A convergent approach to the marine natural product eleutherobin: synthesis of key intermediates and attempts to produce the basic skeleton

Synthesis of (1R,5R,6R)-2-(6-hydroxymethyl-5-isopropyl-2-methylcyclohex-2-enyl)-N- methoxy-N-methylacetamide 8 from R-(-)-phellandrene in six steps, and (3aR*,4S*,6R*,6aS*)- (6-hydroxymethyl-4-methoxy-2,2,6-trimethyltetrahydrofuro[3,4-d][1,3]dioxol- 4-yl)acetic acid methyl ester 17 from tetrabromoacetone and 2-methoxy-5-methylfuran in six steps, provided two key fragments which have been combined to produce intermediates for attempted construction of the basic skeleton of eleutherobin.     

Synthesis of the marine natural product barbamide

The first total synthesis of the trichlorinated natural product barbamide is described. The convergent approach involves coupling (S)-3-trichloromethylbutanoyl chloride with Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) to give 15 followed by addition of the novel secondary amine N-methyl-(S)-dolaphenine 2 (prepared in 6 steps and 24% overall yield from N-Cbz-L-phenylalanine) to give the beta-keto amide 16 which was converted directly to the required (E)-enol ether.     

A six-step synthetic approach to marine natural product (+)-aureol

A concise synthetic approach to the marine natural product (+)-aureol has been achieved from readily available starting materials using obviously fewer steps in comparison to the related report in literature (6 steps versus 12 steps from (+)-sclareolide). Key steps of this protocol include a boron trifluoride-catalyzed domino 1,2-H and 1,2-methyl shifts and a nickel(II)-catalyzed cross-coupling reaction between an alkyl iodide and an aryl Grignard reagent.     

Vinylogous addition of siloxyfurans to benzopyryliums: a concise approach to the tetrahydroxanthone natural products

A concise approach to the tetrahydroxanthone natural products employing vinylogous addition of siloxyfurans to benzopyryliums and a late-stage Dieckmann cyclization has been developed. With this methodology, chiral, racemic forms of the natural products blennolides B and blennolide C have been synthesized in a maximum of four steps from a 5-hydroxychromone substrate. The regio- and diastereoselectivity of the vinylogous additions was probed using computational studies, which suggested the involvement of Diels-Alder-like transition states.     

Synthesis of imatinib: a convergent approach revisited

Abstract  

A classical convergent approach for the synthesis of the anticancer drug imatinib has been substantially improved. Imatinib was assembled by coupling the amine and carboxylic acid precursors by using N,N′-carbonyldiimidazole (CDI) as a condensing agent. Both intermediates have been synthesized by novel efficient methods.     

Synthesis of imatinib: a convergent approach revisited

Abstract  A classical convergent approach for the synthesis of the anticancer drug imatinib has been substantially improved. Imatinib was assembled by coupling the amine and carboxylic acid precursors by using N,N′-carbonyldiimidazole (CDI) as a condensing agent. Both intermediates have been synthesized by novel efficient methods. Graphical abstract        

A ring-closing metathesis approach to a synthesis of the B ring of eleutherobin

A short and efficient RCM route is reported for the construction of the key nine-membered B ring of eleutherobin starting from the readily available 1,2,5,6-diisopropylidene-d-glucose.     

Tandem Diels-Alder/fragmentation approach to the synthesis of eleutherobin

[reaction: see text] A synthesis of 28, the carbon framework of the eleutherobin aglycone, is reported in a 15-step sequence from readily available starting materials. The tandem Diels-Alder reaction of 6 and 7 to produce 18, in which three new rings and six new stereocenters are formed, is a key step in the reaction sequence.     

The nicholas approach to natural product hybrids

The intermolecular Nicholas reaction of terpene-based scaffolds is an excellent access to natural product hybrid compounds. These intermolecular reactions have a low selectivity and are scarcely efficient for non-conjugated cations, but they are highly efficient to produce new terpene structures through an intramolecular reaction pathway. The use of cations derived from natural product derived [Co(2)(CO)(6)]-enyne complexes is, in contrast, a highly efficient regio- and stereoselective procedure to prepare very complex structures, incorporating diverse densely functionalized or labile moieties. Thus, beta-pinene-diterpene-alkaloid or homohybrids can be accessed in totally stereo-, regio- and siteselective fashion. This approach efficiently discriminates between different propargylic positions by selecting the nature of the alcohol, being the enyne-derived cations the most reactive. The chimera 38 with a steroid-terpene-indole skeleton was prepared in this way.     

Synthesis of the penta-oxazole core of telomestatin in a convergent approach to poly-oxazole macrocycles

A protocol for the construction of poly-oxazoles with consecutive 2,4'-linkages is described, and has afforded an efficient route to a penta-oxazole which demarcates a route to telomestatin and related macrocyclic poly-oxazole systems.     

Asymmetric and diastereodivergent approach to key intermediates for the synthesis of homopumiliotoxin 223G and epiquinamide isomer

A stereoselective reaction followed by a sequential cyclization route has been used in the divergent synthesis of 1-hydroxyquinolizidione isomers. Sharpless asymmetric dihydroxylation afforded hydroxyl lactone and the following mesylation provided the required precursor for cyclization.     

The convergent total synthesis and antibacterial profile of the natural product streptothricin F

A convergent, diversity-enabling total synthesis of the natural product streptothricin F has been achieved. Herein, we describe the potent antimicrobial activity of streptothricin F and highlight the importance of a total synthesis that allows for the installation of practical divergent steps for medicinal chemistry exploits. Key features of our synthesis include a Burgess reagent-mediated 1,2-anti-diamine installation, diastereoselective azidation of a lactam enolate, and a mercury(ii) chloride-mediated desulfurization-guanidination. The development of this chemistry enables the synthesis and structure–activity studies of streptothricin F analogs.

The second ever total synthesis of streptothricin F and the first achieved through a diversity-enabling convergent route. The synthesis is achieved in 35 total steps, with a longest linear sequence of 19 steps, and 0.40% overall yield.     

Enantiodivergent synthesis of the key intermediate for a marine natural furanoterpene by chemoenzymatic process

A short chemoenzymatic route to both enantiomers of the key intermediate in the preparation of a marine natural furanoterpene was developed by employing a prochiral malonate derivative as a starting material.     

A concise and convergent synthesis of PA-824

An efficient four-step synthesis of PA-824, a promising antituberculosis drug candidate, has been developed. This concise approach offers significant improvements over the synthetic route currently used for large-scale production.     

Total synthesis of a diastereomer of the marine natural product clavosolide A

The first total synthesis of the reported structure of the sponge metabolite clavosolide A is described using a Prins cyclisation to assemble the tetrahydropyran core followed by manipulation of the side-chain, dimerisation and finally glycosidation.     

A concise approach towards the bicyclo[3.3.1]nonan-9-one core present in the phloroglucin natural product hyperforin

An approach towards the bicyclo[3.3.1]nonan-9-one core present in the bioactive phloroglucin natural product hyperforin is delineated in which the key C8 stereogenic quaternary centre is appropriately installed.     

Improved synthesis of key fragments for the preparation of natural product incednine

A shorter and more efficient synthesis of three key fragments that have been previously described for the preparation of the polyenic macrolactam aglycon of natural product incednine isolated from Actinomyces sp. has been developed. These fragments have been prepared with higher levels of selectivity when compared to the already published procedure.     

Two convergent routes to the left-wing fragment of ciguatoxin CTX3C using O,S-acetals as key intermediates

Ciguatoxins, principal causative toxins of ciguatera seafood poisoning, are large ladderlike polycyclic ethers. Here, we report two convergent routes to synthesis of the multiolefinic left half of ciguatoxins based on a newly developed acyl radical strategy. Remarkably, only 13 steps from the monocyclic E-ring were required to construct the left wing. [reaction: see text]