Baran Lab Stephen Buchwald Tom Maimone -This presentation will try to cover the work of professor Buchwald in somewhat chronological order until 2007. -It is fairly comprehensive, with ~ 125 papers referenced. main topics: I. Zirconium Chemistry (1986-1999) II. Titanium Chemistry (1991-2000) III. Copper Hydride Chemistry (1999-2005) III. Cross-Coupling (Pd, Cu) (1994-present) Biographical: I. Zirconium Chemistry -Born 1955 in Bloomington, IN The chemistry of Zirconium-alkyne complexes: JACS, 1986, 108, 7441. Bond length 1.295 A -Sc.B Brown University 1977: Li (between double and triple) (Kathlyn Parker and David Cane) PMe3 -Ph.D Harvard 1982: Me Cp2Zr Cp2Zr PMe3 (Jeremy Knowles) Cl ZrCP2 -Postdoc Caltech 1982-1984: PMe3 Cp2Zr air and moisture (Robert Grubbs) Me THF sensitive -hobbies include sports, food, and cats (as of 1988) O N and acylic alkynes: Cp2Zr Professional Appointments: Cp2Zr JACS, 1987, 109, 2544 O CN 1984 assistant professor MIT PMe 1989 associate professor MIT 3 R R 1993 full professor MIT Cp2Zr 1997 Camille Dreyfus Professor O R Cp2Zr PMe3 R Cp2Zr ZrCp2 over 300 publications O and acylic alkenes: over 35 patents R R JACS, 1987, 109, 2544. Selected Awards: PMe3 Arthur C. Cope Scholar ACS Organometallic Chemistry Award (2000) Cp Zr Cp2Zr 2 Cp2Zr R Siegfried Medal Award (2006) ACS Creative Work in Synthetic Chemistry (2006) an excellent review: National Academy of Science (2008) Chem. Rev. 1988, 88, 1047 1 Baran Lab Stephen Buchwald Tom Maimone I. Zirconium Chemistry Zirconocene-Thioaldehyde complexes: JACS, 1987, 109, 1591. Cyclopentenone synthesis: JACS, 1989, 111, 9113 JACS, 1988, 110, 3171 Me Me3P Cp O PMe 2 3 ZrCp Zr R SH ZrCp2 Δ 2 R CO Cp2ZrMe2 R S Cp2Zr R S (-CH4) (-CH4) PMe3 R R N C H also see benzyne complexes: JACS, 1986, 108, 7411. N N ZrCp 2 ZrCp2 benzene PMe3 R S Cp2ZrPh2 Cp2Zr Cp2Zr R S 80 °C PMe3 Butenolide Synthesis: TL, 1988, 29, 3445 O Similar elaboration is possible: TL, 1987, 28, 3245. OH O Cp OH I2 O 2 1. Cp2Zr(H)Cl Cp Zr R C N Zr H O+ 2 Cp Zr 3 O 2 N CO Cl R R Cis Difunctionalization of Cyclic olefins: Organomettalics, 1991, 10, 537. Double complexes can be prepared: JACS, 1987, 109, 4396 O ZrCp Cp2 2 Zr CO Li Me ZrCp2 80 °C MeOH ZrCp2 + Cp2Zr(Me)Cl PMe3 E + other SCl2 THF Δ isomers E S Li Cp2Zr ZrCp2 Me 2 Baran Lab Stephen Buchwald Tom Maimone I. Zirconium Chemistry Application to Natural Product Synthesis: Pyrrole Synthesis: JACS, 1989, 111, 776. Duocarmycin pharmacophore: JOC, 1992, 57, 6380. SiMe3 SiMe3 SiMe3 I CH R N 3 Li N R N R I I Cp2Zr Br Cp2Zr Cp2Zr Cl THF CH3 N I O t-BuLi 2 1. BBr3 Cp2Zr(Me)Cl 2. NaH O N MeO N R2 R1 R2 R1 R R CO 1 2 OMe R Cp Zr N 2 R H N SiMe3 Tetrahydropyrroloquinolines: JACS, 1996, 118, 1028. Me I 1. Pd(PPh3)4 Benzothiophene Synthesis: JOC, 1989, 54, 2793 as Me N MeO Br MeO NHMe K2CO3 R R R before HO Et3N Zr S N 2. BBr3 R SiMe3 SCl2 NH2 Cp2Zr TMS TMS 3. MeI N THF CO2Et H Dehydrobufotenine R R R R R Regioselective, Directed Meta Acylation: JACS, 1998, 120, 9119. Indole Synthesis: JACS, 1991, 113, 4685., JACS, 1994, 116, 11797 DG Cp2 DG Me Zr Br ZrCp X t-BuLi 2 X = H R X = I Cp2Zr(Me)Cl N N N Bn Bn Bn t-Buli + O 1. H3O or I2 Cp2Zr(Me)Cl + 2. H3O I I I Cp2Zr DG Me DG DG I Cp2 2 ZrCp2 Zr Δ R-CN ZrCp N N N N 2 Bn Bn Bn R 3 Baran Lab Stephen Buchwald Tom Maimone I. Zirconium Chemistry Interesting Organometallic Structures: Use of Zirconocene in Biaryl Synthesis: JACS, 1999, 121, 9469. cyclic 7-membered cumulene: JACS, 1993, 115, 10394. SiMe R R 3 R ArBr, TMS TMS Cp2 TMS Br Pd (dba) ZrCp2(X) Zr 1. n-BuLi 2 3 TMS Cp2Zr ZrCp ligand Cp Zr ZrCp2 2. Cp2Zr(Me)Cl 2 2 TMS PdAr TMS TMS SiMe TMS 3 desired product product formed R R I Double alkyne Zirconocene Complex: JACS, 1994, 116, 5471 I2 ZrCp2(X) Ar Ar TMS Interesting Organometallic Structures: TMS Cp ZrCl bimetallic Zirconium complex containing an in-plane briding aromatic ring: 2 2 JACS, 1989, 111, 397-398. ZrCp2 Me Me TMS Br Br TMS t-BuLi Cp2Zr ZrCp2 desired product Cp2Zr(Me)Cl Cp ZrCl MeO OMe MeO OMe 2 2 TMS TMS TMS 80°C PhH ZrCp 2 ZrCp2 ZrCp2 H3 C TMS TMS Cp2Zr ZrCp2 TMS actually formed MeO OMe 4 Baran Lab Stephen Buchwald Tom Maimone II. Titanium Chemistry Catalytic Reduction of Esters to Alcohols: JACS, 1991, 113, 5093 O JOC, 1992, 57, 3751 NaOH n-BuLi R OEt Cp TiCl R OSI(OEt) or HCl 2 (10%) 3 R OH (5%) HSi(OEt)3 (2 eq.) Asymmetric Hydrogenation of imines: JACS, 1992, 114, 7562. JOC, 1993, 58, 7627. JACS, 1994, 116, 8952 (scope and limitations) JACS, 1994, 116, 11703 (Kinetic and mech. analysis) N R 1) n-BuLi HN R X (2 eq) R R X Ti H R R 2) PhSiH Ti 3 H2 (2000 psi) (2.5 eq) 65 °C thought to (2 - 10 %) stablize active catalyst presumed active catalyst 5 Baran Lab Stephen Buchwald Tom Maimone II. Titanium Chemistry Kinetic Resolution of Racemic pyrrolines: JACS, 1994, 116, 9373. Asymmetric Hydrogenation of Unfunctionalized trisubstituted usual olefins: JACS, 1993, 115, 12569. suspects R3 Ar Ar R Ar R N 1) n-BuLi 3 R N R N H X (2 eq) R1 R2 X Ti H Ti R R Asymmetric Enamine Hydrogenation: JACS, 1994, 116, 5985 2) PhSiH3 H2 (2000 psi) 1 2 (2.5 eq) 65 °C thought to usual N N (2 - 10 %) stablize active suspects catalyst presumed active catalyst Enantioselective Ketone Hydrosilylation: JACS, 1994, 116, 11667. O 1) n-BuLi 3) OH X (2 eq) Ar R2 Ti aromatic ketone X Ar R 2) Me 4) TBAF 2 give best ee's or HCl OSiMe3 SiMe3 5% H n (5 eq) polymethyl - hydrosiloxane Catalytic Reduction of Lactones to Lactols: JACS, 1995, 117, 12641 JOC, 1997, 62, 8522. Cp2Ti O Cl O O 2 O OH 2 mol% TBAF/Alumina (1%) PMHS (5 eq) 6 Baran Lab Stephen Buchwald Tom Maimone Reductive Enyne Cyclizations with a practical Titanocene reaent: JOC, 1992, 57, 5803. JOC, 1996, 61, 2713. II. Titanium Chemistry JACS, 1996, 118, 9450 One-pot conversion of amides to aldehydes: ACIEE, 1996, 35, 1515. JACS, 1999, 121, 5881 O Ti(O-iPr) (1 eq) + O possibly 4 H3O R R via Cp2TiCl2 R NR2 Ph2SiH2 (1.1 eq) NR2 HTi(O-iPr) EtMgBr CO H 3 X X Cp2Ti X O Me Titanocene-based Indole Synthesis: JACS, 1998, 120, 3068. R N C X = O, C(CO2Et)2 N X can be troublesome, Cp2TiCl2 MeMgBr R Cl Me reacts with catalyst MgBr Ti Ti R Use of R3SiCN as the carbon monoxide equivalent: JACS, 1993, 115, 4912. air and Cp2 Cp2 R moisture R R JACS, 1994, 116, 8593. stable R3Si CN R3Si NC low effective concentration Δ > 95% > 5% of isocyanide R R R Reductive Enone Cyclization: JACS, 1995, 117, 6785. via: Me Br2 JACS, 1996, 118, 3182 Br TiCp2 O Ti HO X Br O 1. Me Cp2Ti Cp2 Cp2Ti(PMe3)2 (10%) R R R PMe (80%) X 3 H Me 1) BnNH2 Ph2SiH2 X Pd(dba)3 Enyne and Dienyne Cycloisomerization: JACS, 1999, 121, 1976. 2. Work up Ph2SiH2 NaOt-Bu R 2) Pd/C γ−Butyrolactone synthesis: JACS, 1996, 118, 5818. Ph2(H)Si Me R JACS, 1997, 119, 4424 CO NH H O 2 4 Cp2Ti(CO)2 Me X X X R O O Cp2Ti PhMe Cp2Ti(PMe3)2 100 °C O CO H N H H Enantioselective Titanium-mediated Pauson-Khand: JACS, 1996, 118, 11688. R JOC, 1999, 64, 5547 JACS, 1999, 121, 7026 - 7033 R CO R OC Ti E CO E O E E typical ee's = 70 - 90 7 Baran Lab Stephen Buchwald Tom Maimone III. Copper Hydride Chemistry Asymmetric reduction of cyclic enones: JACS, 2000, 122, 6797. O O Asymmetric Ester Conjugate Reduction: JACS, 1999, 121, 9473. CuCl (5%) NaOt-Bu (5%) CuCl (5%) Me Me O NaOt-Bu (5%) Me O (S)-p-tol-BINAP (10%) PMHS (1.05 eq.) Me3Si O Si O SiMe3 R R OEt (S)-p-tol-BINAP (10%) R R OEt H PMHS (4 eq.) n PMHS (E) and (Z) isomers give opposite enantiomers of similar ee One-pot Synthesis of 2,3 disubstituted cyclopentanones. OL, 2001, 3, 1129. O Ph2 Asymm. Si O con. red. O O TBAT Bn Ph2SiH2 BnBr R R R R TBAT = (Bu4N)Ph3SiF2 8 Baran Lab Stephen Buchwald Tom Maimone III. Copper Hydride Chemistry Conjugate Reduction by Copper carbene complex: OL, 2003, 5, 2417. Dynamic Kinetic Resolution via conjugate reduction: JACS, 2002, 124, 2892. iPr Me O Me O iPr N A CuCl R OEt NaOt-Bu R OEt N iPr O PHMS O t-BuOH iPr A R R yields typically ~ 90% Total synthesis of Eupomatilone -3: ACIEE, 2005, 44, 6177. O B(OH) OMe 2 Br 1) Pd MeO O MeO CO2Me 2) BH3 THF 3) MnO2 MeO OMe 4) MeO O MgCl OEt OMe O Me O MeO O Enantioselective Lactam/lactone conjugate Reduction: JACS, 2003, 125, 11253. O O O O O usual usual CuCl2 2H2O X suspects X X suspects X (R)-MeO-BIPHEP PMHS NaOt-Bu R R R R O Me O X = O, N-PMP OMe OMe Asymmetric Reduction of enamides: PNAS, 2004, 101, 5821.