Enantioselective Synthesis of Medium‐Sized Lactams via Chiral α,β‐Unsaturated Acylammonium Salts

Medium‐sized lactams are important structural motifs found in a variety of bioactive compounds and natural products but are challenging to prepare, especially in optically active form. A Michael addition/proton transfer/lactamization organocascade process is described that delivers medium‐sized lactams, including azepanones, benzazepinones, azocanones, and benzazocinones, in high enantiopurity through the intermediacy of chiral α,β‐unsaturated acylammonium salts. An unexpected indoline synthesis was also uncovered, and the benzazocinone skeleton was transformed into other complex heterocyclic derivatives, including spiroglutarimides, isoquinolinones, and δ‐lactones.     

A High‐Throughput Assay for Arylamine Halogenation Based on a Peroxidase‐Mediated Quinone–Amine Coupling with Applications in the Screening of Enzymatic Halogenations

Arylhalides are important building blocks in many fine chemicals, pharmaceuticals and agrochemicals, and there has been increasing interest in the development of more “green” halogenation methods based on enzyme catalysis. However, the screening and development of new enzymes for biohalogenation has been hampered by a lack of high‐throughput screening methods. Described herein is the development of a colorimetric assay for detecting both chemical and enzymatic arylamine halogenation reactions in an aqueous environment. The assay is based on the unique UV/Vis spectrum created by the formation of an ortho‐benzoquinone‐amine adduct, which is produced by the peroxidase‐catalysed benzoquinone generation, followed by Michael addition of either a halogenated or non‐halogenated arylamine. This assay is sensitive, rapid and amenable to high‐throughput screening platforms. We have also shown this assay to be easily coupled to a flavin‐dependent halogenase, which currently lacks any convenient colorimetric assay, in a “one‐pot” workflow.     

Synthesis of Substituted Pyridyl‐Pyrimidines as Potential Protein–Protein Interaction Inhibitors

An efficient synthetic method for the preparation of pyridyl‐pyrimidines as potential inhibitors of protein–protein interactions is described. The key transformation is the reaction of a pyrimidine enaminone with phenyl ethyl acetate and NH⁴OAc to yield the desired pyridyl‐pyrimidine.     

Silica Gel as a Promoter of Sequential Aza‐Michael/Michael Reactions of Amines and Propiolic Esters: Solvent‐ and Metal‐Free Synthesis of Polyfunctionalized Conjugated Dienes

We present an efficient, simple, metal‐ and solvent‐free silica‐gel‐promoted synthesis of functionalized conjugated dienes by sequential aza‐Michael/Michael reactions by starting from commercially available primary amines and propiolic esters. The scope and usefulness of the method is demonstrated for 31 examples, including a range of propiolic esters, aliphatic amines, and differently substituted aromatic amines. For aliphatic amines, the products were obtained within 0.5 to 4 h in 52 to 85 % yield, compared with 3.5 to 22 h under classical solution‐phase synthesis, which proceeds with similar or lower yields. The method was found to be particularly useful for weakly nucleophilic aromatic amines, which provided products in 21 to 73 % yield over 2.5 to 9.5 h compared with yields of 0 to 49 % over 1 to 6 d under standard solution‐phase conditions, and for more hydrophobic esters that gave products in yields of 47 to 79 % over 1 to 3 h compared with 0 to 45 % over 4 to 114 h in solvent.     

Cerium Alkoxides—Synthesis, Properties and Their Use in Michael Addition Reaction

Cerium(III) alkoxides served as an effective and attractive promoter for the Michael addition reaction with excellent chemical yields under mild conditions in short reaction time.     

Water—More Than Just a Green Solvent: A Stereoselective One‐Pot Access to All‐Chiral Tetrahydronaphthalenes in Aqueous Media

A facile and highly stereoselective construction of heavily functionalized chiral tetrahydronaphthalene skeletons fused with an oxazolidine moiety has been developed. The process involves an organocatalytic tandem Michael/nitrone formation/intramolecular [3+2] nitrone–olefin cycloaddition in aqueous media. Using rationally designed substrates, the reaction conditions have been optimized and the one‐pot process has been applied to a series of nitroolefin acrylates and aldehydes. The N‐hydroxyphenylamine component used in the second step has also been varied. The stereochemistry of one product has been verified by an X‐ray crystal structure determination. The water used in the strategy not only constitutes an environmentally benign solvent, but also helps to improve the reactivity and stereoselectivity.     

Total Synthesis of (±)‐Aspidophylline A

A total synthesis of aspidophylline A, a pentacyclic akuammiline‐type monoterpene indole alkaloid, is described. The synthesis features: 1) rapid access to a fully functionalized dihydrocarbazole through the desymmetrization of readily available 2‐allyl‐2‐(o‐nitrophenyl)cyclohexane‐1,3‐dione; 2) an intramolecular azidoalkoxylation of an enecarbamate to install both the furoindoline ring and the azido functionality; and 3) an intramolecular Michael addition for the construction of the 2‐azabicyclo[3.3.1]nonane ring system.     

Exploiting the Imidazolium Effect in Base‐free Ammonium Enolate Generation: Synthetic and Mechanistic Studies

N‐Acyl imidazoles and catalytic isothiourea hydrochloride salts function as ammonium enolate precursors in the absence of base. Enantioselective Michael addition–cyclization reactions using different α,β‐unsaturated Michael acceptors have been performed to form dihydropyranones and dihydropyridinones with high stereoselectivity. Detailed mechanistic studies using RPKA have revealed the importance of the “imidazolium” effect in ammonium enolate formation and have highlighted key differences with traditional base‐mediated processes.     

One‐Pot Synthesis of (−)‐Oseltamivir and Mechanistic Insights into the Organocatalyzed Michael Reaction

The one‐pot sequential synthesis of (?)‐oseltamivir has been achieved without evaporation or solvent exchange in 36 % yield over seven reactions. The key step was the asymmetric Michael reaction of pentan‐3‐yloxyacetaldehyde with (Z)‐N‐2‐nitroethenylacetamide, catalyzed by a diphenylprolinol silyl ether. The use of a bulky O‐silyl‐substituted diphenylprolinol catalyst, chlorobenzene as a solvent, and HCO₂H as an acid additive, were key to produce the first Michael adduct in both excellent yield and excellent diastereo‐ and enantioselectivity. Investigation into the effect of acid demonstrated that an acid additive accelerates not only the E–Z isomerization of the enamines derived from pentan‐3‐yloxyacetaldehyde with diphenylprolinol silyl ether, but also ring opening of the cyclobutane intermediate and the addition reaction of the enamine to (Z)‐N‐2‐nitroethenylacetamide. The transition‐state model for the Michael reaction of pentan‐3‐yloxyacetaldehyde with (Z)‐N‐2‐nitroethenylacetamide was proposed by consideration of the absolute configuration of the major and minor isomers of the Michael product with the results of the Michael reaction of pentan‐3‐yloxyacetaldehyde with phenylmaleimide and naphthoquinone.     

Enantioselective Total Synthesis of (+)‐Plumisclerin A

The first and enantioselective total synthesis of (+)‐plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring‐formation protocol was adopted to generate the characteristic tricycle[4.3.1.0^1,5]decane and trans‐fused dihyrdopyran moiety. Scalable enantioselective La^III‐catalyzed Michael reaction, palladium(0)‐catalyzed carbonylation and SmI₂‐mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D‐ring system having six continuous stereogenic centers and two all‐carbon quaternary centers. The trans‐fused dihyrdopyran moiety with an exo side‐chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)‐plumisclerin A.     

Asymmetric Phase‐Transfer‐Catalyzed Intramolecular N‐Alkylation of Indoles and Pyrroles: A Combined Experimental and Theoretical Investigation

Asymmetric phase‐transfer catalysis (PTC) has risen to prominence over the last decade as a straightforward synthetic methodology for the preparation of pharmacologically active compounds in enantiomerically pure form. However, the complex interplay of weak nonbonded interactions (between catalyst and substrate) that could account for the stereoselection in these processes is still unclear, with tentative pictorial mechanistic representations usually proposed. Here we present a full account dealing with the enantioselective phase‐transfer‐catalyzed intramolecular aza‐Michael reaction (IMAMR) of indolyl esters, as a valuable synthetic tool to obtain added‐value compounds, such as dihydro‐pyrazinoindolinones. A combined computational and experimental investigation has been carried out to elucidate the key mechanistic aspects of this process.