Abstract

Abstract

Abstract

Abstract

The enantioselective ring opening of meso-epoxides (from both cyclic and acyclic olefins) with silicon tetrachloride under catalysis by chiral phosphoramides affords enantiomerically enriched chlorohydrins in excellent yields. Experiments designed to elucidate the mechanistic foundation and origins of enantioselectivity are described. From studies on the loading and stoichiometry of the reagent (SiCl₄) and the catalyst [(R)-1] it was established that only one chloride per SiCl₄ is delivered and that the nature of reactive species does not change over the course of the reaction. Kinetic studies together with asymmetric amplification experiments have suggested that more than one catalyst molecule may be bound to SiCl₄ in the stereochemistry-determining transition structure.

Abstract

The complete pentacyclic core of the melodinus alkaloid scandine has been synthesized. The synthetic strategy features two key steps: (1) a tandem nitroalkene conjugate addition/[3+2] cycloaddition of the resulting silyl nitronate and (2) an intramolecular Heck reaction of an aryl iodide with a γ-disubstituted allylic alcohol which set a highly congested, quaternary stereogenic center with the concomitant formation of an aldehyde. Intramolecular reductive amination with this aldehyde completed the pentacyclic core.

This paper chronicles the conceptual development, proof of principle experiments, and recent advances in the palladium-catalyzed cross-coupling reactions of the conjugate bases of organosilanols. The discovery that led to the design and refinement of this process represents a classical illustration of how mechanistic studies can provide a fertile ground for the invention of new reactions. On the basis of a working hypothesis (which ultimately proved to be incorrect) and the desire to effect silicon-based cross-coupling without the agency of fluoride activation, a mild and practical palladium-catalyzed cross-coupling of alkenyl-, aryl-, and heteroaryl silanolates has been developed. The mechanistic underpinnings, methodological extensions, and the successful applications of this technology to the synthesis of complex molecules are described.

Im Jahre 1935 formulierte R. C. Fuson das Prinzip der Vinylogie, um zu erklären, wie sich der Einfluss einer funktionellen Gruppe an einer entfernten Position im Molekül bemerkbar macht, wenn diese über konjugierte Doppelbindungen mit der Gruppe verbunden ist. In polaren Reaktionen ermöglicht dieses Konzept die Erweiterung des elektrophilen oder nucleophilen Charakters einer funktionellen Gruppe über das π-System einer Kohlenstoff-Kohlenstoff-Doppelbindung. Diese vinyloge Erweiterung führt im Fall der Aldolreaktion zum Einsatz “erweiterter” Dienolether, die von γ-enolisierbaren α,β-ungesättigten Carbonylverbindungen abgeleitet sind. Seit 1994 sind einige Methoden für die katalytische enantioselektive vinyloge Aldolreaktion beschrieben worden, mit denen man unterschiedliche Regio- (Orts-), Enantio- und Diastereoselektivitäten erzielen kann. In diesem Aufsatz werden die Bandbreite und die Einschränkungen dieser Transformation sowie ihre Anwendung in der Naturstoffsynthese diskutiert.

Eine beispiellose Gerüstumlagerung stand der Synthese der gespannten Titelverbindung durch eine Tandem-[4+2]/[3+2]-Nitroalken-Cycloaddition anfangs im Wege. Diese dyotrope Umlagerung wurde unterdrückt, und eine Röntgenstrukturanalyse des BF₃-Derivats (siehe Bild) bestätigte die signifikante Planarisierung des zentralen Kohlenstoffatoms im Azafenestran.

In 1935, R. C. Fuson formulated the principle of vinylogy to explain how the influence of a functional group may be felt at a distant point in the molecule when this position is connected by conjugated double-bond linkages to the group. In polar reactions, this concept allows the extension of the electrophilic or nucleophilic character of a functional group through the π system of a carbon–carbon double bond. This vinylogous extension has been applied to the aldol reaction by employing “extended” dienol ethers derived from γ-enolizable α,β-unsaturated carbonyl compounds. Since 1994, several methods for the catalytic, enantioselective, vinylogous aldol reaction have appeared, with which varying degrees of regio- (site), enantio-, and diastereoselectivity can be attained. In this Review, the current scope and limitations of this transformation, as well as its application in natural product synthesis, are discussed.

An unprecedented skeletal reorganization initially hindered a concise route based on a tandem [4+2]/[3+2] nitroalkene cycloaddition for the synthesis of the strained title compound. Conditions to suppress the observed dyotropic rearrangement were developed, and X-ray crystallographic analysis of the BF₃ derivative (see picture) of the azafenestrane revealed significant planarization around the central carbon atom.

Cesium carbonate and cesium hydroxide monohydrate are effective activators for the palladium-catalyzed cross-coupling of aryl(dimethyl)silanols with substituted aryl halides. Extensive optimization studies led to the identification of key variables (solvent, catalyst, additive, and hydration level) that influence the rate and selectivity of the process. Manipulation of these factors provides an effective coupling method of wide scope and generality. Electron-rich aryl(dimethyl)silanols undergo cross-coupling with aryl iodides and aryl bromides in high yields and high selectivity for the desired cross-coupling products. Alternatively, high yields of cross-coupling products could be obtained with electron-poor or ortho-substituted aryl(dimethyl)silanols when activated with cesium hydroxide monohydrate.

The tandem inter [4+2]/intra [3+2] cycloaddition of nitroalkenes in the bridged mode was applied to the stereoselective synthesis of β-D-4-amino-2,4-dideoxycarbagulose, a representative aminocarbasugar. The synthesis required only five steps from known materials and delivered the protected aminocarbasugar (−)-20 in excellent yield (see Scheme 9). The success of the synthetic sequence relies on 1) the ability to incorporate O-substituents at the nitroalkene moiety, 2) the identification of a suitably modified chiral dienophile, and in particular 3) the development of specific experimental conditions and protocols that allow for the formation and isolation of the highly sensitive nitroso acetals. The reduction of the C(1) carbonyl group of (+)-19 gave unexpected stereoselectivity, which could be rationalized by a conformational inversion of the substrate (see Scheme 11).

To provide an opportunity for X-ray analysis of an unsubstituted fenestrane, one of the ring-fusion carbon atoms was replaced with a nitrogen atom to facilitate salt formation; the key strategic step to the first 1-azafenestrane (see scheme) involves the tandem [4+2]/[3+2] cycloaddition of a nitrocyclopentene with butyl vinyl ether. The adduct with borane provided crystals suitable for X-ray analysis, which revealed the planar deformation of the central carbon atom to be modest (116.1 and 116.6°).

Zur Ermöglichung der Röntgenstrukturanalyse eines unsubstituierten Fenestrans wurde formal eines der ringverknüpfenden C-Atome durch ein N-Atom ersetzt: Die Strategie für die Synthese dieser Verbindung, des ersten 1-Azafenestrans, beruht auf einer sequenziellen [4+2]/[3+2]-Cycloaddition von Butylvinylether an ein Nitrocyclopenten (siehe Schema). Mit dem Boran-Addukt des Azafenestrans konnte eine Röntgenstrukturanalyse durchgeführt werden, die ergab, dass die planare Deformation am zentralen C-Atom gering ist (116.1 und 116.6°).

The most basic of aldol constructions, namely the controlled stereoselective self-condensation of aldehydes, has finally found a general solution. Geometrically defined trichlorosilyl enolates of aldehydes display excellent reactivity, near perfect diastereoselectivity, and good (albeit variable) enantioselectivity in their addition to a wide range of aldehydes under catalysis by a chiral bisphosphoramide (see scheme).

Der grundlegendste aller Aldolprozesse, die kontrollierte, stereoselektive Selbstkondensation von Aldehyden, ist ein altes Problem, für das sich nun eine Lösung anbietet: Geometrisch definierte Trichlorsilylenolate von Aldehyden zeigen ausgezeichnete Reaktivität, nahezu perfekte Diastereoselektivität und hohe, wenn auch variable, Enantioselektivität bei der Addition an eine Reihe verschiedenster Aldehyde, wobei ein chirales Bisphosphoramid als Katalysator dient (siehe Schema).

Die Eignung des chiralen Phosphonamids 1 als Katalysator für die enantioselektive Ringöffnung von meso-Epoxiden mit SiCl₄ konnte in Denmarks Labor nicht bestätigt werden. Insbesondere bei der Ringöffnung von Cyclooctenoxid (siehe Schema) erhielten Denmark und Mitarbeiter vollkommen andere Ergebnisse (81–83 % zurückgewonnenes Epoxid und wenig, dazu nahezu racemisches Produkt) als Buono et al. (77 % Ausbeute und >99 % ee).

The aldol addition reaction of trichlorosilyl enol ethers and aldehydes with and without chiral Lewis base catalysts has been kinetically analyzed. The uncatalyzed reactions display classic first-order dependence on each component. The reactions catalyzed by bulky chiral phosphoramide 5 were examined by ReactIR and exhibited first-order dependence on the catalyst. To examine the kinetic behavior of the reaction catalyzed by phosphoramide 4, a Rapid-Injection (RI) NMR apparatus was constructed and employed to allow rapid in-situ mixing and monitoring of the reaction course. The aldol addition catalyzed by 4 displayed second-order dependence on phosphoramide, thus providing direct evidence that two catalyzed pathways (with complimentary stereochemical consequences) exist that depend on phosphoramide structure and concentration. Arrhenius activation parameters for all three reactions showed striking characteristics of negligible enthalpies and extremely high entropies of activation. Comparison of these values was precluded by the existence of complex preequilibria in the catalyzed process.