Ctures to 5 and 6, we noted that their UV-vis (DAD) spectra were
Ctures to five and 6, we noted that their UV-vis (DAD) spectra had been related to those of 1sirtuininhibitor, suggestive of closely related chromophores and molecular structures, though HPLC-HRESI(-)MS analysis recommended that five (C37H30O11, mmu +2.four) and six (C37H30O11, mmu +2.0) had been isomeric MeOH adducts of 4. Attempts at purification of 5 and 6 by reversed phase HPLC proved problematic as instantly post-elution both underwent partial conversion to 7 and eight, a transformation that proceeded to near-completion soon after standing at r.t. for three h (ESI Fig. S13 14). The transformation items 7 and eight exhibited nearly identical UV-vis (DAD) spectra to 5 and six, with HPLC-HRESI(-)MS analysis suggesting that 7 (C36H28O11, mmu +0.six) and eight (C36H28O11, mmu +0.0) wereIL-6R alpha Protein custom synthesis Author Manuscript Author Manuscript Author Manuscript Author ManuscriptOrg Biomol Chem. Author manuscript; obtainable in PMC 2017 October 17.Salim et al.Pageisomeric H2O adducts of four. On concentrating in vacuo and resuspending in MeOH, the mixture of 7 and eight rapidly transformed to a complex mixture of 4sirtuininhibitor, dominated by four. In presenting a plausible mechanism for the biosynthetic/chemical origins of 1sirtuininhibitor (Fig. 4), we speculate that the polyketide precursor, oxanthroquinone (9), undergoes stereospecific methylation to a single (10R) enantiomer of 2, which in turn undergoes dimerisation to (+)oxanthromicin (1). Acid-mediated dehydration of two could deliver an achiral carbocation intermediate that is reversibly quenched with either H2O or MeOH to yield (sirtuininhibitor-hemioxanthromicin A (two) or B (3) respectively. Substantially, the carbocation intermediate could also transform, by way of a mechanism foreshadowed inside a 1979 study directed in the acid-mediated dimerisation of 10-methyleneanthrone,6 to yield a (sirtuininhibitor-spiro-carbocation. The (sirtuininhibitor-spirocarbocation could in turn undergo reversible quenching with either MeOH or H2O to provide the diastereomeric (sirtuininhibitor-spiro-oxanthromicin B1 (five) and B2 (six), or the diastereomeric (sirtuininhibitorspiro-oxanthromicin C1 (7) and C2 (eight), respectively. Finally, the acid-labile doubly benzylic 10-OH moiety in 7 and eight can undergo irreversible dehydration to yield (sirtuininhibitor-spirooxanthromicin A (4) as a stable quinone methide. As well as rationalising the biosynthetic/chemical relationships between 1sirtuininhibitor, this biosynthetic/chemical HB-EGF Protein medchemexpress pathway demonstrates for the very first time that a uncommon spiro dimerisation mechanism, first proposed in 1979,six has a footprint within the all-natural world. To support the structural assignments outlined above, and to supply material for a structure activity relationship (SAR) study, we embarked on the syntheses summarised in Scheme 1. Commercially accessible two,4-dichloro-1,4-benzoquinone was treated together with the Danishefsky diene derived from tiglic aldehyde7 to kind a Diels lder adduct, which on Jones oxidation yielded 2-chloro-8-hydroxy-7-methylnaphthaquinone8 (60 ). A subsequent Diels lder reaction together with the Danishefsky diene derived from ethyl diacetoacetate9 yielded oxanthroquinone ethyl ester (11) (58 ) (ESI Fig. S6a 6b), which on hydrolysis returned oxanthroquinone (9) (88 ). Treatment of synthetic 9 with MeMgBr resulted in regioselective addition to C-10 in preference to C-9, that is chelated towards the adjacent 8hydroxy, to yield (sirtuininhibitor-hemi-oxanthromicin A (two) (45 ). NMR data showed that synthetic samples 9 and two are identical in all respects towards the organic pr.
