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Reunión grupo, Junio 2014

Síntesis. Reunión grupo, Junio 2014. Total Synthesis of (±)- Distomadines A and B Alexandre E. R. Jolibois , William Lewis , and Christopher J. Moody * School of Chemistry , University Park, University of Nottingham , Nottingham NG7 2RD, U.K.

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Reunión grupo, Junio 2014

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  1. Síntesis Reunión grupo, Junio 2014 Total Synthesis of (±)-Distomadines A and B Alexandre E. R. Jolibois , William Lewis , and Christopher J. Moody * School of Chemistry, University Park, University of Nottingham, Nottingham NG7 2RD, U.K. Org. Lett., 2014, 16 (4), pp1064–1067 The total synthesis of distomadines A and B, two structurally unique tetracyclic quinolines, is described. The route features a three-step process to access the pyranoquinolinebutenolide rings via a Suzuki cross coupling of a 5-bromo-4-methoxycarbonylmethoxyquinoline with a vinyl boronate, followed by an α-ketohydroxylation and double cyclization by intramolecular aldol condensation and lactonization. Subsequent manipulation of the side chain to introduce the guanidine fragment completed the synthesis of distomadine B, whereas the distomadine A congener resulted from decarboxylation of a late-stage intermediate.

  2. Síntesis Reunión grupo, Junio 2014 Chris Moody is Sir Jesse Boot Professor of Chemistry and Head of Organic Chemistry at the University of Nottingham. He is a Mancunian and was educated at Manchester Grammar School and King's College, London, before carrying out his PhD research at the University of Liverpool under the supervision of Charles Rees investigating the synthesis and reactions of nitrogen-sulfur ylides. He spent a postdoctoral year at the ETH in Zürich working with Albert Eschenmoseron the stereochemistry of 1,4-elimination reactions before taking up a post in industry at Roche. In 1979 he was appointed to a lectureship at Imperial College, London, and was promoted to a readership in 1989. In 1990 moved to the chair of organic chemistry at Loughborough University, and in 1996 he was appointed Professor of Organic Chemistry at the University of Exeter. He moved to his current post in Nottingham in August 2005. He has published over 390 papers and his work has been recognised with several awards including the RSC Hickinbottom Fellowship and Corday Morgan Medal (both in 1986), the Tilden Medal and Lectureship (2000-2001), the Adrien Albert Medal and Lectureship (2001), an EPSRC Senior Research Fellowship (2000-2005), the Royal Society of Chemistry Award for Synthetic Organic Chemistry (2006), the Pedler Lectureship (2008), the Novartis International Lectureship (2010-2011), and the Royal Society of Chemistry Charles Rees Award (2012). ProfKeith Jones (ICR); Prof Chris Moody (Uni of Nottingham, recipient Of theRSC Charles ReesAward); Dr David Rees (AstexPharmaceuticals)

  3. Síntesis Reunión grupo, Junio 2014 Chris Moody is Sir Jesse Boot Professor of Chemistry and Head of Organic Chemistry at the University of Nottingham. He is a Mancunian and was educated at Manchester Grammar School and King's College, London, before carrying out his PhD research at the University of Liverpool under the supervision of Charles Rees investigating the synthesis and reactions of nitrogen-sulfur ylides. He spent a postdoctoral year at the ETH in Zürich working with Albert Eschenmoseron the stereochemistry of 1,4-elimination reactions before taking up a post in industry at Roche. In 1979 he was appointed to a lectureship at Imperial College, London, and was promoted to a readership in 1989. In 1990 moved to the chair of organic chemistry at Loughborough University, and in 1996 he was appointed Professor of Organic Chemistry at the University of Exeter. He moved to his current post in Nottingham in August 2005. He has published over 390 papers and his work has been recognised with several awards including the RSC Hickinbottom Fellowship and Corday Morgan Medal (both in 1986), the Tilden Medal and Lectureship (2000-2001), the Adrien Albert Medal and Lectureship (2001), an EPSRC Senior Research Fellowship (2000-2005), the Royal Society of Chemistry Award for Synthetic Organic Chemistry (2006), the Pedler Lectureship (2008), the Novartis International Lectureship (2010-2011), and the Royal Society of Chemistry Charles Rees Award (2012). Jesse Boot, 1st Baron Trent (1850 –1931) transformed The Boots Company, founded by his father, John Boot(1815-1860) into a national retailer, which branded itself as "Chemists to the Nation", before he sold his controlling interest to American investors in 1920. Boot was a great benefactor to the City of Nottingham. He donated land for the new University College at Highfields, now the University of Nottingham, which opened in 1928 and was presented with the Freedom of the City of Nottingham in 1920. Boot was knighted in 1909, created a baronet in 1917,and announced in the New Year's Honours of 1929 was elevated to the peerage, and created Baron Trent, of Nottingham in the County of Nottingham on 1929.These latter honours probably owed as much to his solid support of the Liberal Party as to his philanthropy to the city of his birth. He died in Jersey in 1931. The Sir Jesse Boot Chair in Chemistry at the University of Nottingham was named in his honour. http://www.allianceboots.com/our-history.aspx

  4. Síntesis Reunión grupo, Junio 2014 Total Synthesis of (±)-Distomadines A and B Alexandre E. R. Jolibois , William Lewis , and Christopher J. Moody * School of Chemistry, University Park, University of Nottingham, Nottingham NG7 2RD, U.K. Org. Lett., 2014, 16 (4), pp1064–1067 • Aisladas de ascidian Pseudodistomaaureum , New Zealand. (Coppand col., Tetrahedron Lett.2003, 44, 3897-3899) • Distomadina B: se aisló con 2′-deoxyadenosine (mezcla 1:1). • DistomadinaA se elucidópor RMN (a falta de la estereoquímicaabsoluta) • Poseenunararaestructuratetracíclica de pirano[2,3,4-de]quinolinaunida a unabutenolida.

  5. Síntesis Reunión grupo, Junio 2014 Total Synthesis of (±)-Distomadines A and B Alexandre E. R. Jolibois , William Lewis , and Christopher J. Moody * School of Chemistry, University Park, University of Nottingham, Nottingham NG7 2RD, U.K. Org. Lett., 2014, 16 (4), pp1064–1067 • Solo se conoce un compuestosintéticorelacionado con alcaloides de aaptamina con núcleo de piranoquinolina (Abbiatiand col., J. Org. Chem..2012, 77, 10461-10467)

  6. Síntesis Reunión grupo, Junio 2014 Total Synthesis of (±)-Distomadines A and B Alexandre E. R. Jolibois , William Lewis , and Christopher J. Moody * School of Chemistry, University Park, University of Nottingham, Nottingham NG7 2RD, U.K. Org. Lett., 2014, 16 (4), pp1064–1067 • El ácido 2-quinolina carboxílicopresente en la distomadina B espocofrecuente en productosnaturalesmarinos: Primer ejemplo: ácido 3,4-dihidroxiquinolina 2-carboxílico aislado de Aplysinaaerophobaen los años 70

  7. Síntesis Reunión grupo, Junio 2014 Total Synthesis of (±)-Distomadines A and B Alexandre E. R. Jolibois , William Lewis , and Christopher J. Moody * School of Chemistry, University Park, University of Nottingham, Nottingham NG7 2RD, U.K. Org. Lett., 2014, 16 (4), pp1064–1067 • El ácido 2-quinolina carboxílicopresente en la distomadina B espocofrecuente en productosnaturalesmarinos: • Los ácidoquinurénico y xanturénicoson dos de los ejemplosmásconocidos de productosnaturales con esqueletode ácido 2-quinolinacarboxílico Ácidoxanturénicoinduce gametogenesis del Plasmodium falciparum, (parásito de la malaria). Se encuentra en el intestino del mosquito Anopheles Ácido quinurénico metabolito del triptófano con fuerte actividad biológica sobre el sistema nervioso

  8. Síntesis Reunión grupo, Junio 2014 (70%) (94%) (97%) (86%) (76%) (95%) X C17H18BrNO7 • Síntesis de Conrad-Limpach modificada: • Adición de Michael al DMAD • Ciclación al elevar la temperatura

  9. Síntesis Reunión grupo, Junio 2014 (70%) (94%) (97%) (86%) (76%) (95%) X C17H18BrNO7

  10. Síntesis Reunión grupo, Junio 2014 (70%) (94%) (97%) (86%) (76%) (95%) X C17H18BrNO7

  11. Síntesis Reunión grupo, Junio 2014 • • • • • • • • • • • δH (400 MHz; CDCl3): • 8.22 (1 H, d, J 9.4), 7.74 (1 H, d, J 9.4), 7.49 (1 H, s), • 5.45 (2 H, s), 4.96 (2 H, s), • 4.07 (3 H, s), 3.87 (3 H, s), • 3.85 (2 H, q, J 7.1), 1.25 (3 H, t, J 7.1) • • • • • • • • • • • δC (100 MHz; CDCl3): 167.7 (C), 165.6 (C), 161.5 (C), 154.3(C), 147.0 (C), 146.2 (C), 122.1 (C), 104.6 (C), 131.6 (CH),120.4(CH), 102.3 (CH), 94.1 (CH2), 65.2 (CH2), 65.1 (CH2), 53.4 (Me), 52.6 (Me),15.1 (Me) • •

  12. Síntesis Reunión grupo, Junio 2014 X (89%) (93%) (78%) Reactivo de Schwartz Hidrocloruro de zirconoceno o zirconoceno cloruro hidruro Zr-Mediatedhydroboration: stereoselectivesynthesis of vinyl boronicesters Y. D. Wang et al. TetrahedronLett. 2005, 46, 8777-8780 Inserción del alquino Intercambio Vinilo-hidruro

  13. Síntesis Reunión grupo, Junio 2014 (83%) Y C28H27NO9 Mezcla (1:1) de dos regioisómeros Interconvertibles en medio básico (23%) Pirano[2,3,4-de]quinolina tetracíclica ~H

  14. Síntesis Reunión grupo, Junio 2014 (83%) Y C28H27NO9 (23%) Pirano[2,3,4-de]quinolina tetracíclica ~H -H2O -H2O Condensación aldólica + lactonización

  15. Síntesis Reunión grupo, Junio 2014 5.38 d, 10.3 5.35 d, 10.3 3.87 td, 9.7, 4.1 3.83-3.82 m • 5.78 dd, 8.9, 1.9 7.43-7.22 (5 H, m) 2.74 dddd, 14.7, 9.7, 4.1, 1.9 1.86 ddt, 14.7, 8.9, 4.1 • • 7.54 (s) • 7.72 (d, 9.6) 8.05 (d, 9.6) δH (400 MHz; CDCl3): 8.05 (1H, d, J 9.6), 7.72 (1 H, d, J 9.6), 7.54 (1 H, s), 7.43-7.22 (5 H, m), 5.78 (1H, dd, J 8.9, 1.9), 5.38 (1H, d, J 10.3), 5.35 (1H, d, J 10.3), 4.77 (2 H, s), 4.58 (2 H, s), 4.04 (3H, s), 3.87 (1 H, td, J 9.7, 4.1), 3.83-3.72 (3 H, m), 2.74 (1 H, dddd, J 14.7, 9.7, 4.1, 1.9),1.86 (1 H, ddt, J 14.7, 8.9, 4.1), 1.18 (3 H, t, J 7.0).

  16. Síntesis Reunión grupo, Junio 2014 • • • • • • • • • • • • • • • • • • • • • • • • δC (100 MHz; CDCl3): 164.7 (C), 163.2 (C), 159.8 (C), 149.4 (C), 148.0 (C), 145.4 (C), 138.1 (C), 137.5 (C), 135.9 (C), 131.9 (CH), 128.3 (CH),127.7 (CH), 127.6 (CH), 121.2(CH),121.0 (C), 109.5 (C), 105.5 (CH),94.6 (CH2), 93.6 (CH2), 77.4 (CH), 69.4 (CH2),65.2 (CH2), 63.5 (CH2), 53.2 (Me), 34.6 (CH2), 14.9 (Me).

  17. Síntesis Reunión grupo, Junio 2014 (85%) (97%) (94%) ()D-B C17H14N4O6·2HCl (89%) Condiciones de Mitsunobu

  18. Síntesis Reunión grupo, Junio 2014 (90%) (86%) (73%) (77%) ()D-A C16H14N4O4·2HCl (97%)

  19. Estructura Reunión grupo, Junio 2014

  20. Estructura Reunión grupo, Junio 2014 Algunos picos en EM: 270/272 242/244 106 78

  21. Estructura Reunión grupo, Junio 2014

  22. Estructura Reunión grupo, Junio 2014 C15H13BrN2O3 IDH = 15 – 14/2 + 2/2 + 1 = 10 1696 cm-1nC=O 1550 y 1369 cm-1nNO2 IR 13C RMN d (ppm) 198.21 C=O 152.52 C 148.96 CH 138.23 C 137.14 CH 132.08 CH 129.34 CH 127.67 CH 121.96 CH 121.70 C 79.53 CH2 40.56 CH2 38.79 CH3 (x 2) (x2) 11 Csp2 • FALTA: • Br Sustituyente • 2N • 20 • TOTAL: C15H13O • N + NO2 3 Csp3

  23. Estructura Reunión grupo, Junio 2014 X

  24. Estructura Reunión grupo, Junio 2014 8.673 8.670 8.004 8.001 7.997 0.003 0.003 C15H13BrN2O3 0.003 0.006 8.667 8.664 0.004 1H RMN 8.66ppm 1H, ddd 4.8, 1.7, 0.9Hz 0.016 0.026 8.657 8.654 7.99ppm 1H, dt 7.8, 1.0Hz 7.978 7.975 7.971 0.005 8.652 8.649 7.861 7.856 0.005 0.026 7.836 7.830 0.026 7.83ppm 1H, td 7.8, 1.7Hz 0.006 7.810 7.804 Tablas 7.47ppm (2H, d, 8.5Hz) 7.26ppm (CDCl3) 7.20ppm (2H, d , 8.5Hz) c da = 8.59 db = 7.38 dc= 7.75 7.83ppm (1H, td, 7.8, 1.7Hz) d b 7.99ppm (1H, dt, 7.8, 1.0Hz) e a 7.49ppm (1H, ddd, 7.8, 4.8, 0.9Hz) 3Jab= 4-6 3Jac= 0-2.5 3Jad= 0-2.5 3Jae= 0-0.6 3Jbc= 7-9 3Jbd= 0.5-2 8.673 8.670 0.003 0.016 8.667 8.664 AA’XX’ 7.49ppm 1H, ddd 7.8, 4.8, 1.4Hz 0.026 8.66ppm (1H, ddd, 4.8, 1.7, 0.9Hz) 8.657 8.654 8.652 8.649

  25. Estructura Reunión grupo, Junio 2014 X

  26. Estructura Reunión grupo, Junio 2014

  27. Estructura Reunión grupo, Junio 2014 C15H13BrN2O3 Los H de los 2 CH2 son diastereotópicos () Hay 5 señales en 1H RMN de 1H cada una Que corresponden en 13C RMN a CH2CH2 y CH 1H RMN 4.804 4.783 0.0215  4.77ppm 1H, dd 12.3, 6.5Hz * 0.0415  4.763 4.741 2Jgem = 12.3 Hz 4.267 4.244 4.221 4.682 4.654 0.023 0.028 4.65ppm 1H, dd 12.6, 8.4Hz 0.042 4.640 4.612 0.051 4.216 4.193 4.170 0.023 Teórico: 4.22ppm (1H, dddd) 8.4, 7.2, 6.9, 6.5Hz (Jmedia 7.3Hz) Experimental: 4.22ppm (m) 4.22ppm 1H, dt 15.3, 6.9Hz 2Jgem = 18.3 Hz 3.634 3.611 3.855 3.831 0.023 0.024 3.59ppm 1H, dd 18.3, 6.9Hz 3.81ppm 1H, dd 18.3, 7.2Hz 0.061 0.061 3.573 3.550 3.794 3.770

  28. Estructura Reunión grupo, Junio 2014 C15H13BrN2O3 Tenemos: • El NO2 no está en la piridina ni el anillo bencénico (los H aromáticos salen a 7.47 y 7.20) • Un CH2 está muy desapantallado(dC=79.53 y dH=4.77 y 4.65)  estará unido al NO2 • El Br será un sustituyente del anillo bencénico (Csp2 a 121.7ppm)

  29. Estructura Reunión grupo, Junio 2014 C15H13BrN2O3 4 Posibilidades: 7.78 120.3 • 127.4 • 163.5 • • 153.6 • • 7.38 139.2 137.8 7.51 7.01 Los Csp2 cuaternarios en el espectro están a: 152.52, 138.23 y 121.70 Y los H del anillo bencénico a: 7.47 y 7.20 7.78 120.3 • 120.3 • 163.5 • • 153.6 • • 7.38 139.2 147.7 7.51 7.01

  30. Estructura Reunión grupo, Junio 2014 - CO F. a 106 78 F. a - CO 270/272 240/242 EM - CO F. a 78 106 • • + + F. a - CO 270/272 240/242

  31. Estructura Reunión grupo, Junio 2014 C15H13BrN2O3 2 Posibilidades: 7.78 120.3 • 127.4 • 163.5 • • 153.6 • • 7.38 139.2 137.8 7.51 7.01 Los Csp2 cuaternarios en el espectro estan a: 152.52, 138.23 y 121.70 Y los H del anillo bencénico a: 7.47 y 7.20 7.78 120.3 • 120.3 • 163.5 • • 153.6 • • 7.38 139.2 147.7 7.51 7.01

  32. Estructura Reunión grupo, Junio 2014 • HMBC: HeteronuclearMultiple-Bond Correlation • Acoplamientos C-H a mas de 1 enlace 2JC-H y 3JC-H • 1JC-H señales de cruce dobles C15H13BrN2O3 • Jgem = 18.3 Hz •

  33. Reunión grupo, Junio 2014

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