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We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of N-amidinyliminium ions with indoles or benzothiophene. In contrast to reactions of these heterodienes with alkenes, density functional theory (DFT) calculations show that these cycloadditions take place in a concerted asynchronous fashion. The [4 + 2]-cycloaddition of N-amidinyliminium ions (1,3-diaza-1,3-dienes) with indoles and benzothiophene are distinctive, as related [4 + 2]-cycloadditions of N-acyliminium ions (1-oxa-3-aza-1,3-dienes) are apparently unknown.

Recent progress in the development of photocatalytic reactions promoted by visible light is leading to a renaissance in the use of photochemistry in the construction of structurally elaborate organic molecules. Because of the rich functionality found in natural products, studies in natural product total synthesis provide useful insights into functional group compatibility of these new photocatalytic methods as well as their impact on synthetic strategy. In this review, we examine total syntheses published through the end of 2020 that employ a visible-light photoredox catalytic step. To assist someone interested in employing the photocatalytic steps discussed, the review is organized largely by the nature of the bond formed in the photocatalytic step.

The evolution of a strategy to access the family of rearranged spongian diterpenoids harboring a concave-substituted cis-2,8-dioxabicyclo[3.3.0]octan-3-one fragment is described. The approach involves late-stage fragment coupling of a tertiary-carbon radical and an electron-deficient double bond to form vicinal quaternary and tertiary stereocenters with high fidelity. A stereoselective Mukaiyama hydration is the key step in the subsequent elaboration of the cis-2,8-dioxabicyclo[3.3.0]octan-3-one moiety. This strategy was utilized in enantioselective total syntheses of (-)-macfarlandin C and (+)-dendrillolide A. An efficient construction of enantiopure tetramethyloctahydronaphthalenes was developed during the construction of (-)-macfarlandin C.

The enantioselective total synthesis of the rearranged spongian diterpenoid (–)-macfarlandin C is reported. This is the first synthesis of a rearranged spongian diterpenoid in which the bulky hydrocarbon fragment is joined via a quaternary carbon to the highly hindered concave face of the cis-2,8-dioxabicyclo[3.3.0]octan-3-one moiety. The strategy involves a late-stage fragment coupling between a tertiary carbon radical and an electrophilic butenolide resulting in the stereoselective formation of vicinal quaternary and tertiary stereocenters. A stereoselective Mukaiyama hydration that orients a pendant carboxymethyl side chain cis to the bulky octahydronapthalene substituent was pivotal in fashioning the challenging concave-substituted cis-dioxabicyclo[3.3.0]octanone fragment.

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We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of

Simple Summary Cutaneous T cell lymphomas (CTCLs) are a group of blood cancers that cannot be cured with current chemotherapeutical or biological drugs. Patients with advanced disease are severely immunocompromised due to the unchecked expansion of malignant T cells and have low survival rates of less than four years. Hence, new treatment options for CTCLs are urgently needed. In this study the anti-CTCL activity of a new compound, NT1721, was determined in vitro and in two CTCL mouse models. We found that NT1721 increased apoptosis (programmed cell death) in the malignant T cells and reduced tumor growth better than two drugs that are currently clinically used for CTCL treatment (i.e., gemcitabine, romidepsin). These results suggest that NT1721 may represent a potent new agent for the treatment of advanced CTCL. Abstract Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of debilitating, incurable malignancies. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes, accounting for ~65% of CTCL cases. Patients with advanced disease have a poor prognosis and low median survival rates of four years. CTCLs develop from malignant skin-homing CD4+ T cells that spread to lymph nodes, blood, bone marrow and viscera in advanced stages. Current treatments options for refractory or advanced CTCL, including chemotherapeutic and biological approaches, rarely lead to durable responses. The exact molecular mechanisms of CTCL pathology remain unclear despite numerous genomic and gene expression profile studies. However, apoptosis resistance is thought to play a major role in the accumulation of malignant T cells. Here we show that NT1721, a synthetic epidithiodiketopiperazine based on a natural product, reduced cell viability at nanomolar concentrations in CTCL cell lines, while largely sparing normal CD4+ cells. Treatment of CTCL cells with NT1721 reduced proliferation and potently induced apoptosis. NT1721 mediated the downregulation of GLI1 transcription factor, which was associated with decreased STAT3 activation and the reduced expression of downstream antiapoptotic proteins (BCL2 and BCL-xL). Importantly, NT1721, which is orally available, reduced tumor growth in two CTCL mouse models significantly better than two clinically used drugs (romidepsin, gemcitabine). Moreover, a combination of NT1721 with gemcitabine reduced the tumor growth significantly better than the single drugs. Taken together, these results suggest that NT1721 may be a promising new agent for the treatment of CTCLs.

The addition of tertiary carbon radicals generated from N-(acyloxy)phthalimide esters to cyclic α,β-unsaturated ketones and lactones is markedly enhanced by the addition of substoichiometric amounts of a Ln(OTf)3. The reaction is accomplished by irradiation with visible light in the absence of a photosensitizer and is suggested to proceed by excitation of a ternary electron donor-acceptor complex between the NHPI ester, Hantzsch ester, and a Ln(OTf)3.

The evolution of a strategy to access the family of rearranged spongian diterpenoids harboring a concave-substituted

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (−)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening., Canvass, a crowd-sourced library of natural products, was evaluated through HTS in a spectrum of disease-relevant assays to survey the broad biological potential of natural products in drug discovery.

Background Pancreatic cancer is one of the most lethal malignancies due to frequent late diagnosis, aggressive tumor growth and metastasis formation. Continuously raising incidence rates of pancreatic cancer and a lack of significant improvement in survival rates over the past 30 years highlight the need for new therapeutic agents. Thus, new therapeutic agents and strategies are urgently needed to improve the outcome for patients with pancreatic cancer. Here, we evaluated the anti-tumor activity of a new natural product-based epidithiodiketopiperazine, NT1721, against pancreatic cancer. Methods We characterized the anticancer efficacy of NT1721 in multiple pancreatic cancer cell lines in vitro and in two orthotopic models. We also compared the effects of NT1721 to clinically used hedgehog inhibitors and the standard-of-care drug, gemcitabine. The effect of NT1721 on hedgehog/GLI signaling was assessed by determining the expression of GLI and GLI target genes both in vitro and in vivo. Results NT1721 displayed IC50 values in the submicromolar range in multiple pancreatic cancer cell lines, while largely sparing normal pancreatic epithelial cells. NT1721 attenuated hedgehog/GLI signaling through downregulation of GLI1/2 transcription factors and their downstream target genes, which reduced cell proliferation and invasion in vitro and significantly decreased tumor growth and liver metastasis in two preclinical orthotopic mouse models of pancreatic cancer. Importantly, treatment with NT1721 significantly improved survival times of mice with pancreatic cancer compared to the standard-of-care drug, gemcitabine. Conclusions Favorable therapeutics properties, i.e. 10-fold lower IC50 values than clinically used hedgehog inhibitors (vismodegib, erismodegib), a 90% reduction in liver metastasis and significantly better survival times compared to the standard-of-care drug, gemcitabine, provide a rational for testing NT1721 in the clinic either as a single agent or possibly in combination with gemcitabine or other therapeutic agents in PDAC patients overexpressing GLI1/2. This could potentially result in promising new treatment options for patients suffering from this devastating disease.

Despite many recent advances in the radical alkylation of electron-deficient heteroarenes since the seminal reports by Minisci and co-workers, methods for the direct incorporation of tertiary alkyl substituents into nitrogen heteroarenes are limited. This report describes the use of tert-alkyl oxalate salts, derived from tertiary alcohols, to introduce tertiary substituents into a variety of heterocyclic substrates. This reaction has reasonably broad scope, proceeds rapidly under mild conditions, and is initiated by either photochemical or thermal activation. Insights into the underlying mechanism of the higher yielding visible-light initiated process were obtained by flash photolysis studies, whereas computational studies provided insight into the reaction scope.

Radical fragment coupling reactions that unite intricate subunits have become an important class of transformations within the arena of complex molecule synthesis. This Perspective highlights some of the early contributions in this area, as well as more modern applications of radical fragment couplings in the preparation of natural products. Additionally, emphasis is placed on contemporary advances that allow for radical generation under mild conditions as a driving force for the implementation of radical fragment couplings in total synthesis.

Author(s): Tao, Daniel J; Slutskyy, Yuriy; Muuronen, Mikko; Le, Alexander; Kohler, Philipp; Overman, Larry E | Abstract: The structure of L-arabinose (33) in Scheme 3 was incorrect. A correct version of this scheme is shown here. (Figure Presented).

The evolution of a convergent fragment-coupling strategy for the enantioselective total synthesis of trans-clerodane diterpenoids is described. The key bond construction is accomplished by 1,6-addition of a trans-decalin tertiary radical with 4-vinylfuran-2-one. The tertiary radical is optimally generated from the hemioxalate salt of the corresponding tertiary alcohol upon activation by visible light and an Ir(III) photoredox catalyst. The enantioselective total synthesis of trans-clerodane diterpenoid 1 reported here was accomplished in seven steps from 3-methyl-2-cyclohexenone. The synthetic strategy described in this report allows a number of trans-clerodane diterpenoids to be synthesized in enantioselective fashion by synthetic sequences of 10 steps or less. This study illustrates a powerful tactic in organic synthesis in which a structurally complex target structure is disconnected at a quaternary carbon stereocenter to fragments of comparable complexity, which are united in the synthetic pathway by conjugate addition of a nucleophilic tertiary radical to a fragment harboring an electron-deficient C-C double bond.

An increasing number of studies show that an altered epigenetic landscape may cause impairments in regulation of learning and memory-related genes within the aged hippocampus, eventually resulting in cognitive deficits in the aged brain. One such epigenetic repressive mark is trimethylation of H3K9 (H3K9me3), which is typically implicated in gene silencing. Here, we identify, for the first time, an essential role for H3K9me3 and its histone methyl transferase (SUV39H1) in mediating hippocampal memory functions. Pharmacological inhibition of SUV39H1 using a novel and selective inhibitor decreased levels of H3K9me3 in the hippocampus of aged mice, and improved performance in the objection location memory and fear conditioning tasks and in a complex spatial environment learning task. The inhibition of SUV39H1 induced an increase in spine density of thin and stubby but not mushroom spines in the hippocampus of aged animals and increased surface GluR1 levels in hippocampal synaptosomes, a key index of spine plasticity. Furthermore, there were changes at BDNF exon I gene promoter, in concert with overall BDNF levels in the hippocampus of drug-treated animals compared with control animals. Together, these data demonstrate that SUV39H1 inhibition and the concomitant H3K9me3 downregulation mediate gene transcription in the hippocampus and reverse age-dependent deficits in hippocampal memory.SIGNIFICANCE STATEMENTCognitive decline is a debilitating condition associated with not only neurodegenerative diseases but also aging in general. However, effective treatments have been slow to emerge so far. In this study, we demonstrate that epigenetic regulation of key synaptic proteins may be an underlying, yet reversible, cause of this decline. Our findings suggest that histone 3 trimethylation is a probable target for pharmacological intervention that can counteract cognitive decline in the aging brain. Finally, we provide support to the hypothesis that, by manipulating the enzyme that regulates H3K9me3 (using a newly developed specific inhibitor of SUV39H1), it is possible to alter the chromatin state of subjects and restore memory and synaptic function in the aging brain.

Anhand zwolf reprasentativer Beispiele stellen wir in diesem Aufsatz Strategien fur die Totalsynthese komplexer Naturstoffe vor, die zwei oder mehr benachbarte stereogene quartare Kohlenstoffatomen in ihren komplexen Molekulstrukturen enthalten. Das Hauptaugenmerk liegt dabei auf den Methoden zur Konstruktion quartarer stereogener Kohlenstoffzentren, einschlieslich der Synthese desselben Naturstoffs auf verschiedenen Wegen durch unterschiedliche Forschergruppen; dies soll die Vielfalt der Gedankengange sowie die Individualitat kreativer Leistungen verdeutlichen. Ein Kompendium von ausgewahlten Naturstoffen mit zwei oder mehr benachbarten stereogenen quartaren Kohlenstoffatomen sowie von Schlusselreaktionen ihrer jeweiligen Total- oder Partialsynthesen findet sich in den Hintergrundinformationen.

The first total synthesis of a chromodorolide marine diterpenoid is described. The core of the diterpenoid is constructed by a bimolecular radical addition/cyclization/fragmentation cascade that unites two complex fragments and forms two C-C bonds and four contiguous stereogenic centers of (-)-chromodorolide B in a single step. This coupling step is initiated by visible-light photocatalytic fragmentation of a redox-active ester, which can be accomplished in the presence of an iridium or a less-precious electron-rich dicyanobenzene photocatalyst, and employs equimolar amounts of the two addends. Computational studies guided the development of this central step of the synthesis and provide insight into the origin of the observed stereoselectivity.

The addition of tertiary carbon radicals generated by an Ir-catalyzed visible-light photocatalyst to electron-deficient 1,3-dienes proceeds in good yields to append a δ-substituted β,γ-unsaturated carbonyl fragment to a tertiary alcohol or carboxylic acid precursor and construct a new quaternary carbon center.

Tertiary carbon radicals have notable utility for uniting complex carbon fragments with concomitant formation of new quaternary carbons. This article explores the scope, limitations, and certain mechanistic aspects of Okada's method for forming tertiary carbon radicals from N-(acyloxy)phthalimides by visible-light photocatalysis. Optimized conditions for generating tertiary radicals from N-(acyloxy)phthalimide derivatives of tertiary carboxylic acids by visible-light irradiation in the presence of 1 mol % of commercially available Ru(bpy)3(PF6)2, diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (8), and i-Pr2NEt and their coupling in dichloromethane at room temperature with alkene acceptors were developed. Four representative tertiary N-(acyloxy)phthalimides and 15 alkene radical acceptors were examined. Both reductive couplings with electron-deficient alkenes and radical substitution reactions with allylic and vinylic bromides and chlorides were examined with many such reactions occurring in good yield using only a slight excess (typically 1.5 equiv) of the alkene. In general, the yields of these photocatalytic reactions were higher than the analogous transformations of the corresponding N-phthalimidoyl oxalates. Deuterium labeling and competition experiments reveal that the reductive radical coupling of tertiary N-(acyloxy)phthalimides with electron-deficient alkenes can be terminated by both hydrogen-atom transfer and single-electron reduction followed by protonation, and that this mechanistic duality is controlled by the presence or absence of i-Pr2NEt.

The development of a convergent fragment coupling strategy for the enantioselective total syntheses of a group of rearranged spongian diterpenoids that harbor the cis-2,8-dioxabicyclo[3.3.0]octan-3-one unit is described. The key bond disconnection relies on a late-stage fragment coupling between a tertiary carbon radical and an electron-deficient alkene to unite two ring systems and form two new stereocenters, one of which is quaternary, in a stereoselective and efficient manner. This strategy is applied toward scalable 14–15 step syntheses of three rearranged spongian diterpenoids, cheloviolenes A and B, and dendrillolide C.

A short enantioselective synthesis of 6-substituted cis-2,8-dioxabicyclo[3.3.0]octan-3-ones is described. The pivotal step is coupling of a tertiary radical generated directly from a tertiary alcohol with a 3-chloro-5-alkoxybutenolide. This strategy is applied toward scalable 14–15 step syntheses of three rearranged spongian diterpenoids: cheloviolenes A and B and dendrillolide C.

We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1–3, having the 3-arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure–activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner.

A new strategy for enantioselective synthesis of azacyclic molecules in which dynamic kinetic equilibration of diastereomeric iminium ions precedes a stereochemistry-determining sigmatropic rearrangement is reported. The method is illustrated by the synthesis, in high enantiomeric purity (generally 95-99% ee), of a variety of 1-azabicyclic molecules containing angular allyl or 3-substituted 2-propenyl side chains adjacent to nitrogen and up to three stereogenic centers. In these products, the size of the carbocyclic ring is varied widely (5-12 membered); however, useful yields are obtained in forming 1-azabicyclic products containing only fused pyrrolidine and piperidine rings. Chirality transfer from substituents at carbons 1 and 2 of the 3-butenylamine fragment of the starting material is investigated, with methyl and phenyl substituents at the allylic position shown to provide exquisite stereocontrol (generally 98-99% chirality transfer). An attractive feature of the method is the ability to carry out the key transformation in the absence of solvent. Illustrated also is the high yielding conversion of four such products to a new family of bicyclic β-amino acids of high enantiomeric purity.

Evolution of the synthetic strategy that culminated in the first total syntheses of the structurally unique plectosphaeroic acids B (2) and C (3) is described. The successful enantioselective route to (+)-2 and (+)-3 proceeds in 6 and 11 steps from the known hexahydro-2H-pyrazinopyrrolo[2,3-b]indole-1,4-dione 39, which in turn is available in enantiomerically pure form by chemical synthesis. The central challenge in this synthesis endeavor was uniting the hexahydro-2H-pyrazinopyrrolo[2,3-b]indole-1,4-dione and cinnabarinic acid fragments of these marine alkaloids. Critical for achieving this successful C-N bond formation was the use of an iodocinnabarinic acid diester in which the amino group was masked with two Boc substituents, a Cu(I) carboxylate complex and the weak base KOAc. The highly congested C-N bond generated in this coupling, in conjunction with the delicate nature of the densely functionalized coupling partners, provided a striking testament to the power of modern copper-mediated amination methods. Two approaches, one stereoselective, for introducing the methylthio substituents of (+)-plectosphaeroic acid B were developed. The epitrisulfide ring of (+)-plectosphaeroic acid C was formed by ring expansion of an epidisulfide precursor.

ConspectusAllylic amides, amines, and esters are key synthetic building blocks. Their enantioselective syntheses under mild conditions is a continuing pursuit of organic synthesis methods development. One opportunity for the synthesis of these building blocks is by functionalization of prochiral double bonds using palladium(II) catalysis. In these reactions, nucleopalladation mediated by a chiral palladium(II) catalyst generates a new heteroatom-substituted chiral center. However, reactions where nucleopalladation occurs with antarafacial stereoselectivity are difficult to render enantioselective because of the challenge of transferring chiral ligand information across the square-planar palladium complex to the incoming nucleophile.In this Account, we describe the development and use of enantiopure palladium(II) catalysts of the COP (chiral cobalt oxazoline palladacyclic) family for the synthesis of enantioenriched products from starting materials derived from prochiral allylic alcohols. We begin with ini...

© 2016 American Chemical Society. ConspectusAllylic amides, amines, and esters are key synthetic building blocks. Their enantioselective syntheses under mild conditions is a continuing pursuit of organic synthesis methods development. One opportunity for the synthesis of these building blocks is by functionalization of prochiral double bonds using palladium(II) catalysis. In these reactions, nucleopalladation mediated by a chiral palladium(II) catalyst generates a new heteroatom-substituted chiral center. However, reactions where nucleopalladation occurs with antarafacial stereoselectivity are difficult to render enantioselective because of the challenge of transferring chiral ligand information across the square-planar palladium complex to the incoming nucleophile.In this Account, we describe the development and use of enantiopure palladium(II) catalysts of the COP (chiral cobalt oxazoline palladacyclic) family for the synthesis of enantioenriched products from starting materials derived from prochiral allylic alcohols. We begin with initial studies aimed at rendering catalyzed [3,3]-sigmatropic rearrangements of allylic imidates enantioselective, which ultimately led to the identification of the significant utility of the COP family of Pd(II) catalysts. The first use of an enantioselective COP catalyst was reported by Richards' and our laboratories in 2003 for the enantioselective rearrangement of allylic N-arylimidates. Shortly thereafter, we discovered that the chloride-bridged COP dimer, [COP-Cl]2, was an excellent enantioselective catalyst for the rearrangement of (E)-allylic trichloroacetimidates to enantioenriched allylic trichloroacetamides, this conversion being the most widely used of the allylic imidate rearrangements. We then turn to discuss SN2′ reactions catalyzed by the acetate-bridged COP dimer, [COP-OAc]2, which proceed by a unique mechanism to provide branched allylic esters and allylic phenyl ethers in high enantioselectivity. Furthermore, because of the unique nucleopalladation/deoxypalladation mechanism of these SN2′ reactions, they provide exclusively the branched allylic product. Importantly, both enantiomers of the [COP-Cl]2and [COP-OAc]2catalysts are commercially available. We also briefly consider several other enantioselective reactions catalyzed by COP complexes.The mechanism of enantioselective COP-catalyzed allylic rearrangements and allylic substitutions is discussed in some detail. In both reactions, nucleopalladation is found to be the enantiodetermining step. The cyclobutadienyl "floor" of the COP catalyst is critical for transmitting chiral information across the palladium square plane in these reactions. This structural feature enables high enantioselection to be realized in spite of the nearly 180° angle between the catalyst, electrophile and nucleophile in the enantiodetermining step. Our discussion concludes by considering several uses of the COP family of catalysts by other researchers for the enantioselective synthesis of biologically active chiral molecules. We anticipate that additional uses for COP catalysts will emerge in the future. In addition, the structural features of these catalysts that we have identified as important for achieving high enantioselection should be useful in the future development of improved enantioselective Pd(II) catalysts.

Synthetic analogues of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines 10 and 11 presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of 10 and 11 was investigated in host cells and in parasites. Both compounds induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines 10 and 11 on macrophages. The same compounds also promoted anti-inflammatory activity in L. (L.) infantum-infected macrophages cocultived with splenocytes, reducing the production of cytokines MCP-1 and IFN-γ. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a host-independent mechanism.

Visible-light photoredox-catalyzed fragmentation of methyl N-phthalimidoyl oxalate allows the direct construction of a 1,4-dicarbonyl structural motif by a conjugate addition of the methoxycarbonyl radical to reactive Michael acceptors. The regioselectivity of the addition of this alkoxyacyl radical species to electron-deficient olefins is heavily influenced by the electronic nature of the acceptor, behavior similar to that exhibited by nucleophilic alkyl radicals.

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by heterogeneous genetic and epigenetic changes in hematopoietic progenitors that lead to abnormal self-renewal and proliferation. Despite high initial remission rates, prognosis remains poor for most AML patients, especially for those harboring internal tandem duplication (ITD) mutations in the fms-related tyrosine kinase-3 (FLT3). Here, we report that a novel epidithiodiketopiperazine, NT1721, potently decreased the cell viability of FLT3-ITD+ AML cell lines, displaying IC50 values in the low nanomolar range, while leaving normal CD34+ bone marrow cells largely unaffected. The IC50 values for NT1721 were significantly lower than those for clinically used AML drugs (i.e. cytarabine, sorafenib) in all tested AML cell lines regardless of their FLT3 mutation status. Moreover, combinations of NT1721 with sorafenib or cytarabine showed better antileukemic effects than the single agents in vitro. Combining cytarabine with NT1721 also attenuated the cytarabine-induced FLT3 ligand surge that has been linked to resistance to tyrosine kinase inhibitors. Mechanistically, NT1721 depleted DNA methyltransferase 1 (DNMT1) protein levels, leading to the re-expression of silenced tumor suppressor genes and apoptosis induction. NT1721 concomitantly decreased the expression of EZH2 and BMI1, two genes that are associated with the maintenance of leukemic stem/progenitor cells. In a systemic FLT3-ITD+ AML mouse model, treatment with NT1721 reduced tumor burdens by > 95% compared to the control and significantly increased survival times. Taken together, our results suggest that NT1721 may represent a promising novel agent for the treatment of AML.

Convergent synthesis strategies in which a target molecule is prepared by a branched approach wherein two or more complex fragments are combined at a late stage are almost always preferred over a linear approach in which the overall yield of the target molecule is eroded by the efficiency of each successive step in the sequence. As a result, bimolecular reactions that are able to combine complex fragments in good yield and, where important, with high stereocontrol are essential for implementing convergent synthetic strategies. Although intramolecular reactions of carbon radicals have long been exploited to assemble polycyclic ring systems, bimolecular coupling reactions of structurally complex carbon radicals have rarely been employed to combine elaborate fragments in the synthesis of structurally intricate molecules. We highlight in this Account recent discoveries from our laboratories that demonstrate that bimolecular reactions of structurally elaborate tertiary carbon radicals and electron-deficient alkenes can unite complex fragments in high yield using nearly equimolar amounts of the two coupling partners. Our discussion begins by considering several aspects of the bimolecular addition of tertiary carbon radicals to electron-deficient alkenes that commend these transformations for the union of structurally complex, sterically bulky fragments. We then discuss how in the context of synthesizing rearranged spongian diterpenoids we became aware of the exceptional utility of coupling reactions of alkenes and tertiary carbon radicals to unite structurally complex synthetic intermediates. Our initial investigations exploit the early report of Okada that N-(acyloxy)phthalimides reductively fragment at room temperature in the presence of visible light and catalytic amounts of the photocatalyst Ru(bpy)3Cl2 to form carbon radicals that react with alkenes. We show that this reaction of a tertiary radical precursor and an enone can combine two elaborate enantioenriched fragments in good yield with the formation of new quaternary and secondary stereocenters. As a result of the ready availability of tertiary alcohols, we describe two methods that were developed, one in collaboration with the MacMillan group, to generate tertiary radicals from tertiary alcohols. In the method that will be preferred in most instances, the tertiary alcohol is esterified in high yield to give a tert-alkyl hemioxalate salt, which-without purification-reacts with electron-deficient alkenes in the presence of visible light and an Ir(III) photocatalyst to give coupled products having a newly formed quaternary carbon in high yield. Hemioxalate salts containing Li, Na, K, and Cs countercations can be employed in this reaction, whose only other product is CO2. These reactions are carried out using nearly equimolar amounts of the addends, making them ideal for coupling of complex fragments at the late stage in a synthetic sequence. The attractive attributes of the fragment-coupling chemistry that we discuss in this Account are illustrated by an enantioselective total synthesis of a tricyclic trans-clerodane diterpenoid in eight steps and 34% overall yield from commercially available precursors. We anticipate that bimolecular reactions of carbon radicals will be increasingly used for fragment coupling in the future.

The first total synthesis of a chromodorolide diterpenoid is described. The synthesis features a bimolecular radical addition/cyclization/fragmentation cascade that unites butenolide and trans-hydrindane fragments while fashioning two C-C bonds and stereoselectively forming three of the ten contiguous stereocenters of chromodorolide B.

Visible-light photoredox-catalyzed fragmentation of methyl N-phthalimidoyl oxalate allows the direct construction of a 1,4-dicarbonyl structural motif by a conjugate addition of the methoxycarbonyl radical to reactive Michael acceptors. The regioselectivity of the addition of this alkoxyacyl radical species to electron-deficient olefins is heavily influenced by the electronic nature of the acceptor, behavior similar to that exhibited by nucleophilic alkyl radicals.

The stereochemical outcome of reactions of chiral nucleophilic trisubstituted acetonide radicals with electron-deficient alkenes is dictated by a delicate balance between destabilizing non-bonding interactions and stabilizing hydrogen-bonding between substituents on the α and β carbons.

Visible-light photoreductive coupling of 2-arylallyl bromides in the presence of the photocatalyst Ru(bpy)3(PF6)2, a Hantzsch ester, and i-Pr2NEt gives 2,5-diaryl-1,5-dienes in high yield. This method avoids the use of stoichiometric metal reductants and is compatible with the presence of halogen, alkyl, electron-donating, and electron-withdrawing substituents on the aromatic ring.

Strategies for the total synthesis of complex natural products that contain two or more contiguous stereogenic quarternary carbon atoms in their intricate structures are reviewed with twelve representative examples. Emphasis has been put on the methods to create quarternary carbon stereocenters, including syntheses of the same natural product from different groups, thereby showcasing diversity of thought and individual creativity. A compendium of selected natural products containing two or more contiguous stereogenic quarternary carbon atoms and key reactions in their total or partial syntheses is provided in the Supporting Information section.

Alkyl oxalates are new bench-stable alcohol-activating groups for radical generation under visible light photoredox conditions. Using these precursors, the first net redox-neutral coupling of tertiary and secondary alcohols with electron-deficient alkenes is achieved.

Stereoselectivities of the dihydroxylations of cis-bicyclo[3.3.0]octene intermediates for a projected total synthesis of chromodorolide A have been explored experimentally. The reaction occurs unexpectedly on the apparently more hindered (concave) face; this result has been explained through computational studies using B3LYP and B3LYP-D3 methods. Torsional effects are largely responsible for the stereoselectivity encountered in the chromodorolide A synthesis. Many literature examples have been reported on related cases. QM calculations show that the stereoselectivities of dihydroxylations of fused cyclopentenes are influenced by the conformational rigidity or flexibility of the substrate. Torsional, electrostatic, and steric effects can all influence stereoselectivity, and the rigidity or flexibility of conformations of reactants provides a predictive guide to stereoselectivity.

The stereoselective formation of quaternary carbons is one of the most demanding challenges in organic synthesis.1 An especially direct way to construct such stereocenters would be to combine a prochiral tertiary organometallic and a carbon-centered electrophile (Figure 1A). However, this strategy is not mentioned in the numerous reviews of stereoselective synthesis of chiral quaternary carbons,1 and to our knowledge has never been employed in target-directed organic synthesis. This omission undoubtedly derives from the challenge in generating tertiary organometallic intermediates, particularly those containing three alkyl substituents.[2–4] We were recently drawn to explore this undeveloped approach for forming quaternary carbon stereocenters in the context of fashioning the demanding C8–C14 bond and the C8 quaternary stereocenter of rearranged spongian diterpenes such as aplyviolene (4) and dendrillolide A (5) by the reaction of tertiary organocuprate 1 and cyclopentenone 2. This coupling was anticipated to take place from the convex face of nucleophile 1 and from the face of 2 opposite the branched side chain (Figure 1B).[5]

Aplyviolene (1) and macfarlandin E (2, Figure 1A) are representative of the more complex members of the rearranged spongian diterpene class of natural products.[1,2] These diterpenes are structurally defined by attached cis-perhydroazulene and 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one fragments. The substantial challenge in assembling these structures centers on the construction of the sensitive bicyclic lactone subunit and the formation of the C8–C14 σ-bond joining the two ring systems, a challenge augmented by the quaternary nature of C8.[3] We previously reported preparation of the lactone subunits of 1 and 2 by the synthesis of truncated congeners 3 and 4 (Figure 1A),[4] as well as the first total synthesis of aplyviolene (outlined in Figure 1B).[5] In this latter effort, the key C8–C14 σ-bond was formed by Michael addition of tertiary enolate 5 to enone 6.[6] Subsequent elaboration of product 7 provided intermediate 8, which was converted to (−)-aplyviolene along the lines of our earlier synthesis of 3. Undesirable aspects of this first-generation synthesis are the lengthy preparation of the cis-perhydroazulene unit and the need to remove the extraneous ketone carbonyl group from the product of the fragment-coupling step.

From the 19th century to the present, the complex indole alkaloid strychnine has engaged the chemical community. In this review, we examine why strychnine has been and remains today an important target for directed synthesis efforts. A selection of the diverse syntheses of strychnine is discussed with the aim of identifying their influence on the evolution of the strategy and tactics of organic synthesis.