Total Synthesis Research Articles

Total Synthesis of Berkeleyone A and Preaustinoid A through Epoxypolyene Cyclization

AbstractA bioinspired Lewis acid‐catalyzed epoxypolyene cyclization was developed to construct the tetracyclic framework containing a bicyclo[3.3.1]nonane core and seven chiral centers. The usage of this approach for assembling these natural products of 6/6/6/6 tetracyclic skeleton with bicyclo[3.3.1]nonane core is demonstrated by the total synthesis of highly oxidized berkeleyone A and preaustinoid A.

Discovery, Biosynthesis, Total Synthesis, and Biological Activities of Solanapyrones: [4 + 2] Cycloaddition-Derived Polyketides of Fungal Origin.

Solanapyrones are metabolites bearing a 3,4-dehydrodecalin moiety isolated from cultures of different fungi that are associated with plant diseases. Research on solanapyrones resulted in the first report of a Diels-Alderase enzyme implicated in natural product biosynthesis related to the formation of the 3,4-dehydrodecalin core. In addition, several total syntheses of solanapyrones have been reported, which are also connected with the formation of the characteristic cycloaddition-derived 3,4-dehydrodecalin moiety. This Review provides the first comprehensive overview on the chemistry, biosynthesis, and biological activities of solanapyrones under the theme of synthetic and biosynthetic research progress on cycloaddition-derived secondary metabolites.

Efforts toward the Total Synthesis of Thuggacin A.

Thuggacin A (1) is a 17-membered-ring-polyketide antibiotic compound with excellent antituberculosis activity. The total synthesis of thuggacin A has not yet been reported so far. Herein, we disclose our efforts toward the convergent total synthesis of thuggacin A. The key synthetic features include our own one-pot cascade thiazole formation, Evans syn-aldol, Mukaiyama asymmetric aldol reaction, organosilicon-promoted selective alkyne reduction, Shiina macrolactonization, and a nucleophilic ring-opening of epoxide with alkyne to assemble the main framework of thuggacin A. The enantioselective synthesis of trimethylsilyl ethoxymethyl (SEM) derived thuggacin A analogue 2 was achieved in 18 longest linear steps with 2.0% overall yield, and the bioassay of 2 exhibited moderate antituberculosis activity with minimum inhibitory concentration (MIC) of 320 μg/mL.

Expanding the Scope of a One-Pot Double Displacement Protocol to Access the All-Rare-Sugar-Containing Trisaccharide Unit of Pseudomonas stutzeri OX1.

Herein, we have explored a one-pot bis-triflation and regioselective displacement protocol with d-fucose 2,4-diol to access various rare 6-deoxy amino d-sugars. This strategy enabled the first total synthesis of the trisaccharide unit of Pseudomonas stutzeri OX1 strain containing d-perosamine and d-tomosamine. Installation of a 1,2-cis linkage and late-stage N-formylation are the key challenges in the total synthesis, which was accomplished via the longest linear sequence of 21 steps with 1.2% overall yield.

Fe‐Catalyzed α‐C(sp3)−H Amination of N‐Heterocycles

AbstractNitrogen‐heterocycles are privileged structures in both marketed drugs and natural products. On the other hand, C−H amination reactions furnish unconventional and straightforward approaches for the construction of C−N bonds. Yet, most of the known methods rely on precious metal catalysts. Herein we report a site‐selective intermolecular C(sp3)−H amination of N‐heterocycles, catalyzed by inexpensive FeCl2, which allows the functionalization of a wide range of pharmaceutically relevant cyclic amines. The C−H amination occurs site‐selectively in α‐position to the nitrogen atom, even when weaker C−H bonds are present, and furnishes Troc‐protected aminals or amidines. The method employs the N‐heterocycle as limiting reagent and is applicable to the late‐stage functionalization of complex molecules. Its synthetic potential was further illustrated through the derivatization of α‐aminated products and the application to a concise total synthesis of the reported structure for senobtusin. Mechanistic studies allowed to propose a plausible reaction mechanism involving a turnover‐limiting Fe‐nitrene generation followed by fast H atom transfer and radical rebound.

Total Synthesis of Marformycins A and D.

We report the synthesis of the antimicrobial cyclodepsipeptides marformycin A (1) and marformycin D (2) using a solid-phase approach. A scalable solution-phase synthesis of the γ-hydroxypiperazic acid subunit in 2, starting from cis-hydroxyproline, is also described. Structural analysis of 1 and its Leu-epi congener demonstrates conformational differences that may underlie their divergent antimicrobial activities. The described approach enables further development of conformation-activity relationships within this class of depsipeptide natural products.

Ten-Step Total Synthesis of (±)-Phaeocaulisin A Enabled by Cyclopropanol Ring-Opening Carbonylation.

We report an efficient total synthesis of (±)-phaeocaulisin A, a guaianolide sesquiterpene natural product possessing a complex tetracyclic skeleton embedded with an oxaspirolactone and a fused bicyclic lactone, four oxygen-containing stereocenters, and an 8-oxabicyclo[3.2.1]octane core. Our synthesis features a novel palladium-catalyzed cyclopropanol ring-opening carbonylation to access a key γ-ketoester, a chemo- and stereoselective aldol cyclization to form the seven-membered carbocycle, and a cascade ketalization-lactonization to construct the desired tetracyclic skeleton. With these strategically important C-C and C-O bond formation transformations, a 10-step total synthesis of (±)-phaeocaulisin A was achieved. We further developed the cyclopropanol ring-opening carbonylation chemistry to provide an alternative approach to prepare γ-ketoesters. Biologically, the penultimate intermediate with an α-methylene γ-butyrolactone moiety was identified as a promising lead compound with anticancer proliferation activity against a panel of triple-negative or HER2+ breast cancer cell lines.

Total Syntheses of β‐ and γ‐Naphthocyclinones

AbstractAfter half a century from their isolation in 1974, we report the first total syntheses of β‐ and γ‐naphthocyclinones, two dimeric pyranonaphthoquinones featuring an unusual bicyclo[3.2.1]‐octadienone core. The syntheses were achieved with full stereochemical control and functional group management, relying on 1) enantioselective construction of the bicyclic core by Rh‐catalyzed enantioselective 1,4‐addition followed by thiolate‐mediated reductive cyclization, and 2) judicious design of a common chiral, non‐racemic monomer unit that is capable of divergence into the donor and acceptor units, and reunion to construct the bicyclo[3.2.1]octadienone core.

Photoinduced formal [4 + 2] cycloaddition of two electron-deficient olefins and its application to the synthesis of lucidumone.

Electronically mismatched Diels-Alder reaction between two electron-deficient components is synthetically useful and yet underdeveloped under thermal conditions. Herein, a photoinduced formal [4 + 2] cycloaddition of enone with a variety of electron-deficient dienes is described. Key to the success of this stepwise methodology relies on a C - C bond cleavage/rearrangement of the cyclobutane based overbred intermediate via diversified mechanistic pathways. Based on this annulation method, total synthesis of lucidumone is achieved in nine steps.

Enantioselective Electrocatalysis for Cross‐Dehydrogenative Heteroarylation with Indoles, Pyrroles, and Furans

AbstractOxidative cross‐dehydrogenative C−H/C−H functionalizations represent an exemplary approach for synthesizing carbonyl compounds via α‐heteroarylation. Here we present the development of a direct anodic oxidative coupling process between 2‐acylimidazoles and divergent heterocyclic systems including indole, pyrrole, and furan, facilitated by ferrocene‐assisted asymmetric nickel electrocatalysis with high levels of enantioselectivity. Mechanistic investigations indicate that the reaction initially involves the formation of a chiral Ni‐bound α‐carbonyl radical, which is then captured by the heteroarene radical cation via intermolecular stereoselective radical/radical cation coupling. The mild, scalable, and robust reaction conditions allow for a broad substrate scope and excellent functional group tolerance, enabling access to a wide range of chiral hetero‐compounds. The consequential α‐heteroaromatic carbonyl products can potentially be transformed into a plethora of synthetically valuable frameworks, as exemplified by their application in the asymmetric total synthesis of (−)‐COX‐2 inhibitor, (+)‐acremoauxin A, and (+)‐pemedolac.

A New Strategy for the Total Synthesis of Pentacyclic Tubifolidine

A New Strategy for the Total Synthesis of Pentacyclic Tubifolidine

Total Synthesis and Configuration Assignment of (+)-Myxoquaterine-450.

Myxoquaterines represent a recently discovered class of natural products with intriguing biological properties. They were isolated from Pendulasporacea albinea MSr 11954 and display a unique structure combining heterocyclic (pyrrole, oxazoline), hexa-ene, and 2-amino-1,3-diol subunits. We have now synthesized the first example of a myxoquaterine natural product, myxoquaterine-450, in a highly convergent fashion, in which the sensitive hexaene unit was established in the final stages of the synthesis (16 linear steps starting from l-serine). Comparison of the synthetic material with an authentic sample allowed to establish and confirm the constitution and configuration of the natural product.

Total Synthesis and Configuration Assignment of (+)‐Myxoquaterine‐450

Myxoquaterines represent a recently discovered class of natural products with intriguing biological properties. They were isolated from Pendulasporacea albinea MSr 11954 and display a unique structure combining heterocyclic (pyrrole, oxazoline), hexa­ene, and 2‐amino‐1,3‐diol subunits. We have now synthesized the first example of a myxoquaterine natural product, myxoquaterine‐450, in a highly convergent fashion, in which the sensitive hexaene unit was established in the final stages of the synthesis (16 linear steps starting from l‐serine). Comparison of the synthetic material with an authentic sample allowed to establish and confirm the constitution and configuration of the natural product.

Total synthesis of (-)-cylindrocyclophane A facilitated by C-H functionalization.

(-)-Cylindrocyclophane A is a 22-membered C2-symmetric [7.7]paracyclophane that bears bis-resorcinol functionality and six stereocenters. We report a synthetic strategy for (-)-cylindrocyclophane A that uses 10 C-H functionalization reactions, resulting in a streamlined route with high enantioselectivity and efficiency (17 steps). The use of chiral dirhodium tetracarboxylate catalysis enabled the C-H functionalization of primary and secondary positions, which was complemented by palladium-catalyzed C(sp2)-C(sp2) cross-couplings, resulting in the rapid formation of the macrocyclic core and all stereocenters with high regio-, diastereo-, and enantioselectivity. The use of a late-stage palladium-catalyzed fourfold C(sp2)-H acetoxylation installed the bis-resorcinol moieties. This research exemplifies how multilaboratory collaborations can produce substantial modernizations of complex total synthesis endeavors.

Synthesis of the C1-C15 Fragment of Incednine

We report on our progress towards the synthesis of the exotic, delicate and tense polyketidic macrolactam of incednine. This work constitutes a significant advancement towards the total synthesis of a family of molecules of biological and medicinal interest. Some of the key features of this synthesis required evolutions from the initially designed strategy, leading to the use of a HWE to build the C2-C9 tetraene. For this purpose, a polyfunctionalized phosphonate was used and obtained through an unprecedented Pd-catalyzed cross-coupling involving the zinc anion of diethyl methylphosphonate. The resulting desired C1-C15 fragment displays a carboxylic acid ester at C1 and a vinyl iodide at C15, both functions being ready for subsequent amide coupling with the C16-C23 fragment and final Suzuki cyclization respectively.

First Total Synthesis of Deinococcucin A, a Key Glycolipid Found in Cell Membranes of Extremophilic Bacteria.

Deinococcucin A is a secondary metabolite isolated from a gut bacteria of carpenter ant, member of extremophilic Deinoccocus family. The structure is a glycolipid containing N‐acetyl glucosamine, linked in α anomeric position to a chiral 2,3‐dihydroxypropanamide moiety. We succeeded a new strategy starting directly from N‐acetylglucosamine and transforming in an efficient manner an allyl group to the corresponding chiral α‐hydroxyamide. Three key steps were used: the oxidation of primary amine to nitrile using TCCA, as well as its hydrolysis to the corresponding amide using palladium (II) catalyzed conditions. The synthesis was completed in only 10 steps with an overall yield of 3%.

A Comprehensive Review on the Total Synthesis of Antibacterial Furanomycin and Its Analogs

l-(+)-Furanomycin 1 is a miniature antibacterial natural product that contains an α-amino acid core. This non-proteinogenic α-amino acid was first isolated in 1967 by Katagiri and co-workers from the fermentation broth of Streptomyces threomyceticus L-803 (ATCC 15795). It is a substrate of isoleucyl aminoacyl-tRNA synthetase that replaces isoleucine in the protein translation process and exhibits antibacterial properties in vitro. It effectively acts as an antibacterial agent against M. tuberculosis, E. coli, B. subtilis, and some Shigella and Salmonella bacterial species at concentrations as low as the micromolar range. Consequently, synthetic chemists have garnered considerable interest from their specific structure–activity profile, distinctive chemical compositions, and distinct biological profile. This review comprehensively describes cutting-edge synthetic methodologies for synthesizing furanomycin and its analogs reported to date. Therefore, this review will offer an initial perspective on synthesizing furanomycin and its customized compounds.

Terpestacin and Its Derivatives: Bioactivities and Syntheses.

Terpestacin (1), fusaproliferin (2), and their derivatives are a class of sesterterpenes featured by a trans-fused 5/15-membered ring skeleton. There are 45 natural products (1, 2, 4-27, 65-83) isolated from various wild fungi (Fusarium sp., Bipolaris sorokiniana, Arthrinium sp., etc.) or from genetic mutants via biosynthetic gene clusters mining, and 37 derivatives (28-64) produced by semi-synthetic modifications. These compounds show a diverse range of important bioactivities such as antivirus, antimicrobial, cytotoxic, phytotoxic, anti-flammatory, and brine shrimp lethal activities. To date, two racemic and five enantioselective chemical total syntheses of 1 (including 2 and their isomers) have been developed. Over the past decade, a number of biosynthetic gene clusters or their mutants, along with their encoding enzymes responsible for producing sesterterpenes such as terpestacin and its derivatives, have also been identified. This review covers the literature from the year 1993, when 1 was firstly discovered, to May 2024, focusing on the bioactivities and syntheses of 1 and its derivatives or isomers.

Scalable Protecting-Group-Free Total Synthesis of Resibufogenin and Bufalin.

A chemoenzymatic synthesis access to resibufogenin and bufalin was developed in seven steps without protecting groups. Starting with androstenedione (AD), an α-OH was introduced directly at C14 by hydroxylase P-450lun, which was further used as the directing group for hydrogenation to fully control the C17 configuration in the β-orientation after Suzuki cross-coupling. Dehydration of 14α-OH followed by an epoxidation delivered resibufogenin. Simultaneously, bufalin was also obtained via a challenging anaerobic Mukaiyama hydration.

Biosynthesis of (−)‐Vinigrol

(−)‐Vinigrol, as one of the most complex and challenging molecules in total synthesis, the parallel biosynthetic strategy employed by nature for the synthesis of this compound has not yet been identified. Here, we identified a minimal gene cluster encoding a diterpene cyclase (VniA) and a cytochrome P450 (VniB), which completes the synthesis of (−)‐vinigrol through three steps. VniA first cyclizes geranylgeranyl diphosphate to generate an unusual vinigrol‐type diterpene skeleton, and then VniB catalyzes the allylic C(sp3)‐H iterative oxidation. Further genome mining investigation provides new fungal sources for this rare and valuable vinigrol‐type diterpene skeleton.