A Review on the Use of Sodium Triacetoxyborohydride in the Reductive Amination of Ketones and Aldehydes

The aryl C-glycoside structure is, among the plenty of biologically active natural products, one of the distinct motifs embedded. Because of the potential bioactivity as well as the synthetic challenges, these structures have attracted considerable interest, and extensive research toward the total synthesis has been performed. This Review focuses on the synthetic strategies and tactics employed in the total synthesis of this class of natural products. The Introduction describes the historical background, structural features, and synthetic problems associated with aryl C-glycoside natural products. Next the Review summarizes the methods for constructing the aryl C-glycoside bonds. Completed total syntheses—and, in some cases, selected examples of incomplete syntheses—of natural aryl C-glycosides are also summarized. Finally described are the strategies for constructing polycyclic structures, which were utilized in the total syntheses.

Total Synthesis of Aryl C-Glycoside Natural Products: Strategies and Tactics

Reductive amination is an important tool for synthetic organic chemists in the construction of carbon-nitrogen bonds. This reaction, also termed reductive alkylation, involves condensation of an aldehyde or ketone with an amine in the presence of a reducing agent. A wide variety of substrates can be used including aliphatic and aromatic aldehydes and ketones, and even benzophenones. A range of amines from ammonia to aromatic amines, including those with electron-withdrawing substituents, can be employed. For particularly sluggish reactions, such as those involving weakly electrophilic carbonyl groups, poorly nucleophilic amines, or sterically congested reactive centers, additives such as molecular sieves or Lewis acids are often useful.



This chapter focuses on those conditions in which the carbonyl component, amine, and reducing reagent react in the same vessel. This review is restricted to reductive aminations using borohydride and borane reducing agents. This chapter concentrates on reductive amination chemistry mediated by borohydride and other boron-containing reducing agents from 1971, the year when sodium cyanoborohydride was introduced, through the middle of 1999. In addition to reductive aminations of aldehyde and ketone substrates, reactions of related structures including acetals, aminals, ketals, carboxylic acids, nitriles, and dicarbonyls that form a nitrogen-containing ring are reviewed. Intramolecular processes in which the substrate contains both the carbonyl and amine moieties are described. The intramolecular variant is a useful method for preparing cyclic amines. All of the various boron-containing hydride sources in reductive aminations, including labeled metal hydrides, are reviewed. Instances of reductive aminations that failed are described. Applications of this method to a solid support in parallel synthesis in combinatorial chemistry as well as reductive aminations that proceed in tandem with a second reaction such as reductive lactamizations are discussed.


Keywords:

organic reaction(s);
organic synthesis;
reaction(s);
synthesis;
reductive amination;
condensation;
alkylation;
reductive alkylation;
reduction;
amination;
carbonyl;
amine;
reducing agent(s);
borohydride;
borane;
carbon-nitrogen bond(s);
CN bond(s)

Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

Chemistry of α-oxoesters: a powerful tool for the synthesis of heterocycles.

The combination of organocatalysis with metal catalysis has emerged as a potentially powerful tool in organic synthesis. This new concept aims to achieve organic transformations that cannot be accessed by organocatalysis or metal catalysis alone. In our effort to combine organo-enamine catalysis with metal Lewis acid catalysis, we have developed a new class of bifunctional enamine/metal Lewis acid catalysts. These bifunctional catalysts displayed unusually high activity and high stereoselectivity in asymmetric direct aldol reactions. The challenge in the development of Lewis acid/Lewis base catalytic systems lies in the acid-base quenching reaction that leads to catalyst inactivation. A common and elegant approach to solving this problem is the use of a soft acid along with a hard base, or vice versa. Based on this approach, organo-enamine catalysis has been successfully combined with Cu, Ag, Pd, and Au. We use a different strategy to solve the acid-base problem. This new strategy complements the mixed soft/hard approach. In our system, the Lewis base (primary or secondary amine) is tethered to a chelating ligand, which serves as a “trap” for the incoming metal. In this way, the base and the metal Lewis acid are brought into close proximity in one molecule without interacting with each other (Figure 1). The bifunctional enamine/metal Lewis acid catalysts have two unique advantages. First, a large number of metals can be introduced. The Lewis acidity can be easily tuned by simply using a different metal, thereby offering great flexibility to this system. For example, stronger Lewis acids, such as La, can be used to activate the enamine acceptor more strongly. Second, the bifunctional catalysts can potentially convert an intermolecular reaction into a much more efficient intramolecular reaction. In addition, the intramolecular bifunctional nature of the catalysts would also enhance the stereoselectivity of the reaction. With these catalysts, we intend to develop new carbon–carbon or carbon–heteroatom bond-forming reactions involving difficult organic transformations. Herein, we report the first example of a highly chemoand enantioselective inverse-electron-demand hetero-Diels–Alder (HDA) reaction of cyclic ketones with b,g-unsaturated-a-ketoesters catalyzed by primary-amine-based enamine/metal Lewis acid bifunctional catalysts. Asymmetric inverse-electron-demand hetero-Diels– Alder (IED/HDA) reactions of electron-rich alkenes with an electron-deficient a,b-unsaturated ketone offers a valuable synthetic entry into dihydropyran derivatives, which are chemically and biologically of significant importance, allowing the construction of up to three stereogenic centers in one operation. In most of the inverse-electron-demand HDA reactions, enol ethers derived from aldehydes act as the electron-rich alkenes (dienophiles). Very recently, enaminebased organocatalytic asymmetric inverse-electron-demand HDA reactions, in which an in situ formed enamine from a chiral pyrolidine and an aldehyde serves as the dienophile, have been made possible. Ketones are much less reactive compared to aldehydes because of electronic and steric reasons. Asymmetric HDA reactions of ketones, in particular cyclic ketones, have remained a long-standing challenge. We are interested in developing a catalytic asymmetric enamine-based IED/HDA reaction of simple ketones with enones, as it would greatly generalize this method, and open it up to much wider exploitation. To achieve this we believe that the activation of enones should extend beyond hydrogen-bond methods, 8] for example, by using a strong metal Lewis acid. In contrast, the formation of a less congested enamine intermediate using a primary amine catalyst may also contribute to or facilitate this transformation. The primary-amine-based enamine/metal Lewis acid bifunctional catalysts developed in our laboratory appear to be ideal candidates to tackle this difficult problem. We envision that the primary amine/metal Lewis acid bifunctional catalyst would engage enone 3 and the cyclic ketone 2 intramolecularly (Scheme 1). The primary amine would form an enamine in situ with the ketone (A) and the Figure 1. Illustration of primary amine/metal Lewis acid bifunctional catalysts.

Asymmetric inverse-electron-demand hetero-Diels-Alder reaction of six-membered cyclic ketones: an enamine/metal Lewis acid bifunctional approach.

Hetero-Diels-Alder reactions of cyclic ketone derived enamide. A new and efficient concept for the asymmetric Robinson annulation.

A new Lewis acid-catalysed Michael-type addition of heterocyclic enol ethers to hemiacetal vinylogues 1 or to enones in the presence of a hydroxylic compound is described. The 1,5-keto acetals 3 so obtained have been studied with a view to synthetic applications. Acidic hydrolysis of compounds 3 leads in most cases to annulation products 9 in a stereocontrolled manner. Organometallic addition, hydride reduction or reductive amination of 1,5-keto acetals 3 afford, in good yields, the hydroxy acetals 12(and cyclisation products 13) and amino acetals 18, respectively. Acidic treatment of these compounds gave access to oxa- and aza-annulation products 13, 17 and 19 by an efficient kinetically controlled heterocyclisation process. These products can be obtained with high cis-junction selectivities as established by NMR spectroscopy and confirmed by equilibration studies.

Gilles Dujardin

Papers

Hetero-Diels-Alder reactions of cyclic ketone derived enamide. A new and efficient concept for the asymmetric Robinson annulation.

2-Alkoxy-3-oxoalkyl-tetrahydropyrans and -tetrahydrofurans: versatile intermediates in heterocyclic synthesis

A Facile Isomerization Procedure for the Access to Thermodynamic Silyl Enol Ethers

High-pressure hetero-Diels-Alder route to (+/-)-6,6,6-trifluoro-beta-C-naphthyl glycosides.

2-Alkoxy-3-oxoalkyl-tetrahydropyrans and -tetrahydrofurans: Versatile Intermediates in Heterocyclic Synthesis.