Michael A. Kerr

Intramolecular annulations of donor–acceptor cyclopropanes

The intramolecular reaction of donor–acceptor cyclopropanes with various dipoles and dipolar equivalents allows access to a variety of bicyclic adducts with good stereocontrol. The linkers can often be cleaved to provide stereodefined products.

Stereodivergent Methodology for the Synthesis of Complex Pyrrolidines

The intramolecular reaction of oxime ethers and cyclopropane diesters results in the diastereoselective formation of substituted pyrrolo-isoxazolidines which serve as precursors to the ubiquitous pyrrolidine motif. A simple reversal of addition order of catalyst and substrate results in formation of two discrete diastereomers in a highly selective and predictable manner. The adducts are prepared in excellent yields from either enantiomer of an alkoxyamino-tethered cyclopropanediester, allowing efficient access to highly substituted homochiral pyrrolidines.

Zn(II)-Catalyzed synthesis of piperidines from propargyl amines and cyclopropanes.

The reaction of benzyl-protected propargyl amines and 1,1-cyclopropane diesters in the presence of catalytic Zn(NTf(2))(2) allows access to highly functionalized piperidines in excellent yields. The process proceeds via a tandem cyclopropane ring-opening/Conia-ene cyclization.

Total Synthesis of (±)-Mersicarpine

The first total synthesis of the indole alkaloid mersicarpine is reported. Key steps include a beta-dicarbonyl radical cyclization, as well as an oxidation of the benzopyrrole moiety to establish the masked 1,2-dicarbonyl functionality. An X-ray crystal structure and discussion of the 1H NMR behavior of the natural product are also presented.

Total Synthesis of (+)-Isatisine A†

The asymmetric total synthesis of (+)-isatisine A has been accomplished commencing with a Lewis acid-catalyzed cyclization of homochiral (S)-vinylcyclopropane diester and N-tosylindole-2-carboxaldehyde to construct the tetrahydrofuran ring. A palladium-catalyzed oxidative decarboxylation was utilized to obtain the dihydrofuran required for the subsequent dihydroxylation reaction to install the diol present on the tetrahydrofuran ring. The total synthesis was completed by an indole oxidation and electrophilic aromatic substitution sequence to construct isatisine A acetonide, which was then carried forward to the antipode of the natural product. The absolute configuration of the natural enantiomer (−)-isatisine A was determined to be C2(S), C9(R), C10(S), C12(R), and C13(R).

Tandem cyclopropane ring-opening/Conia-ene reactions of 2-alkynyl indoles: a [3 + 3] annulative route to tetrahydrocarbazoles.

A Zn(NTf(2))(2) catalyzed tandem reaction consisting of a nucelophilic ring opening of 1,1-cyclopropanediesters by 2-alkynyl indoles followed by a Conia-ene ring closure results in the efficient one-step synthesis of tetrahydrocarbazoles. The adducts may be further elaborated to carbazoles.

Total synthesis of (+)-isatisine A.

The asymmetric total synthesis of (+)-isatisine A has been accomplished commencing with a Lewis acid-catalyzed cyclization of homochiral (S)-vinylcyclopropane diester and N-tosylindole-2-carboxaldehyde to construct the tetrahydrofuran ring. A palladium-catalyzed oxidative decarboxylation was utilized to obtain the dihydrofuran required for the subsequent dihydroxylation reaction to install the diol present on the tetrahydrofuran ring. The total synthesis was completed by an indole oxidation and electrophilic aromatic substitution sequence to construct isatisine A acetonide, which was then carried forward to the antipode of the natural product. The absolute configuration of the natural enantiomer (-)-isatisine A was determined to be C2(S), C9(R), C10(S), C12(R), and C13(R).

Total Synthesis of (−)‐Allosecurinine

leaves of Securinega suffruticosa. However, its structure was not determined until 1962 when it was isolated once again and studied further. Along with securinine, a small amount of another compound was isolated and was found to be epimeric at the C2 position. This new compound was named allosecurinine. Further work by other research groups has since led to the discovery of several other securinega alkaloids including the enantiomeric forms of both 1 and 2, virosecurinine (3) and viroallosecurinine (4), respectively. The family is currently composed of 20 or more members. There is great interest in this family of alkaloids in the synthetic chemistry community, both for the synthetic challenge represented by their complex ring system and because of the known biological activities of some family members. Securinine, for instance, has been shown to be a g-aminobutyric acid (GABA) receptor antagonist, and many of the plants that produce Securinega alkaloids have been used in traditional folk medicine. Further biological research has shown some members to have antimalarial, antibiotic, and antifungal activities to name but a few. Our interest in the Securinega alkaloids began several years ago with the total synthesis of (+)-phyllantidine 5, a recently isolated natural product containing a tetrahydro-1,2-oxazine ring system. Our focus then fell upon allosecurinine, which, though isolated in 1962 has not been prepared by chemical synthesis, although there is a single synthesis reported for its enantiomer (also naturally occurring), viroallosecurinine. Recently, we have reported a methodology that allows easy access to both 2,5-transand 2,5-cis-substituted pyrrolidines (Scheme 1), and it was decided that its first application would be the synthesis of allosecurinine.

Multicomponent Synthesis of Pyrroles from Cyclopropanes: A One-Pot Palladium(0)-Catalyzed Dehydrocarbonylation/Dehydration†

Ring the changes: The cycloaddition of nitrones with 1-carboallyloxy-1-carbomethoxycyclopropanes yields tetrahydro-1,2-oxazines, which in turn undergo a Tsuji dehydrocarbonylation to give dihydro-1,2-oxazines (see scheme; dba = dibenzylideneacetone). Addition of base to this reaction mixture results in clean conversion to pyrroles. The result is a flexible three-component strategy for the synthesis of tetrasubstituted pyrroles.

Domino Synthesis of Bridged Bicyclic Tetrahydro-1,2-oxazines: Access to Stereodefined 4-Aminocyclohexanols

The intramolecular variant of the homo-[3 + 2]-dipolar cycloaddition of nitrones (generated in situ from an aldehyde and a hydroxylamine) with donor-acceptor cyclopropanes allows for the efficient synthesis of bridged tetrahydro-1,2-oxazines. This domino sequence produces adducts amenable to reductive N-O bond cleavage producing cis-1,4-aminocyclohexanols in excellent yields.