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Reception with Domestic & International Cheeses with Fruit & Crackers, Assorted Sodas & Bottled Waters, Red & White Wines, Imported and Domestic Bottled Beer.
Should participants wish to have something more substantial Ortega Dining Hall will be open and dinner can be purchased for $12. In addition, there are several dining establishments in Isla Vista, off of Madrid Road within walking distance. Consult the maps under venues.
Dinner in Ortega on Sunday is included in the board package ONLY for those staying in Manzanita. Otherwise, pay $12 at the door. For those not staying on campus, there are many places to eat in Isla Vista, the neighboring community.
Isla Vista Eateries
Among the frontier challenges in chemistry in the 21st century are the interconnected goals of increasing control of chemical reactivity while synthesizing and diversifying complex molecules with higher efficiency. Traditional organic methods for installing oxidized functionality rely heavily on acid-base reactions that require extensive functional group manipulations (FGMs). In contrast, nature routinely uses allylic and aliphatic C—H oxidation methods, generally mediated by heme and non-heme iron monooxygenase enzymes, to directly install oxidized functionality into the preformed hydrocarbon framework of complex molecules. Due to their ubiquity in complex molecules and inertness to most organic transformations, C—H bonds have typically been ignored in the context of methods development for total synthesis. The exceptions to this rely on substrate directing groups to facilitate site-selectivity and reactivity. The discovery and development of highly selective oxidation methods for the direct installation of oxygen, nitrogen and carbon into allylic and aliphatic C—H bonds of complex molecules and their intermediates are discussed. Unlike Nature which uses elaborate shape or functional group recognition active sites, this chemistry harnesses the subtle electronic, steric, and stereoelectronic interactions between C—H bonds and small molecule transition metal complexes to achieve high regio-, chemo-, stereo- and site-selectivities with high substrate generality- and without the requirement for directing groups. Our current understanding of these interactions gained through empirical and mechanistic studies will be discussed. A user-friendly catalyst reactivity model that calculates and even predicts the major site of oxidation as well as the magnitude and direction of the site-selectivity in complex substrates as a function of catalyst will be delineated. Novel strategies for streamlining the process of complex molecule synthesis and diversification enabled by these methods will be presented.
In the first part of the lecture, a two-step synthesis of structurally diverse 3-aminoindazoles from readily available starting materials will be presented. This sequence includes a one-pot chemoselective electrophilic activation of tertiary amides and nucleophilic addition of hydrazides to form aminohydrazones. These precursors then participate in an intramolecular ligand-free Pd-catalyzed C-H amination. The azaheterocycles synthesized via this approach were further diversified by subsequent deprotection/functionalization and transition Ru-catalyzed C-H arylation.
In the second part of the presentation, the preparation of tailored novel fluorescent derivatives that features an intramolecular C-H functionalization will be presented. The fluorescent properties can easily be fined tuned by modifying the basic molecular scaffoldN-Heterocyclic carbenes (NHCs) are powerful catalysts for some of the most diverse chemical transformations observed in organocatalysis.1 Beyond acyl anion chemistry they are active in many reactions that are acyl anion free often exploiting normal polarity intermediates.2 A number of our studies in the field of NHC catalysis are focused on reaction discovery using ester, and ester surrogate, substrates. In this presentation recent discoveries in enantioselective catalysis using Lewis basic, and nucleophilic, catalysts will be discussed
Transition metal-catalyzed higher-order carbocyclization reactions provide powerful methods for the stereoselective construction of complex polycyclic systems that are generally not accessible via classical pericyclic reactions.[1] We have demonstrated the merit of the rhodium-catalyzed [m+n+n] carbocyclization reactions of carbon and heteroatom tethered 1,6-enynes with carbon monoxide, alkynes and dienes. More recently we have explored the development of a stereoselective rhodium-catalyzed [3+2+2] carbocyclization of 1,6-alkenylidenecyclopropanes with activated alkynes for the construction of cis-fused bicycloheptadienes,[2] which prompted the isolation of the key metallacycle intermediate[3] and the expansion of the scope of p-fragments to carbon monoxide and allenes.[4,5] The seminar will outline some of these developments and their application to challenging bioactive natural products.
References
1. Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev. 2010, 39, 2791.
2. (a) Evans, P. A.; Inglesby, P. A. J. Am. Chem. Soc. 2008, 130, 12838. (b) Evans, P. A.; Inglesby, P. A.; Kilbride, K. Org. Lett. 2013, 15, 1798. (c) Evans, P. A.; Negru, D. E.; Shang, D. Angew. Chem. Int. Ed. 2015, 54, 4768.
3. Inglesby, P. A.; Bacsa, J.; Negru, D. E.; Evans, P. A. Angew. Chem. Int. Ed. 2014, 53, 3952.
4. Mazumder, S.; Shang, D.; Negru, D. E.; Baik, M.-H.; Evans, P. A. J. Am. Chem. Soc. 2012, 134, 20569.The preparation of heterocyclic motifs provides an exciting platform from which to conduct fundamental research, particularly that which supports the study of the interaction of small molecules with therapeutically-relevant biological targets. Densely packed arrangements of heteroatoms and stereogenic centers constituting these polycyclic subunit challenge the limits of current technology, prompting the need for new strategies for the synthesis of these systems. Novel approaches which have demonstrated our access to these challenging molecular architectures will be presented-- a ruthenium-catalyzed hydrogen transfer of 1,3-diols in the presence of alkyl hydrazines to furnish 1,4-disubstituted pyrazoles and an intramolecular displacement of an a-carbonyl fluoride by a tethered alkoxide to furnish [2.2.1] azabicyclics with excellent stereocontrol will be disseminated. Furthermore, a versatile approach to 5,6-fused heteroaromatics will be described which involves the conjugate addition of a metallated 2-fluoropyridine to substituted nitroolefins followed by a tractable 3-step sequence capable of furnishing these highly important bicyclic arrays.
The emergence of resistance to multiple antimicrobial agents in pathogenic bacteria has become a significant global public health threat. Drug resistant bacterial infections cause considerable patient mortality and morbidity, and rising antibiotic resistance is seriously threatening the vast medical advancements made possible by antibiotics over the past 70 years. The Centers for Disease Control and Prevention (CDC) estimates that over two million people acquire antibiotic resistant bacterial infections each year in the United States, and more than 23,000 people die as a result.
While the development of new antibiotics is one approach for the treatment of multi drug resistant pathogens, the fact remains that bacteria invariably develop resistance to any introduced therapy that relies solely upon a single bacteriostatic/bactericidal mechanism. For example, daptomycin was introduced into the clinic in 2003, and less than a year later the emergence of resistance was observed. As a result, alternative approaches to controlling bacterial infections are sorely needed and underexploited. Once such approach is the identification of genes and pathways that play an important role in bacterial resistance to currently approved antibiotics, and the identification of small molecule adjuvants that target and block these pathways, thereby repotentiating the activity of the antibiotic when administered as a combination therapy. Efforts in our lab towards the development of such adjuvants based upon functionalized 2-aminoimidazoles will be presented, focusing on examples of breaking antibiotic resistance in multidrug resistant Gram-negative pathogens.Asymmetric Brønsted acid catalysis has rapidly emerged as a powerful strategy for the synthesis of chiral, biologically relevant compounds, complementing enzymes and metal complexes. For the past five years we have been interested in developing enantioselective cycloadditions catalyzed by chiral Brønsted acid catalysts.
This talk will present our work in this area, which includes the asymmetric cycloaddition syntheses of various six- and five-membered nitrogen-containing heterocyles.2 We also applied these methodologies in the synthesis of biologically active natural and non-natural products.
The Lycopodium alkaloids have attracted enormous attention in recent years for their medicinal properties as well as the synthetic challenges they present.1
We have used the stereochemically diverse phlegmarine group as a platform to develop new synthetic methods including the use of organocatalysis,2 tandem reactions and stereocontrolled reductions based on radical, homogeneous and directed heterogeneous catalysis. The use of these methods in conjunction with solid supported reagents and pot economy strategies have allowed for easy gram scale synthesis of these compounds in a single flask.3 This presentation will give an overview of this work and illustrate the potential of the underlying strategies to access all of the other Lycopodium alkaloids, their analogs as well as a diverse portfolio of other important heterocyclic nuclei.
The development of the inverse electron demand Diels-Alder (IEDDA) reactions of 1,3,5-triazines has led to the total syntheses of a series of pyrimidine-containing natural products and the preparation of highly functionalized pyrimidine heterocycles.1 The dienophiles of these IEDDA reactions have been limited to electron-rich alkenes and alkynes, such as enamines, ynamines and amidines. Recently, we have discovered that ketones could be employed directly as productive dienophiles in the 1,3,5-triazine IEDDA reactions under conditions, such as using catalytic amount of hydrazine and trifluoroacetic acid. For examples, pyrimidine fused heterocycle 1 and functionalized pyridine-4-amine 2 may be prepared in moderate to excellent yields by applications of the new methods. The details of these investigations will be discussed.
Periploside A is a pregnane hexasaccharide identified from the Chinese medicinal plant Periploca sepium, which features a unique seven-membered formyl acetal bridged orthoester (FABO) motif and shows potent immunosuppressive activities. The total synthesis of this natural product is achieved in a total of 76 steps with the longest linear sequence of 29 steps and 9.2% overall yield.[1] The FABO motif is constructed via a combination of Sinaÿ’s and Crich’s protocol for the formation of orthoester and acetal glycosides, respectively. The 2-deoxy-b-glycosidic linkages are assembled stereoselectively with judicious choice of the glycosylation methods.[2,3] The epimer at the spiro-quaternary carbon in the FABO motif has also been elaborated in a stereo-controlled manner. This epimer, as well as the synthetic analogs bearing FABO motif, retain largely the inhibitory activities of periploside A against the proliferation of T-lymphocyte, indicating the importance of the chemical connection of the FABO motif to their immunosuppressive activities.
Spiroindimicins B-D were isolated in 2012 from Streptomyces sp. SCSIO 03032,1 a deep-sea derived actinomycete collected from the Bay of Bengal. These hexacyclic natural products feature unprecedented [5,5] spirocyclic bisindole scaffolds, and exhibit moderate inhibitory activity and cytotoxicity against a series of cancer cell lines.1 To date there are no reports on the synthesis of any member of this unusual family of natural products. Our synthetic strategy involves a Fischer indolization between phenylhydrazine 1 and ketone 2 to form the pentacycle 3, to which we are currently attempting to append the pyrrole ring and hence complete the syntheses of spiroindimicins B-D.
Nitrogen-containing heterocyclic systems are versatile core structures in organic chemistry because of their presence in many biologically active compounds. The development of new efficient synthetic strategies for the construction of nitrogen-containing heterocycles is of considerable interest. We have developed Lewis acid-promoted stereoselective five-membred ring formation of alkenyl ethenetricarboxylates.1 To promote the cyclization/halogenation, 1-2 equivalents of Lewis acids such as AlCl3, AlBr3, TiCl4, TiBr4 and ZnI2 are required. In this study, catalytic cyclization of allyl amides of ethenetricarboxylate leading to pyrrolidines has been examined. Reaction of allyl amides of ethenetricarboxylate with Sc(OTf)3 (0.2 equiv.) gave 4-hydroxymethyl-2-oxopyrrolidine derivatives stereoselectively (eq 1). The formation of the hydroxymethylpyrrolidines may arise from participation of water in situ. Sc(OTf)3-catalyzed cyclization reactions of the allyl amides with TMSX (X= Cl, Br) also proceeded efficiently to give halogenated 2-oxopyrrolidine derivatives. Catalytic cyclization of amides of ethenetricarboxylate bearing acetal and ether groups has also been examined. The reaction of the amides bearing cyclic acetal in the presence of Sc(OTf)3 gave piperidine derivatives as major products (eq 2). The cyclized products may be formed via internal redox process.2 Similarly, Lewis acid-catalyzed reaction of cyclic ethers gave spiro cyclic piperidine products selectively. The scope and the factors to control selectivities in the catalytic reactions of amides of ethenetricarboxylates are under investigation.
As part of a recent drug development program for the orally active ChK1 inhibitor GDC-0425, we required multi kilogram amounts of active pharmaceutical ingredient (API) to support human clinical studies. The initial discovery chemistry synthesis involved a multi-step conversion from 6-chloro-5-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyridine 1. This route effectively provided initial quantities of API but used undesirable reagents (SEM, NaH, TBAF), high catalyst loadings and required tedious workup and isolation procedures. We set out do develop a first generation process to manufacture ChK1 inhibitor GDC-0425 on multi-kilogram scale. An important part of our process development also needed to address the removal of heavy metals and the development of a crystallization process for the isolation of the penultimate API in high purity.
This presentation will discuss our efforts to secure an efficient and scalable route to the API and steps taken to lead us to the optimal route for GDC-0425 as shown in the scheme below. Highlights of the talk will be the discussion of the (1) carbazole protection strategy, (2) development of an efficient Pd catalyzed cyanation of aryl chloride 2; (3) optimization of the SNAr fluoride displacement of 3; (4) development of the recrystallization process for GDC-0425. The optimized process delivered highly pure API (>99 A% by HPLC) with the desired crystal form in an overall yield of 31 %.Purpose: We present a heterocyclic-based drug delivery platform that optimizes the concentration of a systemic drug at a location of interest. As a therapeutic proof of concept, we apply the system to the construction of an antibiotic agent based on vancomycin.
Background: Our prior studies have shown that an area of the body pre-implanted with a biomaterial containing a bioorthogonal reaction partner (trans-cyclooctene, TCO) can increase by ten times the local concentration of a heterocycle (tetrazine, Tz) carrying a radioactive payload in-vivo. Now we present a platform that localizes and releases small molecules at the desired location (Fig. 1).
Methods/Results: We modified fluorophores and vancomycin with TCO and as well as synthesized an alginate biomaterial modified with tetrazine (Tz-gel). We tested them through in-vivo and in-vitro models over multiple days. The results indicate that the “Catch & Release” method can deliver an increased payload to a local area pre-implantated with the biomaterial. The in-vitro therapeutic efficacy of the releasable vancomycin was comparable to vancomycin when tested in the presence of the Tz-gel against luminescent methicillin sensitive Staph. aureus (MSSA, Xen 29, Perkin Elmer, MA).
Conclusions: We present a drug delivery system that enables medical practitioners to direct drug to specific locations of the body by pre-implanting a biomaterial. This system could have major implications to improve the therapeutic index of new and old drugs.Na(OCP) has been shown to be a versatile precursor for a variety of compounds.[1,2] The versatility and the easy synthesis make this salt a powerful building block. The anion can act as a P− transfer agent [3] and the unsaturated CºP bond can undergo cyclo-addition reactions [4]. Two equivalents of Na(OCP) react with imidoyl chlorides to form 1-aza-3,4-diphospholides in good yields up to 80%. These electron rich diphsopholides were oxidized with hexachloroethane to from the phosphorus coupled dimers.
The reactivity of Na(OCP) towards imidoyl chlorides was transferred to 2-chloro-pyridines and its derivatives. The result is a variety of new products with outstanding properties. The light absorption and emission are easily tuned by the substituents in the backbone. Further studies on the use of those ring systems as building blocks for chelating ligands, and electronic materials will be presented.
[1] Puschmann, F. F. et al., Angew. Chem. Int. Ed., 2011, 50, 8420.
[2] Jupp, A. R., Goicoechea, J. M., J. Am. Chem. Soc., 2013, 135, 19131.
[3] Tondreau, A., Benkö, Z., Harmer, J., Grützmacher, H., Chem. Sci., 2014, 5, 1545.
[4] Benkö, Z., Grützmacher, H., et al., Angew. Chem. Int. Ed., 2014, 53, 1641.
Tuberculosis (TB) remains a leading cause of death worldwide, resulting in 1.5 million deaths annually and yet no rapid, sensitive, and specific diagnostic test exists. Recently two novel terpene nucleosides were isolated from Mycobacterium tuberculosis (MTb) which were identified as 1-tuberculosinyl adenosine (1-TbAd) and N6-tuberculosinyl adenosines (N6-TbAd). In this presentation the first asymmetric total synthesis of the TbAd molecules will be discussed together with the development of specific diagnostic tests for MTb.
A general, scalable, and highly diastereoselective aziridination of N-tert-butanesulfinyl ketimino esters is described. The methodology has been utilized to provide straightforward access to novel, biologically relevant α-quaternary amino esters and derivatives starting from readily available precursors.
1,4-Benzodioxane neolignans are natural products that are a subclass within the lignan family that exhibit remarkable biological effects, including antimicrobial, hepaprotective and cytotoxic activities. In particular, 1,4-benzodioxane lignans with a 9-hydroxymethyl group such as silybin A, one of the components of silymarin (milk thistle extract), have shown inhibitory activity against hepatotoxicants. Nitidanin isolated from Santalum album is an antimalarial agent.
Previous work in our group has developed an enantioselective and flexible synthetic method to produce 1,4-benzodioxanes lignans such as eusiderin and isoamericanin. We now report our efforts to synthesise nitrogen analogues of 1,4-benzodioxane lignans. The synthetic strategy is to convert the 1,4-benzodioxane skeleton into a benzomorpholine. The added nitrogen will allow an additional site for substitution which could allow bio-conjugation and also increase solubility.
We report our synthetic approach towards aza-lignans involving Mitsunobu reaction of an enantiopure secondary alcohol and an amino protected phenol, giving chirally pure aryl ethers which are converted into a benzomorpholine aminol. The N-Boc and O-Bn aminol was then subjected to N-acyliminium aryl addition, under acid condition. Aryl nucleophiles that are found in natural products were added to give a range of aryl benzomorpholine. Functionalization of the aryl bromide in these aryl benzomorpholines allows addition of the side chain.
The oxindole moiety is a core structure in many complex natural products; such natural products often possess interesting biological activities. This structure has also drawn the attention of medicinal chemists because of its potential as an important pharmacophore. In the course of the synthetic studies of spirooxindole skeleton, we focused on the utilities of carbamoyl chloride, which undergo oxidative addition to palladium catalyst. If C(sp3)-H bond activation is occurred after the oxidative addition, oxindoles would be accessed concisely. When we started the project, several groups reported the related cyclization using palladium catalyst via C(sp3)-H bond activation of a methyl group and the following reductive elimination. Thus, we examined the formation of oxindoles from carbamoyl chloride bearing an alkyl group in proper position.
The cyclization of carbamoyl chloride (R1 = Me, R2 = H), which was prepared 2,6-dimethylaniline, proceeded smoothly under the conditions of palladium acetate (3 mol%), di(1-adamantyl)- n-butylphosphine (6 mol%), Cs2CO3 and N-hydroxypivalamide in mesitylene at 120 °C to give oxindole in 88% yield (eq. 1). These conditions could be applied to several substrates having chloro, methoxy groups and so on. Further studies to disclose the reaction scope and apply to the synthesis of natural products are currently underway and will be reported.
In recent years, metal catalysed transformations of alkynes have gain prominence for the synthesis of oxa- and aza-cycles. However, their utility under metal free conditions is still under explored. In a programme directed at the stereoselective synthesis of oxa- and aza-cycles using vinylogous carbonates and carbamates, we demonstrated that the oxonium and iminium ion intermediates generated from these functional groups in the presence of Lewis acids can be trapped with alkynes giving stereoselective access to functionalized 2,3-disubstituted dihydrobenzofurans and indoline derivatives. The regioselectivity of alkyne iminium ion cyclization can be reversed using a tethered hydroxy group as nucleophile. Further, we have also developed divergent synthesis of N-fused indolylidine, indole, and indoline derivatives using alkyne-iminium ion cyclisation. Interestingly, trapping of vinyl cation intermediate generated after alkyne iminium ion cyclisation was found to be dependent on the Lewis/Bronsted acid and solvent used. This talk will highlight some details of these studies.
A simple, highly diastereoselective, Lewis acid catalyzed coupling of cyclic allylic alcohol with carbazole, resorcinol and indole derivatives has been developed. The method was applied for the enantiospecific total syntheses of structurally diverse natural products such as murrayamine-O, machaeriol-D, ∆8-THC, ∆9-THC, epi-perrottetinene and tetracyclic core of fischerindole and hapalindoles, having wide range of biological activities. Synthesis of both natural products and their enantiomers has been achieved with high atom economy, protecting group free manner and in less than 5 steps longest linear sequence in very good overall yield starting from R-(+) and S-(-)-limonene.
The chiral methylenedioxolanone 1 is readily available from (S)-lactic acid but it has not been used as a dipolarophile for 1,3-dipolar cycloaddition before. Diarylnitrones 2 add stereoselectively to give spiro adducts 3, and when these are subjected to flash vacuum pyrolysis at 440 °C, they eliminate ButCHO and CO2 as shown to give b-lactams 4 via an oxacarbene rearrangment.
The enantiomeric methylenedioxolanone 5, conveniently available from (R)-alanine,1 gives products 6 of the opposite enantiomeric series. Synthesis and FVP of the example 7 affords the advanced Ezetimibe precursor 8, thus completing a formal total synthesis of this important cholesterol-lowering drug.
A series of cyclic analogues of hexamethylenebis(3-pyridine)amide was prepared based upon a Ugi-3CR and aza-Diels-Alder reaction as a post-functionalization in a one-pot process. A simple condensations of commercially available diamine and aldehydes followed by isonitrile -addition provides the oxazoles intermediates, finally an aza-Diels-Alder cycloaddition and ring-opening using maleic anhydride provides the desired compounds in modest overall yield (12 examples, 6-69%) in approximately 40 min using microwaves as the heat source and scandium (III) triflate as a catalyst.
Throughout human history, textiles have been integral to daily life, but their exploration in catalysis has been negleted. We demonstrated a facile and permanent immobilization of organocatalysts on the textile nylon using ultraviolet light, which doesn’t require chemical modification for the immobilization. A Lewis basic, a Brønsted acidic, and a chiral organocatalyst immobilized on textile display excellent stability, activity, and recyclability for various reactions. High enantioselectivity (>95:5 er) can be maintained for more than 250 cycles of asymmetric catalysis. Practical and straightforward applications of textile organocatalysis may be beneficial for various fields by providing inexpensive and accessible functionalized catalytic materials.
For peptide cyclization C-terminal carboxyl activation is mandatory. In general, peptide C-terminal activation is accompanied by partial epimerization. By replacing the traditional coupling reagents by the Cu-catalyzed Chan-Lam reaction mildly activated peptide aryl-esters were obtained that were cyclized with complete stereocontrol.
Multicomponent reactions (MCR) are powerful tools toward the synthesis of a large variety of interesting scaffolds even heterocycles. MCR are defined as one pot processes in which three or more reagents are sequentially combined to afford products having the majority of the atoms present in the starting reagents. The main applications of MCR are in Diversity Oriented Synthesis (DOS) and Combinatorial Chemistry (CC). The most important MCR are the isocyanide-based multicomponent reactions (I-MCR) such as Ugi reactions e.g. the classic Ugi-4CR, Ugi-3CR, Ugi-Smiles, Ugi-Nenajdenko, Ugi-Interrupted (Groebke-Blackburn-Bienaymé), and Ugi-azide. This latter allows the synthesis of 1,5-disubstituted Tetrazoles of high interest in medicinal chemistry because their ability to adopt conformations of cis-amide bond of peptides. On this occasion, I will show my results lately published just regarding the use of the Ugi-azide reaction towards the synthesis of 1,5-disubstituted Tetrazole-based hybrid compounds and some of their applications, mainly in medicinal chemistry.
Daphniphyllum alkaloids are a family of complex, polycyclic natural products derived from evergreen shrubs in southern China. The daphnicyclidins represent a subset of these alkaloids as exemplified by daphnicyclidin A (1). A stereocontrolled synthesis of the tricyclic ABC ring system will describe the formation of the amine 2 via a novel nine-membered Z-enone. The discussion will present methodology for an efficient preparation of a-linked bis-enones as well as novel features of reactivity directly leading to functionalized heterocyclic systems. Applications of this methodology for synthesis of the condensed fulvene of 1 will be described.
Primarily associated with sensory neurons and located within specific areas of the central nervous system (CNS), neurokinin-1 (NK-1) is a member of the seven-transmembrane G-protein-coupled receptor family. The tachykinin peptide Substance P is the natural ligand for NK-1 and has been implicated in the pathophysiology of a wide range of dieases including anxiety, asthma, cystitis, emesis, inflammatory bowel disease, migraine, movement disorders, pain, and psoriasis. Merck has identified an octahydro-isoindole-based compound 1 which has significant binding affinity (sub-nanomolar) for the hNK-1 receptor. Compound 1 contains five stereocenters: a central core possessing four contiguous all-trans stereocenters, a pendent bis(trifluoromethyl)benzylic ether, and a cyclopentenone moiety. In order to fully evaluate this compound, an efficient and practical synthesis was required which would allow for the preparation of multi-kilogram quantities to support both pre-clinical and clinical development. Key to the success of the preparation of 1 was control of the relative and absolute stereochemistry. This presentation will address the evolution of a highly efficient asymmetric synthesis of 1.
Diazocompounds are a very interesting class of compounds that can promote a wide range of reactions, such as cyclopropanations, insertion reactions, ylide formation, dimerization and elimination reactions and formation of ketenes by the Wolff rearrangement, among others. An interesting class of these diazocompounds is the α,β-unsaturated diazoketones, which has received little attention when compared to the saturated ones due to the difficulty of its preparation by the usual existing methods. Herein, we would like to describe two methodologies for the preparation of α,β-unsaturated diazoketones with E and Z geometry employing new Horner-Wadsworth-Emmons reagents and their use as efficient platforms in the synthesis of pyrrolidines, indolizidines and piperidines.
Convergent synthesis strategies are fundamental to the efficient preparation of complex organic molecules. As a result, reactions that achieve the high-yielding union of polyfunctional fragments have particular importance in the preparation of structurally intricate organic molecules. Especially demanding are fragment coupling reactions that form sp3-sp3 sigma bonds and two stereocenters. When the two stereocenters reside in different rings and at least one of these stereocenters is quaternary, the challenge is enhanced substantially. This lecture will discuss the previously under appreciated utility of bimolecular reactions of free radicals to couple structurally intricate fragments.
Natural products have long been regarded as “Nature’s medicine chest” providing invaluable platforms for developing front-line drugs. The chemical structures of natural products have evolved over several millennia for a specific biochemical purpose and their molecular frameworks can be considered “privileged scaffolds.” This lecture will showcase how natural products that contain intricate spiroketal scaffolds can be synthesized thus providing a platform to develop novel anticancer and anti-obesity agents.
The virgatolides are a family of natural products containing a rare benzannulated 6,6-spiroketal moiety isolated in 2011 from Pestalotiopsis virgatula.1 Virgatolides A-C exhibit cytotoxicity against HeLa cells (IC50 ~ 20 µM). The first synthesis2 of virgatolide B is described. Phorbaketal A and alotaketal A are two pseudoenantiomeric natural products, containing a unique spiro-sesterterpenoid core structure.3,4 Phorbaketal A possesses moderate cytotoxicity against a range of cancer cell lines, as well as exhibiting osteoblast and mast cell differentiation activity and inhibition of fatty acid synthesis in the liver. Additionally, alotaketal A activates the cAMP signalling pathway at nanomolar concentrations. Our efforts directed towards the enantioselective syntheses of phorbaketal A and alotaketal A will be described.5Pim-1, -2, and -3 are highly homologous and constitutively active serine/threonine kinases. The three Pim isoforms phosphorylate a diverse group of proteins with known roles in proliferation, survival, apoptosis, and differentiation. The identification of oncogene-driven aberrant Pim kinase overexpression in subsets of B-cell malignancies including lymphomas, leukemias, and multiple myeloma, as well as in subsets of solid tumors, has led to intense efforts to identify small molecule Pim kinase inhibitors. A high-throughput screen of our corporate compound collection identified a hit composed of a 1,5-naphthyridine connected to a 6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one. A hit-to-lead optimization campaign resulted in the identification of improved inhibitors based on quinoxaline and quinazolin-4(3H)-one cores. A series of macrocyclic inhibitors in which the quinoxaline core and the dihydro-pyrrolo[3,2-c]pyridinone were connected was also found to possess improved properties. The heterocyclic chemistry of dihydro-pyrrolo[3,2-c]pyridinones, dihydropyrrolo[3,4-b]pyrrolones, and quinazolin-4(3H)-ones will be described, as well as the approaches used to synthesize macrocycles. Finally, the preclinical characterization of the lead molecules and their potential as treatments of Pim-driven malignancies will be presented.
A concise and highly diastereoselective synthesis of the polyfused tetracyclic cores of the Stemoa alkaloids asparagamine A and stemofoline that relies on a 2-propylidine-1,3-(bis)silane bicyclization onto a enantiodefined pyrrolidine 2,5-di(cation) equivalent derived from L-malic acid will be described. A crucial feature of this divergent synthetic approach involves the solvolysis of a transient and highly labile tertiary-propargylic lactamol trifluoroacetate in the strongly ionizing medium 5M LiClO4/Et2O. The acyliminium ion generated in this manner undergoes stereospecific interception by the aforementioned (bis)silane nucleophile (Scheme 1).
The second topic of this discussion will be concerned with highly diastereoselective metalloamination/cyclizations of zinc(II) hydrazides derived from the reaction of diethylzinc and N,N-dimethylhydrazinoalkenes. The resulting organozinc intermediates have been found to undergo facile allylation and acylation, in-situ, to provide the corresponding functionalized piperidines and pyrrolidines respectively (Scheme 2).
The development and application of metal-free catalysts has become an important topic in organic synthesis and catalysis. Recently, chiral Brønsted acids have been shown to be vital alternatives to metal catalysts and examples of highly enantioselective transformations have been reported. These reactions, similar to several enzymatic processes, proceed through ion-pair and hydrogen-bond activation. In this presentation our introduction to enantioselective Brønsted acid catalysis will be shown and new and valuable transformations will be highlighted. Additionally, efforts to delineate the general requirements for performing Brønsted acid as well as synergistic catalysis with the use of visible light or metals will be outlined and the applicability of these catalytic processes to the synthesis of natural product cores and heterocycles will be presented.
A variety of lipid-soluble alkaloids have been detected in amphibian skin, which contains over 20 structural classes and over 800 alkaloids. Many of these poison-frog alkaloids are expected to show interesting biological activities such as inhibitory effects on the neuronal nicotinic acetylcholine receptors (nAChRs).
We envisioned an efficient and flexible synthesis of 5,8-disubstituted, 6,7-dehydro-5,8-disubstituted, and 5,6,8-trisubstituted indolizidines, 1,4-disubstituted quinolizidines, decahydroquinoline-type poison-frog alkaloids using a Michael-type conjugate addition reaction of an enaminoester as the key step as shown below.
Faldaprevir is an HCV Protease Inhibitor for the treatment of Hepatitis C infection. The first small molecule treatment for HCV, the macrocycle BILN 2061, was the predecessor of Faldaprevir. Human clinical isolates following administration of Faldaprevir were found to contain four major human metabolites. Elucidation of the structure of each of these metabolites was achieved through a combination of isotopic labelling, LC-NMR, HPLC-MS, global esterification/chromatography and total synthesis. Implications for the molecular-level inetractions of the drug in the Cyp-3A4 active site will also be discussed.
Our group has been engaged in designing simple and efficient domino strategies for the syntheses of natural products and natural product like molecules. In this lecture, our efforts leading to syntheses of vinigrol, cyclic guanidines and N-heterocyclic amides will be discussed in details.
Vinigrol, a unique diterpene, containing the decahydro-1,5-butanonaphthalene carbon skeleton has been shown to exhibit a broad spectrum of biological activity. Besides the multiple sites of oxygenation, vinigrol contains a tricyclic core having a cis-fused [4.4.0] system bridged by an eight-membered ring and eight contiguous stereocenters. We recently reported an enantioselective formal synthesis of vinigrol, involving a 1-2-3 strategy (one pot and 2-reactions with the formation of 3-rings), leading to the core structure of vinigrol from its stereochemically well-defined acyclic precursor.
The cyclic guanidines and N-heterocyclic amides are important structural units present in biologically active drug molecules. However, the existing methods suffer from harsh conditions, narrow functional group tolerance, poor atom economy, low yielding and so; it warrants an efficient protocol for their syntheses. We have developed a one-pot Cu-catalyzed cascade routes to these unique cyclic guanidines and N-heterocyclic amides from readily available starting materialsMaterials derived from non-edible renewable resources, ideally by-products in food production processes, are valuable starting materials for chemistry. One such raw material, furfural, is produced from hemicellulose derived from agricultural waste products like bagasse, oat hulls and corncobs. Environmentally benign stock-chemicals are important to sustainable development by ensuring a future supply of raw materials. Our group has studied the molecular rearrangement of furfural and its derivatives to streamline the synthesis of molecular building blocks, including a novel class of photochromic material. In this lecture, we will present the development of this chemistry and highlight recent applications of the photochromic material as sensors and their use in light-controlled cargo delivery.
Many important biochemical compounds and drugs of natural origin contain tricyclic spirofuranone ring structures. Analysis of their molecular frames shows a compacted carbon skeleton with angularly fused tricycles of different oxidation states in each of the rings, which together present a real synthetic challenge.
Based on the remarkable core structure similarities among the natural products, we designed a rapid and practical collective synthesis strategy of complex functionalized natural and never-before explored frames. We devised a general and common synthesis of phylogenetically and structurally different tricyclic angularly fused systems via controlled cyclizations of simple key precursors. The novel strategy is short, regio- and stereoselective, and offers the possibility to access a broad spectrum of quaternary carbon-centered spiranoid lactone-based structures. Readily accessible key molecules, which are of lesser complexity than the target natural products, were elaborated by simple synthetic sequences. These yield a broad spectrum of spiranoid lactones of varying complexity.
Only a few of the naturally occurring ring fusion combination sets (mostly five- or six-membered rings) across a broad spectrum of the angularly fused spiranoid lactones are known to exist. Other combinations are extremely rare or do not exist at all. Our methodology enables us to produce new variations of angularly fused structures, providing access to a wide range of compounds that have never before been available and observed. These compounds closely resemble common natural scaffolds and carry potential for becoming valuable drugs/therapeutic agents.
We believe that novel concept will reshape the idea of spiranoid lactone moieties as building blocks in multistep synthesis, thus enabling completely innovative retrosynthetic analyses. Importantly, the application of the invented strategy to easily accessible building blocks will allow for the straightforward preparation of complex systems.
A series of new 1-(1-tert-butyl-1H-imidazol-4-yl)-1H-1,2,3-triazoles were prepared by reactions of corresponding 1-(1-tert-butyl-3-nitroazetidin-3-yl)-1H-1,2,3-triazoles with triethylphosphite with further oxidation. The 1,4-disubstituted triazoles were obtained by addition of azides to substitude acetylenes in the presence of ascorbic acid and copper(II) sulfate. Their structures were confirmed by 1H, 13C NMR, IR, X-Ray, HRMS and elemental analysis. Most of the synthesized compounds were screened in vitro for their antifungal activity against Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Fusarium graminearum, Sclerotinia sclerotiorum, Venturia inaequali and Bipolaris sorokiniana. Some of the compounds displayed activities comparable with those of the commercial fungicide Triadimefon.
There is a pressing need to develop effective drugs for the treatment of vector borne infectious diseases such as malaria and chikungunya. In our research reported here, we utilise two strategies for lead identification. The nature products approach led to two heterocyclic scaffolds for anti-plasmodial drug development while data-mining identified thieno[3,2-b]pyrroles as potential anti-virals against chikungunya. This presentation will provide an overview of our synthetic and biological discoveries in this field.
Spiroketals are ubiquitous in nature occurring in many complex macrolides which exhibit potent biological activity. Most methods for their construction are linear approaches requiring long synthetic sequences to install functional groups prior to a cyclization to form the spiroketal. Although effective, these methods are not convergent and lead to high linear step counts and issues with both material throughput and structure diversification.1 Our approach was to develop a modular fragment-coupling based strategy whereby the sprioketalization is also the fragment coupling step. This convergent approach uses the coupling of an ortholactone and a δ-hyroxyallylsilane to form the sprioketal in a single step, a strategy reported by Markó on very simple substrates.2
The major synthetic challenges were to develop an efficient and functional group tolerant synthesis of ortholactones followed by optimization of the fragment coupling in complex systems. The ortholactone synthesis was achieved through a palladium catalyzed Wacker-type oxidation of dihydropyrans.3 This method was particularly efficient for the construction of both methoxy and spirocyclic variants. These ortholactones could be coupled very efficiently with the allylsilanes to form the spiroketals in high yields as a single stereoisomer. When Bi(OTf)3 was used as a Lewis acid, a fragmentation reaction occurred to form a rearranged γ-lactone product which occurs with a wide range of functionality.Retinitis Pigmentosa (RP) is a family of progressive retinal degenerative diseases that effects small populations. The diseases are associated with many different genes hindering drug development – there are currently no treatments. We have hypothesized that metabolic stress is downstream to many of the gene mutations. Recently, a high throughput screen (HTS) was developed under conditions that mimic RP.[i] Hits from this primary screen were then subjected to a second assay that measures mitochondrial flux capacity, addressing the oxidative stress component affiliated with this neurodegenerative process. Two of these hits, CB11 and CB12, come together to form a pharmacophore from which novel chemical entities were synthesized. From these efforts, a small panel of analogs were developed and tested as a means to optimize protection of mitochondria from metabolic stress. Achieving cellular protection via the cell’s “power house” offers a novel approach towards treating this disease and the potential for addressing other pathologies where mitochondria are part of the degenerative process.
[i] Beeson, Craig Cano; Rohrer, Baerbel; Perron, Nathan R. Compositions and methods for the treatment of degenerative diseases PCT Int. Appl. (2011), WO 2011119869 A1 20110929
A method for the synthesis of highly functionalized 4-aminoquinolines from sulphynamides and amides is presented. The amides are activated by triflic anhydride (Tf2O) and 2-chloropyridine (2-ClPy) and, as Movassaghi et al. have shown, can be used to prepare a wide range of heterocyclic structures.[1] Sulphynamides can be prepared using copper catalysis and alkyl bromides[2] and further derivatized by using Sonogashira chemistry.[3] The main challenge in existing quinoline syntheses is the functionalization at the C-2 and C-3 positions. By combining the Sonogashira approach with the ynamide/amide methodology a wide range of substitutions at C-3 is possible and the C-2 and C-5 to C-8 positions are also accessible. In order to show the broad applicability of the methodology, it was found that the ynamides also readily react with paracyclophane-based amides, creating very interesting planar chiral compounds.
Presented is an account of the first example of a general asymmetric nitrosocarbonyl ene reaction with silyl enol ether derivatives. The procedure is operationally simple and utilizes an easily accessible chiral nitrosocarbonyl precursor (EleNOr), catalytic copper, and air as a benign oxidant. The transformation is both high yielding and highly diastereoselective for a variety of silyl enol ether derivatives including aromatic heterocyclic ketones. A range of non-exclusive post-functionalizations showcases the variety and scope of this method’s potential synthetic applications.
The palladium catalysed Matsuda-Heck-Reaction or arene diazonium salts is a powerful synthetic tool for the coupling of olefins and (heterocyclic) aryl compounds. Highlighted by mild reaction conditions, convenient synthesis[2,3] of very reactive and extremely useful electrophiles, this C-C-bond forming reaction is a highly versatile and efficient reaction for the synthesis of complex structures[4].
To the best of our knowledge, we report the first total syntheses of three known bioactive heterocyclic natural compounds[5,6] and one formal synthesis[7] of the anti-migraine drug Naratriptan, which are presented below. Furthermore, we developed new synthetic pathways for the novel olefins and arene diazonium tetrafluoroborates required, optimized the systems and implement the results in very efficient and atom economic routes.
Our reaction conditions are distinguished by low catalyst loading of inexpensive Pd(OAc)2, short reaction times, excellent functional group tolerance, absence of bases and ligands, full stereoselectivity and good to excellent yields.
Recently, we found that treatment of N,N-dimethyl 2-[(2-(2-alkynylphenyl)ethynyl)anilines 1 with ten mol% of PdCl2 and two equivalents of CuCl2 at refluxing THF for one hour gave the chlorinated benzo[a]carbazoles 2 in excellent yields. The chloroindoles 3 was proposed as the key intermediate and can be prepared separately by reaction of 1 with two equivalents of CuCl2 at refluxing THF. Treatment of 3 with various electrophilic transition metals, such as PdCl2, Pd(OAc)2 and PtCl2, gave carbazoles 2 in good yields. Under the similar reaction conditions, methyl 2-[6-substituted 3(Z)-hexen-1,5-diynyl]benzoates and 2-(2-(2-(2-substituted ethynyl)phenyl)ethynyl)thioanisoles were converted to dibenzo[b,d]pyran-6-ones and benzo[b]naphtho[2,1-d]thiophenes, respectively.
A fragment based approach was used to identify a unique series of LDHA inhibitors with good ligand efficiencies. Subsequent optimization delivered a novel lead series with LDHA cellular activity of 10 μM, selectivity against LDHB, and good physicochemical properties. The overall strategy of identification and optimization, lessons learned, and some guiding principles of the FBDD effort will be presented in the context of the discovery of a fragment-derived lead series for the inhibition of LDHA.
“All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed.”
In the present study, new silver and magnetic nanoparticles were prepared using modified cationic, nonionic surfactants and amino-amidoximes based on rosin as natural products[2, 3]. The produced modified rosin surfactants and amino-amidoximes were used as capping agents for magnetite nanoparticles to prepare hydrophobic coated magnetic powders[4-6]. Water soluble carbohydrates produced from Murrh natural gum were used to produce capped magnetite and silver nanoparticles as natural gums. A new class of monodisperse amphiphilic magnetite and silver nanoparticles were prepared by a simple and inexpensive green method.
The structure and morphology of magnetite and silver capped with modified rosin and Murrh gums were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential, thermogravimetric analysis (TGA) and dynamic light scattering (DLS). The magnetic properties were determined from vibrating sample magnetometer (VSM) analyses. These prepared silver and magnetite nanoparticles were tested as bioactive nanosystems and their antimicrobial effects were investigated.
The mitochondrial permeability transition pore (mtPTP) is a Ca2+-requiring megachannel that permanently opens under pathological conditions and leads to deregulated release of Ca2+ and mitochondrial dysfunction. For the past couple of decades the mtPTP has been implicitly recognized as a therapeutic target for several deadly diseases such as Alzheimer’s disease, muscular dystrophies, myocardial infarction, stroke, and diabetes. Herein we report the results of a high-throughput screening/chemical optimization approach that led to the discovery of two new chemotypes: (a) diarylisoxazole-3-carboxamides and (b) N-phenylbenzamides, which are first subnanomolar inhibitors of the mtPTP. The therapeutic potential and in vivo efficacy of the most potent analogues were validated in a biologically relevant zebrafish model of collagen VI congenital muscular dystrophies.
There is a need for general methods that lead to post-synthetic modification of peptides. Currently, few methods exist for the chemoselective arylation on specific amino acid residues. Organobismuth reagents have recently gained interest due to their versatility in bond formation, functional group tolerance, low cost and low toxicity related to the inorganic bismuth salt. Recently, our group has developed efficient arylation methods using highly functionalized trivalent arylbismuth reagents to form C‒C, C‒O and C‒N bonds.1 In particular, indoles, phenols and aminoalcohols have been successfully arylated in good to excellent yields via substoichiometric copper catalysis in mild conditions. As a result, this method will be further employed as a mean of selective arylation of polypeptides. In this poster, we will present our progress in the development of arylation methods of peptides using triarylbismuthanes.
Isocyanide based multicomponent reactions (IMCRs) followed by cyclization have become a valuable tools of drug discovery oriented synthetic heterocyclic chemistry since they allow synthesizing diverse nature-like heterocyclic small molecules in simple one-pot procedures. Recently we have developed IMCR of various primary diamines and carbonyl compounds that leads to a wide variety of heterocyclic scaffolds with pyrazine, quinaxoline, hetarenopyrazine, 1,4-diazepine, 1,4-benzodiazepine, and other pharmaceutically relevant cores [1].
Here we report post-condensation modification of the discovered IMCR by involving of dimethyl isocyanoacetal as a bifunctional isocyanide component. This enables further cyclization of intermediate pyrazine-2-amines 4 into target imidazopyrazines 5 under acidic conditions. Since no purification is required for intermediates 4, the entire synthesis can be performed in one-pot mode.
Notably, imidazopyrazine core of general formula 5 is a key structural feature of orexin receptor antagonists (2012), kappa receptor agonists, mGluR5 modulators, and TrkA inhibitors.
Scope of the developed tandem reaction including its expansion for the synthesis of spiro-imidazopyrazines and tetrahydroimidazo[1,2-a][1,4]diazepines as well as its application for small molecule libraries synthesis will be discussed.
[1] Kysil, V. et al. Eur. J. Org. Chem. 2010, 1525–1543.
Alan Katritzky, who in 2014 died at the age of 85, was a pioneer in the field of heterocyclic chemistry, the study of molecules possessing rings of carbon atoms along with other elements.
For 60 years, his research was reported in more than 2,300 papers and 200 books – a prodigious output that proved to be of great value to the academic community as well as to the pharmaceutical and agrichemical industries. He maintained his remarkable output until a few days before his death.
Alan was born into a family of Polish immigrants in London. Evacuated in 1940 to Wisbech, Cambridgeshire, he acquired his passion for chemistry at Wisbech high school, preparing his first heterocyclic compound, the barbiturate drug Veronal, on his 15th birthday.
After gaining a first-class degree in chemistry, followed by a doctorate, at Oxford University, he moved to Cambridge University in 1957, becoming a foundation fellow of Churchill College.
In 1962, at the unusually early age of 34, he was appointed professor of chemistry and founding head of the school of chemical sciences at the newly established University of East Anglia in Norwich.
There he rapidly established an undergraduate teaching programme and a strong postgraduate research school, fostering close contacts with the chemical industry. Such practices have since become widely established.
In 1980, he left Norwich to become chair of chemistry at the University of Florida in the US, where he founded a Centre for Heterocyclic Compounds to encourage postgraduate study and to find industrial applications for discoveries in the field. The Katritzky family funded charitable foundations to support students and founded a free online journal, called Arkivoc, that provides researchers in the developing world with a vehicle to publish their work in.
Alan was forceful, direct and resolute in his professional life, and his commitment to his chosen subject was total. In his personal relationships, he was compassionate and warm.
He is survived by his wife, Linde, his children Rupert, Margaret, Erika and Freda, and three grandchildren, Martin, Eric and Elisabeth.
Al Padwa will provide a tribute to Professor Alan Katritzky’s remarkable career in heterocyclic chemistry. In part 2, the chemistry of metal carbene complexes as a method to generate 1,3-dipoles is discussed. This approach bestows chemists with an exceptionally fertile ground for designing and developing new stereoselective bond construction for application toward the synthesis of various alkaloids. Due to their lability, metal carbene complexes are usually generated in situ from their corresponding diazo precursors prior to use. The reaction of a-diazo carbonyl compounds with transition metals such as rhodium(II) carboxylates constitutes a particularly powerful method for generating synthetically useful electrophilic carbene complexes. Earlier work by our group has shown that the rhodium(II) catalyzed reaction of 2-diazo-3-oxobutanoates bearing tethered p-bonds represents a synthetically useful protocol for the construction of a variety of novel polycyclic skeletons. The Rh(II)-catalyzed reactions of the related 2-diazo-2-(1H-indol-2-yl)acetate system has now been examined as a potential route toward scandine, a member of the melodinus family of alkaloids. Attack of the neighboring carbonyl oxygen atom onto the rhodium carbenoid center produces a cyclic 1,3-dipole that undergoes cycloaddition with a tethered alkenyl group. The resulting cycloadduct corresponds to a potential intermediate in a planned synthesis of scandine
Many natural products with interesting biological activity contain azabicyclic or bridged nitrogen containing scaffolds. These conformationally restricted compounds are characterised by a considerable ring strain which may complicate ringclosing reactions.
The lecture will discuss ringclosing methodology for the synthesis of several classes of azabicyclic and azamulticyclic derivatives designed towards agrochemical or medicinal applications.
A dynamic ring closure has been deloped for the synthesis of 7-azabicyclo[2.2.1]heptanes. This skeleton is present in epibatidine, a very active analgesic compound isolated from the skin of the Ecuadorian frog Epipedobates tricolor. Its potency was proven to be 200-fold higher than morphine, however epibatidine cannot be used clinically because of its high toxicity. Different classes of epibatidine analogues have been prepared trying to minimize toxicity while maintaining the analgesic properties.
Gold catalysed ringclosing reactions have been developed for the synthesis of functionalised isoindoles, dehydrothiazoles and pyrroles.The ring closing involves a 5-exodig cyclization, followed by a [1,3]-alkyl shift and a [1,5]-H shift.
Diketopiperazines are well recognized as an important moiety in medicinal active secondary metabolites of plants. We developed a new cyclization for the straightforward synthesis of constrained diketopiperazine analogues of the brevianamide family. This new class of analogues with a 3,5-bridged structure and bearing an alfa-chloro amine function allows the synthesis of a library of compounds using a variety of nucleophiles. We also performed ab initio calculations to get insight on the mechanism of the DKP-tryptophane ring closure.
Since nitrogen-containing heterocyclic rings are common structural motifs in biologically important natural products, development of new synthetic methodologies for construction of these structures have been one of the important research topics in synthetic chemistry. In this lecture, our recently completed total syntheses of polycyclic alkaloids featuring new synthetic strategies will be discussed. We investigated a reductive ring expansion of cyclic ketoximes and applied to a concise total synthesis of (–)-mersicarpine.1 For formation of substituted indolines, we developed a benzyne-mediated cyclization-functionalization sequence and applied this reaction to total syntheses of dictyodendrins A-E.2 A protective group free total synthesis of (–)-rhazinicine was accomplished based on the development of a gold-catalyzed double cyclization cascade.3 In the first total synthesis of (+)-haplophytine, we constructed the characteristic spiroaminal by an oxidative semi-pinacol type rearrangement.4 Dihydrooxepin rings in (–)-acetylaranotin was formed by combination of the vinylogous Rubottom oxidation and the Baeyer-Villiger ring expansion of an enone intermediate.
In general, the synthesis of complex biologically active molecules are problematic but the problems, encountered during the syntheses, can be a good source of inspiration to develop methods. One major challenge is the design of concise strategies as well as chemoselective and efficient methods that rapidly lead to the skeleton framework of natural and/or biologically active heterocyclic compounds.
In this context, we have explored the construction of heterocycles using catalytic reactions involving transition metal catalysts and heat. Metal catalysts and heat can induce rearrangements, cyclizations, functionalizations which can be highly diastereoselective and enantioselective if a chiral ligand is added in the reaction media. These reactions and their applications to the synthesis of heterocyclic natural and non-natural products will be presentedThe GSA lounge for the committee meeting is upstairs in the Multicultural Center
Dragmacidin D is a complex deep-sea marine heterocyclic natural product whose stereochemical identity has remained unclear since its isolation. This bis(indole) pyrazinone alkaloid contains a single stereocenter, whose configuration was proposed based on stereochemistry of another congener, dragmacidin F. Recently, Capon and Jia revised the assignment to 6’’’R based on total synthesis, the first enantioselective preparation of dragmacidin D in 26 steps. We developed an effective direct asymmetric alkylation of arylacetic acids, which enabled the synthesis of (+)-dragmacidin D in 10 steps. Curiously, our own effort confirmed the originally proposed assignment as 6’’’S. We also determined that dragmacidin D undergoes a slow racemization in aqueous solution at pH 6.8, essentially complete within 16 days at room temperature.
The pyrimidine ring represents an important pharmacophor and a key structural motif of numerous natural, as well as synthetic biologically active compounds. Various polysubstituted pyrimidines were studied in our team for their interesting and miscellaneous properties, namely antiviral (as non-nucleoside reverse transcriptase inhibitors), anticancer (as inhibitors of cyclin-dependent kinases), and anti-inflammatory (as inhibitors of nitric oxide and/or prostaglandin E2 production).
Some derivatives, e.g. polysubstituted 5-nitrosopyrimidines, were studied for their ability to form strong intramolecular hydrogen bonds. Such compounds were suggested to structurally (and hopefully also biologically) mimic bicyclic heterocycles like purines or pteridines.
Two possible rotamers were often observed depending on other substituents attached to the pyrimidine moiety and in several cases, they could even be isolated as chemical species.
Finerenone (BAY 94-8862) is a novel potent and selective oral non-steroidal mineralo-corticoid receptor (MR) antagonist blocking deleterious effects of aldosterone. Increased activation of the MR leads to pathological changes in the heart and kidneys, which can be prevented by effective MR antagonism. Finerenone has demonstrated a promising efficacy and safety profile in preclinical studies as well as in Phase IIa. The MR antagonist is currently in clinical Phase IIb development for the treatment of worsening chronic heart failure and diabetic nephropathy and is expected to enter clinical Phase III end of 2015. Synthesis and up-scaling of the novel optical active Dihydropyridine derivative to commercial scale, as well as challenges during process development will be discussed. Application of SMB technique for separation of enantiomers on large scale will be demonstrated. Additionally, the synthesis and characterization of metabolites will be presented.
The common theme in our laboratories is the invention and development of new DoM aromatic chemistry, separate and linked to transition metal catalyzed processes, and their demonstration in bioactive molecule, natural product, and materials construction. In honour of Alan Katritzky, a selection of these themes bearing on heterocyclic chemistry,
including new departures into DMG Dancing and Ir and Ru catalyzed DoM-enhancing
Connections, will be described.
The strong anion stabilizing capacity of the nitrile group permits a-aminonitriles with a primary or secondary amino group to be used as readily available a-aminocarbanion equivalents after deprotonation with a suitable base. These agents are versatile building blocks for the construction of highly substituted amines and N-heterocycles which can be obtained in very short reaction sequences or one-pot procedures. The related rearrangements of nitrile-stabilized ammonium ylides allow ring transformations such as the construction of protoberberine alkaloids in a single step.
1,4-Dihydropyridine (DHP) derivatives have attracted a considerable attention in medicinal chemistry and pharmacology due to the wide range of bioactivities, among which 4-arylated DHPs are also often found as the fundamental framework in drugs such as calcium antagonists and cardiovascular diseases.
On the other hand, we recently reported the novel method for construction of 4-arylated 3,5-dinitro-1,4-DHPs from β-formyl-β-nitroenamine as a reactive building block. Although this reaction serves as dinitro-DHPs that are not easily prepared by other method, the scope of the substrate is limited to highly electron-rich aromatics, and the theoretical maximum yield should be below 67%.
In this context, we have improved this reaction by using the strategy of Hantzsch-type multi-component reaction. Namely, a relevant multi-component reaction between two molecules of β-formyl-β-nitroenamine and an aldehyde is designed (Scheme), and we have succeeded to prepare various kinds of 4-aryl and 4-alkyl-3,5-dinitro-1,4-DHPs in high yields.Methylated melamines are widely used as anti-tumor drugs, insect sterilants, and as monomers for modified melamine-formaldehyde-polymers. Hydroxymethyl(methylmelamines) are metabolites of antitumor agents such as altretamine (hexamethylmelamine) and trimelamol trimethylol(trimethylmelamine)), formed by oxidation of a methyl group and subsequent elimination of formaldehyde. N-vinylmelamine derivatives offer a broad range of industrial applications, not only homopolymerization but also copolymerization with other monomers currently being under investigation. Our recent studies have used methylmelamines as building blocks for the synthesis of functional acrylyate monomers for coatings or in the synthesis of polymer additives.
In attempt to produce new melamine polymers we have prepared different functional triazine compounds for further vinylation and then polymerization. The vinylgroup is usually attached to a free NH-group – the influence of different substituents on the Nitrogen on the rate of vinylation has been investigated and found to be of great importance. All substances were produced by a single-, two- or three step synthesis using cyanuric chloride as starting material. The products were analyzed with GC, mass spectrometry, and NMR and thus full structural elucidation achieved.
At the moment copolymerization of the vinyl melamines with commercially available monomers, such as ethylene, styrene, or methylmethacrylate is being done. Depending on the selected melamine derivative basic polymerization parameters such as catalysts, concentration of reactants, temperature, solvent and reaction time have been studied and optimized.
In order to characterize these new polymer products different analytical approaches were applied. The nitrogen content, as a measure of melamine incorporation, was determined with elemental analysis (CHN). But as this method does not give structural information on the molecular level, we also have used methods such as FTIR, NMR, analytical pyrolysis, or MALDI mass spectrometry for the characterization of our copolymers.
The phenylethanoids are a diverse group of shikimic acid derived natural products, characterised by the presence of a C6C2 moiety. These compounds are of great interest for their structural complexity and wide range of biological functions. Incargranine B is a dimeric phenylethanoid alkaloid, originally assigned an unprecedented indolo[1.7]naphthyridine structure. As a result of biosynthetic speculation, we proposed a dipyrroloquinoline core as a plausible alternative structure. Following a biomimetic strategy, the proposed structure of incargranine B was accessed in six steps, confirming the suggested structural revision and indicating the natural product likely exists as a mixture of two pseudo-enantiomeric diastereomers. Extending upon this biomimetic synthesis, we now propose a unified biosynthetic hypothesis for the entire family of phenylethanoid natural products isolated from plants of the genus incarvillea. Studies towards the biomimetic synthesis of millingtonine and incargranine A will also be presented.
5-Substituted, 3,5-disubstituted, 5,8-disubstituted and 5,6,8-trisubstituted indolizidines belong to a group of alkaloids separated from the skin of poison dart frogs which lived in the tropical rainforest of Central and South America. Some of these indolizidines have shown interesting AChEI activity which is important for the development of new drugs.
A series of substituted indolizidines, including 167B, 195G, 209B, 209D, 209I, 223A, 223AB, synthesized starting from tricyclic lactones will be discussed. Key steps involved : 1) [3,3]-sigmatropic rearrangement to form tricyclic compounds with needed R1 substituent, 2) asymmetric alkylation/epimerization to obtain R2, 3) cyclization to form C7-C8 bond with R3 in correct stereochemistry, 4) construction of R4 (223AB case only), and 5) cleavage of the excess one carbon substituent on C5Saturated N-heterocycles have long been considered as privileged elements for the preparation of bioactive small molecules. Increasing recognition of problems associated with aromatic pharmacophores, such as poor solubility, bioavailability, or pharmacokinetics have further enhanced their importance in drug development.[1] Despite this, their synthesis often have considerable limitations, including harsh reaction conditions, restricted substrate scope, long synthetic routes, and intractable protecting groups. To directly access a variety of saturated N-heterocycles in a single synthetic operation, we have recently introduced SnAP (Stannyl Amine Protocol) reagents, which convert aldehydes and ketones into (thio)morpholines, piperazines, diazepanes, spiro- and other N-heterocycles.[2–6]
The major limitation using the SnAP reagents is the need for stoichiometric copper reagents. We have now identified new ligands and conditions that render the reaction catalytic in copper and expanded the substrate scope including a-bis(substituted) SnAP reagents. These studies, including approaches towards an enantioselective process and insights into the unique reaction mechanism, will be discussed.
References:
1. N. A. Meanwell, Chem. Res. Toxicol. 2011, 24, 1420–1456.
2. C.-V. T. Vo, G. Mikutis, J. W. Bode, Angew. Chem. Int. Ed. 2013, 52, 1705–1708.
3. M. U. Luescher, C.-V. T. Vo, J. W. Bode, Org. Lett. 2014, 16, 1236–1239.
4. C.-V. T. Vo, M. U. Luescher, J. W. Bode, Nat. Chem. 2014, 6, 310–314.
5. W.-J. Siau, J. W. Bode, J. Am. Chem. Soc. 2015, 136, 17726–17729.
6. K. Geoghegan, J. W. Bode, Org. Lett. 2015, 17, 1934–1937.
An expedient synthesis of bicyclic dihydropyran-3-one compounds is realized in a cascade trigged by oxidative gold catalysis. In this reaction, the initially formed α-oxo gold carbene intermediate, generated upon gold-catalyzed oxidation of alkyne, could be trapped by a tethered C-C triple bond, thereby generating a vinyl cation intermediate. This intermediate of highly electrophilicity is likely responsible for the intramolecular concerted C-H insertion. The reaction provides a simple way of constructing functionalized bicyclic system from easily accessible propargyl ethers.
Muironolide A is a fascinating tetrachlorinated marine polyketide isolated from the sponge of Phorbas sp. Only 90 mg had been isolated, and the structure was established by nanoscale NMR techniques. Herein we report the total synthesis of the substance with the assigned structure of muironolide A, propose a revised structure based on NMR data, and complete the enantioselective total synthesis of muironolide A.
Azaindole compound is a potent inhibitor of influenza, and has complex structure which is a challenge for scale up. We use enzymatic desymmetrization of 1,3-bisester-cyclohexane to generate the two chiral centers with high yield (99%) and high ee (99%). The first generation of synthesis employs the displacement of chiral monoBoc-diaminocyclohexane with sulfoxide, followed by urea formation (10 steps); The second generation of synthesis is racemic and need SFC separation (6 steps); The third generation of synthesis employs a Curtius rearrangement of acid to install morpholin urea in one step (7 total steps with 33% overall yield). All steps from last route are high yielding and easy to scale up.
Heterocyclic compounds are an important class of chemical compounds and are present in wide variety of drugs, photo-luminescent substances, agrochemical products, natural products etc.; thus play vital role in medicine, industry and life1. Recent upsurge in the field of synthetic organic chemistry has brought into light many techniques, such as C-H activation,2 transition metal-catalysed cross coupling reactions, multicomponent reactions3 etc., which expanded the horizons in the field of heterocycles, a feat that was never envisaged before. The main aim of our research is to focus our attention on the application of these methodologies for the construction of diversified and complex heterocyclic molecules. Recently, we published Ruthenium catalyzed C-H activation of the nitrogen containing heterocycles, wherein the innate reactivity of the heterocycle can be exploited for regioselective demonstrated C-2’ alkenylation of 2-phenylimidazo[1,2-a]pyridine (Scheme 1A).4 Presently we are exploring synthesis of 2-aminobenzothiazoles from N-phenyl thiouresa by palladium catalysed C-H functionalization/ C-S bond formation (Scheme1B). Salient features and mechanistic aspects will be presented.
A variety of substituted 1-hydroxyacridones were synthesized in a one-pot carbamation/Michael addition/Claisen Condensation/decarboxylation cascade in two steps from commercial phenols in good to excellent yields (41-96%). Furthermore, synthesis of 4-hydoxycarbazoles from quinols was realized through a carbamation/Michael/enolate-aryl coupling/aromatization sequence. This methodology was also applied to a short total synthesis of carbazomycin B.
The Gelsemium alkaloids constitute a significant family of natural products featuring a breadth of both structural and biological diversity. Our efforts toward a unified total synthesis of these molecules will be presented. A focal point of this endeavor is the application of a cascade platinum-catalyzed cycloisomerization/rearrangement to establish the core molecular architecture of these alkaloids. Our analysis of this specific transformation provided a fundamental understanding of this unique process and the facets that govern it. Our studies of this central process and subsequent direct manipulations have culminated in the successful total synthesis of gelsenicine, representing the shortest total synthesis to date of a Gelsemium alkaloid. We envision strategic diversifications will enable the syntheses of a broad array of members in the gelsemium family. Our overall efforts in this project will be presented.
Arylsilanes are of great interest in the fields of organic electronics and photonics, medicinal chemistry, and complex molecule synthesis due to the unique physicochemical features of the aromatic carbon-silicon (C–Si) bond.
We have recently discovered a mild and regioselective C–H bond functionalization of aromatic heterocycles catalysed by a plentiful and inexpensive Earth-abundant metal salt [1]. The method enables the direct silylation of heteroaryl C(sp2)–H bonds that both obviates the need for expensive precious metal catalysts and overcomes various limitations of previous methods. Applications to materials science and to the late-stage derivatization of pharmaceutical substances will be presented.
An efficient synthesis of pyrazolo[1,5-a]quinazolin-5(4H)-ones and pyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5(4H)-ones is reported from the reaction of 2-haloaroyl chlorides with 5-amino-1H-pyrazoles. A similar preparation of benzo[4,5]imidazo[1,2-a]quinazolin-5(6H)-ones and benzo-[4,5]imidazo[1,2-a]pyrido[3,2-e]pyrimidin-5(6H)-ones results from the reaction of 2-haloaroyl chlorides with 2-aminobenzimidazoles. These syntheses take advantage of the 1,3-disposition of electrophilic centers in the acid chloride and a similar arrangement of nucleophilic sites in 5-amino-1H-pyrazole and 2-aminobenzimidazole to form the central six-membered ring by a 3 + 3 strategy. Initial acylation of the amino group of the pyrazole or benzimidazole occurs in DMF containing carbonate base at –10 oC. Subsequent heating, in the same reaction vessel, completes the synthesis via an SNAr ring closure between N1 of the pyrazole or benzimidazole and the 2-haloarylamide. The reaction gives 66–93% yields for the two-step sequence. These compounds are known to intercalate into DNA, and thus, may be useful as antiproliferative agents for cancer treatment. Mechanistic and spectral aspects of the project will also be presented.
This talk will focus on the synthesis of the chemical properties of the macrocyclic inhibitors developed for the EML4 ALK program for the treatment of NSCLC leading to the discovery of the clinical candidate PF-06463922. The work disclosed will feature (i) variations of the heterocyclic tailpiece of the molecule, and the synthetic chemistry to incorporate these into the macrocyclic ring through either macrolactamization or direct arylation, (ii) conformational studies and atropisomerism of specific macrocyclic ring systems, and (iii) optimization and scale-up of the clinical candidate including the evolution of the synthesis of the pyrazole tailpiece.
A scalable, asymmetric synthesis of (3aS,6aS)-6a-(5-bromo-2-fluorophenyl)-1-((R)-1-phenylpropyl)tetrahydro-1H,3H-furo[3,4-c]isoxazole (1), a key intermediate in the synthesis of LY2886721 is reported. Highlights of the synthesis include: (1) The development of an asymmetric [3+2] intramolecular cycloaddition through a combined kinetic modeling and experimental approach; (2) The development of a new synthesis of (R)-N-(1-phenylpropyl)hydroxylamine tosylate (2) which proceeds through a p-anisaldehyde imine and avoids the formation of toxic hydrogen cyanide gas as a by-product. Results of a synthesis executed on the multi-100 kg scale (which proceeded in 36% overall yield) will be discussed.
The turn of the century brought about a pressing need for new, efficient and clean strategies for the chemical synthesis of biorelevant compounds. Our group has studied the use of various molecular rearrangements and atom-economical transformations as particularly appealing means towards the streamlined synthesis of complex small molecule targets.1,2,3
In this lecture, we will present an overview of our research in these areas and how they provide efficient solutions for total synthesis as well as platforms for the discovery of unusual reactivity.
References
[1] (a) Luparia, M.; Oliveira, M.T.; Audisio, D.; Frébault, F.; Maulide, N. Angew. Chem. Int. Ed. 2011, 50, 12631. (b) Audisio, D.; Luparia, M.; Oliveira, M.T.; Frébault, F.; Klütt, D.; Maulide, N. Angew. Chem. Int. Ed. 2012, 51, 7314. (c) Misale, A. ; Niyomchon, S. ; Luparia, M. ; Maulide, N. Angew. Chem. Int. Ed. 2014, 53, 7068.
[2] Huang, X.; Maulide, N. J. Am. Chem. Soc. 2013, 135, 7312.
[3] Jurberg, I.D.; Peng, B.; Wöstefeld, E.; Wasserloos, M.; Maulide, N. Angew. Chem. Int. Ed. 2012, 51, 1950.
Heterocycles are important structural motifs found in various natural products and functional materials. Their syntheses under mild reaction conditions and in highly efficient manners are still much in demand. On the other hand, Au catalysis has lately emerged as a powerful platform for the development of versatile synthetic methods.
In this presentation, two general strategies for the synthesis of N-/O-heterocycles in the context of gold-catalyzed transformations of alkynes will be discussed. In the first strategy, oxidative catalysis using tethered or external nucleophilic oxidants provide rapid access to azetidin-3-ones, tetrahydrobenzazepinones, piperidin-4-ones, azepen-4-ones and other ring systems. In the second strategy, gold catalysis is employed as the ‘spring board’ to provide access to versatile intermediates otherwise difficult to obtain, and their further transformations/rearrangements enable the preparation of heterocycles. Among the various implementations of these strategies to be presented, three selected cases are outlined in the Scheme. Applications of these methods in natural product synthesis will also be discussed
This lecture will describe our development of a light-induced, dual-catalytic method for converting saturated hydrocarbons to alkenes with the simultaneous formation of hydrogen gas. This ‘dehydrogenation’ process uses two mutually compatible, base metal catalysts to generate alkenes and molecular hydrogen by sequential carbon–hydrogen bond cleavages. The sequential, catalyst-mediated hydrogen atom transfers occur at room temperature and call to mind the mechanism of nature’s desaturase enzymes. In the wake of the alkene synthesis, the ‘hydrido’ forms of the catalysts undergo a reaction that liberates hydrogen gas and returns the catalysts to the reaction. Our ongoing efforts to achieve diverse chemical reactions that are attended by dehydrogenations will also be addressed.
Our laboratory is deeply interested in the discovery and development of new reaction methodology en route to the chemical synthesis of complex bioactive molecules. Research in our group at the California Institute of Technology is centered in the general area of synthetic chemistry, with a focus on the development of new strategies for the preparation of complex molecules, including natural products that possess interesting structural, biological, and physical properties. Concurrent to this program of target driven synthesis is a strong effort directed toward the development of new techniques and reaction methods, which will be useful for a range of applications. Typically, the complex target structure is used as an inspiration for the discovery of new reactions and technologies that may eventually be regarded as general synthetic methodology. Consequently, this approach provides access to a) novel, medicinally relevant structures, b) a general method for their synthesis, and c) new synthetic methods that will be beneficial for a host of applications.
The catalytic asymmetric synthesis of all-carbon quaternary stereocenters stands as a significant challenge in synthetic chemistry and we have encountered this problem many times in the course of natural product total syntheses. As a result of such endeavors, we have been developing mild, catalytic methods that allow for efficient and stereoselective construction of these challenging centers. Our recent results and applications of these new methods will be discussed in the lecture.