Aldol-type Reaction Research Articles

Synthesis of Alkyl Thiochromano[2,3-c]pyrrole-9-carboxylate Derivatives Utilizing Benzo[b]thiofuran-2,3-dione, Maleimides, and Alkyl Alcohol/Water Mixtures

AbstractA set of thiochromano[2,3-c]pyrrolidine-1,3-diones, incorporating α-hydroxy esters and their acids at the C-9 position, was prepared via direct interaction involving benzo[b]thiofuran-2,3-diones, maleimides, and alkyl alcohols in water at 90 °C. Structures of the new products were deduced from HRMS and NMR spectral data and confirmed by single-crystal X-ray crystallography. An insight into a proposed pathway involving a sequential Michael conjugate addition (initiated by the sulfur atom) and an aldol-type reaction is presented.

Aldol-Type Reaction of α,α-Difluoromethyl Ketones Catalyzed by an Organosuperbase

Aldol-Type Reaction of α,α-Difluoromethyl Ketones Catalyzed by an Organosuperbase

Sc(OTf)3/BF3·OEt2-Catalyzed Annulation of 3-Formylchromones with Functionalized Alkenes: Access to Diverse 2-Hydroxybenzophenones.

The Sc(OTf)3/BF3·OEt2-catalyzed annulation of 3-formylchromones with functionalized alkenes for the direct construction of 2-hydroxybenzophenones is described. Sc(OTf)3/BF3·OEt2 acts as a synergistic catalyst, providing rapid synthetic access to diversely and highly functionalized 2-hydroxybenzophenones. This reaction has excellent regio- and chemoselectivities and is suitable for late-stage functionalization. The reaction proceeds via [3 + 3] and [4 + 2] cycloaddition processes, through carbonyl-ene, Diels-Alder, or aldol-type reactions. Furthermore, this protocol tolerates the various functional groups present in natural terpenes and steroids.

An NADPH-Dependent Ketoreductase Catalyses the Tetracyclic to Pentacyclic Skeletal Rearrangement in Chartreusin Biosynthesis.

Redox tailoring enzymes play key roles in generating structural complexity and diversity in type II polyketides. In chartreusin biosynthesis, the early 13 C-labeling experiments and bioinformatic analysis suggest the unusual aglycone is originated from a tetracyclic anthracyclic polyketide. Here, we demonstrated that the carbon skeleton rearrangement from a linear anthracyclic polyketide to an angular pentacyclic biosynthetic intermediate requires two redox enzymes. The flavin-dependent monooxygenase ChaZ catalyses a Baeyer-Villiger oxidation on resomycin C to form a seven-membered lactone. Subsequently, a ketoreductase ChaE rearranges the carbon skeleton and affords the α-pyrone containing pentacyclic intermediate in an NADPH-dependent manner via tandem reactions including the reduction of the lactone carbonyl group, Aldol-type reaction, followed by a spontaneous γ-lactone ring formation, oxidation and aromatization. Our work reveals an unprecedented function of a ketoreductase that contributes to generate structural complexity of aromatic polyketide.

Frontispiece: Reductive Aldol‐type Reactions in the Synthesis of Pharmaceuticals

The aldol-type reaction became one of the forefathers of C−C bond formation reactions. Advancements in the synthetic methodology resulted in the development of chemo-, regio-, and stereoselective processes. This Review focuses on reductive aldol-type alkylation methods implemented to the synthesis of ten approved drug substances. Furthermore, retrosynthetic analysis demonstrates that other active pharmaceutical ingredients could be obtained via reductive Aldol-type reactions. For more information, see the Review by S. Runikhina et al. on page 15327 ff.

Reductive Aldol-type Reactions in the Synthesis of Pharmaceuticals.

The efficient chemo-, regio- and stereoselective formation of saturated carbon-carbon fragment is the critical challenge of organic synthesis; therefore, developing new methods for formation of these bonds is paramount. The rising interest for reductive aldol-type reactions is conditioned by its versatile applications, allowing the efficient formation of carbon-carbon bonds. The review aims to highlight the advantages and disadvantage of reductive aldol-type reactions to total synthesis of pharmaceutical substances in order to summarize knowledge and encourage further investigation of the field.

Copper(I)-Catalyzed Asymmetric Vinylogous Aldol-Type Reaction of Allylazaarenes.

A vinylogous aldol-type reaction of allylazaarenes and aldehydes is disclosed that affords a series of chiral γ-hydroxyl-α,β-unsaturated azaarenes in moderate to excellent yields with high to excellent regio- and enantioselectivities. With (R,RP )-TANIAPHOS and (R,R)-QUINOXP* as the ligand, the carbon-carbon double bond in the products is generated in (E)-form. With (R)-DTBM-SEGPHOS as the ligand, (Z)-form carbon-carbon double bond is formed in the major product. In this vinylogous reaction, aromatic, α,β-unsaturated, and aliphatic aldehydes are competent substrates. Moreover, a variety of azaarenes, such as pyrimidine, pyridine, pyrazine, quinoline, quinoxaline, quinazoline, and benzo[d]imidazole are well-tolerated. At last, the chiral vinylogous product is demonstrated as a suitable Michael acceptor towards CuI-catalyzed nucleophilic addition with organomagnesium reagents.

Hydrosilylation and Mukaiyama aldol-type reaction of quinolines and hydrosilylation of imines catalyzed by a mesoionic carbene-stabilized borenium ion.

Aldimines and ketimines containing electron-donating and electron-withdrawing groups can be hydrosilylated with borenium catalysts at as low as 1 mol% catalyst loading at room temperature, providing the corresponding secondary amines in excellent yields. Reactions with 2-phenylquinoline gave the 1,4-hydrosilylquinoline product selectively which can be further functionalized in a one-pot synthesis to give unique γ-amino alcohol derivatives. Control experiments suggest that the borenium ion catalyzes both the hydrosilylation and subsequent addition to the aldehyde.

Stereoselective Synthesis of Multisubstituted α-fluoro-β-lactams

β-Lactams, found in β-lactam antibiotics, are the structurally distorted cyclic compounds being subjected to nucleophilic acyl substitution reaction. α-Fluorination of β -lactams is a simple and expedient approach to control the reactivity of β-lactam ring toward nucleophilic attack, which would hopefully lead to the new design of future antibiotics. From the viewpoint of obtaining multisubstituted α-fluoro-β-lactams, α-bromo-α- fluoro-β-lactams are considered as key compounds for structure functionalization, including nucleophilic substitution reaction, aldol-type reaction and metal-catalyzed crosscoupling reaction. All the reactions can be conducted smoothly to afford a variety of multisubstituted α-fluoro-β-lactams. During the course of the examination, chiral α,α-difluoro- β-lactams and α -bromo-β-fluoro-α-lactams are successfully obtained, which are considered potent precursors for making stereocontrolled multisubstituted α-fluoro-β-lactams.

Unveiling the Chemo- and Stereoselectivities of NHC-Catalyzed Reactions of an Aliphatic Ester with Aminochalcone.

The possible mechanisms and origin of selectivities in N-heterocyclic carbene (NHC)-catalyzed reactions of an aliphatic ester with aminochalcone were studied using density functional theory. Herein, a general mechanistic map involving various types of possible intermediates was discovered, and the corresponding chemoselective pathways were systematically investigated. Based on the computational results, the most energetically favorable reaction pathway mainly involved in the following processes: formation of a homoenolate intermediate via α/β-H elimination, formal Michael addition of a homoenolate intermediate to aminochalcone, intramolecular aldol-type reaction, and ring closure to form the lactam product. Furthermore, the formal Michael addition process was shown to be the stereoselectivity-determining step, generating the RR-configured product preferentially. The chemoselectivity was successfully predicted by comparing the ω + N index of reacting ability for a nucleophile (N) and electrophile (E). This work would provide a general guideline for predicting chemoselectivity in NHC-catalyzed reactions.

Total Synthesis of the Natural Herbicide MBH‐001 and Analogues

The first total synthesis of the natural herbicide MBH‐001 (1) is reported. Structurally it is a 2‐methyloxazol‐5(2H)‐one with a (1‐hydroxyethyl) substituent at the 2‐position. By relying on cyclic nitrones, a flexible route to MBH‐001 and relevant analogues was developed. Key steps include the reaction of a 2‐hydroxyimino ester with an aldehyde to form a 5‐oxo‐2,5‐dihydrooxazole 3‐oxide. In an aldol‐type reaction, the anion of these cyclic nitrones reacted with an aldehyde at the 2‐position. A final reduction of the nitrone to the corresponding imine using zinc led to the target compounds. The cyclic nitrones are also accessible by reacting an α‐keto acid with an oxime. These two versatile synthetic routes enabled us to prepare the first MBH‐001 analogues for structure activity relationship analysis of the herbicidal efficacy. Thus, furthering our aim of developing new herbicides to tackle the ever‐growing problem of weed resistance.

Structure-activity relationship studies on the inhibition of the bacterial translation of novel Odilorhabdins analogues

A structure–activity relationship (SAR) study of NOSO-95179, a nonapeptide from the Odilorhabdin class of antibacterials, was performed by systematic variations of amino acids in positions 2 and 5 of the peptide. A series of non-proteinogenic amino acids was synthesized in high enantiomeric purity from Williams’ chiral diphenyloxazinone by highly diastereoselective alkylation or by aldol-type reaction. NOSO-95179 analogues for SAR studies were prepared using solid-phase peptide synthesis. Inhibition of bacterial translation by each of the synthesized Odilorhabdin analogues was measured using an in vitro test. For the most efficient analogues, antibacterial efficacy was measured against two wild-type Enterobacteriaceae (Escherichia coli and Klebsiella pneumoniae) and against an efflux defective E. coli strain (ΔtolC) to evaluate the impact of efflux on the antibacterial activity.

Mechanism and Origin of Stereoselectivity in Chiral Phosphoric Acid-Catalyzed Aldol-Type Reactions of Azlactones with Vinyl Ethers.

The precise mechanism of the chiral phosphoric acid-catalyzed aldol-type reaction of azlactones with vinyl ethers was investigated. DFT calculations suggested that the reaction proceeds through a Conia-ene-type transition state consisting of the vinyl ether and the enol tautomer of the azlactone, in which the catalyst protonates the nitrogen atom of the azlactone to promote enol tautomerization. In addition, the phosphoryl oxygen of the catalyst interacts with the vinyl proton of the vinyl ether. The favorable transition structure features dicoordinating hydrogen bonds. However, these hydrogen bonds are not involved in the bond recombination sequence and hence the catalyst functions as a template for binding substrates. From the results of theoretical studies and experimental supports, the high enantioselectivity is induced by the steric repulsion between the azlactone substituent and the binaphthyl backbone of the catalyst under the catalyst template effect.

3,3′-Bithiophene-Based Chiral Bisphosphine Oxides as Organocatalysts in Silicon-Derived Lewis Acid Mediated Reactions

This account summarizes the development of new biheteroaromatic chiral bisphosphine oxides. 3,3′-Bithiophene-based phosphine oxides (BITIOPOs) have been successfully used as organocatalysts to promote Lewis base catalyzed, Lewis acid mediated stereoselective transformations. These highly electron-rich compounds, in combination with trichorosilyl derivatives (allyltrichlorosilane and silicon tetrachloride), generate hypervalent silicon species that act as chiral Lewis acids in highly diastereo- and enantioselective organic reactions. Several relevant examples related to these applications are discussed in detail.1 Introduction2 The BITIOPO Family3 Enantioselective Opening of Epoxides4 Enantioselective Allylation of Aldehydes5 Stereoselective Direct (Double) Aldol-Type Reaction with Ketones6 Stereoselective Direct Aldol-Type Reaction with Ester Derivatives7 Conclusions

Total Synthesis of Diocollettines A via an Acid-Promoted Oxa-Michael-Aldol-Acetalization Cascade.

A diastereo- and enantioselective total synthesis of diocollettines A with an unusual oxygen-containing tricyclic ring system has been achieved in 63% overall yield from commercially available 3-phenylpropanal via four steps. The key feature of the present synthesis is an exclusively diastereoselective cascade sequence composed of a trans-selective oxa-Michael addition of 1,3-dihydroxyacetone to a 2,3-dihydropyrylium ion intermediate, intramolecular aldol-type reaction, and intramolecular acetalization.

A Biocatalytically Active Membrane Obtained from Immobilization of 2-Deoxy-d-ribose-5-phosphate Aldolase on a Porous Support.

Aldol reactions play an important role in organic synthesis, as they belong to the class of highly beneficial C-C-linking reactions. Aldol-type reactions can be efficiently and stereoselectively catalyzed by the enzyme 2-deoxy-d-ribose-5-phosphate aldolase (DERA) to gain key intermediates for pharmaceuticals such as atorvastatin. The immobilization of DERA would open the opportunity for a continuous operation mode which gives access to an efficient, large-scale production of respective organic intermediates. In this contribution, we synthesize and utilize DERA/polymer conjugates for the generation and fixation of a DERA bearing thin film on a polymeric membrane support. The conjugation strongly increases the tolerance of the enzyme toward the industrial relevant substrate acetaldehyde while UV-cross-linkable groups along the conjugated polymer chains provide the opportunity for covalent binding to the support. First, we provide a thorough characterization of the conjugates followed by immobilization tests on representative, nonporous cycloolefinic copolymer supports. Finally, immobilization on the target supports constituted of polyacrylonitrile (PAN) membranes is performed, and the resulting enzymatically active membranes are implemented in a simple membrane module setup for the first assessment of biocatalytic performance in the continuous operation mode using the combination hexanal/acetaldehyde as the substrate.

Very Recent Advances in Vinylogous Mukaiyama Aldol Reactions and Their Applications to Synthesis.

It is a challenging objective in synthetic organic chemistry to create efficient access to biologically active compounds. In particular, one structural element which is frequently incorporated into the framework of complex natural products is a β-hydroxy ketone. In this context, the aldol reaction is the most important transformation to generate this structural element as it not only creates new C–C bonds but also establishes stereogenic centers. In recent years, a large variety of highly selective methodologies of aldol and aldol-type reactions have been put forward. In this regard, the vinylogous Mukaiyama aldol reaction (VMAR) became a pivotal transformation as it allows the synthesis of larger fragments while incorporating 1,5-relationships and generating two new stereocenters and one double bond simultaneously. This review summarizes and updates methodology-oriented and target-oriented research focused on the various aspects of the vinylogous Mukaiyama aldol (VMA) reaction. This manuscript comprehensively condenses the last four years of research, covering the period 2016–2019.

Generation of Boron Aza-Enolates by a Nickel-catalyzed Reaction of Triazoles with Pinacolborane and Their Addition to Aldehydes

An aldol-type reaction of boron aza-enolates with aldehydes is reported. N-Sulfonyl-1,2,3-triazoles react with pinacolborane in the presence of a nickel(0) catalyst to generate boron aza-enolates with E geometry. The boron aza-enolates undergo an aldol-type reaction with aldehydes to give β-boroxy imines with syn configuration. The subsequent one-pot reduction with DIBALH gives 1,3-amino alcohols.

Construction of Chiral β-Trifluoromethyl Alcohols Enabled by Catalytic Enantioselective Aldol-Type Reaction of CF3CHN2.

A zinc-/quinine-mediated enantioselective Aldol-type reaction of trifluorodiazoethane (CF3CHN2) with various aldehydes is described. This study demonstrated the feasibility of utilizing CF3CHN2 as an effective hard nucleophile in catalytic asymmetric transformations. Furthermore, the synthetic utility of this protocol is exemplified by the construction of a diverse set of chiral β-trifluoromethylated alcohols, including a valuable HDAC inhibitor precursor.

Asymmetric Vinylogous Aldol-type Reactions of Aldehydes with Allyl Phosphonate and Sulfone

SummaryTwo catalytic asymmetric vinylogous aldol-type reactions of aldehydes with allyl phosphonate and allyl sulfone have been uncovered in good to high yields for the first time. The bulky ligand—(R)-DTBM-SEGPHOS—was found to be the key to perfectly control both regio- and enantioselectivities. Transformations of the vinylogous products (including Horner-Wadsworth-Emmons and Julia olefinations) were successfully realized by virtue of the phosphonate and sulfone moieties. Moreover, the present methodology was successfully applied in the asymmetric synthesis of natural products.