DOCSLIB.ORG

Research Article Stereoselective Synthesis of (+)- -Conhydrine from R

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Research Article Stereoselective Synthesis of (+)- -Conhydrine from R Hindawi Publishing Corporation Organic Chemistry International Volume 2014, Article ID 982716, 7 pages http://dx.doi.org/10.1155/2014/982716 Research Article Stereoselective Synthesis of (+)--Conhydrine from R-(+)-Glyceraldehyde Nageshwar Rao Penumati and Nagaiah Kommu Fine Chemicals Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India Correspondence should be addressed to Nagaiah Kommu; [email protected] Received 22 August 2014; Revised 27 September 2014; Accepted 27 September 2014; Published 20 October 2014 Academic Editor: Ashraf Aly Shehata Copyright © 2014 N. R. Penumati and N. Kommu. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Stereoselective synthesis of (+)--Conhydrine was accomplished from protected (R)-(+)-glyceraldehyde, a familiar carbohydrate predecessor. Our synthetic strategy featured the following two key reactions. One is Zn-mediated stereoselective aza-Barbier reaction of imine 6 with allyl bromide to afford chiral homoallylic amine 7, and the other is ring-closing metathesis. 1. Introduction In view of the interesting biological and structural prop- erties, especially the nitrogen containing alkaloids makes (+)- Exploiting natural products to ascertain a lead has always -Conhydrine 1 as an attractive and challenging synthetic tar- been important technique in drug discovery. Nature pro- get. As mentioned above (+)--Conhydrine 1 was synthesized vides a rich source of bioactive compounds with significant from various synthetic routes which involve a large number biological activity and has therefore received considerable of steps to obtain the target molecule. Thus development attention from the synthetic organic communities. The major of new methods for the synthesis of (+)--Conhydrine 1 class of biologically active molecules containing substituted constitutes an area of current interest. Herein, an efficient piperidines has been widely present in the nature. The efforts synthesis of (+)--Conhydrine 1 has been designed starting to find a short and high yielding synthetic route for this from 2,3-isopropylidene-R-(+)-Glyceraldehyde, by means of class of natural products were always a contemporary interest. Zn-mediated stereoselective Barbier allylation as a key step, Some of the hydroxylated piperidine alkaloids are reported to which was developed previously for the synthesis of different be highly toxic and have drawn significant attention through natural products in our laboratory [19–22]. To the best of our their biological activity [1–3]. knowledge synthesis of (+)--Conhydrine via aza-Barbier Conhydrineisoneoftheclassesofalkaloidswhichwere zinc allylation was not reported so far. isolated by Wertheim from the poisonous plant, Conium maculatum L[4], in 1856. A highly fatal toxin causing 2. Materials and Methods paralysis of the skeletal musculature, 2-(1-hydroxyalkyl)- piperidine is a recurrent unit in many alkaloids such as All reagents were purchased from Aldrich (Sigma-Aldrich, Homopumiliotoxin 223 G 2,Slaframine3,andCastanosper- Bangalore, India). All reactions were monitored by TLC, mine 4 (Figure 1).Sincethepioneeringstudiesonthe performed on silica gel glass plates containing 60 F-254. synthesis of (+)--Conhydrine 1 by Galinovasky and Mulley Column chromatography was performed with Merck 60– [5], various methods have been reported normally based on 120 mesh silica gel. IR spectra were recorded on a Perkin- 1 auxiliarysupportedorchiralpoolapproach[6–18]. Elmer RX-1 FT-IR system. H NMR spectra were recorded on 2 Organic Chemistry International OH HO -OCH), 3.80 (d, J =6.0Hz,1H,HofOCH2), 3.71 (d, J = H 6.8 Hz, 1H, H of OCH2), 3.61 (d, J=5.9 Hz, 1H, allylic NCH2), 3.55 (q, J=8.1 Hz, 1H, allylic NCH2), 2.70 (q, J =5.9 Hz, 1H homoallylic NCH), 2.35 (q, J =7.3Hz,2H,allylicCH2), 1.43 HN N 13 (s, 6H, 2xCH3); C NMR (75 MHz, CDCl3): 137.0, 134.9, 117.7, (+)--Conhydrine 1 Homopumiliotoxin 223 G 2 115.6, 108.6, 77.6, 66.6, 57.9, 50.3, 35.0, 25.3, 25.2; IR (neat): 3404, 3068, 3028, 2926, 2855, 2801, 1640, 1494, 1417, 1368, OAc OH OH −1 H H 1250,1069,1029,994cm ;ESIMS:m/z = 212 (M+H); HRMS HO (ESI): m/z calculated for C12H22NO2 (M+H) 212.1650, found 212.1652. N N H2N HO 2.2. tert-Butyl-allyl((S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl) (−) Slaframine 3 (−) Castanospermine 4 but-3-enyl) Carbamate (8). To a stirred solution of amine 7a (12.7 g, 60 mmol) in 100 mL dry DCM were added triethy- Figure 1: Some important piperidine, quinolizidine and indolizi- lamine (12.12 g, 120 mmol) and catalytic amount of DMAP dine alkaloids. (1 mol %). The reaction mixture was allowed to stir for 30 min ∘ at 0 C. A solution of Boc2O(14.4g,66mmol)in50mL dry DCM was added. The solution was allowed to warm to 13 Bruker-300 MHz spectrometer; CNMR(75MHz)spectra room temperature, stirred for 5 h. The reaction mixture was were recorded on Bruker-Avance spectrometer. Chemical partitioned between water and EtOAc. The combined organic shifts () are reported in parts per million (ppm) downfield layer was washed with brine, dried over anhydrous sodium from internal TMS standard. Peaks are labeled as singlet (s), sulfate, and evaporated. The residue was purified by column doublet (d), triplet (t), quartet (q), and multiplet (m). ESI chromatography (hexane/EtOAc, 9.5 : 0.5) to afford the pure 8 spectra recorded on Micro mass, Quattro LC using ESI+ Boc-protected amine (14.7 g, 79%) as pale yellowish oil. Rf = [] 27 1 software with a capillary voltage of 3.98 kV and ESI mode 0.57 (1 : 9 EtOAc and hexane). D =+21.9(c 1, CHCl3); H positive ion trap detector. Optical rotations were measured NMR(300MHz,CDCl3): 5.90–5.63 (m, 2H, 2xCH of olefin), on Horiba-SEPA-300 digital polarimeter. 5.17–4.99 (m, 4H, 2xCH2 of olefin), 4.14 (q, J =7.8Hz,1H, -OCH), 3.97–3.92 (m, 1H, homoallylic NCH), 3.83 (d, J = 2.1. (S)-N-Allyl-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)but-3-en- 5.9 Hz, 1H, H of OCH2), 3.69 (d, J =6.5Hz,1H,HofOCH2), 1-amine (7). To a stirred solution of glyceraldehyde 5 (13 g, 3.62 (d, J =5.9Hz,1H,allylicNCH2), 3.56 (q, J =8.0Hz, 100 mmol) in dry ether (150 mL) was added anhydrous 1H, allylic NCH2), 2.49–2.46 (m, 1H, allylic CH2), 2.40–2.32 (m, 1H, allylic CH2), 1.47 (s, 3H, -CH3), 1.43 (s, 6H, 2xCH3), magnesium sulfate (20 g). The mixture was cooled in an ice 13 bath and allyl amine (5.75 g, 101 mmol) was added dropwise 1.40 (s, 3H, -CH3), 1.31 (s, 3H, -CH3); C NMR (75 MHz, under nitrogen atmosphere. After stirring for 3 h, the reac- CDCl3): 154.0, 136.4, 135.0, 117.2, 116.8, 109.5, 80.8, 77.4, 66.6, 34.2, 28.2, 26.8; IR (neat): 3078, 2981, 2933, 2693, 1644, 1455, tion mixture was filtered and concentrated under reduced −1 6 1399, 1368, 1312, 1251, 1156, 1066, 994 cm ;ESIMS(m/z): pressure to obtain imine (14 g, 82%) as colorless oil. The + 6 334 (M+Na) ; HRMS (ESI): m/z calculated for C17H29NO4 obtained imine was further used in the next step without + purification. (M+Na) 334.1994, found. 334.2008. To a stirred suspension of activated zinc (10.8 g, 166 mmol) in 100 mL of dry THF was added solution of 2.3. tert-Butyl-allyl-(2S,3S)-1,2-dihydroxyhex-5-en-3-ylcarba- imine 6 (14 g, 83 mmol) in 50 mL of dry THF under nitrogen mate (9). To a stirred solution of Boc–protected amine ∘ atmosphere at 0 C. After 15 min, allyl bromide (19.9 g, 8a (12.44 g, 40 mmol) in MeOH (75 mL), PTSA (0.688 g, ∘ 0.166 mol) was added dropwise over 15 min at 0 Cand 0.4 mmol) was added at room temperature and stirred reaction mixture was stirred for 10 h. After completion for 12 h under nitrogen atmosphere to completion of the of the reaction (monitored by TLC), the reaction was reaction. The reaction mixture was quenched with aqueous quenched with saturated aqueous ammonium chloride saturated NaHCO3 (10 mL) solution, concentrated under ∘ solution (20 mL) at 0 C over 15 min. After being stirred reduced pressure. The crude was partitioned between EtOAc for 1 h, the mixture was filtered through celite pad. The and water. The organic layer was washed with brine and filtrate was concentrated under reduced pressure. The dried over anhydrous Na2SO4.Thesolutionwasconcentrated crude product was partitioned between water and ethyl under reduced pressure and residue was subjected to column acetate. The combined organic layer was washed with brine, chromatography (hexane/EtOAc, 7 : 3) to afford diol 9 (9.5 g, dried over anhydrous Na2SO4, and concentrated under 88%) as yellowish oil. Rf = 0.45 (1 : 1 EtOAc and hexane). reduced pressure. The residue was purified by column [] 27 1 D =+1.9(c 1, CHCl3); H NMR (300 MHz, CDCl3): chromatography (hexane/EtOAc, 2 : 8) to afford the pure 5.91–5.71 (m, 2H, 2xCH of olefin), 5.30–5.14 (m, 4H, 2xCH2 7a compound amine (14 g, 80%) as colorless oil. Rf =0.12 of olefin), 4.16 (q, J = 8.1 Hz, 1H, -OCH), 3.94–3.88 (m, 1H, [] 27 1 (9 : 1 EtOAc and hexane) D =+18.7(c 1, CHCl3); H homoallylic NCH), 3.78 (d, J =7.9Hz,1H,HofOCH2), 3.68 NMR(300MHz,CDCl3): 5.79–5.65 (m, 2H, 2xCH of olefin), (d, J =7.5Hz,1H,HofOCH2), 3.57 (d, J = 5.0 Hz, 1H, allylic 5.17–4.93 (m, 4H, 2xCH2 of olefin), 4.10 (q, J =7.5Hz,1H, NCH2), 3.47 (q, J =8.5Hz,1H,allylicNCH2), 2.43 (d, J = Organic Chemistry International 3 3.0 Hz, 1H, allylic CH2), 2.34 (dd, J = 4.5, 5.3 Hz, 1H, allylic 1H, allylic NCH2), 3.53 (d, J =4.8Hz,1H,allylicNCH2), 2.60– CH2), 1.47 (s, 3H, -CH3), 1.40 (s, 3H, -CH3), 1.31 (s, 3H, - 2.51 (m, 1H, allylic CH2), 2.38–2.30 (m, 1H, allylic CH2), 1.42 13 CH3); C NMR (75 MHz, CDCl3): 153.5, 135.4, 134.9, 117.3, (s, 9H, t-butyl), 1.26–1.22 (m, 2H, CH2), 0.94 (t, J =7.8Hz, 13 116.5, 80.5, 73.4, 64.0, 58.2, 33.5, 28.2; IR (neat): 3412, 3078, 3 3 −1 3H, CH ); C NMR (75 MHz, CDCl ): 154.0, 135.8, 135.0, 2976,2928,1667,1456,1407,1366,1330,1250,1179,996cm ; + 116.9, 116.5, 79.9, 51.3, 30.7, 28.2, 27.0, 10.4; IR (neat): 3386, ESI MS (m/z): 272 (M+H) ; HRMS (ESI): m/z calculated for 3077, 2966, 2925, 2856, 1668, 1456, 1414, 1368, 1254, 1166, + −1 + C14H26NO4 (M+H) 272.1861, found 272.1874.
Load more

Recommended publications
  • Enantioselective Synthesis of Bioactive Molecules Via
    ENANTIOSELECTIVE SYNTHESIS OF BIOACTIVE MOLECULES VIA ASYMMETRIC HYDROXYLATIONS, AMINOALLYLATION AND SYNTHETIC METHODOLOGIES INVOLVING ACTIVATION OF C-H BONDS A THESIS SUBMITTED TO THE UNIVERSITY OF PUNE FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY By TANVEER MAHAMADALI SHAIKH UNDER THE GUIDANCE Dr. A. Sudalai Chemical Engineering and Process Development Division National Chemical Laboratory Pune-411008, INDIA November 2009 Dedicated to my beloved parents & brother Raziya Mahamadali & Sameer NATIONAL CHEMICAL LABOATORY Dr. A. Sudalai Scientist Chemical Engineering & Process Development Division, Pune – 411 008, India Phone (O) : 0091-20-25902174, Fax: 0091-20-25902676, e-mail: [email protected] CERTIFICATE Certified that the work incorporated in the thesis entitled “Enantioselective Synthesis of Bioactive Molecules via Asymmetric Hydroxylations, Aminoallylation and Synthetic Methodologies Involving Activation of C-H Bonds” was carried out by the candidate under my supervision. Such material as had been obtained from other sources has been duly acknowledged in the thesis. November 2009 (Dr. A. Sudalai) Pune Research Supervisor NATIONAL CHEMICAL LABORATORY DECLARATION I here by declare that the thesis entitled “Enantioselective Synthesis of Bioactive Molecules via Asymmetric Hydroxylations, Aminoallylation and Synthetic Methodologies Involving Activation of C-H Bonds” submitted for the degree of Doctor of Philosophy in Chemistry to the University of Pune, has not been submitted by me to any other university or institution. This
    [Show full text]
  • SYNTHESIS Journal Of
    Journal of Synthetic Organic SYNTHESIS Chemistry REPRINT With compliments of the Author Thieme SHORT REVIEW ▌2551 short review Conhydrine: An Account of Isolation, Biological Perspectives and Synthesis l ChinmayConhydrine: A Short Review Bhat,*a Sandesh T. Bugde,b Santosh G. Tilve*b a Centre for Nano and Material Sciences, Jain Global Campus, Jakkasandara Post, Kanakapura Road, Ramanagara District, Karnataka 562 112, India b Department of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India Fax +91(832)6519317; Fax +91(965)7962641; E-mail: [email protected]; E-mail: [email protected] Received: 23.05.2014; Accepted after revision: 06.08.2014 Abstract: Conhydrine is a naturally occurring 2-substituted piperi- dine alkaloid from the plant Conium maculatum L that exists in four different forms and is known for its high toxicity. This article focus- es on the synthesis of conhydrine as its medicinal applications are limited due to its high toxicity. The various asymmetric methods de- veloped for the synthesis of conhydrine are classified based on the methodology: the chiral pool method, the chiral auixiliary method, and asymmetric catalysis. A brief overview of the complete synthet- ic coverage of conhydrine (1948–2014) in different isomeric forms is given. Dr. Chinmay Bhat was born in Sirsi, Karnataka, India. He moved to 1 Introduction the Department of Chemistry, Goa University in 2006 for his M.Sc. 2 Isolation and Biological Perspectives in chemistry. After qualifying CSIR-NET-JRF in 2007, he joined the 3 Synthesis group of Prof. Santosh Tilve in 2008 in the doctoral programme and 3.1 Chiral Pool Methods worked on the asymmetric synthesis of natural products.
    [Show full text]
  • Ethno-Botanic Treatments for Paralysis (Falij) in the Middle East
    Chinese Medicine, 2012, 3, 157-166 http://dx.doi.org/10.4236/cm.2012.34025 Published Online December 2012 (http://www.SciRP.org/journal/cm) Ethno-Botanic Treatments for Paralysis (Falij) in the Middle East Aref Abu-Rabia Ben-Gurion University of the Negev, Beer-Sheva, Israel Email: [email protected] Received April 12, 2012; revised July 24, 2012; accepted August 9, 2012 ABSTRACT The goal of this paper is to describe beliefs and treatments for specific forms of Paralysis (falij) and other nervous dis- orders in the Middle East. Themes to be investigated include, the traditional medicinal practices used to treat Paralysis, as well as their curative methods using traditional herbal medicine. This paper is based on first and secondary sources; interviews with traditional healers, as well as patients who suffered from these disorders. The author found 152 plants species belonging to 58 families (see Appendix) that treat paralysis and other nervous disorders. The most significant plants species are found in the six families of herbs: Labiatae, Compositae, Umbelliferae, Papilionaceae, Liliaceae, and Solanaceae. Keywords: Paralysis; Ethno Botanic Medicine; Middle East 1. Introduction peak in the thirteenth through sixteenth centuries, and later declined during the seventeenth through the nine- The use of plant medicines in the Middle East has his- teenth centuries. Medical information grounded in Arab torical roots in Ancient Arabic medicine, which itself classical medical scholarship of the Middle Ages was was influenced by the ancient medicinal practices of gradually transferred to local traditional healers and to Mesopotamia, Greece, Rome, Persia, and India. During the general public. Arabs relied primarily on their tradi- the Umayyad rule (661-750 A.D.), translations of ancient tional medicine [2].
    [Show full text]
  • Maculatum L.).-Ii Evidence for a Rapid Turnover of the Major Alkaloids
    Phytochcmistry.1961. Vol. 1. pp. 38to 46. Pqamon PressLtd. Printedin lh&id THE ALKALOIDS OF HEMLOCK (CONIUM MACULATUM L.).-II EVIDENCE FOR A RAPID TURNOVER OF THE MAJOR ALKALOIDS J. W. FAIRBAIRN and P. N. SUWAL School of Pharmacy, Brunswick Square, London, W.C.1 (Received 14 February 1961) Abstract-Previous work, based on analyses of samples of &loping fruits collected at weekly intervatS, has been confirmed. Samples wem also collected at 4-hourly and 2-hourly intervals and analyses showed that remarkably rapid changes in the alkaloidal picture took place at short intervals during 24 hr. Further- more, as the coniine (I) content increased, the y-coniceine (II) content decreased and vice versa. This interrelationship was particularly marked during the critical stages of pericarp development, but was not obvious during the development of the vegetative parts, where y-coniceine and conhydrine (III) were the only known alkaloids detected. Since coniine and yconiceine differ only by two hydrogen atoms, it is suggested that these two alkaloids are involved in oxidation-reduction processes in the developing pericarp. The occurrence of the minor alkaloids conhydriie and N-methyl coniine (1V) and the presence of some unknown alkaloids are also reported and commented on. INTRODUCTION IN A previous communication’ it was shown that the total alkaloidal content and the CH(OH)CH$H, proportions of individual alkaloids in hemlock fruit varied with the development of the fruit and with the season. It was suggested that y-coniceine (11) was the precursor of the saturated alkaloids, such as coniine (I), and that this change, which appeared to be rever- sible, is associated with active grbwth.
    [Show full text]
  • Identification and Determination of Unusual Functional Groups
    IDENTIFICATION AND DETERMINATION OF UNUSUAL FUNCTIONAL GROUPS E. SAWICKI U.S. Department of Health, Education and Weifare, Cincinnati, Ohio 45226, U.S.A. INTRODUCTION Many of the unusual and unfamiliar analytical methods of yesterday have become the common methods of today. Therefore, when we speak of "unusual" functional groups we refer to those that are now novel but that may evolve with time and use into the usual and well-known. With advances in knowledge of the physical and chemical properties of organic molecules, new types of functional groups are being found, some of which appear strange and unusual at the moment while others are more sharply delineated sub-divisions of well-known functional groups. The sub-divisional functional group contains the original functional group with additional atoms; for example, one sub-division of a ketonic C =Ü func­ tional group is the -CHz-CO-CH3 grouping. Methods of analysis for compounds containing such a sub-divisional grouping are usually more highly selective. Examples will be given of some well-known families of compounds, each theoretically containing a common functional group which, until recently, had not been exploited for analytical purposes. Environmental health problems have proliferated tremendously in the past 40 years mainly because of the growing complex.ity of the chemical environment in which we live. Examples of this phenomenon are smog and the growing dinginess of the urban atmosphere; this dinginess indicates the accelerating infiltration of our air by man-made pollutants. Because of the increasing chemical pollution of our environment and its sometimes adverse effect on man, other life forms, and man-made objects, it is necessary first to determine the composition of the complicated mixtures with which we are in contact and then to decrease the concentrations ofthe harmful compounds.
    [Show full text]
  • Enzymatic Kinetic Resolution of 2-Piperidineethanol for the Enantioselective Targeted and Diversity Oriented Synthesis "227
    ReviewReview EnzymaticEnzymatic KineticKinetic ResolutionResolution ofof 2-Piperidineethanol2-Piperidineethanol forfor thethe EnantioselectiveEnantioselective TargetedTargeted andand DiversityDiversity OrientedOriented SynthesisSynthesis †† DarioDario PerdicchiaPerdicchia *,*, MichaelMichael S.S. Christodoulou,Christodoulou, GaiaGaia Fumagalli,Fumagalli, FrancescoFrancescoCalogero, Calogero, CristinaCristina MarucciMarucci andand DanieleDaniele PassarellaPassarella ** Received:Received: 22 NovemberNovember 2015;2015; Accepted:Accepted: 1515 DecemberDecember 2015;2015; Published:Published: 242015 December 2015 AcademicAcademic Editor:Editor: VladimírVladimír KˇrenKřen DipartimentoDipartimento didi Chimica,Chimica, UniversitaUniversita deglidegli StudiStudi didi Milano,Milano,Via Via Golgi Golgi 19, 19, 20133 20133 Milano, Milano, Italy; Italy; [email protected]@gmail.com (M.S.C.);(M.S.C.); [email protected]@unimi.it (G.F.);(G.F.); [email protected]@gmail.com (F.C.);(F.C.); [email protected]@unimi.it (C.M.)(C.M.) ** Correspondences:Correspondences: [email protected] [email protected] (D (D.Pe.);.Pe.); [email protected] [email protected] (D.Pa.); (D.Pa.); Tel.:Tel.: +39-02-5031-4155 +39-02-5031-4155 (D.Pe.); (D.Pe.); +39-02-5031-4081 +39-02-5031-4081 (D.Pa.); (D.Pa.); Fax:Fax: +39-02-5031-4139 +39-02-5031-4139 (D.Pe.); (D.Pe.); +39-02-5031-4078 +39-02-5031-4078 (D.Pa.) (D.Pa.) †† This This paper paper is is dedicated dedicated to to the the memory memory of of Brun Brunoo Danieli, Danieli, Professor Professor of of Organic Organic Chemistry, Chemistry, UniversitàUniversità degli degli Studi Studi di di Milano, Milano, 20122 20122 Milano, Milano, Italy. Italy. Abstract:Abstract: 2-Piperidineethanol2-Piperidineethanol ((11)) andand itsits correspondingcorresponding NN-protected-protected aldehydealdehyde ((22)) werewere usedused forfor thethe synthesissynthesis ofof severalseveral natural natural and and synthetic synthetic compounds.
    [Show full text]
  • The Anti Selective Aldol Addition of Ketones to Aldehydes Via N-Amino Cyclic
    The Anti Selective Aldol Addition of Ketones to Aldehydes via N-Amino Cyclic Carbamate Chiral Auxiliaries and the Asymmetric Total Synthesis of (+)- and (-)- Mefloquine Hydrochloride by John Derrick Knight Department of Chemistry Duke University Date:_______________________ Approved: ___________________________ Don M. Coltart, Co-Supervisor ___________________________ Steven W. Baldwin, Co-Supervisor ___________________________ Jiyong Hong ___________________________ Dewey G. McCafferty Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the Graduate School of Duke University 2012 ABSTRACT The Anti Selective Aldol Addition of Ketones to Aldehydes via N-Amino Cyclic Carbamate Chiral Auxiliaries and the Asymmetric Total Synthesis of (+)- and (-)- Mefloquine Hydrochloride by John Derrick Knight Department of Chemistry Duke University Date:_______________________ Approved: ___________________________ Don M. Coltart, Co-Supervisor ___________________________ Steven W. Baldwin, Co-Supervisor ___________________________ Jiyong Hong ___________________________ Dewey G. McCafferty An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the Graduate School of Duke University 2012 Copyright by John Derrick Knight 2012 Abstract In the first part of this dissertation, the first asymmetric anti selective aldol addition of a ketone-derived donor that is independent of the structure of the ketone is described. This transformation is facilitated by the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. Under certain conditions, this transformation not only exhibits near perfect anti selectivity and enantioselectivity but also does so via thermodynamic control. Simple manipulation of the reaction conditions allows for the O-benzylation of the prepared aldol products and the subsequent removal of the ACC auxiliary to give the β-benzyloxy ketone.
    [Show full text]
  • Dynamics and Catalytic Resolution of Selected Chiral Organolithiums Timothy Kum Beng University of Arkansas, Fayetteville
    University of Arkansas, Fayetteville ScholarWorks@UARK Theses and Dissertations 12-2011 Dynamics and Catalytic Resolution of Selected Chiral Organolithiums Timothy Kum Beng University of Arkansas, Fayetteville Follow this and additional works at: http://scholarworks.uark.edu/etd Part of the Analytical Chemistry Commons, and the Organic Chemistry Commons Recommended Citation Beng, Timothy Kum, "Dynamics and Catalytic Resolution of Selected Chiral Organolithiums" (2011). Theses and Dissertations. 212. http://scholarworks.uark.edu/etd/212 This Dissertation is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of ScholarWorks@UARK. For more information, please contact [email protected], [email protected]. DYNAMICS AND CATALYTIC RESOLUTION OF SELECTED CHIRAL ORGANOLITHIUMS DYNAMICS AND CATALYTIC RESOLUTION OF SELECTED CHIRAL ORGANOLITHIUMS A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry By Timothy Kum Beng University of Buea Bachelor of Science in Chemistry, 2001 East Tennessee State University Master of Science in Chemistry, 2004 December 2011 University of Arkansas ABSTRACT One of the most important developments of the last decade has been the emergence of new methods to dynamically resolve racemic organolithiums using stoichiometric amounts of the chiral ligand. When this concept is implemented successfully, it obviates the need for covalently attached chiral auxiliary based methods, asymmetric deprotonation, and asymmetric synthesis of a precursor stannane as ways to access enantioenriched organolithium compounds for use in asymmetric synthesis. Since certain electrophiles consume the chiral ligand, it is desirable to render this process catalytic in the chiral ligand.
    [Show full text]
  • Biosynthesis of Cherylline Using Doubly-Labled Norbelladine-Type Precursors James Lee Amigo Chan Iowa State University
    Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1973 Biosynthesis of cherylline using doubly-labled norbelladine-type precursors James Lee Amigo Chan Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Organic Chemistry Commons Recommended Citation Chan, James Lee Amigo, "Biosynthesis of cherylline using doubly-labled norbelladine-type precursors " (1973). Retrospective Theses and Dissertations. 5064. https://lib.dr.iastate.edu/rtd/5064 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. INFORMATION TO USERS This material was produced from a microfilm copy of the original document. While the most advanced technological means to photograph and reproduce this document have been used, the quality is heavily dependent upon the quality of the original submitted. The following explanation of techniques is provided to help you understand markings or patterns which may appear on this reproduction. 1. The sign or "target" for pages apparently lacking from the document photographed is "Missing Page(s)". If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting thru an image and duplicating adjacent pages to insure you complete continuity. 2. When an image on the film is obliterated with a large round black mark, it is an indication that the photographer suspected that the copy may have moved during exposure and thus cause a blurred image.
    [Show full text]
  • Research Project Thesis
    Research Project Thesis A novel approach to the total synthesis of the piperidine alkaloid (+)-α- conhydrine Iain Alisdair McGeoch Supervisor: Dr. Andrew Sutherland Abstract Alkaloids are known for their broad spectrum of pharmacological activity. The piperidine alkaloid conhydrine is an alkaloid for which pharmacological roles have not yet been investigated, although it is known that other alkaloids including the 2-(1- hydroxyalkyl)piperidine motif in conhydrine exhibit important therapeutic activities, e.g. as antiviral or antitumour agents. A novel approach to the total synthesis of a particular conhydrine diastereomer, (+)-α- conhydrine, will be examined. The synthetic strategy chosen will proceed via two key transformations: an ether-directed, palladium(II)-catalysed aza-Claisen rearrangement as the source of stereoselectivity, and a ring-closing metathesis that will form the piperidine core of the target molecule. The confirmation of the validity of the methodology employed in the synthesis of (+)-α-conhydrine could lead into the application of the same methodology to the synthesis of other natural products or bioactive molecules exhibiting similar structural patterns to that of conhydrine. 1 Acknowledgements I would like to thank Dr. Andrew Sutherland for giving me the chance of undertaking a challenging project within his research group. Furthermore, his day-to-day guidance and his full attention on problems I encountered during the course of the project were invaluable. Equally important was the faultless project supervision of Andrew Jamieson, an excellent person and a professional in every single aspect. I have learnt much more than I expected from the project, both at a practical and theoretical level. Finally, I would also like to thank the rest of the Henderson laboratory group for its help and for creating a great environment to work in.
    [Show full text]
  • The Killer of Socrates: Coniine and Related Alkaloids in the Plant Kingdom
    molecules Review The killer of Socrates: Coniine and Related Alkaloids in the Plant Kingdom Hannu Hotti and Heiko Rischer * ID VTT Technical Research Centre of Finland Ltd., P.O. Box 1000, 02044 Espoo, Finland; [email protected] * Correspondence: heiko.rischer@vtt.fi; Tel.: +358-40-720-6834 Received: 27 October 2017; Accepted: 12 November 2017; Published: 14 November 2017 Abstract: Coniine, a polyketide-derived alkaloid, is poisonous to humans and animals. It is a nicotinic acetylcholine receptor antagonist, which leads to inhibition of the nervous system, eventually causing death by suffocation in mammals. Coniine’s most famous victim is Socrates who was sentenced to death by poison chalice containing poison hemlock in 399 BC. In chemistry, coniine holds two historical records: It is the first alkaloid the chemical structure of which was established (in 1881), and that was chemically synthesized (in 1886). In plants, coniine and twelve closely related alkaloids are known from poison hemlock (Conium maculatum L.), and several Sarracenia and Aloe species. Recent work confirmed its biosynthetic polyketide origin. Biosynthesis commences by carbon backbone formation from butyryl-CoA and two malonyl-CoA building blocks catalyzed by polyketide synthase. A transamination reaction incorporates nitrogen from L-alanine and non-enzymatic cyclization leads to γ-coniceine, the first hemlock alkaloid in the pathway. Ultimately, reduction of γ-coniceine to coniine is facilitated by NADPH-dependent γ-coniceine reductase. Although coniine is notorious for its toxicity, there is no consensus on its ecological roles, especially in the carnivorous pitcher plants where it occurs. Lately there has been renewed interest in coniine’s medical uses particularly for pain relief without an addictive side effect.
    [Show full text]
  • Computational Analysis, Visualization and Text Mining of Metabolic Networks
    COMPUTATIONAL ANALYSIS, VISUALIZATION AND TEXT MINING OF METABOLIC NETWORKS by XINJIAN QI Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr. Gültekin Özsoyoğlu Department of Electrical Engineering and Computer Science CASE WESTERN RESERVE UNIVERSITY January, 2014 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of ____Xinjian Qi____________________________________________ candidate for the Doctor of Philosophy___degree *. (signed) __Dr. Gültekin Özsoyoğlu__________________________ (chair of the committee) __________Dr. Andy Podgurski______________________________ __________Dr. M. Cenk Cavusoğlu__________________________ __________Dr. Nicola Lai___________________________________ __________Dr. Z. Meral Özsoyoğlu__________________________ ___________________________________________________________ (date) _____June 24, 2013____ *We also certify that written approval has been obtained for any proprietary material contained therein. Table of Contents Table of Contents ................................................................................................................ 1 List of Tables ...................................................................................................................... 6 List of Figures ..................................................................................................................... 7 Acknowledgements ..........................................................................................................
    [Show full text]