New Glycosyl Thio-carboamino Peptides as New Tools for

Chapter 4

New Glycosyl Thio-carboamino Peptides as New Tools for Glycobiology

Downloaded by MONASH UNIV on November 1, 2014 | http://pubs.acs.org Publication Date: September 1, 2008 | doi: 10.1021/bk-2008-0990.ch004

Zbigniew J. Witczak Department of Pharmaceutical Sciences, School of Pharmacy, Wilkes University, Wilkes-Barre, PA 18766

New developments in glycobiology require determination of the precise functional domain of the carbohydrate ligand and follow up process for the specific binding affinity to glycoproteins through specific glycopeptide moieties. Small glycopeptide derivatives linked to the carbohydrate moiety via nonhydrolyzable link developed in our laboratory might serve as potential new tools to study this phenomenon. Our synthetic studies utilizing stereoselective Michael addition of reactive thiols to new conjugated enones and converting them into carbopeptides are presented in this short review.

Introduction As recognition molecules, carbohydrates play critical roles in many biological functions. Discovery and identification of these critically important bioactive carbohydrates constitutes a unique challenge to determine the precise functional domain of the carbohydrate ligand to design and develop new classes of glycochemicals. This identification, including potent enzyme inhibitors and receptor ligands for peptide, oligonucleotide and small molecules through introduction of carbohydrate molecular diversity, via functionalization or © 2008 American Chemical Society

In Chemical Glycobiology; Chen, X., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.

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80 combinatorial chemistry into the drug discovery process, is a timely and widely accepted tool. However, the importance of glycoprotein and glycolipids found at the cell surface is critical in communication between bacteria and many viruses. Carbohydrate functionalized glycopeptides are excellent molecular tools to study these phenomena. Moreover, new synthetic procedures utilizing reactive carbohydrate enones as valuable synthons will open new alternative and efficient routes to accomplish this preparative task. We have developed several methods for the preparation of S-linked thiodisaccharides and mixed C-S-thiodisaccharides linked via (1-4)-; (1-3)-; (1-2)-; and recently (1-5)- positions (1-6). Our first method uses a stereoselective Michael addition of active thiols to conjugated enones, such as levoglucosenone (1) and its isomeric isolevoglucosenone (2). Both simple and small bicyclic enones are important and efficient chiral starting materials for the synthesis of many analogs of complex natural products (7-24). Our laboratory (7) was the first to synthesize the (+)enantiomer of levoglucosenone and its 5-hydroxymethyl analog, starting from the known precursor, 5-hydroxymethyl-1,6-anhydro-a-aftro-hexopyranose. The high chemical reactivity of the conjugated system in levoglucosenone is an excellent reason to further develop new synthetic approaches for the synthesis of a variety of natural products targets that require stereoselective coupling with the sugar unit. As our need for larger quantities and variety of conventionally functionalized enones increased, we have been constantly exploring methods that would make them more readily available for exploratory studies and multistep synthesis. One of such reactive enones originally synthesized by Klemer and Jung (25) and currently explored by us is 4,6-dideoxy-l,2-0-isopropylidene-D-g/j>cm?-pent-4-enopyranos-3-ulose (3).

1

2

3

Scheme 1. Levoglucosenone 1, isolevoglucosenone 2, and 4,6-dideoxy-1,2-0isopropylidene-D-glycero-pent-4-enopyranose-3-ulose 3

The enone (3) serves as new convenient building block for a stereoselective functionalization reaction, particularly as a Michael addition reaction acceptor (Scheme 1).


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Synthetic Studies


The stereoselective, one-step synthesis of (l,4)-S-thiodisaccharides (7-2) is a classical example (Scheme 2) of exploiting the excellent functionality of levoglucosenone as Michael reaction acceptor. The methodology of functionalization of C-2 either via conventional and stereoselective reduction, or oximation and then stereoselective reduction of the oximino functionality is unique in providing both classes of S-thio-disaccharides. Moreover, the C-2 amino functionalized nonhydrolyzable S-thio-disaccharide, after deprotection of C-2 acetamido function represents a convenient molecular scaffold for the generation of diverse libraries of peptidomimetics as a selected class of glycoconjugates.

CH CN/Et N 3

3

OAc

( AcO AcO

+

ÔAcV

L- Selectride Ac 0/Py

NH OH/Py 2

2

OAc

OAc

ÛMC

yf-s

AcOOAc B F E t 0 / A c 0 or TFA/Ac 0 or 3

2

9-BBN/THF Ac 0/Py Et Si0S0 CF /Ac 0

2

2

2

3

Et Si0S0 CF /Ac 0 3

2

3

2

3

2

I

2

ÔAc .OAc

S. HO-^-T^ V - 0 OH / W)Me

AcO AcO

OAc


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New Perspectives Although developments in the chemistry of carbohydrate enones levo- and isolevoglucosenone (during the last ten years) that uses modern reagents as tools in organic synthesis as presented in this short review, will definitely change our perception of their growing potential. The aggressive promotion and utilization of this chemistry must continue, to encourage more extensive study in many different directions. Moreover, the excellent chiral functionality of arabinose enone and its functionalized new synthons will create additional possibilities of interdisciplinary approaches not only in pure synthetic organic chemistry but also in peptide and combinatorial chemistry. The latter is especially appealing for functionalizing this molecule by creating a number of useful scaffolds.

Scheme 11. Stereoselective functionalization of enone 3 via Michael addition of nitromethane/reduction and thiacetic acid/nitromethane reduction approach.

The most useful scaffolds would have modified functional groups such as N H , -SH, at C-5 and C-3'. Our laboratory is developing a new family of arabinose-based scaffolds with these functional groups at the above positions (Scheme 11). 2

Conclusion Through a number of new developments and synthetic methods devoted to the subject during the last ten years, one can easily conclude that this fascinating


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topic is growing and will continue to grow. The variety of methods for the fiinctionalization of these classical building blocks as reactive enones provides a number of attractive stereoselective approaches to various classes of optically active derivatives of particular interest including sulfur and nitrogen peptides as well as rare carbohydrates. Additionally, the combinatorial utilization of carbohydrate scaffolds based on enones fiinctionalization will also constitute attractive and relatively cheap starting materials. This rich selection of potential approaches, combined with further developments of new procedures and modem reagents, creates an enormous opportunity for the field of glycobiology to be at the frontier for many years to come.

References 1. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11. 12. 13. 14. 15. 16.

Witczak, Z. J.; Sun, J.; Mielguj, R. Bioorg. Med. Chem. Lett. 1995, 5, 2169. Witczak, Z. J.; Chhabra, R.; Chen, H.; Xie, Q. Carbohydr. Res. 1997, 301, 167. Witczak, Z. J.; Chhabra, R.; Boryczewski, D. J. Carbohydr. Chem. 2000, 19, 543. Witczak, Z. J.; Kaplon, P. Kolodziej, M . Monatshefte fur Chemie, 2002, 133, 521. Witczak, Z. J.; Chen, H.; Kaplon, P. Tetrahedron: Asymmetry, 2000, 11, 519. Witczak, Z.J. Lorchak, D.; Nguyen, N. Carbohydr. Res. 2007, 342, 1929. Witczak, Z. J.; Mielguj, R. Synlett 1996, 108. For reviews see; Levoglucosenone and Levoglucosans Chemistry and Applications Witczak, Z. J. Ed. ATL Press Science Publishers; Mt. Prospect, IL 1994; Witczak, Z. J. in Studies in Natural Products Chemistry, Atta-UrRahman, Ed. Vol. 14, Elsevier Science Publishers, Amsterdam, 1993, pp. 267-282; Miftakhov, M . S.; Valeev, F. Α.; Gaisina, I. N . Uspekhi Khimi, 1994, 63, 922; B. Becker, J. Carb. Chem. 2000, 19, 253.. Witczak, Z. J. Pure Appl. Chem. 1995, 66, 2189. Blake, A. J.; Cook, Τ. Α.; Forsyth, A. C.; Gould, R. O.; Paton, R. M . Tetrahedron 1992, 48, 8053. Blake, A. J.; Gould, R. O.; Paton. R. M.; Taylor, P. G. J. Chem. Res. Synopses 1993, 289. Isobe, M.; Fukami, N.; Nishikawa,T.; Goto, T. Heterocycles 1987, 25, 521. Ward, D. D.; Shafizadeh, F. Carbohydr. Res. 1981, 93, 287. Bamba, M.; Nishikawa, T.; Isobe, M. Tetrahedron Lett. 1996, 37, 8199. Matsumoto, K.; Ebata, T.; Koseki, K.; Okano, K.; Kawakami, H.; Matsushita, H. Carbohydr. Res. 1993, 246, 345. Ebata, T.; Matsumoto, K.; Yoshikoshi, H.; Koseki, K.; Kawakami, H.; Mashushita, H. Heterocycles, 1990, 31, 423.


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17. 18. 19. 20. 21. 22.


23. 24. 25. 26. 27. 28.

Mori, M.; Chuman, T.; Kato, Κ. Carbohydr. Res. 1984, 129, 73. Witczak, Z. J.; Li, Y. Tetrahedron Lett. 1995, 36, 2595. Taniguchi, T.; Nakamura, K.; Ogasawara, K. Synlett 1996, 971. Blattner, R.; Page, D. M. J. Carbohydr. Chem. 1994, 13, 27. Witczak, Z. J.; Chabra, R.; Chojnacki, J. Tetrahedron Lett. 1997, 38, 2215. Nishikawa, T.; Araki, H.; Isobe, M. Biosci. Biotechnol. Biochem. 1998, 62, 190. Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Synthesis 1999, 341. Gomez, M.; Quincoces, J.; Peske, K.: Michalik, M. J. Carbohydr. Chem. 1999, 18, 851. Klemer, A. Jung G. Chem Ber. 1981, 114, 1192 Hanessian S. Tetrahedron Lett. 1967, 8, 1549. Witczak Z.J.; Kaplon, P.; Dey, P.M. Carbohydr. Res. 2003, 338, 11. R. N. Comber, J.D. Friedrich, J. A. Secrist III, J. Med. Chem., 1992, 35, 3567.


New Glycosyl Thio-carboamino Peptides as New Tools for

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