Baran Lab Sir Jack Baldwin Savvas N. Georgiades

JACK E. BALDWIN-SHORT BIO REARRANGEMENTS

♦♦♦ Born in in 1938. >>> 2,3-Sigmatropic rearrangements ♦♦♦ Undergraduate studies at Imperial College, London. Obtained his B.Sc. (1st class) in 1960. a e ♦♦♦ Graduate studies at Imperial under the b (concerted, favored at low T) a e supervision of Nobel laureate, Professor Sir d c . Structure elucidation of b d byssochalmic acid using chemical methods. c Awarded his Ph.D. in 1964. e a e ♦♦♦ Appointed assistant lecturer at Imperial a (stepwise, radical d b dissocation-recombination, College in 1965. b d ♦♦♦ 1967-Moved to the US to join Pennsylvania c c favored at high T) State University as Assistant Professor of Chemistry. ♦♦♦ 1969-Promoted to Associate Professor. Sulfonium ylids, Chem. Commun. 1968, 18, 1083-1084 ♦♦♦ 1970-Joined the chemistry department at MIT. 1) Et OBF Ph C ♦♦♦ 1971-Promoted to full Professor. Ph 3 4 2) n-BuLi/THF/-70 oC ♦♦♦ March 1972-Returned to the UK as the Daniel Professor of Chemistry at King's S College. S ♦♦♦ November 1972-Back to MIT. ♦♦♦ 1978-Elected Fellow of the Royal Society and appointed Waynflete Professor of Ph Chemistry at the University of , UK. Ph ♦♦♦ Held the Waynflete chair at Dyson Perrins Laboratory and then at the Chemistry Research Laboratory for 27 years until his retirement in 2005. Sulfonium ylids, Chem. Commun. 1971, 7, 359 ♦♦♦ 1997. Awarded a knighthood for his contributions to organic chemistry. ♦♦♦ Still maintains an active group at Oxford University. OH 1) Br OH ♦♦♦ Awarded many prestigious awards and prizes. ♦♦♦ Published more than 600 papers. Second most cited author in Chemical n-BuLi/THF Communications. Author of their most cited publication ever, "Rules for Ring Closure". o 2) Me3OBF4 -40 C BF4 SH S AREAS OF INVESTIGATION O ♦♦♦ Biomimetic synthesis of natural products, especially sponge alkaloids and fungal O metabolites. ♦♦♦ Development of synthetic methodology. ♦♦♦ Chemical and biological studies on the biosynthesis of beta-lactam antibiotics. Sulfonium ylid ♦♦♦ Parallel synthesis methodology. readily undergoes 2,3-rearrangement S S

1 Baran Lab Sir Jack Baldwin Savvas N. Georgiades

Allylic ether anions, Tetrahedron Lett. 1970, 5, 353-356 Allylic disulfides, J. Am. Chem. Soc. 1971, 93, 6307-6308

OH OH Benzene O t-BuLi/THF S rt/98% S S PPh + 3 S -20 oC: 83/17 S S S Mechanism? 25 oC: 77/23

All carbon anionic, Chem. Commun. 1970, 3, 165-166 Nucleophilic carbenes, Chem. Commun. 1972, 6, 354-355

Cl Br H 1) Li/THF/-70 oC Ts N S Ts N SMe 1) NaH MeS N N 2) -20 oC/5h H H KOH o + SMe S 2) 65 C S (T dependence of product distribution)

>>> 3,3-Sigmatropic rearrangements N-Ammonio-amidates, Chem. Commun. 1970, 1, 31-32 Reformatsky-Claisen, Chem. Commun. 1973, 4, 117-118 1) Deprotonation 2) 35 oC/1 min OZnBr OZnBr NH2 HN Br O R2 R1 Br N quantitative N R2 R2 O O Benzene/80 oC/ O Zn R R1 1 H H H H O O O H H R R R4 >90% 4 1) Deprotonation 4 R R o R3 3 3 NH 2) 130 C/30 min N N X N N N Br Enol phosphate variant, Chem. Commun. 1973, 4, 117-118 O O 1971 O Diazenes, J. Am. Chem. Soc. , 93, 788-789 O O P OR O P OR RO P OR Cl OR Cl O 3,3-Rearrangement OR Cl C OR O 70% Cl 3 Cl O N N + N N N N

2 Baran Lab Sir Jack Baldwin 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 Chem. Commun. 1976, 18, 734-736 ∆ Chem. Commun. 1976, 18, 736-738 S O (previously observed and believed to + SO proceed in cheletropic concerted fashion) Chem. Commun. 1977, 3, 77 Chem. Commun. 1977, 7, 233-235 J. Or g. Chem. 1977, 42, 3846-3852 Tetrahedron 1982, 38, 2939-2947 S OH O o ♦♦♦ S O 35 C Mechanism? S Rules apply to cyclic transition states leading to ring formation or intramolecular S group transfer. Nucleophilic, radical and cationic processes follow the rules, but not electrocyclic reactions! H sulfenic acid 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.

At high T (>150 oC) olefin products are observed. Given that mixtures of cis and ♦♦♦ EXO process-breaking bond positioned exocyclic to smallest formed ring. trans 2-butene are obtained, SO loss likely goes through radical pathway (T- ENDO process-breaking bond positioned endocyclic to smallest formed ring. dependent). ♦♦♦ 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 TET T<0 oC X Y X Y O N N X

a=109 o TRIG X Y Burgi-Dunitz O T<0 oC Y N (exclusively angle N trans) O X a=120 o X Multisubstituted aziridine oxide gives rise to alternative products. DIG Concerted or radical? Y Y

3 Baran Lab Sir Jack Baldwin Savvas N. Georgiades

>>> Tetrahedral Systems (TET) >>> Digonal Systems (DIG)

X X Y X X X X X X Y X X Y Y Y Y Y Y Y Y 4-EXO-DIG 3-EXO-TET 4-EXO-TET 5-EXO-TET 3-EXO-DIG 5-EXO-DIG 6-EXO-TET 7-EXO-TET forbidden forbidden 6-EXO-DIG 7-EXO-DIG allowed allowed allowed allowed allowed allowed allowed allowed

X Y Y X Y Y Y Y X X XY X X X XY X Y Y

3-ENDO-DIG 4-ENDO-DIG 3-ENDO-TET 4-ENDO-TET 5-ENDO-TET 6-ENDO-TET 7-ENDO-TET 5-ENDO-DIG 6-ENDO-DIG ??? forbidden forbidden 7-ENDO-DIG ??? forbidden forbidden forbidden allowed allowed allowed

>>> Trigonal Systems (TRIG) >>> Example of favored vs. disfavored process

O Y X 5-EXO-TRIG X X X O X MeO C N Y 2 H Y MeO2C Y Y OMe CO2Me 3-EXO-TRIG 4-EXO-TRIG 5-EXO-TRIG 7-EXO-TRIG NH2 X allowed 6-EXO-TRIG allowed allowed allowed allowed 5-ENDO-TRIG N MeO2C H >>> Example of exception for second row element: Y X Y Y X X XY X Y CO2Me CO Me 2 Base 6-ENDO-TRIG 3-ENDO-TRIG 4-ENDO-TRIG 5-ENDO-TRIG 7-ENDO-TRIG SH forbidden forbidden forbidden allowed allowed 5-ENDO-TRIG S

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>>> Example of competing allowed processes >>> Ring closures involving enolates

(predominant- 6-EXO-TRIG kinetically preferred) O O Y (ENOLENDO)-EXO-TET Base 5-member or smaller disfavored (treat as ENDO-TRIG) 6-member or larger favored (treat as ENDO-TRIG) HO MeO O MO X CO2Me (kinetically Y 6-ENDO-TRIG disfavored) (ENOLEXO)-EXO-TET O All sizes favored (treat as EXO-TRIG) ♦♦♦ In cases where an EXO and an ENDO process compete, EXO appears to be OM 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. 5-(ENOLENDO)-EXO-TET

>>> Turning a forbidden into an allowed cyclization process X Example: Br O

O MO O 5-EXO-TET 5-ENDO-TRIG O OH X O NaOMe/MeOH Y (ENOLENDO)-EXO-TRIG OH OH 5-member or smaller disfavored (treat as ENDO-TRIG) H+ MO 6-member or larger favored (treat as ENDO-TRIG) 5-EXO-TRIG OH OH Y (ENOLEXO)-EXO-TRIG OH OH All sizes favored (treat as EXO-TRIG) OM OH OH

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BETA-LACTAM TRANSFORMATIONS >>> Conversion of penicillin sulfoxides into 6,7-epi-1-oxocephams: Tetrahedron 1980, 36, 1628-1630 >>> Ring expansion of penicillins to cephalosporins Chem. Commun. 1987, 2, 104-106 O R H O Ac2O/Me3P=O/ R H N toluene/reflux/ N H R H S 95% S OsO /85% R Br Ph3SnAllyl/AIBN/ N 4 N benzene/reflux/3 h S O O S 94% N Mechanism? N O O N O O N CO2Me CO2Me O O CO Me CO Me O 2 2 R H R H H N N Cl R H Br Ph SnH/AIBN/ R N 3 N S S Cl /93% SnCl2 S benzene/reflux/2 h OH 2 OH R (40%) O O N N O O S (35%) OH OH N N O O CO Me O O CO2Me 2 CO Me 2 CO2Me Trans:Cis=5:3 H R H H R R H Ph SnH/AIBN/ R N O N Cl N S 3 N S benzene/reflux/2 h * + R (49%) O O O O N OH N Br N S (39%) N O O O O 27% CO Me 30% CO Me CO Me 2 2 2 O O

>>> Ring expansion of penicillins to 3-exomethylene cephalosporins R H R H Tetrahedron Lett. 1991, 32, 7093-7096 N Cl N SnCl2 or AgBF4 OH OH R H I O O N N N S OH OH 30% conversion O O O R H (instability of SM) CO Me CO Me N N 2 2 Vitamin B12 S >95:5 exo:endo O R H CO Me Co(I) O 2 N N O R H o O * N S 20-30 min/20 C O OH CO2Me N O O N I 93% conversion CO2Me O >98:2 exo:endo 26% CO2Me

6 Baran Lab Sir Jack Baldwin Savvas N. Georgiades

>>> Convertion of penam sulfoxides to stable azetidinone sulfenic acids >>> Conversion of n-membered lactams to (n+1)-membered oxonitrogen heterocycles Tetrahedron Lett. 1998, 39, 6983-6986 Chem. Commun. 1993, 18, 1434-1435 Only this diastereomer gives 1) Me SOCH /DMSO/rt/97% O stable sulfenic acid! 2 2 CO2Bn 2) Rh (CF CO ) /1,2-DCE/ CO Bn Pht 2 3 2 4 2 O S reflux/77% N S N N Boc N Mechanism? O O O Boc N O O BnO2C CO2Bn 1) Me2SOCH2/DMSO/rt 2) Rh2(CF3CO2)4/1,2-DCE/ CO2CHPh2 Pht CO2CHPh2 Benzene/H2O/ S reflux o N heat/150 C Silica gel N O N O Boc ~90% 56% O Boc BnO C TEA (cat)/benzene 2 O ambient T/50 min SYNTHETIC METHODOLOGY 70% OH MeO N >>> Synthesis of substituted pyrrolidines by SmI -mediated ring closure S 2 o Pht S O 1) LDA/THF/95 C Tetrahedr on 1994, 50, 9425-9438 N 2) CF SO Me/ Tetrahedr on 1994, 50, 9411-9424 3 3 N O -95 oC-rt/1 h/52% O 1) R BnO2C BnO C Br 2 NH CO Ph 2 N 2 p-TSA (cat)/DMF/ Et3N/toluene OTBDMS R o Pht MeO C OTBDMS 100 C/1 h/57% S 2 MeO C 2) PhOCOCl/NaHCO3/ 2 H O/EtOAc N 2 Methyl propiolate/ O o t benzene/50 C/ CO2Bn DIBAL/toluene/ SmI2/ BuOH/ -78 oC HMPA/THF/0 oC R 30 min/72% CO2Ph O N N CO2Ph CO Me 78% 70-80% Pht S 2 R OTBDMS HO OHC OTBDMS N O (R=H, alkyl, TMS)

BnO2C

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>>> Carbocyclic ring expansions via free radical pathways >>> Free radical macrocyclization via propiolate esters

Chem. Commun. 1988, 21, 1404-1406 Tetrahedron 1992, 48, 3413-3428 Tetrahedron 1989, 45, 909-922 Tetrahedron 1991, 47, 6795-6812 Propiolic acid/ O Tetrahedron 1992, 48, 3385-3412 DCC/DMAP/ Ph3SnH/AIBN/ OH EtOAc O benzene/reflux X X O O OLi O n 55-70% n 40-60% I O X=SePh LiSnBu3 Br X=Br NaI/acetone/rt X=I HMPA Br 90-100% SnBu3 SnBu3 75% n=9-11: 14-16 membered trans a,b-unsaturated lactones O n<9: Reduction at radical center prevents cyclization Me Bu3SnH/AIBN/ benzene/reflux 78% >>> C-C Coupling of terminal alkenes via sulfonylation-alkylation- Mechanism? desulfinylation sequence Chem. Commun. 1988, 11, 702-704 1) n-BuLi/THF/0-20 oC Further refinement to macrocyclic lactones 2) Prenyl bromide/THF/ o O 1) MeSO2I -78-20 C O O 2) Base Me H /Pd-C 3) AcOH quench 2 Me O EtOAc mCPBA/DCM Me 65-70% 85%

(R)-(+)-Limonene SO Me H SO Me 52% 92% 2 2 (±)-Dihydrorecifeiolide 1) n-BuLi/THF/-78 oC Another synthetically useful variant 2) EtOAc/THF/-78-20 oC Al/Hg/THF/ o 3) AcOH quench H2O/20 C O O Bu SnH (cat)/AIBN (cat)/ 80% I 3 H Mechanism? benzene/reflux/81%

Mechanism? O S SnBu3 bisabolenes O 71% O

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>>> Synthesis of trisubstituted allenes >>> Thermal ene reaction of aldehydes and tbutyl- or phenylhydrazones Tetr ahedron Lett. 1995, 36, 7925-7928 Chem. Commun. 1984, 16, 1095-1096 Tetr ahedr on 1986, 42, 4247-4252 OTs 1) BuLi/-78 oC 1) NaSMe SO Me R3 R3 2 SO2Me R3 2) Oxone 2) R2X + N N N E =alkyl halides, aldehydes, N Li N E+ 80% (75-85%) R2 N ketones, crotonates R1 R 1 R1 R R Not methyl acrylate or 1 2 R1 R2 R R Li 1 E 2 acrylonitrile SO2Me o o 1) BuLi/-78 C R2 1) BuLi/-78 C R2 R2 Toluene/reflux/ 2) R3X 2) EtOAc N R2 N H 24 h/argon N R3 R1 C R3 N (80-92%) R 3) Al/Hg/THF/H O 1 2 X 55-60% (75-95%) H R1 H X R1 R =Ph, tBu (R1,R2,R3=alkyl, alkenyl, benzyl, etc) 2 X=CO2Me, CN 1) TFA/20 oC/1-4 h/argon 2) (CO2H)2/H2O/Et2O/ O >>> Preparation of chloro-3-cumulenes 20 oC/5-16h/argon Chem. Commun. 1984, 3, 152-153 X 50-90% R1

o O Cl 1) Ph3PBr2/DMF/0 C Cl H o N CuCl2/HCl (2M) 2) Ph3P/62% Zn/HOAc/60 C/1.5 h Ph N 56% 45-52% OH OH Cl PPh Cl R Br 3 1 H O Pd/C/H /50 oC/12-24 h/50% 1) LiHMDS C Cl 2 HN C 45-51% 2) O R1 88% o 1) PtO2/H2/20 C/24 h + - 2) MeOH/HCl NH3 Cl Mechanism?

R1 X

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>>> Functionalization of unactivated methyl groups through organopalladation >>> Formation of 1H-pyrazolo[4,3-c]pyridines from bis-acetylenic-N-benzoyl- hydrazones Chem. Commun. 1985, 3, 126-127 Tetrahedron 1985, 41, 699-711 Tetrahedron 2004, 60, 933-938 R O NH Cl N HO HO 1) Pyridine HO MeCOCl/AlCl / N TMS 3 NaPdCl / N Pd 2) Pb(OAc)4 (1 eq) N OCOMe o 4 CH2Cl2/0 C/100% NH2NHR/MeOH NaOAc 2 3) NaBH4 85% 96% (50-90%)

TMS TMS + (E) TMS R R >>> Formation of 1,2,4-triazepines and oxatriazaindenones from bis- PhCOCl/AlCl / N acetylenic ketones 3 N Ph N CH2Cl2/reflux o N 33% aq. NH3/EtOH/85 C J. Org. Chem. 2005, 70, 3307-3308 O (35-70%) (50-75%) O N Mechanism? R Ph 1 OH Various solvents TMS R=Ph, p-NO2C6H4, m-NO2C6H4 CO2Et R1 CO2Et Various H Boc NN Boc N NH temperatures N >>> Oxidative Rearrangement of 6-Methoxypyran-2-ones N H H R2 Org. Lett. 2005, 7, 3705-3707 R2 CH Cl /TFAA/reflux/ (R1,R2=Ph or alkyl) 2 2 3 h/82% (R1=R2=Ph) THF or CH2Cl2/ O O O Mechanism? TBAF/reflux/2 h/ 1) LDA/THF/0 oC 87% (R =R =Ph) 1) TFAA/CH2Cl2 1 2 2) NaOH 2) CO2 OH Ph Ph F COC Ph 3 CO Et MeO O MeO O N N 2 F COC N N 3 N N OH OR N 1) NaH/THF/DMF RO CO Et O O2/CDCl3/ 2 CO2Et N 2) R-X 5-35 days O O N Ph O H Mechanism? O Ph MeO O O MeO O O Ph MeO 40-80% One-pot procedures! Baldwin invokes a second molecule to explain product formation!

10 Baran Lab Sir Jack Baldwin Savvas N. Georgiades

>>> Dimerization of butenolides Org. Lett. 2003, 5, 3049-3052 >>> Formation of substituted pyrano[3,2-c]pyridines via Diels-Alder rxn of J. Org. Chem. 2004, 69, 9100-9108 3-methylenepyridin-4-ones: Tetrahedr on Lett. 2005, 46, 4633-4637 Tetrahedr on Lett. 2006, 47, 39-41 Et N/TBDMSOTf/ O 3 mCPBA/CH Cl / OH CH Cl /30 oC/18 h O 2 2 O O 2 2 rt/30 min OTBDMS O 1) / tBuLi 60-85% 45-55% OMe OMe OMe OH R BH3.DMS R R O 52% (2 steps) R Br 2) DMF N N N R=Alkyl: O O 1) (TMS) S/NaOMe/ SOCl /CH Cl / 2 2 2 2 Cl CoCl(Ph P) / rt/18 h or 3 3 O O O benzene/rt/2 h O O O O NN SOCl /pyridine/ 25-80% 2 OBoc o THF/-78 oC/30 min R=H: 130 C R Diastereomeric R mixtures 35-70% O O 2) Boc2O/Et3N N 45% (2 steps) N O O Boc O O R O Examples: O OMe O R n=1-2 O n=1-2 O O H O O (R=alkyl) O O (51%) O O (50-55%) O O N N O O O OMe O R O O O R1 OMe O R1 O R MeO OH O R2 n=1-2 (75-80%) O O n=1-2 O O O R (R=alkyl, alkenyl, Ph) O O 2 O O O (R1,R2=alkyl) (50-70%) N O O N No rxn with simple alkenes

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>>> Synthesis of oxa-tricyclo[5.3.1.01,5]undecanones >>> Preparation of epoxyisonitriles from thiooximes

Tetrahedron 2005, 61, 3025-3032 Tetr ahedron Lett. 1990, 31, 2051-2054 Tetr ahedron Lett. 1990, 31, 2047-2050 Propargyl bromide/ 1) TBDMSCl/imidazole/DMF/rt/91% OO Bu4NHSO4 (cat)/ TolS 2) n-BuLi/DMF/THF/-78 oC-rt/98% NHCHO NaOH (15M)/ N PPh3/ OHCHN o O 3) NaBH4/MeOH/0 C-rt/98% HO toluene/0 oC-rt/99% propylene oxide O O O DCM/-40 oC HO TBDMSO H OAc Mechanism? TBAF/THF/0 oC-rt/91% (R=H) CN O O O (CF3SO2)2O O OTBDMS or p-TSA/H O/MeOH/0 oC/ O OH Various ring sizes, substituents on ring 2 DIPEA/-78 oC R 10 min/93% (R=TMS) R

R=H n-BuLi/TMSCl/THF/ Aromatic exo-epoxide variant -78 oC-rt/90% R=TMS TolS N NC O O Various substituents (X), t O BuOOH/VO(acac)2/ fused aromatics HO o AcO DCM/0 oC-rt/ Ac2O/DMAP/TEA/0 C-rt O O X X Mechanism? O R O R Application in the total synthesis of trichoviridin 83% (R=H) 86% (R=H) Chem. Commun. 1996, 1, 41-42 68% (R=TMS) 78% (R=TMS)

O OTBDMS OH TEA/toluene/reflux OTMS OH O Precursor to tropolone OH Mechanism? natural products O O 7 steps O O R N STol NC 86% (R=H) (trichoviridin) 74% (R=TMS)

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TOTAL SYNTHESES H N O Ph >>> Synthesis of tabtoxinine beta-lactam HO Chem. Commun. 1985, 22, 1549-1550 (naturally occuring inhibitor of glutamine synthase) Et4NIO4/ O O DCM NHBoc Sealed tube/ CN N O Ph CN Cl 90-100 oC/ Cl Pyridine/ KMnO4/Bu4NHSO4/ CN 1) NaBH (OCOCF )/58% benzene/H O/rt/98% 24 h/85% reflux/72% O O 3 3 O 2 CN 73% (single N O Ph 2) Boc-ON/DCM/83% N O Ph regioisomer) O O H H 1) 98% Formic acid/99% NHBoc O NHBoc N N HO C 2) PPh3/di-2-pyridyl disulfide/ O O HO C (1.5 equiv) 2 10% Pd-C/EtOH/ 2 Ph O Cl o MeCN/80 C/2 h/63% H /100% OH O O O 2 o N O Ph pyridine/DCM/25 C/57% N O Ph N O Ph NH2 O O O HO HO2C O O Ph O (+5% diester) Ph O O

t >>> Biomimetic synthesis of acromelic acid A Tetrahedr on 1998, 54, 7465-7484 CO2 Bu MeO (neuroexcitatory activity) TfO 1) n-BuLi/THF/-78 oC BnO OH OBn (HO) B OBn CO Me 1) BnBr/K CO /DMF/91% 2) B(OMe)3 2 2 OH 2 3 Br OBn N 2) NBS/CCl4/rt/49% 3) NH4Cl/H2O BnO OBn COPh OMe OMe t Pd(Ph3P)4/DME/NaCO3 (aq)/ CO2 Bu OMe LiCl/heat/67% N PhOC CO2Me MeO MeO HO2C HO2C HO CO2Me 1) Ag CO on celite/DCM/rt O NH 2 3 MeO C Conc. HCl/ H2/Pd black/ 2) Pb(OAc) /MeOH/DCM/0 oC/81% 2 o 4 100 C/100% NH3/rt/100% EtOAc/rt/100% HO O O Mechanism? CO tBu t 2 R/S=15:1 CO2 Bu N CO2H CO2H N HN HN PhOC CO2Me CO Me CO H CO H PhOC 2 HCl 2 2

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>>> Synthesis of 5,5',6,6'-tetrahydroxy-3,3'-biindolyl Tetrahedron 2004, 60, 3695-3712 (antioxidant from beetroot)

"Dead-end" route Bu3Sn SnBu3 OBn BnO BnO BnCl/K2CO3/acetone/ 1) I2/HgO/CH2Cl2/ OBn HO o BnO BnO I 65 C/4 days/87% rt/15 h/78% O

2) HNO3 (aq.)/ Pd(Ph P) /CuI/CsF/ HO BnO BnO NO 3 4 AcOH/rt/2 h/94% 2 DMF/40 oC/2 h/92% O2N NO2 OBn O OBn BnO BnO BnO N Reduction OBn p-TSA/benzene/mol. BnO OH (various conditions) sieves/85 oC/2 days/25% O /3 months 2 OBn OBn BnO NO CYCLIZATION! Mechanism? Mechanism?

H N NH NH2 N OBn 2 2 N OBn O

Productive route 1) Iron powder/AcOH/benzene/ O o 1) BnCl/K CO /DMF/ cyclohexane/SiO2/120 C/30 min/61% HO 2 3 BnO NO BnO NO BnO H 120 oC/15 h/99% 2 2 Mechanism? 2) nBuLi/THF/-78 oC/15 min N HO 2) MeNO2/NH4OAc/ BnO 70% HNO3/AcOH/ BnO BnO NO2 o AcOH/120 oC/40 min/98% rt/2 h/97% 3) TIPSCl/-78 C/2 h TIPS 95% (2 steps) TIPS H OH I OBn N I /Hg(OAc) /CH Cl / Pd(PhCN)2Cl2/TDAE/ N 2 2 2 2 1) TBAF/THF/ 0 oC/2 h/100% BnO DMF/50 oC/1.5 h/68% rt/10 min/82% OH OBn HO or NIS/THF/rt/ BnO N BnO 2) H2/Pd black/ 20 min/83% TIPS THF/18 h/94% HO N BnO N H TIPS

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>>> Studies towards a biomimetic synthesis of pyridomacrolidin (protein tyrosine kinase inhibitor) Org. Lett. 2003, 5, 2351-2354 Tetrahedron 2006, 62, 4603-4614

CO2Me 1) H2NOBn/xylene/ OH O OH O Me2NH/Et2O/ CSA (cat.)/reflux/ 1) LiOH/THF/H2O/ Pb(OAc)4/benzene/ CO2Me CO Me O rt/1 h/100% CO2Me 24 h/93% 2 OBn rt/2 h/100% 70 oC/20 h/25% O N

2) NaCNBH3/EtOH/ DMAP (cat.)/Et N/ 2) CDI/THF/12 h N NH 3 O N O N O HCl/rt/12 h/79% THF/0 oC/30 min/84% 3) NaH/rt/5 h OBn 86% (2 steps) OBn OBn OH O

O HO 1) OH O Br2/CH2Cl2/ O HO reflux/12 h/72% Br B OH O OH O HO OH OH PhI(OAc) /CH Cl / N O Pd(Ph3P)4/Na2CO3/ 2 2 2 H THF/reflux/12 h/71% O reflux/24 h/60% O H O H OBn 2) 10% Pd-C/dioxane/ N O N O N (A/B=1.4:1) H /rt/2 h/90% 2 HO O O O Applicable to various unfunctionalized cyclic H H A B O HO enones OH O OH O Tetrahedron 2005, 61, 1773-1784 AlCl3/toluene/ H 95 oC/2 days/40% O H O H + N O N O HO (B/C/D=1:2:5) OH O O O H H A B O H HO HO N O OH OH O OH O O H O Pyridomacrolidin O H + H O OH N O N O O O O D H C H

15 Baran Lab Sir Jack Baldwin Savvas N. Georgiades

>>> Biomimetic synthesis of (+)-Panepophenanthrin (novel inhibitor of the ubiquitin-activating enzyme) Org. Lett. 2003, 5, 2987-2988 Tetrahedron 2006, 62, 9892-9901

O O OAc Pig pancreas OAc Br2/CHCl3/ 1) NaBH (aq.)/ OH 4 lipase/pH=7/ LiOH/Et2O/MeOH/ o Br o Br Br 0 C/98% Et2O/0 C/85% rt/3 days 35%, >99% ee 0 oC-rt/72% Br

Br 2) Acetylation Br Kinetic +deacylated ent Br 39%, >99% ee resolution O O O OAc OAc +ent +ent

o 1) DMP/CH2Cl2/0 C OH OH O O OH m-CPBA/CH2Cl2/ 2) NaHCO3/Na2S2O3 0 oC/85% Br 55% (2 steps) Br Bu3Sn 1) Neat/rt/overnight/>99% 2) NH4F/MeOH/rt/89% O O O 3) TESCl/2,6-lutidine/ Pd2dba3/Ph3As/ O CH Cl /0 oC/90% toluene/110 oC/92% 2 2 OTES OTES

OH O

O O

H H OH HO HO O

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