ABC Ring Research Articles

Concise Total Synthesis of (-)-Codeine.

Codeine and morphine are among the few natural products that are used directly as drugs for medical treatment. However, the availability of these is widely dependent on natural resources. Herein, we report an efficient enantioselective seven-step synthesis of (-)-codeine starting from simpler starting materials. The key steps involve microwave-assisted intramolecular cascade double heck cyclization to access the ABCE ring of opium alkaloids with the required stereocenters in one pot. A photoinduced intramolecular hydroamination of carboxamide forms the D ring and completes the pentacyclic core of the morphinans. Following that, an oxidation followed by global reduction leads to the formation of (-)-codeine. Our synthesis relies on simple and classical reactions to address the opium alkaloids and will serve as an efficient route to access the other morphinans.

Synthesis of (±)-zeapyranolactone, a noncanonical strigolactone isolated from maize, and determination of its overall relative configuration

Strigolactones are a class of apocarotenoids known as rhizosphere semiochemicals and plant hormones. They are classified as either canonical, with a tricyclic lactone (ABC ring) and a butenolide (D ring) comprising their basic skeleton, or noncanonical, deviating from the basic skeleton. Here, zeapyranolactone, a noncanonical strigolactone isolated from maize, was synthesized for the first time as a racemic and diastereomeric mixture, and its relative stereochemistry was determined by three-dimensional electron diffraction crystallography as 4S*,4aS*,2′R*. The synthetic route developed is straightforward and does not rely on the use of typical protective groups.

Synthesis of the ABC ring system of kadlongilactones.

A racemic approach towards the synthesis of the ABC (7/7/5) ring system of Schisandra triterpenoid kadlongilactones is described. The synthesis features two key transformations: (1) conjugate addition followed by iodolactonization to build the cis-fused 7/7 ring; and (2) conjugate addition-Rubottom oxidation cascade followed by ring-closing metathesis to construct the 7/7/5 tricyclic ring.

Synthesis of the ABC Ring of Calyciphylline A-Type Alkaloids by a Stereocontrolled Aldol Cyclization: Formal Synthesis of (±)-Himalensine A.

A synthetic approach to a functionalized ABC-tricyclic framework of calyciphilline A-type alkaloids, a building block toward this class of alkaloids, is reported. The key synthetic steps involve a radical cyclization to form the hydroindole system and piperidine ring closure through a stereocontrolled aldol cyclization. The resulting alcohol allows the methyl group to be installed in the bowl-shaped azatricyclic structure; this crucial reaction takes place with configuration retention. The synthesis of azatricyclic compound I constitutes a formal synthesis of himalensine A.

Intramolecular (4+3) Cycloadditions of Oxidopyridinium Ions: Towards Daphnicyclidin A.

N-alkylation of 5-hydroxynicotinic acid esters with electrophiles containing diene functionality produces salts that undergo intramolecular (4+3) cycloaddition reactions upon heating in the presence of base. Initial studies used a three-carbon tether to join the pyridinium ion and diene, revealing some aspects of the inherent selectivity of the reaction with such substrates. Much more challenging was the synthesis of related species possessing only a two-carbon tether. Nevertheless, the cycloaddition of such compounds was successful, leading directly to the ABC ring system of the alkaloid daphnicyclidin A.

First synthesis of an ABCE ring substructure of daphnicyclidin A.

The ABCE tetracyclic ring system of daphnicyclidin A was prepared using an intramolecular (4 + 3) cycloaddition of an oxidopyridinium ion as the key step. This route consists of a 10-step synthesis with an overall yield of 20.2%. This result offers support for the use of this strategy for total synthesis of daphnicyclidin A.

Studies toward norzoanthamine: Ireland–Claisen rearrangements of α,β-unsaturated esters in a stereocontrolled synthesis of trans-fused 2-cyclohexen-1-ones

The enantiocontrolled preparation of the trans-fused ABC ring system of norzoanthamine is described. The synthesis strategy has incorporated studies of Ireland–Claisen rearrangements of esters derived from 3,3-dimethylacrylic acid. Stereocontrol results from competing chair- and boat-like transition states. Introduction of a nitroalkene by application of a modified Henry reaction facilitates an intramolecular Diels–Alder cycloaddition for an effective and simple transformation to the desired conjugated decalone. A fully functionalized AB ring system leads to the cyclization of the trans-fused cyclohexenone to complete the ABC system via ring-closing metathesis.

Synthetic Studies on Cyclocitrinol: Construction of the ABC Ring System Based on Epoxy–Nitrile Cyclization

AbstractThe stereoselective synthesis of a model compound containing the ABC ring system of cyclocitrinol was accomplished. After connecting a C ring allyltitanium segment with an A ring bi­cyclo[4.1.0]heptanone segment, the seven-membered B ring moiety was constructed by an intramolecular cyclization reaction of an epoxy nitrile. The enone moiety was introduced through an oxidative decyanation reaction, and the bicyclo[4.4.1]undecane skeleton with the highly strained olefin moiety was formed through a ring-opening reaction of the bicyclo[4.1.0]heptane substructure.

Dramatic influence of ester steric hindrance on the diastereoselectivity of a Michael addition towards the synthesis of the ABC tricycle of hexacyclinic acid

During our studies toward the synthesis of the ABC ring system of hexacyclinic acid, we observed an unexpected influence of the steric bulk of the ester group of the Michael acceptor in a key conjugate addition. We propose an eight-membered ring transition state to explain the formation of the undesired diastereomer in the case of unhindered esters.

Total Synthesis of Farnesin through an Excited-State Nazarov Reaction.

The asymmetric total synthesis of farnesin, a rearranged ent-kaurenoid, was achieved through a convergent approach involving photo-Nazarov and intramolecular aldol cyclizations to build the syn-syn-syn hydrofluorenol ABC ring system and bicyclo[3.2.1]octane CD ring system in the first application of a UV-light-induced excited-state Nazarov cyclization of a non-aromatic dicyclic divinyl ketone in a total synthesis. Unlike the conventional acid-promoted ground-state Nazarov reaction, the excited-state Nazarov reaction enables stereospecific formation of the highly strained syn-syn-syn-fused hydrofluorenone scaffold through a disrotatory cyclization.

Total Synthesis of Farnesin through an Excited‐State Nazarov Reaction

AbstractThe asymmetric total synthesis of farnesin, a rearranged ent‐kaurenoid, was achieved through a convergent approach involving photo‐Nazarov and intramolecular aldol cyclizations to build the syn‐syn‐syn hydrofluorenol ABC ring system and bicyclo[3.2.1]octane CD ring system in the first application of a UV‐light‐induced excited‐state Nazarov cyclization of a non‐aromatic dicyclic divinyl ketone in a total synthesis. Unlike the conventional acid‐promoted ground‐state Nazarov reaction, the excited‐state Nazarov reaction enables stereospecific formation of the highly strained syn‐syn‐syn‐fused hydrofluorenone scaffold through a disrotatory cyclization.

Cover Feature: A Formal Synthesis of Camptothecin via a Photocatalytic Decarboxylative Radical Addition (Eur. J. Org. Chem. 35/2019)

The Cover Feature shows a novel strategy for the formal synthesis of camptothecin, which can be isolated from Camptotheca acuminate (also called happy tree) and used as an anti-cancer agent in traditional Chinese medicine. The key step is a photo-catalytic decarboxylative radical Michael addition for the efficient construction of the pentacyclic parent core by visible light. As is symbolically illustrated in the cartoon, the shining sunlight can directly transform the ABC rings to the main structure of camptothecin in five steps. This work provides an alternative method for the synthesis of biologically relevant Camptotheca analogues. More information can be found in the Full Paper by F. Chen et al.

Asymmetric synthesis of ABC tricyclic systems in Daphniphyllum alkaloid

Efficient synthetic routs for the direct and rapid construction of [5-6-6] ABC tricyclic systems of daphmanidin A-type and calyciphylline A-type alkaloids have been successfully developed. For the daphmanidin A-type, the synthesis of [5-6-6] tricyclic framework utilize a HCl-mediated intramolecular Aldol reaction to construct the bicyclo[2.2.2]octane core and a thermal condensation to afford the ABC ring system. In addition, for the calyciphylline A-type, an improved synthesis of ABC [5-6-6] tricyclic system was developed, featuring an introduction of methyl ester group at C2 before the Pd-catalyzed intramolecular oxidative alkylation to construct the desired bowl-shape tricyclic core with stereochemical control.

A Formal Synthesis of Camptothecin via a Photocatalytic Decarboxylative Radical Addition

A convergent fragment‐coupling strategy for the synthesis of camptothecin is described. The key step is a photocatalytic decarboxylative radical Michael addition that attaches the ABC rings to the E ring fragment, constructing the main structure of camptothecin in five steps. This work illustrates a new strategy for the synthesis of alkaloids of the camptothecin family.

Stereoselective Synthesis of the ABC Ring System of Aspterpenacids

Aspterpenacids A and B are sesterterpenoids that possess a unique and highly congested 5/3/7/6/5 fused ring system. These compounds also contain a sterically encumbered isopropyl trans-hydrindane motif and a cyclopropane motif bearing two quaternary centers, which make them remarkably challenging synthetic targets. Herein, we report the successful construction of the key highly substituted ABC ring system in a stereoselective manner.

Total Synthesis of (±)-Prostratin

Summary Prostratin, a highly complex diterpene natural product, is a pre-clinical candidate in developing a cure for HIV-1 infection and also a potent and selective inhibitor of several tumors. Despite nearly 40 years of progress, prostratin and related natural products still present formidable challenges for synthetic chemists. Here, we report a total synthesis of (±)-prostratin that proceeds in 23 steps from cyclopentadiene. The synthetic strategy includes rapid assembly of the tricyclic core and highly controlled establishment of the densely functionalized C ring, featuring an array of stereoselective transformations including alkoxide-guided 1,4-additions and cyclopropane formation. This work should enable further explorations of chemical and biological spaces based on prostratin and related natural products.

Synthesis of the ABC framework of tamulamides A and B

Synthesis of the fused tetrahydrofuran motif comprising the ABC rings of the marine ladder polyethers tamulamides A and B has been achieved via two different polyepoxide cascade strategies. Investigations into a triepoxide cascade under aqueous conditions revealed the importance of the electronic nature of the cascade end-group with this initial approach. Ultimately, a diepoxide cascade under basic conditions proved most successful, providing the ABC tetrahydropyran triad in 41% yield.

Oxamidation of Unsaturated O-Alkyl Hydroxamates: Synthesis of the Madangamine Diazatricylic (ABC Rings) Skeleton.

A novel approach to the diazatricyclic madangamine ABC ring system and the synthesis of an advanced, differentially protected intermediate for the synthesis of madangamine D is reported. Central to the success of this approach is the iodine(III)-mediated intramolecular oxamidation of an unsaturated O-methyl hydroxamate, a π-N+-type cyclization which proceeds in high yield and with complete regioselectivity to generate the 2-azabicyclo[3.3.1]nonane (morphan) system encompassing rings A and C.

Synthesis of bicyclic tripeptides inspired by the ABC-ring system of vancomycin through ruthenium-based cyclization chemistries

The synthesis of a bicyclic tripeptide that mimics the ABC ring system of vancomycin is described by using a ring closing metathesis (RCM) – peptide coupling – ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) strategy.

Total Synthesis of (+)-Gracilamine Based on an Oxidative Phenolic Coupling Reaction and Determination of Its Absolute Configuration.

The enantioselective total synthesis of (+)-gracilamine (1) is described. The strategy features a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza-Michael reaction to construct the ABCE ring system. The configuration at C3a in 1 was controlled by the stereocenter at C9a, which was selectively generated (91 % ee) by an organocatalytic enantioselective aza-Friedel-Crafts reaction developed by our research group. This synthesis revealed that the absolute configuration of (+)-gracilamine is 3aR, 4S, 5S, 6R, 7aS, 8R, 9aS.