Synthesis of the diazonamide A macrocyclic core.

Abstract

A model system for the originally proposed diazonamide A macrocycle was completed using a highly convergent Suzuki coupling/Dieckmann-type cyclization strategy. The model macrocycle contains an acetal moiety at C(11) corresponding to the C(11) hemiacetal of the natural product. Assembly of the C(11) acetal moiety was accomplished using a DMAP catalyzed O- to C-acyl transfer reaction to set the C(10) quaternary center followed by a reduction/deprotection sequence to close the C(11) acetal. The oxazolyl-indole portion of diazonamide A was made using a Schollkopf reaction to furnish the oxazole from a protected indole-3-carboxylic ester while oxazole-borane methodology was used to install the C(29) methyl group. A Suzuki coupling then linked the oxazolyl-indole fragment and the acetal moiety to furnish the C(16)--C(18) biaryl bond. The key macrocycle was finally formed by an imino-Dieckmann cyclization to close the C(29)--C(30) bond. Following the structural revision of the diazonamides, a macrocycle similar to the previous system was synthesized containing the N(2) nitrogen at C(11) instead of the O(3) oxygen. The newly established aminal moiety at C(11) was installed by first acylating an oxindole at C(10) with Mander's reagent (CNCO₂Me) to set the quaternary center, followed by a NaBH₄ reduction of an imide with subsequent aminal ring closure. A stable palladium (II) complex, generated from the oxazolyl-indole fragment, was used as the cross coupling partner for bond formation with a phenylstannane subunit in the aminal moiety to form the C(16)--C(18) biaryl bond. The key macrocycle was once again formed by an imino-Dieckmann cyclization, after aminal nitrogen N(2) protection with a MOM group. Macrocyclization had to be carried out at low temperature, below the threshold for atropisomer interconversion to maximize efficient material recovery.