Photobiocatalytic Strategies for Organic Synthesis.

Biocatalysis has revolutionized chemical synthesis, providing sustainable methods for preparing various organic molecules. In enzyme-mediated organic synthesis, most reactions involve molecules operating from their ground states. Over the past 25 years, there has been an increased interest in enzymatic processes that utilize electronically excited states accessed through photoexcitation. These photobiocatalytic processes involve a diverse array of reaction mechanisms that are complementary to one another. This comprehensive review will describe the state-of-the-art strategies in photobiocatalysis for organic synthesis until December 2022. Apart from reviewing the relevant literature, a central goal of this review is to delineate the mechanistic differences between the general strategies employed in the field. We will organize this review based on the relationship between the photochemical step and the enzymatic transformations. The review will include mechanistic studies, substrate scopes, and protein optimization strategies. By clearly defining mechanistically-distinct strategies in photobiocatalytic chemistry, we hope to illuminate future synthetic opportunities in the area.

Enantioselective Deaminative Alkylation of Amino Acid Derivatives with Unactivated Olefins.

Herein, we report the first Ni-catalyzed enantioselective deaminative alkylation of amino acid and peptide derivatives with unactivated olefins. Key for success was the discovery of a new sterically encumbered bis(oxazoline) ligand backbone, thus offering a de novo technology for accessing enantioenriched sp3-sp3 linkages via sp3 C-N functionalization. Our protocol is distinguished by its broad scope and generality across a wide number of counterparts, even in the context of late-stage functionalization. In addition, an enantioselective deaminative remote hydroalkylation reaction of unactivated internal olefins is within reach, thus providing a useful entry point for forging enantioenriched sp3-sp3 centers at remote sp3 C-H sites.

sp3 Bis-Organometallic Reagents via Catalytic 1,1-Difunctionalization of Unactivated Olefins.

A catalytic 1,1-difunctionalization of unactivated olefins en route to sp3 bis-organometallic B,B(Si)-reagents is described. The protocol is characterized by exceptional reaction rates, mild conditions, wide scope, and exquisite selectivity pattern, constituting a new platform to access sp3 bis-organometallics.

Copper mediated C(sp2)-H amination and hydroxylation of phosphinamides.

Copper mediated C(sp2)-H amination and hydroxylation of arylphosphinic acid are accomplished by adopting phosphinamide as the directing group. This method is distinguished by its wide substrate scope and excellent functional group tolerance, thus allowing for the rapid preparation of organophosphorus compounds in organic synthesis.

Site-Selective 1,2-Dicarbofunctionalization of Vinyl Boronates through Dual Catalysis.

A modular, site-selective 1,2-dicarbofunctionalization of vinyl boronates with organic halides through dual catalysis is described. This reaction proceeds under mild conditions and is characterized by excellent chemo- and regioselectivity. It thus represents a complementary new technique for preparing densely functionalized alkyl boron architectures from simple and accessible precursors.

Site-Selective Catalytic Deaminative Alkylation of Unactivated Olefins.

A catalytic deaminative alkylation of unactivated olefins is described. The protocol is characterized by its mild conditions, wide scope, including the use of ethylene as substrate, and exquisite site-selectivity pattern for both α-olefins and internal olefins, thus unlocking a new catalytic platform to forge sp3-sp3 linkages, even in the context of late-stage functionalization.

Site-Selective Ni-Catalyzed Reductive Coupling of α-Haloboranes with Unactivated Olefins.

A mild, chemo- and site-selective catalytic protocol that allows for incorporating an alkylboron fragment into unactivated olefins is described. The use of internal olefins enables C-C bond-formation at remote sp3 C-H sites, constituting a complementary and conceptually different approach to existing borylation techniques that are currently available at sp3 centers.

Nickel-Catalyzed Umpolung Arylation of Ambiphilic α-Bromoalkyl Boronic Esters.

A nickel-catalyzed reductive arylation of ambiphilic α-bromoalkyl boronic esters with aryl halides is described. This platform provides an unrecognized opportunity to promote the catalytic umpolung reactivity of ambiphilic reagents with aryl halides, thus unlocking a new cross-coupling strategy that complements existing methods for the preparation of densely functionalized alkyl-substituted organometallic reagents from simple and readily accessible precursors.

Identification of monodentate oxazoline as a ligand for copper-promoted ortho-C-H hydroxylation and amination.

The use of a weakly coordinating monodentate directing group for copper mediated ortho-hydroxylation and amination reactions allows for the identification of an external oxazoline ligand as a promoter.

Switchable Site-Selective Catalytic Carboxylation of Allylic Alcohols with CO2.

A switchable site-selective catalytic carboxylation of allylic alcohols has been developed in which CO2 is used with dual roles, both facilitating C-OH cleavage and as a C1 source. This protocol is characterized by its mild reaction conditions, absence of stoichiometric amounts of organometallic reagents, broad scope, and exquisite regiodivergency which can be modulated by the type of ligand employed.

Cu(II)-Mediated C(sp(2))-H Hydroxylation.

A Cu(II)-mediated ortho-C-H hydroxylation using a removable directing group has been developed. The reaction exhibits considerable functional group tolerance. The use of O2 as an oxidant is crucial for the reactivity. Water is also found to significantly improve this reaction.

Cu(II)-catalyzed coupling of aromatic C-H bonds with malonates.

A new Cu(II)-catalyzed oxidative coupling of arenes with malonates has been developed using an amide-oxazoline directing group. The reaction proceeds via C(sp(2))-H activation and malonate coupling, followed by intramolecular oxidative N-C bond formation. A variety of arenes bearing different substituents are shown to be compatible with this reaction.

Cu(OAc)2-catalyzed coupling of aromatic C-H bonds with arylboron reagents.

Cu-catalyzed coupling of aryl C-H bonds with arylboron reagents was accomplished using a readily removable directing group, which provides a useful method for the synthesis of biaryl compounds. The distinct transmetalation step in this Cu-catalyzed C-H coupling with aryl borons provides unique evidence for the formation of an aryl cupperate intermediate.

Exceedingly fast copper(II)-promoted ortho C-H trifluoromethylation of arenes using TMSCF3.

The direct ortho-trifluoromethylation of arenes, including heteroarenes, with TMSCF3 has been accomplished by a copper(II)-promoted C-H activation reaction which completes within 30 minutes. Mechanistic investigations are consistent with the involvement of C-H activation, rather than a simple electrophilic aromatic substitution (SE Ar), as the key step.

Cu(II)-mediated ortho C-H alkynylation of (hetero)arenes with terminal alkynes.

Cu(II)-promoted ortho alkynylation of arenes and heteroarenes with terminal alkynes has been developed to prepare aryl alkynes. A variety of arenes and terminal alkynes bearing different substituents are compatible with this reaction, thus providing an alternative disconnection to Sonogashira coupling.

Cu(II)-mediated C-H amidation and amination of arenes: exceptional compatibility with heterocycles.

A Cu(OAc)2-mediated C-H amidation and amination of arenes and heteroarenes has been developed using a readily removable directing group. A wide range of sulfonamides, amides, and anilines function as amine donors in this reaction. Heterocycles present in both reactants are tolerated, making this a broadly applicable method for the synthesis of a family of inhibitors including 2-benzamidobenzoic acids and N-phenylaminobenzoates.

Ru(II)-catalyzed ortho-C-H amination of arenes and heteroarenes at room temperature.

The Ru(II)-catalyzed ortho-C-H amination directed by a weakly coordinating amide auxiliary with O-benzoyl hydroxylamines at room temperature has been achieved. This reaction is compatible with heterocycles including pyrazole, thiophene, benzothiophene, furan, benzofuran, and indole.