Andrew S. Kende

Analysis of Structural Requirements for Ah Receptor Antagonist Activity: Ellipticines, Flavones, and Related Compounds

A number of studies have examined the structure-activity relationships for the agonist activity of Ah receptor (AhR) ligands. Fewer studies have considered the structural basis for potential antagonist properties. Certain ellipticine derivatives have been reported to bind to the AhR and inhibit the ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to transform the AhR to a form that recognizes a dioxin-responsive enhancer element (DRE) upstream of the cytochrome P4501A1 gene. In the present study, over 30 ellipticine derivatives and structurally related compounds were examined for their ability to bind to the AhR, activate it to a DRE-binding form, induce the luciferase gene under control of a DRE-containing enhancer, and block activation of the AhR by TCDD. The ability of several ellipticine derivatives to inhibit TCDD-elicited DRE binding and TCDD-induced luciferase activity was inversely related to their ability to alone stimulate these responses. The most potent antagonist activity was related to good AhR binding characteristics in terms of conforming to previously predicted 14 x 12 x 5 A van der Waals dimensions and the presence of an electron-rich ring nitrogen at or near a relatively unsubstituted X-axis terminal position. Based on these data, a number of flavone derivatives were synthesized and tested for their relative agonist/antagonist activity. These additional data were consistent with the hypothesis that an electron-rich center near or along a lateral position of the van der Waals binding cavity is a characteristic that enhances AhR antagonist activity.

Controlled reduction of nitroalkanes to alkyl hydroxylamines or amines by samarium diiodide

Abstract Alkyl hydroxylamines and alkyl amines have been prepared from nitroalkanes and SmI 2 under mild conditions in moderate to good yields.

Synthesis of a Calicheamicin Deoxyaglycone Model by an Intramolecular Acetylide Cyclization

Abstract Reaction of enediyne aldehyde 16 with LiN(SiMe 3 ) 2 leads to intramolecular acetylide cyclization to the epimeric carbinols 17 comprising a deoxyaglycone model for the calicheamicins. NOE studies permit stereochemical assignments for these epimers, which in turn suggest that C-8 stereochemistry (calicheamicin numbering) assigned for the calicheamicins may require revision.

An improved variant of the julia olefin synthesis: reductive elimination of β-hydroxy imidazolyl sulfones by samarium dhodide

The reductive elimination reaction of β-hydroxy imidazolyl sulfones to afford the corresponding olefins can be accomplished under mild conditions and in good yields using SmI 2 , offering a convenient modification of the Julia olefin synthesis

Regioselective C-3 Alkylations of Oxindole Dianion

Abstract Oxindole is converted to its dianion by treatment with two equivalents each of n-BuLi and TMEDA. Alkylations with a number of common electrophiles define the scope of synthetically useful transformations leading to 3-monosubstituted and 3,3-disubstituted oxindoles.

The regiospecific total synthesis of lavendamycin methyl ester

Abstract The total synthesis of the methyl ester of the antibiotic lavendamycin (4a) by an 8-step sequence from 8-methoxyquinaldic acid (6) is described.

Total synthesis of (±)-stemonamide and (±)-isostemonamide

Two different approaches to the alkaloids stemonamide and isostemonamide using N-acyliminium chemistry are described. The approach using an aldol spirocyclization to construct the second contiguous spirocenter was successful. The total synthesis of these products was completed by 1,4-addition of an appropriate side chain, α-methylenation by Mannich reaction, double bond isomerization and closure of the azepine ring.

Asymmetric [4+3] cycloadditions from chiral α-chloro imines

Abstract The first asymmetric [4+3] cycloadditions of 2-aminoallyl cations derived from chiral α-chloro imines to furan and pyrrole systems are reported. The absolute configuration of the major enantiomer of the bicyclic ketone 4a derived from the cycloadducts has been elucidated, and possible rationales for the observed stereoselectivity are discussed.

Chemoselective catalytic oxidation of sulfides to sulfones with tetrapropylammonium perruthenate (TPAP)

Abstract Tetrapropylammonium perruthenate has been found to be an efficient catalyst for the conversion of sulfides to sulfones. The method is highly chemoselective and isolated double bonds are generally unaffected.

Enantioselective synthesis of the α,α-dimethyl-β-hydroxy : Acid subunit of the oxazolomycin antibiotics

Reaction of the Sn(II) enolate, generated by the action of SnCl2-LiAlH4 on oxazolidinone 5, with benzaldehyde or conjugated Z-enal 8 yields respectively oxazinedione 6 or 9 with not less than 97 : 3 diastereoselectivity. Removal of the chiral auxiliary from 9 produces a homochiral model of the C1′-C5′ subunit of the oxazolomycin antibiotics.