Synthesis of Pleuromutilin.

Synthesis of a potent inhibitor of bacterial protein synthesis, pleuromutilin, is described. Assembly of the critical cyclooctane fragment relies on an oxidative ring-expansion, and complete stereochemical relay in the synthetic sequence is enabled by the judicious choice of tactics. The requisite connectivity pattern of the perhydroindanone motif is rapidly established in a sequence of cycloaddition and radical cyclization events. Application of this strategy allows for preparation of the target natural product in 16 steps from commercially available material.

Synthesis of rearranged indole diterpenes of the paxilline type.

Covering: up to 2021Rearranged indole diterpenes of the paxilline type comprise a large group of fungal metabolites that possess diverse structural features and potentially useful biological effects. The unique indoloterpenoid motif, which is common to all congeners, was first confirmed by crystallographic studies of paxilline. This family of natural products has fascinated organic chemists for the past four decades and has inspired numerous syntheses and synthetic approaches. The present review highlights efforts that have laid the foundation and introduced new directions to this field of natural product synthesis. The introduction includes a summary of biosynthetic considerations and biological activities, the main body of the manuscript provides a detailed discussion of selected syntheses, and the review concludes with a brief outlook on the future of the field.

A Concise Enantioselective Approach to Quassinoids.

A synthetic approach to quassinoids is described. The route to the tetracyclic core relies on an efficient and selective annulation between two unsaturated carbonyl components that is initiated by catalytic hydrogen atom transfer from an iron hydride to an alkene. Application of this strategy allows for enantioselective synthesis of quassin, which is prepared in 14 steps from commercially available starting material.

New Methods and Strategies in the Synthesis of Terpenoid Natural Products.

Indoloterpenoids of the paxilline type belong to a large family of secondary metabolites that exhibit unique molecular architectures and a diverse set of biological activities. More than 100 congeners identified to date share a common structural motif that contains an indole moiety fused to a rearranged diterpenoid fragment. The representative physiological and cellular effects attributed to this family of natural products include neurological and insecticidal activities, modulation of lipid balance, and inhibition of mitosis. The uniting polycyclic motif combined with the diversity of individual structural features of paxilline indoloterpenoids and the broad scope of their biological activities have fascinated organic chemists for the past four decades and have led to the development of numerous syntheses. In this Account, we describe our contributions to this field and how they in turn shape new directions that are developing in our laboratory.We begin with the discussion of our strategy for the synthesis of the shared indoloterpenoid core. To address stereochemical challenges encountered in earlier reports, we planned to leverage a suitably substituted cyclopentanone in a polycyclization to form the desired trans-decalin motif. This polycyclization relied on a radical-polar crossover cascade initiated by hydrogen atom transfer. The original process exhibited poor diastereoselectivity, but we discovered an efficient solution to this problem that took advantage of intramolecular tethering effects, culminating in short synthesis of emindole SB. During these studies, we also identified indium-mediated alkenylation of silyl enol ethers with alkynes as a suitable method for the synthesis of highly substituted ß,γ-unsaturated ketones that was critical to achieving brevity of our route. We subsequently developed a catalytic version of this transformation that allowed for a formal bimolecular ene reaction that exhibited unusual and potentially useful selectivity in construction of quaternary centers.To test the scope and limitations of our approach to paxilline indoloterpenoids and identify potential improvements, we developed a synthesis of the more complex congener nodulisporic acid C. The convergent assembly of this natural product was enabled by identification of new elements of stereocontrol in the radical-polar crossover polycyclization en route to the polycyclic terpenoid motif and development of a highly diastereoselective enyne cycloisomerization to access the indenopyran motif and a ketone arylation protocol to unite the two complex fragments.In subsequent studies, we expanded the radical-polar crossover cascade underlying our approach to paxilline indoloterpenoids to a bimolecular setting, which allowed for annulation of two unsaturated carbonyl components to produce functionalized cyclohexanes. This transformation is particularly well suited for installation of fully substituted carbons and can be complementary to the venerable Diels-Alder reaction. The utility of the new annulation was tested in the synthesis of forskolin, allowing for rapid construction of the complex polycyclic motif in this densely functionalized labdane diterpenoid.Over the past five years, our initial forays into the synthesis of paxilline indoloterpenoids have grown into a program that incorporates development of new synthetic methods and pursues artificial assembly of terpenoid natural products from several different families. We are encouraged by the increasing diversity of structural motifs made accessible by application of this chemistry and continue to discover new aspects of the underlying reactivity.

Catalytic Asymmetric Radical-Polar Crossover Hydroalkoxylation.

Asymmetric intramolecular hydrofunctionalization of tertiary allylic alcohols is described. This metal hydride-mediated catalytic radical-polar crossover reaction delivers corresponding epoxides in good to high enantioselectivity and constitutes the first example of asymmetric hydrogen atom transfer-initiated process. A series of modified cobalt salen complexes has proven optimal for achieving good efficiency and asymmetric induction. Experimental data suggest that cationic cobalt complexes may be involved in the enantiodetermining step, where cation-π interactions in the catalyst contribute to the asymmetric induction.

A Radical-Polar Crossover Annulation To Access Terpenoid Motifs.

A new catalytic radical-polar crossover annulation between two unsaturated carbonyl compounds is described. The annulation proceeds under exceptionally mild conditions and provides direct and expedient access to complex terpenoid motifs. Application of this chemistry allows for synthesis of forskolin, a densely functionalized terpenoid, in 14 steps from commercially available material.

Catalytic enantioselective conjugate addition en route to paxilline indoloterpenoids.

Development of enantioselective synthesis of precursor en route to paxilline indoloterpenoids is described. Evaluation of 25 diphosphine-based ligands has led to identification of JosiPhos derivative that allows for asymmetric conjugate addition of homoprenyl Grignard reagent to 2-methylcyclopent-2-en-1-one in excellent yield and with appreciable levels of enantioinduction. Application to the conjugate addition of other Grignard reagents is demonstrated.

Catalytic Radical-Polar Crossover Reactions of Allylic Alcohols.

Radical-polar crossover hydrofunctionalizations of tertiary allylic alcohols are described. Depending on the structure of the catalyst, corresponding epoxides or semipinacol rearrangement products are selectively obtained in good yields. Experimental evidence points to the participation of alkylcobalt complexes as electrophilic intermediates.

Twelve-Step Asymmetric Synthesis of (-)-Nodulisporic Acid C.

A short, enantioselective synthesis of (-)-nodulisporic acid C is described. The route features two highly diastereoselective polycyclizations en route to the terpenoid core and the indenopyran fragment and a highly convergent assembly of a challenging indole moiety. Application of this chemistry allows for a 12-step synthesis of the target indoloterpenoid from commercially available material.

A Concise Approach to Anthraquinone-Xanthone Heterodimers.

A synthetic approach to anthraquinone-xanthone heterodimers is described. The route to the pentacyclic core features an efficient assembly of a benzocycloheptenone via a new intramolecular oxidative arylation of an enol ether and a Hauser-Kraus annulation-aldol reaction sequence to access the characteristic bicyclo[3.2.2]nonene motif. Acremoxanthone A is synthesized in 10 steps from commercially available material to demonstrate the application of this approach.

A Catalytic Intermolecular Formal Ene Reaction between Ketone-Derived Silyl Enol Ethers and Alkynes.

A catalytic formal ene reaction between ketone-derived silyl enol ethers and terminal alkynes is described. This transformation is uniquely capable of bimolecular assembly of 2-siloxy-1,4-dienes and can be used to access ß,γ-unsaturated ketones containing quaternary carbons in the α-position.

Synthesis of (+)-7,20-Diisocyanoadociane and Liver-Stage Antiplasmodial Activity of the Isocyanoterpene Class.

7,20-Diisocyanoadociane, a scarce marine metabolite with potent antimalarial activity, was synthesized as a single enantiomer in 13 steps from simple building blocks (17 linear steps). Chemical synthesis enabled identification of isocyanoterpene antiplasmodial activity against liver-stage parasites, which suggested that inhibition of heme detoxification does not exclusively underlie the mechanism of action of this class.

A Concise Approach to Paxilline Indole Diterpenes.

A synthetic approach to paxilline indole diterpenes is described. The route to the pentacyclic core relies on a new regioselective alkenylation of ketones and a tandem radical addition-aldol reaction sequence to access vicinal quaternary stereocenters. Emindole SB, the simplest member of the family, is synthesized in 11 steps from commercially available material to demonstrate the application of this approach.

Stereoinversion of tertiary alcohols to tertiary-alkyl isonitriles and amines.

The SN2 reaction (bimolecular nucleophilic substitution) is a well-known chemical transformation that can be used to join two smaller molecules together into a larger molecule or to exchange one functional group for another. The SN2 reaction proceeds in a very predictable manner: substitution occurs with inversion of stereochemistry, resulting from the 'backside attack' of the electrophilic carbon by the nucleophile. A significant limitation of the SN2 reaction is its intolerance for tertiary carbon atoms: whereas primary and secondary alcohols are viable precursor substrates, tertiary alcohols and their derivatives usually either fail to react or produce stereochemical mixtures of products. Here we report the stereochemical inversion of chiral tertiary alcohols with a nitrogenous nucleophile facilitated by a Lewis-acid-catalysed solvolysis. The method is chemoselective against secondary and primary alcohols, thereby complementing the selectivity of the SN2 reaction. Furthermore, this method for carbon-nitrogen bond formation mimics a putative biosynthetic step in the synthesis of marine terpenoids and enables their preparation from the corresponding terrestrial terpenes. We expect that the general attributes of the methodology will allow chiral tertiary alcohols to be considered viable substrates for stereoinversion reactions.

Synthesis of a potent antimalarial amphilectene.

7-Isocyano-11(20),14-epiamphilectadiene, the most potent of antimalarial amphilectenes, is synthesized in seven steps from readily available materials. The synthesis is enabled by a new dendrimeric triene (Danishefsky [3]-dendralene) and a new method for stereo- and chemoselective isocyanation. This chemistry provides a useful entry into an underexplored yet promising family of antimalarial terpenoids.

Synthesis of highly strained terpenes by non-stop tail-to-head polycyclization.

Non-stop carbocationic polycyclizations of isoprenoids have been called the most complex chemical reactions occurring in nature. We describe a strategy for the initiation of tail-to-head polycyclization that relies on the sequestration of the counteranion away from the carbocation, which allows full propagation of the cationic charge. If the anion is mobile, Coulombic forces hold this species in close proximity to the carbocation and cause preemptive termination through elimination. Anion sequestration is crucial for effecting the biomimetic synthesis of complex and unstable terpenes, including the highly strained funebrenes. This study illustrates the deleterious role of the counterion in tail-to-head carbocationic polycyclization reactions, which to the best of our knowledge has not been rigorously explored. These observations are also expected to find use in the design and control of cationic polycyclization along biosynthetic pathways that have previously been inaccessible in bulk solvent.

A stereoselective hydroamination transform to access polysubstituted indolizidines.

Stereoselective, intramolecular, formal hydroamination of dienamines via directed hydroboration is reported. Four stereocenters are set in the process. Natural and unnatural indolizidine alkaloids can be synthesized from simple unsaturated amines using the title process.

Chemical synthesis enables biochemical and antibacterial evaluation of streptolydigin antibiotics.

Inhibition of bacterial transcription represents an effective and clinically validated anti-infective chemotherapeutic strategy. We describe the evolution of our approach to the streptolydigin class of antibiotics that target bacterial RNA polymerases (RNAPs). This effort resulted in the synthesis and biological evaluation of streptolydigin, streptolydiginone, streptolic acid, and a series of new streptolydigin-based agents. Subsequent biochemical evaluation of RNAP inhibition demonstrated that the presence of both streptolic acid and tetramic acid subunits was required for activity of this class of antibiotics. In addition, we identified 10,11-dihydrostreptolydigin as a new RNAP-targeting agent, which was assembled with high synthetic efficiency of 15 steps in the longest linear sequence. Dihydrostreptolydigin inhibited three representative bacterial RNAPs and displayed in vitro antibacterial activity against S. salivarius . The overall increase in synthetic efficiency combined with substantial antibacterial activity of this fully synthetic antibiotic demonstrates the power of organic synthesis in enabling design and comprehensive in vitro pharmacological evaluation of new chemical agents that target bacterial transcription.

Synthesis of streptolydigin, a potent bacterial RNA polymerase inhibitor.

Streptolydigin is a highly potent, broad-spectrum antibiotic produced by Streptomyces lydicus, which inhibits bacterial RNA polymerase. We describe the first synthesis of streptolydigin, which was assembled in a highly convergent and fully stereocontrolled fashion with a longest linear sequence of 24 steps starting from commercially available precursors. The assembly process entailed preparation of fully elaborated streptolic and ydiginic subunits of the natural product, followed by a highly efficient union in a three-step one-pot procedure, which included Dieckmann cyclization with a concomitant imide opening, Horner-Wadsworth-Emmons olefination, and desilylation.