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The mechanistic pathway for the formation of 1,2-oxazetes by reaction of olefins with nitrous anhydride has been clarified. The initial reaction intermediate, a β-nitroso nitrite ester that is sensitive to light, undergoes O-NO fission to form a β-nitroso alkoxy radical, even with ambient fluorescent lighting but much faster with blue light irradiation. The oxygen of the alkoxy radical subsequently adds to the adjacent nitroso group to generate a cyclic four-membered nitrosyl radical. The 1,2-oxazete is then produced by elimination to generate the C═N bond. No 1,2-oxazete formation occurs in the dark.

Triflyl nitrate is easily generated from tetra-n-butylammonium nitrate in CH2Cl2 solution and serves as an effective nitrating agent for a wide range of unsaturated substrates to form nitro olefins.

Concise stereocontrolled synthetic routes to the C2-symmetric azatetraquinane 1 (or, also, the enantiomer) are described. The successful execution of the synthesis involved innovation in the method...

Nitrosyl triflate (TfONO) can be generated

A study of [3 + 2] cycloaddition reactions of a bicyclic nitrone with various cyclopentenes has clarified the diastereomeric preferences as a function of the olefinic structure. It has also identified an important stereochemical difference between nitrones and the analogous azomethine ylides in [3 + 2] cycloaddition reactions.

Concise stereocontrolled synthetic routes to the C

A useful catalytic enantioselective approach has been developed for the synthesis of chiral ketamine analogs using Rh(II)-catalyzed amination of triisopropylsilyl enol ethers to form α-amino ketones with O-(4-nitrophenyl)hydroxylamine as nitrogen donor in 81-91% ee.

A new enantio-and diastereoselective process has been developed for the efficient conversion of farnesol and other oligoprenyl alcohols to chiral 10-, 14-, and 18-membered cyclization products, including germacrenol, (+)-costunolide, 3-β-elemol, and epi-mukulol. The key cyclization reaction utilizes ω-bromo aldehyde substrates, a chiral ligand, and indium powder as the reagent at -78 °C and generates 10-, 14-, and 18-membered cyclic products in 70-74% yield and 94-95% ee.

Diverse examples are provided of enantioselective sequences for the transformation of cycloalkenes to either chiral trans-β-substituted cycloalkanols or chiral α-amino ketones.

Frank H. Westheimer integrated physical and organic chemistry to become an important contributor to the field that came to be called ‘physical organic chemistry’. He then went on to apply physical organic chemistry to the study of biological transformations. He identified fundamental classes of chemical reactions, studied in detail how they occurred in a relevant non-biological format and then investigated corresponding enzymatic reactions. These included oxidation–reduction, decarboxylation and phosphate transfer reactions. In the process, he made fundamental observations in the field of bio-organic chemistry he had helped to create. This line of research led to conceptual advances relevant to the ability of enzymes to distinguish enantiotopic and diastereotopic centres in their substrates, the perturbation of p K a values in enzymatic active sites as a source of catalytic power, and the broad range of transition state structures available for reactions at electrophilic phosphorus. These studies prompted similar work across many classes of enzymatic reactions. These experiments also benefitted from Westheimer's guidance in the application of kinetic isotope effects to probe reaction transition states, his invention of molecular mechanics to understand molecular dynamics, his widely cast studies on how organic reactivity depends on the molecular environment and his demonstration that photochemistry could be used to probe structure in complex biological systems.

A simplified effective synthetic process is described for the diastereoselective synthesis of the chiral C2-symmetric CF3-ureas (R,R)-15 and (S,S)-15 from (S)-α-phenylethylamine, glyoxal and CF3I.

A novel strategy for accessing cyclic α-amino ketones enantioselectively has opened a simple synthetic route to the antidepressant (2R,6R)-hydroxynorketamine and numerous analogues. Mechanistically guided catalyst selection was essential in an initial olefin epoxidation step. In a second crucial step, the epoxide was subjected to a novel O → N displacement that occurred with retention of configuration through the use of Al- or Ti-based azides, which promote epoxide activation and internal cis delivery of N3 to carbon.

The scope of enantioselective (4 + 2)-cycloaddition reactions has been expanded to include reactive olefinic components that are equivalents of three inoperable and unstable ethylene derivatives: 1-hydroxy-2-aminoethylene, 1,2-diaminoethylene, and β-aminoacrylic acid. In this way, a variety of otherwise unavailable functionalized (4 + 2)-cycloadducts have been synthesized from 1,3-dienes with high enantioselectivity (92-98%) and in good yields. The research leading up to this synthetic advance has also produced some surprising insights on reactivity and positional selectivity in catalytic enantioselective (4 + 2)-cycloaddition.

A method is described for the joining of two α-lithiated C(sp3) stereocenters efficiently and with retention of configuration. The key step involves the effective removal of two electrons from a chiral organocuprate R2CuLi, by i-propyl 2,4-dinitrobenzoate to form a Cu(III) complex that undergoes at −90 °C accelerated reductive elimination enantioselectively and exclusively without the formation of free radicals.

The previously unknown 5-spirocyclohexylisoimidazole has been made efficiently and simply by reaction of ammonia, glyoxal hydrate, and cyclohexanone. It is a very useful precursor for the diastereocontrolled synthesis of many C2-symmetric 1,2-diamines, a class which is important for the generation of a variety of C2-symmetric reagents and catalysts for enantioselective synthesis.

A new and practical method has been developed for the transformation of racemic α-bromo ketones to chiral α-azido and α-amino ketones with high enantioselectivity using phase transfer, ion-pair mediated reactions with a recoverable chiral quaternary salt (10 mol %) as catalyst in fluorobenzene-water. The process has been generalized to a variety of other attachments including of C, O, S, and NHR.

Enol ethers, β-dicarbonyl compounds and the Mn(III) reagent Mn(3)O(OAc)(7) react under mild conditions to form 1-alkoxy-1.2-dihydrofurans in good (70-98%) yields. The latter are readily converted to furans by acid-catalyzed elimination of ROH.

The coordination of chiral ligands to Lewis acid metal derivatives, a useful strategy for enantioselective, electrophilic catalysis, generally leads to a lower level of catalytic activity than that of the original uncomplexed compound. Activation by further attachment of a proton or strong Lewis acid to the complex provides a way to overcome the deactivating effect of a chiral ligand. The research described herein has demonstrated that further enhancement of catalytic activity is possible by the judicious placement of fluorine substituents in the chiral ligand. This approach has led to a new, second-generation family of chiral oxazaborolidinium cationic species which can be used to effect many Diels–Alder reactions in >95% yield and >95% ee using catalyst loadings at the 1–2 mol % level. The easy recovery of the chiral ligand makes the application of these new catalysts especially attractive for large-scale synthesis.

The previously unknown 5-spirocyclohexylisoimidazole has been made efficiently and simply by reaction of ammonia, glyoxal hydrate, and cyclohexanone. It is a very useful precursor for the diastereocontrolled synthesis of many C

Lithiation of α-C-H groups in organic substrates by RLi or R2NLi followed by silylation with R'3SiCl generally provides analogous products regardless of the R' group of R'3SiCl. A striking exception using 3,4-benzothiophane as substrate depending on whether R' is methyl, phenyl, or isopropyl is demonstrated. With R' = Me or Ph, the geminal α,α-bis-silylated products result whereas with i-Pr3SiCl the trans-α,α'-bis-silylated sulfide is formed. The latter pathway provides ready access to the C2-symmetric enantiomers of trans-2,5-bis(triisopropylsilyl)-3,4-benzothiophane.

The 1:1 complex of o,o'-dichloro-R-BINOL and SbCl5 initiates the enantioselective cationic polycyclization of polyunsaturated substrates at a predictable π-bond which may be either terminal or, as shown herein, internal. The extension of this powerful construction to internal π-bonds expands the scope of this method and opens up very short pathways to numerous chiral polycyclic molecules, including natural products and their analogues. Especially simple synthetic routes are disclosed that provide access to dysideapalaunic acid, dehydroabietic acid, and epipodocarpic acid and illustrate the value of this enantioselective approach.

The enantioselective reduction of prochiral 4,4-disubstituted 2,5-cyclohexadienones to chiral 2-cyclohexenones has been accomplished by the use of a carefully selected chiral bisphosphine–CuI complex and diisobutylaluminum hydride–hexamethylphosphoric triamide complex. This reagent has provided access to a key bicyclic intermediate for the total synthesis of the natural enantiomer of the pentacyclic sesterterpene retigeranic acid that involves spatial discrimination between CH3 and CH2CH2R substituents, an operation that has been elusive previously. In addition, a second method for desymmetrization is described using catalytic enantioselective [4 + 2]-cycloaddition of cyclopentadiene to prochiral 4,4-disubstituted 2,5-cyclohexadienones.

The activation of second-generation fluorinated oxazaborolidines by the strong acid triflimide (Tf2NH) in CH2Cl2 solution leads to highly active chiral Lewis acids that are very effective catalysts for (4 + 2) cycloaddition. We report herein that this catalytic activity can be further enhanced by the use of Tf2NH in combination with the biscoordinating Lewis acid TiCl4 or SnCl4 as a coactivator. The effective increase in acidity of an exceedingly strong protic acid is greater for biscoordinating TiCl4 and SnCl4 than for monocoordinating salts, even the strong Lewis acids AlBr3 and BBr3 in CH2Cl2 or CH2Cl2/toluene. The increase in the effective acidity of Tf2NH can be understood in terms of a stabilized cyclic anionic complex of Tf2N(-) and TiCl4, which implies a broader utility than that described here. The utility of Tf2NH-TiCl4 activation of fluorinated oxazaborolidines is documented by examples including the first enantioselective (4 + 2) cycloaddition to α,β-unsaturated acid chlorides.

A novel method is demonstrated for the diastereoselective conversion of a monocyclic enone to a pair of bicyclic intermediates which enable the stereocontrolled enantioselective syntheses of retigeranic acids A and B.

The di-tert-butylisobutylsilyl (BIBS) protecting group offers new possibilities for synthetic processes because of its steric bulk, robustness of its derivatives, and other special properties.

The removal of the iodide ion from indium triiodide by means of reactive Ag(I) salts leads to the formation of the highly reactive ligandless cation InI2+, which is unusual in having two vacant low-lying p-orbitals. This bivalent Lewis acidity leads to an especially high affinity for the two orthogonal π-bonds of carbon–carbon triple bonds. Consequently, the double-coordinating InI2+ is an especially effective reagent for the selective activation of C≡C and the catalytic initiation of cationic cyclization processes. A number of such reactions are described to demonstrate synthetic utility.

The experiments described here clarify the mechanism and origin of the enantioselectivity of the oxidation of racemic secondary alcohols catalyzed by chiral Mn(III)-salen complexes using HOBr, Br(2)/H(2)O/KOAc or PhI(OAc)(2)/H(2)O/KBr as a stoichiometric oxidant. Key points of the proposed pathway include (1) the formation of a Mn(V)-salen dibromide, (2) its subsequent reaction with the alcohol to give an alkoxy-Mn(V) species, and (3) carbonyl-forming elimination to produce the ketone via a highly organized transition state with intramolecular transfer of hydrogen from carbon to an oxygen of the salen ligand.

The presence of an ether oxygen within a chain undergoing cation-polyene cyclization has a profound influence on the stereochemistry of this important construction, apparently due to nucleophilic participation of oxygen in the cyclization process and formation of an oxonium intermediate, leading to bent fused ring systems.

Diels-Alder reactions of various combinations of maleimides and 1,3-dienes with cationic oxazaborolidines as catalysts have been shown to be highly efficient and enantioselective.

Electron-pair repulsion in 2-methoxyheteroarenes is important for N, but not for O or S heteroatoms.

This paper reports a method for highly enantioselective Diels-Alder reaction with an acetylene equivalent to produce chiral-bridged dienes. These dienes, by coordination to Rh(I), can serve as catalysts for the enantioselective addition of vinyl or aryl groups to alpha,beta-unsaturated ketones.

It is proposed that facial selectivity in the Jacobsen epoxidation is determined by electrostatic and steric factors with a two-step pathway involving a carbocationic intermediate.

Chirale Oxazaborolidine konnen mit starken Protonensauren oder durch Koordination von AlBr3 am Stickstoffatom aktiviert werden und bilden dabei sehr starke chirale Lewis-Sauren. Die entstehenden chiralen Bor-Elektrophile (siehe Struktur) sind leistungsfahige chirale Katalysatoren, die [4+2]-, [3+2]- und [2+2]-Cycloadditionen mit hoher Enantioselektivitat vermitteln. In den letzten Jahrzehnten hat in der Chemie eine Revolution stattgefunden, die auserhalb unserer Disziplin – und selbst in anderen Wissenschaften – praktisch unbemerkt geblieben ist. Grundlegend gewandelt hat sich: 1) unser Verstandnis davon, wie chemische Reaktionen ablaufen, 2) unsere Fahigkeit, neue Reaktionen zu entwickeln, 3) unsere Fahigkeit, Reaktionen nutzbar zu machen, die zur Synthese einer riesigen Vielfalt an nutzlichen oder komplexen Molekulen gefuhrt haben, und 4) unsere Fahigkeit, chemische Prinzipien und chemisches Wissen zum Verstandnis biologischer und medizinischer Fragestellungen anzuwenden. Im Bereich der Synthesechemie ist eine ganz neue Art von Wissenschaft herangewachsen, die eine nahezu perfekte Kontrolle der absoluten und relativen Stereochemie ermoglicht und mit der gezielten Entwicklung von Katalysatoren einhergeht, deren Funktionsweisen vor Jahren noch unvorstellbar schienen. Dieser Aufsatz befasst sich mit einem speziellen Aspekt dieser Chemie, der erst in den letzten Jahren aufgetaucht ist: der Erzeugung und Anwendung der supersauren chiralen Oxazaborolidiniumionen in der enantioselektiven Katalyse. Die Fortschritte in diesem Bereich sind vielschichtiger Natur und betreffen 1) die Bildung der Katalysatoren, 2) die Aufklarung der detaillierten Mechanismen, uber die sich Reaktionen steuern und beschleunigen lassen, 3) Erkenntnisse uber die katalysierten Reaktionen und 4) die Entwicklung und Optimierung von Syntheseverfahren.

An effective strategy has been developed for the efficient site-selective epoxidation of poylolefinic isoprenoid alcohols, based on the use of an internal control element for intramolecular reaction. The approach is illustrated by application to a series of polyisoprenoid alcohols (polyprenols) at substrate concentration of 0.5 mM. With polyprenol substrates having the hydroxyl function at one terminus, the internal epoxidation can be directed at the double bond of the polyprenol, which is either four or five away from the terminal hydroxyprenyl subunit.

The synthesis of two very powerful and pleasant new odorants has been carried out from a common intermediate.

Bromolactamization of the N-Boc derivatives of unsaturated amides using N-bromosuccinimide and lithium t-butoxide in tetrahydrofuran occurs smoothly to give excellent yields of bromo N-Boc α-lactams, which are valuable as synthetic intermediates.

Three different methods have been developed that effectively utilize chiral oxiranes derived from Katsuki-Sharpless epoxidation of allylic alcohols as initiating groups for cationic cyclization of unsaturated substrates to form chiral polycycles. This type of transformation has previously been problematic. These employ either epoxy-methoximes, vinyl-substituted oxiranes, or hydroxymethyl oxiranes. All three approaches are described in detail. In addition, this research has led to possible explanations for previously encountered difficulties in this area and provided two new insights into the Lewis acid activation of oxiranes. The methodology described herein constitutes a valuable link between two powerful synthetic constructions, enantioselective Katsuki-Sharpless epoxidation and cationic polycyclization reactions.

Three different methods have been developed that effectively utilize chiral oxiranes derived from Katsuki-Sharpless epoxidation of allylic alcohols as initiating groups for cationic cyclization of unsaturated substrates to form chiral polycycles. This type of transformation has previously been problematic. These employ either epoxy-methoximes, vinyl-substituted oxiranes, or hydroxymethyl oxiranes. All three approaches are described in detail. In addition, this research has led to possible explanations for previously encountered difficulties in this area and provided two new insights into the Lewis acid activation of oxiranes. The methodology described herein constitutes a valuable link between two powerful synthetic constructions, enantioselective Katsuki-Sharpless epoxidation and cationic polycyclization reactions.

Removal of an iodide ion from InI3 by reactive Ag(I) produces the desired ligandless cation InI2+ as an effective agent in the title process.

This letter describes a combined photochemical and X-ray crystallographic study of routes for the synthesis of cyclobutane or ladderane structures by a [2+2]-cycloaddition pathway and leads to a clearer definition of the 3-D structural requirements for such processes in the solid state.

[Structure: see text] Under special conditions, N-phthaloyl-alpha-amino acid amides of 8-aminoquinoline can be either acetoxylated or arylated selectively at the beta-carbon. In certain cases, arylation can be effected at the gamma-carbon.

The ouabain isomers 1, 6, 20, 21, and 22 have been synthesized and shown to be readily separable by HPLC, which indicates that they do not correspond to a putative endogenous ouabain-like cardioregulator. 11-epi-Ouabain (1) is of interest as a safer alternative to ouabain.

Methods have been developed for the regioselective formation of both aldol condensation products from a non-symmetrical dialdehyde derived from 5α-cholestan-3-one. The findings disclosed herein, as well as their mechanistic implications, should assist in achieving selective intramolecular aldol closures in other contexts.

Chiral 2-cyclopropenyl-4-tolyl sulfones, available by the [2 + 1]-cycloaddition of tosyldiazomethane to acetylenes under catalysis by the Rh(II) complex 1, provide a number of unusual transformations and useful chiral products. This chemistry is dominated by the unusual strain and reactivity of the cyclopropene ring system.

This paper describes the synthesis of mixed Rh2(II) complexes containing bridging acetate and R,R-diphenyl-N-triflylimidazolidinone (DPTI) ligands (1, 2, and 9−19), and their function as enantioselective catalysts for the conversion of ethyl diazoacetate and terminal acetylenes to chiral cyclopropenes. Of these catalysts, 1 and 10 functioned with the highest enantioselectivity, in accord with a mechanistic model in which one of the ligand bridges is broken in the intermediate Rh−carbene complex. The synthetic results allow conclusions with regard to kinetically and thermodynamically favored pathways for the synthesis of mixed acetate−DPTI complexes. A new C2-symmetric complex having only two anti-DTBTI bridges (23) is shown to be a highly effective chiral catalyst, as expected from the model.

The chiral oxazaborolidinium salt 1 (X = TfO) is an excellent catalyst for the cyanosilylation of methyl ketones promoted by trimethylsilyl cyanide and diphenylmethyl phosphine oxide as co-reactants (to generate Ph(2)MePOTMS(N=C:) as a reactive intermediate). The face selectivity of this reaction parallels that previously observed for the corresponding reaction of aldehydes. A unifying and rational mechanistic explanation is provided for these enantioselective reactions. Evidence is presented to support the importance of alpha-C-H...O hydrogen bonding, pi,pi-interaction of the complexed ketonic carbonyl with the mexyl group of 1, and an early transition state for high enantioselectivity. The cyanosilylation reaction described herein provides access to many useful chiral compounds.