The past six decades have seen awe-inspiring progress in the science of synthesis. In academia, the assembly of complex molecules (natural products) still poses a challenge, but is no longer a limitation. Yet, application of natural products in industry is still limited. This limitation is reflected by a lack of novel lead structures with a new mode of action — one of the main challenges pharmaceutical industry faces today. With complexity still being a challenge but no longer the limitation, natural products and their unique structures are now ideally suited to fill this gap. However, “target oriented synthesis” (TOS) still dominates the synthetic community, but is not suited for structure diversification. This imposes a poor “return on investment” (ROI) to natural product research in industry. The diminished ROI of TOS is owned to tailor made synthetic routes, strictly applicable to a single molecule with no flexibility, and thus disproportionally increasing time and financial efforts in the search for new lead structures. In this research proposal, the applicant devises an alternative strategic concept termed “Cooperative Synthesis by Molecular Deconvolution” (CoSyMoDe), providing an alternative to TOS, and thus serves as a versatile tool for lead structure discovery. In contrast to TOS, CoSyMoDe targets the most complex congener (alpha) in a set of natural products. All other congeners are obtained by synthetic deconvolution of alpha, rendering the overall process more facile, additionally providing access to a whole set of targets, and thus improving the ROI. To showcase the versatility of CoSyMoDe we have picked one of the most challenging, bioactive, and prominent set of target structures, the taxane diterpenes. Amongst them “cyclotaxanes”, are most complex, and have eluded their total synthesis up to date. We will demonstrate the potential of CoSyMoDe, by solving this synthetic conundrum and thereby push the limits of organic synthesis.
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