The synthesis of a C(1)-C(24) advanced southern hemisphere fragment towards the total synthesis of spirastrellolide E has been achieved. Highlights of the route include a highly convergent Type I Anion Relay Chemistry (ARC) tactic for fragment assembly, in conjunction with a directed, regioselective gold-catalyzed alkyne functionalization to generate the central unsaturated [6,6]-spiroketal.

The diethoxyphosphonate group comprises an effective agent to achieve negative charge migration in Type II Anion Relay Chemistry (ARC). The process involves a [1,4]-phosphorus-Brook rearrangement that proceeds via a phosphacyclic intermediate leading to an anion that can be captured by reactive electrophiles. In the absence of an exogenous electrophile, the anion derived via phosphorus migration undergoes internal displacement of the phosphonate group to produce a diasteriomeric mixture of cyclopropanes.

Synthetic analysis of spirastrellolide E envisioned to entail a cross-metathesis union of the northern and southern hemispheres followed by a Sharpless epoxidation/methylation sequence to achieve the C(22,23) stereogenicity leads to the design of a C(1)–C(23) advanced southern hemisphere exploiting a gold-catalyzed directed spiroketalization as a key step. Stereochemical analysis of this strategic transformation provides insight on the impact of the directing group carbinol stereogenicity on the reaction efficiency and, in turn, permits the conversion of the minor isomer of the spiroketal precursor to the requisite congener for successful spiroketalization.