DOCSLIB.ORG

New Methodologies for the Asymmetric Syntheses of Amines and Nitrogen Heterocycles from Enantiopure Sulfinimines

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
New Methodologies for the Asymmetric Syntheses of Amines and Nitrogen Heterocycles from Enantiopure Sulfinimines NEW METHODOLOGIES FOR THE ASYMMETRIC SYNTHESES OF AMINES AND NITROGEN HETEROCYCLES FROM ENANTIOPURE SULFINIMINES (N-SULFINYL IMINES) A Dissertation Submitted to The Temple University Graduate Board In Partial Fulfillment of the Requirement for the Degree DOCTOR OF PHILOSOPHY By Hui Qiu January, 2012 Examining Committee Member: Dr. Franklin A. Davis, Department of Chemistry, Temple University Dr. Rodrigo B. Andrade, Department of Chemistry, Temple University Dr. Chris Schafmeister, Department of Chemistry, Temple University Dr. Kevin Cannon Department of Chemistry, Pennsylvania State University © by Hui Qiu 2012 All Rights Reserved ii ABSTRACT New methodologies for the asymmetric syntheses of amines and nitrogen heterocycles from enantiopure sulfinimines (N-sulfinyl imines) By Hui Qiu Doctor of Philosophy Temple University, January, 2012 Doctoral Advisory Committee Chair: Professor Franklin A. Davis, Ph.D. The objective of this research was to development new methodologies for the asymmetric syntheses of amine and natural products from enantiopure sulfinimines (N- sulfinyl imines). In this context, new methods was devised for the asymmetric synthesis of 2,5-cis and trans-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates, prepared by an intramolecular metal carbenoid N-H insertion from a sulfinimine derived -amino -diazo -ketophosphonate. Horner-Wadsworth-Emmos reaction of the 3-oxo pyrrolidine 2-phosphonates and aldehydes provided Pyrrolidine enones. Hydrogenation (Pd/H2) of the pyrrolidine enones gave cis-2,5-disubstituted pyrrolidines. Luche reduction the pyrrolidine enones followed by a TFA-NaBH3CN mediated hydroxy iii directed reduction provided the 2,5-trans products. (+)-Preussin, a potent antiviral and antitumor agent was prepared in 9 steps in 28% overall yield from the sulfinimine. An acid catalyzed intramolecular Mannich cyclization of a sulfinimine-derived N- sulfinyl syn--methyl -amino ketones was employed for the asymmetric synthesis of 2,3,5,6-tetrasubstituted piperidinones. The -amino ketones were prepare by treatment of prochiral lithium Weinreb amide enolates with enantiopure (E)-N-(4- (benzyloxy)butylidene)-2,4,6-triisopropylbenzenesulfinamide. This new methodology was highlighted in the first asymmetric synthesis of the poison frog alkaloid (-)- indolizidine 221T. By manipulation of water concentration in tetrahydrofuran, syn- and anti-2,3- diamino esters were prepared by treatment of the lithium enolate of N- (diphenylmethylene) glycine ethyl ester with sulfinimines. Anhydrous THF afforded enantiopure syn-2,3-diamino esters with a syn/anti selectivity of better than 25:1. In a THF-H2O the anti-2,3-diamino esters were formed. The mechanism involves the generation of H2O-LDA species in the formation of enolate which inhibited the retro- Mannich fragmentation in the diamino ester species. (SR,2S,3R)-(-)-Ethyl-2-(N,N- dibenzylamino)-3-N-(p-toluenesulfinyl)amino-pent-4-enoate was employed in an improved total synthesis of the anti-tumor antibiotic (-)-agelastatin A. A series of N-sulfinyl aza-Morita-Baylis-Hillman products were prepared by addition of vinylaluminum and N-methylmorpholine-N-oxide reagents to enantiopure N- (p-toluenesufinyl)- and N-(2-methypropanesulfinyl)-derived sulfinimines from the least hindered direction via a non-chelation control mechanism. Hydrogenation of the these acrylates with a rhodium(I) catalyst afforded anti--substituted--amino esters with a iv anti/syn selectivity of better than 17:1. This new methodology is useful for the asymmetric synthesis of anti--alkyl--amino esters, which are valuable chiral building blocks for the preparation of biologically active nitrogen-containing natural products. v ACKNOWLEDGEMENTS There are so many people I need thank for their help during my study at Temple University. I know it is impossible to mention all of the names here, I would like to express my gratitude to all of them. First of all, I would like to thank my advisor Dr. Franklin A. Davis. Without his help and guidance, I have no chance to finish my Ph.D. study. As a professional researcher, Dr. Davis taught me to do my chemistry carefully, creatively and happily. He always encourages me to challenge myself to be the best. Besides knowledge in chemistry, he also teaches me many other things about life, family. From him, I learned “chemistry comes first, but family is even more important.” All of these are truly valuable for me. I would also like thank my committee members Dr. John R. Williams, Dr. Andrade, who have given me support all the way. Dr. Kevin Cannon, who was once my instructor of “organic synthesis”, taught me many advanced knowledge of chemistry, which is really helpful in my later research in chemistry. Dr. Andrade, who is really nice, illustrated the mechanism to me with patience whenever I ask him questions. Dr. John R. Williams is a very good instructor. What he taught in his class about total synthesis is truly necessary for me to accumulate knowledge of different reactions. Other faculty should be recognized includes Dr. Alfred Findeisen for his nice work as the organic chemistry laboratory coordinator. Also I have deep gratitude to my colleagues at department of chemistry, especially Dr. Junyi Zhang, Dr. Minsoo Song who worked as a postdoctoral fellow and mentored my research and my friends Dr. Yongzhong Wu, Dr. Bin Yang, Dr. vi Ramachandar Tokalo, Dr. Dr. He Xu (Leo), Dr. Kerisha Bowen, Dr. Jianghe Deng, Dr. Paul Gaspari, Dr. Naresh Theddu, Mr. Yanfeng Zhang, Mr Venkata Velvadapu, Mr. Narendra V. Gaddiraju and Mr. Peng Xu. I would also like to thank my wife, Jing Chai, without your encouragement, my road would be much more difficult with no doubt. My parents, Xianzhu Li and Zhangfa Qiu, thanks for letting me know the importance of education and providing me the opportunity of studying in USA. Life is just like climbing different mountains. The milestone I have reached today is just the beginning of another climb. vii TABLE OF CONENTS Page ABSTACT………………………………………………………………………………iii ACKNOWLEDGEMENTS ………………...……………………………………….....vi LIST OF TABLES…………………………………………………….………………...xi LIST OF FIGURES…………………………………………………………...............xiii CHAPTER 1. ASYMMETRIC SYNTHESIS OF TRANS-2,5-DISUBSTITUTED PYRROLIDINES. 1.1. Introduction………………………………………………………...................1 1.2. Cyclization (SN2)……………………………………………………………...2 1.2.1. Intramolecular cyciliztion………………………………………..........2 1.2.2. Intermolecular cyclization reaction…………………………………..5 1.2.2.1. Halides as leaving groups……………………………….....5 1.2.2.2. 1,4-diol derivatives as leaving groups………………………..6 1.2.2.3. Miscellaneous examples…………………………………...7 1.3. Cyclization (SN2’)………………………………………………………….....8 1.4. Aza-Michael reaction…………………………………………………….....10 1.5. Radical cyclization………………………………………………………...14 1.6. Iodocyclization…………………………………………………………….14 1.7. Metal catalyzed cyclization………………………………………………....16 1.8. 1, 3 Dipolar reaction……………………………………………………..….20 viii 2. ASYMMETRIC SYNTHESIS OF TRANS- OR CIS-2,5-DISUBSTITUTED PYRROLIDINES. 2.1. Indroduction……………………………………………………………….26 2.2. Present study. …………………………………………………………......28 2.2.1. Previous syntheses of (+)-preussin………………………………...29 2.2.2. Total synthesis (+)-preussin and its analogs……………………… 31 2.2.2.1. Synthesis of (+)-3-oxo pyrrolidine 2-phosphonate………..31 2.2.2.2. Synthesis of (+)-preussin and cis-2,5-disubstituted pyrrol..32 2.2.2.3. Synthesis of trans-2,5-disubstituted pyrrolidines derivatives of (+)-preussin………………………………………..34 3. ASYMMETRIC SYNTHESIS AND UTILIZATION OF POLYSUBSTITUTED PIPERIDINE AS BUILDING BLOCKS. 3.1. Introduction……………………………………………………………. 36 3.2. Present study……………………………………………………………39 3.2.1. Synthesis of cis -alkyl--amino ketone…………………………..40 3.2.2. Synthesis of 2,3,4,5-tetrasubstitutued piperidine via Mannich r e a c t i o n … … … … … … … … … … … … … … … … … … … … . 4 1 3.2.3. Total synthesis of (-)-221T…………….…………………………..44 4. ASYMMETRIC SYNTHESIS AND UTILIZATION OF ANTI- AND SYN-2,3- DIAMINO ESTERS. 4.1. Introduction……………………………………………………………….48 4.2. Present study……………………………………………………………...51 4.2.1. Synthesis of syn-2,3-diamino ester from sulfinimines (N-sulfinyl ix imines…………..…………………………………………………..51 4.2.2. Mechanism exploration..........................................................................54 4.2.3. Total synthesis of (-)-agelastatin A from sulfinimine-derived syn-,- diamino ester……………………………………………………57 5. SYNTHESIS OF ANTI-LKYL-AMINO ESTERS. 5.1. Indroduction……………………………………………………………….62 5.2. Previous syntheses of -substituted -amino esters from sulfinimine…..62 5.3. Present study………………………………………………………………65 5.3.1. Synthesis of -alkyl -amino ester from enantiopure sulfinimine...65 5.3.1.1. Synthesis of -amino-acrylate via aza-Morita-Baylis- Hillman (MBH) reaction……………………………...65 5.3.1.2. Hydrogenation of aza-MBH adducts with organometallic catalysts………………………………………………...69 6. EXPERIMENTAL SECTION……………………………………………………..72 REFERENCE…………………………………………………………………………131 x LIST OF TABLES Table 1.1. Intramolecular cyclizations between amines and tosylates……………….7 Table 1.2. SN2’cyclizations of 59 catalyzed by Iridium complex…………………...10 Table 1.3. aza-Michael cyclizations of (-)-68 in the presence of bases…………….12 Table 1.4. Asymmetric synthesis of 106a-b by Yb catalyzed cyclizations………...18 Table 1.5. 1,3-Dipolar reactions between 119 and alkene 120……………………..20 Table 1.6. 1,3-Dipolar reactions of 124 with dipolarophiles 125a,b……………….21 Table 1.7. Three components 1,3-dipolar reactions catalyzed by rhodium complex.23 Table 3.1. Synthesis of
Load more

Recommended publications
  • Rediscovering Sulfinylamines As Reagents for Organic Synthesis Thomas Q
    Minireview Chemistry—A European Journal doi.org/10.1002/chem.202100321 Rediscovering Sulfinylamines as Reagents for Organic Synthesis Thomas Q. Davies[a] and Michael C. Willis*[a] Chem. Eur. J. 2021, 27, 1–11 1 © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH These are not the final page numbers! �� Wiley VCH Dienstag, 25.05.2021 2199 / 204270 [S. 1/11] 1 Minireview Chemistry—A European Journal doi.org/10.1002/chem.202100321 Abstract: Sulfinylamines (RÀ N=S=O), monoaza analogues of of their use in the one-pot syntheses of sulfoximines and sulfur dioxide, have been known for well over a century, and sulfonimidamides. Also covered are the reactions of sulfinyl- their reactivity as sulfur electrophiles and in Diels-Alder amines with carbon-centred radicals, their use for formation reactions is well-established. However, they have only rarely of heterocycles through cycloadditions, and catalytic enantio- been used in organic synthesis in recent decades despite the selective allylic oxidation of alkenes via a hetero-ene reaction. increasing prominence of compounds containing N=S=O These examples highlight the different reactivity modes of functionality, such as sulfoximines and sulfonimidamides. This sulfinylamines and their underappreciated potential for Minireview aims to bring wider visibility to the unique forming molecules which contain high- or low-valent sulfur, chemistry enabled by this class of compounds. We focus on or even no sulfur at all. advances from the last 10 years, including the first examples
    [Show full text]
  • 1,2,4-Triazine Sulfonamides: Synthesis by Sulfenamide Intermediates, in Vitro Anticancer Screening, Structural Characterization, and Molecular Docking Study
    molecules Article 1,2,4-Triazine Sulfonamides: Synthesis by Sulfenamide Intermediates, In Vitro Anticancer Screening, Structural Characterization, and Molecular Docking Study Danuta Branowska 1, Zbigniew Karczmarzyk 1,*, Ewa Woli ´nska 1, Waldemar Wysocki 1, Maja Morawiak 2 , Zofia Urba ´nczyk-Lipkowska 2 , Anna Bielawska 3 and Krzysztof Bielawski 3 1 Faculty of Exact and Natural Sciences, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland; [email protected] (D.B.); [email protected] (E.W.); [email protected] (W.W.) 2 Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; [email protected] (M.M.); zofi[email protected] (Z.U.-L.) 3 Medical University of Bialystok, Department of Medicinal Chemistry and Drug Technology, J. Kilinskiego 1, 15-089 Bialystok, Poland; [email protected] (A.B.); [email protected] (K.B.) * Correspondence: [email protected]; Tel.: +48-25-643-1017 Received: 24 March 2020; Accepted: 14 May 2020; Published: 16 May 2020 Abstract: In this study, we synthesized novel sulfonamides with a 1,2,4-triazine moiety according to pharmacophore requirements for biological activity. All the synthesized compounds were tested in vitro to verify whether they exhibited anticancer activity against the human breast cancer cell lines MCF-7 and MDA-MB-231. Among them, two most active ones, having IC50 values of 50 and 42 µM, respectively, were found to show higher anticancer activity than chlorambucil used as the reference in the in vitro tests. In addition, two other compounds, which had IC50 values of 78 and 91 µM, respectively, exhibited a similar level of activity as chlorambucil.
    [Show full text]
  • Reduction of Organic Functional Groups Using Hypophosphites Rim Mouselmani
    Reduction of Organic Functional Groups Using Hypophosphites Rim Mouselmani To cite this version: Rim Mouselmani. Reduction of Organic Functional Groups Using Hypophosphites. Other. Univer- sité de Lyon; École Doctorale des Sciences et de Technologie (Beyrouth), 2018. English. NNT : 2018LYSE1241. tel-02147583v2 HAL Id: tel-02147583 https://tel.archives-ouvertes.fr/tel-02147583v2 Submitted on 5 Jun 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THESE de DOCTORAT DE L’UNIVERSITE DE LYON EN COTUTELLE AVEC L'UNIVERSITÉ LIBANAISE opérée au sein de l’Université Claude Bernard Lyon 1 École Doctorale de Chimie-École Doctorale des Sciences et Technologies Discipline : Chimie Soutenue publiquement le 07/11/2018, par Rim MOUSELMANI Reduction of Organic Functional Groups Using Hypophosphites Devant le jury composé de Mme. Micheline DRAYE Université Savoie Mont Blanc Rapporteure M. Mohammad ELDAKDOUKI Université Arabe de Beyrouth Rapporteur Mme. Emmanuelle SCHULZ Université Paris 11 examinatrice M. Abderrahmane AMGOUNE Université Lyon 1 Président M. Mahmoud FARAJ Université Internationale Libanaise examinateur Mme. Estelle MÉTAY Université Lyon 1 Directrice de thèse M. Ali HACHEM Université Libanaise Directeur de thèse M. Marc LEMAIRE Université Lyon 1 Membre invité M.
    [Show full text]
  • United States Patent Office
    3,454,590 United States Patent Office Patented July 8, 1969 2 3,454,590 New compounds that can be produced by the process BENZOTHAZO-LE-2-SULFNAMIDES are benzothiazole-2-sulfinamides where R and R in the Alan Jeffrey Neale, Llangollen, Wales, and Terence above formula each represent an aliphatic or cyclo James Rawlings, Penicuik, Scotland, assignors to aliphatic group and the total number of carbon atoms Monsanto Chemicals Limited, London, England, in R and R' is at least four, and sulfinamides where R a British company No Drawing. Filed June 1, 1967, Ser. No. 642,717 and R are linked to form a saturated cyclic system with Claims priority, application Great Britain, June 17, 1966, the nitrogen atom. 27,184/66 The invention includes a process in which a new com nt. C. C07d 91/44, 29/34 pound as defined above is employed as an accelerator U.S. CI. 260-306.6 3 Claims O for the Vulcanization of rubber. Sulfinamides that can be produced by oxidation of the corresponding sulfenamides in the process defined above ABSTRACT OF THE DISCLOSURE can also be obtained by reaction of a benzothiazole-2-sul finyl halide with an appropriate amine. In particular, sul This disclosure is benzothiazole-2-sulfinamides of the 5 finamides in which the sulfinamide grouping is represented formula by the formula: S N R R C-S-N -s-N Né y 20 R. can be obtained by reaction of the sulfinyl halide with where R and R' are each an aliphatic or cycloaliphatic an amine having the formula HNRR.
    [Show full text]
  • Tert-Butanesulfinamides As Nitrogen Nucleophiles in Carbon-Nitrogen
    tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon-Nitrogen Bond Forming Reactions Johana Ramirez Hernandez, Fabrice Chemla, Franck Ferreira, Olivier Jackowski, Julie Oble, Alejandro Perez-Luna, Giovanni Poli To cite this version: Johana Ramirez Hernandez, Fabrice Chemla, Franck Ferreira, Olivier Jackowski, Julie Oble, et al.. tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon-Nitrogen Bond Forming Reactions. CHIMIA, Schweizerische Chemische Gesellschaft, 2016, 70 (1), pp.84-92. 10.2533/chimia.2016.84. hal-01292458 HAL Id: hal-01292458 https://hal.sorbonne-universite.fr/hal-01292458 Submitted on 23 Mar 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 84 CHIMIA 2016, 70, No. 1/2 The French connecTion doi:10.2533/chimia.2016.84 Chimia 70 (2016) 84–92 © Swiss Chemical Society tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon–Nitrogen Bond Forming Reactions Johana Ramirez Hernandez, Fabrice Chemla, Franck Ferreira, Olivier Jackowski, Julie Oble, Alejandro Perez-Luna*, and Giovanni Poli Abstract: The use of tert-butanesulfinamides as nitrogen nucleophiles in carbon–nitrogen bond forming reac- tions is reviewed. This field has grown in the shadow of the general interest in N-tert-butanesulfinyl imines for asymmetric synthesis and occupies now an important place in its own right in the chemistry of the chiral amine reagent tert-butanesulfinamide.
    [Show full text]
  • Syntheses and Reactions of Sulfinimines
    i SYNTHESIS AND REACTIONS OF SULFINIMINES Leonid Kotei Sasraku-Neequaye This thesis is submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy at the University of East Anglia June, 2010 © This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that no quotation from this thesis or any information derived thereof may be published without the author’s prior written consent ii DECLARATIONS I declare that the work contained within this thesis, submitted by myself for the degree of Doctor of Philosophy is my own original work, except where due reference is made and has not previously been submitted by me for a degree at this or any other university. Leonid Kotei Sasraku-Neequaye iii ABSTRACT A large majority of drugs and drug candidates incorporate amine functionality and these include important compounds such as morphine, quinine and nicotine. N-Sulfinyl-imines (sulfinimines) are a versatile class of intermediates in organic synthesis particularly for the preparation of amines and amine derivatives. We herein report an efficient and cost effective one-pot synthesis of sulfinimines in enantiopure form (>99.8% ee) and in relatively high yields. In our investigations, we developed the scheme that involves the use of 1,2,3- oxathiazolidine-2-oxide derived from (1R, 2S)-(-)-norephedrine as a chiral auxiliary. Opening of the 1,2,3-oxathiazolidine-2-oxide with a mesityl Grignard reagent followed by treatment of the crude mixture with lithium hexamethyldisilasane afforded the mestyl sulfinamide in 72% yield and 76% recovery of the chiral auxiliary.
    [Show full text]
  • Diastereoselective Synthesis of 2,4,6-Trisubstituted Piperidines Via Aza-Prins Cyclization
    The University of Southern Mississippi The Aquila Digital Community Honors Theses Honors College Spring 5-2018 Diastereoselective Synthesis of 2,4,6-Trisubstituted Piperidines via aza-Prins Cyclization John A. Hood University of Southern Mississippi Follow this and additional works at: https://aquila.usm.edu/honors_theses Part of the Organic Chemistry Commons Recommended Citation Hood, John A., "Diastereoselective Synthesis of 2,4,6-Trisubstituted Piperidines via aza-Prins Cyclization" (2018). Honors Theses. 605. https://aquila.usm.edu/honors_theses/605 This Honors College Thesis is brought to you for free and open access by the Honors College at The Aquila Digital Community. It has been accepted for inclusion in Honors Theses by an authorized administrator of The Aquila Digital Community. For more information, please contact [email protected]. The University of Southern Mississippi Diastereoselective Synthesis of 2,4,6-Trisubstituted Piperidines via aza-Prins Cyclization by John A. Hood A Thesis Submitted to the Honors College of The University of Southern Mississippi in Partial Fulfillment of the Requirements for the Degree of Bachelor of Science in the Department of Chemistry and Biochemistry May 2018 ii Approved by: ____________________________________ Matthew G. Donahue, Ph.D., Thesis Advisor Department of Chemistry and Biochemistry ____________________________________ Vijay Rangachari, Ph.D., Chair Department of Chemistry and Biochemistry ____________________________________ Ellen Weinauer, Ph.D., Dean Honors College iii Abstract The nitrogen heterocycles are shared amongst 59% of Food and Drug Administration (FDA) approved small molecule pharmaceuticals with the six-membered piperidine representing the most common moiety. Given the versatility and potential to yield derivatives with broad biological activities, the discovery of new chemical methods to generate these heterocycles in a more time and cost-efficient manner is desired.
    [Show full text]
  • Final Program in Pdf Format
    35th Reaction Mechanisms Conference University of California, Davis Davis, CA June 22 – 25, 2014 Welcome ..................................................................................................................2 Program ..................................................................................................................3 RMC Information and Governing Board ............................................................6 Previous Reaction Mechanism Conferences .......................................................7 Sponsors ..................................................................................................................9 UC Davis Campus Map .......................................................................................10 Program at a Glance ............................................................................................11 Speaker Abstracts ................................................................................................12 List of Participants ...............................................................................................29 Index of Poster Presenters...................................................................................35 Poster Abstracts ...................................................................................................36 1 Welcome from the Program Chair It is with great pleasure that I welcome you to the 35th Reaction Mechanisms Conference on the beautiful campus of UC Davis. The RMC, to me, is a special conference that
    [Show full text]
  • The Utilization of Sulfinimines (N-Sulfinyl Imines) in The
    THE UTILIZATION OF SULFINIMINES (N-SULFINYL IMINES) IN THE ASYMMETRIC SYNTHESIS OF SUBSTITUTED PYRROLIDINES A Dissertation Submitted to the Temple University Graduate Board In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY By Kerisha Andrea Bowen May 2009 ABSTRACT The Utilization of Sulfinimines (N-Sulfinyl Imines) Towards the Sythesis of Nitrogen Containing Compounds By Kerisha A. Bowen Doctor of Philosophy Temple University, 2009 Doctoral Advisory Committee Chair: Professor Franklin A. Davis, Ph.D. The objective of this research was the development of new methods for the asymmetric synthesis of nitrogen containing compounds. As one part of this goal, 3,4- dihydroxyprolines and their derivatives were prepared from sulfinimines (N-sulfinyl imines). During this project new methods were developed for asymmetric hydroxylation and decarboxylation of 3-oxo-2-carboxylate pyrroldines. The application of this new methodology was realized by the total synthesis of the α- and β-glycosidases inhibitor (+)-lentginosine. It was also found that electrophiles regioselectively add to the 4-position of 3-oxo-2- carboxylate-5-substituted pyrrolidines. The addition is accomplished through lithium diisopropyl amide generation of the pyrrolidine dianion. This addition was also compatible with 3-oxo-2-phosophono-5-substituted pyrroldines. Furthermore air oxidation of these pyrrolidines give the corresponding pyrroles. This procedure represents the first general preparation procedure for 2-phonopyrroles, which have been examined as HIV protease inhibitors. ii A range of β-amino carbonyl compounds were prepared from N-sulfinyl β-amino Weinreb amides in a concise and efficient procedure. A general method for the preparation of a variety of β-amino carbonyl compounds arose from the addition of an assortment of organometallic reagents to the Weinreb amides.
    [Show full text]
  • N-Tert-Butanesulfinyl Imines in the Asymmetric Synthesis of Nitrogen-Containing Heterocycles
    N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles Joseane A. Mendes1, Paulo R. R. Costa2, Miguel Yus3,4,5, Francisco Foubelo3,4,5 and Camilla D. Buarque*1 Review Open Access Address: Beilstein J. Org. Chem. 2021, 17, 1096–1140. 1Department of Chemistry, Pontifical Catholic University of Rio de https://doi.org/10.3762/bjoc.17.86 Janeiro Puc-Rio, CEP 22435-900, Brazil, 2Laboratory of Bioorganic Chemistry, Institute of Research of Natural Products, Health Science Received: 26 January 2021 Center, Federal University of Rio de Janeiro UFRJ, CEP 21941-590, Accepted: 22 April 2021 Brazil, 3Centro de Innovación en Química Avanzada Published: 12 May 2021 (ORFEO-CINQA), Universidad de Alicante, Apdo.99, 03080 Alicante, Spain, 4Departamento de Química Orgánica, Facultad de Ciencias, Associate Editor: B. Nay Universidad de Alicante, Apdo. 99,03080 Alicante, Spain and 5Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. © 2021 Mendes et al.; licensee Beilstein-Institut. 99, 03080 Alicante, Spain License and terms: see end of document. Email: Camilla D. Buarque* - [email protected] * Corresponding author Keywords: asymmetric synthesis; chiral auxiliary; natural products; nitrogen-containing heterocycles; N-tert-butanesulfinyl imines Abstract The synthesis of nitrogen-containing heterocycles, including natural alkaloids and other compounds presenting different types of bi- ological activities have proved to be successful employing chiral sulfinyl imines derived from tert-butanesulfinamide. These imines are versatile chiral auxiliaries and have been extensively used as eletrophiles in a wide range of reactions. The electron-with- drawing sulfinyl group facilitates the nucleophilic addition of organometallic compounds to the iminic carbon with high diastereo- isomeric excess and the free amines obtained after an easy removal of the tert-butanesulfinyl group can be transformed into enantioenriched nitrogen-containing heterocycles.
    [Show full text]
  • Acid Catalyzed Alcoholysis of Sulfinamides: Unusual Stereochemistry, Kinetics and a Question of Mechanism Involving Sulfurane Intermediates and Their Pseudorotation
    Molecules 2015, 20, 2949-2972; doi:10.3390/molecules20022949 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Article Acid Catalyzed Alcoholysis of Sulfinamides: Unusual Stereochemistry, Kinetics and a Question of Mechanism Involving Sulfurane Intermediates and Their Pseudorotation Bogdan Bujnicki, Józef Drabowicz and Marian Mikołajczyk * Department of Heteroorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź, Poland; E-Mails: [email protected] (B.B.); [email protected] (J.D.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +48-42-681-5832. Academic Editor: Derek J. McPhee Received: 19 December 2014 / Accepted: 3 February 2015 / Published: 11 February 2015 Abstract: The synthesis of optically active sulfinic acid esters has been accomplished by the acid catalyzed alcoholysis of optically active sulfinamides. Sulfinates are formed in this reaction with a full or predominant inversion of configuration at chiral sulfur or with predominant retention of configuration. The steric course of the reaction depends mainly on the size of the dialkylamido group in the sulfinamides and of the alcohols used as nucleophilic reagents. It has been found that bulky reaction components preferentially form sulfinates with retention of configuration. It has been demonstrated that the stereochemical outcome of the reaction can be changed from inversion to retention and vice versa by adding inorganic salts to the acidic reaction medium. The unusual stereochemistry of this typical bimolecular nucleophilic substitution reaction, as confirmed by kinetic measurements, has been rationalized in terms of the addition-elimination mechanism, A-E, involving sulfuranes as intermediates which undergo pseudorotations.
    [Show full text]
  • Green Chemistry in Chemical Education and Synthetic
    Green Chemistry in Chemical Education and Synthetic Applications of Sulfinamides Björn Blomkvist Doctoral Thesis Stockholm 2020 Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av doktorsexamen i kemi med inriktning mot organisk kemi fredagen den 24 januari kl 10.00 i sal F3, KTH, Lindstedtsvägen 26, Stockholm. Avhandlingen försvaras på engelska. Opponent är Prof. José Alemán, Universidad Autónoma de Madrid, Spanien. I ISBN 978-91-7873-400-9 ISSN 1654-1081 TRITA-CBH-FOU-2020:1 © Björn Blomkvist, 2020 Universitetsservice US AB, Stockholm II Voor mijn liefste III Björn Blomkvist, 2020: “Green Chemistry in Chemical Education and Synthetic Applications of Sulfinamides”, KTH Chemical Science and Engineering, Royal Institute of Technology, SE-100 44 Stockholm, Sweden. Abstract The preparation of chiral molecules, i.e. compounds that are not identical to their mirror image, is of great interest in the field of organic chemistry. The preparation of a enantiomerically pure molecules is crucial in the development of new pharmaceuticals, agrochemicals and more, since the building blocks of life are chiral and the interactions between enantiomers and receptor are different. Furthermore, an important aspect of chemistry is sustainability, developing new synthetic procedures where green chemistry has been incorporated. In chapter 2, the use of Brønsted acid catalysis as well as a combined Brønsted acid and aminocatalytic procedure for the preparation of the chiral synthon tert- butane N-sulfinyl imine. Using HBF4Y6H686I6ANHI<6K:I=:HJA;>CNA>B>C: in high yields in 2 h. Changing the catalyst to HBF4Y 6C9 6C>A>ne both improved the yields and shortened the reaction time to only 30 min.
    [Show full text]