Asymmetric Aldol Research Articles

Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates.

A practical enantioselective N-selective nitroso aldol reaction of α-methylmalonamates with a nitrosoarene is reported. The reaction employs the Takemoto thiourea catalyst for the induction of enantioselectivity, and the corresponding optically active oxyaminated malonamates were obtained in reasonably good yields.

Organo-catalysis as emerging tools in organic synthesis: aldol and Michael reactions

Abstract Organocatalysis has occupied sustainable position in organic synthesis as a powerful tool for the synthesis of enantiomeric-rich compounds with multiple stereogenic centers. Among the various organic molecules for organocatalysis, the formation of carbon–carbon is viewed as a challenging issue in organic synthesis. The asymmetric aldol and Michael addition reactions are the most significant methods for C–C bond forming reactions. These protocols deliver a valuable path to access chiral molecules, which are useful synthetic hybrids in biologically potent candidates and desirable versatile pharmaceutical intermediates. This work highlighted the impact of organocatalytic aldol and Michael addition reactions in abundant solvent media. It focused on the crucial methods to construct valuable molecules with high enantio- and diastereo-selectivity.

Asymmetric Intramolecular Aldol Reactions Mediated by Chiral Triamines Bearing a Pyrrolidine Scaffold to Provide a Wieland–Miescher Ketone

Asymmetric Intramolecular Aldol Reactions Mediated by Chiral Triamines Bearing a Pyrrolidine Scaffold to Provide a Wieland–Miescher Ketone

Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination.

Chiral total syntheses of both enantiomers of the anti-MRSA active plymuthipyranone B and all of the both enantiomers of three unnatural and synthetic analogues were performed. These two pairs of four chiral compounds are composed of the same 3-acyl-5,6-dihydro-2H-pyran-2-one structure. The starting synthetic step utilized a privileged asymmetric Mukaiyama aldol addition using Ti(OiPr)4/(S)-BINOL or Ti(OiPr)4/(R)-BINOL catalysis to afford the corresponding (R)- and (S)-δ-hydroxy-β-ketoesters, respectively, with highly enantiomeric excess (>98%). Conventional lactone formation and successive EDCI-mediated C-acylation produced the desired products, (R)- and (S)-plymuthipyranones B and three (R)- and (S)- synthetic analogues, with an overall yield of 42–56% with a highly enantiomeric excess (95–99%). A bioassay of the anti-MRSA activity against ATCC 43300 and 33591 revealed that (i) the MICs of the synthetic analogues against ATCC 43300 and ATCC 33591 were between 2 and 16 and 4 and 16 μg/mL, respectively, and those of vancomycin (reference) were 1 μg/mL. (ii) The natural (S)-plymuthipyranone B exhibited significantly higher activity than the unnatural (R)-antipode against both AACCs. (iii) The natural (R)-plymuthipyranone B and (R)-undecyl synthetic analogue at the C6 position exhibited the highest activity. The present work is the first investigation of the SAR between chiral R and S forms of this chemical class.

Synthesis of 1,2-Diamine Bifunctional Catalysts for the Direct Aldol Reaction Through Probing the Remote Amide Hydrogen

Background: While proline can catalyze the asymmetric direct aldol reactions, its catalytic activity and catalyst turnover are both low. To improve the catalytic efficiency, many prolinebased organocatalysts have been developed. In this regard, prolinamide-based bifunctional catalysts have been demonstrated by us and others to be highly efficient catalysts for the direct aldol reactions. Results: Using the β-acetamido- and β-tosylamidoprolinamide catalysts, the highly enantio- and diastereoselective direct aldol reactions between enolizable ketones and aldehydes were achieved (up to >99% ee, 98:2 dr). A low catalyst loading of only 2-5 mol % of the β-tosylamidoprolinamide catalyst was needed to obtain the desired aldol products in good to high yields and high stereoselectivities. Methods: By carefully adjusting the hydrogen bonding ability of the remote β-amide hydrogen of the 1,2-diamine-based prolinamide bifunctional catalysts, the catalytic activity and the asymmetric induction of these catalysts were significantly improved for the direct aldol reaction between aldehydes and enolizable ketones. Conclusion: Some highly efficient 1,2-diamine-based bifunctional prolinamide catalysts have been developed through probing the remote β-amide hydrogen for its hydrogen bonding capability. These catalysts are easy to synthesize and high enantioselectivities may be achieved at very low catalyst loadings.

Synthesis of a Conformationally Stable Atropisomeric Pair of Biphenyl Scaffold Containing Additional Stereogenic Centers.

The synthesis of a new CF3-containing stereogenic atropisomeric pair of ortho-disubstituted biphenyl scaffold is presented. The atropisomers are surprisingly conformationally stable for isolation. X-ray structures show that their stability comes from an intramolecular hydrogen bond formation from their two hydroxyl groups and renders the spatial arrangement of their peripheral CF3 and CH3 groups very different. The synthesized stereogenic scaffold proved to be effective in catalyzing the asymmetric N-nitroso aldol reaction of enamine and nitrosobenzene. Compared to similar scaffolds without CF3 groups, one of our atropisomer exhibits an increase in enantioselectivity in this reaction.

Multifunctional phosphoramide-(S)-prolinamide derivatives as efficient organocatalysts in asymmetric aldol and Michael reactions

Knowledge accumulated in the field of organocatalysis led to the design and synthesis of three novel and efficient organocatalysts for the stereoselective aldol and Michael reactions in the presence of water.

Highly enantioselective asymmetric direct aldol reaction promoted by aziridine amides constructed on chiral terpene scaffold.

Optically pure, diastereomeric aziridine amides built on the chiral skeletons of camphor, fenchone, and menthone have proven to be highly efficient ligands for enantioselective asymmetric direct aldol reaction in the presence of water and zinc triflate. Desired products were formed in moderate to high chemical yields (up to 95%) and with enantiomeric excess up to 99%. The influence of the stereogenic centers located at the aziridine subunit on the stereochemical course of the reaction is discussed.

ChemInform Abstract: Stereoselective Total Synthesis of Cryptomoscatone F1.

A concise stereoselective total synthesis of cryptomoscatone F1 has been accomplished by utilization of asymmetric acetate aldol reaction, Brown’s asymmetric allylation, and olefin cross-metathesis as key transformations.

Asymmetric Aldol and Michael Reactions in Water Using Organocatalysts Immobilized on a Thermoresponsive “Linear” Block Copolymer

Asymmetric Aldol and Michael Reactions in Water Using Organocatalysts Immobilized on a Thermoresponsive “Linear” Block Copolymer

A One-Pot Tandem Strategy in Catalytic Asymmetric Vinylogous Aldol Reaction of Homoallylic Alcohols

Reported is a rationally-designed one-pot sequential strategy that allows homoallylic alcohols to be employed in a catalytic, asymmetric, direct vinylogous aldol reaction with a series of activated acyclic ketones, including trifluoromethyl ketones, γ-ketoesters, and α-keto phosphonates, in high yields (up to 95%) with excellent regio- and enantio-selectivity (up to 99% ee). This modular combination, including Jones oxidation and asymmetric organocatalysis, has satisfactory compatibility and reliability even at a 20 mmol scale, albeit without intermediary purification.

Stereoselective Total Synthesis of Cryptomoscatone F1

A concise stereoselective total synthesis of cryptomoscatone F1 has been accomplished by utilization of asymmetric acetate aldol reaction, Brown’s asymmetric allylation, and olefin cross-metathesis as key transformations.

Competition for binaphthyl catalysts

Organic Chemistry The binaphthyl framework has proven extremely effective in biasing a broad range of chemical reactions toward just one of two mirror-image products. The motif was first applied as a ligand in metal catalysis, and more recently as a conjugate base in acid catalysis. Gheewala et al. report a class of chiral carbon acids based around a cyclopentadiene framework that are easily accessible from readily available precursors. The compounds are showcased as highly selective catalysts for asymmetric Mukaiyama Mannich and oxocarbenium aldol reactions. Science , this issue p. [961][1] [1]: /lookup/doi/10.1126/science.aad0591

Zinc-Catalyzed Asymmetric Mannich and Aldol Reactions Using Fluorinated Ketones

Zinc-Catalyzed Asymmetric Mannich and Aldol Reactions Using Fluorinated Ketones

ChemInform Abstract: The Asymmetric Synthesis of Tetrahydrolipstatin

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The Asymmetric Synthesis of Tetrahydrolipstatin

AbstractThe various syntheses of the over‐the‐counter anti‐obesity drug tetrahydrolipstatin (also known as Orlistat) are reviewed. The 31 various syntheses cover the development of enantioselective natural products synthesis since the first synthesis of tetrahydrolipstatin (THL) by Schneider in 1987. After Schneider's landmark synthetic effort there have been numerous total and formal syntheses of THL, which have involved a diverse range of approaches. These various syntheses can be classified by the methods that were used to install the stereochemistry, for instance, chiral auxiliary, asymmetric aldol, asymmetric allylation/crotylation, asymmetric reductions, asymmetric resolutions, asymmetric oxidations, and chiron approach. These routes also feature the elegant use of a chiral phosphate template, a tandem [2+2]‐Mukaiyama aldol‐lactonization, an anti‐aldol segment via a non‐aldol route, a Prins cyclization, and an epoxide carbonylation.

ChemInform Abstract: The Synthesis of Chiral Benzothiazine and Thiazinoquinoline Derivatives.

The syntheses of a series of enantiopure conformationally restricted benzothiazine and thiazinoquinoline derivatives are presented. Key starting materials are 3-aminoacetophenone and (S)-S-methyl-S-phenylsulfoximine. By using a short reaction sequence, the 8-amino-2,1-benzothiazine derivative was readily prepared, which served as a valuable intermediate for the synthesis of additional derivatives. Initial experiments show that employing such compounds in copper-catalyzed asymmetric Mukaiyama-type aldol reactions provided products with moderate enantioselectivity.

Asymmetric Copper-Catalyzed Detrifluoroacetylative Aldol Reactions

Asymmetric Copper-Catalyzed Detrifluoroacetylative Aldol Reactions

Advances in Immobilized Organocatalysts for the Heterogeneous Asymmetric Direct Aldol Reactions

The aim of this article is to collect the results published from the beginning (2000) on asymmetric direct aldol reactions taking place in the presence of immobilized chiral organocatalysts. The seven groups of organocatalysts discussed are: asymmetric direct aldol reactions catalyzed by: (1) covalently bonded immobilized hydroxyproline organocatalysts; (2) covalently bonded immobilized prolinamide organocatalysts; (3) covalently bonded immobilized peptide organocatalysts; (4) other covalently bonded immobilized chiral organocatalysts; (5) chiral organocatalysts bonded by ionic groups; (6) chiral organocatalysts with adsorptive bonding; and (7) other types of immobilized chiral organocatalysts. The main objective of this article based on results obtained by using about 360 immobilized organocatalysts, to bring to the focus of catalyst systems in which the aldol reactions yield beta-hydroxyketones of maximal optical purity, while keeping catalyst concentrations and reaction times as low and as short as possible. Trends recognized in data obtained in this field of investigation may mark out further tasks for the purpose of practical application.

The first total synthesis of (+)-goniothalesacetate and syntheses of (+)-altholactone, (+)-gonioheptolide A, and (−)-goniofupyrone by an asymmetric acetate aldol approach

The first stereoselective total synthesis of (+)-goniothalesacetate and total synthesis of several bioactive styryl lactones, (+)-altholactone, (+)-gonioheptolide A, and (-)-goniofupyrone have been achieved from an advanced intermediate, which can be derived from L-(+)-DET.