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The current Account gives an insight into the synthesis of some N-heterocyclic β-amino acid derivatives and various functionalized saturated azaheterocycles accessed from substituted cycloalkenes via ring C=C bond oxidative cleavage followed by ring closing across double reductive amination. The ring-cleavage protocol has been accomplished according to two common approaches: a) Os-catalyzed dihydroxylation/NaIO4 vicinal diol oxidation and b) ozonolysis. A comparative study on these methodologies has been investigated. Due to the everincreasing relevance of organofluorine chemistry in drug research as well as of the high biological potential of β-amino acid derivatives several illustrative examples to the access of various fluorine-containing piperidine or azepane β-amino acid derivatives are also presented in the current Account.1 Introduction2 Olefin-Bond Transformation by Oxidative Ring Cleavage3 Synthesis of Saturated Azaheterocycles via Oxidative Ring-Opening/Ring-Closing Double Reductive Amination3.1 Importance of Fluorine-Containing Azaheterocycles in Pharmaceutical Research3.2 Synthesis of Azaheterocyclic Amino Acid Derivatives with a Piperidine or Azepane Framework through Oxidative Ring Opening/Reductive Amination3.2.1 Synthesis of Piperidine β-Amino Esters3.2.2 Synthesis of Azepane β-Amino Esters3.2.3 Synthesis of Fluorine-Containing Piperidine γ-Amino Esters3.3 Synthesis of Tetrahydroisoquinoline Derivatives through Oxidative Ring Opening/Reductive Amination Protocol3.4 Synthesis of Functionalized Benzazepines through Reductive Amination3.4.1 Synthesis of Benzo[c]azepines3.4.2 Synthesis of Benzo[d]azepines3.5 Synthesis of Various N-Heterocycles via Ozonolysis/Reductive Amination3.5.1 Synthesis of Compounds with an Azepane Ring3.5.2 Synthesis of Piperidine β-Amino Acids and Piperidine-Fused β-Lactams3.5.3 Synthesis of γ-Lactams with a Piperidine Ring3.5.4 Synthesis of other N-Heterocycles4 Summary and Outlook5 List of Abbreviations

Carbon dioxide is arguably one of the most stable carbon-based molecules, yet enzymatic carbon fixation processes enabled the sustainable life cycle on Earth. Chemical reactions involving CO2-functionalization often suffer from low efficiency with highly reactive substrates. We recently reported mild carboxylation of aldehydes to furnish α-keto acids – a building block for chiral α-amino acids via reductive amination. Here, we discuss potential reaction mechanisms of aldehyde carboxylation reactions based on two promoters: NHCs and KCN in the carboxylation reaction. New DFT mechanistic studies suggested a lower reaction barrier for a CO2-functionalization step, implying a potential role of CO2 in prebiotic evolution of organic molecules in the primordial soup.1 Introduction: Aldehydes, Benzoins, Carboxylic Acids2 CO2-Activation: NHC, Cyanide, Lewis Acid and Water3 A Breslow Intermediate: Benzoin Reaction vs. Carboxylation with CO2 4 Carboxylation in the Primordial Soup5 Conclusion

Reductive cross-amination between imine intermediates generated through partial hydrogenation of aniline or nitroarene derivatives and alkylamines is an ideal method for obtaining N-alkylated cyclohexylamine derivatives; however, no such transformations have hitherto been established. Here, we report a highly selective reductive cross-amination using aniline derivatives and alkylamines catalyzed by heterogeneous Rh/Pt bimetallic nanoparticles under mild conditions. The catalyst was recovered and reused for five runs, keeping high activity. In this reaction, imine intermediates generated during the course of partial hydrogenation of aniline derivatives were trapped immediately by strongly interacting primary alkylamines with the catalyst, which caused a highly selective transformation to give the desired products, while suppressing dicyclohexylamine formation.

A novel synthetic approach was developed for the construction of the 1,2,3,4-tetrahydroisoquinoline framework possessing varied functions. The synthetic strategy was based on oxidative ring opening of some indene derivatives through their C=C bond, followed by double reductive amination of the dicarbonyl intermediates with various primary alkyl- or fluoroalkylamines.

A convenient and facile method was developed for the synthesis of 1,2,3-trisubstituted indolines. Starting from indole derivatives and ketones/aldehydes, the corresponding indoline products could be obtained with high yield by the hexamethylphosphoramide (HMPA) catalyzed indole Friedel–Crafts reaction, reduction and direct reductive amination process.

Formal total syntheses of (–)-indolizidines 205A, 207A, and 235B have been accomplished using Evans aldol, Horner–Wadsworth–Emmons olefination and reductive cyclization as key reactions.

A novel methodology for the synthesis of 3,3-difluoropiperidines has been developed. The target compounds are prepared in three steps using a robust protocol and simple starting materials. The incorporation of the fluorine is achieved by using the cheap and easily available ethyl 2-bromo-2,2-difluoroacetate as building block. Using this methodology, a new potent in vitro phosphodiesterase 2A (PDE2A) inhibitor containing the functionalized fluorinated piperidine scaffold has been prepared.

The synthesis of six-, seven-, and eight-membered cis-dihydroxy azacycles has been accomplished from d -ribose using Vasella reductive amination as a key step and utilization of hydroboration–oxidation, Mitsunobu reaction, and ring-closing metathesis (RCM) reactions in a facile manner. These homologous dihydroxylated heterocyclic scaffolds were subjected to the glycosidase inhibition assays. However, only a moderate inhibitory activity for three out of five compounds was observed against α-glucosidases with a high degree of selectivity.

Synthetic studies on acochlearine are described. The pentacyclic A/B/C/E/F ring system of acochlearine was constructed from a bicyclic enone via chemoselective reductive amination, one-pot bromination–intramolecular Mannich reaction cascade, and 6π-electrocyclization.

Tubulysins are the most potent antimitotic agents known so far. We are interested in the conformational effect of tubulysin and herein we report the design and synthesis of a conformationally rigid cyclic analogue of Tuv N-methyl tubulysin. A conformationally rigid tetrahydropyran moiety was incorporated into the Tuv fragment via enantioselective hetero Diels–Alder reaction to prevent the rotation of the Tuv chain. The following diastereoselective reductive amination yielded the (4-methylamino)tetrahydropyranyl Tuv fragment, which was coupled to d-Mep-l-Ile dipeptide fragment and Tup fragment sequentially.

A preliminary investigation into the prospect of a common synthetic intermediate for the synthesis of a variety of indole alkaloids has led to a synthesis of substituted piperidinones and the corresponding piperidines. These common natural product cores are accessed via a reductive amination–lactamization sequence of dimethyl 3-ethyl-3-formylpimelate. The synthetic utility of this initial study has been displayed in the formal synthesis of (±)-quebrachamine.

Strategies for the one-pot formation of secondary aryl amines from the corresponding nitro aryls by utilizing reductive amination procedures are discussed. The extension of this chemistry where a Suzuki–Miyaura cross-coupling is conducted between a boronic acid and bromonitrobenzene prior to the reductive amination in one-pot is also presented.

Reductive amination of aldehyde and amine proceeded smoothly in the presence of benzothiazoline as efficient hydrogen source by means of 20 mol% trifluoroacetic acid to give the corresponding amines in excellent yields. Hydrogen-donor abilities of benzothiazoline, benzimidazoline, and benzoxazoline were compared.

The potential of peptides as drug candidates is limited by theirpoor pharmacokinetic properties. Many peptides have a short half-life,in vivo half-life, and insufficient oral availability. Inspired bythe N-methylation of peptides as a promising way to rationally improvekey pharmacokinetic characteristics, we report our efforts towardan easy synthesis of new monomers N β -Fmoc- N β -Me-aza-β 3 -aminoacids. These synthetic building blocks will be useful for solid-phasesynthesis of new peptidomimetics.

Two unnatural conformationally constrained cyclic amino acid derivatives with the piperidine skeleton were synthesized in enantiomerically pure forms. The key step in the synthesis of these amino acids is the highly diastereoselective functionalization of the oxo group in a 4-oxo-pipecolic acid derivative.

A concise and straightforward synthesis of two amino-DNJ derivatives,6-amino-6-deoxy-DNJ and 6-amino-1,6-dideoxy- L- TALOnojirimycin is described from a commercialand cheap starting material. The methodology employed takes advantageof dia-stereoselective reductive amination to achieve thetwo non-natural iminosugars in three and five steps, respectively.

A route to spiroisoxazolinopiperidinylbenzamides has been developed. N-Boc-4-piperidone underwent a Wittig olefination and Boc-deprotection followed by a nucleophilic substitution reaction with 4-fluoro-3-nitrobenzoic acid to yield the starting scaffold 3 in excellent yields. Diversification of the acid with primary amines, followed nitrile oxide formation in situ (aryl oximes treated with bleach) and subsequent 1,3-dipolar cycloaddition to the exomethylene moiety delivered the spiroisoxazolinopiperdines. Reduction of the arylnitro group followed by acylation with acid chlorides or reductive amination with aldehydes yielded the spiroisoxazolinopiperidinylbenzamide library.

The synthesis of polyamines is often a laborious task that usually requires the use of complex protection schemes in combination with harsh alkylation steps. Here, we report the development of a convenient strategy for the generation of various linear as well as branched lipophilic polyamine structures on solid phase. The sequential use of Aloc-, o-nosyl-, and Dde groups for differentiation between the primary and secondary amines and Fukuyama alkylation and reductive amination for elongation and modification of the backbone enabled the synthesis of both, linear as well as branched polyamines. The mild deprotection conditions facilitated the synthesis of acid- and base-labile conjugates. This strategy was applied for the synthesis of a range of fluorescently labelled polyamine conjugates with varying degrees of lipophilic substitution.

Nickel nanoparticles have been found to catalyse the reductive amination of aldehydes by transfer hydrogenation with isopropanol at 76 °C.

A synthetic entry to CIS-3a-methyl-3-methyleneoctahydroindol-5-ones employing ozonolysis, chemoselective methylenation, and double reductive amination of 2-(1-formylvinyl)-2-methyl-1,4-cyclohexanedione monoethylene acetal is described. The same process using a 2-methoxycarbonyl derivative gave a TRANS-diastereoselectivity in the formation of the azabicyclic compound . Diastereoselective hydroboration of the exocyclic methylene of CIS-octahydroindole derivative gives a valuable synthetic intermediate for DAPHNIPHYLLUM alkaloid synthesis.

t: We report a new organocatalytic cascade reaction. A combination of the amine substrate with a catalytic amount of a Bronsted acid merges enamine and iminium catalysis with Bronsted acid catalysis in a new organocatalytic cascade reaction. We found that the aniline substrate itself in combination with a catalytic amount of PTSA·H 2 O can function as an aminocatalyst accomplishing an aldol condensation-conjugate reduction cascade, which terminates in a Bronsted acid catalyzed reductive amination incorporating the amine substrate into the final product. This transformation furnishes trans-3-substituted cyclohexyl amines in good yields and good diastereoselectivities.

anti-Selective synthesis of aldols with quaternary carbon centers was achieved by germanium(II)-mediated reductive cross-aldol reaction of tertiary α-bromo aldehydes with both aromatic and aliphatic aldehydes. One-pot direct reduction and reductive amination of the aldol products were performed to give the corresponding 1,3-diol and 1,3-amino alcohol with stereocontrolled quaternary carbon centers.

2-Dialkylamino-4H-1,3,2-benzodioxaborins, salicyl alcohol derived aminoboranes, serve as efficient and mild iminium ion generators in the reductive amination of aldehydes with NaBH 4 . Using a diisopropylamino derivative, a variety of amines including secondary and primary amines, and ammonia can participate to the reductive amination in aprotic organic solvents without the use of acidic promoters.

A short synthetic route to polyhydroxylated spirocyclic glucose-based L-proline analogues is described from easily prepared 2,3,4,6 tetra-O-benzyl-D-glucono-lactone. The synthesis involves C-glycosylation of an exocyclic glucose-based epoxide with allyltributylstannane that affords functionalized C-ketosides containing an α-hydroxy ester moiety. Oxidation of the alcohol function, followed by stereoselective reductive amination provides an amine that undergoes iodine-induced aminocyclization to provide spirocyclic glucose-proline hybrids bearing an iodomethylene side-chain. The iodo function of the side-chain can be converted into other functional groups such as ester and hydroxyl groups, thereby allowing additional modifications to the pyrrolidine ring.

Reduction of N-protected aza-β 3 -amino esters and oxidation of the alcohols afford aza-β 3 -amino aldehydes. Conden- sation of unprotected aza-β 3 -amino esters to the resultant alde- Unnatural oligomers are synthetic compounds designed to mimic peptides and others biopolymers and increased their bioavailability. 1 Within the past decade, these com- pounds have emerged as important research targets in drug discovery as well as conformational analysis. Research on solid phase syntheses of oligomers with a defined sequence is proliferating as a consequence. Well-designed oligomers can be formed on a support by repeating the same types of coupling reactions. They can have chemically diverse side chains, but they need to have unproteolytically labile amide bonds. One class of nonhydrolysable peptides are reduced peptides. 2 Peptide nucleic acid (PNA), which is a DNA analogues (the phosphodiester backbone has been replaced by a pseudopeptide backbone), is composed of a backbone built up from aminoethylglycine units or reduced dipeptide backbone (Fig 1), that makes them very stable in biological fluids. 3 In spite of its resistance to cellular enzymes such as nu- cleases and proteases, the major limitations confounding its application are poor solubility in aqueous media, inefficient cellular uptake, due to the uncharged back- bone and ambiguity in orientational selectivity of bind- ing. 4

This review summarizes the authors' studies in the past decade aimed at developing a synthetic oligosaccharide-based glycoconjugate vaccine to prevent a serious human disease caused by the Gram negative bacterium Shigelladysenteriae type 1. Starting from simple monosaccharides, oligosaccharides as large as a 24 monosaccharide-containing linear polymer, were assembled. Under suitable conditions, oligosaccharides containing 4 to 16 hexopyranose residues were covalently attached to an immunogenic protein. The serum response to the synthetic glycoconjugates depends, both on the size of the oligosaccharides, and on the molar ratio of the oligosaccharides to the carrier protein. Also reviewed are studies of the fine specificities of the interaction between oligosaccharides and anti-polysaccharide monoclonal antibodies as well as conformational studies of the synthetic oligosaccharides. 1 Polysaccharide-Based Vaccines 1.1 Surface Polysaccharides of Bacteria 1.2 Immunologic Properties of Polysaccharides 1.3 Polysaccharide-Protein Conjugates 1.3.1 Methods for the Conjugation of Polysaccharides to Proteins 1.3.2 Immunogenicity of Polysaccharide-Protein Conjugates 1.4 Synthetic Oligosaccharides Can be Superior to Natural Polysaccharides for Glycoconjugate Vaccines 1.5 Potentials of the O-Specific Polysaccharides of Shigellae for Vaccine Development 2 Chemical Synthesis of Oligosaccharides Related to the O-Specific Polysaccharide of S. dysenteriae Type 1 2.1 General Strategy 2.2 Synthesis of the Monosaccharide Building Blocks 2.2.1 The L-Rhamnose Moiety 2.2.2 The D-Galactose Moiety 2.2.3 The D-Glucosamine Synthons 2.3 Synthesis of a Complete Repeating Unit 2.4 Construction of Extended Oligosaccharides 2.5 The Lipophilic Protecting Group-Based Approach to Oligosaccharides 3 Covalent Attachment of the Oligosaccharides to Human Serum Albumin 3.1 Conjugation through a Secondary Spacer, Using Reductive Amination 3.2 Conjugation through Diels-Alder Cycloaddition Reactions 4 The Molecular Specificity of the Non-Covalent Binding between O-Specific Polysaccharide-Specific Antibodies and Oligosaccharides Related to the O-Specific Polysaccharide 5 Conformational Studies 6 Immunogenicity of the Protein Conjugates of the Synthetic Oligosaccharides in Mice 7 Conclusions and Future Prospects.

New polyhydroxylated indolizidine and quinolizidine analogs of castanospermine are efficiently obtained by a double reductive amination of enantiopure cyclic ketoaldehydes. As rigidified mimics of disaccharides, these compounds are expected to exhibit significant antidiabetic properties.

A high yielding reductive amination procedure for ­ketones and aldehydes under neutral conditions is described. The key advantage for the method is the applicability to acid-sensitive substrates, and the procedure is applicable to a wide range of primary and secondary amines, on a multigram scale.

A solid-phase synthesis of 6-sulfonylamino morphinan has been developed. The morphinan derivatives were designed as selective opioid ligands. The sulfonamide moiety was introduced by reductive amination of a ketone on solid phase, followed by sulfonylation of the resulting amine. Using this methodology, the synthesis of three combinatorial libraries was accomplished to prepare 339 morphinan derivatives with over 70% purity.

A new facile solid phase synthesis of 2-oxo-1,4-piperazines is described, α-N-Boc-amino aldehydes, which were generated in situ by oxidation of commercially available α-amino alcohols promoted by a polymer supported bromite, were used for the reductive amination of Merrifield-resin bound amino acids. N-substitutions of the resulting secondary amine followed by Boc removal and finally, basic promoted cyclative cleavage affords trisubstituted 2-oxo-1,4-piperazines in good yields and excellent purity. The procedure utilizes readily available building blocks and is amenable to generate large libraries in a discrete manner.

We report the use of benzylamine as the amine component in Hantzsch ester mediated and chiral Bronsted acid catalyzed enantioselective reductive aminations of ketones. The method is noteworthy because the benzyl group is easily removable, and amine product purification is achieved through Hantzsch ester oxidation product removal via basic hydrolysis.

A highly diastereoselective silver-catalysed cyclisation of a 2-substituted (β-allenic hydroxylamine is reported. The resulting trans-isoxazolidine is converted into two Nuphar alkaloids by a sequence involving cross-metathesis and intramolecular reductive amination.

An efficient synthesis of N-benzyl-1 H-benzotriazoles utilizing a two-step reductive amination reaction on solid supports has been achieved. The method is suitable for combinatorial synthesis.

A practical route to 2,6-diazaspiro[3.3]heptanes is described by way of reductive amination of a readily available aldehyde with primary amines or anilines. Cyclisation proceeds in high yield and the methods reported are amenable to either library or large-scale synthesis.

A short and convergent synthesis of the naturally occurring sesquiterpenoid piperidine alkaloid (-)-nupharamine is presented starting from (-)-isopinocampheol via cross metathesis and reductive animation as the key steps.