Expanding Reaction Profile of Allyl Carboxylates via 1,2-Radical Migration (RaM): Visible-Light-Induced Phosphine-Catalyzed 1,3-Carbobromination of Allyl Carboxylates.

Allyl carboxylates are useful synthetic intermediates in a variety of organic transformations, including catalytic nucleophilic/electrophilic allylic substitution reactions and 1,2-difunctionalization reactions. However, the catalytic 1,3-difunctionalization of allyl carboxylates remains elusive. Herein, we report the first photoinduced, phosphine-catalyzed 1,3-carbobromination of allyl carboxylates, affording a range of valuable substituted isopropyl carboxylates (sIPC). The transformation has broad functional group tolerance, is amenable to the late-stage modification of complex molecules and gram-scale synthesis, and expands the reaction profiles of allyl carboxylates and phosphine catalysis. Preliminary experimental and computational studies suggest a non-chain-radical mechanism involving the formation of an electron donor-acceptor complex, 1,2-radical migration (RaM), and Br-atom transfer processes. We anticipate that the 1,2-RaM reactivity of allyl carboxylates and the phosphine-catalyzed radical reaction will both serve as a platform for the development of new transformations in organic synthesis.

Excited-State Palladium-Catalyzed α-Selective C1-Ketonylation.

C-Glycosides are important carbohydrate mimetics found in natural products, bioactive compounds, and marketed drugs. However, stereoselective preparation of this class of glycomimetics remains a significant challenge in organic synthesis. Herein, we report an excited-state palladium-catalyzed α-selective C-ketonylation strategy using readily available 1-bromosugars to access a range of C-glycosides. The reaction features excellent α-selectivity and mild conditions that tolerate a wide range of functional groups and complex molecular architectures. The resulting α-ketonylsugars can serve as versatile precursors for their ß-isomers and other C-glycosides. Preliminary experimental and computational studies of the mechanism suggest a radical pathway involving the formation of palladoradical and glycosyl radical that undergoes polarity-mismatched coupling with silyl enol ether, affording the desired α-ketonylsugars. Insight into the reactivity and mechanism will inspire new reaction development and provide straightforward access to both α- and ß-C-glycosides, greatly expanding the chemical and patent spaces of glycomimetics.

C2-ketonylation of carbohydrates via excited-state palladium-catalyzed 1,2-spin-center shift.

C2-ketonyl-2-deoxysugars, sugars with the C2-hydroxyl group replaced by a ketone side chain, are important carbohydrate mimetics in glycobiology and drug discovery studies; however, their preparation remains a vital challenge in organic synthesis. Here we report the first direct strategy to synthesize this class of glycomimetics from readily available 1-bromosugars and silyl enol ethers via an excited-state palladium-catalyzed 1,2-spin-center shift (SCS) process. This step-economic reaction features broad substrate scope, has a high functional group tolerance, and can be used in late-stage functionalization of natural product- and drug-glycoconjugates. Preliminary experimental and computational mechanistic studies suggested a non-chain radical mechanism involving photoexcited palladium species, a 1,2-SCS process, and a radical Mizoroki-Heck reaction.

Excited-State Palladium-Catalyzed Radical Migratory Mizoroki-Heck Reaction Enables C2-Alkenylation of Carbohydrates.

Excited-state palladium catalysis has emerged as a promising strategy for developing novel and valuable reactions. Herein, we report the first excited-state Pd-catalyzed 1,2-radical migratory Mizoroki-Heck reaction that enables C2-alkenylation of carbohydrates using readily available 1-bromosugars and alkenes. The reaction tolerates a wide variety of functional groups and complex molecular architectures, including derivatives of natural products and marketed drugs. Preliminary mechanistic studies and DFT calculations suggest the involvement of visible-light-induced photoexcitation of Pd species, 1,2-spin-centered-shift (SCS) process, and Heck-type cross-coupling reaction. The reaction expands the reactivity profile of excited-state Pd catalysis and provides a streamlined protocol for the preparation of a wide variety of C2-alkenylated carbohydrate mimetics to aid the discovery and development of new therapeutics, agrochemicals, and materials.

Visible-light-induced photoacid catalysis: application in glycosylation with O-glycosyl trichloroacetimidates.

The development of visible-light-induced photoacid catalyzed glycosylation is reported. The eosin Y and PhSSPh catalyst system is applied to realize glycosylation with different glycosyl donors upon light irradiation. The reaction shows a broad substrate scope, including both glycosyl donors and acceptors, and highlights the mild nature of the reaction conditions.

Nickel-Catalyzed Radical Migratory Coupling Enables C-2 Arylation of Carbohydrates.

Nickel catalysis offers exciting opportunities to address unmet challenges in organic synthesis. Herein we report the first nickel-catalyzed radical migratory cross-coupling reaction for the direct preparation of 2-aryl-2-deoxyglycosides from readily available 1-bromosugars and arylboronic acids. The reaction features a broad substrate scope and tolerates a wide range of functional groups and complex molecular architectures. Preliminary experimental and computational studies suggest a concerted 1,2-acyloxy rearrangement via a cyclic five-membered-ring transition state followed by nickel-catalyzed carbon-carbon bond formation. The novel reactivity provides an efficient route to valuable C-2-arylated carbohydrate mimics and building blocks, allows for new strategic bond disconnections, and expands the reactivity profile of nickel catalysis.

Excited-State Palladium-Catalyzed 1,2-Spin-Center Shift Enables Selective C-2 Reduction, Deuteration, and Iodination of Carbohydrates.

Excited-state catalysis, a process that involves one or more excited catalytic species, has emerged as a powerful tool in organic synthesis because it allows access to the excited-state reaction landscape for the discovery of novel chemical reactivity. Herein, we report the first excited-state palladium-catalyzed 1,2-spin-center shift reaction that enables site-selective functionalization of carbohydrates. The strategy features mild reaction conditions with high levels of regio- and stereoselectivity that tolerate a wide range of functional groups and complex molecular architectures. Mechanistic studies suggest a radical mechanism involving the formation of hybrid palladium species that undergoes a 1,2-spin-center shift followed by the reduction, deuteration, and iodination to afford functionalized 2-deoxy sugars. The new reactivity will provide a general approach for the rapid generation of natural and unnatural carbohydrates.

Total Synthesis of (-)-Pepluanol†B: Conformational Control of the Eight-Membered-Ring System.

The first total synthesis of the Euphorbia diterpenoid pepluanol B in both racemic and enantioenriched form involves 20 steps from a known bicyclic diol. This synthesis features an unprecedented bromo-epoxidation to control the eight-membered-ring conformation. In addition, salient reactions for the construction of the tetracyclic backbone include a sterically challenging aldol reaction to establish the quaternary center, a ring closing metathesis (RCM) to forge the eight-membered ring, and a diastereoselective cyclopropanation to assemble the embedded cyclopropane motif.

Metal-free photocatalytic thiol-ene/thiol-yne reactions.

The organic photocatalyst (9-mesityl-10-methylacridinum tetrafluoroborate) in the presence of visible light is used to initiate thiol-ene and thiol-yne reactions. Thiyl radicals are generated upon quenching the photoexcited catalyst with a range of thiols. The highlighted mild nature of the reaction conditions allows a broad substrate scope of the reactants. Relying on this efficient metal-free condition, both thiol-ene and thiol-yne reactions between carbohydrates and peptides could be realized in excellent yields.

Stereoselective Synthesis of 2-Deoxyglycosides from Glycals by Visible-Light-Induced Photoacid Catalysis.

The direct, photoacid-catalyzed synthesis of 2-deoxyglycosides from glycals is reported. A series of phenol-conjugated acridinium-based organic photoacids were rationally designed, synthesized, and studied alongside the commercially available phenolic catalyst eosin Y. In the presence of such a photoacid catalyst and light, synthetic glycals were activated and coupled with a range of alcohols to afford 2-deoxyglycosides in good yields and with excellent α-selectivity.

Visible-Light-Mediated Thiol-Ene Reactions through Organic Photoredox Catalysis.

Synthetically useful radical thiol-ene reactions can be initiated by visible-light irradiation in the presence of an organic photocatalyst, 9-mesityl-10-methylacridinum tetrafluoroborate. The key thiyl radical intermediates are generated upon quenching of the photoexcited catalyst with a variety of thiols. The success of this method requires only the use of near-stoichiometric levels of alkene coupling partners. Using these highly efficient metal-free conditions, thiol-ene reactions between carbohydrates and peptides can be accomplished in excellent yields.

Bioinspired Collective Syntheses of Iboga-Type Indole Alkaloids.

We present the application of a bioinspired collective synthesis strategy in the total syntheses of seven iboga-type indole alkaloids: (±)-tabertinggine, (±)-ibogamine, (±)-ibogaine, (±)-ibogaine hydroxyindolenine, (±)-3-oxoibogaine hydroxyindolenine, (±)-iboluteine, and (±)-ervaoffines D. In particular, tabertinggine and its congeners serve as iboga precursors for the subsequent biomimetic transformations into other iboga-type alkaloids.

Bioinspired Total Syntheses of Isospongian-type Diterpenoids (-)-Kravanhins†A and C.

The first bioinspired total syntheses of (-) kravanhins A and C were accomplished from a labdane diterpenoid derivative. The key reactions involve a photooxidation and a one-pot sequential aldol cyclization and lactonization, which provide a new plausible biosynthetic pathway for the kravanhins and other symbiotic members.

Domino intramolecular Diels-Alder reactions to construct a 6/6/5/5 fused tetracyclic framework.

Domino intramolecular Diels-Alder (IMDA) reactions towards the 6/6/5/5 fused tetracyclic natural products were developed in satisfactory yield and high stereoselectivity. Four rings, six contiguous stereocenters and four C-C bonds were formed in a single operation. 4-epi-Hydromitchellene B was also synthesised efficiently via this strategy.

Asymmetric Total Synthesis of (-)-Kravanhin†B.

The first asymmetric total synthesis of kravanhin B has been accomplished with a linear reaction sequence of 13 steps starting from (R)-(-)-carvone. The synthesis features an intramolecular aldol cyclization to construct the desired cis-fused decalin skeleton and an acid-catalyzed dehydration and olefin isomerization to install the γ-butenolide ring.

Bioinspired total synthesis of gymnothelignan N.

Bioinspired total synthesis of gymnothelignan N was accomplished in 13 steps and 6.7% overall yield. The synthesis features a syn Evans aldol reaction, an intramolecular hydrogenative dehydration reaction, and a phenol oxidative dearomatization/Friedel-Crafts reaction, which provides a new plausible biosynthetic pathway for the gymnothelignans and other symbiotic members. Meanwhile, another tetrahydrofuran-type lignan beilschmin A was also synthesized.

PtCl2-catalyzed tandem enyne cyclization/1,2 ester migration reaction controlled by substituent effects of all-carbon 1,6-enynyl esters.

On the move: A novel PtCl2-catalyzed tandem 1,6-enyne cyclization/1,2-acyloxy migration reaction was developed, which was shown to be controlled by substitution effects. Using this method, a series of substituted enol esters containing the cyclopentenyl motif were prepared in moderate to high yields.

Concise formal synthesis of (+)-neopeltolide.

A concise formal synthesis of (+)-neopeltolide (1) has been accomplished. The synthesis demonstrated high atom efficiency employing only one step of functional group protection. Key steps involved iridium-catalyzed double asymmetric carbonyl allylation, palladium-catalyzed intramolecular alkoxycarbonylation, ruthenium-catalyzed olefin isomerization, and ring-closing metathesis.

Total synthesis of cyanolide A.

The total synthesis of cyanolide A has been achieved in 14 steps from commercially available (S)-2-ethyloxirane, exploiting the palladium-catalyzed intramolecular alkoxycarbonylation as the key step to construct the tetrasubstituted cis-tetrahydropyran ring with high stereoselectivity.