Spirooxindol-1,3-oxazine Alkaloids: Highly Potent and Selective Antitumor Agents Evolved from Iterative Structure Optimization.

Spirooxindole-1,3-oxazines are a small and structurally unique class of spirooxindole alkaloids. To date, only four of these compounds have been isolated from natural sources, and their biological properties remained unknown thus far. Dioxyreserpine is a synthetic spirooxindole-1,3-oxazine, that can readily be prepared from the Rauvolfia alkaloid (-)-reserpine by catalytic photooxygenation. While dioxyreserpine itself was now identified as a moderately effective antitumoral agent, structurally modified analogs of it emerged as a new class of highly potent and selective growth inhibitors of various human cancers, including pancreatic cancers. Systematic structural optimization ultimately led to an inhibitor displaying low-micromolar IC50 -values against six cancer cell lines as well as selective apoptosis induction in vitro.

A short total synthesis of (±)-mersicarpine via visible light-induced cascade photooxygenation.

A short total synthesis of the Kopsia alkaloid (±)-mersicarpine is presented. As the key step, a visible light-induced catalytic cascade photooxygenation was utilized, to convert a 3,3-disubstituted tetrahydrocarbazole intermediate, in one step, into a perhydropyrido[1,2-a]indole dione as the immediate precursor to the natural product. The synthesis of mersicarpine was achieved with an overall yield of 12% over 13 steps.

Lewis Acid-Catalyzed Carbofunctionalization of Uncommon C,N-Diacyliminium Ions: Controlling Regio- and Enantioselectivity.

The tricyclic azepino[1,2-a]indole acetates 7, readily accessible by visible-light-driven catalytic photooxygenation of cyclohepta[b]indoles 1, are convenient precursors to novel and uncommon cyclic C,N-diacyliminium ions 3. We report here the first Lewis acid-catalyzed C-C bond forming reactions of these species with TMSCN and silyl enol ethers as nucleophiles and utilizing TIPSOTf as well as Sc(OTf)3 as catalysts. Employing Sc(OTf)3/pybox complexes as a chiral catalyst system, regio- and enantioselective asymmetric alkylations with silyl enol ethers were achieved.

Total Synthesis of a Partial Structure from Arabinogalactan and Its Application for Allergy Prevention.

Arabinogalactan, a microheterogeneous polysaccharide occurring in plants, is known for its allergy-protective activity, which could potentially be used for preventive allergy treatment. New treatment options are highly desirable, especially in a preventive manner, due to the constant rise of atopic diseases worldwide. The structural origin of the allergy-protective activity of arabinogalactan is, however, still unclear and isolation of the polysaccharide is not feasible for pharmaceutical applications due to a variation of the activity of the natural product and contaminations with endotoxins. Therefore, a pentasaccharide partial structure was selected for total synthesis and subsequently coupled to a carrier protein to form a neoglycoconjugate. The allergy-protective activity of arabinogalactan could be reproduced with the partial structure in subsequent in vivo experiments. This is the first example of a successful simplification of arabinogalactan with a single partial structure while retaining its allergy-preventive potential.

Visible-Light Cascade Photooxygenation of Tetrahydrocarbazoles and Cyclohepta[b]indoles: Access to C,N-Diacyliminium Ions.

Tetrahydrocarbazoles and perhydrocyclohepta[b]indoles undergo a catalytic cascade singlet oxygenation in alkaline medium, which leads to chiral tricyclic perhydropyrido- and perhydroazepino[1,2-a]indoles in a single operation. These photooxygenation products are new synthetic equivalents of uncommon C,N-diacyliminium ions and can be functionalized with the aid of phosphoric acid organocatalysis.

Synthesis of a cyanoethylidene derivative of 3,6-anhydro-d-galactose and its application as glycosyl donor.

Starting from 1,2,4-tri-O-acetyl-3,6-anhydro-alpha-d-galactopyranose, 4-O-acetyl-3,6-anhydro-1,2-O-(1-cyanoethylidene)-alpha-d-galactopyranose (7) was synthesized by treatment with cyanotrimethylsilane. Additionally, 3,4-di-O-acetyl-1,2-O-(1-cyanoethylidene)-6-O-tosyl-alpha-d-galactopyranose was prepared from the corresponding bromide and both cyanoethylidene derivatives were used as donors in glycosylation reactions. The coupling with benzyl 2,4,6-tri-O-acetyl-3-O-trityl-beta-d-galactopyranoside provided exclusively the beta-linked disaccharides in approximately 30% yield. The more reactive methyl 2,3-O-isopropylidene-4-O-trityl-alpha-l-rhamnopyranoside gave with donors 3 and 7 the corresponding disaccharides in nearly 60% yield. Furthermore, the synthesis of 3,6-anhydro-4-O-trityl-1,2-O-[1-(endo-cyano)ethylidene]-alpha-d-galactopyranose, which can be used as a monomer for polycondensation reaction is described.