Total synthesis of siphonazole and its O-methyl derivative, structurally unusual bis-oxazole natural products

The details of the first syntheses of the unusual bis-oxazole natural products siphonazole and its O-methyl derivative are reported. The cinnamyl substituted oxazole was constructed using diazocarbonyl chemistry, whereby the cinnamamide was reacted with the rhodium carbene derived from methyl 2-diazo-3-oxobutanoate to give a beta-ketoamide that was cyclodehydrated to the corresponding oxazole-4-ester. Reduction to the corresponding aldehyde was followed by coupling with a zinc reagent derived from methyl 2-iodomethyl-5-methyloxazole-4-carboxylate, also prepared using rhodium carbene chemistry, to give, after oxidation of the resulting secondary alcohol, the desired bis-oxazole ketone. The syntheses were completed by hydrolysis of the ester and coupling of the 2,4-pentadienylamine side chain.     

The synthetic challenge of diazonamide A, a macrocyclic indole bis-oxazole marine natural product

The complex structure of the marine metabolic diazonamide A comprises a dichlorinated indole bis-oxazole heteroaromatic fragment, and a [b]-fused dihydrobenzofuran-dihydroindole unit containing an animal carbon, all incorporated within a strained double macrocyclic array. This review details the synthetic studies on this fascinating natural product starting from early studies on the original structure (1991-2001), through the synthesis of the originally proposed structure and the subsequent structural revision, to the eventual successful syntheses of the natural product itself. Throughout we focus on the innovative ways in which synthetic chemists have approached the challenges posed by this natural product.     

The first total synthesis of the natural product angoluvarin

The total synthesis of angoluvarin, a member of the dihydrochalcone family of natural products, is reported. Starting with 2-bromophenol, the synthesis was accomplished in eight steps with an overall yield of 2%. This represents the first reported synthesis of angoluvarin.     

Divergent strategy in natural product total synthesis

Divergent strategy in natural product synthesis allows the comprehensive synthesis of family natural products. Efficient formulation of this idea requires the biosynthetic/biosynthesis-inspired insight toward the well-orchestrated design of a pluripotent late-stage intermediate, in concomitant with the applicability of the intermediates for versatile transformations. This digest focuses on the actual applications of those strategies in natural product synthesis with an emphasis on the recipes for the choice of the common intermediates.     

Novel total synthesis of the anticancer natural product dysidiolide

The marine natural product dysidiolide has been synthesized in a highly diastereoselective fashion that features the sequential transfer of chirality from a cyclohexenone precursor.     

Concise total synthesis of the marine natural product ageladine A

A total synthesis of ageladine A has been achieved by exploiting a Pictet-Spengler-type condensation between 2-aminohistamine and 4,5-dibromo-2-formylpyrrole as the key step.     

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.     

Enantioselective total synthesis of bioactive natural product (+)-Sch 642305: a structurally novel inhibitor of bacterial DNA primase and HIV-1 Tat transactivation

The total synthesis of the bioactive natural product (+)-Sch 642305 has been achieved from a readily available chiral building block using an RCM protocol to construct the key decalactone moiety; our approach is notable for its built-in flexibility and is diversity oriented.     

Toward a total synthesis of the novel polyketide natural product spiculoic acid A

[chemical reaction: see text]. An enantioselective approach toward the recently isolated marine natural product, spiculoic acid A, conceptualized along the proposed biogenetic hypothesis, involving an intramolecular Diels-Alder reaction as the pivotal step, is delineated. Access to a structurally embellished bicyclic core of the natural product has been accomplished.     

Parallel synthesis of bis-oxazole peptidomimetics

The parallel synthesis of bis-oxazole peptidomimetics starting from Boc-aminoacids and Serine-methyl ester is described. This work presents the synthesis of oxazole aminoacid building blocks in solution phase and their utilization for the solid phase peptide synthesis of a library of diverse bis-oxazole peptidomimetics in good overall yields.     

First total synthesis of a natural product containing a chiral,beta-diketone: synthesis and stereochemical reassignment of siphonarienedione and siphonarienolone

The first total syntheses of siphonarienolone and siphonarienedione are described. The development of a stereoselective synthesis of beta-diketones facilitated the synthesis of the latter compound. The synthesis of the structures proposed for the natural products afforded compounds whose spectral data did not match those of the natural products. However, the synthesis of compounds isomeric to the proposed structures at C(4) and C(5) afforded compounds identical to the natural products, thereby reassigning the stereochemistry of the natural products.     

Recent advances of desymmetrization protocol applied in natural product total synthesis

Desymmetrization synthesis strategy has simplified and improved the efficiency of synthesis, which attracted great attention in the past few decades. Since the strategy has been developed rapidly and got a wide range of applications in natural product total synthesis, the rules are urgent to be summarized. In this Letter, the recent developments of desymmetrization protocol in natural product total synthesis were summarized.     

Enantioselective total synthesis of a novel polyketide natural product (+)-integrasone, an HIV-1 integrase inhibitor

Enantioselective total synthesis of the recently isolated, novel polyketide natural product (+)-integrasone has been accomplished from the readily available Diels-Alder adduct of cyclopentadiene and p-benzoquinone. An enzymatically desymmetrized epoxyquinone building block has been elaborated through a series of regio- , chemo- and stereocontrolled steps to the final bicyclic framework of the natural product.     

Recent applications of gold-catalyzed cascade reactions in total synthesis of natural product

From the point of the view of the synthetic efficiency, the concept ‘step economy’ was required in total synthesis of natural product. Recently, versatile gold-catalyzed cascade reactions have been developed, and relating reports on practical applications in total synthesis has increased. This digest focuses and summarizes the gold-catalyzed reaction cascades in natural product synthesis during last five years with brief discussion on the reaction mechanism of the key gold-catalyzed cascade transformations.     

Enantioselective total synthesis of a natural iridoid

The first total synthesis of 6-hydroxy-7-(hydroxymethyl)-4-methylenehexahydrocyclopenta[c]pyran-1(3H)-one has been accomplished. A key feature of the synthesis includes facile construction of the bicyclic lactone intermediate via intramolecular Pd(0)-catalyzed allylic alkylation and the efficient transformation of this intermediate into the iridoid skeleton employing silicon tethered radical cyclization.     

The first total synthesis of natural grenadamide

A concise, high yielding route to the naturally occurring enantiomer of grenadamide utilizing a 3,6-disubstituted 1,2-dioxine starting material is presented. The route allows for ease in synthesizing grenadamide derivatives varying at cyclopropyl carbons 2 and 3, with access to both enantiomers. Evidence for phosphorus-assisted deprotonation of 1,2-dioxines is also discussed.