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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, 471-490.
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, 4539-4565.
Kiefel, M. J.; von Itzstein, M. 2002, 102, 471-490.
Enzymatic Synthesis of O-Sialosides
Kiefel, M. J.; von Itzstein, M. Chem. Rev. 2002, 102, 471-490.
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, 4539-4565.
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, 4539-4565.
Kiefel, M. J.; von Itzstein, M. 2002, 102, 471-490.
Sialyl Glycosylation Methods
Direct – “formation of O-
Indirect – “afford O-sialosides
sialosides in one synthetic
step”
• 2-halogeno derivatives
– Cl, Br, F
• 2-thio derivatives
– alkyl, aryl, xanthates
• 2-phosphites
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, 4539-4565.
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, 4539-4565.
2-Thio Derivatives
• Widely applied for the synthesis of sialic acidcontaining oligosaccharides
• Good chemical stability
• Can be transformed into
other glycosyl donors
Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.
2-Phosphite Derivatives
• Widely applied for O-sialylation
• Require catalytic amount
of activator
Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.
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, 4539-4565.
C-3 Auxiliaries
• Utilizing neighboring group participation to form
2,3-trans-glycosides
Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.
Indirect Methods
Drawbacks:
– Additional steps
– Stereoselective
installation of the C-3
auxiliary
Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.
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, 1126-1129.
Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387-2391.
N-acetyl-5-N,4-O-Carbonyl Protected
Thiosialoside Donors
Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387-2391.
N-acetyl-5-N,4-O-Carbonyl Protected
Thiosialoside Donors
Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387-2391.
N-acetyl-5-N,4-O-Carbonyl Protected
Thiosialoside Donors
Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387-2391.
Probing the Nitrile Effect
Crich, D.; Li, W. J. Org. Chem. 2007, 72, 7794-7797.
Probing the Nitrile Effect
Crich, D.; Li, W. J. Org. Chem. 2007, 72, 7794-7797.
Probing the Nitrile Effect
Crich, D.; Li, W. J. Org. Chem. 2007, 72, 7794-7797.
Role of Oxazolidinone
Crich, D., et al. Angew. Chem. Int. Ed. 2012, 51, 11105-11109.
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, 11105-11109.
Role of Oxazolidinone
Crich, D., et al. Angew. Chem. Int. Ed. 2012, 51, 11105-11109.
Role of Oxazolidinone
Kancharla, P. K.; Kato, T.; Crich, D. J. Am. Chem. Soc. 2014, 136, 5472-5480.
Isothiocyanato Moiety
Crich, D., et al. Angew. Chem. Int. Ed. 2015, 54, 1275-1278.
Isothiocyanato Moiety
Crich, D., et al. Angew. Chem. Int. Ed. 2015, 54, 1275-1278.
Isothiocyanato Moiety
Crich, D., et al. Angew. Chem. Int. Ed. 2015, 54, 1275-1278.
5-Ureido-Modified Sialyl Donor
Kiso, M., et al. Org. Lett. 2016, 18, 1454-1457
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, 4539-4565.
Demchenko, A. V.; Boons, G-J. Chem. Eur. J. 1999, 5, 1278-1283.
α(28)-linked Dimers
Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.
α(28)-linked Dimers
Demchenko, A. V.; Boons, G-J. Chem. Eur. J. 1999, 5, 1278-1283.
α(28)-linked Dimers
De Meo, C.; Demchenko, A. V.; Boons, G-J. J. Org. Chem. 2001, 66, 5490-5497.
α(28)-linked Dimers
• Cleave colominic acid
– Homopolymer of Neu5Acα(28)Neu5Ac
Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.
α(29)-linked Dimers
• High reactivity of C-9 hydroxyl group
Boon, G-J.; Demchenko, A. V. Chem. Rev. 2000, 100, 4539-4565.
α(29)-linked Dimers
Demchenko, A. V.; Boons, G-J. Chem. Eur. J. 1999, 5, 1278-1283.