Photoredox-catalyzed deoxyfluorination of activated alcohols with Selectfluor®.

Herein we disclose a deoxyfluorination of alcohols with an electrophilic fluorine source via visible-light photoredox catalysis. This radical-mediated C-F coupling is capable of fluorinating secondary and tertiary alcohols efficiently, complementing previously reported nucleophilic deoxyfluorination protocols.

Catalytic Asymmetric Synthesis of Bicycloprolines by a 1,3-Dipolar Cycloaddition/Intramolecular Alkylation Strategy.

The diastereoselective one-pot synthesis of hexahydrocyclopenta[b]pyrrole derivatives (bicycloprolines) has been achieved by base-mediated reactions of (E)-tert-butyl 6-bromo-2-hexenoate with α-imino esters. The catalytic asymmetric version of this process has been efficiently achieved using the Cu(I)/(R)-DTBM-Segphos complex as a catalyst following a two-step 1,3-dipolar cycloaddition/intramolecular alkylation sequence.

Palladium-Catalyzed C-H Arylation of α,ß-Unsaturated Imines: Catalyst-Controlled Synthesis of Enamine and Allylic Amine Derivatives.

A unique chemo- and regioselective α- and γ-arylation of palladium azapentadienyl intermediates is presented. Two distinct catalysts and sets of conditions successfully controlled the regioselectivity of the arylation. These methods provide the first umpolung C-H functionalization of azapentadienyl palladium intermediates and enable the divergent synthesis of allylic amine and enamine derivatives, which are of significant interest in the pharmaceutical industry.

Highly selective copper-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides with acyclic 1,3-dienes.

The first examples of the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with acyclic activated 1,3-dienes (and 1,3-enynes) are described. Under copper catalysis, a selective cycloaddition at the terminal γ,δ-C=C bond is observed. In addition, depending on the ligand used, either the exo or the endo adduct can be obtained with high selectivity. Under appropriate reaction conditions, the acyclic 1,6-addition product is detected, suggesting a stepwise mechanism. The resulting C4-alkenyl-substituted pyrrolidines are suitable substrates for further access to polycyclic systems, as highlighted by the preparation of hexahydrochromeno[4,3-b]pyrrole and the tetracyclic core of the alkaloid gracilamine.

Redefining the Synthetic Logic of Medicinal Chemistry. Photoredox-Catalyzed Reactions as a General Tool for Aliphatic Core Functionalization.

C(sp3)-rich aliphatic motifs in drug molecules are strongly associated with clinical success. Historically, the availability of compound libraries based on C(sp3)-rich cores has been limited due to the challenging direct functionalization of aliphatic rings. Instead, most small molecule drug-like libraries are diversified around central aromatic rings. Herein, we present a general approach to the synthesis of diversified libraries featuring aliphatic core rings via photoredox catalysis under mild conditions.

Rapid Optimization of Photoredox Reactions for Continuous-Flow Systems Using Microscale Batch Technology.

Photoredox catalysis has emerged as a powerful and versatile platform for the synthesis of complex molecules. While photocatalysis is already broadly used in small-scale batch chemistry across the pharmaceutical sector, recent efforts have focused on performing these transformations in process chemistry due to the inherent challenges of batch photocatalysis on scale. However, translating optimized batch conditions to flow setups is challenging, and a general approach that is rapid, convenient, and inexpensive remains largely elusive. Herein, we report the development of a new approach that uses a microscale high-throughput experimentation (HTE) platform to identify optimal reaction conditions that can be directly translated to flow systems. A key design point is to simulate the flow-vessel pathway within a microscale reaction plate, which enables the rapid identification of optimal flow reaction conditions using only a small number of simultaneous experiments. This approach has been validated against a range of widely used photoredox reactions and, importantly, was found to translate accurately to several commercial flow reactors. We expect that the generality and operational efficiency of this new HTE approach to photocatalysis will allow rapid identification of numerous flow protocols for scale.

Pyrrole and oligopyrrole synthesis by 1,3-dipolar cycloaddition of azomethine ylides with sulfonyl dipolarophiles.

A procedure for the synthesis of functionalized, substituted pyrroles by 1,3-dipolar cycloaddition of azomethine ylides has been developed. This protocol is based on the metal-catalyzed cycloaddition of alpha-iminoesters with sulfonyl dipolarophiles, followed by the base-promoted elimination of the sulfonyl groups. A wide variety of 2,5-disubstituted and 2,3,5- and 2,4,5-trisubstituted pyrroles have been prepared in satisfactory yields from 1,2-bis(sulfonyl ethylene), beta-sulfonylenones, and beta-sulfonylacrylates. This method can be applied in an iterative and straightforward manner to the construction of oligopyrroles, from bipyrroles to pentapyrroles. Iterative [n+1] and [n+2] approaches have been devised, the latter involves double 1,3-dipolar cycloaddition from pyrrolyl-based bis(iminoesters).

Cu-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with beta-phenylsulfonyl enones. Ligand controlled diastereoselectivity reversal.

A catalytic asymmetric procedure for the 1,3-dipolar cycloaddition of (E)-beta-phenylsulfonyl enones with azomethine ylides to provide highly functionalized pyrrolidine derivatives is described. In the presence of chiral Cu(I)-Segphos catalysts the adducts were obtained with high regio-, diastereo-, and enantioselectivity. Interestingly, a switch from endo to exo selectivity was observed when Segphos or DTBM-Segphos ligand was used.

Enantioselective synthesis of α-heteroarylpyrrolidines by copper-catalyzed 1,3-dipolar cycloaddition of α-silylimines.

α-Heteroarylpyrrolidines have been efficiently prepared via 1,3-dipolar cycloaddition between silylimines and activated olefins. In the presence of Cu(CH3CN)4PF6/Walphos as catalytic system, high levels of enantioselectivity (up to ≥99% ee) and diastereoselectivity were achieved (major formation of C-2/C-4 trans-substituted pyrrolidines). The reaction is compatible with a broad variety of dipolarophiles including maleimides, maleates, fumarates, nitroalkenes, and vinylsulfones. The resulting cycloadducts can be transformed into bioactive pyrrolidine derivatives.

Enantioselective synthesis of 4-aminopyrrolidine-2,4-dicarboxylate derivatives via Ag-catalyzed cycloaddition of azomethine ylides with alkylidene azlactones.

A catalytic highly enantioselective silver-DTBM-segphos catalyzed cycloaddition of α-iminoesters with alkylidene azlactones is reported. This procedure provides an effective access to 4-aminopyrrolidine-2,4-dicarboxylate derivatives with high diastereo- and enantioselectivity.

Cu-catalyzed asymmetric [3+2] cycloaddition of α-iminoamides with activated olefins.

A variety of 2-amido pyrrolidines, including Weinreb-type amides, have been prepared with very high exo diastereoselectivity and enantioselectivitiy in the reaction of α-iminoamides with activated alkenes catalyzed by Cu(I)-Segphos ligands.