Synthesis and Stability Studies of a Simplified, Thiazole-Containing Macrocycle of the Anticancer Agent Salarin C

Abstract

While salarin C (SalaC) is a potent marine cytotoxin, Kashman demonstrated that congeners which had undergone Wasserman rearrangement exhibit little to no cytotoxicity. Given that thiazoles are known to undergo Wasserman rearrangement at a significantly reduced rate, we hypothesized that a thiazole-containing SalaC would exhibit greater stability without significantly altering the macrocyclic conformation. Herein, we describe the synthesis of a simplified, thiazole-containing macrocycle which demonstrates significantly improved stability under identical aerobic conditions.

Figure 1.

Structures of salarins A-J (SalaA-J) with SalaD-J represented as partial structures. The relative stereochemistry of diols and chlorohydrins in SalaG, H, F, and I is unknown.

Figure 2.

(a) Structures of simplified thiazole- and oxazole-containing macrocycles 3a, b. (b) Overlay of minimized lowest energy conformations (B3LYP/6-31G) of the two macrocycles (oxazole 3b, green; thiazole 3a, gold) showing minimal change in lowest energy conformations. (c) Close-up views of the thiazole and oxazole overlays with two different perspectives.

Scheme 1.

Aerobic instability of SalaC (2) toward ¹O₂ leading to SalaA (1) via a Wasserman rearrangement.

Scheme 2.

Simplification of SalaC and retrosynthesis of thiazole and oxazole-SalaC macrocycles 3a and 3b.

Scheme 3.

Synthesis of a simplified thiazole-containing SalaC macrocycle 3a.

Scheme 4.

Synthesis of a simplified oxazole-containing, SalaC macrocycle 3b as a comparator.