In the investigation of efficient chemical transformations, the carbon-carbon bond-forming reactions play an outstanding role. In this context, organocatalytic processes have achieved considerable attention. 1 Beside their facile reaction course, selectivity, and environmental friendliness, new synthetic strategies are made possible. Particularly, the inversion of the classical reactivity (Umpolung) opens up new synthetic pathways. 2 In nature, the coenzyme thiamine (vitamin B1), a natural thiazolium salt, utilizes a catalytic variant of this concept in biochemical processes as nucleophilic acylations. 3 The catalytically active species is a nucleophilic carbene. 4

Organocatalysis by N-Heterocyclic Carbenes

Asymmetric enamine catalysis.

Small-molecule H-bond donors in asymmetric catalysis.

4.2.8. Reductive Coupling 3109 5. Reaction of Aromatic Compounds 3110 5.1. Electrophilic Substitutions 3110 5.2. Radical Substitution 3111 5.3. Oxidative Coupling 3111 5.4. Photochemical Reactions 3111 6. Reaction of Carbonyl Compounds 3111 6.1. Nucleophilic Additions 3111 6.1.1. Allylation 3111 6.1.2. Propargylation 3120 6.1.3. Benzylation 3121 6.1.4. Arylation/Vinylation 3121 6.1.5. Alkynylation 3121 6.1.6. Alkylation 3121 6.1.7. Reformatsky-Type Reaction 3122 6.1.8. Direct Aldol Reaction 3122 6.1.9. Mukaiyama Aldol Reaction 3124 6.1.10. Hydrogen Cyanide Addition 3125 6.2. Pinacol Coupling 3126 6.3. Wittig Reactions 3126 7. Reaction of R,â-Unsaturated Carbonyl Compounds 3127

Organic Reactions in Aqueous Media with a Focus on Carbon−Carbon Bond Formations: A Decade Update

Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C-F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal-fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.

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Introduction of Fluorine and Fluorine-Containing Functional Groups

α-Amino acids are the most important naturally occurring amino acids assembling into polypeptides with a wide range of vital biological functions, and hence the development of an efficient and reliable method for the preparation of optically active α-amino acids and their derivatives with sufficient structural diversity has been a field of considerable interest. Main purpose of this review is to illustrate the range of asymmetric approaches available for the laboratory preparation of optically active α-amino acids by using chiral phase-transfer catalysts. The key process is revealed to be stereoselective functionalization (alkylation, Michael addition, aldol reaction) of the Schiff base of α-amino acid esters including glycine tert-butyl ester with either cinchona alkaloid-derived quaternary ammonium salts or purely synthetic chiral ammonium salts as catalyst, providing a practical route to a variety of optically active α-alkyl-α-amino acids, α, α-dialkyl-α-amino acids and β-hydroxy-α-amino acids. In addition, highly stereoselective N-terminal alkylation of Schiff base-activated peptides by chiral phase-transfer catalysis is also described.

Enantioselective Synthesis of α-Amino Acids by Chiral Phase-Transfer Catalysis

Regioselectivity Switch in Chiral Amine-Catalyzed Asymmetric Addition of Aldehydes to Reactive Enals.

An exceedingly high chemoselective Mukaiyama aldol reaction of saturated aldehydes in the presence of unsaturated aldehydes (benzaldehyde and α,β-enals) has been realized for the first time by using the structurally unique enol tris(2,6-diphenylbenzyl)silyl ether under the influence of BF3·OEt2 as a Lewis acid. Among unsaturated aldehydes, benzaldehyde is found to be more reactive than α,β-enals. The structural uniqueness of the enol tris(2,6-diphenylbenzyl)silyl ether can be visualized by X-ray crystallography as well as 1H and 13C NMR spectroscopy.

A Highly Chemoselective Mukaiyama Aldol Reaction of Saturated Aldehyde over Unsaturated Aldehyde with Enol Tris(2,6-diphenylbenzyl)silyl Ether.

By the end of the 20 th century several advantages of organocatalysis, for example environmental friendliness, operational simplicity, mild reaction conditions etc., had led to its recognition as a powerful principle for the establishment of practical organic synthetic methods. Over the two decades since then tremendous effort has been devoted to the design of novel organocatalysts able to realize unprecedented reactions. In this review our recent results on the design and development of various types of organocatalysts, such as organobase, organoacid, organoacid/base and organoradical catalysts, and their application to a wide variety of synthetic transformations are described. Scheme 1. Asymmetric, phase─ transfer alkylation of a prochiral, protected glycine derivative. Vol.75 No.11 2017 ( 55 ) 1141 (Scheme 2). The observed chiral ef ciency could be ascribed to the considerable difference in catalytic activity between the rapidly equilibrated, diastereomeric homo─ and heterochiral catalysts; namely, homochiral (S,S)─ 5a is primarily responsible for the ef cient asymmetric phase─ transfer catalysis (PTC) to produce 2a with high enantiomeric excess, whereas heterochiral (R,S)─ 5a displays low reactivity and stereoselectivity. This unique phenomenon provides a powerful strategy for the molecular design of chiral catalysts, and quaternary ammonium bromides possessing a sterically demanding substituent such as (S)─ 5b and (S)─ 5c exhibited higher enantioselectivity (92% ee and 95% ee, respectively) in the asymmetric benzylation of 1a. Our further efforts toward simplifying the catalyst have led to the design of new, polyamine─ based, chiral phase─ transfer catalysts of type 6 in the expectation of achieving the multiplier effect of chiral auxiliaries as illustrated in Scheme 3. 9 The chiral ef ciency of such polyamine─ based, chiral phase─ transfer catalysts (S)─ 6 was examined by carrying out asymmetric alkylation of glycine derivatives under phase─ transfer conditions. Among various commercially available polyamines investigated, spermidine─ and spermine─ based polyammonium salts were found to show moderate enantioselectivity. Interestingly, introduction of the 3,4,5─ tri uorophenyl group at the 3,3’─ positions of chiral binaphthyl moieties as in (S)─ 6b resulted in the inversion of absolute con guration of product, affording ent ─ 2a with excellent enantioselectivity. This nding led to the discovery that chiral quaternary ammonium bromide 7 (now registered as Simpli ed Maruoka Catalyst ), possessing exible, straight─ chain alkyl groups instead of a rigid binaphthyl moiety, functions as an unusually active chiral phase─ transfer catalyst. Most notably, the reaction of 1a with various alkyl halides proceeded smoothly under mild phase─ transfer conditions in the presence of only 0.01─ 0.05 mol % of (S)─ 7 to afford the corresponding alkylation products 2a with excellent enantioselectivities (Scheme 3). 10 The synthetic utility of our chiral phase─ transfer catalysts was highlighted by the facile synthesis of L─ Dopa ester and its analogues, which have usually been prepared by either asymmetric hydrogenation of eneamides or enzymatic processes, and have been tested as potential drugs for the treatment of Parkinson’s disease. Catalytic phase─ transfer alkylation of protected glycine tert ─ butyl ester 1a with the requisite benzyl bromide 8 in toluene─ 50% KOH aqueous solution proceeded smoothly at 0 °C under the in uence of (R,R)─ 3e (1 mol %) to furnish fully protected L─ Dopa tert ─ butyl ester, which was subsequently hydrolyzed with 1 M citric acid in THF at room temperature to afford the corresponding amino ester 9 in 81% yield with 98% ee. Debenzylation of 9 under catalytic hydrogenation conditions produced the desired L─ Dopa tert ─ butyl ester 10 in 94% yield (Scheme 4). 11 In addition to chiral α ─ monoalkyl─ α ─ amino acids, nonproteinogenic, chiral α,α ─ dialkyl─ α ─ amino acids possessing stereochemically stable, quaternary carbon centers are also signi cant synthetic targets, not only because they are often effective enzyme inhibitors, but also because they are indispensable for the elucidation of enzymatic mechanisms. Accordingly, numerous studies have been conducted to develop truly ef cient methods for their preparation, and phase─ transfer catalysis has made some unique contributions. Since the aldimine Schiff base 1b can be readily prepared from glycine, direct stereoselective introduction of two different side chains Scheme 2. Design of new C 2─ symmetric, chiral phase─ transfer catalysts. Scheme 4. Asymmetric synthesis of L─ Dopa ester. Scheme 3. Design of new, powerful, C 2─ symmetric, chiral phase─ transfer catalysts. ( 56 ) J. Synth. Org. Chem., Jpn. 1142 to 1b by appropriate chiral phase─ transfer catalysis would provide an attractive and powerful strategy for the asymmetric synthesis of structurally diverse α,α ─ dialkyl─ α ─ amino acids in one pot (Scheme 5). Of course, asymmetric mono─ alkylation of aldimine Schiff base 11 derived from an α ─ alkyl─ α ─ amino acid would also provide α,α ─ dialkyl─ α ─ amino acids as indicated in Scheme 5. This possibility of a one─ pot, asymmetric double alkylation has been realized by using a N ─ spiro, chiral quaternary ammonium bromide of type 3e (Scheme 6). 12 In addition, asymmetric monoalkylation of α ─ alkyl─ α ─ amino acid derivatives appears feasible by using (S,S)─ 3e 5b or (S)─ 7 10b to furnish various types of α,α ─ dialkyl─ α ─ amino acids (Scheme 7). Peptide modi cation provides a useful strategy for ef cient target screening and optimization of lead structures in the application of naturally occurring peptides as pharmaceuticals. The introduction of side chains directly to a peptide backbone represents a powerful method for the preparation of unnatural peptides. An achiral glycine subunit has generally been used for this purpose. However, control of the stereochemical outcome of these transformations in an absolute sense is not easy, especially in the modi cation of linear peptides, and hence development of an ef cient and practical approach to establish suf cient stereoselectivity and general applicability has been crucially important. Accordingly, we examined the chirality transfer in the diastereoselective alkylation of the dipeptide, Gly─ L─ Phe derivative 15 (Scheme 8). Firstly, use of tetrabutylammonium bromide (TBAB) resulted in only low diastereoselectivity (8% de). Interestingly, the reaction with catalyst (S,S)─ 3c or (R,R)─ 3c afforded DL─ 16 (55% de) or LL─ 16 (20% de), respectively, suggesting (R,R)─ 3c is a mismatched catalyst for this diastereofacial differentiation of 15. Changing the 3,3’─ aromatic substituents (Ar) of 3 dramatically increased the stereoselectivity, and almost complete diastereocontrol (97% de) was realized with (S,S)─ 3f. 13 The catalytic asymmetric cyanation of imines, the Strecker reaction, represents one of the most direct and viable methods for the asymmetric synthesis of α─ amino acids and their derivatives. Numerous recent efforts in this eld have led to the establishment of highly ef cient and general protocols, although the use of either alkylmetal cyanide or anhydrous hydrogen cyanide, generally at low temperature, is inevitable. We disclosed the rst example of a phase─ transfer─ catalyzed, highly enantioselective Strecker reaction of aldimines using aqueous KCN based on the molecular design of chiral quaternary ammonium salt (R)─ 17, having a tetranaphthyl backbone, as a highly ef cient organocatalyst (Scheme 9). 14 Scheme 5. New strategy for asymmetric synthesis of α,α ─ dialkyl─ α ─ amino acids. Scheme 6. One─ pot dialkylation sequence for asymmetric synthesis of α,α ─ dialkyl─ α ─ amino acids. Scheme 7. Asymmetric synthesis of α,α ─ dialkyl─ α ─ amino acids by asymmetric alkylation of α ─ alkyl─ α ─ amino acid derivatives. Scheme 8. Stereoselective alkylation of peptides under asymmetric phase─ transfer catalysis. Scheme 9. Asymmetric Strecker reaction under phase─ transfer catalysis. Vol.75 No.11 2017 ( 57 ) 1143 The uoride─ mediated generation of nucleophiles from organosilicon compounds for selective bond─ forming reactions is very useful in organic synthesis. This approach implies the possibility of developing an asymmetric version based on the use of a chiral, nonracemic uoride ion source as represented by chiral quaternary ammonium bi uorides of type 18. Indeed, the asymmetric nitroaldol reaction and conjugate addition of silyl nitronates are found to be highly ef cient under the in uence of chiral quaternary ammonium bi uorides (S,S)─ 18a~b (Scheme 10). 15,16 3. Design of Organoacid Catalysts 3.1 With Axially Chiral Dicarboxylic Acids Based on Binaphthyl Structures Over the last decade, chiral organoacid catalysis has attracted great attention as a useful tool for asymmetric transformations. Several types of Brønsted acid, including urea/ thioureas, diols and phosphoric acids, have been widely utilized as chiral organoacid catalysts. 17 On the other hand, one archetypal class of Brønsted acids, the carboxylic acids, had rarely been employed in chiral organoacid catalysts, an exception being the mandelic acid─ based catalyst developed by Yamamoto and Momiyama. 18 Because the acidity of carboxylic acids lies between that of thioureas and phosphoric acids, they would be expected to show unique reactivity, unachievable with other organoacid catalysts. In this context, our group designed the new binaphthyl─ based organoacid catalysts (R)─ 19a─ d containing a dicarboxylic acid core, and successfully demonstrated their synthetic versatility in asymmetric reactions (Scheme 11). We rst revealed the unique catalytic activity of (R)─ 19a in the asymmetric Mannich reaction of N ─ Boc imines with diazoacetates, furnishing β ─ amino─ α ─ diazoesters in high yields with excellent enantioselectivities (Scheme 12a). 19 Although the chiral phosphoric acid─ catalyzed Mannich reaction of N ─ acyl imines wi

The Design of Environmentally-Benign, High-Performance Organocatalysts for Asymmetric Catalysis

Efficient catalytic asymmetric synthesis of 1,1-disubstituted tetrahydro-β-carbolines has been achieved via asymmetric alkylation of 1-cyanotetrahydro-β-carbolines using a binaphthyl-modified N-spiro-type chiral phase-transfer catalyst. This is a valuable example of hitherto difficult highly enantioselective alkylations at α-carbon of the cyano group under phase-transfer conditions.

Keiji Maruoka

Papers

Enantioselective Synthesis of α-Amino Acids by Chiral Phase-Transfer Catalysis

Regioselectivity Switch in Chiral Amine-Catalyzed Asymmetric Addition of Aldehydes to Reactive Enals.

A Highly Chemoselective Mukaiyama Aldol Reaction of Saturated Aldehyde over Unsaturated Aldehyde with Enol Tris(2,6-diphenylbenzyl)silyl Ether.

The Design of Environmentally-Benign, High-Performance Organocatalysts for Asymmetric Catalysis

Catalytic Asymmetric Synthesis of 1,1‐Disubstituted Tetrahydro‐β‐carbolines by Phase‐Transfer Catalyzed Alkylations.