The total synthesis of spongistatin 1 (1) and spongistatin 2 (2) has been achieved through an advanced-stage intermediate. The synthesis is highlighted by a highly convergent assembly of the four key fragments (the C1-C15 AB fragment 2, the C16-C28 CD fragment 3, the C29-C43 EF fragment 4, and the C44-C51 side chain 5) at a very advanced stage of the synthesis with minimal functional group interconversion. The CD fragment 3 functions as the central building block to which the other fragments are attached. The synthesis of the AB and CD spiroketal fragments is accomplished through the addition of a metalated gamma-pyrone to a beta-alkoxy aldehyde followed by spiroketalization. The EF subunit was assembled with high diastereoselectivity relying on asymmetric aldol reactions of chlorotitanium enolates of N-propionyl oxazolidinethiones and a double diastereoselective boron aldol to join the E and F fragments. Wittig coupling of the CD and EF fragments followed by a diastereoselective aldol reaction between the CDEF ketone and an AB aldehyde set the stage for attachment of the C44-C51 side chains and final macrolactonization and deprotection.
Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral tool compound with selectivity over other metalloproteases. Due to irreversible inhibition of cytochrome P450 3A4 for this chemical class, the risk of potential drug-drug interactions was managed by optimizing the series for subcutaneous injection.
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