An Abiotic Strategy for the Enantioselective Synthesis of Erythromycin B

Abstract

Sweet success: The classical approach to macrolide antibiotics involves a macrocyclization followed by the introduction of the carbohydrate residue(s). Now for the first time, a glycosylated seco‐acid (see scheme, left) was cyclized to give an intermediate that was converted into a naturally occurring macrolide, as exemplified by the synthesis of erythromycin B (right).

Natural Products as Platforms To Overcome Antibiotic Resistance

“…With the main scaffold in hand, only glycosylation and protecting group manipulations remained, ultimately furnishing erythromycin B in 30 steps from 49 , or 23 from known material. Following this report, the Martin Laboratory published other work toward a more streamlined synthesis featuring changes in the order of operations in the endgame, notably the sequence in which macrolactonization and glycosylation are carried out. , …”

Total Synthesis of Desmethyl Macrolide Antibiotics

“…Prior art from Martin 37 and Tatsuta 38 suggested we could perform a site-selective glycosylation at the desired C-5 hydroxyl position. In the event, we were unable to carry out such a transformation using donor 10, silver(I) trifluoromethanesulfonate (AgOTf), and 2,6-di-tert-butyl-4-methylpyridine (DTBMP).…”

“…Recourse to basic fluoride sources (e.g., TBAF) resulted in the removal of both TES and TBS protecting groups at C-5 and C-3, respectively (Scheme 10). Prior art from Martin 37 and Tatsuta 38 suggested we could perform a site-selective glycosylation at the desired C-5 hydroxyl position. In the event, we were unable to carry out such a transformation using donor 10, silver(I) trifluoromethanesulfonate (Ag-OTf), and 2,6-di-tert-butyl-4-methylpyridine (DTBMP).…”

Polyketide stereotetrads in natural products

“…The most recent total synthesis of erythromycins was published in 2003 by Martin et al (Scheme 26). 36 The synthesis of the syn, syn, syn stereotetrad fragment started with Evans aldol chemistry to give the aldol adduct 201 as the only isomer (step a). After several reaction steps, which concentrated on the synthesis of the left half of erythromycin B, two missing stereocenters of the syn, syn, syn stereotetrad were created via asymmetric crotylation (step e).…”