The number of steps required to synthesize molecules with interesting biological activities can be signifcantly lowered by: 1) the design and development of new reactions that rapidly introduce target-relevant molecular complexity, 2) reducing the complexity of the molecules using function-oriented synthesis, and 3) designing the synthesis to enable late-stage diversification. A synthesis of clinprost and subsequent analogues, compounds of importance for neuroprotection, will be presented that makes use of all three of these concepts to produce a step-economical process (see figure below).The synthesis presented utilizes three sequential transition metal-catalyed reactions to install the molecular complexity. The Pd(0)-catalyzed decarboxylative coupling with allylic transposition was novel due to the lack of an anion stabilizing group adjacent to the ester. The Rh(I)-catalyzed reaction assembles the bicyclic core, diastereoselectively sets the stereocenters, and is the first [2+2+1] cycloaddition between two tethered dienes. The Ru(II)-catalyzed cross-metathesis reaction enables the desired late-stage diversification. These results, along with more recent developments, will be presented.

Synergistic use of step-saving strategies in the synthesis of clinprost

248th National Meeting (2014)

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