Alois Fürstner

Olefin Metathesis and Beyond

The advent of well-defined catalysts for olefin metathesis which combine high activity, durability, and excellent tolerance towards polar functional groups has revolutionized the field. The past decade has seen the rapid embrace of these reagents as tools for advanced organic and polymer chemistry and the success of this development is witnessed by a plethora of elegant applications to the synthesis of natural and nonnatural products. This review article provides an overview of these developments and intends to familiarize the reader with some very recent advances which hold the promise to expand the scope of the reaction even further. Moreover, the positive impact of metathesis on the fundamental logic of retrosynthetic planning is demonstrated by means of typical examples. Finally, it will be shown that metathesis is by no means restricted to alkenes as substrates, and some comments on metathesis reactions following unconventional mechanistic pathways will also be presented.

Preparation, Structure, and Reactivity of Nonstabilized Organoiron Compounds. Implications for Iron-Catalyzed Cross Coupling Reactions

A series of unprecedented organoiron complexes of the formal oxidation states -2, 0, +1, +2, and +3 is presented, which are largely devoid of stabilizing ligands and, in part, also electronically unsaturated (14-, 16-, 17- and 18-electron counts). Specifically, it is shown that nucleophiles unable to undergo beta-hydride elimination, such as MeLi, PhLi, or PhMgBr, rapidly reduce Fe(3+) to Fe(2+) and then exhaustively alkylate the metal center. The resulting homoleptic organoferrate complexes [(Me 4Fe)(MeLi)][Li(OEt 2)] 2 ( 3) and [Ph 4Fe][Li(Et 2O) 2][Li(1,4-dioxane)] ( 5) could be characterized by X-ray crystal structure analysis. However, these exceptionally sensitive compounds turned out to be only moderately nucleophilic, transferring their organic ligands to activated electrophiles only, while being unable to alkylate (hetero)aryl halides unless they are very electron deficient. In striking contrast, Grignard reagents bearing alkyl residues amenable to beta-hydride elimination reduce FeX n ( n = 2, 3) to clusters of the formal composition [Fe(MgX) 2] n . The behavior of these intermetallic species can be emulated by structurally well-defined lithium ferrate complexes of the type [Fe(C 2H 4) 4][Li(tmeda)] 2 ( 8), [Fe(cod) 2][Li(dme)] 2 ( 9), [CpFe(C 2H 4) 2][Li(tmeda)] ( 7), [CpFe(cod)][Li(dme)] ( 11), or [Cp*Fe(C 2H 4) 2][Li(tmeda)] ( 14). Such electron-rich complexes, which are distinguished by short intermetallic Fe-Li bonds, were shown to react with aryl chlorides and allyl halides; the structures and reactivity patterns of the resulting organoiron compounds provide first insights into the elementary steps of low valent iron-catalyzed cross coupling reactions of aryl, alkyl, allyl, benzyl, and propargyl halides with organomagnesium reagents. However, the acquired data suggest that such C-C bond formations can occur, a priori, along different catalytic cycles shuttling between metal centers of the formal oxidation states Fe(+1)/Fe(+3), Fe(0)/Fe(+2), and Fe(-2)/Fe(0). Since these different manifolds are likely interconnected, an unambiguous decision as to which redox cycle dominates in solution remains difficult, even though iron complexes of the lowest accessible formal oxidation states promote the reactions most effectively.

Ruthenium carbene complexes with imidazolin-2-ylidene ligands allow the formation of tetrasubstituted cycloalkenes by RCM

Abstract Chemically quite robust ruthenium carbene complexes 2–8 bearing one or two imidazolin-2-ylidene ligands are highly active catalysts for all types of ring closing metathesis reactions (RCM). Importantly, they even allow the formation of tetrasubstituted alkenes that were previously out of reach of ruthenium-based metathesis catalysts.

A Cheap Metal for a “Noble” Task: Preparative and Mechanistic Aspects of Cycloisomerization and Cycloaddition Reactions Catalyzed by Low-Valent Iron Complexes

Reaction of ferrocene with lithium in the presence of either ethylene or COD allows the Fe(0)-ate complexes 1 and 4 to be prepared on a large scale, which turned out to be excellent catalysts for a variety of Alder-ene, [4+2], [5+2], and [2+2+2] cycloadditon and cycloisomerization reactions of polyunsaturated substrates. The structures of ferrates 1 and 4 in the solid-state reveal the capacity of the reduced iron center to share electron density with the ligand sphere. This feature, coupled with the kinetic lability of the bound olefins, is thought to be responsible for the ease with which different enyne or diyne substrates undergo oxidative cyclization as the triggering event of the observed skeletal reorganizations. This mechanistic proposal is corroborated by highly indicative deuterium labeling experiments. Moreover, it was possible to intercept two different products of an oxidative cyclization manifold with the aid of the Fe(+1) complex 6, which, despite its 17-electron count, also turned out to be catalytically competent in certain cases. The unusual cyclobutadiene complex 38 derived from 6 and tolane was characterized by X-ray crystallography.

From Understanding to Prediction: Gold- and Platinum-Based π-Acid Catalysis for Target Oriented Synthesis

During the last century, conceptual advances in organometallic chemistry were often rapidly embraced by target oriented synthesis. Feedback provided by such preparative scrutiny has greatly benefitted method development; particularly prominent are examples from the entire cross coupling arena, as well as olefin metathesis. Seen against this backdrop, it is somewhat surprising that the explosive growth of research into π-acid catalysis has not yet yielded a matching number of implementations into the synthesis of structurally complex targets of biological significance. In contrast to the massive output of methodological and mechanistic investigations, few studies illustrate the strategic use of gold, silver, or platinum catalysis in late stages of such multistep endeavors. These elaborate and highly precious compounds demand utmost confidence in the reliability and robustness of the method to be applied. In this Account, we analyze the possible reasons for this imbalance, after a short summary of the conceptual basis of carbophilic activation of π-bonds with the aid of soft transition metal cations or complexes. We pinpoint mechanistic subtleties, which, at least in part, produce a great deal of structural diversity but can jeopardize predictive power. With the advances in the understanding of π-acid catalyzed processes in general, however, this uncertainty is gradually vanishing and the entire field is transitioning from comprehension to prediction. This is expected to foster advanced applications, while recent progress in asymmetric gold catalysis further improves the preparative significance. The presented work in this Account illustrates our own commitment to the field as well as our growing confidence in the maturity of platinum and gold catalysis. The carbophilic activation of π-bonds, particularly of alkynes, provides a method to manipulate functional groups that is orthogonal to traditional carbonyl chemistry. We illustrate this notion by presenting a new approach to hydroxypyrone derivatives that has enabled the total synthesis of the fragile polyunsaturated cyclophane derivative neurymenolide A. The synthesis of the pyrrole alkaloid streptorubin by an enyne cycloisomerization is equally instructive. In addition, different manifestations of transannular hydroxyl addition reactions across alkyne partners mark the late stages of our conquests of amphidinolide F, polycavernoside A, and spirastrellolide F. Together with a few model studies and a personal selection of recent highlights from other groups, these examples augur well for future applications of π-acid catalysts in the realm of target oriented synthesis.

Steering the Surprisingly Modular π-Acceptor Properties of N-Heterocyclic Carbenes: Implications for Gold Catalysis

Whereas the excellent s-donor qualities of N-heterocyclic carbenes (NHCs) are undisputed and extensively used as an enabling feature for homogeneous catalysis, the p-acceptor properties of such ligands are usually considered weak or even negligible. Only in the last decade has experimental and in silico 4] evidence been acquired that suggests that the p acidity of NHCs deserves more serious consideration, even though this issue is still a matter of debate. 5] The case study outlined herein may help to clarify this aspect. Rather than relying on the interpretation of spectroscopic and structural fingerprints, we present reactivity data which demonstrate that the course of three mechanistically distinct gold-catalyzed processes can be determined solely by changing the pacceptor properties of the ancillary NHC ligand. We previously introduced the cyclophanic NHCs 2–4 as novel analogues of the known imidazopyridine-2-ylidene derivatives 1 (Table 1). These chiral compounds exhibit interesting spectroscopic characteristics and are studied in some detail by our research group. As part of these investigations, the energies of the orbital occupied by the carbene lone pair of electrons (Es) [9] and of the lowest unoccupied orbital with a nonzero coefficient at the carbene center (Ep) [9] were determined by density functional theory (DFT) calculations at the BP86(RI)/TZVP level. The computed data revealed various salient features (Table 1): whereas the Es values of the parent NHC 1a (R = Me) and its cyclophanic counterpart 2 are almost identical, the Ep value drops significantly from 0.63 eV in 1a to 1.14 eV in 2 ; moreover, the energy of the p-type acceptor orbital is highly responsive to the type of substituents present on the top layer; thus, the Ep values of the tetrafluoroand tetramethoxy-substituted carbenes 3 and 4 are almost 0.5 eV apart. These findings are readily explained by the representation of the p acceptor orbital in Figure 1,

Elementary Steps of Gold Catalysis: NMR Spectroscopy Reveals the Highly Cationic Character of a "Gold Carbenoid"

What are you? Even though the metal-induced ring opening of 3,3-disubstituted cyclopropenes is known to serve as a genuine carbene generator, the use of Au(I) in this reaction leads to a reactive intermediate with highly cationic character. This result has important implications for gold catalysis in general, which in the past has been commonly attributed to the intervention of gold carbenes.

Indenylidene Complexes of Ruthenium: Optimized Synthesis, Structure Elucidation, and Performance as Catalysts for Olefin Metathesis—Application to the Synthesis of the ADE-Ring System of Nakadomarin A

An optimized and large scale adaptable synthesis of the ruthenium phenylindenylidene complex 3 is described which employs commercially available diphenyl propargyl alcohol 5 as a stable and convenient carbene source. Previous ambiguities as to the actual structure of the complex have been ruled out by a full analysis of its NMR spectra. A series of applications to ring closing metathesis (RCM) reactions shows that complex 3 is as good as or even superior to the classical Grubbs carbene 1 in terms of yield, reaction rate, and tolerance towards polar functional groups. Complex 3 turns out to be the catalyst of choice for the synthesis of the enantiopure core segment 77 of the marine alkaloid nakadomarin A 60 comprising the ADE rings of this target. Together with a series of other examples, this particular application illustrates that catalyst 3 is particularly well suited for the cyclization of medium-sized rings by RCM. Other key steps en route to nakadomarin A are a highly selective intramolecular Michael addition setting the quaternary center at the juncture of the A and D rings and a Takai-Nozaki olefination of aldehyde 73 with CH2I2, Ti(OiPr)4 and activated zinc dust.

Alkyne Metathesis: Development of a Novel Molybdenum-Based Catalyst System and Its Application to the Total Synthesis of Epothilone A and C

Sterically hindered molybdenum(III) amido complexes of the general type [Mo[(tBu)(Ar)N]3] (1), upon treatment with CH2Cl2 or other halogen donors, have been converted into highly effective catalysts for all kinds of alkyne metathesis reactions. Although the actual nature of the propagating species formed in situ is still elusive, halogen transfer to the Mo center of 1 plays a decisive role in the activation of such precatalysts. It was possible to isolate and characterize by X-ray crystallography some of the resulting molybdenum halide derivatives such as 15, 16 and 20 which themselves were shown to be catalytically active. Numerous applications illustrate the performance of the catalytic system 1/CH2Cl2 which operates under mild conditions and tolerates an array of polar functional groups. The wide scope allows the method to be implemented into the total synthesis of sensitive and polyfunctional natural products. Most notable among them is a concise entry into the potent anticancer agents epothilone A (86) and C (88). The macrolide core of these targets is forged by ring closing alkyne metathesis (RCAM) of diyne 113, followed by Lindlar hydrogenation of cycloalkyne 114 thus formed. Since this strategy opens a stereoselective entry into (Z)-alkene 115, the approach is inherently more efficient than previous syntheses based on conventional RCM.

Alkyne Metathesis on the Rise

The early years of alkyne metathesis were marked by a somewhat ironic state of affairs: the proposed mechanism was swiftly validated and more than one effective catalyst became available shortly after the discovery of this transformation; surprisingly, however, the impact on synthesis remained very limited for a long period of time. Recent advances, however, suggest that this situation is about to change: the remarkable activity, functional-group tolerance, and reliability of the latest generation of catalysts open the door for highly advanced applications. The resulting (cyclo)alkynes are amenable to numerous postmetathetic transformations, which diversify the product portfolio and bring many different structural motifs into reach. Since the catalysts have also evolved from the glovebox to the benchtop, there should be little barrier left for a wider use of this reaction in organic synthesis.