Baran Group Meeting Cobalt in Organic Synthesis Klement Foo Background -CpCo moiety (14 e species) highly dienophilic. -Cobalt-59 – 1st row Group IX TM -Cobalt dyes used for centuries – glass, pottery and glazes. -Originally confused with Cu – both form blue compounds. -German name "Kobald" – "evil spirits" – describing a mineral that is both hard to mine and O detrimental to health (when heated emits As4O6). -1 of the 3 naturally occuring magnetic metals (Ni/Fe/Co) Co Co -10 to 30 ppm on earth – cobalite/smaltite/chloranthite. -Cobalt-60 – radioactive isotope used to find and treat diseases. Organometallics. VCH:Weinham, 1989, pp 277, 348 Schilling Test - determines if a person is making and using Vit. B12 properly. Treat for cancer. -can form 19, 20 and 21 e sandwich complexes + eg. CpCoC6Me6, [(C6Me6)2Co] , [(C6Me6)2Co]. -Cobaltcarbonyls exist as clusters: Co2(CO)8, Co4(CO)12, Co6(CO)16... Cobalt in Nature Vitamin B12 -first compound with a M–C bond in natural product -soluble in water. Comic book -suffix: cobalamin; prefix: depends on upper axial ligand. -cyano (CN), hydroxo (OH), methyl and adenosyl. Oxidation State - Common OS of Co is I, II, III Co(II) -d7 complex. -forms both Td and Oh complexes –depends on ligand strength. -small Δoct and Δtet difference. Outline Co(III) Characteristic Organic Reactions of Cobalt -d6 complex. -almost exclusively Oh complexes. 1. Pauson-Khand Reaction 2. Nicholas Reaction 3+ - Co2+ E = +1.82 eV Co + e 3. Cyclotrimerization 4. Carbonylation Some Organocobalt compounds -high affinity to π bonds of carbon-carbon, carbon-oxygen and carbon-nitrogen. Other Reactions of Cobalt -forms mutually bridged bond between 2 π bonds of acetylene and Co–Co bond. 5. Radical Chemistry of Cobalt R R' 6. Vit. B12-type Co Reactions 7. Mention of Mukaiyama Co Chemistry (OC)3Co Co(CO)3 Page 1 Baran Group Meeting Cobalt in Organic Synthesis Klement Foo 1. Pauson–Khand Reaction 1.5 Modifications to Pauson-Khand 1.5.1 'Interrupted' Intramolecular PK – 'insertion of O2' instead of CO 1.1 Mechanistic Outline O L not R O O Co2(CO)8 R R R R C RL R heat, air (OC)6Co2 [2+2+1] O S R RS R = CN, (CH2)2OTBS, Et, CH2Ph Krafft, JACS 1996, 118, 6080 S S RL R R L S L S 1.5.2 Formal [5+1]/[2+2+1] vs. [5+1]/[2+2]-cycloaddition – epoxyalkyne + olefin +CO R R R R R (OC)5Co2 L H R R R O H O R O O O O (OC) Co (CO) Co (OC) Co (CO) Co 3 2 3 2 (OC)3Co (CO)2Co O Co (CO) R 2 8 R or R heat R' R' 1.2 Pauson–Khand in Total Synthesis CO or N2 H H R' O Me H R = H, Me OH [5+1]/[2+2+1] [5+1]/[2+2] H H H Me O Liu, JOC 2006, 72, 567 N Me OH -If R = Me, heating under CO gives the [5+1]/[2+2+1] adduct; H H H H heating under N2 gives [5+1]/[2+2] adduct. If R = H, only [5+1]/[2+2+1] adduct in CO O or N2. H H N O O - reason unclear - speculated to be due to avoidance of quaternary center generation. O O OH (+)-Epoxydictymene (±)-13-Deoxyserratine (-)-Dendrobine Paecilomycine A 1.5.3 Sequential Staudinger/PK – Fused Tricyclic β-Lactam Schreiber Cassayre Cassayre Danishefsky R JACS 1994, 116, 5505 ACIE 2002, 41, 1783 JACS 1999, 121, 6072 ACIE 2007, 46, 2199 1.TMSOTf, Co2(CO)6 ArNH2 Ar Co (CO) R CH(OEt)2 2. DIPEA N 2 6 1.3 Pauson–Khand Readings Ts ClOC N R = H, Me, SiMe3, Ph n O N n -S. Gibson, N. Mainolfi, ACIE 2005, 44, 3022 Ts -O. Geis, H. Schmalz, ACIE 1998, 37, 911 n = 1, 2 -Nakamura, Chem. Rev. 2004, 104, 2127 –TM catalyzed heterocycle syntheses -Buchwald, JACS 1999, 121, 7026 –Ti (in place of Co) Assymmetric PK 1.4 Scope and Limitations Bertrand, JOC 2008, 73, 8469 -Excellent method for 5-membered ring synthesis – atom economical and has potential flexibility - Pioneered by Alcaide et. al. -Long reaction time - addressed by use of tertiary amine N-oxides (xs) to generate free coordination - [4.6.5] and [4.7.5] tricyclic lactam sites at Co by removal of CO ligand. Recent eg. OL 2009, 11, 3104. available -Stoichiometric use of Co - addressed with development of catalytic systems, eg. Co2(CO)8/P(OPh)3; indenylCo(cod); Co(acac)2/NaBH4. eg. Photoactivation of Co2(CO)8: JACS 1996, 118, 2285. -Use of other metals - Ru/Ni/Ti - not covered here. -Existing problems: Assymmetric Pauson–Khand, Limited choice of alkyne substrate (terminal). Page 2 Baran Group Meeting Cobalt in Organic Synthesis Klement Foo 1.5.4 Asymmetric Pauson-Khand Reaction - PNSO ligand works as it is bridging; olefin inserts to Co where S* is bound. - Sterics and higher ! -acidity of sulfinyl ligand favor olefin coordination. Sulfur chirality - 3 approaches: chiral substrates (most common), chiral ligand or chiral amine-oxide promoter. directs olefin insertion into 1 of 2 Co–C bonds. 1.5.4.1 Chirally-modified substrates in Total Synthesis 2. Nicholas Reaction H H 2.1 Mechanistic Outline O O H OR' X Nu H H H OR' 1. Nu- (+)-Hirsutene R' = chiral auxiliary (OC)6Co2 2. [O] Greene, JACS 1990, 112, 9388 R1 R1 For similar total syntheses see JOC 1995, 60, 6670 and JOC 1996, 61, 9016. [O] Using chiral substrates - in this case a chiral ynamine R1 X R1 R1 Nu LA Nu- O Toluene, -30 oC H NR2* (OC) Co Co(CO) (OC) Co Co(CO) *R2N 3 3 3 3 (OC)3Co Co(CO)3 JOC 2000, 65, 7291 2.2 Scope 1.5.4.2 Chiral amine-oxide promoter - Reactions of propargyl halides with ! -systems required >1 alkyl or Ph substitutents EDGs ==> limited use of propargyl cation as synthons. - Dicobalt hexacarbonyl group efficiently stabilizes the cation. (also used as alkyne PG) - SN1 type reaction - Thermodynamic control (Lewis acid catalyzed). Kerr, Synlett 1995, 1085 2.3 Readings on Nicholas Reaction - Although modest ee 44%, first innovative use of chiral amine N-oxide. - Named reaction in Organic Synthesis - for a brief introduction. - can use achiral reagents - JACS 1998, 120, 900 - for Phys Org study on electrophilicity of propargylium ions and compatible nucleophiles. 1.5.4.3 Chiral Ligands - Large number of studies in this field: one major challenge remains – use of symmetrical 2.4 Nicholas Reaction in Total Syntheses alkynes. OR O - Symmetrical alkynes less reactive; chiral phosphine ligand too far away to direct olefin OBn H H insertion, thus end up with an almost racemic product. H H O H i–Bu Me(H2C)4 O O O H NH O Ar N O H H Ar P S O O Tol HO R ß-Lactam Precursor OC Co Co CO (+)-Secosyrin 1 (+)-Epoxydictymene OC CO NMO, rt, CH2Cl2 to thienamycin Mukai Schreiber H ee >90% Jacobi JACS 1994, 116, 5505 R R R JOC 1996, 61, 2413 JOC 1997, 62, 8095 Riera, OL 2009, 11, 4346 Page 3 Baran Group Meeting Cobalt in Organic Synthesis Klement Foo - Tricyclic ethers: [5.6.5] and [5.9.5] poor yield; [5.7.5] and [5.8.5] trans favored; [5.10.5] 2.4.1 Total synthesis of Velloziolide not isolable - dimerizes to give 20-membered-ring. - Benzo-fused ε−lactone unit - 1st synthesis. - Tricyclic amines: [5.7.5] gives excellent cis selectivity; [5.8.5] cis favored; others not - Derived propargyldicobalt cation stable despite the EWG (CO2Me). favored. - Use of 2 Nicholas reactions. - Tricyclic lactones: not successful; also dimerizes to give diolides (ThD controlled). Also featured in JOC 2005, 70, 9088. CO2Me O MeO O Co2(CO)6 O 2.6 Using ThD to advantage O 1. Rh/C, MeOH O 1. Bu2BOTf O R 2. MeLi HO MeO2C 1. Co2(CO)8 2. [O] BnO 2. cat. TfOH BnO HO BnO O OH Li R 3. Et3N, I2 OH R O Nicholas OBn OBn CO2Me OBn O MeO O Co (CO) 1. Me CuLi R = SiMe3: β/α > 99 BF –OEt O 2 6 O 2 3 2 1. Bu BOTf 2. DIBAL-H 2 CO2Me Inouye, OL 2003, 5, 625 2. [O] - Mitsunobu conditions not α/β selective. - Nicholas gives high β−selectivity since ThD conditions cause epimerization of α anomer Nicholas to β counterpart. O OR O O O 3. [2+2+2] Cyclotrimerization with Co O MeC(OEt)3 1. BCl3 O EtCO2H 2. AgNO3 3.1 Mechanistic Outline R R CO2Me R = CH2Cl2 L R OH velloziolide -L -L R R R = H L M L M L M ML n n n LnM n Green, JOC 2009, 74, 7411 L L LnM "template" R coordination to 2.5 Tandem Intramolecular Nicholas/PK for Synthesis of Tricycles R - R satisfy 18 e rule R - Endocyclic cyclization is one of the least studied. Endocyclic cyclization using R +2 LnM alcohol, amine and carboxylic acid as nucleophiles are studied here, where the latter LnM two are unprecedented. H 3.2 Scope and Limitations Z d.r. dependent on - Catalytic Co (usually CpCo(CO) ). H reaction conditions 2 n O - Other metal alternatives such as Rh, Ru, Ir and Pd. n = 1 – 10 H Z - Used widely to create complicated polycycles. OMe n Co (CO) 2 8 PK 3.3 [2+2+2] Cyclotrimerization with Co in Total Syntheses (OC) Co O N N.B. Bond angle 6 2 (OC)6Co2 reduced to 138º Nicholas H H Z OMe Z H n n H H Oestrone N H (±)-Strychnine Shea, JOC 2008, 74, 3680 Vollhardt O Vollhardt HO H JACS 1979, 101, 215 O OL 2000, 2, 2479 Page 4 Baran Group Meeting Cobalt in Organic Synthesis Klement Foo SiMe3 Other Total Syntheses: SiMe 3 - Diterpene: Illudol – JACS 1991, 113, 381.