No description available.

In an attempt to expand the scope of titanacyclobutenes, malonate-derived ,-alkylpropargyl dibromides and ,-bis(bromopropargyl) malonates were prepared and examined for their reactivity with titanocene reagents. Unfortunately, all of the ,-alkylpropargyl dibromomalonates failed, presumably from chelation of the carbonyl oxygen followed by radical or nucleophilic attack. The ,-bis(bromopropargyl) malonate substrates allowed the successful synthesis of ester-functionalized allenyl or alkynyl-substituted bicyclic titanacyclobutene complexes. Allenyl-substitution is favoured when the being formed ring is small. When ring strain is minimal, cycloalkynes are obtained. An impressive example of a twelve-membered macrobicyclic titanacyclobutene was achieved, supported by extensive NMR spectroscopy and X-ray crystallography. 3-Propargyltitanium(III) complexes were synthesized and displayed equilibrium behaviour between the monomeric propargyl and dimeric di(titanacyclobutene) forms. Both steric and electronic effects are believed to be contributing factors for dimerization. Bimetallic titanacyclobutenes are obtained from the reaction of an epoxide and titanocene monochloride in the presence of a 3-propargyltitanium(III) complex.

No description available.

Macrocyclization is a synthetically challenging step in the total synthesis of natural products. The success of chemical approaches such as the Corey-Nicolaou, Yamaguchi and Keck macrolactonization is heavily based on the confirmation and stereochemistry of the substrate. While there have been some advances in computational modeling, it has been difficult to predict whether the above-mentioned reactions will work. We have begun characterizing polyketide thioesterase catalytic activity and substrate tolerance to find more efficient and dependable routes towards macrolactonization and macrolactamization.

In 2006, an amphoteric molecule containing both an aldehyde and an unprotected amine was reported in the Yudin group by Dr. Ryan Hili. The unprotected aziridine aldehyde exists as homochiral dimers. Furthermore, due to the reversibility of the hemiacetal formation, the free aldehyde is available to undergo a wide array of reactions including an Ugi multicomponent reaction to give the final peptide macrocycle. Thus far, the mechanistic pathway involved in the Ugi reaction between S-trans aziridine aldehyde dimer and L-amino acids in the presence of tert-butyl isocyanide has given high diastereoselectivity whereas low diastereoselectivity is observed if the aziridine dimer is of the opposite stereochemistry. Herein, preliminary results show that a S-cis aziridine aldehyde with either a D or L-secondary amino acid gives high diastereoselectivity showing that the reaction is under Felkin-Ahn control.

In 2006, an amphoteric molecule containing both an aldehyde and an unprotected amine was reported in the Yudin group by Dr. Ryan Hili. The unprotected aziridine aldehyde exists as homochiral dimers. Furthermore, due to the reversibility of the hemiacetal formation, the free aldehyde is available to undergo a wide array of reactions including an Ugi multicomponent reaction to give the final peptide macrocycle. Thus far, the mechanistic pathway involved in the Ugi reaction between S-trans aziridine aldehyde dimer and L-amino acids in the presence of tert-butyl isocyanide has given high diastereoselectivity whereas low diastereoselectivity is observed if the aziridine dimer is of the opposite stereochemistry. Herein, preliminary results show that a S-cis aziridine aldehyde with either a D or L-secondary amino acid gives high diastereoselectivity showing that the reaction is under Felkin-Ahn control.

Macrocyclization is a synthetically challenging step in the total synthesis of natural products. The success of chemical approaches such as the Corey-Nicolaou, Yamaguchi and Keck macrolactonization is heavily based on the confirmation and stereochemistry of the substrate. While there have been some advances in computational modeling, it has been difficult to predict whether the above-mentioned reactions will work. We have begun characterizing polyketide thioesterase catalytic activity and substrate tolerance to find more efficient and dependable routes towards macrolactonization and macrolactamization.

Fungal polyketides are a diverse class of natural products that possess many pharmacological properties, including anticancer properties. These properties are evident in the resorcylic acid lactones, a family of polyketides, including zearalenone and radicicol, which shows potent inhibition of tumour cell growth. The key step in the biosynthesis of these lactones is macrocyclization of a linear carboxylic acid into the macrolactone. This reaction is catalyzed by a polyketide synthase (PKS) thioesterase enzyme. Bacterial PKS thioesterases (TEs) have been extensively studied and their substrate specificity has been characterized in vitro. They are highly substrate selective for the macrocyclization reaction. Since Fungal PKS TEs show little sequence homology to bacterial TEs, we have begun investigating their substrate specificity. In particular we are examining the ability of fungal TEs to macrocyclize compounds with varying ring sizes, stereogenic configuration, and nucleophiles. Herein we present the synthesis of a number of diverse TE substrates and the in vitro macrocyclization results for the TEs from zearalenone and radicicol biosynthetic pathway with these substrates.

Fungal polyketides are a diverse class of natural products that possess many pharmacological properties, including anticancer properties. These properties are evident in the resorcylic acid lactones, a family of polyketides, including zearalenone and radicicol, which shows potent inhibition of tumour cell growth. The key step in the biosynthesis of these lactones is macrocyclization of a linear carboxylic acid into the macrolactone. This reaction is catalyzed by a polyketide synthase (PKS) thioesterase enzyme. Bacterial PKS thioesterases (TEs) have been extensively studied and their substrate specificity has been characterized in vitro. They are highly substrate selective for the macrocyclization reaction. Since Fungal PKS TEs show little sequence homology to bacterial TEs, we have begun investigating their substrate specificity. In particular we are examining the ability of fungal TEs to macrocyclize compounds with varying ring sizes, stereogenic configuration, and nucleophiles. Herein we present the synthesis of a number of diverse TE substrates and the in vitro macrocyclization results for the TEs from zearalenone and radicicol biosynthetic pathway with these substrates.

(-)-Gymnodimine is a member of a growing family of spirocylic imine containing marine natural products. The construction of the complete skeleton of (-)- gymnodimine has been accomplished in a convergent manner in 23 steps (the longest linear sequence). A highly diastereo- and enantioselective Diels-Alder reaction employing bis(oxazoline)·Cu(II) catalyst provided the spirolactam core structure of gymnodimine bearing a quaternary carbon stereogenic center. An improved procedure for hydrostannylation of the hindered internal triple bond in 96a was discovered by slow addition of tributyltin hydride to minimize formation of hydrogenated byproduct. Fragment coupling featured a Nozaki-Hiyama-Kishi reaction between a vinyl iodide derived from the spirolactam and a tetrahydrofuran moiety. The macrocyclization was realized through a rather unusual intramolecular opening of an activated Ntosyllactam by an alkyllithium species generated in situ. The butenolide was appended through a vinylogous Mukaiyama aldol addition of silyloxyfuran 155 to the ketone 163 under meticulously controlled conditions. The generality of this process was explored in some detail. Addition of silyloxyfurans to cyclohexanones proceeds with moderate to good diastereoselectivities. The potential application of this process to the synthesis of butenolide and g-lactone containing natural products was demonstrated by further transformations of the addition adducts. Finally, toward our goal of developing an enzyme-linked immunosorbent assay (ELISA) for gymnodimine monitoring a hapten derived from the tetrahydrofuran has been synthesized. Even though the raised antibodies failed to recognize the natural product itself, the results provided some information regarding the essential structural elements of an efficient hapten.