A Method for the Catalytic Enantioselective Synthesis of Chiral α-Azido and α-Amino Ketones from Racemic α-Bromo Ketones, and Its Generalization to the Formation of Bonds to C, O, and S.

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.

Enantioselective Conversion of Oligoprenol Derivatives to Macrocycles in the Germacrene, Cembrene, and 18-Membered Cyclic Sesterterpene Series.

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-ß-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.

Method for Highly Enantioselective Ligation of Two Chiral C(sp3) Stereocenters.

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.

Acceleration of Enantioselective Cycloadditions Catalyzed by Second-Generation Chiral Oxazaborolidinium Triflimidates by Biscoordinating Lewis Acids.

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,ß-unsaturated acid chlorides.

Cationic Chiral Fluorinated Oxazaborolidines. More Potent, Second-Generation Catalysts for Highly Enantioselective Cycloaddition Reactions.

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.

A systematic study of functionalized oxiranes as initiating groups for 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.

Diiodoindium(III) cation, InI2⁺, a potent yneophile. Generation and application to cationic cyclization by selective π-activation of C≡C.

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.

Useful catalytic enantioselective cationic double annulation reactions initiated at an internal π-bond: method and applications.

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.

Specific and Strong Acceleration of Nitrosation by Nitrosyl Sulfonates Using the Bis-Coordinating Lewis Acid TiCl4 or SnCl4.

Nitrosyl triflate is an excellent donor of NO+ to C═C and very unreactive benzenoids, in contrast to the much less reactive nitrosyl mesylate. However, both of these reagents are strongly activated by the bis-coordinating Lewis acids TiCl4 and SnCl4 and become super reactive NO+ donors. Strong catalysis and activation are even observed with the inherently less electrophilic nitrosyl trifluoroacetate. Monocoordinating strong Lewis acids, e.g., MeAlCl2, are relatively ineffective.

Mechanism of the Reaction of Olefins with Nitrous Anhydride (O═N-O-N═O) to Form 1,2-Oxazetes.

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 ß-nitroso nitrite ester that is sensitive to light, undergoes O-NO fission to form a ß-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.

Two Unprecedented Reactions of Nitrosyl Triflate: NO+-Induced Cationic Cascade Cyclization and C═C Oxidative Cleavage.

Nitrosyl triflate is shown to react with olefins in a CH2Cl2 solution by three different pathways depending on structure and reaction conditions: (1) cationic cyclization, (2) C═C cleavage, and (3) allylic nitrosation. Possible reaction pathways are described.

Synthesis of Tetracyclic C2-Symmetric Ketiminium Salts and Evaluation as Catalysts for Epoxidation.

Short synthetic routes to the nonplanar tetracyclic ketiminium salt A and two close analogs are described. These are helical nonplanar structures as shown by X-ray crystallography.

Synthetically Useful Transformations of Olefins via Cationic 1,2-Oxazetium Intermediates.

Nitrosyl triflate serves as a NO+ donor in reactions with many olefinic substrates to form reactive, cationic 1,2-oxazetium cycloadducts that can be converted selectively into a wide range of useful products depending on reagents and conditions.

Highly enantioselective proton-initiated polycyclization of polyenes.

This report describes the synthesis of a range of chiral polycyclic molecules (tricyclic to pentacyclic) from achiral polyene precursors by enantioselective proton-initiated polycyclization promoted by the 1:1 complex of o,o'-dichloro-BINOL and SbCl(5). Excellent yields (ca. 90% per ring formed) and enantioselectivety (20:1 to 50:1) were obtained. The process is practical as well as efficient, because the chiral ligand is both readily prepared from R,R- or S,S-BINOL and easily recovered from the reaction mixture by extraction.

A tetradentate ligand for the enantioselective Ti(IV)-promoted oxidation of sulfides to sulfoxides: origin of enantioselectivity.

A detailed stereomechanistic analysis has led to the design of a new tetradentate ligand for the enantioselective Ti(IV)-catalyzed oxidation of unsymmetrical sulfides to sulfoxides with high selectivity. The pathway of this oxidation and the closely related and long-known Kagan-Modena oxidation have been clarified to identify the likely origin of the enantioselectivity.

Nitrosyl Triflate and Nitrous Anhydride, Same Mode of Generation, but Very Different Reaction Pathways. Direct Synthesis of 1,2-Oxazetes, Nitroso or Bisoxazo Compounds from Olefins.

Nitrosyl triflate (TfONO) can be generated in situ from tetra-n-butylammonium nitrite and triflic anhydride (1:1) in CH2Cl2 solution at ca. -30 °C. It acts as a powerful and soluble nitrosating agent with a wide range of olefinic or aromatic substrates. Nitrous anhydride (O═N-O-N═O) can be generated in the same way using tetra-n-butylammonium nitrite and triflic anhydride (2:1) in CH2Cl2 solution at ca. -30 °C. Each reagent has been isolated and characterized. They react with olefins to give different products. Nitrosyl triflate is an excellent reagent for generating either vinylic or allylic nitroso compounds or their dimeric bisoxazo derivates. Nitrous anhydride efficiently converts many olefins to 1,2-oxazetes in a single step, making this class of compounds readily available from olefins for the first time. We have also discovered another route to 1,2-oxazetes involving a novel rearrangement/isomerization of allylic nitroso compounds which is catalyzed by Pd-C/H2.

A powerful new construction of complex chiral polycycles by an indium(III)-catalyzed cationic cascade.

InI(3) and InBr(3) have been found to be effective catalysts for the π activation of C≡C bonds to initiate the conversion of chiral propargylic alcohols or silyl ethers to polycyclic products in excellent yields and with high stereoselectivity. The method has been applied to the synthesis of chiral fused hexacyclic ring systems with the creation of multiple new stereocenters. The power and scope of the method are illustrated by a variety of examples.

A Useful Method for the Conversion of Olefins to Nitro Olefins.

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.

Contrasting Diastereoselectivity between Cyclic Nitrones and Azomethine Ylides. Stereocontrolled Pathways to cis-anti-anti-cis-Oxazatetraquinanes from a Bicyclic Nitrone.

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.

Unraveling the C2-Symmetric Azatetraquinane System. Simple, Enantioselective Syntheses.

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 methodology for [3+2] cycloaddition and stereochemical control.