Robert D. Walkup

Stereoselectivity in the syntheses of substituted 2-(2-tetrahydrofuranyl)acrylates via intramolecular oxymercurations or oxypalladations of allenes

Abstract Allenes bearing a hydroxyl or a trialkylsilyloxy group gamma to the allene group underwent oxymetallations in the presence of mercury(II) or palladium(II) to form tetrahydrofuranyl vinylmetal complexes which could undergo palladium-mediated carbonylations in methanol to form methyl 2-(2-tetrahydrofuranyl)acrylates. The oxymercurations of the silyloxy allenes proceeded with high cis selectivity.

Studies on the syntheses of the aplysiatoxins: Synthesis of a selectively-protected form of the C27 – C30 (dihydroxybutanoate) moiety of oscillatoxin A

Abstract A protected form of (R)-3,4-dihydroxybutanoic acid bearing a benzyl protecting group at the C 4 hydroxyl and a dimethylthexylsilyl protecting group at the C 3 hydroxyl was synthesized via a selective Ag(l)-mediated monobenzylation of (R)-methyl 3,4-dihydroxybutanoate. An alternative synthetic route from a chiral allylic ether was successful but problematic. The acid could be cleanly coupled to a model for the C 3 – C 11 moiety of the aplysiatoxins.

A palladium-catalyzed cyclization-carbonylation-coupling reaction between aryl halides and γ-Hydroxyallenes to form aryl (tetrahydrofuran-2-yl)vinyl ketones

Abstract γ-Hydroxyallenes undergo cyclization-carbonylation-coupling with aryl (and one alkenyl) halides in the presence of catalytic Pd(PPh 3 ) 4 , base, and CO to form the title ketones in good yields. The reaction was temperature dependent: at 80 °C, the CO insertion did not readily occur, while at 55–60 °C the ketone products predominated. Yields for the Pd(0)-catalyzed cyclization-coupling reaction (without insertion) improved when tert -butyl isocyanide was added (with no CO present), implying that a good π acid ligand improves the cyclization-coupling reactions between arylpalladium(II) halides and γ-hydroxyallenes.

Synthesis of the C1′–C11′ portion of pamamycin-607 via a stereoselective oxymercuration of a gamma—silyloxyallene and a stereospecific magnesium—methanol reduction

The C1′–C11′ portion of the antibiotic pamamycin-607, a novel homologue and C2-epimer of nonactic acid, was synthesized in six steps from 4,5-hexadien-1-ol via a novel cis-selective oxymercuration/transpalladation/methoxycarboxylation of a γ-silyloxyallene and a syn-selective reduction of a 2-(2-tetrahydrofuranyl)acrylate using magnesium in methanol. Spectroscopic properties of a derivative of the synthetic C1′–C11′ portion match those of material derived from the natural product.

Expeditious synthesis of a key C9–C21 subunit of the aplyslatoxine and oscillatoxins

Abstract The C9–C21 portion of the aplysiatoxin/oscillatoxin bluegreen algal metabolites was synthesized as the 9-aldehyde bearing a tert -butyldimethylsilyl ether group on the C11 hydroxyl and a trimethylsilylethoxymethyl ether group on the C20 hydroxyl. Featuring an asymmetric aldol and an asymmetric oxazaborolldine reduction, the synthesis proceeded with high (>90%) stereoselectivity in 13 steps and 5–7% overall yield from commercial starting material.

Synthesis of a C1C14 subunit of the macrodiolide antibiotics pamamycin-607 and pamamycin-635B

A nonracemic C1C14 portion of the antibiotics pamamycin-607 and -635B was prepared using a route which features two stereoselective aldol reactions (including an apparent kinetic resolution via the Evans aldol reaction), a stereospecific intramolecular oxymercuration of a γ-silyloxyallene, a stereospecific conjugate reduction of a β-alkoxy-α-methylene carboxylate ester, and use of the 2,6-di-tert-butyl-4-methoxyphenyl ester group to “protect” a carboxylate function from reactions which normally occur at ester groups.

Synthesis of a nucleoside analog bearing a branched difunctional sidechain using the palladium-mediated cyclization of a γ-oxoallene

Abstract The aldehyde 8 was synthesized in high yield and with excellent stereoselectivity by treating a protected 3-hydroxypropanal with Coreys chiral B-propargyl boradiazoline reagent. Cyclization of this γ-oxoallene with palladium(II) in the presence of methanol and carbon monoxide produced the furanoside 9 with excellent stereoselectivity for the D-deoxyribose geometry. The furanoside 9 was converted to the branched extended sidechain deoxythymidine analog 11 by reduction, protection, and β-stereoselective Vorbruggen coupling. The hydroboration/oxidation of 10 to yield the doexyribofuranoside analog 13 , bearing two sidechain hydroxyl groups, was also demonstrated.

Access to cis-2,5-disubstituted iodovinyltetrahydrofurans via the cyclization of γ-silyloxyallenes using n-iodosuccinimide

Abstract Treatment of γ-( tert -butyldimethylsiloxy)- or γ-(trimethylsiloxy)allenes bearing various groups at the ether carbon with N-iodosuccinimide resulted in the formation of iodocyclization products, 1-iodo-1-(tetrahydrofuran-2′-yl)ethenes, in good yields and with high selectivity for the cis diastereomer.

An α-alkylation/reduction of ketones via radical cyclizations of β-chloroethylsilyl enol ethers

Abstract β-Chloroethyldimethylsilyl enol ether derivatives of five ketones were allowed to react with tributylstannane in the presence of AIBN to yield the products of “reductive α-alkylation,” 1-oxa-2-silacyclohexanes, plus ethyldimethylsilyl enol ether byproducts from direct reduction. The unstable oxasilacyclohexanes were treated with methyllithium to yield, upon workup, γ(trimethylsilyl) alcohols.

Silicon-functionalized silyl enol ethers: A novel dialkylchlorosilyl enol ether and its conversion to alkoxy- and aminosilyl enol ethers

Abstract The lithium enolate derived from 3,3-dimethyl-2-butanone (pinacolone) reacted with dichlorodimethylsilane to yield a chlorosilyl enol ether, 3,3-dimethyl-2-(chlorodimethylsilyloxy)-1-butene, which reacts with numerous oxygen and nitrogen nucleophiles to yield silicon-functionalized silyl enol ethers.