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The first total synthesis of nominal harziane diterpenoid is disclosed, whose spectral characteristics did not match those of the reported natural product. Stereochemical analysis and subsequent synthesis of the epimeric tertiary alcohol led to reassignment of configuration of the natural product. At the heart of the synthesis is an enyne cycloisomerization that sets a key quaternary stereocenter within a cyclobutane with high diastereocontrol. The route features strategies for the synthesis of the highly congested 6–5–7–4 carbon skeleton characteristic of the caged harziane diterpenoids.

Electron-transfer photocatalysis provides access to the elusive and unprecedented N-pyridyl radical cation from selected N-substituted pyridinium reagents. The resulting C(sp2 )-H functionalization of (hetero)arenes furnishes versatile intermediates for the development of valuable aminated aryl scaffolds. Mechanistic studies that include the first spectroscopic evidence of a spin-trapped N-pyridyl radical adduct implicate SET-triggered, pseudo-mesolytic cleavage of the N-X pyridinium reagents mediated by visible light.

An iridium-catalyzed cyclocondensation of amino alcohols and aldehydes is reported. Intramolecular allylic substitution by an enamine intermediate and subsequent in situ reduction furnishes 3,4-disubstituted piperidines with high enantiospecificity and good diastereoselectivity. The modular approach and the broad functional group tolerance provide access to diverse piperidine derivatives, which were further functionalized to give a versatile set of products.

The first total synthesis of the tetracyclic sesquiterpenoid (+)-dendrowardol C is described. It relies on an intramolecular aldol reaction to forge the central bicyclic scaffold and subsequent cyclobutane formation by cyclization of a γ-triflyloxy ketone. Key is the treatment of the latter with lithium naphthalenide. Finally, the diastereoselective hydroboration of a 1,1-disubstituted double bond is enabled by a chiral CoI catalyst.

Recent developments of stereoselective biocatalytic and chemocatalytic methods are discussed. The review provides a guide to the use of biocatalytic methods in the area of chemical synthesis with focused attention on retrosynthetic considerations and analysis. The transformations presented are organized according to bond disconnections and attendant synthetic methods. The review is expected to lead to better understanding of the characteristics and distinctions of the two complementary approaches. It depicts for researchers in bio- and chemocatalysis a road map of challenges and opportunities for the evolution (and at times revolution) in chemical synthesis.

The first total synthesis of the marine polyketide (±)-hippolachnin A has been achieved in nine linear steps and an overall yield of 9 %. Rapid access to the oxacyclobutapentalene core structure was secured by strategic application of an ene cyclization.

An enantioselective allyl-allylsilane cross-coupling involving racemic branched allylic alcohols and allylsilanes is reported. An iridium-(P,olefin) phosphoramidite complex enables the transformation with high regio- and stereoselectivity under operationally simple conditions. The utility of the coupling is demonstrated in a concise catalytic, enantioselective synthesis of a pyrethroid insecticide protrifenbute.

Revised: the total synthesis of gomerone C results in revision of the stereochemical assignment at C3. The synthetic strategy relies on a late-stage Conia-ene reaction, which efficiently forms the bicyclo[3.2.1]octane containing the bridgehead chloride and generates an exocyclic olefin, which can be used as a flexible handle for further elaboration. The two contiguous quaternary centers are installed by means of a Diels-Alder reaction.

The direct route: iridium-catalyzed direct conversion of branched allylic alcohols into enantioenriched branched primary allylic amines is highly regio- and enantioselective.

Revised version: the first total synthesis of indoxamycin B leads to a stereochemical reassignment of the natural product. The synthetic route features an efficient carboannulation sequence to rapidly access the dihydroindenone system. Moreover, a series of Au(I)-catalyzed transformations served in the construction of the sterically congested core framework.

A complex catalytic system is developed to produce substituted cyclopentanones with high enantio- and diastereoselectivity.

The new approach includes diazotation of trifluoroethylamine (I) followed by ZrCl4-promoted reaction of the resulting trifluorodiazoethane with aldehydes.

The systematic modification of natural products through diverted total synthesis is a powerful concept for the systematic modification of natural products with the aim of studying mechanistic aspects of their biological activity. This concept offers far-reaching opportunities for discovery at the interface of biology and chemistry. It is underpinned by the power of chemical synthesis, which manifests itself in the ability to modify structure at will. Its implementation, when combined with innovative design, enables the preparation of unique mechanistic probes that can be decisive in differentiating and validating biological hypotheses at the molecular level. This Review assembles a collection of classic and current cases that illustrate and underscore the scientific possibilities for practitioners of chemical synthesis.

Cyclohexyne generated in situ is used for the facile synthesis of polycyclic medium-sized rings.

The use of molecular editing in the elucidation of the mechanism of action of amphotericin B is presented. A modular strategy for the synthesis of amphotericin B and its designed ana- logues is developed, which relies on an efficient gram-scale synthesis of various subunits of amphotericin B. A novel method for the coupling of the mycosa- mine to the aglycone was identified. The implementation of the approach has enabled the preparation of 35- deoxy amphotericin B methyl ester. In- vestigation of the antifungal activity and efflux-inducing ability of this am- photericin B congener provided new clues to the role of the 35-hydroxy group and is consistent with the in- volvement of double barrel ion chan- nels in causing electrolyte efflux.

Light as a reagent: A highly functionalized structure that serves as a daphnane template can be formed by the photorearrangement of a 2,5-cyclohexadienone subunit within a complex tricyclic ring system. The chemistry we describe should not only find use in the total synthesis of resiniferatoxin and related daphnanes, but should also provide useful templates for access to complex analogues.

A single, convenient reaction protocol and the same set of readily available starting materials suffice for the modular synthesis of all possible polypropionate diastereomers. This general method for the diastereoselective synthesis of syn, anti, and methyl ketone aldol adducts utilizes a powerful MgII -mediated, hydroxy-directed nitrile oxide cycloaddition. The free hydroxy group provides an ideal synthetic handle enabling the rapid assembly of complex polyketide structures. TBS=tBuMe2 Si.

The role of the bifunctional catalyst is decisive: The magnesium ion as Lewis acid and its nucleophilic iodide counterion contribute in synergy to the successful ring expansion of the cyclopropane 1 by aldimine 2 [Eq. (1)]. This reaction offers a novel route to spiro[pyrrolidin-3,3'-oxindoles] 3.

The potent bryostatin antitumor agents are currently in phase II clinical trials for the treatment of a variety of forms of cancer. Aldol reactions and directed reductions are among the essential steps for the formation of fragments A-C in the total synthesis of the title compound. Coupling of these fragments by sulfone-based olefination and alkylation reactions was followed by macrocyclization and introduction of the enoate moieties on rings B and C.

A highly convergent total synthesis of macrolactin A (1) utilizes modern asymmetric catalytic C–C coupling methods. The longest linear sequence in the route is 16 steps with an average yield of 86% per step. This total synthesis is valuable, because 1, which has been shown to possess activity against HIV, is not readily accessible from its natural source, a taxonomically unclassified deep-sea bacterium.

Not only skin deep: A fluorescein-amphotericin B conjugate with a new piperazine linker (see structure) was prepared and used as a probe of the biomembrane and the mechanism of action of amphotericin B both in vivo and in liposomal experiments. The amphotericin B analogue localizes at the membrane of yeast cells but is internalized by mammalian cells.