Tandem Homologation-Acylation Chemistry: Single and Double Homologation.

Treatment of ß-dicarbonyls with the Furakawa-variant of the Simmons-Smith reagent results in homologation and production of an intermediate zinc enolate. Treatment of the enolate with various acylating agents generate products with both γ-dicarbonyl functionality and ß-dicarbonyl functionality. In situ exposure of the acylated product to additional zinc carbenoid effects a second regiospecific homologation reaction.

Syntheses of papyracillic acids: application of the tandem chain extension-acylation reaction.

A synthetic approach to the papyracillic acid family of natural products has been developed. The spiroacetal core is rapidly assembled through an unprecedented zinc carbenoid-mediated tandem chain extension-acylation reaction. Subsequent functional group manipulation provided access to papyracillic acid B and 4-epi-papyracillic acid C. The successful preparation of these molecules resulted in the clarification of structural assignments of members of this family of natural products.

A combined DFT and NMR investigation of the zinc organometallic intermediate proposed in the syn-selective tandem chain extension-aldol reaction of ß-keto esters.

The tandem chain extension-aldol (TCA) reaction of ß-keto esters provides an α-substituted γ-keto ester with an average syn:anti selectivity of 10:1. It is proposed that the reaction proceeds via a carbon-zinc bound organometallic intermediate potentially bearing mechanistic similarity to the Reformatsky reaction. Evidence, derived from control Reformatsky reactions and a study of the structure of the TCA intermediate utilizing DFT methods and NMR spectroscopy, suggests the γ-keto group of the TCA intermediate plays a significant role in diastereoselectivity observed in this reaction. Such coordination effects have design implications for future zinc mediated reactions.

Tandem chain extension-Mannich reaction: an approach to ß-proline derivatives.

A zinc carbenoid-initiated chain extension reaction provides access to an organometallic intermediate, which can be used to capture activated imines. Deprotection of the nitrogen and reduction provides access to racemic derivatives of ß-proline. The relative stereochemistry of the ß-proline can be controlled through use of different activating groups on the imine nitrogen.

Small organic solutes in sticky droplets from orb webs of the spider Zygiella atrica (Araneae; Araneidae): ß-alaninamide is a novel and abundant component.

In northeastern North America, Zygiella atrica often build their orb webs near the ocean. We analyzed individual field-built Z. atrica webs to determine if organic low-molecular-mass solutes (LMM) in their sticky droplets showed any unusual features not previously seen in orb webs of other species living in less salty environments. While two of the three most abundant organic LMM (putrescine (butane-1,4-diamine) and GABamide (4-aminobutanamide)) are already well-known from webs of inland spiders, the third major LMM, ß-alaninamide (3-aminopropanamide), a homolog of GABamide, has not been detected in sticky droplets from any other araneoid spiders (27 species). It remains to be established, however, whether or not use of ß-alaninamide is related to proximity to saltwater. We observed variability in organic LMM composition in Z. atrica webs that appeared to be influenced more by an undetermined factor associated with different collecting locations and/or collection dates than by different genders or instars. Shifts in composition when adult females were transferred from the field to the laboratory were also observed. Structural similarities and inverse correlations among ß-alaninamide, GABamide, and N-acetylputrescine suggest that they may form a series of LMM fulfilling essentially the same, as yet unknown, role in the webs of those species in which they occur.

The tandem chain extension aldol reaction used for synthesis of ketomethylene tripeptidomimetics targeting hPEPT1.

The rationale for targeting the human di-/tripeptide transporter hPEPT1 for oral drug delivery has been well established by several drug and prodrug cases. The aim of this study was to synthesize novel ketomethylene modified tripeptidomimetics and to investigate their binding affinity for hPEPT1. Three related tripeptidomimetics of the structure H-Phe-ψ[COCH(2)]-Ser(Bz)-X(aa)-OH were synthesized applying the tandem chain extension aldol reaction, where amino acid derived ß-keto imides were stereoselectively converted to α-substituted γ-keto imides. In addition, three corresponding tripeptides, composed of amide bonds, were synthesized for comparison of binding affinities. The six investigated compounds were all defined as high affinity ligands (K(i)-values <0.5 mM) for hPEPT1 by measuring the concentration dependent inhibition of apical [(14)C]Gly-Sar uptake in Caco-2 cells. Consequently, the ketomethylene replacement for the natural amide bond and α-side chain modifications appears to offer a promising strategy to modify tripeptidic structures while maintaining a high affinity for hPEPT1.

A mechanistic investigation into the zinc carbenoid-mediated homologation reaction by DFT methods: is a classical donor-acceptor cyclopropane intermediate involved?

An extensive density functional theory (DFT, M05-2X) investigation has been performed on the zinc carbenoid-mediated homologation reaction of ß-keto esters. The mechanistic existence of a classical donor-acceptor cyclopropane intermediate was probed to test the traditional school of thought regarding these systems. Calculations of the carbenoid insertion step, following enolate formation, unmasked two possible pathways. Pathway B was shown to explain the proposed, but spectroscopically unobservable donor-acceptor cyclopropane intermediate, while the second (pathway A) reveals an alternative to the classical intermediate in that a cyclopropane transition state leads to product.

Stereoselective formation of a functionalized dipeptide isostere by zinc carbenoid-mediated chain extension.

The application of a zinc carbenoid-mediated chain-extension reaction to a functionalized peptide isostere is reported. The cleavage site of human CVM protease was utilized as a target for testing the synthetic methodology. The utility of this chain-extension reaction is demonstrated in the preparation of an amino acid-derived alpha-unsubstituted gamma-keto ester, which is incorporated into a framework that mimics a tetrapeptide. The identification of a suitable protecting group strategy facilitated the application of a tandem reaction for the incorporation of an alpha-side chain, and the use of an oxazolidinone auxiliary provided excellent diastereocontrol in a tandem chain-extension-aldol reaction. Stereoselectivity of the tandem chain-extension-aldol reaction was determined through application of a CAN-mediated oxidative cleavage reaction.

Formation of gamma-lactones through CAN-mediated oxidative cleavage of hemiketals.

The generation of substituted gamma-lactones can be accomplished through application of a tandem chain extension-aldol reaction, followed by CAN-mediated oxidative cleavage of the aldol product. The oxidative cleavage requires the intermediacy of a hemiketal and the presence of an alpha-heteroatom. Formation of the gamma-lactone through the oxidative cleavage is used to assign stereochemistry of the aldol reaction and as the final step in a short synthesis of members of the phaseolinic acid family of natural products.

Tandem Chain Extension-Iodomethylation Reactions: Formation of alpha-Functionalized gamma-Keto Carbonyls.

Sequential exposure of a zinc-organometallic intermediate, generated through a zinc carbenoid-mediated chain extension reaction of a beta-keto carbonyl, to trimethylsilylchloride and iodine provided regioselective formation of an alpha-iodomethyl-gamma-keto carbonyl. The iodomethyl functionality can be further manipulated to provide side chains that are potential mimics of alpha-amino acid side chains.

Studies on the Diastereoselective Preparation of Bis-cyclopropanes.

The identification of two natural products, FR-900848 and U-106305, has stimulated interest concerning the relationship between configurational isomerism, conformational isomerism, and biological activity of polycyclopropanes. Efforts to investigate the relationship between configurational and conformational isomerism through molecular modeling suggest that significantly different three-dimensional structures will result from unique primary structures. Any effort to address these issues demands that stereoselective methods for the preparation of polycyclopropanes be developed. We have investigated the application of zinc-carbenoid cyclopropanation in the presence of chiral dioxaboralanes to the preparation of eight stereochemically unique bicyclopropanes. The trans-vinylcyclopropane starting materials demonstrated very little substrate-induced stereoselectivity, while the cis-vinylcyclopropane demonstrates modest to excellent stereocontrol. A model for the substrate-based stereocontrol is proposed. We also used the spectroscopic data gathered in this investigation to probe the substrate-mediated stereocontrol in the rhodium(II)-catalyzed cyclopropanation of vinylcyclopropanes with ethyl diazoacetate.

Formal synthesis of (+)-brefeldin A: application of a zinc-mediated ring expansion reaction.

An efficient formal synthesis of (+)-brefeldin A was accomplished through a synthetic approach that relied upon three keys steps. The five-membered ring was generated in a stereocontrolled fashion through application of a tandem conjugate addition-intramolecular cyclization method developed by Toru. Ring-closing metathesis provided access to a twelve-membered beta-keto lactone, which was ring-expanded to the alpha,beta-unsaturated-gamma-keto lactone through a zinc carbenoid-mediated reaction. Conversion of this lactone to (+)-brefeldin A has been reported previously.

Stereocontrolled formation of ketomethylene isosteres through tandem chain extension reactions.

A zinc-mediated chain extension reaction is the key step in the preparation of gamma-keto amides derived from amino acids. The use of tandem reaction sequences, in which the intermediate zinc enolate is trapped with electrophilic reagents, results in the incorporation of alpha-substituents, which mimic the side chains found in natural amino acid systems. Use of the chiral amino acid L-proline as a stereo-directing element provides a diastereoselective route to various ketomethylene isosteres.

Ring expansions of beta-keto lactones with zinc carbenoids: syntheses of (+)-patulolide A and (+/-)-patulolide B.

A one-pot ring expansion/oxidation/elimination method has been developed in which beta-keto lactones are converted efficiently to alpha,beta-unsaturated-gamma-keto lactones. The reaction can be successfully applied to a variety of ring sizes. Alkene stereochemistry is dependent upon ring size and reaction conditions. The method was applied to the synthesis of (+)-patulolide A.

Zinc carbenoid-mediated chain extension: preparation of alpha,beta-unsaturated-gamma-keto esters and amides.

An efficient one-pot preparation of alpha,beta-unsaturated-gamma-keto esters and amides has been developed. A zinc carbenoid-mediated chain extension of a beta-dicarbonyl substrate provides access to an intermediate zinc enolate, which is treated sequentially with a halogen and amine base. This method has been applied to a variety of ester and amide starting materials, as well as to amino acid-derived substrates and to a formal synthesis of (R,R)-(-)-pyrenophorin.