Development of a Synthetic Platform for Ent-Pimaranes Reveals their Potential as Novel Non-Redox Active Ferroptosis Inhibitors.

We present a comprehensive account on the evolution of a synthetic platform for a subfamily of ent-pimaranes. For the most complex member, norflickinflimiod C, five distinct strategies relying on either cationic or radical polyene cyclizations to construct the requisite tricyclic carbon scaffold were explored. Insights from early and late stage oxidative and reductive dearomatization studies ultimately led to a mild, rhodium-catalyzed arene hydrogenation for the final synthetic route.

A General Entry to Meroterpenoids: Synthesis of Applanatumol E, H, and I, Lingzhilactone B, Meroapplanin B, and Lingzhiol.

meroterpenoids are fungal derived hybrid natural product class containing a 1,2,4-trisubstituted benzene ring and a polycyclic terpenoid part. The representatives applanatumol E, H and I, lingzhilactone B, and meroapplanin B share the same bicyclic lactone moiety connected to the arene. Employing photo-Fries rearrangements as the key step enabled a general entry to these natural products.

Total Synthesis of Ganoapplanin Enabled by a Radical Addition/Aldol Reaction Cascade.

The total synthesis of the meroterpenoid ganoapplanin, an inhibitor of T-type voltage-gated calcium channels, is reported. Our synthetic approach is based on the convergent coupling of a readily available aromatic polyketide scaffold with a bicyclic terpenoid fragment. The three contiguous stereocenters of the terpenoid fragment, two of which are quaternary, were constructed by a diastereoselective, titanium-mediated iodolactonization.

Synthesis of C3--virenose and anomerically activated derivatives.

A 9-step synthetic route to a protected form of the C3-epimer of virenose from -fucose is described. C3--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 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--substituted biaryl subunit was installed by base-induced ring expansion of a readily available 1,3-indandione.

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.

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.

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

The first asymmetric total synthesis of the diterpenoid waixenicin A, a potent and highly selective TRPM7 inhibitor, is reported. The characteristic -fused oxabicyclo[7.4.

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.

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.

Total Synthesis and Late-Stage C-H Oxidations of -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.

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.

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.

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.

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 2 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.

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.

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.

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.

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.

Total Synthesis of (+)-Cornexistin.

Herein, we describe the first total synthesis of (+)-cornexistin as well as its 8-epi-isomer starting from malic acid. The robust and scalable route features a Nozaki-Hiyama-Kishi reaction, an auxiliary-controlled syn-Evans-aldol reaction, and a highly efficient intramolecular alkylation to form the nine-membered carbocycle. The delicate maleic anhydride moiety of the nonadride skeleton was constructed from a β-keto nitrile.