The reaction of heteroaryl iodides with i-PrMgBr (ca. 1.0 equiv) in THF provides the corresponding magnesiated heterocycles. Functional groups such as an ester, cyano, or chloride functions are tolerated in these new Grignard reagents if the exchange can be performed below -20 degrees C. This is the case for all heterocycles bearing electron-withdrawing groups or chelating functions facilitating the iodine-magnesium exchange. In many cases, the exchange can be extended to heteroaryl bromides, and a case of a chlorine-magnesium exchange is described with tetrachlorothiophene. This new preparation of functionalized heteroarylmagnesium compounds provides after reaction with various electrophiles a new entry to a broad range of polyfunctional pyridines, imidazoles, furanes, thiophenes, pyrroles, antipyrines, and uracil derivatives. The application of the halogen-magnesium exchange in the solid phase allows the performance of solid-phase synthesis, with potential applications for combinatorial chemistry.
A formal total synthesis of oximidine II has been achieved, employing a Suzuki-type coupling approach to construct the highly strained, polyunsaturated 12-membered macrolactone. To achieve this goal, benefit was derived from the stability of potassium alkenyltrifluoroborates to establish conditions for the macrocyclization. The stereocontrolled formation of the cis-1,2-diol subunit was accomplished using a diastereoselective, reagent controlled addition to a chiral aldehyde utilizing the Carreira protocol. Advantage was taken of the Snieckus hydroborating reagent to gain access to the key trifluoroborate needed for the macrocyclization.
Inhibitors of histone deacetylases (HDAC) are currently developed for the treatment of cancer. These include compounds with a sulfur containing head group like depsipeptide, alkylthiols, thiocarboxylates, and trithiocarbonates with a carbonyl group in the alpha-position. In the present investigation, we report on the synthesis and comprehensive SAR analysis of HDAC inhibitors bearing a tri- or dithiocarbonate motif. Such trithiocarbonates are readily accessible from either preformed or in situ prepared alpha-halogenated methylaryl ketones. A HDAC isotype selectivity and a substrate competitive mode-of-action is shown for defined analogues. Exploration of the head group showed the necessity of the dithio-alpha-carbonyl motif for potent HDAC inhibition. Highly potent, substrate competitive HDAC6 selective inhibitors were identified (12ac:IC 50 = 65 nM and K i = 110 nM). Trithiocarbonate analogues with an aminoquinoline-substituted pyridinyl-thienoacetyl cap demonstrate a cytotoxicity profile and potency comparable to that of suberoylanilide hydroxamic acid (SAHA) as an approved cancer drug.
[reaction: see text]. Starting from a nonracemic planar-chiral arene tricarbonyl chromium complex, an epimer of the bioactive marine diterpene helioporin B was synthesized in a highly stereoselective fashion. The stereostructure of the product (11-epi-helioporin B) corresponds to that of other serrulatane-type natural products. In a key step of the synthesis, 2-lithioacetonitrile undergoes conjugate nucleophilic addition to an unsaturated complex. Remarkably, this addition occurs in an endo mode, i.e., from the complexed face of the pi-ligand.
[formula: see text] Starting from a nonracemic planar-chiral arene tricarbonyl chromium complex, the serrulatane diterpenoid (+)-20-methoxy-serrulat-14-en-7,8-diol was synthesized in a highly stereoselective fashion. The key step of the synthesis is an endo-selective conjugate nucleophilic addition of lithio-methylphenyl sulfone to a 1-ethylidene-tetralin-Cr(CO)3 derivative. By employing different substrates and nucleophiles it was shown that the surprising and rather general endo selectivity must result from a unique complex induced proximity effect under participation of the Cr(CO)3 moiety.
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