A simplified catalytic system for direct catalytic asymmetric aldol reaction of thioamides; application to an enantioselective synthesis of atorvastatin

A new catalytic system was developed for the direct catalytic asymmetric aldol reaction of thioamides. The new lithium-free Cu catalyst (second-generation catalyst) exhibited enhanced catalytic efficiency over the previously developed catalyst comprising [Cu(CH₃CN)₄]PF₆/Ph-BPE/LiOAr (first-generation catalyst), which required a tedious catalyst preparation process. In the reaction with the second-generation catalyst, the intermediate Cu-aldolate functioned as a Brønsted base to generate thioamide enolate, efficiently driving the catalytic cycle. The present aldol methodology culminated in a concise asymmetric synthesis of atorvastatin (Lipitor^®: atorvastatin calcium), a widely prescribed HMG-CoA reductase inhibitor for lowering low-density lipoprotein cholesterol.     

Direct catalytic enantio- and diastereoselective aldol reaction of thioamides

A direct catalytic asymmetric aldol reaction of thioamides using a soft Lewis acid/hard Br?nsted base cooperative catalyst comprising (R,R)-Ph-BPE/[Cu(CH(3)CN)(4)]PF(6)/LiOAr is described. Exclusive enolate generation from thioacetamides through a soft-soft interaction with the soft Lewis acid allowed for a direct aldol reaction to α-nonbranched aliphatic aldehydes, which are usually susceptible to self-condensation under conventional basic conditions. A hard Lewis basic phosphine oxide has emerged as an effective additive to constitute a highly active ternary soft Lewis acid/hard Br?nsted base/hard Lewis base cooperative catalyst, enabling a direct enantio- and diastereoselective aldol reaction of thiopropionamides. Strict control of the amount of the hard Lewis base was essential to drive the catalytic cycle efficiently with a minimized retro-aldol pathway, affording syn-aldol products with high stereoselectivity. Divergent transformation of the thioamide functionality is an obvious merit of the present aldol methodology, allowing for a facile transformation of the aldol product into the corresponding aldehyde, ketone, amide, amine, and ketoester. An aldehyde derived from the direct aldol reaction was subjected to a second direct aldol reaction, which proceeded in a catalyst-controlled manner to provide 1,3-diols with high stereoselectivity.     

Solvent-free asymmetric aldol reaction organocatalyzed by (S)-proline-containing thiodipeptides under ball-milling conditions

An efficient, solvent-free ball-milling protocol for the asymmetric aldol reaction between cyclohexanone and cyclopentanone with various aromatic aldehydes using a novel series of (S)-proline-containing dipeptides and thiodipeptides 1a–f as organocatalysts is reported. In general, (S)-proline-containing thiodipeptides proved to be better organocatalysts relative to their analogous amides. In particular, thiodipeptide (S,S)-1d catalyzed the stereoselective formation of the expected aldol products with excellent diastereo- and enantioselectivity (up to 98:2 anti/syn dr and up to 96% ee). This observation may be ascribed to the increased N–H acidity of the thioamide segment that leads to stronger H-bonding interaction with the aldehyde carbonyl at the transition state and thus higher stereoinduction. Furthermore, thiodipeptide 1f proved to be an efficient organocatalyst for the aldol reaction of acetone with isatin and isatin derivatives (ee 56–86%).     

Enantioselective synthesis of bridgehead hydroxyl bicyclo[2.2.2]octane derivatives via asymmetric allylindation

A recent new strategy for the transformation of mono-dioxolane protected 1,3-cyclohexadione into bridgehead hydroxyl bicyclo[2.2.2]octane derivatives, based on allylindation followed by ozonolysis and intramolecular aldol addition, was modified to include asymmetric allylindation. This enabled the first enantioselective synthesis of (1R,4R,6S)-endo-4-(tert-butyl-dimethyl-silyloxy)-6-hydroxy-bicyclo[2.2.2]octan-2-one and (1S,4S,6R)-endo-4-(tert-butyl-dimethyl-silyloxy)-6-hydroxy-bicyclo[2.2.2]octan-2-one in high enantiomeric excess. Issues concerning the non-reproducibility of the asymmetric allylindation were also addressed.     

Synthesis of novel chiral Schiff-base ligands and their application in asymmetric nitro aldol (Henry) reaction

Chiral Schiff-bases prepared from chiral amino alcohols catalyze the enantioselective Henry (nitro aldol) reaction between nitromethane and p-nitrobenzaldehyde in the presence of Cu(OTf)₂ and Zn(OTf)₂. Zn(OTf)₂ promoted the reaction yield, while Cu(OTf)₂ promoted the enantiomeric excess. The highest enantioselectivities were observed with ligand 3 (44% ee) and ligand 5 (47% ee).     

Enantioselective synthesis of a key intermediate aldehyde toward the polyene macrolide filipin III,based on a chiral oxazaborolidinone-promoted asymmetric aldol reaction

A versatile preparation of an enantiopure aldehyde useful for the asymmetric total synthesis of filipin III was developed using a chiral oxazaborolidinone-promoted asymmetric aldol reaction with a dithiolane silyl nucleophile. The sign and magnitude of the specific rotation of the aldehyde, (4R,5R)-2,2-dimethyl-5-formyl-4-pentyl-1,3-dioxane, were reconfirmed.     

Titanium mediated asymmetric aldol reaction with α-fluoropropionimide enolates

Aldol reaction utilising Evans N-(α-fluoropropyl)-2-oxazolidinones with TiCl₄ have been explored. Reactions of N-(α-fluoropropyl)-2-oxazolidinones with aliphatic aldehydes generated α-fluoro-β-hydroxy-aldol products with high diastereoselectivities. When (αR)- and (αS)-N-(α-fluoropropyl)-2-(4S)-oxazolidinones were explored as substrates they gave rise to identical aldol diastereoisomer products. Examination of the enolates formed in each case by ¹⁹F NMR, after treatment with TiCl₄, indicated that both preparations gave the same predominant enolate. This was assumed to be the E-enolate. The α-fluoro-β-hydroxy-aldol products were removed from the auxiliary either by alcoholysis or reduction and converted to the corresponding α,β-difluoro products by treatment with Deoxofluor™.     

Concise enantioselective synthesis of duloxetine via direct catalytic asymmetric aldol reaction of thioamide

Direct catalytic asymmetric aldol reaction of thioamide offers a new entry to the concise enantioselective synthesis of duloxetine. The direct aldol protocol was scalable (>20 g) to afford the aldol product in 92% ee after LiAlH(4) reduction, and 84% of the chiral ligand was recovered after recrystallization. The following four steps of transformation delivered duloxetine.     

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.     

Ligand design for dual enantioselective control in Cu-catalyzed asymmetric conjugate addition of R2Zn to cyclic enone

A new chiral N-heterocyclic carbene (NHC) ligand derived from a natural α-aminoester has been designed and synthesized. The coupling of N-methylbenzimidazole with an α-chloroacetamide derivative, which was prepared from chloroacetyl chloride and (S)-serine methyl ester, gave the corresponding ester/amide-functionalized azolium compound 20. The reaction of 2-cyclohexen-1-one (17) with Et₂Zn in the presence of catalytic amounts of Cu(OTf)₂ and 20 produced (R)-3-ethylcyclohexanone (18) as a major product. In contrast, the enantioselective conjugate addition (ECA) reaction catalyzed by Cu(OTf)₂ under the influence of a hydroxy-amide-functionalized azolium compound 15, which was derived from (S)-tert-leucinol, produced (S)-18 in preference to (R)-18. A series of azolium salts were synthesized from (S)-serine esters, and the reaction conditions for the ECA reaction were optimized to produce (R)-18 with 69% ee. The best results were obtained in the case of the reaction of 4,4-dimethyl-2-cyclohexen-1-one (34) with Et₂Zn catalyzed by Cu(OTf)₂ in combination with azolium compounds. When the reaction of 34 with Et₂Zn was carried out in the presence of catalytic amounts of Cu(OTf)₂ and 20, (S)-3-ethyl-4,4-dimethylcyclohexanone (35) was obtained with 97% ee, whereas the ECA reaction under the influence of hydroxy-amide-functionalized azolium 15 afforded (R)-35 with >99% ee. In this manner, the reversal of enantioselectivity was achieved by controlling the structure of chiral ligands.     

Efficient total synthesis of manzacidin B

The highly diastereoselective synthesis of the marine natural product, (?)-manzacidin B, is described. A novel copper-catalyzed aldol reaction of the α-methylserine-derived aldehyde with an isocyanoacetate possessing (1R)-camphorsultam as the chiral auxiliary proceeded in a highly diastereoselective manner to give the (4R,5R,6R)-adduct, which was converted into manzacidin B in a few steps.     

Tetrahydrobenzo[5]helicenediol derivatives as additives for efficient proline-catalyzed asymmetric List-Lerner-Barbas aldol reactions of bulky aldehyde substrates

Proline-catalyzed asymmetric List-Lerner-Barbas aldol reactions of bulky aldehyde substrates could be efficiently carried out with dibromo-substituted helical diols P-4a/M-4a as additives. In the case of 9-anthraldehyde, the aldol product was obtained in 83% yield and 99% ee. An edge-to-face π-π stacking between the anthracenyl group in TS(R) and the phenyl group of the additive might contribute to the increase of enantioselectivity.     

Enantioselective construction of quaternary asymmetric carbon centers using an aldol reaction of trimethoxysilyl enol ethers catalyzed by lithium binaphtholate

An aldol reaction of 2,2-disubstituted trimethoxysilyl enol ethers with aldehydes catalyzed by a dilithium salt of (R)-3,3′-dichlorobinaphthol afforded the corresponding aldol adducts with quaternary carbon centers in high anti-selectivities (syn:anti = ∼1:50) and enantioselectivities (∼90% ee).     

Synthesis of enantiomerically pure (3R,4R,5R)-4-hydroxy isoleucine lactone

A short four-step synthesis of (3R,4R,5R)-4-hydroxyisoleucine lactone with total control of stereochemistry is reported, the key intermediate being the didehydroamino acid derivative arising from an aldol dehydration reaction between a glycine anion equivalent and butan-2,3-dione.     

Synthetic studies on statins. Part 1: a short and cyanide-free synthesis of atorvastatin calcium via an enantioselective aldol strategy

A short and cyanide-free enantioselective synthesis of atorvastatin calcium has been achieved starting from a commercially available highly substituted 1,4-diketone in an overall yield of 40%. The key step in this approach is the asymmetric aldol reaction of an aldehyde with diketene in the presence of Ti(O-i-Pr)₄–Schiff base complex to create the (5R)-stereochemistry of atorvastatin calcium.     

Solvent-free asymmetric direct aldol reactions organocatalysed by recoverable (Sa)-binam-l-prolinamide

The combination of (S_a)-binam-l-Pro (5 mol %) and benzoic acid (10 mol %) was used as catalysts in the direct aldol reaction between different aliphatic ketones and 4-nitrobenzaldehyde under solvent-free reaction conditions. Three different procedures are assayed: magnetic stirring (method A), magnetic stirring after previous dissolution in THF and evaporation (method B), and ball mill technique (method C), methods A and B being the simplest. These reaction conditions allowed us to reduce the amount of required ketone to 2 equiv to give the aldol product in similar reaction times and regio-, diastero-, and enantioselectivities than in organic or aqueous solvents.     

Catalytic asymmetric hetero-Diels–Alder route to a key intermediate for the synthesis of calyxin L

A catalytic asymmetric formal synthesis of diarylheptanoid natural product calyxin L has been achieved by incorporating an enantio- and diastereoselective hetero-Diels–Alder (HDA) reaction, a Suzuki–Miyaura coupling, and a stereocontrolled catalytic hydrogenation of 2,4,6-trisubstituted dihydropyran as the key steps. The HDA reaction between 4-(4-benzyloxyphenyl)-2-triethylsilyloxy-1,3-butadiene and (4-benzenesulfonyloxyphenyl)propynal catalyzed by dirhodium(II) tetrakis[(R)-3-(benzene-fused-phthalimido)-2-piperidinonate], Rh₂(R-BPTPI)₄, provided cis-2,6-disubstituted tetrahydropyran-4-one in 91% yield with 91% ee.     

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%.     

Dicationic (BINAP)palladium-catalyzed enantioselective aldol reaction of aldehydes with a silyl enol ether: a simplified practical procedure

The dicationic ((R)-BINAP)palladium-catalyzed enantioselective aldol reaction of benzaldehyde with 1-phenyl-1-trimethylsilylethene has been reinvestigated regarding the reaction conditions in the presence of ((R)-BINAP)palladium chloride and AgSbF₆ with 3 Å molecular sieves. The simplified practical procedure with 1 mol % catalyst loading realized the high performance of 98% yield and 76% ee with reliable reproducibility.     

Group IB organometallic chemistry: XVI. Complex formation between 2-(dimethylamino)-phenylcopper with copper(I) or silver halides. Synthesis and structural characterization of hexanuclear (2-Me2NC6H4)4Cu6-nMnX2 (M = Cu or Ag) cluster compounds

The $\text{2}\text{1}$ complexes (2RCu · MX) between 2-(dimethylamino)phenylcopper (RCu) and CuX (X = Cl, Br or I) or AgBr have been prepared in two ways (i) from the $\text{2}\text{3}$ reaction of 2-(dimethylamino)phenyllithium with cuprous halide and (ii) from the reaction of RCu with excess of the metalIB halide.The structure of bis[(2-dimethylamino)phenylcopper] cuprous bromide, which is dimeric (R₄Cu₆Br₂) in the solid state, has been determined by X-ray analysis. The bonding in this hexanuclear cluster (CuCu ranging from 2.48 to 2.70 Å, multicenter bonded aryl groups) is discussed. Molecular weight determinations and ¹H NMR spectroscopy reveal a similar hexanuclear structure for the R₄Cu₆X₂ complexes in benzene solution. NMR spectroscopy indicates that in solution the mixed-metal cluster compounds R₄Cu_6-nAg_nBr₂ are not stable but enter into interaggregate exchange reactions. A possible pathway involving trinuclear species R₂Cu_3-nAg_nX as intermediates is proposed.