Metal‐Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing

Abstract

Many pharmaceuticals feature biaryl motifs that are crucial for their binding to the target. Yet, benchmark methods for selective cross-couplings rely on highly toxic heavy metal catalysts, which are unfavorable in the synthesis of pharmaceuticals. Metal-free coupling reactions, on the other hand, may require harsh conditions and lack selectivity. We report a novel, metal-free cross-coupling reaction that involves the tethering of two phenyl groups by a temporary, traceless sulfonamide linker that directs a photochemical aryl fusion into a single coupling product. The perfect regio- and chemoselectivity of the reaction could be rationalized by a cyclic intermediate, which fragments into the biaryl and volatile side products. Using a flow reactor, we synthesized numerous substituted biaryl building blocks for important therapeutics in high yields, such as antibiotics, antitumor, neuroprotective and cholesterol-lowering agents as well as antiarthritic non-steroidal antiinflammatory drugs (NSAIDs). The new method was successfully employed in a total synthesis of cannabinol, an important analgesic and antiemetic therapeutic. We also report a metal-free synthesis of key building blocks used for the preparation of sartans, antihypertensive agents that rank among the top blockbuster drugs worldwide. This safe and convenient protocol is a valuable alternative for the widely used metal-dependent aryl cross-coupling methods.

Multistep synthesis of a valsartan precursor in continuous flow

“…The active pharmaceutical ingredient (API) belongs to the class of sartans, which feature a biphenyl moiety as common structural unit. The biaryl scaffold plays a crucial role in the oral bioavailability as well as the binding of the API to the biological target [3,4]. Valsartan 1 was first introduced onto the market as Diovan® by Novartis in 1997 [5,6].…”

Metal‐Free Aryl Cross‐Coupling Directed by Traceless Linkers

“…Light‐driven coupling of the aryl moieties is feasible by the leading transition underlying S 2 of 1 a , which features a bonding character between C1 and C5 (Figure C). In addition, the S 2 state coincides with the experimentally determined maximum turnover at 5.28 eV (235 nm) . Evolution of the adiabatic PECs of the low‐lying excited states reduces the energetic barrier to enable photosplicing of 1 a in the excited states to only 0.69 eV along the IRC.…”

“…Regioselective biaryl syntheses have been achieved through intramolecular aryl coupling and rearrangement, yet parts of the linkers remain in the product . Recently, we found that bis‐aryl‐substituted sulfonamides can be contracted photochemically, and thereby permit the regioselective fusion of two aryl groups . Using a UV photoreactor, we demonstrated the preparative applicability of the reaction in the synthesis of building blocks for a series of clinically relevant pharmaceuticals.…”

Metal-Free Aryl Cross-Coupling Directed by Traceless Linkers

“…In addition, the S 2 state coincides with the experimentally determined maximum turnover at 5.28 eV (235 nm). [12] Evolution of the adiabatic PECs of the low-lying excited states reduces the energetic barriert oe nable photosplicing of 1a in the excited states to only 0.69 eV along the IRC. It is notable that reversal of the substrate polarity( 1aa in lieu of 1a)l eads to a congruent model and activation barrier(0.77 eV for S 1 ).…”

“…[11] Recently,w ef ound that bisaryl-substituted sulfonamides can be contracted photochemically,a nd therebyp ermitt he regioselective fusion of two aryl groups. [12] Using aU Vp hotoreactor,w ed emonstrated the preparative applicability of the reaction in the synthesis of buildingb locks for as eries of clinically relevant pharmaceuticals. Remarkably,a ll required anchor groups to tether the aryls as sulfonamides are cleanly extruded as volatile fragments (ammonia,s ulfur dioxide, formaldehyde) to yield the ipso-ipsocoupled biaryl product ( Figure 1A).…”