T. Andrew Mitchell

Expanded Substrate Scope and Improved Reactivity of Ether-forming Cross-Coupling Reactions of Organotrifluoroborates and Acetals

Mixed acetals and organotrifluoroborates undergo BF(3)·OEt(2)-promoted cross-couplings to give dialkyl ethers under simple, mild conditions. A survey of reaction partners identified a hydroxamate leaving group that improves the regioselectivity and product yield in the BF(3)·OEt(2)-promoted coupling reaction of mixed acetals and potassium alkynyl-, alkenyl-, aryl- and heteroaryltrifluoroborates to access substituted dialkyl ethers. This leaving group enables the reaction to proceed rapidly under mild conditions (0 °C, 5-60 min) and permits reactions with electron-deficient potassium aryltrifluoroborates that are less reactive with other acetal substrates. A study of the reaction mechanism and characterization of key intermediates by NMR spectroscopy and X-ray crystallography identified a role for the hydroxamate moiety as a reversible leaving group that serves to stabilize the key oxocarbenium intermediate and the need for a slight excess of organodifluoroborane to serve as a catalyst. A secondary role for the boron nucleophile as an activating ligand was also considered. These studies provide the basis for a general class of reagents that lead to dialkyl ethers by a simple, predictable cross-coupling reaction.

Synthesis of dialkyl ethers from organotrifluoroborates and acetals.

The formation of ethers by C-O bond formation under harsh basic or acidic conditions is an entrenched synthetic disconnection in organic chemistry. We report a strategic alternative that involves the BF(3).OEt(2)-promoted coupling of stable, easily prepared acetals with widely available potassium aryl-, alkenyl-, and alkynyltrifluoroborates. This fast, operationally simple process offers straightforward access to dialkyl ethers, many of which would be difficult to prepare using classical methods. The use of MOM-protected alcohols and acetal-protected aldehydes enables ether formation without recourse to protecting-group manipulations or strong bases.

Diastereoselective, three-component cascade synthesis of tetrahydrofurans and tetrahydropyrans employing the tandem Mukaiyama aldol-lactonization process.

A full account of studies leading to the development of a cascade sequence that generates as many as two C-C bonds, one C-O bond, and three new stereocenters providing substituted tetrahydrofurans (THFs) from simple gamma-ketoaldehydes and thiopyridyl ketene acetals is described. The process involves a tandem Mukaiyama aldol-lactonization (TMAL) and accumulated evidence suggests the intermediacy of a silylated beta-lactone that is intercepted by the pendant ketone. Formation of a cyclic oxocarbenium is followed by reduction with silicon-based nucleophiles leading to a highly diastereoselective synthesis of tetrahydrofurans. This cascade process has now been extended to the synthesis of tetrahydropyrans from simple delta-ketoaldehydes. The stereochemical outcome of the cascade processes described was determined by NOE correlations, coupling constant analysis, and X-ray crystallography of the derived oxygen heterocycles and is in accord with established and recently proposed models for nucleophilic additions to cyclic 5- and 6-membered oxocarbenium ions. The utility of this process was demonstrated by the synthesis of the tetrahydrofuran fragment of colopsinol B.

Unique Reactivity of anti- and syn-Acetoxypyranones en Route to Oxidopyrylium Intermediates Leading to a Cascade Process

Unique reactivity of anti- and syn-acetoxypyranones was observed in oxidopyrylium-alkene [5 + 2] cycloadditions. The subtle interplay between the corresponding acetoxypyranone conformation and steric bulk of tertiary amine bases causes syn-acetoxypyranones to undergo [5 + 2] cycloaddition appreciably faster than anti-acetoxypyranones. Additionally, the efficiency of a cascade process that afforded a novel tetracyclic lactol was determined to be dependent on the relative stereochemistry of each diastereomer, the amine base utilized, and the addition of water.

Highly Diastereoselective, Tandem, Three-Component Synthesis of Tetrahydrofurans from Ketoaldehydes via Silylated β-Lactone Intermediates†

Processes that form multiple bonds and stereocenters in a single reaction, without the isolation of intermediates, are known as tandem, domino, multicomponent, or cascade reactions. They are powerful complexity-building reactions. We have developed stereoselective routes to both cis and trans b-lactones 5 through tandem Mukaiyama aldollactonization (TMAL) processes between thiopyridyl ketene acetal 2 and aldehyde 1 (Scheme 1, pathway a). This methodology has been utilized in total syntheses of ( )-panclicin D, orlistat and its congeners, okinonellins, brefeldin A, and belactosin C. In the course of these studies, we identified several by-products (e.g. b-chlorosilylester 4 ; Scheme 1, pathway b) that led us to propose the silylated b-lactone intermediate 3 in the TMAL process. Thus we considered methods for intercepting these intermediates to enable the study of useful complexity-building processes. Mead and Pillai have reported Lewis acid promoted reductive cyclizations of simple keto-b-lactones for tetrahydrofuran (THF) synthesis. This approach suggested the possibility of utilizing aldehyde substrates bearing pendant ketones that could undergo reductive cyclization in the TMAL process (Scheme 2). The THF motif is commonly found in natural products, and while several approaches toward these heterocycles exist, many routes rely on C O bond formation of relatively complex substrates or proceed through oxocarbenium ions derived from O-glycosides. Herein we describe the development of a tandem, threecomponent synthesis of THFs 9 from g-ketoaldehydes 6, thiopyridyl ketene acetals 2, and silyl nucleophiles in which up to two C C bonds, one C O bond, and three new stereocenters are generated.

FURTHER INVESTIGATION OF PYRANONE ACTIVATION

I. General Methods II. General Procedures for Acid-Mediated Reactions (Tables 1 & 2) III. Characterization of Cycloadduct 2 and By-products 3 & 4 IV. Preparation and Characterization of Pyranone 1c V. General Procedure for Microwave-Assisted Reactions (Table 3) VI. General Procedure for Microwave-Assisted Reactions (Table 4) VII. Preparation and Characterization of Acetoxypyranones 1c-g VIII. Computational Methods and Experimental Parameters IX. Spectra of Acetoxypyranones 1c-g

Oxidopyrylium-Alkene [5 + 2] Cycloaddition Conjugate Addition Cascade (C3) Sequences: Scope, Limitation, and Computational Investigations

Oxidopyrylium-alkene [5 + 2] cycloaddition conjugate addition cascade (C3) sequences are described. Intramolecular cycloadditions involving terminal alkenes, enals, and enones were investigated. Substrates with tethers of varying lengths delivered five- and six-membered carbocycles and heterocycles thus demonstrating the scope and limitation of the cycloaddition-conjugate addition cascade. Several experiments and theoretical calculations provide evidence for the proposed mechanistic pathway.