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Synthetic studies towards Ristocetin A and related compounds using arene-ruthenium chemistry

Lee, Kieseung
http://rave.ohiolink.edu/etdc/view?acc_num=case1062528216

Abstract Details

1995, Doctor of Philosophy, Case Western Reserve University, Chemistry.
As part of the overall project directed toward the total synthesis of glycopeptide antibiotics, e.g., Vancomycin and Ristocetin A, a formal total synthesis of K-13 was studied. The aryl ether bond was constructed between the dipeptide and the Ru-complex of a p-chlorophenylalanine derivative under very mild conditions and subsequent demetallation using a sunlamp gave the diaryl ether intermediate in good yield, (CH3CN)3Ru+CpPF6- was recovered in high yield from this demetallation. Among the various carboxyl protecting groups examined, the 2-bromoethyl ester was found to be the best behaved during Ru-metallation, condensation and demetallation reactions, but a serious problem during deprotection was observed. This problem was finally solved by conversion of 2-bromoethyl ester to the 2-iodoethyl ester followed by its deprotection using SmI2, but the procedure still needs to be optimized. The deprotection of 2-bromoethyl esters using reported methods usually gave 2-hydroxyethyl esters as the major products presumably via neighboring group participation of the carboxyl oxygen. A general study of a new protocol for removing the 2-bromoethyl ester group was studied, by using a two-step sequ ence. The N-Benzyloxycarbonyl group was determined to be very stable, and the N-t-Butoxycarbonyl-protecting group is relatively stable under these conditions. To evaluate coupling reagents for the problematic 16-membered ring cycloamidation, 16-membered rings mimicking the "northern" parts of Vancomycin and Ristocetin A were designed as 3.9 and 3.28, and various macrocyclization methods were investigated. The aryl ether bond was formed under very mild conditions (-78°C, 15 min then rt, 1.5 h) via Ru-mediated S NAr reaction and the subsequent two steps (Demetallation and Finkelstein reaction) were successfully optimized. Among the four macrocyclization methods examined for 3.42, the pentafluorophenyl ester/Et 3N method gave the best overall yield, two cyclization products being obtained. For 3.41, three different variations (one-step and two-step sequence) based on the pentafluorophenyl ester intermediate 3.50 were examined but no cyclization products were observed. The total syntheses of OF4949-III and IV were examined based on the results obtained in K-13 and BCF-model studies t-Butyldimethylsilylether protecting group of phenol was well-behaved in hydrogenation and Evans azidation reaction conditions, but deprotection required anhydrous TBAF. The methoxyethoxymethyl ester protecting group was successfully introduced in the presence of a phenolic group. The dipeptide which has polar groups such as acetamide and amide groups was successfully Ru-metaliated to give an important intermediate 4.4 in almost quantitative yield.* (Abstract shortened by UMI.) ftn*Please refer to the dissertation for diagrams
Anthony Pearson (Advisor)
250 p.
Chemistry, Organic
Ristocetin A; Arene-ruthenium chemistry

Recommended Citations

Citations

  • Lee, K. (1995). Synthetic studies towards Ristocetin A and related compounds using arene-ruthenium chemistry [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1062528216

    APA Style (7th edition)

  • Lee, Kieseung. Synthetic studies towards Ristocetin A and related compounds using arene-ruthenium chemistry. 1995. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1062528216.

    MLA Style (8th edition)

  • Lee, Kieseung. "Synthetic studies towards Ristocetin A and related compounds using arene-ruthenium chemistry." Doctoral dissertation, Case Western Reserve University, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1062528216

    Chicago Manual of Style (17th edition)

case1062528216
589
© 1995, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12