Synthetic Studies on Quinine: Quinuclidine Construction via a Ketone Enolate Regio- and Diastereoselective Pd-Mediated Allylic Alkylation OMe N OH N Deidre M. Johns, Makoto Mori, and Robert M. Williams Department of Chemistry, Colorado State University Organic Letters 2006, ASAP Current Literature, August 12, 2006 Grace Woo @ Wipf Group 1600s/Europe 1900s-present/Versatile Catalysts and Timeline-Quinine Quinine was first used to Ligands in Asymmetric Synthesis treat malaria in Rome in Site of attachment to a polymer 1631, where malaria was chain epidemic and caused countless deaths in Europe. Derivatization Site Stereochemical HO N differentiation 10 Site of quaternary salt 11 3 formation N 2 7 5 2' N 8 1 9 6 1' N 1940s-present/Total Syntheses 4' 1820/Pelletier and Caventou OH Woodward and Doering Two French chemists isolated 8' 5' cinchonidine, R=H Uskokovic quinine from the bark of cinchona 7' quinine, R=OMe R Stork tree which are found in the eastern Jacobsen slopes of the Andes mountains from OMe Kobayashi N Venezuela to Bolivia, and the natives OH N called the cinchona tree “quina-quina” (“bark of barks’, Williams known as “fever stick”). Natives 1820-1930s/Searching for Alternative Methods Bark was dried, ground to a fine powder and mixed into Pelletier and Caventou, Hofmann, Rabe a liquid (usually wine) before being served. Streaker (1854 Emperical formula C20H24N2O2) Effective muscle relaxant and antipyretic agents. Perkins, Prostenik and Prelog D. A. Casteel in Burgers Medicinal Chemistry and Drug Discovery, 5th Ed., Vol. 5 (Ed.: M. E. Wolff), Wiley, NewYork, 1997, Chap. 59, p. 16. Grace Woo @ Wipf Group Treatments Cinchona has been used for a number of medical reasons such as: • Treats malaria • Kills parasites • Reduces fever • Regulates heartbeat • Calms nerves • Stimulates digestion • Kills germs • Reduces spasms • Kills insects • Relieves pain • Kills bacteria and fungi • Dries secretions Malaria has been designated as “the most significant disease for world civilization over the past three millennia”. … and the quinine, the most celebrated cinchona alkaloid that was claimed as “the drug to have relieved more human suffering than any other in history’. D. A. Casteel in Burgers Medicinal Chemistry and Drug Discovery, 5th Ed., Vol. 5 (Ed.: M. E. Wolff), Wiley, NewYork, 1997, Chap. 59, p. 16. Grace Woo @ Wipf Group 1918/Rabe and Kindlers’ Synthetic Development of Quinine “Uber die Partialle Synthesedes Chinins” /C8-N1 Bond Disconnection OMe N OH N OMe OMe NaOEt, EtOH; MeO OMe 1 NaBrO 25%, overall O H 8 N N + N N H Br O O H O N N N N quinotoxine quinidinone quininone Al powder NaOEt/EtOH; 12% MeO MeO OMe OMe OH H H OH H N H N N N + + + OH OH H H H H N N N N epiquinidinine quinidinine quinine epiquinine The first major step towards the synthesis of quinine! P. Rabe, K. Kindler, Ber. Dtsch. Chem. Ges. 1918, 51, 466. Grace Woo @ Wipf Group April 11, 1944/Woodward’s Formal Total Synthesis of Quinine C8-N1 Bond Disconnection 1. NaOMe, MeOH, 1. H2NCH(OEt)2; 94% N 220 oC; 65% HO 2. 80% H SO ; NaOH, N HO CHO 2 4 2. H2, Pt, AcOH HO Ac crystallization, H+; 64% N 3. Ac2O; 95% Me 2 3. Piperidine, HCHO, EtOH; 61% 3 4 1. H , Ra/Ni, EtOH, 150 oC CH2CO2Et 2 H 205 bar; 1:1 cis(cryst)/trans(oil) 1. EtO-N=O, NaOEt, EtOH; 68% H Me 2. H Cr O , AcOH, Et O, H O 2. H2, Pt, AcOH NMe3I 2 2 7 2 2 N H diastereomer separation; 28% O Ac 3. MeI, K2CO3; 91% H N Me 5 6 Ac CO Et 2 H CH2CO2Et OMe 1. 60% KOH, 180 oC; H KCNO; 40% 1. , NaOEt N N 2. dilute HCl, EtOH, reflux; 100% H N Bz 3. PhCOCl, K CO ; 96% N 2. 6 N HCl,reflux; 50% O 2 3 3. resolution w/ Bz D-dibenzoyl tartrate; 11% 8, quinotoxine 7, Homomeroquinene OMe H H 8 N Rabe's 1918 protocol 1 N OH H 1, quinine R. B.Woodward,W. E. Doering, JACS 1944, 30 mg 66, 849; R. B. Woodward, W. E. Doering, OMe JACS 1945, 67, 860. Grace Woo @ Wipf Group 57 Years Later…2001/Stork’s First Stereoselective Total Synthesis of Quinine-C6-N1 Bond Disconnection OTBDPS Me MeO i. LDA, THF, -78 oC 1. DMSO, (ClCO)2, TEA; 85% ii. ; 70% N TBDPSO 2. PPh3, THF; 81% OH N 3 3. NaBH4, MeOH/THF; 91% MeO 15 16 OHC N3 14 N OTBDPS OH H HF, ACN; 95% MsCl, py, DCM N N N N ACN, reflux; 68% H H H H MeO MeO 17 18 19 N N OMe H H N 1. NaH, DMSO N OH 2. O ; 78% 2 H 1, quinine OMe G. Stork, et al JACS 2001, 123, 3239. Grace Woo @ Wipf Group 2004/Jacobsen’s First Catalytic Asymmetric Total Syntheses of Quinine and Quinidine C8-N1 Bond Disconnection O O O EtO P O O N Ph EtO H n-BuLi, THF N Ph 20 H + >50:1 E/Z; 84% O TBSO 22 TBSO H 21 O O Ra/Ni, H2, 650 psi; methylcyanoacetate, N Ph 89% H (S,S)-23, t-BuOH, C H ; 6 12 CN 91%, 92%ee 24 TBSO CO2Me O Cbz NH 1. LAH, THF; CBz2O, 25 TEA; 51% N tBu 2. TPAP, NMO, DCM TBSO CO2Me 3. methyltriphenylphosphonium TBSO bromide, KOtBu; 73% cis/trans=1:1.7 26 ]LDA tBu 3:1 Cbz N Al O 1. TBAF, THF 2. TPAP, NMO, DCM; 86% tBu 3. Cl2CHB(pinacolate), CrCl2, LiI, THF; >20:1 E/Z, 79% B O O 27 tBu 2 (S,S)-23 Grace Woo @ Wipf Group I. T. Raheem, S. N. Goodman, E. N. Jacobsen, JACS 2004, 126, 706. 2004/Jacobsen’s Catalytic Asymmetric Total Syntheses of Quinine and Quinidine C8-N1 Bond Disconnection Cbz Cbz Br N N PCy2 1. Pd(OAc) , 28, K PO , THF; MeO 2 3 4 MeO OMe + >20:1 E/Z, 89% N B MeO O O 28 28 27 29 N Cbz H N 1. ADmix-!, CH3SO2NH2, Et2AlCl, thioanisole o tBuOH, H2O; >96:4 dr, 88% "W, 200 C, 20 min; 68% H N 2. 1. Trimethylorthoacetate, N OH PPTS (cat), DCM O MeO H ii. acetyl bromide, DCM 1, quinine iii. K2CO3, MeOH; 81% 30 N OMe 16 longest linear steps with overall yields of ca. 5% I. T. Raheem, S. N. Goodman, E. N. Jacobsen, JACS 2004, 126, 706. Grace Woo @ Wipf Group 2004-5/Kobayashi’s Stereocontrolled Synthesis of Quinine and Quinidine C8-N1 Bond Disconnection HO 9 steps PivO o-NO2C6H4SeCN, AcO 1. TeocCl, K2CO3, THF; 92% PBu3 then H2O2; 83% 2. NaH, EtOH; 82% TBDPSO NTeoc OH TBDPSO NBn 32 30 31 MeO P(=O)(OEt)2 MeO 1. 3% HCl MeOH 35 NTeoc 2. PCC; 77% OHC N TBDPSO NTeoc NTeoc NaH, THF; 95% N 33 34 36 MeO MeO HO AD-mix-!; 72% i. MeC(OMe)3, PPTS O NTeoc ii. TMSCl NTeoc OH iii. K2CO3, MeOH; 86% N N 37 38 MeO H O CsF 78% NTeoc H N 9 steps from intermediate DMF-tBuOH N OH 31, with overall yields of N 39 H 1, quinine ca. 22.1% OMe J. Igarashi, M. Katsukawa, Y.-G. Wang, H. P. Acharya, Y. Kobayashi, TL 2004, 45, 3783; J. Igarashi, Y. Kobayashi, TL 2005, 46, 6381 Grace Woo @ Wipf Group 2006/Williams’ Synthetic Studies on Quinine C3-C4 Bond Disconnection Rabe Williams Disconnection Jacobsen 3 Kobayashi 2 Disconnection 7 4 5 8 N 1 6 9 OH Stork Disconnection N 1, quinine OMe 3 4 3 H NHR3 X2 4 1 N N X O 1 Pd(0)-mediated 8 R O 6 8 4 OH cyclization OR1 OH MeO OAc (C3-C4 ring closure) N N N OMe 42 OMe 41 40, 7-hydroxyquinine Ph O O NHR3 44, Willliam's lactone 1 asymmetric Ph N R O 2 8 CO2R aldol Cbz MeO (setting stereo- + chemistries at C8/C9) N CHO 43 MeO D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap. N Grace Woo @ Wipf Group 45 2006/Williams’ Synthetic Studies on Quinine Asymmetric Aldol Reaction CHO MeO NHBoc Ph O O 1. H2, Pd/C Ph Ph Ph Ph 45 N 2. ZnCl2, MeOH TESO o CO2Me NaHMDS 1. TBAF, -78 C to rt; 76% Ph OTES 3. Pb(OAc)4 CbzN O CbzN O N MeO TBSCl; 97% Cbz 2. TESOTf, DMAP; 99% 4. H , Pd/C, (Boc) O; MeO 2 2 O OTBS 79%, 4 steps N 44 46 N 48 Preparation of Piperidine Derivative 47, >30:1 dr NHBoc 1. DIBALH; 81% AcO 7 OMs H TESO 2. BnO(CH2)3MgBr; 87% BocN CO2Me H 3. Ac2O OTES TESO MeO BocHN MeO MeO 4. H2, Pd/C OAc Q NHBoc N 5. MsCl N OAc 48 N 49 C8-C7 conformation required 50 for cyclization of C7-(R) 1. DIBALH; 81% 2. BnO(CH2)3MgBr; 87% AcO 7 HO OMs BocN H OBn 1. DMP; 85% NaH. THF; OTES 99% TESO AcO OTES BocHN BocHN 2. DIBALH; MeO MeO 67%, >20:1 dr MeO OAc Q NHBoc 3. Ac2O 4. H , Pd/C N N 2 N H 5. MsCl; 77%, 3 steps C8-C7 conformation required 51 52 53 for cyclization of C7-(S) D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap. Grace Woo @ Wipf Group 2006/Williams’ Synthetic Studies on Quinine Completion of Allylic Alkylation Precursor BocN HN TESO TESO BnO 1. LAH; 94% I MeO OAc 2.