Asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters to functionalized chiral allylic alcohols via dynamic kinetic resolution

An iridium catalyzed asymmetric hydrogenation of racemic exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution to functionalized chiral allylic alcohols was developed. With the chiral spiro iridium catalysts Ir-SpiroPAP, a series of racemic exocyclic γ,δ-unsaturated β-ketoesters bearing a five-, six-, or seven-membered ring were hydrogenated to the corresponding functionalized chiral allylic alcohols in high yields with good to excellent enantioselectivities (87 to >99% ee) and cis-selectivities (93 : 7 to >99 : 1). The origin of the excellent stereoselectivity was also rationalized by density functional theory calculations. Furthermore, this protocol could be performed on gram scale and at a lower catalyst loading (0.002 mol%) without the loss of reactivity and enantioselectivity, and has been successfully applied in the enantioselective synthesis of chiral carbocyclic δ-amino esters and the β-galactosidase inhibitor isogalactofagomine.

An iridium catalyzed asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution was developed, providing efficient protocol for enantioselective synthesis of functionalized chiral allylic alcohols.     

Preparation of N-protected allylic amines and α-methylene-β-amino acids from vinylalumination/Baylis-Hillman products via tandem SN2′ substitution-Overman rearrangement

S_N2′ reaction on the acetates obtained from vinylalumination or Baylis-Hillman products, followed by in situ reduction afforded allylic alcohols. Upon conversion to trichloroacetimidates and [3,3]-sigmatropic rearrangement, the corresponding N-protected β-substituted allylic amines were obtained in good yields. Utilization of hydroxy group as the nucleophile furnished allylic hydroxy esters, which were converted to protected α-methylene-β-amino acids via Overman rearrangement.     

Lewis acid-catalyzed oxidative rearrangement of tertiary allylic alcohols mediated by TEMPO

Two methods for the oxidative rearrangement of tertiary allylic alcohols have been developed. Most of tertiary allylic alcohols studied were oxidized to their corresponding transposed carbonyl derivatives in excellent to fair yields by reaction with TEMPO in combination with PhIO and Bi(OTf)₃ or copper (II) chloride in the presence or not of oxygen. Other primary oxidants of TEMPO such as PhI(OAc)₂, mCPBA, and Oxone^® were unsatisfactory giving the enone in modest to low yields.     

Asymmetric synthesis of γ-chiral borylalkanes via sequential reduction/hydroboration using a single copper catalyst

The synthesis of γ-chiral borylalkanes through copper-catalyzed enantioselective S_N2′-reduction of γ,γ-disubstituted allylic substrates and subsequent hydroboration was reported. A copper–DTBM-Segphos catalyst produced a range of γ-chiral alkylboronates from easily accessible allylic acetate or benzoate with high enantioselectivities up to 99% ee. Furthermore, selective organic transformations of the resulting γ-chiral alkylboronates generated the corresponding γ-chiral alcohol, arene and amine compounds.

Copper-catalyzed reductive hydroboration of γ,γ-disubstituted allylic substrates enables preparation of γ-chiral alkylboron compounds in a one-pot cascade manner.     

Synthesis of optically active 2-fluoroalk-1-en-3-yl esters and chirality transfer in their Claisen-type rearrangements

A series of enantioenriched long chain 2-fluoroalk-1-en-3-ols 1 has been prepared by lipase-catalyzed resolution of the racemic compounds synthesized from terminal alkenes. The lipase of Candida antarctica was shown to be the most efficient one in terms of enantioselectivity. Transesterification of the fluorinated allylic alcohols 1 was superior over the hydrolysis in a phosphate buffer of the corresponding acetates 2. Lipase-catalyzed acetylation of allylic alcohols 1 in organic medium gave (S)-(−)-3-acetoxy-2-fluoroalk-1-enes of chain lengths C₁₀, C₁₆ and C₁₈ with 68-89% yield and 92-96% ee, while the remaining (R)-(+)-2-fluoroalk-1-en-3-ols were isolated with 54-96% yield and 72-86% ee. The absolute configuration was assigned by comparison of measured and calculated CD-spectra, and unambiguously by ¹H and ¹⁹F NMR spectroscopy using a modified Mosher's method. From the optically active fluorinated allylic alcohols 1 corresponding esters 2 such as propionates, 3,3,3-trifluoropropionates and Boc-glycinates were synthesized. These compounds were rearranged to 2-substituted 4-fluoroalk-4-enecarboxylic acids 3 applying modified conditions of the [3,3]-sigmatropic Ireland-Claisen rearrangement. While a complete chirality transfer from C-3 of the allylic esters to C-2 of the carboxylic acids or 2-amino acids, respectively, occurred in rearrangements of the propionates and Boc-glycinates, racemic 2-(trifluoromethyl)alk-4-enecarboxylic acids were formed from the allylic trifluoropropionates. The configurational lability of the latter products is caused by the strongly acidic proton in α-position to the trifluoromethyl and the carboxyl groups under the basic rearrangement conditions.     

Task-specific ionic liquid and CO2-cocatalysed efficient hydration of propargylic alcohols to α-hydroxy ketones

The hydration of propargylic alcohols is a green route to synthesize α-hydroxy ketones. Herein a CO₂-reactive ionic liquid (IL), [Bu₄P][Im], was found to display high performance for catalyzing the hydration of propargylic alcohols in the presence of atmospheric CO₂, and a series of propargylic alcohols could be converted into the corresponding α-hydroxy ketones in good to excellent yields. In the IL/CO₂ reaction system, CO₂ served as a cocatalyst by forming α-alkylidene cyclic carbonates with propargylic alcohols, and was released via the rapid hydrolysis of the carbonates catalysed by the IL. This is the first example of the efficient hydration of propargylic alcohols under metal-free conditions.     

New Nitrogen,Sulfur-, and Selenium-Donating Ligands Derived from Chiral Pyridine Amino Alcohols. Synthesis and Catalytic Activity in Asymmetric Allylic Alkylation

Although many chiral ligands for asymmetric catalysis have been developed, there is still a need for new structures allowing the modular approach. Recently, easy synthesis of chiral pyridine-containing β-amino alcohols has been elaborated by opening respective epoxides with enantiomeric 1-phenylethylamine. This paper reports the synthetic transformation of β-amino alcohols into the new complexing pyridine-containing seleno- and thioethers. The amino alcohols were effectively converted to cyclic sulfonamidates, which were reacted with thiolates or phenyl selenide nucleophile. The reaction was diastereoselective, and its outcome depended on the configuration at the substitution center. The problem was discussed considering DFT optimized structures of both diastereomeric sulfonamidates. New amino-aldimine ligands were also synthesized from chiral pyridine-containing diamines. Nine new chiral ligands were tested in the Tsuji-Trost allylic alkylation resulting in the enantiomerically enriched product in up to 75% ee. The observed stereochemical induction agrees with the prevailing nucleophilic attack at the allylic carbon laying opposite to the complexing nitrogen of pyridine in η³-allylic intermediate complexes.     

Direct Ferrier rearrangement on unactivated glycals catalyzed by indium(III) chloride

Anhydrous InCl₃ has been shown to efficiently catalyze the Ferrier rearrangement by a direct allylic substitution of the hydroxyl group at C-3 position of glycals to afford the corresponding 2,3-unsaturated glycosides in high yields at ambient temperature. This methodology obviates the need for protecting and/or activating the C-3 hydroxyl group of glycals. The reaction works in equal ease with both 4,6-di-O-benzyl-d-glucal and 4,6-di-O-benzyl-d-galactal. The mildness of InCl₃ makes this approach compatible for glycosyl acceptors with acid labile groups. The generality of the reaction has been demonstrated with a diversity of alcohols, phenols, and sugar nucleophiles.     

Palladium-catalyzed cross-coupling of α-bromocarbonyls and allylic alcohols for the synthesis of α-aryl dicarbonyl compounds

The palladium-catalyzed coupling of olefins and organohalides is a versatile approach for synthesizing complex molecules from simple starting materials. We have developed a palladium-catalyzed coupling of α-bromocarbonyl compounds with allylic alcohols for the generation of acyclic aryl-substituted dicarbonyl compounds. The reaction proceeds via a tandem olefin insertion of an α-acyl radical followed by a 1,2-aryl migration. In addition to providing preliminary evidence for a free radical mediated mechanism, we demonstrate unprecedented levels of 1,3-stereoinduction for the 1,2-migration step.     

Novel Oxidovanadium Complexes with Redox-Active R-Mian and R-Bian Ligands: Synthesis,Structure, Redox and Catalytic Properties

A new monoiminoacenaphthenone 3,5-(CF₃)₂C₆H₃-mian (complex 2) was synthesized and further exploited, along with the already known monoiminoacenaphthenone dpp-mian, to obtain oxidovanadium(IV) complexes [VOCl₂(dpp-mian)(CH₃CN)] (3) and [VOCl(3,5-(CF₃)₂C₆H₃-bian)(H₂O)][VOCl₃(3,5-(CF₃)₂C₆H₃-bian)]·2.85DME (4) from [VOCl₂(CH₃CN)₂(H₂O)] (1) or [VCl₃(THF)₃]. The structure of all compounds was determined using X-ray structural analysis. The vanadium atom in these structures has an octahedral coordination environment. Complex 4 has an unexpected structure. Firstly, it contains 3,5-(CF₃)₂C₆H₃-bian instead of 3,5-(CF₃)₂C₆H₃-mian. Secondly, it has a binuclear structure, in contrast to 3, in which two oxovanadium parts are linked to each other through V=O···V interaction. This interaction is non-covalent in origin, according to DFT calculations. In structures 2 and 3, non-covalent π-π staking interactions between acenaphthene moieties of the neighboring molecules (distances are 3.36–3.40 Å) with an estimated energy of 3 kcal/mol were also found. The redox properties of the obtained compounds were studied using cyclic voltammetry in solution. In all cases, the reduction processes initiated by the redox-active nature of the mian or bian ligand were identified. The paramagnetic nature of complexes 3 and 4 has been proven by EPR spectroscopy. Complexes 3 and 4 exhibited high catalytic activity in the oxidation of alkanes and alcohols with peroxides. The yields of products of cyclohexane oxidation were 43% (complex 3) and 27% (complex 4). Based on the data regarding the study of regio- and bond-selectivity, it was concluded that hydroxyl radicals play the most crucial role in the reaction. The initial products in the reactions with alkanes are alkyl hydroperoxides, which are easily reduced to their corresponding alcohols by the action of triphenylphosphine (PPh₃). According to the DFT calculations, the difference in the catalytic activity of 3 and 4 is most likely associated with a different mechanism for the generation of ^●OH radicals. For complex 4 with electron-withdrawing CF₃ substituents at the diimine ligand, an alternative mechanism, different from Fenton’s and involving a redox-active ligand, is assumed.     

An Efficient Approach to 2-CF3-Indoles Based on ortho-Nitrobenzaldehydes

The catalytic olefination reaction of 2-nitrobenzaldehydes with CF₃CCl₃ afforded stereoselectively trifluoromethylated ortho-nitrostyrenes in up to 88% yield. The reaction of these alkenes with pyrrolidine permits preparation of α-CF₃-β-(2-nitroaryl) enamines. Subsequent one pot reduction of nitro-group by Fe-AcOH-H₂O system initiated intramolecular cyclization to afford 2-CF₃-indoles. Target products can be prepared in up to 85% yields. Broad synthetic scope of the reaction was shown as well as some followed up transformations of 2- CF₃-indole.     

Synthesis and Modeling of Ezetimibe Analogues

Ezetimibe is a well-known drug that lowers blood cholesterol levels by reducing its absorption in the small intestine when joining to Niemann-Pick C1-like protein (NPC1L1). A ligand-based study on ezetimibe analogues is reported, together with one-hit synthesis, highlighted in the study. A convenient asymmetric synthesis of (2S,3S)-N-α-(R)-methylbenzyl-3-methoxycarbonylethyl-4-methoxyphenyl β-lactam is described starting from Baylis–Hillman adducts. The route involves a domino process: allylic acetate rearrangement, stereoselective Ireland–Claisen rearrangement and asymmetric Michael addition, which provides a δ-amino acid derivative with full stereochemical control. A subsequent inversion of ester and acid functionality paves the way to the lactam core after monodebenzylation and lactam formation. It also shows interesting results when it comes to a pharmacophore study based on ezetimibe as the main ligand in lowering blood cholesterol levels, revealing which substituents on the azetidine-2-one ring are more similar to the ezetimibe skeleton and will more likely bind to NPC1L1 than ezetimibe.     

A new approach to the synthesis of trifluoromethylated products of the [3,3]-sigmatropic rearrangement

CH-acids of general formula CF₃CH(X)CF₃ (X = CF₃, CO₂R) react with 2,3-unsaturated alcohols in the presence of bases to give trifluoromethylated products of the [3,3]-sigmatropic rearrangement. These reactions provide a convenient method for the synthesis of 2-alkenyl-2-trifluoromethylmalonates.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1273–1277, July, 1994.     

Regiospecific and diastereoselective aldol reaction of chiral N-sulfinyl metalloenamines with α,β-unsaturated trifluoromethyl ketones: Asymmetric synthesis of tertiary trifluoromethyl allylic carbinols

Regiospecific and diastereoselective aldol type reaction of chiral N-sulfinyl metalloenamines with α,β-unsaturated trifluoromethyl ketones was reported, which affords the corresponding tertiary trifluoromethyl allylic carbinols in high yields with good diastereoselectivities (dr up to 90:10). The reduction of the condensation product 3a with LiBHEt₃ and Catecholborane provides CF₃-substituted syn- and anti-1,3-amino alcohols 5a and 5b in high yields with excellent diastereoselectivities (dr > 99:1).     

Organic reactions in a solid matrix—IV: Oxirane rearrangement on modified-alumina

Rearrangement of methyldialkyl-substituted oxiranes to the corresponding allylic secondary alcohols with active Al₂O₃ is accompanied by carbonium ion rearrangements. The effect of modifying the Al₂O₃ with various bases or salts has been studied. With NaOH-modified Al₂O₃, the carbonium ion-rearrangements are significantly suppressed, and rearrangement to the allylic alcohols becomes the major pathway. Rearrangement of 2,10-epoxypinane (both isomers) on Al₂O₃-NaOH is reported.     

Palladium-catalyzed asymmetric allylic alkylation (AAA) with alkyl sulfones as nucleophiles

An efficient palladium-catalyzed AAA reaction with a simple α-sulfonyl carbon anion as nucleophiles is presented for the first time. Allyl fluorides are used as superior precursors for the generation of π-allyl complexes that upon ionization liberate fluoride anions for activation of silylated nucleophiles. With the unique bidentate diamidophosphite ligand ligated palladium as catalyst, the in situ generated α-sulfonyl carbon anion was quickly captured by the allylic intermediates, affording a series of chiral homo-allylic sulfones with high efficiency and selectivity. This work provides a mild in situ desilylation strategy to reveal nucleophilic carbon centers that could be used to overcome the pK_a limitation of “hard” nucleophiles in enantioselective transformations.

A variety of “hard” α-sulfonyl carbanions of aryl, heteroaryl and alkyl sulfones were successfully employed as nucleophiles in palladium-catalyzed asymmetric allylic alkylation with excellent enantioselectivities.     

A hexanuclear gold carbonyl cluster

The hexanuclear gold carbonyl cluster [PPh₄]₂[Au₆(CF₃)₆Br₂(CO)₂] (4) has been obtained by spontaneous self-assembly of the following independent units: CF₃AuCO (1) and [PPh₄][Br(AuCF₃)₂] (3). The cyclo-Au₆ aggregate 4, in which the components are held together by unassisted, fairly strong aurophilic interactions (Au···Au ∼310 pm), exhibits a cyclohexane-like arrangement with chair conformation. These aurophilic interactions also result in significant ν(CO) lowering: from 2194 cm^–1 in the separate component 1 to 2171 cm^–1 in the mixed aggregate 4. Procedures to prepare the single-bridged dinuclear component 3 as well as the mononuclear derivative [PPh₄][CF₃AuBr] (2) are also reported.     

Nucleophilic and organometallic displacement reactions of allylic compounds: stereo-and regiochemistry

Allylic alcohols, esters, halides and related compounds have been of mechanistic and synthetic interest for years. This Report focuses on the stereo- and regiochemical aspects of three reaction types: the S_N2' reaction (bimolecular nucleophilic substitution with allylic rearrangement); displacement reactions effected by organometallic reagents; the conversion of allylic alcohols into halides.     

Highly Enantioselective Synthesis of Linear β-Amino Alcohols

β-Amino alcohols derived from α-amino acids have been extensively used as a powerful source of chirality. Transforming the alcohol moiety into a good leaving group has allowed the rearrangement of these β-amino alcohols and the introduction of a large number of nucleophiles through the anchimeric participation of the nitrogen atom. An overview on the recent progress realized on the rearrangement of these β-amino alcohols in the presence of (CF₃CO)₂O and H₂SO₄ is reported.     

Copper‐Catalyzed Trifluoromethylation of Trisubstituted Allylic and Homoallylic Alcohols

An efficient copper‐catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols with Togni’s reagent has been developed. This strategy, accompanied by a double‐bond migration, leads to various branched CF₃‐substituted alcohols by using readily available trisubstituted cyclic/acyclic alcohols as substrates. Moreover, for alcohols in which β‐H elimination is prohibited, CF₃‐containing oxetanes are isolated as the sole product.