A novel palladium-catalyzed cycloalkylation to isoxazoline 2-oxides. Application for the asymmetric synthesis of carbanucleosides.

Trost, Barry M.; Li, Leping; Guile, Simon D.

doi:10.1021/ja00048a083

Cited by 147 publications

(74 citation statements)

References 3 publications

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“…In fact Trost et al reported a Pd 0 -catalysed cycloalkylation of nitro compounds to isoxazoline-2-oxide. [31] The reaction with palladium(II) acetate (Table 1, entry 7) was then repeated on a larger scale and deeply examined, but only the 4,5-dihydroisoxazole cycloadduct was found. [32] It turned out that copper(II) salts are excellent catalysts for these reactions.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 4,5‐Dihydroisoxazoles by Condensation of Primary Nitro Compounds with Alkenes by Using a Copper/Base Catalytic System

Cecchi

Sarlo

Machetti

2008

Chemistry A European J

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A new procedure for the synthesis of 4.5-dihydroisoxazoles by condensation of primary nitro compounds with olefins by using a copper/base catalytic system is described. The catalytic effect of copper(II) salts is evidenced by comparison of the reaction rates. Thus, activated nitro compounds react faster than with organic catalysis by tertiary amines, whereas nitroalkanes, unable to condense with dipolarophiles in the presence of the base alone, undergo the reaction on addition of a copper(II) catalyst. The observed occurrence of induction periods in most reactions is ascribed to an equilibrium preceding the rate-determining step, and gives a hint as to the proposed reaction mechanism. The results indicate that this method might be of practical and general utility for synthetic practice.

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Section: Resultsmentioning

confidence: 99%

Synthesis of 4,5‐Dihydroisoxazoles by Condensation of Primary Nitro Compounds with Alkenes by Using a Copper/Base Catalytic System

Cecchi

Sarlo

Machetti

2008

Chemistry A European J

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“…Stereo-and regioselective introduction of the adenine moiety by Pd-catalyzed substitution of the allylic acetate gave (À)-17 [16]. The best results (55%) in this conversion were obtained with NaH as base and [Pd(PPh 3 ) 4 ] as catalyst; in the absence of base or in the presence of weaker bases such as Et 3 N or Cs 2 CO 3 , no conversion to the desired product was observed.…”

Section: Ohmentioning

confidence: 98%

Bisubstrate Inhibitors for the Enzyme Catechol O‐Methyltransferase (COMT): Dramatic Effects of Ribose Modifications on Binding Affinity and Binding Mode

Lerner

Siegrist

Schweizer

et al. 2003

Helvetica Chimica Acta

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Inhibition of the enzyme catechol O‐methyltransferase (COMT) is of significant interest in the therapy of Parkinson's disease. Described herein are structural analogs of the potent bisubstrate inhibitor (−)‐1 (IC50=9 nM; Table 1) for COMT, with target modifications of the central ribose moiety. Their synthesis involves, as key intermediates, adenosine derivatives, which are transformed to the potential bisubstrate inhibitors by a similar sequence of six steps (Schemes 1–4). The compounds were submitted to an enzymatic assay for determination of their in vitro inhibitory activity against COMT, and the inhibition mechanism with respect to the binding side of the cofactor S‐adenosylmethionine (SAM) was analyzed by kinetics measurements (Fig. 3). Both binding affinity and binding mode were exceedingly sensitive towards modifications of the ribose moiety (Table 1). Removal of the 2′‐OH group upon changing from (−)‐1 to (−)‐2 (IC50=28 μM) led to a reduction in binding affinity by more than three orders of magnitude. At the same time, competitive inhibition kinetics with respect to the SAM binding site was maintained, thereby supporting a bisubstrate binding mode. Unlike (−)‐2, the dideoxyribose inhibitor (−)‐3 (IC50=3 μM) showed a mixed and the cyclopentane derivative (+)‐4 (IC50=1 μM) an uncompetitive inhibition mechanism with respect to the SAM binding site. In the complex of the latter, the adenine‐substituted cyclopentane ring orients most probably towards the surface of the enzyme into the surrounding solution. The enantiomeric compounds (−)‐5 (IC50=43 μM) and (+)‐5 (IC50=141 μM), wherein the ribose had been replaced by a pyrrolidine ring, showed only low binding affinity.

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“…32) Purines and pyrimidines have also been successfully employed and has led to the synthesis of numerous carbanucleosides including carbovir, aristeromycin, and neplanocin A. 33,34) In work directed towards the synthesis of prostacyclin analogs, oxygen nucleophiles (phenols) have been successfully employed. 35) Carbon nucleophiles work equally well.…”

Section: Type B Enantiodiscriminationmentioning

confidence: 99%

Pd Asymmetric Allylic Alkylation (AAA). A Powerful Synthetic Tool.

Trost

2002

Chem. Pharm. Bull.

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307

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Chiral compounds have many applications. None are more important than those related to biological targets. The chiral nature of biological receptors make chiral ligands common objectives as pharmaceuticals and agrichemicals. Thus, developing efficient synthetic methods to such compounds represents an important challenge. In spite of great advances, resolution methods still frequently represent the most economical method for commercial production in spite of the fact that the theoretical yield of the single desired enantiomer cannot exceed 50% unless the opposite enantiomer can be converted to the desired one. Using starting materials from the chiral pool also constitutes a common strategy. More recently, attention has shifted to inducing chirality into achiral precursors. Two tacts have been explored. In one, chiral auxiliaries, normally emanating from the chiral pool, are covalently attached to prochiral substrates.1) The advantage of this approach is the high degree of success in transmitting chiral information in this more controlled strategy. However, it suffers from numerous drawbacks. First, it requires stoichiometric amounts of the chiral auxiliary which ultimately is not part of the final product. It also requires additional steps to add and subsequently remove the chiral auxiliary. Clearly, the conceptually most attractive strategy is employing asymmetric catalytic reactions. 2)Some of these have achieved great success. Two of the most successful have been asymmetric catalytic hydrogenation and asymmetric catalytic oxidation of alkenes, notably epoxidation. These two reactions, in addition to virtually every other asymmetric catalytic reaction, share a common feature-the enantiodiscriminating event involves recognizing the enantiotopic faces of a prochiral p-unsaturation such as a carbonyl group or a double bond. Furthermore, each of these reactions also involve formation of just one bond type-a C-H bond in the case of hydrogenation and a C-O bond in the case of oxidation.Catalytic asymmetric allylic alkylation differs from virtually all other catalytic processes in two important ways. In the first, there are many enantiodiscriminating mechanisms, not just one. As shown in Fig. 1, there are at least five such mechanisms. As in most other catalytic asymmetric reactions, differentiating the enantiotopic faces of a p-unsaturation is one mechanism (Fig. 1, A). A second mechanism is differentiating enantiopic leaving groups (Fig. 1, B). Mechanism C involves differentiating enantiotopic termini of a pallylmetal intermediate. Since this intermediate derives from a chiral racemic precursor in which the chirality of the substrate is lost, this deracemization constitutes a dynamic kinetic asymmetric transformation (DYKAT). Mechanism D is a varient of mechanism A wherein the p-allylmetal intermediates interconvert faster than they are attacked by a nucleophile and asymmetric induction derives from differential rates of reaction of the two diastereomeric intermediates. This mechanism allows employment of either an ...

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A novel palladium-catalyzed cycloalkylation to isoxazoline 2-oxides. Application for the asymmetric synthesis of carbanucleosides.

Cited by 147 publications

References 3 publications

Synthesis of 4,5‐Dihydroisoxazoles by Condensation of Primary Nitro Compounds with Alkenes by Using a Copper/Base Catalytic System

Synthesis of 4,5‐Dihydroisoxazoles by Condensation of Primary Nitro Compounds with Alkenes by Using a Copper/Base Catalytic System

Bisubstrate Inhibitors for the Enzyme Catechol O‐Methyltransferase (COMT): Dramatic Effects of Ribose Modifications on Binding Affinity and Binding Mode

Pd Asymmetric Allylic Alkylation (AAA). A Powerful Synthetic Tool.

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