Olivomycin A is a member of the aureolic acid group of antitumor antibiotics. Three members of this group (olivomycin A, chromomycin A3 and mithramycin) have been used clinically for the treatment of various tumors, but toxicity limits their usefulness. Various studies establish that the oligosaccharides play key roles in the recognition and binding of the aureolic acids to DNA. We propose to complete a highly stereoselective synthesis of olivomycin A, thereby defining a strategy that may be useful for the synthesis of analogues with unnatural oligosaccharides and improved therapeutic indices. Syntheses of the aglycone, olivin, and the AB disaccharide have been completed, and a highly stereoselective method for the synthesis of aryl Beta-2-deoxyglycosides has been developed for use in coupling of the AB disaccharide to the aglycone. The last remaining problem is the establishment of an efficient method for the synthesis of the three 2-deoxy-Beta-glycosidic linkages that occur in the CDE trisaccharide. While CD disaccharides 41 and 44 were synthesized in the preceding grant period, the selectivity for the Beta-glycosides was less than desired owing to the unanticipated nucleophile dependent, configurational instability of the 2alpha-phenylselenyl glycosyl acetates 37 and 38 that were used as the glycosyl donors. Efforts in the coming grant year will focus on the 2alpha-phenylthio glycoside donors 102-106 since preliminary results indicate that the 2alpha-PhS substituted glycosides show no tendency to epimerize via reversible episulfonium ion intermediates. The prospects that this synthesis will be completed in the next grant period are very good. Studies of the exo-anomeric effect as a stereocontrol element in asymmetric and acyclic diastereoselective synthesis will be continued. In the preceding grant period we discovered that the chiral (Z)-gamma- alkoxyallylstannane 64 containing a mannosyl auxiliary exhibits excellent diastereofacial control in BF3 catalyzed reactions with chiral aldehydes. The generality of this process for the synthesis of syn diols 124 will be fully explored. Improved auxiliaries (e.g., 137) will develop if required to maximize stereoselectivity. This strategy will be extended to the development of a chiral (E)-gamma-mannosylallylchromium reagent 142 for the enantioselective synthesis of anti diols 125. This """"""""alpha- hydroxyallylation"""""""" methodology should prove very useful in the synthesis of carbohydrates and other polyhydroxylated natural products. Two targets of immediate interest are castanospermine (150) and swainsonine (151). Synthetic methodology previously developed in our laboratory will be applied in highly stereoselective total syntheses of mycalamides A and B, a group of potent antiviral and antitumor agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM038907-04
Application #
3295675
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1988-07-01
Project End
1995-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Indiana University Bloomington
Department
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Bates, Robert H; Shotwell, J Brad; Roush, William R (2008) Stereoselective syntheses of the C(1)-C(9) fragment of amphidinolide C. Org Lett 10:4343-6
Va, Porino; Roush, William R (2007) Total Synthesis of Amphidinolide E and Amphidinolide E Stereoisomers. Tetrahedron 63:5768-5796
Va, Porino; Roush, William R (2006) Total synthesis of amphidinolide E. J Am Chem Soc 128:15960-1
Lambert, William T; Roush, William R (2005) Synthesis of the A-B subunit of angelmicin B. Org Lett 7:5501-4
Tinsley, Jennifer M; Roush, William R (2005) Total synthesis of asimicin via highly stereoselective [3 + 2] annulation reactions of substituted allylsilanes. J Am Chem Soc 127:10818-9
Mertz, Eric; Tinsley, Jennifer M; Roush, William R (2005) [3 + 2]-annulation reactions of chiral allylsilanes and chiral aldehydes. studies on the synthesis of bis-tetrahydrofuran substructures of annonaceous acetogenins. J Org Chem 70:8035-46
Tinsley, Jennifer M; Mertz, Eric; Chong, Pek Y et al. (2005) Synthesis of (+)-bullatacin via the highly diastereoselective [3+2] annulation reaction of a racemic aldehyde and a nonracemic allylsilane. Org Lett 7:4245-8
Heitzman, Cheryl L; Lambert, William T; Mertz, Eric et al. (2005) Efficient protiodesilylation of unactivated C(sp3)-SiMe2Ph bonds using tetrabutylammonium fluoride. Org Lett 7:2405-8
Roush, William R; Neitz, R Jeffrey (2004) Studies on the synthesis of landomycin A. Synthesis of the originally assigned structure of the aglycone, landomycinone, and revision of structure. J Org Chem 69:4906-12
Shotwell, J Brad; Roush, William R (2004) Synthesis of the C11-C29 fragment of amphidinolide F. Org Lett 6:3865-8

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