Olefin Cross‐Metathesis: Studies towards the Total Synthesis of (+)‐Bitungolide F

A stereoselective synthesis of (5S,6S)‐6‐[(2S,5S,7R,8E,10E)‐5‐(benzyloxy)‐7‐{[(tert‐butyl)dimethylsilyl]oxy}‐11‐phenylundeca‐8,10‐dien‐2‐yl]‐5‐ethyl‐5,6‐dihydro‐2H‐pyran‐2‐one (=(+)‐9‐O‐benzyl‐11‐O‐[(tert‐butyl)dimethylsilyl]bitungolide F) is reported. The strategy involves Gilman reaction, olefin cross‐metathesis, and Horner? Wadsworth? Emmons olefination as key steps.     

Total Synthesis of Aurofusarin: Studies on the Atropisomeric Stability of Bis‐Naphthoquinones

An efficient annulation involving pyrone addition to a quinone and Dieckmann condensation was developed for rapid assembly of a γ‐naphthopyrone monomeric precursor to the bis‐naphthoquinone natural product aurofusarin. Dimerization was achieved through Pd^II‐catalyzed dehydrogenative coupling. Further studies employing asymmetric nucleophilic epoxidation indicate that the atropisomers of aurofusarin and derivatives are not configurationally stable at ambient temperature.     

Total Synthesis of the 7,10‐Epimer of the Proposed Structure of Amphidinolide N,Part I: Synthesis of the C1–C13 Subunit

Amphidinolide N, the structure of which has been recently revised, is a 26‐membered macrolide featuring allyl epoxide and tetrahydropyran moieties with 13 chiral centers. Due to its challenging structure and extraordinary potent cytotoxicity, amphidinolide N is a highly attractive target of total synthesis. During our total synthesis studies of the 7,10‐epimer of the proposed structure of amphidinolide N, we have synthesized the C1–C13 subunit enantio‐ and diastereoselectively. Key reactions include an l ‐proline catalyzed enantioselective intramolecular aldol reaction, Evans aldol reaction, Sharpless asymmetric epoxidation and Tamao–Fleming oxidation. To aid late‐stage manipulations, we also developed the 4‐(N‐benzyloxycarbonyl‐N‐methylamino)butyryl group as a novel ester protective group for the C9 alcohol.     

9‐Membered Carbocycle Formation: Development of Distinct Friedel–Crafts Cyclizations and Application to a Scalable Total Synthesis of (±)‐Caraphenol A

Explorations into a series of different approaches for 9‐membered carbocycle formation have afforded the first reported example of a 9‐exo‐dig ring closure via a Au^III‐promoted reaction between an alkyne and an aryl ring as well as several additional, unique Friedel–Crafts‐type cyclizations. Analyses of the factors leading to the success of these transformations are provided, with the application of one of the developed 9‐membered ring closures affording an efficient and scalable synthesis of the bioactive resveratrol trimer caraphenol A. That synthesis proceeded with an average yield of 89 % per step (7.8 % overall yield) and has provided access to more than 600 mg of the target molecule.     

Synthesis and properties of phosphorus containing polyester‐amides derived from 1,4‐bis(3‐aminobenzoyloxy)‐2‐(6‐oxido‐6H‐dibenz〈c,e〉〈1,2〉oxaphosphorin‐6‐yl) phenylene

A series of polyester‐amides that contain phosphorus were synthesized by low temperature solution condensation of 1,4‐bis(3‐aminobenzoyloxy)‐2‐(6‐oxido‐6H‐dibenz〈c,e〉〈1,2〉oxaphosphorin‐6‐yl) phenylene (III) with various aromatic acid chlorides in N‐methyl pyrrolidone (NMP). All polyester‐amides are amorphous and readily soluble in many organic solvents such as dimethylacetamide (DMAc), NMP, dimethylsulfoxide, and dimethylformamide at room temperature or on heating. Light yellow and flexible films of these polyester‐amides could be cast from the DMAc solutions. The polymers with an inherent viscosity of 0.26–0.72 dL/g were obtained in quantitative yields. These polyester‐amides have good mechanical properties (G′ of ∼ 10⁹ Pa up to 200°C) and good thermal and flame retardant properties. The glass transition temperatures of these polyester‐amides ranged from 250 to 273°C. The degradation temperatures (T_d 5%) in nitrogen ranged from 466 to 478°C and the char yields at 800°C were 59.6–65.2%. The limiting oxygen indexes of these polyester‐amides ranged from 35 to 43. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 891–899, 1999     

Palladium‐Catalzyed Atroposelective 16‐Membered Macrocyclization: Total Synthesis of Isoplagiochin D†

Isoplagiochin D is a ring‐strained macrocyclic bisbibenzylis, which showed stable axial chirality in one biaryl structure, and semistable axial chirality in the other biaryl moiety. We reported here an unprecedented example for the catalytically asymmetric synthesis of ring‐strained atropisomers via Pd‐catalyzed macrocyclization between benzyl halides and carbenes. This newly developed Pd‐catalyzed asymmetric macrocyclization protocol enabled us a quick synthesis of isoplagiochin D in a highly enantioselective manner.     

Traceless Preparation of C‐Terminal α‐Ketoacids for Chemical Protein Synthesis by α‐Ketoacid–Hydroxylamine Ligation: Synthesis of SUMO2/3

A novel protecting group for enantiopure α‐ketoacids delivers C‐terminal peptide α‐ketoacids directly upon resin cleavage and allows the inclusion of all canonical amino acids, including cysteine and methionine. By using this approach, SUMO2 and SUMO3 proteins were prepared by KAHA ligation with 5‐oxaproline. The synthetic proteins containing homoserine residues were recognized by and conjugated to RanGAP1 by SUMOylation enzymes.     

Concise and Enantioselective Total Synthesis of (−)‐Mehranine, (−)‐Methylenebismehranine,and Related Aspidosperma Alkaloids

We report an efficient and highly stereoselective strategy for the synthesis of Aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent diastereoselectivity due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the Aspidosperma alkaloids (?)‐mehranine and (+)‐(6S,7S)‐dihydroxy‐N‐methylaspidospermidine. A late‐stage dimerization of (?)‐mehranine mediated by scandium trifluoromethanesulfonate completed the first total synthesis of (?)‐methylenebismehranine.     

Total Synthesis of (+)‐6‐epi‐Ophiobolin A

The ophiobolin sesterterpenes are notable plant pathogens which have recently elicited significant chemical and biological attention because of their intriguing carbogenic frameworks, reactive functionalities, and emerging anticancer profiles. Reported herein is a total synthesis of (+)‐6‐epi‐ophiobolin A in 14 steps, a task which addresses construction of the synthetically challenging spirocyclic tetrahydrofuran motif as well as several other key stereochemical problems. This work demonstrates a streamlined synthetic platform to complex ophiobolins leveraging disparate termination modes of a radical polycyclization cascade for divergent elaboration and functionalization.     

Synthetic Studies toward C‐Glucosidic Ellagitannins: A Biomimetic Total Synthesis of 5‐O‐Desgalloylepipunicacortein A

C‐glucosidic ellagitannins constitute a subclass of bioactive polyphenolic natural products with strong antioxidant properties, as well as promising antitumoral and antiviral activities that are related to their capacity to interact with both functional and structural proteins. To date, most synthetic efforts toward ellagitannins have concerned glucopyranosic species. The development of a synthetic strategy to access C‐glucosidic ellagitannins, whose characteristic structural feature includes an atropoisomeric hexahydroxydiphenoyl (HHDP) or a nonahydroxyterphenoyl (NHTP) unit that is linked to an open‐chain glucose core by a C‐aryl glucosidic bond, is described herein. The total synthesis of the biarylic HHDP‐containing 5‐O‐desgalloylepipunicacortein A ( 1 β ) was achieved by either using the natural ellagic acid bis‐lactone as a precursor of the requested HHDP unit or by implementing an atroposelective intramolecular oxidative biarylic coupling to forge this HHDP unit. Both routes converged in the penultimate step of this synthesis to enable a biomimetic formation of the key C‐aryl glucosidic bond in the title compound.     

Studies of a Diazo Cyclopropanation Strategy for the Total Synthesis of (−)‐Lundurine A

The bioactive Kopsia alkaloids lundurines A–D are the only natural products known to contain indolylcyclopropane. Achieving their syntheses can provide important insights into their biogenesis, as well as novel synthetic routes for complex natural products. Asymmetric total synthesis of (?)‐lundurine A has previously been achieved through a Simmons–Smith cyclopropanation strategy. Here, the total synthesis of (?)‐lundurine A was carried out using a metal‐catalyzed diazo cyclopropanation strategy. In order to avoid a carbene C?H insertion side reaction during cyclopropanation of α‐diazo‐ carboxylates or cyanides, a one‐pot, copper‐catalyzed Bamford–Stevens diazotization/diazo decomposition/cyclopropanation cascade was developed, involving hydrazone. This approach simultaneously generates the C/D/E ring system and the two chiral quaternary centers at C2 and C7.