Syntheses of Cyclopropyl Analogues of Disorazoles A₁ and B₁ and Their Thiazole Counterparts

Abstract

Modular syntheses of disorazoles A1 and B1 analogues in which the epoxide moieties of the natural products were replaced with cyclopropyl units have been achieved. Targeted as part of a structure–activity relationships study, these syntheses were successfully extended to the thiazole counterparts of these analogues. The retrosynthetically defined fragments were assembled through Yamaguchi esterification, Cu/Pd-catalyzed cross-coupling, Yamaguchi macrolactonization, and Cu-catalyzed cross-coupling as the key reactions. Further synthetic and biological investigations of such analogues are expected to lead to the discovery and development of potential payloads for antibody–drug conjugates as targeted cancer therapies.

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

“…Ultimate precursor 30 and synthetic disorazole B 1 ( 2 ) exhibited identical physical data to those previously observed in our first total synthesis, thereby confirming the absolute configurations of building block 19 and its precursor 25 (Scheme A). This symmetrical total synthesis of disorazole B 1 ( 2 ) proceeded in 17 total number of steps and in 3% overall yield (12 steps longest linear sequence from 21 ) from readily available building blocks 21 , 26 , and 18 , , as opposed to our first total synthesis, which required a total of 29 steps and gave the desired natural product in 1.8% overall yield (15 steps longest linear sequence) starting from propargyl alcohol …”

“…Scheme depicts the construction of the defined building blocks 19 (Scheme A) and 20 (Scheme B) and their sequential coupling with our previously synthesized iodide building block 18 , and elaboration to disorazole B 1 ( 2 ) (Scheme C). Thus, commercially available acetylene diethoxyacetal 21 was treated with NaI in the presence of H 2 SO 4 to afford the corresponding vinyl iodide aldehyde, which was reacted with the anion of the commercially available methyl ester phosphonate 22 (KHMDS, 18-crown-6) to afford selectively ( Z , E )-methyl ester iodide 23 (78% overall yield).…”

“…With both fragments 19 and 20 readily available, their assembly with previously synthesized fragment 18 , proceeded as summarized in Scheme C. Thus, iodide 18 was converted to its phosphonium salt (PPh 3 , i -Pr 2 NEt), which underwent Wittig olefination with epoxy aldehyde 19 as facilitated with ylide formation (LHMDS, DMPU) to afford epoxy vinyl iodide 29 (64% yield for the two steps).…”

“…The synthetic strategy for the streamlined total synthesis of disorazole B 1 analogues 3 (biscyclopropyl disorazole B 1 ) and 4 (biscyclopropyl bisacetylene disorazole B 1 ) was derived from the retrosynthetic analysis indicated in Scheme A. Requiring key building blocks 18 , , 20 (Scheme B), and 33 and proceeding through advanced monomeric precursor iodo acetylene 32 , the total synthesis of these analogues proceeded as summarized in Scheme . While intermediates 20 (Scheme B) and 18 , were available to us from our earlier studies, the requisite iodo aldehyde 33 was prepared from readily available allylic alcohol 34 through the dual path shown in Scheme B.…”

“…We also subsequently disclosed the application of our developed modular synthetic strategies toward these natural products to the synthesis of the corresponding biscyclopropyl and bisthiazolyl analogues of both disorazoles A 1 ( 1 ) and B 1 ( 2 ), including biscyclopropyl disorazole B 1 ( 3 , Figure ). In this article we report a streamlined, symmetrical total synthesis of disorazole B 1 ( 2 ) and its application to, in addition to the previously reported biscyclopropyl disorazole B 1 ( 3 ), several new analogues (i.e., 4 – 12 , Figure ), and their biological evaluation and that of the parent compound disorazole B 1 ( 2 ), as antitumor agents.…”