Scott D. Rychnovsky

Stereochemistry of alternating polyol chains: 13C NMR analysis of 1,3-diol acetonides

Abstract Acetonides of syn and anti 1,3-diols (4,6-dialkyl-2,2-dimethyl-1,3-dioxanes) can be easily and unambiguously distinguished by 13C NMR. The stereochemistry of many alternating (1,3,5...) polyol chains can be determined by preparation and 13C NMR analysis of two frame-shifted polyacetonide derivatives.

Preparation of 2-lithiotetrahydropyrans: kinetic and thermodynamic generation of alkyllithium reagents

Abstract Both axial and equatorial 2-lithiotetrahydropyrans are readily prepared from 2-(phenylthio)-tetrahydropyrans. Axial 2-lithiotetrahydropyrans are formed selectively on reducing 2-(phenylthio)-tetrahydropyrans with lithium di- tert -butylbiphenylide, and equatorial 2-lithiotetrahydropyrans are formed selectively by thermal equilibration of the axial isomers.

1-methylcyclopropyl (MCP) ethers as protecting groups

Abstract Terminal 1,2- or 1,3-diol acetonides can be converted regioselectively into secondary 1-methylcyclopropyl (MCP) ether or primary triethylsilyl ethers under mild conditions. MCP ethers are stable to a variety of conditions and can be removed by treatment with NBS or DDQ.

Reductive lithiation of alkyl 2-thiopyridyl ethers to generate optically pure α-alkoxylithium reagents

Abstract Enantiomerically pure 4-lithio-2-alkyl-1,3-dioxanes, 11 and 13 , were prepared by reductive lithiation of alkyl 2-thiopyridyl ether 10 , which was in turn prepared by Barton radical decarboxylation of the homologous acid. The optical activity was introduced by chirality transfer to and from the stereogenic acetal center.

Oxepanes from an unusual acetal cleavage of 6,8-dioxabicyclo[3.2.1]octanes

On treatment with BF3·OEt2 and TMSCN, epoxy ketone 1 cyclized to the bicyclic acetal 2, which then cleaved to give primarily the oxepane 5 as a single stereoisomer. Reductive decyanation of 5 led to the oxepane 7, a structural unit present in the brevetoxin family of natural products. The scope and limitations of this reaction sequence were investigated.

Synthesis and revised configuration of (+)-combretastatin D-1

Abstract (+)-Combretastatin D-1 was prepared with modest enantioselectivity by Jacobsen epoxidation of combretastatin D-2 acetate. The configuration of (+)-combretastatin was shown to be (3 R ,4 S ) based on precedent from the Jacobsen epoxidation, and an advanced Mosher ester analysis of a derivative. The stereochemistry of natural (−)-combretastatin should be corrected to (3 S ,4 R ).

Regiospecificity of acetal cleavage to an enol ether using a carbon-13 labeled acetonide

Abstract Labeled acetonide 3 was prepared and used to study the mechanism of an acetal cleavage reaction.

A reverse-phase HPLC assay for measuring the interaction of polyene macrolide antifungal agents with sterols

A quick and simple affinity chromatography method for gauging the interaction of polyene antifungal agents with sterols has been developed. The required affinity columns are prepared from a standard C-18 reverse-phase HPLC column by injecting a measured quantity of sterol under conditions where it is completely retained. After the assay, the sterol is eluted with a less polar solvent and the column reused. By comparing the elution volume of a polyene injected onto the sterol-free column (Ve) with that of the polyene injected onto the sterol-doped column (V), an association constant (Ka) for the polyene-sterol complex was determined. Association constants of different amphotericin B-sterol and pimaricin-sterol complexes were determined and correlated with the polyenes ability to induce membrane permeability and its antifungal properties. This procedure provides a new tool for screening polyene macrolides for antifungal therapy.

Convergent synthesis of the spiroacetal fragment of milbemycin β1

Milbemycin spiroacetal 4 was prepared from (4S,5R)-4,5-dimethylpentan-5-olide 5 and (R)-1-(benzyloxymethyl)oxirane by alkylation and stereoselective reductive decyanation of the intermediate spiroacetal cyanohydrin 7.