trans-Hydrogenation, gem-Hydrogenation, and trans-Hydrometalation

Perspective Cite This: J. Am. Chem. Soc. 2019, 141, 11−24

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trans-Hydrogenation, gem-Hydrogenation, and transHydrometalation of Alkynes: An Interim Report on an Unorthodox Reactivity Paradigm Alois Fürstner*

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Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany Scheme 1. Conceptual Framework

ABSTRACT: cis-Delivery of H2 to the π-system of an unsaturated substrate is the canonical course of metal catalyzed hydrogenation reactions. The semireduction of internal alkynes with the aid of [Cp*Ru]-based catalysts violates this rule and affords E-alkenes by direct transhydrogenation. A pathway involving σ-complexes and metallacyclopropenes accounts for this unconventional outcome. Connected to this process is an even more striking reactivity mode, in which both H atoms of H2 are delivered to one and the same C atom. Such gemhydrogenation of stable carbogenic compunds is a fundamentally new transformation that leads to the formation of discrete metal carbene complexes. Computational studies suggest that the trans- and the gem-pathway have similar barriers, but polar substituents in the vicinity of the reacting triple bond provide opportunities for imposing selectivity and control. Moreover, it is shown that catalytic trans-hydrogenation is by no means a singularity: rather, the underlying principle is also manifest in trans-hydroboration, trans-hydrosilylation, trans-hydrogermylation, and trans-hydrostannation, which are equally paradigm-changing processes. These reactions are robust and distinguished by excellent compatibility with many (reducible) functional groups and have already stood the test of natural product synthesis in a number of demanding cases.

of selectivity that (Z)-selective olefin metathesis (RCM) is not always able to match.8,9 The examples shown in Scheme 2 are representative: the classical Lindlar catalyst (Pd(Pb)/CaCO3, quinolone) worked nicely in the neurymenolide case,10,11 whereas nickel boride (Ni(OAc)2·4H2O/NaBH4, ethylenediamine) was the catalyst of choice for the formation of hybridalactone;12 the leiodermatolide synthesis, in contrast, required the use of stoichiometric Zn(Cu/Ag) in protic medium as a reducing agent to ensure selective reduction of the triple bond without affecting the other π-systems of this polyunsaturated substrate.13,14 These (and many other) examples show that the practitioner can actually choose among various methods in case optimization is required. The situation is much less comfortable when it comes to alkyne semireduction to the corresponding E-alkene. Although dissolving metal reductions using (earth) alkali metals in liquid ammonia or amines are usually highly E-selective, they show a very narrow functional group compatibility and therefore hardly ever qualify for advanced applications.15 The same is true for the use of metal hydrides such as LiAlH4 or Red-Al, which, above all, work only for propargylic alcohols and few other types of substrates.16−18 Alternative procedures that have been applied to more than a handful of examples are basically missing.19 The disparity in the number of available methods for stereocomplementary alkyne semireduction hardly comes as a surprise. Basically all (transition) metal catalysts afford Zalkenes in the first place as long as they do not involve hydrogen atom (H·) transfer.20,21 This outcome reflects a highly conserved sequence of events, starting off with oxidative insertion of the metal center (or surface site) into the H−H

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INTRODUCTION During the past decade, our group developed a new generation of catalysts for alkyne metathesis such as [PhCMo(OSiPh3)3], which outperform all predecessors in terms of activity and functional group compatibility.1,2 They capitalize on the synergy between a molybdenum alkylidyne core and the silanolate ligand sphere. Moreover, reversible adduct formation with phenanthroline renders them bench-stable and hence easy to use. These catalysts have served numerous exigent applications.3,4 Most notable is the ease with which they promote macrocyclization via ring closing alkyne metathesis (RCAM).3,5,6 Only in rare cases, however, does the cyclic alkyne formed by RCAM per se constitute the actual target.7 To harness its full potential, alkyne metathesis needs to be combined with enabling downstream chemistry. Semireduction of the triple bond with formation of the corresponding (macrocyclic) alkene is an obvious possibility (Scheme 1). In fact, this tactic provides a reliable entry into macrocyclic Z-alkenes, with levels © 2018 American Chemical Society

Received: September 10, 2018 Published: November 13, 2018 11

DOI: 10.1021/jacs.8b09782 J. Am. Chem. Soc. 2019, 141, 11−24

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Journal of the American Chemical Society

selective cell migration inhibitors and hence potential lead compounds in the quest for antimetastatic drug candidates. Our approach capitalized on the formation of the core unit at the C6−C7 bond via RCAM, which worked nicely despite the strained character of the resulting 12-membered ring 1 (Scheme 3).25 Since none of the known procedures for E-

Scheme 2. Late-Stage Applications of Prototype Methods for Alkyne cis-Reduction

Scheme 3. E-Alkene Formation en Route to Lactimidomycin

selective semireduction would apply to such a functionalized cycloalkyne, we resorted to an indirect solution commencing with ruthenium catalyzed trans-hydrosilylation. This powerful methodology had been introduced shortly after the turn of the millennium by the Trost group and became rapidly embraced by the synthetic community (see below).26,27 In fact, reaction of 1 with BnMe2SiH in the presence of [Cp*Ru(MeCN)3]PF6 as the catalyst furnished the trans-addition product 2 in good yield.25 Subsequent treatment with TBAF entailed cleavage of the C-silyl residue and the O-TES-protecting group as well as elimination of the benzoate substituent with formation of the enoate motif. Since attachment of the glutarimide side chain to the resulting product 3 via asymmetric Mukaiyama aldol chemistry was also straightforward, a scalable entry into lactimidomycin (and a host of analogues for biological profiling) was secured.25

bond, followed by migratory insertion of the substrate’s π-bond into the resulting metal hydride, and final reductive elimination of the product.20,22 Since these elementary steps are under frontier orbital control, a suprafacial cis-selective hydrogen delivery will invariably ensue, independent of whether the chosen catalyst is homogeneous or heterogeneous in nature. While over-reduction can be a serious problem, stereoselectivity hardly ever is (cf. Scheme 2). Occasional imperfections are usually caused by secondary processes before or after the actual hydrogenation step.23 This canonical scenario implies that the development of an E-selective alkyne semihydrogenation catalyst likely mandates paradigm change. Summarized below are our initial steps toward this goal. The available evidence suggests that direct alkyne trans-hydrogenation is indeed possible;24 importantly, it is not a singularity but only one incarnation of a more general reactivity mode. The underlying principle is also manifest in trans-hydrometalation reactions which pave the way to certain trisubstituted alkene motifs in a stereodefined format. Finally, our investigation unveiled a true paradox in that an alkyne may even succumb to gem-hydrogenation. This striking observation is without precedent; we have reasons to believe, however, that it opens exciting new vistas for metal carbene chemistry.

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trans-HYDROGENATION In an attempt to rationalize the then rather unique transhydrosilylation reaction, we wondered whether the isolobal relationship between [R3Si] and [H] might make an analogous trans-hydrogenation of an alkyne possible. Such a reaction would violate the paradigms of canonical transition metal catalyzed hydrogenation. Even the few (transfer) hydrogenation reactions known in the literature that result in net trans-reduction usually commence with cis-delivery of H2 to the substrate followed by Z → E isomerization of the double bond initially formed;28,29 however, this latter step is fast and facile only if the alkene carries at least one aryl substituent and/or is notably polarized. Therefore the scope of these procedures tends to be narrow and none of them works well for ordinary dialkylalkynes.28 Reports of truly direct transdelivery, in contrast, are exceedingly rare.30,31 We were therefore pleased to find that hydrogenation of cycloalkyne 4 as the model compound with catalytic amounts of [Cp*Ru(MeCN) 3 ]PF 6 , [Cp*RuCl(cod)]/AgOTf, [Cp*RuCl(cod)], or [Cp*RuCl]432 in CH2Cl2 as the preferred solvent furnished 5 with good to excellent E-selectivity (Scheme 4).33 The bulky Cp* ligand proved mandatory; hydrogen overpressure (5−10 atm) was initially used but later found not to be necessary: in most cases the reaction proceeds with appreciable rates under 1 atm of H2 (balloon), although

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NATURAL PRODUCT SYNTHESIS AS THE TEASER The lack of a functional group tolerant method for the transhydrogenation of alkynes was painfully encountered during the first total synthesis of lactimidomycin.25 This and related macrolides of the glutarimide estate had been claimed to be 12


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Journal of the American Chemical Society Scheme 4. Leading Finding and Model Compounds

Scheme 5. Propargyl Alcohol Derivatives as Privileged Substrates

group in binding to the catalyst, tertiary propargyl alcohols tend to be good substrates for trans-hydrogenation.34,36 The arguably most important shortcoming, however, is positional isomerization of the newly formed olefin and/or over-reduction.33,34 Only in favorable cases are these side reactions negligible; even for the original test substrate 4, these side reactions consumed 7−19% of the material (depending on the exact reaction conditions).33,37 The total synthesis of brefeldin A, a fungal metabolite that disrupts the Golgi apparatus of eukaryotic cells, illustrates this aspect (Scheme 6).38 With an E/Z ratio of 99:1, the

certain substrates do require gentle heating.34 Importantly, control experiments showed that the E-selectivity is not caused by Z → E isomerization but represents an inherent virtue.33 Since the catalyst system proved highly alkynophilic, the reaction shows a remarkable compatibility with functional groups.33,34 Arguably most notable is the fact that terminal as well as internal alkenes usually pass uncompromised. Likewise, aldehydes, ketones, esters, amides, acetals, nitriles, sulfonates, sulfonamides, methyl and silyl ethers, aryl bromides, an aniline, an unprotected carboxylic acid, free −OH groups, and even an aryl thioether were found to remain intact. The same is true for substituents as easy to reduce as a nitro group or the N−O bond of a Weinreb amide. Important limitations, however, must also be mentioned. Specifically, substrates able to bind to the [Cp*Ru] fragment via kinetically stable η4 or η6 coordination35 usually fail to react.33,34 For this very reason, 1,3-dienes, 1,3-enynes, and (electron-rich) arenes often represent catalyst poisons; hence, the method does not (yet) apply to enyne 1 passed through en route to lactimidomycin. The deleterious influence of such a competing ligand, however, can be overcome in case the substrate carries an unprotected propargyl alcohol: as the −OH group engages with chloride-containing ruthenium centers by forming a peripheral hydrogen bond (see below), it favors binding of the propargylic acetylene unit even if competitive coordination sites are present in the substrate. The formation of the plant metabolite E-suberenol (7) is instructive in that the electron-rich resorcinol subunit did not prevent productive trans-hydrogenation of the side chain from occurring (Scheme 5).34 Note that even for this rather simple compound the use of Red-Al or LiAlH4 as the textbook methods for the trans-reduction of propargyl alcohols is precluded; these reagents would destroy the cyclic enoate comprised in the coumarin ring. The favorable chemo- and stereoselectivity of the new trans-hydrogenation is also apparent from the semireduction of substrate 8 to the odoriferous tobacco constituent 9:34 only the alkyne was found to react whereas the alkene and the carbonyl group remained intact. For the assistance provided by the hydroxy

Scheme 6. Alkyne trans-Hydrogenation and Competing Isomerization: The Brefeldin A Case

stereoselectivity of product 11 left nothing to be desired. The reducible enoate, the lactone, and the TBS-ethers all remained intact during alkyne trans-hydrogenation; this ensemble of functional group would certainly not subsist under dissolving metal conditions. Yet, the isolated yield of 11 was only 56% (>1 g scale) because overreduction and isomerization of the disubstituted alkene to the trisubstitued position at the bridgehead in 12a,b consumed part of the valuable material. Although separable in this particular case, such byproducts render product isolation challenging. Unexplained at the time when this application was carried out was the observation that the side products seem to arise largely during the trans-hydrogenation itself; once formed, alkene 11 is quite stable and does not engage in secondary processes to any significant extent. Productive trans-hydro13


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Importantly, the metal has not broken the H−H bond; rather the σ-bond serves as the actual ligand in line with the experimental result shown in Scheme 7. This intermediate evolves via rate-determining H-delivery to the activated triple bond into a metallacyclopropene B (η2-vinyl complex)45 which transforms in a concerted process into the desired E-alkene F: importantly, the stereodetermining transition state conncecting B and F is low-lying (ΔΔG‡ = 5.1 kcal·mol−1 for 2butyne).34,44 Moreover, the product-forming step is strongly exergonic and therefore almost certainly irreversible. The computed barrier for the formation of the Z-alkene is notably higher (3.4 kcal·mol−1 in case of 2-butyne), thus explaining the experimentally observed excellent E/Z ratios. The scenario is qualitatively the same for 2-butyne and for 2-butyne-1-ol, although the propargylic −OH substituent lowers all barriers to a significant extent.34 The arguably most striking and counterintuitive result, however, is the fact the metallacyclopropene B can also evolve into a discrete half-sandwich ruthenium carbene of type C.34,44 For 2-butyne as the substrate, the transition state connecting B and C was computed by DFT to be 1.2 kcal·mol−1 higher in energy than the barrier of the concerted pathway from B to F, but 0.5 kcal·mol−1 lower in energy at the CCSD(T) level.34 Details apart, carbene formation can definitely compete with the concerted pathway, especially when polar functional groups reside in the vicinity, which are able to coordinate onto and hence stabilize an emerging carbene center. DFT also revealed that the fate of the piano-stool ruthenium carbene C is largely selectivity-determining:34,44 it can evolve into the desired E-alkene F, into a positional alkene isomer, or into the saturated product as the result of over-reduction. These different outlets have similar barriers and are therefore hard to predict with certainty; all of them follow an associative mechanism requiring coordination of a second molecule of H2 as a barrier-lowering ancillary ligand to the ruthenium carbene initially formed.34,44 All major conclusions drawn from the computational investigations are in excellent accord with preparative and spectroscopic data. Most notably, PHIP experiments unequivocally confirmed direct trans-delivery of H2 to the alkyne unit34,44 as well as the in situ formation of metal carbene intermediates: depending on the chosen substrate, these species can either be very minor constituents or may be generated in essentially quantitative yield when stabilizing substituents are present in vicinity. Furthermore, p-H2 based exchange spectroscopy (2D 1H-OPSY-EXSY)46 showed that the fate of the metal carbene is determined by an associative pathway triggered by coordination of a second H2 molecule to the ruthenium center (Figure 1): this opens a gateway to the desired E-alkene and to the side products alike. In full agreement with DFT, OPSY-EXSY proved beyond doubt that a carbene of type C is linked to the desired E-alkene, positional alkene isomers as well as the corresponding over-reduced product; the NMR data hence confirm that such carbenes can be catalytically competent.34,44

genation and the undesirable side reactions hence seem to be intimately linked, which makes a purely empirical optimization of the reaction conditions difficult. A better understanding for the reigning mechanism, which must explain the unorthodox stereochemical course of the reaction as well as the observed product spectrum, was therefore deemed a top priority.

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A NON-CANONICAL MECHANISM In a first foray it was shown that the well characterized cationic dihydrogen σ-complex 1339 is capable of catalyzing the hydrogenation of the model substrate 4 with high E-selectivity (Scheme 7).33 With a σ-complex identified as a possible Scheme 7. A σ-H2 Complex as Precatalyst

starting point,40,41 more detailed investigations into the mechanism were carried out using para-hydrogen (p-H2) induced polarization transfer (PHIP) as an exquisitely sensitive NMR technique.42,43 It enhances the signals originating from the reacting p-H2 by up to 4 orders of magnitude over the conventional Boltzmann-governed NMR polarization. This massive effect allows even fleeting intermediates to be detected, analyzed, and tracked, under the proviso that the H atoms are transferred in a pairwise manner and the protons in the resulting products are mutually coupled. PHIP data in combination with computational studies at the DFT and even the coupled cluster (CCSD(T) level of theory provided a fairly detailed picture of the mechanism of transhydrogenation and the side reactions innately linked to it (Scheme 8).34,44 DFT leaves no doubt about initial formation of a complex of type A loaded with the alkyne and H2. Scheme 8. trans- and gem-Hydrogenation as Intertwined Processes (Key Intermediates Only)

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gem-H2 DELIVERY: HYDROGENATIVE FORMATION OF METAL CARBENE COMPLEXES The computational and spectroscopic data summarized above draw the picture of a rather involved process: thus, alkyne trans-hydrogenation can proceed via two channels that bifurcate already at the stage of a metallacyclopropene B as the last common intermediate.34,44 The concerted path is 14


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Figure 1. Relevant strips of the 2D 1H-OPSY-EXSY spectrum (CD2Cl2, 298 K, ppm) showing cross peaks which link the carbene formed by gem-hydrogenation of a propargyl alcohol substrate with pH2/[Cp*Ru(cod)Cl] with the corresponding E-alkene, the positional alkene isomer, the over-reduced product, and H2.

Figure 2. Formation of a Pianostool Ruthenium Carbene by gemHydrogenation; Structure of the Complex in the Solid State.

become important in the discussion of the trans-hydrometalation reactions outlined below.50 Yet another feature of complex 15 warrants comment: thus, the newly formed ruthenium carbene resides distal to the ether but proximal to the protic substituent. This pattern is reasonably general and allows the site of carbene formation to be predicted, even though steric effects may synergize or counteract.34 Carbonyl groups seem to exert a less pronounced steering effect: while ynones and ynoates are hydrogenated such that the metal carbene is distal to the CO group, this preference can be overturned if an ether group is present.34 Piano-stool ruthenium carbenes of the type formed by gemhydrogenation of alkynes have not been investigated in great detail.51 Our data show that it requires binding of a second H2 molecule for them to reenter the catalytic cycle leading to net hydrogenation of the substrate. It seems possible to outperform this pathway by other fast (intermolecular) processes even under an H2 atmosphere. If so, the newly discovered gemalkyne hydrogenation would open an unprecedented gateway for harnessing genuine carbene reactivity. The examples shown in Scheme 10 provide proof-ofconcept.34 They document that enynes can undergo intramolecular cyclopropanation, rather than hydrogenation, when reacted with catalytic [Cp*RuCl]4 under H2 atmosphere. This outcome is counterintuitive since cyclopropanes are, a priori, amenable to hydrogenolytic C−C bond cleavage.52,53 Equally striking is the ring expansion that takes place upon hydro-

highly selective for the formation of the desired E-alkene, whereas the stepwise path involving a discrete ruthenium carbene opens competing exits that result in side product formation. For further reaction optimization, it will be important to gain control over this scenario. From a conceptual viewpoint, however, the formation of metal carbenes by hydrogenation of an alkyne is arguably of highest significance. This unorthodox transformation implies that both hydrogen atoms of H2 are delivered in a consecutive but pairwise fashion to one and the same carbon atom of the substrate. In a formal sense, the triple bond behaves like a 1,2dicarbene synthon (Scheme 9):47 one “carbene” intercepts the Scheme 9. Formalism Underlying gem-Hydrogenation: Alkynes as 1,2-Dicarbene Synthons

[Cp*Ru] fragment, whereas the vicinal “carbene” site inserts into the H−H bond. To the best of our knowledge, geminal hydrogenation of a stable carbogenic compound is a fundamentally new reactivity mode without precedent in the literature.48,49 The PHIP and DFT data suggest that the degree of carbene formation is substrate dependent.34 Polar substituents in vicinity to the reacting triple bond (i) favor this pathway by lowering the barrier, (ii) largely determine the stability of the resulting carbene, and (iii) exert a directing effect and hence allow the site of carbene formation to be controlled. These conclusions nicely concur with a host of crystallographic data.34,44 The X-ray structure of 15 formed by hydrogenation of 14 with the aid of [Cp*RuCl]4 is representative (Figure 2). It constitutes the ultimate proof for hydrogenative metal carbene formation; at the same time, it shows two different modes by which lateral −OR groups can stabilize the reactive carbene functionality. Specifically, the −OMe substituent engages in a regular Lewis acid/base interaction with the Ru-center, whereas the −OH group entertains a strong hydrogen bond with the −Cl ligand on the metal. Collectively, these interactions render the specific carbene 15 rather unreactive. The ability of the polarized [Ru−Cl] unit to serve as a hydrogen bond acceptor will

Scheme 10. Harnessing Genuine Carbene Reactivity

15


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Journal of the American Chemical Society genation of 18, which implies regioselective formation of a metal carbene intermediate proximal to the −OH group and distal to the ether. Finally, the furan formation by formal [3 + 2] cycloaddition upon hydrogenation of acetylenedicarboxylate 20 also speaks for the intervention of a discrete metal carbene upon gem-hydrogenation of the triple bond. 34,54 The opportunities provided by the new reactivity paradigm that alkynes can serve as stable and safe metal carbene precursors are actively pursued in in this laboratory.

Scheme 12. Regiocontrol by Proper Choice of Catalyst

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trans-HYDROSILYLATION The pathfinding discovery of alkyne trans-hydrosilylation reported by Trost and co-workers shortly after the turn of the millennium had relied on the use of cationic ruthenium complexes, most notably [Cp*Ru(MeCN)3]PF6.26,27 This methodology was rapidly embraced by the synthetic community and found numerous applications, which have been comprehensively reviewed.55 The mild conditions and remarkable functional group tolerance form the basis for this success story. The available data suggest that the reaction finds its limitations with alkynes, in which coordination of the bulky [Cp*Ru] fragment to the triple bond is precluded on steric grounds.56 Likewise, 1,3-enynes tend to be problematic; one way to force them to react is to use neat R3SiH.57 In mechanistic terms, the reaction is almost certainly another incarnation of the reactivity mode transpiring in transhydrogenation. This interpretation is in excellent agreement with early computational studies which pointed toward formation and evolution of ruthenacyclopropenes as the key intermediates.58,59 The competing formation of discrete metal carbenes, however, is unlikely. A drawback of the original Trost system is the low regioselectivity observed in the trans-hydrosilylation of unsymmetrical alkynes.26 This imperfection is effaced upon protodesilylation (usually with a mild fluoride source),26,60 which explains why this downstream chemistry has been most widely used.55 The problem can be circumvented by rendering trans-hydrosilylation intramolecular,61,62 as exemplified by the homopropargylic alcohol derivative 22 (Scheme 11):63 in this

the site proximal to the −OH group.64−66 Other protic substituents such as (sulfon)amides exert a similar directing effect, with the counterintuitive trend that the regioselectivity increases with increasing −XH acidity.64 These empirical observations can be rationalized on the basis of a host of spectroscopic and crystallographic data. Thus, addition of a propargyl alcohol (amide) to [Cp*RuCl]4 leads to the formation of well-defined adducts which are distinguished by massive deshielding of the alkyne C atoms (Δδ ≈ 50−70 ppm, Figure 3).64,65 Moreover, the distinctive

Scheme 11. Intramolecular trans-Hydrosilylation/Oxidation Sequence

Figure 3. Structural and spectroscopic data of complex 24 formed from [Cp*Ru−Cl] and a propargyl alcohol.

downfield shift of the −OH proton indicates hydrogen bonding in solution. Crystallographic data revealed that the polarized [Ru−Cl] unit of the catalyst serves as an effective hydrogen bond acceptor;67 the structure of complex 24 in the solid state is representative.65,68 The coordinated triple bond is elongated and notably bent away from linearity, which implies appreciable back-donation of electron density from the metal d-orbitals into the empty π* orbital of the substrate. Orbital interaction diagrams confirmed the massive activation of the alkyne upon coordination to the [Cp*RuCl] fragment.65 Actually, both orthogonal π-systems of the triple bond seem to be engaged in π-donation, which outweighs the net back-donation from the [Cp*RuCl] HOMO. Although perhaps oversimplified, it is legitimate to view the bound alkyne as a four-electron donor ligand.65 The orbital interaction diagrams are qualitatively the same for 2-butyne and for 2-butyn-1-ol. A hydroxy group hence does not change the intrinsic reactivity of the π-complex, yet the enthalpic gain

case, the use of [(C6H6)RuCl2] as the catalyst also gave a good result. The silacycles thus formed enable a more productive use of the C−Si bond, as illustrated by Tamao−Fleming oxidation of 23 to unveil the aldol substructure of gelsemoxonine. Changing the catalyst is another way to enforce a regioselective course (Scheme 12). Thus, our group has shown that it suffices to replace the cationic ruthenium complex [Cp*Ru(MeCN)3]PF6 by the neutral analogue [Cp*RuCl]4 to reach almost exclusive trans-hydrosilylation at 16


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reported at the outset of our investigations. After considerable experimentation, we managed to grow crystals of complex 25 stabilized by (iPr)3P as an ancillary ligand (Figure 4).64 This

resulting from the peripheral hydrogen bonding increases the affinity to the catalyst.65 Propargyl alcohols are hence privileged substrates not because they are more reactive but because they bind particularly well.

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trans-HYDROBORATION The notion that metal catalyzed trans-addition to alkynes might be a more general reactivity mode rather than a singularity encouraged us to extend the concept. We found pinacolborane ((pin)BH) to be a suitable partner, which adds trans to internal alkynes in the presence of a [Cp*Ru]-based complex (Scheme 13).69 This course is paradoxical since Scheme 13. cis- and trans-Hydroboration; Structure of a Prototype trans-Addition Product in the Solid State

Figure 4. Top: Structure of the σ-stannane complex 25 in the solid state; bottom: proposed rationale for the observed regioselectivity in trans-hydrometalations of propargyl alcohols and related protic substrates with catalysts comprising a [Cp*Ru−Cl] unit; for sake of clarity, • signifies a CMe edge of the Cp* ring in the Newman-type projection of the loaded catalyst and the ensuing metallacyclopropene.

hydroboration is the textbook example of a strictly orbitalcontrolled suprafacial syn-addition reaction.70 The few violations of the reigning principle, according to which hydroboration proceeds via a four-membered cyclic transition state, are basically the result of secondary processes and usually mandate polarized triple bonds.71−73 The new ruthenium catalyzed method affords good to excellent E/Z ratios in most cases investigated. Exceptions were found with sterically hindered substrates74 and strained cycloalkynes, which favor cis-addition. The choice of borane is critical in that 9-H-9-BBN proved too reactive, whereas the electron-rich arene ring of catecholborane poisons the catalyst, likely via formation of kinetically stable η6-adducts; (pin)BH is therefore currently the best choice.69 With regard to the mechanism, ruthenacyclopropenes are again believed to be key intermediates.75 In preparative terms, the scope of the reaction is similar to that of the other trans-hydrometalations described herein. One major difference, however, has to be noted: (pin)BH reacts with unprotected −OH groups, whereas R3EH (E = Si, Ge, Sn) does not; this process is faster than the catalyzed transaddition. This propensity deprives us of the ability to control the regiochemical course of trans-hydroboration by taking advantage of the formation of a peripheral hydrogen bonding array between a protic site in the substrate and a chloridecontaining ruthenium catalyst. The regiochemical course of ruthenium catalyzed trans-hydroborations of unsymmetrical internal alkynes is therefore largely determined by steric factors.

additive is detrimental for catalysis because it occupies the coordination site to be taken by the alkyne substrate; one may argue, however, that the structure of 25 in the solid state is relevant for this very reason. It shows that the Sn−H bond is elongated but not broken; spectroscopic data nicely corroborate that 25 is a true σ-complex.64 Particularly noteworthy is the fact that the distance between the chloride atom on ruthenium (3.202 Å) and the tin center is well below the sum of the van der Waals radii (4.00 Å); the Snatom is on the way of becoming pentavalent.64 The attractive force manifest in this structural attribute is thought to play a key role in controlling the regiochemical course of transhydrometalation (Figure 4, bottom): Although it is the metal center that activates either reaction partner, the chloride on ruthenium imparts directionality on the loaded catalyst and the derived transition state. Specifically, the polarized [Ru−Cl] unit locks the propargyl alcohol substrate in place via a peripheral hydrogen bond and, at the same time, steers the incoming nucleophile through a hypervalent interaction. This well-ordered array ultimately translates into generally excellent regioselectivity. Under this proviso, it is also evident why transhydrostannations tend to be more regioselective than transhydrosilylations (germylations),64,65,77 as the crucial Cl····E interaction is stronger for E = Sn than for E = Si, Ge.78 DFT studies confirm the close mechanistic ties between trans-hydrostannation, trans-hydrosilylation, trans-hydroboration, and trans-hydrogenation. The only major difference between these different manifestations of a common principle relates to the competing intervention of discrete metal carbenes formed by gem-hydrogenation.34,44 The computational data basically exclude an analogous gem-delivery pathway of R3E−H (E = Si, Ge, Sn) or (pin)B−H for the tested [Cp*Ru] catalysts.58,59,65,75 In preparative terms, trans-hydrostannation is arguably the most general and selective of the different trans-addition processes described herein, at least at the present stage of development.64−66,79 It is distinguished by a remarkable

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trans-HYDROSTANNATION AND GERMYLATION During our mechanistic investigations into trans-hydrogenation we learned that a σ-complex of the type [Cp*Ru(H2)] likely triggers this unorthodox transformation.33,34 This insight suggested that other reagents able to engage with a [Cp*Ru] fragment in a similar manner might react analogously.40,41 Although σ-complexes of stannanes had been known for some time,76 no example comprising Ru as the central metal was 17


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synthesis of two neuroprotective cerebrosides, which differ from each other only in the configuration of the double bond in the lipidic tail region (Scheme 15).81 Using diyne 28 as

substrate scope; so far, only a few alkynes were tested for which trans-hydrosilylation gave better results.64 Moreover, trans-hydrostannation shows unrivaled levels of chemo- and stereoselectivity and is particularly responsive to steering by −OH groups or other protic substituents. Advantage can be taken from the assistance provided by such peripheral hydrogen bonding also in other ways (Scheme 14):65 thus,

Scheme 15. Exhaustive and Selective trans-Hydrostannation of a Diyne

Scheme 14. An “Armed” Substrate

precursor, distannation at low temperature followed by protodestannation of 29 furnished the E,E-configured product typhonoside F. More interesting in conceptual terms is the preparation of the E,Z-isomer typhonoside E: In this case, the site-selective trans-hydrostannation of the propargyl alcohol subunit of 28 gains an additional strategic role: the R3Sn− group protects the E-alkene in 30 against further reduction and hence enables safe “off-site” Lindlar hydrogenation of the lateral π-system.81,82 This particular example also showcases the superior performance of trans-hydrostannation, since transhydrosilylation of 28 failed even when attempted in an entropically favored intramolecular format.81

the presence of an −OH group allows compounds to be turned over that would poison the catalyst otherwise. While a regular 1,3-enyne can bring the trans-addition to a halt because of tight binding to the [Cp*Ru] fragment as depicted in G and H, analogous substrates armed with a propargylic −OH substituent react well, likely because they can reach a productive binding mode J. The case of enyne 26 illustrates this aspect;80 the resulting product 27 can be elaborated into (+)-aspicillin, an iconic macrolide with a prominent history in natural product synthesis. Likewise, many arylalkynes fail to undergo [Cp*Ru]-catalyzed trans-hydrogenation and transhydrometalation because of competitive binding of the arene to the catalyst.66 Once again, they can be “armed” by a strategically placed protic site, which itself can even be part of a heterocyclic ring.65 Furthermore, the enhanced affinity of propargyl alcohols to the catalyst can be translated into favorable site selectivity when working with substrates comprising more than one πsystem.64,65,81 The effect pertains even to 1,3-diynes in which the individual triple bonds are conjugated and hence electronically coupled. Interestingly, the site-selective transhydrostannation of the propargylic alkyne unit is favored upon heating, whereas simultaneous stannation of both triple bonds prevails at or below room temperature.81 This somewhat counterintuitive trend likely reflects the tighter binding of the propargylic entity that persists even upon warming. Moreover, preliminary data suggest that the simultaneous activation of both conjugated triple bonds favored at low temperature might involve two [Cp*Ru] fragments at the same time.81 The ability to achieve either a site-selective or an exhaustive trans-hydrostannation of a diyne provides opportunities for target-oriented synthesis as exemplified by a recent total

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NOVEL DOWNSTREAM CHEMISTRY The applications shown in Schemes 14 and 15 engage the product primarily formed by trans-hydrostannation into nothing but simple protodestannation leading to allyl alcohols of type L. Though this reaction is undoubtedly useful, recourse to organotin chemistry is easier to justify when more productive use is made of the C−Sn bond. To this end, our group has pursued various opportunities for the downstream functionalization of complex alkenylstannanes. Of course, the rich arsenal of organotin chemistry developed in the past is applicable too.83 Scheme 16 summarizes the progress made so far. The arguably most relevant transformation is the stereoretentive Cmethylation to give trisubstitued alkenes of type M. This particular structural motif is found in innumerous polyketide natural products, and any stereoselective access route to it is therefore potentially enabling. We found three expedient ways to do so, which require a single step and work in the presence of many polar and apolar functional groups.84 Thus, it suffices to treat the stannane precursor with MeI, tetra-n-butylammonium phosphinate as an essentially nonbasic tin scavenger, and copper thiophene-2-carboxylate (CuTC) as a promoter. The 18


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Journal of the American Chemical Society Scheme 16a

Lam−Evans coupling reaction using Cu(OAc)2 and Et3N in DMSO at slightly elevated temperature.89 Interestingly, the resulting product P features the acetate not at the site of initial attack but rather at the adjacent −OH group; the acyl transfer likely occurs within the coordination sphere of copper prior to reductive elimination. In any case, the new protocol affords selectively protected acyloin derivatives under exceedingly mild conditions. The chiral center adjacent to the unveiled carbonyl group is not racemized, and various functional groups are tolerated that would not subsist under the standard Tamao− Fleming conditions used for the oxidation of related alkenylsilanes.89

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APPLICATIONS The alkyne trans-addition reactions discussed above continue to pose fascinating mechanistic questions but have already reached a level of maturity where they become useful from a synthetic vantage point. They make products available that can be difficult to obtain otherwise. This aspect is underlined by a growing number of applications to target oriented synthesis.90 Our approach to the macrolide antibiotic dihydrocineromycin B is deemed instructive (Scheme 17).91 The approach

a

Reagents and conditions: (a) CuTC, Ph2PO2NBu4, DMF; (b) Ph2PO2NBu4, MeI, CuTC (after short delay), DMSO; (c) [(cod)Pd(Me)Cl], THF; (d) MeI, CuI, LiOtBu, DMF/2-methylTHF; (e) Pd(OAc)2 cat., Ph3As cat., TFA (40 mol %), 1,4-benzoquinone, CO (1 atm), MeOH; (f) AgOP(O)Ph2, F-TEDA-PF6, acetone; (g) Cu(OAc)2, Et3N, DMSO.

desired products are usually formed in high yields without significant protodestannation interfering; in some cases, however, it proved advantageous to supplement the mixture with catalytic amounts of Pd(PPh3)4.84 The use of commercial [(cod)Pd(Me)Cl] represents an alternative to this multicomponent recipe.85 Although this reagent is expensive, it is recommended especially when working with small amounts of (precious) compounds. Finally, we found that the corresponding alkenylsilanes (E = Si) react with CuI/LiOtBu and MeI to furnish the desired product M.84 This transformation is thought to proceed via a sequence of Brook rearrangement followed by alkylation of the intermediate thus formed. Another prominent motif in nature is N, again because it is of polyketide origin. Trisubstituted alkenes of this type can be obtained in stereodefined format in a single operation by methoxycarbonylation of the organotin precursor.86 To this end, the substrate is exposed to catalytic amounts of Pd(OAc)2, Ph3As, and benzoquinone as the terminal oxidant in MeOH under CO atmosphere; it is mandatory to supplement the mixture with trifluoroacetic acid as a cocatalyst, which lowers the LUMO of the quinone and hence facilitates the reoxidation of the palladium catalyst; at the same time the acid probably marshals the encounter of the different components.86 The acidic conditions notwithstanding, protodestannation was insignificant in most cases and various acid sensitive functional groups were also found to survive. The stereoselective formation of (polyfunctionalized) alkenyl fluorides proves challenging despite the massive recent advances in organofluorine chemistry in general.87 Tin/ fluorine exchange to give products of type O helps to fill the gap. We found that the reaction is readily accomplished with FTEDA-PF6 in combination with nonhygroscopic and bench stable silver phosphinate serving as a π-affine promotor and nonbasic tin scavenger.88 Competing protodestannation was insignificant in most cases, whereas the compatibility of the method with many different functional groups proved to be excellent. Finally, reference is made to a method that entails formal oxidation of the C−Sn bond. This is accomplished by a Chan−

Scheme 17. Target- and Diversity-Oriented Total Synthesis via trans-Hydrometalation

involved ring closing alkyne metathesis (RCAM) followed by hydroxy-directed trans-hydrostannation of the propargyl alcohol subunit embedded in the macrocyclic frame of 32; as expected, this transformation was exquisitely regio- and stereoselective (α/β > 20:1, E/Z > 20/1); the reducible enoate and the elimination-prone tertiary alcohol went uncompromised. Final C-methylation of 33 according to the procedure developed for this purpose in our laboratory (see above) furnished the desired natural product.91 In a previous total synthesis, the trisubstituted Δ8,9-alkene of dihydrocineromycin B had been forged by regular olefin metathesis (RCM) in only 40% yield, despite the high loading of the second-generation Grubbs catalyst (25 mol %).92 The results summarized in Scheme 17 hence suggest that RCAM in 19


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Journal of the American Chemical Society combination with trans-hydrometalation is certainly a competitive, if not even superior, tactic.8,100 An additional bonus of passing through an alkenylstannane is the fact that this functional group can serve as a versatile springboard for “diverted total synthesis”.93,94 This aspect is also evident from the dihydrocineromycin case, since compound 33 has not only been transformed into the proper natural product but also into a collection of analogues featuring deep-seated structural “point mutations” (Scheme 17).91,86,88 The notion that alkyne metathesis in general enables stereoselective access to certain trisubstituted alkene motifs is deemed a conceptual advance. This strategy also underlies the first total synthesis of disciformycin A and B (Scheme 18), even though the exceptionally fragile character of the key intermediates rendered all late-stage maneuvers exceptionally demanding.85

Whereas the nannocycstin case demonstrates that ruthenium-catalyzed trans-hydrometalation is not disturbed by a peptidic microenvironment, the synthesis of fluoroalkene 40 shows how to make productive use of a peptidic linkage (Scheme 19).88 As in the case of a propargylic −OH group, an Scheme 19. Regio- and Stereoselective Synthesis of Fluoroalkenes

Scheme 18. Furhtrer Example of Trisubstitued Alkenes by RCAM/trans-Hydrometalation

amide or sulfonamide exerts a directing effect by engaging the polarized [Ru−Cl] unit of the incoming catalyst into hydrogen bonding to the N−H entity.65 This is the likely reason why the propargyl amide 38 furnished a single fluoroalkene isomer upon trans-hydrostannation followed by Sn/F exchange.88 In this context, it is emphasized that fluoroalkenes can be regarded as lipophilic, conformationally locked amide isosteres of improved metabolic stability (compare Q/R).96 Analogous fluoroalkene formation has also been successful in the prostaglandin series. Given the sensitivity of this class of natural products, this particular application highlights the mildness of the new procedure.88 At the same time, a conceptual aspect deserves mentioning: whereas the literature route to 41 had started with fluoroacetic acid and carried the fluorine tag from step one onward through the entire sequence,97 the new trans-addition chemistry enabled latestage fluorination of a polyfunctionalized intermediate.88 The preparation of the fluorinated cerebroside derivative 42 follows the same logic, although competing protodestannation during Sn/F exchange could not be fully suppressed in this particular case.81 The ability to form trisubstituted enoates of type N by methoxycarbonylation of alkenylstannanes empowered a formal total synthesis of the antibiotic tubelactomicin A (Scheme 20).86 Kinetic dynamic resolution under transfer hydrogenation conditions allowed the readily available compound 43 to be reduced on scale to the corresponding syn-aldol (dr >20:1); reduction of the ester then gave diol 44 as the substrate for trans-hydrostannation. This key transformation provided product 45 in 88% yield (3 g scale). After protection of the primary alcohol, the material was subjected to methoxycarbonylation and the resulting trisubstituted enoate 46 was elaborated into 47, which intercepts a previous total synthesis of the target.86 The first total synthesis of the rather unusual lipid paecilonic acid takes advantage of the ability of alkenylstannanes to undergo Chan−Lam−Evans coupling (Scheme 21).89 When viewed as an intramolecular acyloin acetal, the core of this target can be deconvoluted into propargyl alcohol 49. This key intermediate was reached in isomerically pure form by

A recent total synthesis of the highly cytotoxic cyclodepsipeptide nannocystin Ax echoes and confirms the conclusions spelled out above (Scheme 18).95 Once again, a sequence of RCAM followed by trans-hydrostannation worked well, despite the dense decoration of the compounds. This particular application also showed that the directing ability of the propargylic alcohol subunit in the ruthenium catalyzed trans-hydrometalation of 36 was not compromised by the protic amide linkages in the periphery; the high chemoselectivity is also noteworthy. Since the trisubstituted Δ5,6alkene unit and the neighboring C7-OMe had been proposed to be an innate part of the pharmacophore of this myxobacterial metabolite, the ability to attain late-stage modifications at this critical site was particularly useful. Indeed, testing of a compound collection comprising synthetic nannocystin Ax and 10 non-natural analogues provided valuable insights into structure/activity relationships.95 20


Perspective


to elaborate, sensitive, and polyfunctionalized target compounds including bioactive natural products of distinct estate. These transformations represent different manifestations of a more general reactivity mode, which connects hydrogenation and hydrometalation with the perhaps underappreciated chemistry of metallacyclopropenes and even discrete metal carbenes. It will be interesting to learn which other reagents and substrates can be coaxed to follow a similar path. We suppose that redox isomerization falls into this category: in this case, the substrate itself carries the H atom to be transferred to the triple bond once activated by a metal catalyst;98,99 the pertinent intermediates might well resemble those governing the reactions with external H-sources. This aspect, however, requires further scrutiny. Why [Cp*Ru]-based catalysts currently dominate the field is the other big and largely unanswered question. Although the understanding for how they operate has largely improved in recent years, it remains opaque why only a few other catalysts are known that behave alike; none of them is similarly general, effective, and selective. It can be safely predicted that any generalization in this regard will widen the field. The possibility of generating metal carbene complexes by gem-hydrogenation (and perhaps related means in the future) is a particularly tantalizing aspect. Actually, it is striking that this reactivity mode has not been discovered in the long and overly successful history of catalytic hydrogenation. In any case, our group is committed to further contribute to the advancement of this exciting research area.

Scheme 20. Formal Total Synthesis of Tubelactomicin

Scheme 21. Total Synthesis of Paecilonic Acid A

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Alois Fürstner: 0000-0003-0098-3417 Notes

The author declares the following competing financial interest(s): Patent filed for trans-hydroboration and transhydrostannation.

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ACKNOWLEDGMENTS I thank all co-workers and collaboration partners involved in this project for their invaluable intellectual and experimental conributions; their names appear in the references. Generous financial support by the MPG and the AvH is also gratefully acknowledged.

organocatalytic trans-dihydroxylation of the commercial enal 48 and catalytic asymmetric aldehyde alkynylation. transHydrostannation of 49 afforded multigram amounts of the αstannylated product 50. The subsequent unmasking of the acyloin entity on treatment of 50 with Cu(OAc)2/Et3N gave product 51 without any sign of epimerization of the chiral center next to the ketone. Because the in situ acylation of the free −OH group during the course of the reaction ensured orthogonality of the alcohol protecting groups, 51 could be directly subjected to hydrogenolytic cleavage of the benzyl ethers. Exposure of the resulting crude diol to HCl induced acetal formation; cleavage of the remaining acetate then completed this short, efficient, and scaleable total synthesis.89

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REFERENCES

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CONCLUSIONS AND OUTLOOK Before the turn of the millennium, metal-induced or metalcatalyzed trans-addition reactions to alkynes were oddities of hardly any relevance. It is fair to say that this situation has changed: a number of processes with attractive application profiles have become available, which qualify for applications 21


Perspective


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(9) For Z-selective RCM, see: (a) Hoveyda, A. H. J. Org. Chem. 2014, 79, 4763. (b) Ogba, O. M.; Warner, N. C.; O’Leary, D. J.; Grubbs, R. H. Chem. Soc. Rev. 2018, 47, 4510. (10) Chaładaj, W.; Corbet, M.; Fürstner, A. Angew. Chem., Int. Ed. 2012, 51, 6929. (11) For other pertinent examples, see: (a) Fürstner, A.; Mathes, C.; Lehmann, C. W. Chem. - Eur. J. 2001, 7, 5299. (b) Fürstner, A.; Stelzer, F.; Rumbo, A.; Krause, H. Chem. - Eur. J. 2002, 8, 1856. (c) Fürstner, A.; De Souza, D.; Parra-Rapado, L.; Jensen, J. T. Angew. Chem., Int. Ed. 2003, 42, 5358. (d) Fürstner, A.; Turet, L. Angew. Chem., Int. Ed. 2005, 44, 3462. (e) Fürstner, A.; Bindl, M.; Jean, L. Angew. Chem., Int. Ed. 2007, 46, 9275. (12) (a) Hickmann, V.; Kondoh, A.; Gabor, B.; Alcarazo, M.; Fürstner, A. J. Am. Chem. Soc. 2011, 133, 13471. (b) Hickmann, V.; Alcarazo, M.; Fürstner, A. J. Am. Chem. Soc. 2010, 132, 11042. (13) (a) Mailhol, D.; Willwacher, J.; Kausch-Busies, N.; Rubitski, E. E.; Sobol, Z.; Schuler, M.; Lam, M.-H.; Musto, S.; Loganzo, F.; Maderna, A.; Fürstner, A. J. Am. Chem. Soc. 2014, 136, 15719. (b) Willwacher, J.; Kausch-Busies, N.; Fürstner, A. Angew. Chem., Int. Ed. 2012, 51, 12041. (14) For another advanced case, see: Willwacher, J.; Fürstner, A. Angew. Chem., Int. Ed. 2014, 53, 4217. (15) (a) Pasto, D. J. In Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8; pp 471−488. (b) Dieter, R. K. Science of Synthesis; Thieme: Stuttgart, 2006; Vol. 8; pp 43−132. (c) Kaiser, E. M. Synthesis 1972, 1972, 391. (d) Brandsma, L.; Nieuwenhuizen, W. F.; Zwikker, J. W.; Mäeorg, U. Eur. J. Org. Chem. 1999, 1999.775 (16) Saito, S. Science of Synthesis; Thieme: Stuttgart, 2004; Vol. 7, p 86. (17) For optimized procedures, see: (a) Denmark, S. E.; Jones, T. K. J. Org. Chem. 1982, 47, 4595. (b) Jones, T. K.; Denmark, S. E. Org. Synth. 1986, 64, 182. (c) Igawa, K.; Tomooka, K. Angew. Chem., Int. Ed. 2006, 45, 232. (d) Houpis, I. N. Top. Organomet. Chem. 2011, 42, 103. (18) (a) Rossi, R.; Carpita, A. Synthesis 1977, 1977, 561. (b) Hojo, M.; Masuda, R.; Takagi, S. Synthesis 1978, 1978, 284. (c) Zweifel, G.; Lewis, W.; On, H. P. J. Am. Chem. Soc. 1979, 101, 5101. (d) Eisch, J. J.; Gopal, H.; Rhee, S.-G. J. Org. Chem. 1975, 40, 2064. (e) Eisch, J. J.; Foxton, M. W. J. Org. Chem. 1971, 36, 3520. (f) Kinoshita, H.; Yaguchi, K.; Tohjima, T.; Hirai, N.; Miura, K. Tetrahedron Lett. 2016, 57, 2039. (19) Cr(+2) has been used in a small number of cases; see: (a) Castro, C. E.; Stephens, R. D. J. Am. Chem. Soc. 1964, 86, 4358. (b) Smith, A. B.; Levenberg, P. A.; Suits, J. Z. Synthesis 1986, 1986, 184. (c) Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1995, 117, 8106. (d) Fürstner, A. Chem. Rev. 1999, 99, 991. (20) (a) Kluwer, A. M.; Elsevier, C. J. In Handbook of Homogeneous Hydrogenation; de Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, 2007, Vol. 1, pp 375−411. (b) Blaser, H.-U.; Schnyder, A.; Steiner, H.; Rössler, F.; Baumeister, P. In Handbook of Heterogeneous Catalysis, 2nd ed.; Ertl, G., Knözinger, H., Schüth, F., Weitkamp, J., Eds.; Wiley-VCH: Weinheim, 2008; Vol. 7, pp 3284−3308. (c) Rylander, P. N. Hydrogenation Methods; Academic Press: London, 1985. (21) For a review on H-atom transfer via transition-metal hydrides, see: (a) Crossley, S.W. M.; Obradors, C.; Martinez, R. M.; Shenvi, R. A. Chem. Rev. 2016, 116, 8912. (b) Eisenberg, D. C.; Norton, J. R. Isr. J. Chem. 1991, 31, 55. (22) Hartwig, J. F. Organotransition Metal Chemistry. From Bonding to Catalysis; University Science Books: Mill Valley, CA, 2010. (23) Partial in situ isomerization of the alkene to be hydrogenated can alter the substrate and result in formal “trans” addition. Likewise, the product, once formed, can engage in thermodynamically driven isomerization processes. (24) The term trans-hydrogenation (boration, silylation, germylation, stannation) of an alkyne as used herein denotes a reaction in which the H- and the E-unit (E = H, BR2, SiR3, GeR3, SnR3) end up 22


Perspective

Journal of the American Chemical Society metal conditions; see: Benkeser, R. A.; Belmonte, F. G. J. Org. Chem. 1984, 49, 1662. Likewise, it is not uncommon to find similar amounts of over-reduced and/or isomerized byproducts in the crude material formed by many of the classical cis-selective semi-hydrogenation protocols. (38) Fuchs, M.; Fürstner, A. Angew. Chem., Int. Ed. 2015, 54, 3978. (39) Jia, G.; Ng, W. S.; Lau, C. P. Organometallics 1998, 17, 4538. (40) Kubas, G. J. Metal Dihydrogen and σ-Bond Complexes; Kluwer Academic/Plenum Publishers: Dordrecht, Netherlands, 2001. (41) (a) Kubas, G. J. Catal. Lett. 2005, 104, 79. (b) Lachaize, S.; Sabo-Etienne, S. Eur. J. Inorg. Chem. 2006, 2006, 2115. (c) Crabtree, R. H. Angew. Chem., Int. Ed. Engl. 1993, 32, 789. (42) (a) Bowers, C. R.; Weitekamp, D. P. Phys. Rev. Lett. 1986, 57, 2645. (b) Pravica, M. G.; Weitekamp, D. P. Chem. Phys. Lett. 1988, 145, 255. (c) Bowers, C. R.; Weitekamp, D. P. J. Am. Chem. Soc. 1987, 109, 5541. (43) (a) Eisenberg, R. Acc. Chem. Res. 1991, 24, 110. (b) Duckett, S. B.; Mewis, R. E. Acc. Chem. Res. 2012, 45, 1247. (c) Bargon, J.; Giernoth, R.; Harthun, A.; Ulrich, C. In Organic Synthesis via Organometallics OSM 5; Helmchen, G., Dibo, J., Flubacher, D., Wiese, B., Eds.; Vieweg: Wiesbaden, 1997; pp 147−154. (44) Leutzsch, M.; Wolf, L. M.; Gupta, P.; Fuchs, M.; Thiel, W.; Farès, C.; Fürstner, A. Angew. Chem., Int. Ed. 2015, 54, 12431. (45) Frohnapfel, D. S.; Templeton, J. L. Coord. Chem. Rev. 2000, 206−207, 199. (46) For the OPSY filter, see: (a) Aguilar, J. A.; Elliott, P. I. P.; Lopez-Serrano, J.; Adams, R. W.; Duckett, S. B. Chem. Commun. 2007, 1183. (b) Aguilar, J. A.; Adams, R. W.; Duckett, S. B.; Green, G. G. R.; Kandiah, R. J. Magn. Reson. 2011, 208, 49. (47) This character can also surface under totally different conditions; see: (a) Alabugin, I. V.; Gold, B. J. Org. Chem. 2013, 78, 7777. (b) Fürstner, A. Chem. Soc. Rev. 2009, 38, 3208. (48) Free carbenes and vinylidenes can insert into H2; see: (a) Kötting, C.; Sander, W. J. Am. Chem. Soc. 1999, 121, 8891. (b) Zuev, P. S.; Sheridan, R. S. J. Am. Chem. Soc. 2001, 123, 12434. (c) Frey, G. D.; Lavallo, V.; Donnadieu, B.; Schoeller, W. W.; Bertrand, G. Science 2007, 316, 439. (d) Henkel, S.; Sander, W. Angew. Chem., Int. Ed. 2015, 54, 4603. (49) For an interesting discussion, see: Berke, H. ChemPhysChem 2010, 11, 1837. (50) For yet another way to make use of this interaction, see: Rummelt, S. M.; Cheng, G.-J.; Gupta, P.; Thiel, W.; Fürstner, A. Angew. Chem., Int. Ed. 2017, 56, 3599−3604; Corrigendum: 2017, 56, 5652. (51) For applications that supposedly involve such species, see: (a) Monnier, F.; Vovard-Le Bray, C.; Castillo, D.; Aubert, V.; Dérien, S.; Dixneuf, P. H.; Toupet, L.; Ienco, A.; Mealli, C. J. Am. Chem. Soc. 2007, 129, 6037. (b) Vovard-Le Bray, C.; Dérien, S.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2009, 48, 1439. (c) Le Paih, J.; Vovard-Le Bray, C.; Dérien, S.; Dixneuf, P. H. J. Am. Chem. Soc. 2010, 132, 7391. (d) Vovard-Le Bray, C.; Dérien, S.; Dixneuf, P. H.; Murakami, M. Synlett 2008, 2008, 193. (e) Cambeiro, F.; López, S.; Varela, J. A.; Saá, C. Angew. Chem., Int. Ed. 2012, 51, 723. (f) Cambeiro, F.; López, S.; Varela, J. A.; Saá, C. Angew. Chem., Int. Ed. 2014, 53, 5959. (g) Padin, D.; Cambeiro, F.; Fañanás-Mastral, M.; Varela, J. A.; Saá, C. ACS Catal. 2017, 7, 992. (h) Qiu, L.; Huang, D.; Xu, G.; Dai, Z.; Sun, J. Org. Lett. 2015, 17, 1810. (i) Ng, F.-N.; Lau, Y.-F.; Zhou, Z.; Yu, W.Y. Org. Lett. 2015, 17, 1676. (j) Tortoreto, C.; Achard, T.; Zeghida, W.; Austeri, M.; Guénée, L.; Lacour, J. Angew. Chem., Int. Ed. 2012, 51, 5847. (k) Austeri, M.; Rix, D.; Zeghida, W.; Lacour, J. Org. Lett. 2011, 13, 1394. (52) For a somewhat related case for ruthenium carbene by redox isomerization followed by intramolecular cyclopropanation, see: Trost, B. M.; Breder, A.; O’Keefe, B. M.; Rao, M.; Franz, A. W. J. Am. Chem. Soc. 2011, 133, 4766. (53) For ruthenacyclopentadienes as dicarbene equivalents in cyclopropanation reactions, see: (a) Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2003, 125, 12143. (b) Schmid, R.; Kirchner, K. Eur. J. Inorg. Chem. 2004, 2004, 2609.

(54) A very recent publication using p-H2 showed that the free acetylene dicarboxylate undergoes trans-hydrogenation with formation of fumarate rather than [3 + 2] cycloadditon, see: Ripka, B.; Eills, J.; Kourilova, H.; Leutzsch, M.; Levitt, M. H.; Münnemann, K. Chem. Commun. 2018, 54, 12246. (55) Frihed, T. G.; Fürstner, A. Bull. Chem. Soc. Jpn. 2016, 89, 135. (56) For instructive illustrations of scope and limitations, see: (a) Fürstner, A.; Bonnekessel, M.; Blank, J. T.; Radkowski, K.; Seidel, G.; Lacombe, F.; Gabor, B.; Mynott, R. Chem. - Eur. J. 2007, 13, 8762. (b) Lehr, K.; Mariz, R.; Leseurre, L.; Gabor, A.; Fürstner, A. Angew. Chem., Int. Ed. 2011, 50, 11373. (c) Lehr, K.; Schulthoff, S.; Ueda, Y.; Mariz, R.; Leseurre, L.; Gabor, B.; Fürstner, A. Chem. - Eur. J. 2015, 21, 219. (d) Mata, G.; Wölfl, B.; Fürstner, A. Chem. - Eur. J. 2018, DOI: 10.1002/chem.201805490. (57) Lacombe, F.; Radkowski, K.; Seidel, G.; Fü rstner, A. Tetrahedron 2004, 60, 7315. (58) Chung, L. W.; Wu, Y.-D.; Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2003, 125, 11578. (59) Ding, S.; Song, L.-J.; Chung, L. W.; Zhang, X.; Sun, J.; Wu, Y.D. J. Am. Chem. Soc. 2013, 135, 13835. (60) Fürstner, A.; Radkowski, K. Chem. Commun. 2002, 2182. (61) (a) Trost, B. M.; Ball, Z. T.; Jöge, T. Angew. Chem., Int. Ed. 2003, 42, 3415. (b) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2003, 125, 30. (c) Trost, B. M.; Ball, Z. T.; Laemmerhold, K. M. J. Am. Chem. Soc. 2005, 127, 10028. (62) For use of a different catalyst system, see: (a) Denmark, S. E.; Pan, W. Org. Lett. 2002, 4, 4163. (b) Denmark, S. E.; Pan, W. Org. Lett. 2003, 5, 1119. (63) Diethelm, S.; Carreira, E. M. J. Am. Chem. Soc. 2015, 137, 6084. (64) Rummelt, S. M.; Radkowski, K.; Roşca, D.-A.; Fürstner, A. J. Am. Chem. Soc. 2015, 137, 5506. (65) Roşca, D.-A.; Radkowski, K.; Wolf, L. M.; Wagh, M.; Goddard, R.; Thiel, W.; Fürstner, A. J. Am. Chem. Soc. 2017, 139, 2443. (66) Rummelt, S. M.; Fürstner, A. Angew. Chem., Int. Ed. 2014, 53, 3626. (67) (a) Aullón, G.; Bellamy, D.; Brammer, L.; Bruton, E. A.; Orpen, A. G. Chem. Commun. 1998, 653. (b) Kovács, A.; Varga, Z. Coord. Chem. Rev. 2006, 250, 710. (68) Such H-bonding can also be intermolecular as observed for certain secondary propargyl alcohols; see ref 65. (69) Sundararaju, B.; Fürstner, A. Angew. Chem., Int. Ed. 2013, 52, 14050. (70) Brown, H. C. Hydroboration; W. A. Benjamin Inc.: New York, 1962. (71) trans-Hydroborations of terminal alkynes likely proceed via metal vinylidene intermediates; in this case, it is the alkyne proton rather than the H-atom of the borane reagent that ends up trans to boron as proven by labeling studies. See: (a) Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc. 2000, 122, 4990. (b) Gunanathan, C.; Hölscher, M.; Pan, F.; Leitner, W. J. Am. Chem. Soc. 2012, 134, 14349. See also: (c) Gorgas, N.; Alves, L. G.; Stöger, B.; Martins, A. M.; Veiros, L. F.; Kirchner, K. J. Am. Chem. Soc. 2017, 139, 8130. For methods that seem to proceed via carbenes rather than vinylidenes and might be true trans-hydroborations, see: (d) Obligacion, J. V.; Neely, J. M.; Yazdani, A. N.; Pappas, I.; Chirik, P. J. J. Am. Chem. Soc. 2015, 137, 5855. (e) Jang, W. J.; Lee, W. L.; Moon, J. H.; Lee, J. Y.; Yun, J. Org. Lett. 2016, 18, 1390. (72) For an interesting outer-sphere process, see: Yang, Y.; Jiang, J.; Yu, H.; Shi, J. Chem. - Eur. J. 2018, 24, 178. (73) For leading references, see the following and literature cited therein: (a) Kim, H. R.; Yun, J. Chem. Commun. 2011, 47, 2943. (b) Nagao, K.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc. 2014, 136, 10605. (c) Shimoi, M.; Watanabe, T.; Maeda, K.; Curran, D. P.; Taniguchi, T. Angew. Chem., Int. Ed. 2018, 57, 9485. (d) Fritzemeier, R.; Gates, A.; Guo, X.; Lin, Z.; Santos, W. L. J. Org. Chem. 2018, 83, 10436. (e) Yuan, K.; Suzuki, N.; Mellerup, S. K.; Wang, X.; Yamaguchi, S.; Wang, S. Org. Lett. 2016, 18, 720. (74) In ref 69, the products formed in the [Cp*Ru]-catalyzed hydroboration of 4,4-dimethyl-2-butyne have been misassigned 23


Perspective

Journal of the American Chemical Society (Table 3, entry 2); actually, they are the regioisomeric Z- rather than E-alkenes. (75) Song, L.-J.; Wang, T.; Zhang, X.; Chung, L. W.; Wu, Y.-D. ACS Catal. 2017, 7, 1361. (76) For a pioneering study, see: Schubert, U.; Kunz, E.; Harkers, B.; Willnecker, J.; Meyer, J. J. Am. Chem. Soc. 1989, 111, 2572. (77) For trans-hydrogermylations, see also: (a) Matsuda, T.; Kadowaki, S.; Yamaguchi, Y.; Murakami, M. Org. Lett. 2010, 12, 1056. (b) Matsuda, T.; Kadowaki, S.; Murakami, M. Chem. Commun. 2007, 2627. (78) For pertinent σ-silane ruthenium complexes, see: (a) Gutsulyak, D. V.; Churakov, A. V.; Kuzmina, L. G.; Howard, J. A. K.; Nikonov, G. I. Organometallics 2009, 28, 2655. (b) Osipov, A. L.; Vyboishchikov, S. F.; Dorogov, K. Y.; Kuzmina, L. G.; Howard, J. A. K.; Lemenovskii, D. A.; Nikonov, G. I. Chem. Commun. 2005, 3349. (79) Alternative methods for trans-hydrostannation of alkynes are not discussed herein; they use strong Lewis acids or frustrated Lewis pairs or operate under free radical conditions; a compilation of leading references is found in ref 55; for a recent example, see: Forster, F.; Rendón López, V. M.; Oestreich, M. Organometallics 2018, 37, 2656. (80) Schaubach, S.; Michigami, K.; Fürstner, A. Synthesis 2016, 49, 202. (81) Mo, X.; Letort, A.; Roşca, D.-A.; Higashida, K.; Fürstner, A. Chem. - Eur. J. 2018, 24, 9667. (82) For related use of C-silyl substituents as protecting and directing groups, see: (a) Gallenkamp, D.; Fürstner, A. J. Am. Chem. Soc. 2011, 133, 9232. (b) Fürstner, A.; Nagano, T. J. Am. Chem. Soc. 2007, 129, 1906. (c) Nagano, T.; Pospíšil, J.; Chollet, G.; Schulthoff, S.; Hickmann, V.; Moulin, E.; Herrmann, J.; Müller, R.; Fürstner, A. Chem. - Eur. J. 2009, 15, 9697. (d) Bressy, C.; Bargiggia, F.; Guyonnet, M.; Arseniyadis, S.; Cossy, J. Synlett 2009, 2009, 565. (83) (a) Main Group Metals in Organic Synthesis, Vol. 1−2; Yamamoto, H., Oshima, K., Eds.; Wiley-VCH: Weinheim, 2004. (b) Dobbs, A. P.; Chio, F. K. I. In Comprehensive Organic Synthesis II, 2nd ed.; Knochel, P., Molander, G. A., Eds.; Elsevier: Amsterdam, 2014; Vol. 8; pp 964−998. (84) Huwyler, N.; Radkowski, K.; Rummelt, S. M.; Fürstner, A. Chem. - Eur. J. 2017, 23, 12412. (85) Kwon, Y.; Schulthoff, S.; Dao, Q. M.; Wirtz, C.; Fürstner, A. Chem. - Eur. J. 2018, 24, 109. (86) Sommer, H.; Fürstner, A. Org. Lett. 2016, 18, 3210. (87) Drouin, M.; Hamel, J.-D.; Paquin, J.-F. Synthesis 2018, 50, 881. (88) Sommer, H.; Fürstner, A. Chem. - Eur. J. 2017, 23, 558. (89) Sommer, H.; Hamilton, J. Y.; Fürstner, A. Angew. Chem., Int. Ed. 2017, 56, 6161. (90) See ref 55 for a comprehensive treatise of trans-hydrosilylation in natural product synthesis. (91) Rummelt, S. M.; Preindl, J.; Sommer, H.; Fürstner, A. Angew. Chem., Int. Ed. 2015, 54, 6241. (92) Reddy, G. V.; Kumar, R. S. C.; Siva, B.; Babu, K. S.; Rao, J. M. Synlett 2012, 23, 2677. (93) Wilson, R. M.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2010, 49, 6032. (94) (a) Szpilman, A. M.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 9592. (b) Fürstner, A. Isr. J. Chem. 2011, 51, 329. (c) Wach, J.-Y.; Gademann, K. Synlett 2012, 2012, 163. (95) Meng, Z.; Souillart, L.; Monks, B.; Huwyler, N.; Herrmann, J.; Müller, R.; Fürstner, A. J. Org. Chem. 2018, 83, 6977. (96) (a) Allmendinger, T.; Furet, P.; Hungerbühler, E. Tetrahedron Lett. 1990, 31, 7297. (b) Allmendinger, T.; Felder, E.; Hungarbühler, E. Tetrahedron Lett. 1990, 31, 7301. (97) Grieco, P. A.; Schillinger, W. J.; Yokoyama, Y. J. Med. Chem. 1980, 23, 1077. (98) (a) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 1995, 117, 9586. (b) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 2008, 130, 11970. (99) For an improved catalyst, see: (a) Schaubach, S.; Gebauer, K.; Ungeheuer, F.; Hoffmeister, L.; Ilg, M. K.; Wirtz, C.; Fürstner, A.

Chem. - Eur. J. 2016, 22, 8494. (b) Gebauer, K.; Fürstner, A. Angew. Chem., Int. Ed. 2014, 53, 6393. (100) For yet another recent illustration of this aspect, see: Karier, P.; Ungeheuer, F.; Ahlers, A.; Anderl, F.; Wille, C.; Fürstner, A. Angew. Chem., Int. Ed. 2018, DOI: 10.1002/anie.201812096.

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trans-Hydrogenation, gem-Hydrogenation, and trans-Hydrometalation

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