Baran GM Kharasch Reaction and its Related Transformations Klement Foo Background Asymmetric Development (only in 1990s) - 1895–1957 - Main players: Andrus, Pfaltz, Katsuki - defined the "peroxide effect" - earliest asymmetric development was diastereoselective using chiral anti-Markovnikov via radical additions auxiliaries. - Born Russian but migrated to the USA at age of 13. - best result 30% ee. - Obtained PhD from University of Chicago - Trained Nobel Laureate H. C. Brown Potential for asymmetric Kharasch oxidation depends on the ability of L on - In 1942 (WWII), joined the American Synthetic Cu(III) to induce asymmetric formation of benzoate. Rubber Research Program - polymerization of Bisisoxazoline as ligand: styrene 5 mol % What is the Kharasch Reaction? Y O O Y 1) Allyic oxidation with radicals 2) The Kharasch modified Grignard rxn Y N N Y Cu X=tBu/Ph 3) Addition of poly-halogenated alkanes across olefin O X OTf X Y=H/Me OBz O o Kharasch Allylic Oxidation and its Development Ph O CH3CN, -20 C 2 days - First reported in 1959 by Kharasch ~81% ee O OBz 5 equiv OBz 50% Cu(I) cat. no way to predict which ligand is best O o R Ph O PhH, 80 C R require screening of X/Y Andrus, TL 1995, 36, 2945 Mechanism: cyclooctene slow conversion/ low ee O O acyclic olefins like allylbenzene and 1-octene has been done Cu(I) O O Cu(II) O O Ph O Ph O N N O2CPh diffusion O2CPh controlled O OH (6mol%) O CPh R R CuOTf (5mol%) 2 o 90% ee 63% ee 13% ee geometry retained Acetone, 0 C 9% barrier of rotation 50% 41% 2o radical O (~20 kcal/mol) Ph favored OBz Cu(II) R Pfaltz, TL 1995, 36, 1831 Ph O O -Cu(I) attack at least O Cu(III) hindered C. R Andrus went on to show that weakening perester bond would increase 9:1 regio R (can be 1:1 using AcOH, homolysis and thus increase formation of Cu(II) complex. However Beckwith, JACS 1986, 108, 8230. CuCl, tBuOOH) different peresters require different Cu catalyst: CuBr to CuPF6(CH3CN)4. Walling, JACS 1961, 83, 3877. Kochi, JACS 1965, 87, 4866. T 1997, 53, 6229 Page 1 Baran GM Kharasch Reaction and its Related Transformations Klement Foo O O O Also studied are proline derived ligands. Best results yet: Observed correlation between coordinating ability of ligand to % ee N N O O stereocontrol increases with the use of more rigid alkenes (cyclic alkenes) tBu Ph Ph Muzart, T:A 1995, 6, 147; Andrus, T 2002, 58, 845 O CuPF6 2 NO2 o CH3CN, -20 C Recent Development: O2N 17 days 96% ee O OCOPh 44% R1 L, Cu(OTf) , R O 2 2 t N PhCO Bu, Shorter reaction time generally give lower ee (>84% ee) R 3 R 90% ee n=1 Able to achieve 99% ee with cyclopentene. N PhNHNH2 O R=H n 97% ee n=2 Andrus, JACS 2002, 124, 8806 R1 n acetone R1=R2=Me/Et/Cp n=1, 2 R2 O or R =Me R =tBu 1 2 Boyd, CC 2008, 5535 Biaryl atropisomeric oxazolines as ligand: Ligand can perform asymmetric cyclopropanation of styrene (88–95% ee) -wider bite angle between 2 nitrogens, forcing allyl radical and X Cu(I/II) X benzoate closer together. Y Y Y X tBuOOCOAr OCOAr Y Y Y O -(S,S,S) ligand shown here. Also available (S,R,S) O3 then NaBH4 N Ph -recoverable by 80% N Ph -73–78% ee for oxidation of cyclopentene and meso X=CH2/CR2/O/NR symmetrising O cyclohexene Y=H/OR NaIO4 Y Y Andrus, JOC 1997, 62, 9365 ArOCO then OH Andrus, T 2000, 56, 5775 NaBH4 X Pyridine based igands: H H H H HO OH HO OCOAr only successful for Y=H and X=CH2 and CR2 O O R up to 70% ee Clark, TL 2004, 45, 9447 R N N N (62–75% ee R N N R for cycloheptene) Kharasch Variant (Schiff base as ligand) PINDY t PhCO3 Bu, OCOAr OMOM Singh, TL 1996, 37, 2633 Kocovsky, OL 2000, 2, 3047 CuPF6(CH3CN)4 (3 mol %) AcO OH O H H O OCOPh C3 Symmetric oxazole as ligand: N N N 81% ee N 3 3 H Ar=Ph 84% ee precursor O H H H OCOPh (3 mol %) N O 88% ee for cyclopentene 38% overall Ar=4-NO2Ph > 99% ee to 2-deoxy- O 58% ee N 15 gram scale streptamine 3 H Ar 85% ee Transforming to 4-NO2Ph then recrystallizing enhances ee. Katsuki, SL 1995, 1245 SL 1999, 8, 1231 OCOPh Hayashi, OL 2009, 11, 3314 Page 2 Baran GM Kharasch Reaction and its Related Transformations Klement Foo 3. Synthesis of Polyether Toxin Frameworks - Brevetoxin B Summary: tBuOOH (0.2 eq) -Asymmetric Kharasch allylic oxidation has reached >90% ee AcOH (0.8 eq) -But is greatly hampered by the long reaction times (days) and only applicable mostly on simple cyclic substrates. Cu2Cl2 cat. -More complicated or acyclic olefins tend to give mixtures of regioisomers. 80 oC, 52 h OR 82% For detailed reviews on stereocontrol/regiocontrol/mechanistric studies R = OAc then OH see: Andrus, T 2002, 58, 845; C.Eur.J 2008, 14, 9274. Applications of Kharasch Allylic Oxidation OAc 1. Synthesis of Leukotriene B4 Alvarez, JOC 1994, 59, 2848 Selective OBz O 4. Synthesis of Chrysanthemic acid ozonolysis H LB4 t OBz OMe PhCO3 Bu, LDA OCOPh 74% CuCl, PhH 75% O CO2Et CO2Et common intermediate 60% H CO2Et to 12 routes to LB4 reported -previously made from OBz 6 steps from 2-deoxy-D-ribose -or 12 steps from D-xylose CO2Et actual 2. Synthesis of Oleanolic Acid -Reported regioisomer does not obey Kharasch reaction mechanism -Found by Andrus that the other regioisomer was actually formed, but t gives same products. Angelo, TL 1976, 28, 2441 1. PhCO3 Bu H CuBr, PhCl 118 oC, 4 h, 81% 5. CH2OH O 2. NaOH, H O H MeOH-THF H CuCl, O t H TBSO 98% TBSO PhCO3 Bu, O H H H PhH, 4 d H <10% Corey, JACS 1993, 115, 8873 H H OH BzO OH Guerriero, C&B 2005, 2, 657 Page 3 Baran GM Kharasch Reaction and its Related Transformations Klement Foo 2. Total synthesis of Branimycin 6. Oxidation of oxazolines/thiazolines t O R PhCO3 Bu, OTBS 1 X R1 CuBr, heat X OH R 1. CrO3, 2 R2 Stoichiometric Cu needed TBS OMe O N N ester group crucial for reactivity 3,5-dimethyl- OTBS protection pyrazole OTBS CO2R CO2R OMe 2. CeCl3, X=O or S MOMO NaBH4 OTBS R2=H or Me 65% 2 steps - stereochemistry is due to rigid structure R1=no limit for Cu-mediated OTBS alkyl/aryl. Allow 2o or 3o H of subtrate OMe - 3 steps. Machart, ACIE 2010, 49, 2050 to remain intact if R1= another recent and notable synthesis which employ same strategy: Stock, JACS, 2009, 131, 11402 (Codeine and Morphine) H or iPr or Cy Meyers, JOC 1996, 61, 8207 NHR SePh 3. NCS, py, PhSeNa cat. Ph2Se2 Cl EtOH 70% OH Other applications of Kharasch allylic oxidation: Arcadi, TL 1997, 38, 2329; Bateson, JCS PT1 1991, 2399; Welzel, 63% 87% 1. BH3.SMe2 T 1998, 54, 10753. 2. NaOH, H2O2 Not many applications of Kharasch reaction in synthesis. Scianowski, T 2009, 65, 10162 4. Total Synthesis of ß-Erythroidine Asymmetric Allylic Oxidation in Synthesis - A field that still requires a lot of development. Many synthetic targets OH O O O N N HO contain allylic alcohols, with stereocenters at the alcohol FG. 1 KHMDS O2, rose bengal N - Most commonly seen (in fact >80% of Scifinder hits on this topic) used O O DME hv, then NH2CSNH2 1,2-reduction of enone, where desired stereochem of OH is due to rigid HMPA 73% O structure of substrate - eg. steroids... O O 91% O O O O 1. Routes to AB system of Taxoids (see last week's GM) Alcohol stereochem. defined by cycloaddition KOH, of singlet oxygen. MeI, Et4NBr OBn cat. OBn H H H Ti(OiPr) H SnCl 4 O 2 OBn mCPBA OBn 84% O O 97% O OH OH HO N O O - 3 steps to allylic alcohol SL 1998, 897 Funk, OL 2006, 8, 3689 O O Page 4 Baran GM Kharasch Reaction and its Related Transformations Klement Foo 2. Enantioselective borane reduction (of enones) 5. Total synthesis of Frondosin B Ph H Ph O catecholborane (1.5 eq) HO R R Ph R O R H Ph O N R R B cat. OH O (–) (0.15 eq) 97% ee o BH3 (0.6-2 eq) n N B -78 C, 40 h n Ph Ph n=2, 98% ee 1 min Me R R O OH 89% ee Ovaska, OL 2009, 11, 2715 H Corey, JACS 1987, 109, 5551 For allylic C-H oxidation see White, Nature 2009, 547 O R 3. Chiral LA for enantioselective allylic oxidation A good way to stereoselectively form allylic alcohols (late stage) in total O O synthesis is needed. What other methods are there anyway? Ph S S Ph OAc Pd(OAc)2 (10 mol %) Methods to obtain chiral allylic alcohols R salenCr(III)X (10 mol %) R 1. Enzymatic DKR Resolution R=alkyl, ester, amide, AcOH (1.1 eq), BQ (2 eq) 69-92% alcohol EtOAc, RT, 48 h ~50-60% ee Ph CALB Ph Subtilisin Ph rac. cat. surfactants -for reactions that do not tolerate strongly coordinating ligands OCOR ROCOR OH ROCOR OCOR -weakly coordinating bissulfoxide catalyze C-H cleavage rac.