Mechanistic Study on Gold(I)-Catalyzed Unsaturated Spiroketalization Reaction

The mechanism of metal-catalyzed spiroketalization of propargyl acetonide is explored by employing DFT with the B3LYP/6-31+G(d) method. Acetonide is used as a regioselective regulator in the formation of monounsaturated spiroketal. The energies of transition states, intermediates, reactants and products are calculated to provide new insight into the mechanism of the reaction. The energetic features, validation of the observed trends in regioselectivity are conferred in terms of electronic indices via FMO analysis. The presence of acetonide facilitates a stepwise spiroketalization as it masks the competing nucleophile, and thus hydroxyl group present, exclusively acts as a nucleophile. The vinyl gold intermediate 3 is formed from 2 via activation barrier TS1. This is the first ring formation, which is 6-exo-dig cyclization. The intermediate 3 is converted into allenyl ether 4, which isomerizes to the intermediate oxocarbenium ion 5 via activation barrier TS2. The intermediate 5 cyclizes to 6 via TS3. This is the second ring formation. The intermediate 6 on protodeauration turns into 6,6-monounsaturated spiroketal 7. It is concluded that acetonide as a protecting group serves the purpose, and thus a wide range of spiroketals can be prepared, regioselectivity.

The Synthesis of Azasugars Using an I2-mediated Carbamate Annulation

<p>The biological activity of azasugars has largely been attributed to their ability to mimic the oxocarbenium ion-like transition state formed during reactions with carbohydrate-processing enzymes and, for this reason, functional and stereochemical modifications of the azasugar scaffold have led to the development of specific and potent glycosidase inhibitors. Given the potential of azasugars as glycosidase inhibitors, we were interested in developing efficient methodology for their synthesis. This thesis highlights synthetic methodology developed to produce amino-imino-hexitols as azasugar scaffolds. Key in the synthesis of the amino-imino-hexitols was the application of a stereoselective Strecker reaction, without the need for chiral Lewis acids or catalysts, and an extension of an I2-mediated carbamate annulation to cyclise functionalised and protected alkenylamines. Sixteen amino-imino-hexitols were synthesized, including ten previously undisclosed substrates with the D-galacto, D-talo, and L-altro configurations. The novel amino-imino-hexitols were then tested for their ability to act as glycosidase inhibitors and substrates of the D-talo configuration showed promising inhibitory effects. Mechanistic considerations of the I2-mediated carbamate annulation are discussed and although the exact annulation mechanism has yet to be determined, experimental studies have revealed that an aziridine is not an intermediate in the reaction. Factors influencing the diastereoselectivity of the carbamate annulation are also explored. Furthermore, an in depth analysis of the high cis-selectivity of the carbamate annulation is investigated using density functional theory to calculate the transition states of iodocyclisations en route to the formation of carbamates. Taken as a whole, the applicability of the carbamate annulation to a variety of alkenylamines and an understanding of the factors controlling the diastereoselectivity of the reaction should make this methodology a valuable addition to the synthetic chemist’s toolbox.</p>

The Synthesis of Azasugars Using an I2-mediated Carbamate Annulation

<p>The biological activity of azasugars has largely been attributed to their ability to mimic the oxocarbenium ion-like transition state formed during reactions with carbohydrate-processing enzymes and, for this reason, functional and stereochemical modifications of the azasugar scaffold have led to the development of specific and potent glycosidase inhibitors. Given the potential of azasugars as glycosidase inhibitors, we were interested in developing efficient methodology for their synthesis. This thesis highlights synthetic methodology developed to produce amino-imino-hexitols as azasugar scaffolds. Key in the synthesis of the amino-imino-hexitols was the application of a stereoselective Strecker reaction, without the need for chiral Lewis acids or catalysts, and an extension of an I2-mediated carbamate annulation to cyclise functionalised and protected alkenylamines. Sixteen amino-imino-hexitols were synthesized, including ten previously undisclosed substrates with the D-galacto, D-talo, and L-altro configurations. The novel amino-imino-hexitols were then tested for their ability to act as glycosidase inhibitors and substrates of the D-talo configuration showed promising inhibitory effects. Mechanistic considerations of the I2-mediated carbamate annulation are discussed and although the exact annulation mechanism has yet to be determined, experimental studies have revealed that an aziridine is not an intermediate in the reaction. Factors influencing the diastereoselectivity of the carbamate annulation are also explored. Furthermore, an in depth analysis of the high cis-selectivity of the carbamate annulation is investigated using density functional theory to calculate the transition states of iodocyclisations en route to the formation of carbamates. Taken as a whole, the applicability of the carbamate annulation to a variety of alkenylamines and an understanding of the factors controlling the diastereoselectivity of the reaction should make this methodology a valuable addition to the synthetic chemist’s toolbox.</p>

Lyophyllin, a Mushroom Protein from the Peptidase M35 Superfamily Is an RNA N-Glycosidase

Ribosome-inactivating proteins (RIPs) hydrolyze the N-glycosidic bond and depurinate a specific adenine residue (A-4324 in rat 28S ribosomal RNA, rRNA) in the conserved α-sarcin/ricin loop (α-SRL) of rRNA. In this study, we have purified and characterized lyophyllin, an unconventional RIP from Lyophyllum shimeji, an edible mushroom. The protein resembles peptidase M35 domain of peptidyl-Lys metalloendopeptidases. Nevertheless, protein either from the mushroom or in recombinant form possessed N-glycosidase and protein synthesis inhibitory activities. A homology model of lyophyllin was constructed. It was found that the zinc binding pocket of this protein resembles the catalytic cleft of a classical RIP, with key amino acids that interact with the adenine substrate in the appropriate positions. Mutational studies showed that E122 may play a role in stabilizing the positively charged oxocarbenium ion and H121 for protonating N-3 of adenine. The tyrosine residues Y137 and Y104 may be used for stacking the target adenine ring. This work first shows a protein in the peptidase M35 superfamily based on conserved domain search possessing N-glycosidase activity.

End-of-life upcycling of robust polyurethanes using a room temperature, mechanism-based degradation

A major challenge in developing recyclable polymeric materials is the inherent conflict between the properties required during and after its life span. In particular, materials must be strong and durable when in use, but undergo complete and rapid degradation upon end-of-life. We report a new mechanism for degrading polyurethanes called CyclizAtion-Triggered CHain (CATCH) cleavage that achieves this duality. CATCH cleavage features a simple glycerol-based acyclic acetal unit as a kinetic and thermodynamic trap for gated chain-shattering. Thus, an organic acid induces transient chain breaks with oxocarbenium ion formation and subsequent intramolecular cyclization to depolymerize fully the polyurethane backbone at room temperature. With minimal chemical modification, the resulting degradation products can be repurposed into strong adhesives and photochromic coatings demonstrating the potential for upcycling. The CATCH cleavage strategy for low-energy input breakdown and subsequent upcycling may be generalizable to a broader range of synthetic polymers and their end-of-life waste streams.

Enantioselective, Catalytic Multicomponent Synthesis of Homoallylic Amines Enabled by Hydrogen-Bonding and Dispersive Interactions

We report a one-step catalytic, enantioselective method for the preparation of homoallylic <i>N</i>-Boc amines directly from acetals. Reactive iminium ion intermediates are generated <i>in situ</i> through the combination of an acetal, a chiral thiourea catalyst, trialkylsilyl triflate, and <i>N</i>-Boc carbamate, and are subsequently trapped by a variety of allylsilane nucleophiles. No homoallylic ether byproducts are detected, consistent with allylation of the iminium intermediate being highly favored over allylation of the intermediate oxocarbenium ion. Acetals derived from aromatic aldehydes possessing a variety of functional groups and substitution patterns yield homoallylic amines with excellent levels of enantiomeric enrichment. Experimental and computational data are consistent with an anchoring hydrogen-bond interaction between the protoiminium ion and the amide of the catalyst in the enantiodetermining transition state, and with stereodifferentiation achieved through specific non-covalent interactions (NCIs) with the catalyst pyrenyl moiety. Evidence is provided that the key NCI in the major pathway is a π-stacking interaction, contrasting with the cation–π interactions invoked in previously studied reactions promoted by the same family of aryl-pyrrolidino-H-bond-donor catalysts.

Enantioselective, Catalytic Multicomponent Synthesis of Homoallylic Amines Enabled by Hydrogen-Bonding and Dispersive Interactions

We report a one-step catalytic, enantioselective method for the preparation of homoallylic <i>N</i>-Boc amines directly from acetals. Reactive iminium ion intermediates are generated <i>in situ</i> through the combination of an acetal, a chiral thiourea catalyst, trialkylsilyl triflate, and <i>N</i>-Boc carbamate, and are subsequently trapped by a variety of allylsilane nucleophiles. No homoallylic ether byproducts are detected, consistent with allylation of the iminium intermediate being highly favored over allylation of the intermediate oxocarbenium ion. Acetals derived from aromatic aldehydes possessing a variety of functional groups and substitution patterns yield homoallylic amines with excellent levels of enantiomeric enrichment. Experimental and computational data are consistent with an anchoring hydrogen-bond interaction between the protoiminium ion and the amide of the catalyst in the enantiodetermining transition state, and with stereodifferentiation achieved through specific non-covalent interactions (NCIs) with the catalyst pyrenyl moiety. Evidence is provided that the key NCI in the major pathway is a π-stacking interaction, contrasting with the cation–π interactions invoked in previously studied reactions promoted by the same family of aryl-pyrrolidino-H-bond-donor catalysts.

A Platform for Alkene Carbofunctionalization with Diverse Nucleophiles

A general system achieving three-component intermolecular carbofunctionalization of alkenes is presented. A range of substituted alkenes are functionalized with α-bromo carbonyl electrophiles and nitrogen, oxygen, and carbon nucleophiles. Mechanistic findings support the intermediacy of a cyclic oxocarbenium ion.

A Platform for Alkene Carbofunctionalization with Diverse Nucleophiles

A general system achieving three-component intermolecular carbofunctionalization of alkenes is presented. A range of substituted alkenes are functionalized with α-bromo carbonyl electrophiles and nitrogen, oxygen, and carbon nucleophiles. Mechanistic findings support the intermediacy of a cyclic oxocarbenium ion.