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>

Prebiotic Synthesis of α-Amino Acids and Orotate from α-Ketoacids Potentiates Transition to Extant Metabolic Pathways

The Strecker reaction of aldehydes is the preeminent pathway to explain the prebiotic origins of a-amino acids. However, biology employs transamination of a-ketoacids to give rise to amino acids which are then transformed to nucleobases, implying subsequent evolution of the biosynthetic pathways – abiotically or biotically. Herein, we show that a-ketoacids react with cyanide and ammonia sources to form the corresponding a-amino acids – via the Bucherer-Bergs pathway. An efficient prebiotic transformation of oxaloacetate to aspartate via N-carbamoyl aspartate enables the simultaneous formation of dihydroorotate, paralleling the biochemical synthesis of orotate as the precursor to pyrimidine nucleobases. Glyoxylate forms both glycine and orotate, and reacts with malonate and urea to form aspartate and dihydroorotate. These results, along with the previously demonstrated protometabolic analogs of the Krebs cycle suggest that there can be a natural emergence of congruent forerunners of biological pathways with the potential for seamless transition from prebiotic chemistry to modern metabolism.

Development of Chiral N-Alkoxyamide Strategy and Application to Asymmetric Total Synthesis of Fasicularin

The asymmetric total synthesis of fasicularin by a chiral N-alkoxyamide strategy is reported. Incorporation of the chiral alkoxy group to an amide nitrogen changes the original reactivity of the amide, enabling two key transformations: aza-spirocyclization and the reductive Strecker reaction. In the aza-spirocyclization, DFT calculations indicate that pyramidalization of the alkoxyamide nitrogen is crucial to control the reactivity. The chiral alkoxy group is also used as a stereocontrol element to establish two consecutive stereocenters. The iridium-catalyzed reductive Strecker reaction of the N-alkoxylactam provides the aminonitrile with high diastereoselectivity.

Preparation of (mono)sulfonates: Suitable precursors for unnatural sulfonolipids

Aiming at the preparation of the novel unnatural, non-isosteric sulfonolipids bearing one, two and three acyl groups 8, 9 and 10, their precursors hydroxyl-containing sulfonates have been prepared from a variety of hydroxyl-containing halogenides and epoxides using the Strecker reaction. Thus, the sulfonates 16 and 22 were prepared pure, while the sulfonate 27 could only be prepared as a by-product using 1,4-dibromo-2,3-butanediol 26 and in low yields. For these reactions, probable pathways leading to the isolated or spectroscopically identified products are proposed. Conclusions about the relative nucleophilicity of SO32- compared to AsO33 - (as well as HO- which is present in their aqueous solutions) were drawn based on the yields of the corresponding arsonic acids and sodium sulfonates. The IR (KBr) and 1H NMR (D2O) spectra of sulfonates (and in some cases of their sulfonic acids) are analyzed and discussed.