Second Generation of Aldol Reaction - Accounts of Chemical

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Second Generation of Aldol Reaction Wafa Gati* and Hisashi Yamamoto* Molecular Catalyst Research Center, Chubu University, 1200 Matsumoto, Kasugai, Aichi 487-8501, Japan CONSPECTUS: Since the discovery of the Mukaiyama aldol reaction more than 40 years ago, several landmark publications have inspired researchers in the field. The Mukaiyama AR is one of the most significant named reactions in organic synthesis. In the past few decades, development of the modern AR has been at the forefront in addressing the challenges of regio-, chemo-, diastereo-, and enantioselectivity in organic synthesis. All of these selectivity challenges maybe present in a single pair of reactants, thus controlling the outcome of such a process has great practical value. More than 10 years ago, our group became involved in this iconic carbon− carbon bond-forming process and attempted to very closely investigate all possible features of the AR to solve several issues still encountered by chemists, most notably the selectivity challenges mentioned above. In this context, our group initiated the second generation of the AR based on a Lewis or Brønsted acid-catalyzed process in conjunction with the use of a “super silyl” (tris(trimethylsilyl)silyl) directing group, which has demonstrated unrivalled properties in controlling the outcome of the AR. Using the extraordinary power of the super silyl group, we were able to develop new methods and concepts that broadly impacted the ability to control the selectivity attributes and thus allowed for a highly stereoselective construction of polyketide, halogenated polyketide, polypropionate, and polyol scaffolds through inter- and/or intramolecular aldolization protocols. Our diastereoselective ARs of super silyl enol ethers and aldehydes have shown great efficiency and modularity in producing exclusively and preferentially syn- or anti-adducts, creating up to four new adjacent stereocenters in a one-pot sequential manner and under mild reaction conditions. The super silyl-directed AR does not only provide a solution to stereochemistry control challenges, but also offers an efficient, modular and high yielding technique toward nontrivial construction of complex architectures with unprecedented ease. We believe that the new Lewis- or Brønsted-acid-catalyzed super-silyl-directed AR processes chronicled in our laboratories have come to maturity and now offer a “road map” for strategic stereoselective synthesis of polyketide-like units. Herein we report our recent achievements in the diastereoselective C−C bond formation, through the super-silyl-directed AR, toward the synthesis of complex and sophisticated hydroxy aldehydes. We would like to note that due to the extremely broad range of work reported in this field, only stereoselective AR involving aldehyde-derived super SEEs will be discussed in this Account.

1. INTRODUCTION

new protective group that exhibits unrivalled reactivity in a wide number of transformations. As a breakthrough was made with the Mukaiyama AR in the past few years with the use of the powerful directing super silyl group, a new process, now called the second generation of AR, has emerged. The Yamamoto group has thus focused on the Lewis and Brønsted acid-catalyzed version of the AR (Scheme 1), which will be discussed throughout this Account. Since Mukaiyama’s seminal work on the titanium-catalyzed reaction of silyl enol ether (SEE) with aldehydes and ketones,1b the AR has become one of the most powerful synthetic reactions5 for the construction of the β-hydroxy carbonyl and/ or 1,3-diol motifs typically found in various polyketides.6 Although many advances have been achieved in this field, only a few cases of aldehyde-crossed ARs have been reported, suffering mainly from limited scope.7−9 In 1980, Heathcock et al. reported a stereoselective version of aldol condensation using preformed lithium enolates of a variety of ethyl ketones and propionic acid derivatives which

The aldol reaction (AR) has been among the most powerful tools for C−C bond formation since its discovery by Kane in 1848. Since 1973, the Mukaiyama AR has enabled the prediction of the stereochemical outcome of a directed AR between a preformed enolate and a carbonyl function to form β-hydroxycarbonyl compounds.1 The discovery of this process was a breakthrough in the field of organic synthesis. It has now become one of the most powerful methods for solving stereocontrol issues, especially in the assembly of complex natural products. Recently, silyl groups have been involved as active participants in many seminal works on Mannich, HosomiSakurai and Mukaiyama ARs.2 The important and unique profile of silicon protecting groups, regarding their commercial availability, ease of preparation, facile and selective cleavage under mild conditions, in addition to their thermal and chemical stabilities,3 have made these groups remarkably useful in many synthetic reactions, particularly in the Mukaiyama AR. In the past few years, the tris(trimethylsilyl)silyl group, known in the literature as the “super silyl” group,4 has emerged as a © XXXX American Chemical Society

Received: May 20, 2016

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DOI: 10.1021/acs.accounts.6b00243 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research Scheme 1. Overview of the Second Generation of AR Developed by Our Group

substitution pattern on the silicon, numerous research groups have tried to find an alternative to the enoxytrichlorosilylane, which is usually prepared in low yields and requires sensitive handling, notably purification by distillation under high pressure and storage at a low temperature. Subsequently, various silyl protecting groups (TMS, TES, TIPS, TBS, etc.) were successfully applied to a variety of C−C bond-forming reactions, particularly the Mukaiyama AR. Nevertheless, most of the SEEs bearing these silyl groups are UV inactive, which makes them undetectable in TLC analysis. Interestingly, silyl groups that contain Si−Si bonds are UV active, allowing for straightforward TLC analysis. Recently, as the tris(trialkylsilyl)silyl group has been remarkably successful when employed in radical reactions, it has subsequently been incorporated into ARs after experimental and theoretical calculations, demonstrating that a bulky super silyl group could stabilize the SEE and increase its reactivity.13 In 2005, our group reported a highly diastereoselective [2 + 2] cyclization of aldehyde-derived super SEEs and acrylate derivatives. It was found that the TTMSS group plays a dramatic role in diastereselectivity control, since TBS- and

were found to give low selectivity when reacted with benzaldehyde.10 A few years later, Mukaiyama and other research groups independently conducted extensive investigations on the AR using boron, lithium, tin, titanium, and silicon enolates to reveal its various features, notably diastereo- and enantioselectivity, the possible use of other chiral and achiral Lewis acids, and the effect of the substituent on the enolates.11,12 In 2001, Denmark et al. reported a landmark strategy using dimeric phosphoramide Lewis base catalysis for the enantioselective AR of trichlorosiloxy-protected enol ethers with aldehydes. It has been speculated that upon activation of the weak Lewis acidic silicon moiety present in the enoxytrichlorosilane by the creation of the nσ* type interaction between the silicon atom and the strong and neutral Lewis base, a hyperconjugated silicon is generated, thus increasing the polarization and rendering the silicon atom sufficiently Lewis acidic to activate the aldehyde into a more nucleophilic enolate, allowing the aldolization reaction to proceed.8a Intrigued by the high selectivity obtained using the directing trichlorosilyl group, which highlights the importance of the B


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Accounts of Chemical Research

SiNTf2) provided consistently high yields of the desired 1:1 aldol adduct with aliphatic, branched, aromatic, and α,β−γ,δunsaturated aldehydes.15 This observation further confirmed the different reactivity of both triflimide anion and triflic anion, and is in accordance with our previous observations16 in addition to those reported by Ghosez and co-workers.17 Interestingly, (S)-2-phenylpropanal successfully reacted with the acetaldehyde-derived SEE and showed a high Felkin selectivity, providing two adjacent stereocenters in good yield. Furthermore, β-triisopropylsiloxy aldehyde delivered an unexpected syn-adduct, in contrast to the previous anti-selectivity obtained by Evans and co-workers,18 which highlight the effect of the bulky super silyl as a directing group in AR. It is worth noting that the reaction requires only 0.05 mol % of catalyst loading to achieve high yields. In fact, we believe that our Lewis acid catalyst formed upon addition of triflimide to a solution of SEE leads to the in situ formation of the true catalyst SiNTf2. Since it is known that silyltriflimides are sensitive to moisture, a small amount of water in the reaction mixture decomposes the catalyst to regenerate HNTf2 and form the corresponding silanol (SiOH), which reacts with a second equivalent of SiNTf2 and provides the inert SiOSi and HNTf2, thus creating an anhydrous environment and allowing the regenerated triflimide to react with the SEE and provide the desired silyl triflimide catalyst (Scheme 4, cycle A). The in situ-

TIPS-protected SEEs produced no adduct under the same conditions (Scheme 2). Therefore, the TTMSS group was proven to be an excellent functional group for this reaction, as it is among the strongest electron donators to π-systems.14 Scheme 2. Influence of the Silyl Group on the [2 + 2] Cyclization of Aldehyde-Derived SEE and Acrylate Derivatives

2. THE MUKAIYAMA ALDOL REACTION

Scheme 4a

2.1. Acetaldehyde-Derived SEE

Unsurprisingly, and based on previous observations for the [2 + 2] cyclization reaction, when the Mukaiyama AR was performed with a TBS enol ether and octanal in the presence of triflimide, only trace amounts (99:1 in favor of the syn-adduct.

Scheme 7. Influence of Organoiodide Additives on AR

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Accounts of Chemical Research Scheme 8. Diastereoselective Synthesis of Protected α,β-Dioxyaldehydes

Scheme 9. Conformational Explanation of the syn-Selectivity Outcome of Sequential AAR

approach based on sequential reactions, which would save bulk materials, time and labor, is greatly desired. Thus, relying on our successfully developed diastereoselective super silylgoverned cross-AR we wondered whether we could extend our procedure to access polyketide-like scaffolds in a one-pot manner with wide applicability and reasonable control of the stereochemical outcome. In this context, our group described a sequential AAR between 2.2 equiv of acetaldehyde-derived super SEE and pivalaldehyde, using the optimal condition of the Lewis acidcatalyzed protocol previously described for cross-ARs. With the use of as little as 0.05 mol % loading of triflimide, the reaction succeeded in generating β,δ-dihydroxy aldehydes in a good yield and with perfect control of the diastereoselectivity (Scheme 9).15 The high syn-selectivity obtained through this double AR could be attributed to the steric size of the extraordinarily bulky super silyl group.2,13,30 In fact, the steric

It is worth highlighting the tolerance of the developed process for the use of different protecting groups in the same molecule, as it is a rather valuable option to discriminate among chemically similar hydroxyl groups and, thus, a selective deprotection would be feasible. Furthermore, to the best of our knowledge, our protocol is the first straightforward highly diastereoselective construction method of the most interesting units present in natural and unnatural polyols.

3. SEQUENTIAL ALDOL−ALDOL REACTIONS (AARs) Polyketides and polypropionates have long been of great use in the construction of complex architectures. Although considerable efforts have been made toward developing a one-pot procedure to access such motifs,29 it can very often be complicated when considering the handling of a multistereocenter molecule that usually requires a long and painful number of steps to control the stereochemistry. Evidently, a new F


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Accounts of Chemical Research Scheme 10. Sequential AAR with α-Alkylated SEEs

Scheme 11. Triple AAR

confirmed by our group.27,28 Thus, to our delight, we were able to obtain the desired triple aldol products in good yields and diastereoselectivities (Scheme 11). However, due to the significant steric bulkiness of the products, the process stops at the third addition and no further aldol addition was observed.

encumberment of this group not only slowed the rate of the addition of the second SEE to induce a high diastereoselctivity but also governed the intermediate in such a way that it avoids unfavorable steric interaction between the Lewis acidcoordinated oxygen and the R group that is present in conformation B, thus fostering the conformation A that would exclusively give the syn-adduct (Scheme 9). In a similar fashion, we applied our double aldol process to propionaldehyde-derived (Z)-SEE and, to our delight, we were able to access a 2,3,4,5-all-syn product with over 94% diastereoselectivity (Scheme 10, eq A).24 Interestingly, when we switch to the (E)-SEE we preferentially obtained the 2,3,4,5all-anti product with a good yield and selectivity (Scheme 10, eq B), thus proving this method highly flexible and convenient for polypropionate construction, with the ability to control the relative stereochemistry by controlling the Z/E geometry of the starting SEE. Furthermore, these aldol products can themselves undergo further additions, allowing for a rapid construction of complex polyketide fragments with excellent step economy. Similarly, the α-halogenated acetaldehyde-derived SEE was successfully employed in our sequential AAR, allowing for a one-pot, highly diastereoselective assembly of novel halogenated polyketide-like fragments. Although the first addition proceeds through an anti transition state, the second addition provided the syn,syn,syn-configured double aldol product in an excellent yield and diastereoselectivity (Scheme 10, eq C).26 Intrigued by the high reactivity and selectivity observed, we wondered how far this aldol cascade addition could go. Toward this end, up to five equivalents of the acetaldehyde-derived SEE were subjected to AAR. After several optimizations, it was found that the third addition of the SEE is likely too slow to proceed and, thus, the use of phenyl iodide as cocatalyst is necessary, stipulating that it may react with the in situ formed silyltriflimide to form the cationic and sterically less demanding complex {[RI-Si(TMS)3]+NTf2−}, a principle that was later

4. SEQUENTIAL ALDOL−CARBANION ADDITION REACTIONS Although we were pleased with the results obtained for the developed double and triple AARs under Lewis acid catalysis, we believed that our cross-aldol process would also tolerate a sequential basic reaction and, thus, the possibility of following the AR with the addition of a basic reagent. It was anticipated that the addition of a Grignard reagent in the same pot would be tolerated and would allow the generation of an additional stereocenter with high diastereoselectivity. Indeed, using allyl, vinyl, or alkynyl magnesium chloride formed the corresponding allylic, homoallylic, and propargylic alcohols, respectively, with acceptable all-syn-selectivity (Scheme 12, eq A).31 Furthermore, when dioxygenated SEE was applied, we were able to create 1,2,3-triol motifs bearing up to four contiguous stereocenters with almost complete control of diastereochemistry. A broad substrate scope was described allowing for the construction of synthetically useful substitution (i.e., allyl, vinyl, propargyl, etc.) which could be of great use for further transformations (Scheme 12, eq B).27 Additionally, the aldol-Grignard reaction sequence was also investigated with α-halogenated super SEE and was found to proceed smoothly, providing the desired halogenated 1,3-diols with similarly satisfying results to those previously achieved (Scheme 12, eq C).26 To the best of our knowledge, this is the first example of a highly diastereoselective one-pot, sequential, strong acid-strong base system. G


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Recently, our group reported the first example of a sequential inter/intramolecular AAR of preformed disilyl enol ethers and aldehydes.34 Promoted by a very low catalytic amount of either triflimide or pentafluorophenylbis(triflyl)methane, the disilyl enol ether first undergoes an intermolecular AR with an aldehyde, followed by an intramolecular aldolization between the intermediary aldehyde and the second SEE functionality present in the starting disilyl enol ether. Thus, a broad scope of 5-, 6-, and 7-membered aldol adducts were obtained, generating up to five contiguous stereocenters with an unprecedented control of the diastereoselectivity in a single pot (Scheme 13). It is worth highlighting that the success of our asymmetric AR relies on the crucial role of the in situ-formed silyl species that acts as a silyl shuttle from the starting material to the product.

Scheme 12. Sequential Aldol-Grignard Addition with Super SEE

6. APPLICATIONS OF SUPER-SILYL-DIRECTED AR There is no doubt that the AR is one of the top 10 most useful and fundamental tools for C−C bond formation toward the construction of complex molecules in particular natural products.11b Likewise, diastereoselective ARs of acetaldehydederived super SEEs mediated by Lewis or Brønsted acid catalyst have found applications in complex polyketide synthesis. Bearing in mind that among the benefits of our judicious choice of the extremely bulky super silyl as the directing group is the π-facial selectivity of a β-oxygenated aldehyde giving a 1,3-stereoinduction, we turned our attention to the synthesis of the natural product Tolypothrix, which contains six alternating stereocenters.35 With its 1,3-all-syn stereochemistry, we anticipated that our previously developed triple AR could be applied to afford the desired β,δ,ζ-tri-super siloxy aldehyde, starting from an acetaldehyde-derived SEE and hexanal in the presence of triflimide (Scheme 14). Unsurprisingly, having in hand our desired aldehyde precursor with a good 1,3-syn stereocontrol, a further AR was necessary to assemble the rest of the main linear chain. Fortunately, the use of lithium hexamethyldisilazide in the presence of a large excess of lithium trifluoroborate predominantly afforded the 1,5-syn-adduct with an acceptable yield and diastereoselectivity. Finally, a deprotection/methylation sequence provided the racemic form of our targeted natural product in a 10-step procedure starting from commercially available materials. It is worth noting that Mori et al.36 and Taylor et al.37 have independently reported 21- and 16-step total synthesis to the enantiopure form of this natural product, respectively. As we were curious to further investigate the power of super silyl aldol methods in diversity-oriented synthesis, we later became interested in the intermediate spiroketal subunit,

5. INTER-/INTRAMOLECULAR SEQUENTIAL AR Despite the extensive progress brought to asymmetric intermolecular AR, the asymmetric intramolecular version has been, however, much less investigated and only a few examples have been reported thus far. Indeed, while the proline-catalyzed Hajor−Parrish−Eder−Sauer−Wiechert reaction illustrated the 6-enolendo aldolization process toward direct access to cyclic ketones,32 the List group later discovered that the asymmetric intramolecular enolexo aldolization version of dicarbonyl compounds promoted by proline affords the corresponding cyclic β-hydroxy aldehydes.33 Nevertheless, both protocols dealt with the formation of six-membered rings and have not been extended to different ring sizes. Scheme 13. Inter-/Intramolecular Sequential AAR

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thus making the construction of a long polyol chain quite arduous. In this context, with our highly diastereoselective strategy toward α,β-dioxygenated aldehydes and 1,2,3-triols in mind, we decided to investigate the possible construction of pentose and hexose-like scaffolds (Scheme 16).27 First, we proceeded to the aldol reaction of (R)-2-phenylpropanal with our SEE of choice promoted by as low as 0.5 mol % of triflimide in the presence of a substoichiometric amount of phenyl iodide to afford the expected syn,syn-adduct with excellent Felkin selectivity. Then, a Wittig olefination followed by a ring-closing metathesis and a subsequent hydroxylation provided the pentose derivative with an excellent all-syn stereochemistry. In a similar fashion, we considered the possibility of a hexoselike structure synthesis in a three-step strategy based on a sequential addition of a nucleophile in the same pot after the AR had proceeded, allowing for the isolation of the vinylic triol in a good yield and with good diastereoselectivity. For the endgame synthesis of the hexose skeleton, we started with a high-yielding ring-closing metathesis followed by osmium cishydroxylation, which produced the desired targeted molecule with perfect control of all six stereogenic centers.

Scheme 14. Total Synthesis of Tolypothrix Hexaether

bearing 6-stereodefined centers, previously used by Danishefsky in his total synthesis of avermectin A1a.38 Upon application of our recently developed stereoselective propanal-aldol acetoneAR sequence, we were pleased to obtain the corresponding Felkin controlled ketone in a 57% yield and with very good diastereoselectivity (>95:5) (Scheme 15). A subsequent second AR between the in situ formed enolborinate and the (S)-βsiloxy butanal provided a highly expected 1,3- and 1,5-anti selective aldol adduct in a 74% yield. To our delight, a sequence of spiroketalization/oxidation afforded the enol triflate. Finally, a Pd-catalyzed reduction followed by a selective oxidative cleavage of the terminal olefin allowed us to complete the formal synthesis of avermectin’s important spiroketal intermediate.39 Interestingly, a sequence of three ARs, governed by a super silyl group, which can be independently controlled, was the key feature in the success of our stereodivergent approach to the advanced intermediate toward such a complex natural product. Encouraged by these unique results, we recently endeavored to achieve straightforward synthesis of sugar derivatives by the application of the highly diastereoselective Mukaiyama AR of dioxygenated enol ethers. Usually, the synthetic access to complex natural sugar architectures goes through the assembly of poly oxygenated aldehydes that demand lengthy procedures,

7. SUMMARY In summary, due to the unique properties of the super silyl group, we have developed the second generation of AR, achieving a highly diastereoselective construction of relatively complex building blocks with unprecedented ease. Some of the salient points of this reaction are (1) the need for an extremely low loading of either Lewis or Brønsted acids to offer a highyielding and selective outcome, (2) the extreme bulkiness of the super silyl protecting/directing group can induce stereochemistry along up to five bonds, and (3) with the growing demand for the development of shorter routes for the construction of sophisticated and complex structures, we believe that our sequential super silyl-governed ARs will bring solutions to a variety of total syntheses suffering from a lack of redox-economy procedures. Altogether, the second generation of AR now represents a “road map” to the stereoselective construction of polyketides, polypropionates, halogenated polyketides, and polyols using an efficient and modular method based on super silyl chemistry.

Scheme 15. Formal Synthesis of Avermectin A1a

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Accounts of Chemical Research Scheme 16. Synthesis of Pentose and Hexose-like Scaffolds

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chloride. J. Am. Chem. Soc. 1974, 96, 7503−7509. (d) Saigo, K.; Osaki, M.; Mukaiyama, T. A New Method for the Preparation of βHydroxyesters. The Titanium Tetrachloride-Promoted Reaction of Ketene Alkyl Trialkylsilyl Acetals with Carbonyl Compounds. Chem. Lett. 1975, 4, 989−990. (e) Fujisawa, H.; Sasaki, Y.; Mukaiyama, T. Magnesium Bromide Diethyl Etherate Mediated Highly Diastereoselective Aldol Reaction between an Aldehyde and a Silyl Enol Ether. Chem. Lett. 2001, 30, 190−191. (2) Colvin, E. W. Silicon in Organic Synthesis; Butterworths Monographs in Chemistry and Chemical Engeneering Series; Butterworths: London, 1981; Vol. 23, pp 428. (3) (a) Greene, W. T.; Wuts, P. G. M. In Protective Groups in Organic Synthesis, 3rd ed.; Greene, W. T., Wuts, P. G. M., Eds.; Wiley: New York, 1999. (b) White, J. D.; Carter, R. G. Silyl Ethers. In Compounds of Group 15 (As, Sb, Bi) and Silicon Compounds; Fleming, I., Ed.; Science of Synthesis: Houben-Weyl Methods of Molecular Transformations Series; Georg Thieme Verlag: New York, 2001; Vol. 4, pp 371−412. (c) Larson, G. L. In The Chemistry of Organic Silicon Compounds; Patai, S., Rappoport, Z., Eds.; The Chemistry of Functional Groups Series; Patai, S. S., Series Ed.; Wiley-Interscience: New York, 1989; Vol. 1, pp 763−808. (d) Weber, W. P. In Reactivity and Structure Concepts in Organic Chemistry; Springer: New York, 1983; Vol. 14. (e) Miura, K.; Hosomi, A. In Main Group Metals in Organic Synthesis; Yamamoto, H., Oshima, K., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Vol. 2, pp 409−592. (f) Boxer, B. M.; Albert, J. B.; Yamamoto, H. Aldrichimica Acta 2009, 42, 3−15. (4) The term super silyl was coined by Hans Bock: Bock, H.; Meuret, J.; Ruppert, K. Super silyl” Compounds (R3Si)3SiSi(SiR3)3 and (R3Si)3SiC6H4Si(SiR3)3: Structures and Properties. Angew. Chem., Int. Ed. Engl. 1993, 32, 414−416. (5) (a) Mukaiyama, T. The Directed Aldol Reaction. Org. React. 1982, 28, 203−331. (b) Heathcock, C. H. In Additions to C-X π-Bonds, Part 2; Heathcock, C. H., Ed.; Comprehensive Organic Synthesis Series; Trost, B. M., Fleming, I., Series Eds.; Pergamon: Oxford, 1992; Vol. 2, pp 133−319. (c) Bach, T. Catalytic Enantioselective C-C CouplingAllyl Transfer and Mukaiyama Aldol Reaction. Angew. Chem., Int. Ed. Engl. 1994, 33, 417−419. (d) Nelson, S. G. Catalyzed Enantioselective Aldol Additions of Latent Enolate Equivalents. Tetrahedron: Asymmetry 1998, 9, 357−389. (e) Carreira, E. M. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 3, pp 996−1066. (f) Mahrwald, R. Diastereoselection in Lewis-Acid-Mediated Aldol Additions. Chem. Rev. 1999, 99, 1095−1120. (6) (a) Rychnovsky, S. D. Oxo Polyene Macrolide Antibiotics. Chem. Rev. 1995, 95, 2021−2040. (b) Koskinen, A. M. P.; Karisalmi, K. Polyketide Stereotetrads in Natural Products. Chem. Soc. Rev. 2005, 34, 677−690. (7) For non stereoselective ARs, see: (a) Hoaglin, R. I.; Kubler, D. G.; Leech, R. E. The Chemistry of α,β-Unsaturated Ethers. II. Condensation with Aldehydes. J. Am. Chem. Soc. 1958, 80, 3069−

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Wafa Gati Graduated from University of Monastir (Tunisia) in 2010 with a M.S. in chemistry. She then began graduate studies in chemistry under the guidance of Professor Gwilherm Evano at Lavoisier Institute, University of Versailles (France) where she focused on the synthesis of nitrogen-containing heterocycles through carbometalation of ynamides. Upon completion of her Ph.D. in 2013, Dr. Gati moved to Chubu University (Japan) to undertake postdoctoral research in asymmetric Lewis acid catalysis in the Yamamoto group. Her most recent work has been centered around super silyl chemistry and Mukaiyama aldol reaction. Her interests include organometallics, asymmetric catalysis, and total synthesis. Hisashi Yamamoto received his Bachelor from Kyoto University under the supervision of Professors H. Nozaki and R. Noyori and Ph. D. from Harvard University under the mentorship of Professor E. J. Corey. His first academic position was as Assistant Professor and lecturer at Kyoto University, and in 1977 he was appointed Associate Professor of Chemistry at the University of Hawaii. In 1980, he moved to Nagoya University where he became Professor in 1983. In 2002, he moved to United States as Arthur Holly Compton Distinguished Service Professor at the University of Chicago. He moved again from Chicago to Nagoya in 2012, where he is Professor and Director of Molecular Catalyst Research Center at Chubu University (Japan).

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ACKNOWLEDGMENTS We are grateful to our colleagues for their contributions to the work described in this Account. We are also thankful to Grantin-Aid for Scientific Research (No. 23225002), Nippon Pharmaceutical Chemicals Co., Ltd and Advance Electric Co., Inc.

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REFERENCES

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