Baran Group Meeting Lisa M. Barton The Barton Family Tree 3/11/17 Sir Derek H.R. Barton Professor from 1946 until death in 1998 *See Baran Group Meeting, Gutekunst, 2010 Paul De Mayo Severyn Sternhell Samir Z. Zard Jack E. Baldwin D. John Faulkner University of Western Ontario University of Sydney and École polytechnique Imperial College Imperial College Graduate Student 53'–54' CSIRO Graduate Student 79'–83' *See Baran group meeting *See Baran group Graduate Student 58'–60' by Georgiades, 2006 meeting by O'Malley, 2005 Graduate Student 60–65' Graduate Student –65' David Crich Philip D. Magnus Anthony G.M. Barrett University of Illinois at Derrick L.J. Clive Imperial College Imperial College, Norwestern, Chicago and Wayne State University of Alberta *See Baran group and Colorado State University Graduate Student meeting by Yan, 2013 Graduate Student 73–75' Graduate Student 81'–84', Graduate Student 65'–68' Post Doc 84'–85' E. W. Warnhoff Gerhard Quinkert Bertram O Fraser–Reid Ezio Rizzardo Robert Vyent Stick William B. Motherwell University of Technical University of Braunschweig University of Waterloo CSIRO University of Western Imperial College and UCL Western Ontario and Goethe University and Duke Post Doc 73'–74' Australia Post Doc 75'–77' Post Doc 54'–56' Post Doc 57'–59' Post Doc 64'–66' Post Doc 73'–75' Darshan Ranganathan Steven Ley Steve Davies Gerhard Bringmann Jieping Zhu Delhi University and Indian Imperial, Cambridge and Oxford University of Munster and École polytechnique Institute of Technology Trinity College Post Doc 77'–78' Wurzburg Post Doc 91'–92' Post Doc 66'–69' *See Baran group Post Doc 78'–79' meeting by Jorgensen, 2012 Post Doc 74'–75' *Covered in previous group meetings Baran Group Meeting Lisa M. Barton The Barton Family Tree 3/11/17 Samir Z. Zard Synthesis of the Core of Structure Polycyclic Alkaloids SCSOEt 1) AIBN, nBu SnH NBoc 3 • B.Sc. first at the American University of Beirut then at Imperial NBoc MeO O 79% College (1978) 2) TBAF OMe OMe N SCSOEt 93% • Ph.D. at ICSN under Sir Derek Barton (1979-83) N TBS TBS • Director of Research - Exceptional Class at the CNRS and 10%dilauroyl peroxide CO Me Professor of Organic Chemistry at the École polytechnique 3 steps reflux DCE 2 66% MeO (1986-present) NBoc OMe • Recipient of the Organic Chemistry Division of the French H N N Chimcal Socity (1992), Clavel-Lespiau Prize (1995), Rhodia H N TFA reflux H Prize (2000), Dargelos Prize (2006), Novartis Chemistry N N 71% CO M Lectureship (2006-07), Silver Medal of the CNRS (2007) and H 4:1 cis:trans 2 O H MeO e Croix de Chevalier de la Légion d'Honneur (2007) (±)–cis- MeO2C H OMe • Over 47 authorships with Barton including the reduction of xanthates, synthesis of pyrroles, deethyleburnamonine Tett. Lett. 2002, 43, 4683 decarboxylation, deoxygenation, the synthesis of corticosteroids, and multiple radical additions ( )–Matrine ± CO2tBu MeO2C CO2Me O O both pieces 3 steps Xanthates Radical Chemistry in Total Synthesis from commerically + •Xanthates can serve as a reversive radical trap to extend the lifetime of R•, allowing the radical N N N available starting H S material to undergo inter– and intramolecular reactions that would not normally occcur H H H O EtO S S H cat. lauroyl peroxide R benzene S OEt R MeO C CO Me MeO C CO Me MeO C CO Me Peroxide 2 2 2 2 2 2 S Benefits O O O R S R' ' • reagents are cheep H H S EtO R • no metals N N SCSOEt N SCSOEt S R • can be run at high EtOSCS CO2tBu + H H + H H EtO R R concentrations and in water CO2tBu CO2tBu cat. lauroyl peroxide R' • scalable N benzene N 3:1 N • initiators other than peroxides 80% can be used 18% R S S O O O ' • high functional group tolerance S R 30% R • can easily remove with nBu3Sn lauroyl peroxide OEt S OEt 2-propanol R SH 89% heat S MeO C CO Me R OEt MeO2C CO2Me MeO2C CO2Me 2 2 O O O BH3•Me2S; H 1) CF CO H H H 2M HCl, N 3 2 N N reflux 90% Have been used to access: (±)–Matrine H H 2) Barton's H H H H • Bridging rings • heterocyclic structures from α-chloroketones 85% H CO tBu CO2tBu conditions 2 • β-lactam 4 membered ring • alkaloid structures 56% • homodimers • many more Chem. Eur. J. 2006, 12, 6002 N N N 3:1 • Not covered: the use of xanthates as chain-transfer agents in controlled radical polymerization O O 65% O Ang. Chem. Int. Ed. 1998, 37, 1128 Baran Group Meeting Lisa M. Barton The Barton Family Tree 3/11/17 Nitrogen Centered Radicals O Thiocarbazones O SAr lauroyl peroxide O S H H 1)TFA H H OTBS N S MeO OTBS 88% MeO O A N 60% H2N 2) ArSH N S A S Ph H N 80% N Ph H BnO BnO cystalline, made in one step Bu3SnH O O 1)LAH from methylhydrazine, CS2 and AIBN only trans ring junctions observed 66% MeI 14:1 para/ortho 2)DMDO 92% N S HO N HO SO Ar N 65% N N H 2 S MeO H H Ph Ph Ph H SnBu3 1)H2, Pd/C MeO OTBS Ph H H quant Tett. Lett. 1995, 36, 8791 N HO 2) Na/Hg N Oxime Derivatives Ph Fortucine 50% BnO (originally assigned as kirkine) O O 1) NH2OH, HCl O O Bu3SnH 88% Angew. Chem. 2008, 47, 1436 2)BzCl, pyridine N AIBN N N Ph Ph (–)-dendrobine Ph Ph H NHMe Can also be used to open strained ring systems 1) Im2CO OBz 1) Bu3SnH, 2) MeNHOH N AIBN CN Me N 1) NH2OH, HCl 3) BzCl, Et3N 71% OH 2) BzCl, pyridine + H H OH 49% O O 2) aq KOH O CN Me 68% 3) Bu3SnH (+)-trans- AIBN 1) CH Br 89% 3% O vervenol 2 O K2CO3 With hydroxamic acids: 2) Ac2O, pyr Bu3SnH 88% 1) MeNHOH AIBN 2) BzCl, pyridine 1)TMSI, HMDS 1)Co (CO) 60% Et AlCN O N O N 2 8 N 2 2) PhSeBr 2) NMO•H O O O O 77% 2 NM MeBzON 72% ACN e Cl Me H H Me H 3) MCPBA 3) Pd/C, H2 Tetrahedron. 1995, 51, 6517 OAc 60% OAc 51% OAc Use In Total Synthesis 1) NaBH4 O 2) O OTBS BnO 1)NaBH4 Cl pTsOH 1) O 2) PhOC(S)Cl N LDA CH3 O O N O O OTBS DMAP MeONa N Dioxane/ N MeO MeS2CPhN N 60% H H MeOH H2O O H H Me Product MeS2CPhN O Me 3) Bu SnH, H Me H 81% 3 NC OAc NC OAc VAZO 75% based 2) TBSOTf N NC * OH on BnO 83% Quant. NPhCS2Me recovered O diastereomer MeO JACS. 1999,121, 6072 1:1 at indicated center Baran Group Meeting Lisa M. Barton The Barton Family Tree 3/11/17 O O William B. Motherwell Fromation Biaryls Me S R R N –SO Me • B.Sc. and Ph.D. from University of Glasgow under 2 NH James S. Roberts as a Carnegie scholarship holder (1972) • Recieved an ICI Fellowship to conduct independent research at O O the University of Stirling (1972-74) R Me S nBu SnH • Schering–Plough Postdoctoral Fellow with Barton at N 3 AIBN [1,5] Ipso Substiution Imperial College (1975-77) X • Charge de Recherche under Barton at Institut de Chimie des OR Substances Naturelles (ICSN) (1978-83) O O O • Lecturer and Reader at Imperial College (1983-93) R O R Me S Me S • Alexander Williamson Chair of Chemistry at University College •Ortho R group strongly N N London (1993-2012) then Emeritus Professor favors ipso substitution • Visiting professor at Auckland University, Paris-Sud University •Meta favors [1,6] addition and Bordeaux University, Merck-Frosset Lecturer in Canada (1994) •Para has much less of • Fellow of the Royal Society of Edinburgh (2007) an effect • Recipient of Royal Society of Chemistry's Corday-Morgan medal, the Bader award, the RSC •Yields vary widely [1,6] Direct Substiution Tilden Medals and Lectureships (1998-99), the Silver Medal of the ICSN depending on substitution • Editor of Tetrahedron Reports • Co-authored 72 papers with Barton including the radical decarboxylation, radical Can also be used to form hetero–biaryls: deoxygenation, functionalization of saturated hydrocarbons with the GIF system and Me Organobismuth chemistry R1 R1 R1 R1 R1 NH N S S R1: Anomeric Carbohydrate Difluormethylene Derivatives N N N O 87% 69% 38% 29% 64% 19% incorporation AIBN CF2 Glycoside Derivatives 33% [1,6] addition 13% incorporation AIBN made in 1 step from sugar lactones para to NHMe on R1 para to NHMe on R1 OP OP OP OP RX, O F F F O F O O nBu SnH, Also investigated [1,6] vs [1,7] addition R %A %B SPh PhSH 3 R AIBN OR AIBN R F F F F O 4–CH 10 0 O S-centered O O C-centered O O OH 3 O radical O O O O S R radical O R S 2,4,6–CH3 0 36 Only 1 isomer O majority products give only 1 isomer I O 79-92% X H , 14–40% if R nucleophilic radical 2-CO2Me 0 90 Can be further reduced 2 B Pd/C EtO P 27–51% if electrophilic radical A EtO SePh Tetrahedron. 2015, 71, 6701 nBu3SnH OP O AIBN Formation other Heterocycles O S O O F OP O O H O S O F X nBu SnH F Poorer stereoselectivity 1 3 O R R1 O P(OEt)2 compared to other methods, AIBN Mechanism? F O substrate dependent High stereoselectivity O when X=O: 14–73% X= O or S when X=S: 0-94% 78-98% R2 R2 Originally were trying to make substituted styrene derivatives Heterocycles.