A concise synthesis of the cortistatin core

We describe a concise and convergent route to the core matrix of the cortistatin steroidal alkaloids. The salient features of the synthesis are the Snieckus cascade methodology and the Masamune alkylative dearomatization. This chemistry lends itself to a total synthesis of the cortistatins and to the development of a SAR program based on diverted total synthesis.     

Stereoselective synthesis of core structure of cortistatin A

A stereoselective synthesis of the core structure of cortistatin A (1), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, is described. An 8-oxabicyclo[3.2.1]octene system, a characteristic B-ring structure of 1, was elaborated by a 7-endo selective intramolecular Heck cyclization and a subsequent acid-mediated oxy-Michael reaction.     

Concise synthesis of the xenibellols core

We describe herein a concise synthesis of an intermediate, via 2,3-Wittig rearrangement and Williamson etherification, en route to the natural products, xenibellols A and B.     

Concise and enantioselective synthesis of the aminocyclitol core of hygromycin A

[reaction: see text] Stereoselective aminohydroxylation and dihydroxylation using osmium(VIII) oxidants enabled the short and efficient synthesis of the aminocyclitol core of hygromycin A. In addition to allowing the selective introduction of the heteroatoms N and O, the use of osmium (via an osmate ester) as a protecting group for a 1,2-glycol is also reported. This tactic allowed efficient differentiation of otherwise equivalent hydroxyl groups and allowed us to complete the synthesis in short order (14 steps) and excellent overall yield (12%).     

Concise synthesis of the tricyclic core of lycoposerramine S

The tricyclic core of lycoposerramine S has been synthesised in 10 steps from a symmetrical cyclohexadiene precursor by way of a desymmetrising free-radical cyclisation and iodocyclisation.     

Scalable synthesis of cortistatin A and related structures

Full details are provided for an improved synthesis of cortistatin A and related structures as well as the underlying logic and evolution of strategy. The highly functionalized cortistatin A-ring embedded with a key heteroadamantane was synthesized by a simple and scalable five-step sequence. A chemoselective, tandem geminal dihalogenation of an unactivated methyl group, a reductive fragmentation/trapping/elimination of a bromocyclopropane, and a facile chemoselective etherification reaction afforded the cortistatin A core, dubbed "cortistatinone". A selective Δ(16)-alkene reduction with Raney Ni provided cortistatin A. With this scalable and practical route, copious quantities of cortistatinone, Δ(16)-cortistatin A (the equipotent direct precursor to cortistatin A), and its related analogues were prepared for further biological studies.     

Concise, stereocontrolled synthesis of the citrinadin B core architecture

A concise, stereocontrolled synthesis of the citrinadin B core architecture from scalemic, readily available starting materials is disclosed. Highlights include ready access to both cyclic tryptophan tautomer and trans-2,6-disubstituted piperidine fragments, an efficient, stereoretentive mixed Claisen acylation for the coupling of these halves, and further diastereoselective carbonyl addition and oxidative rearrangement for assembly of the core.     

Short-step synthesis and structure-activity relationship of cortistatin A analogs

An improved method for synthesizing structurally simplified analogs of cortistatin A (1), a novel anti-angiogenic steroidal alkaloid from a marine sponge, was developed. In contrast to previous methods, step- and redox-economical synthesis was achieved using a known α-bromoketone as the starting material. The structure-activity relationship study revealed that the isoquinoline portion was strictly recognized by the target molecule. Surprisingly, the introduction of the acetamide moiety on the A-ring structure dramatically enhanced the selective antiproliferative activity against endothelial cells. This new method can be easily applied to gram-scale synthesis and enabled us to prepare various analogs, which were focused on the participation of the side chain and A-ring structure.     

Concise synthesis of (+)-serinolamide A

Serinolamide A, isolated from a species of marine cyanobacteria, exhibits a moderate agonist effect and selectivity for the CB₁ cannabinoid receptor, which is unusual for marine natural products. Herein, we reported a highly efficient enantiospecific first total synthesis of (+)-serinolamide A from l-serine in nine steps with 30% overall yield. The synthesis method provides a facile, practicable, and economical approach for the preparation of other similar endocanabinoid lipids.     

Concise synthesis of bicyclic aminals and their evaluation as precursors to the sarain core

A number of bicyclic aminals have been prepared in a stereospecific manner as potential precursors to the core structure of the sarain alkaloids. Rearrangement of these aminals to new diazabicyclic and diazatricyclic systems has been observed under various conditions.     

Concise formal synthesis of (+)-pyripyropene A

A concise enantioselective synthesis of A/B bicyclic segment of naturally occurring α-pyrone meroterpenoid pyripyropene A is achieved in 9 steps (LLS) and 7.5% yield starting from R-(?)-carvone. The significant points of the synthesis include: (1) an intramolecular 1, 3-dipolar cycloaddition reaction to construct the A ring and assemble C4 quaternary carbon stereocenter as well; (2) reductive cleavage of the oxazole motif utilized Raney Ni/B(OCH₃)₃.     

Concise, regiocontrolled synthesis of yangjinhualine A

The first synthesis of yangjinhualine A, a recently isolated α,β-disubstituted γ-hydroxybutenolide from the Chinese medicinal herb Datura metel L., has been accomplished in concise, entirely regiocontrolled fashion through the combined use of Suzuki-Miyaura cross-coupling and 2-silyloxyfuran oxyfunctionalization.     

Concise synthesis of dl-febrifugine

Racemic compound (1) of the antimalarial agents febrifugine (d-1) was synthesized using an stereoselective Michael reaction of an omega-amidoenone (5) which was prepared by the Wittig reaction of piperidinediol (7).     

Concise synthesis of the core structure of madreporanone by Rh-catalyzed [3+2] cycloaddition

A model study toward total synthesis of madreporanone, a novel diterpene isolated from Azorella madreporica, was investigated. The [3.3.0] bicyclic core of madreporanone bearing a cis-configured isopropyl group and two vicinal quaternary carbon centers was stereoselectively constructed via an intramolecular Rh-catalyzed [3 + 2] cycloaddition in a single step.     

Efficient and stereoselective installation of isoquinoline: formal total synthesis of cortistatin A

The highly stereoselective attachment of isoquinoline onto the steroidal framework of cortistatin A has been achieved. Our strategy features a Ce-mediated nucleophilic addition of an isoquinoline unit to the sterically congested ketone followed by formation of the phenyl thiocarbamate, and subsequent stereoselective radical reduction. The new method results in a formal total synthesis of cortistatin A.     

Concise total synthesis of phidianidine A and B

The shortest total synthesis of cytotoxic indole alkaloids phidianidine A and B is described. Rapid assembly of the 1,2,4-oxadiazole core from a novel N-hydroxyguanidine and the corresponding indole-3-acetic acid chloride led to formal syntheses of phidianidine A and B in only three steps from known compounds. Deprotection under standard conditions provided the trifluoroacetate salts of phidianidine A and B in quantitative yield.     

Concise total synthesis of calothrixins A and B

The concise total synthesis of calothrixins A and B has been accomplished by utilizing the one-pot formation of hexatriene as a key intermediate via the palladium-catalyzed tandem cyclization/cross-coupling reaction of triethyl(indol-2-yl)borate. In another key transformation, the indolo[3,2-j]phenanthridine core was prepared in high yield via Cu(I)-mediated 6π-electrocyclization.