Synthetic Studies on : 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 in 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 of 7' quinine, R=OMe R Stork which are found in the eastern Jacobsen slopes of the mountains from OMe Kobayashi N Venezuela to , and the natives OH N called the cinchona tree “quina-quina” (“bark of barks’, Williams known as “ 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 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 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 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. TMSOTf, 2,6-lut. MeO OTMS K2CO3, TEA, DMF; 93%, 2 steps N N 53 54

BnO

BnO 1. 1N HCl N O 2. (COCl)2, DMSO, TEA; TESO 90%, 2 steps H N

MeO OTMS OH 56

N N

55 OMe

D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap. Grace Woo @ Wipf Group 2006/Williams’ Synthetic Studies on Quinine-Key Transformation Pd(O)-Mediated Allylic Alkylation-C3-C4 Bond Formation

Allylic Alkylation of Malonic Ester Derivatives

BnO H H CO2Me CO2Me O 1. CNCO Me O O 2 H H H N NaHMDS; 86% N N 8 + 2. Bu SnOMe OTES 3 OTES OTES Pd2(dba)3 N P(2-furyl)3; 67%, 4 diast N N OMe OMe OMe 56 57 (5%) 59 (11%) 58 (epi-C8, 9%) 60 (epi-C8, 42%)

TMSCl, LHMDS, -78 oC; 59% Regio- and Diastereoselective Allylic Alkylation of Ketone-Derived TMS Enol Ether

BnO H preformed ketone enolate Bu SnF 3 O HO TMSO Pd (dba) 2 3 H N N N N H N P(2-furyl)3 DIBALH H + OH + OH OTES OTES OTES OH OTES N N N N N OMe OMe OMe OMe OMe 40 61 62 63 (2%) 64 (39%) 7-hydroxyquinine D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap. TBAF; 88% Grace Woo @ Wipf Group 2006/Williams’ Synthetic Studies on Quinine Plausible Mechanism for the Key Pd(O)-Mediated Allylic Alkylation

Pd-Sandwich Complex Formation

BnO

TMSO H N

OTES

N OMe 61

Pd-mediated etherification, Claisen Rearrangement Sequence

D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap.

Grace Woo @ Wipf Group Summary

• While the quinine has played an important historical role in , the first stereoselective total synthesis was accomplished by Stork et al, only five years ago. • Since, the Stork’s asymmetric synthesis of quinine, only a handful of alternative syntheses has been published, in which most of them following the classical Rabe’s C8- N1 disconnection strategy to build the quinuclidine ring system. • In Williams group, the synthesis of 7-hydroxyquinine was accomplished by featuring a C3-C4 Pd-mediated SN2’-type cyclization reaction to construct the quinuclidine ring system. • In addition, the establishment of the C8/C9 stereogenic centers were set by the asymmetric aldol reaction developed in Williams’ group, • While 7-hydroxyquinine was successfully synthesized in Williams’ group, this quinine analogue was found to be inactive against two strains of falciparum, a parasite that causes malaria. • The further application of this innovative approach to the total synthesis of the Cinchona is currently being investigated in Williams’ group.

Relevent Readings:

T.S. Kaufmann and E. A. Ruveda ACIE 2005, 44, 854. OMe N

K.K.J. Gawronski Synthesis 2001, 7, 961. OH N

Grace Woo @ Wipf Group