The synthesis of the C-1-C-28 ABCD fragment of spongistatin is described. Anti-selective boron-mediated aldol coupling of a CD spiroketal ketone fragment to an AB spiroketal aldehyde unit forms the desired C1-C28 advanced intermediate. Other features include the double conjugate addition of a dithiol to an ynone to generate the key beta-keto-dithiane unit required for the synthesis of the AB spiroketal fragment. [reaction: see text]

A practical and efficient route to the CD spiroketal (C-16-C-28) of the spongistatins is reported. Two stereocenters are introduced from chiral building blocks with the remainder introduced by substrate-controlled transformations. The key beta-keto-1,3-dithiane intermediate is generated by a dithiol conjugate addition to an ynone and the 1,3-dithiane unit in the C-ring plays a key role in the spiroketalization and subsequent epimerization. The synthesis requires 24 steps, with a longest linear sequence of 19 steps in an overall yield of 14.5% (for the longest linear sequence). [reaction: see text]

RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.

The spongistatins comprise an important family of architecturally complex marine macrolides that display extraordinary antitumor activities against a variety of human cancer cell lines. These unique natural products were isolated independently by Pettit, Kitagawa and Fusetani in 1993, [1] although the absolute structure remained unknown until confirmation by synthesis in 1997.[2] The spongistatin family includes 9 macrolides, all of which possess remarkable growth inhibition properties against the US National Cancer Institutes panel of sixty human cancer cell lines. Spongistatin 1 (1) was extremely potent against a subset of highly chemoresistant tumor types, with typical GI 50 values of 2.5-3.5 10 À1 m. Cell lines derived from human melanoma were also found to be especially sensitive to Spongistatin 1, [1f, h] the most active of this family of macrolides (Scheme 1).Spongistatin 1 (1) comprises a 42-membered macrolide ring, 24 asymmetric centers, a chlorodiene sidechain, two spiroketals (of which only one contains full anomeric stabilization) and two pyranyl units. The complex molecular architecture and exciting biological profile of these natural products have attracted significant interest resulting in total syntheses by six groups. [2][3] Our initial synthetic analysis for 1 was consistent with established endgame strategies and corresponded to a C1ÀC41(OH) macrolactonization and C28ÀC29 Wittig olefination, resulting in two advanced fragments (ABCD fragment 2 and EF fragment 3) and hence enabling a convergent approach to the target (Scheme 1). [2][3] Furthermore, we recognized the utility of the anti-selective aldol coupling demonstrated by the groups of Evans, [2a] Paterson, [3d] Heathcock [3f] and more recently Smith [3a] and Crimmins, [3e] to join the AB and CD units together to form the basis of fragment 2 in their total syntheses. Accordingly, we envisaged that appropriately protected AB aldehyde 4 and Scheme 1. Structure and retrosynthetic analysis of Spongistatin 1 (1). TES = triethylsilyl, TBS = tert-butyldimethylsilyl, PMB = p-methoxybenzyl.

Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective continued...