Research Programs – Organometallic Chemistry 2.4 Advances in Metal-Carbene Chemistry Department of Organometallic Chemistry by Alois Fürstner ABSTRACT: The major lines of research in this Department continue to be: (i) alkyne metathesis, (ii) iron catalyzed C-C-bond formation, (iii) π-acid catalysis using platinum, gold and rhodium complexes, and (iv) unorthodox catalytic addition reactions. All areas are prospering, including the application of the in-house methodology to target-oriented synthesis; yet, it was the field of ruthenium-catalyzed addition chem- istry which led to the most perplexing and (hopefully) significant results. For the unexpected intervention of discrete metal carbenes as reac- tive intermediates, the major findings in this area are discussed together with our recent contributions to the related field of rhodium carbene chemistry. Ruthenium. cis-Delivery of H2 to a π-system of an unsaturated cal outcome is astounding, if one considers that conventional trans- substrate is the canonical course of metal catalyzed hydrogenation hydroboration is the textbook example for a cis-addition process via reactions. This stereochemical paradigm remained basically unchal- a four-membered transition state under frontier-orbital control. All lenged since the pioneering work of Sabatier until our group re- newly discovered trans-hydrometalation reactions break this fun- ported the semi-reduction of internal alkynes with the aid of damental stereochemical rule; importantly, they are robust, distin- [Cp*Ru]-based catalysts. The reaction clearly violates this funda- guished by excellent functional group compatibility, and have mental rule and affords E-alkenes by direct trans-hydrogenation already stood the test of natural product synthesis in a number of (Scheme 1). Answering the question as to how this unorthodox demanding cases (see below).1 transformation might proceed and whether it is a singularity or the Scheme 2. Mechanism of trans- and gem-Hydrogenation manifestation of a more general reactivity mode became a top E-alkene Cp* 1 H priority in our laboratory. Ru Cll H + R R Scheme 1. Prototypical trans-Hydrogenation Reaction alkyne H2 A O O Cp* O Cp* [Cp*RuCl(cod)] cat., H2, CH2Cl2 O Cl Ru O O O O H concerted Cl Ru R H E = H B E:Z 98:2 H H R trans-hydrogenation R H R H2 A combined experimental and theoretical approach provided stepwise trans-hydrogenation - compelling evidence that trans-hydrogenation can actually be gem hydrogenation Cp* Cp* reached by two distinctly different yet interconnected pathways H 2 Ru Ru σ overreduction Cl H Cll (Scheme 2). A -complex of type A is initially formed, which R D R evolves via the rate-determining H-delivery to the activated triple isomerization R R C H H H H bond into a metallacyclopropene B. It is at this stage that the reac- H tion pathway bifurcates: thus, B can transform in a concerted pro- 2 cess into the desired E-alkene E by passing through a low-lying genuine carbene reactivity stereo-determining transition state; this product-forming step is Only in the case of the trans-hydrogenation can the metallacy- strongly exergonic and therefore almost certainly irreversi- clopropene B evolve by a second pathway, in which both H-atoms ble. The computed barrier for the formation of the Z-alkene of H2 are transferred to one and the same C-atom of the substrate is notably higher, which explains the experimentally observed (Scheme 2). This geminal delivery, which entails formation of a excellent E/Z ratios. discrete metal carbene C, is without precedent in the literature. Reagents other than H2 able to form σ-complexes similar to A Computational studies at the DFT and the CCSD(T)) level sug- should undergo analogous trans-addition to alkynes. In fact, we gest that the trans- and the gem-pathway have similar barriers, but were able to accomplish closely related trans-hydroboration, trans- polar substituents in vicinity to the reacting triple bond foster hydrosilylation (previously described by the Trost laboratory), carbene formation and allow regioselectivity to be imposed on this trans-hydrogermylation and trans-hydrostannation reactions, remarkable transformation (Figure 1). Moreover, it has been un- which are equally paradigm-changing processes.1 The stereochemi- ambiguously shown by spectroscopic means (PHIP NMR) that the Research Programs – Organometallic Chemistry resulting carbenes are kinetically competent intermediates rather Several attempts at harnessing genuine carbene reactivity by al- than thermodynamic sinks off the catalytic cycle; they evolve via kyne gem-hydrogenation have already been successful.2 Most associative H2-dependent processes into the desired E-alkene (and notably, it is possible to intercept the carbene primarily formed possible by-products). The spectroscopic evidence is in excellent with tethered olefins (Scheme 3); this allows either cyclopropenes accord with the computational results.2 or cyclic olefins to be formed; it is the substitution pattern of the substrate that determines the course of the reaction.4 In any case, the new “hydrogenative cyclopropanation” stands in striking con- HO OMe 1 trast to the hydrogenolytic cleavage of cyclopropanes commonly used in organic synthesis. Likewise, the “hydrogenative metathesis” [Cp*Ru(cod)Cl] is an entirely new manifold to be distinguished from classical enyne p-H CD Cl 2, 2 2 metathesis, because it delivers cyclic olefins rather than 1,3-dienes as the product. The available data allow a fairly detailed mechanis- Me Cl Ru O tic picture to be drawn, especially with regard to the fate of the H 2 O secondary carbene formed during the actual metathetic C−C bond H H 4 cleavage. δ C = 340.9 ppm 2 = trans-Hydrometalation. As mentioned above, the concerted JH,H -16.0 Hz pathway of trans-hydrogenation (A → B → E) finds correspond- ence in ruthenium catalyzed trans-additions of pinacolborane 1 Figure 1. Formation of a Pianostool Ru-Carbene by gem- (pinBH) or R3EH (E = Si, Ge, Sn) to internal alkynes. During the Hydrogenation; Structure of the Complex in the Solid State report period, these reactions were subject to extensive scrutiny. Scheme 3. Hydrogenative Cyclopropanation and Hydrogena- They are distinguished by excellent stereo- as well as regioselectivi- 5 tive Metathesis ty, especially when working with propargylic substrates: spectro- scopic, crystallographic and computational evidence suggests that a H2 (1 bar) H H nascent hydrogen bond between the protic substituent and the [Cp*RuCl]4 cat. polarized [Ru−Cl] unit of the catalyst locks the substrate in place; MeO [Ru] MeO 93% MeO at the same time, the –Cl ligand steers the incoming reagent via a hypervalent interaction with the R3E− group (Scheme 4). These hydrogenative cyclopropanation synergistic effects impose directionality on the ligand sphere of the H2 (1 bar) H H loaded catalyst F, which ultimately translates into excellent levels of cat. [Cp*RuCl]4 selectivity.5 MeO [Ru] MeO 93% MeO Scheme 4. Directed trans-Hydrometalation and Novel Down- hydrogenative metathesis stream Chemistry H H OAc H OH R1 R2 K R1 R2 L From a conceptual viewpoint, the formation of discrete metal O H carbenes by hydrogenation of an alkyne is arguably of the highest H ER3 significance. In a formal sense, the triple bond behaves as a 1,2- R1 R1 H OH H OH dicarbene synthon: one “carbene” intercepts the [Cp*Ru] frag- R3E-H Ru R1 R2 1 2 − R R ment, whereas the vicinal “carbene” site inserts into the H H bond Cl ER3 Me 2 (Figure 1). To the best of our knowledge, the geminal hydrogena- R OH O H R2 F G H 1,2 tion of a stable carbogenic compound is a new reactivity mode. H OH This counterintuitive entry into ruthenium carbenes raises new H OH proximal / trans delivery 1 2 R R = R1 R2 questions and opens exciting chemical opportunities. Even though E Si, Ge, Sn COOMe F we were able to isolate and even crystallize numerous examples, it is J I not intuitive whether such pianostool ruthenium complexes exhibit Fischer-carbene or Schrock-alkylidene character. For two repre- sentative complexes, however, has it been possible to record the solid-state 13C NMR spectra and to analyze the chemical shift tensors of the carbene signals.3 Details apart, this advanced spectro- scopic technique drew the portrait of a family of metal carbenes that amalgamates purely electrophilic behavior with characteristics more befitting metathesis-active Grubbs catalysts. Moreover, we were able to show that less electron-rich CpR ligands facilitate carbene formation by gem-hydrogenation.3 Research Programs – Organometallic Chemistry OH HO H O Me was the formation of the macrocyclic precursor 4 by alkyne me- O OH HO O OH tathesis (this laboratory) followed by hydroxy-directed trans- OH H hydrostannation (this laboratory) and subsequent methoxycar- O O brefeldin A OH ACIE 2015, 54, 3978 O bonylation of the resulting stannane 5 (this laboratory). Treatment B aspicillin dihydrocineromycin 2017, 49, 202 ACIE 2015, 54, 6339 of compound 6 thus formed with Cs2CO3 in MeOH triggered a O Synthesis O cascade comprised of (i) deacetylation, (ii) stereoselective O O C19H39 O HN transannular Michael addition with formation of the challenging OH OH O O HO O C H HO 8 17 medium-sized ring, (iii) β-elimination with concomitant cleavage O O OH OH F typhonoside of the carbonate, (iv) attack of the released alkoxide onto the prox- OH Chem. Eur. J. 2018 24 9667 disciformycin B HO , , OH O imal ester with formation of a butenolide ring 8, and (iv) front-side O OH HO HO Chem. Eur. J. 2018, 24, 109 MeO attack of MeOH from the medium onto this Michael acceptor, OH O OH O which is rendered particularly reactive by the bridgehead alkene OH F H O HO moiety. Final ether cleavage then furnished the target compound in O O O 6 sinulariadiolide excellent overall yield.