Zhiwei Miao

Enantioselective Synthesis of Tertiary α‐Hydroxy Phosphonates Catalyzed by Carbohydrate/Cinchona Alkaloid Thiourea Organocatalysts

Functionalization of Ca H bonds in phosphonic acid compounds have attracted extensive attention because of their use in pharmaceutical applications and excellent inhibitory bioactivities towards several important groups of enzymes, including rennin, HIV protease, and various classes of protein tyrosine kinases and phosphatases. It has been established that the biological activity of phosphonic acids is largely determined by the absolute configuration of the stereogenic a-carbon atom. The development of methodologies for their preparation, particularly in enantiomerically enriched forms has received deserved attention. Although some asymmetric methods for preparing a-hydroxy phosphonates have been described, including both enzymatic and chemical methods, these methods are primarily concentrated on the synthesis of secondary a-hydroxy phosphonates. To the best of our knowledge, there are only a few examples of organocatalyst-promoted aldol reactions with acyl phosphonates to produce tertiary a-hydroxy phosphonates. For the past decade, hydrogen-bond catalysis has received a great deal of attention because of their high asymmetryinducing ability and ready availability. Chiral thioureabased organic molecules have proven to be extraordinarily useful as catalysts for the enantioselective activation of imine and carbonyl derivatives toward nucleophilic addition. Bifunctional cinchona alkaloid derivatives possessing hydrogen-bonding moieties, such as thiourea, have been widely used in a diverse range of asymmetric organic reactions in recent years. In the meantime, a large number of carbohydrates have been used as ligands for numerous enantioselective reactions. Additionally, organocatalysts derived from the combination of carbohydrates and tertiary amine thioureas have been reported in recent years. However, there is no precedent for the combination of both cinchona alkaloid and carbohydrate moieties in a single chiral organic molecule for asymmetric reactions. The objective of this work is to explore the viability of integrating cinchona alkaloid and carbohydrate fragments into a unique thiourea derivative for enantioselective addition of trimethylsilyl cyanide (TMSCN) to acylphosphonates to produce tertiary a-hydroxy phosphonates. The catalytic asymmetric cyanation of carbonyl compounds is a well-studied reaction in asymmetric catalysis. We initially investigated the use of catalysts 1–6 (Figure 1) for

Bifunctional primary amine-thiourea–TfOH (BPAT·TfOH) as a chiral phase-transfer catalyst: the asymmetric synthesis of dihydropyrimidines

An enantioselective Biginelli reaction has been developed by using a bifunctional primary amine-thiourea-TfOH (BPAT·TfOH) as a chiral phase-transfer catalyst and t-BuNH(2)·TFA as an additive in saturated brine at room temperature. The corresponding dihydropyrimidines were obtained in moderate-to-good yields with up to 99% ee under mild conditions. A plausible transition state has been proposed to explain the origin of the activation and the asymmetric induction.

Mannich type reactions of chlorophosphites, phosphoramides and aldehydes (ketones) under solvent-free and catalyst-free conditions—synthesis of N-phosphoramino α-aminophosphonates

A convenient and rapid method was developed for the synthesis of various N-phosphoramino α-aminoalkylphosphonates through Mannich type reactions under catalyst- and solvent-free conditions with excellent yields.

Stereoselective Synthesis of α‐Amino(phenyl)methyl(phenyl)phosphinic Acids with O‐Pivaloylated D‐Galactosylamine as Chiral Auxiliary

a-Aminophosphonic and -phosphinic acids are the phosphorus analogues of a-aminocarboxylic acids, and therefore have biological importance both in themselves and as building blocks for peptides. Many natural and synthetic aminophosphonic acids exhibit a variety of biological properties including enzyme inhibitors, such as synthase, HIV protease, renin, phosphatase activity, PTPases, and potent antibiotics. The configuration at the a-carbon atom in the a-aminophosphinic acids plays a decisive role in the biological properties of these types of compound. Numerous optically active aminoalkylphosphonic acids have already been obtained from natural resources and by synthesis. Typical examples include the addition of dialkyl phosphite or its lithium salt to an imine bearing a chiral auxiliary, with or without Lewis acid catalysis, respectively. Carbohydrates are valuable as enantiomerically pure starting materials in chiral pool syntheses of many chiral natural products and drugs. The polyfunctionality of carbohydrates is useful for binding or coordinating a substrate. Carbohydrate derivatives are efficient auxiliaries for stereodifferentiation in many stereoselective chiral syntheses. A notable example is the paper by Kunz, in which the use of carbohydrates as chiral templates to promote Mannichtype reaction and the stereoselective synthesis of a-aminophosphonic acid derivatives is reported. The nucleophilic addition of a dialkyl or diaryl phosphite to imines or oxoiminium derivatives, the Pudovik reaction, is one of the most convenient methods for the preparation of a-aminophosphonates, key intermediates in the synthesis of a-aminophosphonic acids. Chiral auxiliaries proved to be good to excellent in inducing asymmetry on the imine carbon atom resulting in enantiopure a-aminophosphinates. Lewis acid catalysts are required for induction of the enantioselectivity in the phosphorylation reaction. Recently, we reported that b-N-glycoside-linked a-aminophosphonic acids derivatives can be synthesized diastereoselectively by the Lewis acid induced addition of diethyl phosphite to Schiff bases of 2,3,4,6-tetra-O-pivaloyl-b-d-galactopyranosylamine (1). We here report on an asymmetric synthesis of a-aminoACHTUNGTRENNUNG(phenyl)methyl ACHTUNGTRENNUNG(phenyl)phosphinic acids in which O-pivaloylated glycosylamines serve as the stereodifferentiating ACHTUNGTRENNUNGauxiliaries. The synthesis of b-N-glycoside-linked a-aminophosphonates started with the condensation of amine 1 and arylaldehyde 2. The formation of the corresponding N-galactosylaldimines 3 proceeded smoothly at room temperature under dehydrating conditions. Higher temperatures and longer reaction times led preferentially to the formation of the undesired conjugated enamines. Under these conditions, the Schiff bases 3 of aromatic aldehydes are obtained in crystalline form. The amount of the corresponding aanomer can be restricted to less than 4 %, and imines 3 of aliphatic aldehydes cannot be isolated in a crystalline form by this method. The imines 3 and equivalent amounts of ethyl phenylphosphinate (4) were kept at room temperature in THF and the reaction was run until the imine was consumed to furnish the eight diastereomeric N-galactosylarylphosphonoglycine esters 5 in high yield. The mixture 5 was treated with 1 m hydrogen chloride in methanol at room temperature giving the easily separable carbohydrate template 6 and the a-aminobenzylphosphonate hydrochloride 7 in quantitative yield. Under these conditions, the amount of deglycosylation was minimized, and no loss of anomeric purity was observed (Scheme 1). [a] Y. Wang, Y. Wang, J. Yu, Prof. Dr. Z. Miao, Prof. Dr. R. Chen State Key Laboratory and Institute of Elemento-Organic Chemistry Nankai University, Weijin Road 94, Tianjin 300071 (P. R. China) Fax: (+86) 22-2350-2351 E-mail : miaozhiwei@nankai.edu.cn [b] Prof. Dr. Z. Miao Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education) Tsinghua University, Qinghuayuan, Beijing 100084 (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200901419.

Efficient syntheses of phosphonylated isochromenes by regioselective 6-endo-dig addition to carbon-carbon triple bond catalyzed by Pd(OAc)2

Palladium(II)-catalyzed cycloisomerization of [(2-alkynylphenyl)hydroxymethyl]phosphonates 6 provides an efficient route to phosphonylated isochromenes 7 in THF at room temperature and the reaction proceeded in a regioselective manner leading to the 6-endo-dig products 7 in moderate to excellent yields.

Asymmetric synthesis of spiro[chroman-3,3′-pyrazol] scaffolds with an all-carbon quaternary stereocenter via a oxa-Michael–Michael cascade strategy with bifunctional amine-thiourea organocatalysts

An efficient chiral bifunctional amine-thiourea catalysed cascade oxa-Michael–Michael addition of 4-alkenyl pyrazolin-3-ones to (E)-2-(2-nitrovinyl)phenol for the synthesis of chiral heterocyclic systems containing spiro[chroman-3,3′-pyrazol] scaffolds has been developed. This reaction afforded the desired products in high to excellent yields (up to 98%) with moderate to high enantioselectivities (up to 99%) and diastereoselectivities (up to 20:1) under low catalyst (15 mol%) concentration. This catalytic asymmetric reaction provides an efficient route toward the synthesis of chiral spiro[chroman-3,3′-pyrazol] derivatives containing three contiguous stereocenters which possess potential pharmaceutical activities.

Highly regio- and diastereoselective construction of spirocyclopenteneoxindole phosphonates through a phosphine-catalyzed [3 + 2] annulation reaction

A phosphine-catalyzed [3 + 2] annulation of MBH phosphonates with isatylidene malononitriles is developed. The described method, which is different from most traditional phosphorus ylide intermediate reaction modes of MBH carbonates with isatylidene malononitriles, represents a novel approach to highly regioselective and diastereoselective synthesis of spirocyclopenteneoxindole phosphonates.

Efficient Synthesis of Isoquinoline Derivatives via AgOTf/Cu(OTf)2-Cocatalyzed Cyclization of 2-Alkynyl Benzaldoxime

Abstract An efficient, AgOTf and Cu(OTf)2 multicatalytic intramolecular cycloisomerization of 2-alkynylbenzaldoxime is reported. Isoquinoline N-oxides have been found to be deoxygenated to the corresponding quinolines in good yields in dimethylformamide/dichloroethane (v/v 5:1) as solvent at 120 °C. GRAPHICAL ABSTRACT

The diastereoselective synthesis of methyl 5-deoxy-5-(dialkylphosphono)-5-(dialkylphosphorylamido)-2,3-O-isopropylidene-β-d-ribofuranosides

A convenient method has been developed for the diastereoselective synthesis of methyl 5-deoxy-5-(dialkylphosphono)-5-(dialkylphosphorylamido)-2,3-O-isopropylidene-beta-d-ribofuranosides under mild conditions, namely the reaction of a dialkyl phosphoramidate with a dialkyl phosphite and methyl 2,3-O-isopropylidene-beta-D-ribo-pentodialdo-1,4-furanoside in acetyl chloride in a one-pot procedure.

An environmentally benign approach for the synthesis of 3,3′-pyrrolidonyl spirooxindole derivatives via a cascade Knoevenagel–Michael–cyclization multicomponent reaction

A series of 3,3′-pyrrolidonyl spirooxindole derivatives have been synthesized in good yields from the cascade Knoevenagel–Michael–cyclization multicomponent reaction of isatin, malononitrile and α-isothiocyanato imide in the presence of a catalytic amount of triethylamine “on water” assisted with ultrasonic irradiation. The advantages of this method include high efficiency, mild reaction conditions and environmentally benign reagents. The current process provides a simple and green method for creating diversity-oriented syntheses of this intriguing class of compounds with potential biological activities.