Synthesis of the C13-C27 Fragment of Madeirolide A Using Visible-Light-Promoted Radical Cyclization.

The convergent synthesis of a fully elaborated C13-C27 fragment of madeirolide A has been achieved. The key features of the synthesis include the stereocontrolled construction of both the THF and THP rings via visible-light-induced iridium-catalyzed radical cyclization and the late-stage union of the two oxacyclic subunits through nickel-catalyzed decarboxylative cross-coupling.

Carbofunctionalization of Terminal Alkynes via Rhodium Catalysis Enabling Formations of Four Different Bonds.

Described here is the oxygenative carbofunctionalization of terminal alkynes mediated by combined rhodium catalysis that enables regioselective quadruple formation of C-C, C-H, C-O, and C-heteroatom bonds. Mechanistic studies suggest that a disubstituted rhodium vinylidene complex is generated upon C-C bond formation at the terminal alkyne with tethered electrophiles such as alkyl halides, aldehydes, imines, and Michael acceptors. Subsequent intermolecular transfer oxygenation of the rhodium vinylidene with pyridine N-oxide generates a rhodium-complexed ketene intermediate that reacts with a variety of heteroatom nucleophiles to give rise to cyclic carboxylic acid derivatives.

Evolution of a Synthetic Strategy for Garsubellin A.

Garsubellin A is a thirty-carbon meroterpenoid capable of enhancing the enzyme choline acetyltransferase whose decreased level is associated with the symptoms of Alzheimer's disease. Due to the potentially useful biological activity along with the novel molecular architecture, this plant metabolite has remained a popular synthetic target. Herein we report a full account of our synthetic investigations that have led to the enantioselective total synthesis of garsubellin A, establishing its absolute stereostructure. The protecting group-free, twelve-step synthetic route has enabled the syntheses of the natural (-)-garsubellin A and its unnatural (+)-antipode.

Enantioselective Total Synthesis of (+)-Garsubellin†A.

Garsubellin A is a meroterpene capable of enhancing the enzyme choline acetyltransferase whose decreased level is believed to play a central role in the symptoms of Alzheimer's disease. Due to the potentially useful biological activity together with the novel bridged and fused cyclic molecular architecture, garsubellin A has garnered substantial synthetic interest, but its absolute stereostructure has been undetermined. We report here the first enantioselective total synthesis of (+)-garsubellin A. Our synthesis relies on stereoselective fashioning of a cyclohexanone framework and double conjugate addition of 1,2-ethanedithiol that promotes aldol cyclization to build the bicyclic [3.3.1] skeleton. The twelve-step, protecting group-free synthetic route has enabled the syntheses of both the natural (-)-garsubellin A and its unnatural (+)-antipode for biological evaluations.

Mechanism of Cyanine5 to Cyanine3 Photoconversion and Its Application for High-Density Single-Particle Tracking in a Living Cell.

Cyanine (Cy) dyes are among the most useful organic fluorophores that have found a wide range of applications in single-molecule and super-resolution imaging as well as in other biophysical studies. However, recent observations that blueshifted derivatives of Cy dyes are formed via photoconversion have raised concerns as to the potential artifacts in multicolor imaging. Here, we report the mechanism for the photoconversion of Cy5 to Cy3 that occurs upon photoexcitation during fluorescent imaging. Our studies show that the formal C2H2 excision from Cy5 occurs mainly through an intermolecular pathway involving a combination of bond cleavage and reconstitution while unambiguously confirming the identity of the fluorescent photoproduct of Cy5 to be Cy3 using various spectroscopic tools. The carbonyl products generated from singlet oxygen-mediated photooxidation of Cy5 undergo a sequence of carbon-carbon bond-breaking and -forming events to bring about the novel dye-to-dye transformation. We also show that the deletion of a two-methine unit from the polymethine chain, which results in the formation of blueshifted products, commonly occurs in other cyanine dyes, such as Alexa Fluor 647 (AF647) and Cyanine5.5. The formation of a blueshifted congener dye can obscure the multicolor fluorescence imaging, leading to misinterpretation of the data. We demonstrate that the potentially deleterious photoconversion, however, can be exploited to develop a new photoactivation method for high-density single-particle tracking in a living cell without using UV illumination and cell-toxic additives.

Silyloxymethanesulfinate as a sulfoxylate equivalent for the modular synthesis of sulfones and sulfonyl derivatives.

An efficient protocol for the modular synthesis of sulfones and sulfonyl derivatives has been developed utilizing sodium tert-butyldimethylsilyloxymethanesulfinate (TBSOMS-Na) as a sulfoxylate (SO2 2-) equivalent. TBSOMS-Na, easily prepared from the commercial reagents Rongalite™ and TBSCl, serves as a potent nucleophile in S-alkylation and Cu-catalyzed S-arylation reactions with alkyl and aryl electrophiles. The sulfone products thus obtained can undergo the second bond formation at the sulfur center with various electrophiles without a separate unmasking step to afford sulfones and sulfonyl derivatives such as sulfonamides and sulfonyl fluorides.

Transition Metal Vinylidene- and Allenylidene-Mediated Catalysis in Organic Synthesis.

With their mechanistic novelty and various modalities of reactivity, transition metal unsaturated carbene (alkenylidene) complexes have emerged as versatile intermediates for new reaction discovery. In particular, the past decade has witnessed remarkable advances in the chemistry of metal vinylidenes and allenylidenes, leading to the evolution of a diverse array of new catalytic transformations that are mechanistically distinct from those developed in the previous two decades. This review aims to provide a survey of the recent achievements in the development of organic reactions that make use of transition metal alkenylidenes as catalytic intermediates and their applications to organic synthesis.

Rhodium-Catalyzed Tandem Addition-Cyclization-Rearrangement of Alkynylhydrazones with Organoboronic Acids.

Transition metal-mediated catalysis routinely enables substrates of multiple π-systems to be efficiently coupled with various carbon nucleophiles along with simultaneous ring formation. This transformation, however, remains unexplored in connection with pericyclic processes. Reported here is a protocol for cycloalkene synthesis based on the merger of rhodium catalysis and a retro-ene reaction. The approach allows alkyne-tethered hydrazones and organoboronic acids to undergo a cascade of addition-cyclization-rearrangement reactions to provide cycloalkene products. The process is initiated by the rhodium-catalyzed addition-cyclization and completed with the allylic diazene rearrangement. The reaction can also be rendered asymmetric by using chiral diene ligands for the rhodium catalyst, whereby enantioselective addition to the C═N bond establishes the C-N stereocenter whose chirality is transferred to an allylic C-H center via suprafacial rearrangement.

Sulfonamidation of Aryl and Heteroaryl Halides through Photosensitized Nickel Catalysis.

Herein we report a highly efficient method for nickel-catalyzed C-N bond formation between sulfonamides and aryl electrophiles. This technology provides generic access to a broad range of N-aryl and N-heteroaryl sulfonamide motifs, which are widely represented in drug discovery. Initial mechanistic studies suggest an energy-transfer mechanism wherein C-N bond reductive elimination occurs from a triplet excited NiII complex. Late-stage sulfonamidation in the synthesis of a pharmacologically relevant structure is also demonstrated.

Synthesis of the C1-C10 Fragment of Madeirolide A.

The synthesis of a fully elaborated C1-C10 fragment of madeirolide A has been achieved via a strategy based on a series of stereospecific processes. The concise synthetic route also features an iridium-catalyzed visible light induced radical cyclization for construction of the THP ring and a palladium-catalyzed glycosylation for formation of the α-cineruloside linkage.

Heme-binding-mediated negative regulation of the tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) by IDO2.

Indoleamine 2,3-dioxygenases (IDOs) are tryptophan-catabolizing enzymes with immunomodulatory functions. However, the biological role of IDO2 and its relationship with IDO1 are unknown. To assess the relationship between IDO2 and IDO1, we investigated the effects of co-expression of human (h) IDO2 on hIDO1 activity. Cells co-expressing hIDO1 and hIDO2 showed reduced tryptophan metabolic activity compared with those expressing hIDO1 only. In a proteomic analysis, hIDO1-expressing cells exhibited enhanced expression of proteins related to the cell cycle and amino acid metabolism, and decreased expression of proteins related to cell survival. However, cells co-expressing hIDO1 and hIDO2 showed enhanced expression of negative regulators of cell apoptosis compared with those expressing hIDO1 only. Co-expression of hIDO1 and hIDO2 rescued the cell death induced by tryptophan-depletion through hIDO1 activity. Cells expressing only hIDO2 exhibited no marked differences in proteome profiles or cell growth compared with mock-transfectants. Cellular tryptophan metabolic activity and cell death were restored by co-expressing the hIDO2 mutant substituting the histidine 360 residue for alanine. These results demonstrate that hIDO2 plays a novel role as a negative regulator of hIDO1 by competing for heme-binding with hIDO1, and provide information useful for development of therapeutic strategies to control cancer and immunological disorders that target IDO molecules.

Nitrogen-centered radical-mediated C-H imidation of arenes and heteroarenes via visible light induced photocatalysis.

The C-H imidation of arenes and heteroarenes has been achieved via visible light induced photocatalysis. In the presence of an iridium(III) photoredox catalyst, the reaction of aromatic substrates with N-chlorophthalimide furnishes the N-aryl products at room temperature through a nitrogen-centered radical mediated aromatic substitution.

Tandem Diels-Alder and retro-ene reactions of 1-sulfenyl- and 1-sulfonyl-1,3-dienes as a traceless route to cyclohexenes.

A pericyclic approach for the synthesis of six-membered ring structures is described. The method employs 1,3-dienes with a 1-sulfur substituent in a tandem sequence of Diels-Alder and retro-ene reactions. In this pairing of [4 + 2] cycloaddition and 1,5-sigmatropic rearrangement, 1-sulfenyl-1,3-dienes engage in Diels-Alder reactions with electron-deficient dienophiles. Subsequently, the sulfenyl group of the cycloadducts is oxidized and unmasked to form allylic sulfinic acids, which undergo sterospecific reductive transposition via sulfur dioxide extrusion. The sequence can also include an inverse electron demand Diels-Alder reaction by using a 1-sulfonyl-1,3-diene. This combination of two pericyclic events offers novel stereocontrolled access to cyclohexenes that are inaccessible via a direct [4 + 2] cycloaddition route.

Rhodium-catalyzed oxygenative [2 + 2] cycloaddition of terminal alkynes and imines for the synthesis of ß-lactams.

A rhodium-catalyzed oxygenative [2 + 2] cycloaddition of terminal alkynes and imines has been developed, which gives ß-lactams as products with high trans diastereoselectivity. In the presence of a Rh(I) catalyst and 4-picoline N-oxide, a terminal alkyne is converted to a rhodium ketene species via oxidation of a vinylidene complex and subsequently undergoes a [2 + 2] cycloaddition with an imine to give rise to the 2-azetidinone ring system. Mechanistic studies suggest that the reaction proceeds through a metalloketene rather than free ketene intermediate. The new method taking advantage of catalytic generation of a ketene species directly from a terminal alkyne provides a novel and efficient entry to the Staudinger synthesis of ß-lactams under mild conditions.

A paradoxical pattern of indoleamine 2,3-dioxygenase expression in the colon tissues of patients with acute graft-versus-host disease.

Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme for tryptophan catabolism that plays an important role in the induction of immune tolerance. It is induced in the colon and exerts its effects there, regulating T-cell proliferation and survival. To address the role of IDO in acute graft-versus-host disease (AGVHD) after human allogeneic hematopoietic stem cell transplantation, we analyzed the relationship between IDO expression in colon tissues and clinical outcomes among 41 AGVHD patients who were diagnosed as gut AGVHD by a colon mucosal biopsy within 100 days posttransplantation. By in situ immunohistochemical analyses, IDO expression was measured in colon mucosal mononuclear cells (MNCs) and endothelial cells (ECs) in GVHD areas. High IDO expression in MNCs and low IDO expression in ECs had a trend toward a lower nonrelapse mortality (p = 0.157 and p = 0.062, respectively). Multivariate analysis showed that high MNC combined with low EC IDO expression (p = 0.046), as well as low disease risk (p = 0.012), are associated with lower nonrelapse mortality. Paradoxical upregulation of IDO expression in colon MNCs and ECs may represent a new predictive factor for prognosis in gut AGVHD after human allogeneic hematopoietic stem cell transplantation.

Rhodium-catalyzed oxygenative addition to terminal alkynes for the synthesis of esters, amides, and carboxylic acids.

A gem of a couple: The title reaction of terminal alkynes with O and N nucleophiles proceeds in the presence of [{Rh(cod)Cl}2], P(4-FC6H4)3, and 4-picoline N-oxide. Alcohols, amines, and water add to the terminal alkynes to give esters, amides, and carboxylic acids, respectively. The reaction involves formation of a rhodium vinylidene, oxidation to a ketene by oxygen transfer, and nucleophilic addition.

The role of regulatory T cells during the attenuation of graft-versus-leukemia activity following donor leukocyte infusion in mice.

We investigated how the graft-versus-leukemia (GVL) effect is attenuated in the tumor microenvironment using a murine model of non-myeloablative allo-HSCT (NM-HSCT) plus delayed donor leukocyte infusion (DLI) in a haploidentical B6→F1 strain combination. In-line with aggravated leukemia growth, the proportions of effector T cells expressing IFN-γ (Teffs) in spleen were reduced and attenuated GVL activity was found to be accompanied by a rebound in CD4(+)Foxp3(+) regulatory T cells (Tregs) in tumor-draining lymph nodes and tumor tissues. DLI-derived Tregs and Teffs may be potential indicators of presence of leukemic progression after DLI in this GVL model.

Nickel-catalyzed reductive cyclization of organohalides.

A mild and convenient nickel-catalyzed method for free-radical cyclization of organohalides is described. The use of a NiCl(2)•DME/Pybox complex as the catalyst and zinc powder in methanol efficiently promotes the reductive cyclization of various unsaturated alkyl halides to give carbo-, oxa-, and azacycles as products in high yields.