Rhodium-Catalyzed Alkene Difunctionalization with Nitrenes.

The Rh(II) -catalyzed oxyamination and diamination of alkenes generate 1,2-amino alcohols and 1,2-diamines, respectively, in good to excellent yields and with complete regiocontrol. In the case of diamination, the intramolecular reaction provides an efficient method for the preparation of pyrrolidines, and the intermolecular reaction produces vicinal amines with orthogonal protecting groups. These alkene difunctionalizations proceed by aziridination followed by nucleophilic ring opening induced by an Rh-bound nitrene generated in situ, details of which were uncovered by both experimental and theoretical studies. In particular, DFT calculations show that the nitrogen atom of the putative [Rh]2 =NR metallanitrene intermediate is electrophilic and support an aziridine activation pathway by N⋅⋅⋅N=[Rh]2 bond formation, in addition to the N⋅⋅⋅[Rh]2 =NR coordination mode.

Catalytic intermolecular alkene oxyamination with nitrenes.

The Rh(II)-catalyzed intermolecular addition of nitrenes to aromatic and aliphatic alkenes provides vicinal amino alcohols with yields of up to 95 % and complete regioselectivity. This 1,2-oxyamination reaction involves the formation of an aziridine intermediate that undergoes in situ ring opening. The latter is induced by the Rh-bound nitrene that behaves as a Lewis acid.

Gold (III) Chloride-Catalyzed 6-endo-trig Oxa-Michael Addition Reactions for Diastereoselective Synthesis of Fused Tetrahydropyranones.

Alkynones were treated with boron trifluoride diethyl etherate to generate ß-iodoallenolates, which underwent intramolecular aldol reactions to produce cycloalkenyl alcohols. Diastereoselective oxa-Michael ring closure could then be induced by treatment with a catalytic amount of gold(III) chloride, affording highly functionalized tetrahydropyran-containing ring systems.

Cascade cyclizations of acyclic and macrocyclic alkynones: studies toward the synthesis of phomactin A.

A study of the reactivity and diastereoselectivity of the Lewis acid promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. In these reactions, a ß-iodoallenolate intermediate is generated via conjugate addition of iodide to an alkynone followed by an intramolecular aldol reaction with a tethered aldehyde to afford a cyclohexenyl alcohol. The Lewis acid magnesium iodide (MgI2) was found to promote irreversible ring closure, while cyclizations using BF3·OEt2 as promoter occurred reversibly. For both acyclic and macrocyclic alkynones, high diastereoselectivity was observed in the intramolecular aldol reaction. The MgI2 protocol for cyclization was applied to the synthesis of advanced intermediates relevant to the synthesis of phomactin natural products, during which a novel transannular cation-olefin cyclization was observed. DFT calculations were conducted to analyze the mechanism of this unusual MgI2-promoted process.

Experimental and theoretical studies on the Nazarov cyclization/Wagner-Meerwein rearrangement sequence.

Highly functionalized cyclopentenones can be generated by a chemoselective copper(II)-mediated Nazarov/Wagner-Meerwein rearrangement sequence of divinyl ketones. A detailed investigation of this sequence is described including a study of substrate scope and limitations. After the initial 4π electrocyclization, this reaction proceeds via two different sequential [1,2]-shifts, with selectivity that depends upon either migratory ability or the steric bulkiness of the substituents at C1 and C5. This methodology allows the creation of vicinal stereogenic centers, including adjacent quaternary centers. This sequence can also be achieved by using a catalytic amount of copper(II) in combination with NaBAr(4)(f), a weak Lewis acid. During the study of the scope of the reaction, a partial or complete E/Z isomerization of the enone moiety was observed in some cases prior to the cyclization, which resulted in a mixture of diastereomeric products. Use of a Cu(II)-bisoxazoline complex prevented the isomerization, allowing high diastereoselectivity to be obtained in all substrate types. In addition, the reaction sequence was studied by DFT computations at the UB3LYP/6-31G(d,p) level, which are consistent with the proposed sequences observed, including E/Z isomerizations and chemoselective Wagner-Meerwein shifts.

A macrocyclic ß-iodoallenolate intermediate is key: synthesis of the ABD core of phomactin A.

An enantioselective strategy for the synthesis of phomactin natural products is described. The Lewis acid triggered cyclization of a ß-iodoallenolate embedded in a 12-membered macrocycle was used to obtain a highly functionalized bicyclo[9.3.1]pentadecane in good yield and high diastereoselectivity. This iodoenone contains the substituents of the AD ring system of the phomactin family of natural products, appropriate for further functionalization. Synthesis of the oxadecalin core of phomactin A from the AD iodoenone intermediate was achieved. In this unusual strategy, rings A and B are both fashioned within a macrocyclic precursor.

Beta-iodoallenolates as springboards for annulation reactions.

Beta-iodoallenolates II, generated from alkynones I with tetra-n-butylammonium iodide and a Lewis acid, underwent selective single or double annulation, depending on the Lewis acid promoter. Treatment with TiCl(4) gave cyclohexenyl alcohols III, whereas BF(3) x OEt(2) gave oxadecalins IV. The scope and limitations of the two annulation reactions are described.