Steven Ley 03/10 2012

Baran Group Meeting Lars Jørgensen Steven Ley 03/10 2012

Biography Major Prizes and Awards Born December 10, 1945 in Stamford, 1980 Corday Morgan Medal and Prize (Royal Society of Chemistry) Lincolnshire, England. 1981 The 1981-1983 Hickinbottom Research Fellowship (joint 1st recipient) (RSC) 1983 Pfizer Academic Award (1st recipient) (Pfizer PLC) Education 1988 Tilden Lectureship and Medal (Royal Society of Chemistry) 1969 BSc (first class hons) from 1989 Award for Organic Synthesis (Royal Society of Chemistry) Loughbourough University. 1992 Pedler Lectureship, Medal and Prize (Royal Society of Chemistry) 1969-1972 PhD from Loughbourough 1993 Simonsen Lectureship and Medal (Royal Society of Chemistry) University (Prof. H. Heaney). 1993 Award for Natural Product Chemistry (Royal Society of Chemistry) 1972-74 Postdoc at Ohio State University 1994 Adolf Windaus Medal (German Chemical Society - Georg-August University) (Prof. Leo. A. Paquette) 1995 The Novartis Research Fellowship (1995 - 2007) (Novartis) 1995 The Flintoff Medal (Royal Society of Chemistry) 1974-75 Postdoc at Imperial College (Prof. Sir 1996 The Dr. Paul Janssen Prize for Creativity in Organic Synthesis (Janssen R. F.) Derek H.R. Barton) 1996 George Kenner Prize and Lectureship (University of Liverpool) 1997 The Bakerian Lecturer (The Royal Society) 1998 The Rhône-Poulenc Lectureship, Medal and Prize (Royal Society of Chemistry) Academic Career 1999 The GlaxoWellcome Award for Outstanding Achievement in Organic Chemistry 1976-83 Lecturer, Imperial College (1st recipient) 1983-92 Prof. of Organic Chemistry, Imperial College 2000 The Davy Medal (The Royal Society) 1989-92 Head of Department, Imperial College 2001 Haworth Memorial Lectureship, Medal and Prize (Royal Society of Chemistry) 1992-present BP (1702) Prof. of Organic Chemistry, Cambridge University 2001 August-Wilhelm-von Hofmann Medal (Gesellschaft Deutscher Chemiker) 1992-present Head of Organic Chemistry, Cambridge University 2001 The Pfizer Award for Innovative Science (1st chemist recipient) 1993-present Fellow of Trinity College, Cambridge University 2003 The Ernest Guenther Award in the Chemistry of Natural Products (American Chemical Society) 2003 Royal Society Wolfson Merit Award Research Interests 2003 Industrially-Sponsored Award in Carbohydrate Chemistry (The Royal Society of Natural products Chemistry) Medicinal chemistry 2004 The Messel Medal Lecture (The Society of Chemical Industry) Asymmetric organocatalysis 2006 The Robert Robinson Lectureship, Medal and Prize (The Royal Society of Solid-supported reagents Chemistry) Microwave chemistry 2006 The Nagoya Gold Medal (Banyu Life Science Foundation International, Japan) Flow chemistry 2007 Award for Creative Work in Synthetic Organic Chemistry (ACS) 2008 High Throughput Drug Discovery Methodologies Award (The Royal Society of Methodology Chemistry) - Ley's TPAP reagent 2009 Heinrich Wieland Prize awarded for outstanding achievements in the synthesis of - -allyl tricarbonyliron complexes key natural products (Boehringer Ingelheim) - 1,2-diacetals and dispiroketals 2009 Tetrahedron Prize for Creativity in Organic Chemistry 2010 Paracelsus Prize (Swiss Chemical Society) 2011 Royal Medal (Royal Society) Baran Group Meeting Lars Jørgensen Steven Ley 03/10 2012

Early Years Post Doc with Prof. Leo Paquette (12 papers)

PhD with Prof. Harry Heaney (17 papers) Synthesis of (-)-Triquinacene-2-carboxylic Acid

NC Benzyne cycloaddition and their rearrangements I K2CO3 conc. HCl NMe2 NC I2, Pb(OAc)4 THF/H2O NC reflux 250W then MeO if CN 82% O O tungsten lamp O O CH N R=H 2 2 O OH F F 56% 68% R R F F EtOH/H2O O heat 1. Burgess reagent, 56% F NMe F NMe 2 2 Me 2. KOH, EtOH, ~quant. F F if R=Me

HO J. Chem. Soc., Chem. Commun. 1970, 1184 O (-)-Triquinacene-2-carboxylic acid

Me Me Me F O F F F Me J. Am. Chem. Soc., 1974, 96, 312 F Me F Me F F H+ F Me F OMe F OMe F OMe F F F F NC CN

Fe(CO) + 3 H NC CN NC NC CAN NC NC NC NC R OH Fe(CO)3 CN O CN F Me F F O O Me OH Me F F F J. Am. Chem. Soc., 1975, 97, 7273 O F Me F Me F Me F F H+ F Alkali Metal Reduction Studies of cis- and trans-Bicyclo[6.1.0]nona-2,4,6-trienes in J. Chem.Soc., Perkin Trans. 1, 1974, 2711 Liquid Ammonia

N-Alkylation of indoles H Me H Me Me 2e- H =

R-I or BnBr N N KOH H Me H Me DMSO R H H J. Chem. Soc., Perkin Trans. 1, 1973, 499 2e- = Org. Synth., 1974, 54, 58 Me

J. Am. Chem. Soc., 1974, 96, 6670 Baran Group Meeting Lars Jørgensen Steven Ley 03/10 2012

Post doc work and other publication with Prof. Barton (28 papers) Removal of 1,3 -Dithiolan Protecting Groups by Benzeneseleninic Anhydride

Initial project: The Stability of N,N-Dialkylthiohydroxylamines O O Se Se R S Ph O Ph R X O Li/NH S R S R S 3 N S X X J. Chem. Soc., Chem. Commun., 1977, 751-752 J. Chem. Soc., Chem. Commun., 1975, 855 Oxidation of Phenols to ortho-Quinones using Diphenylseleninic Anhydride Dehydrogenation of steroidal ketones using benzeneseleninic anhydride OH O O O O O O O Se Se Ph O Ph Se Se Se Ph O Ph Ph syn-elimination 1976 O O O J. Chem. Soc., Chem. Commun., , 985 H H H Regeneration of Ketones from Hydrazones, Oximes, and Semicarbazones by Benzeneseleninic Anhydride In contrast to selenium dioxide, is relatively unreactive towards olefins

O O J. Chem. Soc., Chem. Commun., 1978, 130-131 R R H Se Se N Ph O Ph Ar N R O R mechanism? THF parent ketone Conversion of Thiocarbonyl Compounds into Their Corresponding Oxo Derivatives O O Se Se S Ph O Ph O 1977 R R' R R' J. Chem. Soc., Chem. Commun., , 445 X Y X Y xanthates, thioesters, thiocarbonates, Oxidation of Aldehyde Hydrazones, Hydrazo Compounds, and Hydroxylamines thioamides, and thiones J. Chem. Soc., Chem. Commun., 1978 with Benzeneseleninic Anhydride , 393-394

O O O Oxidation of Alcohols using Benzeneseleninic Anhydride H Se Se H H Ph O Ph N N Ar N R Ar N R O O THF H OH Se Se O acylazo-derivatives Ph O Ph R R' R R'

J. Chem. Soc., Chem. Commun., 1978, 276-277 J. Chem. Soc., Chem. Commun., 1978, 952-954 Preparation of Aldehydes and Ketones by Oxidation of Benzylic Hydrocarbons with Benzeneselenininic Anhydride O O O Se Se Ph O Ph Ar R Ar R Tetrahedron Lett., 1979, 3331 Baran Group Meeting Lars Jørgensen Steven Ley 03/10 2012

Entering the Field of Natural Product Synthesis Selenium mediated C-C bond forming cyclization

- drimane sesquiterpenes O

N SePh H H

CO2Me O O CO2Me CO2Me ZnI2 CO2Me Pd/C, H2 CO2Me O E E MeO2C HCl (trace) O O E = CO2Me PhSe

110 C MeOH H H 95% 80% e lit e cinnamolide /C LiAlH 3 4 O t. C n 90% 2 a J. Chem. Soc., Chem. Commun., 1980, 1028 g u A q ~ J. Chem. Soc., Chem. Commun., 1980, 1173 OAc OAc OH O OH O Tetrahedron Lett., 1981, 2601

OAc SeO2 OAc Ac2O, pyr OH 3 steps 80% ~quant. H H H H Total Synthesis of hirsutene [P P drimenin O h 4 ] 1. K2CO3, MeOH Swern [R u 2. DMSO, TFAA O 95% 3 N SePh SePh O 5 2 C O 45% % l HO C H E HO 3 ] HO 2 O CHO O 2 steps O OHC OH Cunninghamella CHO elegans CHO CO2H SnCl4 H H H 45% H H 90% H HO H H H warburganal daniol polygidial isodrimeninol LDA then LAH 66% J. Chem. Soc., Chem. Commun., 1981, 507 O , 1981, 3909 SePh N SePh OH Tetrahedron Lett. SePh O SePh O J. Chem. Soc., Perkin Trans. 1, 1983, 1579 H H H 1. Raney Ni, 83% O

2. CH Br Zn 2 2, Bu3P H H TiCl4, 97% H H 63% H H hirsutene

J. Chem. Soc., Chem. Commun., 1982, 1252 Tetrahedron, 1985, 41, 4765 Baran Group Meeting Lars Jørgensen Steven Ley 03/10 2012

-Allyltricarbonyliron lactone complexes OMe

HO O O OMe 1. PtO2, H2 Fe(CO) (OC) Fe O O O 3 3 O 2. DIBALH CO, 240 atm O Fe2(CO)9 3. PhSO2H H H + H O O PhO2S O O O O THF 140 C, PhH H H O -lactone H

O O OH

O O O OMe H OH HO Fe2(CO)9 Fe(CO) (OC) Fe CO, 240 atm avermectin B1a O O 3 3 O steps O S O O O OH THF + H 140 C, PhH O H acrolein -lactone oleandrose

Spiroketals and 2-benzenesulfonyl cyclic ethers J. Chem. Soc., Perkin Trans. 1, 1991, 667-692

R O OR CAN steps

(OC) Fe O OH EtOH O OH O O O R 3 O R PhSO2H, ROH, O O PhSO2H, O O MgBr2, Et3N CaCl2 MgBr2 O OH CaCl2 -lactone valilactone N H H

PhSO2H OSiR3 Tetrahedron, 1991, 47, 9299 1. BuLi R O R R R 2. RX O SO Ph AlCl O R 2 3 O R

RMgBr, ZnBr2 O or Fe(CO)3 1. BuLi 1. BuLi O OH HO OH R O R NaBH(OAc)3 steps 2. I(CH2)4OTHP 2. RX taurospongin A O 3. H+ 3. NaNaphth. O R TBSO OTBS TBSO OTBS spiroketals

Org. Biomol. Chem., 2003, 1, 1664 Tetrahedron Lett., 1985, 26, 535 Tetrahedron, 1986, 42, 4333 Tetrahedron, 1989, 45, 4293 Baran Group Meeting Lars Jørgensen Steven Ley 03/10 2012

Dispiroketals and 1,2-Diacetals Just one example: R3 OMe OMe LHMDS 6 O O R O OR O O THF OH 2 3 2 OMe O OMe O O R 4R O 1R then aldehyde O R1 R O R Desymmetrized Glycolic Acid de% > 92+ O OR5 Org. Biomol. Chem., 2004, 2, 3608-3617 3 R Org. Biomol. Chem., 2004, 2, 3618-3627

TBDPSO Ley TPAP oxidation

HO O HO SEt OH O HO (n-Pr)4NRuO4 (5 mol%) / NMO (1.5 eqv) (S) (S) (R) R' R'' R' R'' O Ph O Ph DCM or CH CN, 4Å molecular sieves, r.t. Ph O Ph O 3 (R) 1 or 2 alcohols aldehyde CSA (cat.) CSA (cat.) or R = H, alkyl, aryl, alkenyl, alkynyl ketone Ph Ph 1994 TBDPSO Synthesis, , 639. (Times cited > 1000) O O 1987 4 EtS 2 J. Chem. Soc., Chem. Commun., , 1625. O O O O O SEt O TBDPSO 3 HO 3 O OH O Primary alcohols can be oxidized in the presence of a variety of functional groups, Ph Ph including tetrahydropyranyl ethers, epoxides, acetals, silyl ethers, peroxides, lactones, alkenes, alkynes, esters, amides, sulfones, and indoles. Tetrahedron: Asymmetry, 1994, 5, 2609 Oxidation of substrates with labile alfa-centers proceeds without epimerization. This reagent also works well on a small scale where other methods, such as those employing activated Dimethyl Sulfoxide reagents, are inconvenient. For large scale OMe OMe OMe R R O 1 oxidations it is necessary to moderate these reactions by cooling and by slow HO R 2 OMe CSA, MeOH R O R1 R + or or O R2 HO OMe R portionwise addition of the TPAP. OMe R R O CH(OMe) 3 OMe chiral diol OMe The neutral conditions of these oxidations have been utilized to provide improved MeO2C OH yields with acid sensitive substrates compared to the well established Swern method. chiral diol: HO Br D-mannitol L-ascorbic acid etc. MeO C OH OH 2 Secondary nitro compounds have been selectively oxidized to the corresponding keto compounds. Example: OMe OMe OMe butane-2,3-dione The selective oxidation of 1,4 and 1,5 primaryœsecondary diols to lactones is a HO Br (MeO3)3CH, CSA O KHMDS O O O O O 3 O valuable application of this reagent. OH Br O MeOH OMe OMe OMe Desymmetrized Glycolic Acid Chem. Rev., 2001, 101, 53 Electronic Encylopaedia of Reagents f or Organic Synthesis Baran Group Meeting Lars Jørgensen Steven Ley 03/10 2012

Bengazole A Rapamycin TBSO H PMBO MeO OMe OPMB O OMe LiHMDS steps O O O OTES OMe OMe O N TosMic N O OMe 92 % N steps O H HO Boc O O O K2CO3 O O OHC O O OMe MeO O 82% O N OMe OMe N OH TBDPSO O

Me3Sn 1. NCS, pyr O OMe 2. Cs2CO3, I [Pd(PFur ) Cl ] diasteroselective OMe 3 2 2 S NC 69 % O2 nitrile oxide [3+2] O TosMIC cycloaddition O TBSO TBSO OMe

MeO MeO MeO N O OH O N O OMe OH O O O OTES O O OTES O N steps N N O N Alloc O O OH OH N O Br O O Boc O O TBDPSO O MeO 5 steps O MeO

OMe O OMe

HO2C bengazole A Angew. Chem. Int. Ed. 2006, 45, 6714 OTES

1. catechol, DCC, DMAP, 88 % Pinitol (microbial oxidation in synthesis) 2. K2CO3, 81 % TBSO TBSO

1. BzCl, pyr O MeO MeO OH DMAP OBz Pseudomonas putida 84%

OH 2. mCPBA OBz O O OTES OH O OH OTES 73% N N Alloc O O O O O O O MeO 1. LiHMDS, 78 % O MeO CSA (cat.) TES MeOH O OMe O OMe 2. [Pd(PPh3)4] O ~ quant. dimedone, 80 % O

OH OH OH OTES 1. PIDA MeO OH MeO OBz MeO OBz Et3N OsO4, NMO 2. Dess-Martin, 88 % over 2 steps 3. HF Pyr, 61 % HO OH MeOH HO OBz 58 % OBz HO OH OH

MeO Tetrahedron, 1989, 45, 3463 O O OH N O O O O MeO HO Angew. Chem., Int. Ed. 2007, 46, 591-597 O OMe Chem. Eur. J , 15, 2874-2914 . 2009 (-)-rapamycin Baran Group Meeting Lars Jørgensen Steven Ley 03/10 2012

1. BuLi, then Okadaic Acid O O I Me 1. TPAP, NMO, Me PhO S O sieves 2 O 2. PPh3, CBr4 O Me HO O 70%, 2 step O H H Me Me OH 2. CSA (cat.) 3. BuLi, 100% H H 90%, 2 steps HO2C O O Me name? O O O C HO Me H H OH Me O O H H OH Me OMe okadaic acid O OH MeO H O OBn 1. LDA O OBn PMBO Ph t Ph Ph 2. KOBu O 1. TBDPSCl OTBDPS PMBO P OHC H O + O S O S H H B Me O OBn Me O H H 3. TFA, H H 2. mCPBA O PMBO OMe OMe O H O/DCM H N O O O 2 O H O O O S O O S H H O S OMe Me O H OH Me O O OTBDPS Ph B C H A BuLi, Me2AlCl O OBn then PMBO Me O 8 steps C B H 70% O O H H O H Me Ph Ph Ph Ph 1. BuLi, CuCN, LiCl, (vinyl)SnBu , O O 3 O O glycolic acid, O 1. LDA, MeI, 87% O then BF3 Et2O O Ph P HBr, 89% 2. LDA, allyl-Br, 95% 3 O O 70% O O OTBDPS O O O O H O O O Me 3. Sharpless 2. BH SMe A O O asym. dihydr., 82% O 3 2, O then H O NaHMDS O O Ph 4. Sharpless- 2 2 H 87% Kolb, 80% 66% O O Ph Ph 3. 10% TPAP, NMO, Ph H H H OTIPS Me sieves Ph 78% Me O O OTBDPS H H O 1. MeLi, LiBr Me OMe t O 1. KOBu , BuLi O O O Me 91% then Bu3SnCl O O O O H H 2. Ag2O, MeI, 2. MeLi, TMEDA OH Me O O O OTBDPS ultrasound O OTBDPS H H H 54%, 2 steps OTIPS Me H 98% H Ph

Ph 1. TBAF, 90% Ph 2. Ca, NH3, 30% O Me O O O 1. AcOH, H O, THF O OH H 2 O O steps O 2. NaBH Me O O 3 A O O OTBDPS OMe OH O H 3. NaH, BnBr H H OBn Me O HO2C O O Me Ph O O O Ph OTBDPS HO Me H H OH Me O O H H H OH Me okadaic acid

J. Chem. Soc., Perkin Trans. 1, 1998, 3907œ3911 Baran Group Meeting Lars Jørgensen Steven Ley 03/10 2012

Thapsigargin (+)-Okaramine C

O OMOM CO Me H H H H 2 Ph 1. H2O2, NaOH THPO CO Me CO Me N Se PhSe 2 HO 2 HO CO2Me MeOH, 88% NaOMe steps THPO TBDPSO NHZ NZ NZ NH MeOH wet mCPBA 1. H3PO4 (aq) 2. LiCl, TFA, 95% CO2Me OEt O 3. DHP, PPTS (cat) Cl 95% H H N H N H O O OTES N N H PPTS K2CO3 2. H2, Pd/C H 87% Boc Boc (S)-carvone name and mech? Boc 89% 85% 93% over 2 steps Grubbs' 2nd g. 88% O 1. NHTeoc EtO OMOM P CO2H HO2C EtO OMOM OMOM H H H 1. EDCI, 81% AD-mix alfa TBDPSO O TBDPSO OH TBDPSO 90% N H O 2. NaH H H O H OEt OTES OTES OTES name and mech? HATU, Et3N 95% steps 2. TAS-F, 97%

O O O H H H OMOM OH OH HO H H HO NH HO H NH Lindlar's cat. NH 1. TPAP, NMO Br 73% 1. TBAF, 98% N H N N TBDPSO HO OMOM TBDPSO O O 2 HO HO O NH NH N H N H N H NH 2. Amberlyst 15 2. TPAP, NMO O O DIPEA H H O O 95% H O OH acetone 93% H CuCl OH O O OH 85% 70% O O (+)-okaramine C

1. TMSCl, Et3N 88% 2. DMDO, 99% Org. Biomol. Chem. 2004, 2, 2415

SEMO OR SEMO OR HO OR H H 1. SEMCl, DMAP H 93% 1. O O RO O 3 O RO O O RO O 2. LiHMDS, PhSeCl O 2. DIPA PhSe H O 90%, dr 5:1 H O O O O

O O O 1. Zn(BH4)2 2. TBAF 3. EDTA 80% O O OH O SEMO H O O H steps HO HO O O HO OH O OH O O

O thapsigargin O

Angew. Chem., Int. Ed., 2003, 42, 5996 Chem. Eur. J., 2007, 13, 5688 Org. Lett. 2007, 9, 663 Baran Group Meeting Lars Jørgensen Steven Ley 03/10 2012

Azadirachtin Solid-Supported Reagents in Chemistry: (+)-Plicamine

O OH CO Me OH OH O O 2 CO Me OBn 2 1. TMSCl/MeOH 1. HO O OBn O HO C 2. NEt2 2. NMe3BH4 MW, 180 C OPMB O NHMe OBn 3. NH2Me 3. TFAA, N HO O 80% O NHMe HO O H2N CO2H H2N MeO2C OPMB O O MeO2C N O F C O OBn O O O 3 O OMe O N N OMe I(OAc) 3 steps 2

O MeO O CO Me CO Me 2 2 N N O OBn O OBn S S O HO C HO C O O 1. NMe3BH4 O O CF2SO3H O O NMe Bu3SnH, AIBN OBn OBn N CF3 2. TMSCHN N CF3 N CF3 O O O 2 O O TBSO O 80% TBSO O SO H MeO2C MeO C O 3 O O O O 2 O O OMe OMe NMe3OH MeOH - NEt3(NaCO3) 1. MeO Br MeO MeO 1. CrO N N 3 N SO H HO 2. 3 O O O O O O O 2. 3. montmorillonite K10 CO Me CO Me NH N N 2 2 O HN O O O OBn O OH HO steps O O OMe SH O O O O O OBn OH HO TBSO O AcO OH HO MeO2C MeO2C O O (+)-plicamine azadirachtin - 14 steps with an overall yield of 35% - using only immobilized reagents and scavengers. See also Hans Renata's GM on Limoniods

Angew. Chem. Int. Ed. 2007, 46, 7629 œ7632 Angew. Chem. Int. Ed. 2002, 41, 2194-2197 Angew. Chem. Int. Ed. 2007, 46, 7633 œ7635 Tetrahedron 2002, 58, 6285-6304 Chem. Eur. J. 2008, 14, 10683 œ 10704 Angew. Chem. Int. Ed. 2008, 47, 9402 œ 9429 Reviews by S.L. on Solid-Supported Reagents: Nature Reviews Drug Discovery 2002, 1, 573-586. Il Farmaco 2002, 57, 321œ330. Baran Group Meeting Lars Jørgensen Steven Ley 02/11 2012

Flow Chemistry: Oxomaritidine LiHMDS

O X Y O X Y + OH OH R OEt R NMe3N3

OH OH Org. Biomol. Chem. 2010, 8, 1798œ1806 MeCN/THF (1:1), 70 C Pd/C, H PhPnBu 2 2 THF Br N3 MeO MeO RT O OMe OMe then 55 C N NH MeO MeO I CO, MeOH, Pd (cat.) OMe NMe3RuO4 OMe OMe R R

MeCN/THF TFAA, (1:1), 70 C O OH CH2Cl2 Org. Biomol. Chem. 2011, 9, 6903œ6908

O OH

I(O2CF3)2 MeO NMe3OH MeO I Heck cross coupling H MeO N R MeO MeO N R CF N CF3 oxomaritidine 3 MeO O O Synlett 2011, 18, 2643œ2647

- first multi-step flow through preparation of a natural product. I2 - no distillation, crystallization, or column chromatography. O O - 5 hours from SM to natural product, 35-70 L/min. 94% - overall yield: 40%, purity: >90% N I- 208 g in 9 hrs N Agitating f low reactor H I H Chem. Commun. 2006, 2566-2568 Org. Process Res. Dev. 2011, 15, 693œ697

NH2 NMe CuI NH PPh H 3 2 N N N R' + N3 R O3 R R' R R O R'' R'' R' R' O R''' R''' Org. Biomol. Chem. 2007, 5, 1559œ1561 Org. Lett., 2010, 12, 1596œ1598

ReactIR Flow Cell: Analytical Tool for Flow Chemistry

10% Pd/C, H (Org. Process Res. Dev., 2010, 14, 393œ404) N N 2 N N

N N N N N N H H H Chem. Commun. 2010 Cbz H-Cube In-line evaporation for solvent switching ( , 46, 2450-2452)

Microwaves in flow chemistry (Org. Biomol. Chem., 2007, 5, 2758œ2761) Synlett 2006, 6, 889œ892