Ernest G. Nolen
Research Projects Description
Synthesis of Methylene
Isosteres of Glycosyl Amino Acids and Glycosyl Phosphates
Glycosylation of proteins and lipids is a post-translational
modification important for numerous physiological processes (1).
These glycoconjugates act in protein folding, altering the physico-chemical
properties and activity, and adorn the landscape of the cell surface,
influencing cell–cell and cell–matrix interactions.
Our attention has been directed toward isosteric
mimics, which entail methylene substitution for the anomeric oxygen, the
so-called C-linked glycosyl amino acids, C-linked glycosyl phosphonates,
and C-linked glycosyl lipids, Figure 1. While such an exchange (CH2
for O) does slightly alter the bond angle, bond lengths, and the
dihedral angles, there is ample precedent to suggest the conformational
change is not insurmountable for binding (2) The methylene
isostere offers a great deal of stability, in that degradation by
glycosidases, reaction with glycosyltransferases, acid hydrolysis of the
anomeric acetal, and b-elimination from the serine are all
Our goal is to
provide convenient synthetic routes to C-linked glycosyl amino acids and
C-linked glycolipids, as well as their biosynthetic precursors. Previous synthetic work on C-linkages has explored a wide variety of C-C
bond forming reactions (see suggested reading).
significant effort, many of the synthetic approaches require expensive starting
materials, are limited in scope to the preparation of only one anomeric
stereochemistry, and lose the isosteric relationship by excessively lengthening
the intervening carbon chain. While
our work does not remedy all these shortcomings, it does offer complementary
approaches to these biologically significant materials and is well-suited for
serious undergraduate research. The
proposed syntheses are short, are adaptable to a variety of biomimetics, and
utilitize chemistry that is well precedented and not experimentally tedious.
Synthesis of C-Glycosyl
Our previous work
in this area involved alkylation of iodides 3
with the enolate derived from Williams’ Boc-protected diphenyloxazinone 4,
Scheme 1. The iodides originated from a-C-allyl
glycosides, which are readily prepared and well-known in the literature. Although this reaction was stereoselective and provided access to the
isosteric glycosyl serine 5, and to
as well, it was not amenable to acetyl glycosides or N-acetyl precursors (3).
A more functional
group-tolerant reaction methodology for C-glycosyl amino acid synthesis was
utilized in our lab by employing the Grubbs’ second generation catalyst (4)
for the olefin cross-metathesis (CM) between C-allyl
glycoside 6 and vinyl glycines 8-10,
prepared from methionine or glutamic acid (5), Scheme 2. A explosion of reports have appeared since the catalyst has become
commercially available and these have been recently reviewed (6). This methodology has provided a concise entry into glycosyl
amino acids in which the intervening carbon chain contains three or more
methylenes. In our hands and in
accordance with others, the linking carbon chain between the glycoside and the
amino acid cannot be made shorter than three carbons (e.g., serine mimics require only two methylenes) without seriously
diminishing the yield, as evidenced by >70% recovered C-vinyl glycoside 7 in
all attempted reactions utilizing this cross-metathesis partner and our vinyl
Students working in
my lab have enjoyed recent success, attested to by the five undergraduate
co-authors on publications in the past two years. As a mentor, the PI works alongside the students as they gain
confidence learning the techniques involved in running reactions, purifying
products on our new Isco Flash Chromatography station, and identifying
structures. The acquisition of a
new 400 MHz NMR has greatly simplified training on how to acquire NMR data, and
has focused much more attention on the interpretation of data with students.
The recent purchase of an ion-trap GC-MS and the soon to be acquired
MALDI-TOF mass spectrometer facilitate molecular weight determination for
characterization of products.
|Jennifer Potter ('04) writing up the
results of a reaction in her laboratory notebook. (Spring 2004)
||Michael Orlando ('04) loading a sample into
Colgate's Bruker 400 MHz NMR spectrometer. (Spring 2004)
See the entire issue of Science. 2001, 291(9), 2263-2502.
(a) J. Jiménez-Barbero, J. F. Espinosa, J. L. Asensio, F. J. Canada, A.
Poveda Adv. Carbohydrate Chem. Biochem. 2001, 56, 235-85. The
Conformation of C-Glycosyl Compounds. (b)
L. M. Mikkelsen, M. J. Hernaiz, M. Martin-Pastor, T. Skrydstrup, J. Jiménez-Barbero
J. Am. Chem. Soc. 2002, 124, 14940-51. Conformation
of Glycomimetics in the Free and Protein-Bound State: Structural and Binding
Features of the C-glycosyl Analogue of the Core Trisaccharide -D-Man-(1>3)-[-D-Man-(1>6)]-D-Man.
E. G. Nolen, M. M. Watts, D. J. Fowler
Lett. 2002, 4, 2963-65. Synthesis
of C-Linked Glycopyranosyl Serines via a Chiral Glycine Enolate Equivalent.
(a) H. E. Blackwell, D. J. O’Leary, A. K. Chatterjee, R. A.
Washenfelder, D. A. Bussmann, R. H. Grubbs J.
Am. Chem. Soc. 2000, 122, 58-71. New
Approaches to Olefin Cross-Metathesis. (b)
M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs Org.
Lett. 1999, 1, 953-56. Synthesis
and Activity of a New Generation of Ruthenium-Based Olefin Metathesis Catalysts
Coordinated with 1,3-Dimesityl-4,5-dihydroimidazol-2-ylidene Ligands.
E. G. Nolen, A. J. Kurish, K. A. Wong, M. D. Orlando
Tetrahedron Lett. 2003, 44,
2449-53. Short, stereoselective synthesis of C-glycosyl asparagines
via an olefin cross-metathesis.
S. J. Connon, S. Blechert Angew.
Chem. Int. Ed. 2003, 42,
1900-23. Recent Developments in Olefin Cross-Metathesis.
The preparation of C-glycosyl
amino acids has been reviewed by Dondoni (1). Since that review there have been
several reports toward the development of concise and broadly applicable routes
to C-glycosyl amino acids, including our own (see publication list), and others utilizing the Ramberg-Bäcklund
rearrangement (2), acetylide couplings (3), and an asymmetric Strecker reaction
(4) The C-phosphonate analogs have
been prepared as mimics for the UDP-glycosides and glycolipids (5)
General approaches to form
the C-glycosidic bond to phosphonates include anomeric radical additons to
unsaturated phosphonates (6), Wittig chemistry with concomitant ring closures
(7) elaboration from C-allyl
glycosides (8) and phosphonate anion addition to glyconolactones (9) Application
of some of these approaches has led to the preparation of some UDP-glycosyl
mimics (10), decaprenolphosphoarabinose analogues (11), muramic acid derivatives
(12) mannosyl phosphate mimics (13), and a bacterial peptidoglycan analogue
Citations most closely
related to our work include Dondoni (15) McGarvey (16) and Postema (17).
Asparagine Ethylene Isosteres via Sugar Acetylenes and Garner Aldehyde
Coupling. (b) Dondoni, A.; Mariotti, G.; Marra, A.; Massi, A. Synthesis 2001,
Synthesis of b-Linked
Glycosyl Serine Methylene Isosteres via Ethynylation of Sugar Lactones.
S. P. Vincent, A. Schleyer, C.-H. Wong J.
Org. Chem. 2000, 65,
4440-4443. Asymmetric Strecker Synthesis of C-Glycopeptide.
For a review see F. Nicotra, Synthesis of Glycosyl Phosphate Mimics. In Carbohydrate
Mimics; Y. Chapleur, Ed.; Wiley-VCH:Weinheim, 1998, pp 67-85.
H.-D. Junker, W.D. Fessner Tetrhedron Lett.
1998, 39, 269-72. Diastereoselective
Synthesis of C-Glycosylphosphonates via Free-Radical Glycosylation.
R. B. Meyer, Jr., T. E. Stone, P. K. Jesthi J.
Med. Chem. 1984, 27,
an Isosteric Analogue of a-D-Ribofurnaose
O. Gaurat, J. Xie, J.-M. Valéry Tetrahedron
Lett. 2000, 41, 1187-89. A concise
synthesis of C-glycosyl phosphate and phosphonate analogues of N-acetyl-a-D-glucosamine-1-phosphate.
(a) F. Orsini, A. Caselli Tetrahedron Lett. 2002, 43,
7259-61.SmI2-mediated reactions of diethyl
iodomethylphosphonate with esters and lactones: a highly stereoselective
syntheiss of a precursor of the C-glycosyl
analogue of thymidine 5’-b-L-rhamnosyl)diphosphate.
(b) A. Dondoni, A. Marra, C. Pasti Tetrahedron:
Asymmetry 2000, 11, 305-17. Stereoselective
synthesis of C-glycosylphosphonates from their ketols. Reconsideration of an abandoned route.
A. Schäfer, J. Thiem J. Org. Chem. 2000,
65, 24-29. Synthesis of
Novel Donor Mimetics of UDP-Gal, UDP-GlcNAc, and UDP-GalNAc as Potential
C. A. Centrone, T. L. Lowary J. Org.
Chem. 2002, 67, 8862-70. Synthesis
and Antituberculosis Activity of C-Phosphonate
Analogues of Decaprenolphosphoarabinose, a Key Intermediate in the
Biosynthesis of Mycobacterial Arabinogalactan and Lipoarabinomannan.
G. Brooks, P. D. Edwards, J. D. I. Hatto, T. C. Smale, R. Southgate Tetrahedron
1995, 51, 7999-8014. Synthesis
of Derivatives of Muramic Acid and C-1 Homologated a-D-Glucose
as Potential Inhibitors of Bacterial Transglycosylase.
V. S. Borodkin, M. A. J. Ferguson, A. V. Nikolaev Tetrahedron Lett. 2001, 42,
5305-08. Synthesis of b-D-Galp-(1→4)-a-D-Manp methanephosphonate, a substrate
analogue for the elongating a-D-mannosyl
phosphate transferase in the Leishmania.
(a)L. Qiao, J. C. Vederas J. Org. Chem.
1993, 58, 3480-82. Synthesis of a C-Phosphonate Disaccharide as a Potential Inhibitor of
Peptidoglycan Polymerization of Transglysosylase. (b) Zahra, J.; Hennig, L.; Findeisen, M.; Giesa, S.; Welzel, P.;
Muller, D.; Sheldrick, W. S. Tetrahedron 2001, 57,
9437-9452. Synthesis of a
building block for phosphonate analogues of moenomycin A(12) from D-tartaric
acid. (c) Abu Ajaj, K.; Hennig, L.; Findeisen, M.; Giesa, S.; Muller, D.;
Welzel, P. Tetrahedron 2002, 58, 8439-8451. Synthesis of a complex disaccharide precursor of phosphonate
analogues of the antibiotic moenomycin A(12).
A. Dondoni, P. P. Giovannini, A. Marra J.
Chem. Soc., Perkin Trans. 1, 2001,
2380-88. A concise C-glycosyl
amino acid synthesis by alkenyl C-glycoside–vinyloxazolidine
cross-metathesis. Synthesis of
glycosyl serine, asparagine and hydroxynorvaline isosteres.
G. J. McGarvey, T. E. Benedum, F. W. Schmidtmann Org. Lett. 2002, 4,
3591-94. Development of Co- and Post-Translational Synthethic
Strategies to C-Neoglycopeptides.
(a) M. H. D. Postema, J. L. Piper Org.
Lett. 2003, 5, 1721-23. Synthesis of Some Biologically Relevant b-C-Glycoconjugates. b) D. Calimente and M. H. D.
Org. Chem. 1999, 64, 1770-71. Preparation of C-1 Glycals via Olefin Metathesis. A Convergent and Flexible
Approach to C-Glycoside Synthesis. See
also: E. A. Voight, C. Rein, S. D. Burke J.
Org. Chem. 2002, 67,
of Sialic Acids via Desymmetrization by Ring-Closing Metathesis
A. Dondoni, A. Marra Chem. Rev. 2000,
100, 4395-4422. Methods for Anomeric Carbon-Linked and Fused Sugar
Amino Acid Synthesis: The
Gateway to Artificial Glycopeptides.
(a) D. E. Paterson, F. K. Griffin, M.-L. Alcaraz, R. J. K. Taylor Eur.
J. Org. Chem. 2002, 1323-1336. A
Ramberg-Bäcklund Approach to the Synthesis of C-Glycosides, C-Linked
Disaccharides, and C-Glycosyl
Amino Acids. (b) Y. Ohnishi, Y.
Ichikawa Bioorg. & Med. Chem. Lett.
2002, 12, 997-99. Stereoselective
synthesis of a C-glycoside
analogue of N-Fmoc-serine b-N-acetylglucosamine by Ramberg-Bäcklund rearrangement.
(a) Dondoni, A.; Mariotti, G.; Marra, A.
J. Org. Chem. 2002, 67,
4475-4486. Synthesis of
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