Selective Aldol Reaction Research Articles

The mechanism of sugar produced from simple glycolaldehyde derivative at ambient conditions

AbstractA benchmark of sugar produced from simple glycolaldehyde derivative has been achieved at ambient conditions (Science, 2004, 305, 1752), which is the most important step to produce life in nature. However, the mechanism has never been clearly understood. Here, we report a reaction mechanism which includes a two‐step synthesis of sugars by selective aldol reactions based on the density functional theory (DFT) calculations. Results show that the prochirality of attacking orientation of the enamine intermediate and steric effect in proton transfer is the main cause for stereochemical preference. This work provides the theoretical insight of sugar produced in glycolaldehyde procedure and may assist the improvement of catalyst design for this procedure.

The Stereocontrolled Total Synthesis of Polyketide Natural Products: A Thirty-Year Journey

Abstract The diverse and complex structures of polyketide natural products have stimulated the imagination of synthetic chemists for decades. Captivated by their often impressive biological activities and their dazzling array of stereochemically-rich motifs, we have been motivated to achieve their efficient and stereocontrolled total synthesis. This review captures snapshots from our thirty-year foray into the total synthesis of 18 polyketide natural products, detailing the unique challenges, discoveries and revelations made en route to eventual success. Notably, crucial to each of these campaigns was the judicious application of highly selective aldol reactions to iteratively configure the densely oxygenated stereoclusters that characterise this fascinating class of bioactive natural products.

ChemInform Abstract: Ligand‐Promoted, Boron‐Mediated Chemoselective Carboxylic Acid Aldol Reaction.

AbstractThe first carboxylic acid selective aldol reaction mediated by boron compounds is developed.

Ligand-Promoted, Boron-Mediated Chemoselective Carboxylic Acid Aldol Reaction.

The first carboxylic acid selective aldol reaction mediated by boron compounds and a mild organic base (DBU) was developed. Inclusion of electron-withdrawing groups in the amino acid derivative ligands reacted with BH3·SMe2 forms a boron promoter with increased Lewis acidity at the boron atom and facilitated the carboxylic acid selective enolate formation, even in the presence of other carbonyl groups such as amides, esters, ketones, or aliphatic aldehydes. The remarkable ligand effect led to the broad substrate scope including biologically relevant compounds.

Anti-Selective Aldol Reactions of Pentafluorosulfanylacetic Acid Esters with Aldehydes Mediated by Dicyclohexylchloroborane.

Aldol reactions of pentafluorosulfanyl (SF5)-substituted acetic acid esters with both aromatic and aliphatic aldehydes proceeded with excellent anti-diastereoselectivity and good to high yields using dicyclohexylchloroborane/triethylamine. This methodology enabled the synthesis of hitherto unknown α-SF5-β-hydroxy esters. Using a norephedrine-based auxiliary, high asymmetric induction was observed. The stereochemistry of products was assigned by NMR spectroscopy and proved by X-ray diffraction analysis. The intermediate enolate was identified as a highly unstable species.

Syntheses and Biological Evaluation of Costunolide, Parthenolide, and Their Fluorinated Analogues.

Inspired by the biosynthesis of sesquiterpene lactones (SLs), herein we report the asymmetric total synthesis of the germacrane ring (24). The synthetic strategy features a selective aldol reaction between β,γ-unsaturated chiral sulfonylamide 15a and aldehyde 13, as well as the intramolecular α-alkylation of sulfone 21 to construct a 10-membered carbocylic ring. The key intermediate 24 can be used to prepare the natural products costunolide and parthenolide (PTL), which are the key precursors for transformation into other SLs. Furthermore, the described synthetic sequences are amenable to the total synthesis of SL analogues, such as trifluoromethylated analogues 32 and 45. Analogues 32 and 45 maintained high activities against a series of cancer cell lines compared to their parent PTL and costunolide, respectively. In addition, 32 showed enhanced tolerance to acidic media compared with PTL. To our surprise, PTL and 32 showed comparable half-lives in rat plasma and in the presence of human liver microsomes.

Synthesis of a C20-Deoxygenated Spirangien Derivative for Target Identification

The synthesis of a C20-deoxygenated spirangien derivative is described that allows the incorporation of various affinity labels for target identification of this potent natural product. The synthesis takes advantage of two major building blocks that can be accessed in 8 and 14 steps, respectively. The endgame joins both fragments through a selective aldol reaction and final protecting group manipulations furnish the target molecule.

Synthesis of β-Hydroxy-α-haloesters through Super Silyl Ester Directed Syn-Selective Aldol Reaction

Super silyl haloesters including chloro- and bromoacetate were synthesized and utilized for aldol reactions to give syn-β-hydroxy-α-haloacetates in good yields with high diastereoselectivities. β-Hydroxy-α-fluoroacetate was obtained by lithiation of super silyl bromofluoroacetate. Sequential Darzens reactions provided cis-glycidic esters in moderate yields.

Stereoselective synthesis of the C15–C30 subunit of dolabelides A–D

A highly stereoselective synthesis of the C15–C30 subunit of the cytotoxic macrolides dolabelides A–D has been accomplished by utilizing anti selective aldol reaction, Wittig olefination for the introduction of a trisubstituted (E)-double bond, selective hydroboration, Brown asymmetric allylation, Wilkinson hydrogenation and stereoselective keto reduction for the installation of C19 hydroxy group as key steps.

The First Organocatalysed Direct Aldol Reaction of 2-Hydroxycyclobutanone

L-Tryptophan has been shown to catalyse the enantio- selective aldol reaction between 2-hydroxycyclobutanone and an aromatic aldehyde in DMF solution. The reaction is completely re- gioselective and gives the 2,2-disubstituted cyclobutanone in up to 80% yield. The major adduct is obtained with ee values up to 67%, and has an anti relative configuration which contrasts with the se- lectivity of organocatalysed aldol reactions conducted on acyclic hydroxyacetone substrates.

Structurally Informed Site-Directed Mutagenesis of a Stereochemically Promiscuous Aldolase To Afford Stereochemically Complementary Biocatalysts

2-Keto-3-deoxygluconate aldolase from the hyperthermophile Sulfolobus solfataricus is a highly thermostable type I aldolase that can catalyze carbon-carbon bond formation using nonphosphorylated substrates. However, it exhibits poor diastereocontrol in many of its aldol reactions, including the reaction of its natural substrates, pyruvate and D-glyceraldehyde, which afford a 55:45 mixture of D-2-keto-3-deoxygluconate (D-KDGlu) and D-2-keto-3-deoxy-galactonate (D-KDGal). We have employed detailed X-ray crystallographic structural information of this aldolase bound to these diastereoisomeric aldol products to selectively target specific amino acids for mutation for the rapid creation of stereochemically complementary mutants that catalyze either (Re)- or (Si)-facial selective aldol reactions to afford either D-KDGlu or D-KDGal with good levels of diastereocontrol.

Mimicking Aldolases through Organocatalysis: syn-Selective Aldol Reactions with Protected Dihydroxyacetone

A practical organocatalytic strategy designed to mimic the l-rhamnulose 1-phosphate and D-fructose 1,6-diphosphate aldolases has been developed and shown to be effective in the preparation of carbohydrates and polyol derivatives. Threonine-based catalysts facilitated the aldol reaction of protected dihydroxyacetone or protected hydroxacetone with a variety of aldehydes to provide syn-aldol products with good yields and ee's up to 98%.

Corrigendum. Highly selective direct aldol reaction organocatalyzed by (S)-BINAM-L-prolinamide and benzoic acid using α-chalcogen-substituted ketones as donors. [ARKIVOC 2007 (iv) 260-269

Corrigendum. Highly selective direct aldol reaction organocatalyzed by (S)-BINAM-L-prolinamide and benzoic acid using α-chalcogen-substituted ketones as donors. [ARKIVOC 2007 (iv) 260-269

Total Synthesis of Cyclic Diterpene Tonantzitlolone Based on a Highly Stereoselective Substrate‐Controlled Aldol Reaction and Ring‐Closing Metathesis

The total synthesis of the cyclic diterpene ent-tonantzitlolone (ent-1) is presented. Key steps for assembling the macrocyclic core structure of 1 are a highly selective aldol reaction and an E selective ring-closing metathesis reaction. A detailed investigation of these two steps and the final transformations towards the completion of the synthesis is disclosed.

Two‐Step Synthesis of Carbohydrates by Selective Aldol Reactions

AbstractFor Abstract see ChemInform Abstract in Full Text.

Two-step synthesis of carbohydrates by selective aldol reactions.

Studies of carbohydrates have been hampered by the lack of chemical strategies for the expeditious construction and coupling of differentially protected monosaccharides. Here, a synthetic route based on aldol coupling of three aldehydes is presented for the de novo production of polyol differentiated hexoses in only two chemical steps. The dimerization of alpha-oxyaldehydes, catalyzed by l-proline, is then followed by a tandem Mukaiyama aldol addition-cyclization step catalyzed by a Lewis acid. Differentially protected glucose, allose, and mannose stereoisomers can each be selected, in high yield and stereochemical purity, simply by changing the solvent and Lewis acid used. The reaction sequence also efficiently produces (13)C-labeled analogs, as well as structural variants such as 2-amino- and 2-thio-substituted derivatives.

Selective aldol reactions of acetals on mesoporous silica catalyst

Mukaiyama-aldol reactions of carbonyl compounds with silyl enol ethers were well catalyzed on siliceous mesoporous materials (MCM-41). The reactivity of acetals was much higher than that of aldehyde. The reactions proceeded selectively at 273–298 K on the catalyst of 30 mg per mmol of the substrate.

Synthetic study on L-755,807: asymmetric synthesis of the epoxy-γ-lactam moiety

The optically active epoxy-γ-lactam moiety (−)- 4 of the B 2 selective bradykinin inhibitor L-755,807 1 was prepared from ( S)-aldehyde 7 via an anti selective aldol reaction as the key step.

Anti‐Selective Aldol Reactions of Amino Acid Ester Enolates. Application to the Synthesis of α‐Alkylated β‐Hydroxy Amino Acids

AbstractDeprotonation of N‐protected esters of the amino acids alanine 1, ethylglycin 6, valine 7, and phenylalanine 8 with LDA and subsequent addition of various metal salts result in the formation of a probably chelated metal enolate. Aldol reactions of these enolates with aldehydes afford the anti isomers of α‐alkylated α‐amino‐β‐hydroxy acids in a highly diastereoselective fashion. Best results are obtained with titanium enolates, bulky aliphatic aldehydes, and sterically demanding amino acids.

ChemInform Abstract: Highly Selective Aldol Reaction of Dibenzoylmethanes with Formaldehyde Catalyzed by Cobalt Schiff Base Complex under Neutral Conditions.

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