Amination of quinolones with morpholine derivatives

The aromatic nucleophilic substitution reaction of 7-chloroquinolone carboxylic acid and its ethyl ester with cyclic amines under microwave irradiation conditions was investigated. ¹H NMR spectroscopy was used to monitor the progress of the substitution reaction. The reaction proceeded in high yield with simple cyclic amines and was less efficient for sterically more demanding bimorpholine derivatives. A Pd-catalyzed amination of quinolone carboxylic acid ethyl ester with bimorpholine derivatives provided new C-7 bimorpholino-substituted quinolone derivatives.     

Enantioselective Aldol Reactions Catalyzed by Chiral Phosphine Oxides

The development of enantioselective aldol reactions catalyzed by chiral phosphine oxides is described. The aldol reactions presented herein do not require the prior preparation of the masked enol ethers from carbonyl compounds as aldol donors. The reactions proceed through a trichlorosilyl enol ether intermediate, formed in situ from carbonyl compounds, which then acts as the aldol donor. Phosphine oxides activate the trichlorosilyl enol ethers to afford the aldol adducts with high stereoselectivities. This procedure was used to realize a directed cross‐aldol reaction between ketones and two types of double aldol reactions (a reaction at one/two α position(s) of a carbonyl group) with high diastereo‐ and enantioselectivities.     

Carbene‐Catalyzed Enantioselective Aldol Reaction: Post‐Aldol Stereochemistry Control and Formation of Quaternary Stereogenic Centers

The dominated approaches for asymmetric aldol reactions have primarily focused on the aldol carbon–carbon bond‐forming events. Here we postulate and develop a new catalytic strategy that seeks to modulate the reaction thermodynamics and control the product enantioselectivities via post‐aldol processes. Specifically, an NHC catalyst is used to activate a masked enolate substrate (vinyl carbonate) to promote the aldol reaction in a non‐enantioselective manner. This reversible aldol event is subsequently followed by an enantioselective acylative kinetic resolution that is mediated by the same (chiral) NHC catalyst without introducing any additional substance. This post‐aldol process takes care of the enantioselectivity issues and drives the otherwise reversible aldol reaction toward a complete conversion. The acylated aldol products bearing quaternary/tetrasubstituted carbon stereogenic centers are formed in good yields and high optical purities.     

Synthesis of (2S,2′S)-bimorpholine N,N′-quaternary salts as chiral phase transfer catalysts

(2S,2′S)-Bimorpholine was synthesized starting from (R,R)-tartaric acid ester acetal in six steps in 50% of the total yield. Key steps include: cyanide catalyzed amidation and one-step cyclization with p-toluenesulfonyl imidazole. Derivatization of N,N′-dibenzyl bimorpholine afforded quaternary bimorpholinium salts, which were used as chiral phase transfer alkylation catalysts.     

Amino Acids Catalyzed Direct Aldol Reactions in Aqueous Micelles

Since the discovery of its roles as a good small-organic-molecule catalyst in intramolecular aldol reactions, pro line has drawn considerable attention in synthetic chemistry due to its similarity to the type-Ⅰ aldolases. Recently,List and others have reported some new direct asymmetric intermolecular reactions catalyzed by proline, including aldol, Mannich, Michael, and other analogous reactions. Except for two recent examples, [1,2] proline catalyzed aldol reactions in aqueous micelles have not been reported, nor have other amino acids as organocatalysts in directly catalyzing aldol reaction been reported. Herein we wish to present our recent results regarding environmentally be nign direct aldol reactions catalyzed by amino acids including proline, histidine and arginine in aqueous media.     

Titanium(IV) alkoxide ligand exchange with alpha-hydroxy acids: the enantioselective aldol addition

Ligand exchange of titanium(IV) alkoxides with alpha-hydroxy acids presents an unexpected and novel approach to enantioselective aldol additions of aldehydes and ketones. The aldol products were isolated in a high degree of syn-diastereoselectivity. High enantioselectivities were observed by using simple optically pure alpha-hydroxy acids in this novel aldol addition.     

Catalytic asymmetric aldol reactions in aqueous media

Nature has perfected the stereospecific aldol reaction by using aldolase enzymes. While virtually all the biochemical aldol reactions use unmodified donor and acceptor carbonyls and take place under catalytic control in an aqueous environment, the chemical domain of the aldol addition has mostly relied on prior transformation of carbonyl substrates, and the whole process traditionally is carried out in anhydrous solvents. The area of aqua-asymmetric aldol reactions has received much attention recently in light of the perception both of its green chemistry advantages and its analogy to eon-perfected enzyme catalysis. Both chiral metal complexes and small chiral organic molecules have been recently reported to catalyze aldol reactions with relatively high chemical and stereochemical efficiency. This tutorial review describes recent developments in this area.     

Sequential hydroformylation/aldol reactions: versatile and controllable access to functionalised carbocycles from unsaturated carbonyl compounds

Three different modes of hydroformylation/aldol reaction sequences involving either acid-catalysed aldol reactions, Mukaiyama aldol addition of pre-formed enolsilanes or aldol addition of in situ generated boron enolates can be applied to unsaturated ketones and ketoesters to afford the corresponding carbocyclic aldol adducts in good yields proceeding through the intermediate activated ketoaldehydes. In selected cases, complimentary, synthetically useful diastereoselectivities were observed in the products.     

Isoleucine-catalyzed direct asymmetric aldol addition of enolizable aldehydes

Isoleucine-catalyzed direct enantioselective aldol additions between enolizable aldehydes are reported. Intermediate acetal structures dictate the configurative outcome and were supported by a hydrogen bond. This direct isoleucine-catalyzed aldol addition represents a welcome complement to both proline- and histidine-catalyzed aldol additions of enolizable aldehydes.     

One-pot, catalytic, asymmetric synthesis of polypropionates

[reaction: see text] The opening of methylketene dimer, followed by aldol reactions of the resulting enolate, provides a convenient access to syn,syn-dipropionate aldol adducts of a variety of aldehydes. These aldol adducts are useful precursors in the synthesis of complex polypropionates.     

Modern aldol methods for the total synthesis of polyketides

The aldol reaction is one of the most important methods for the stereoselective construction of polyketide natural products, not only for nature but also for synthetic chemistry. The tremendous development in the field of aldol additions during the last 30 years has led to more and more total syntheses of complicated natural products. This Review illustrates by means of selected syntheses of natural products the new variants of the aldol addition. This includes aldol additions with various metal enolates, as well as metal-complex-catalyzed, organocatalytic, and biocatalytic methods.     

NMR investigations on the proline-catalyzed aldehyde self-condensation: Mannich mechanism, dienamine detection, and erosion of the aldol addition selectivity

The proline-catalyzed self-condensation of aliphatic aldehydes in DMSO with varying amounts of catalyst was studied by in situ NMR spectroscopy. The reaction profiles and intermediates observed as well as deuteration studies reveal that the proline-catalyzed aldol addition and condensation are competing, but not consecutive, reaction pathways. In addition, the rate-determining step of the condensation is suggested to be the C-C bond formation. Our findings indicate the involvement of two catalyst molecules in the C-C bond formation of the aldol condensation, presumably by the activation of both the aldol acceptor and donor in a Mannich-type pathway. This mechanism is shown to be operative also in the oligomerization of acetaldehyde with high proline amounts, for which the first in situ detection of a proline-derived dienamine was accomplished. In addition, the diastereoselectivity of the aldol addition is evidenced to be time-dependent since it is undermined by the retro-aldolization and the competing irreversible aldol condensation; here NMR reaction profiles can be used as a tool for reaction optimization.     

Three-component glycolate Michael reactions of enolates, silyl glyoxylates, and α,β-enones

Silyl glyoxylates react with enolates and enones to afford either glycolate aldol or Michael adducts. Product identity is controlled by the countercation associated with the enolate. Reformatsky nucleophiles in the presence of additional Zn(OTf)(2) result in aldol coupling (A), while lithium enolates provide the Michael coupling (B). Deprotonation of the aldol product A with LDA induces equilibration to form the minor diastereomer of Michael product B. This observation suggests that formation of the major diastereomer of Michael product B does not occur via an aldol/retro-aldol/Michael sequence.     

The Mukaiyama Aldol Reaction: 40 Years of Continuous Development

A directed cross‐aldol reaction of silyl enol ethers with carbonyl compounds, such as aldehydes and ketones, promoted by a Lewis acid, a reaction which is now widely known as the Mukaiyama aldol reaction. It was first reported in 1973, and this year marks the 40th anniversary. The directed cross‐aldol reactions mediated by boron enolates and tin(II) enolates also emerged from the Mukaiyama laboratory. These directed cross‐aldol reactions have become invaluable tools for the construction of stereochemically complex molecules from two carbonyl compounds. This Minireview provides a succinct historical overview of their discoveries and the early stages of their development.     

Asymmetric aldol additions: use of titanium tetrachloride and (-)-sparteine for the soft enolization of N-acyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones.

Asymmetric aldol additions using chlorotitanium enolates of N-acyloxazolidinone, oxazolidinethione, and thiazolidinethione propionates proceed with high diastereoselectivity for the Evans or non-Evans syn product depending on the nature and amount of the base used. With 1 equiv of titanium tetrachloride and 2 equiv of (-)-sparteine as the base or 1 equiv of (-)-sparteine and 1 equiv of N-methyl-2-pyrrolidinone, selectivities of 97:3 to > 99:1 were obtained for the Evans syn aldol products using N-propionyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. The non-Evans syn aldol adducts are available with the oxazolidinethione and thiazolidinethiones by altering the Lewis acid/amine base ratios. The change in facial selectivity in the aldol additions is proposed to be a result of switching of mechanistic pathways between chelated and nonchelated transition states. The auxiliaries can be reductively removed or cleaved by nucleophilic acyl substitution. Iterative aldol sequences with high diastereoselectivity can also be accomplished.     

Organocatalytic asymmetric aldol reaction in the presence of water

Water was found to be a suitable solvent for the l-prolinethioamide catalysed aldol reaction of various cyclic ketones with aromatic aldehydes. Treatment of 4-nitrobenzaldehyde with as little as 1.2 equiv. of cyclohexanone in the presence of the protonated catalyst 1-TFA, afforded aldol products in high yields (up to 97%) with high diastereo- and enantioselectivity (up to >5 : 95 dr and 98% ee). The use of a high excess of ketone was avoided by conducting the aldol addition in the presence of water. Furthermore, different 'salting-out' and 'salting-in' salts were investigated and it was proven that the rate of acceleration and the stereochemical outcome of the reaction are affected by hydrophobic aggregation. Scope and limitation studies revealed that electron deficient aldehydes afforded aldol products with high stereoselectivity in the presence of 1-Cl(2)CHCO(2)H. It was shown that various cyclic ketones, under the conditions found, gave aldol products with fair yields, even if they are used in substoichiometric amounts (1.2 to 2.0 equiv.).     

Aldol reactions of 2-thioxotetrahydropyrimidin-4(1H)-ones: stereoregulations from endo- and exocyclic chiral centres

The steric regulations imparted by the substituent at N1 in lithium mediated asymmetric aldol reactions of conformationally restricted 3-aryl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones governed the formation of anti aldol adducts, by a kinetic reaction pathway. The preferential formation of the anti aldol diastereomers was also assisted by the steric effects of the electrophile through diastereofacial selection while the electronic effects of the aryl group at N3 remained subtle. Incorporation of an endocyclic methyl group at C6 witnessed the diastereoselective formation of an anti aldol adduct by regulation of π-facial selectivity. The absolute configurations of the aldol adducts were determined by computational calculations and NMR experiments, and confirmed by single crystal X-ray analysis.     

Asymmetric aldol reaction via memory of chirality

Asymmetric aldol reactions of α-amino acid derivatives via memory of chirality were developed. Chiral oxazolidones with contiguous tetra- and trisubstituted chiral centers were obtained in 78-94% ee by the asymmetric aldol reaction followed by intramolecular acylation.     

Diastereo- and enantioselective hydrogenative aldol coupling of vinyl ketones: design of effective monodentate TADDOL-like phosphonite ligands

We report the first enantioselective reductive aldol couplings of vinyl ketones, which were achieved through the design of a novel monodentate TADDOL-like phosphonite ligand. Specifically, hydrogenation of commercially available methyl vinyl ketone (MVK) or ethyl vinyl ketone (EVK) in the presence of aldehydes 1a-7a using cationic rhodium catalysts modified by chiral TADDOL-like phosphonite ligands AP-I and AP-IV produces aldol adducts 1b-7b and 1c-7c with excellent control of relative and absolute stereochemistry. The absolute stereochemical assignments of the aldol adducts are made in analogy to that determined for the 5-bromophthalimido derivative of aldol adduct 1b and the 2-bromo-5-nitrobenzoate of 3b, which were established by single-crystal X-ray diffraction analysis using the anomalous dispersion method.     

Enantioselective aldol reaction of chiral acyl thiazolidine thione derived boron enolates

The compatability of an acyl thiazolidine thione as a chiral auxillary in boron enolate chemistry has been demonstrated by an enantioselective aldol condensation. The aldol products provide direct access to chiral β-lactams.