The Dimethoxyphenylbenzyl Protecting Group: An Alternative to the <i>p</i>‑Methoxybenzyl Group for Protection of Carbohydrates

A reliable reagent system for the cleavage of 4-(3,4-dimethoxyphenyl)­benzyl (DMPBn) ethers under acidic conditions has been established. Treatment of DMPBn-protected mono- and pseudodisaccharides with TFA in anhydrous CH₂Cl₂ and 3,4-(methylenedioxy)­toluene as a cation scavenger resulted in the selective cleavage of the DMPBn ether giving the corresponding deprotected products in moderate to high yields. Examples are reported which show that allyl, benzyl, and <i>p</i>-bromobenzyl ethers, esters, and glycosidic linkages are stable to these reaction conditions. The selective cleavage of allyl, <i>p</i>-bromobenzyl, and PMB ethers in protected carbohydrates containing DMPBn ethers are also demonstrated. This work establishes the 4-(3,4-dimethoxyphenyl)­benzyl ether as an effective and robust alternative to <i>p</i>-methoxybenzyl as a protecting group for alcohols

Resolution of Orthogonally Protected <i>myo</i>-Inositols with Novozym 435 Providing an Enantioconvergent Pathway to Ac₂PIM₁

Orthogonally protected chiral <i>myo-</i>inositol derivatives are important intermediates for higher order <i>myo</i>-inositol-containing compounds. Here, the use of the immobilized enzyme Novozym 435 to efficiently catalyze the acetylation of the 5<i>R</i> configured enantiomer of racemic 1,2-<i>O</i>-isopropylidene-<i>myo</i>-inositols possessing chemically and sterically diverse protecting groups at O-3 and O-6 is described. The resolutions were successful with allyl, benzyl, 4-bromo-, 4-methoxy-, 4-nitro-, and 4-(3,4-dimethoxyphenyl)­benzyl, propyl, and propargyl protection at O-6 in combination with either allyl or benzyl groups at O-3. Bulky protecting groups slow the rate of acetylation. No reaction was observed for 3,6-di-<i>O</i>-triisopropylsilyl-1,2-<i>O</i>-isopropylidene-<i>myo</i>-inositol. The utility of this methodology was demonstrated by the first reported synthesis of an Ac₂PIM₁ (<b>9</b>), which used both enantiomers of the resolved 3-<i>O</i>-allyl-6-<i>O</i>-benzyl-1,2-<i>O</i>-isopropylidene-<i>myo</i>-inositol in a convergent synthesis

The Rapid and Facile Synthesis of Oxyamine Linkers for the Preparation of Hydrolytically Stable Glycoconjugates

The synthesis of a number of <i>N</i>-glycosyl-<i>N</i>-alkyl-methoxyamine bifunctional linkers is described. The linkers contain an <i>N</i>-methoxyamine functional group for conjugation to carbohydrates and a terminal group, such as an amine, azide, thiol, or carboxylic acid, for conjugation to the probe of choice. The strategy for the linker synthesis is rapid (3–4 steps) and efficient (51–96% overall yield), and many of the linkers can be synthesized using a three-step one-pot strategy. Moreover, the linkers can be conjugated to glycans in excellent yield and they show excellent stability toward hydrolytic cleavage

Synthesis and Mass Spectral Characterization of Mycobacterial Phosphatidylinositol and Its Dimannosides

A family of naturally occurring mycobacterial phosphatidylinositol (PI) and its dimannosides (PIM₂, AcPIM₂, and Ac₂PIM₂) that all possess the predominant natural 19:0/16:0 phosphatidyl acylation pattern were prepared to study their mass spectral fragmentations. Among these, the first synthesis of a fully lipidated PIM (i.e., (16:0,18:0)­(19:0/16:0)-PIM₂) was achieved from (±)-1,2:4,5-diisopropylidene-d-<i>myo</i>-inositol in 16 steps in 3% overall yield. A key feature of the strategy was extending the utility of the <i>p</i>-(3,4-dimethoxyphenyl)­benzyl protecting group for its use at the <i>O</i>-3 position of inositol to allow installation of the stearoyl residue at a late stage in the synthesis. Mass spectral studies were performed on the synthetic PIMs and compared to those reported for natural PIMs identified from a lipid extract of <i>M</i>. <i>bovis</i> BCG. These analyses confirm that fragmentation patterns can be used to identify the structures of specific PIMs from the cell wall lipid extract

Synthesis and Activity of 6″-Deoxy-6″-thio-α-GalCer and Peptide Conjugates

A major challenge in the development of highly defined synthetic vaccines is the codelivery of vaccine components (i.e., antigen and adjuvant) to secondary lymphoid tissue to induce optimal immune responses. This problem can be addressed by synthesizing vaccines that comprise peptide antigens covalently attached to glycolipid adjuvants through biologically cleavable linkers. Toward this, a strategy utilizing previously unreported 6″-deoxy-6″-thio analogues of α-GalCer that can undergo chemoselective conjugation with peptide antigens is described. Administration of these conjugate vaccines leads to enhanced priming of antigen specific T cells. This simple vaccine design is broadly applicable to multiple disease indications such as cancer and infectious disease