Total Synthesis of the Allenic Macrolide (+)-Archangiumide.

Archangiumide is the first known macrolide natural product comprising an endocyclic allene. For the ring strain that this linear substructure might entail, it was planned to unveil the allene at a very late stage of the projected total synthesis; in actual fact, this was achieved as the last step of the longest linear sequence by using an otherwise globally deprotected substrate. This unconventional timing was made possible by a gold catalyzed rearrangement of a macrocyclic propargyl benzyl ether derivative that uses a -PMB group as latent hydride source to unveil the signature cycloallene; the protecting group therefore gains a strategic role beyond its mere safeguarding function. Although the gold catalyzed reaction per se is stereoablative, the macrocyclic frame of the target was found to impose high selectivity and a stereoconvergent character on the transformation. The required substrate was formed by ring closing alkyne metathesis (RCAM) with the aid of a new air-stable molybdenum alkylidyne catalyst.

An Efficient and Scalable "Second Generation" Total Synthesis of the Marine Polyketide Limaol Endowed with Antiparasitic Activity.

The cluster of four skipped exo-methylene substituents on the "northern" wing of limaol renders this dinoflagellate-derived marine natural product unique in structural terms. This arguably non-thermodynamic array gains kinetic stability by virtue of populating local conformations which impede isomerization to a partly or fully conjugated polyene. This analysis suggested that the difficulties encountered during the late stages of our first total synthesis of this polyketide had not been caused by an overly fragile character of this unusual substructure; rather, an unfavorable steric microenvironment about the spirotricyclic core was identified as the likely cause. To remedy the issue, the protecting groups on this central fragment were changed; in effect, this amendment allowed all strategic and practical problems to be addressed. As a result, the overall yield over the longest linear sequence was multiplied by a factor of almost five and the material throughput increased more than eighty-fold per run. Key-to-success was a gold-catalyzed spirocyclization reaction; the reasons why a Brønsted acid cocatalyst is needed and the origin of the excellent levels of selectivity were delineated. The change of the protecting groups also allowed for much improved fragment coupling processes; most notably, the sequence of a substrate-controlled carbonyl addition reaction followed by Mitsunobu inversion that had originally been necessary to affix the southern tail to the core could be replaced by a reagent controlled asymmetric allylation. Finally, a much-improved route to the "northern" sector was established by leveraging the power of asymmetric hydrogenation of a 2-pyrone derivative. Limaol was found to combine appreciable antiparasitic activity with very modest cytotoxicity.

Elucidating the Electronic Nature of Rh-based Paddlewheel Catalysts from 103 Rh NMR Chemical Shifts: Insights from Quantum Mechanical Calculations.

The tremendous importance of dirhodium paddlewheel complexes for asymmetric catalysis is largely the result of an empirical optimization of the chiral ligand sphere about the bimetallic core. It was only recently that a H(C)Rh triple resonance 103 Rh NMR experiment provided the long-awaited opportunity to examine - with previously inconceivable accuracy - how variation of the ligands impacts on the electronic structure of such catalysts. The recorded effects are dramatic: formal replacement of only one out of eight O-atoms surrounding the metal centers in a dirhodium tetracarboxylate by an N-atom results in a shielding of the corresponding Rh-site of no less than 1000 ppm. The current paper provides the theoretical framework that allows this and related experimental observations made with a set of 19 representative rhodium complexes to be interpreted. In line with symmetry considerations, it is shown that the shielding tensor responds only to the donor ability of the equatorial ligands along the perpendicular principal axis. Axial ligands, in contrast, have no direct effect on shielding but may come into play via the electronic c i s ${cis}$ -effect that they exert onto the neighboring equatorial sites. On top of these fundamental interactions, charge redistribution within the core as well as the electronic t r a n s ${trans}$ -effect of ligands of different donor strengths is reflected in the recorded 103 Rh NMR shifts.

Molybdenum(VI) Nitrido Complexes with Tripodal Silanolate Ligands. Structure and Electronic Character of an Unsymmetrical Dimolybdenum µ-Nitrido Complex Formed by Incomplete Nitrogen Atom Transfer.

In contrast to a tungsten nitrido complex endowed with a tripodal silanolate ligand framework, which was reported in the literature to be a dimeric species with a metallacyclic core, the corresponding molybdenum nitrides 3 are monomeric entities comprising a regular terminal nitride unit, as proven by single-crystal X-ray diffraction (SC-XRD). Their electronic character is largely determined by the constraints imposed on the metal center by the podand ligand architecture. 95Mo nuclear magnetic resonance (NMR) and, to a lesser extent, 14N NMR spectroscopy allow these effects to be studied, which become particularly apparent upon comparison with the spectral data of related molybdenum nitrides comprising unrestrained silanolate, alkoxide, or amide ligands. Attempted nitrogen atom transfer from these novel terminal nitrides to [(tBuArN)3Mo] (Ar = 3,5-dimethylphenyl) as the potential acceptor stopped at the stage of unsymmetric dimolybdenum µ-nitrido complex 13a as the first intermediate along the reaction pathway. SC-XRD, NMR, electron paramagnetic resonance, and ultraviolet-visible spectroscopy as well as magnetometry in combination with density functional theory allowed a clear picture of the geometric and electronic structure of this mixed-valent species to be drawn. 13a is formally best described as an adduct of the type [(Mo[O])+III-(µN)-III-(Mo[N])+VI], S = 1/2 complex with (Mo[O])+III in the low-spin configuration, whereas related complexes such as [(AdS)3Mo-(µN)-Mo(NtBuAr)3] (19; Ad = 1-adamantyl) have previously been regarded in the literature as mixed-valent Mo+IV/Mo+V species. The spin population at the two Mo centers is uneven and notably larger at the more reduced Mo[O] atom, whereas the only spin present at the (µN) bridge is derived from spin polarization.

Total Synthesis of the Guangnanmycin A Alcohol.

Guangnanmycin A is a recently discovered congener of the well-known antitumor drug lead leinamycin; its macrolactam ring, however, is even more strained than that of the parent compound. The first synthetic foray towards this challenging target is reported, which relies on molybdenum-catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed by ruthenium-catalyzed redox isomerization of the propargyl alcohol thus formed; the resulting enone enabled the introduction of the yet missing exo-methylene group by a modified Peterson olefination. The signature disulfide moiety of guangnanmycin A was installed by strain-driven thia-Michael addition followed by conversion of the thioether thus formed into an unsymmetric disulfide with the aid of (methylthio)dimethylsulfonium tetrafluoroborate and MeSSMe. While this sequence furnished racemic guangnanmycin A alcohol in good overall yield, the final oxidation to the corresponding acid failed, most likely because of the exceptional sensitivity of the strained scaffold.

Collective and Diverted Total Synthesis of the Strasseriolides: A Family of Macrolides Endowed with Potent Antiplasmodial and AntitrypanosomalActivity.

The strasseriolide macrolides show promising in vitro and in vivo activities against P. falciparum and T. cruzi, the parasites causing malaria and Chagas disease, respectively. However, the as yet poor understanding of structure/activity relationships and the fact that one family member proved systemically toxic for unknown reasons render a more detailed assessment of these potential lead compounds difficult. To help overcome these issues, a collective total synthesis was devised. The key steps consisted of a ring closing alkyne metathesis (RCAM) reaction to forge a common macrocyclic intermediate followed by a hydroxy-directed ruthenium catalyzed trans-hydrostannation of the propargyl alcohol site thus formed. The resulting alkenyltin derivative served as the central node of the synthesis blueprint, which could be elaborated into the natural products themselves as well as into a set of non-natural analogues according to the concept of diverted total synthesis. The recorded biological data confirmed the potency of the compounds and showed the lack of noticeable cytotoxicity. The "northern" allylic alcohol subunit was recognized as an integral part of the pharmacophore, yet it provides opportunities for chemical modification.

Total Synthesis of Njaoamine C by Concurrent Macrocycle Formation.

In conceptual terms, the first total synthesis of the cytotoxic marine natural product njaoamine C differs from all known approaches toward related alkaloids of the manzamine superfamily in that both macrocyclic rings enveloping the diazatricyclic core are concomitantly formed; this goal was reached by double ring closing alkyne metathesis (dRCAM). The success of this maneuver does not merely reflect a favorable preorientation of the four alkyne chains that need to be concatenated in the proper pairwise manner but is also the outcome of dynamic covalent chemistry involving error correction by the chosen "canopy" molybdenum alkylidyne catalyst. The end game downstream of dRCAM capitalizes on the striking chemoselectivity of palladium-catalyzed hydrostannation, which selects for (hetero)arylalkynes even in the presence of sterically much more accessible dialkylalkynes or alkenes; for this preference, the method complements the classical repertoire of hydrometalation and semireduction reactions.

Total Syntheses of Nominal and Actual Prorocentin.

The dinoflagellate-derived polyether prorocentin is a co-metabolite of the archetypical serine/threonine phosphatase inhibitor okadaic acid. Whereas a structural relationship cannot be missed and a biosynthetic link was proposed, it is currently unknown whether there is any parallel in the bioactivity profile of these natural products. However, it was insinuated in the past that the structure assigned to prorocentin might need to be revised. Indeed, re-examination of the published spectra cast doubts as to the constitution of the fused/spirotricyclic BCD-ring system in the core. To clarify this issue, a flexible synthesis blueprint was devised that allowed us to obtain the originally proposed structure as well as the most plausible amended structure. The key to success was late-stage gold-catalyzed spirocyclization reactions that furnished the isomeric central segments with excellent selectivity. The lexicon of catalytic transformations used to make the required cyclization precursors comprised a titanium-mediated ester methylenation/metathesis cascade, a rare example of a gold-catalyzed allylic substitution, and chain extensions via organocatalytic asymmetric aldehyde propargylation. A wing sector to be attached to the isomeric cores was obtained by Krische allylation, followed by a superbly selective cobalt-catalyzed oxidative cyclization of the resulting di-unsaturated alcohol with the formation of a 2,5-trans-disubstituted tetrahydrofuran; the remaining terminal alkene was elaborated into an appropriate handle for fragment coupling by platinum-catalyzed asymmetric diboration/oxidation. The assembly of the different building blocks to the envisaged isomeric target compounds proved that the structure of prorocentin needs to be revised as disclosed herein.

From the Glovebox to the Benchtop: Air-Stable High Performance Molybdenum Alkylidyne Catalysts for Alkyne Metathesis.

Molybdenum alkylidynes endowed with tripodal silanolate ligands belong to the most active and selective catalysts for alkyne metathesis known to date. This paper describes a new generation that is distinguished by an unprecedented level of stability and practicality without sacrificing the chemical virtues of their predecessors. Specifically, pyridine adducts of type 16 are easy to make on gram scale, can be routinely weighed and handled in air, and stay intact for many months outside the glovebox. When dissolved in toluene, however, spontaneous dissociation of the stabilizing pyridine ligand releases an active species of excellent performance and functional group tolerance. Specifically, a host of polar and apolar groups, various protic sites, and numerous basic functionalities proved compatible. The catalysts are characterized by crystallographic and spectroscopic means, including 95Mo NMR; their activity and stability are benchmarked in detail, and the enabling properties are illustrated by advanced applications to natural product synthesis. For the favorable overall application profile and ease of handling, complexes of this new series are expected to replace earlier catalyst generations and help encourage a more regular use of alkyne metathesis in general.

Taming of Furfurylidenes by Chiral Bismuth-Rhodium Paddlewheel Catalysts. Preparation and Functionalization of Optically Active 1,1-Disubstituted (Trifluoromethyl)cyclopropanes.

Although 2-furyl-carbenes (furfurylidenes) are prone to instantaneous electrocyclic ring opening, chiral [BiRh]-paddlewheel complexes empowered by London dispersion allow (trifluoromethyl)furfurylidene metal complexes to be generated from a bench-stable triftosylhydrazone precursor. These reactive intermediates engage in asymmetric [2+1] cycloadditions and hence open entry into valuable trifluoromethylated cyclopropane or -cyclopropene derivatives in optically active form, which are important building blocks for medicinal chemistry but difficult to make otherwise.

Total Syntheses of Scabrolide A and Nominal Scabrolide B.

The marine natural product scabrolide A was obtained by isomerization of the vinylogous 1,4-diketone entity of nominal scabrolide B as the purported pivot point of the biosynthesis of these polycyclic norcembranoids. Despite the success of this maneuver, the latter compound itself turned out not to be identical with the natural product of that name. The key steps en route to the carbocyclic core of these targets were a [2,3]-sigmatropic rearrangement of an allylic sulfur ylide to forge the overcrowded C12-C13 bond, an RCM reaction to close the congested central six-membered ring, and a hydroxy-directed epoxidation/epoxide opening/isomerization sequence to set the "umpoled" 1,4-dicarbonyl motif and the correct angular configuration at C12.

Nickel-Catalyzed Enantioselective Coupling of Aldehydes and Electron-Deficient 1,3-Dienes Following an Inverse Regiochemical Course.

The nickel catalyzed reductive coupling of aldehydes with sorbate esters and related electron-deficient 1,3-dienes are known in the literature to occur at the π-bond proximal to the ester to afford aldol-type products. In stark contrast to this established path, a VAPOL-derived phosphoramidite ligand in combination with a bench-stable nickel precatalyst brokers a regiocomplementary course in that C-C bond formation proceeds exclusively at the distal alkene site to give deoxypropionate type products carrying an acrylate handle; they can be made in either anti- or syn-configured form. In addition to this enabling reverse pathway, the reaction is distinguished by excellent levels of chemo-, diastereo-, and enantioselectivity; moreover, it can be extended to the catalytic formation of F3C-substituted stereogenic centers. The use of a dienyl pinacolboronate instead of a sorbate ester is also possible, which opens access to valuable chiral borylated building blocks in optically active form.

C-H Insertion via Ruthenium Catalyzed gem-Hydrogenation of 1,3-Enynes.

gem-Hydrogenation of an internal alkyne with the aid of [Cp*RuCl]4 as the precatalyst is a highly unorthodox transformation, in which one C atom of the triple bond is transformed into a methylene group, whereas the second C atom gets converted into a ruthenium carbene. In the case of 1,3-enynes bearing a propargylic steering substituent as the substrates, the reaction occurs regioselectively, giving rise to vinyl carbene complexes that adopt interconverting η1/η3-binding modes in solution; a prototypical example of such a reactive intermediate was characterized in detail by spectroscopic means. Although both forms are similarly stable, only the η3-vinyl carbene proved kinetically competent to insert into primary, secondary, or tertiary C-H bonds on the steering group itself or another suitably placed ether, acetal, orthoester, or (sulfon)amide substituent. The ensuing net hydrogenative C-H insertion reaction is highly enabling in that it gives ready access to spirocyclic as well as bridged ring systems of immediate relevance as building blocks for medicinal chemistry. Moreover, the reaction scales well and lends itself to the formation of partly or fully deuterated isotopologues. Labeling experiments in combination with PHIP NMR spectroscopy (PHIP = parahydrogen induced polarization) confirmed that the reactions are indeed triggered by gem-hydrogenation, whereas kinetic data provided valuable insights into the very nature of the turnover-limiting transition state of the actual C-H insertion step.

From Serendipity to Rational Design: Heteroleptic Dirhodium Amidate Complexes for Diastereodivergent Asymmetric Cyclopropanation.

A heteroleptic dirhodium paddlewheel complex comprising three chiral carboxylate ligands and one achiral acetamidate ligand has recently been found to be uniquely effective in catalyzing the asymmetric cyclopropanation of olefins with α-stannylated (silylated and germylated) α-diazoacetate derivatives. A number of control experiments in combination with detailed computational studies provide compelling evidence that an interligand hydrogen bond between the -NH group of the amidate and the ester carbonyl group of the reactive rhodium carbene intermediate plays a quintessential role in the stereodetermining transition state. The penalty for distorting this array outweighs steric arguments and renders two of the four conceivable transitions states unviable. Based on this mechanistic insight, the design of the parent catalyst is revisited herein: placement of appropriate peripheral substituents allows high levels of diastereocontrol to be imposed upon cyclopropanation, which the original catalyst lacks. Because the new complexes allow either trans- or cis-configured stannylated cyclopropanes to be made selectively and in excellent optical purity, this transformation also marks a rare case of diastereodivergent asymmetric catalysis. The products are amenable to stereospecific cross coupling with aryl halides or alkenyl triflates; these transformations appear to be the first examples of the formation of stereogenic quaternary carbon centers by the Stille reaction; carbonylative coupling is also achieved. Moreover, tin/lithium exchange affords chiral lithium enolates, which can be intercepted with a variety of electrophilic partners. The virtues and inherent flexibility of this new methodology are illustrated by an efficient synthesis of two salinilactones, extremely scarce bacterial metabolites with signaling function involved in the self-regulatory growth inhibition of the producing strain.

Classifying and Understanding the Reactivities of Mo-Based Alkyne Metathesis Catalysts from 95Mo NMR Chemical Shift Descriptors.

The most active alkyne metathesis catalysts rely on well-defined Mo alkylidynes, X3Mo≡CR (X = OR), in particular the recently developed canopy catalyst family bearing silanolate ligand sets. Recent efforts to understand catalyst reactivity patterns have shown that NMR chemical shifts are powerful descriptors, though previous studies have mostly focused on ligand-based NMR descriptors. Here, we show in the context of alkyne metathesis that 95Mo chemical shift tensors encode detailed information on the electronic structure of these catalysts. Analysis by first-principles calculations of 95Mo chemical shift tensors extracted from solid-state 95Mo NMR spectra shows a direct link of chemical shift values with the energies of the HOMO and LUMO, two molecular orbitals involved in the key [2 + 2]-cycloaddition step, thus linking 95Mo chemical shifts to reactivity. In particular, the 95Mo chemical shifts are driven by ligand electronegativity (σ-donation) and electron delocalization through Mo-O π interactions, thus explaining the reactivity patterns of the silanolate canopy catalysts. These results further motivate exploration of transition metal NMR signatures and their relationships to electronic structure and reactivity.

Lessons from Natural Product Total Synthesis: Macrocyclization and Postcyclization Strategies.

Macrocyclic natural products are plentiful in the bacteria, archaea, and eukaryote domains of life. For the significant advantages that they provide to the producing organisms, evolution has learned how to implement various types of macrocyclization reactions into the different biosynthetic pathways and how to effect them with remarkable ease. Mankind greatly benefits from nature's pool, not least because naturally occurring macrocycles or derivatives thereof serve as important drugs for the treatment of many serious ailments.In stark contrast, macrocyclization reactions are usually perceived as difficult to accomplish by purely chemical means. While it is true that ring closure necessarily entails an entropic loss and may result in the buildup of (considerable) ring strain that must be compensated for in one way or the other, it is also fair to note tremendous methodological advances during the last decades that greatly alleviated this traditional "macrocycle challenge". It is therefore increasingly possible to explore the advantages provided by large as well as medium-size ring systems in a more systematic manner. This venture also holds the promise of increasing the "chemical space" amenable to drug development to a considerable extent.In consideration of this and other important long-term perspectives, it is appropriate to revisit the current state of the art. To this end, a number of vignettes are presented, each of which summarizes a total synthesis project targeting macrocyclic natural products of greatly different chemotypes using a variety of transformations to reach these goals. Although we were occasionally facing "dead ends", which are also delineated for the sake of a complete picture, these case studies illustrate the notion that the formation of a certain macrocyclic perimeter is (usually) no longer seriously limiting. In addition to substantial progress in the "classical" repertoire (macrolactonization and macrolactamization (pateamine A, spirastrellolide, and belizentrin)), various metal-catalyzed reactions have arguably led to the greatest leaps forward. Among them, palladium-catalyzed C-C bond formation (roseophilin and nominal xestocyclamine A) and, in particular, alkene and alkyne metathesis stand out (iejimalide, spirastrellolide, enigmazole, ingenamine, and sinulariadiolide). In some cases, different methods were pursued in parallel, thus allowing for a critical assessment and comparison.To the extent that the macrocyclic challenge is vanishing, the opportunity arises to focus attention on the postmacrocyclization phase. One may stipulate that a well-designed cyclization precursor does not only ensure efficient ring closure but also fosters and streamlines the steps that come after the event. One way to do so is dual (multiple) use in that the functional groups serving the actual cyclization reaction also find productive applications downstream from it rather than being subject to simple defunctionalization. In this context, better insight into the conformational peculiarities of large rings and the growing confidence in their accessibility in a stereochemically well defined format rejuvenate the implementation of transannular reactions or reaction cascades that can lead to rapid and substantial increases in molecular complexity. The examples summarized herein showcase such possibilities, with special emphasis on tranannular gold catalysis and the emerging ruthenium-catalyzed trans-hydrometalation chemistry for the selective functionalization of alkynes.

Total Synthesis of Mycinamicin IV as Integral Part of a Collective Approach to Macrolide Antibiotics.

The total synthesis of the 16-membered macrolide mycinamicin IV is outlined, which complements our previously disclosed, largely catalysis-based route to the aglycone. This work must also be seen in the context of our recent conquest of aldgamycin N, a related antibiotic featuring a similar core but a distinctly different functionalization pattern. Taken together, these projects prove that the underlying blueprint is integrative and hence qualifies for a collective approach to this prominent class of natural products. In both cases, the final glycosylation phase mandated close attention and was accomplished only after robust de novo syntheses of the (di)deoxy sugars of the desosamine, chalcose, mycinose and aldgarose types had been established. Systematic screening of the glycosidation promoter was also critically important for success.

Total Synthesis of the Tetracyclic Pyridinium Alkaloid epi-Tetradehydrohalicyclamine†B.

The first total synthesis of a tetracyclic marine pyridinium alkaloid hinged on recent advances in chemoselectivity management: While many classical methods failed to afford the perceptively simple pyridine-containing core of the target, nickel/iridium photoredox dual catalysis allowed the critical C-C bond to be formed in good yield. Likewise, ring closing alkyne metathesis (RCAM) worked well in the presence of the unhindered pyridine despite the innately Lewis acidic Mo(+6) center of the alkylidyne catalyst. Finally, an iridium catalyzed hydrosilylation was uniquely effective in reducing a tertiary amide without compromising an adjacent pyridine and the lateral double bonds; this transformation is largely without precedent. The second strained macrocycle enveloping the core was closed by intramolecular N-alkylation with formation of the pyridinium unit; the reaction proceeded site- and chemoselectively in the presence of an a priori more basic tertiary amine.

Chiral Bismuth-Rhodium Paddlewheel Complexes Empowered by London Dispersion: The C-H Functionalization Nexus.

Heterobimetallic [BiRh] tetracarboxylate catalysts endowed with 1,3-disilylated phenylglycine paddlewheels benefit from interligand London dispersion. They were originally designed for asymmetric cyclopropanation but are now shown to perform very well in asymmetric C-H functionalization reactions too. Because of the confined ligand sphere about the derived donor/acceptor carbenes, insertions into unhindered methyl groups are kinetically favored, although methylene units also react with excellent levels of asymmetric induction; even gaseous ethane is a suitable substrate. Moreover, many functional groups in both partners are tolerated. The resulting products are synthetically equivalent to the outcome of traditional asymmetric ester alkylation, allylation, benzylation, propargylation and aldol reactions and therefore constitute a valuable nexus to more conventional chemical logic.

An Anionic Dinuclear Ruthenium Dihydrogen Complex of Relevance for Alkyne gem-Hydrogenation.

During an investigation into the fate of ruthenium precatalysts used for light-driven alkyne gem-hydrogenation reactions with formation of Grubbs-type ruthenium catalysts, it was found that the reaction of [(IPr)(η6 -cymene)RuCl2 ] with H2 under UV-irradiation affords an anionic dinuclear σ-dihydrogen complex, which is thermally surprisingly robust. Not only are anionic σ-complexes in general exceedingly rare, but the newly formed species seems to be the first example lacking any structural attributes able to counterbalance the negative charge and, in so doing, prevent oxidative insertion of the metal centers into the ligated H2 from occurring.