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.     

Reductive aldol coupling of divinyl ketones via rhodium-catalyzed hydrogenation: syn-diastereoselective construction of beta-hydroxyenones

Catalytic hydrogenation of divinyl ketones 1a and 1e in the presence of diverse aldehydes 2a-e at ambient temperature and pressure using cationic rhodium catalysts ligated by tri-2-furyl phosphine enables formation of aldol products 3a-e and 5a-e, respectively, with high levels of syn diastereoselection. Through an assay of counterions (Rh(COD)2X), Rh(COD)2SbF6 is identified as the optimum precatalyst for reductive aldol couplings of this type. For para-substituted styryl vinyl ketones 1b-e, a progressive increase in isolated yield is observed for electron-releasing para substituents. [reaction: see text].     

Dinuclear asymmetric Zn aldol additions: formal asymmetric synthesis of fostriecin

Direct asymmetric aldol reactions constitute a powerful methodology for the efficient synthesis of complex natural products. Herein we report the first application of our recently reported dinuclear Zn-catalyzed direct aldol addition of alkynyl ketones to aldehydes in a short and efficient formal asymmetric synthesis of fostriecin, a potent cyctotoxic natural product. This work highlights not only the power of the aldol methodology but also the utility of the akynyl silane aldol adducts, as it is subsequently utilized in a vinyl silane cross-coupling reaction which affords the target molecule in 14 steps for the longest linear sequence in 8.5% overall yield.     

镧系元素化合物在有机合成中的应用 —————— 酮在LnCl~3 / K 及 K 作用下的反应

本文研究了酮在LnCl~3/K (Ln=Nd,Gd)及K作用下的反应,并发现共轭酮发生还原偶联, 脂肪酮发生羟醛缩合.并给出了可能的机理.     

The synthesis of bicyclo[2.2.2]octan-2-ones by sequential michael reactions

The reaction of cross-conjugated dienolate anions derived from substituted cyclohexenones with methyl acrylate and vinyl ketones has been studied. Bicyclo[2.2.2]octan-2-ones are formed by a sequential Michael mechanism; however, the reactions of vinyl ketones must be conducted under amine-free conditions. Unexpecedly, the conjugate base from 2,3-dimethylcyclohex-2-enone gives only a single Michael adduct with vinyl ketones, and if forced to react further undergoes an intramolecular aldol condensation. An alternative Diels-Alder approach to the bicyclo[2.2.2]octanone products is shown to be effective.     

Lewis base-catalyzed conjugate reduction and reductive aldol reaction of alpha,beta-unsaturated ketones using trichlorosilane

Lewis bases such as Ph3P=O and HMPA catalyze the 1,4-reduction of alpha,beta-unsaturated ketones with trichlorosilane, and because the 1,2-reduction of aldehydes scarcely proceeded under the conditions, one-pot reductive aldol reactions with aldehydes were successfully achieved; preliminary studies using a chiral Lewis base revealed a high potential for enantioselective catalysis.     

Selective 1,5-alkylidenecarbene insertion reactions on [3.2.1] oxabicyclic ethers: a new approach toward the AB ring system of ingenol

Two methods to achieve the formal aldol reaction between acetone and two oxabicyclic [3.2.1] ketones are reported. The trimethylsilyl-protected beta-hydroxy ketones are converted by a Wittig reaction into vinyl chlorides as synthetic precursors to alkylidenecarbenes. Selective 1,5 C-H over 1,5 O-Si insertion has been applied to the synthesis of a model for the ABC ring system of ingenol.     

Rhodium-catalyzed reductive aldol reactions using aldehydes as the stoichiometric reductants

Chelated acyl rhodium hydrides, generated from the addition of [Rh(dppe)]ClO4 to beta-sulfide-substituted aldehydes, can function as the stoichiometric reductants in reductive aldol processes. Unsaturated nitriles, esters, and ketones can be used as enolate equivalents, and a variety of simple alpha- and beta-substituted aldehydes can be employed. The use of a second, more electrophilic, aldehyde allows three-component reactions to be performed.     

Enantioselective reductive aldol reaction using tertiary amine as hydride donor

An efficient method was developed for the enantioselective reductive aldol reaction of α,β-unsaturated ketones with aldehydes in the presence of a Lewis base catalyst; conjugate reduction using a tertiary amine and trichlorosilyl triflate, followed by an aldol reaction with BINAP dioxide (BINAPO) as an organocatalyst, gave the corresponding product in high yield with high stereoselectivity.     

Dramatic ligand effect in catalytic asymmetric reductive aldol reaction of allenic esters to ketones

A general catalytic asymmetric reductive aldol reaction of allenic esters to ketones is described. Two distinct constitutional isomers were selectively produced depending on the reaction conditions. A combination of CuOAc/(R)-DTBM-SEGPHOS/PCy3 as the catalyst predominantly produced gamma-cis-products in high yield with excellent enantioselectivity (up to 99% ee). The reaction was applicable to both aromatic and aliphatic ketones, including unsaturated ketones. On the other hand, CuF-Taniaphos complexes produced alpha-aldol products with high diastereo- and enantioselectivity (up to 84% ee). The new Taniaphos derivative L3, containing di(3,5-xylyl)phosphine and morpholine units, produced optimum results in the alpha-selective reaction. The products are versatile chiral building blocks in organic synthesis. Furthermore, the basic reaction pattern (i.e., conjugate addition-aldol reaction) was extended to a catalytic enantioselective alkylative aldol reaction to ketones using dialkylzinc reagents as the initiator.     

Asymmetric induction in hydrogen-mediated reductive aldol additions to alpha-amino aldehydes catalyzed by rhodium: selective formation of syn-stereotriads directed by intramolecular hydrogen-bonding

Rhodium-catalyzed hydrogenation of methyl vinyl ketone and ethyl vinyl ketone in the presence of N-Boc-alpha-aminoaldehydes 3a-8a at ambient temperature and pressure results in reductive C-C coupling to furnish aldol adducts 3b-8b and 3c-8c, respectively, which incorporate stereotriads that embody high levels of syn-aldol selectivity accompanied by high levels of anti-Felkin-Anh control. The collective data are consistent with a catalytic mechanism involving addition of the Z(O)-rhodium enolate to the sterically less-encumbered aldehyde pi-face of an intramolecularly hydrogen-bonded chelate through a Zimmerman-Traxler type transition structure. Stereochemical assignments are supported by single-crystal X-ray diffraction analysis of 5b-O-3,5-dinitrobenzoate, iso-5b, N-Me-iso-5b-O-3,5-dinitrobenzoate, and 7b. As revealed by HPLC analysis, optical purity of the stereochemically labile alpha-aminoaldehydes is completely preserved under the conditions of hydrogen-mediated aldol coupling. Deletion of the intramolecular hydrogen bond, as in the case of N-methyl-N-Boc-l-leucinal N-Me-5a, inverts stereoselectivity to furnish the Felkin-Anh product N-Me-iso-5b in 17% yield. Additionally, reactions performed in the presence of tert-amyl alcohol (10 equiv) exhibit markedly lower levels of anti-Felkin-Anh control (7:1 versus > or = 20:1). The collective studies suggest that intramolecular hydrogen bonding plays a key role in both activating the alpha-aminoaldehyde toward addition and directing facial selectivity.     

Cu(I)-catalyzed reductive aldol cyclizations: diastereo- and enantioselective synthesis of beta-hydroxylactones

[reaction: see text] Copper bisphosphine complexes catalyze the intramolecular reductive aldol reaction of alpha,beta-unsaturated esters with ketones, affording five- and six-membered beta-hydroxylactones in high stereoselectivities. Utilization of chiral nonracemic bisphosphines render the cyclizations enantioselective.     

Studies on the synthesis of the inostamycin natural products: a reductive aldol/reductive Claisen approach to the C10-C24 ketone fragment

[reaction: see text] An approach to the C10-C24 ketone fragment of the inostamycin family of polyether antibiotics is described. The synthetic strategy utilizes an asymmetric Rh-catalyzed reductive aldol reaction and a stereoselective Rh-catalyzed reductive Claisen rearrangement as the key steps in formation of alkene and vinyl iodide synthons, respectively.     

Racemic and asymmetric cobalt-catalysed reductive aldol couplings of α,β-unsaturated amides with ketones

In the presence of diethylzinc as a stoichiometric reductant, substoichiometric quantities of an appropriate cobalt source catalyse diastereoselective reductive aldol coupling reactions of α,β-unsaturated amides with ketones. The use of a readily available oxazolidine as a chiral auxiliary imparts high levels of asymmetric induction in these reactions.     

Vinyl Triflate–Aldehyde Reductive Coupling–Redox Isomerization Mediated by Formate: Rhodium-Catalyzed Ketone Synthesis in the Absence of Stoichiometric Metals

Direct conversion of aldehydes to ketones is achieved via rhodium-catalyzed vinyl triflate-aldehyde reductive coupling-redox isomerization mediated by potassium formate. This method circumvents premetalated C-nucleophiles and discrete redox manipulations typically required to form ketones from aldehydes.     

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.).     

A Total Synthesis of FK-506(1)

A total synthesis of FK-506 (1) is presented. The synthesis features a highly convergent approach utilizing a block coupling strategy. Top and bottom half sections of the molecule are coupled by addition of a vinyl cuprate with a spiroenone. The alpha-allyl aldol functionality is revealed by a reductive opening of the spiroenone system. The labile alpha,beta-diketoamide hemiketal portion of the molecule is prepared by a late stage generation and oxidation of a masked enediol. Top and bottom half segments are themselves derived by coupling of smaller subunits, resulting in a very convergent route.     

Catalytic enantioselective intermolecular reductive aldol reaction to ketones

We describe the first example of a catalytic enantioselective intermolecular reductive aldol reaction. Three types of reactions were studied: (1) reactions between acetophenone and methyl acrylate; (2) reactions between symmetric ketones and β-substituted α,β-unsaturated esters; and (3) reactions between acetophenone derivatives and an allenic ester. Although only moderate enantioselectivity was obtained in the first reaction type, high to excellent enantioselectivity was realized in the enantio-induction at the α-position in the second reaction type and at the δ-position in the third reaction type. Specifically, the third reaction type afforded the corresponding tertiary alcohols with up to 99% ee. Pre-activation of the nucleophile by silyl enolate formation is not necessary in these one-pot catalytic enantioselective reductive aldol reactions.     

Diastereoselective synthesis of 4-hydroxypiperidin-2-ones via Cu(I)-catalyzed reductive aldol cyclization

[chemical reaction: see text]. 4-Hydroxypiperidin-2-ones may be prepared in highly diastereoselective fashion using a Cu(I)-catalyzed reductive aldol cyclization of alpha,beta-unsaturated amides with ketones. Used in combination with proline-catalyzed asymmetric Mannich reactions, this methodology enables the enantioselective synthesis of more highly functionalized piperidin-2-ones and hydroxylated piperidines.     

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.