Intermolecular Aldol Reaction Research Articles

Total Synthesis of Principinol B.

We have accomplished the first and asymmetric total synthesis of principinol B, a grayanoid possessing an oxabicyclo[3.2.1] architecture. A functionalized 5/7/6/5 tetracyclic intermediate was assembled in a convergent manner by a diastereoselective intermolecular aldol reaction and subsequent carbonyl-olefin metathesis of two enantiomerically enriched fragments. The oxabicyclo[3.2.1] architecture containing a 6,10-ether bridge was constructed by the Williamson ether synthesis.

Total Synthesis of Principinol B

AbstractWe have accomplished the first and asymmetric total synthesis of principinol B, a grayanoid possessing an oxabicyclo[3.2.1] architecture. A functionalized 5/7/6/5 tetracyclic intermediate was assembled in a convergent manner by a diastereoselective intermolecular aldol reaction and subsequent carbonyl–olefin metathesis of two enantiomerically enriched fragments. The oxabicyclo[3.2.1] architecture containing a 6,10‐ether bridge was constructed by the Williamson ether synthesis.

Recent Advances in Asymmetric Synthesis of Pyrrolidine-Based Organocatalysts and Their Application: A 15-Year Update

In 1971, chemists from Hoffmann-La Roche and Schering AG independently discovered a new asymmetric intramolecular aldol reaction catalyzed by the natural amino acid proline, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction. These remarkable results remained forgotten until List and Barbas reported in 2000 that L-proline was also able to catalyze intermolecular aldol reactions with non-negligible enantioselectivities. In the same year, MacMillan reported on asymmetric Diels-Alder cycloadditions which were efficiently catalyzed by imidazolidinones deriving from natural amino acids. These two seminal reports marked the birth of modern asymmetric organocatalysis. A further important breakthrough in this field happened in 2005, when Jørgensen and Hayashi independently proposed the use of diarylprolinol silyl ethers for the asymmetric functionalization of aldehydes. During the last 20 years, asymmetric organocatalysis has emerged as a very powerful tool for the facile construction of complex molecular architectures. Along the way, a deeper knowledge of organocatalytic reaction mechanisms has been acquired, allowing for the fine-tuning of the structures of privileged catalysts or proposing completely new molecular entities that are able to efficiently catalyze these transformations. This review highlights the most recent advances in the asymmetric synthesis of organocatalysts deriving from or related to proline, starting from 2008.

Piericones A and B as Potent Antithrombotics: Nanomolar Noncompetitive Protein Disulfide Isomerase Inhibitors with an Unexpected Chemical Architecture

Extracellular protein disulfide isomerase (PDI) is a promising target for thrombotic-related diseases. Four potent PDI inhibitors with unprecedented chemical architectures, piericones A-D (1-4), were isolated from Pieris japonica. Their structures were elucidated by spectroscopic data analysis, chemical methods, quantum 13C nuclear magnetic resonance DP4+ and electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Piericones A (1) and B (2) were nanomolar noncompetitive PDI inhibitors possessing an unprecedented 3,6,10,15-tetraoxatetracyclo[7.6.0.04,9.01,12]pentadecane motif with nine contiguous stereogenic centers. Their biosynthetic pathways were proposed to include a key intermolecular aldol reaction and an intramolecular 1,2-migration reaction. Piericone A (1) significantly inhibited in vitro platelet aggregation and fibrin formation and in vivo thrombus formation via the inhibition of extracellular PDI without increasing the bleeding risk. The molecular docking and dynamics simulation of 1 and 2 provided a novel structure basis to develop PDI inhibitors as potent antithrombotics.

Total Synthesis of Isorosthin L and Isoadenolin I.

Total syntheses of two Isodon diterpenes, isorosthin L and isoadenolin I, are reported. The synthetic strategy features a quick assembly of two simple building blocks through a diastereoselective intermolecular aldol reaction and a subsequent radical cyclization for efficient construction of a rather complex advanced intermediate bearing a quaternary stereocenter present in all Isodon diterpenes. Oxidative cleavage of the C-C bond in the cyclopentane enabled the conversion to a lactone moiety which is desired for the construction of the molecular skeleton through reductive coupling with an aldehyde carbonyl group.

Total Synthesis of Isorosthin L and Isoadenolin I

AbstractTotal syntheses of two Isodon diterpenes, isorosthin L and isoadenolin I, are reported. The synthetic strategy features a quick assembly of two simple building blocks through a diastereoselective intermolecular aldol reaction and a subsequent radical cyclization for efficient construction of a rather complex advanced intermediate bearing a quaternary stereocenter present in all Isodon diterpenes. Oxidative cleavage of the C−C bond in the cyclopentane enabled the conversion to a lactone moiety which is desired for the construction of the molecular skeleton through reductive coupling with an aldehyde carbonyl group.

Secondary-sphere modification in proline catalysis: old friend, new connection.

In this work, we exploit our strategy of in situ secondary-sphere modification of organocatalysts to improve the reactivity and selectivity of amino catalysts. Herein, the carboxylic acid moiety of proline was targeted as a site for modification under catalytic reaction conditions with boronic acids. Intermolecular aldol reactions between aromatic aldehydes and cyclopentanone were selected as a proof-of-concept because cyclopentanone as an aldol donor was often associated with decreased selectivity compared to its 6-membered ring analog, hexanone. Our secondary-sphere modification strategy, using naturally occurring L-proline amino acid, enabled reactions at room temperature with high levels of diastereo- and enantio-selectivity and short reaction times. NMR and HR-MS studies shed light on the nature of the catalyst structure and on the role of water in our reactions.

Intermolecular domino Michael/aldol reactions of α,β-unsaturated esters, aromatic aldehydes, and various nucleophiles promoted with a catalytic amount of a guanidine base in DMSO

In DMSO, a catalytic amount of Barton's base (2-t-butyl-1,1,3,3-tetramethylguanidine, BTMG) effectively catalyzed intermolecular three-component reactions of α,β-unsaturated esters, aldehydes, and carbon-, sulfur-, or nitrogen-pronucleophiles to give three-component addition products with the formation of two new σ-bonds: pronucleophiles and aldehydes reacted with α,β-unsaturated esters at their β-positions and α-positions, respectively. Mechanism studies suggested that these reactions proceeded by the first intermolecular Michael addition of anionic nucleophiles that were formed from pronucleophiles with a catalytic amount of BTMG, followed by intermolecular aldol reactions of transient ester enolates even in the presence of more than stoichiometric amounts of acidic pronucleophiles. High nucleophilicity over Brønsted basicity of transient enolates in polar solvents was observed for transient ester enolates rather than ketone enolates.

Theoretical investigation of Prolyl‐Histidine‐catalyzed intermolecular aldol reaction

AbstractThe mechanism of aldol reaction of acetone and benzaldehyde catalyzed by Prolyl‐Histidine dipeptide was studied using density functional theory (DFT) method at ωB97XD/6‐31G(d,p) level. The calculated results indicated that this reaction consisted of the following processes: (I) the formation of alcohol intermediate with acetone and Pro‐His by water assistance; (II) the formation of enamine by alcohol dehydration; (III) the formation of imine complexes by electrophilic addition of enamine and benzaldehyde; and (IV) the formation of aldol products by imine complex combining with water to obtain S or R type products after removing the catalyst. The calculated results show that the generation of enamine is the rate‐determining step, and the main product is cis‐enamine with a free energy barrier of 19.6 kcal/mol. The calculated enantiomeric excess (ee) value of aldol product is 100%.

Catalytic intermolecular aldol reactions of transient amide enolates in domino Michael/aldol reactions of nitroalkanes, acrylamides, and aldehydes

Aldol reactions of amide enolates formed by addition of nitronates to acrylamides proceeded with catalytic amounts of KOH in DMSO.

Data-Driven Collective Variables for Enhanced Sampling.

Designing an appropriate set of collective variables is crucial to the success of several enhanced sampling methods. Here we focus on how to obtain such variables from information limited to the metastable states. We characterize these states by a large set of descriptors and employ neural networks to compress this information in a lower-dimensional space, using Fisher's linear discriminant as an objective function to maximize the discriminative power of the network. We test this method on alanine dipeptide, using the nonlinearly separable data set composed by atomic distances. We then study an intermolecular aldol reaction characterized by a concerted mechanism. The resulting variables are able to promote sampling by drawing nonlinear paths in the physical space connecting the fluctuations between metastable basins. Lastly, we interpret the behavior of the neural network by studying its relation to the physical variables. Through the identification of its most relevant features, we are able to gain chemical insight into the process.

Prolinamide‐Catalysed Asymmetric Organic Transformations

AbstractProline was reported as an enantioselective organocatalyst for direct asymmetric aldol reaction in the early 1971 s by two independent groups of researchers and the reaction was called the Hajos‐Parrish‐Eder‐ Sauer Wiechert reaction. The breakthrough of enantioselective organocatalysis was demonstrated by List and co‐workers in 2000 for intermolecular aldol reaction between benzaldehydes and ketone using proline as a catalyst. After this report many researchers were applied the proline as a catalyst for other organic transformation. The proline has a carboxylic functional group which can easily convert to the amide and known as prolinamide. Prolinamides were found to be a better catalyst compared to proline in the most of cases. In this review article we are compiling the results of the prolinamides catalyzed asymmetric organic transformation with insight of the mechanism of catalysis.

Construction of a 6/5/9-membered tricyclic structure of cladiellins via radical-polar crossover reaction.

A three-component coupling reaction of structurally simple 6-8 was successfully applied for expeditious synthesis of the 6/5/9-membered tricyclic structure 3 of cladieunicellin D (1) and klysimplexin U (2). Upon treatment with the Et3B/O2 reagent system, α-alkoxyacyl telluride 6, six-membered enone 7, and (Z)-4-hexenal (8) were linked in one pot to provide the densely functionalized 5 via sequential decarbonylative radical generation, radical addition, boron enolate formation, and intermolecular aldol reaction. Subsequent Lewis acid-promoted reductive etherification and SiO2-induced C10-epimerization gave rise to the cis-fused five-membered ether of 4. Finally, cyclization of the nine-membered ring was achieved by the ring-closing metathesis reaction, giving rise to 3. Compound 3 possesses the six stereocenters of 1 and 2, and would thus serve as an advanced intermediate for their total syntheses.

Studies towards the Synthesis of Portentol

AbstractA highly stereoselective and competent approach for studies towards the synthesis of Portentol has been described. The salient features of the synthesis are the utilization of desymmetrization protocol, Crimmin's non‐Evans syn aldol reaction, C−C bond formation through an intermolecular Aldol reaction and Barton‐McCombie deoxygenation.

Forging Fluorine‐Containing Quaternary Stereocenters by a Light‐Driven Organocatalytic Aldol Desymmetrization Process

AbstractReported herein is a light‐triggered organocatalytic strategy for the desymmetrization of achiral 2‐fluoro‐substituted cyclopentane‐1,3‐diketones. The chemistry is based on an intermolecular aldol reaction of photochemically generated hydroxy‐o‐quinodimethanes and simultaneously forges two adjacent fully substituted carbon stereocenters, with one bearing a stereogenic carbon–fluorine unit. The method uses readily available substrates, a simple chiral organocatalyst, and mild reaction conditions to afford an array of highly functionalized chiral 2‐fluoro‐3‐hydroxycyclopentanones.

Forging Fluorine-Containing Quaternary Stereocenters by a Light-Driven Organocatalytic Aldol Desymmetrization Process.

Reported herein is a light‐triggered organocatalytic strategy for the desymmetrization of achiral 2‐fluoro‐substituted cyclopentane‐1,3‐diketones. The chemistry is based on an intermolecular aldol reaction of photochemically generated hydroxy‐o‐quinodimethanes and simultaneously forges two adjacent fully substituted carbon stereocenters, with one bearing a stereogenic carbon–fluorine unit. The method uses readily available substrates, a simple chiral organocatalyst, and mild reaction conditions to afford an array of highly functionalized chiral 2‐fluoro‐3‐hydroxycyclopentanones.

First total synthesis of (−)-salprzelactone

The first enantioselective total synthesis of (−)-salprzelactone, a seco-norabietane diterpenoid has been accomplished in only three steps. Key transformations of the synthesis include an intermolecular aldol reaction and lactonization.

Automatic Reaction Pathway Search via Combined Molecular Dynamics and Coordinate Driving Method.

We proposed and implemented a combined molecular dynamics and coordinate driving (MD/CD) method for automatically searching multistep reaction pathways of chemical reactions. In this approach, the molecular dynamic (MD) method at the molecular mechanics (MM) or semiempirical quantum mechanical (QM) level is employed to explore the conformational space of the minimum structures, and the modified coordinate driving (CD) method is used to build reaction pathways for representative conformers. The MD/CD method is first applied to two model reactions (the Claisen rearrangement and the intermolecular aldol reaction). By comparing the obtained results with those of the existing methods, we found that the MD/CD method has a comparable performance in searching low-energy reaction pathways. Then, the MD/CD method is further applied to investigate two reactions: the electrocyclic reaction of benzocyclobutene-7-carboxaldehyde and the intramolecular Diels-Alder reaction of ketothioester with 11 effectively rotatable single bonds. For the first reaction, our results can correctly account for its torquoselectivity. For the second one, our method predicts eight reaction channels, leading to eight different stereo- and regioselective products. The MD/CD method is expected to become an efficient and cost-effective theoretical tool for automatically searching low-energy reaction pathways for relatively complex chemical reactions.

Synthesis of Ophiocerins A, B and C, Botryolide E, Decarestrictine O, Stagonolide C and 9‐epi‐Stagonolide C Employing Chiral Hexane‐1,2,3,5‐tetraol Derivatives as Building Blocks

An organocatalytic approach to the synthesis of (2R,3S)‐hexane‐1,2,3,5‐tetraol (11) derivatives (in the forms of different stereoisomers and bearing different protecting groups) has been developed. The key chiral intermediates 11 were prepared with complete stereocontrol through the proline‐catalyzed intermolecular aldol reaction between acetone and d‐glyceraldehyde acetonide. The synthetic utility of the intermediates was demonstrated by their transformation into the title hydroxylated pyrans and a variety of unsaturated lactones through standard synthetic protocols.

Highly stereoselective direct aldol reaction of 4-formylcoumarins with acetone catalyzed by L-proline in water–acetone mixtures

ABSTRACTOrganocatalyzed direct intermolecular aldol reactions have been developed for substituted 4-formylcoumarins with acetone in water using L-proline and phthalimido-prolinamide catalysts without use of additives. Stereoselective products obtained were in excellent yields (up to 97%) with high purity (up to 99%) and enatioselectivities (up to 95%). The isolated compounds were confirmed by infrared, NMR, high-performance liquid chromatography, and mass spectrometry and some of them by single-crystal x-ray crystallography.