The aplyronines are a family of antimitotic marine macrolides that disrupt cytoskeletal dynamics by dual targeting of both actin and tubulin. Given their picomolar cytotoxicity profile and unprecedented mode of action, the aplyronines represent an excellent candidate as a novel payload for the development of next-generation antibody-drug conjugates (ADCs) for cancer chemotherapy. Enabled by an improved second-generation synthesis of the macrolactone core 5, we have achieved the first total synthesis of the most potent congener aplyronine D together with a highly stereocontrolled synthesis of aplyronine A. To facilitate step economy, an adventurous site-selective esterification of the C7 hydroxyl group was performed to install the N,N,O-trimethylserine pharmacophore to directly afford aplyronines A and D. Toward the assembly of ADCs incorporating an aplyronine warhead, the C29-ester derivative 4 featuring an Fmoc-amino substituted linker attached to the actin-binding tail region was also prepared by adapting this flexible endgame.

An efficient, convergent synthesis of a differentially protected C20-C38 segment of the brasilinolides is described. Iterative 1,4-syn aldol additions and ketone reductions were employed to construct the two related stereotetrads, while a sequence of Horner-Wadsworth-Emmons (HWE) coupling, CBS reduction, and Sharpless AE installed the epoxy alcohol functionality.

A non-empirical fully ionic description, with the anion wavefunctions in their compressed but still spherically symmetrical states optimal for the crystal, is presented for the cohesive energetics of two cubic phases of three solid iodides, KI, RbI and CsI. The non-correlated part of the energy is computed using the RELCRION program which takes full account of relativistic effects. Both the dispersive attractions and energies arising from electron correlations of short range are computed.For each polymorph stable under ambient conditions, the rock-salt (B1) phases of KI and RbI and the eightfold coordinated (B2) phase of CsI, the cohesion is slightly underestimated. The lattice energy deficits of around 22 kJ mol −1 for KI and RbI are reduced to around 13 kJ mol −1 for CsI, with overestimations of some 0.2 au in the equilibrium cation-anion separations R decreasing as the metal becomes more electropositive. The prediction that the B2 phase of CsI is more stable (by 6 kJ mol −1 ) than the B1 polymorph agrees with experiment. For both KI and RbI, the zinc-blende polymorph is predicted to lie some 37 kJ mol −1 in energy above the B1 polymorph.An additional potential, plausibly ascribed to slight covalency, correcting these underestimations is derived semi-empirically.

Analysis of bound structures and SAR studies led to the function-oriented simplification of the aplyronines; a convergent and modular synthetic platform then enabled the total synthesis and biological evaluation of four novel analogues.

Two highly convergent syntheses of a fully protected C1-C19 polyol subunit of the brasilinolide family of immunosuppressive macrolides are described, exploiting boron-mediated 1,5-anti aldol couplings to form the C8-C9 and C13-C14 bonds.