Complexity-Building Reaction Development and the Total Synthesis of Pactamycin

The diastereoselective synthesis of b-hydroxy ketones via quaternary Claisen condensation is described. This was accomplished via three-component coupling technology incorporating a Reformatsky reagent, silyl glyoxylates, and enantioenriched b-lactones. An unusual case of 1,4-stereoinduction was observed, transmitting the b-lactone stereochemistry to the developing fully-substituted stereocenter. The product scaffold was designed for quick access to the common leustroducsin family core subunit and applied to the formal synthesis of leustroducsin B. -- Several approaches for the construction of the pactamycin core are presented. A prevailing strategy includes the rapid formation of the fully-substituted C1 stereocenter with a pendant ketone functional handle for which to test nucleophilic addition. Highly diastereoselective additions were permitted by the use of cerium trichloride, leading to a chelation-controlled stereochemical hypothesis. Four of the five core stereocenters were completed, but a challenging C2 amination could not be completed. The results of various strategies for the amino incorporation are discussed, and an optimized route to an advanced intermediate is described. -- The amination problem faced in the pactamycin core synthesis led to the invention and development of a novel a-amination protocol employing nitrones and imidoyl chlorides. Upon combination of the two reaction partners, spontaneous [3,3]-rearrangement occurred generating α-carbamoyl enamides, or enediamide products based upon the availability of enolizable protons. Treatment of the products with sodium phenylthiolate induced hydrolysis to give protected α-amino ketones in moderate yield. -- The enantioselective total synthesis of pactamycin is detailed. A de novo approach to this target was pursued using an asymmetric Mannich addition to install the C2 amino functionality early in the route. A symmetry-breaking diketone monoreduction occurred with high selectivity allowing for rapid core construction. Several unanticipated stereochemical complexities allowing for the ultimate target completion were discovered ex post facto leading to a serendipitous, concise route to pactamycin. The molecule was completed in fifteen steps, less than half that of the single reported synthesis known to date. The flexibility and efficiency afforded by this route allow for derivitization toward analogue synthesis. These structural manipulations may attenuate pactamycin's cytotoxicity which currently precludes its medicinal application.Doctor of Philosoph

Polyelectrolyte-Linked Film Assemblies of Nanoparticles and Nanoshells: Growth, Stability, and Optical Properties

Multi-layer films of nanoparticles and nanoshells featuring various polymeric linkage molecules have been assembled and their optical properties characterized. The growth dynamics, including molecular weight effects, and stability of the various nanoparticle film constructions, using both single polymer as well as combinations of alternating charge polyelectrolytes as linking mechanisms, are presented. The polymeric linkers studied include poly-L-lysine, poly-L-arginine, poly(allylamine hydrochloride), and polyamidoamine dendrimers. Significantly air stable films were achieved with the use of multi-layered polymeric bridges between the nanoparticles and nanoshells. Optical sensitivity normally observed with these nanomaterials in solution was observed for their corresponding film geometries, with the nanoshell films exhibiting a markedly higher ability to report their local dielectric environment

α-Amination of keto-nitrones via Multihetero-Cope rearrangement employing an imidoyl chloride reagent

α-Aminations of ketone-derived nitrones have been developed via [3,3]-rearrangement of the intermediates generated upon condensation with imidoyl chlorides. Careful reagent selection provides synthetically attractive amino protecting groups. The enediamide or α′-carbamoyl enamide products can be hydrolyzed to the desired carbonyl, or exposed to electrophiles for further α-functionalization

Asymmetric Synthesis of the Aminocyclitol Pactamycin, a Universal Translocation Inhibitor

An asymmetric total synthesis of the aminocyclopentitol pactamycin is described, which delivers the title compound in 15 steps from 2,4-pentanedione. Critical to this approach was the exploitation of a complex symmetry-breaking reduction strategy to assemble the C1, C2, and C7 relative stereochemistry within the first four steps of the synthesis. Multiple iterations of this reduction strategy are described, and a thorough analysis of stereochemical outcomes is detailed. In the final case, an asymmetric Mannich reaction was developed to install a protected amine directly at the C2 position. Symmetry-breaking reduction of this material gave way to a remarkable series of stereochemical outcomes leading to the title compound without recourse to non-strategic downstream manipulations. This synthesis is immediately accommodating to the facile preparation of structural analogs

Formal Synthesis of Leustroducsin B via Reformatsky/Claisen Condensation of Silyl Glyoxylates

A formal synthesis of leustroducsin B has been completed. The synthesis relies upon a recently developed Reformatsky/Claisen condensation of silyl glyoxylates and enantioenriched β-lactones that establishes two of the molecule's three core stereocenters and permits further elaboration to an intermediate in Imanishi's synthesis via reliable chemistry (Prasad reduction, asymmetric pentenylation, Mitsunobu inversion)

Remote Stereoinduction in the Acylation of Fully Substituted Enolates: Tandem Reformatsky/Quaternary Claisen Condensations of Silyl Glyoxylates and β-Lactones

Reformatsky reagents react sequentially with silyl glyoxylates and β-lactones to give highly functionalized Claisen condensation products. A heretofore undocumented instance of stereochemical 1,4-induction results in efficient transmission of β-lactone stereochemistry to the emerging fully-substituted stereocenter. Second-stage transformations reveal that the five heteroatom-containing functionalities embedded within the products are entirely chemo-differentiated, a circumstance that permits rapid assembly of the leustroducsin B core substructure

Diastereocontrolled Construction of Pactamycin’s Complex Ureido Triol Functional Array

An advanced intermediate in a projected synthesis of pactamycin has been prepared. Early installation of the C1-dimethylurea functionality allows for its participation in a diastereoselective, chelation-controlled addition of organometal nucleophiles to the C5 prochiral ketone. Four of the molecule's six stereocenters are set with a ketone functional handle provided for subsequent manipulation

Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: Insight into functional group effects and biological activity

The synthesis and biological analysis of a number of novel congeners of the aminocyclopentitol pactamycin is described. Specific attention was paid to the preparation of derivatives at crucial synthetic branch points of the parent structure, and biological assays revealed a number of insights into the source of pactamycin’s biological activity. Additionally, the encapsulation of pactamycin and select derivatives into the PRINT© nanoparticle technology was investigated as a proof-of-concept, and evidence of bioactivity modulation through nanoparticle delivery is demonstrated. This work has provided heretofore unrealized access to a large number of novel compounds for further evaluation

Silyl Glyoxylates. Conception and Realization of Flexible Conjunctive Reagents for Multicomponent Coupling

This Perspective describes the discovery and development of silyl glyoxylates, a new family of conjunctive reagents for use in multicomponent coupling reactions. The selection of the nucleophilic and electrophilic components determines whether the silyl glyoxylate reagent will function as a synthetic equivalent to the dipolar glycolic acid synthon, the glyoxylate anion synthon, or the α-keto ester homoenolate synthon. The ability to select for any of these reaction modes has translated to excellent structural diversity in the derived three- and four-component coupling adducts. Preliminary findings on the development of catalytic reactions using these reagents are detailed, as are the design and discovery of new reactions directed toward particular functional group arrays embedded within bioactive natural products