Development and Applications of Disulfonimides in Enantioselective Organocatalysis.

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Development and Applications of Disulfonimides in Enantioselective Organocatalysis Thomas James, Manuel van Gemmeren, and Benjamin List* Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany development of methodologies utilizing the originally reported catalysts and their analogues, significant work has also been devoted to the design and synthesis of new catalyst motifs aimed at addressing challenges in this area, such as low stereoinduction with small, unbiased substrate molecules.7−13 Another limitation has been the requirement for relatively basic substrates such as imines, in order to provide sufficient activation.14,15 These limitations have spurred interest in the development of more acidic catalysts, e.g., for the activation of ketones, aldehydes, or even olefins. As a result of these endeavors, several new catalyst types have been reported within the last few years (Figure 1). The group of Yamamoto developed N-triflyl phosphoramides 2 as more acidic analogues of the corresponding BINOLCONTENTS phosphoric acids 1.16 In 2008 the groups of List and Ishihara 1. Introduction A independently reported BINOL-disulfonic acid 31,17−19 and in 2. Historical Development, Design, and Syntheses the following year the List group also reported the design, of Chiral Enantiopure Disulfonimides B synthesis, and first use of disulfonimides (DSIs) 4 in 2.1. Design of Chiral Enantiopure Disulfonimides enantioselective catalysis.20 Analogous disulfurylimides (JINand Historical Context B GLEs) 5 were introduced by the Berkessel group in 2010.21 In 2.2. Syntheses of Chiral Enantiopure Disulfoniparallel to the development of these catalyst motifs, several mide Catalysts D studies were conducted aiming at the quantification of their 3. Applications of Chiral Enantiopure Disulfonirespective acidities. In 2011 the groups of Berkessel and mides in Enantioselective Brønsted Acid Catalysis F O’Donoghue reported the UV/vis spectroscopic determination 3.1. Enantioselective Aminoalkylation of Indoles F of such pKa values in dimethylsulfoxide (DMSO).22 Their 3.2. Enantioselective Steroid Synthesis G results suggested that all catalysts shown have pKa values in a 3.3. Enantioselective Strecker Reactions H comparably narrow range, which is in contrast to the generally 4. Applications of Chiral Enantiopure Disulfoniobserved strong differences in catalytic activity. However, in mides in Enantioselective Lewis Acid Catalysis I 2013 the values obtained in this study for N-triflyl 4.1. Enantioselective Reactions Proceeding via a phosphoramides 2 and disulfurylimides 5 were called into Mukaiyama Aldol Manifold I question through a report by Rueping, Leito, and co-workers, 4.2. Mukaiyama−Mannich Reactions Including who obtained significantly more varied values in acetonitrile as Vinylogous Cases L solvent and suggested that these compounds should have 4.3. Hosomi−Sakurai and Related Three-Componegative pKa values in DMSO.23 Although the latter authors did nent Aminoallylation Reactions P not report an acidity for disulfonimides 4, it can reasonably be 4.4. Catalytic Enantioselective Abramov Reacassumed that these species should also be ascribed a higher tions R acidity than that found in the study by Berkessel and 5. Conclusions and Outlook R O’Donoghue. Finally, in 2014 Li, Cheng, and co-workers Author Information R reported a computational study calculating pKa values for a Corresponding Author R wide range of catalysts structures in DMSO.24,25 These results Notes R corroborate the assessment by Rueping, Leito, and colleagues, Biographies R ascribing negative pKa values to N-triflyl phosphoramides 2 and Acknowledgments S disulfurylimides 5 as well as values around zero to References S disulfonimides 4. The new catalyst types shown in Figure 1 differ significantly in their success in enantioselective applications. In fact, the 1. INTRODUCTION Since the groundbreaking reports by the groups of Akiyama and Terada on the use of BINOL-derived phosphoric acids as organocatalysts,1,2 the area of enantioselective Brønsted acid catalysis has been intensively investigated.3−6 Apart from the © XXXX American Chemical Society

Special Issue: 2015 Frontiers in Organic Synthesis Received: March 3, 2015

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DOI: 10.1021/acs.chemrev.5b00128 Chem. Rev. XXXX, XXX, XXX−XXX

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Figure 1. Chiral Brønsted acids for enantioselective catalysis and their acidities.

most acidic species, disulfurylimides 5 and bissulfonic acids 3, have not found application in highly enantioselective catalysis to date. However, the latter have since been employed successfully in the form of their salts.17,26−28 This indicates that, while high acidity may be desirable for the activation of weak electrophiles, a too high acidity may be detrimental for enantioselection, presumably by enabling mechanisms proceeding through separated ion pairs. Following this argument, the most promising candidates for the activation of challenging substrates would be those that are more acidic than BINOLphosphoric acids yet not acidic enough for complete ion pair separation.29−34 Accordingly, N-triflyl phosphoramides 2 have found widespread application in enantioselective methodologies, which have been comprehensively reviewed.14,15 Finally, chiral, enantiopure disulfonimides 4 also fall into this apparent optimum in acidity. Although they were originally designed as Lewis acid organo-(pre)-catalysts (vide infra),20 disulfonimides 4 have recently been recognized as powerful Brønsted acid organocatalysts as well. Their design, syntheses, and applications in enantioselective catalysis will be at the focus of this review.

Figure 2. Design components of BINOL-derived disulfonimides.

TRIP-BINOL phosphoric acid catalyst,4 would result in a sterically demanding environment around the disulfonimide motif. Furthermore, electronic contributions from 3,3′-substituents may allow fine-tuning of the acidity at the disulfonimide motif. Introduction of further backbone substitution again facilitates the tuning of acidity through resonance contributions. Similar influences of backbone substitution were studied by Dughera and co-workers on the achiral ortho-benzenedisulfonimide system.37 It should be noted that all these modification handles have been used with great success in the development of BINOL-derived phosphoric acid catalysts.6 Examples of their application on disulfonimides will be discussed later. Apart from these modifications on the BINOL-based disulfonimide backbone, several other structural variations have been reported recently (Figure 3). The first reports of disulfonimides derived from BINOL emerged in 2009 through reports by the List and Giernoth groups.20,38 Whereas the List group introduced the 3,3′arylated catalyst 4a as a highly efficient catalyst for the Mukaiyama-aldol reaction, Giernoth and co-workers subsequently reported the synthesis and characterization of the 3,3′unsubstituted parent compound, which had also been described in 2008 in a dissertation by our graduate student S. Hoffmann.39 In 2011, Dughera, Ghigo, and colleagues reported the synthesis of an axially chiral ortho-benzenedisulfonimide derivative 6a, which was applied in asymmetric Strecker reactions in 2012 with moderate success.40 In an extension of

2. HISTORICAL DEVELOPMENT, DESIGN, AND SYNTHESES OF CHIRAL ENANTIOPURE DISULFONIMIDES 2.1. Design of Chiral Enantiopure Disulfonimides and Historical Context

The binaphthyl backbone, introduced to asymmetric catalysis by Noyori et al.,35 has found applications in diverse areas of asymmetric synthesis.36 This is at least partially due to its rigid structure, imparting C2 axial chirality, and the aromatic nature of the binaphthyl system, allowing facile introduction of substitution into the backbone. The design of new disulfonimides exploits these components to both subtly modify the steric demand around the catalytically active disulfonimide motif and modulate acidity of the N−H through donation or removal of electrons from the extensive π-system (Figure 2). It was hypothesized that the introduction of bulky groups into the 3,3′-positions, in analogy to the widely employed B


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Figure 3. Timeline of structural developments beyond 3,3′-arylated binapthyl derivatives.

Scheme 1. Seminal Reports of Chiral Disulfonimides Based on a BINOL Backbone; Where Synthetic Approaches Diverged, the Procedures Reported by Giernoth and Co-workers Are in Italics

Scheme 2. Lee Synthesis of 3,3′-Substituted BINOL-Derived Disulfonimides

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this work, doubly axially chiral catalysts such as 4b were reported by Dughera and co-workers in 2014, which could improve on the previous results.41 In the same year, List and co-workers reported the synthesis and application of (biaryl)hydroxy acids (HYDRAs, 7a),42 which due to internal activation feature a significantly increased catalytic activity.43

increase of acidity, the introduction of nitro-substituents was studied. Indeed, after careful optimization of reaction conditions, the site-selective dinitration of disulfonimide catalysts was achieved, thus enabling the synthesis of more Brønsted-acidic disulfonimide derivatives 13 (Scheme 3).

2.2. Syntheses of Chiral Enantiopure Disulfonimide Catalysts

Scheme 3. List’s Modification of Disulfonimides by Backbone Nitration, Leading to More Acidic Catalysts

The two approaches toward BINOL-disulfonimides reported in 2009 employed very similar methods to install the target motif as outlined in Scheme 1.20,38 Commencing from commercially available BINOL 8b, List and co-workers installed aromatic groups at the 3,3′-positons utilizing well-known methodology, thus obtaining BINOL-derivative 8a. Common to both approaches was the incorporation of the 2,2′-sulfur centers through the thermally induced Newman−Kwart rearrangement of bis(O-arylthiocarbamate) 9. Subsequent oxidative cleavage of the resulting bis(S-arylthiocarbamate) 10a to the bis-sulfonic acid and activation to the disulfonyl chloride 11a was demonstrated by the List group. Complementary to this approach, it was found that treatment of 10b with Nchlorosuccinimide led directly to the disulfonyl chloride 11b in a one-step protocol. Final cyclization of the disulfonyl chloride with a source of ammonia gave the disulfonimide motif, which was acidified postpurification to give the free acid 4. Although this route allowed for the first time access to disulfonimide 4a bearing 3,3′-substituents, the synthesis required at least five linear steps from the installation of the substituents, which was a route deemed too lengthy for efficient synthesis of catalysts bearing diverse 3,3′-groups. In 2010 Lee and co-workers reported a synthesis of catalysts 4, which showcased a late-stage introduction of the 3,3′-substituents (Scheme 2).44 Starting from racemic BINOL 8b, Lee and coworkers employed an approach analogous to those previously discussed, featuring a Newman−Kwart rearrangement and direct oxidative chlorination. However, cyclization was performed with (S)-α-methylbenzylamine to give two chromatographically separable diastereoisomers (R,S)- and (S,S)-12. Subsequent hydrogenative cleavage of the methylbenzyl group gave the unsubstituted disulfonimide 4b. At this point double ortho-lithiation was employed, exploiting the directing ability of the disulfonimide motif. Trapping of the bis-lithiated species with the appropriate electrophile allowed access to either the brominated or iodinated disulfonimide 4c or 4d. To install aryl groups at the 3,3′-positions, Suzuki−Miyaura cross-coupling was utilized with a variety of aryl boronic acids, which facilitated the efficient synthesis of a small library of disulfonimides bearing 3,3′-diaryl substitution (e.g., 4a, 4e, and 4f). Modified variants of this route, starting from enantiomerically pure BINOL, have been widely adopted in the synthesis of chiral disulfonimides and are now routinely prepared on the multigram scale. Indeed, this approach has also been employed in the synthesis of chiral bis-sulfonic acids by Ishihara and coworkers.45 The first example of a backbone-modified, BINOL-derived disulfonimide catalyst was introduced in 2014 by the List group.46 Rather than developing a linear sequence with the desired substitution pattern, a modification of the preformed catalyst 4g was envisaged, which would allow the synthesis to rely on the established synthetic methodology and only require the development of the final modification step. Aiming at the

Likewise, in the pursuit of more acidic disulfonimide catalysts, the concept of activation via internal assistance through hydrogen bonding (Brønsted acid-assisted Brønsted acid (BBA) according to the Yamamoto classification)43 was investigated by the List group. As such, novel (biaryl)hydroxyl acids (HYDRAs) were developed that exploit internal hydrogen bonding between the hydroxyl and disulfonimide motifs to increase the NH acidity.42 This novel class of highly acidic catalyst 7 was accessed in a one-pot lithiation/alkylation sequence from the enantiomerically pure 3,3′-unsubstituted disulfonimide 8b, thus trapping the bis-lithiated species with appropriate benzophenone derivatives (Scheme 4). Scheme 4. Synthesis of Highly Acidic HYDRA Catalysts by List et al.

It was found that catalysts derived from benzophenone derivatives containing electron-withdrawing groups (such as bis[3,5-bis(trifluoromethyl)phenyl]methanone) were stable to acidification conditions giving the free Brønsted acids. When less electron-deficient benzophenone derivatives were employed, decomposition resulting in a ring opening of the central disulfonimide motif was routinely observed during acidification. This HYDRA class of disulfonimide catalyst was found to be highly active in challenging transformations, significantly outperforming known disulfonimide catalysts (as discussed in section 4.1). It should be noted that the List group also described the synthesis of analogous internally activated BINOL-phosphoric acids, even though no synthetic applications have been described to date. D


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(S,S)-19 in good yields. Finally, treatment of 19 with sodium methoxide induced the cleavage of the chiral auxiliary, giving the disulfonimide 6a after acidification by treatment with an acidic resin. Subsequently, a similar methodology was employed to the synthesis of 3,6-diaryl-substituted ortho-benzenedisulfonimides 6b, 6d, and 6e bearing one or two rotationally hindered biaryl axes. In this case, several steps were required to obtain the respective isatin derivatives 25a−c (Scheme 6). Their synthesis began with nitroanilines 20, which were first iodinated to give 21 and subsequently converted to diiodides 22 by a diazotization followed by treatment with tetrabutylammonium iodide. Reduction of the nitro group delivered the diiodo anilines 23, which were then converted into the desired isatin diiodides 24. Double Suzuki−Miyaura cross-coupling, for which different conditions were found to be optimal depending on the substrate combination, delivered isatin derivatives 25 bearing one (25a) or two (25b and 25c) configurationally stable chiral biaryl axes. It should be noted that the overall yield of 25b was comparably low and that the authors reported an alternative approach for this intermediate in the same study. With isatins 25a−c in hand, a sequence analogous to the previously reported synthesis for the disulfonimide with one biaryl axis delivered the corresponding chiral ortho-benzenedisulfonimide derivatives. Access to their enantiopure forms was gained through a separation of enantiomers by semipreparative chiral HPLC on the disulfonyl chloride stage.41 It should be noted that, during the synthesis of compounds 6e and 6b, which bear two stable chiral biaryl axes, no diastereoselectivity was observed. Therefore, 50% of the material was obtained as the meso-form and could not be further converted to enantiopure catalysts. Accordingly, after the separation of stereoisomers each enantiomer of these doubly axially chiral disulfonyl chlorides was obtained in ∼25% yield, which could then be processed to the desired enantiopure orthobenzenedisulfonimide catalysts 6.

Although BINOL-derived disulfonimides have, by far, received the most attention from the synthetic community, recent reports have emerged outlining the synthesis of axially chiral ortho-benzenedisulfonimide derivatives. Key to the development of chiral ortho-benzenedisulfonimide derivatives was controlling the atropisomerism around the biaryl backbone. This was addressed by the introduction of substituents orthoto the biaryl axis, thus hindering rotation and generating a stable chiral axis, as highlighted in Figure 4.

Figure 4. Minimization of atropisomerisomeric racemization by hindered rotation in chiral disulfonimides.

The synthesis of a first generation of axially chiral orthobenzenedisulfonimide derivatives 6a was reported by Dughera, Ghigo, and co-workers in 2011, starting from isatin derivative 14 (Scheme 5).47 The incorporation of the 2-methyl phenyl group was achieved using Suzuki−Miyaura coupling conditions giving 15, and subsequent oxidative ring opening gave the required 3arylanthanilic acid 16. Incorporation of the sulfur centers was achieved by trapping the benzyne generated upon diazotization of amine 16 with carbon disulfide in the presence of isoamyl alcohol, giving 17 in good yield. Oxidative cleavage of the dithiolane by treatment with chlorine gas in aqueous conditions gave the disulfonyl chloride 18. Cyclization to the sulfonimide 19 was achieved upon treatment of the disulfonyl chloride 18 with enantiomerically pure 1-phenylethylamine. Subsequent separation of the diastereoisomers by preparative high-performance liquid chromatography (HPLC) gave both (R,S)- and

Scheme 5. Dughera/Ghigo Synthesis of Axially Chiral Disulfonimide 6a

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Scheme 6. Dughera Synthesis of (Bis-)axially Chiral Disulfonimides 6b, 6d, and 6e

Scheme 7. Enantioselective Aminoalkylation of Indoles with Aldimines by Lee et al.

3. APPLICATIONS OF CHIRAL ENANTIOPURE DISULFONIMIDES IN ENANTIOSELECTIVE BRøNSTED ACID CATALYSIS

disulfonimide and the protonated substrate. Indeed, reports demonstrating the utility of chiral disulfonimides in asymmetric Brønsted acid catalysis are emerging.40,41,46,48 Herein we discuss approaches employing chiral enantioenriched disulfonimides that are understood to proceed via Brønsted acid catalysis.

Enantioselective catalysis with Brønsted acids has been most widely demonstrated with BINOL-derived phosphoric acids developed by the groups of Akiyama and Terada.1−6 The potential exploitation of disulfonimides in asymmetric Brønsted acid catalysis appears to be equally promising for several reasons. First, they are more acidic than the phosphoric acid catalysts, which potentially allows for the activation of less basic substrates such as aldehydes, ketones, and olefins. Second, binaphthyl disulfonimides are C2-symmetric, as opposed to the pseudo-C2-symmetry of BINOL phosphoric acids. Third, the proton-carrying active site is buried somewhat deeper in the pocket of the disulfonimide as compared to that of the corresponding phosphate. This could potentially enhance the stereochemical communication between the deprotonated

3.1. Enantioselective Aminoalkylation of Indoles

In 2011 Lee and co-workers described enantioselective alkylation reactions mediated by the chiral, enantiopure disulfonimide 4a.48 Treatment of N-sulfonyl aldimines 27 with indoles 26 in the presence of disulfonimide 4a, in toluene under cryogenic conditions, resulted in the formation of secondary sulfonamides 28 in good to excellent yields and with generally high levels of stereocontrol (Scheme 7). This methodology showed to be general for various Nsulfonyl groups, aldimines, and indoles, representative examples of which are shown. Interestingly, the authors propose a mode F


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highly acidic disulfonimide 13, which catalyzed the Torgov cyclization with high levels of stereocontrol (Scheme 8).46 Interestingly, although BINOL-derived phosphoric acids were found to catalyze this transformation at elevated temperatures, poor stereoselectivity was observed. Importantly, non-nitrated variants of the disulfonimide catalyst catalyzed the reaction with promising enantioinduction at 0 °C. However, their catalytic activity did not enable sufficiently low reaction temperatures for very high selectivities. The development of the highly acidic disulfonimide 13, bearing nitro groups in the 5,5positions on the BINOL backbone, allowed a significant reduction in reaction temperature, which resulted in high levels of enantioselectivity. This approach showed tolerance for variation of A, B, C, and D rings, including substitution at the C−D junction, which allowed for accessing several enantioenriched tri- and tetracyclic dienes with high stereoselection (e.g., 30a−c). Mechanistically, the Torgov cyclization constitutes a stepwise process, in which a stereodetermining Prins-cyclization is followed by a slow dehydration step (Scheme 9). The authors found the use of a temperature program optimal, thus conducting the Prins-cyclization at −40 °C and subsequently raising the temperature to −5 °C for the dehydration step. Importantly, the temperature in the terminal step was also found to influence the stereochemical outcome of the overall process. The stereodetermining Prins addition step was found to become reversible if elevated temperatures were employed, thus causing an erosion of the previously achieved enantioselection. The utility of this methodology was demonstrated by the shortest reported gram-scale synthesis of (+)-estrone, which utilized the enantioselective cyclization as the key step and proceeded with excellent yield and with very high levels of stereocontrol (Scheme 10). Accordingly, the intermediate 29a was accessed via allyl alcohol 32 in two steps from commercially available 6-methoxy1-tetralone 31. The subsequent Torgov cyclization using a modified variant of the newly developed protocol and a single recrystallization gave access to enantiopure Torgov’s diene 30a, which was then processed to estrone methyl ether 33 following protocols described by Corey and co-workers.53 Final

of action by analogy to models of both BINOL-derived phosphoric acids and proline-based binaphthyl sulfonamides (Figure 5). In this model the disulfonimide acts both as a

Figure 5. Activation mode proposed by Lee et al. demonstrating the proposed bifunctional nature of the disulfonimide motif.

Brønsted acid, activating the imine, and as a hydrogen bond acceptor, thus coordinating and activating the incoming indole nucleophile. Although this model does not explain the absolute sense of stereocontrol (the imine is attacked from the Si-face leading to (R)-configured products), the coordination of both reaction partners offers a good rationalization for the observed high degree of stereocontrol. 3.2. Enantioselective Steroid Synthesis

One of the most powerful approaches to biologically relevant steroids was reported in 1963 by Ananchenko and Torgov; it exploited an intramolecular, Brønsted acid-mediated, Prins-type addition of a styrene derivative to a cyclic diketone.49 Despite the elegance of this approach to the Torgov diene, which is an important intermediate in steroid synthesis and was typically accessed in its enantioenriched form by significantly less straightforward routes,50−55 a highly enantioselective variant of the Torgov cyclization remained elusive. However, it should be noted that researchers from Schering reported studies toward this goal, which did not result in high selectivities and turnover numbers.56,57 Upon investigation of an enantioselective variant of this transformation, List and co-workers developed the novel

Scheme 8. Disulfonimide-Catalyzed Enantioselective Torgov Cyclization by List et al.

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Scheme 9. Mechanism of the Disulfonimide-Catalyzed Enantioselective Torgov Cyclization by List et al.

Scheme 10. Shortest Total Synthesis of (+)-Estrone Reported to Date, Utilizing the Enantioselective Torgov Cyclization by List et al. As the Key Step

in the presence of either 6d, 6e, or 6b at −20 °C, giving the αamino nitriles 36 in good yields with good to high levels of enantioselectivity. In a preceding study the authors reported a moderate enantioselection when utilizing 6a for the same reaction at higher reaction temperatures. Interestingly, based upon analogy to previously calculated results, the authors propose a Brønsted acid catalyzed mechanism, in which ion pairing between an iminium species and anionic disulfonimide results in the observed enantioselectivity. The authors note that significantly better enantioinduction was enabled by the C2symmetric catalysts 6e and 6b bearing two configurationally stable chiral biaryl axes. The additional observation that steric bulk on the substituent increases stereocontrol may foreshadow future developments in the design of ortho-benzenedisulfonimide-derived chiral disulfonimide catalysts.

deprotection with BBr3 yielded the targeted (+)-estrone (34), thus completing the shortest synthesis of this steroid reported to date. 3.3. Enantioselective Strecker Reactions

The Strecker synthesis of α-amino nitriles has received attention from numerous groups since its discovery in 1850 due to the versatility of the products in the synthesis of valuable enantioenriched building blocks such as α-amino acids.58,59 The intensive research aiming at the development of asymmetric variants of this reaction has resulted in a variety of both metalbased and organocatalytic methodologies.60,61 An enantioselective metal-free approach to the Strecker synthesis was reported by Dughera et al. using chiral derivatives of obenzenedisulfonimide (Scheme 11).40,41 The one-pot, three-component condensation of acetophenone 35, aniline, and TMSCN was found to proceed smoothly H


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catalysis compared to previously known strong Brønsted acids as outlined in Scheme 13. It was found that treating 2-naphthaldehyde (37a) with silyl ketene acetal 38a failed to give the ester 39a in the presence of phosphoric acid 1a, phosphoramide 2a, or disulfonic acid 3a. However, the addition of disulfonimide 4a gave ester 39a in near quantitative yield with highly promising levels of stereoinduction. Subsequently, after optimization of the reaction conditions, the scope of this approach was investigated and this methodology was found to be widely applicable to various aldehydes and silyl ketene acetals (Table 1). Product 39a resulting from the model system was obtained in near quantitative yield and with excellent stereoselectivities (97:3 e.r.) under the optimized conditions (entry 1). Further aromatic and α,β-unsaturated substrates reacted smoothly with the same nucleophile, giving, for example, 39b and 39c in high yields and enantioselectivities (entries 2−3). Similarly, acetate aldol products 39d and 39e could be obtained with equally good results (entries 4−5). Using the formation of 39e as model system, the authors demonstrated that exceptionally low catalyst loadings of down to 0.01 mol % could be utilized before a detrimental effect on the stereoselectivity was observed (entries 5−8). This is particularly noteworthy because metalbased catalyst systems for this reaction typically require high to very high catalyst loadings (often 20%)64−67 due to the competition with a nonenantioselective silylium ion background catalysis pathway (Scheme 14).68,79 Finally, the authors demonstrated that promising yet nonsatisfying results were obtained when the reported protocol was applied to aliphatic substrates (product 39f, entry 9). Mechanistically there are two potential pathways that account for the observed reactivity. The first possible pathway, proceeding through a protonated aldehyde intermediate in analogy to that presented in the phosphoric acid catalyzed Mukaiyama−Mannich reaction,1 was deemed to be unlikely due to the lack of correlation between activity and Brønsted acidity. A second, more likely pathway involving an N-silyl disulfonimide is outlined below, which was proposed based on precedence from nonenantioselective catalysis (Scheme 15).68−71 Initial protodesilylation of the silyl ketene acetal 38 by disulfonimide 4 generates the catalytically active species 40.70,71 Indeed, NMR studies show that silyl ketene acetal 38 readily silylates the disulfonimide 4, validating the initial Lewis acid formation. The presence of the Brønsted-basic 2,6-di-tert-butyl4-methylpyridine in control reactions was tolerated within this transformation, eliminating any potential Brønsted acid aldehyde activation. As such, it is proposed that the silylated disulfonimide 40, which was shown to exist as a mixture of Nand O-silylated tautomers, can subsequently activate the aldehyde through O-silylation, generating the oxonium ion. Asymmetric induction is realized due to the stereochemical communication within the ion pair 41, consisting of disulfonimide anion and the oxonium species, during the enantiodetermining addition of a second molecule of silyl ketene acetal to give a second ion pair 42, a clear case of asymmetric counteranion-directed catalysis (ACDC). Subsequent silyl transfer may occur through several pathways: Ion pair 42 may directly liberate the silylated disulfonimide 40 under concomitant formation of the observed product, thus completing the catalytic cycle. Alternatively, a silyl transfer onto another molecule of aldehyde may take place. In this latter mechanism, an ion pair 43 would be formed, from which

Scheme 11. Dughera Approach to the Enantioselective Strecker Synthesis of α-Amino Nitriles

4. APPLICATIONS OF CHIRAL ENANTIOPURE DISULFONIMIDES IN ENANTIOSELECTIVE LEWIS ACID CATALYSIS As discussed in the previous section, disulfonimides are strong Brønsted acids. However, upon treatment with an appropriate silylating agent, typically the nucleophile employed in the respective reaction, these motifs become very strong Lewis acids.20,62 Subsequently, the silylated disulfonimides are capable of Lewis acid activation of substrates that remain challenging for Brønsted acid activation, such as aldehydes. The activation of such substrates is proposed to proceed through a cationic intermediate that may, due to Coulombic pairing with a chiral enantiopure disulfonimide anion, undergo an enantioselective transformation: a case of asymmetric counteranion-directed catalysis (ACDC) as exemplified in Scheme 12.29−34,63 Herein we summarize advances in the area of chiral disulfonimidecatalyzed reactions, which reportedly proceed through a Lewis acid activation pathway. Scheme 12. Schematic Example of Proposed Lewis Acid Catalysis Mediated by Disulfonimides

4.1. Enantioselective Reactions Proceeding via a Mukaiyama Aldol Manifold

Seminal investigations on the employment of chiral enantioenriched disulfonimides in Lewis acid catalysis were reported by List and co-workers in 2009. 20 These initial studies demonstrated the exquisite behavior of the newly developed BINOL-derived disulfonimide 4a in silicon-mediated Lewis acid I


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Scheme 13. Comparison of Strongly Brønsted-Acidic Motifs in the Mukaiyama Aldol Reaction

likely based on results published in a dissertation conducted in the List group.72 In 2013, the List group reported a mechanistic study on this reaction system,62 in which its kinetics were studied utilizing the reaction progress kinetic analysis methodology developed by the Blackmond group.73 A rate law was derived for a model reaction, showing that the overall process is first order in silyl ketene acetal and catalyst and has a noninteger order of ∼0.55 in aldehyde. From this it was concluded that the attack of the silyl ketene acetal on the activated oxonium ion 41 (or 43) is the slowest step of the catalytic cycle, but that the aldehyde activation is an equilibrium, such that the aldehyde concentration can partially influence the rate (while it should be zero order, if only the addition step were rate-limiting). Inspired by this highly enantioselective methodology, further investigations probed the scope of this transformation, and capitalizing upon the ability of π-systems to transfer electron density throughout a series of conjugated olefins,74,75 List and co-workers reported the vinylogous and bisvinylogous Mukaiyama aldol reaction.76 The selective vinylogous γalkylation of dienol silyl ethers 44 was found to proceed smoothly in the presence of disulfonimide 4a giving γ-hydroxy esters 46, a motif commonly found in natural product, in high yields and regioselectivity (>50:1 γ/α), and with excellent stereoselectivity (Scheme 16, left). This disulfonimide-catalyzed methodology showed much wider substrate tolerance than many of the previously reported asymmetric methodologies.77−83 Variation of the silyl groups was well-tolerated, as were substitution patterns of the parent ester. Electron-rich and neutral aryl aldehydes were superior in terms of reactivity compared to electron-deficient substrates, presumably due to facile formation of the silyl oxonium species, although high levels of enantioselectivities were retained (46a and 46b). Branched and unbranched aliphatic aldehydes were also suitable substrates for this methodology, although the yields and enantioselectivities were diminished (46c). Application of this methodology to trienol silyl ethers 45 allowed access to the first highly enantioselective catalytic bisvinylogous Mukaiyama aldol reaction (Scheme 16, right). As predicted by density functional theory (DFT) calculations, α/ terminal selectivity was less pronounced compared to the

Table 1. Selected Examples of the Disulfonimide-Catalyzed Enantioselective Mukaiyama Aldol Reaction

product could be eliminated, thus closing the catalytic cycle and giving 41. Finally, the complex ion pair 43 could also serve as the activated species being attacked by silyl ketene acetal 38. In this case ion pair 42 would result from product liberation, likewise closing the catalytic cycle. These complex scenarios were considered based on findings in analogous achiral systems described by Yamamoto and co-workers.70,71 and later deemed J


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Scheme 14. Proposed Mechanism of Metal-Based Catalytic Aldol Reaction Resulting in the Liberation of a Silylium Species

be synthetically demanding. As such, only limited examples of enantioselective syntheses of 2,6-disubstituted dihydropyrones existed whereas enantioselective approaches to 2,5,6-trisubstituted dihydropyrones were unknown.90−93 Initial screening of conditions showed that the HDA reaction was readily catalyzed by disulfonimide catalysts, with the best enantioselectivities being observed with disulfonimide 4h bearing perfluoroisopropyl groups, which presumably modulate both the electronic and steric demands of the naphthyl-3,3′substituents. A wide variety of dienes 48 were well-tolerated under these conditions, giving substituted dihydropyrones in good to excellent yields with high enantioselectivities (e.g., 49a and 49b, Scheme 17). Variation of the dienophile was similarly well-tolerated with aromatic and heteroaromatic aldehydes (e.g., 49b−d), as well as cinnamaldehyde-derived substrates, giving the expected products in high yields and with high stereoselectivity. The utility of this approach was demonstrated by the first enantioselective synthesis of a potent aromatase inhibitor in two steps starting from 49d.94,95 Mechanistically, the analysis of the unquenched reaction mixture enabled the isolation of a reaction intermediate, which clearly indicated that the heteroDiels−Alder products are obtained by a stepwise process involving a vinylogous Mukaiyama aldol reaction, followed by an intramolecular cyclization under the acidic and desilylating conditions employed for quenching. Mukaiyama aldol reactions of silyl enol ethers, which lack a strong polarization of the C−C double bonds, are typically more challenging due to the reduced nucleophilicity of the πsystem.96 The development of new, more acidic disulfonimide motifs has allowed access to substrates that were previously unable to be activated by disulfonimides 4. List and co-workers recently demonstrated a new Brønsted acid assisted disulfonimide catalyst. These (biaryl)hydroxy acids (HYDRAs 7) were found to be sufficiently acidic to activate nonpolarized silyl enol ethers; namely, 1,2-bis(trimethylsilyloxy)cycloalkenes 50, enantioselective aldol reactions of which were previously unknown (Scheme 18).42 Initial development focused on the aldol reaction between 6bromo naphthaldehyde (37b) and cyclopentene 50. A comparison of disulfonimide 4a and HYDRA 7 showed that similar enantioinductions were obtained with both catalysts at 0 °C, albeit with significantly differing catalytic activities. As a consequence of this differing catalytic activity, only HYDRA 7 enabled the catalysis of the target reaction at lower temper-

Scheme 15. Mechanistic Considerations on the Disulfonimide-Catalyzed Mukaiyama Aldol Reaction

vinylogous substrates, although significant (up to 9:1 ε/α) regioselectivites were observed. A variety of aromatic aldehydes (47a and 47b) and cinnamaldehyde derivatives (47c) were well-tolerated, giving high yields of expected products with high levels of stereocontrol. It was also found that an aliphatic aldehyde was a suitable substrate with promising reactivity, although with significantly reduced stereoselectivity. Encouraged by the observation that dienes were welltolerated under these reaction conditions, attentions were focused on the formal Hetero-Diels−Alder reaction (HDA).84 The employment of dienol silyl ethers in Diels−Alder reactions has been explored extensively, finding applications in the synthesis of many complex molecules. Since the initial observation by Danishefsky et al. that hetero-Diels−Alder reactions between aldehydes and 1-methoxy-3(trimethylsilyloxy)butadiene (Danishefsky’s diene) were accelerated by Lewis acids,85,86 many asymmetric variants using chiral Lewis acids have emerged.87−89 One significant limitation is that the syntheses of the appropriate dienes have proven to K


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Scheme 16. Vinylogous and Bisvinylogous Mukaiyama Aldol Reactions Reported by List et al.

Scheme 17. Disulfonimide-Catalyzed Formal Hetero-Diels−Alder Reactions

atures (−78 °C), thus delivering adduct 51a in high yield, diastereo- and enantioselectivity. Subsequent extension of this catalytic system showed that various 1,2-bis(trimethylsilyloxy)cycloalkenes were suitable substrates, giving 51b, 51c, and 51d in good yields and selectivities. To quantify the high catalytic activity of this new catalyst type, the authors conducted kinetic experiments that indicated that HYDRA-type disulfonimides are 2−3 orders of magnitude more active than 3,3′-arylated disulfonimides. The high Lewis acidity of the silylated species was also confirmed by an accompanying computational study, and the authors highlighted the potential of such active catalysts by conducting nonenantioselective catalysis at catalyst loadings as low as 10

ppm, which is particularly remarkable as organocatalysis has traditionally been criticized for its requirement of high catalyst loadings.97 4.2. Mukaiyama−Mannich Reactions Including Vinylogous Cases

Given the plethora of natural and pharmaceutically relevant compounds that contain chiral amine functional groups, it is hardly surprising that numerous methods have been developed to facilitate their synthesis in an efficient and controlled manner.98 Among the methods available to the synthetic chemist, the enantioselective Mannich reaction between an enol derivative and an imine is attractive due to the formation of a new C−C bond and the concomitant generation of a new L


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Scheme 18. Mukaiyama Aldol Reactions with Weakly Nucleophilic 1,2-Bis(Trimethylsilyloxy)cycloalkenes Enabled by Highly Acidic HYDRA-Type Disulfonimides

δ-Amino-β-ketoesters are versatile building blocks, finding applications in the synthesis of numerous piperidine- and pyrrolidine-containing heterocyclic systems. Established methods allowing access to this class of compound are heavily reliant on enantioenriched compounds, such as those from the chiral pool or on employing chiral auxiliaries, whereas catalytic asymmetric methodologies are extremely rare.102,103 Inspired by the findings outlined above, List and co-workers extended the scope of this type of transformation to allow enantioselective access to δ-amino-β-ketoester derivatives 56 utilizing the Mukaiyama−Mannich reaction manifold (Scheme 20).104 It was found that treating N-Boc imine 58a with silyloxydiene 59a in the presence of chiral disulfonimides furnished the carbamate 60a in >95% yields. Subsequent optimization of this transformation identified the disulfonimide 4i as the optimal catalyst, allowing synthesis of the carbamate 60a in 96% yield with an enantiomeric ratio of 95:5. With optimized conditions in hand, the scope and limitations of this transformation were explored. This methodology was found to be widely applicable to a variety of N-Boc imines. Electron-rich arenes proceeded smoothly, giving the expected carbamates, such as 60b and 60c, in excellent yields with good levels of stereocontrol. Furthermore, electron-deficient arenes, bearing halogens at the 3-position, and hetero aryl substrates were found to be appropriate substrates giving carbamates, exemplified by 60d, in high yields and enantioselectivity. However, aliphatic aldehydes gave disappointingly low yields and enantiomeric ratios. The utility of this methodology was highlighted by its incorporation in a formal total synthesis of (−)-lasubin (57) from carbamate 60b. Furthermore, to demonstrate the versatility of the products derived from this methodology, several additional downstream transformations were described (Scheme 21). Starting with model product 60a, the authors conducted an alcoholysis, leading to β-ketoester 62a. Subsequent saponification and decarboxylation led to β-amino ketone 63, which was obtained without loss of enantiopurity. The same product was also obtained by direct hydrolysis of 60a. Further nucleophiles employed under similar conditions led to the formation of Weinreb amide 64a, β-ketoamide 64b, β-ketothioester 65, and

stereocenter.99,100 Typically, the instability of the imine species toward hydrolytic decomposition, a problem that is highly prevalent with alkyl imines, can limit the utility of these reactions. To overcome this limitation, the List group recently reported the utilization of α-amino sulfones, a common, hydrolytically stable, imine precursor, in the direct Mukaiyama−Mannich reaction with ester enolate equivalents to give enantiomerically enriched β3-amino esters.101 It was found that treating α-N-Boc-amino sulfones 52 with commercially available silyl ketene acetals in the presence of disulfonimide 4i, bearing extended π-systems at the 3,3′ positions, led to the formation of β3-amino esters such as 53a in excellent yields with high levels of stereocontrol, as shown in Scheme 19. This methodology was found to be tolerant of a wide variety of aromatic substrates under optimized reaction conditions. Electron-rich sulfones proved to be excellent substrates, giving, for example, the dimethoxyphenyl-substituted product 53b in 92% yield with good stereocontrol. Extended π-systems, such as sulfones derived from 1- or 2-naphthaldehyde, were welltolerated as were heterocycles exemplified by the synthesis of the furan 53c. Furthermore, this methodology was demonstrated to be extendable to aliphatic systems, such as 53d, in good yields although with diminished enantioselectivity. In the context of this study, extensive NMR spectroscopic analyses of the model system were undertaken, leading to a proposed catalytic cycle shown in Scheme 17. It was found that the imine generation via silylation of the N-Boc amino sulfone giving 54a followed by elimination is rate-determining and requires one equivalent of the nucleophile employed, thus yielding the imine, which is activated by the silylated catalyst to give 56a and the corresponding silylated sulfonate 55. The imine was suggested to engage in a catalytic cycle analogous to the Mukaiyama aldol reaction discussed above, delivering the silylated N-Boc protected Mannich adduct 57a in two tautomeric forms (the silyl group binding to the O- or Natoms of the carbamate group, respectively), both of which are converted to the N-Boc protected Mannich product 53a upon desilylation during workup. M


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Scheme 19. Disulfonimide-Catalyzed Mukaiyama−Mannich Reactions of α-N-Boc-Amino Sulfones

Scheme 20. Disulfonimide-Catalyzed Vinylogous Mukaiyama−Mannich Reactions of N-Boc Imines

β-ketoester 62b. While δ-amino-β-ketoester 62a was obtained indirectly in this study, Wang and List recently extended the N


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Scheme 21. Versatility of Products Obtained from the Vinylogous Mukaiyama−Mannich Reaction of N-Boc Imines

Scheme 22. Disulfonimide-Catalyzed Vinylogous Mukaiyama−Mannich Reactions of N-Boc Imines Utilizing Acyclic Silyl Ketene Acetals

Scheme 23. Disulfonimide-Catalyzed Hosomi−Sakurai Reaction of Aldehydes with Methallyltrimethylsilane and Its Derivatives

nucleophile scope of the vinylogous Mukaiyama−Mannich reaction to encompass acyclic nucleophiles, thus giving direct access to this type of compound (Scheme 22). At slightly higher temperatures (−30 °C) and utilizing the same disulfonimide catalyst 4i as before, the authors obtained the phenyl-substituted product 62a in high yield and with high enantioenrichments. This methodology was shown to tolerate significant steric bulk on the imine, as exemplified by the

excellent results obtained with the 1-naphthyl-derived product 62c. Likewise, both electron-donating substituents as in 62d and electron-withdrawing substituents as in 62e were welltolerated, although stereoselectivity was slightly reduced for electron-poor substrates. O


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4.3. Hosomi−Sakurai and Related Three-Component Aminoallylation Reactions


The coupling of carbonyl-derived electrophiles with allyltrimethylsilane, mediated by a strong Lewis acid, was first reported in 1976 by Hosomi and Sakurai.105 In the following decades, numerous groups have investigated this transformation, reporting elegant enantioselective strategies using various Lewis acids such as the titanium system developed by the Carreira group106 or the cyclic alkoxyboranes (CABs) developed by the Yamamoto group.107,108 The first demonstration of the chiral disulfonimide-catalyzed Hosomi−Sakurai reaction was reported in 2012 (Scheme 23).109 After extensive screening of reaction conditions, it was found that allyltrimethylsilane was incompatible with a highly enantioselective methodology, giving high yields but modest enantioselectivities of allylation products. However, employing the more electron-rich methallyltrimethylsilane enabled significantly lower reaction temperatures and thus afforded the methallylation products in excellent yields with high levels of stereocontrol. It was found that treating benzaldehyde (37c) with methallyltrimethylsilane (67a) in the presence of the disulfonimide 4j and silyl ketene acetal (SKA) 38a resulted in the formation of the model alcohol 68a in 82% yield and in a 92:8 ratio of enantiomers. The optimized conditions were then applied to a variety of both aldehydes and methallyltrimethylsilane derivatives. Both electron-rich (toward 68b) and electron-deficient aldehydes (toward 68d) were well-tolerated as were aldehydes bearing extended π-systems or heteroaryl groups (toward 68c). Variation of methallyltrimethylsilane derivatives showed that a wide range of groups could be accepted at the 2-position including alkyl (toward 68e) and aryl (toward 68f) groups. During the development of reaction conditions, it was found that the addition of silyl ketene acetal 38a facilitated the reaction at temperatures below −35 °C. The mechanism proposed by analogy to the Mukaiyama aldol reaction, demonstrating the likely role of the silyl ketene acetal, is outlined in Scheme 24. Initial catalyst activation can occur by protodesilylation of methallyltrimethylsilane (67a) giving isobutylene 70, although this is proposed to be sluggish at reduced temperatures and is more efficiently performed by silyl ketene acetal 38a to give ester 69 and silylated catalyst 40, which may exist in either Nsilyl or O-silyl forms. Subsequent silylation of the aldehyde by the active catalyst generates the oxonium species as part of a chiral ion pair 41 with the disulfonimide anion. Subsequent nucleophilic addition of methallyltrimethylsilane (67a) leads to the formation of a new ion pair 71, which can undergo subsequent desilylation to deliver the observed product 72 and concomitantly reform the active catalyst. To further investigate the proposed mechanism and gain insight on the nature of the suggested ion pair 71, the authors undertook initial mechanistic studies in the form of crossover experiments.70,71 As shown in the mechanistic scheme above, two silyl transfer pathways A and B were considered. Importantly, while pathway A is possible both for ionic catalysts/intermediates as well as intermediates mostly covalent in character, pathway B was only deemed possible if the intermediate is sufficiently ionic, as it requires the disulfonimide to dissociate from its original silyl group and take up the silyl group formerly located on the nucleophile. The study conducted to differentiate between these cases is summarized

in Scheme 25 and involved the treatment of benzaldehyde (37c) with two subtly different methallylsilane derivatives 73. It was found that, upon treating benzaldehyde (37c) with two allylsilanes 73a and 73b, crucially varying in both the silyl group and the allyl group, in the presence of disulfonimide 4a at room temperature gave a combination of all four potential products 74a−d. The presence of silanes 74a and 74d demonstrated that both allyl and silyl groups from the same molecule of allylsilane derivative (73a or 73b, respectively) can be retained in the product molecule. This may be a consequence of either formation of a pentavalent silicon species or an ion pair pathway (pathways A and B, respectively). However, the identification of the silanes 74b and 74c showed that the allyl and silyl groups can be switched. These products arise from an ion pair mechanism wherein pathway B must be operational. Enantioenriched homoallylic amines are highly valued building blocks and find application in the syntheses of numerous natural products and pharmaceutical compounds.110−112 The application of the Hosomi−Sakurai methodology to the three-component coupling of an aldehyde 37, 9-fluorenylmethyl carbamate (FmocNH2 , 75), and allyltrimethylsilane (67b), reported in 2013, provides access to this important class of compounds in a highly efficient and enantioselective manner (Scheme 26).113 The coupling of 2-naphthaldehyde (37a), 9-fluorenylmethyl carbamate (FmocNH2, 75), and allyltrimethylsilane (67b), mediated by the disulfonimide 4k was found to proceed under very mild conditions giving carbamate 76a in good yield and enantioselectivity. The versatility of this approach was demonstrated by variation of aldehyde component to incorporate electron-rich arenes (toward 76b), extended πsystems (toward 76c), and, most notably, even aliphatic aldehydes (toward 76d). The utility of this approach was demonstrated by the enantioselective synthesis of β-amino acid P


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Scheme 26. Disulfonimide-Catalyzed Three-Component Aminoallylation of Aldehydes

Scheme 27. Disulfonimide-Catalyzed Enantioselective Abramov Reactions

77 via oxidative olefin cleavage, showcasing the general possibility to access this type of medicinally relevant compounds by utilizing the presented methodology.114 This reaction is mechanistically intriguing, as the authors propose it to proceed through Lewis acid catalysis, despite the facts that water is liberated during the condensation of

carbamate and aldehyde and that silylated disulfonimides are considered to be incompatible with water in the reaction mixture. However, the authors observed that at least three equivalents of allyltrimethylsilane were required for the reaction to proceed efficiently. This can be explained considering that each molecule of water can quench two molecules of active Q


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catalyst, thus regenerating the Brønsted acid form of the disulfonimide and producing one equivalent of bis(trimethylsilyl)ether. The authors proposed that two processes take place in parallel: the continuous drying of the reaction mixture through self-healing cycles and the desired addition of allyltrimethylsilane to the imine formed by condensation of aldehyde and carbamate. Further support for this working model was provided as the authors could show that preformed imines activated by a preformed silylated disulfonimide gave nearly identical results as the catalytic system proposed to be involving the in situ formation of these species.

further demonstrate the utility of this approach, the methodology was demonstrated with N-Boc-benzaldimine. Typically such a class of substrate would be incompatible with the classical Abramov conditions, because of their susceptibility to hydrolysis. However, this methodology proved to be applicable, giving carbamate 80 in good yield although with diminished enantioselectivity compared to the parent aldehyde.

5. CONCLUSIONS AND OUTLOOK Since seminal reports on the application of disulfonimides as precatalysts for reactions exploiting silicon Lewis acid catalysis, chiral disulfonimides have received significant attention. As such, chiral catalysts bearing the disulfonimide motif have found applications in a diverse array of methodologies, exploiting the Lewis acidic nature of the silylated DSI and, more recently, the ability of the disulfonimide motif to act as a strong Brønsted acid. The ability to readily synthetically manipulate BINOL-derived disulfonimides is one of the key factors of the initial design of this class of catalyst, allowing both the steric confinement of the reactive center and subtle acidity tuning through electronic contributions. Unlike chiral phosphoric acids, the application of chiral disulfonimides as counteranions in metal-catalyzed processes has yet to be realized. Given the plethora of transition metal mediated transformations that employ a triflimide counteranion,122 this promises to be an exciting field of research, which will continue to expand upon the asymmetric counteraniondirected catalysis (ACDC) concept. Although a significant body of work has been produced in this area, the exact mechanism of action of disulfonimides, in both Lewis and Brønsted acid catalysis, remains far from being fully understood. It is expected that ongoing mechanistic studies will shed light in this area, facilitating ongoing development of catalysts, which may allow for addressing some of the limitations of current enantioselective Brønsted and Lewis acid catalysis, such as low turnover numbers and frequencies.

4.4. Catalytic Enantioselective Abramov Reactions

The addition of trialkyl phosphites or silyl esters of dialkyl phosphites to carbonyl compounds, known as the Pudovik and Abramov reactions, respectively, results in the generation of αhydroxyphosphonates, a class of compounds that have received plentiful attention from the chemical community.115,116 These phosphorus derivatives of α-hydroxycarboxylic acids have demonstrated important biological activity and uses in synthetic methodology.117 As such, robust methodology giving highly enantioenriched α-hydroxyphosphonates is highly desirable. Numerous efforts in this area have been reported that mediate this transformation utilizing, for example, chiral organic bases or metal-based chiral Lewis acids. Interestingly, dialkylphosphites predominantly exist as their unreactive dialkyl phosphonate form, which can be considered analogous to keto−enol tautomerization carbonyl compounds. A common approach to controlling keto−enol tautomerization is to generate silyl enol ethers, as extensively employed in the Mukaiyama aldol reaction. Similarly, Abramov introduced the silyl esters of dialkyl phosphites, which perform excellently in the hydrophosponylation of aldehydes without the sluggish reactivity that can be attributed to dialkyl phosphonate formation.118−120 In 2014 List and co-workers reported the first enantioselective Abramov reaction of aldehydes 37 and silyl esters of dialkyl phosphites 78, through a Lewis acid manifold inspired by the Mukaiyama aldol reaction (Scheme 27).121 Reaction optimization identified that disulfonimide 4a efficiently catalyzed the coupling of naphthaldehyde (37a) and the commercially available trimethylsilyl phosphite 78a, giving the α-hydroxyphosphonate 79a in excellent yield and enantiomeric ratio after acidic desilylation. While phosphites bearing isopropyl groups were found to be optimal, a wide variety of phosphites were well-tolerated. Interestingly, αhydroxyphosphonates bearing P-stereogenic centers, such as 79b, were accessible with this methodology, proceeding in good yields and enantioselectivities, but only poor diastereoselectivites were obtained. Importantly, it was found that the use of silylated nucleophiles was critical to reactivity and the corresponding dialkyl phosphites failed to give product under identical reaction conditions. Subsequent investigation into the scope of the aldehyde coupling partner showed that a wide variety of diverse compounds are appropriate substrates in this transformation, although different catalysts were found to be optimal depending on the respective substrate. Aromatic aldehydes possessing electron-donating and electron-withdrawing groups (toward 79c) were well-tolerated, as were aldehydes containing conjugated π-systems, such as cinnamaldehyde derivatives (toward 79d). Furthermore, aldehydes possessing secondary Lewis basic sites were tolerated, giving products such as 79e in good yields and stereoselectivities. To

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Thomas James was born in 1986 in Halifax, England. He received a first class M.Chem. degree in 2009 from the University of Leeds. Subsequently he was awarded a Ph.D. in 2013 from the same R


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Investigator Award, the Astra Zeneca Research Award in Organic Chemistry, the Otto Bayer Prize, the Horst Pracejus Prize, the Ruhr Prize, the Mukaiyama Award, and the Cope-Scholar Award.

institution for research on the development of methodology for the synthesis of medicinally relevant heterocycles under the guidance of Prof. Adam Nelson. In 2013 he joined Prof. Benjamin List’s group at the Max-Planck-Institut für Kohlenforschung as postdoctoral fellow, conducting research in the areas of asymmetric counteranion-directed catalysis and enantioselective heterogeneous organocatalysis.

ACKNOWLEDGMENTS Generous support by the Max-Planck-Society, the European Research Council (Advanced Grant “High Performance Lewis Acid Organocatalysis, HIPOCAT”), and the Fonds der Chemischen Industrie (fellowship to M.v.G.) is gratefully acknowledged. We would like to thank all the members of our group for their contributions to the projects outlined in this review and our excellent analytical service departments (GC, HPLC, and NMR) at the institute. REFERENCES (1) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Enantioselective Mannich-Type Reaction Catalyzed by a Chiral Brønsted Acid. Angew. Chem., Int. Ed. 2004, 43, 1566−1568. (2) Uraguchi, D.; Terada, M. Chiral Brønsted Acid-Catalyzed Direct Mannich Reactions via Electrophilic Activation. J. Am. Chem. Soc. 2004, 126, 5356−5357. (3) Akiyama, T. Stronger Brønsted Acids. Chem. Rev. 2007, 107, 5744−5758. (4) Adair, G.; Mukherjee, S.; List, B. A powerful Brønsted acid catalyst for asymmetric synthesis. Aldrichim. Acta 2008, 42, 31−39. (5) Kampen, D.; Reisinger, C. M.; List, B. Chiral Brønsted Acids for Asymmetric Organocatalysis. In Asymmetric Organocatalysis; List, B., Ed.; Springer: Berlin/Heidelberg, Germany, 2009; Vol. 291, pp 1−37. (6) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Complete Field Guide to Asymmetric BINOL-Phosphate Derived Brønsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Brønsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates. Chem. Rev. 2014, 114, 9047−9153. (7) Chen, Y.-Y.; Jiang, Y.-J.; Fan, Y.-S.; Sha, D.; Wang, Q.; Zhang, G.; Zheng, L.; Zhang, S. Double axially chiral bisphosphorylimides as novel Brønsted acids in asymmetric three-component Mannich reaction. Tetrahedron: Asymmetry 2012, 23, 904−909. (8) Č orić, I.; List, B. Asymmetric spiroacetalization catalysed by confined Brønsted acids. Nature 2012, 483, 315−319. (9) Liao, S.; Č orić, I.; Wang, Q.; List, B. Activation of H2O2 by Chiral Confined Brønsted Acids: A Highly Enantioselective Catalytic Sulfoxidation. J. Am. Chem. Soc. 2012, 134, 10765−10768. (10) Č orić, I.; Vellalath, S.; Müller, S.; Cheng, X.; List, B., Developing Catalytic Asymmetric Acetalizations. In Inventing Reactions; Gooßen, L. J., Ed.; Springer: Berlin/Heidelberg, Germany, 2013; Vol. 44, pp 165− 193. (11) Kim, J. H.; Č orić, I.; Vellalath, S.; List, B. The Catalytic Asymmetric Acetalization. Angew. Chem., Int. Ed. 2013, 52, 4474− 4477. (12) Wu, K.; Jiang, Y.-J.; Fan, Y.-S.; Sha, D.; Zhang, S. Double Axially Chiral Bisphosphorylimides Catalyzed Highly Enantioselective and Efficient Friedel−Crafts Reaction of Indoles with Imines. Chem.Eur. J. 2013, 19, 474−478. (13) Zhuo, M.-H.; Jiang, Y.-J.; Fan, Y.-S.; Gao, Y.; Liu, S.; Zhang, S. Enantioselective Synthesis of Triarylmethanes by Chiral Imidodiphosphoric Acids Catalyzed Friedel−Crafts Reactions. Org. Lett. 2014, 16, 1096−1099. (14) Cheon, C. H.; Yamamoto, H. Super Brønsted acid catalysis. Chem. Commun. 2011, 47, 3043−3056. (15) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W.; Atodiresei, I. Modulating the Acidity: Highly Acidic Brønsted Acids in Asymmetric Catalysis. Angew. Chem., Int. Ed. 2011, 50, 6706−6720. (16) Nakashima, D.; Yamamoto, H. Design of Chiral N-Triflyl Phosphoramide as a Strong Chiral Brønsted Acid and Its Application to Asymmetric Diels−Alder Reaction. J. Am. Chem. Soc. 2006, 128, 9626−9627.

Manuel van Gemmeren was born in Madrid, Spain, in 1985. He studied chemistry at the Albert-Ludwigs-Universität Freiburg, where he received his diploma in 2010. He completed his doctorate (summa cum laude) at the MPI for Coal Research in 2014 after conducting studies on asymmetric counteranion-directed Lewis acid organocatalysis as a Kekulè-fellow in the group of Prof. Benjamin List. Currently, Manuel is conducting postdoctoral studies as a FeodorLynen-fellow in the group of Prof. Ruben Martin at the ICIQ in Tarragona.

Benjamin List was born in 1968 in Frankfurt, Germany. He graduated from Freie University Berlin (1993) and received his Ph.D. (1997) from the University of Frankfurt. After postdoctoral studies (1997− 1998) as a Feodor Lynen Fellow of the Alexander von Humboldt foundation at The Scripps Research Institute, he became a Tenure Track Assistant Professor there in January 1999. Subsequently, he developed the first proline-catalyzed asymmetric intermolecular aldol-, Mannich-, Michael-, and α-Amination reactions. He moved to the Max-Planck-Institut für Kohlenforschung in 2003 as a group leader and became director in 2005. He has been the managing director of the institute from 2012 until 2014 and serves as an honorary professor at the University of Cologne (since 2004). His research interests are new catalysis concepts and chemical synthesis in general. He has pioneered and contributed several concepts including aminocatalysis, enamine catalysis, and asymmetric counteranion-directed catalysis (ACDC). His accomplishments have been recognized by several awards including the Carl Duisberg Memorial Award, the Degussa Prize for Chiral Chemistry, the Lieseberg Prize, the Novartis Young S


Chemical Reviews

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Recent Achievements in Enantioselective Borrowing Hydrogen by the Combination of Iron- and Organocatalysis.

Enantioselective Formal α-Methylation and α-Benzylation of Aldehydes by Means of Photo-organocatalysis.

A combined continuous microflow photochemistry and asymmetric organocatalysis approach for the enantioselective synthesis of tetrahydroquinolines.

A general, enantioselective synthesis of N-alkyl terminal aziridines and C2-functionalized azetidines via organocatalysis.

Enantioselective cycloaddition of münchnones onto [60]fullerene: organocatalysis versus metal catalysis.

Enantioselective α-Alkylation of Aldehydes by Photoredox Organocatalysis: Rapid Access to Pharmacophore Fragments from β-Cyanoaldehydes.

Chiral phosphines in nucleophilic organocatalysis.

Activation of carboxylic acids in asymmetric organocatalysis.

Development of catalysts and ligands for enantioselective gold catalysis.

Supramolecular polymers for organocatalysis in water.

The development of highly active acyclic chiral hydrazides for asymmetric iminium ion organocatalysis.

Peptide aptamers: development and applications.

Technological Microbiology: Development and Applications.

Development and Applications of Portable Biosensors.

Enantioselective template-directed [2+2] photocycloadditions of isoquinolones: scope, mechanism and synthetic applications.

Asymmetric synthesis of tetrahydroquinolines through supramolecular organocatalysis.

Development of (trimethylsilyl)ethyl ester protected enolates and applications in palladium-catalyzed enantioselective allylic alkylation: intermolecular cross-coupling of functionalized electrophiles.

Metal-templated chiral Brønsted base organocatalysis.

Misoprostol: discovery, development, and clinical applications.

Towards high-performance Lewis acid organocatalysis.

The Orthology Ontology: development and applications.

Homo-Roche ester derivatives by asymmetric hydrogenation and organocatalysis.

Cholinesterase-like organocatalysis by imidazole and imidazole-bearing molecules.

Development of angiogenesis inhibitors for clinical applications.