Synthesis of gamma-hydroxybutenolides applying crossed aldol condensation in the presence of a bulky lewis acid and their anti-tumor activity

An improved synthesis of gamma-hydroxybutenolides 1a-d was achieved via crossed aldol condensation between aldehydes 2a-d and the protected gamma-hydroxy-beta-methylbutenolides 3 or 4 using the bulky Lewis acid, aluminum tris(2,6-diphenylphenoxide) (ATPH). Using this same methodology, the gamma-hydroxybutenolides 17a-d having various heteroaromatic rings were synthesized and their anti-tumor activities were evaluated.     

Mixed Crossed Aldol Condensation between Conjugated Esters and Aldehydes Using Aluminum Tris(2,6-diphenylphenoxide)

The combined use of aluminum tris(2,6-diphenylphenoxide) (ATPH) and lithium 2,2,6,6-tetramethylpiperidide (LTMP) has proven to be effective for the mixed crossed aldol condensation between conjugated esters and various aldehydes. An example is shown in Equation (1).     

Ni(II) bis(oxazoline)-catalyzed enantioselective syn aldol reactions of N-propionylthiazolidinethiones in the presence of silyl triflates

An enantioselective aldol reaction of N-propionylthiazolidinethione and representative aldehydes is disclosed. The reaction is catalyzed by [Ni(S,S)-t-BuBox](Otf)2. Enolization is effected by 2,6-lutidine, and TMSOTf facilitates catalyst turnover. Syn diastereoselectivities range from 88:12 to 97:3, and enantioselectivities are 90% or greater. Both aromatic and enolizable aliphatic aldehydes are included within the scope of this aldol addition process.     

Anti-selective direct catalytic asymmetric aldol reaction of thiolactams

An anti-selective direct catalytic asymmetric aldol reaction of thiolactam is described. A soft Lewis acid/hard Br?nsted base cooperative catalyst comprised of mesitylcopper/(R,R)-Ph-BPE exhibited high catalytic performance to produce an anti-aldol product with high stereoselectivity. The highly chemoselective nature of the present catalysis allows for the use of enolizable aldehydes as aldol acceptors. The diverse transformations of the thiolactam moiety highlight the synthetic utility of the present anti-aldol protocol.     

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.     

Molecular recognition of alpha,beta-unsaturated carbonyl compounds using aluminum tris(2,6-diphenylphenoxide) (ATPH): structural and conformational analysis of ATPH complexes and application to the selective vinylogous aldol reaction

Various alpha,beta-unsaturated carbonyl compounds were coordinated with aluminum tris(2,6-diphenylphenoxide) (ATPH) to give the corresponding Lewis acid-base complexes in a distinctive coordination fashion (selective coordination). ATPH recognizes carbonyl substrates and subsequently orients itself as it forms a stable complex through selective coordination with the carbonyl oxygen. Selective coordination also confers a conformational preference to each carbonyl compound under the steric and electronic influence of ATPH, which enables the vinylogous aldol reaction of alpha,beta-unsaturated carbonyl compounds to give the corresponding gamma-aldol products with different regio- and stereoselectivities.     

Catalytic enantioselective thioester aldol reactions that are compatible with protic functional groups

This communication reports highly enantioselective and diastereoselective methyl malonic acid half thioester (MeMAHT) aldol reactions that are compatible with protic functional groups and enolizable aldehydes, affording syn S-phenyl thiopropionates.     

gem‐Difluoroolefination of Diaryl Ketones and Enolizable Aldehydes with Difluoromethyl 2‐Pyridyl Sulfone: New Insights into the Julia–Kocienski Reaction

The direct conversion of diaryl ketones and enolizable aliphatic aldehydes into gem‐difluoroalkenes has been a long‐standing challenge in organofluorine chemistry. Herein, we report efficient strategies to tackle this problem by using difluoromethyl 2‐pyridyl sulfone as a general gem‐difluoroolefination reagent. The gem‐difluoroolefination of diaryl ketones proceeds by acid‐promoted Smiles rearrangement of the carbinol intermediate; the gem‐difluoroolefination is otherwise difficult to achieve through a conventional Julia–Kocienski olefination protocol under basic conditions due to the retro‐aldol type decomposition of the key intermediate. Efficient gem‐difluoroolefination of aliphatic aldehydes was achieved by the use of an amide base generated in situ (from CsF and tris(trimethylsilyl)amine), which diminishes the undesired enolization of aliphatic aldehydes and provides a powerful synthetic method for chemoselective gem‐difluoroolefination of multi‐carbonyl compounds. Our results provide new insights into the mechanistic understanding of the classical Julia–Kocienski reaction.     

Bifunctional Brønsted Base Catalyzes Direct Asymmetric Aldol Reaction of α‐Keto Amides

The first enantioselective direct cross‐aldol reaction of α‐keto amides with aldehydes, mediated by a bifunctional ureidopeptide‐based Brønsted base catalyst, is described. The appropriate combination of a tertiary amine base and an aminal, and urea hydrogen‐bond donor groups in the catalyst structure promoted the exclusive generation of the α‐keto amide enolate which reacted with either non‐enolizable or enolizable aldehydes to produce highly enantioenriched polyoxygenated aldol adducts without side‐products resulting from dehydration, α‐keto amide self‐condensation, aldehyde enolization, and isotetronic acid formation.     

Aluminum Bis(trifluoromethylsulfonyl)amides: New Highly Efficient and Remarkably Versatile Catalysts for C - C Bond Formation Reactions

Superacid-derived aluminum catalysts R(2)AlNTf(2) (2 - 5 mol%) are highly efficient and versatile and are suitable promoters for the allylation and pentadienylation of aldehydes, aldol reactions, aldol cross-coupling of ketones, and Michael additions (several products are shown). Furthermore, they can be converted into chemoselective Lewis acids. Tf=trifluoromethanesulfonyl.     

Diastereoselective addition of organolithiums to 1,3-oxazolidines complexed with aluminum tris(2,6-diphenylphenoxide) (ATPH)

1,3-Oxazolidines were easily obtained by condensation of N-substituted (R)-phenylglycinol with aldehydes. Addition of organolithium reagents to 1,3-oxazolidines by complexation with the bulky Lewis acid aluminum tris(2,6-diphenylphenoxide) (ATPH) readily produced the corresponding chiral amines with good yield and high diastereoselectivity. The configuration of the new stereogenic center was shown to be opposite to that of adducts obtained for the same 1,3-oxazolidines using Grignard reagents. The best diastereoselectivity was achieved using N-isopropyl-1,3-oxazolidines. The mechanism of addition was deduced by determining the stereochemistry of the iminium-aluminum complex by NOE experiments.     

Multinuclear enantiopure titanium self‐assembly complexes—synthesis,characterization and application to organic synthesis

Hexa‐ and nonanuclear titanium complexes were obtained by self‐assembly of titanium(IV)‐tert‐butoxide and D ‐mandelic acid. Suitable single crystals of these complexes were characterized by X‐ray structure analysis. When used with these complexes, aldol adducts were isolated with a high degree of regioselectivity in direct aldol additions of aromatic and aliphatic aldehydes to functionalized unsymmetrical ketones. High syn‐diastereoselectivities were obtained in aldol additions of enolizable aldehydes with hydroxyacetone and methoxyacetone. Copyright © 2007 John Wiley & Sons, Ltd.     

Stereoselective aldol additions of titanium enolates of N-acetyl-4-isopropyl-thiazolidinethione

The addition of chlorotitanium enolates of N-acetyl isopropyl thiazolidine-2-thione to aldehydes was investigated. The stereoselectivity of the aldol products was controlled by the number of equivalents of base added. The syn aldol product was obtained preferentially when 2 equiv of Lewis acid and 1 equiv of base were employed. The anti aldol product was obtained preferentially when 1 equiv of Lewis acid and 2 equiv of base were employed for unsaturated aldehydes. Unexpected results were found with hindered aldehydes when 2 equiv of base were employed.     

Lewis base activation of Lewis acids: catalytic, enantioselective addition of silyl ketene acetals to aldehydes

The concept of Lewis base activation of Lewis acids has been reduced to practice for catalysis of the aldol reaction of silyl ketene acetals and silyl dienol ethers with aldehydes. The weakly acidic species, silicon tetrachloride (SiCl4), can be activated by binding of a strongly Lewis basic chiral phosphoramide, leading to in situ formation of a chiral Lewis acid. This species has proven to be a competent catalyst for the aldol addition of acetate-, propanoate-, and isobutyrate-derived silyl ketene acetals to conjugated and nonconjugated aldehydes. Furthermore, vinylogous aldol reactions of silyl dienol ethers are also demonstrated. The high levels of regio-, anti diastereo-, and enantioselectivity observed in these reactions can be rationalized through consideration of an open transition structure where steric interactions between the silyl cation complex and the approaching nucleophile are dominant.     

"Amphiphilic" Cleavage of gamma-Stannyl Ketones with ATPH/RLi: Application to Enone Fragmentation by the Conjugate Addition - Cleavage Sequence

The use of a combined Lewis acid/base system consisting of aluminum tris(2,6-diphenylphenoxide) (ATPH) and MeLi has allowed the electrophilically activated nucleophilic ("amphiphilic") cleavage of C(alpha)-C(beta) bonds in gamma-stannyl ketones. Through combination with the conjugate addition of alpha-stannyl carbanion to enone, this approach constitutes a novel two-step conjugate addition - cleavage sequence that leads to functionalized ketones (see reaction).     

Reaction of 2-silylmethylcyclopropyl ketones with in situ oxirane-derived aldehydes and formation of 2-hydroxymethyl tetrahydrofurans

The enolates formed from Lewis acid treatment of (2-trimethylsilylmethyl)cyclopropyl alkyl and aryl ketones reacted with aldehydes formed in situ from alkoxy-, aryl- and vinyl-substituted oxiranes to generate aldol products in good yields. Selected aldol products were conveniently transformed into highly substituted tetrahydrofurans under oxidative conditions.     

Convenient preparation of 1-amidoindenes

Lewis acid-catalyzed alpha-amidoalkylation of enolizable aldehydes with N-(alpha-benzotriazolyl-alpha-arylalkyl)amides followed by intramolecular Friedel-Crafts cyclization provides a convenient route to 2-substituted 1-amidoindenes.     

Diastereoselective aldol reactions of enolates generated from vicinally substituted trimethylsilylmethyl cyclopropyl ketones

[reaction: see text] Vicinally substituted trimethylsilylmethyl cyclopropyl ketones undergo facile desilylative ring opening with Lewis acids under mild conditions. The enolates, thus generated, undergo aldol addition with aldehydes and ketones. The diastereoselectivity of the reaction with aldehydes depends on the nature of the Lewis acid used. The resulting aldol product is easily converted into a substituted tetrahydrofuran derivative.     

Platinum(II) complex-catalyzed enantioselective aldol reaction with ketene silyl acetals in DMF at room temperature

[{(R)-binap}Pt(μ-OH)]₂2X is a weak Lewis acid, which can catalyze the enantioselective aldol reaction of aldehydes with ketene silyl acetals in DMF at room temperature. The platinum(II) complex-catalyzed the enantioselective aldol reaction of aldehydes with 1-methoxy-2-methyl-(1-trimethylsilyloxy)propene gave the corresponding aldols in high yields with enantioselectivity up to 92%. With 5 mol % loading of the complexes, the enantioselective aldol reaction of aldehydes with 1-benzyloxy-1-(trimethylsilyloxy)propene smoothly proceeded in DMF containing 10% HMPA as to predominantly give anti-propionates with enantioselectivity up to 89%, irrespective of the silyl nucleophile geometry.     

Unprecedented Encapsulation of Carbonyl Guest with Designer Lewis Acid Receptor

A reaction chamber is formed by a cage compound in which a dicarbonyl guest molecule is encapsulated by two bowl-shaped aluminum tris(2,6-diphenylphenoxide) molecules through Lewis acid–base interactions (structure of complex with 1,4-dimethylpiperazine-2,5-dione depicted). The carbonyl compound held inside the molecular capsule is effectively protected against the approach of external nucleophiles. On the other hand, the chamber is large enough to allow Diels–Alder cycloadditions to take place under mild conditions and with high selectivity.