Barry Lygo

Alkylation reactions of anions derived from 2-benzenesulphonyl tetrahydropyran and their application to spiroketal syntiesis

Abstract Reaction of 3,4-dihydro-2H-pyran or 2-methoxytetrahydropyran with benzenesulphinic acid gave 2-benzenesulphonyl tetrahydropyran (1)., Deprotonation of (1) follwed by alkylation with carbonyl compounds or halides gave cyclic enol ether addition products by spontaneous elimination of benzenesulphinic acid. Interception of the initial addition products with aldehydes by reductive desulphonylation to give alkylated tetrahydropyran derivatives proeeeded in moderate yield using sodium naphthalenide. Several of the cystic enol ether addition products were further converted to spiroketals including syntheses of natural product pheromones from Dacus oleae and Paravespula vulgaris .

A highly convergent total synthesis of the spiroacetal macrolide (+)-milbemycinβ1

Abstract A highly convergent synthesis of the macrolide natural product milbemycin β1 is reported. The key features of this synthesis include the introduction of the C11-C15 side chain by selective ring opening of a symmetrical 1,4-pentane bis-epoxide (3) followed by reaction with the anion derived from the 2,3-trans-dimethyl-6-phenylsulphonyl pyran (2) to afford the “northern” C11-C25 fragment (33) of milbemycin β1. Coupling of the derived C11-C25 aldehyde unit (37) with a C1-C10 southern zone fragment (5) was achieved via a novel deconjugative vinyl sulphone anion sequence to give a product containing all the carbon substituents of the natural product. Final manipulations involved macrolactonisation and subsequent introduction of the important 3,4-double bond by selenoxide syn-elimination. Methylation of the C-5 hydroxyl group was accomplished as the penultimate step with methyl iodide and silver (I) oxide under ultrasonication.

Preparation and reactions of 2-benzenesulphonyltetrahydropyran

Abstract The anion derived from 2-benzenesulphonyltetrahydropyran (1) reacts with various electrophiles to give alkylated or acylated products some of which are useful precursors for spiroketal synthesis.

Wittig and Horner-Wittig coupling reactions of 2-substituted cyclic ethers and their application to spiroketal synthesis

Abstract Wittig and Horner-Wittig coupling reactions of tetrahydropyran or tetrahydrofuran 2-triphenylphosphonium salts or 2-diphenylphosphine oxides with aldehydes and lactols affords good yields of the corresponding enol ethers. In selected examples these enol ether products may be further converted to spiroketals some of which are natural pheromones derived from Dacus oleae and Paravespula vulgaris .

Synthesis of methyl-1,6-dioxaspiro[4,5]decanes using organoselenium mediated cyclization reactions

Abstract Three naturally occurring methyl-1,6-dioxaspiro[4.5]decanes have been prepared in good yield using organoselenium mediated reactions during the crucial cyclization process.

A new route to spiro-ketals using the Horner-Wittig reaction of 2-diphenylphosphinoxy cyclic ethers

Abstract Two insect pheromones along with other spiro-ketals have been synthesised by a new route which involves Horner-Wittig coupling of 2-diphenylphosphinoxy cyclic ethers with aldehydes and lactols followed by acid catalysed cyclisation.

Synthesis of spiroacetals using organoselenium-mediated cyclisation reactions. X-Ray molecular structure of (2S,8R)-8-methyl-2-phenyl-1,7-dioxaspiro[5.5]undecan-4(R)-ol

Alkenyl hydroxyketones undergo cyclisation via their hemiacetal form, in the presence of N-phenylselenophthalimide (NPSP) and a Lewis acid, to give the corresponding phenylseleno-substituted spiroacetals. Using this methodology the synthesis of trans- and cis-2-methyl-1,6-dioxaspiro-[4.4]nonane (1), trans- and cis-2-ethyl-1,6-dioxaspiro[4,4]nonane (chalcogran)(2), trans- and cis-2-methyl-1,6-dioxaspiro[4,5]decane (3), trans-7-methyl-1,6-dioxaspiro[4.5]decane (4), trans-2-methyl-1,7-dioxaspiro[5.5]undecane (5), and (2S,8R)-8-methyl-2-phenyl-1,7-dioxaspiro[5.5]undecane-4-one (6) has been achieved, after reductive removal of selenium using Raney-nickel in diethyl ether. Compound (2) is the principal aggregation pheromone from Pityogenes chalcographus(L), whilst compounds (3) and (4) constitute the pheromone components of the common wasp, Paravespula vulgaris. The structure of the spiroacetal (6) was determined as a result of X-ray crystallography of a later derivative, obtained by sodium borohydride reduction of (6).

Larger scale preparation of optically-active allylic alcohols

An efficient and practical synthesis of optically-active allylic alcohols from 2,3-epoxytoluene-p-sulfonates by the in situ formation of the epoxy iodides and their subsequent reduction with zinc–copper couple has been established. Application of this procedure to the larger-scale synthesis of (S)-(+)-but-3-en-2-ol from (2S,3S)-3-methylglycidyl toluene-p-sulfonate has also been investigated.

Synthesis of (±)-cis-6-methyltetrahydropyran-2-ylacetic acid, a natural product from Viverra civetta, using organoselenium-mediated cyclisation reactions

Two highly stereoselective syntheses of the natural product (±)-cis-6-methyltetrahydropyran-2-ylacetic acid (1) are described. The shorter of these is a three-step synthesis involving kinetic alkylation of the dianion derived from benzyl acetoacetate with 4-bromobut-1-ene, followed by organoselenium mediated cyclisation with N-phenylselenophthalimide, to give benzyl 6-phenylselenomethyl-5,6-dihydro-4H-pyran-2-ylacetate (11) and benzyl 6-phenylselenomethyltetrahydropyran-2-ylideneacettate (12), which upon reaction with Raney nickel under 100 atm of hydrogen directly affords compound (1).

Synthesis of the spiroacetal unit related to the avermectins and milbemycins

A route to enantiomerically pure 1,7-dioxaspiro[5.5]undecanes as important building blocks for milbemycin/avermectin synthesis is described, involving the Wittig reaction of a substituted cyclic ether with aldehydes, followed by spiroacetalisation.