Baran Lab Sir Jack Baldwin Savvas N. Georgiades JACK E. BALDWIN-SHORT BIO REARRANGEMENTS ♦ Born in London in 1938. ♦ Undergraduate studies at Imperial College, London. Obtained his B.Sc. (1st class) in 1960. ♦ Graduate studies at Imperial under the supervision of Nobel laureate, Professor Sir Derek Barton. Structure elucidation of byssochalmic acid using chemical methods. Awarded his Ph.D. in 1964. ♦ Appointed assistant lecturer at Imperial College in 1965. ♦ 1967-Moved to the US to join Pennsylvania State University as Assistant Professor of Chemistry. ♦ 1969-Promoted to Associate Professor. ♦ 1970-Joined the chemistry department at MIT. ♦ 1971-Promoted to full Professor. ♦ March 1972-Returned to the UK as the Daniel Professor of Chemistry at King's College. ♦ November 1972-Back to MIT. ♦ 1978-Elected Fellow of the Royal Society and appointed Waynflete Professor of Chemistry at the University of Oxford, UK. ♦ Held the Waynflete chair at Dyson Perrins Laboratory and then at the Chemistry Research Laboratory for 27 years until his retirement in 2005. ♦ 1997. Awarded a knighthood for his contributions to organic chemistry. ♦ Still maintains an active group at Oxford University. ♦ Awarded many prestigious awards and prizes. ♦ Published more than 600 papers. Second most cited author in Chemical Communications. Author of their most cited publication ever, "Rules for Ring Closure". >>> 2,3-Sigmatropic rearrangements a a b e c e (concerted, favored at low T) b d c d a b e a d b c (stepwise, radical dissocation-recombination, favored at high T) d c Sulfonium ylids, Chem. Commun. 1968 , 18, 1083-1084 1) Et3 OBF4 2) n-BuLi/THF/-70 o C Ph S Ph C S Ph Ph Sulfonium ylids, Chem. Commun. 1971 , 7, 359 OH 1) Br OH n-BuLi/THF -40 oC 2) Me3 OBF4 BF4 SH AREAS OF INVESTIGATION ♦ Biomimetic synthesis of natural products, especially sponge alkaloids and fungal metabolites. ♦ Development of synthetic methodology. ♦ Chemical and biological studies on the biosynthesis of beta-lactam antibiotics. ♦ Parallel synthesis methodology. e O S O Sulfonium ylid readily undergoes 2,3-rearrangement S S 1 Sir Jack Baldwin Baran Lab Allylic ether anions, Tetrahedr on Lett. 1970, 5, 353-356 Allylic disulfides, J. Am. Chem. Soc. 1971, 93, 6307-6308 OH OH O t-BuLi/THF -20 83/17 25 oC: 77/23 S All carbon anionic, Chem. Commun. 1970, 3, 165-166 1) Li/THF/-70 2) -20 oC/5h oC Ts + (T dependence of product distribution) HN quantitative N H Br R2 N N X N Br Diazenes, J. Am. Chem. Soc. 1971, 93, 788-789 N N N R1 H O O 1) Deprotonation 2) 130 o C/30 min N N PPh3 S Mechanism? S Br H N Ts S SMe KOH N H N SMe S 1) NaH MeS 2) 65 o C S Reformatsky-Claisen, Chem. Commun. 1973, 4, 117-118 1) Deprotonation 2) 35 oC/1 min O NH S S >>> 3,3-Sigmatropic rearrangements N-Ammonio-amidates, Chem. Commun. 1970 , 1, 31-32 N S Nucleophilic carbenes, Chem. Commun. 1972, 6, 354-355 Cl Br Benzene rt/98% S + o C: NH2 Savvas N. Georgiades + N N R3 OZnBr O OZnBr R2 O Zn H R4 R1 H R3 O Benzene/80 o C/ H R4 >90% R2 R1 O H H R4 R3 Enol phosphate variant, Chem. Commun. 1973 , 4, 117-118 O O O O P OR P Cl OR 3,3-Rearrangement RO OR Cl O O Cl3 C OR 70% Cl Cl O O P OR OR O N N 2 Sir Jack Baldwin Baran Lab Savvas N. Georgiades >>> Rearrangements of strained dipolar species BALDWIN'S RULES FOR RING CLOSURE Episulfoxides, J. Am. Chem. Soc. 1971, 93, 2810-2812 >>> Primary literature ∆ S O (previously observed and believed to proceed in cheletropic concerted fashion) + SO S OH O 35 oC S O Mechanism? S ♦ Rules apply to cyclic transition states leading to ring formation or intramolecular group transfer. Nucleophilic, radical and cationic processes follow the rules, but not electrocyclic reactions! thiosulfoxylate ♦ Rules only apply to first row elements-"violations" reported for larger atoms (S, Si, etc) due to larger atomic radii/orbital size/bond lengths. S H Chem. Commun. 1976, 18, 734-736 Chem. Commun. 1976, 18, 736-738 Chem. Commun. 1977, 3, 77 Chem. Commun. 1977, 7, 233-235 J. Or g. Chem. 1977, 42, 3846-3852 T etrahed ron 1982, 38, 2939-2947 sulfenic acid At high T (>150 o C) olefin products are observed. Given that mixtures of cis and trans 2-butene are obtained, SO loss likely goes through radical pathway (Tdependent). ♦ EXO process-breaking bond positioned exocyclic to smallest formed ring. ENDO process-breaking bond positioned endocyclic to smallest formed ring. ♦ The rationale lies in the stereochemical requirements of the transition state (distances/ angles) and ability of the system to achieve the required trajectory. Aziridine-N-oxides, J. Am. Chem. Soc. 1971 , 93, 4082-4084 a=180 o H OH T<0 oC N N O Y X Y X X a=109 N TET O T<0 oC N TRIG X Y Y Burgi-Dunitz angle (exclusively trans) O Multisubstituted aziridine oxide gives rise to alternative products. Concerted or radical? o X a=120 o DIG Y X Y 3 Sir Jack Baldwin Baran Lab >>> Digonal Systems (DIG) >>> Tetrahedral Systems (TET) Y X X X X Y 3-EXO-TET allowed X 4-EXO-TET allowed X Y 3-ENDO-TET ??? Savvas N. Georgiades Y Y 5-EXO-TET allowed X X Y X 4-ENDO-TET ??? X 6-EXO-TET allowed 7-EXO-TET allowed X Y 6-ENDO-TET forbidden 3-EXO-DIG forbidden X X 4-EXO-DIG forbidden X Y X 3-ENDO-DIG forbidden 4-ENDO-DIG forbidden X Y Y 5-EXO-DIG allowed Y Y 7-ENDO-TET forbidden X Y Y Y Y 5-ENDO-TET forbidden X Y 6-EXO-DIG allowed 7-EXO-DIG allowed Y X 5-ENDO-DIG allowed Y 6-ENDO-DIG allowed X Y 7-ENDO-DIG allowed >>> Trigonal Systems (TRIG) >>> Example of favored vs. disfavored process Y X X X Y 3-EXO-TRIG allowed 4-EXO-TRIG allowed X Y 5-EXO-TRIG allowed Y MeO2C Y 6-EXO-TRIG allowed 7-EXO-TRIG allowed O 5-EXO-TRIG O X MeO2 C OMe NH2 CO2 Me X 5-ENDO-TRIG MeO2C X Y X Y X Y 4-ENDO-TRIG forbidden 5-ENDO-TRIG forbidden N H >>> Example of exception for second row element: X Y X Y CO2Me 3-ENDO-TRIG forbidden N H 6-ENDO-TRIG allowed 7-ENDO-TRIG allowed SH CO2Me Base 5-ENDO-TRIG S 4 Sir Jack Baldwin Baran Lab >>> Example of competing allowed processes Savvas N. Georgiades >>> Ring closures involving enolates (predominantkinetically preferred) 6-EXO-TRIG O (ENOLENDO)-EXO-TET Y O 5-member or smaller disfavored (treat as ENDO-TRIG) 6-member or larger favored (treat as ENDO-TRIG) Base O HO MeO MO X CO2Me (kinetically disfavored) 6-ENDO-TRIG O Y (ENOLEXO)-EXO-TET All sizes favored (treat as EXO-TRIG) ♦ In cases where an EXO and an ENDO process compete, EXO appears to be predominant for TRIG systems whereas ENDO is predominant for DIG systems. ♦ In many cases kinetics rather than thermodynamics dictate the outcome of the cyclization reaction. OM 5-(ENOLENDO)-EXO-TET >>> Turning a forbidden into an allowed cyclization process O Br Example: X O MO O 5-EXO-TET 5-ENDO-TRIG X OH O NaOMe/MeOH Y OH H O OH + 5-EXO-TRIG (ENOLENDO)-EXO-TRIG 5-member or smaller disfavored (treat as ENDO-TRIG) 6-member or larger favored (treat as ENDO-TRIG) MO OH OH Y (ENOLEXO)-EXO-TRIG OH All sizes favored (treat as EXO-TRIG) OH OM OH OH 5 Sir Jack Baldwin Baran Lab >>> Conversion of penicillin sulfoxides into 6,7-epi-1-oxocephams: BETA-LACTAM TRANSFORMATIONS T etr ahedron 1980, 36, 1628-1630 >>> Ring expansion of penicillins to cephalosporins Chem. Commun. 1987, 2, 104-106 H N R Br S O Br S H N R Ph 3SnH/AIBN/ benzene/reflux/2 h N H N R R (40%) S (35%) N CO2Me Ph 3SnH/AIBN/ benzene/reflux/2 h S S O Br N O H N R H N R R (49%) S (39%) N O CO2 Me CO2 Me O O 27% R S N S Cl2/93% CO2Me H N Cl N OH O CO 2Me CO2Me * O + OH N O O 30% CO2Me Trans:Cis=5:3 H N R SnCl2 OH O OH OsO4/85% N CO2Me O O H N O OH O O CO2 Me S O S O O O 94% CO2Me N H N O O CO2Me H N R S N N O R H N R Ph3 SnAllyl/AIBN/ benzene/reflux/3 h Ac2 O/Me3 P=O/ R toluene/reflux/ 95% O Mechanism? O H N R O O Savvas N. Georgiades Cl N O O O >>> Ring expansion of penicillins to 3-exomethylene cephalosporins H N R O S N CO2Me H N R O Vitamin B12 Co(I) 20-30 min/20 o C S N H N R O S 30% conversion (instability of SM) >95:5 exo:endo O O 93% conversion >98:2 exo:endo SnCl2 or AgBF4 OH H N R O OH O N O CO2Me N CO2Me I N O H N R Cl OH O I O H N R T etrahed ron Lett. 1991, 32, 7093-7096 * N OH CO2Me O OH O 26% CO2Me CO2Me 6 Sir Jack Baldwin Baran Lab >>> Convertion of penam sulfoxides to stable azetidinone sulfenic acids T etr ahedron Lett. 1998, 39, 6983-6986 Savvas N. Georgiades >>> Conversion of n-membered lactams to (n+1)-membered oxonitrogen heterocycles Chem. Commun. 1993, 18, 1434-1435 Only this diastereomer gives stable sulfenic acid! Pht O O N S S O O N O N N O 1) Me 2SOCH2/DMSO/rt/97% 2) Rh 2(CF3CO2 )4/1,2-DCE/ reflux/77% CO2Bn O BnO2 C Pht 1) Me2 SOCH2/DMSO/rt 2) Rh2 (CF3 CO2)4/1,2-DCE/ reflux Silica gel 56% O OH N S O N O CO2 CHPh2 S N O N CO 2CHPh 2 N O Boc O Boc BnO2C TEA (cat)/benzene ambient T/50 min 70% SYNTHETIC METHODOLOGY MeO Pht 1) LDA/THF/95 oC 2) CF3SO3Me/ -95 oC-rt/1 h/52% S N >>> Synthesis of substituted pyrrolidines by SmI2-mediated ring closure T etrahedr on 1994, 50, 9425-9438 T etrahedr on 1994, 50, 9411-9424 O BnO2C 1) R BnO2C p-TSA (cat)/DMF/ 100 o C/1 h/57% N Boc Mechanism? Boc CO2 Bn Benzene/H2O/ heat/150 oC ~90% CO2 Bn Pht S Br NH2 MeO2C OTBDMS N CO2 Bn O Pht S N O CO2Me DIBAL/toluene/ -78 oC 78% R 2) PhOCOCl/NaHCO3/ H2 O/EtOAc O Methyl propiolate/ benzene/50 oC/ 30 min/72% N Et3N/toluene N R OHC CO2Ph MeO2 C SmI 2/t BuOH/ HMPA/THF/0 oC R OTBDMS 70-80% CO2Ph OTBDMS N CO2Ph HO OTBDMS (R=H, alkyl, TMS) BnO 2C 7 Sir Jack Baldwin Baran Lab >>> Carbocyclic ring expansions via free radical pathways >>> Free radical macrocyclization via propiolate esters Tetrahedr on 1992, 48, 3413-3428 Chem. Commun. 1988 , 21, 1404-1406 T etr ahedron 1989 , 45, 909-922 T etr ahedron 1991 , 47, 6795-6812 T etr ahedron 1992 , 48, 3385-3412 O OLi X O I LiSnBu 3 Propiolic acid/ DCC/DMAP/ OH EtOAc 55-70% n HMPA SnBu3 Br Bu 3SnH/AIBN/ benzene/reflux O n 40-60% O O O NaI/acetone/rt 90-100% n=9-11: 14-16 membered trans a,b-unsaturated lactones n<9: Reduction at radical center prevents cyclization 75% O X Ph3 SnH/AIBN/ benzene/reflux X=SePh X=Br X=I Br SnBu3 Savv as N. Georgiades Me >>> C-C Coupling of terminal alkenes via sulfonylation-alkylationdesulfinylation sequence 78% Mechanism? Chem. Commun. 1988, 11, 702-704 1) n-BuLi/THF/0-20 oC 2) Prenyl bromide/THF/ -78-20 oC 3) AcOH quench Further refinement to macrocyclic lactones O O Me H2/Pd-C EtOAc O Me 1) MeSO2I 2) Base O mCPBA/DCM Me 65-70% 85% (R)-(+)-Limonene 52% H SO Me 2 SO2Me 92% (±)-Dihydrorecifeiolide 1) n-BuLi/THF/-78 oC 2) EtOAc/THF/-78-20 oC 3) AcOH quench Another synthetically useful variant O I SnBu3 Bu 3SnH (cat)/AIBN (cat)/ benzene/reflux/81% Mechanism? O Al/Hg/THF/ H2O/20 oC 80% H Mechanism? O S bisabolenes 71% O O 8 Sir Jack Baldwin Baran Lab >>> Synthesis of trisubstituted allenes >>> Thermal ene reaction of aldehydes and t butyl- or phenylhydrazones T etr ahedron Lett. 1995, 36, 7925-7928 80% R1 R1 1) BuLi/-78 oC 2) EtOAc R2 R3 R1 3) Al/Hg/THF/H2 O (75-95%) R1 C 56% OH N Li R3 E+ N R1 Li N R2 R1 N R3 N H X N N 55-60% X R1 Cl O X R1 50-90% 1) Ph 3PBr2/DMF/0 o C 2) Ph 3P/62% H N Cl Zn/HOAc/60 Br PPh 3 Cl Not methyl acrylate or acrylonitrile R2 R2 Toluene/reflux/ 24 h/argon H E E+ =alkyl halides, aldehydes, ketones, crotonates N 1) TFA/20 o C/1-4 h/argon 2) (CO2 H)2 /H2O/Et2O/ 20 oC/5-16h/argon Chem. Commun. 1984, 3, 152-153 CuCl2/HCl (2M) N R2=Ph, t Bu X=CO2Me, CN >>> Preparation of chloro-3-cumulenes Cl R3 R2 R1 H R3 R2 R2 (R1, R2 , R3=alkyl, alkenyl, benzyl, etc) OH N R2 R1 SO2 Me (80-92%) SO2 Me (75-85%) R1 1) BuLi/-78 o C 2) R3 X Chem. Commun. 1984, 16, 1095-1096 Tetr ahedr on 1986, 42, 4247-4252 o SO2Me 1) BuLi/-78 C 2) R2X OTs 1) NaSMe 2) Oxone Savvas N. Georgiades oC/1.5 h Ph 45-52% 2) C O Mechanism? C N R1 H 1) LiHMDS O O Cl o Pd/C/H2/50 C/12-24 h/50% 45-51% 88% HN R1 1) PtO2/H2 /20 oC/24 h 2) MeOH/HCl NH3+ Cl R1 X 9 Sir Jack Baldwin Baran Lab >>> Functionalization of unactivated methyl groups through organopalladation Chem. Commun. 1985, 3, 126-127 T etrahed ron 1985, 41, 699-711 HO HO N NaPdCl4/ NaOAc >>> Formation of 1H-pyrazolo[4,3-c]pyridines from bis-acetylenic-N-benzoylhydrazones Tetr ahedr on 2004, 60, 933-938 R N NH O Cl 1) Pyridine HO N 2) Pb(OAc)4 (1 eq) 2 3) NaBH4 Pd N Savvas N. Georgiades 85% OCOMe MeCOCl/AlCl 3/ CH2Cl2/0 oC/100% TMS NH2NHR/MeOH (50-90%) 96% TMS TMS + (E) R >>> Formation of 1,2,4-triazepines and oxatriazaindenones from bisacetylenic ketones N N PhCOCl/AlCl 3/ CH2Cl2/reflux O J. Org. Chem. 2005 , 70, 3307-3308 Ph 33% aq. NH3/EtOH/85 oC (35-70%) Mechanism? OH Various solvents R1 CO2Et Boc N H H N NH Ph F3COC N N H Ph F3 COC N N N N N One-pot procedures! Org. Lett. 2005, 7, 3705-3707 Ph CO2 Et O MeO N CO2Et O O OH MeO OR O2 /CDCl3/ 5-35 days Ph MeO O 1) TFAA/CH2 Cl 2 2) NaOH O 1) NaH/THF/DMF 2) R-X N N H O 1) LDA/THF/0 oC 2) CO2 OH N O N Ph R=Ph, p-NO2C6H4, m-NO2C6H4 >>> Oxidative Rearrangement of 6-Methoxypyran-2-ones R2 THF or CH2 Cl 2/ TBAF/reflux/2 h/ 87% (R1=R2 =Ph) O Ph TMS CO2Et CH2 Cl 2/TFAA/reflux/ 3 h/82% (R1 =R2=Ph) Mechanism? CO2Et Ph Boc R2 (R1, R2=Ph or alkyl) N Various temperatures R N (50-75%) O R1 N TMS O MeO O O Mechanism? RO O MeO O O 40-80% Baldwin invokes a second molecule to explain product formation! 10 Sir Jack Baldwin Baran Lab >>> Dimerization of butenolides O O Org. Lett. 2003, 5, 3049-3052 J. Or g. Chem. 2004, 69, 9100-9108 T etrahedr on Lett. 2005 , 46, 4633-4637 Et3N/TBDMSOTf/ CH2Cl2 /30 oC/18 h OTBDMS R R Tetrahedr on Lett. 2006 , 47, 39-41 O 45-55% 60-85% >>> Formation of substituted pyrano[3,2-c]pyridines via Diels-Alder rxn of 3-methylenepyridin-4-ones: OH O mCPBA/CH2 Cl 2/ rt/30 min O Cl R N R=H: N OBoc 2) Boc 2O/Et3N 45% (2 steps) O O O O O N R O O O n=1-2 O O O O O O O O O n=1-2 O H (51%) N N O O OMe O (50-55%) O O O O (R=alkyl) O O N Boc O O 130 oC R O O O N R O O N O O Examples: OMe OH BH3.DMS O 52% (2 steps) 1) (TMS)2S/NaOMe/ O O 25-80% Diastereomeric mixtures OMe 2) DMF N O SOCl2/pyridine/ THF/-78 oC/30 min 35-70% / t BuLi O CoCl(Ph3P)3 / benzene/rt/2 h O 1) Br O SOCl2 /CH2Cl2 / rt/18 h or OMe R R R=Alkyl: Savvas N. Georgiades O O OMe R1 MeO O (R1,R2=alkyl) O O OMe R2 n=1-2 O O R1 R R2 N R OH n=1-2 (50-70%) O O (75-80%) (R=alkyl, alkenyl, Ph) N No rxn with simple alkenes 11 Sir Jack Baldwin Baran Lab >>> Synthesis of oxa-tricyclo[5.3.1.01,5]undecanones >>> Preparation of epoxyisonitriles from thiooximes T etr ahedron 2005 , 61 , 3025-3032 T etr ahedron Lett. 1990, 31, 2051-2054 T etr ahedron Lett. 1990, 31, 2047-2050 Propargyl bromide/ Bu4NHSO 4 (cat)/ NaOH (15M)/ toluene/0 oC-rt/99% 1) TBDMSCl/imidazole/DMF/rt/91% 2) n-BuLi/DMF/THF/-78 oC-rt/98% 3) NaBH4/MeOH/0 o C-rt/98% HO O TolS O O N HO or p-TSA/H2O/MeOH/0 oC/ 10 min/93% (R=TMS) R R=H R=TMS (CF3SO2)2O O OH R O DCM/0 oC-rt/ Mechanism? O Various ring sizes, substituents on ring Aromatic exo-epoxide variant TolS O 2/ CN DIPEA/-78 o C n-BuLi/TMSCl/THF/ -78 oC-rt/90% tBuOOH/VO(acac) O H OAc Mechanism? TBAF/THF/0 oC-rt/91% (R=H) OTBDMS OHCHN DCM/-40 oC O TBDMSO O NHCHO PPh3/ propylene oxide O O Savvas N. Georgiades HO Ac2O/DMAP/TEA/0 oC-rt AcO O R O N NC O O O O X Various substituents (X), fused aromatics X R Application in the total synthesis of trichoviridin 83% (R=H) 78% (R=TMS) 86% (R=H) 68% (R=TMS) Chem. Commun. 1996, 1, 41-42 O OTBDMS TEA/toluene/reflux OTMS O Mechanism? O Precursor to tropolone natural products R 86% (R=H) 74% (R=TMS) OH OH O OH O 7 steps N STol O NC (trichoviridin) 12 Sir Jack Baldwin Baran Lab TOTAL SYNTHESES >>> Synthesis of tabtoxinine beta-lactam (naturally occuring inhibitor of glutamine synthase) Sealed tube/ 90-100 oC/ 24 h/85% Cl Cl N CN Pyridine/ CN reflux/72% Chem. Commun. 1985 , 22, 1549-1550 Et4NIO4/ DCM O Ph Ph O O (1.5 equiv) N O Ph pyridine/DCM/25 C/57% O N O O Ph >>> Biomimetic synthesis of acromelic acid A (neuroexcitatory activity) 1) BnBr/K 2CO3/DMF/91% Br OH 2) NBS/CCl /rt/49% 4 OBn O O O Ph NH2 HO CO2t Bu MeO BnO CO2Me OBn N OBn OMe OH O TfO OMe OMe O O T etrahedr on 1998, 54, 7465-7484 1) n-BuLi/THF/-78 (HO)2B 2) B(OMe)3 OBn 3) NH4Cl/H2O H N O Ph oC Ph 10% Pd-C/EtOH/ H2/100% O O (+5% diester) O O N O O N H N Ph KMnO4/Bu4 NHSO4/ benzene/H2 O/rt/98% O Ph 2) Boc-ON/DCM/83% O 1) 98% Formic acid/99% 2) PPh3/di-2-pyridyl disulfide/ O MeCN/80 oC/2 h/63% HO2C o 1) NaBH3 (OCOCF3 )/58% O NHBoc Cl NHBoc CN O O HO2C OH Ph 73% (single regioisomer) NHBoc HO2C O O O CN N H N HO Savvas N. Georgiad es BnO COPh CO2t Bu Pd(Ph3P)4 /DME/NaCO 3 (aq)/ LiCl/heat/67% N PhOC CO2 Me MeO HO2C MeO HO CO2Me Conc. HCl/ 100 oC/100% 1) Ag 2CO3 on celite/DCM/rt MeO2 C 2) Pb(OAc)4/MeOH/DCM/0 oC/81% H2/Pd black/ EtOAc/rt/100% HO Mechanism? R/S=15:1 PhOC CO2 tBu N CO2Me N PhOC O NH NH3/rt/100% O CO2t Bu CO2Me HO2 C O CO2H HN HCl CO2H HN CO2 H CO2H 13 Sir Jack Baldwin Baran Lab Savvas N. Georgiades Tetrahedr on 2004, 60, 3695-3712 >>> Synthesis of 5,5',6,6'-tetrahydroxy-3,3'-biindolyl (antioxidant from beetroot) Bu3Sn "Dead-end" route BnCl/K2CO3/acetone/ 65 oC/4 days/87% HO HO Reduction (various conditions) BnO OBn BnO BnO 1) I2/HgO/CH2Cl2 / rt/15 h/78% BnO I BnO 2) HNO3 (aq.)/ AcOH/rt/2 h/94% BnO NO2 OBn Pd(Ph3P)4 /CuI/CsF/ DMF/40 oC/2 h/92% p-TSA/benzene/mol. BnO sieves/85 oC/2 days/25% OBn O2N NO2 BnO OH N O2 /3 months OBn Mechanism? NH2 NH2 BnO O Mechanism? NO CYCLIZATION! OBn O OBn BnO H2N SnBu3 O N OBn BnO N OBn OBn Productive route O HO 1) BnCl/K2 CO3/DMF/ o H 120 C/15 h/99% HO 2) MeNO2/NH4 OAc/ BnO AcOH/120 oC/40 min/98% BnO NO2 1) Iron powder/AcOH/benzene/ cyclohexane/SiO2/120 oC/30 min/61% BnO NO2 Mechanism? BnO 70% HNO3/AcOH/ rt/2 h/97% BnO NO2 2) nBuLi/THF/-78 oC/15 min 3) TIPSCl/-78 o C/2 h 95% (2 steps) TIPS TIPS I2/Hg(OAc)2/CH2Cl2 / 0 oC/2 h/100% I BnO Pd(PhCN)2Cl2/TDAE/ DMF/50 oC/1.5 h/68% N H N OBn 1) TBAF/THF/ rt/10 min/82% OBn or NIS/THF/rt/ 20 min/83% BnO N BnO 2) H2/Pd black/ THF/18 h/94% TIPS BnO N N BnO OH OH HO HO N H TIPS 14 Sir Jack Baldwin Baran Lab Savvas N. Georgi ades Org. Lett. 2003, 5, 2351-2354 Tetrahedron 2006, 62, 4603-4614 >>> Studies towards a biomimetic synthesis of pyridomacrolidin (protein tyrosine kinase inhibitor) 1) H 2NOBn/xylene/ CSA (cat.)/reflux/ CO 2Me 24 h/93% Me2NH/Et2O/ CO2Me rt/1 h/100% 2) NaCNBH3/EtOH/ HCl/rt/12 h/79% N OH O O CO 2Me NH OBn OH Br2/CH2Cl 2/ reflux/12 h/72% Br CO 2Me N O B OBn O OH O N O Pd(Ph3P)4/Na2CO3/ THF/reflux/12 h/71% 2) 10% Pd-C/dioxane/ H 2/rt/2 h/90% O PhI(OAc)2/CH 2Cl2/ reflux/24 h/60% O HO HO O Pb(OAc)4/benzene/ 70 oC/20 h/25% O H OH O N O OH O N O O H B OH A H OH O N O O C O O H O H N O B OH O N O OH O + N O O H O H OH O H HO HO O O + H OH N O H O HO O HO H Applicable to various unfunctionalized cyclic enones T etrahed ron 2005, 61, 1773-1784 O H (B/C/D=1:2:5) A OH OBn OBn (A/B=1.4:1) N O H N O AlCl3/toluene/ 95 oC/2 days/40% H O OH O H OH O HO OH O 2) CDI/THF/12 h 3) NaH/rt/5 h 86% (2 steps) DMAP (cat.)/Et3N/ O THF/0 oC/30 min/84% O 1) HO N 1) LiOH/THF/H 2O/ OBn rt/2 h/100% H O Pyridomacrolidin O D 15 Sir Jack Baldwin Baran Lab Savvas N. Georgi ades Org. Lett. 2003, 5, 2987-2988 Tetrahedron 2006, 62, 9892-9901 >>> Biomimetic synthesis of (+)-Panepophenanthrin (novel inhibitor of the ubiquitin-activating enzyme) O O Br2/CHCl3/ 0 oC/98% Br 1) NaBH4 (aq.)/ Et2O/0 oC/85% Br 2) Acetylation O +ent O Br Pig pancreas lipase/pH=7/ rt/3 days Br Kinetic resolution OAc +ent OH m-CPBA/CH2Cl2/ 0 oC/85% OAc Br Br 35%, >99% ee Br +deacylated ent 39%, >99% ee OH O Br O O O OTES Pd2dba3/Ph3As/ toluene/110 oC/92% OH Br O OH 1) Neat/rt/overnight/>99% 2) NH 4F/MeOH/rt/89% Bu3Sn O 3) TESCl/2,6-lutidine/ CH2Cl2/0 oC/90% LiOH/Et 2O/MeOH/ 0 oC-rt/72% OAc 1) DMP/CH2Cl2/0 oC 2) NaHCO3/Na2S2O3 55% (2 steps) O OAc OTES OH O O O HO H HO OH H O 16