Nonenzymatic Asparagine Motif Synthesis by Photoredox-Catalyzed Carbamoylation of Dehydroalanine.

Post-translational modifications of proteins based on the amino acid residue dehydroalanine (Dha) have been widely adopted in molecular biology to expand their structural and functional capabilities. However, the construction of highly important amide C(sp2)-C(sp3) linkages on peptides through cross-coupling remains unexplored. In this article, we describe a photoredox-catalyzed C(sp2) amidation that enables the mutation of Dha to an asparagine (Asn) motif. This amide installation strategy reported herein will guide us to create more additional derivatives of peptides, which may elucidate the mode of action and address an important area of unmet medical need.

One-Pot Sequential Synthesis of 3,3'- or 2,3'-Bis(indolyl)methanes by Using 1,3-Dithiane as the Methylene Source.

A simple and efficient method for structurally diverse symmetrical and unsymmetrical 3,3'- and 2,3'-bisindolylmethanes has been developed through a one-pot sequential reaction using 1,3-dithiane as the methylene source. The important AhR agonists ICZ and malassezin were synthesized with excellent efficiency by this straightforward approach.

Total Synthesis of Complex Peptidyl Nucleoside Antibiotics: Asymmetric De Novo Syntheses of Miharamycin†B and Its Biosynthetic Precursor.

Miharamycins belong to a class of peptidyl nucleoside antibiotics with a unique nine-carbon pyranosyl amino acid core and a rare 2-aminopurine moiety. Herein, we report the de novo total synthesis of miharamycin B and its biosynthetic precursor from 3-bromofuran and Garner's aldehyde through a modified Achmatowicz reaction. Many challenges were resolved toward the de novo synthesis of miharamycin B, including the introduction of a dense array of functional groups, the stereoselective construction of consecutive stereocenters, dealing with the variability of the anomeric positions, and promoting site-selectivity in the cyclization to form the tetrahydrofuran ring. This de novo synthesis strategy enables efficient preparation of 3'-substituted saccharides, allowing the study of their structure-activity relationships and mode of action, and meets the growing demand for the development of novel antibiotics inspired by miharamycin natural products.

Enantioselective α-Functionalization of 1,3-Dithianes by Iridium-Catalyzed Allylic Substitution.

An iridium-catalyzed asymmetric allylic substitution reaction with 2-alkoxy carbonyl-1,3-dithianes has been achieved with high regio- and enantioselectivities. The transformation provides a new method for the enantioselective α-functionalization of dithianes. The corresponding dithiane-containing products are easily converted into many other derivatives with high yields and enantioselectivities.

Dithiane-Induced [3+2] Cycloaddition Tactic for the Convergent Synthesis of Dihydropyrrole and Pyrrole Derivatives.

An efficient transition-metal-free tactic for the convergent synthesis of substituted dihydropyrroles and pyrroles by ß-chloro-vinyl dithiane cyclization with a broad range of imines was developed. [3+2] Cyclization and aromatization occur under these reaction conditions providing biologically relevant dihydropyrroles and pyrroles in good yields.

Alcohol-mediated direct dithioacetalization of alkynes with 2-chloro-1,3-dithiane for the synthesis of Markovnikov dithianes.

An alcohol-mediated dithioacetalization process that gains direct access to the corresponding Markovnikov-selective 1,3-dithianes using unactivated alkynes and nonthiolic/odorless 2-chloro-1,3-dithiane in a highly efficient manner has been developed. This methodology has the advantage of having mild reaction conditions, and the dithioacetalization process gives good to excellent yields with high Markovnikov-selectivity.

Di-tert-butyl peroxide-mediated atom-transfer radical addition of 2-chlorodithiane to aryl alkynes under mild conditions.

Atom transfer radical addition (ATRA) of 2-chlorodithiane onto aryl alkynes through the use of di-tert-butyl peroxide as an oxidant at room temperature directly affords a variety of synthetically valuable ß-chloro-(Z)-vinyl dithianes in good yields with high regioselectivities and without the assistance of any transition metals. It provides an operationally simple pathway to access vinyl dithianes with controlled formation of a new C(sp(2) )C bond and a C(sp(2) )Cl bond.

Metal-Free Difunctionalization of Alkynes with 2-Chlorodithiane for Synthesis of ß-Ketodithianes.

Dithianes are versatile umpolung intermediates in organic synthesis but have rarely been employed in radical cross-coupling reactions. Here we describe the oxidative coupling method for alkyne difunctionalization under metal-catalyst-free conditions. The efficient protocol directly affords a variety of ß-ketodithianes in good to excellent yields with high regioselectivities. It provides a general pathway for accessing valuable dithianes with controlled formation of a new C-C bond and a C-O bond via a radical coupling pathway.

Stereoselective Synthesis of Highly Substituted 1,3-Dienes through Dual 1,3-Sulfur Rearrangement of Dithianes with Alkynylsilanes.

Herein, we report a C3 and C1 coupling approach between vinyl 1,3-dithiane derivatives and alkynylsilanes for the construction of highly substituted conjugated dienes. Through the regioselective dual 1,3-sulfur migration process, this method enabled the synthesis of a wide range of highly substituted (E)-1,3-dienes stereoselectively in moderate to high yields, which provided one alternative way to synthesize the corresponding conjugated dienones.

Site-selective synthesis of indanyl-substituted indole derivatives via 1,3-dithiane induced Nazarov cyclization.

We report an efficient site-selective synthetic method to C2 and C3 indanyl-substituted indole derivatives via 1,3-dithianyl induced Nazarov-type cyclization. In particular, C2-selective indanyl-substituted indoles were directly obtained by a BF3·Et2O-promoted sequence of intramolecular C3-C2 migration and Nazarov-type cyclization process.

Indium-catalyzed inter- and intramolecular dithianyl-alkyne metathesis reactions.

Herein, we reported an efficient indium catalyzed dithianyl-alkyne metathesis (DAM) reaction. This strategy allows for the formation of a new C-C double bond and valuable C-S bonds during the metathesis event, and was successfully applied to the synthesis of diverse vinyl dithianyl substituted organic molecules.

Metal-Free Late-Stage Alkylation of Tryptophan and Tryptophan-Containing Peptides with 1,3-Dithiane Derivatives.

Late-stage diversification of structurally complex peptides has enormous potential for drug discovery and molecular imaging. We report a simple, metal-free, late-stage reductive C2 alkylation of tryptophan and tryptophan-containing peptides using readily available 1,3-dithianes. This alkylation protocol has a wide substrate scope and an excellent tolerance for reactive functional groups.

Regioselective Alkenylation of Five-Membered Heteroarenes via a Dual 1,3-Sulfur Rearrangement.

Herein, we report a protocol for the stereoselective C-H alkenylation of five-membered heteroarenes including pyrroles (containing free NH pyrrole), thiophenes, and furans with 1,3-dithiane derivatives through dual 1,3-sulfur rearrangements. The site-selective and regioselective alkenylation of the five-membered heteroarenes proceeded in good yields via vinyl thionium ions to produce C2 or C5 Heck-type products, respectively.

C-H Alkenylation of Indoles through a Dual 1,3-Sulfur Migration Process.

Methods for the modification of indole derivatives are powerful techniques in organic, medicinal, and biomolecular chemistry. Here, we report a protocol for the C-H alkenylation of N-H indoles with ß-chlorovinyl dithianes to furnish alkenyl indoles through dual 1,3-sulfur rearrangements. This alkenylation protocol could selectively prepare a variety of vinyl indoles in moderate to high yields with excellent functional group tolerance.

Site-selective C-H alkylation of myo-inositol via organic photoredox catalysis.

Site-selective photoredox reactions with aromatic olefins enable direct alkylation of unprotected myo-inositol at C4. The efficacy of these reactions can be finely tuned by modifying the structures of HAT reagents. These reactions open the possibility of selective C-H alkylations of myo-inositol without the need for multi-step protection-deprotection strategies.

Synthesis of a monophosphoryl derivative of Escherichia coli lipid A and its efficient coupling to a tumor-associated carbohydrate antigen.

Monophosphoryl lipid A is a safe and potent immunostimulant and vaccine adjuvant, which is potentially useful for the development of effective carbohydrate-based conjugate vaccines. This paper presents a convergent and efficient synthesis of a monophosphoryl derivative of E. coli lipid A that has an alkyne functionality at the reducing end, which is suitable for coupling with various molecules. The coupling of this derivative to an N-modified analogue of tumor-associated antigen GM3 through click chemistry is also presented.

Application of a domino Friedel-Crafts acylation/alkylation reaction to the formal syntheses of (+/-)-taiwaniaquinol B and (+/-)-dichroanone.

An efficient acid-promoted domino Friedel-Crafts (FC) acylation/alkylation reaction has been developed for the construction of the core 6,5,6-ABC tricyclic skeleton of taiwaniaquinoids. The formal total syntheses of diterpenoids (+/-)-taiwaniaquinol B and (+/-)-dichroanone based on this strategy have been achieved.

Dithiane Induced Cycloaddition/Aromatization Tactic for the Synthesis of Multisubstituted Furans.

The development of a new transition-metal-free tactic for convergent, one-pot synthesis of multisubstituted furans by ß-chloro-vinyl dithiane cyclization with aldehydes is described. Key to the success was the development of a new vinylidene dithiane site as a donor allene that generates the active dihydrofuran, which undergoes in situ aromatization under mild conditions.

Direct Regioselective [3 + 2]-Cyclization Reactions of Ambivalent Electrophilic/Nucleophilic ß-Chlorovinyl Dithianes: Access to Cyclopentene Derivatives.

The highly regioselective and operationally straightforward [3 + 2] cyclizations of ß-chlorovinyl dithianes with α,ß-unsaturated carbonyl compounds have been developed. This protocol provides direct access to highly functionalized cyclopentenes with perfect chemo- and regioselectivities under extremely mild reaction conditions. In particular, the unprecedented cyclization allows for the selective preparation of hydroxylated cyclopentenes.

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.