TY - JOUR
T1 - A convergent approach toward fidaxomicin
T2 - Syntheses of the fully glycosylated northern and southern fragments
AU - Hollibaugh, Ryan
AU - Yu, Xueliang
AU - De Brabander, Jef K.
N1 - Funding Information:
This work was supported by the NIH (grant GM111329 ) and the Robert A. Welch Foundation (grant I-1422 ). J. K. De Brabander holds the Julie and Louis Beecherl, Jr., Chair in Medical Science. HRMS data were obtained from the Shimadzu Center for Advanced Analytical Chemistry (SCAAC) at UT Arlington.
Funding Information:
This work was supported by the NIH (grant GM111329) and the Robert A. Welch Foundation (grant I-1422). J. K. De Brabander holds the Julie and Louis Beecherl, Jr. Chair in Medical Science. HRMS data were obtained from the Shimadzu Center for Advanced Analytical Chemistry (SCAAC) at UT Arlington.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/12/4
Y1 - 2020/12/4
N2 - Efficient approaches that enable the synthesis of analogs of natural product antibiotics are needed to keep up with the emergence of multiply-resistant strains of pathogenic organisms. One promising candidate in this area is fidaxomicin, which boasts impressive in vitro anti-tubercular activity but has poor systemic bioavailability. We designed a flexible synthetic route to this target to enable the exploration of new chemical space and the future development of analogs with superior pharmacokinetics. We developed a robust approach to each of the key macrocyclic and sugar fragments, their union via stereoselective glycosylation, and a convergent late-stage macrolide formation with fully glycosylated fragments. Although we were able to demonstrate that the final Suzuki cross-coupling and ring-closing metathesis steps enabled macrocycle formation in the presence of the northern resorcylic rhamnoside and southern novioside sugars, these final steps were hampered by poor yields and the formation of the unwanted Z-macrocycle as the major stereoisomer.
AB - Efficient approaches that enable the synthesis of analogs of natural product antibiotics are needed to keep up with the emergence of multiply-resistant strains of pathogenic organisms. One promising candidate in this area is fidaxomicin, which boasts impressive in vitro anti-tubercular activity but has poor systemic bioavailability. We designed a flexible synthetic route to this target to enable the exploration of new chemical space and the future development of analogs with superior pharmacokinetics. We developed a robust approach to each of the key macrocyclic and sugar fragments, their union via stereoselective glycosylation, and a convergent late-stage macrolide formation with fully glycosylated fragments. Although we were able to demonstrate that the final Suzuki cross-coupling and ring-closing metathesis steps enabled macrocycle formation in the presence of the northern resorcylic rhamnoside and southern novioside sugars, these final steps were hampered by poor yields and the formation of the unwanted Z-macrocycle as the major stereoisomer.
KW - Lipiarmycin
KW - Macrolide antibiotics
KW - Ring closing metathesis
KW - Tiacumicin
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U2 - 10.1016/j.tet.2020.131673
DO - 10.1016/j.tet.2020.131673
M3 - Article
C2 - 33191957
AN - SCOPUS:85093663875
SN - 0040-4020
VL - 76
JO - Tetrahedron
JF - Tetrahedron
IS - 49
M1 - 131673
ER -