Total Synthesis and Configurational Assignment of Chondramide A

Abstract

The first total synthesis of the cyclodepsipeptide chondramide A (2 b) is described. This depsipeptide is composed of four subunits, namely L‐alanine, N‐Me‐D‐tryptophan, 3‐amino‐2‐methoxy‐propionic acid (β‐tyrosine derivative), and a 7‐hydroxy‐alkenoic acid. While the configuration of the stereogenic centers in the 7‐hydroxy‐alkenoic acid were known, the configuration of the tyrosine derivative required clarification and turned out to be (2S,3R) or (2L,3L), respectively. The synthesis of the 3‐amino‐2‐methoxy‐3‐arylpropanoic ester 20 b relied on an asymmetric dihydroxylation yielding diol ent‐15 a followed by a regioselective Mitsunobu substitution leading to 3‐azido‐2‐hydroxypropanoate 18 b. We could also show that the ester bond in the seco compound 26 b can be fashioned by a Mitsunobu esterification by using hydroxy ester (7S)‐7 and the tripeptide acid 25 b. This synthesis should allow for the preparation of various analogues.

Synthesis of Chondramide A Analogues with Modified β‐Tyrosine and Their Biological Evaluation

“…16 Accordingly, this implied the use of differently substituted β-amino esters 8 that had to be synthesized from substituted trans -cinnamic esters 9 . At this point, taking into account the compatibility of the substituents at the aromatic ring with all the synthetic steps, we have chosen eight cinnamic esters 9b–e , 9g–i , and 9k as precursors for the desired chondramide analogues (Scheme 2).…”

“…Initially, the reaction was carried out in a mixture of TFA/CH 2 Cl 2 (1:30, vol/vol) as previously described. 16 The progress of the deprotection was easily monitored by TLC and NMR and under these conditions the conversion was not complete even after 2 d. In particular, the carboxylic ester cleavage is quite slow. However with more concentrated acid (1:10, vol/vol) complete and clean deprotection was observed for each compound after about 20 h. Interestingly, under these reaction conditions the TBS groups of 22g and 22h were quantitatively transformed to the corresponding TFA esters, as suggested by NMR of the crude products.…”

“…15 Subsequently, we reported the total synthesis of chondramide A (chon A). 16 Instead of a β-tyrosine, this chondramide contains a 3-amino-2-methoxy-3-arylpropanoic acid, whose configuration was determined to be (2 S ,3 S ). The ester bond could be established either by Yamaguchi esterification or via a Mitsunobu reaction 17 that was then followed by macrolactam formation.…”

Chapter 2. Chondramides and Chivosazoles – Two Metabolites Which Interfere with the Actin Cytoskeleton

“…11,12 Retrosynthetically, chondramide A was constructed from two fragments, vhydroxyester 31 and the peptide fragment 35 (Figure 2.4). A Yamaguchi esterification should then lead to the fully functionalised, linear precursor 36.…”

Synthetic Chondramide A Analogues Stabilize Filamentous Actin and Block Invasion by Toxoplasma gondii

“…44−47 Taking advantage of these developments, we previously reported schemes for efficient chemical synthesis of 2 as a means of generating increased diversity of chondramides, and these compounds were shown to disrupt actin and inhibit mammalian cell division. 45,47 In the present study, we compared the activities of natural compounds 2 – 4 as well as 10 previously described synthetic analogues ( 2b – k ) for their ability to stabilize F-actin in vitro and block infection of T. gondii in vitro . Although the compounds tested here do not show selectivity for parasite over host actin, they nonetheless are potent inhibitors of parasite invasion and provide useful leads for future development of more specific compounds.…”