Quaternary Stereogenic Centers through Enantioselective Heck Arylation of Acyclic Olefins with Aryldiazonium Salts: Application in a Concise Synthesis of (R)‐Verapamil

Abstract

We describe herein a highly regio- and enantioselective Pd-catalyzed Heck arylation of unactivated trisubstituted acyclic olefins to provide all-carbon quaternary stereogenic centers. Chiral N,N ligands of the pyrimidine- and pyrazino-oxazoline class were developed for that purpose, providing the desired products in good to high yields with enantiomeric ratios up to >99:1. Both linear and branched substituents on the olefins were well-tolerated. The potential of this new method is demonstrated by the straightforward synthesis of several O-methyl lactols and lactones containing quaternary stereocenters, together with a concise enantioselective total synthesis of the calcium channel blocker verapamil.

Enantioselective, Noncovalent, Substrate‐Directable Heck–Matsuda and Oxidative Heck Arylations of Unactivated Five‐Membered Carbocyclic Olefins

“…We initiated our studies with the arylation of olefin 1 by using Pd(TFA) 2 (TFA=trifluoroacetic acid), Pyrabox ligand L1 , and 2,6‐di‐ tert ‐butyl‐4‐methylpyridine (DTBMP) as a base in solvents of different polarities (Table ). Commonly used MeOH led to a low yield and diastereoselectivity (Table , entry 5), but good enantioselectivity.…”

Enantioselective Heck Arylation of Acyclic Alkenol Aryl Ethers: Synthetic Applications and DFT Investigation of the Stereoselectivity

“…We started our investigation with the Heck‐Matsuda arylation of ( E )‐alkenyl phenyl ether 1 a using the 4‐chlorophenyldiazonium salt 2 a (a readily available and very stable aryldiazonium salt) and our previously reported reaction conditions for similar Heck‐Matsuda reactions (Table ), i. e., Pd(TFA) 2 as the palladium source in combination with the pyrazine‐bisoxazoline ligand, ( S )‐PyraBox L1 , basic zinc carbonate as base and methanol as a solvent at 40 °C (entry 1, Table ). From the outset of our studies, we envisioned the potential β ‐elimination of the expected β ‐aryloxy aldehyde as a critical issue, and we, therefore, reasoned that trapping the aldehyde in situ with methanol could be a convenient way to circumvent the aforementioned problem .…”

“…As in previous investigations, we assumed that Curtin‐Hammett conditions apply to the migratory insertion and, that the redox relay is efficient at converting the migratory insertion products, alkyl palladium complexes, into the reaction products (aldehydes or ketones) . The redox relay process was previously investigated by Sigman and coworkers and, in general, it is an efficient process with both PyOx and PyraBox ligands . In essence, this transformation consists of a series of syn β ‐hydride eliminations and palladium hydride migratory insertions.…”

“…[14,[50][51][52] The redox relay process was previously investigated by Sigman and coworkers and, in general, it is an efficient process with both PyOx and PyraBox ligands. [15,52] In essence, this transformation consists of a series of syn β-hydride eliminations and palladium hydride migratory inser-tions. Under these assumptions, the product distribution should be determined by the difference in free energy of activation of the corresponding migratory insertion transition states.…”

“…[1][2][3][4][5] Recent developments in the enantioselective Heck arylations have focused mostly on the use of chiral bisphosphine monoxides (BPMO), [6] P,Nligands, N,N-ligands, [7] and phase-transfer chiral counterions, [8,9] although the popular bidentate phosphines are still commonplace. [10,11] Additionally, the introduction of selectivity-inducing strategies, such as the use of redox relay, [12][13][14][15][16][17][18][19][20][21][22][23][24][25] and directing groups have also greatly improved and extended the scope of this reaction. [26][27][28][29][30][31] However, in spite of its tremendous success involving nonactivated and cyclic electron-rich alkenes, the effective arylation of acyclic electron-rich alkenes has been lagging behind significantly.…”