Methods for α-Sialylation Caroline Braun Townsend Group Meeting May 11, 2016

Sialic Acids Family of 2-keto-3-deoxy-nononic acids – Neuraminic acid: C-5 amino derivative

Biosynthesis of Neu5Ac Kiefel, M. J.; von Itzstein, M. Chem. Rev. 2002, 102,

Sialosides in Nature Equatorial glycosides: α-anomer Terminal sugars of glycoproteins – N- or O-linked – Linkage to galactosides: α(2  3) or α(2  6) Disialosyl structures as constituents of glycoproteins and lipids – Neu5Acα(2  8)Neu5Ac – Neu5Acα(2  9)Neu5Ac Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, Kiefel, M. J.; von Itzstein, M. 2002, 102,

Enzymatic Synthesis of O-Sialosides Kiefel, M. J.; von Itzstein, M. Chem. Rev. 2002, 102,

Synthetic Glycosidic Bond Formation Stereochemical control – Neighboring group participation (C-2) – Reaction conditions (i.e. solvent, temperature, and promoter) – Structure of donor and acceptor Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100,

Neu5Ac Donors & Stereochemical Control Issues to address: – No neighboring C-3 functionality – Prone to 2,3-elimination – Sterically hindered anomeric center Sialyl donors possess “unusual” anomeric leaving groups. Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, Kiefel, M. J.; von Itzstein, M. 2002, 102,

Sialyl Glycosylation Methods Direct – “formation of O- sialosides in one synthetic step” 2-halogeno derivatives – Cl, Br, F 2-thio derivatives – alkyl, aryl, xanthates 2-phosphites Indirect – “afford O-sialosides in 2 or more synthetic steps, one of which may be a glycosylation” Auxiliaries at C-3 – 3-O, 3-Br, 3-S, 3-Se Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100,

2-Halogeno Derivatives 2-Chloro: synthesis of simple glycosides of Neu5Ac, or glycosylations with primary alcohols 2-Bromo: high reactivity and low stability 2-Fluoro: consistent β-selectivity Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100,

2-Thio Derivatives Widely applied for the synthesis of sialic acid- containing oligosaccharides Good chemical stability Can be transformed into other glycosyl donors Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100,

2-Phosphite Derivatives Widely applied for O-sialylation Require catalytic amount of activator Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100,

Evaluation of Direct Methods 2-Cl provides the best selectivity for glycosylations with simple alcohols and 1° carbohydrate alcohols Alternatives (2-SR, 2-SAr, 2-xanthate, 2-phosphites) are better for hindered carbohydrates – Better selectivity when acceptors have free diol or triol Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100,

C-3 Auxiliaries Utilizing neighboring group participation to form 2,3-trans-glycosides Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100,

Indirect Methods Drawbacks: – Additional steps – Stereoselective installation of the C-3 auxiliary Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100,

N-acetyl-5-N,4-O-Carbonyl Protected Thiosialoside Donors Oxazolidinone trans-fused ring sialyl donors – Takahashi, De Meo, and Crich De Meo, C., et al. Org. Lett. 2012, 14, Crich, D.; Li, W. J. Org. Chem. 2007, 72,

N-acetyl-5-N,4-O-Carbonyl Protected Thiosialoside Donors Crich, D.; Li, W. J. Org. Chem. 2007, 72,

N-acetyl-5-N,4-O-Carbonyl Protected Thiosialoside Donors Crich, D.; Li, W. J. Org. Chem. 2007, 72,

N-acetyl-5-N,4-O-Carbonyl Protected Thiosialoside Donors Crich, D.; Li, W. J. Org. Chem. 2007, 72,

Probing the Nitrile Effect Crich, D.; Li, W. J. Org. Chem. 2007, 72,

Probing the Nitrile Effect Crich, D.; Li, W. J. Org. Chem. 2007, 72,

Probing the Nitrile Effect Crich, D.; Li, W. J. Org. Chem. 2007, 72,

Role of Oxazolidinone Crich, D., et al. Angew. Chem. Int. Ed. 2012, 51,

Role of Oxazolidinone For derivatives 4 and 5 “the dipole moment of the heterocyclic system is aligned parallel to the pyranose C4-O4 and C5-N5 bonds, thereby enhancing their inherent electron-withdrawing ability.” Crich, D., et al. Angew. Chem. Int. Ed. 2012, 51,

Role of Oxazolidinone Crich, D., et al. Angew. Chem. Int. Ed. 2012, 51,

Role of Oxazolidinone Kancharla, P. K.; Kato, T.; Crich, D. J. Am. Chem. Soc. 2014, 136,

Isothiocyanato Moiety Crich, D., et al. Angew. Chem. Int. Ed. 2015, 54,

Isothiocyanato Moiety Crich, D., et al. Angew. Chem. Int. Ed. 2015, 54,

Isothiocyanato Moiety Crich, D., et al. Angew. Chem. Int. Ed. 2015, 54,

5-Ureido-Modified Sialyl Donor Kiso, M., et al. Org. Lett. 2016, 18,

α(2  8)-linked Dimers Low nucleophilicity of C-8 hydroxyl of Neu5Ac – Steric effects – Interactions with the acetamido group at C-5 – Internal hydrogen bonding Early reports utilized participating auxiliaries at C-3 Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, Demchenko, A. V.; Boons, G-J. Chem. Eur. J. 1999, 5,

α(2  8)-linked Dimers Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100,

α(2  8)-linked Dimers Demchenko, A. V.; Boons, G-J. Chem. Eur. J. 1999, 5,

α(2  8)-linked Dimers De Meo, C.; Demchenko, A. V.; Boons, G-J. J. Org. Chem. 2001, 66,

α(2  8)-linked Dimers Cleave colominic acid – Homopolymer of Neu5Acα(2  8)Neu5Ac Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100,

α(2  9)-linked Dimers High reactivity of C-9 hydroxyl group Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100,

α(2  9)-linked Dimers Demchenko, A. V.; Boons, G-J. Chem. Eur. J. 1999, 5,