The targeted degradation of proteins by reprogramming E3 ligases with bifunctional small molecules is an exciting area of chemical biology because it promises a set of chemical tools for achieving the same task as siRNA or CRISPR/Cas9. Although there are hundreds of E3 ligases in the human proteome only a few have been shown to be reprogrammable to target new proteins. Recently various arylsulfonamides were shown to induce degradation of the splicing factor RBM39 via the RING type E3 ligase CRL4 DCAF15 . Here we identify the arylsulfonamide most amenable to chemical modifications and demonstrate its behaviour in bifunctional reprogramming.

This article provides adetailed report of our efforts to synthesize the dithiodiketopiperazine (DTP) natural products (À)-epicoccin Ga nd (À)-rostratin Au sing ad ouble C(sp 3)ÀHa ctivation strategy.T he strategy's viability was first establishedo namodel system lacking the C8/C8' alcohols. Then, an efficient stereoselective route including an organocatalytic epoxidation was secured to access ak ey bis-triflate substrate. This bis-triflate served as the functional handles for the key transformation of the synthesis:adouble C(sp 3)À Ha ctivation.T he successful double activation opened access to ac ommon intermediate for both natural products in high overall yield and on am ultigram scale. After several unsuccessful attempts, this intermediate was efficientlyc onverted to (À)-epicoccin Ga nd to the more challenging (À)-rostratin Av ia suitable oxidation/reduction and protecting group sequences, and via af inal sulfuration that occurredi ng ood yield andh igh diastereoselectivity.T hese efforts culminated in the synthesis of (À)-epicoccin Ga nd (À)-rostratin Ai n high overall yields (19.6 %o ver 14 steps and 12.7 %o ver 17 steps, respectively), with the latter being obtained on a 500 mg scale. Toxicity assessments of these natural products and several analogues (including the newly synthesized epicoccin K) in the leukemia cell line K562 confirmed the importance of the disulfide bridge for activity and identified dianhydrorostratin Aa sa20x more potent analogue.

<p>Supplementary Figure S2</p>

<p>Supplementary Figure S6</p>

<p>Supplementary Data</p>