Toward the total synthesis of spirastrellolide A. Part 3: Intelligence gathering and preparation of a ring-expanded analogue

Different methods for the formation of the C.25–C.26 bond of spirastrellolide A (1) are evaluated that might qualify for the end game of the projected total synthesis, with emphasis on metathetic ways to forge the macrocyclic frame

Total Synthesis of Neurymenolide A Based on a Gold-Catalyzed Synthesis of 4-Hydroxy-2-pyrones

Treat me gently: For a selective synthesis of the unusually sensitive cyclophanic α-pyrone neurymenolide A, the chosen catalysts must be able to distinguish between six different sites of unsaturation, without scrambling any of the skipped π systems. This challenge was met with a new gold-catalyzed pyrone synthesis in combination with a molybdenum-catalyzed ring-closing alkyne metathesis

Coordination Chemistry of Ene-1,1-diamines and a Prototype "Carbodicarbene"

Carbophilic Lewis acids can polarize a coordinated π-bond by a slippage mechanism. A series of stable ylid- or enolate gold complexes of ene-1,1-diamines not only emulate this property, but also reveal the exceptional donor capacity of such electron-rich olefin ligands. Moreover, the first metal complex of a tetraaminoallene is reported, which features a prototype “carbodicarbene” ligand bound to a transition-metal template

Nickel-Catalyzed Enantioselective Synthesis of Pre-Differentiated Homoallylic syn- or anti-1,2-Diols from Aldehydes and Dienol Ethers

Nickel catalysis allied with cyclodiphosphazane or VAPOL-derived phosphoramidite ligands provides selective access to monoprotected vicinal diols by reductive coupling of dienol ethers and aldehydes. The observed regioselectivity is unprecedented, in that the diene reacts at the least nucleophilic and most hindered C atom that is attached to the oxygen substituent rather than at the terminal position. Notably, both syn and anti diastereomers of the products can be accessed depending on the configuration of the diene partner with usually excellent diastereo- and enantioselectivity

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

Hydrogenative Cycloisomerization and Sigmatropic Rearrangement Reactions of Cationic Ruthenium Carbenes Formed by Catalytic Alkyne gem-Hydrogenation

gem-Hydrogenation of propargyl alcohol derivatives with [CpXRu(MeCN)3]PF6 (CpX=substituted cyclopentadienyl) as catalysts affords cationic pianostool ruthenium carbene complexes which are so electrophilic that they attack a tethered olefin to furnish cyclopentene products; cyclopropanation or metathesis do not compete with this novel transformation. If the transient carbenes carry appropriate propargylic substituents, however, they engage in ([2,3]-sigmatropic) rearrangements to give enol esters (carbonates, carbamates, sulfonates) or alkenyl halides. Both pathways are unprecedented in the vast hydrogenation literature. The proposed mechanistic scenarios are in line with labeling experiments and spectroscopic data; most notably, PHIP NMR spectroscopy (PHIP=parahydrogen induced polarization) provides compelling evidence that the reactions are indeed triggered by highly unorthodox gem-hydrogenation events

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

Canopy Catalysts for Alkyne Metathesis: Investigations into a Bimolecular Decomposition Pathway and the Stability of the Podand Cap

Molybdenum alkylidyne complexes with a trisilanolate podand ligand framework (“canopy catalysts”) are the arguably most selective catalysts for alkyne metathesis known to date. Among them, complex 1a endowed with a fence of lateral methyl substituents on the silicon linkers is most reactive, although fairly high loadings are required in certain applications. It is now shown that this catalyst decomposes readily via a bimolecular pathway, which engages the Mo≡CR entities in a stoichiometric triple bond metathesis event to furnish RC≡CR and the corresponding dinuclear complex 8 with a Mo≡Mo core. In addition to the regular analytical techniques, 95Mo NMR was used to confirm this unusual outcome. This rapid degradation mechanism is largely avoided by increasing the size of the peripheral substituents on silicon, without unduly compromising the activity of the resulting complexes. When chemically challenged, however, canopy catalysts can open the apparently somewhat strained tripodal ligand cages; this reorganization leads to the formation of cyclo-tetrameric arrays composed of four metal alkylidyne units linked together via one silanol arm of the ligand backbone. The analogous tungsten alkylidyne complex 6 endowed with a tripodal tris-alkoxide (rather than siloxide) ligand framework is even more susceptible to such a controlled and reversible cyclo-oligomerization. The structures of the resulting giant macrocyclic ensembles were established by single crystal X-ray diffraction

A New Ligand Design Based on London Dispersion Empowers Chiral Bismuth–Rhodium Paddlewheel Catalysts

Heterobimetallic bismuth–rhodium paddlewheel complexes with phenylglycine ligands carrying TIPS-groups at the meta-positions of the aromatic ring exhibit outstanding levels of selectivity in reactions of donor/acceptor and donor/donor carbenes; at the same time, the reaction rates are much faster and the substrate scope is considerably wider than those of previous generations of chiral [BiRh] catalysts. As shown by a combined experimental, crystallographic, and computational study, the new catalysts draw their excellent application profile largely from the stabilization of the chiral ligand sphere by London dispersion (LD) interactions of the peripheral silyl substituents

Preparation, Modification, and Evaluation of Cruentaren A and Analogues

An expeditious total synthesis of the highly cytotoxic F-ATPase inhibitor cruentaren A (1) is described based on a ring-closing alkyne metathesis (RCAM) reaction for the formation of the macrocylic ring. Other key transformations comprise a C-acylation of the benzyl lithium reagent derived from orsellinic acid ester 9 with Weinreb amide 7, a CBS reduction of the resulting ketone 10, and a Soderquist propargylation of aldehyde 21 with allenylborane (S)-27 to set the C-15 chiral center of the required alcohol fragment 25. The RCAM precursor 33 was assembled by acylation of 25 with acid fluoride 32, since more conventional methods for ester bond formation were unproductive. Moreover, the choice of the protecting groups, in particular for the secondary alcohol at C-9, which is prone to engage in translactonization, turned out to be critical; a relatively stable TBDPS ether had to be chosen for this site, which was removed in the final step of the synthesis with aqueous HF since other fluoride sources met with failure. The successful synthetic route was then expanded beyond the natural product, bringing a series of analogues into reach that feature incremental but deep-seated structural modifications. Three of these fully synthetic compounds turned out to be as or even more cytotoxic than cruentaren A itself against L-929 mouse fibroblast cells, reaching IC50 values as low as 0.7 ng mL−1