Synthesis of Those Sectors of Saccharomicin A and B ContainingSaccharosamine and the Discovery of a Novel 4-H-1,3-OxazineSynthesis Open Access
Balthaser, Bradley R (2009)
Abstract
Abstract Synthesis of Those Sectors of Saccharomicin A and B Containing Saccharosamine and the Discovery of a Novel 4-H-1,3-Oxazine Synthesis
By Bradley R. Balthaser Saccharomicin A and B are heptadecaglycosides which have been found to possess significant antibiotic activity against a wide array of Gram-positive and Gram-Negative bacteria. These structures possess several interesting structural features and are a composite of five deoxy sugars, including the rare amino sugar saccharosamine. The synthesis of those sectors of the saccharomicins which contain saccharosamine has been accomplished. Glycosylation of a racemic β-lactam with a fucosyl trichloroimidate provided the congested linkage of the C4-position of saccharosamine. Ring opening and functionalization of β-lactam moiety provided a key alkyne alcohol intermediate. A tungsten-catalyzed cycloisomerization of alkyne alcohols to glycals developed by our group was then use to provide fucosyl-saccharosamine glycal key intermediates, of which three analogues were ultimately produced. The racemic nature of the β-lactam moiety al owed the L-fucose-D-saccharosamine and the L-fucose-L-saccharosamine motifs to be accessed by a divergent route. Manipulation of each disaccharide to its peracetylated form al owed comparison to a degradation product from saccharomicin B, for which the peracetylated L-fucose-L-saccharosamine analogue was found to match as the antipode.
The L-fucosyl-L-saccharosamine glycal intermediate provided the opportunity for an extremely efficient Brønsted acid-promoted glycosylation to be carried out with appropriately functionalized glycosyl acceptors. This process provided access to digitoxose and rhamnose-affixed trisaccharides in 92% and 93% yield respectively. The syntheses of these trisaccharides were carried out such that the protecting group of the terminal fucosyl unit was orthogonal to the reducing end of each analogue, such that each compound might serve as a building block for further studies. During the course of these studies, an unexpected tungsten-catalyzed cycloisomerization of propargyl amides to 4-H-1,3-oxazines was discovered. Methods for the construction of these oxazines are rare, and the isomerization
represented a novel, and more mild methodology than those previously reported.
Preliminary investigations into the scope of this transformation were undertaken.
Table of Contents
Table of Contents Synthesis of Those Sectors of Saccharomicin A and B Containing Saccharosamine
1. Introduction and Background …………………………………………………. 1 1.1. Selected amino sugar containing antibiotics…………………………….... 2 1.2. Saccharomicins A and B……………………………………………………. 9 1.2.1. Biogenesis and antibiotic activity of the saccharomicins…………. 9 1.2.2. Characterization of the saccharomicins and the enantiomeric identity of its pyranosides ……………………………………………… 11 1.2.3. Previous synthetic work on the saccharomicins…………………... 16 1.3. Synthetic work relevant to the saccharosamine-containing sectors of the saccharomicins………………………………………………………………. 16 1.3.1. Previous syntheses and glycosylations of saccharosamine…….. 16 1.3.2. Tungsten catalyzed cycloisomerization of alkyne alcohols……… 22 1.4. Retrosynthetic analysis of the saccharosamine containing segments of saccharomicin A and B……………………………………………………… 28 2. Results and Discussion……………………………………………………….. 35 2.1. Synthesis of peracetylated L-fucose-L-saccharosamine, antipodal degradation product of saccharomicin B………………………………….. 35 2.2. Synthesis of peracetylated L-fucose-D-saccharosamine disaccharide… 51 2.3. Synthesis of L-fucose-L-saccharosamine-D-digitoxose and L-fucose-L- saccharosamine-D-rhamnose trisaccharide building blocks……………. 56 2.4. A cursory investigation of a tungsten-catalyzed cycloisomerization of propargyl amides, discovered in route to the saccharomicins………….. 75
3. Experiments.................................................... 85
3.1 Experimental procedures..................................... 85
3.1.1. Experimental procedures of section 2.1.............. 86
3.1.2. Experimental procedures of section 2.2............. 112
3.1.3. Experimental procedures of section 2.3............. 126
3.1.4. Experimental procedures of section 2.4............. 161
3.2. Pertinent COSY NMR spectra............................. 172
3.3. X-Ray database in the saccharomicin synthesis.... 178
4. References..................................................... 214
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