Synthesis of the Tetracyclic Spiro-naphthoquinone Chartspiroton.

Chartspiroton is a recently discovered naphthoquinone natural product that features a spiro-fused benzofuran lactone. We report its first synthesis via an 11-step linear sequence. The sterically hindered tetra-ortho-substituted biaryl subunit was installed by base-induced ring expansion of a readily available 1,3-indandione. This step also liberated the fully substituted naphthalene core unit at the same time. The unique spiro-fused benzofuran lactone of the natural product was constructed via late-stage oxidation of an advanced naphthoquinone.

Synthesis of C3-epi-virenose and anomerically activated derivatives.

A 9-step synthetic route to a protected form of the C3-epimer of virenose from D-fucose is described. C3-epi-virenose is the carbohydrate unit of the bioactive polyketide elsamicin B and part of the carbohydrate unit of elsamicin A. The developed route enabled preparation of anomerically activated forms of this unique C6-deoxy sugar, including derivatives with 1-acetyl, 1-acetylthio, 1-trichloroacetimidate, 1-bromo, and 1-fluoro substituents.

Synthesis of Waixenicin A: Exploring Strategies for Nine-Membered Ring Formation.

We present a comprehensive account on our efforts behind the recently published synthesis of waixenicin A. Our approach for constructing the dihydropyran ring relied on an Achmatowicz rearrangement. For the assembly of the nine-membered ring, four distinct strategies were investigated. Our initial attempts using radical-based addition/fragmentation reactions targeting the C7-C11 bond proved unsuitable for accessing the 6/9-bicycle. By employing anionic fragmentation conditions at the furfuryl alcohol stage, we successfully reached a 5/9-bicycle. However, subsequent ring-expansion was unsuccessful. Alternative approaches, such as Nozaki-Hiyama-Kishi or Heck reactions to connect the C6-C7 bond, also encountered difficulties, with no nine-membered ring formation observed. Our first breakthrough came from our attempts to install the C5-C6 bond via an intramolecular alkylation. Surprisingly, subsequent functional group modifications proved unexpectedly challenging, necessitating a redesign of our synthetic route. Drawing from all our investigations, we concluded that construction of the C9-C10 bond would enable efficient nine-membered ring alkylation and would facilitate the installation of the desired substitution pattern along the southern periphery. Exploration of this strategy yielded further surprises but ultimately led to the successful synthesis of waixenicin A and 9-deacetoxy-14,15-deepoxyxeniculin. For the latter compound, a bioinspired one-step rearrangement to xeniafauranol A was achieved.

A Divergent Polyene Cyclization for the Total Synthesis of Greenwayodendrines, Greenwaylactams, Polysin and Polyveoline.

We present a concise asymmetric total synthesis (5-8 steps) of nine sesquiterpenoid alkaloids featuring four different tetra-/pentacyclic scaffolds. To this end, a novel, bioinspired indole N-terminated cationic tricyclization has been developed, enabling the divergent synthesis of greenwayodendrines and polysin. Subtle variation of the C2-substituted indole cyclization precursor allowed switching between indole N- and C-termination. For the latter, a subsequent Witkop oxidation enabled conversion of the cyclopentene-fused indole into the eight-membered benzolactam to directly furnish the family of greenwaylactams. In addition, a diastereomeric C-termination product has been elaborated to provide access to polyveoline.

Total Syntheses of (+)-Waixenicin A, (+)-9-Deacetoxy-14,15-deepoxyxeniculin, and (-)-Xeniafaraunol A.

The first asymmetric total synthesis of the Xenia diterpenoid waixenicin A, a potent and highly selective TRPM7 inhibitor, is reported. The characteristic trans-fused oxabicyclo[7.4.0]tridecane ring system was constructed via a diastereoselective conjugate addition/trapping sequence, followed by an intramolecular alkylation to forge the 9-membered ring. While a ß-keto sulfone motif enabled efficient ring-closure, the subsequent radical desulfonylation suffered from (E)/(Z)-isomerization of the C7/C8-alkene. Conducting the sequence with a trimethylsilylethyl ester allowed for a fluoride-mediated decarboxylation that proceeded without detectable isomerization. The acid-labile enol acetal of the delicate dihydropyran core was introduced at an early stage and temporarily deactivated by a triflate function. The latter was critical for the introduction of the side chain. Diverting from a common late-stage intermediate provided access to waixenicin A and 9-deacetoxy-14,15-deepoxyxeniculin. A high-yielding base-mediated dihydropyran-cyclohexene rearrangement of 9-deacetoxy-14,15-deepoxyxeniculin led to xeniafaraunol A in one step.

Investigations into Simplified Analogues of the Herbicidal Natural Product (+)-Cornexistin.

We report the design, synthesis and biological evaluation of simplified analogues of the herbicidal natural product (+)-cornexistin. Guided by an X-Ray co-crystal structure of cornexistin bound to transketolase from Zea mays, we attempted to identify the key interactions that are necessary for cornexistin to maintain its herbicidal profile. This resulted in the preparation of three novel analogues investigating the importance of substituents that are located on the nine-membered ring of cornexistin. One analogue maintained a good level of biological activity and could provide researchers insights in how to further optimize the structure of cornexistin for commercialization in the future.

Total Synthesis of the Dihydrooxepine-Spiroisoxazoline Natural Product Psammaplysin A.

We report a general synthetic entry to dihydrooxepine-spiroisoxazoline (DOSI) natural products that culminated in the first racemic total synthesis of psammaplysin A. For the synthesis of the unique spirocyclic fragment we employed a strategy that features two key transformations: (1) a diastereoselective Henry reaction/cyclization sequence to access the C7 hydroxylated isoxazoline scaffold in one step and (2) a regioselective Baeyer-Villiger ring expansion to install the fully substituted dihydrooxepine and avoid the risk of a previously observed oxepine-arene oxide rearrangement. The overall synthesis proceeds in 13 steps from an inexpensive starting material.

Short, Divergent, and Enantioselective Total Synthesis of Bioactive ent-Pimaranes.

We present the first total synthesis of eight ent-pimaranes via a short and enantioselective route (11-16 steps). Key features of the divergent synthesis are a Sharpless asymmetric dihydroxylation, a Brønsted acid catalyzed cationic bicyclization, and a mild Rh-catalyzed arene hydrogenation for rapid access to a late synthetic branching point. From there on, selective functional group manipulations enable the synthesis of ent-pimaranes bearing different modifications in the A- and C-rings.

KS0365, a novel activator of the transient receptor potential vanilloid 3 (TRPV3) channel, accelerates keratinocyte migration.

BACKGROUND AND PURPOSE: Ca2+ signalling mediated by the thermosensitive, non-selective, Ca2+ -permeable transient receptor potential channel TRPV3 is assumed to play a critical role in regulating several aspects of skin functions, such as keratinocyte proliferation, differentiation, skin barrier formation and wound healing. Studying the function of TRPV3 in skin homeostasis, however, is still constrained by a lack of potent and selective pharmacological modulators of TRPV3. EXPERIMENTAL APPROACH: By screening an in-house compound library using fluorometric intracellular Ca2+ assays, we identified two chemically related hits. The more potent and efficient TRPV3 activator 2-(2-chloro-3-isopropylcyclopent-2-en-1-yl)-4-methylphenol (KS0365) was further evaluated in fluo-4-assisted Ca2+ assays, different Ca2+ imaging approaches, electrophysiological studies, cytotoxicity and migration assays. KEY RESULTS: KS0365 activated recombinant and native mouse TRPV3 more potently and with a higher efficacy compared with 2-APB and did not activate TRPV2 or TRPV4 channels. The activation of TRPV3 by KS0365 super-additively accelerated the EGF-induced keratinocyte migration, which was inhibited by the TRP channel blocker ruthenium red or by siRNA-mediated TRPV3 knockdown. Moreover, KS0365 induced strong Ca2+ responses in migrating front cells and in leading edges of keratinocytes. CONCLUSIONS AND IMPLICATIONS: The selective TRPV3 activator KS0365 triggers increases in [Ca2+ ]i with most prominent signals in the leading edge and accelerates migration of keratinocytes. TRPV3 activators may promote re-epithelialization upon skin wounding.

Total Synthesis and Late-Stage C-H Oxidations of ent-Trachylobane Natural Products.

Herein, we present our studies to construct seven ent-trachylobane diterpenoids by employing a bioinspired two-phase synthetic strategy. The first phase provided enantioselective and scalable access to five ent-trachylobanes, of which methyl ent-trachyloban-19-oate was produced on a 300 mg scale. During the second phase, chemical C-H oxidation methods were employed to enable selective conversion to two naturally occurring higher functionalized ent-trachylobanes. The formation of regioisomeric analogs, which are currently inaccessible via enzymatic methods, reveals the potential as well as limitations of established chemical C-H oxidation protocols for complex molecule synthesis.

Total Synthesis and Late-Stage C-H Oxidations of ent-Trachylobane Natural Products.

Herein, we present our studies to construct seven ent-trachylobane diterpenoids by employing a bioinspired two-phase synthetic strategy. The first phase provided enantioselective and scalable access to five ent-trachylobanes, of which methyl ent-trachyloban-19-oate was produced on a 300 mg scale. During the second phase, chemical C-H oxidation methods were employed to enable selective conversion to two naturally occurring higher functionalized ent-trachylobanes. The formation of regioisomeric analogs, which are currently inaccessible via enzymatic methods, reveals the potential as well as limitations of established chemical C-H oxidation protocols for complex molecule synthesis.

Ring Expansion of 1-Indanones to 2-Halo-1-naphthols as an Entry Point to Gilvocarcin Natural Products.

Herein, we describe a two-step ring expansion of 1-indanones to afford 2-chloro/bromo-1-naphthols (32 examples). The developed method shows broad functional group tolerance, benefits from mild reaction conditions, and enables rapid access to the tetracyclic core of gilvocarcin natural products. The orthogonally functionalized products allow for selective postmodifications as exemplified in the total synthesis of defucogilvocarcin M. For the selective oxidation of the chromene, a mild and regioselective oxidation protocol (DDQ and TBHP) was developed.

Bifunctional Polyene Cyclizations: Synthetic Studies on Pimarane Natural Products.

Polyene cyclizations generate molecular complexity from a linear polyene in a single step. While methods to initiate these cyclizations have been continuously expanded and improved over the years, the majority of polyene substrates are still limited to simple alkyl-substituted alkenes. In this study, we took advantage of the unique reactivity of higher-functionalized bifunctional alkenes. The realization of a polyene tetracyclization of a dual nucleophilic aryl enol ether involving a transannular endo-termination step enabled the total synthesis of the tricyclic diterpenoid pimara-15-en-3α-8α-diol. The highly flexible and modular route allowed for the preparation of a diverse library of cyclization precursors specifically designed for the total synthesis of the tetracyclic nor-diterpenoid norflickinflimiod C. The tetracyclization of three diversely substituted allenes enabled access to complex pentacyclic products and provided a detailed insight into the underlying reaction pathways.

Evolution of a Strategy for the Total Synthesis of (+)-Cornexistin.

Herein is given a full account of the evolution of the first total synthesis of (+)-cornexistin. Initial efforts were based on masking the reactive maleic anhydride moiety as a 3,4-substituted furan and on forming the nine-membered carbocycle in an intramolecular Conia-ene or Nozaki-Hiyama-Kishi (NHK) reaction. Those strategies suffered from low yields and were jeopardized by a late-stage installation of the Z-alkene, as well as the stereocenters along the eastern periphery. These issues were addressed by employing a chiral-pool strategy that involved construction of the crucial stereocenters at C2, C3 and C8 at an early stage with installation of the maleic anhydride as late as possible. The successful approach featured an intermolecular NHK coupling to install the Z-alkene, a syn-Evans-aldol reaction to forge the stereocenters along the eastern periphery, an intramolecular allylic alkylation to close the nine-membered carbocycle, and a challenging stepwise hydrolysis of a ß-keto nitrile to furnish the maleic anhydride.

The 2nd Alpine Winter Conference on Medicinal and Synthetic Chemistry.

The second biannual Alpine Winter Conference on Medicinal and Synthetic Chemistry (short: Alpine Winter Conference) took place January 19-23, 2020, in St. Anton in western Austria. There were roughly 180 attendees from around the globe, making this mid-sized conference particularly conducive to networking and exchanging ideas over the course of four and a half days. This report summarizes the key events and presentations given by researchers working in both industry and academia.

Synthesis of Pyrroles via Consecutive 6π-Electrocyclization/Ring-Contraction of Sulfilimines.

We present a modular, synthetic entry to polysubstituted pyrroles employing readily available 2,5-dihydrothiophenes. Ring-opening of the heterocycle provides access to a panel of 1,3-dienes which undergo pyrrole formation in the presence of inexpensive chloramine-T trihydrate. The transformation is conducted in an open flask and proceeds at ambient temperatures (23 °C) in nondry solvents. A careful adjustment of the electronics and sterics of the 1,3-diene precursor allows for the isolation of key intermediates. DFT studies identified a reaction mechanism that features a 6π-electrocyclization of a sulfilimine intermediate followed by spontaneous ring-contraction to reveal the pyrrole skeleton.

Rapid Assembly of Tetrasubstituted Furans via Pummerer-Type Rearrangement.

Despite the many methods available for the synthesis of furans, few methods remain that allow for the custom-made assembly of fully substituted furans. Here we report a powerful protocol to rapidly construct tetrasubstituted, orthogonally functionalized furans under mild reaction conditions. The developed method involves the regioselective ring-opening of readily available 2,5-dihydrothiophenes followed by an oxidative cyclization to provide the heterocycle. The selective oxidation at sulfur is promoted by N-chlorosuccinimide as an inexpensive reagent and proceeds at ambient temperature in high yield within 30 min. The obtained furans serve as exceptionally versatile intermediates and were shown to participate in a series of valuable postmodifications. The fate of the initial sulfonium intermediate was investigated by mechanistic experiments, and computational studies revealed the existence of an unprecedented Pummerer-type rearrangement. The potential for organic synthesis is highlighted by the total synthesis of bisabolene sesquiterpenoids (pleurotins A, B, and D).

Beyond the Isoprene Pattern: Bifunctional Polyene Cyclizations.

Polyene cyclizations are capable of producing molecular complexity in a single step. While classical systems are limited to simple alkyl substitution patterns only, bifunctional polyenes take advantage of the unique reactivity of higher-functionalized alkenes. Here, we highlight the potential of these variants for the synthesis of structurally complex polycycles involving unprecedented termination steps. We also want to provide a stimulus for the development of novel modes of cyclization that involve bifunctional units to enable efficient synthesis of yet inaccessible natural products.

Total Synthesis of Oxepin and Dihydrooxepin Containing Natural Products.

The construction of oxepin and dihydrooxepin containing natural products represents a challenging task in total synthesis. In the last decades, a variety of synthetic methods have been reported for the installation of these structural motifs. Herein, we provide an overview of synthetic methods and strategies to construct these motifs in the context of natural product synthesis and highlight the key steps of each example.

Synthesis of Vicinal Quaternary All-Carbon Centers via Acid-catalyzed Cycloisomerization of Neopentylic Epoxides.

We report our studies on the development of a catalytic cycloisomerization of 2,2-disubstituted neopentylic epoxides to produce highly substituted tetralins and chromanes. Termination of the sequence occurs via Friedel-Crafts-type alkylation of the remote (hetero)arene linker. The transformation is efficiently promoted by sulfuric acid and proceeds best in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as the solvent. Variation of the substitution pattern provided detailed insights into the migration tendencies and revealed a competing disproportionation pathway of dihydronaphthalenes.