Baran Group Meeting I.S. Young So Many Hof(f)man(n)s 5/10/2008

Hof(f)man(n)s Discussed Hof(f)man(n) #2 (Many contributions to chemistry) - K. A. Hofmann and J. Sand (Paper from 1900, no other info available) - studied under Justus von Liebig (University of - oxymercuration of alkenes Giessen) - taught in Bonn, London and Berlin August Wilhelm von Hofmann (1818-1892) - many named reaction and aniline dyes - first to use molecular models (colors still conserved)

Felix Hoffmann (1868-1946) - invented many named reactions - first useful synthesis of aspirin and heroin August Wilhelm Albert Hofmann (1906-2008) von Hofmann - his student (Perkin) responsible for aniline dyes - father of LSD and first synthesis of psilocybin

Roald Hoffmann (Cornell University) Hofmann Rearrangement (Ber. 1881, 14, 2725.) - organic and inorganic chemist, 1981 Nobel Prize (orbital symmetry) O For base sensitive substrates Br2 O H2O C can use hypervalent iodine or Robert V. Hoffman (Professor Emeritus, New Mexico State University) R R-NH2 R NH2 NaOH N -CO lead tetraacetate - chemistry of N-sulfonyloxy compounds 2

Example from Recent Literature (J. Am. Chem. Soc. 1998, 120, 8259) Reinhard W. Hoffmann (Professor at University of Marburg, Germany) - natural product synthesis and reactive organometallic compounds OMe OMe OMe PMPO MOMO PMPO MOMO HO H. Martin R. Hoffmann (Professor at Hannover University, Germany) O Br2 O NaOMe - chiral allyl cations, chemistry of cinchona alkaloids, natural product Steps O synthesis O MeOH O HO MeO O N N H N Hof(f)man(n) #1 (not much known on this one) 2 O Me O (K. A.) Hofmann-Sand Reaction (not the Hofmann with all the other reactions) (+)-cepharamine Oxymercuration of double bonds Hofmann Elimination (Annalen der Chemie und Pharmacie 1851, 78, 253) O OAc O O H H H Br R2 R2 R2 Hg Br2 1 MeI 1 Ag2O 1 + Hg(OAc) OMe OMe R R R R2 OMe 2 I 1 CH OH OH -H O R 3 N R3 N R4 H2O 3 N 4 2 MeO MeO R3 R4 R R Me Heat Me Berichte der deutschen chemischen Gesellschaft 1900, 33, 1340 - 1353 alkene formed often does not follow Zaitsev's rule

1 Baran Group Meeting I.S. Young Which Hof(f)man(n) is Which? 5/10/2008

Recent Example of Hofmann Elimination (Tetrahedron Lett. 1989, 30, 5989) Hofmann-Martius Reaction (Ber. 1871, 4, 742) OMe R NH NH NH 1) CH I O 2 2 MeO 3 MeO O - Similar to Fries Rearrangement 2) 20% NaOH R EtOAc steps HO + - R-group must be able an efficient cation stabilizer 85% H O O O O H R NMe2 (+)-picrasin Recent Example of Hofmann-Martius Reaction (Org. Lett. 2006, 8, 3497)

Me Ph Ph Me Hofmann-Löffler-Freytag Reaction (Ber. 1883, 16, 558) Me PhMe/80 oC Cl N 2 NH or CF CO H NH N 3 2 (cat) MeHN O N NaOH O PhH/25 oC H (aq) ligroin Cl 71 or 82%

H2SO4(aq) Creation of the Textile Dyeing Industry N N - Hofmann had his student Cl H HO (Perkin) attempt to oxidize N aniline to quinine Recent Example of Hofmann-Loffler-Freytag (Chem. Pharm. Bull. 1985, 33, 3187) MeO - led to black tar that made a bright purple solution in ethanol 1) Hg-lamp N NCS, DCM quinine CF3CO2H - purple solution was used to 0 oC 5h, r.t. N H N Cl N William Henry Perkin dye silk, Perkin became rich 2) 5% KOH, EtOH H C CH reflux, 2h, 39% Synthesis of first synthetic dye H3C CH3 3 3 Me Me N core of kobusine NH2 NH2

K2Cr2O7 H N N NH + 2 Hofmann Isocyanide Synthesis (aka carbylamine test) Me (impurity) + CHCl3 + KOH N qualitative test NH heat 2 C mauveine A

"smell of isocyanides described by Hofmann and Guatier as " highly specific, almost prior to mauveine, purple dye came from the fresh mucus secretion from tthe overpowering, horrible, and extremely distressing" hypobranchial gland of a medium sized predatory sea snail (extremely expensive!!!)

2 Baran Group Meeting I.S. Young Which Hof(f)man(n) is Which? 5/10/2008 Hof(f)man(n) #3 - Bayer Pharmaceutical Chemist Hof(f)man(n) #5 - of Woodward-Hoffmann Rule Fame - synthesized aspirin (1897) and heroin (1897) in forms that could be used medicinaly - professor at Cornell University AcO - interests lie in the application of theoretical and computational OAc methods to inorganic and organic systems CO H 2 O N - Awards include: 1981 Nobel Prize Priestly Medal ACS Organic and Inorganic Award H Arthur C. Cope Award aspirin AcO National Medal of Science heroin Felix Hoffmann - also has an interest in and writes poetry Roald Hoffmann Hof(f)man(n) #4 - Father of LSD (and psilocybin)

- first to synthesize, ingest and study the psychodelic Hof(f)man(n) #6 - Professor Emeritus, New Mexico State effects of LSD (synthesis 1938, test 1943) - was a chemist at Sandos (now Novartis) α-oxidation and installation of a leaving group (Synthesis 1985, 760) - accidently absorbed some through fingertip, then rode bike home (purposely ingested 0.25 mg the next day, 1 O see results below) R OAc Ethyl Acetate R2 Methanol R1 + (Ar-SO2-O)2 R3 - recently passed away (april 29, 2008, age 102) R2 R3 81-95% Albert Hofmann OSO2Ar O O Ar = O2N HN HO P N NMe - O H O Also applied to enamines (J. Org. Chem. 1985, 50, 5148) and Robert V. Hoffman β-ketoesters (J. Org. Chem, 1990, 55 ,1267) psilocybin LSD N H N H C-to-N Rearrangement of N-(Arylsulfonoxy)amine (J. Org. Chem. 1988, 53, 3317) First Accidental Experience With LSD - "In a dreamlike state, with eyes closed, I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After some two hours, this condition faded away." NH2 filter through warm o N (Ar-SO2-O)2 SiO2 (-78 C) to rt Second (0.25 mg experience), excerpts - commenting on his neighbour " She was no 82% longer Mrs. R. but rather a malevolent, insidious witch with a colored mask." EtOAc -78 oC "A demon had invaded me, had taken possesion of my body, mind and soul. I jumped Yields typically not this high, generally 40-80% up and screamed, trying to free myself of him, but sank down again and lay helpless on the sofa."

3 Baran Group Meeting I.S. Young Which Hof(f)man(n) is Which? 5/10/2008

Synthesis of α-azidoketones (J. Org. Chem. 1994, 59, 2902) Synthesis of 2-Oxazolone-4-carboxylates (J. Org. Chem. 2002, 67, 1102) O O - installation of halogen can be difficult O X - N O R1 N3 1 3 O R R OEt p-TsOH 2 - doesn't work well when β-hydrogens R (X = Cl, Br) R2 + O N MeO NH2 X O Toluene Solution Reflux X = ONs (AgOTf for X = Br) R CO2Et X = Br O O - -ONs can be installed regiospecifically ONs 1 N - N3 - reaction conditions milder than halide (rt) The Products can be hydrolyzed (ester), acylated (nitrogen), reduced (ester) R 3 R1 2 - yields range from 68-96% R R2

Generation and Trapping of α-Lactams by Weak Nucleophiles Hof(f)man(n) #7 - Professor, University of Marburg, Germany (J. Org. Chem. 2000, 65, 2591)

General Reaction Main Research Focuses O O O O R 1) Total Synthesis of Natural Products Base R Nu: N Nu EtO2C R EtO 2) Chiral Organometallic Reagents EtO N N OMs O 3) Stereoselective allylboration reactions If a primary amine and excess base is used. Reinhard W. Hoffmann O O O NaH (1.2 eq) C6H11 N Example of Research Focus 1 and 3 (J. Am. Chem. Soc. 1997, 119, 7499) C6H11 NBn 65% EtO N BnNH2 THF, rt, 10h Previous work by others (for references see original paper) OMs O Br H H Sonication no nucleophile added H O Lewis Acid HO HO O or Protic Acid O O O + OAc NaH CH O O O CH3 O N 3 83% H EtO N H sonication M OMs EtO M = TMS BF3 Et2O Major M = trialkyltin BF3 Et2O Major Preparation of phosphonomethyl ureas M = tributyltin triflic acid Major O O O CH3 (+)-Laurencin Yields are low and the example to form the cis has never NaH P CH3 P N N been exploited further EtO N + EtO OEt N THF OEt 79% OMs H O 4 Baran Group Meeting I.S. Young So Many Hof(f)man(n)s 5/10/2008

Laurencin Continued - Use of Masking Strategy Interesting transformations along the way to the tetrahydropyran O iBu2Al OH MeO O HO N MeO O MeO OTBS Me N B OiPr 2. s-BuLi 3. O 1. DIBAL O OMe OBn H H Me OBn OH O -78 oC -78 oC KH, THF, 0 oC O Yb(OTf) Li 55 % Cl CCHCl, -78 -> 20 oC 3 2 79% MeCN O MeLi, -78 -> -40 oC 2. aq pH 7 2% H2O MeO rt N O HO 1) pinacolborane O B O 35% Me O Cp2ZrClH O O O + MeO Li O O B O 2) CH2ICl, n-BuLi B o OBn OTBS O O OMe OBn OTBS -100 -> 20 C 67% MeO OMe OMe

What happens when the additional stereocenter is included? Research Area #2 - Chiral Grignard Chemistry O 1. DIBAL 2. s-BuLi So What is the Deal with the Chrial Grignard Reagents? MeO 3. HO HO O H N B OMe 2 Pd / C Debate about mechanism of Grignard Addition Me O - ionic could lead to enantioenriched products O 97% O 4. aq pH 7 - single electron transfer would likely lead to racemic products O - chiral Grignards reagents can act as mechanistic probes as well 38% TBSO TBSO as form new asymmetric centers is process is ionic single diastereomer TBSO This completed formal synthesis, nine steps remained to form (+)-Laurencin Preparation of Chiral Grignard (Angew. Chem. Int. Ed. 2000, 39, 3072) (halogen metal exchange on enantiomerically pure halide not an option) Example of Research Focuse 1 and 3 Org. Lett. 2006, 8, 3829 Cl Retrosynthesis HO organolithium O Cl addition OH O Cl S Jimenezin 5 eq. EtMgCl ClMg O 5 Ph MgCl O O S hydroformylatoin/Wittig 8 THF, -78 to - 30 oC H H H H Julia-Kocienski Ph OH O e.e. ca. 90% enantiomerically pure HO OH racemizes with half- O O o HO OH life of 5 h at -10 C.

O OH H H OH O O

5 Baran Group Meeting I.S. Young Which Hof(f)man(n) is Which? 5/10/2008

Reactions of Chiral Grignards (Angew. Chem. Int. Ed. 2000, 39, 3072) (Org. Lett. 2001, 3, 1945) Preparation of Conjunctive Reagent S 1) PhNCS 56% yield O ClMg Ph Ph 2) H2O O N Ph 93% ee B B O O H O tBuLi o Cl -78 C, Et2O O 92% ClMg MoOPH HO O Ph Ph 84% yield THF 92% ee O

1) PhS-CH2-N3 Ac N Ac ClMg o KOH NH Ph -60 C N N SPh Reagent allows for allylboration and subsequent cycloreversion of the Ph Ph 2) Ac2O dioxene ring to install an additional enal unit. 82% yield O Kumada Couplings (Chem. Commun. 2003, 732) 92% ee OTBS B O ClMg Ph Ph + Ph Br + Ph O O PdCl dppf 2 57% yield 3% yield ca. 90% e.e. 5d, -78 oC O toluene, rt, 2d 88% ee then reflux 2h THF OTBS OH I Phenalamide A2 (Org. Lett. 1999, 1, 1713) Ph 2 OH O O Ph N H 69% 9:1 alkene isomers (major is all E, after dehydration all manipulaitons had Horner-Emmons OH to be performed in the dark)

OTBS O O

Ph + (EtO)2P Hof(f)man(n) #8 - Professor, University of Hannover O N H - has impressive pedigree: PhD - Ingold allylboration OTBS Postdoc - Cram and Woodward

OTBS O O O Major Areas of Research: 1) Total Synthesis of Natural Products Ph + B O O 2) Chemistry of the Cinchona Alkaloids 3) Allyl Cation Chemistry H. Martin R. 4) Methodology Development Retro is standard for these molecules: allylboration, aldol, Wittig, etc. One interesting Hoffmann step will be highlighted.

6 Baran Group Meeting I.S. Young Which Hof(f)man(n) is Which? 5/10/2008

Cinchona Alkaloid Chemistry (Research Area 2) Synlett 1996, 690. For mechanism see paper, it is crazy

- approximately 700 t/year are isolated from the bark of the Cinchona tree LiAlH4, iPrOH, THF; OMe o - quinine is a traditional antimalarial drug, quinidine treats irregular heart beat then O2, r.t. -> 45 C N - cinchonidine and cinchonine and their salts crystallize well (resolutions) N OMe - are used as chiral ligands (Sharpless Asymmetric Dihydroxylation) OH H - N HO - used for the resolution of naproxen quinine N quinocorine

R R mechanism involves radical, radical ion-SET and ionic chemistry with sequential oxidation and also hydrogenation steps, all in a single flask. Has been caried out on N N 100 kg scale.

Preparation of bidentate ligands (Tetrahedron 2000, 56, 4453) OH HO "psuedoenantiomers" H H N N 1) MsCl or or R = OMe quinine 2) Phosphide R = OMe quinidine N R = H cinchonidine R = H cinchonine N N HO N Ph2P

- it has been suggested that the Cinchona bases "are unlikely to find application as Ph P HO 2 Ligand 1 chiral building blocks" J. Crosby, Chirality in Industry, 1992, pp 19-20. quinocorine quincoridine Ligand 2 - it was HMR Hoffmann's goal to prove this statement incorrect Applications of Ligands (For references see within Eur. J. Org. Chem. 2004, 4293, not HMRH) Known Reaction (W. E. Doering, J. Am. Chem. Soc. 1946, 68, 586.)

Hydrosilylation HO H OMe OMe Ligand 2 O R: 54% ee N N Ox. Ph2SiH2 OH O Ligand 1 H enantiomer S: 1% ee N N KOtBu O Beznene Kumada-Corriru H 3 O2 Ligand 2 O MgCl R: 65% ee - CO2 Mechanism of the last step??? Br + MeO Ligand 1 N enantiomer S: 86% ee H N

7 Baran Group Meeting I.S. Young Which Hof(f)man(n) is Which? 5/10/2008

Further Applications (note: diamine Ligands this time) First Cinchona Rearrangement (Angew. Chem. Int. Ed. 1999, 38, 2540). (Org. Biomol. Chem. 2003, 1, 2522, not HMRH)) OH

Ligand 3 N H O N AgOBz MeOH 92% ee N N H N Q Q [IrCl(COD)] 2 Ligand 3 H 2 Q OMe Br H OH Q = quinoline H Ligand 4

H N N Stereospecific Capture of Rearrangement Product by Nucleophiles 94% ee 2 Ligand 4

H OMe H Preparation of Baylis-Hillman Catalyst (Tetrahedron 1998, 54, 3495) 1) Bu3Sn BF3 OEt2 N 2) KF, H O N Me Me 2 OMe KBr O H3PO4 OMe H OH BF3 OEt2 N OMe H CO2Me 53% N H N H OSiMe3 H N N (E:Z = 1:1) catalyst 5 N DCM, MTBE (20:1), 70% OH

Application to Asymmetric Baylis-Hillman Reaction note: the quinoline portion is not on the substrate (J. Am. Chem. Soc. 1999, 121, 10219; Not HMRH)

10 mol % O OH O CF3 O CF3 catalyst 5 There are many, many more reactions published by Hoffmann on the chemistry of the cinchona alkaloids, for a recent review by Hoffmann see: Eur. J. Org. Chem. H -55 oC, DMF O CF3 2004, 4293. + O CF3 O N O N 2 2 58% yield, 91% ee

- First practical example of asymmetric Baylis-Hillman reaction - it was previously noted that a suitably disposed hydroxyl group on the amine catalyst increases yield and ee, the catalyst with -OMe instead of -OH on the quinoline led to grealy decreased ee (10%)

8 Baran Group Meeting I.S. Young Which Hof(f)man(n) is Which? 5/10/2008

Chiral Allyl Cation Chemistry (Angew. Chem. Int. Ed. 1998, 37, 1266) 2,5-dimethylfuran O OH General Reaction OTMS TMSOTf OBn DIBAL OBn furan OBn DCM, -78 oC O THF, -78 oC OTES O O LDA, TESCl TMSOTf O o OMe THF, -78 C OMe DCM, -78 oC OBn 53% 94% quantitative MeO O 1) NaH, CS , CH I OMe 72% 2 3 OMe THF, 0 oC, 77% racemic 2) Bu3SnH, AIBN Preparation of Mixed Chiral Acetal and Reaction toluene, 95 oC O 92% O O 1-phenylethanol OMe BF3 OEt2 OH OBn OMe AcBr OMe n-BuLi, ether o 1) m-CPBA, 85% O DCM, 0 C O O O Me 89% 92% BRSM O OMe Br 72% 2) H2, Pd / C, 85% both enantiomers of Ph 1-phenylethanol available HO O

Improved Reaction Conditions (Chem. Eur. J. 2000, 6, 684) Studies Towards Phorboxazole and Bryostatin 1 using Allyl Cations

Methodology Applicable to Natural Products with O 2 furan O R OTES 2,6-cis Tetrahydropyrans O LDA, TESCl TMSOTf R1 o N O Ph THF, -78 C O Ph DCM, -95 oC O O Phorboxazole A and B Tetrahedron 1999, 55, 4315 A: R1 = OH, R2 = H O OMe OMe 67% yield 76% de Ph B: R1 = H, R2 = OH OMe O O - the smaller Methoxy group is the leaving group under Lewis acid conditions OMe N - Switching the phenyl of the auxilary to a naphthyl increased de to 100% (no yield given) O O O O H OH Application of this Methodology to Natural Product Synthesis OH (Tetrahedron Lett. 1998, 39, 8259 and Tetrahedron 2002, 58, 6199) Br H HO H OAc HO MeO C Northern Half of Bryostatin 1 2 O O O O O O Org. Lett. 2001, 3, 929 OHH O H O dictyoxetane OH OH Hoffmann's concern was with construction of the dioxatricyclic framework

9 Baran Group Meeting I.S. Young Which Hof(f)man(n) is Which? 5/10/2008

Reasearch Area 4 - Development of New Methodologies SmI2 Mediated Pinacolization of Diketones (Tetrahedron 1996, 52, 11783 and Tetrahedron 1996, 52, 11799) Deprotection of SEM Group Using MgBr2 (Org. Lett. 2000, 2, 1447) Me Me OH SEM protecting group can be difficult to remove, especially in a selective manner HO SmI O O 2 HO OH Me - Is quite resistant to TBAF, but TFA will remove (Harsh!!) TMS ΔE = 33.9 kcal mol-1 O Me Me 76% yield Me - MgBr in ether/MeNO is a good mild selective alternative to TFA and other 2 2 The large increase in strain energy, and the facility of the reaction suggests that this harsh conditions process could be applied to the synthesis of cyclobutanes, which are usually prepared by ionic or photochemical processes. Examples of Utility Me 1.5 eq TBAF OH o S OSEM O O OH O THF, 0 C, 1.5 h CH3 Me SmI 99% S 2 ΔE = 41.4 kcal mol-1 Me Me 32% yield H HO Me S OSEM O O OTBDPS O ylangene

S yield not great, but the ring system is quite complex for one-step generation MgBr (14 eq) S OH O O OTBDPS 2 CH Et O/MeNO CH3 3 2 2 Me S SmI2 81% 94% O HO HO HO 12 eq. TBAF, 4 A MS O OH DMPU, 45 oC, 0.5 h decomposition yield very high in many examples and a variety of tricyclic ring systems were generated

More Almost Total Syntheses from the HMR Hoffmann Group CN OSEM OBn OSEM OTBDPS CHO J. Org. Chem. 1993, 58, 6163. TESO HO O - naturally occuring antimalarial compounds CN OH OBn OH OTBDPS 20 eq MgBr2 OHC Et2O/MeNO2, 8 h - originally assigned structure was incorrect TESO OH 94% - key steps are Knoevenagel condensation, hetero-Diels-Alder and aromatization alcohols, esters, benzyl groups, dithians, methoxy acetals, TBS, TIPS, TBDPS and Robustadial A, isopropyl = β cyanohydrins are all tolerated under SEM deprotection conditions Robustadial B, isopropyl = α

10 Baran Group Meeting I.S. Young Which Hof(f)man(n) is Which? 5/10/2008

Precursor to Robustadial Continued

MeO C O MeO2C O 2 OHC + HOAc (1.8 M) O KOAc (0.1 eq) O mechanism? MS 3 A, hydroquinone 100 oC, 20 h, 80% BSA, DDQ dioxane 110 oC

MeO2C O MeO C O 2 1) KF, HBr, DMF

2) Acetone, K2CO3 (MeO) SO TMSO OMe 2 2 85% (2 steps) MeMgI ether selenation/oxidation, α-halogenation reflux α-oxidation, and DDQ alone failed or 98% gave low yields. BSA necessary

HO 1) 85% H O , p-TsOH O 2 2 MeO O 2) pyr. (CF3CO)2O 3) CF3CO2H, H2O/CH2Cl2

4) Acetone, K2CO3,(MeO)2SO2 OMe OMe 74%, 4 steps mechanism???

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