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Catalytic, enantioselective vinylogous Michael reactions Christoph Schneider* and Falko Abels
Received 13th February 2014, Accepted 25th March 2014
Recent progress in the field of catalytic, enantioselective vinylogous Michael reactions of latent dienolates is described which furnish optically highly enriched chiral 1,7-dioxo compounds of great utility in one syn-
DOI: 10.1039/c4ob00332b
thetic operation. Emphasis is given to new catalysis modes which realise this challenging transformation
www.rsc.org/obc
with high regio- as well as enantioselectivity.
Introduction Enolate-based reactions are the pillars of synthetic organic chemistry and furnish highly functionalised products of great value for natural and non-natural product synthesis. Extending the enolate moiety further by a conjugated vinyl group relays the polarity and reactivity of the original enolate towards the
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany. E-mail: [email protected]; Fax: (+49)341/97-36599; Tel: (+49)341/97-36559
Christoph Schneider earned his PhD degree in 1992 from the University of Göttingen for work in natural product synthesis with Prof. Lutz F. Tietze followed by a postdoctoral assignment with Prof. David A. Evans at Harvard University (USA). During 1994–1998 he completed his habilitation at the University of Göttingen during which time his group developed the silyloxyCope rearrangement of aldol proChristoph Schneider ducts. Subsequently he was invited for visiting professorships to the University of Szeged (Hungary) in 1999 and the University of Toronto (Canada) in 2000. During 2001–2003 he had an appointment as an associate professor at the University of Saarbrücken and was appointed as a full professor at the University of Leipzig in 2003 where he has remained since then. His research interests are in the area of stereoselective synthesis with a special focus on catalytic enantioselective methods and their application in natural product synthesis.
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end of this new dienolate which can react as a highly reactive four-carbon nucleophile with a broad range of electrophiles at the γ-rather than at the α-site (vinylogous reactivity).1 Vinylogous carbon–carbon bond-forming processes of dienolates have become highly attractive processes in synthetic chemistry as they not only extend an existing carbon chain by a four-carbon fragment in one synthetic operation but also are able to assemble complex organic molecules with new stereogenic centres and functional groups which can be easily modified further.2 Currently, much effort is devoted to establishing catalytic, enantioselective protocols to execute these reactions. Being the
Falko Abels studied chemistry at the University of Leipzig and at Monash University, Melbourne. He earned his master of science degree in 2009 from the University of Leipzig for work on organocatalytic access toward tetrahydropyridines. After a short internship with Merck, Darmstadt, he completed his PhD thesis in the Schneider research group (2010–2013) on indolizidine and quinolizidine Falko Abels synthesis with a scholarship from Evonik Industries. In January 2014 he joined BASF (Ludwigshafen).
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Review
classical enolate-based reactions, the vinylogous aldol2,3 and Mannich2,4 reactions have been studied in great detail and quite a number of highly regio- as well as stereoselective and efficient methods have been developed for this purpose. In contrast, the corresponding vinylogous Michael reaction has not yet received the same attention despite the fact that it typically furnishes highly valuable, unsaturated chiral 1,7dioxo compounds in one synthetic operation. At least one of the reasons may be the difficult control of regioselectivity in these reactions. Here both reaction partners contain two competing reactive sites (α- vs. γ-site within the latent dienolate and 1,2- vs. 1,4-reactivity of the Michael acceptor) and in addition to any stereochemical issues altogether four regioisomeric combinations result, of which the desired γ-1,4-selective coupling is only one of the possible combinations (Scheme 1). Thus, only in the last decade significant progress has been achieved in this area and the last few years have seen a rapidly emerging field. This review will mainly focus on the period from 2010 to the end of 2013; for earlier work the reader is referred to other excellent review articles.2 The currently rapidly expanding field of dienamine and trienamine organocatalysis is beyond the scope of this review, and only select examples can be presented herein. For more in-depth presentations the reader is referred to informative reviews which have recently appeared.5 In the first part of this review we will discuss vinylogous Michael reactions of 5-membered electron-rich heterocycles reacting from the endocyclic position. In the second part, catalytic, enantioselective processes utilising acyclic latent dienolates as well as those with exocyclic reactive sites will be presented. Vinylogous Michael reactions with 5-membered heterocycles Electron-rich 5-membered heteroaromatics such as 2-silyloxy furans and pyrroles have been known for quite some time to undergo nucleophilic addition reactions to electrophilic
Scheme 1 Regioisomeric products in reactions of dienolates with Michael acceptors.
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Organic & Biomolecular Chemistry
Scheme 2
Stereocontrol with MacMillan catalyst.7
π-bonds highly regioselectively in the 5-position of the heterocycle with formation of a butenolide and pyrrolidone system, respectively.6 In 2003 MacMillan and his co-workers published a landmark paper7 on the first enantioselective vinylogous Mukaiyama–Michael reaction of 2-silyloxy furans 1 and α,β-unsaturated aldehydes 2 which proceeded in good diastereoselectivity and excellent enantioselectivity (Scheme 2). As an organocatalyst they employed the chiral imidazolidinone 3 which, through reversible condensation with the aldehyde, generated the chiral and highly reactive α,β-unsaturated iminium ion (LUMO-lowering). Due to its rigid s-trans-conformation the nucleophilic approach on the Si-face was effectively shielded by the benzyl group of the chiral catalyst allowing the approach of the furan preferentially on the Re-face (Scheme 2). Besides the inherent preference of the heterocycle for an attack at the 5-position within the furan the sterically demanding tert-butyl group within the imidazolidinone ring prevented a 1,2-nucleophilic attack onto the iminium ion thereby steering the reaction in the desired γ-1,4-coupling mode. This reaction was successfully extended to reactions of more highly substituted silyloxy furans 4 even with additional 5-substituents creating a quaternary chiral centre adjacent to a tertiary stereogenic centre in the products 5. Based upon this methodology the natural product spiculisporic acid (6) was successfully synthesized in few steps (Scheme 3). The same type of transformation can be realised even more atom-economically using 5-alkyl-3H-2-furanones as starting materials and taking advantage of their inherent acidity. Thus, Alexakis and co-workers have developed the direct enantioselective vinylogous Michael reaction of angelica lactones 7 to α,β-unsaturated aldehydes using a 3-phenoxy-proline-derived organocatalyst (Scheme 4)8 furnishing highly attractive and valuable γ-butenolides 8 in good yields, moderate diastereoselectivity and excellent enantioselectivity from readily available and renewable resources. Based on precedents established previously for metal-catalysed, enantioselective vinylogous conjugate additions of 2-silyloxy furans to imides and enones,9 Feng and co-workers employed a chiral scandium-N,N-dioxide-complex to catalyse the vinylogous Michael reaction of 2-silyloxy furans 9 to chalcones 10 (Scheme 5).10 Under carefully optimized conditions the product butenolides 11 were obtained in high yields,
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Scheme 6 esters.11
Scheme 3 Vinylogous Mukaiyama–Michael reaction according to MacMillan.7
Scheme 4
Direct vinylogous Michael reaction with angelica lactones.8
Chiral copper-bisoxazoline-catalysed addition to cyclic oxo
(Scheme 6). Butenolide-containing cyclic β-keto esters 13 were obtained with good yields, excellent diastereocontrol, and modest to high enantioselectivity depending upon the ester group and the substitution within the cyclic oxo ester. The products were subsequently converted into useful building blocks for natural product synthesis.11 Wang and co-workers established the direct conjugate addition of 5H-2-furanone (14) to enones 15 catalysed by a chiral bifunctional amine-thiourea catalyst 16, which Takemoto had introduced earlier (Scheme 7).12,13 However, the scope of this reaction was limited to chalcones and enantioselectivities did not exceed 84% ee. A transition state14 was proposed wherein the thiourea moiety interacted with the chalcones while the tertiary amine abstracted a proton from the γ-butenolide thereby directing it to the conjugate double bond. Ye et al. soon after showed that they were able to catalyse the same type of reaction with only 10 mol% of an L-valinederived triamine catalyst 17 (Scheme 8) and 10 mol% of an amino acid additive.15 The enantioselectivity was outstanding and exceeded 95% ee for all substrates while the diastereo-
Scheme 7 Chiral bifunctional thiourea-catalysed direct vinylogous Michael reaction.12,14 Scheme 5 Chiral scandium Mukaiyama–Michael reaction.10
complex-catalysed
vinylogous
complete anti-diastereoselectivity and generally >90% ee with only 5 mol% of the catalyst employed. The tendency of the products to crystallise provided further options for optical enrichment. A chiral copper-bisoxazoline complex was successfully employed by the group of Chabaud and Guillou to effect the addition of 2-silyloxy furans to cyclic unsaturated oxo esters 12
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Scheme 8
Triamine-catalysed direct vinylogous Michael reaction.15
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selectivity ranged from 2 : 1 to >20 : 1 in favour of the antistereoisomer. The scope of this process was much broader and included all types of enones 18. As a transition state the authors proposed the formation of an iminium ion with the primary amine of the catalyst while the secondary amine and sulfonamide moiety directed the γ-butenolide via proton abstraction to one of the enantiotopic faces of the conjugate double bond. A similar strategy was pursued by the group of Li who employed a simple cyclohexyl-trans-1,2-diamine 19 in combination with an acid additive as a chiral catalyst which furnished the products with exceptional diastereo- and enantioselectivity (Scheme 9).16 They proposed a di-iminium mechanism to account for the syn-diastereoselectivity of the reaction. A quinine-derived chiral organocatalyst 20 was developed for the addition of various β,γ-butenolides 7 (angelica lactones) to 3-aroyl acrylates and 1,2-diaroyl ethylenes 21 proceeding with exceptional diastereo- and enantioselectivities and delivering highly functionalised products 22 of great value for organic chemistry (Scheme 10).17 The catalysis mode most likely rests on a bifunctional activation of both the butenolide and the Michael acceptor. The basic amine abstracts a proton from the acidic butenolide while the acidic free phenol activates the Michael acceptor via protonation and formation of a hydrogen bridge. That proposal was substantiated through the result using the parent quinine lacking the free phenol which gave rise to only marginal levels of enantioselectivity.
Scheme 9 Primary-amine-catalysed reaction.16
Scheme 10
direct
Quinine-based strategy.17
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vinylogous
Michael
A cooperative chiral metal-organo-catalyst system for a direct vinylogous Michael reaction of various 5-aryl-3H-2-furanones and chalcones 15 was established by the group of Wang (Scheme 11).18 A combination of the two commercially available components quinine and BINOL together with the Lewis acid Al(OiPr)3 or La(OiPr)3, respectively (each at a 10 mol%level), catalysed this process with typically excellent diastereoand enantioselectivity. The aluminium or lanthanum-BINOL Lewis acid was assumed to play a double role: assistance in a Brønsted base-activation of the butenolide and a Lewis acidactivation of the enone at the same time possible in a highly organised transition state. Besides α,β-unsaturated carbonyl compounds, nitro alkenes 23 are highly reactive and frequently employed Michael acceptors. In this context Terada et al. recently reported the vinylogous Michael reaction of α-thio substituted furanone 24 catalysed by an axially chiral guanidine base 25 (Scheme 12).19 From related studies on the corresponding vinylogous aldol reaction,20 they learned that 25 might function as an appropriate organobase catalyst for this reaction as well. In the event, with only 5 mol% of chiral guanidine base 25, densely functionalised and very interesting γ-butenolides 26 were formed in moderate to very good yields and excellent diastereo- and enantioselectivity. The products were shown to be readily derivatised into β-alkyl-substituted butenolides.
Scheme 11 reaction.18
Organo/metal-catalysed
Scheme 12
Chiral guanidine-catalysed vinylogous Michael reaction.19
direct
vinylogous
Michael
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Scheme 13 Cinchona alkaloid-based thiourea catalyst for the vinylogous Michael reaction to nitro alkenes.21
The group of Mukherjee developed a range of chiral thiourea-catalysed conjugate addition reactions of 3H-2-furanone 27. The vinylogous Michael reaction with nitro alkenes 23 was successfully catalysed with the cinchona alkaloid-based thiourea catalyst 28 which delivered γ-butenolides 29 with a quaternary and a tertiary chiral centre adjacent to each other and in remarkable diastereo- and enantioselectivity (Scheme 13).21 Again the organocatalyst most likely behaved as a bifunctional catalyst activating and positioning both components at the same time in a highly ordered transition state assembly. Hydrogen bonding from the thiourea to the nitro alkene and abstraction of a proton from the butenolide through the basic amine set the stage for a highly stereoselective carbon–carbon bond forming process. A related process utilised maleimides 30 as Michael acceptors (Scheme 14).22 Here a thiourea catalyst 31 with a different chiral backbone was employed to deliver products with good stereoselectivity. Both the γ-substituent within the furanone 32 and the N-substituent within the maleimide could be varied to a large extent and the products 33 were obtained with at least 95% ee. Catalyst recycling was shown for three consecutive times, demonstrating the practicality of this process. The scope of this reaction was significantly expanded using α,β-unsaturated butyrolactam 34 as a nucleophile. Shibasaki and co-workers reported in 2010 a vinylogous Michael reaction with nitro alkenes 23 as Michael acceptors which was catalysed by a dinuclear chiral nickel-complex 35 (Scheme 15).23 With only 1 to 2.5 mol% of 35 almost quantitative yields of nitroalkyl-substituted unsaturated butyrolactams 36 were obtained as basically single stereoisomers at 50 °C in dioxane.
Scheme 14 Chiral thiourea-catalysed vinylogous Michael reaction to maleimides.22
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Review
Scheme 15 alkenes.23
Chiral nickel-catalysed vinylogous Michael reaction to nitro
Soon thereafter Chen and co-workers reported the first organocatalytic direct vinylogous Michael addition of Boc-protected α,β-unsaturated γ-butyrolactam 34 to a broad range of α,β-unsaturated aldehydes 37 via the well-established iminium activation mode with the prolinol ether catalyst (Scheme 16).24 After careful optimisation of reaction conditions the products 38 were obtained in generally good yields and excellent enantioselectivity for substituted cinnamaldehydes as the starting material. β-Alkyl-substituted enals such as crotonaldehyde proved less reactive and selective, however, and furnished products in only moderate yield and lower enantioselectivity. The vinylogous Michael products were shown to be highly versatile. Thus, Michael product 38a was smoothly converted into the corresponding indoline via a highly stereoselective two-step reductive amination-aza Michael process followed by a copper-catalysed intramolecular N-arylation reaction upon Boc-deprotection (Scheme 16). Independently Ye and Wang and their respective groups reported the direct vinylogous Michael reaction of Boc-protected α,β-unsaturated γ-butyrolactam 34 with enones 39. Ye and co-workers again employed their L-valine-derived triamine catalyst 17 (15 mol%) in combination with an amino acid additive (15 mol%) which had been successful before in the corresponding reaction with the 5H-2-furanone substrate (vide supra).15 Increasing the temperature from ambient tempera-
Scheme 16 reaction.24
Diphenylprolinol ether-catalysed direct vinylogous Michael
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ture to 35 °C significantly reduced reaction times and delivered products 40 with generally good yields, very good diastereoselectivity and excellent enantioselectivity of at least 98% ee. Notably, the substrate scope of this process was very broad, as aliphatic α,β-unsaturated ketones including cyclic ones could be employed as Michael acceptors with equal success (Scheme 17). In addition, several examples of useful transformations of the corresponding Michael products documented the synthesis potential of this process. Mechanistically, the chiral catalyst was assumed to act via iminium ion activation via the primary amine and a hydrogen-bonding network over the secondary amine and the sulfonamide moiety to activate the butyrolactam as a nucleophile. Wang and his group utilised the cinchona alkaloid-based thiourea 41 for this transformation which gave rise to a less broadly applicable process (Scheme 18).25 Although diastereoand enantioselectivity remained excellent for reactions with chalcones no reaction took place with aliphatic enones. Quite interestingly, the diastereoselectivity of the reaction was reversed in comparison to the Ye protocol. Here the anti-diastereomer was formed predominantly. Wang and his group reported a magnesium-3,3′-Ph2-BINOLcatalyzed process for this transformation which furnished products with 91–97% ee and good yields when chalcones 42 were employed as enones (Scheme 19).26 With aliphatic enones either yields or selectivities decreased. Preliminary results indicate, however, that this protocol is readily applicable to conjugate additions towards other Michael acceptors. Thus, reaction of 34 with an α,β-unsaturated N-acyl pyrrole as an enone surrogate furnished the vinylogous Michael product in promising yield and stereoselectivity. Due to the high carbonyl activity of
Scheme 19 BINOL-magnesium-catalysed direct vinylogous Michael reaction to enones.26
N-acyl pyrroles this protocol holds great potential for further synthetic modifications. The same group recently discovered a related process using 3-methyl-4-nitro-5-alkenyl isoxazoles 43 as well as α,β-unsaturated trichloromethyl ketones 44 as Michael acceptors.27 Here the chiral quinine-derived squaramide organocatalyst 45 was employed to effect the carbon–carbon bond forming process at elevated temperature with good levels of stereocontrol (Scheme 20). This process is, however, limited to aryl- and heteroaryl-substituted Michael acceptors. An interesting cycloannulation reaction, which most likely involved a vinylogous Michael reaction of 34 as the initial step of a domino-type process, was developed by Wang and coworkers. Depending upon the exact substitution within the pyrazolone ring either catalyst 46a or 46b was optimal to trigger the reaction of 34 with unsaturated pyrazolones 47 to furnish densely functionalised dihydropyranopyrrolidinones 48 in one synthetic operation, in good yields, as single diastereomers and with high enantioselectivity (Scheme 21).28 Remarkably, the reaction could be extended to openchain N-tosyl-2-methylenebut-3-enoates delivering bicyclic
Scheme 17 Triamine-catalysed direct vinylogous Michael reaction of butyrolactams.15
Scheme 18
Thiourea-catalysed process with enones.25
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Scheme 20 Squaramide-catalysed vinylogous Michael reactions with isoxazoles.27
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Scheme 23 Scheme 21
Alkylidene malonates in the vinylogous Michael reaction.30
Thiourea-catalysed cycloannulation process.28
dihydropyranolactams both in excellent yields and enantioselectivities. The simple quinidine 49 has been shown to be a moderately enantioselective chiral organocatalyst which catalysed the vinylogous Michael reaction of Boc-protected α,β-unsaturated γ-butyrolactam 34 to nitro alkenes 23 (Scheme 22).29 Nitroalkyl-substituted α,β-unsaturated butyrolactams 50 were obtained as products in good yields and as single syn-diastereomers. The corresponding reactions with a dihydroquinine derivative 51 as a chiral catalyst delivered products with opposite but reduced enantioselectivity. Alkylidene malonates 52 have been also employed as Michael acceptors. Towards this goal Feng and co-workers utilised the chiral guanidine base 53 as an organocatalyst which at a 5 mol% level delivered products in generally good yields, 95 : 5 diastereoselectivity and >90% ee (Scheme 23).30 As activation mode for this catalytic system the authors proposed a bifunctional Brønsted acid–Brønsted base mechanism to deliver the nucleophilic butyrolactam onto the hydrogen-bonded alkylidene malonate in a highly ordered intramolecular transition state. Vinylogous Michael reactions of exocyclic or acyclic nucleophiles A powerful acyclic vinylogous donor undergoing highly regioand stereoselective Michael additions at the γ-site was inde-
Scheme 22 Cinchona alkaloid-catalysed vinylogous Michael reaction to nitro alkenes.29
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pendently introduced by the groups of Chen and Jørgensen in 2005.31,32 α,α-Dicyano olefins 54 were shown to react exclusively at the γ-position when treated with nitro styrenes 55 and catalytic amounts of (DHQD)2PYR (56) to deliver multifunctional products 57 with excellent yields and high levels of diastereo- and enantioselectivity (Scheme 24).31 This process could be readily extended to reactions with diazodicarboxylates 59 with alkylidene cyanoacetates or α,α-dicyano alkenes 58 to deliver γ-aminated products 60 with excellent enantioselectivity when employing the pseudoenantiomeric catalyst (DHQ)2PYR (61) (Scheme 25).32 Building on these precedents the Chen group subsequently showed that conjugate additions of α,α-dicyano olefins 54 to α,β-unsaturated aldehydes and ketones can also be conducted successfully with a suitable organocatalyst – diphenylprolinol (62) for reactions with enals and 9-amino-9-deoxy-epiquinine (63) or its pseudo enantiomer 64 and an acidic additive for reactions with enones (Scheme 26).33,34 Addition products (65 or 66) were obtained with generally good yields, exclusive antidiastereoselectivity and excellent enantiocontrol. As a documentation of the synthetic versatility of the Michael products carrying the α,α-dicyano alkene motif, the Michael product 66a derived from the reaction with an enone was converted into the corresponding tricyclic annulated product in good yield with identical enantiomeric access and as a single diastereomer (Scheme 26).
Scheme 24 Vinylogous Michael reaction of α,α-dicyano alkenes and nitro alkenes.31
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Scheme 25
Organic & Biomolecular Chemistry
Reaction of α,α-dicyano alkenes and diazodicarboxylates.32
Scheme 27 Benzoquinones in vinylogous Michael reactions with α,α-dicyano alkenes.35
Scheme 28 Vinylogous Michael reaction of α,α-dicyano alkenes with arenesulfonylalkylindoles.36
Scheme 26 Direct vinylogous Michael reactions of α,α-dicyano alkenes with enals and enones.33,34
α,α-Dicyano olefins 67 readily react with para-benzoquinones 68 with good to excellent diastereo- and enantioselectivities when treated with cinchona alkaloid dimers (Scheme 27). For such reactions (DHQD)2PHAL (69) was shown to serve this purpose best and delivered the conjugate addition products 70 in generally good yields, good to excellent diastereoselectivities and with up to 99% ee.35 The group of Jing recently reported reactions of α,α-dicyano alkenes with arenesulfonylalkylindoles 71 under basic conditions and with Takemoto’s amino thiourea catalyst 16. Highly functionalized C3-alkyl-substituted indoles 72 were obtained with good to very good diastereo- and enantioselectivities (Scheme 28).36 The sulfonylalkylindole served as a precursor to in situ formed α,β-unsaturated imine which was further activated and positioned by the thiourea catalyst.
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A cascade process involving a vinylogous Michael reaction as an initial step of the sequence was recently shown to furnish highly substituted and complex spiro-oxindoles 73 as products.37 The same rosin-derived thiourea organocatalyst 46a which had been employed before in the synthesis of dihydropyranopyrrolidinones 48 (Scheme 21) gave rise to these medicinally important scaffolds. Mechanistically this reaction proceeded through vinylogous Michael reaction of the α,α-dicyano alkene toward the 3-alkylidene oxindole followed by enolate capture by one cyano group to close the ring. Excellent yields as well as diastereo- and enantioselectivities were observed in these reactions which delivered the products as almost single stereoisomers (Scheme 29). In 2010 Xie et al. disclosed the direct, enantioselective vinylogous Michael reaction of 3-cyano-4-methyl-coumarins 74 towards α,β-unsaturated ketones 75 catalysed by 9-amino-9deoxy-epiquinine (76) as an organocatalyst.38 Interestingly, no
Scheme 29 Synthesis of complex spiro-oxindoles initiated by a vinylogous Michael reaction.37
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Scheme 30
Direct vinylogous Michael reaction of coumarins.38
acidic co-catalyst was required in this reaction and best results in terms of yield and selectivity were obtained without an acidic additive. Following this protocol, optically active and highly functionalised coumarin derivatives were assembled in an atom-economic fashion (Scheme 30). As catalysis mode they proposed an iminium ion-based reaction mechanism with concomitant deprotonation of the highly acidic proton from the terminal methyl group through the basic quinine moiety. Utilising a dienamine catalysis mode which had been developed previously by the Jørgensen group,39 Melchiorre and his co-workers in 2010 nicely established a vinylogous Michael reaction of simple and unmodified β-alkyl-substituted enones 76 with nitro alkenes proceeding with remarkable efficiency and selectivity when catalysed with the quinine-derived primary amine organocatalyst 77 (Scheme 31).40 β-Nitroalkylsubstituted cyclohexenones 78 containing two contiguous stereogenic centres were obtained with good diastereo- and typically excellent enantioselectivity. Here an acid co-catalyst – either ortho-fluorobenzoic acid (OFBA) (30 mol%) or salicylic acid (40 mol%) – had to be employed to efficiently direct the reaction manifold towards a γ-site-selective addition.
Scheme 31 Extended dienamine approach for the direct vinylogous Michael reaction of β-alkyl cyclohexenones with nitro alkenes.40
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Review
The control of regioselectivity in this reaction was extremely challenging as altogether three different dienamines may form upon deprotonation of the α,β-unsaturated iminium ion 79 resulting in four different reactive sites (α, α′, γ, γ′). Building on precedents established by Yamamoto and co-workers in their studies on vinylogous aldol reactions catalysed by bulky aluminum complexes, it was shown that selective formation of the exocyclic, extended 1-dienamine 80 was strongly favoured over both the endocyclic, extended 1-dienamine as well as the cross-conjugated 2-dienamine 81 mainly for steric constraints imposed by the chiral catalyst and the acid co-catalyst (Scheme 32).41 Benzylidene malononitrile could also be employed in this reaction albeit with only moderate yield and stereoselectivity; however, with the more highly conjugated 3-phenylallylidene malononitrile 82 the reaction pathway switched to a formal [4 + 2]-cycloaddition and densely substituted bicyclo[2.2.2]octanes 83 were formed from the cross-conjugated 2-dienamines with very high levels of both diastereo- as well as enantioselectivity (Schemes 33 and 34).42 A catalyst-dependent stereodivergence gave rise to opposite diastereomers based upon different hydrogen bonding interactions. Thus, a catalyst combination of 9-amino-9-deoxyepiquinidine (84a) along with salicylic acid (86a) furnished endo-adducts efficiently with both excellent diastereo- and enantioselectivity (Scheme 33) while the catalyst 6′-hydroxy-9-amino-9-deoxyepiquinidine (84b) gave rise to exo-adducts with slightly reduced levels of stereocontrol (Scheme 34). The successful isolation of intermediates resulting from an initial Michael reaction led to the conclusion that this process in fact proceeded through a domino-Michael–Michael reaction. Another dienamine-catalysed formal hetero Diels–Alder reaction of enals 87 and β,γ-unsaturated α-keto esters 88 was discovered by Jørgensen and his group delivering highly substi-
Scheme 32
Equilibrium of dienamine isomers.41
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Scheme 33 Formal [4 + 2]-cycloaddition of enones and alkylidene malononitriles.42
Scheme 34
Formal [4 + 2]-cycloaddition/exo-selective approach.42
tuted and densely functionalised dihydropyrans 89 with very good diastereo- as well enantioselectivity (Scheme 35).43 The proline-derived, bifunctional, chiral squaric diamide organocatalyst 90 activated the enal through dienamine formation resulting in HOMO-raising while the tethered squaramide moiety coordinated to the α-keto ester via hydrogen bonding and hence LUMO-lowering of the Michael acceptor. γ-Methyl alkylidene oxindoles 91 easily react with nitro alkenes in the presence of the cinchona alkaloid-based thiourea catalyst 92 to deliver γ-(nitro)alkylated alkylidene oxindoles 93 with very high yields and remarkable stereoselectivity after a short reaction time at ambient temperature (Scheme 36).44 Typically only one diastereomer was formed which was almost optically pure. In contrast to other organocatalysed reactions this protocol was not limited to nitro styrenes, but was also applicable to β-alkyl- and β-heteroaromatic-substituted nitro alkenes. As we have discussed
Scheme 35 reaction.43
Formal
squaramide-catalysed
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hetero
Scheme 36 Alkylidene reactions.44
oxoindoles
in
direct
vinylogous
Michael
before, the catalysis mode rests on the bifunctional nature of the chiral organocatalyst 92 which activated both the nitro olefin via hydrogen bonding and the nucleophile via proton abstraction at the same time. In addition, they demonstrated that this protocol was successfully extended to reactions of 3-alkylidene oxindoles 94 having a prostereogenic site at the γ-position (Scheme 37).45 By employing the same catalyst 92 or its pseudo-enantiomer, functionality-rich oxindoles 95 carrying two vicinal stereocentres were obtained with outstanding levels of regio- and enantioselectivity and good to very good diastereoselectivities for all cases studied. A highly interesting formal [4 + 2]-cycloaddition reaction based upon a selective, in situ γ-deprotonation of enones was recently disclosed by Wang and his group (Scheme 38).46 They treated E-configured β-alkylated chalcones 96 with a chiral magnesium salene complex (20 mol%) and 4 Å molecular
Scheme 37 Alkylidene oxoindoles with prostereogenic γ-site in direct vinylogous Michael reactions.45
Diels–Alder Scheme 38
Formal [4 + 2]-cycloaddition of β-alkylated chalcones.46
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sieves which gave rise to selective metal dienolate formation and upon subsequent reaction with nitro alkenes to the synthesis of nitro cyclohexenols 97 in one synthetic operation and typically excellent enantio- and good diastereoselectivity. While E-configured chalcones worked more rapidly and efficiently, Z-configured chalcones gave rise to the products as well, albeit in lower yields and only after pre-isomerisation. Although no explicit mechanistic proposal has been made, this reaction might as well proceed via a domino-vinylogous Michael–intramolecular Henry reaction rather than a concerted process. In 2012 the first highly enantio- as well as regioselective vinylogous Michael reaction of acyclic, linear dienol silyl ethers 98 using asymmetric iminium ion-catalysis was established by Schneider and co-workers. Reaction of 98 with β-aryl, β-heteroaryl-, and β-silyl-substituted enals 99 in the presence of 20 mol% of the Hayashi–Jørgensen catalyst furnished precious chiral 1,7-dioxo compounds 100 in typically good yields, complete regioselectivity and excellent enantiocontrol of at least 97% ee (Scheme 39).47 The bulky mesityl-group effectively blocked the α-site within the dienol silyl ether directing the reaction completely to its γ-site. This process could successfully be extended to γ-alkyl-substituted dienol silyl ethers which furnished products with two new stereogenic centres which were formed with good diastereocontrol, additionally. Here only 3 Z-configured dienol silyl ethers gave rise to rapid consumption of the starting material and furnished products with good diastereoselectivity. Presumably an extended open transition state with minimized gauche-interactions between the γ-methyl group and β-substituent of the enal accounted for the observed anti-configuration in the products. Particularly noteworthy was the reaction of the β-silyl enal which proceeded rapidly to give 100a in 90% isolated yield and basically as a single enantiomer (>99% ee). In order to make this process synthetically more readily applicable the mesityl group within the dienolate component was subsequently replaced by the sterically and electronically similar 2,5-dimethyl pyrrole moiety. With 101 as a new latent
Review
Scheme 40 Vinylogous Mukaiyama–Michael reaction of acyclic dienolates based on N-acyl pyrroles.48
Scheme 41 Conversion of vinylogous Michael products 102 into synthetically useful chiral 1,7-dioxo compounds.48
dienolate the process was shown to be even more efficient as the catalyst loading could be reduced to 5–10 mol% while yields, diastereoselectivity and enantiocontrol were maintained at almost the same excellent level (Scheme 40).48 However, small amounts of the corresponding undesired α-regioisomers were typically produced suggesting that the blocking effect of the 2,5-dimethyl pyrrole moiety was not as pronounced as in the case of the mesityl group. More importantly, synthetically useful amounts of stereoisomerically pure 1,7-dioxo compounds 102 were isolated in all cases studied through chromatography. Finally, the products obtained could subsequently be derivatised into useful synthetic intermediates through hydrolysis, transesterification, reduction, and alkylation in high yields demonstrating the synthetic versatility of this transformation (Scheme 41).
Conclusion
Scheme 39 Vinylogous Mukaiyama–Michael reaction of acyclic dienol silyl ethers.47
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The vinylogous Michael reaction has emerged as a powerful synthetic strategy to access highly functionalized 1,7-dioxo compounds or analogues thereof, which are of great value for organic synthesis. Metal- and increasingly organocatalysed protocols have been developed to execute these reactions in a highly regio-, diastereo-, and enantioselective manner. Whereas the focus has traditionally been on the use of electron-rich five-membered heterocycles such as silyloxy furans or butenolides, more and more processes have recently utilized acyclic vinylogous donors, furnishing synthetically even more
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broadly applicable products. Both direct vinylogous Michael reactions of unfunctionalised substrates as well as indirect Mukaiyama-type processes of preformed silyl nucleophiles have been demonstrated to proceed with partially outstanding levels of selectivity and efficiency. The future will most certainly see further progress in this field and more catalytic protocols will emerge which are even more selective and efficient.
Acknowledgements Generous financial support for our own work in this area was provided by the Deutsche Forschungsgemeinschaft (SCHN 441/10-1). We would like to thank the Evonik Foundation for a predoctoral fellowship awarded to F. A.
Notes and references 1 R. C. Fuson, Chem. Rev., 1935, 16, 1–27. 2 (a) G. Casiraghi, F. Zanardi, G. Appendino and G. Rassu, Chem. Rev., 2000, 100, 1929–1972; (b) G. Casiraghi, F. Zanardi, L. Battistini and G. Rassu, Synlett, 2009, 1525– 1542; (c) H.-L. Cui and Y.-C. Chen, Chem. Commun., 2009, 4479–4486; (d) G. Casiraghi, L. Battistini, C. Curti, G. Rassu and F. Zanardi, Chem. Rev., 2011, 111, 3076–3154; (e) Q. Zhang, X. Liu and X. Feng, Curr. Org. Synth., 2013, 10, 764–785. 3 (a) V. Bisai, Synthesis, 2012, 1453–1463; (b) S. V. Pansare and E. K. Paul, Chem. – Eur. J., 2011, 17, 8770–8779; (c) S. E. Denmark, J. R. Heemstra and G. L. Beutner, Angew. Chem., Int. Ed., 2005, 44, 4682–4698; (d) T. Brodmann, M. Lorenz, R. Schaeckel, S. Simsek and M. Kalesse, Synlett, 2009, 174–192; (e) M. Kalesse, Top. Curr. Chem., 2005, 244, 43–76. 4 (a) S. K. Bur and S. F. Martin, Tetrahedron, 2001, 57, 3221– 3242; (b) S. F. Martin, Acc. Chem. Res., 2002, 35, 895–904; (c) C. Schneider and M. Sickert, Catalytic, enantioselective, vinylogous Mannich reactions, in Chiral Amine Synthesis, ed. T. C. Nugent, Wiley-VCH, 2010, 157–177. 5 (a) D. B. Ramachary and Y. V. Reddy, Eur. J. Org. Chem., 2012, 865–887; (b) J.-L. Li, T.-Y. Liu and Y.-C. Chen, Acc. Chem. Res., 2012, 45, 1491–1500; (c) E. Arceo and P. Melchiorre, Angew. Chem., Int. Ed., 2012, 51, 5290–5292; (d) I. Kumar, P. Ramaraju and N. A. Mir, Org. Biomol. Chem., 2013, 11, 709–716; (e) H. Jiang, L. Albrecht and K. A. Jørgensen, Chem. Sci., 2013, 4, 2287–2300. 6 (a) M. W. Carson, G. Kim, M. F. Hentemann, D. Trauner and S. J. Danishefsky, Angew. Chem., Int. Ed., 2001, 40, 4450–4452; (b) J. Christoffers, H. Frey and A. Rosiak, Addition and conjugate addition reactions to carbonyl compounds, in Iron Catalyzed Organic Chemistry, ed. J. Christoffers, Wiley-VCH, 2008. 7 S. P. Brown, N. C. Goodwin and D. W. C. MacMillan, J. Am. Chem. Soc., 2003, 125, 1192–1194.
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33 J.-W. Xie, L. Yue, D. Xue, X.-L. Ma, Y.-C. Chen, Y. Wu, J. Zhu and J.-G. Deng, Chem. Commun., 2006, 1563–1565. 34 J.-W. Xie, W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y.-C. Chen, Y. Wu, J. Zhu and J.-G. Deng, Angew. Chem., Int. Ed., 2007, 46, 389–392. 35 J. Aleman, C. B. Jacobsen, K. Frisch, J. Overgaard and K. A. Jørgensen, Chem. Commun., 2008, 632–634. 36 X.-L. Zhu, W.-J. He, L.-L. Yu, C.-W. Cai, Z.-L. Zuo, D.-B. Qin, Q.-Z. Liu and L.-H. Jing, Adv. Synth. Catal., 2012, 354, 2965– 2970. 37 X.-M. Shi, W.-P. Dong, L.-P. Zhu, X.-X. Jiang and R. Wang, Adv. Synth. Catal., 2013, 355, 3119–3123. 38 X. Huang, Y.-H. Wen, F.-T. Zhou, C. Chen, D.-C. Xu and J.-W. Xie, Tetrahedron Lett., 2010, 51, 6637–6640. 39 S. Bertelsen, M. Marigo, S. Brandes, P. Dinér and K. A. Jørgensen, J. Am. Chem. Soc., 2006, 128, 12973–12980. 40 G. Bencivenni, P. Galzerano, A. Mazzanti, G. Bartoli and P. Melchiorre, Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 20642–20647.
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Review
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REVIEW
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Catalytic, enantioselective vinylogous Michael reactions Christoph Schneider* and Falko Abels
Received 13th February 2014, Accepted 25th March 2014
Recent progress in the field of catalytic, enantioselective vinylogous Michael reactions of latent dienolates is described which furnish optically highly enriched chiral 1,7-dioxo compounds of great utility in one syn-
DOI: 10.1039/c4ob00332b
thetic operation. Emphasis is given to new catalysis modes which realise this challenging transformation
www.rsc.org/obc
with high regio- as well as enantioselectivity.
Introduction Enolate-based reactions are the pillars of synthetic organic chemistry and furnish highly functionalised products of great value for natural and non-natural product synthesis. Extending the enolate moiety further by a conjugated vinyl group relays the polarity and reactivity of the original enolate towards the
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany. E-mail: [email protected]; Fax: (+49)341/97-36599; Tel: (+49)341/97-36559
Christoph Schneider earned his PhD degree in 1992 from the University of Göttingen for work in natural product synthesis with Prof. Lutz F. Tietze followed by a postdoctoral assignment with Prof. David A. Evans at Harvard University (USA). During 1994–1998 he completed his habilitation at the University of Göttingen during which time his group developed the silyloxyCope rearrangement of aldol proChristoph Schneider ducts. Subsequently he was invited for visiting professorships to the University of Szeged (Hungary) in 1999 and the University of Toronto (Canada) in 2000. During 2001–2003 he had an appointment as an associate professor at the University of Saarbrücken and was appointed as a full professor at the University of Leipzig in 2003 where he has remained since then. His research interests are in the area of stereoselective synthesis with a special focus on catalytic enantioselective methods and their application in natural product synthesis.
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end of this new dienolate which can react as a highly reactive four-carbon nucleophile with a broad range of electrophiles at the γ-rather than at the α-site (vinylogous reactivity).1 Vinylogous carbon–carbon bond-forming processes of dienolates have become highly attractive processes in synthetic chemistry as they not only extend an existing carbon chain by a four-carbon fragment in one synthetic operation but also are able to assemble complex organic molecules with new stereogenic centres and functional groups which can be easily modified further.2 Currently, much effort is devoted to establishing catalytic, enantioselective protocols to execute these reactions. Being the
Falko Abels studied chemistry at the University of Leipzig and at Monash University, Melbourne. He earned his master of science degree in 2009 from the University of Leipzig for work on organocatalytic access toward tetrahydropyridines. After a short internship with Merck, Darmstadt, he completed his PhD thesis in the Schneider research group (2010–2013) on indolizidine and quinolizidine Falko Abels synthesis with a scholarship from Evonik Industries. In January 2014 he joined BASF (Ludwigshafen).
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Review
classical enolate-based reactions, the vinylogous aldol2,3 and Mannich2,4 reactions have been studied in great detail and quite a number of highly regio- as well as stereoselective and efficient methods have been developed for this purpose. In contrast, the corresponding vinylogous Michael reaction has not yet received the same attention despite the fact that it typically furnishes highly valuable, unsaturated chiral 1,7dioxo compounds in one synthetic operation. At least one of the reasons may be the difficult control of regioselectivity in these reactions. Here both reaction partners contain two competing reactive sites (α- vs. γ-site within the latent dienolate and 1,2- vs. 1,4-reactivity of the Michael acceptor) and in addition to any stereochemical issues altogether four regioisomeric combinations result, of which the desired γ-1,4-selective coupling is only one of the possible combinations (Scheme 1). Thus, only in the last decade significant progress has been achieved in this area and the last few years have seen a rapidly emerging field. This review will mainly focus on the period from 2010 to the end of 2013; for earlier work the reader is referred to other excellent review articles.2 The currently rapidly expanding field of dienamine and trienamine organocatalysis is beyond the scope of this review, and only select examples can be presented herein. For more in-depth presentations the reader is referred to informative reviews which have recently appeared.5 In the first part of this review we will discuss vinylogous Michael reactions of 5-membered electron-rich heterocycles reacting from the endocyclic position. In the second part, catalytic, enantioselective processes utilising acyclic latent dienolates as well as those with exocyclic reactive sites will be presented. Vinylogous Michael reactions with 5-membered heterocycles Electron-rich 5-membered heteroaromatics such as 2-silyloxy furans and pyrroles have been known for quite some time to undergo nucleophilic addition reactions to electrophilic
Scheme 1 Regioisomeric products in reactions of dienolates with Michael acceptors.
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Scheme 2
Stereocontrol with MacMillan catalyst.7
π-bonds highly regioselectively in the 5-position of the heterocycle with formation of a butenolide and pyrrolidone system, respectively.6 In 2003 MacMillan and his co-workers published a landmark paper7 on the first enantioselective vinylogous Mukaiyama–Michael reaction of 2-silyloxy furans 1 and α,β-unsaturated aldehydes 2 which proceeded in good diastereoselectivity and excellent enantioselectivity (Scheme 2). As an organocatalyst they employed the chiral imidazolidinone 3 which, through reversible condensation with the aldehyde, generated the chiral and highly reactive α,β-unsaturated iminium ion (LUMO-lowering). Due to its rigid s-trans-conformation the nucleophilic approach on the Si-face was effectively shielded by the benzyl group of the chiral catalyst allowing the approach of the furan preferentially on the Re-face (Scheme 2). Besides the inherent preference of the heterocycle for an attack at the 5-position within the furan the sterically demanding tert-butyl group within the imidazolidinone ring prevented a 1,2-nucleophilic attack onto the iminium ion thereby steering the reaction in the desired γ-1,4-coupling mode. This reaction was successfully extended to reactions of more highly substituted silyloxy furans 4 even with additional 5-substituents creating a quaternary chiral centre adjacent to a tertiary stereogenic centre in the products 5. Based upon this methodology the natural product spiculisporic acid (6) was successfully synthesized in few steps (Scheme 3). The same type of transformation can be realised even more atom-economically using 5-alkyl-3H-2-furanones as starting materials and taking advantage of their inherent acidity. Thus, Alexakis and co-workers have developed the direct enantioselective vinylogous Michael reaction of angelica lactones 7 to α,β-unsaturated aldehydes using a 3-phenoxy-proline-derived organocatalyst (Scheme 4)8 furnishing highly attractive and valuable γ-butenolides 8 in good yields, moderate diastereoselectivity and excellent enantioselectivity from readily available and renewable resources. Based on precedents established previously for metal-catalysed, enantioselective vinylogous conjugate additions of 2-silyloxy furans to imides and enones,9 Feng and co-workers employed a chiral scandium-N,N-dioxide-complex to catalyse the vinylogous Michael reaction of 2-silyloxy furans 9 to chalcones 10 (Scheme 5).10 Under carefully optimized conditions the product butenolides 11 were obtained in high yields,
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Review
Scheme 6 esters.11
Scheme 3 Vinylogous Mukaiyama–Michael reaction according to MacMillan.7
Scheme 4
Direct vinylogous Michael reaction with angelica lactones.8
Chiral copper-bisoxazoline-catalysed addition to cyclic oxo
(Scheme 6). Butenolide-containing cyclic β-keto esters 13 were obtained with good yields, excellent diastereocontrol, and modest to high enantioselectivity depending upon the ester group and the substitution within the cyclic oxo ester. The products were subsequently converted into useful building blocks for natural product synthesis.11 Wang and co-workers established the direct conjugate addition of 5H-2-furanone (14) to enones 15 catalysed by a chiral bifunctional amine-thiourea catalyst 16, which Takemoto had introduced earlier (Scheme 7).12,13 However, the scope of this reaction was limited to chalcones and enantioselectivities did not exceed 84% ee. A transition state14 was proposed wherein the thiourea moiety interacted with the chalcones while the tertiary amine abstracted a proton from the γ-butenolide thereby directing it to the conjugate double bond. Ye et al. soon after showed that they were able to catalyse the same type of reaction with only 10 mol% of an L-valinederived triamine catalyst 17 (Scheme 8) and 10 mol% of an amino acid additive.15 The enantioselectivity was outstanding and exceeded 95% ee for all substrates while the diastereo-
Scheme 7 Chiral bifunctional thiourea-catalysed direct vinylogous Michael reaction.12,14 Scheme 5 Chiral scandium Mukaiyama–Michael reaction.10
complex-catalysed
vinylogous
complete anti-diastereoselectivity and generally >90% ee with only 5 mol% of the catalyst employed. The tendency of the products to crystallise provided further options for optical enrichment. A chiral copper-bisoxazoline complex was successfully employed by the group of Chabaud and Guillou to effect the addition of 2-silyloxy furans to cyclic unsaturated oxo esters 12
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Scheme 8
Triamine-catalysed direct vinylogous Michael reaction.15
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Review
Organic & Biomolecular Chemistry
selectivity ranged from 2 : 1 to >20 : 1 in favour of the antistereoisomer. The scope of this process was much broader and included all types of enones 18. As a transition state the authors proposed the formation of an iminium ion with the primary amine of the catalyst while the secondary amine and sulfonamide moiety directed the γ-butenolide via proton abstraction to one of the enantiotopic faces of the conjugate double bond. A similar strategy was pursued by the group of Li who employed a simple cyclohexyl-trans-1,2-diamine 19 in combination with an acid additive as a chiral catalyst which furnished the products with exceptional diastereo- and enantioselectivity (Scheme 9).16 They proposed a di-iminium mechanism to account for the syn-diastereoselectivity of the reaction. A quinine-derived chiral organocatalyst 20 was developed for the addition of various β,γ-butenolides 7 (angelica lactones) to 3-aroyl acrylates and 1,2-diaroyl ethylenes 21 proceeding with exceptional diastereo- and enantioselectivities and delivering highly functionalised products 22 of great value for organic chemistry (Scheme 10).17 The catalysis mode most likely rests on a bifunctional activation of both the butenolide and the Michael acceptor. The basic amine abstracts a proton from the acidic butenolide while the acidic free phenol activates the Michael acceptor via protonation and formation of a hydrogen bridge. That proposal was substantiated through the result using the parent quinine lacking the free phenol which gave rise to only marginal levels of enantioselectivity.
Scheme 9 Primary-amine-catalysed reaction.16
Scheme 10
direct
Quinine-based strategy.17
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vinylogous
Michael
A cooperative chiral metal-organo-catalyst system for a direct vinylogous Michael reaction of various 5-aryl-3H-2-furanones and chalcones 15 was established by the group of Wang (Scheme 11).18 A combination of the two commercially available components quinine and BINOL together with the Lewis acid Al(OiPr)3 or La(OiPr)3, respectively (each at a 10 mol%level), catalysed this process with typically excellent diastereoand enantioselectivity. The aluminium or lanthanum-BINOL Lewis acid was assumed to play a double role: assistance in a Brønsted base-activation of the butenolide and a Lewis acidactivation of the enone at the same time possible in a highly organised transition state. Besides α,β-unsaturated carbonyl compounds, nitro alkenes 23 are highly reactive and frequently employed Michael acceptors. In this context Terada et al. recently reported the vinylogous Michael reaction of α-thio substituted furanone 24 catalysed by an axially chiral guanidine base 25 (Scheme 12).19 From related studies on the corresponding vinylogous aldol reaction,20 they learned that 25 might function as an appropriate organobase catalyst for this reaction as well. In the event, with only 5 mol% of chiral guanidine base 25, densely functionalised and very interesting γ-butenolides 26 were formed in moderate to very good yields and excellent diastereo- and enantioselectivity. The products were shown to be readily derivatised into β-alkyl-substituted butenolides.
Scheme 11 reaction.18
Organo/metal-catalysed
Scheme 12
Chiral guanidine-catalysed vinylogous Michael reaction.19
direct
vinylogous
Michael
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Scheme 13 Cinchona alkaloid-based thiourea catalyst for the vinylogous Michael reaction to nitro alkenes.21
The group of Mukherjee developed a range of chiral thiourea-catalysed conjugate addition reactions of 3H-2-furanone 27. The vinylogous Michael reaction with nitro alkenes 23 was successfully catalysed with the cinchona alkaloid-based thiourea catalyst 28 which delivered γ-butenolides 29 with a quaternary and a tertiary chiral centre adjacent to each other and in remarkable diastereo- and enantioselectivity (Scheme 13).21 Again the organocatalyst most likely behaved as a bifunctional catalyst activating and positioning both components at the same time in a highly ordered transition state assembly. Hydrogen bonding from the thiourea to the nitro alkene and abstraction of a proton from the butenolide through the basic amine set the stage for a highly stereoselective carbon–carbon bond forming process. A related process utilised maleimides 30 as Michael acceptors (Scheme 14).22 Here a thiourea catalyst 31 with a different chiral backbone was employed to deliver products with good stereoselectivity. Both the γ-substituent within the furanone 32 and the N-substituent within the maleimide could be varied to a large extent and the products 33 were obtained with at least 95% ee. Catalyst recycling was shown for three consecutive times, demonstrating the practicality of this process. The scope of this reaction was significantly expanded using α,β-unsaturated butyrolactam 34 as a nucleophile. Shibasaki and co-workers reported in 2010 a vinylogous Michael reaction with nitro alkenes 23 as Michael acceptors which was catalysed by a dinuclear chiral nickel-complex 35 (Scheme 15).23 With only 1 to 2.5 mol% of 35 almost quantitative yields of nitroalkyl-substituted unsaturated butyrolactams 36 were obtained as basically single stereoisomers at 50 °C in dioxane.
Scheme 14 Chiral thiourea-catalysed vinylogous Michael reaction to maleimides.22
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Review
Scheme 15 alkenes.23
Chiral nickel-catalysed vinylogous Michael reaction to nitro
Soon thereafter Chen and co-workers reported the first organocatalytic direct vinylogous Michael addition of Boc-protected α,β-unsaturated γ-butyrolactam 34 to a broad range of α,β-unsaturated aldehydes 37 via the well-established iminium activation mode with the prolinol ether catalyst (Scheme 16).24 After careful optimisation of reaction conditions the products 38 were obtained in generally good yields and excellent enantioselectivity for substituted cinnamaldehydes as the starting material. β-Alkyl-substituted enals such as crotonaldehyde proved less reactive and selective, however, and furnished products in only moderate yield and lower enantioselectivity. The vinylogous Michael products were shown to be highly versatile. Thus, Michael product 38a was smoothly converted into the corresponding indoline via a highly stereoselective two-step reductive amination-aza Michael process followed by a copper-catalysed intramolecular N-arylation reaction upon Boc-deprotection (Scheme 16). Independently Ye and Wang and their respective groups reported the direct vinylogous Michael reaction of Boc-protected α,β-unsaturated γ-butyrolactam 34 with enones 39. Ye and co-workers again employed their L-valine-derived triamine catalyst 17 (15 mol%) in combination with an amino acid additive (15 mol%) which had been successful before in the corresponding reaction with the 5H-2-furanone substrate (vide supra).15 Increasing the temperature from ambient tempera-
Scheme 16 reaction.24
Diphenylprolinol ether-catalysed direct vinylogous Michael
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ture to 35 °C significantly reduced reaction times and delivered products 40 with generally good yields, very good diastereoselectivity and excellent enantioselectivity of at least 98% ee. Notably, the substrate scope of this process was very broad, as aliphatic α,β-unsaturated ketones including cyclic ones could be employed as Michael acceptors with equal success (Scheme 17). In addition, several examples of useful transformations of the corresponding Michael products documented the synthesis potential of this process. Mechanistically, the chiral catalyst was assumed to act via iminium ion activation via the primary amine and a hydrogen-bonding network over the secondary amine and the sulfonamide moiety to activate the butyrolactam as a nucleophile. Wang and his group utilised the cinchona alkaloid-based thiourea 41 for this transformation which gave rise to a less broadly applicable process (Scheme 18).25 Although diastereoand enantioselectivity remained excellent for reactions with chalcones no reaction took place with aliphatic enones. Quite interestingly, the diastereoselectivity of the reaction was reversed in comparison to the Ye protocol. Here the anti-diastereomer was formed predominantly. Wang and his group reported a magnesium-3,3′-Ph2-BINOLcatalyzed process for this transformation which furnished products with 91–97% ee and good yields when chalcones 42 were employed as enones (Scheme 19).26 With aliphatic enones either yields or selectivities decreased. Preliminary results indicate, however, that this protocol is readily applicable to conjugate additions towards other Michael acceptors. Thus, reaction of 34 with an α,β-unsaturated N-acyl pyrrole as an enone surrogate furnished the vinylogous Michael product in promising yield and stereoselectivity. Due to the high carbonyl activity of
Scheme 19 BINOL-magnesium-catalysed direct vinylogous Michael reaction to enones.26
N-acyl pyrroles this protocol holds great potential for further synthetic modifications. The same group recently discovered a related process using 3-methyl-4-nitro-5-alkenyl isoxazoles 43 as well as α,β-unsaturated trichloromethyl ketones 44 as Michael acceptors.27 Here the chiral quinine-derived squaramide organocatalyst 45 was employed to effect the carbon–carbon bond forming process at elevated temperature with good levels of stereocontrol (Scheme 20). This process is, however, limited to aryl- and heteroaryl-substituted Michael acceptors. An interesting cycloannulation reaction, which most likely involved a vinylogous Michael reaction of 34 as the initial step of a domino-type process, was developed by Wang and coworkers. Depending upon the exact substitution within the pyrazolone ring either catalyst 46a or 46b was optimal to trigger the reaction of 34 with unsaturated pyrazolones 47 to furnish densely functionalised dihydropyranopyrrolidinones 48 in one synthetic operation, in good yields, as single diastereomers and with high enantioselectivity (Scheme 21).28 Remarkably, the reaction could be extended to openchain N-tosyl-2-methylenebut-3-enoates delivering bicyclic
Scheme 17 Triamine-catalysed direct vinylogous Michael reaction of butyrolactams.15
Scheme 18
Thiourea-catalysed process with enones.25
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Scheme 20 Squaramide-catalysed vinylogous Michael reactions with isoxazoles.27
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Review
Scheme 23 Scheme 21
Alkylidene malonates in the vinylogous Michael reaction.30
Thiourea-catalysed cycloannulation process.28
dihydropyranolactams both in excellent yields and enantioselectivities. The simple quinidine 49 has been shown to be a moderately enantioselective chiral organocatalyst which catalysed the vinylogous Michael reaction of Boc-protected α,β-unsaturated γ-butyrolactam 34 to nitro alkenes 23 (Scheme 22).29 Nitroalkyl-substituted α,β-unsaturated butyrolactams 50 were obtained as products in good yields and as single syn-diastereomers. The corresponding reactions with a dihydroquinine derivative 51 as a chiral catalyst delivered products with opposite but reduced enantioselectivity. Alkylidene malonates 52 have been also employed as Michael acceptors. Towards this goal Feng and co-workers utilised the chiral guanidine base 53 as an organocatalyst which at a 5 mol% level delivered products in generally good yields, 95 : 5 diastereoselectivity and >90% ee (Scheme 23).30 As activation mode for this catalytic system the authors proposed a bifunctional Brønsted acid–Brønsted base mechanism to deliver the nucleophilic butyrolactam onto the hydrogen-bonded alkylidene malonate in a highly ordered intramolecular transition state. Vinylogous Michael reactions of exocyclic or acyclic nucleophiles A powerful acyclic vinylogous donor undergoing highly regioand stereoselective Michael additions at the γ-site was inde-
Scheme 22 Cinchona alkaloid-catalysed vinylogous Michael reaction to nitro alkenes.29
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pendently introduced by the groups of Chen and Jørgensen in 2005.31,32 α,α-Dicyano olefins 54 were shown to react exclusively at the γ-position when treated with nitro styrenes 55 and catalytic amounts of (DHQD)2PYR (56) to deliver multifunctional products 57 with excellent yields and high levels of diastereo- and enantioselectivity (Scheme 24).31 This process could be readily extended to reactions with diazodicarboxylates 59 with alkylidene cyanoacetates or α,α-dicyano alkenes 58 to deliver γ-aminated products 60 with excellent enantioselectivity when employing the pseudoenantiomeric catalyst (DHQ)2PYR (61) (Scheme 25).32 Building on these precedents the Chen group subsequently showed that conjugate additions of α,α-dicyano olefins 54 to α,β-unsaturated aldehydes and ketones can also be conducted successfully with a suitable organocatalyst – diphenylprolinol (62) for reactions with enals and 9-amino-9-deoxy-epiquinine (63) or its pseudo enantiomer 64 and an acidic additive for reactions with enones (Scheme 26).33,34 Addition products (65 or 66) were obtained with generally good yields, exclusive antidiastereoselectivity and excellent enantiocontrol. As a documentation of the synthetic versatility of the Michael products carrying the α,α-dicyano alkene motif, the Michael product 66a derived from the reaction with an enone was converted into the corresponding tricyclic annulated product in good yield with identical enantiomeric access and as a single diastereomer (Scheme 26).
Scheme 24 Vinylogous Michael reaction of α,α-dicyano alkenes and nitro alkenes.31
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Scheme 25
Organic & Biomolecular Chemistry
Reaction of α,α-dicyano alkenes and diazodicarboxylates.32
Scheme 27 Benzoquinones in vinylogous Michael reactions with α,α-dicyano alkenes.35
Scheme 28 Vinylogous Michael reaction of α,α-dicyano alkenes with arenesulfonylalkylindoles.36
Scheme 26 Direct vinylogous Michael reactions of α,α-dicyano alkenes with enals and enones.33,34
α,α-Dicyano olefins 67 readily react with para-benzoquinones 68 with good to excellent diastereo- and enantioselectivities when treated with cinchona alkaloid dimers (Scheme 27). For such reactions (DHQD)2PHAL (69) was shown to serve this purpose best and delivered the conjugate addition products 70 in generally good yields, good to excellent diastereoselectivities and with up to 99% ee.35 The group of Jing recently reported reactions of α,α-dicyano alkenes with arenesulfonylalkylindoles 71 under basic conditions and with Takemoto’s amino thiourea catalyst 16. Highly functionalized C3-alkyl-substituted indoles 72 were obtained with good to very good diastereo- and enantioselectivities (Scheme 28).36 The sulfonylalkylindole served as a precursor to in situ formed α,β-unsaturated imine which was further activated and positioned by the thiourea catalyst.
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A cascade process involving a vinylogous Michael reaction as an initial step of the sequence was recently shown to furnish highly substituted and complex spiro-oxindoles 73 as products.37 The same rosin-derived thiourea organocatalyst 46a which had been employed before in the synthesis of dihydropyranopyrrolidinones 48 (Scheme 21) gave rise to these medicinally important scaffolds. Mechanistically this reaction proceeded through vinylogous Michael reaction of the α,α-dicyano alkene toward the 3-alkylidene oxindole followed by enolate capture by one cyano group to close the ring. Excellent yields as well as diastereo- and enantioselectivities were observed in these reactions which delivered the products as almost single stereoisomers (Scheme 29). In 2010 Xie et al. disclosed the direct, enantioselective vinylogous Michael reaction of 3-cyano-4-methyl-coumarins 74 towards α,β-unsaturated ketones 75 catalysed by 9-amino-9deoxy-epiquinine (76) as an organocatalyst.38 Interestingly, no
Scheme 29 Synthesis of complex spiro-oxindoles initiated by a vinylogous Michael reaction.37
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Scheme 30
Direct vinylogous Michael reaction of coumarins.38
acidic co-catalyst was required in this reaction and best results in terms of yield and selectivity were obtained without an acidic additive. Following this protocol, optically active and highly functionalised coumarin derivatives were assembled in an atom-economic fashion (Scheme 30). As catalysis mode they proposed an iminium ion-based reaction mechanism with concomitant deprotonation of the highly acidic proton from the terminal methyl group through the basic quinine moiety. Utilising a dienamine catalysis mode which had been developed previously by the Jørgensen group,39 Melchiorre and his co-workers in 2010 nicely established a vinylogous Michael reaction of simple and unmodified β-alkyl-substituted enones 76 with nitro alkenes proceeding with remarkable efficiency and selectivity when catalysed with the quinine-derived primary amine organocatalyst 77 (Scheme 31).40 β-Nitroalkylsubstituted cyclohexenones 78 containing two contiguous stereogenic centres were obtained with good diastereo- and typically excellent enantioselectivity. Here an acid co-catalyst – either ortho-fluorobenzoic acid (OFBA) (30 mol%) or salicylic acid (40 mol%) – had to be employed to efficiently direct the reaction manifold towards a γ-site-selective addition.
Scheme 31 Extended dienamine approach for the direct vinylogous Michael reaction of β-alkyl cyclohexenones with nitro alkenes.40
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Review
The control of regioselectivity in this reaction was extremely challenging as altogether three different dienamines may form upon deprotonation of the α,β-unsaturated iminium ion 79 resulting in four different reactive sites (α, α′, γ, γ′). Building on precedents established by Yamamoto and co-workers in their studies on vinylogous aldol reactions catalysed by bulky aluminum complexes, it was shown that selective formation of the exocyclic, extended 1-dienamine 80 was strongly favoured over both the endocyclic, extended 1-dienamine as well as the cross-conjugated 2-dienamine 81 mainly for steric constraints imposed by the chiral catalyst and the acid co-catalyst (Scheme 32).41 Benzylidene malononitrile could also be employed in this reaction albeit with only moderate yield and stereoselectivity; however, with the more highly conjugated 3-phenylallylidene malononitrile 82 the reaction pathway switched to a formal [4 + 2]-cycloaddition and densely substituted bicyclo[2.2.2]octanes 83 were formed from the cross-conjugated 2-dienamines with very high levels of both diastereo- as well as enantioselectivity (Schemes 33 and 34).42 A catalyst-dependent stereodivergence gave rise to opposite diastereomers based upon different hydrogen bonding interactions. Thus, a catalyst combination of 9-amino-9-deoxyepiquinidine (84a) along with salicylic acid (86a) furnished endo-adducts efficiently with both excellent diastereo- and enantioselectivity (Scheme 33) while the catalyst 6′-hydroxy-9-amino-9-deoxyepiquinidine (84b) gave rise to exo-adducts with slightly reduced levels of stereocontrol (Scheme 34). The successful isolation of intermediates resulting from an initial Michael reaction led to the conclusion that this process in fact proceeded through a domino-Michael–Michael reaction. Another dienamine-catalysed formal hetero Diels–Alder reaction of enals 87 and β,γ-unsaturated α-keto esters 88 was discovered by Jørgensen and his group delivering highly substi-
Scheme 32
Equilibrium of dienamine isomers.41
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Scheme 33 Formal [4 + 2]-cycloaddition of enones and alkylidene malononitriles.42
Scheme 34
Formal [4 + 2]-cycloaddition/exo-selective approach.42
tuted and densely functionalised dihydropyrans 89 with very good diastereo- as well enantioselectivity (Scheme 35).43 The proline-derived, bifunctional, chiral squaric diamide organocatalyst 90 activated the enal through dienamine formation resulting in HOMO-raising while the tethered squaramide moiety coordinated to the α-keto ester via hydrogen bonding and hence LUMO-lowering of the Michael acceptor. γ-Methyl alkylidene oxindoles 91 easily react with nitro alkenes in the presence of the cinchona alkaloid-based thiourea catalyst 92 to deliver γ-(nitro)alkylated alkylidene oxindoles 93 with very high yields and remarkable stereoselectivity after a short reaction time at ambient temperature (Scheme 36).44 Typically only one diastereomer was formed which was almost optically pure. In contrast to other organocatalysed reactions this protocol was not limited to nitro styrenes, but was also applicable to β-alkyl- and β-heteroaromatic-substituted nitro alkenes. As we have discussed
Scheme 35 reaction.43
Formal
squaramide-catalysed
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hetero
Scheme 36 Alkylidene reactions.44
oxoindoles
in
direct
vinylogous
Michael
before, the catalysis mode rests on the bifunctional nature of the chiral organocatalyst 92 which activated both the nitro olefin via hydrogen bonding and the nucleophile via proton abstraction at the same time. In addition, they demonstrated that this protocol was successfully extended to reactions of 3-alkylidene oxindoles 94 having a prostereogenic site at the γ-position (Scheme 37).45 By employing the same catalyst 92 or its pseudo-enantiomer, functionality-rich oxindoles 95 carrying two vicinal stereocentres were obtained with outstanding levels of regio- and enantioselectivity and good to very good diastereoselectivities for all cases studied. A highly interesting formal [4 + 2]-cycloaddition reaction based upon a selective, in situ γ-deprotonation of enones was recently disclosed by Wang and his group (Scheme 38).46 They treated E-configured β-alkylated chalcones 96 with a chiral magnesium salene complex (20 mol%) and 4 Å molecular
Scheme 37 Alkylidene oxoindoles with prostereogenic γ-site in direct vinylogous Michael reactions.45
Diels–Alder Scheme 38
Formal [4 + 2]-cycloaddition of β-alkylated chalcones.46
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sieves which gave rise to selective metal dienolate formation and upon subsequent reaction with nitro alkenes to the synthesis of nitro cyclohexenols 97 in one synthetic operation and typically excellent enantio- and good diastereoselectivity. While E-configured chalcones worked more rapidly and efficiently, Z-configured chalcones gave rise to the products as well, albeit in lower yields and only after pre-isomerisation. Although no explicit mechanistic proposal has been made, this reaction might as well proceed via a domino-vinylogous Michael–intramolecular Henry reaction rather than a concerted process. In 2012 the first highly enantio- as well as regioselective vinylogous Michael reaction of acyclic, linear dienol silyl ethers 98 using asymmetric iminium ion-catalysis was established by Schneider and co-workers. Reaction of 98 with β-aryl, β-heteroaryl-, and β-silyl-substituted enals 99 in the presence of 20 mol% of the Hayashi–Jørgensen catalyst furnished precious chiral 1,7-dioxo compounds 100 in typically good yields, complete regioselectivity and excellent enantiocontrol of at least 97% ee (Scheme 39).47 The bulky mesityl-group effectively blocked the α-site within the dienol silyl ether directing the reaction completely to its γ-site. This process could successfully be extended to γ-alkyl-substituted dienol silyl ethers which furnished products with two new stereogenic centres which were formed with good diastereocontrol, additionally. Here only 3 Z-configured dienol silyl ethers gave rise to rapid consumption of the starting material and furnished products with good diastereoselectivity. Presumably an extended open transition state with minimized gauche-interactions between the γ-methyl group and β-substituent of the enal accounted for the observed anti-configuration in the products. Particularly noteworthy was the reaction of the β-silyl enal which proceeded rapidly to give 100a in 90% isolated yield and basically as a single enantiomer (>99% ee). In order to make this process synthetically more readily applicable the mesityl group within the dienolate component was subsequently replaced by the sterically and electronically similar 2,5-dimethyl pyrrole moiety. With 101 as a new latent
Review
Scheme 40 Vinylogous Mukaiyama–Michael reaction of acyclic dienolates based on N-acyl pyrroles.48
Scheme 41 Conversion of vinylogous Michael products 102 into synthetically useful chiral 1,7-dioxo compounds.48
dienolate the process was shown to be even more efficient as the catalyst loading could be reduced to 5–10 mol% while yields, diastereoselectivity and enantiocontrol were maintained at almost the same excellent level (Scheme 40).48 However, small amounts of the corresponding undesired α-regioisomers were typically produced suggesting that the blocking effect of the 2,5-dimethyl pyrrole moiety was not as pronounced as in the case of the mesityl group. More importantly, synthetically useful amounts of stereoisomerically pure 1,7-dioxo compounds 102 were isolated in all cases studied through chromatography. Finally, the products obtained could subsequently be derivatised into useful synthetic intermediates through hydrolysis, transesterification, reduction, and alkylation in high yields demonstrating the synthetic versatility of this transformation (Scheme 41).
Conclusion
Scheme 39 Vinylogous Mukaiyama–Michael reaction of acyclic dienol silyl ethers.47
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The vinylogous Michael reaction has emerged as a powerful synthetic strategy to access highly functionalized 1,7-dioxo compounds or analogues thereof, which are of great value for organic synthesis. Metal- and increasingly organocatalysed protocols have been developed to execute these reactions in a highly regio-, diastereo-, and enantioselective manner. Whereas the focus has traditionally been on the use of electron-rich five-membered heterocycles such as silyloxy furans or butenolides, more and more processes have recently utilized acyclic vinylogous donors, furnishing synthetically even more
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broadly applicable products. Both direct vinylogous Michael reactions of unfunctionalised substrates as well as indirect Mukaiyama-type processes of preformed silyl nucleophiles have been demonstrated to proceed with partially outstanding levels of selectivity and efficiency. The future will most certainly see further progress in this field and more catalytic protocols will emerge which are even more selective and efficient.
Acknowledgements Generous financial support for our own work in this area was provided by the Deutsche Forschungsgemeinschaft (SCHN 441/10-1). We would like to thank the Evonik Foundation for a predoctoral fellowship awarded to F. A.
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Organic & Biomolecular Chemistry
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