Alkenes are found in a great number of biologically active molecules and are employed in numerous transformations in organic chemistry. Many olefins exist as E or higher energy Z isomers. Catalytic procedures for stereoselective formation of alkenes are therefore valuable; nonetheless, methods for synthesis of 1,2-disubstituted Z olefins are scarce. Here we report catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and allylic amides, employed thus far only in E-selective processes; the corresponding disubstituted alkenes are formed in up to >98% Z selectivity and 97% yield. Transformations, promoted by catalysts that contain the highly abundant and inexpensive molybdenum, are amenable to gram scale operations. Use of reduced pressure is introduced as a simple and effective strategy for achieving high stereoselectivity. Utility is demonstrated by syntheses of anti-oxidant C18 (plasm)-16:0 (PC), found in electrically active tissues and implicated in Alzheimer’s disease, and the potent immunostimulant KRN7000.

A new generation of alkyne metathesis catalysts, which are distinguished by high activity and an exquisite functional group tolerance, allows the scope of this transformation to be extended beyond its traditional range. They accept substrates that were previously found problematic or unreactive, such as propargyl alcohol derivatives, electron-deficient and electron-rich acetylenes of various types, and even terminal alkynes. Moreover, post-metathetic transformations other than semi-reduction increase the structural portfolio, as witnessed by the synthesis of a annulated phenol derivative via ring-closing alkyne metathesis (RCAM) followed by a transannular gold-catalyzed Conia-ene reaction. Further examples encompass a post-metathetic transannular ketone-alkyne cyclization with formation of a trisubstituted furan, a ruthenium-catalyzed redox isomerization, and a Meyer-Schuster rearrangement/oxa-Michael cascade. These reaction modes fueled model studies toward salicylate macrolides, furanocembranolides, and the cytotoxic macrolides acutiphycin and enigmazole A; moreover, they served as the key design elements of concise total syntheses of dehydrocurvularin (27) and the antibiotic agent A26771B (36).

A protocol for the stereospecific coupling of chiral secondary and tertiary boronic esters with lithiated N-heteroaromatics is described. The process involves initial boronate complex formation followed by addition of Troc-Cl, which activates the nitrogen and induces 1,2-migration. Oxidative workup furnishes the coupled product with >98% es.

Lactimidomycin (1) was described in the literature as an exquisitely potent cell migration inhibitor. Encouraged by this claim, we developed a concise and scalable synthesis of this bipartite glutarimide-macrolide antibiotic, which relies on the power of ring-closing alkyne metathesis (RCAM) for the formation of the unusually strained 12-membered head group. Subsequent deliberate digression from the successful path to 1 also brought the sister compound isomigrastatin (2) as well as a series of non-natural analogues of these macrolides into reach. A careful biological re-evaluation of this compound collection showed 1 and progeny to be potently cytotoxic against a panel of cancer cell lines, even after one day of compound exposure; therefore any potentially specific effects on tumor cell migration were indistinguishable from the acute effect of cell death. No significant cell migration inhibition was observed at sub-toxic doses. Although these findings cannot be reconciled with some reports in the literature, they are in accord with the notion that lactimidomycin is primarily a ribosome-binder able to effectively halt protein biosynthesis at the translation stage.

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The generation of carbon radicals by halogen-atom and group transfer reactions is generally achieved using tin and silicon reagents that maximize the interplay of enthalpic (thermodynamic) and polar (kinetic) effects. In this work, we demonstrate a distinct reactivity mode enabled by quantum mechanical tunneling that uses the cyclohexadiene derivative γ-terpinene as the abstractor under mild photochemical conditions. This protocol activates alkyl and aryl halides as well as several alcohol and thiol derivatives. Experimental and computational studies unveiled a noncanonical pathway whereby a cyclohexadienyl radical undergoes concerted aromatization and halogen-atom or group abstraction through the reactivity of an effective H atom. This activation mechanism is seemingly thermodynamically and kinetically unfavorable but is rendered feasible through quantum tunneling.

The synthesis of aziridine derivatives through metal-mediated nitrene addition reactions to olefins [Eq. (1)] has been extensively developed in the last decades; quantitative conversions as well as complete enantioselection have been already described. [1,2] However, in spite of the large number of reports related to the alkene aziridination reaction by this method and the synthetic interest of vinylaziridines, [3] only few have dealt with conjugated dienes as the substrate. Copper-, [4] manganese-, and ruthenium-based [5] catalysts have provided good yields of vinylaziridines formed by the exclusive aziridination of one C = C bond of the diene, although with the following limitations: 1) only symmetric dienes were employed and 2) selectivity, intended as cis/trans (or trans/cis) ratio, was low. These two drawbacks strongly prevent the synthetic application of this method.In fact, vinylaziridines are commonly synthesized by stoichiometric procedures based on nucleophilic intramolecular substitution. Thus, the Darzens-type reaction (Scheme 1, path a) is one of the oldest and most flexible methods for preparation of functional aziridine derivatives including vinylaziridines.

A concise and largely catalysis-based approach to the potent algal toxin polycavernoside A (1) is described that intercepts a late-stage intermediate of a previous total synthesis; from there on, this challenging target can be reached in a small number of steps. Key to success was a sequence of a molybdenum-catalyzed ring-closing alkyne metathesis (RCAM) reaction to forge the macrocyclic frame, followed by a gold-catalyzed and strictly regioselective transannular hydroalkoxylation of the resulting cycloalkyne that allows the intricate oxygenation pattern of the macrolactone ring of 1 to be properly set. The required cyclization precursor 5 was assembled by the arguably most advanced fragment coupling process based on an Evans-Tishchenko redox esterification known to date, which was optimized to the extent that the precious coupling partners could be used in an almost equimolar ratio (6/7 1:1.3). The preparation of these building blocks features, inter alia, the power of the Sc(OTf)(3)-catalyzed Leighton crotylation as well as the superb selectivities of alkene cross metathesis, asymmetric keto-ester hydrogenation, and the Jacobsen epoxidation/epoxide resolution technologies.