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

Subscriber access provided by The Libraries of the | University of North Dakota

Perspective

trans-Hydrogenation, gem-Hydrogenation and trans-Hydrometalation of Alkynes. An Interim Report on an Unorthodox Reactivity Paradigm Alois Fürstner J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09782 • Publication Date (Web): 13 Nov 2018 Downloaded from http://pubs.acs.org on November 13, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

trans-Hydrogenation, gem-Hydrogenation and transHydrometalation of Alkynes. An Interim Report on an Unorthodox Reactivity Paradigm Alois Fürstner Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany ABSTRACT: cis-Delivery of H2 to the -system of an unsaturated substrate is the canonical course of metal catalyzed hydrogenation reactions. The semi-reduction of internal alkynes with the aid of [Cp*Ru]-based catalysts violates this rule and affords E-alkenes by direct trans-hydrogenation. A pathway involving -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 gem-hydrogenation 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 vicinity to the reacting triple bond provide opportunities for imposing selectivity and control. Moreover, it is shown that catalytic transhydrogenation 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.

INTRODUCTION During the last decade, our group developed a new generation of catalysts for alkyne metathesis such as [PhCMo(OSiPh3)3], which outperform all ancestors 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 Scheme 1. The Conceptual Framework gem-hydrogenation

trans-hydrogenation R2

R1

canonical cis-hydrogenation

H2 / catalyst

R1

R2 H H

R

1

R

2

overreduction H H R1

R2

H

H

H

R2

H H

R

1

H

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 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 reducing agent to ensure selective reduction of the triple bond without affecting the other -systems of this polyunsaturated substrate.13,14 These (and many other) examples show that the practitioner can actually choose amongst various methods in case optimization is required. The situation is much less comfortable when it comes to alkyne semi-reduction to the corresponding E-alkene. Although dissolving metal reductions using (earth) alkali metals in liquid ammonia or amines are usually highly Eselective, they show a very narrow functional group compatibility and therefore hardly ever qualify for

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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.16,17,18 Alternative procedures that have been applied to more than a handful of examples are basically missing.19 Scheme 2. Late-Stage Applications of Prototype Methods for Alkyne cis-Reduction

H AcO

RCAM 88%

O

H

H2 (1 atm) Lindlar catalyst RO

quinoline EtOH/1-hexene 84%

O

H H2 (1 atm) P2-Ni cat.

O H

K2CO3

H

84%

This canonical scenario implies that the development of an E-selective alkyne semi-hydrogenation catalyst likely mandates paradigm change. Summarized below are our initial steps towards 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 transhydrometalation reactions which pave the way to certain trisubstitued alkene motifs in 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. NATURAL PRODUCT SYNTHESIS AS THE TEASER The lack of a functional group tolerant method for the trans-hydrogenation 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 selective cell migration inhibitors and hence potential lead compounds in the quest for antimetastatic drug candidates.

H

O

EtOH

O H O H

H

O

R = Ac Neurymenolide A R = H

RCAM 79%

H

O

Page 2 of 17

O H O H

hybridalactone

Scheme 3. E-Alkene Lactimidomycin

RCAM 61% HO

O

aq. THF/MeOH

O

O

92%

O

RCAM 85%

OBz

H HO

O

OBz

OTES

BnMe2SiH

O

1

O

2

leiodermatolide

O O

to

SiMe2Bn

O

MOMO

Route

[Cp*Ru(MeCN)3]PF6 cat.

OTES

H HO

En

Zn(Cu/Ag)

HO

MOMO

Formation

TBAF, 73%

O

over both steps

O

O OH

HN O 3

The disparity in the number of available methods for stereo-complementary alkyne semi-reduction hardly comes as a surprise. Basically all (transition) metal catalysts afford Z-alkenes 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 bond, followed by migratory insertion of the substrate’s -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

O

HO

O

O O

O

Lactimidomycin

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 12membered ring 1 (Scheme 3).25 Since none of the known procedures for E-selective semi-reduction 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 got 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

ACS Paragon Plus Environment

Page 3 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

asymmetric Mukaiyama aldol chemistry was also straightforward, a scalable entry into lactimidomycin (and a host of analogues for biological profiling) was secured.25 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 trans-delivery, in contrast, are exceedingly rare.30,31

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. Scheme 5. Propargyl Priviledged Substrates

[Cp*RuCl]4 (2 mol%) MeO

O

O

O O

O

O

H

O

H2 (10 atm), CH2Cl2, 30 min

O HO

O

O MeO

5 88%, E:Z = 95:5

H

5 E:Z = 98:2

89%

Br

N

4

O

6

87%, E:Z = 95:5

66%, E:Z = 96:4

OH

O SMe

OMe

X COOMe

67%, E:Z = 97:3 88%, E:Z = 99:1 X = CHO 86% X = CN 85% OH

Ts N

O

62% (E:Z > 98:2)

OH

Ts N

OH

67% O

4

OMe OMe

74% (E:Z = 97:3)

H2 (1 atm) CH2Cl2, 84%

[Cp*RuCl]4 (2 mol%) H2 (1 atm) DCE, 70°C, 60%

OH

H

H MeO

O

O

7

OH H

H

O

9

O

AgOTf (5 mol%) 4

as

O

Cl

O

O

6

8

Ru

Derivatives

OH

OH

Scheme 4. Leading Finding and Model Compounds (5.5 mol%)

Alcohol

O O

8 80%, E:Z = 92:8

NO2 O

We were therefore pleased to find that hydrogenation of cycloalkyne 4 as the model compound with catalytic amounts of [Cp*Ru(MeCN)3]PF6, [Cp*RuCl(cod)]/AgOTf, [Cp*RuCl(cod)] or [Cp*RuCl]4 32 in CH2Cl2 as the preferred solvent furnished 5 with good to excellent Eselectivity (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 one atmosphere of H2 (balloon), although certain substrates do require gentle heating.34 Importantly, control experiments showed that the E-selectivity is not caused

Important limitations, however, must also be mentioned. Specifically, substrates able to bind to the [Cp*Ru] fragment via kinetically stable 4 or 6 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 Esuberenol (7) is instructive in that the electron rich resorcinol subunit did not prevent productive transhydrogenation 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 chemoand stereoselectivity of the new trans-hydrogenation is also apparent from the semi-reduction 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 group in binding to the catalyst, tertiary

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

propargyl alcohols tend to be good substrates for transhydrogenation.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 Scheme 6. Alkyne trans-Hydrogenation and Competing Isomerization: The Brefeldin A Case OTBS O TBSO

10

O

RCAM 67% [Cp*Ru(MeCN)3]PF6 cat. H2 (30 bar), CH2Cl2

H

OTBS

O

H

O

TBSO

OTBS

O O

Page 4 of 17

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

TBSO H

11 (E:Z = 99:1) 56% @ 1.15 g scale

H

OTBS

X

O O

TBSO aq. HCl

94% 12a,b (20%, combined)

H HO

OH

Ru

O

O

O

O

O

13 O

(10 mol%)

H2 (10 atm), -78°C to RT 4

O

H H

quant. (NMR)

O

O

5 E:Z = 95:5

H

O

H

Brefeldin A H

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 stereoselectivity of product 11 left nothing to be desired. The reducible enoate, the lactone and the TBSethers all remained intact during alkyne transhydrogenation; 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 by-products 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-hydrogenation 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

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 trans-hydrogenation 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. Importantly, the metal has not broken the HH bond; rather the -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 (2-vinyl complex)45 which transforms in a concerted process into the desired Ealkene F: importantly, the stereo-determining transition state conncecting B and F is low-lying (G≠ = 5.1

kcalmol-1 for 2-butyne).34,44 Moreover, the productforming 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

ACS Paragon Plus Environment

Page 5 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

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 vicinity, which are able to coordinate onto and hence stabilize an emerging carbene center.

Scheme 8. trans- and gem-Hydrogenation Intertwined Processes (Key Intermediates Only) Cp*

E-alkene

Cll

Ru

R

alkyne + H2

H H R

A Cp*

Cl R

Cp*

Ru H

Cl

F

Ru H

R

H

concerted trans-hydrogenation

H2

Cp* Cl

Ru

R H

H R

Ru

H

H2

R

R

H

H

D

H

gem-H2 DELIVERY: HYDROGENATIVE FORMATION OF METAL CARBENE COMPLEXES

genuine carbene reactivity

O

O H H

H

C

H

H2 Cl R

H

O H

H

H

1.7 1.8 O

Ru

1.9

Cl

2.5

H H

2.6 2.7 5.35

5.25

4.60

2.20

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

Ru

Cll

E

Cp*

H

positional isomers

R

B

gemhydrogenation

Cp*

H H

H R

R

stepwise trans-hydrogenation

overreduction

as

mechanism requiring coordination of a second molecule of H2 as a barrier-lowering ancillary ligand to the ruthenium carbene initially formed.34,44

1.40

1.35

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 p-H2/[Cp*Ru(cod)Cl] with the corresponding E-alkene, the positional alkene isomer, the over-reduced product as well as H2. DFT also revealed that the fate of the piano-stool ruthenium carbene C is largely selectivitydetermining: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

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 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 1,2-dicarbene synthon (Scheme 9):47 one “carbene” intercepts the [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.

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 9. The Formalism Underlying gemHydrogenation: Alkynes as 1,2-Dicarbene Synthons [Ru] R

1

R

2

H2

[Ru]

H

seems possible to outperform this pathway by other fast (intermolecular) processes even under an H2 atmosphere. If so, the newly discovered gem-alkyne hydrogenation would open an unprecedented gateway for harnessing genuine carbene reactivity.

[Ru] R2

R1

Page 6 of 17

H

R1

R2 H H

Scheme 10. Harnessing Genuine Carbene Reactivity [Cp*RuCl]4 cat. H2 (1 bar)

OMe

HO

MeO

14

[Cp*Ru(cod)Cl]

H

OMe OMe Ru Cp*

H2 (1 bar)

18

O

CH2Cl2

Me

H

Cl

O 19 (85%, >95%, NMR)

15 O

H H C = 340.9 ppm

OEt

2

H = 2.09/3.11 ppm 2

MeO 17

[Cp*RuCl]4 cat. HO

O

[Ru]

OMe

p-H2, CD2Cl2

Cl Ru O

MeO

93%

16

H2 (1 bar), THF

EtO

JH,H = -16.0 Hz

[Cp*RuCl]4 (1.25 mol%)

O

67%

O

[Ru]

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 hydrogen bond acceptor will 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 gem-hydrogenation 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

O

OEt

O EtO

OEt

EtO EtO

O

O

O

20

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

O

OEt

EtO

O

21

EtO

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 hydrogenation of 18, which implies regioselective formation of a metal carbene intermediates 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. trans-HYDROSILYLATION The pathfinding discovery of alkyne trans-hydrosilylation reported by Trost and coworkers 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-

ACS Paragon Plus Environment

Page 7 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

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 trans-hydrogenation. This interpretation is in excellent agreement with early computational studies which pointed towards 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 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. Scheme 11. Intramolecular /Oxidation Sequence HO

O

N H O Boc

22

O

2. 3 M HCl, 97%

Ru N OMe

N OMe

H C6H13

SiR3 R3SiH C6H13

alpha/trans

PF6 H3CCN Ru NCCH3 H3CCN

[Ru] (5 mol%)

X OH

H O  = 5.07 ppm H

24

Scheme 12. Regiocontrol by Proper Choice of Catalyst

OH

Cl

O

N H O H Gelsemoxonine

OH

C = 130.1 ppm C = 154.7 ppm

N H O Boc

23

HO

O

O

Me2Si

[RuCl2(C6H6)]2 58%

1. KHF2, Ac2O H2O2, 65%

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 (  50-70 ppm, Figure 3).64,65 Moreover, the distinctive 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 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 * orbital of the substrate.

trans-Hydrosilylation

(Me2SiH)2NH, then N OMe

[Cp*Ru(MeCN)3]PF6 by the neutral analogue [Cp*RuCl]4 to reach almost exclusive trans-hydrosilylation at the site proximal to the -OH group.64,65,66 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

SiR3

Ru

C6H13

X

H

Ru

X Ru X Ru

X = Cl

beta/trans

R3SiH

[Ru]

Solvent

Yield (%)

:

Et3SiH

[Cp*Ru(MeCN)3]PF6

CH2Cl2

86

43:57

[Cp*RuCl]4

pentane

99

100:0

BnMe2SiH

[Cp*RuCl]4

pentane

92

100:0

(EtO)3SiH

[Cp*RuCl]4

pentane

86

100:0

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

Figure 3. Structural and Spectroscopic Data of Complex 24 formed from [Cp*RuCl] and a Propargyl Alcohol. Orbital interaction diagrams confirmed the massive activation of the alkyne upon coordination to the [Cp*RuCl] fragment.65 Actually, both orthogonal systems of the triple bond seem to be engaged in 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 -complex, yet the enthalpic gain 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. trans-HYDROBORATION The notion that metal catalyzed trans-addition to alkynes might be a more general reactivity mode rather than a

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

singularity encouraged us to extent 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 hydroboration is the textbook example of a strictly orbital-controlled and hence suprafacial synaddition 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.71,72,73 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 6-adducts; (pin)BH is therefore currently the best choice.69 With regard to the mechanism, ruthenacyclopropenes are again believed to be key intermediates.75 Scheme 13. cis- and trans-Hydroboration; Structure of a Prototype trans-Addition Product in the Solid State H BX2 R

R R

X2BH

H

BX2

R

R

cis-addition

A

RH R

[Cp*Ru] cat. R trans-hydroboration

H R

Page 8 of 17

complexes of stannanes had been known for some time,76 no example comprising Ru as the central metal was reported at the outset of our investigations. After considerable experimentation, we managed to grow crystals of complex 25 stabilized by (iPr)3P as ancillary ligand (Figure 4).64 This 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 -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 Sn-atom 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 trans-hydrostannations tend to be more regioselective than trans-hydrosilylations (germylations),64,65,77 as the crucial ClE interaction is stronger for E = Sn than for E = Si, Ge.78

BX2

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 trans-addition. This propensity deprives us of the ability to control the regiochemical course of transhydroboration by taking advantage of the formation of a peripheral hydrogen bonding array between a protic site in the substrate and a chloride-containing ruthenium catalyst. The regiochemical course of ruthenium catalyzed trans-hydroborations of unsymmetrical internal alkynes is therefore largely determined by steric factors. trans-HYDROSTANNATION AND GERMYLATION During our mechanistic investigations into transhydrogenation we learned that a -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 -

iPr3P Ru H H = -10.29 ppm

Cl

SnBu3

Sn = +57.0 ppm (JSn,H = 192 Hz)

H R3M-H

MR3

OH

Ru

Ru

M = Si, Ge, Sn

Cl O

H

H

H MR3 Cl

O H

OH MR3

proximal & trans delivery

Figure 4. Top: Structure of the -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 Newmantype projection of the loaded catalyst and the ensuing metallacyclopropene

ACS Paragon Plus Environment

Page 9 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

DFT studies confirm the close mechanistic ties between trans-hydrostannation, trans-hydrosilylation, transhydroboration 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 gemhydrogenation.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 Scheme 14. An “Armed” Substrate

R

Ru

R3MH

Ru R

R

R 3M

G

HO R

[Cp*Ru]

R

H R

I

H

Cl Ru

Cl Ru

no / slow turnover

R

O

HO

R3MH

R

alpha/trans

J

H

R MR3

K

R

trans-hydrometalation 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 -system.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 trans-hydrostannation 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 Scheme 15. Exhaustive and Hydrostannation of a Diyne

O

CH2Cl2, 66% RCAM 91%

OH

trans-

C9H19

Bu3SnH SnBu3

O 27

26

H

OH

50% (71% brsm) NBoc SnBu3

C9H19 OH

H

C9H19

O

SnBu3

29

O

DCE, reflux

H

O Aspicilin

[Cp*RuCl]4 cat.

28

OH

NBoc SnBu3

OH

Bu3SnH

O

[Cp*RuCl]4 cat. CH2Cl2, -20°C 80-84%

HO

OH

NBoc

Bu3SnH

O

[Cp*RuCl]4 cat.

O

Selective

OH

30

H

Lindlar

O

O

In preparative terms, trans-hydrostannation is arguably the most general and selective of the different transaddition processes described herein, at least at the present stage of development.64,65,66,79 It is distinguished by a remarkable substrate scope; so far, only 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, 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 likely 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

HO HO

OH O

C19H39

HN

NBoc SnBu3

O

OH

C8H17 OH

H

H

O

OH

H

OH

31

Typhonoside F O

HO HO

OH O HO

C19H39

HN O

OH OH

C8H17 Typhonoside E

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 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 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 siteselective trans-hydrostannation of the propargyl alcohol subunit of 28 gains an additional strategic role: the R3Sngroup protects the E-alkene in 30 against further

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

reduction and hence enables safe “off-site” Lindlar hydrogenation of the lateral -system.81,82 This particular example also showcases the superior performance of trans-hydrostannation, since trans-hydrosilylation of 28 failed even when attempted in entropically favored intramolecular format.81 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 and useful.83 Scheme 16 summarizes the progress made so far. The arguably most relevant transformation is the stereoretentive C-methylation 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-nbutylammonium phosphinate as an essentially non-basic tin scavenger and copper thiophene-2-carboxylate (CuTC) as promoter. The 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 Scheme 16.a H R

OH

1

R2

L

H H H OAc R1

H

a)

R2

R

O

H

g)

P

R1

OH R2 M

1

Me

OH

E = Sn: b) or c) E = Si: d)

2  R ER3

e) f) H R

OH

1

R F

H 2

O

R

1

OH R2 COOMe

N

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/2methylTHF; e) Pd(OAc)2 cat., Ph3As cat., TFA (40 mol%), 1,4-benzoquinone, CO (1 atm), MeOH; f) AgOP(O)Ph2, FTEDA-PF6, acetone; g) Cu(OAc)2, Et3N, DMSO a

Page 10 of 17

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 co-catalyst, 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 F-TEDA-PF6 in combination with nonhygroscopic and bench stable silver phosphinate serving as a -affine promotor and non-basic 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-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 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

ACS Paragon Plus Environment

Page 11 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

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 involved ring closing alkyne metathesis (RCAM) followed by hydroxy-directed transhydrostannation of the propargyl alcohol subunit embedded in the macrocyclic frame of 32; as expected, this transformation was exquisitely regio- and stereoselective (/ > 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 8,9-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 combination with transhydrometalation is certainly a competitive, if not even superior tactic.8

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 Scheme 18. Furhtrer Example of Trisubstitued Alkenes by RCAM/trans-Hydrometalation Bu3SnH [Cp*RuCl]4 cat.

O O

O

O

O

OH

OH

O

34

O O

O

35 + regioisomer

OH

disciformycin B HO Cl

O O

NMe

N H

H N O

Cl

OR Cl OH

O

O

Bu3SnH [Cp*RuCl]4 cat. O

80%

O

NMe

Ph

HO

RCAM 66-83%

36

NMe

nannocystin Ax

H N

N H

O

O

SnBu3

Cl

O O

OH

O

O

O

H

OH

OH

OH

MeO

OH

OH

O SnR3

O O

O

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

O

O

N H Me

H N O

O

HO OH

H

OH

OR Cl OH

O Ph

37

Cl OH ten non-natural analogues

O Ph

MeO

O

RCAM 87%

O

O

O

O

78%

69%

77%

OH

OH OH

OH

Bu3Sn

Bu3SnH

Me OH

[Cp*RuCl2]n cat.

O

OH 92%

83%, E:Z > 20:1 O

O

32

O

81%

O

33

O

Dihydrocineromycin B

84%

OAc

O

OH

O

F OH

O

O

OH

O

O

An additional bonus of passing through an alkenylstannane is the fact that this functional group can serve as 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 deepseated structural “point-mutations” (Scheme 17).91,86,88

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 transhydrostannation 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 transhydrometalation of 36 was not compromised by the protic amide linkages in the periphery; the high chemoselectivity is also noteworthy. Since the trisubstituted 5,6-alkene unit and the neighboring C7OMe had been proposed to be 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 ten non-natural analogues provided valuable insights into structure/activity relationships.95 Scheme 19. Regio- and Stereoselective Synthesis of Fluoroalkenes

The notion that alkyne metathesis in general enables stereoselective access to certain trisubstituted alkene motifs is deemed a conceptual advance. This strategy also

ACS Paragon Plus Environment

Journal of the American Chemical Society Ph

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Ph

Ph

O

O

NHCbz

N H

NH

Ph

Bu3SnH [Cp*RuCl]4 cat. H 9C 4

O

38

H H 9C 4

NH

NHCbz

N H

F-TEDA-PF6

SnBu3 AgOP(O)Ph 2 83%

39

Ph H

HO

H

C9H19

Q

OH

42

R

Bu3SnH OTIPS OH

F

N H

O

N H

2. Pd(OAc)2 cat., Ph3As cat.

H

TFA (40 mol %) 1,4-benzoquinone CO (1 atm), MeOH

OTIPS

OTBS

OTIPS

46

70% O O

OH

HO

OMe

MOMO

Scheme 20. Formal Total Synthesis of Tubelactomicin

OMe

HO

H

O

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 late-stage 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

88%

O

1. TBSCl, DMAP, 91%

OH 45

Whereas the nannocycstin case demonstrates that ruthenium catalyzed trans-hydrometalation is not disturbed by a peptidic micro-environment, the synthesis of fluoroalkene 40 shows how to make productive use of a peptidic linkage (Scheme 19).88 Just like a propargylic OH group, an 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 transhydrostannation 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

[Cp*RuCl2]n cat.

44

SnBu3

O

N

H

HO

TIPSO

HO

H

O 41

40

F

O

tBuO

43

H

NBoc F

OH

N H

NH

NHCbz

H 9C 4

OMe F

O

O

O HO

O

Ph

O

Page 12 of 17

O

47

O

OH

SnBu3

Tubelactomicin A

OH

Scheme 21. Total Synthesis of Paecilonic Acid A OH

O

11

BnO

12

OMe

OBn

O

49 48 OH Bu3SnH

H OMe

BnO

[Cp*RuCl]4 cat. 83%

SnBu3

OBn

O

50 OAc

Cu(OAc)2 Et3N

BnO

OMe O

OBn

O

51

77% OH O 12

11

O

OH O Paecilonic acid A

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 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 methoxycarborbonylation 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

ACS Paragon Plus Environment

Page 13 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

propargyl alcohol 49. This key intermediate was reached in isomerically pure form by organocatalytic transdihydroxylation of the commercial enal 48 and catalytic asymmetric aldehyde alkynylation. transHydrostannation of 49 afforded multigram amounts of the -stannylated 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 CONCLUSIONS AND OUTLOOK Before the turn of the millennium, metal induced or metal catalyzed 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 has become available, which qualify for applications 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 Hsources. 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 was largely improved in recent years, it remains opaque why only 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. AUTHOR INFORMATION

Corresponding Author *[email protected] ORCID Alois Fürstner: 0000-0003-0098-3417 Notes Patents filed for hydrostannation

trans-hydroboration

and

trans-

ACKNOWLEDGEMENTS I like to thank all coworkers 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.

REFERENCES (1) Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner, A. J. Am. Chem. Soc. 2010, 132, 11045. (2) Heppekausen, J.; Stade, R.; Kondoh, A.; Seidel, G.; Goddard, R.; Fürstner, A. Chem. Eur. J. 2012, 18, 10281. (3) Fürstner, A. Angew. Chem., Int. Ed. 2013, 52, 2794. (4) They even prompt the cleavage of the NN triple bond of aryldiazonium salts, see: Lackner, A. D.; Fürstner, A. Angew. Chem., Int. Ed. 2015, 54, 12814. (5) (a) Fürstner, A.; Seidel, G. Angew. Chem., Int. Ed. 1998, 37, 1734. (b) Fürstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108. (c) Fürstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 1999, 121, 9453-9454. (6) Fürstner, A. Angew. Chem., Int. Ed. 2014, 53, 8587. (7) For an example, see: Ungeheuer, F.; Fürstner, A. Chem. Eur. J. 2015, 21, 11387. (8) Fürstner, A. Science 2013, 341, 1229713. (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. For other pertinent examples, see: (b) (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. Sci. Synth.; Thieme: Stuttgart, 2006, Vol. 8; pp 43-132. (c) Kaiser, E. M. Synthesis 1972, 391. (d)

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Brandsma, L.; Nieuwenhuizen, W. F.; Zwikker, J. W.; Mäeorg, U. Eur. J. Org. Chem. 1999, 775. (16) Saito, S. Sci. Synth.; Thieme: Stuttgart, 2004, Vol. 7, pp 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. 2012, 42, 103. (18) (a) Rossi, R.; Carpita, A. Synthesis 1977, 561. (b) Hojo, M.; Masuda, R.; Takagi, S. Synthesis 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, 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: 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 trans to each other. For the formalism of nomenclature, however, the resulting products are correctly termed Z-configured for E = SiR3, GeR3, SnR3 but E-configured for E = H, BR2. (25) (a) Micoine, K.; Fürstner, A. J. Am. Chem. Soc. 2010, 132, 14064. (b) Micoine, K.; Persich, P.; Llaveria, J.; Lam, M.-H.; Maderna, A.; Loganzo, F.; Fürstner, A. Chem. Eur. J. 2013, 19, 7370. (26) (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726. (b) Trost, B. M.; Ball, Z. T.; Jöge, T. J. Am. Chem. Soc. 2002, 124, 7922. (c) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005, 127, 17644. (27) Trost, B. M.; Ball, Z. T. Synthesis 2005, 853. (28) Short review: Swamy, K. C. K.; Reddy, A. S.; Sandeep, K.; Kalyani, A. Tetrahedron Lett. 2018, 59, 419. (29) For leading references, see: (a) Abley, P.; McQuillin, F. J. J. Chem. Soc. D 1969, 1503. (b) Tani, K.; Iseki, A.; Yamagata, T. Chem. Commun. 1999, 1821. (c) Yoshida, T.; Youngs, W. J.; Sakaeda, T.; Ueda, T.; Otsuka, S.; Ibers, J. A. J. Am. Chem. Soc. 1983, 105, 6273. (d) Shirakawa, E.; Otsuka, H.; Hayashi, T. Chem. Commun. 2005, 5885. (e) Cho, C. S.; Kim, D. T.; Shim, S. C. Bull. Korean Chem. Soc. 2009, 30, 1931. (f) Luo, F.; Pan, C.; Wang, W.; Ye, Z.; Cheng, J. Tetrahedron 2010, 66, 1399. (g) Shen, R.; Chen, T.; Zhao, Y.; Qiu, R.; Zhou, Y.; Yin, S.; Wang, X.; Goto, M.; Han, L.-B. J. Am. Chem. Soc. 2011, 133, 17037. (h) Li, J.; Hua, R. Chem.Eur. J. 2011, 17, 8462. (i) Srimani, D.; Diskin-Posner, Y.;

Page 14 of 17

Ben-David, Y.; Milstein, D. Angew. Chem., Int. Ed. 2013, 52, 14131. (j) Chen, T.; Xiao, J.; Zhou, Y.; Yin, S.; Han, L.-B. J. Organomet. Chem. 2014, 749, 51. (k) Richmond, E.; Moran, J. J. Org. Chem. 2015, 80, 6922. (l) Liu, Y.; Hu, L.; Chen, H.; Du, H. Chem.Eur. J. 2015, 21, 3495. (m) Karunananda, M. K.; Mankad, N. P. J. Am. Chem. Soc. 2015, 137, 14598. (n) Higashida, K.; Mashima, K. Chem. Lett. 2016, 45, 866. (o) Kusy, R.; Grela, K. Org. Lett. 2016, 18, 6196. (p) Tokmic, K.; Fout, A. R. J. Am. Chem. Soc. 2016, 138, 13700. (q) Neumann, K. T.; Klimczyk, S.; Burhardt, M. N.; BangAndersen, B.; Skrydstrup, T.; Lindhardt, A. T. ACS Catal. 2016, 6, 4710. (r) Karunananda, M. K.; Mankad, N. P. Organometallics 2017, 36, 220. (s) Fu, S.; Chen, N.-Y.; Liu, X.; Shao, Z.; Luo, S.-P.; Liu, Q. J. Am. Chem. Soc. 2016, 138, 8588. (t) Furukawa, S.; Komatsu, T. ACS Catal. 2016, 6, 2121; (u) Zhou, Y.-P.; Mo, Z.; Luecke, M.-P.; Driess, M. Chem. Eur. J. 2018, 24, 4780. (v) Musa, S.; Ghosh, A.; Vaccaro, L.; Ackermann, L.; Gelman, D. Adv. Synth. Catal. 2015, 357, 2351. (30) Dinuclear hydridorhodium clusters were shown to be intrinsically E-selective catalysts but their lifetime is extremely limited and Z-alkene formation takes rapidly over; to the best of our knowledge, this method has not found any applications, see: (a) Burch, R. R.; Muetterties, E. L.; Teller, R. G.; Williams, J. M. J. Am. Chem. Soc. 1982, 104, 4257. (b) Burch, R. R.; Shusterman, A. J.; Muetterties, E. L.; Teller, R. G.; Williams, J. M. J. Am. Chem. Soc. 1983, 105, 3546. (31) For a pioneering NMR study on trans-hydrogenation using p-H2 as tool, see: Schleyer, D.; Niessen, H. G.; Bargon, J. New. J. Chem. 2001, 25, 423. (32) [Cp*RuCl]4 dis-ensembles upon addition of an alkyne into the monomeric units, see: (a) Fagan, P. J.; Mahoney, W. S.; Calabrese, J. C.; Williams, I. D. Organometallics 1990, 9, 1843. (b) Fagan, P. J.; Ward, M. D.; Calabrese, J. C. J. Am. Chem. Soc. 1989, 111, 1698. (33) Radkowski, K.; Sundararaju, B.; Fürstner, A. Angew. Chem., Int. Ed. 2013, 52, 355. (34) Guthertz, A.; Leutzsch, M.; Wolf, L. M.; Gupta, P.; Rummelt, S. M.; Goddard, R.; Farès, C.; Thiel, W.; Fürstner, A. J. Am. Chem. Soc. 2018, 140, 3156. (35) For representative examples of Cp*Ru complexes featuring such coordination modes, see ref. 32 and the following: (a) Gill, T. P.; Mann, K. R. Organometallics 1982, 1, 485. (b) Steines, S.; Englert, U.; Drießen-Hölscher, B. Chem. Commun. 2000, 217. (36) Primary and secondary propargyl alcohols also work but can engage in competing redox isomerization to the corresponding enals or enones, see ref. 34; this aspect, however, still awaits a more comprehensive study. (37) We parenthetically note that overeduction and isomerization has also been observed upon alkyne transreduction under dissolving 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 by-products 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 -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, 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.

ACS Paragon Plus Environment

Page 15 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

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 147154. (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. Res. 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: Angew. Chem. Int. Ed. 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, 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, 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.; Ellis, 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 certain 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.; Fürstner, 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 transhydroborations, see: (d) Obligacion, J. V.; Neely, J. M.; Yuzdani, 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. 2017, 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 (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.

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(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 -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, 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 2017, 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, 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 transhydrosilylation 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, 23, 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.; Hungerbühler, E. Tetrahedron Lett. 1990, 31, 7301. (97) Grieco, P. A.; Schillinger, W. J.; Yokoyama, Y. J. Med. Chem. 1980, 23, 1077.

Page 16 of 17

(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.

ACS Paragon Plus Environment

Page 17 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

canonical cis-addition R1 H-E R2

trans-addition

[Cp*Ru] cat [Ru] R2 1 R gem-hydroH H genation (E = H)

H

E

R1

R2

H

R2

R1

E

E = H, SiR3, GeR3, SnR3 genuine

carbene reactivity

ACS Paragon Plus Environment

17