DOCSLIB.ORG

Fischer Indolization Strategy Toward the Total Synthesis of (–)-Goniomitine

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Fischer Indolization Strategy Toward the Total Synthesis of (–)-Goniomitine HETEROCYCLES, Vol. 95, No. 2, 2017 1245 HETEROCYCLES, Vol. 95, No. 2, 2017, pp. 1245-1253. © 2017 The Japan Institute of Heterocyclic Chemistry Received, 19th September, 2016, Accepted, 13th December, 2016, Published online, 15th February, 2017 DOI: 10.3987/COM-16-S(S)80 A FISCHER INDOLIZATION STRATEGY TOWARD THE TOTAL SYNTHESIS OF (–)-GONIOMITINE Beau P. Pritchett, Jun Kikuchi, Yoshitaka Numajiri, and Brian M. Stoltz* This manuscript is dedicated to Prof. Masakatsu Shibasaki for his 70th birthday. The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Blvd. MC101-20, Pasadena, CA 91125 (USA); Email: [email protected] Abstract – A Fischer indolization strategy toward the core of (–)-goniomitine is reported. Initial investigations into the Pd-catalyzed asymmetric allylic alkylation of dihydropyrido[1,2-a]indolone (DHPI) substrates are also discussed. (–)-Goniomitine (1, Figure 1), isolated from the bark of Gonomia Malagasy, is differentiated from other Aspidosperma alkaloids (e.g., 2–4) by its unique aminal-containing tetracyclic core.1 There are currently seven reported total syntheses of (±)-goniomitine (1),2 along with three asymmetric total syntheses.3 We anticipated that sufficiently rapid assemblage of the highlighted tricyclic subunit, combined with our group’s expertise in the asymmetric synthesis of all-carbon quaternary centers,4 would facilitate an efficient catalytic enantioselective synthesis of (–)-goniomitine (1). OH N N N N Et Et Et H Et N N N HN H H H H CO2Me (–)-goniomitine (1) (+)-aspidospermidine (2) (–)-quebrachamine (3) (+)-vincadifformine (4) Figure 1. Representative Aspidosperma Alkaloids In our initial retrosynthetic analysis of (–)-goniomitine (1), we believed that late-stage redox manipulations and alcohol deprotection could furnish the natural product from lactam 5 (Scheme 1). We expected the quaternary center in lactam 5 could arise from the enantioselective Pd-catalyzed decarboxylative allylic alkylation of racemic β-amidoester 6. Importantly, we believed that 1246 HETEROCYCLES, Vol. 95, No. 2, 2017 enantioconvergent construction of the quaternary center would offer significant improvement over the comparatively poor stereocontrol featured in previous enantioselective syntheses of (–)-goniomitine (1).3 Disconnection of the ethyl and alloc groups revealed key dihydropyrido[1,2-a]indolone (DHPI) 7, which we anticipated could be accessed via the Fischer indolization of 1,3-cyclohexanedione 8. OH hydroamination/ OBn OBn reduction/ Pd-catalyzed deprotection allylic alkylation N N N H Et HN O O Et Et O O (–)-goniomitine (1) 5 6 OBn O C-acylation/ Fischer OBn C-alkylation indolization N O O 7 keto-8 Scheme 1. Initial Retrosynthesis of (–)-Goniomitine The acid-promoted Fischer indolization reaction, first discovered in 1883, is one of the most robust and widely utilized methods for the synthesis of substituted indoles from carbonyl precursors.5 Ketones and aldehydes can be converted to the respective arylhydrazones under either Brønsted or Lewis acidic conditions (Scheme 2A). The arylhydrazone intermediate undergoes tautomerization to the corresponding enehydrazine, followed by a [3,3]-sigmatropic rearrangement and finally elimination of ammonia to deliver an indole product. This venerable transformation has seen widespread use in the realm of total synthesis,6 and has been rendered enantioselective in an elegant desymmetrization reaction of meso cyclic ketones.7 Of particular relevance to our synthetic plan toward (–)-goniomitine (1) was a report from Teuber and co-workers describing a Fischer indolization protocol for the synthesis of DHPI products Scheme 2. A) General Fischer Indolization Reaction. B) DHPI Synthesis via Fischer Indolization of 1,3-Cyclohexanediones HETEROCYCLES, Vol. 95, No. 2, 2017 1247 (Scheme 2B).8 They found that treatment of 2-substituted 1,3-cyclohexanediones (9) with phenylhydrazine and sulfuric acid first gives tricycle 10, which undergoes sequential hydrolysis and N-acylation to furnish DHPI 11. Our studies on the Pd-catalyzed allylic alkylation of the previously unexplored DHPI substrate class commenced with C3-methyl DHPI 13, which is readily available from 2-methyl-1,3-cyclohexanedione (12, Scheme 3).8 DHPI 13 was smoothly acylated using LHMDS and allyl cyanoformate. Subsequent site-selective alkylation with iodomethane delivered racemic β-amidoester 15 in 77% overall yield from 13. We found that subjecting 15 to the catalyst complex derived from Pd2(pmdba)3 (5 mol%) and (S)-(CF3)-t-BuPHOX (L1, 12.5 mol%) in toluene at 60 °C resulted in minimal conversion, despite prolonged reaction times (Table 1, Entry 1). Full consumption of starting material was only achieved after switching from toluene to TBME as solvent, and raising the loading of Pd2(pmdba)3 and ligand to 10 mol% and 25 mol%, respectively (Entry 2). Under these conditions, we were able to isolate α-quaternary DHPI 16 in 60% yield and 90% enantiomeric excess. O H2SO4 LHMDS; PhNHNH allyl cyanoformate MeI, K2CO3 2 N N THF, –78 °C → 0 °C DMF, 50 °C O O (80% yield) O (97% yield) O (79% yield) O 12 13 14 CF3 O Table 1: Pd-Catalyzed Allylic Alkylation of 15 (4-CF3-C6H4)2P N Pd (pmdba) ligand entry 2 3 solvent time [h] yield [%] ee [%] L1 mol% mol% N N Pd2(pmdba)3 1 5 12.5 toluene 72 <10% 90 O solvent, 60 °C O O 2 10 25 TBME 24 60 90 O 15 16 Scheme 3. Synthesis of C3-Methyl α-Quaternary DHPI 16 Regarding the total synthesis of (–)-goniomitine (1), our first challenge was to establish a regioselective C-alkylation of 1,3-cyclohexanedione (17) with (2-benzyloxy)ethyl iodide (18). Although Ma and co-workers have previously reported this transformation, we were unsuccessful in our attempts to reproduce their work.9 We discovered that slightly different conditions afforded the desired C-alkylated product 8 in 70% yield as the enol tautomer (Scheme 4). After investigating several conditions for the Fischer indolization reaction, it was discovered that subjecting enol-8 to 2N HCl in refluxing toluene furnished key DHPI 7, albeit in an unsatisfactory range of 10–33% yield. Nevertheless, we were able to synthesize β-amidoester 6 from DHPI 7 in 55% yield over a two-step sequence analogous to that 1248 HETEROCYCLES, Vol. 95, No. 2, 2017 described above (cf. Schemes 3 and 4), which put us in position to test the allylic alkylation chemistry on the real system. Once again, we observed that TBME as solvent, along with high catalyst loading, was required to deliver α-quaternary allylic alkylation product 5 in a disappointing 59% yield and 87% enantiomeric excess. I OBn OBn O (18 , 1.1 equiv) O 2N HCl 1. LHMDS; allyl cyanoformate KOH (2 equiv) OBn PhNHNH2 THF, –78 → 0 °C EtOH/H2O, 100 °C toluene, 110 °C N 2. EtI, K2CO3, DMF, 50 °C O OH (70% yield) (10–33% yield) O (55% yield, 2 steps) 17 enol-8 7 OBn OBn OH L1 (25 mol%) Pd2(pmdba)3 (10 mol%) N N N TBME, 60 °C H Et O O Et O (59% yield, 87% ee) Et HN O 6 5 (–)-goniomitine (1) Scheme 4. Synthesis of α-Quaternary DHPI 5 Toward (–)-Goniomitine (1) Previous studies by our group have revealed that electron-withdrawing substituents on the lactam nitrogen atom provide the best results in the allylic alkylation chemistry.4b We therefore hypothesized that a C3-alkyl substituent might be too electron-donating, and thus reevaluated our synthetic plan. Gratifyingly, C3-brominated substrate 19 performed exceptionally well in the Pd-catalyzed allylic alkylation, delivering α-quaternary DHPI 20 in 83% yield and 96% ee (Scheme 5). We were then able to advance this compound to (–)-goniomitine (1) in just three steps and 29% overall yield.10 Br Br OH L1 (12.5 mol%) three steps Pd (pmdba) (5 mol%) N N 2 3 N H TBME, 60 °C Et HN O O Et O (83% yield, 96% ee) Et O (–)-goniomitine (1) 19 20 Scheme 5. Strategic Bromination Enables a Total Synthesis of (–)-Goniomitine (1) To summarize, we employed a Fischer indolization protocol to synthesize a key tricyclic DHPI intermediate (7) toward (–)-goniomitine (1) in three steps from commercial materials. While this transformation failed to deliver the product in good yield, sufficient material was made available to study the Pd-catalyzed enantioselective allylic alkylation of the DHPI substrate class. As a result, we discovered a critical electronic effect at the C3 position of the indole moiety that led to the first catalytic enantioselective total synthesis of (–)-goniomitine (1). HETEROCYCLES, Vol. 95, No. 2, 2017 1249 EXPERIMENTAL Unless stated otherwise, reactions were performed at ambient temperature (23 °C) in flame-dried glassware under an argon atmosphere using dry, deoxygentated solvents (distilled or passed over a column of activated alumina).11 Commercially available reagents were used as received. Reactions requiring external heat were modulated to the specified temperatures using an IKAmag temperature controller. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 pre-coated plates (250 nm) and visualized by UV fluorescence quenching, potassium permanganate, or p-anisaldehyde staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 40-63 nm) was used 12 for flash chromatography. (S)-(CF3)-t-BuPHOX, and tris(4,4’-methoxydibenzylideneacetone)- 13 dipalladium(0) [Pd2(pmdba)3] were prepared by known methods. Phenyl hydrazine was purified immediately before use. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. 1H and 13C NMR spectra were recorded on a Varian Inova 500 (500 MHz and 126 MHz, respectively) and are reported in terms of chemical shift relative to CHCl3 (δ 7.26 and 77.16, respectively). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Infrared (IR) spectra were recorded on a Perkin Elmer Paragon 1000 Spectrometer and are reported in frequency of absorption (cm-1).
Load more

Recommended publications
  • Fluorescent Aminal Linked Porous Organic Polymer for Reversible Iodine Capture and Sensing Muhammad A
    www.nature.com/scientificreports OPEN Fluorescent aminal linked porous organic polymer for reversible iodine capture and sensing Muhammad A. Sabri1, Mohammad H. Al‑Sayah2, Susan Sen2, Taleb H. Ibrahim1 & Oussama M. El‑Kadri2* A novel triazene-anthracene-based fuorescent aminal linked porous organic polymer (TALPOP) was prepared via metal free-Schif base polycondensation reaction of 9,10-bis-(4,6-diamino-S‑triazin‑ 2-yl)anthracene and 2-furaldehyde. The polymer has exceptional chemical and thermal stabilities and exhibit good porosity with Brunauer–Emmett–Teller surface area of 401 m2g−1. The combination of such porosity along with the highly conjugated heteroatom-rich framework enabled the polymer to exhibit exceptional iodine vapor uptake of up to 314 wt % and reversible iodine adsorption in solution. Because of the inclusion of the anthracene moieties, the TALPOP exhibited excellent 3 −1 detection sensitivity towards iodine via forescence quenching with Ksv value of 2.9 × 10 L mol . The cost efective TALPOP along with its high uptake and sensing of iodine, make it an ideal material for environmental remediation. Nuclear energy is becoming one of the most feasible alternative sources to meet the ever-increasing energy demand and minimize the emission of greenhouse gases because of its high-density energy, minimal carbon footprints, and low operation cost1–4. Despite such advantages, the potential emissions of radioactive material 129 131 3 14 85 (such as I and I, H, CO2, and Kr) from nuclear energy power plants is a major drawback of this tech- nology due to the serious environmental and health efect of these materials4,5.
    [Show full text]
  • Synthesis and Structural Studies of a New Class of Quaternary Ammonium
    Rivera et al. Chemistry Central Journal 2011, 5:55 http://journal.chemistrycentral.com/content/5/1/55 RESEARCHARTICLE Open Access Synthesis and structural studies of a new class of quaternary ammonium salts, which are derivatives of cage adamanzane type aminal 1, 3, 6, 8-tetraazatricyclo[4.3.1.13,8]undecane (TATU) Augusto Rivera1*, John Sadat-Bernal1, Jaime Ríos-Motta1, Michal Dušek2 and Lukáš Palatinus2 Abstract Background: Novel mono N-alkyl quaternary ammonium salts (3a-f) were prepared using the Menschutkin reaction from the cage adamanzane type aminal 1,3,6,8-tetraazatricyclo[4.3.1.13,8]undecane (TATU) and alkyl iodides, such as methyl, ethyl, propyl, butyl, pentyl and hexyl iodide (2a-f), in dry acetonitrile at room temperature. Results: The structures of these new quaternary ammonium salts were established using various spectral and electrospray ionization mass spectrometry (ESI-MS) analyses. Compound (3b) was also analyzed using X-ray crystallography. Conclusion: It was noted that alkyl chain length did not significantly affect the reaction because all employed alkyl iodide electrophiles reacted in a similar fashion with the aminal 1 to produce the corresponding mono N- quaternary ammonium salts, which were characterized by spectroscopic and analytical techniques. Background amines with haloalkyls [7]. We found that no reaction Cage aminals of the adamanzane type are tricyclic ter- occurred when N-alkylation was attempted using alkyl tiary tetraamines, which can act as bases or as nucleo- bromides and chlorides. Compound 1 reacts with alkyl philes. The main subject of research in our laboratory iodides in dry acetonitrile at room temperature to pro- (Universidad Nacional, Bogotá) is the reactivity of these duce mono N-alkyl ammonium quaternary salts (3a-f) polyamine bases toward nucleophiles and electrophiles.
    [Show full text]
  • Synthesis of Monocyclic Diaziridines and Their Fused Derivatives
    Special Issue Reviews and Accounts ARKIVOC 2008 (i) 128-152 Synthesis of monocyclic diaziridines and their fused derivatives Nina N. Makhova,* Vera Yu. Petukhova, and Vladimir V. Kuznetsov N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47, Leninsky prosp., 119991 Moscow, Russian Federation E-mail: [email protected] Abstract Diaziridines and their fused analogues have a wide-range potential as a test subjects for theoretical and practical application. This review covers our investigations focused on the development of optimal methods for the synthesis of monocyclic and fused diaziridine derivatives. Several approaches to the preparation of monocyclic diaziridine derivatives were developed: (1) a synthesis of 3,3-di- and 1,3,3-trialkylmono- and α,ω-bis(diaziridin-1-yl)alkanes from ketoxime O-sulfonates and ammonia, and primary aliphatic amines, respectively, as well as of practically previously inaccessible 3-monoalkyldiaziridines from ammonium salts of aldoxime O-sulfonic acids and ammonia (2) a synthesis of diaziridines from carbonyl compounds, primary aliphatic amines, and aminating reagents in water (or a water–MeOH mixture) at controlled pH of the medium, as well as from carbonyl compounds, amines and N-chloroalkylamines in aprotic solvents in the presence of K2CO3, and (3) a synthesis of 1,2,3-trialkyldiaziridines from N- chloroalkylamines without carbonyl compounds in the presence of primary aliphatic amines at high pressure. As regards fused diaziridine derivatives, general and simple methods were developed to prepare four types of these structures: 1,5-diazabicyclo[3.1.0]hexanes, 1,6- diazabicyclo[4.1.0]heptanes, 1,3,5-triazabicyclo[3.1.0] hexanes, including the parent compound and 2,4-nonsubstituted structures, and 1,3,6-triazabicyclo[3.1.0]hexanes, the latter being previously unknown.
    [Show full text]
  • Derivatives of the Triaminoguanidinium Ion, 6. Aminal-Forming Reactions with Aldehydes and Ketones [9]
    Z. Naturforsch. 2020; 75(3)b: 317–326 Jan Szabo and Gerhard Maas* Derivatives of the triaminoguanidinium ion, 6. Aminal-forming reactions with aldehydes and ketones https://doi.org/10.1515/znb-2019-0216 [9]. Some years ago, we started to study the chemistry of Received December 5, 2019; accepted January 19, 2020 salts 3, which in particular were expected to undergo mul- tiple functionalization based on the nucleophilicity of the Abstract: Cyclic aminals (N,N-acetals) could be prepared benzyl-NH nitrogen atom. Thus, 3-Cl was found to undergo by the reaction of N,N′,N″-triaminoguanidinium sul- threefold N-carbamoylation with various arylisocyanates fate, N,N′,N″-tris(benzylamino)guanidinium chloride or and thiocarbamoylation (leading to thiourea derivatives) N,N′,N″-tris(benzylamino)guanidine with formaldehyde with arylisothiocyanates [10]. In a similar manner, triple or acetone. In all cases, 1,2,4,5-tetrazinane derivatives N-acylation with acid chlorides produced N,N′,N″-tris(N- were obtained, which were structurally confirmed by X-ray acyl-N-benzylamino)guanidines, which under the action crystal structure determinations. In two cases, 1:1 cocrys- of aqueous NaOH could be transformed into mesoionic tals of two different tetrazinane products were isolated. On 1,2,4-triazolium-3-aminides [11]. Reactions of salts 3 with the other hand, the reaction of N,N′,N″-tris(benzylamino) aldehydes or ketones have not been reported so far. guanidinium chloride with benzaldehyde yielded a The presence of three amino groups in the cations of 3-(2-benzylidenehydrazin-1-yl)-1H-1,2,4-triazole.
    [Show full text]
  • Indoles Indoles Are Very Commonly Encountered in Nature and Many
    Indoles Indoles are very commonly encountered in nature and many, many individual examples which have biological implcations. Below is a very small selection of examples. CO2H H HO MeO MeO CO H NH2 NH2 NHAc 2 N N N H H H N tryptophan seratonin melatonin (Essential amino acid) (neurotransmitter) (diurnal rhythym) O OH Cl indomethacin Et O N (rheumatoid arthritic) MeHN S N O NMe2 N vincristine H Et N MeO2C H (leukemia treatment) H H sumatriptin OAc MeO N (migraines) CO2Me CHO OH Although these compounds are simply benzo- fused pyrroles, they have their own set of ring synthesis reactions that are disctinct from pyrrole syntheses. A. Fischer Indole Synthesis Reviews: Gribble, G. W. J. Chem. Soc., Perkin trans 1 2000 , 1045; Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006 , 106 , 2875. The Fischer Indole Synthesis is the reaction of a hydrazine derivative of a ketone or aldehyde formed from an aryl hydrazine. It is a multistep process involving a sigmatropic rearrangement, much like the Cope or Claisen rearrangement. It can occur purely thermally, but is normally done at much lower temperature in the presence of a protic acid or Lewis acid. Polyphosphoric acid, 100 oC are often used conditions. 2 R2 R -H O acid or + R1 2 N R1 Lewis acid NH R1 2 N ∆ N H ∆∆ N H O R2 H Here is the mechanism: 2 R R2 2 2 R [3,3]- R R1 -H+ R1 H+ R1 sigmatropic R1 rearr. N+ + N H N N NH N H N H N + 2 H H H H -H+ H +H+ 2 2 R2 R R2 -H+ R 1 H +H+ R R1 R1 R1 + + + NH NH2 .
    [Show full text]
  • Synthesis and Characterization of Covalent Adaptable Networks
    Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 3-19-2018 Synthesis and Characterization of Covalent Adaptable Networks Comprised of Dynamic Imine and Aminal Covalent Bonds Albert Chao Louisiana State University and Agricultural and Mechanical College, [email protected] Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Part of the Organic Chemistry Commons, and the Polymer Chemistry Commons Recommended Citation Chao, Albert, "Synthesis and Characterization of Covalent Adaptable Networks Comprised of Dynamic Imine and Aminal Covalent Bonds" (2018). LSU Doctoral Dissertations. 4506. https://digitalcommons.lsu.edu/gradschool_dissertations/4506 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. SYNTHESIS AND CHARACTERIZATION OF COVALENT ADAPTABLE NETWORKS COMPRISED OF DYNAMIC IMINE AND AMINAL COVALENT BONDS A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Chemistry by Albert Chao B.A., University of Cincinnati, 2010 May 2018 Acknowledgements I would like to thank my advisor Prof. Donghui Zhang for her guidance, mentorship, and financial support on the projects I have worked on during the past 5 years in graduate school at Louisiana State University. Prof. Donghui Zhang allowed me to think independently and develop projects from the beginning to the end. When I lost interest on each project, her patience and encouragement always turned failure into success.
    [Show full text]
  • Synthesis and Chemistry of Indole
    Synthesis and Chemistry of Indole 1. Introduction: ➢ Indole is a benzo[b]pyrrole formed by the fusion of benzene ring to the 2,3 positions of pyrrole nucleus. ➢ The word “Indole” is derived from the word India, as the heterocycle was first isolated from a blue dye “Indigo” produced in India during sixteenth century. ➢ In 1886, Adolf Baeyer isolated Indole by the pyrolysis of oxindole with Zn dust. Oxindole was originally obtained by the reduction of isatin, which in turn was isolated by the oxidation of Indigo. ➢ Commercially indole is produced from coal tar ➢ Indole is the most widely distributed heterocyle ➢ Indole nucleus is an integral part of thousands of naturally occurring alkaloids, drugs and other compounds. By Dr. Divya Kushwaha 2. Synthesis of Indole 2.1. Fischer Indole Synthesis: ➢ This reaction was discovered in 1983 by Emil Fischer and so far remained the most extensively used method of preparation of indoles. ➢ The synthesis involves cyclization of arylhydrazones under heating conditions in presence of protic acid or lewis acids such as ZnCl2, PCl3, FeCl3, TsOH, HCl, H2SO4, PPA etc. ➢ The starting material arylhydrazoles can be obtained from aldehydes, ketones, keto acids, keto esters and diketones etc. ➢ Reaction produces 2,3-disubtituted products. Unsymmetrical ketones can give a mixture of indoles. 2.2 Madelung Synthesis: ➢ Base catalyzed cyclization of 2-(acylamino)-toluenes under very harsh conditions (typically sodium amide or potassium t-butoxide at 250-300oC). ➢ Limited to the synthesis of simple indoles such as 2-methyl indoles without having any sensitive groups. By Dr. Divya Kushwaha Mechanism: ➢ A modern variant of madelung reaction is performed under milder conditions by the use of alkyllithiums as bases.
    [Show full text]
  • Exploiting Intramolecularity: Exploring Aldehyde-Catalyzed Intermolecular Hydroaminations and Mixed Aminal Chemistry by Didier A
    Exploiting Intramolecularity: Exploring Aldehyde-Catalyzed Intermolecular Hydroaminations and Mixed Aminal Chemistry By Didier Alexandre Bilodeau Thesis submitted to the Faculty of Graduate and Postdoctoral Studies University of Ottawa In partial fulfillment of the requirements for the M.Sc. degree in the Ottawa-Carleton Chemistry Institute University of Ottawa Candidate Supervisor Didier Alexandre Bilodeau Dr. André M. Beauchemin © Didier Alexandre Bilodeau, Ottawa, Canada, 2018 Abstract Hydroamination reactions are very attractive to form new C-N bonds, though broadly applicable synthetic methods do not exist. The hydroamination of unactivated alkenes is especially difficult to accomplish given its negative reaction entropy, as well as potentially being a thermodynamically unfavourable transformation with some substrates. Thus, previously reported systems have often consisted of biased intramolecular systems or metal-catalyzed intermolecular variations operating at low temperatures. Recently, our group discovered that intermolecular Cope-type hydroamination of unactivated alkenes is achievable through the use of aldehydes as catalysts. These organocatalysts act solely through promoting the pre-association of reacting partners, hydroxylamines and allyl amines, in order to induce temporary intramolecularity; thus allowing for very mild reaction conditions and access to important 1,2-Diamine motifs. Aldehyde Catalyzed Intermolecular Cope-Type Hydroamination Catalysis through Temporary Intramolecularity This thesis presents studies expanding upon initial reports of aldehyde-catalyzed Cope-type intermolecular hydroamination. In the scope of these studies standard conditions were developed to compare aldehyde catalytic activity. These evaluations led to further strengthening our understanding of hypothesized trends in aldehydes’ catalytic efficiencies, ii notably the impact of electronic, steric and solvent effects. Furthermore, the possibility of using a catalytic precursor species for hydroamination was evaluated.
    [Show full text]
  • The Synthesis of Tryptophan Derivatives, 2
    Graduate Theses, Dissertations, and Problem Reports 2009 The synthesis of tryptophan derivatives, 2- and/or 3-substituted indoles, progress toward dilemmaones A-C, and synthetic studies towards fistulosin via palladium-catalyzed reductive N- heteroannulation Christopher Andrew Dacko West Virginia University Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation Dacko, Christopher Andrew, "The synthesis of tryptophan derivatives, 2- and/or 3-substituted indoles, progress toward dilemmaones A-C, and synthetic studies towards fistulosin via palladium-catalyzed reductive N-heteroannulation" (2009). Graduate Theses, Dissertations, and Problem Reports. 4454. https://researchrepository.wvu.edu/etd/4454 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. The Synthesis of Tryptophan Derivatives, 2- and/or 3- Substituted Indoles, Progress Toward Dilemmaones A-C, and Synthetic Studies Towards Fistulosin via Palladium-Catalyzed Reductive N-Heteroannulation Christopher Andrew Dacko Dissertation submitted to the Eberly College of Arts and Sciences at West Virginia University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry Björn C.
    [Show full text]
  • Indole & Pyrrole Synthesis: Cliffsnotes (Richter, 2004)
    9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting Disclaimer: Indole: This lecture will only cover methodology for the construction of the indole and pyrrole ring systems, rather than functionalionalization of pre-existing heterocycles, Nature: which would be the topic of another series of lectures. – The most abundant heterocycle in nature – Found in tryptophan, indole-3-acetic acid (plant growth hormone), Partial List of Transforms Discussed: serotonin (neurotransmitter), natural products, drugs – Isolated industrially from coal tar 1. Batcho-Leimgruber Indole Synthesis – Biosynthesis of tryptophan 2. Reissert Indole Synthesis CO H 3. Hegedus Indole Synthesis 15 2 3 serine 4. Fukuyama Indole Synthesis glucose Steps NH Steps N 5. Sugasawa Indole Synthesis 2 H 6. Bischler Indole Synthesis anthranilate 7. Gassman Indole Synthesis tryptophan 8. Fischer Indole Synthesis 9. Japp-Klingemann Indole Synthesis Reactivity: 10. Buchwald Indole Synthesis C–4 C–3 11. Bucherer Carbazole Synthesis C–5 C–2 12. Japp-Maitland Carbazole Synthesis C–6 N 13. Larock Indole Synthesis C–7 H 14. Bartoli Indole Synthesis 15. Castro Indole Synthesis – Isoelectronic with naphthalene (slightly lower stabilization energy) 16. Hemetsberger Indole Synthesis – Indole has a higher stabilization energy than benzene 17. Mori-Ban Indole Synthesis – Very weakly basic: pKa of protonated indole: –2.4 18. Graebe-Ullmann Carbazole Synthesis – Protonation occurs at C–3 preferentially 19. Madelung Indole Synthesis – Easily oxidized (atmospheric oxygen) – very electron rich 20. Nenitzescu Indole Synthesis – Less prone to oxidation of EWG's on the ring – less electron rich 21. Piloty Pyrrole Synthesis – Electrophilic attack occurs at C–3 (site of most electron density) 13 22.
    [Show full text]
  • Copper-Catalysed Amination of Alkyl Iodides Enabled by Halogen-Atom Transfer
    ARTICLES https://doi.org/10.1038/s41929-021-00652-8 Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer Bartosz Górski1,3, Anne-Laure Barthelemy 1,3, James J. Douglas 2, Fabio Juliá 1 ✉ and Daniele Leonori 1 ✉ Despite the fact that nucleophilic displacement (SN2) of alkyl halides with nitrogen nucleophiles is one of the first reactions introduced in organic chemistry teaching, its practical utilization is largely limited to unhindered (primary) or activated (α-carbonyl, benzylic) substrates. Here, we demonstrate an alternative amination strategy where alkyl iodides are used as radical precursors instead of electrophiles. Use of α-aminoalkyl radicals enables the efficient conversion of the iodides into the corresponding alkyl radical by halogen-atom transfer, while copper catalysis assembles the sp3 C–N bonds at room temperature. The process provides SN2-like programmability, and application in late-stage functionalization of several densely functionalized pharmaceuticals demonstrates its utility in the preparation of valuable N-alkylated drug analogues. itrogen-rich molecules form the structural basis of almost species10. The potential of these two elementary steps to assemble a every pharmaceutical and agrochemical lead, as well as broad array of sp3 C–Y bonds (Y = C, N, O, S, halogen) represents a many other high-value products like food additives and powerful opportunity for modular fragment coupling11. N 1 organic materials . A large fraction of these chemotypes contain Despite these prominent features, copper catalysis has seen lim- bonds between nitrogenated residues and saturated carbons, which ited applications to the amination of unactivated alkyl halides12,13. makes the development of methods for sp3 C–N bond construction As shown in Fig.
    [Show full text]
  • Spontaneous Macrocyclization Through Multiple Dynamic Cyclic Aminal Formation Chemcomm
    Volume 57 Number 10 4 February 2021 Pages 1167–1268 ChemComm Chemical Communications rsc.li/chemcomm ISSN 1359-7345 COMMUNICATION Ezequiel Pérez-Inestrosa, Ignacio Alfonso et al . Spontaneous macrocyclization through multiple dynamic cyclic aminal formation ChemComm View Article Online COMMUNICATION View Journal | View Issue Spontaneous macrocyclization through multiple dynamic cyclic aminal formation† Cite this: Chem. Commun.,2021, 57, 1190 a bc bc Daniel Carbajo,‡ Antonio Jesu´s Ruiz-Sa´nchez, ‡ Francisco Na´jera, bc a Received 29th October 2020, Ezequiel Pe´rez-Inestrosa * and Ignacio Alfonso * Accepted 30th December 2020 DOI: 10.1039/d0cc07184f rsc.li/chemcomm The use of aminals in dynamic covalent chemistry is slightly under- diamines and carbonyl compounds. This reversible reaction explored, probably due to their inherent instability. Here we report has been applied to the synthesis of open-chain unsym- the spontaneous [2+2] macrocyclization of tetrakis(aminals). Their metrical aminals,14 the controlled evaporation of volatile car- unexpected stability and structural modularity, the dynamic nature of bonyl compounds,8,22 induce movement through a molecular 23 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. the connections and their water tolerance make them appealing systems track and the preparation of a dynamic chemical network that for future applications as stimulus-responsive materials. self-directs its amplification.24 Inspired by a previous research25 we envisioned to study the Dynamic covalent chemistry (DCvC) has experienced an important reaction between amino and aldehyde building blocks allowing development in the last two decades, based on the use of reversible a large structural and functional diversity, including the possible covalent bonds to generate exchanging mixtures under formation of dynamic aminals.
    [Show full text]