ABSTRACT
Saxitoxin (STX) is the archetype of a large family (>50) of architecturally distinct, bisguanidinium natural products. Among this collection of isolates, two members, 11-saxitoxinethanoic acid (11-SEA) and zetekitoxin AB (ZTX), are unique, bearing carbon substitution at C11. A desire to efficiently access these compounds has motivated the development of new tactical approaches to a late-stage C11-ketone intermediate 26, designed to enable C-C bond formation using any one of a number of possible reaction technologies. Highlights of the synthesis of 26 include a metal-free, silylpyrrole oxidative dearomatization reaction and a vinylsilane epoxidation-rearrangement cascade to generate the requisite ketone. Nucleophilic addition to 26 makes possible the preparation of unnatural C11-substituted STXs. Olefination of this ketone is also demonstrated and, when followed by a redox-neutral isomerization reaction, affords 11-SEA.
Subject(s)
Biological Products , Saxitoxin , Oxidation-Reduction , Saxitoxin/analogs & derivativesABSTRACT
The hydrindane (bicyclo[4.3.0]nonane) structural motif (1) and related cis-1-hydrindanone skeleton (2) are common substructures in many natural products. Herein, we describe efficient access to substituted cis-1-hydrindanones enabled by a sequence of Michael reactions. A copper-catalyzed intermolecular Michael addition of a cyclic silyl ketene acetal to a ß-substituted-α-alkoxycarbonyl-cyclopentenone enables construction of a quaternary center and is followed, after incorporation of an additional Michael acceptor, by a second, intramolecular addition of a nucleophilic ß-ketoester. This strategy affords stereoselective access to substituted bicyclic cis-hydrindanone ring systems containing up to three contiguous stereocenters.
ABSTRACT
The fluorination of unactivated C(sp(3) )-H bonds remains a desirable and challenging transformation for pharmaceutical, agricultural, and materials scientists. Previous methods for this transformation have used bench-stable fluorine atom sources; however, many still rely on the use of UV-active photocatalysts for the requisite high-energy hydrogen atom abstraction event. Uranyl nitrate hexahydrate is described as a convenient, hydrogen atom abstraction catalyst that can mediate fluorinations of certain alkanes upon activation with visible light.
ABSTRACT
Methods for functionalizing carbon-hydrogen bonds are featured in a new synthesis of the tricyclic core architecture that characterizes the indoxamycin family of secondary metabolites. A unique collaboration between three laboratories has engendered a design for synthesis featuring two sequential C-H functionalization reactions, namely a diastereoselective dirhodium carbene insertion followed by an ester-directed oxidative Heck cyclization, to rapidly assemble the congested tricyclic core of the indoxamycins. This project exemplifies how multi-laboratory collaborations can foster conceptually novel approaches to challenging problems in chemical synthesis.
ABSTRACT
A new, concise synthesis of the CCR-5 receptor antagonist maraviroc (UK-427,857) from 3-phenyl-1-propanol has been completed in four steps featuring a site-selective C-H functionalization.
