Elias A. Couladouros

The Chemistry and Biology of Alkannin, Shikonin, and Related Naphthazarin Natural Products

Wound healing properties of plant extracts that contain the naphthoquinone natural products alkannin (1) and shikonin (2) have been known for many centuries. More recently, the biological properties of 1, 2, and related derivatives have been demonstrated experimentally, and their production both by cell cultures and chemical synthesis has been studied extensively.

Stereocontrolled second generation syntheses of the ABC and FG ring systems of brevetoxin B

Abstract Stereocontrolled, second generation syntheses of the ABC and FG ring systems of brevetoxin B (1) are described. The two key intermediates 2 and 3 , representing the ABC and FG ring frameworks, were prepared from 2-deoxy-D-ribose via short and efficient sequences. The synthesis of 2 proceeded via the epoxy alcohol cyclization precursors 6 and 7 , and the Horner-Emmons cyclization precursor 5 , to give the desired tricyclic system in 3.6% overall yield. The synthesis of 3 proceeded via the epoxy alcohol cyclization precursors 10 and 11 to give the desired bicyclic system in a 11.5% overall yield. Both syntheses represent improvements over the previous procedures and allow for rapid and facile entries into the ABC and FG ring systems of this complex natural product.

Inhibition of topoisomerase I by naphthoquinone derivatives

Alkannin and shikonin are naturally occurring naphthoquinones. We have tested several derivatives of the title compounds and we have found that naphthoquinones bearing at least one phenolic hydroxyl group are potent inhibitors of topoisomerase I. The ability of the tested compounds to complex Zn++ parallels with a few exceptions their topoisomerase I inhibition properties while their intercalation and redox properties do not.

Biomimetic Explorations Towards the Bisorbicillinoids: Total Synthesis of Bisorbicillinol, Bisorbibutenolide, and Trichodimerol**

Strikingly simple cascade dimerization sequences can be used to assemble the complex frameworks of bisorbicillinoids such as bisorbicillinol (1), bisorbibutenolide (2), and trichodimerol (3). The mechanistic facets of the biomimetic total syntheses of these bioactive natural products were also explored. Inspection of the unique molecular architecture of these compounds reveals that they are likely to be assembled in nature by a dimerization of two oxidized forms of sorbicillin.

A Short Biomimetic Approach to the Fully Functionalized Bicyclic Framework of Type A Acylphloroglucinols

A biomimetic approach toward type A polyprenylated acylphloroglucinols (PPAPs) is described. The method is based on a C-alkylation-cation cyclization reaction sequence, leading to a convenient buildup of molecular complexity, employing the simple and readily available deoxycohumulone and an appropriately functionalized hydroxy halide. Thus, a versatile construction of the fully functionalized bicyclic framework of type A PPAPs (5) was achieved.

A general synthetic route towards γ- and δ-lactones. Total asymmetric synthesis of (−)-muricatacin and the mosquito oviposition pheromone (5R,6S)-6-acetoxy-hexadecanolide

Abstract Five (or six) membered asymmetric lactones are synthesized from γ-butyrolactone (or δ-valerolactone) in a straightforward way using the following reaction sequence: reduction, Wittig-Schlosser coupling, Sharpless asymmetric dihydroxylation, oxidation and lactonization. Thus, (−)-muricatacin is synthesized in six steps (43 % overall yield). Furthermore, (5 R ,6 s )-6-acetoxy-hexadecanolide is prepared in eight steps (38% overall yield) via a carbonate ester, utilizing a novel lactonization with inversion of stereochemistry.

Synthesis and Evaluation of Three Novel Scyphostatin Analogues as Neutral Sphingomyelinase Inhibitors

Low-molecular-weightinhibit ors of sphingomyelinases have attracted considerable attention as molecular tools for the investigation of the enzymatic mechanism of the various isoforms of these enzymes and for clarification of their biological role, as well as the role of the product of their action on sphingomyelin (ceramide), in apoptosis and signal-transduction processes. In addition, such molecules might prove valuable for the development of new therapies for various inflammatory and autoimmune diseases. [1]

A New Efficient Route for Multigram Asymmetric Synthesis of Alkannin and Shikonin

A short and convergent approach for the synthesis of alkannin, shikonin and shikalkin is presented. A Hauser-type annulation of cyanophthalide 26 with enone 7 affords the complete aromatic system in just one step with concomitant attachment of the entire side chain. Subsequent Coreys oxazaborolidine mediated asymmetric reduction of the above advanced intermediate, leads to the required isomer in high enantiomeric excess. Finally, a selective and high yielding deprotection protocol furnishes the title compounds as pure crystalline precipitates. Thus, a multigram synthesis of shikonin, alkannin and shikalkin is achieved in high yield and enantioselectivity.

Biomimetische Studien zu den Bisorbicillinoiden: Totalsynthese von Bisorbicillinol, Bisorbibutenolid und Trichodimerol

Durch verbluffend einfache Kaskaden-Dimerisierungen konnen die komplexen Geruste von Bisorbicillinoiden wie Bisorbicillinol 1, Bisorbibutenolid 2 und Trichodimerol 3 aufgebaut werden. Bei der biomimetischen Totalsynthese dieser bioaktiven Naturstoffe wurden auch mechanistische Aspekte untersucht. Eine Analyse des einzigartigen Molekulaufbaus dieser Verbindungen ergab, das sie in der Natur wahrscheinlich durch Dimerisierung von zwei Molekulen einer oxidierten Form von Sorbicillin gebildet werden.

Total Synthesis of Combretastatins D

Targeting the wrong isomer, we achieved a synthesis of two natural combretastatins, thanks to an unusual dehydration mechanism and the original incorrect assignment of the natural product. The key step for both syntheses was the application of a Mitsunobu-type macrolactonization of saturated seco acids (below). The synthetic route is effective, simple, and convergent, and may be useful for the synthesis of related derivatives.