1,4-Asymmetric induction in the titanium-mediated aldol reactions of α-benzyloxy methyl ketones

Good levels of 1,4-anti asymmetric induction are obtained in the TiCl₃(i-PrO)-mediated aldol reaction of α-benzyloxy methyl ketones with achiral aldehydes. Such methodology represents a new approach to the substrate-controlled acetate aldol reaction, which can be useful to design more efficient synthesis.     

Superior substrate control on diastereoselection in boric Lewis acid-promoted aldol reactions. Asymmetric synthesis of a 3,4-syn homologous series of ethyl 3,5-dihydroxy-2,4-dimethyl-5-phenylpentanoates

The BF₃·OEt₂-promoted aldol reaction of chiral syn- and anti-α-methyl-β-siloxy aldehydes with a silyl ketene acetal resulted in essentially complete syn Felkin selection. Even in the asymmetric aldol reaction using chiral oxazaborolidinones, the substrate control with respect to diastereoselection was found to overcome the promoter (catalyst) control which would normally occur depending on the stereocenter of the chiral boranes.     

syn-Diastereoselective glycolate aldol addition reactions of an N(3)-(p-methoxyphenoxy)acetyloxazolidine-2-thione

An N₃-(p-methoxyphenoxy)acetyloxazolidine-2-thione has been synthesized and employed in glycolate asymmetric aldol addition reactions with aromatic and aliphatic aldehydes. It was determined that the titanium tetrachloride medicated aldol reaction afforded diastereoselectivities that ranged from 75:25 to 94:6 when the reaction was conducted at ?78 °C. The absolute stereochemistry of the aldol adducts was determined by ¹H NMR spectroscopy and X-ray crystallography. The ¹H NMR spectra of the aldol adducts contained a signal (the α-proton of the glycolate position of the aldol side chain) that was highly deshielded due to conformational restriction about the N(3)-(p-methoxyphenoxy)acetyl side chain and the oxazolidine-2-thione auxiliary.     

Direct catalytic asymmetric aldol reaction of thioamides: a concise asymmetric synthesis of (R)-fluoxetine

A direct catalytic asymmetric aldol reaction of aromatic aldehydes and thioamides is described. A soft Lewis acid/hard Brønsted base cooperative catalyst comprising (R,R)-Ph-BPE/[Cu(CH₃CN)₄]PF₆/Li(OC₆H₄-p-OMe) promoted the title reaction efficiently, triggered by in situ generation of the active thioamide enolate through a soft–soft interaction of Cu(I) and the thioamide. The aldol product was transformed into (R)-fluoxetine, an antidepressant agent.     

1,4-syn-Asymmetric induction in the titanium-mediated aldol reactions of chiral methyl α-silyloxy ketones

Good levels of 1,4-syn asymmetric induction are obtained in the TiCl₄-mediated aldol reaction of methyl α-silyloxy ketones with achiral aldehydes. Such methodology represents a new approach to the substrate-controlled acetate aldol reaction, which can be useful to design more efficient syntheses of natural products.     

(2S,5S)-Pyrrolidine-2,5-dicarboxylic acid,an efficient chiral organocatalyst for direct aldol reactions

Enantioselective aldol reaction of ketones with aldehydes catalyzed by (2S,5S)-pyrrolidine-2,5-dicarboxylic acid in the presence of an equal molar amount of Et₃N was described. By using the new chiral organocatalyst, the direct aldol condensation products were obtained in reasonable yields and up to 90% ee.     

First total synthesis of salinipyrone A using highly stereoselective vinylogous Mukaiyama aldol reaction

A synthetic approach for the total synthesis of salinipyrone A has been developed. Key steps involve the TiCl₄-mediated vinylogous Mukaiyama aldol reaction (VMAR) of chiral ketene silyl N,O-acetal with propionaldyhyde, an aldol condensation, Witting olefination, and a cyclization. The synthesis proceeds in eight steps.     

A simple and scalable procedure for TiCl4-promoted aldol reaction

TiCl₄-promoted aldol reaction was carried out by adding TiCl₄ to a solution of the aldol reaction substrates and (i-Pr)₂NEt (DIPEA) in CH₂Cl₂. Compared to the conventional order of addition (sequentially adding TiCl₄, DIPEA, and piperonal to the lactone 2 in CH₂Cl₂), this simplified procedure, gave a much cleaner reaction that could be executed on large scale and without cryogenic cooling. However this procedure provided no stereoselectivity.     

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.     

(μ-Hydroxo)-platinum complex-catalyzed enantioselective aldol reaction of aldehydes with 1-methoxy-2-methyl-1-(trimethylsilyloxy)propene in DMF

[((R)-BINAP)Pt(μ-OH)]₂·2OTf catalyzed the enantioselective aldol reaction of aldehydes with 1-methoxy-2-methyl-(1-trimethylsilyloxy)propene at room temperature in dry DMF in high yields with enantioselectivity up to 92%. This is a versatile example of the catalytic enantioselective aldol reaction using a silyl ketene acetal promoted by (μ-hydroxo)-platinum complexes under mild conditions.     

New chiral bis(diphenylphospholane) ligands: design, synthesis, and application to catalytic enantioselective aldol reaction to ketones

New chiral bidentate diphenylphospholanes were designed targeting a catalytic enantioselective aldol reaction to ketones. Ligands 5l and 5m having cis-2-butenyl and cyclopropyl groups at the linker part, respectively, were identified as effective chiral ligands for a CuF-catalyzed enantioselective aldol reaction to ketones. Catalysts prepared from CuF·3PPh₃·2EtOH and these ligands produced ketone aldol products with up to 66% ee, which is promising particularly for this extremely difficult and important catalytic enantioselective carbon-carbon bond forming reaction. The enantioselectivity was strongly dependent on the linker structure. Construction of a deep chiral pocket around the copper metal with stable bidentate chelation is the key to meaningful enantioinduction.     

Chiral 1,2-diaminocyclohexane as organocatalyst for enantioselective aldol reaction

A simple and commercially available chiral 1,2-diaminocyclohexane as catalyst, hexanedioic acid as co-catalyst could efficiently catalyze the asymmetric aldol reaction in MeOH-H₂O. Cyclic ketones as aldol substrates gave the anti-β-hydroxyketone products with moderate to good yields, diastereoselectivity and enantioselectivity (up to 78% yield, >20:1 anti/syn, 94% ee). Hydroxyacetone as aldol substrate afforded the syn-α, β-dihydroxyketones as major products in up to 85% yield with good enantioselectivity (up to >20:1 syn/anti, 93% ee).     

BINAM-prolinamides as recoverable catalysts in the direct aldol condensation

New BINAM-prolinamides were developed and tested as organocatalysts in the direct aldol condensation between aldehydes and several aliphatic ketones. C₂-symmetrical (Sa)-BINAM-l-prolinamide gives the best enantioselectivities for this transformation, being recovered and reused after the reaction by simple extractive techniques. The reaction was performed in DMF/H₂O at 0 °C to give the aldol products in up to 95% ee for acetone. For 2-butanone, the corresponding iso-regioisomers were regioselectively obtained in up to 96% ee working in DMF at rt. In the case of cyclohexanone, dr up to 10:1 in favour of the anti products, which were obtained in 90–93% ee, was achieved.     

Novel C 2-symmetric bis-oxazoline ligands

Two novel C ₂-symmetric bis-oxazoline ligands were synthesized and their complexes with Cu(OAc)₂ were studied as catalysts in the enantioselective Henry reaction of 4-nitrobenz-aldehyde with nitromethane giving high yield of nitro aldol with ee up to 40%.     

Addition of lithium ethyl fluoroacetate to cis and trans α,β-epoxyaldehydes. Access to C2 fluorinated butyrolactones

The aldolisation reaction of lithium ethyl fluoroacetate with cis and trans α,β-epoxyaldehydes in their racemic forms proceeds with good C₃-OH diastereoselectivity and much less at the C₂-F carbon atom. A two-step reaction on the major aldol compounds (iodination, lactonisation) led to racemic functionalised C₂ fluorinated lactones, possessing a C₂/C₃cis relationship between the fluorine and hydroxyl groups.     

Rate enhancement by water in a TiCl4-mediated stereoselective vinylogous Mukaiyama aldol reaction

A remarkable enhancement in the rate of a TiCl₄-mediated stereoselective vinylogous Mukaiyama aldol reaction (VMAR) using vinylketene silyl N,O-acetal 1 was observed in the presence of water.     

The convergent synthesis of novel cytotoxic certonardosterol D2 from diosgenin

Certonardosterol D₂, a polyhydroxysterol isolated from starfish Certonardoa semiregularis with exceptionally potent antitumor activity, was stereoselectively synthesized from natural rich diosgenin via the protocol of Julia olefination and Evans aldol reaction.     

A kinetically controlled direct aldol addition of α-chloro thioesters via soft enolization

Herein we report that simple α-chloro thioesters undergo soft enolization and direct aldol addition to aldehydes in the presence of MgBr₂·OEt₂ and i-Pr₂NEt. At ?78 °C the reaction proceeds in a kinetically controlled manner giving good diastereoselectivity. Significantly, the transformation is applicable to both enolizable and nonenolizable aldehydes. Moreover, excellent stereoselectivity results when a chiral nonracemic α-hydroxy aldehyde derivative is used. To our knowledge, this is the first report of a kinetically controlled soft enolization-based aldol addition.     

A ceric ammonium nitrate based oxidative cleavage pathway for the asymmetric aldol adducts of oxadiazinones derived from (1R,2S)-N-p-methoxybenzylnorephedrine

An N₄-p-methoxybenzyloxadiazinone has been prepared from (1R,2S)-norephedrine through a process of reductive amination, N-nitrosation, reduction, and cyclization. The oxadiazinone was acylated and employed in the asymmetric aldol addition reaction with aromatic and aliphatic aldehydes to yield aldol adducts in isolated yields ranging from 54% to 90%. Selected aldol adducts were treated with ceric ammonium nitrate in aqueous acetonitrile to afford the desired β-hydroxycarboxylic acids through a tandem process of oxidative cleavage of the N₄-p-methoxybenzyl group and acidic hydrolysis of the N₃-acyl side chain. The β-hydroxycarboxylic acids were recovered in high diastereomeric purity as determined by 500 MHz ¹H NMR spectroscopy and the absolute configuration was confirmed by polarimetry. The chiral auxiliary unit, the 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one (oxadiazinone), was converted into its corresponding 3,6-dihydro-2H-1,3,4-oxadiazin-2-one (oxadiazinone) through an oxidative pathway promoted by the ceric ammonium nitrate.     

Convergent synthesis of panclicin-D via intramolecular SN2 displacement approach

A convergent enantioselective synthesis of panclicin-D has been reported from simple octanal using syn aldol reaction via intramolecular S_N2 displacement reaction for the first time towards the construction of anti-β-lactones in panclicin-D. The key steps involved are C-allylation, asymmetric aldolization under Crimmins condition, intramolecular S_N2 displacement, and Mitsunobu esterification reaction.