Daniel P. Furkert

Total Synthesis of the Initially Reported and Revised Structures of the Neuroprotective Agent Palmyrolide A

The total syntheses of the initially reported and revised structures of the neuroprotective agent palmyrolide A are reported. The key macrocyclization step was achieved using a sequential ring closing metathesis/olefin isomerization reaction. The synthetic work described herein serves to confirm the recent structural revision of this unusual natural product.

Synthesis of the Tetracyclic Core of Berkelic Acid Using Gold(I)-Catalyzed Hydroarylation and Oxidative Radical Cyclizations

A synthetic approach to the tetracyclic core of berkelic acid is reported using gold(I)-catalyzed intramolecular hydroarylation and oxidative radical cyclizations to effect the key ring-forming steps. The carboxylic acid was introduced via a late-stage palladium-catalyzed carbonylation to afford the core tetracycle with the correct relative stereochemistry for the natural product.

Total synthesis of heronapyrrole C

A flexible total synthesis of the 2-nitropyrrole-derived marine natural product, (+)-heronapyrrole C, is reported. The approach is based on regioselective access to key building blocks containing the rare 4-substituted 2-nitropyrrole motif. Sharpless asymmetric epoxidation and dihydroxylation and a Shi epoxidation were used to introduce the five stereogenic centers of the bis-THF-diol side chain. The N-benzoyloxymethyl (Boz) protecting group was crucial for functionalization of the 2-nitropyrrole moiety and enabling final deprotection under mild conditions.

Total synthesis of the macrocyclic N-Methyl enamides palmyrolide A and 2S-sanctolide A.

Full details of the total syntheses of the initially reported and revised structures of the neuroprotective agent palmyrolide A are reported. The key macrocyclization step was achieved using a sequential ring-closing metathesis/olefin isomerization reaction. Furthermore, the total synthesis of the related macrolide (2S)-sanctolide A is reported. The synthesis used key elements from the synthesis of palmyrolide A, including the RCM/olefin isomerization sequence. The synthetic work described herein serves to facilitate the assignment of stereochemistry of the natural product sanctolide A and demonstrates the utility of this approach for the synthesis of macrocyclic tertiary enamide natural products.

Total synthesis of virgatolide B.

The first total synthesis of the benzannulated spiroketal virgatolide A is presented. Key features include sp(3)-sp(2) Suzuki coupling of an enantiomerically enriched β-trifluoroboratoamide and an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective Mukaiyama aldol reaction followed by global deprotection/cyclization with regioselectivity governed by internal hydrogen bonding.

Synthesis of the 1,6,8-trioxadispiro[4.1.5.2]tetradec-11-ene ring system present in the spirolide family of shellfish toxins and its conversion into a 1,6,8-trioxadispiro[4.1.5.2]-tetradec-9-en-12-ol via base-induced rearrangement of an epoxide

The synthesis of the 1,6,8-trioxadispiro[4.1.5.2]tetradec-11-enes 12 present in the shellfish toxins spirolides B and D 2, is reported. The two spirocentres were constructed via iterative radical oxidative cyclization of hydroxyalkyl dihydropyran 14 and hydroxyalkyl spiroacetal 13 using iodobenzene diacetate and iodine. This procedure initially afforded a 1 : 1 : 1 : 1 mixture of bis-spiroacetals 12a : 12b : 12c : 12d, however subsequent acid catalysed equilibration afforded a 3 : 1 : 0.9 thermodynamic mixture of 12a : 12b : 12c. The major bis-spiroacetal 12a underwent stereoselective epoxidation using dimethyldioxirane to alpha-epoxide 33a. Subsequent base induced rearrangement of this epoxide 33a using lithium diethylamide in pentane afforded allylic alcohol 34a, that was converted to the more thermodynamically favoured homoallylic alcohol 11a upon treatment with lithium pyrrolidinylamide in tetrahydrofuran. Homoallylic alcohol 11a possesses a hydroxyl group at C-12 as required for introduction of the tertiary alcohol group present at this position in spirolides B 1 and D 2.

Synthesis of the novel 1,7,9-trioxadispiro[4.1.5.2]-tetradecane ring system present in the spirolides

Abstract A synthesis of bis-spiroacetal 13 which constitutes the bis-spiroacetal moiety of the complex marine biotoxins, spirolides 1 and 2 is described. The synthetic strategy adopted is based on assembly of a suitably protected acyclic hydroxyketone precursor. Key intermediate 25 was synthesised as a mixture of diastereomers from 1,3-propanediol using an iterative Grignard addition/hydroboration strategy and converted to cis-enone 28. Attempted acid catalysed cyclisation of 28 to a spiroacetal was unsuccessful, however, the analagous saturated precursor 30 readily afforded spiroacetal 31. Oxidative cyclisation of 31 then gave bis-spiroacetal 32. In an alternative route, bis-spiroacetal 32 was synthesised by selective deprotection of diketone 34. Selective deprotection of acetylene 25 gave methoxyl acetal 36 which formed unsaturated spiroacetal 37 upon semi-hydrogenation. Finally, oxidative cyclisation of bis-spiroacetal 37 afforded the target bis-spiroacetal 13.

Synthesis of the spirocyclic framework of sesterterpenoid natural products.

A convergent synthetic route to the sesterterpenoid framework of the bioactive phorbaketal and alotaketal natural product families has been established. The synthetic approach hinges on a Hosomi-Sakurai coupling of complex acetal and allylsilane coupling partners, followed by DDQ-promoted oxidative cyclization of highly unsaturated advanced intermediates. This robust synthetic approach enables further investigations into the members of these natural product families and readily provides access to analogues for biological testing.

Total synthesis of chaetoquadrins A-C.

The first total synthesis of the monoamine oxidase inhibitors chaetoquadrins A-C has been accomplished. Key steps in the synthesis include an aromatic Claisen rearrangement, asymmetric boron aldol reaction and acid-mediated spiroketalization. Comparison of spectral data for the synthetic spiroketals confirmed the proposed structure for these natural products.

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis.

Rising resistance to current clinical antibacterial agents is an imminent threat to global public health and highlights the demand for new lead compounds for drug discovery. One such potential lead compound, the peptide antibiotic teixobactin, was recently isolated from an uncultured bacterial source, and demonstrates remarkably high potency against a wide range of resistant pathogens without apparent development of resistance. A rare amino acid residue component of teixobactin, enduracididine, is only known to occur in a small number of natural products that also possess promising antibiotic activity. This review highlights the presence of enduracididine in natural products, its biosynthesis together with a review of analogues of enduracididine. Reported synthetic approaches to the cyclic guanidine structure of enduracididine are discussed, illustrating the challenges encountered to date in the development of efficient synthetic routes to facilitate drug discovery efforts inspired by the discovery of teixobactin.