Formal Synthesis of the Anti‐Angiogenic Polyketide (−)‐Borrelidin under Asymmetric Catalytic Control

Abstract

Borrelidin (1) is a polyketide that possesses extremely potent anti-angiogenesis activity. This paper describes its formal total synthesis by the most efficient route to date. This modular approach takes optimal benefit of asymmetric catalysis and permits the synthesis of analogues; in addition, the high yields and selectivities obtained eliminate the need for separation of stereoisomers. The upper half of borrelidin has been accessed by iterative copper-catalysed asymmetric conjugate addition of methylmagnesium bromide, whereas synthesis of the lower half of the molecule was achieved by relying on asymmetric hydrogenation and cross-methathesis as key steps.

Total synthesis, stereochemical elucidation and biological evaluation of Ac2SGL; a 1,3-methyl branched sulfoglycolipid from Mycobacterium tuberculosis

“…38 The aliphatic tail was introduced by reduction of the thioester, transformation of the alcohol formed into a leaving group and substitution using the desired Grignard reagent. Subsequently, the silyl ether was removed and the resulting primary alcohol was oxidized to afford 3 in yields corresponding to those reported.…”

CD1b Tetramers Identify T Cells that Recognize Natural and Synthetic Diacylated Sulfoglycolipids from Mycobacterium tuberculosis

“…Chemical synthesis of AM Ac 2 SGL consisted of a separate synthesis of hydroxyphthioceranic acid and a subsequent assembly of AM Ac 2 SGL. Hydroxyphthioceranic acid was synthesized by the combination of efficient asymmetric Cu-catalyzed iterative conjugated addition protocol with lithiation/borylation strategy in the later stage of synthesis (Des Mazery et al , 2005; López et al , 2006; ter Horst, Feringa and Minnaard, 2007a; Casas-Arce et al , 2008; Madduri and Minnaard, 2010; Geerdink, Horst, Lepore, Mori, Puzo, Anna K H Hirsch, et al , 2013; Geerdink and Minnaard, 2014; Rasappan and Aggarwal, 2014).…”

“…Carbamate 5 could be constructed from building blocks 6 and 7 by lithiation/borylation. Boronate 6 would be derived from 8 via Cu-catalysed iterative conjugate additions (Des Mazery et al , 2005; López et al , 2006; ter Horst, Feringa and Minnaard, 2007a, 2007b; Madduri and Minnaard, 2010) followed by lithiation/borylation, and carbamate 7 could be obtained by Cu-catalysed iterative conjugate additions followed by carbamoylation of alcohol.…”

Preparation and Applications of 4-Methoxybenzyl Esters in Organic Synthesis

“…For example, in a formal synthesis of (−)-borrelidin, hydrolysis using lithium hydroxide was performed on PMB ester 88 to avoid concurrent cleavage of the tetrahydropyranyl (THP) ether (Scheme 25). 81 This method was also utilized by Shioiri and co-workers in their synthesis of the lignan vibsanol, which required carboxylic acid 91 as a starting material. 82 Protection of vanillic acid ( 90 ) resulted in the formation of both the PMB ester and the PMB ether.…”

“…81 Here, aldehyde 117 was used in a samarium iodide-promoted Reformatsky reaction with 4-methoxybenzyl 2-bromoacetate ( 118 ). A mixture of isomers resulted from this reaction, but both alcohols could be oxidized to the identical ketone and then reduced selectively utilizing a chiral ruthenium catalyst to access a single stereoisomer of the β-hydroxy ester.…”