John R. Stille

Heterocycle formation through aza-annulation: A stereochemically controlled route to (±)-lupinine.

Abstract The aza-annulation of an acyclic β-enaminoester with acryloyl chloride was found to be a very efficient method for nitrogen heterocycle formation. Stereospecific hydrogenation of the unsaturated dihydropyridone generated from aza-annulation gave a single disubstituted lactam product. The cis stereochemical relationship of the substituents was confirmed by transformation of the lactam to (±)-lupinine.

Aza-annulation as a route to hydroxylated alkaloid lipids. The synthesis of (±)-prosopinine

Abstract The total synthesis of (±)-prosopinine is described. Aza-annulation was used to generate the six-membered nitrogen heterocycle, stereochemical control was achieved through the use of the δ-lactam template, and homologation of the lactam introduced the alkyl chain substituent on the piperidine ring.

5-Formyl salicylaldehyde as a linker for the synthesis of benzofuran containing insulin sensitivity enhancer compounds

Abstract 5-Formyl salicylaldehyde was prepared by treatment of 4-hydroxybenzaldehyde with HMTA in TFA. Reaction of this dialdehyde with α-haloacetyl aryl compounds gave 2,5-disubstituted benzofurans, from which an Insulin Sensitivity Enhancer compound was prepared.

Decahydroquinoline construction through aza-annulation: A stereoselective synthesis of (±)-5-epipumiliotoxin C.

Abstract Aza-annulation of activated acrylic acid derivatives with 3-benzylamino-2-cyclohexenone led to the efficient formation of the corresponding bicyclic lactam. Stereospecific hydrogenation of this unsaturated lactam resulted in the selective formation of the cis fused bicyclic alkaloid, and subsequent elaboration at C-5 and C-2 completed the synthesis of the decahydroquinoline alkaloid (±)-5-epipumiliotoxin C.

“Conformationally restricted β-amino acid isosteres prepared through regioselectively controlled aza-annulation.”

Abstract A variety of electron withdrawing substituents were used to enhance the aza-annulation of enamines with acryloyl chloride, to direct the regioselectivity of alkene formation, and to facilitate hydrogenation of the unsaturated annulation product. The resulting δ-lactam products were β-amino acid analogs with structural features similar to those of established peptide isosteres.

AZA-ANNULATION AS A VERSATILE APPROACH TO THE SYNTHESIS OF NON-BENZODIAZEPENE COMPOUNDS FOR THE TREATMENT OF SLEEP DISORDERS

Abstract The aza-annulation of enamino ester substrates has been demonstrated as an efficient alternative to the syntheses of non-benzodiazepine sleep inducers. Enamino ester substrates derived from aryl, thiophene, and indole functionality were prepared from the corresponding ethyl amines by isothiocyanate formation followed by acid catalyzed cyclization.

Stereochemical consequences of the lewis acid-promoted 3-aza-cope rearrangement of N-alkyl-N-allyl enamines

Abstract Internal and relative asymmetric induction were examined for the electrophile promoted 3-aza-Cope rearrangement of substituted N -alkyl- N -allyl enamines. In general, internal asymmetric induction was highly variable, and was dependent both upon the nature of the electrophilic reagent and substrate. However, substitution at C-4 of the substrate served to anchor the transition state of the substrates, and product selectivity was typically > 95:5. When the N -alkyl substituent was tethered to C-4, ring expansion from a five- to a nine-membered ring was obtained. The key features necessary for the stereoselective [3,3] rearrangement of N -alkyl- N -allyl enamies were determined through these studies. In the absence of a substituent at C-4, internal asymmetric induction that resulted from chair:boat transition state selectivity was highly variable, and was dependent both on the nature of the electrophilic reagent and substrate. In general, poor selectivity was obtained in these studies, and placement of a chiral peripheral substituent on the nitrogen did not improve selectivity through relative asymmetric induction. Substitution at C-4 was critical to the stereoselective rearrangement of these substrates, and incorporation of a methyl group at C-4 served to anchor the transition state of the acyclic substrates in the chair conformation. In these examples, chair:boat selectivity was typically > 95:5, and resulted in selective product formation. Rearrangement of a cyclic substrate, tethered at the C-4 and nitrogen positions, also generated products with a high degree of control over transition state geometry. Based on these studies, the scope and limitations of the charge accelerated [3,3] rearrangement of N -alkyl- N -allyl enamies has been outlined for future use.

Carbocycle formation via intramolecular insertion of alkynes into titanium-carbon bonds

Abstract Treatment of alkyl titanocene chloride complexes with the Lewis acids EtAlCl 2 or Me 2 AlCl resulted in intramolecular insertion of a tethered alkyne into the TiC bond. Regioselective alkyne insertion produced exocyclic trisubstituted alkene products resulting from four-, five-, and six-membered ring formation. In the case of cyclohexane formation, the alkyne was found to insert with syn stereoselectivity.

Competitive intramolecular TiC versus AlC alkene insertions: Examining the role of Lewis acid cocatalysts in Ziegler-Natta alkene insertion and chain transfer reactions

Abstract Mechanistic aspects of Ziegler-Natta olefin insertion, which include catalyst/cocatalyst interactions, chain propagation, and chain termination, have been examined for systems which model the Cp2Ti(Cl)R/RAlCl2 and Cp2Ti(Cl)R/MgX2 catalyst complexes. The reaction of (2-butyl-6-hepten-1-yl)titanocene chloride with (2-propyl-6-hepten-1-yl)aluminum dichloride:diethyl etherate produced 78% cyclization of the titanocene ligand, while less than 2% of the ligand originating on aluminum cyclized. In a complementary experiment, the reaction of (2-propyl-6-hepten-1-yl)titanocene chloride and (2-butyl-6-hepten-1-yl)aluminum dichloride:diethyl etherate again produced only intramolecular insertion of the titanium ligand (58%). Based on these results, equilibration of ligands through transmetallation between titanium and aluminum did not occur under these reaction conditions, and selective insertion into the titanium-carbon bond was confirmed for this process. Similarly, ligand cyclization with Cp2Ti(Cl)R/MgX2 also occurred through insertion into the titanium-carbon bond. The product distribution generated by the MgX2 was highly solvent dependent. Cyclization in CH2Cl2 was very efficient, while reaction in toluene generated numerous products. Included in the toluene reaction mixture were compounds that resulted from ligand transposition/chain transfer of the titanium ligand.

An Apparatus for the Efficient Removal of H2O from Reaction Mixtures

Abstract An apparatus has been designed that facilitates the azeotropic removal of H2O from a reaction mixture. Representative condensation reactions in which this apparatus was used include acetal, imine, and enamine formation.