Charles K. Zercher

Zinc Carbenoid-mediated Chain Extension of β-Keto Amides

Abstract The reaction of β-keto amides with ethyl(iodomethyl)zinc provides access to a wide variety of γ-keto amides, including primary, secondary, and tertiary amides. Although the reaction of α-substituted β-keto amides are in many cases unsatisfactory, the method can be applied to a broad spectrum of substrates that possess imide and olefinic functionality.

PREPARATION OF THE ZARAGOZIC ACID CORE THROUGH THE REARRANGEMENT OF AN OXONIUM YLIDE

Abstract The diastereoselective formation of a 2,8-dioxabicyclo[3.2.1]octane skeleton was accomplished through the generation and rearrangement of a bicyclic oxonium ylide. The skeleton which was formed is common to the zaragozic acid family and possesses appropriate functionality for further manipulation. The study also revealed the first example of an exocyclic 2,3-shift from a acetal-derived oxonium ylide.

Olefin cross-metathesis in the preparation of polycyclopropanes: formal synthesis of FR-900848

Abstract Olefin cross-metathesis was used for the efficient incorporation of an E -olefin between two cyclopropane residues. The generation of a bis-cyclopropyl alkene homodimer, followed by cross metathesis with a terminal vinyl polycyclopropane, provided excellent yields of the targeted compounds with good olefin stereoselectivity. The strategy was applied to generation of a quinta-cyclopropane intermediate found in a previous synthesis of the natural product FR-900848.

Diastereoselective synthesis of bicyclopropanes

Abstract Diastereoselective cyclopropanation of a trans-substituted vinyl cyclopropane was studied. The stereochemistry of the major and minor isomers was assigned by diastereoselective synthesis of the two isomers.

Chain Extension of Amino Acid Skeletons: Preparation of Ketomethylene Isosteres

Ketomethylene isosteric replacements for peptide bonds were generated through a zinc carbenoid-mediated chain extension reaction in which a variety of amino acid-derived β-keto esters are converted to γ-keto esters in a single step. The reaction tolerates a variety of protecting groups and amino acid side chains with no epimerization of the amino acid stereocenter.

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 β-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.

Small organic solutes in sticky droplets from orb webs of the spider Zygiella atrica (Araneae; Araneidae): β-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, β‐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 β‐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 β‐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.

Formation of γ-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.

A Divergent Diastereoselective Approach to Bicyclopropanes

Abstract The diastereoselective cyclopropanation of three stereoisomerically unique vinylcyclopropanes was studied. The selective preparation of six stereoisomeric bicyclopropanes was accomplished by an iterative reagent-controlled process. With the exception of the cis-syntrans-bicyclopropane, all isomers can be prepared in a diastereomeric excess of greater than 5:1.

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.