Synthesis of the spirochroman core of dihypoestoxide and stereochemical proposal for the natural product

The tricyclic spirochroman core of dihypoestoxide has been synthesized from geranoic acid in seven steps using a hetero-Diels-Alder cycloaddition as a key step, thus providing support for the proposed biosynthesis of the natural product. Furthermore, analysis of the (13)C NMR data obtained for all four diastereoisomers of the synthetic spirochroman core has allowed us to propose a full stereochemical assignment for dihypoestoxide.     

A total synthesis of millingtonine A

A total synthesis of millingtonine A, a diglycosylated alkaloid, has been accomplished. Millingtonine A possesses a unique racemic tricyclic core structure not known from any other natural or synthetic source until now. The synthesis features a key bond-forming radical Ueno-Stork cyclization to form the heterocyclic core.     

Total synthesis of (±)-spiniferin-1 via a polyfluoroalkanosulfonyl fluoride induced homoallylic carbocation rearrangement reaction

A facile total synthesis of marine natural product (±)-spiniferin-1 has been accomplished in eight steps with 28.9% overall yield, involving a rearrangement reaction initiated by polyfluoroalkanosulfonyl fluoride to construct the 1,6-methano[10]annulene core of the natural product as a key step.     

Convergent and diastereoselective synthesis of the polycyclic pyran core of saudin

The natural product saudin was found to induce hypoglycemia in mice and, therefore, could be an appealing lead structure for the development of new agents to treat diabetes. A diastereoselective tandem Stille-oxa-electrocyclization reaction has been developed which provides access to the core structure of saudin in a rapid and convergent manner. This new reaction has been extended to the convergent preparation of a series of polycyclic pyran systems. Progress has been made on the advancement of these complex pyran systems toward the natural product. A complete account of these synthetic efforts is presented.     

Synthetic studies on the cornexistins: synthesis of (+/-)-5-epi-hydroxycornexistin

The synthesis of 5-epi-hydroxycornexistin (44), a diastereoisomer of the herbicidal natural product hydroxycornexistin (2) has been completed. Palladium mediated sp(2)-sp(3) coupling of the stannane 25 and the chloride 31 and ring-closing metathesis of the resulting diene 32 has been used to construct the tricyclic lactone 34a, which possesses the nine-membered carbocyclic core found in the natural product, in good yield. The synthesis of 5-epi-hydroxycornexistin (44) has established the feasibility of using a furan as precursor for the cyclic anhydride unit present in the natural product and has demonstrated the viability of other late-stage transformations that will be used to prepare hydroxycornexistin (2).     

Formal synthesis of (±)-methyl rocaglate using an unprecedented acetyl bromide mediated Nazarov reaction

To date the prototype Nazarov cyclization of a cross-conjugated pentadienone to the core structure of the rocaglate natural products has not been successful (9 into 12). It has been found that this conversion can be achieved by the use of acetylbromide in excellent yield and results in a strategically very direct route to these antitumor agents.     

Progress toward the synthesis of the transtaganolide/basiliolide natural products: an Ireland-Claisen approach

Efforts toward the synthesis of the transtaganolide natural product family are described. A highly efficient Ireland-Claisen/Diels-Alder approach has been developed, which rapidly constructs the highly oxygenated and stereochemically rich core of these natural products.     

Acid-catalyzed synthesis of bicyclo[3.n.1]alkenediones

An acid-catalyzed Dieckmann-type reaction has been developed to access functionalized bicyclo[3.2.1]alkenediones. This methodology has been successfully extended to more substituted and larger ring homologues, providing a new and efficient route to the core of numerous attractive natural products and their analogues.     

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.     

Enantiospecific approach to the tricyclic core structure of tricycloillicinone, ialibinones, and takaneones via ring-closing metathesis reaction

Enantiospecific synthesis of the tricyclic core structure present in the biologically active natural products tricycloillicinone, ialibinones, and takaneones, starting from the readily available campholenaldehyde employing a transannular RCM reaction as the key step, has been accomplished.     

Stereoselective synthesis of the cyclic ether core of (+)-laurenyne

A concise enantioselective synthesis of the cyclic ether core of the marine natural product (+)-laurenyne has been accomplished using ring-closing metathesis for medium-ring construction.     

Towards an enantiospecific total synthesis of garsubellin A and related phloroglucin natural products: the α-pinene approach

The first enantiospecific approach to garsubellin A and related phloroglucin natural product nemorosone, of contemporary interest from (−)-α-pinene, has been delineated. Through a series of stereospecific operations, the requisite stereochemistry of the prenyl groups has been secured. Kende cyclization has been employed as the key step to construct the functionalized bicyclo[3.3.1]nonane core.     

A new synthesis of (−)-epipyriculol: a phytotoxic metabolite

A convenient synthesis of the phytotoxic natural product epipyriculol has been accomplished in 17 steps from methyl l-tartrate. The synthetic strategy is based upon the use of a butanediacetal-protected scaffold as central core from which the alkenyl side chains were assembled.     

A novel construction of dibenzofuran-1,4-diones by oxidative cyclization of quinone-arenols

A novel oxidative cyclization of quinone-arenols 5 leading to products 6 with a dibenzofuran-1,4-dione structure, which forms the core of several natural products, has been developed and applied to the synthesis of violet-quinone (4).     

Iminium Ion Cascade Reactions: Stereoselective Synthesis of Quinolizidines and Indolizidines

A novel iminium ion cascade reaction has been developed that allows for the stereoselective synthesis of a variety of substituted aza-fused bicycles. The combination of amino allylsilanes and aldehydes (or ketones) was used to synthesize a number of quinolizidines and indolizidines in a one-pot reaction sequence. This technology has been used to effect the facile syntheses of several indolizidine and quinolizidine natural products including (±)-epilupinine, (±)-tashiromine, and (−)-epimyrtine. Substrate scope has been examined varying the type of amino allylsilanes (primary, secondary, and conjugated) and carbonyl compounds (aldehydes and ketones) to give a variety of fused ring structures. Varying the components chosen allows for the inclusion of synthetically useful functional groups at different positions on the core structure. The methodology has been used to construct the tricyclic core structures present in the cylindricine family and halichlorine.     

Synthesis of the carbocyclic core of the cornexistins by ring-closing metathesis

An advanced intermediate in the synthesis of the phytotoxins cornexistin and hydroxycornexistin has been synthesized. Sequential palladium-mediated sp(2)-sp(3) fragment coupling and ring-closing diene metathesis have been used to construct the nine-membered carbocyclic core found in the natural products. [reaction--see text]     

Total synthesis of (-)-callipeltoside A

A total synthesis of (-)-callipeltoside A (1) has been achieved. The core macrocycle was made via a dual macrolactonization/pyran hemiketal formation reaction, developed to circumvent issues related to the reversible nature of acylketene formation from β-keto lactone substrates. Initial approaches to the core of the natural product that revolved around ring-closing metathesis (RCM) and relay ring-closing metathesis (RRCM) reactions are also described.     

Total Synthesis of (+)-Sch 725680: Inhibitor of Mammalian A-, B-, and Y-Family DNA Polymerases

The total synthesis of (+)-Sch 725680, a member of the hydrogenated azaphilone family, has been accomplished. The synthesis confirmed the absolute configuration and biological activities of the natural product. A key reaction to construct a hydrogenated azaphilone core skeleton is a Ti-mediated aldol reaction.     

Synthetic studies toward longeracemine: a SmI2-mediated spirocyclization and rearrangement cascade to construct the 2-azabicyclo[2.2.1]heptane framework

Longeracemine, a member of the Daphniphyllum family of alkaloids contains a novel carbon framework featuring a highly functionalized 2-azabicyclo[2.2.1]heptane core as part of an overall 5/6/5/5/6/5 skeleton. A synthetic intermediate containing the core of longeracemine has been efficiently prepared by employing a stereoselective SmI₂-mediated cascade reaction to advance a 7-azabicyclo[2.2.1]heptadiene to a 2-azabicyclo[2.2.1]heptene that is functionally poised for conversion to the natural product.

A synthetic intermediate containing the core of longeracemine, that is functionally poised for conversion to the natural product, has been efficiently prepared by employing a stereoselective SmI₂-mediated cascade reaction.     

Tandem Rh(i)-catalyzed [(5+2)+1] cycloaddition/aldol reaction for the construction of linear triquinane skeleton: total syntheses of (+/-)-hirsutene and (+/-)-1-desoxyhypnophilin

A tandem reaction involving a Rh(I)-catalyzed two-component [(5+2)+1] cycloaddition and an aldol condensation has been developed to construct the tricyclo[6.3.0.02,6]undecane skeleton and its heteroatom-imbedded analogues. Meanwhile, this method has been successfully applied to natural product synthesis for the first time. The present strategy enables a straightforward approach to the natural linear triquinane skeleton, as demonstrated by concise and step economical syntheses of hirsutene and 1-desoxy-hypnophilin, whereby the linear triquinane core is diastereoselectively established in one manipulation with correct placement of all stereocenters, including two quarternary centers. This first application of the Rh(I)-catalyzed [(5+2)+1] cycloaddition in natural product synthesis highlights the efficiency of this methodology for constructing complex fused ring systems.