aldol-Tishchenko Reaction Research Articles

Mechanistic Investigations of Chiral Lithium Binaphtholate Catalysis for Asymmetric Aldol-Tishchenko Reaction of α-Fluoroarylketones.

In this study, we analyzed the asymmetric aldol-Tishchenko reaction of α-fluoroarylketones with aldehydes in the presence of chiral lithium binaphtholate, which was readily prepared from a chiral BINOL derivative and lithium tert-butoxide. This tandem reaction afforded enantiomerically enriched 2-fluoro-1,3-diols with three contiguous stereogenic centers in high yield and with high diastereo- and enantioselectivities. Moreover, mechanistic investigations of the lithium binaphtholate-catalyzed enantioselective aldol-Tishchenko reaction were performed based on the kinetic isotope effect and computational analyses.

Enantioselective Synthesis of Acyclic Stereotriads Featuring Fluorinated Tetrasubstituted Stereocenters.

Elaboration of enantioenriched complex acyclic stereotriads represents a challenge for modern synthesis even more when fluorinated tetrasubstituted stereocenters are targeted. We have been able to develop a simple strategy in a sequence of two unprecedented steps combining a diastereoselective aldol-Tishchenko reaction and an enantioselective organocatalyzed kinetic resolution. The aldol-Tishchenko reaction directly generates a large panel of acyclic 1,3-diols possessing a fluorinated tetrasubstituted stereocenter by condensation of fluorinated ketones with aldehydes under very mild basic conditions. The anti 1,3-diols featuring three contiguous stereogenic centers are generated with excellent diastereocontrol (typically >99 : 1 dr). Depending upon the precursors both diastereomers of stereotriads are accessible through this flexible reaction. Furthermore, from the obtained racemic scaffolds, development of an organocatalyzed kinetic resolution enabled to generate the desired enantioenriched stereotriads with excellent selectivity (typically er >95 : 5).

Potassium Base-Promoted Diastereoselective Synthesis of 1,3-Diols from Allylic Alcohols and Aldehydes through a Tandem Allylic-Isomerization/Aldol-Tishchenko Reaction.

This study reports the first base-promoted aldol-Tishchenko reactions of allylic alcohols with aldehydes initiated by allylic isomerization. The reaction enables the diastereoselective synthesis of a variety of 1,3-diols with three contiguous stereogenic centers. Unlike commonly reported systems, our method allows the use of readily available allylic alcohols as nucleophiles instead of enolizable aldehydes and ketones.

Stereoselective Installation of Five Contiguous Stereogenic Centers in a Double Aldol-Tishchenko Cascade and Evaluation of the Key Transition State through DFT Calculation.

The stereoselective formation of 5 contiguous chiral centers in a single pot reaction is demonstrated using an aldol, aldol–Tishchenko reaction of N-tert-butyl sulfinimines. One diastereoisomer (from 32 possibilities) predominates, and a series of cyclic and acyclic 3-amino-1,5-diol derivatives are synthesized in good yields (up to 80%) and excellent diastereoselectivities (up to >98:2 dr). Investigations support two reversible aldol steps, and multiple intermediates which are funnelled through a remarkably selective, irreversible, Tishchenko reduction, in a Curtin–Hammett phenomenon. DFT calculations using a disolvated (THF) model reveal the factors controlling stereoselectivity in the final irreversible Tishchenko step.

Aldol–Tishchenko Reaction of α-Oxy Ketones: Diastereoselective Synthesis of 1,2,3-Triol Derivatives

Abstractα-Oxy ketones, easily accessible by conventional routes, can be selectively deprotonated generating an enolate intermediate, which upon treatment with paraformaldehyde undergoes an aldol–Tishchenko reaction, leading to relevant 1,2,3-triol fragments in a totally diastereoselective manner. The excellent stereocontrol in the generation of a quaternary stereocenter is attributed to stereoelectronic effects in the Evans intermediate. This methodology allows overcoming some limitations of our previously reported strategy, based on the reaction of α-lithiobenzyl ethers with esters and paraformaldehyde, broadening the scope of the obtained polyols. Synthetic applications of this process include the preparation of a new dilignol model and some functionalized oxetanes.

Mechanism and Origins of Stereoselectivity of the Aldol-Tishchenko Reaction of Sulfinimines.

Density functional theory computations have elucidated the mechanism and origins of stereoselectivity in McGlacken’s aldol-Tishchenko reaction for the diastereoselective synthesis of 1,3-amino alcohols using Ellman’s t-butylsulfinimines as chiral auxiliaries. Variations of stereochemical outcome are dependent on the nature of the ketone starting materials used, and the aspects leading to these differences have been rationalized. The intramolecular hydride transfer step is the rate- and stereochemistry-determining step, and all prior steps are reversible.

Merging α-Lithiation and Aldol-Tishchenko Reaction to Construct Polyols from Benzyl Ethers.

α-Lithiobenzyl ethers, generated by selective α-lithiation, undergo an aldol-Tishchenko reaction upon treatment with carboxylic esters and paraformaldehyde. The reaction of the organolithium with the carboxylate generates an intermediate enolate that, after formaldehyde addition, affords 1,2,3-triol derivatives in a straightforward and one-pot manner. These products are obtained as single diastereoisomers bearing a quaternary stereocenter. The complete diastereocontrol of the aldol-Tishchenko process is attributed to stereoelectronic preferences in the transition state.

Shifting zwitterion reactivity

Framework Catalysis Phosphines are often ligands for transition metal catalysts, but they can catalyze reactions at unsaturated carbon atoms by forming phosphonium zwitterions. For example, triphenylphosphine forms a zwitterion with methylvinylketone that acts as a nucleophile to convert n -alkyl aldehydes to β-hydroxy enones (the Morita-Baylis-Hillman reaction). Bauer et al. show that when the reaction is conducted in metal-organic framework compounds with linkers bearing amino groups, rather than in solution, the phosphonium zwitterion can act as an electrophile. The products—1- and 3- n -alkylesters of 2-alkyl-1,3-diols—form through the Aldol-Tishchenko reaction. J. Am. Chem. Soc. 10.1021/jacs.7b10928 (2017).

Preparation of anti-1,3-Amino Alcohol Derivatives Through an Asymmetric Aldol-Tishchenko Reaction of Sulfinimines

Preparation of anti-1,3-Amino Alcohol Derivatives Through an Asymmetric Aldol-Tishchenko Reaction of Sulfinimines

Asymmetric Aldol-Tishchenko Reaction of Sulfinimines.

Methods for the preparation of 1,3-amino alcohols and their derivatives containing two stereogenic centers usually involve a two-step installation of the chiral centers. An aldol-Tishchenko reaction of chiral sulfinimines which involves the first reported reduction of a C═N in this type of reaction is described. Two and even three chiral centers can be installed in one synthetic step, affording anti-1,3-amino alcohols in good diastereo- and enantioselectivity.

ChemInform Abstract: Efficient Preparation of 1,3‐Diol Derivatives with Three Contiguous Stereocenters by an Enantioselective Direct Aldol—Tishchenko Reaction.

AbstractBenzaldehyde is found to be optimal for the process which gives 1,3‐diols with three contiguous stereocenters in good enantioselectivity.

ChemInform Abstract: Samarium‐Promoted Asymmetric Aldol—Tishchenko Reaction: Synthesis of Amino Acid‐Derived 4‐Amino‐1,3‐diols.

AbstractEnantiopure title compounds (V) are obtained after reduction of aldol—Tishchenko adducts formed with moderate diastereoselectivity from chiral amino ketones (I) and aliphatic aldehydes.

Efficient Preparation of 1,3-Diol Derivatives with Three Contiguous Stereocenters by an Enantioselective Direct Aldol–Tishchenko Reaction

1,3-Diol derivatives with three contiguous stereocenters were efficiently prepared by an enantioselective direct aldol–Tishchenko reaction catalyzed by dilithium 3,3′-diphenylbinaphtholate. The reactions of acyclic ketones as aldol donors gave 1,2- syn -1,3- anti -diol derivatives, whereas the reactions of cyclic ketones as aldol donors gave 1,2- anti -1,3- anti -diol derivatives. Sequential aldol–aldol–Tishchenko reactions gave a triol derivative with five consecutive chiral centers.

Samarium‐Promoted Asymmetric Aldol–Tishchenko Reaction: Synthesis of Amino Acid‐Derived 4‐Amino‐1,3‐diols

AbstractA samarium‐mediated novel synthesis of enantiopure 4‐amino‐1,3‐diols is carried out through a samarium‐promoted aldol–Tishchenko reaction starting from chiral α′‐amino‐α‐chloro ketones (derived from natural α‐amino acids) and aldehydes. The process takes place with moderate levels of stereoselectivity and in high yields. A mechanism is proposed to explain these results while the absolute configuration and structure of the aldol–Tishchenko adducts were established by X‐ray analysis. This method has also been utilized for the synthesis of enigmols, 1‐deoxysphingoid base analogues.

Construction of quaternary carbon centers by a base-catalyzed enantioselective aldol reaction and related reactions of trimethoxysilyl enol ethers

The aldol reactions of trimethoxysilyl enol ethers catalyzed by lithium binaphtholate were found to be powerful tools for the construction of quaternary asymmetric carbon centers. The stereoselectivities were greatly affected by the presence of water. Trimethoxysilyl enol ether derived from a cyclic ketone, such as cyclohexanone, was used as a substrate to obtain the anti-adduct preferentially under anhydrous conditions; by contrast, the syn-adduct was preferentially obtained under aqueous conditions with high stereoselectivity. The aldol-Tishchenko reaction of a trimethoxysilyl enol ether derived from acyclic ketones proceeded to give monoacyl 1,3-diol derivatives in high enantioselectivities.

Lithium Binaphtholate Catalyzed Direct Asymmetric Aldol-Tishchenko Reaction

The direct aldol-Tishchenko reaction of ketones with aldehydes catalyzed by a chiral lithium binaphtholate is described. Initially, a mixture of monobenzoyl 1,3-diols is formed. Subsequent hydrolysis generates the 1,3-diols as single diastereomers and in high yield and enantiomeric excess. The catalyst is inexpensive and can be easily prepared.

ChemInform Abstract: Direct Enantioselective Aldol—Tishchenko Reaction Catalyzed by Chiral Lithium Diphenylbinaphtholate.

AbstractChiral lithium catalyst is effective in the aldol—Tishchenko, aldol—aldol—Tishchenko and Evans—Tishchenko reactions to afford the products with high yields and enantioselectivities.

Stereocontrolled total synthesis of (±)-3β-hydroxy-9β-pimara-7,15-diene, a putative biosynthetic intermediate of momilactones

The total synthesis of (±)-3β-hydroxy-9β-pimara-7,15-diene ( 1), a putative biosynthetic intermediate of the momilactones, was accomplished stereoselectively. Our methodology for the synthesis of 1 featured the stereoselective construction of the C-13 quaternary carbon center via the aldol-Tishchenko reaction. 3β-Hydroxy-9β-pimara-7,15-diene ( 1) was identified by full-scan GC–MS analysis as an endogenous compound in elicited rice cells.

Asymmetric aldol-Tishchenko reaction catalyzed by Yb-complexes with basic amino acid-derived ligands

Simple amino acid-derived esters have been identified as promising chiral sources for the ytterbium-catalyzed aldol-Tishchenko reaction of aromatic aldehydes with aliphatic ketones. The 1,3- anti-diols with three stereogenic centers were isolated in excellent yields, complete anti-diastereocontrol and enantioselectivities of up to 50% ee.

ChemInform Abstract: A Novel Utilization of Acylsilanes in Organic Synthesis

AbstractReview: ca. 50 refs.