Ever since its discovery in 1991, diazonamide A (1) has been eyed by synthetic chemists as a potential target because of its puzzling molecular architecture and potent biological activity. The race to synthesize this intriguing natural product was further complicated at the end of last year when a synthesis was completed only to prove that the originally proposed structure was in error. The new structural assignment (2) required retooling of synthetic strategies toward the new target. A total synthesis of diazonamide A has now been achieved confirming its newly proposed structure.

The total synthesis of a new member of the pederin family of natural products, psymberin 1, was accomplished. Using a recently reported novel and efficient PhI(OAc)2 mediated oxidative entry to 2-(N-acylaminal)-substituted tetrahydropyrans as the key step, this total synthesis was executed in a convergent and efficient manner. The longest linear sequence of this synthesis was 22 steps starting from known 6.

As an especially unique target for chemical synthesis, diazonamide A has the potential to be constructed through a plethora of synthetic routes, each attended by different challenges and opportunities for discovery. In this article, we detail our second total synthesis of diazonamide A through a sequence entirely distinct from that employed in our first campaign, one whose success required the development of several special strategies and tactics. We also disclose our complete studies regarding the chemical biology of diazonamide A and its structural congeners, and more fully delineate the scope of our protocol for Robinson-Gabriel cyclodehydration using pyridine-buffered POCl(3).

With the addition of a tenth ring, the exchange of an oxygen atom for a nitrogen in the heart of the molecule, and a different terminal residue, the revised architecture for diazonamide A (1) provided an even more challenging molecular puzzle for chemical synthesis than its predecessor. In this article, we detail the first successful total synthesis of diazonamide A, an endeavor which not only verified its proper connectivities and established the stereochemistry of its previously unassignable C-37 chiral center, but which also was attended by the development of several new synthetic strategies and tactics.

β-Phosphatoxyalkyl radical reactions were studied experimentally and computationally. The 1,1-dibenzyl-2-(diphenylphosphatoxy)-2-phenylethyl radical (1) reacted to give the migration product 2-benzyl-2-(diphenylphosphatoxy)-1,3-diphenylpropyl radical (2) and the elimination product 2-benzyl-1,3-diphenylallyl radical (3) in a variety of solvents. A modest kinetic solvent effect for reactions of 1 was found. Variable temperature studies in THF and acetonitrile gave Arrhenius functions with similar log A terms; the entropies of activation are ∼−5 eu. A deuterated analogue of radical 1 reacted in THF and acetonitrile with rate constants indistinguishable from those of 1, but the ratio of products 2:3 increased for the deuterated radical requiring kinetic isotope effects (KIEs) in reactions following the rate-limiting step. In aqueous acetonitrile solutions, the β,β-dibenzylstyrene radical cation (4) was detected as a short-lived intermediate, and the rate constants for formation of 3 and 4 indicated that both species derived from a common intermediate. The 1,1-dimethyl-2-(dimethylphosphatoxy)ethyl radical (C1) was studied computationally. Transition states for concerted phosphate migrations and phosphoric acid elimination were found with energies in the order [1,2]-migration < [1,3]-elimination < [3,2]-migration; each transition state was more polarized than radical C1. A transition state for homolytic fragmentation of C1 to give 2-methylpropene and the dimethylphosphatoxyl radical could not be found, but the reaction from the ensemble of these two entities to give the 2-methylallyl radical and phosphoric acid was followed computationally. KIEs and solvent dielectric effects were computed for each concerted reaction of C1. The results indicate that radical 1 reacts in all solvents studied by a common pathway involving initial heterolysis. The first-formed contact pair of radical cation 4 and diphenyl phosphate anion collapses to products 2 and 3 and, as a minor process, evolves to diffusively free radical cation 4 in aqueous acetonitrile solutions. A model for heterolytic fragmentation of β-ester radicals involving contact and solvent-separated ion pairs is presented.

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