Antonio C. B. Burtoloso

Chemical Synthesis of the GHIJKLMNO Ring System of Maitotoxin.

As the largest secondary metabolite to be discovered as of yet, the polyether marine neurotoxin maitotoxin constitutes a major structural and synthetic challenge. After its originally proposed structure ( 1) had been questioned on the basis of biosynthetic considerations, we provided computational and experimental support for structure 1. In an effort to provide stronger experimental evidence of the molecular architecture of maitotoxin, its GHIJKLMNO ring system 3 was synthesized. The (13)C NMR chemical shifts of synthetic 3 matched closely those corresponding to the same domain of the natural product providing strong evidence for the correctness of the originally proposed structure of maitotoxin ( 1).

α,β-Unsaturated Diazoketones as Useful Platforms in the Synthesis of Nitrogen Heterocycles

Among the different types of diazocarbonyl substrates found in the literature to date, α,β-unsaturated diazoketones have proven to be very promising as multifunctional intermediates. Possessing a diazo group, a ketone function and a double bond all together in a single molecule, these compounds constitute versatile building blocks for synthesis. For example, double bond functionalization, followed by intramolecular insertion reactions, can be a short alternative to prepare several rings or heterocyclic compounds. Although there are many efficient methods to prepare diazoketones, very few can be extended to the synthesis of the a,β-unsaturated diazoketones; this is likely responsible for their limited application in synthesis. Unfortunately, the classical methods to prepare saturated- or aryl-diazoketones (acylation of diazomethane with acyl chlorides or mixed anhydrides) are not suitable for preparing a,β-unsaturated diazoketones, since pyrazolines (dipolar cycloaddition products from the reaction between diazomethane and the double bond) are formed. Although Danheisers two-step detrifluoroacetylative procedure (starting from a,β-unsaturated methyl ketones) is considered the best general method, it cannot be applied to the synthesis of all types of a,β-unsaturated diazoketones. For example, the synthesis of more complex unsaturated diazoketones, as well as those with epimerizable stereocenters in the γ position, was never described before. Another point is related to the geometry of the double bond, since practically all examples described thus far refer to unsaturated diazoketones with E geometry. In recent years, our research group developed two new Horner-Wadsworth-Emmons reagents (containing a diazocarbonyl function) that could be easily applied in the one-step preparation of α,β-unsaturated diazoketones from aldehydes. Not only were we able to selectively synthesize E- and Z-unsaturated diazoketones, but also to employ these useful platforms in the short synthesis of several nitrogen heterocycles such as indolizidines, quinolizidines, piperidines, and pyrrolidines. Our purpose in this Account is to introduce this class of diazoketone and provide a brief historical overview, culminating in how we developed a general methodology to prepare them. In continuation, we wish to call of the readers attention to these important building blocks, showing how we could apply them to the synthesis of several nitrogen heterocycles, including the very short preparation of some popular alkaloids. The reader will also notice that the combination of these three important functions in the same molecule makes these compounds special as well as provides powerful platforms to access many important molecules in a direct fashion.

Preparation of α,β-unsaturated diazoketones employing a Horner-Wadsworth-Emmons reagent.

A new method for the preparation of α,β-unsaturated diazoketones from aldehydes and a Horner-Wadsworth-Emmons reagent is reported. The method was applied to the short synthesis of two substituted pyrrolidines.

α,β-Unsaturated Diazoketones as Platforms in the Asymmetric Synthesis of Hydroxylated Alkaloids. Total Synthesis of 1-Deoxy-8,8a-diepicastanospermine and 1,6-Dideoxyepicastanospermine and Formal Synthesis of Pumiliotoxin 251D

A versatile and concise approach for the stereoselective synthesis of mono-, di-, and trihydroxylated indolizidines is presented in four to six steps from Cbz-prolinal and a diazophosphonate. The key steps involved a Wolff rearrangement, followed by a stereoselective dihydroxylation/epoxidation reaction, from an α,β-unsaturated diazoketone. The strategy also permits extension to the synthesis of many natural hydroxylated indolizidine alkaloids as demonstrated in the formal synthesis of pumiliotoxin 251D.

Catalyst-Free Insertion of Sulfoxonium Ylides into Aryl Thiols. A Direct Preparation of β-Keto Thioethers

Insertion of sulfoxonium ylides into the S-H bond of aryl thiols without the need for a catalyst is demonstrated, furnishing β-keto thioethers in excellent yield in most cases. The method overcomes traditional syntheses that employ metal catalysts in combination with diazo compounds or toxic and hard-prepared haloketones. The experimental setup consists of mixing the reagents in acetonitrile at room temperature. Additional experimental as well as kinetic isotopic effect studies give some insight into the mechanism of this reaction.

Stoichiometric and irreversible cysteine-selective protein modification using carbonylacrylic reagents

Maleimides remain the reagents of choice for the preparation of therapeutic and imaging protein conjugates despite the known instability of the resulting products that undergo thiol-exchange reactions in vivo. Here we present the rational design of carbonylacrylic reagents for chemoselective cysteine bioconjugation. These reagents undergo rapid thiol Michael-addition under biocompatible conditions in stoichiometric amounts. When using carbonylacrylic reagents equipped with PEG or fluorophore moieties, this method enables access to protein and antibody conjugates precisely modified at pre-determined sites. Importantly, the conjugates formed are resistant to degradation in plasma and are biologically functional, as demonstrated by the selective imaging and detection of apoptotic and HER2+ cells, respectively. The straightforward preparation, stoichiometric use and exquisite cysteine selectivity of the carbonylacrylic reagents combined with the stability of the products and the availability of biologically relevant cysteine-tagged proteins make this method suitable for the routine preparation of chemically defined conjugates for in vivo applications.

SmI2-mediated couplings of α-amino acid derivatives. Formal synthesis of (-)-pumiliotoxin 251D and (±)-epiquinamide.

The coupling between cyclic and acyclic α-amino acid derivatives and methyl acrylate, mediated by samarium diiodide, is described. The method constitutes a powerful tool to construct indolizidine, quinolizidine, and piperidine systems in a straightforward two-step fashion. The formal synthesis of (-)-pumiliotoxin 251D and (±)-epiquinamide is achieved after two or three steps from these amino acid derivatives.

Three-Step Synthesis of (±)-Preussin from Decanal

A straightforward and stereoselective synthesis of the alkaloid preussin is described starting from decanal and diethyl 3-diazo-2-oxopropylphosphonate. The key steps are an aza-Michael reaction from an α,β-unsaturated diazoketone followed by a highly stereoselective Cu-catalyzed ylide formation and then a [1,2]-Stevens rearrangement. This strategy is feasible for extension to preussin analogues, demonstrating its utility for the rapid construction of all-cis-substituted pyrrolidines.

Preparation of Z-α,β-Unsaturated Diazoketones from Aldehydes. Application in the Construction of Substituted Dihydropyridin-3-ones

The stereoselective preparation of α,β-unsaturated diazoketones with Z geometry is described from aldehydes and a new olefination reagent. When prepared from amino aldehydes, these diazoketones could be converted to substituted dihydropyridin-3-ones in just one step, after an intramolecular N-H insertion reaction. The straightforward synthesis of a natural trihydroxylated piperidine demonstrates the utility of these unsaturated diazoketones for the rapid construction of piperidines.

Synthesis of Alkaloids: Recent Advances in the Synthesis of Phenanthroindolizidine Alkaloids

Phenanthroindolizidine alkaloids are a well-known class of compounds due to their interesting biological activities, especially anticancer ones. Represented by more than 60 substances, they are mainly isolated from plants of the Moraceae and Asclepiadaceae families. In the last 30 years, a great effort has been made aiming the synthesis of these compounds and analogues to be applied in medicinal chemistry.