Total synthesis and structure confirmation of elatenyne: success of computational methods for NMR prediction with highly flexible diastereomers

Elatenyne is a small dibrominated natural product first isolated from Laurencia elata. The structure of elatenyne was originally assigned as a pyrano[3,2-b]pyran on the basis of NMR methods. Total synthesis of the originally proposed pyrano[3,2-b]pyran structure of elatenyne led to the gross structure of the natural product being reassigned as a 2,2'-bifuranyl. The full stereostructure of this highly flexible small molecule was subsequently predicted by Boltzmann-weighted DFT calculations of (13)C NMR chemical shifts for all 32 potential diastereomers, with the predicted structure being in accord with the proposed biogenesis outlined below. Herein we report two complementary total syntheses of elatenyne, which confirm the computer-predicted stereostructure. Additionally, the total syntheses of (E)-elatenyne and a related 2,2'-bifuranyl, laurendecumenyne B, are reported. This work has not only allowed the full structure determination of all of these natural products but also provides excellent supporting evidence for their proposed biogenesis. The total synthesis of elatenyne demonstrates that DFT calculations of (13)C NMR chemical shifts coupled with biosynthetic postulates, comprise a very useful method for distinguishing among large numbers of highly flexible, closely related molecules.     

A Concise Total Synthesis of (±)‐Vibralactone

Disclosed is a five‐step synthesis of (±)‐vibralactone, a biologically active terpenoid natural product. A key photochemical valence isomerization of 3‐prenyl‐pyran‐2‐one produces both the all‐carbon quaternary stereocenter and the β‐lactone at an early stage. Cyclopropanation of the resulting bicyclic β‐lactone produces a strained housane structure that is converted to the natural product through a sequential ring expansion and reduction strategy. This concise and modular route to the natural product provides the shortest total synthesis of (±)‐vibralactone reported to date.     

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.     

Total synthesis of bryostatin 1

Bryostatin 1 is a marine natural product that is a very promising lead compound because of the potent biological activity it displays against a variety of human disease states. We describe herein the first total synthesis of this agent. The synthetic route adopted is a highly convergent one in which the preformed, heavily functionalized pyran rings A and C are united by "pyran annulation", the TMSOTf-promoted reaction between a hydroxyallylsilane appended to the A-ring fragment and an aldehyde contained in the C-ring fragment, with concomitant formation of the B ring. Further elaborations of the resulting very highly functionalized intermediate include macrolactonization and selective cleavage of just one of five ester linkages present.     

Desymmetrization of a centrosymmetric diepoxide: efficient synthesis of a key intermediate in a total synthesis of hemibrevetoxin B

The preparation of an established intermediate in a total synthesis of hemibrevetoxin B is described. The acid-catalyzed cyclization of trans-4,5-epoxyoctane-2,7-dione exhibited a valuable mixture of kinetic and thermodynamic control: stereospecific epoxide opening was followed by equilibration of the products to provide the required trans-fused octahydropyrano[3,2-b]pyran ring system. Two-directional elaboration, by acetal substitution, ozonolysis, and sulfur ylide-mediated epoxidation, provided a centrosymmetric diepoxide. The key step of the synthesis was the first desymmetrization of a centrosymmetric molecule in natural product synthesis: Jacobsen asymmetric epoxide hydrolysis and acetonization provided the known synthetic intermediate in 97% yield and >95% ee over two steps. The exploitation of the center of symmetry of the AB ring system of the natural product contributed greatly to the efficiency (eight steps, 34% overall yield) of the synthesis.     

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.     

FR901464: total synthesis, proof of structure, and evaluation of synthetic analogues

The natural product FR901464 (1) was isolated by the Fujisawa Pharmaceutical Co. and shown to have intriguing biological properties including impressive antitumor activity. In this paper we describe the first total synthesis of 1 in full detail. A chiral building block synthetic strategy was used to assemble the target: optically active components were generated using asymmetric catalytic reactions, and these fragments were coupled together at a late stage in a convergent synthesis. In particular, a versatile, asymmetric hetero-Diels-Alder (HDA) reaction was developed in the context of this synthesis and used with great effectiveness for the preparation of the two densely functionalized pyran rings. The flexible nature of the synthetic route also allowed us to prepare a series of analogues of 1. These compounds were used to prove the relative stereochemistry of the natural product as well as to probe the importance of certain structural features of FR901464 with regard to biological activity.     

Total synthesis of a stereoisomer of bistramide C and assignment of configuration of the natural product

After the isolation of the bioactive polyether bistramide C from the marine ascidian Lissoclinum bistratum in 1988, NMR spectroscopic investigations over the next 12 years reduced the total number of possible stereoisomers of this compound from 1024 to 32. Based on the preparation of segments of the natural product as well as the total synthesis of a randomly selected stereoisomer of bistramide C, the stereochemical puzzle could be further simplified to eight possible stereoisomers. A convergent three-segment coupling strategy, the use of a common, D-glucose-derived intermediate for the preparation of pyran rings in two segments, a stereoselective photo-spiroketalization, and the use of azides to minimize protective group manipulations before segment couplings are highlights of the synthetic approach. The total synthesis also provided the key segments for a chiroptical analysis according to van't Hoff's principle of optical superposition, which was crucial for the assignment of a sole relative and absolute configuration of the natural product. Bistramide C represents therefore the first member of this class of structurally unusual marine polyethers whose configuration is known as a result of the combined use of synthetic and chiroptical tools.     

18O assisted analysis of a γ,δ-epoxyketone cyclization: synthesis of the C16-C28 fragment of ammocidin D

The C16-C28 fragment common to the cytotoxic macrolide ammocidin D has been prepared by a stereospecific 5-exo closure of a γ,δ-epoxyketone followed by a rearrangement to a pyran acetal. The reaction pathway was traced by (18)O labeling of the keto carbonyl and observation of (18)O induced (13)C shifts in the pyran acetal product. NMR data of the synthetic C16-C28 fragment compared favorably to the natural product providing support of the assigned stereochemistry.     

Enantioselective Total Synthesis of the Putative Biosynthetic Intermediate Ambruticin J

The family of anti-fungal natural products known as the ambruticins are structurally distinguished by a pair of pyran rings adorning a divinylcyclopropane core. Previous characterization of their biosynthesis, including the expression of a genetically modified producing organism, revealed that the polyketide synthase pathway proceeds via a diol intermediate, known as ambruticin J. Herein, we report the first enantioselective total synthesis of the putative PKS product, ambruticin J, according to a triply convergent synthetic route featuring a Suzuki-Miyaura cross-coupling and a Julia-Kocienski olefination for fragment assembly. This synthesis takes advantage of synthetic methodology previously developed by our laboratory for the stereoselective generation of the trisubstituted cyclopropyl linchpin.     

Convergent total syntheses of callipeltosides a, B, and C

Going for the hat-trick: The synthesis of the entire callipeltoside family of natural products is described. Key to this synthesis was the coupling of the di-ene-yne and pyran fragments by a diastereoselective alkenylzinc addition allowing rapid access to the common aglycon. Attachment of each relevant L-configured sugar resulted in the first total synthesis of callipeltoside B, and the syntheses of callipeltosides?A and C.     

Progress toward the total synthesis of saudin: development of a tandem Stille-oxa-electrocyclization reaction

[reaction: see text] A diastereoselective tandem Stille-oxa-electrocyclization reaction provides access to the core of the diterpenoid natural product saudin. Additionally, this new reaction sequence was extended to the convergent preparation of related polycyclic pyran systems.     

Recent trends in synthetic strategies using magnetic nanostructures as green catalysts in synthesis of pyran analogues

In recent years, magnetic nanoparticles and nanocomposites play an important role as a nanocatalyst in the creation of a wide range of bioactive heterocycles with extraordinarily high activity and selectivity, low energy consumption, and extended life. Among all heterocycles, many natural products, pharmaceuticals, and bioactive compounds contain pyran scaffolds which have a wide range of uses in biomedical research, industry, and medicine. Additionally, these are also widely used in the synthesis of novel heterocyclic systems as precursors. This study focused on recent advances in the last 5 years in using various magnetic recoverable and recycled nanoparticles and nanocomposites to synthesize pyran derivatives and their pharmacological activity. This article has been classified into three subsections: (i) MNPs-metal nanocomposite catalyzed reactions, (ii) MNPs-organic based nanocomposite catalyzed reactions, and (iii) MNPs-ionic liquid nanocomposite catalyzed reactions and (iv) MNPs-acid based nanocomposite to describe catalytic efficiency of magnetic nanocomposites for the synthesis of pyran derivatives. A comparative study of nanocomposites and different approaches for green synthesis of pyrans by highlighting the advantages and disadvantages along with catalyst recovery and recyclability has been mentioned, which will help scientists to probe and stimulate the study of these scaffolds.     

Total Synthesis of Fontanesine B and Its Isomer: Their Antiproliferative Activity against Human Colorectal Cancer Cells

A concise synthesis of pyrano[3,2‐e]indole alkaloid fontanesine B by a Fischer indolization is described. This key Fischer indolization starts with the pyran‐ring and alkene intact, facilitating potential synthetic applications. Furthermore, fontanesine B and its isomer were evaluated for in vitro antiproliferative activity against human colorectal cancer cells. The isomer of fontanesine B showed higher antiproliferative activity than the natural product, fontanesine B ( 2 ).     

Studies toward the asymmetric synthesis of the right part of the mycalamides

Described herein is the asymmetric synthesis of a functionalized, trioxadecalin unit that comprises the right-hand part of the mycalamides and related natural products. The synthetic route involves a 16-step sequence that accomplishes the formation of two heterocyclic rings and the generation of five stereocenters. The synthesis commenced with a C2-symmetric starting material, diethyl D-tartrate, and took advantage of a relay of diastereoselective reactions to extend this four-carbon chain and introduce new chiral centers. Subsequent electrophile-mediated cyclization afforded the desired pyran ring, which was then transformed into the desired, functionalized trioxadecalin skeleton.     

The Stereoselective Total Synthesis of (6S)‐5,6‐Dihydro‐6‐[(2R)‐2‐hydroxy‐6‐phenylhexyl]‐2H‐pyran‐2‐one via Prins Cyclization

The stereoselective total synthesis of an antiproliferative and antifungal α‐pyrone natural product (6S)‐5,6‐dihydro‐6‐[(2R)‐2‐hydroxy‐6‐phenylhexyl]‐2H‐pyran‐2‐one is described. The key steps involved are the Prins cyclization, Mitsunobu reaction, and ring‐closing metathesis reaction.     

Multicomponent Reactions of Furan‐2,3‐diones: Synthesis and Characterizations of Furo[3,2‐c]pyran‐4‐ones

Furo[3,2‐c]pyran‐4‐ones, which possess a natural‐product skeleton, are synthesized via a simple, one‐pot, three‐component reaction of furan‐2,3‐diones with dialkyl acetylenedicarboxylates and Ph₃P.     

Insights into the Dual Activity of a Bifunctional Dehydratase‐Cyclase Domain

Oxygen‐containing heterocycles are a common structural motif in polyketide natural products and contribute significantly to their biological activity. Here, we report structural and mechanistic investigations on AmbDH3, a polyketide synthase domain with dual activity as dehydratase (DH) and pyran‐forming cyclase in ambruticin biosynthesis. AmbDH3 is similar to monofunctional DH domains, using H51 and D215 for dehydration. V173 was confirmed as a diagnostic residue for cyclization activity by a mutational study and enzymatic in vitro experiments. Similar motifs were observed in the seemingly monofunctional AmbDH2, which also shows an unexpected cyclase activity. Our results pave the way for mining of hidden cyclases in biosynthetic pathways. They also open interesting prospects for the generation of novel biocatalysts for chemoenzymatic synthesis and pyran‐polyketides by combinatorial biosynthesis.     

Nickel-mediated inter- and intramolecular reductive cross-coupling of unactivated alkyl bromides and aryl iodides at room temperature

A nickel-mediated intermolecular reductive cross-coupling reaction of unactivated alkyl bromides and aryl iodides at room temperature has been developed and successfully extended to less explored intramolecular versions and tandem cyclization-intermolecular cross-coupling. Highly stereoselective (or stereospecific) synthesis of linear-fused perhydrofuro[2,3-b]furan (pyran) and spiroketal skeletons allows rapid access to these useful building blocks, which would be potentially valuable in the synthesis of relevant natural products. A rational explanation for the formation of contiguous stereogenic centers is given.     

6H-二苯并[b,d]吡喃-6-酮及其衍生物的合成方法研究进展

6H-二苯并[b,d]吡喃-6-酮类化合物因其广泛的生物活性以及荧光性能而越来越受到化学家们的关注。本文综述了6H-二苯并[b,d]吡喃-6-酮类化合物的主要合成方法,包括分子内关环法、碳氢键活化法、合成苯环法、氧化法,并比较了这四类合成方法的优缺点。今后,如何高效、经济、绿色地合成在特定位置含特定取代基的6H-二苯并[b,d]吡喃-6-酮及其类似物,仍是天然产物合成领域的一个重大课题。