Enantioselective Flow Synthesis of Rolipram Enabled by a Telescoped Asymmetric Conjugate Addition–Oxidative Aldehyde Esterification Sequence Using in Situ-Generated Persulfuric Acid as Oxidant

Abstract

A novel approach is reported for the enantioselective flow synthesis of rolipram comprising a telescoped asymmetric conjugate addition–oxidative aldehyde esterification sequence followed by trichlorosilane-mediated nitro group reduction and concomitant lactamization. The telescoped process takes advantage of a polystyrene-supported chiral organocatalyst along with in situ -generated persulfuric acid as a robust and scalable oxidant for direct aldehyde esterification. This approach demonstrates significantly improved productivity compared with earlier methodologies while ensuring environmentally benign metal-free conditions.

Asymmetric Flow Reactions Catalyzed by Immobilized Diphenylprolinol Alkyl Ether: Michael Reaction and Domino Reactions

“…There are some successful examples in flow chemistry using immobilized diphenylprolinol ether catalyst [13] . In the Michael reaction of α,β‐unsaturated aldehyde and nitroalkane, Kappe and coworkers reported a flow reaction using an immobilized diphenylprolinol ether catalyst [13k,m] . As we had previously developed an effective immobilized organocatalyst 2 , we report in this paper the application of this catalyst to the flow reaction of α,β‐unsaturated aldehyde and nitroalkane.…”

Asymmetric Michael Addition in Synthesis of β-Substituted GABA Derivatives

“…This three-step process implied (1) an initial organocatalytic flow synthesis based on telescoped flow asymmetric conjugate addition, (2) oxidative aldehyde esterification sequence using in situ-generated persulfuric acid [H 2 SO 5 ] as oxidant, and (3) a final nitro reduction and lactamization. The process is initiated by an enantioselective Michael-type addition of nitromethane with the appropriately substituted cinnamaldehyde derivative (E)-101 (Scheme 26) in the presence of cross-linked polystyrene-supported cis-4-hydroxydiphenylprolinol tert-butyldimethylsilyl (TBS) ether as the chiral catalyst for the formation of the γ-nitroaldehyde (S)-102, which was obtained after adjusting the reaction conditions in 94% ee and 97% of conversion [93]. Taken into account that the initial chiral γ-nitroaldehyde (S)-102 was labile and could decompose during purification, it was oxidized efficiently towards the corresponding γ-nitroester (S)-103 by the action of the oxidizing agent persulfuric acid [H 2 SO 5 ], in situ generated by the reaction of concentrated sulfuric acid with H 2 O 2 in a continuous-flow oxidative esterification.…”

Harnessing a Continuous‐Flow Persulfuric Acid Generator for Direct Oxidative Aldehyde Esterifications

“…[15] We recently communicated a three-step flow process for the enantioselective synthesis of the phosphodiesterase IV inhibitor rolipram, where a chiral γ-nitroester key intermediate was obtained by means of persulfuric acid-mediated direct aldehyde esterification. [16] Based on this preliminary finding as well as the well-established capability of flow reactors for in situ generation and concomitant utilization of highly reactive or other hazardous reagents, [15] we speculated that the synthetic applicability of persulfuric acid can largely be advanced by exploiting the continuous-flow generator concept. In this manner, by forming the potentially dangerous oxidant in situ, the safety hazards can be minimized and persulfuric acid can be harnessed as a simple and easily scalable oxidant within a closed continuous-flow reactor environment.…”