Een reported for the synthesis of poly-substituted piperidines,[7,8] highlighted by Bergman
Een reported for the synthesis of poly-substituted piperidines,[7,8] highlighted by Bergman and Ellman’s recent contribution.[9] Catalytic asymmetric approaches to polysubstituted piperidines, however, stay scarce with all the notable exception of the effective aza-Diels-Alder reaction.[10] Complementary approaches to piperidines relying around the union of two or extra fragments with concomitant manage of stereochemistry inside the approach will be of substantial value.[11,12] Herein, we report a partial option to this trouble relying on an asymmetric rhodium catalyzed cycloaddition of an alkyne, HDAC Biological Activity alkene and isocyanate, bringing three components with each other wherein two of the 3 are attached by a removal linker. We sought to create a catalytic asymmetric strategy to access piperidine scaffolds using the rhodium (I) catalyzed [2+2+2] cycloaddition. When the fully intermolecular reaction faces many GSK-3 Source challenges, for example competitive insertion with the alkene element more than insertion of a second alkyne to type a pyridone and regioselectivity of component*[email protected], Homepage:franklin.chm.colostate.edu/rovis/Rovis_Group_Website/Home_Page.html. ((Dedication—-optional)) Supporting facts for this article is obtainable around the WWW beneath angewandte.org or from the author.Martin and RovisPageinsertion, the use of a cleavable tether in the isocyanate backbone offers a answer to these obstacles (Scheme 1).[135] Goods of net intermolecular [2+2+2] cycloaddition would be accessed just after cleavage of the tether, permitting for the synthesis of substituted piperidine scaffolds within a catalytic asymmetric style. In this communication, we report the use of a cleavable tether in the rhodium catalyzed [2+2+2] cycloaddition between oxygenlinked alkenyl isocyanates and alkynes to access piperidine scaffolds soon after cleavage of your tether. The merchandise are obtained in high enantioselectivity and yield. Differentially substituted piperidines with functional group handles for further manipulation may be accessed inside a short sequence, in which the stereocenter introduced in a catalytic asymmetric fashion controls the diastereoselectivity of two additional stereocenters. Our investigations began using the oxygen-linked alkenyl isocyanate shown to participate in the rhodium (I) catalyzed [2+2+2] cycloaddition (Table 1).[1f] As with preceding rhodium (I) catalyzed [2+2+2] cycloadditions, [Rh(C2H4)2Cl]2 proved to be one of the most effective precatalyst.[16,17] A number of TADDOL primarily based phosphoramidite ligands provided the vinylogous amide. However, poor product selectivity (Table 1, Entry 1) and low yield (Table 1, Entries two, 3) are observed. BINOL based phosphoramidite ligands like Guiphos B1 supplied vinylogous amide with low enantioselectivity (Table 1, Entry 4). The not too long ago developed electron withdrawing phosphoramidite, CKphos, proved to become the ideal ligand (Table 1, entry five).[18] Working with CKphos, vinylogous amide was obtained in 77 yield and 94 ee. As expected with CKphos, item selectivity favored three more than four by 19:1.[19] With optimal conditions in hand, the alkyne scope was explored (Table 2). Aryl alkynes with electron donating and electron withdrawing groups take part in the reaction with moderate to higher yield and high enantioselectivity (3aj). Substitution in the ortho-and meta- positions (3fj) is tolerated without the need of decrease in yield or enantioselectivity. Heteroaromatic alkynes and enynes are also competent substrates inside the reaction, offering 3k and.
