Streamlined Symmetrical Total Synthesis of Disorazole B₁ and Design, Synthesis, and Biological Investigation of Disorazole Analogues

Abstract

Taking advantage of the C 2-symmetry of the antitumor naturally occurring disorazole B1 molecule, a symmetrical total synthesis was devised with a monomeric advanced intermediate as the key building block, whose three-step conversion to the natural product allowed for an expeditious entry to this family of compounds. Application of the developed synthetic strategies and methods provided a series of designed analogues of disorazole B1, whose biological evaluation led to the identification of a number of potent antitumor agents and the first structure–activity relationships (SARs) within this class of compounds. Specifically, the substitutions of the epoxide units and lactone moieties with cyclopropyl and lactam structural motifs, respectively, were found to be tolerable for biological activities and beneficial with regard to chemical stability.

Synthesis and Biological Evaluation of C(13)/C(13′)‐Bis(desmethyl)disorazole Z**

“…[25] Other than this, the only examples that we are aware of are the double Suzuki coupling in Hoveyda's synthesis of disorazole C 1 [9] and Nicolaou's double Sonogashira coupling in the synthesis of disorazole B 1 and disorazole analogues. [5,26] As depicted in Scheme 1, macrocyclization precursor 4 was to be obtained by the esterification of carboxylic acid 5 with alcohol 6. The former would be elaborated from acid 7 by amide coupling with the trimethylsilylethyl (TMSE) ester of serine ( 8), [27] followed by cyclodehydration.…”

Recognition of Symmetry as a Powerful Tool in Natural Product Synthesis

“…An example of the latter is the total synthesis of disorazole B1 (5) reported by Nicolaou and coworkers in 2020 (Scheme 2). 3 The key intermediate of the sequence was dimerized via a Sonogashira coupling and the resulting intermediate was subsequently reduced using Lindlar's catalyst to afford the natural product. This synthesis proceeded in 17 total steps with 3% overall yield (12 longest linear sequence or LLS) in comparison to their previous approach, which required the independent preparation of two distinct fragments and a total of 29 total steps with 1.8% overall yield (15 LLS).…”

Extending the Structure‐Activity Relationship of Disorazole C1: Exchanging the Oxazole Ring by Thiazole and Influence of Chiral Centers within the Disorazole Core on Cytotoxicity

“…Herein, we wish to report the application of our strategy to the synthesis of three new analogues of disorazole C 1 , and their biological evaluation. In the last years, several analogues of the disorazoles have been synthesized by Wipf et al, [8,9] Kalesse et al, [10] and Nicolaou et al; [11,12] biological studies performed on these derivatives and on the natural members have contributed to the comprehension of the structure-activity relationships (SARs) of these fascinating molecules. However, not much is known about the role of the heterocyclic moiety and the configuration of the chiral centers in the biological activity.…”