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REVIEW
Cite this: DOI: 10.1039/c5ob00407a
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Gold and silver catalysis: from organic transformation to bioconjugation Vanessa Kar-Yan Lo, Anna On-Yee Chan and Chi-Ming Che* This review focuses on gold (including gold(I) and gold(III) complexes, and gold nanoparticles) and silver(I) catalysis, including aerobic oxidation, activation of C–H bonds and activation of C–C multiple bonds, and their applications in the modification of biomolecules, including oligosaccharides, peptides and poly-
Received 28th February 2015, Accepted 7th May 2015
peptides, reported since the year 2000. Because of the high carbophilicity of gold and silver compounds, gold or silver-catalysed/mediated organic transformations feature high functional group tolerance,
DOI: 10.1039/c5ob00407a
excellent regio-, diastereo- or enantioselectivity and/or high product turnover numbers under mild
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reaction conditions.
1.
Introduction
Gold has long been regarded to be chemically inert. This fallacy was not discarded until the year 2000,1 and there is presently a surge of interest in studying the catalytic activities of gold compounds, from simple gold salts to gold complexes with well-defined structures and solid-supported gold nanoparticles. Compared to other transition metal catalysts, gold compounds show high carbophilicity, rendering them Lewis acids for the activation of C–C multiple bonds for nucleophilic attack, with high functional group tolerance under mild reaction conditions.2,3 Though the role of gold catalysts may be
State Key Laboratory of Synthetic Chemistry and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China. E-mail: [email protected]; Fax: +852 2915 5176; Tel: +852 2859 2154
Vanessa Kar-Yan Lo
Vanessa Kar-Yan Lo obtained her BSc degree (first class honors) in 2004 from The University of Hong Kong. She then continued her study in Professor Chi-Ming Che’s research group, and received her PhD degree in 2009 from The University of Hong Kong on coinage metalcatalyzed reactions. She is currently a Post-Doctoral Fellow at the Department of Chemistry of this university.
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similar to that of H+ catalysts,4 many organic transformations have been found to be unique to gold catalysts. Compared to the now extensive literature on gold catalysis, studies on the catalytic activity of silver compounds are relatively sparse.5,6 Yet, silver(I) complexes demonstrate catalytic activities comparable to those of their gold(I) counterparts in certain organic transformations, but in a more cost effective manner. One well-known example is the asymmetric aldol reaction of α-isocyanocarboxylates with aldehydes reported by Ito, Sawamura and Hayashi catalysed by either gold(I) or silver(I) complexes.7,8 The in situ generated gold(I) or silver(I) catalysts, supported by chiral ferrocenylphosphine ligands bearing a tether containing a tertiary amine, both catalysed the asymmetric aldol reaction in high product yields and with excellent enantioselectivity, despite the slow addition of α-isocyanocarboxylates in silver(I)-catalysed reactions for high enantioselectivity.7b,c,8 As shown in recent works, silver(I)
Anna On-Yee Chan obtained her BSc degree in 2006 from the University of Hong Kong (HKU). She received her PhD degree in 2010 from HKU on development of transition metal mediated bioconjugation reactions, under the supervision of Prof. Chi-Ming Che. She is now working as a Post-Doctoral Fellow at the Department of Chemistry of HKU. Anna On-Yee Chan
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compounds also show π-Lewis acidity for the activation of C–C multiple bonds for nucleophilic attack.5,6b,c Though most silver(I) catalysis investigations have mainly focused on the use of simple silver(I) salts or in situ generated silver(I) complexes,5,6a–c there is currently an increasing number of studies on the use of structurally defined silver(I) complexes in catalytic organic transformations.6d This review discusses a selection of the research on gold (including gold(I) and gold(III) complexes, and gold nanoparticles) and silver(I) catalysis, and their further application in the modification of biomolecules such as oligosaccharides, peptides and polypeptides. At the very outset, we extend our sincere apologies that we are unable to report on all of the vast number of reports on gold and silver catalysis.
2. Aerobic oxidation In the pursuit of a “green oxidant” for organic oxidation with practical interest, dioxygen is the best choice because (1) it is abundant and readily available in the atmosphere, and (2) the only by-product formed after the oxidation reaction is water, which is environmentally benign.9,10 Solid-supported gold nanoparticles (AuNPs) are catalytically active in the aerobic oxidation of organic functional groups.3f,11,12 An example is the aerobic oxidative dehydrogenation of secondary amines to imines.13 After Angelici and co-workers reported the aerobic oxidation of secondary amines to imines by bulk gold powder (∼103 nm particle size),14 Che and co-workers found that AuNPs of 14.5 nm supported on powdered graphite are catalytically active in the aerobic
Chi-Ming Che obtained his PhD degree in 1982 from The University of Hong Kong (HKU) under the supervision of Professor Chung-Kwong Poon. From 1980 to 1983, he studied at the California Institute of Technology under the supervision of Professor Harry B. Gray. Thereafter, he directly returned to HKU and was promoted to Chair Professor in chemistry in 1992 and Dr Hui Wai-Haan Chair of Chemistry in Chi-Ming Che 1999. Professor Che was elected as a member of the Chinese Academy of Sciences in 1995 and a foreign associate of the National U.S. Academy of Sciences in 2013. He received the First Class Prize of the State Natural Science Award from China in 2007. His research interests include inorganic and organic synthesis, metal–ligand multiple bonds, metal-catalyzed organic transformations, organometallic and inorganic photochemistry, luminescent materials, and inorganic medicines. He has published over 860 papers in leading chemistry journals, and is listed in ISI Highly Cited Researchers.
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oxidative dehydrogenation of benzylic amines to imines, and the similar conversion of N-substituted 1,2,3,4-tetrahydroisoquinolines to amides (Scheme 1).15 Further inter- or intramolecular nucleophilic attack of these imines or iminium cations for the production of α-substituted tetrahydroisoquinoline and benzimidazoles in a one-pot synthesis was subsequently demonstrated. Compared to bulk gold powder, AuNPs are better catalysts for this reaction because of their higher density of active sites and larger surface area-to-volume ratios. The graphite-supported AuNPs catalysts can be easily recovered by centrifugation and reused for 10 consecutive runs without deterioration of product yields (>94% isolated yield for each cycle). The “AuNPs/C + O2” protocol worked well for a wide range of oxidation reactions of secondary and tertiary arylamines (Scheme 1). Synthesis of benzimidazole compounds from onepot oxidative coupling of o-phenylenediamine with benzaldehydes was also achieved with this “AuNPs/C + O2” protocol with complete substrate conversion and high product yields (90–99%). Mechanistic studies by competition and deuterium labeling experiments suggest that amine coordinates to the surface Auδ+ sites, followed by a rate-determining C–H bond cleavage at the benzylic position. The oxygen molecule acts as a hydrogen acceptor to regenerate the Auδ+ active site for the next catalytic cycle (Scheme 2). Apart from graphite, silica can also be used as the solid support for AuNPs to facilitate various organic transformations.16 Che and co-workers reported silica-supported AuNP catalysts for a one-pot, tandem aerobic oxidative cyclisation reaction to form N-containing polyheterocyclic compounds (Scheme 3).17 Using dioxygen gas as the oxidant, oxidative cyclisation reaction of anilines with aldehydes gave the corresponding quinolines in moderate to excellent product yields (45–95%). Tolidine and aniline, with electron-deficient substituents, were also examined. These produced the corresponding quinolines in 60% and 17% yields, respectively. Using this “AuNPs/SiO2 + O2” protocol, the reaction of aldehydes with polycyclic anilines resulted in the formation of N-containing polyheterocyclic compounds in moderate to excellent yields (62–96%). Mechanistic studies suggest that AuNPs/SiO2 acts as both a Lewis acid catalyst for the Mannich reactions and as a catalyst for dehydrogenation (Scheme 4). In recent years, there has been a surge of interest in the development of transition metal complexes with high-energy, long-lived excited states for light induced aerobic oxidative C–H functionalisation reactions.18 These photochemically active metal complexes are able to harvest light energy and act as photosensitisers for the production of reactive singlet oxygen species.19,20 Similar to their isoelectronic platinum(II) congeners,21 several cyclometallated gold(III) complexes were found to have high-energy, long-lived emissive excited states in solution. Che and co-workers developed a luminescent organogold(III) complex with long-lived triplet excited states for light-induced oxidative C–H bond functionalization and hydro-
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Scheme 1 Aerobic oxidative dehydrogenation of benzylic amines to imines and N-substituted tetrahydroisoquinolines to amides catalysed by graphite-supported AuNPs.
Scheme 2 Proposed mechanism for the aerobic oxidative dehydrogenation of benzylic amines to imines catalysed by graphite-supported AuNPs.
Scheme 4 Proposed mechanism for AuNPs-catalysed aerobic oxidative cyclisation of aniline with aldehyde to give quinoline.
Scheme 3 Aerobic oxidative cyclisation reactions of anilines with aldehydes for N-containing polyheterocyclic compounds catalysed by silica gel-supported AuNPs.
gen production (Scheme 5).22 Upon bubbling dioxygen gas together with light irradiation (λ > 385 nm), bis-cyclometallated gold(III) (R-Cnp^N^Cnp) complexes (R-HCnp^N^CnpH = 4-R-2,6-dinaphthalen-2-yl-pyridine, R = C6H4-p-OMe) bearing an N-heterocyclic (NHC) ligand (0.15 mol%) catalysed the oxidation of secondary benzylamines to imines with complete substrate conversion and excellent product yields (89–98%) in 2.5 h. Oxidative cyanation at the α-position of the amine group
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Scheme 5 Oxidative dehydrogenation of secondary amines to imines and oxidative cyanation of N-aryltetrahydroisoquinolines by in situ generated singlet oxygen catalysed by a bis-cyclometallated gold(III) (C^N^C) complex bearing an NHC ligand.
of N-aryltetrahydroisoquinolines with NaCN/acetic acid gave products in good to excellent yields (82–92%) under light irradiation and O2 bubbling for 1.5 h. The bis-cyclometallated gold(III) complex is also active in light-induced hydrogen production with triethanolamine and [Co(dmgH)2( py)Cl] complex
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in a degassed CH3CN/H2O mixture. A turnover number of 350 was obtained for hydrogen production under irradiation for 4 h. The extended π-conjugated (C^N^C) ligand system is essential for enhancing the radiative decay by increasing the transition dipole and oscillator strength of the S0→S1 transition, while at the same time suppressing the non-radiative decay by decreasing excited state structural distortion. The involvement of NHC as a strong σ-donor ligand pushes the dσ* orbital to a higher-lying energy, which in turn increases the luminescence efficiency of the bis-cyclometallated gold(III) complex.
3. Activation of C–H bonds The three-component coupling reaction of aldehydes, amines and alkynes (A3 coupling)23 catalysed by gold24 or silver25 salts was first reported by Li and co-workers. It is envisioned that the metal acetylide generated by deprotonation of the terminal alkyne undergoes nucleophilic attack of the iminium ion formed by the condensation of the aldehyde and secondary amine to give propargylamine as the product. Che and Wong reported the use of a gold(III) salen complex (H2salen = N,N′bis(salicylidene)ethylenediimine)26 or a gold(III)(C^N) complex (HC^N = 2-phenylpyridine or 2-benzylpyridine)27 as the catalyst for the A3 coupling reaction (Scheme 6). Compared to simple gold salts, the gold(III) complexes are structurally defined. By systematically tuning the steric and electronic effects of the substituent(s) on the ligand(s), the reactivity and selectivity of the gold(III) catalyst can be modulated. With the use of (S)-prolinol or its derivatives as the amine component, stereoselective synthesis of optically active propargylamines was achieved in up to 97% yields with diastereomeric ratios of up to 99 : 1 (Scheme 6). Compared to gold(III) salen complex, gold(III)(C^N) complexes are more stable. The gold(III)(C^N) complex (HC^N = 2-phenylpyridine) can be repeatedly used as the catalyst in the A3 coupling reaction for 10 cycles, revealing a total product turnover number of 812. The plot of aldehyde conversion versus time indicates that an induction period of about 2 h was required for this complex to become catalytically active.27a
Scheme 6 Stereoselective A3 coupling reaction catalysed by gold(III) salen or gold(III)(C^N) complexes.
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Scheme 7 Synthesis of propargylamine-modified artemisinin derivatives via the gold(III) salen complex-catalysed A3 coupling reaction.
Che and Wong applied the gold(III) salen complex-catalysed A3 coupling reaction of aldehyde, amine and alkyne to the modification of artemisinin.26 Artemisinin, which is a potent anti-malarial and carcinoma-combating compound, is found in the Chinese herb Artemisia annua (sweet wormwood).28 The main challenge in the modification of artemisinin is to retain the endoperoxide moiety, which is essential for the biological activities of artemisinin.29 Propargylamine-modified artemisinin derivatives exhibit strong cytotoxicities (IC50 = 1.1–9.9 μM) to the human hepatocellular carcinoma cell line (HepG2) as depicted in Scheme 7.
4. 4.1.
Activation of C–C multiple bonds Activation of alkynes
After the development of the gold(III) salen complex-catalysed diastereoselective A3 coupling reaction with (S)-prolinol as the amine component, Che and Wong reported the conversion of the optically active propargylamines ( products of the A3 coupling reaction) to 1,3-disubstituted axially chiral allenes catalysed by KAuCl4 under mild conditions (Scheme 8).30 By treating optically active propargylamine with 10 mol% KAuCl4 in CH3CN at 40 °C for 24 h, 1,3-disubstituted axially chiral allenes were obtained in high product yields up to 93% with excellent enantioselectivities (up to 97%). This gold(III)-catalysed transformation of optically active propargylamines to axially chiral allenes was applied to the modification of artemisinin with the endoperoxide bridge remaining intact.30 The allene-modified artemisinin derivatives were prepared as single diastereomers in moderate to good yields (up to 76%). These derivatives exhibited strong cytotoxicities to a human hepatocellular carcinoma cell line (HepG2) as depicted in Scheme 9.
Scheme 8
Gold(III)-catalysed synthesis of axially chiral allenes.
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Scheme 9
Review
Synthesis of allene-modified artemisinin derivatives. Scheme 11 Proposed mechanism of gold-catalysed or silver-mediated synthesis of axially chiral allenes from optically active propargylamines.
Scheme 10 Silver(I)-mediated synthesis of axially chiral allenes under thermal or microwave-assisted conditions.
Further study on the reactivity of axially chiral allenes revealed that the variation of enantioselectivity of the axially chiral allene product was the result of a subsequent gold-catalysed racemisation reaction, which was also noted by other research groups.31 A possible mechanism involving coordination of gold catalyst to the C–C double bond of allenes was proposed by Krause and co-workers,31b which accounts for the finding that allenes with electron-donating substituents are more prone to racemisation. This led to the exploration of new transition metal catalysts for the transformation of optically active propargylamines to 1,3-disubstituted axially chiral allenes. Silver(I) compounds, which are also known to activate C–C multiple bonds, were able to mediate the same stereospecific transformation reaction to give axially chiral allenes in good to excellent yields (up to 95%) and with excellent enantioselectivities (98–99% ee; Scheme 10).32 It is worth noting that an allene bearing an –OMe substituent was obtained in 91% ee with 50 mol% AgNO3 (vs. 3% ee for 10 mol% KAuCl4). Under microwave-assisted conditions, the reaction time of this silver(I)-mediated transformation was shortened to 20 min with an almost complete point-to-axial chirality transfer. This microwave-assisted reaction proceeded well for 1,3-alkylarylallenes and 1,3-dialkylallenes in good yields (up to 85%) with excellent enantioselectivities (96–99% ee), while only low product yields were found under conventional thermal conditions (Scheme 10). A mechanism involving the activation of an alkyne moiety by a gold(I) species (in situ generated from KAuCl4) or a silver(I) ion, followed by an intramolecular 1,5-hydride transfer, was proposed (Scheme 11) based on the results of deuterium labeling experiments and ESI-MS analysis of the crude reaction mixture. DFT (density functional theory) calculations on
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the reaction mechanism reported by Wang and co-workers are also in support of a silver(I)-catalysed 1,5-hydride shift mechanism.33 In addition to the activation of alkynes by gold(I) or silver(I) complexes for hydride attack, several gold(I)-catalysed tandem reactions involving hydroamination of alkynes have been developed.2,34 As aminations of alkynes give imine or enamine intermediates, a second attack by carbon nucleophiles onto these intermediates can lead to the formation of multiple C–C bonds and C–N bonds in a one-pot manner. Inspired by cooperative catalysis of “metal complex + organic molecule”,35 Che and co-workers developed a protocol of “gold(I) complex + chiral Brønsted acid” for the enantioselective tandem intermolecular hydroamination/transfer hydrogenation of alkynes with anilines.36 In the presence of 1–2 mol% the gold(I) catalyst [{(tBu)2(o-biphenyl)P}AuCl]/ AgOTf, 5–10 mol% chiral phosphoric acid and a stoichiometric amount of Hantzsch ester as the hydrogen source, enantiomerically enriched secondary amines with ee values of 83–96% were obtained in 54–98% isolated yields (Scheme 12). This reaction worked well for a wide variety of aryl, alkenyl and aliphatic alkynes and anilines with different electronic properties. Mechanistic studies suggested that the reaction proceeds via two independent catalytic reactions. The gold(I) catalyst is responsible for the activation of alkyne that undergoes nucleophilic attack by aniline to generate an imine intermediate, followed by an enantioselective hydrogen transfer
Scheme 12 Gold(I)-catalysed enantioselective tandem intermolecular hydroamination/transfer hydrogenation of alkynes with anilines.
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Scheme 15 Gold(I)-catalysed diastereoselective tandem intermolecular hydroamination/transfer hydrogenation of alkynes with 2-substituted indolines.
Scheme 13 Proposed mechanism for gold(I)-catalysed enantioselective tandem intermolecular hydroamination/transfer hydrogenation of alkynes with anilines.
Scheme 16 Proposed mechanism for gold(I)-catalysed tandem intermolecular hydroamination/transfer hydrogenation of alkynes with indolines.
Scheme 14 Gold(I)-catalysed tandem intermolecular hydroamination/ transfer hydrogenation of alkynes with indolines.
from the Hantzsch ester, catalysed by the chiral phosphoric acid, to produce the secondary amine (Scheme 13). The substrate scope of the tandem intermolecular hydroamination/transfer hydrogenation of alkynes catalysed by the catalytic system “gold(I) complex + Brønsted acid” was extended to secondary amines (Scheme 14).37 Indolines and N-methylanilines underwent the tandem reaction smoothly with aliphatic or aryl terminal alkynes to yield tertiary amines in moderate to excellent yields (54–99%). When 2-substituted indoline derivatives were used as the substrates, tertiary amines were synthesized with excellent diastereoselectivity, ranging from 12 : 1 to over 20 : 1 (Scheme 15). The reaction mechanism of the gold(I)-catalysed tandem intermolecular hydroamination/transfer hydrogenation of alkynes by indolines was studied experimentally and computationally. 31P NMR analysis and ESI-MS analysis of the crude reaction mixture revealed that the reaction proceeds via the coordination of the gold(I) catalyst to alkyne, followed by the nucleophilic attack of indoline to form an Au(I)–enamine adduct intermediate. Isotopic labeling experiments using a deuterated Hantzsch ester confirmed the subsequent hydride
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transfer to the proposed enamine intermediate in the presence of the gold(I) catalyst. DFT calculation of the reaction mechanism provides the additional information that the BF4− anion assists in proton transfer after the formation of the Au(I)– enamine adduct for the transfer hydrogenation with the Hantzsch ester (Scheme 16). In the presence of 5 mol% the (N-heterocyclic carbene)gold(I) catalyst [Au(IPr)Cl] (IPr = N,N′-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene), primary anilines underwent highly regioselective tandem hydroamination/hydroarylation with 2 equivalents of aliphatic or aryl alkynes under microwave irradiation to give substituted 1,2-dihydroquinolines in up to 94% isolated yields (Scheme 17).38 Compared to conventional thermal conditions, microwave irradiation shortened the reaction time from 12–24 h to less than 70 min with a broadened substrate scope. 2-Aminophenones reacted with only 1 equivalent of alkyne to yield 2,4-disubstituted quinolines (Scheme 17). Mechanistic studies revealed the formation of an enamine or ketimine intermediate from gold(I)-catalysed hydroamination of the first equivalent of alkyne. Gold(I)-catalysed nucleophilic attack of the second equivalent of alkyne to the enamine intermediate led to the formation of propargylamine, which underwent intramolecular hydroarylation to give 1,2-dihydroquinoline, while intramolecular condensation/ annulation occurred in the presence of o-alkylcarbonyl or arylcarbonyl substituents to yield quinolines (Scheme 18).
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Scheme 20 Gold(I)-catalysed regioselective tandem synthesis diversely-substituted pyrrolo[1,2-a]quinolines in aqueous medium.
Scheme 17 Gold(I)-catalysed regioselective tandem hydroamination/ hydroarylation of alkynes under microwave irradiation.
Scheme 18 Proposed mechanism for gold(I)-catalysed tandem hydroamination/hydroarylation of alkynes.
Quinolines generated from the reaction between 2-aminophenone and alkynes could be enantioselectively reduced by Hantzsch ester in the presence of chiral phosphoric acid. Under the same protocol of “gold(I) complex + chiral Brønsted acid” as mentioned above, highly substituted tetrahydroquinolines were asymmetrically synthesised from 2-aminobenzaldehydes or 2-aminophenones with alkynes in a one-pot manner (Scheme 19).39 This cascade reaction showed high regio(single product formation), diastereo- (up to >20 : 1 dr) and enantioselectivity (up to 99% ee). Examination of the biological activity of these tetrahydroquinolines revealed that the stereochemistry of these compounds altered the binding inter-
Scheme 19 Gold(I)-catalysed regio-, diastereo- and enantioselective one-pot gold(I)/chiral Brønsted acid-catalysed cascade synthesis of diversely substituted tetrahydroquinolines.
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action of these compounds to purinergic (P2Y1) receptors, suggesting a potential application of these compounds as drug candidates. In the presence of 2–5 mol% gold(I) catalyst [{(tBu)2(o-biphenyl)P}AuCl]/AgSbF6, N-(pent-4-ynyl)aniline reacted with alkynes in water to form diversely-substituted pyrrolo[1,2-a]quinolines (Scheme 20).40 This reaction exhibited high substrate generality for both the N-( pent-4-ynyl)aniline and the alkyne. An aqueous medium was found to be essential for the reaction. Mechanistic studies41 revealed that water is involved in the first step of gold(I)-catalysed hydration of the terminal alkyne moiety of N-(pent-4-ynyl)aniline to generate a ketone. This ketone group undergoes intramolecular condensation readily with the secondary amine to form an enamine intermediate, followed by a gold(I)-catalysed intermolecular nucleophilic attack of alkyne to generate an isolatable propargylamine product. These steps can take place at room temperature. At elevated temperature, a gold(I)-catalysed intramolecular hydroarylation of alkyne occurred, leading to the formation of highly substituted pyrrolo[1,2-a]quinolines as the final products (Scheme 21). Preliminary tests showed that the pyrrolo-[1,2-a]quinoline generated from this tandem reaction exhibits stronger cytotoxicity to HeLa (cervical epithelioid carcinoma) cells compared to that of a normal lung fibroblast (CCD-19Lu) cell line, revealing the potential of this class of compounds as anti-cancer drugs. The activation of the C–C triple bond of alkynes for stereoselective synthesis of complex organic molecules via tandem reactions can also be achieved with simple silver(I) salts. In the presence of 10 mol% AgOTf, 3 equivalents of 1-alkylindoles
Scheme 21 Proposed mechanism of gold(I)-catalysed regioselective tandem synthesis of diversely-substituted pyrrolo[1,2-a]quinolines from N-( pent-4-ynyl)aniline and alkyne.
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Scheme 22 Silver(I)-catalysed stereoselective tandem synthesis of multiply-substituted tetrahydrocarbazoles. Scheme 24 Gold(I)-catalysed intramolecular hydroamination alkenes under thermal or microwave-assisted conditions.
Scheme 23 Proposed mechanism of silver(I)-catalysed stereoselective tandem synthesis of multiply-substituted tetrahydrocarbazoles.
reacted with 1 equivalent of 5-pentyn-1-aldehydes to give multiply-substituted tetrahydrocarbazoles with trans : cis ratios of up to 10 : 1 (Scheme 22).42 Mechanistic investigation using deuterium labeling experiments and ESI-MS analysis of the crude reaction mixture revealed a dual function of the Ag(I) catalyst: (1) as a Lewis acid for the activation of the aldehyde moiety for aldol reaction with indole to form a 3-alkylidene3H-indolium cation intermediate (Scheme 23); and (2) as a π-Lewis acid for the activation of C–C multiple bonds in the reaction intermediates for the 5-exo-dig cyclisation and nucleophilic addition of alkene by indole moieties (Scheme 23).
4.2.
Activation of alkenes
Compared to alkynes, addition of nucleophiles to alkenes is more difficult. The alkene π* orbitals are higher in energy level, which means a larger energy gap with the HOMO of the nucleophile.43 Therefore, a robust Lewis acid catalyst is essential for the activation of alkenes for nucleophilic addition by significantly lowering the energy of the alkene π* orbitals, which in turn facilitates the nucleophilic addition reaction.
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Similar to hydroamination of alkynes, the hydroamination of alkenes can be catalysed by gold(I) complexes.2,34a In 2006, Che and co-workers reported the intramolecular tandem isomerisation–hydroamination of alkenes by sulfonamides, aniline derivatives and benzamides catalysed by [Au(PR3)Cl]/ AgOTf (R = phenyl or cyclohexyl) under conventional thermal conditions and microwave irradiation (Scheme 24).44 In the presence of 5 mol% [Au(PPh3)Cl]/AgOTf in toluene at 100 °C for 12–24 h, tosylamide or o-substituted benzenesulfonamides were converted to cyclic sulfonamides in excellent isolated yields (95–99%). The intramolecular hydroamination of aliphatic alkenes with sulfonamides requires a longer reaction time (72 h) to reach completion, but the reaction can be accelerated to 10–40 min under microwave irradiation. Intramolecular hydroamination of benzamides catalysed by the gold complex at 100 °C for 30 h generated the corresponding cyclic products with 50–90% isolated yields. The reaction time was shortened to 30 min by subjecting the reaction mixture to microwave irradiation, leading to 57–60% isolated yields of the cyclic products. Intermolecular hydroamination of alkenes with sulfonylamides could be achieved with the same catalytic system under microwave irradiation for 40 min. After reporting the activation of alkenes for hydroamination reactions by gold(I) complexes, Che and co-workers extended the scope of this type of nucleophilic addition reaction to carbon nucleophiles. Using the same catalytic system for alkene hydroamination, intermolecular hydroarylation of alkenes with indoles was developed (Scheme 25).45 In the presence of 2–5 mol% [Au(PPh3)Cl]/AgOTf in toluene at 70–85 °C, coupling of indoles at the C-3 position with aryl alkenes or conjugated dienes was achieved in isolated yields of 60–95%. The hydroarylation of aliphatic alkenes was achieved with the same gold(I) catalytic system under microwave irradiation in 1,2-dichloroethane, leading to the desired coupling products in moderate to excellent isolated yields (42–90%). Deuterium labeling experiments suggest a mechanism whereby the alkene moiety is first activated by the cationic [Au(PPh3)]+ species for nucleophilic attack of the indole to generate an organogold(I) intermediate. This intermediate then undergoes protonolysis to cleave the Au–C bond and gives the desirable product, releasing the cationic [Au(PPh3)]+ species for the next catalytic cycle (Scheme 26).
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Scheme 28 Gold(I)-catalysed intramolecular hydroalkylation of unactivated alkenes with β-ketoamide. Scheme 25 Gold(I)-catalysed intermolecular hydroarylation of alkenes with indoles under thermal or microwave-assisted conditions.
Scheme 29 Proposed mechanism of gold(I)-catalysed intramolecular hydroalkylation of alkenes with β-ketoamide.
Scheme 26 Proposed mechanism of gold(I)-catalysed hydroarylation of styrene and its derivatives with indoles.
In addition to the activation of alkenes for nucleophilic attack by indoles, Che and co-workers also reported a gold(III)catalysed intermolecular hydroarylation of unactivated alkenes with electron-rich arenes and heteroarenes (Scheme 27).46 Using a co-catalyst system of 5 mol% AuCl3 and 15 mol% AgSbF6, arenes with electron-donating substituents or thiophene were added onto styrene derivatives with good to excellent isolated product yields (58–96%). Unactivated alkenes, including aliphatic alkenes, were successfully hydroarylated with anisole to give the desirable products in 58–98% isolated yields. It is envisioned that this reaction proceeds via a mechanism similar to the previous intermolecular hydroarylation of alkenes by indoles (Scheme 26).45
Scheme 27 Gold(III)-catalysed intermolecular hydroarylation of unactivated alkenes with electron-rich arenes and thiophene.
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1,3-Dicarbonyl compounds are another class of common carbon nucleophiles for C–C bond formation.47 Che and coworkers reported the use of [{(tBu)2(o-biphenyl)P}AuCl]/AgOTf as a catalyst for the intramolecular hydroalkylation of unactivated alkenes with a 1,3-dicarbonyl moiety. In the presence of 5 mol% gold(I) catalyst, alkene-bearing β-ketoamides underwent exo-trig cyclisation to give lactams in 91–99% isolated yields without the detection of endo products (Scheme 28).48 A reaction mechanism involving the activation of alkenes by a cationic gold(I) catalyst, followed by exo-trig addition of the enol form of β-ketoamide, was proposed based on the results from deuterium labeling experiments (Scheme 29). The use of simple ketones as carbon nucleophiles for C–C bond formation through hydroalkylation of unactivated alkenes is more challenging than 1,3-dicarbonyl compounds because of the significantly lower enol/ketone equilibrium constant. After reporting the intramolecular hydroalkylation of alkenes with β-ketoamides catalysed by gold(I) complexes,48 Che and co-workers extended their study using simple α-ketones as the nucleophiles for intramolecular hydroalkylation of alkenes (Scheme 30).49 Using 5 mol% [Au(IPr)Cl]/ AgClO4 in toluene at 90 °C, alkenyl aryl ketones bearing electron-donating and electron-withdrawing substituents on the aryl group cyclised to give the desired products in good to excellent isolated yields (71–99%) favouring trans configuration (diastereomeric ratio = 1.5 : 1–10.3 : 1). The reaction also worked well for α-ketones bearing N-tethers or C-tethers with a
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Scheme 30 Gold(I)-catalysed intramolecular hydroalkylation of unactivated alkenes with ketones.
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Scheme 32 Gold(III) porphyrin-catalysed intramolecular cycloisomerisation of allenones.
Scheme 31 Gold(I)/silver(I) co-catalysed cascade intermolecular N-Michael addition/intramolecular hydroalkylation of unactivated alkenes with ketones.
benzyl ether moiety, giving the desired cyclised products in 71–78% isolated yields. Results from deuterium labeling experiments support a reaction mechanism similar to that of hydroalkylation using 1,3-dicarbonyl compounds as the nucleophile, involving the activation of the alkene moiety by the coordination of the gold(I) catalyst, followed by nucleophilic attack of the enol form of the ketone. Protonolysis of the alkyl–gold intermediate gives the final cyclised product and releases the gold catalyst for the next catalytic cycle. Cascade reactions have the advantages of the combined characteristic features of two transition metal catalysts to give: (1) unique reactivity, (2) a shortened synthetic route and (3) less chemical waste.50 Che and co-workers reported the cascade intermolecular N-Michael addition or intramolecular hydroalkylation of unactivated alkenes with ketones using [{(tBu)2(o-biphenyl)P}AuCl]/AgClO4 as the catalyst (Scheme 31).51 α,β-Unsaturated ketones, bearing electron-withdrawing or electron-donating substituents on the phenyl ring underwent N-Michael addition, followed by hydroalkylation of alkenes with the enol form of ketone, in a cascade manner, to produce pyrrolidine compounds in 52–92% isolated yields with diastereomeric ratios ranging from 1 : 1 to 5.5 : 1, favouring the trans isomer (Scheme 31). Reaction of 2-methylene-3,4-dihydronaphthalen-1(2H)-one with N-tosylallylamine proceeded smoothly to give the spiro-product in a 52% isolated yield with a 1.8 : 1 dr. The cascade reaction mechanism was supported by control experiments. 4.3.
presence of a Lewis acid catalyst.34a,53,54 However, unlike alkynes, which only allow nucleophilic addition over 2 carbon centers, allenes possess 3 possible carbon centers for nucleophilic attack. This feature poses a challenge with respect to the regioselectivity of the addition reactions.55 In 2006, Che and co-workers reported the cycloisomerisation of allenones catalysed by the gold(III) porphyrin complex [Au(TPP)Cl] (H2TPP = meso-tetraphenylporphyrin; Scheme 32).56 In the presence of 1 mol% [Au(TPP)Cl] and 10 mol% trifluoroacetic acid (TFA), allenones with mono-, dior tri-substitution(s) were cycloisomerised into furans in good to excellent product yields (73–98% isolated yields) without the detection of an allenone dimer. The [Au(TPP)Cl] catalyst was recycled and retained its catalytic activity after 10 consecutive runs, attaining a total product turnover number of 8300. The reaction was proposed to have been initiated by a reversible binding of the CvCvC moiety of allenone to [Au(TPP)]+, facilitating the nucleophilic attack of the carbonyl oxygen to the terminal allenic carbon to form a five-membered ring structure. The short-lived furyl–gold intermediate then undergoes protonolysis, in the presence of TFA, to regenerate the [Au(TPP)]+ catalyst for the next catalytic cycle (Scheme 33). This mechanism was supported by both deuterium labeling and competition experiments. In contrast to the high regioselectivity in the intramolecular nucleophilic attack of allenes, the control of regioselectivity in the intermolecular nucleophilic addition of allenes is quite challenging. In 2011, Che and co-workers reported the first enantioselective intermolecular hydroarylation of 1,3-diarylsubstituted allenes with indoles, catalysed by 2.5 mol% binuc-
Activation of allenes
Allenes, bearing a pair of consecutive C–C double bonds, can be considered as isomeric forms of alkynes.52 Similar to alkynes, allenes are highly prone to nucleophilic attack in the
Org. Biomol. Chem.
Scheme 33 Proposed mechanism of gold(III) porphyrin catalysed intramolecular cycloisomerisation of allenones.
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5. Bioconjugation reactions
Scheme 34 Enantioselective intermolecular hydroarylation of 1,3diaryl-substituted allenes with indoles catalysed by binuclear gold(I) complex.
lear gold(I) complex [{(S)-(−)-MeO-biphep}(AuCl)2]/AgOTf (Scheme 34).57 This reaction features excellent regioselectivity favouring a nucleophilic attack of the indole moiety to the sp2 hybridised carbon centers, leading to the formation of single products when symmetric allenes were used as the reactant. This reaction also exhibited a wide substrate scope and functional group tolerance. Indoles bearing different substituents at the N-position or on the phenyl ring reacted with 1,3-disubstituted aryl allenes to give the desired products in 73–90% isolated yields with 7–63% ee. Substituents at the para-position of the aryl groups of the allenes had little effect on the product yield and enantioselectivity. Mechanistic studies by competition experiments, deuterium labeling experiments, 31P NMR analysis of the crude reaction mixture and DFT calculations suggest that the reaction was initiated by coordination of cationic gold(I) ion to the allene. This facilitates the nucleophilic attack by indole to give a gold–allene–indole intermediate. Protonolysis of this intermediate releases the desired product and regenerates the gold catalyst for the next catalytic cycle (Scheme 35).
Scheme 35 Proposed mechanism of gold(I)-catalysed enantioselective intermolecular hydroarylation of 1,3-diaryl-substituted allenes with indoles.
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After successfully demonstrating the gold(III)(C^N) complexcatalysed A3 coupling reaction of aldehydes, amines and alkynes,27 Che and Wong applied this reaction to the bifunctional modification of oligosaccharides.58 In the presence of 1 equivalent of [Au(C^N)Cl2] (HC^N = benzylpyridine), aldehydes derived from unprotected D-raffinose, D-stachyose and methyl α-D-galactopyranoside were modified by concurrent incorporation of two different functionalities at a single site in water or phosphate buffered saline in air from room temperature to 40 °C (Scheme 36). This reaction was highly selective towards aldehydes, displayed high functional group tolerance and showed high substrate conversion (up to 99%) under mild conditions. The simultaneous attachment of two biophysical probes, biotin and a fluorescent dansyl group, to the unprotected oligosaccharide aldehyde derivatives was achieved via this gold(III)(C^N) complex-catalysed A3 coupling reaction. Further functionalisation of the propargylamine-modified oligosaccharides by subsequent Huisgen 1,3-dipolar cycloaddition of alkyne and azide (i.e., click reaction) was also observed to proceed efficiently, revealing that the goldmediated reaction is highly compatible with this popular bioorthogonal reaction. The activation of the CvC bonds of allenes, catalysed by the gold(I) compound, was applied to selective peptide modification. Che and Wong reported selective cysteine modification via an allene–thiol coupling reaction in the presence of 10 equivalents of AuCl/AgOTf.59 The reaction showed good versatility and functional group compatibility. Mono-substituted or 1,3-disubstituted allenes bearing aldehydes, alcohols or coumarin moieties were found to react smoothly with the peptide STSSSCNLSK to yield exclusive cysteine-modified products at room temperature in 1 h, showing excellent chemoselectivity towards S–H groups over N–H and O–H moieties (Scheme 37). The allene–thiol coupling reaction proceeded well regardless of the position of cysteine in the peptide. The reaction also worked well with the structurally complex peptide DTT-
Scheme 36 Bifunctional modification of oligosaccharides via the A3 coupling reaction catalysed by [Au(C^N)Cl2] with oligosaccharides as the aldehyde component.
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Scheme 37
Gold(I)-mediated selective cysteine modification with allenes.
Scheme 38
Cysteine modification of DTT-reduced RNaseA.
tions,54c,64 enriching the toolbox of synthetic organic chemistry. Close analogues of gold(I) catalysts, silver(I) complexes possess potential as catalysts for organic transformations. If the light-instability and oxidising power of silver(I) complexes can be controlled, it is envisioned that silver(I) complexes can achieve the same catalytic activity as their gold counterparts in a more cost-effective manner. Scheme 39 Proposed mechanism of gold(I)-mediated selective cysteine modification with allenes using molecular oxygen as the terminal oxidant.
reduced RNaseA (DTT = dithiothreitol), leading to single modification at Cys-95 with 24% substrate conversion (Scheme 38). To elucidate the structure of the product from this allene– thiol coupling reaction, the reaction of allene with thiophenol or benzyl thiol in the presence of 10 mol% AuCl was attempted and Z-hydroxy vinyl thioether was found instead of the 1,2 or 1,3-adducts.60 Mechanistic study suggested an oxidative allene–thiol coupling with molecular oxygen as the terminal oxidant (Scheme 39).
6. Conclusions The development of gold catalysis has advanced enormously over the last decade. These reactions have been used as key steps in the total synthesis of natural products and organic molecules with biological activity.3e,61 Recent reports on the characterisation of gold–carbene62 and gold-allenylidene complexes63 may lead to unprecedented carbene transfer reac-
Org. Biomol. Chem.
Acknowledgements This work was supported by grants from the Innovation and Technology Commission (HKSAR, China) to the State Key Laboratory of Synthetic Chemistry.
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49 Y.-P. Xiao, X.-Y. Liu and C.-M. Che, Angew. Chem., Int. Ed., 2011, 50, 4937. 50 Recent review: C. M. R. Volla, I. Atodiresei and M. Rueping, Chem. Rev., 2014, 114, 2390. 51 Y.-P. Xiao, X.-Y. Liu and C.-M. Che, Beilstein J. Org. Chem., 2011, 7, 1100. 52 The Chemistry of the Allenes, ed. S. R. Landor, Academic Press, London, 1982. 53 Modern Allene Chemistry, ed. N. Krause and A. S. K. Hashmi, Wiley-VCH, Weinheim, vol. 2, 2004. 54 Recent reviews: (a) R. W. Bates and V. Satcharoen, Chem. Soc. Rev., 2002, 31, 12; (b) S. Ma, Chem. Rev., 2005, 105, 2829; (c) Y.-M. Wang, A. D. Lackner and F. D. Toste, Acc. Chem. Res., 2014, 47, 889. 55 (a) A. S. K. Hashmi, Angew. Chem., Int. Ed., 2000, 39, 3590; (b) N. Krause and C. Winter, Chem. Rev., 2011, 111, 1994; (c) M. P. Muñoz, Chem. Soc. Rev., 2014, 43, 3164. 56 C.-Y. Zhou, P. W. H. Chan and C.-M. Che, Org. Lett., 2006, 8, 325. 57 M.-Z. Wang, C.-Y. Zhou, Z. Guo, E. L.-M. Wong, M.-K. Wong and C.-M. Che, Chem. – Asian J., 2011, 6, 812. 58 K. K.-Y. Kung, G.-L. Li, L. Zou, H.-C. Chong, Y.-C. Leung, K.-H. Wong, V. K.-Y. Lo, C.-M. Che and M.-K. Wong, Org. Biomol. Chem., 2012, 10, 925. 59 A. O.-Y. Chan, J. L.-L. Tsai, V. K.-Y. Lo, G.-L. Li, M.-K. Wong and C.-M. Che, Chem. Commun., 2013, 49, 1428. 60 Selected examples: (a) A. Ogawa, J.-i. Kawakami, N. Sonoda and T. Hirao, J. Org. Chem., 1996, 61, 4161; (b) N. Morita and N. Krause, Angew. Chem., Int. Ed., 2006, 45, 1897; (c) N. Bongers and N. Krause, Angew. Chem., Int. Ed., 2008, 47, 2178; (d) Menggenbateer, M. Narsireddy, G. Ferrara, N. Nishina, T. Jin and Y. Yamamoto, Tetrahedron Lett., 2010, 51, 4627. 61 Reviews: (a) B. Alcaide, P. Almendros and J. M. Alonso, Org. Biomol. Chem., 2011, 9, 4405; (b) M. Rudolph and A. S. K. Hashmi, Chem. Soc. Rev., 2012, 41, 2448; (c) Y. Zhang, T. Luo and Z. Yang, Nat. Prod. Rep., 2014, 31, 489. 62 R. E. M. Brooner and R. A. Widenhoefer, Chem. Commun., 2014, 50, 2420. 63 (a) M. M. Hansmann, F. Rominger and A. S. K. Hashmi, Chem. Sci., 2013, 4, 1552; (b) X.-S. Xiao, W.-L. Kwong, X. Guan, C. Yang, W. Lu and C.-M. Che, Chem. – Eur. J., 2013, 19, 9457. 64 Selected examples on gold-catalysed cyclopropanation reaction with gold-carbene as proposed intermediate: (a) M. J. Johansson, D. J. Gorin, S. T. Staben and F. D. Toste, J. Am. Chem. Soc., 2005, 127, 18002; (b) J. Xiao and X. Li, Angew. Chem., Int. Ed., 2011, 50, 7226; (c) T. Lauterbach, M. Ganschow, M. W. Hussong, M. Rudolph, F. Rominger and A. S. K. Hashmi, Adv. Synth. Catal., 2014, 356, 680.
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Gold and silver catalysis: from organic transformation to bioconjugation Vanessa Kar-Yan Lo, Anna On-Yee Chan and Chi-Ming Che* This review focuses on gold (including gold(I) and gold(III) complexes, and gold nanoparticles) and silver(I) catalysis, including aerobic oxidation, activation of C–H bonds and activation of C–C multiple bonds, and their applications in the modification of biomolecules, including oligosaccharides, peptides and poly-
Received 28th February 2015, Accepted 7th May 2015
peptides, reported since the year 2000. Because of the high carbophilicity of gold and silver compounds, gold or silver-catalysed/mediated organic transformations feature high functional group tolerance,
DOI: 10.1039/c5ob00407a
excellent regio-, diastereo- or enantioselectivity and/or high product turnover numbers under mild
www.rsc.org/obc
reaction conditions.
1.
Introduction
Gold has long been regarded to be chemically inert. This fallacy was not discarded until the year 2000,1 and there is presently a surge of interest in studying the catalytic activities of gold compounds, from simple gold salts to gold complexes with well-defined structures and solid-supported gold nanoparticles. Compared to other transition metal catalysts, gold compounds show high carbophilicity, rendering them Lewis acids for the activation of C–C multiple bonds for nucleophilic attack, with high functional group tolerance under mild reaction conditions.2,3 Though the role of gold catalysts may be
State Key Laboratory of Synthetic Chemistry and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China. E-mail: [email protected]; Fax: +852 2915 5176; Tel: +852 2859 2154
Vanessa Kar-Yan Lo
Vanessa Kar-Yan Lo obtained her BSc degree (first class honors) in 2004 from The University of Hong Kong. She then continued her study in Professor Chi-Ming Che’s research group, and received her PhD degree in 2009 from The University of Hong Kong on coinage metalcatalyzed reactions. She is currently a Post-Doctoral Fellow at the Department of Chemistry of this university.
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similar to that of H+ catalysts,4 many organic transformations have been found to be unique to gold catalysts. Compared to the now extensive literature on gold catalysis, studies on the catalytic activity of silver compounds are relatively sparse.5,6 Yet, silver(I) complexes demonstrate catalytic activities comparable to those of their gold(I) counterparts in certain organic transformations, but in a more cost effective manner. One well-known example is the asymmetric aldol reaction of α-isocyanocarboxylates with aldehydes reported by Ito, Sawamura and Hayashi catalysed by either gold(I) or silver(I) complexes.7,8 The in situ generated gold(I) or silver(I) catalysts, supported by chiral ferrocenylphosphine ligands bearing a tether containing a tertiary amine, both catalysed the asymmetric aldol reaction in high product yields and with excellent enantioselectivity, despite the slow addition of α-isocyanocarboxylates in silver(I)-catalysed reactions for high enantioselectivity.7b,c,8 As shown in recent works, silver(I)
Anna On-Yee Chan obtained her BSc degree in 2006 from the University of Hong Kong (HKU). She received her PhD degree in 2010 from HKU on development of transition metal mediated bioconjugation reactions, under the supervision of Prof. Chi-Ming Che. She is now working as a Post-Doctoral Fellow at the Department of Chemistry of HKU. Anna On-Yee Chan
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compounds also show π-Lewis acidity for the activation of C–C multiple bonds for nucleophilic attack.5,6b,c Though most silver(I) catalysis investigations have mainly focused on the use of simple silver(I) salts or in situ generated silver(I) complexes,5,6a–c there is currently an increasing number of studies on the use of structurally defined silver(I) complexes in catalytic organic transformations.6d This review discusses a selection of the research on gold (including gold(I) and gold(III) complexes, and gold nanoparticles) and silver(I) catalysis, and their further application in the modification of biomolecules such as oligosaccharides, peptides and polypeptides. At the very outset, we extend our sincere apologies that we are unable to report on all of the vast number of reports on gold and silver catalysis.
2. Aerobic oxidation In the pursuit of a “green oxidant” for organic oxidation with practical interest, dioxygen is the best choice because (1) it is abundant and readily available in the atmosphere, and (2) the only by-product formed after the oxidation reaction is water, which is environmentally benign.9,10 Solid-supported gold nanoparticles (AuNPs) are catalytically active in the aerobic oxidation of organic functional groups.3f,11,12 An example is the aerobic oxidative dehydrogenation of secondary amines to imines.13 After Angelici and co-workers reported the aerobic oxidation of secondary amines to imines by bulk gold powder (∼103 nm particle size),14 Che and co-workers found that AuNPs of 14.5 nm supported on powdered graphite are catalytically active in the aerobic
Chi-Ming Che obtained his PhD degree in 1982 from The University of Hong Kong (HKU) under the supervision of Professor Chung-Kwong Poon. From 1980 to 1983, he studied at the California Institute of Technology under the supervision of Professor Harry B. Gray. Thereafter, he directly returned to HKU and was promoted to Chair Professor in chemistry in 1992 and Dr Hui Wai-Haan Chair of Chemistry in Chi-Ming Che 1999. Professor Che was elected as a member of the Chinese Academy of Sciences in 1995 and a foreign associate of the National U.S. Academy of Sciences in 2013. He received the First Class Prize of the State Natural Science Award from China in 2007. His research interests include inorganic and organic synthesis, metal–ligand multiple bonds, metal-catalyzed organic transformations, organometallic and inorganic photochemistry, luminescent materials, and inorganic medicines. He has published over 860 papers in leading chemistry journals, and is listed in ISI Highly Cited Researchers.
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oxidative dehydrogenation of benzylic amines to imines, and the similar conversion of N-substituted 1,2,3,4-tetrahydroisoquinolines to amides (Scheme 1).15 Further inter- or intramolecular nucleophilic attack of these imines or iminium cations for the production of α-substituted tetrahydroisoquinoline and benzimidazoles in a one-pot synthesis was subsequently demonstrated. Compared to bulk gold powder, AuNPs are better catalysts for this reaction because of their higher density of active sites and larger surface area-to-volume ratios. The graphite-supported AuNPs catalysts can be easily recovered by centrifugation and reused for 10 consecutive runs without deterioration of product yields (>94% isolated yield for each cycle). The “AuNPs/C + O2” protocol worked well for a wide range of oxidation reactions of secondary and tertiary arylamines (Scheme 1). Synthesis of benzimidazole compounds from onepot oxidative coupling of o-phenylenediamine with benzaldehydes was also achieved with this “AuNPs/C + O2” protocol with complete substrate conversion and high product yields (90–99%). Mechanistic studies by competition and deuterium labeling experiments suggest that amine coordinates to the surface Auδ+ sites, followed by a rate-determining C–H bond cleavage at the benzylic position. The oxygen molecule acts as a hydrogen acceptor to regenerate the Auδ+ active site for the next catalytic cycle (Scheme 2). Apart from graphite, silica can also be used as the solid support for AuNPs to facilitate various organic transformations.16 Che and co-workers reported silica-supported AuNP catalysts for a one-pot, tandem aerobic oxidative cyclisation reaction to form N-containing polyheterocyclic compounds (Scheme 3).17 Using dioxygen gas as the oxidant, oxidative cyclisation reaction of anilines with aldehydes gave the corresponding quinolines in moderate to excellent product yields (45–95%). Tolidine and aniline, with electron-deficient substituents, were also examined. These produced the corresponding quinolines in 60% and 17% yields, respectively. Using this “AuNPs/SiO2 + O2” protocol, the reaction of aldehydes with polycyclic anilines resulted in the formation of N-containing polyheterocyclic compounds in moderate to excellent yields (62–96%). Mechanistic studies suggest that AuNPs/SiO2 acts as both a Lewis acid catalyst for the Mannich reactions and as a catalyst for dehydrogenation (Scheme 4). In recent years, there has been a surge of interest in the development of transition metal complexes with high-energy, long-lived excited states for light induced aerobic oxidative C–H functionalisation reactions.18 These photochemically active metal complexes are able to harvest light energy and act as photosensitisers for the production of reactive singlet oxygen species.19,20 Similar to their isoelectronic platinum(II) congeners,21 several cyclometallated gold(III) complexes were found to have high-energy, long-lived emissive excited states in solution. Che and co-workers developed a luminescent organogold(III) complex with long-lived triplet excited states for light-induced oxidative C–H bond functionalization and hydro-
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Scheme 1 Aerobic oxidative dehydrogenation of benzylic amines to imines and N-substituted tetrahydroisoquinolines to amides catalysed by graphite-supported AuNPs.
Scheme 2 Proposed mechanism for the aerobic oxidative dehydrogenation of benzylic amines to imines catalysed by graphite-supported AuNPs.
Scheme 4 Proposed mechanism for AuNPs-catalysed aerobic oxidative cyclisation of aniline with aldehyde to give quinoline.
Scheme 3 Aerobic oxidative cyclisation reactions of anilines with aldehydes for N-containing polyheterocyclic compounds catalysed by silica gel-supported AuNPs.
gen production (Scheme 5).22 Upon bubbling dioxygen gas together with light irradiation (λ > 385 nm), bis-cyclometallated gold(III) (R-Cnp^N^Cnp) complexes (R-HCnp^N^CnpH = 4-R-2,6-dinaphthalen-2-yl-pyridine, R = C6H4-p-OMe) bearing an N-heterocyclic (NHC) ligand (0.15 mol%) catalysed the oxidation of secondary benzylamines to imines with complete substrate conversion and excellent product yields (89–98%) in 2.5 h. Oxidative cyanation at the α-position of the amine group
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Scheme 5 Oxidative dehydrogenation of secondary amines to imines and oxidative cyanation of N-aryltetrahydroisoquinolines by in situ generated singlet oxygen catalysed by a bis-cyclometallated gold(III) (C^N^C) complex bearing an NHC ligand.
of N-aryltetrahydroisoquinolines with NaCN/acetic acid gave products in good to excellent yields (82–92%) under light irradiation and O2 bubbling for 1.5 h. The bis-cyclometallated gold(III) complex is also active in light-induced hydrogen production with triethanolamine and [Co(dmgH)2( py)Cl] complex
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in a degassed CH3CN/H2O mixture. A turnover number of 350 was obtained for hydrogen production under irradiation for 4 h. The extended π-conjugated (C^N^C) ligand system is essential for enhancing the radiative decay by increasing the transition dipole and oscillator strength of the S0→S1 transition, while at the same time suppressing the non-radiative decay by decreasing excited state structural distortion. The involvement of NHC as a strong σ-donor ligand pushes the dσ* orbital to a higher-lying energy, which in turn increases the luminescence efficiency of the bis-cyclometallated gold(III) complex.
3. Activation of C–H bonds The three-component coupling reaction of aldehydes, amines and alkynes (A3 coupling)23 catalysed by gold24 or silver25 salts was first reported by Li and co-workers. It is envisioned that the metal acetylide generated by deprotonation of the terminal alkyne undergoes nucleophilic attack of the iminium ion formed by the condensation of the aldehyde and secondary amine to give propargylamine as the product. Che and Wong reported the use of a gold(III) salen complex (H2salen = N,N′bis(salicylidene)ethylenediimine)26 or a gold(III)(C^N) complex (HC^N = 2-phenylpyridine or 2-benzylpyridine)27 as the catalyst for the A3 coupling reaction (Scheme 6). Compared to simple gold salts, the gold(III) complexes are structurally defined. By systematically tuning the steric and electronic effects of the substituent(s) on the ligand(s), the reactivity and selectivity of the gold(III) catalyst can be modulated. With the use of (S)-prolinol or its derivatives as the amine component, stereoselective synthesis of optically active propargylamines was achieved in up to 97% yields with diastereomeric ratios of up to 99 : 1 (Scheme 6). Compared to gold(III) salen complex, gold(III)(C^N) complexes are more stable. The gold(III)(C^N) complex (HC^N = 2-phenylpyridine) can be repeatedly used as the catalyst in the A3 coupling reaction for 10 cycles, revealing a total product turnover number of 812. The plot of aldehyde conversion versus time indicates that an induction period of about 2 h was required for this complex to become catalytically active.27a
Scheme 6 Stereoselective A3 coupling reaction catalysed by gold(III) salen or gold(III)(C^N) complexes.
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Scheme 7 Synthesis of propargylamine-modified artemisinin derivatives via the gold(III) salen complex-catalysed A3 coupling reaction.
Che and Wong applied the gold(III) salen complex-catalysed A3 coupling reaction of aldehyde, amine and alkyne to the modification of artemisinin.26 Artemisinin, which is a potent anti-malarial and carcinoma-combating compound, is found in the Chinese herb Artemisia annua (sweet wormwood).28 The main challenge in the modification of artemisinin is to retain the endoperoxide moiety, which is essential for the biological activities of artemisinin.29 Propargylamine-modified artemisinin derivatives exhibit strong cytotoxicities (IC50 = 1.1–9.9 μM) to the human hepatocellular carcinoma cell line (HepG2) as depicted in Scheme 7.
4. 4.1.
Activation of C–C multiple bonds Activation of alkynes
After the development of the gold(III) salen complex-catalysed diastereoselective A3 coupling reaction with (S)-prolinol as the amine component, Che and Wong reported the conversion of the optically active propargylamines ( products of the A3 coupling reaction) to 1,3-disubstituted axially chiral allenes catalysed by KAuCl4 under mild conditions (Scheme 8).30 By treating optically active propargylamine with 10 mol% KAuCl4 in CH3CN at 40 °C for 24 h, 1,3-disubstituted axially chiral allenes were obtained in high product yields up to 93% with excellent enantioselectivities (up to 97%). This gold(III)-catalysed transformation of optically active propargylamines to axially chiral allenes was applied to the modification of artemisinin with the endoperoxide bridge remaining intact.30 The allene-modified artemisinin derivatives were prepared as single diastereomers in moderate to good yields (up to 76%). These derivatives exhibited strong cytotoxicities to a human hepatocellular carcinoma cell line (HepG2) as depicted in Scheme 9.
Scheme 8
Gold(III)-catalysed synthesis of axially chiral allenes.
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Scheme 9
Review
Synthesis of allene-modified artemisinin derivatives. Scheme 11 Proposed mechanism of gold-catalysed or silver-mediated synthesis of axially chiral allenes from optically active propargylamines.
Scheme 10 Silver(I)-mediated synthesis of axially chiral allenes under thermal or microwave-assisted conditions.
Further study on the reactivity of axially chiral allenes revealed that the variation of enantioselectivity of the axially chiral allene product was the result of a subsequent gold-catalysed racemisation reaction, which was also noted by other research groups.31 A possible mechanism involving coordination of gold catalyst to the C–C double bond of allenes was proposed by Krause and co-workers,31b which accounts for the finding that allenes with electron-donating substituents are more prone to racemisation. This led to the exploration of new transition metal catalysts for the transformation of optically active propargylamines to 1,3-disubstituted axially chiral allenes. Silver(I) compounds, which are also known to activate C–C multiple bonds, were able to mediate the same stereospecific transformation reaction to give axially chiral allenes in good to excellent yields (up to 95%) and with excellent enantioselectivities (98–99% ee; Scheme 10).32 It is worth noting that an allene bearing an –OMe substituent was obtained in 91% ee with 50 mol% AgNO3 (vs. 3% ee for 10 mol% KAuCl4). Under microwave-assisted conditions, the reaction time of this silver(I)-mediated transformation was shortened to 20 min with an almost complete point-to-axial chirality transfer. This microwave-assisted reaction proceeded well for 1,3-alkylarylallenes and 1,3-dialkylallenes in good yields (up to 85%) with excellent enantioselectivities (96–99% ee), while only low product yields were found under conventional thermal conditions (Scheme 10). A mechanism involving the activation of an alkyne moiety by a gold(I) species (in situ generated from KAuCl4) or a silver(I) ion, followed by an intramolecular 1,5-hydride transfer, was proposed (Scheme 11) based on the results of deuterium labeling experiments and ESI-MS analysis of the crude reaction mixture. DFT (density functional theory) calculations on
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the reaction mechanism reported by Wang and co-workers are also in support of a silver(I)-catalysed 1,5-hydride shift mechanism.33 In addition to the activation of alkynes by gold(I) or silver(I) complexes for hydride attack, several gold(I)-catalysed tandem reactions involving hydroamination of alkynes have been developed.2,34 As aminations of alkynes give imine or enamine intermediates, a second attack by carbon nucleophiles onto these intermediates can lead to the formation of multiple C–C bonds and C–N bonds in a one-pot manner. Inspired by cooperative catalysis of “metal complex + organic molecule”,35 Che and co-workers developed a protocol of “gold(I) complex + chiral Brønsted acid” for the enantioselective tandem intermolecular hydroamination/transfer hydrogenation of alkynes with anilines.36 In the presence of 1–2 mol% the gold(I) catalyst [{(tBu)2(o-biphenyl)P}AuCl]/ AgOTf, 5–10 mol% chiral phosphoric acid and a stoichiometric amount of Hantzsch ester as the hydrogen source, enantiomerically enriched secondary amines with ee values of 83–96% were obtained in 54–98% isolated yields (Scheme 12). This reaction worked well for a wide variety of aryl, alkenyl and aliphatic alkynes and anilines with different electronic properties. Mechanistic studies suggested that the reaction proceeds via two independent catalytic reactions. The gold(I) catalyst is responsible for the activation of alkyne that undergoes nucleophilic attack by aniline to generate an imine intermediate, followed by an enantioselective hydrogen transfer
Scheme 12 Gold(I)-catalysed enantioselective tandem intermolecular hydroamination/transfer hydrogenation of alkynes with anilines.
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Scheme 15 Gold(I)-catalysed diastereoselective tandem intermolecular hydroamination/transfer hydrogenation of alkynes with 2-substituted indolines.
Scheme 13 Proposed mechanism for gold(I)-catalysed enantioselective tandem intermolecular hydroamination/transfer hydrogenation of alkynes with anilines.
Scheme 16 Proposed mechanism for gold(I)-catalysed tandem intermolecular hydroamination/transfer hydrogenation of alkynes with indolines.
Scheme 14 Gold(I)-catalysed tandem intermolecular hydroamination/ transfer hydrogenation of alkynes with indolines.
from the Hantzsch ester, catalysed by the chiral phosphoric acid, to produce the secondary amine (Scheme 13). The substrate scope of the tandem intermolecular hydroamination/transfer hydrogenation of alkynes catalysed by the catalytic system “gold(I) complex + Brønsted acid” was extended to secondary amines (Scheme 14).37 Indolines and N-methylanilines underwent the tandem reaction smoothly with aliphatic or aryl terminal alkynes to yield tertiary amines in moderate to excellent yields (54–99%). When 2-substituted indoline derivatives were used as the substrates, tertiary amines were synthesized with excellent diastereoselectivity, ranging from 12 : 1 to over 20 : 1 (Scheme 15). The reaction mechanism of the gold(I)-catalysed tandem intermolecular hydroamination/transfer hydrogenation of alkynes by indolines was studied experimentally and computationally. 31P NMR analysis and ESI-MS analysis of the crude reaction mixture revealed that the reaction proceeds via the coordination of the gold(I) catalyst to alkyne, followed by the nucleophilic attack of indoline to form an Au(I)–enamine adduct intermediate. Isotopic labeling experiments using a deuterated Hantzsch ester confirmed the subsequent hydride
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transfer to the proposed enamine intermediate in the presence of the gold(I) catalyst. DFT calculation of the reaction mechanism provides the additional information that the BF4− anion assists in proton transfer after the formation of the Au(I)– enamine adduct for the transfer hydrogenation with the Hantzsch ester (Scheme 16). In the presence of 5 mol% the (N-heterocyclic carbene)gold(I) catalyst [Au(IPr)Cl] (IPr = N,N′-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene), primary anilines underwent highly regioselective tandem hydroamination/hydroarylation with 2 equivalents of aliphatic or aryl alkynes under microwave irradiation to give substituted 1,2-dihydroquinolines in up to 94% isolated yields (Scheme 17).38 Compared to conventional thermal conditions, microwave irradiation shortened the reaction time from 12–24 h to less than 70 min with a broadened substrate scope. 2-Aminophenones reacted with only 1 equivalent of alkyne to yield 2,4-disubstituted quinolines (Scheme 17). Mechanistic studies revealed the formation of an enamine or ketimine intermediate from gold(I)-catalysed hydroamination of the first equivalent of alkyne. Gold(I)-catalysed nucleophilic attack of the second equivalent of alkyne to the enamine intermediate led to the formation of propargylamine, which underwent intramolecular hydroarylation to give 1,2-dihydroquinoline, while intramolecular condensation/ annulation occurred in the presence of o-alkylcarbonyl or arylcarbonyl substituents to yield quinolines (Scheme 18).
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Scheme 20 Gold(I)-catalysed regioselective tandem synthesis diversely-substituted pyrrolo[1,2-a]quinolines in aqueous medium.
Scheme 17 Gold(I)-catalysed regioselective tandem hydroamination/ hydroarylation of alkynes under microwave irradiation.
Scheme 18 Proposed mechanism for gold(I)-catalysed tandem hydroamination/hydroarylation of alkynes.
Quinolines generated from the reaction between 2-aminophenone and alkynes could be enantioselectively reduced by Hantzsch ester in the presence of chiral phosphoric acid. Under the same protocol of “gold(I) complex + chiral Brønsted acid” as mentioned above, highly substituted tetrahydroquinolines were asymmetrically synthesised from 2-aminobenzaldehydes or 2-aminophenones with alkynes in a one-pot manner (Scheme 19).39 This cascade reaction showed high regio(single product formation), diastereo- (up to >20 : 1 dr) and enantioselectivity (up to 99% ee). Examination of the biological activity of these tetrahydroquinolines revealed that the stereochemistry of these compounds altered the binding inter-
Scheme 19 Gold(I)-catalysed regio-, diastereo- and enantioselective one-pot gold(I)/chiral Brønsted acid-catalysed cascade synthesis of diversely substituted tetrahydroquinolines.
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action of these compounds to purinergic (P2Y1) receptors, suggesting a potential application of these compounds as drug candidates. In the presence of 2–5 mol% gold(I) catalyst [{(tBu)2(o-biphenyl)P}AuCl]/AgSbF6, N-(pent-4-ynyl)aniline reacted with alkynes in water to form diversely-substituted pyrrolo[1,2-a]quinolines (Scheme 20).40 This reaction exhibited high substrate generality for both the N-( pent-4-ynyl)aniline and the alkyne. An aqueous medium was found to be essential for the reaction. Mechanistic studies41 revealed that water is involved in the first step of gold(I)-catalysed hydration of the terminal alkyne moiety of N-(pent-4-ynyl)aniline to generate a ketone. This ketone group undergoes intramolecular condensation readily with the secondary amine to form an enamine intermediate, followed by a gold(I)-catalysed intermolecular nucleophilic attack of alkyne to generate an isolatable propargylamine product. These steps can take place at room temperature. At elevated temperature, a gold(I)-catalysed intramolecular hydroarylation of alkyne occurred, leading to the formation of highly substituted pyrrolo[1,2-a]quinolines as the final products (Scheme 21). Preliminary tests showed that the pyrrolo-[1,2-a]quinoline generated from this tandem reaction exhibits stronger cytotoxicity to HeLa (cervical epithelioid carcinoma) cells compared to that of a normal lung fibroblast (CCD-19Lu) cell line, revealing the potential of this class of compounds as anti-cancer drugs. The activation of the C–C triple bond of alkynes for stereoselective synthesis of complex organic molecules via tandem reactions can also be achieved with simple silver(I) salts. In the presence of 10 mol% AgOTf, 3 equivalents of 1-alkylindoles
Scheme 21 Proposed mechanism of gold(I)-catalysed regioselective tandem synthesis of diversely-substituted pyrrolo[1,2-a]quinolines from N-( pent-4-ynyl)aniline and alkyne.
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Scheme 22 Silver(I)-catalysed stereoselective tandem synthesis of multiply-substituted tetrahydrocarbazoles. Scheme 24 Gold(I)-catalysed intramolecular hydroamination alkenes under thermal or microwave-assisted conditions.
Scheme 23 Proposed mechanism of silver(I)-catalysed stereoselective tandem synthesis of multiply-substituted tetrahydrocarbazoles.
reacted with 1 equivalent of 5-pentyn-1-aldehydes to give multiply-substituted tetrahydrocarbazoles with trans : cis ratios of up to 10 : 1 (Scheme 22).42 Mechanistic investigation using deuterium labeling experiments and ESI-MS analysis of the crude reaction mixture revealed a dual function of the Ag(I) catalyst: (1) as a Lewis acid for the activation of the aldehyde moiety for aldol reaction with indole to form a 3-alkylidene3H-indolium cation intermediate (Scheme 23); and (2) as a π-Lewis acid for the activation of C–C multiple bonds in the reaction intermediates for the 5-exo-dig cyclisation and nucleophilic addition of alkene by indole moieties (Scheme 23).
4.2.
Activation of alkenes
Compared to alkynes, addition of nucleophiles to alkenes is more difficult. The alkene π* orbitals are higher in energy level, which means a larger energy gap with the HOMO of the nucleophile.43 Therefore, a robust Lewis acid catalyst is essential for the activation of alkenes for nucleophilic addition by significantly lowering the energy of the alkene π* orbitals, which in turn facilitates the nucleophilic addition reaction.
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Similar to hydroamination of alkynes, the hydroamination of alkenes can be catalysed by gold(I) complexes.2,34a In 2006, Che and co-workers reported the intramolecular tandem isomerisation–hydroamination of alkenes by sulfonamides, aniline derivatives and benzamides catalysed by [Au(PR3)Cl]/ AgOTf (R = phenyl or cyclohexyl) under conventional thermal conditions and microwave irradiation (Scheme 24).44 In the presence of 5 mol% [Au(PPh3)Cl]/AgOTf in toluene at 100 °C for 12–24 h, tosylamide or o-substituted benzenesulfonamides were converted to cyclic sulfonamides in excellent isolated yields (95–99%). The intramolecular hydroamination of aliphatic alkenes with sulfonamides requires a longer reaction time (72 h) to reach completion, but the reaction can be accelerated to 10–40 min under microwave irradiation. Intramolecular hydroamination of benzamides catalysed by the gold complex at 100 °C for 30 h generated the corresponding cyclic products with 50–90% isolated yields. The reaction time was shortened to 30 min by subjecting the reaction mixture to microwave irradiation, leading to 57–60% isolated yields of the cyclic products. Intermolecular hydroamination of alkenes with sulfonylamides could be achieved with the same catalytic system under microwave irradiation for 40 min. After reporting the activation of alkenes for hydroamination reactions by gold(I) complexes, Che and co-workers extended the scope of this type of nucleophilic addition reaction to carbon nucleophiles. Using the same catalytic system for alkene hydroamination, intermolecular hydroarylation of alkenes with indoles was developed (Scheme 25).45 In the presence of 2–5 mol% [Au(PPh3)Cl]/AgOTf in toluene at 70–85 °C, coupling of indoles at the C-3 position with aryl alkenes or conjugated dienes was achieved in isolated yields of 60–95%. The hydroarylation of aliphatic alkenes was achieved with the same gold(I) catalytic system under microwave irradiation in 1,2-dichloroethane, leading to the desired coupling products in moderate to excellent isolated yields (42–90%). Deuterium labeling experiments suggest a mechanism whereby the alkene moiety is first activated by the cationic [Au(PPh3)]+ species for nucleophilic attack of the indole to generate an organogold(I) intermediate. This intermediate then undergoes protonolysis to cleave the Au–C bond and gives the desirable product, releasing the cationic [Au(PPh3)]+ species for the next catalytic cycle (Scheme 26).
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Scheme 28 Gold(I)-catalysed intramolecular hydroalkylation of unactivated alkenes with β-ketoamide. Scheme 25 Gold(I)-catalysed intermolecular hydroarylation of alkenes with indoles under thermal or microwave-assisted conditions.
Scheme 29 Proposed mechanism of gold(I)-catalysed intramolecular hydroalkylation of alkenes with β-ketoamide.
Scheme 26 Proposed mechanism of gold(I)-catalysed hydroarylation of styrene and its derivatives with indoles.
In addition to the activation of alkenes for nucleophilic attack by indoles, Che and co-workers also reported a gold(III)catalysed intermolecular hydroarylation of unactivated alkenes with electron-rich arenes and heteroarenes (Scheme 27).46 Using a co-catalyst system of 5 mol% AuCl3 and 15 mol% AgSbF6, arenes with electron-donating substituents or thiophene were added onto styrene derivatives with good to excellent isolated product yields (58–96%). Unactivated alkenes, including aliphatic alkenes, were successfully hydroarylated with anisole to give the desirable products in 58–98% isolated yields. It is envisioned that this reaction proceeds via a mechanism similar to the previous intermolecular hydroarylation of alkenes by indoles (Scheme 26).45
Scheme 27 Gold(III)-catalysed intermolecular hydroarylation of unactivated alkenes with electron-rich arenes and thiophene.
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1,3-Dicarbonyl compounds are another class of common carbon nucleophiles for C–C bond formation.47 Che and coworkers reported the use of [{(tBu)2(o-biphenyl)P}AuCl]/AgOTf as a catalyst for the intramolecular hydroalkylation of unactivated alkenes with a 1,3-dicarbonyl moiety. In the presence of 5 mol% gold(I) catalyst, alkene-bearing β-ketoamides underwent exo-trig cyclisation to give lactams in 91–99% isolated yields without the detection of endo products (Scheme 28).48 A reaction mechanism involving the activation of alkenes by a cationic gold(I) catalyst, followed by exo-trig addition of the enol form of β-ketoamide, was proposed based on the results from deuterium labeling experiments (Scheme 29). The use of simple ketones as carbon nucleophiles for C–C bond formation through hydroalkylation of unactivated alkenes is more challenging than 1,3-dicarbonyl compounds because of the significantly lower enol/ketone equilibrium constant. After reporting the intramolecular hydroalkylation of alkenes with β-ketoamides catalysed by gold(I) complexes,48 Che and co-workers extended their study using simple α-ketones as the nucleophiles for intramolecular hydroalkylation of alkenes (Scheme 30).49 Using 5 mol% [Au(IPr)Cl]/ AgClO4 in toluene at 90 °C, alkenyl aryl ketones bearing electron-donating and electron-withdrawing substituents on the aryl group cyclised to give the desired products in good to excellent isolated yields (71–99%) favouring trans configuration (diastereomeric ratio = 1.5 : 1–10.3 : 1). The reaction also worked well for α-ketones bearing N-tethers or C-tethers with a
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Scheme 30 Gold(I)-catalysed intramolecular hydroalkylation of unactivated alkenes with ketones.
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Scheme 32 Gold(III) porphyrin-catalysed intramolecular cycloisomerisation of allenones.
Scheme 31 Gold(I)/silver(I) co-catalysed cascade intermolecular N-Michael addition/intramolecular hydroalkylation of unactivated alkenes with ketones.
benzyl ether moiety, giving the desired cyclised products in 71–78% isolated yields. Results from deuterium labeling experiments support a reaction mechanism similar to that of hydroalkylation using 1,3-dicarbonyl compounds as the nucleophile, involving the activation of the alkene moiety by the coordination of the gold(I) catalyst, followed by nucleophilic attack of the enol form of the ketone. Protonolysis of the alkyl–gold intermediate gives the final cyclised product and releases the gold catalyst for the next catalytic cycle. Cascade reactions have the advantages of the combined characteristic features of two transition metal catalysts to give: (1) unique reactivity, (2) a shortened synthetic route and (3) less chemical waste.50 Che and co-workers reported the cascade intermolecular N-Michael addition or intramolecular hydroalkylation of unactivated alkenes with ketones using [{(tBu)2(o-biphenyl)P}AuCl]/AgClO4 as the catalyst (Scheme 31).51 α,β-Unsaturated ketones, bearing electron-withdrawing or electron-donating substituents on the phenyl ring underwent N-Michael addition, followed by hydroalkylation of alkenes with the enol form of ketone, in a cascade manner, to produce pyrrolidine compounds in 52–92% isolated yields with diastereomeric ratios ranging from 1 : 1 to 5.5 : 1, favouring the trans isomer (Scheme 31). Reaction of 2-methylene-3,4-dihydronaphthalen-1(2H)-one with N-tosylallylamine proceeded smoothly to give the spiro-product in a 52% isolated yield with a 1.8 : 1 dr. The cascade reaction mechanism was supported by control experiments. 4.3.
presence of a Lewis acid catalyst.34a,53,54 However, unlike alkynes, which only allow nucleophilic addition over 2 carbon centers, allenes possess 3 possible carbon centers for nucleophilic attack. This feature poses a challenge with respect to the regioselectivity of the addition reactions.55 In 2006, Che and co-workers reported the cycloisomerisation of allenones catalysed by the gold(III) porphyrin complex [Au(TPP)Cl] (H2TPP = meso-tetraphenylporphyrin; Scheme 32).56 In the presence of 1 mol% [Au(TPP)Cl] and 10 mol% trifluoroacetic acid (TFA), allenones with mono-, dior tri-substitution(s) were cycloisomerised into furans in good to excellent product yields (73–98% isolated yields) without the detection of an allenone dimer. The [Au(TPP)Cl] catalyst was recycled and retained its catalytic activity after 10 consecutive runs, attaining a total product turnover number of 8300. The reaction was proposed to have been initiated by a reversible binding of the CvCvC moiety of allenone to [Au(TPP)]+, facilitating the nucleophilic attack of the carbonyl oxygen to the terminal allenic carbon to form a five-membered ring structure. The short-lived furyl–gold intermediate then undergoes protonolysis, in the presence of TFA, to regenerate the [Au(TPP)]+ catalyst for the next catalytic cycle (Scheme 33). This mechanism was supported by both deuterium labeling and competition experiments. In contrast to the high regioselectivity in the intramolecular nucleophilic attack of allenes, the control of regioselectivity in the intermolecular nucleophilic addition of allenes is quite challenging. In 2011, Che and co-workers reported the first enantioselective intermolecular hydroarylation of 1,3-diarylsubstituted allenes with indoles, catalysed by 2.5 mol% binuc-
Activation of allenes
Allenes, bearing a pair of consecutive C–C double bonds, can be considered as isomeric forms of alkynes.52 Similar to alkynes, allenes are highly prone to nucleophilic attack in the
Org. Biomol. Chem.
Scheme 33 Proposed mechanism of gold(III) porphyrin catalysed intramolecular cycloisomerisation of allenones.
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5. Bioconjugation reactions
Scheme 34 Enantioselective intermolecular hydroarylation of 1,3diaryl-substituted allenes with indoles catalysed by binuclear gold(I) complex.
lear gold(I) complex [{(S)-(−)-MeO-biphep}(AuCl)2]/AgOTf (Scheme 34).57 This reaction features excellent regioselectivity favouring a nucleophilic attack of the indole moiety to the sp2 hybridised carbon centers, leading to the formation of single products when symmetric allenes were used as the reactant. This reaction also exhibited a wide substrate scope and functional group tolerance. Indoles bearing different substituents at the N-position or on the phenyl ring reacted with 1,3-disubstituted aryl allenes to give the desired products in 73–90% isolated yields with 7–63% ee. Substituents at the para-position of the aryl groups of the allenes had little effect on the product yield and enantioselectivity. Mechanistic studies by competition experiments, deuterium labeling experiments, 31P NMR analysis of the crude reaction mixture and DFT calculations suggest that the reaction was initiated by coordination of cationic gold(I) ion to the allene. This facilitates the nucleophilic attack by indole to give a gold–allene–indole intermediate. Protonolysis of this intermediate releases the desired product and regenerates the gold catalyst for the next catalytic cycle (Scheme 35).
Scheme 35 Proposed mechanism of gold(I)-catalysed enantioselective intermolecular hydroarylation of 1,3-diaryl-substituted allenes with indoles.
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After successfully demonstrating the gold(III)(C^N) complexcatalysed A3 coupling reaction of aldehydes, amines and alkynes,27 Che and Wong applied this reaction to the bifunctional modification of oligosaccharides.58 In the presence of 1 equivalent of [Au(C^N)Cl2] (HC^N = benzylpyridine), aldehydes derived from unprotected D-raffinose, D-stachyose and methyl α-D-galactopyranoside were modified by concurrent incorporation of two different functionalities at a single site in water or phosphate buffered saline in air from room temperature to 40 °C (Scheme 36). This reaction was highly selective towards aldehydes, displayed high functional group tolerance and showed high substrate conversion (up to 99%) under mild conditions. The simultaneous attachment of two biophysical probes, biotin and a fluorescent dansyl group, to the unprotected oligosaccharide aldehyde derivatives was achieved via this gold(III)(C^N) complex-catalysed A3 coupling reaction. Further functionalisation of the propargylamine-modified oligosaccharides by subsequent Huisgen 1,3-dipolar cycloaddition of alkyne and azide (i.e., click reaction) was also observed to proceed efficiently, revealing that the goldmediated reaction is highly compatible with this popular bioorthogonal reaction. The activation of the CvC bonds of allenes, catalysed by the gold(I) compound, was applied to selective peptide modification. Che and Wong reported selective cysteine modification via an allene–thiol coupling reaction in the presence of 10 equivalents of AuCl/AgOTf.59 The reaction showed good versatility and functional group compatibility. Mono-substituted or 1,3-disubstituted allenes bearing aldehydes, alcohols or coumarin moieties were found to react smoothly with the peptide STSSSCNLSK to yield exclusive cysteine-modified products at room temperature in 1 h, showing excellent chemoselectivity towards S–H groups over N–H and O–H moieties (Scheme 37). The allene–thiol coupling reaction proceeded well regardless of the position of cysteine in the peptide. The reaction also worked well with the structurally complex peptide DTT-
Scheme 36 Bifunctional modification of oligosaccharides via the A3 coupling reaction catalysed by [Au(C^N)Cl2] with oligosaccharides as the aldehyde component.
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Scheme 37
Gold(I)-mediated selective cysteine modification with allenes.
Scheme 38
Cysteine modification of DTT-reduced RNaseA.
tions,54c,64 enriching the toolbox of synthetic organic chemistry. Close analogues of gold(I) catalysts, silver(I) complexes possess potential as catalysts for organic transformations. If the light-instability and oxidising power of silver(I) complexes can be controlled, it is envisioned that silver(I) complexes can achieve the same catalytic activity as their gold counterparts in a more cost-effective manner. Scheme 39 Proposed mechanism of gold(I)-mediated selective cysteine modification with allenes using molecular oxygen as the terminal oxidant.
reduced RNaseA (DTT = dithiothreitol), leading to single modification at Cys-95 with 24% substrate conversion (Scheme 38). To elucidate the structure of the product from this allene– thiol coupling reaction, the reaction of allene with thiophenol or benzyl thiol in the presence of 10 mol% AuCl was attempted and Z-hydroxy vinyl thioether was found instead of the 1,2 or 1,3-adducts.60 Mechanistic study suggested an oxidative allene–thiol coupling with molecular oxygen as the terminal oxidant (Scheme 39).
6. Conclusions The development of gold catalysis has advanced enormously over the last decade. These reactions have been used as key steps in the total synthesis of natural products and organic molecules with biological activity.3e,61 Recent reports on the characterisation of gold–carbene62 and gold-allenylidene complexes63 may lead to unprecedented carbene transfer reac-
Org. Biomol. Chem.
Acknowledgements This work was supported by grants from the Innovation and Technology Commission (HKSAR, China) to the State Key Laboratory of Synthetic Chemistry.
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49 Y.-P. Xiao, X.-Y. Liu and C.-M. Che, Angew. Chem., Int. Ed., 2011, 50, 4937. 50 Recent review: C. M. R. Volla, I. Atodiresei and M. Rueping, Chem. Rev., 2014, 114, 2390. 51 Y.-P. Xiao, X.-Y. Liu and C.-M. Che, Beilstein J. Org. Chem., 2011, 7, 1100. 52 The Chemistry of the Allenes, ed. S. R. Landor, Academic Press, London, 1982. 53 Modern Allene Chemistry, ed. N. Krause and A. S. K. Hashmi, Wiley-VCH, Weinheim, vol. 2, 2004. 54 Recent reviews: (a) R. W. Bates and V. Satcharoen, Chem. Soc. Rev., 2002, 31, 12; (b) S. Ma, Chem. Rev., 2005, 105, 2829; (c) Y.-M. Wang, A. D. Lackner and F. D. Toste, Acc. Chem. Res., 2014, 47, 889. 55 (a) A. S. K. Hashmi, Angew. Chem., Int. Ed., 2000, 39, 3590; (b) N. Krause and C. Winter, Chem. Rev., 2011, 111, 1994; (c) M. P. Muñoz, Chem. Soc. Rev., 2014, 43, 3164. 56 C.-Y. Zhou, P. W. H. Chan and C.-M. Che, Org. Lett., 2006, 8, 325. 57 M.-Z. Wang, C.-Y. Zhou, Z. Guo, E. L.-M. Wong, M.-K. Wong and C.-M. Che, Chem. – Asian J., 2011, 6, 812. 58 K. K.-Y. Kung, G.-L. Li, L. Zou, H.-C. Chong, Y.-C. Leung, K.-H. Wong, V. K.-Y. Lo, C.-M. Che and M.-K. Wong, Org. Biomol. Chem., 2012, 10, 925. 59 A. O.-Y. Chan, J. L.-L. Tsai, V. K.-Y. Lo, G.-L. Li, M.-K. Wong and C.-M. Che, Chem. Commun., 2013, 49, 1428. 60 Selected examples: (a) A. Ogawa, J.-i. Kawakami, N. Sonoda and T. Hirao, J. Org. Chem., 1996, 61, 4161; (b) N. Morita and N. Krause, Angew. Chem., Int. Ed., 2006, 45, 1897; (c) N. Bongers and N. Krause, Angew. Chem., Int. Ed., 2008, 47, 2178; (d) Menggenbateer, M. Narsireddy, G. Ferrara, N. Nishina, T. Jin and Y. Yamamoto, Tetrahedron Lett., 2010, 51, 4627. 61 Reviews: (a) B. Alcaide, P. Almendros and J. M. Alonso, Org. Biomol. Chem., 2011, 9, 4405; (b) M. Rudolph and A. S. K. Hashmi, Chem. Soc. Rev., 2012, 41, 2448; (c) Y. Zhang, T. Luo and Z. Yang, Nat. Prod. Rep., 2014, 31, 489. 62 R. E. M. Brooner and R. A. Widenhoefer, Chem. Commun., 2014, 50, 2420. 63 (a) M. M. Hansmann, F. Rominger and A. S. K. Hashmi, Chem. Sci., 2013, 4, 1552; (b) X.-S. Xiao, W.-L. Kwong, X. Guan, C. Yang, W. Lu and C.-M. Che, Chem. – Eur. J., 2013, 19, 9457. 64 Selected examples on gold-catalysed cyclopropanation reaction with gold-carbene as proposed intermediate: (a) M. J. Johansson, D. J. Gorin, S. T. Staben and F. D. Toste, J. Am. Chem. Soc., 2005, 127, 18002; (b) J. Xiao and X. Li, Angew. Chem., Int. Ed., 2011, 50, 7226; (c) T. Lauterbach, M. Ganschow, M. W. Hussong, M. Rudolph, F. Rominger and A. S. K. Hashmi, Adv. Synth. Catal., 2014, 356, 680.
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