A planar-chiral complex proved to be most effective in an asymmetric Heck reaction

The synthesis and desymmetrisation of bicyclo[4.4.0]decadienes is described; the enantioselective Heck reaction using JOSIPHOS as a planar-chiral complex produces a tetracyclic system with three stereogenic centers in up to 84% enantiomeric purity.     

Copper-catalysed meso-bislactone ring opening using Grignard and mixed triorganozinc reagents

An efficient copper-mediated S_N2′ ring-opening reaction of a meso-bislactone has been developed using Grignard reagents and, for the first time, mixed triorganozinc reagents.     

Studies on organolithium-induced alkylative desymmetrisation of epoxides: synthesis of enantioenriched β-amino cycloheptenols from 6,7-epoxy-8-azabicyclo[3.2.1]octanes

The synthesis and enantioselective α-deprotonation—double ring opening of 6,7-epoxy-8-azabicyclo[3.2.1]octanes 5 using organolithiums in the presence of (−)-sparteine or (4S)-2,2′-(1-ethylpropylidene)bis-4-(1-methylethyl)-4,5-dihydrooxazole, giving amino cycloheptenols in up to 85% yield and 82% ee is described. The impact of different reaction variables on reaction profiles has been studied, including the nature of organolithium, solvent, ligand, temperature and epoxide structure. The reactions proved to be dependent on all these variables, in particular on the structure of substrate. A mixed organolithium system (PrⁱLi/TMSCH₂Li) has been successfully used to introduce potentially versatile allylsilane functionality.