29 cyclopropanation

Myers Chem 115 Cyclopropanation Reviews: • Bonding Orbitals in Cyclopropane (Walsh Model): Roy, M.-N.; Lindsay, V N G.; Charette, A B Stereoselective Synthesis: Reactions of Carbon– Carbon Double Bonds (Science of Synthesis); de Vries, J G., Ed.; Thieme: Stuttgart, 2011, Vol 1.; 731–817 Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A B Chem Rev 2003, 103, 977–1050 Davies, H M L.; Beckwith, R E J Chem Rev 2003, 103, 2861–2903 Li, A-H.; Dai, L X.; Aggarwal, V K Chem Rev 1997, 97, 2341–2372 eS (") • Applications of Cyclopropanes in Synthesis eA (") Carson, C A.; Kerr, M A Chem Soc Rev 2009, 38, 3051–3060 Reissig, H.-U.; Zimmer, R Chem Rev 2003, 103, 1151–1196 Gnad, F.; Reiser, O Chem Rev 2003, 103, 1603–1624 ! • Cyclopropane Biosynthesis Thibodeaux, C J.; Chang, W.-c.; Liu, H.-w Chem Rev 2012, 112, 1681–1709 de Meijere, A Angew Chem Int Ed 1979, 18, 809–886 General Strategies for Cyclopropanation: Introduction • via carbenoids "MCH2X" H H HH H H H H H H H H • via carbenes generated by decomposition of diazo compounds RCHN2 R • Cyclopropanes are stable but highly strained compounds (ring strain ~29 kcal/mol) • C–C bond angles = 60º (vs 109.5º for normal Csp3–Csp3 bonds) • Substituents on cyclopropanes are eclipsed H–C–H angle is ~120º As a result, the C–H bonds have higher s character compared to normal sp3 bonds • via Michael addition and ring closure RCH–LG EWG EWG LG EWG R • Because of their inherent strain, the reactivity of cyclopropanes is more closely analogous to that of alkenes than that of alkanes R RCH2 EWG LG EWG LG EWG R Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A B Chem Rev 2003, 103, 977–1050 James Mousseau, Fan Liu Myers Chem 115 Cyclopropanation • Diastereoselective cyclopropanation is possible in the presence of directing groups: Simmons-Smith Reaction –– Zinc Reagents in Cyclopropanation • Original Report: OH OH CH2I2, Zn(Cu) H CH2I2, Zn(Cu) (±) Et2O, 35 ºC 48% Et2O, 35 ºC 63% (±) OCH3 H CH3O H CH2I2, Zn(Cu) H Et2O, 35 ºC ~60% (±) (±) H H Dauben, W G.; Berezin, G H J Am Chem Soc 1963, 85, 468–472 Simmons, H E.; Smith, R D J Am Chem Soc 1958, 80, 5323–5324 • Interestingly, excess carbenoid can reverse the directing effect of alcohols • Reaction Overview: Zn R1 "ZnCH2I" R1 H R2 OZnR' OZnR' H OBn OBn OZnR' H I CH2 H R1 H R2 R2 Butterfly transition state OBn H Zinc Reagent dr yield Zn(CH2I)2 (1 equiv) >25:1 >95% EtZnCH2I (9 equiv) 1:>25 >95% Charette, A B.; Marcoux, J F Synlett, 1995, 1197–1207 • The reaction is proposed to proceed through a "butterfly" transition state • Directed cyclopropanation is also possible in acyclic systems: Simmons, H E Org React 1973, 20, 1–133 OH OH OH • Zinc cyclopropanating reagents can be generated in various ways Both Zn metal and ZnEt2 can be used Et2Zn, CH2I2 CH3 CH3 CH3 CH2Cl2, –10 °C 97% H H 130 • Many zinc reagents for cyclopropanation have been developed: : Charette, A B.; Lebel, H J Org Chem 1995, 60, 2966–1967 • Diastereoselectrive cyclopropanation has been used in tandem asymmetric organozinc additions: I Simmons and Smith O I I I Zn Zn Zn I H3C Denmark Furukawa F3C Zn I Shi O EtO P EtO Zn HBEt2, PhCH3, 23 ºC Et2Zn, i-PrCHO I Charette Ph General applicability Highly reactive carbenoid for unreactive alkenes Highly stable carbenoid H3C Ph CH3 O N OH H3C OH (4 mol%) –78 ! –10 ºC CH3 CH3 ZnEt2, CH2I2 CH2Cl2, 23 ºC OH CH3 Ph H CH3 75%, 99% ee dr >20:1 Kim, H Y.; Lurain, A E.; Garcia-Garcia, P.; Carroll, P J.; Walsh, P J J Am Chem Soc 2005, 127, 13138–13139 James Mousseau, Fan Liu Myers Chem 115 Cyclopropanation • Asymmetric Simmons-Smith Reaction Using Chiral Auxiliaries • Stoichiometric Promoter for Asymmetric Simmons-Smith Cyclopropanation • Allylic alcohols: • A chiral dioxaborolane auxiliary prepared from tetramethyltartramide and butylboronic acid has been shown to be effective in the asymmetric cyclopropanation of allylic alcohols • A hydrogen peroxide work-up is employed to remove boron side-products OBn O BnO BnO Et2Zn, CH2I2 Ph O OBn OH O BnO BnO toluene, –35 ! ºC A (1.1 equiv) Ph O OH OH 98%, dr >50:1 via OBn O BnO BnO O Me O Zn EtZn C H2I BnO BnO + >98%, 93% ee then 30% aq H2O2 OBn Ph HO OH ! 23 ºC Tf2O, C5H5N DMF, H2O, C5H5N 160 ºC, 90% Me Et H Zn(CH2I)2, DME, CH2Cl2 O O via H C O O N(CH3)2 (H3C)2N CHO O B n-Bu O O Charette, A B.; Côté, B.; Marcoux, J.-F J Am Chem Soc 1991, 113, 8166–8167 B H A O O Zn Ph H O N(CH3)2 N(CH3)2 I • Allylic amines: Charette, A B.; Juteau, H.; Lebel, H.; Molinaro, C J Am Chem Soc 1998, 120, 11943–11952 Ph OH H3C N CH3 Et2Zn, CH2I2 Ph CH2Cl2, °C Ph OH H3C N CH3 95%, dr = 98:2 • Allylic alcohols are cyclopropanated selectively: Ph CH3 OH • ",#-Unsaturated carbonyls: H H3C O H3C CO2i-Pr O OH i-PrO2C O CO2i-Pr CO2i-Pr OH H O H H3C then 30% aq H2O2 OH 80%, 95% ee Nicolaou, K C.; Sasmal, P K.; Rassais, G.; Reddy, M V.; Altmann, K H.; Wartmann, M.; O'Brate, A.; Giannakakou, P Angew Chem Int Ed 2003, 42, 3515–3520 • The cyclopropanation of allenic alcohols affords spiropentane derivatives: hexanes, –20 °C Et H3C H3C Et2Zn, CH2I2 C5H5NH•OTs, C6H6 80 ºC, 79% pTSA, THF CH3 Zn(CH2I)2, DME, CH2Cl2 H3C Aggarwal, V K.; Fang, G Y.; Meek, G Org Lett 2003, 5, 4417–4420 (EtO)3CH, NH4NO3 (cat.) EtOH, 23 ºC ent-A (1.1 equiv) CH3 H3C H2O, 65 ºC yield not provided O O OH C CO2i-Pr CO2i-Pr Et H A (1.1 equiv) Zn(CH2I)2, DME, CH2Cl2 –10 ! 23 ºC then 10% aq NaOH OH MO Et Et Et H H Et 70%, 97% ee 90%, dr = 97:3 Mash, E A.; Nelson, K A J Am Chem Soc 1985, 107, 8256–8258 Mori, A.; Arai, I.; Yamamoto, H Tetrahedron 1986, 42, 6447–6458 Charette, A B.; Jolicoeur, E.; Bydlinkski, G A S Org Lett 2001, 3, 3293–3295 James Mousseau, Fan Liu Myers Chem 115 Cyclopropanation • The dioxaborolane promoter can be used to prepare 1,2,3-trisubstituted cyclopropanes • Unfunctionalized alkenes can undergo asymmetric Simmons–Smith cyclopropanation in presence of a valine/proline dipeptide • In the example shown, the intermediate borinate was used directly for Suzuki coupling: • Selectivity is higher for trisubstituted alkenes than for disubstituted alkenes O O (H3C)2N Ph OH Et2Zn CH2Cl2, ºC Ph OZnEt A (1.2 equiv) N(CH3)2 O Ph O B C (1.25 equiv) Ph O n-Bu ZnEt H Ph H O n-Bu B B-Zn Exchange O Pd(PPh3)4 (5 mol%) CH2Cl2, –78 ! –40 ºC Ph H3C N CH3 C absolute stereochemistry not reported Long, J.; Yuan, Y.; Shi, Y J Am Chem Soc 2003, 125, 13632–13633 • Catalytic Enantioselective Simmons-Smith Cyclopropanation Reactions • Chiral bis-sulfonamides have been used to direct asymmetric Simmons–Smith reactions of allylic alcohols: Ph PhI, KOH THF, 65 ºC ºC, CH2Cl2 83%, 90% ee CO2CH3 O B n-Bu O ZnEt Ph Et2Zn, CH2I2 BocHN EtZnI•OEt2, CHI3 N(CH3)2 O H O (H3C)2N ZnI O Ph OH D (10 mol %) 59%, 92% ee, >20:1 dr OH Et2Zn, ZnI2, Zn(CH2I)2 NHSO2CH3 OH CH2Cl2, ºC 92%, 89% ee Zimmer, L E.; Charette, A B J Am Chem Soc 2009, 131, 15624–15626 NHSO2CH3 D • Homoallylic ethers can be cyclopropanated using a zinc phosphate, prepared in situ from a chiral phosphoric acid: OBn B B (1.2 equiv) Et2Zn, CH2I2 OBn CH2Cl2, ºC 85%, 93% ee Denmark, S E.; O'Connor, S P J Org Chem 1997, 62, 584–594 • "Taddolates" can also be used: E via Ar Ar = E (25 mol %) Ar O O P O OH O O P O OZnCH2I Ar Ar OH Zn(CH2I)2, 4Å MS CH2Cl2, ºC 85%, 92% ee OH Et Et O O Ph Ph Ph O i-PrO Ti O Ph Oi-Pr Charette, A B.; Molinaro, C.; Brochu, C J Am Chem Soc 2001, 123, 12168–12175 Lacasse, M.-C.; Poulard, C Charette, A B J Am Chem Soc 2005, 127, 12440–12441 James Mousseau, Fan Liu Myers Chem 115 Cyclopropanation • A bifunctional Al-complex is an effective cyclopropanation catalyst and is believed to bind both the Zn and the allylic alcohol: ligand (10 mol%) Et2AlCl (10 mol%) TBDPSO OH H3C TBDPSO I TMS CH3 CO2Et LiTMP, HMPA THF, toluene, –95 ºC ligand TMS CO2Et O O NH via Te+ OH Et2Zn, CH2I2 CH2Cl2, 23 ºC 99%, 90% ee • Telluronium ylides can also be used: 81%, 97% ee N OH HO Ph Ph O Zn N Al N O O Cl ZnEt Liao, W.-W.; Li, K Tang, Y J Am Chem Soc 2003, 125, 13030–13031 • Camphor-derived sulfur ylides can be employed for stereoselective cyclopropanations of Michaelacceptor olefins: Shitama, H.; Katsuki, T Angew Chem Int Ed 2008, 47, 2450–2453 Cyclopropanation via Michael Addition and Ring Closure –– Asymmetric Cyclopropanation Through Chiral Ylides • In an early report, optically enriched oxosulfonium F was prepared in steps, which stereoselectively cyclopropanates Michael-acceptors: O H3C S p-tolSO2N3, Cu CH3OH, 65 ºC O p-tol H SO H3C O Ph H F, NaH Ph H3C Me3OBF4 Na2CO3 S N p-tol DMSO, 23 ºC O BF4– CH3 H3C CH3 Br Ph S OH acetone H3C –20 ºC, 92% CH3 Ph CH3 S OH CO2CH3 CO2Me t-BuOK Ph THF, –78 ºC Ph 71% Ph 77%, 99% ee dr > 99:1 S N(CH3)2 H3C p-tol F O H H3C CH3 Ph Ph H 94%, 35% ee – O BF4 H S N(CH3)2 Ph p-tol H O H3C OH Johnson, C R.; Schroeck, C W J Am Chem Soc 1968, 90, 6852–6854 H3C Br H3C S CH3 OH CH3 Ph Ph acetone –20 ºC, 92% H3C S OH CH2 COPh COPh t-BuOK Ph THF, –78 ºC Ph Ph 78%, 96% ee dr > 99:1 Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W,; Li, K.; Tang, Y.; Wu, Y.-D.; Dai, L.-X J Am Chem Soc 2006, 128, 9730–9740 James Mousseau, Fan Liu Myers Chem 115 Cyclopropanation • Catalytic Enantioselective Ylide Cyclopropanations • Cinchona alkaloids have been employed to generate chiral ammonium ylides, which stereoselectively cyclopropanates Michael-acceptors: O Br + Et2N G (20 mol%) Cs2CO3 O Ph • Chiral sulfoxonium intermediates can be generated in situ by trapping of a rhodium carbenoid: Ph O Ph Et2N CH3CN, 80 ºC 94%, 97% ee N N Ts Rh2(OAc)4 (10 mol%) O + O CO2Et H Na+ O NR3 Cs2CO3 O NR3Br– Et2N O 91% ee, dr = 88:12 " O Ph Et2N O oC catalyst J Rh2(OAc)4 O N O BnEt3N+Cl- (20 mol%) 1,4-dioxane, 40 CO2Et Ph J (20 mol%) N RhII Ph NR3+ Ph Ph H R* S S O N H CH3 O O CO2Et R* CH3 J OCH3 O Cl H (20 mol%) Na2CO3, NaBr O O N H O OCH3 N CH3CN, 80 ºC 79%, 95% ee H G: R = H H: R = CH3 R Aggarwal, V K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M Angew Chem Int Ed 2001, 40, 1433–1436 • Asymmetric cyclopropanation through a chiral iminium intermediate: Papageorgiou, C D.; Cubillo de Dios, M A.; Ley, S V.; Gaunt, M J Angew Chem Int Ed 2004, 43, 4641–4644 Johansson, C C C.; Bremeyer, N.; Ley, S V.; Owen, D R.; Smith, S C.; Gaunt, M J Angew Chem Int Ed 2006, 45, 6024–6028 N H • Lanthanum complexes were also found to be effective: O Li O O OH OH La(O-i-Pr)3 THF, ºC ! 23 ºC MeLi, THF * ºC ! 23 ºC O H3C S CH H3C + Ph CH3 CH3 THF, toluene 4Å MS, –55 ºC 73%, 94% ee La O H H3C CH3 O S Ph H CHCl3, –10 ºC 85%, 95% ee, dr = 30:1 O Ph n-Pr H O H O Li O I * I (10 mol%) NaI (10 mol%) O O O O Li n-Pr * + CO2H (20 mol%) Kunz, R K.; MacMillan, D W C J Am Chem Soc 2005, 127, 3240–3241 O Ph CH3 CH3 Kakei, H.; Sone, T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M J Am Chem Soc 2007, 129, 13410–13411 David W Lin, Fan Liu Myers Chem 115 Cyclopropanation Asymmetric Cyclopropanation using Metal Carbenes • Transition metals catalyze the cyclopropanation of electron-rich olefins via carbenoids formed from electron-deficient diazo compounds • Since the initial report, extensive research has been done to develop other C2-symmetric Cu(I) and Ru(II) oxazoline complexes various linker groups used here • The catalytic cycle proceeds via a Fischer-type (electrophilic) metal carbene formed from diazo precursors: R1 various groups used here R1 N2 R2 R3 R2 ML* R2 R1 R3 MLn N2 R1 R3 t-Bu transition state R2 N t-Bu catalyst • Many alkenes can be used, with styrenes and enol ethers being the most common electron-rich alkene Fischer-type (electrophilic) metal carbene O N H H H MLn O • The reaction proceeds with retention of the olefin geometry: O • This methodology is most effective for three classes of diazo substrates: R • Diazo substrates with one electron-withdrawing group R' OR'' + CO2R'' R' catalyst N2 R R = aryl, alkyl, OR • Diazo substrates with two electron-withdrawing groups • Diazo substrates with one electron-withdrawing group and one electron-donating group • Up to three stereocenters can be formed • Cu(I) and Ru(II) oxazoline complexes typically give trans-1,2-cyclopropanes selectively: • Diazo Substrates with One Electron-Withdrawing Group • The use of C2-symmetric Cu(I) oxazoline complexes for cyclopropanation was first reported by Evans: I (1 mol%) CuOTf (1 mol%) O + Ph OEt N2 t-BuO2C F Ph Ph + CHCl3, 23 ºC 77% CO2Et 99% ee Ph CO2Et O F 97% ee + Ph trans:cis = 81:19 Cu H H3C I (0.12 mol%) CuOTf (0.1 mol%) O + OEt N2 CHCl3, ºC 91%, >99% ee H3C CO2Et H3C CH3 O H3C O N N t-Bu O CH3 F F H Ph 93% ee trans-cyclopropane (major) t-Bu Cu H N N t-Bu disfavored t-Bu CO2t-Bu favored 56% dr = 81:19 t-BuO2C Ph CH3 N N O CH t-Bu CuOTf•I Ot-Bu N2 t-Bu O CH CO2t-Bu O CH3 Ph H F 89% ee cis-cyclopropane (minor) I Evans, D A.; Woerpel, K A.; Hinman, M M.; Faul, M M J Am Chem Soc 1991, 113, 726–728 Haufe, G.; Rosen, T C.; Meyer, O G J.; Fröhlich, R.; Rissanen, K J Fluorine Chem 2002, 114, 189–198 David W Lin, Fan Liu Myers • Examples of Cu(I)- and Ru(II)-catalyzed enantioselective cyclopropanations: I (2.5 mol%) CuOTf (2 mol%) PhNHNH2 (2 mol%) O O Chem 115 Cyclopropanation OEt CO2CH3 N2 • Chiral Ir(III)-salen complexes afford cis-1,2-cyclopropanes with high enantioselectivities: O H EtO2C CH2Cl2, ! 20 ºC 91% ee (crude) CO2Me O H Ot-Bu N2 III (1 mol%) p-CF3C6H4 THF, –78 ºC 73%, 97% ee dr = 97:3 after recrystallization: 53%, >99% ee N F3C N Ir CO2t-Bu O O X Ph Ph O Böhm, C.; Reiser, O Org Lett 2001, 3, 1315–1318 • Intramolecular reactions can also proceed with high enantioselectivities: CH3 O O I (0.12 mol%) [Cu(MeCN)4]PF6 (1 mol%) CH3 O O CH2Cl2, 23 ºC 82%, 90% ee N2 Ot-Bu BzO H F3C Ot-Bu N2 CH2Cl2, ! 20 ºC 85%, 99% ee dr = 96:4 CO2t-Bu IV (1 mol%) DMAP (50 mol%) EtO2C II (0.5 mol%) III, X = p-Tol BzO • Co(II)-porphyrin complexes can cyclopropanate electron-deficient alkenes enantioselectively: Doyle, M P.; Peterson, C S.; Parker Jr., D L Angew Chem Int Ed 1996, 35, 1334–1336 O THF, –78 ºC 87%, 94% ee dr = 96:4 Suematsu, H.; Kanchiku, S.; Uchida, T.; Katsuki, T J Am Chem Soc 2008, 130, 10327–10337 O O N2 III (1 mol%) CO2t-Bu PhCH3, 23 ºC 92%, 91% ee dr = 99:1 O F3C H3C EtO2C CO2t-Bu O Ph H2N O N IV (1 mol%) DMAP (50 mol%) Ru Ph H2O Cl N CO Ph Ph O PhCH3, 23 ºC 77%, 97% ee dr = 99:1 O NH N N HN Co Ot-Bu CH3 CH3 3,5-di-t-BuPh O NH N2 H3C H3C CH3 N N HN O O 3,5-di-t-BuPh CO2t-Bu H2N H3C CH3 IV H3C CH3 O II Ito, J.-i.; Ujiie, S.; Nishiyama, H., Chem.–Eur J 2010, 16, 4986–4990 Chen, Y.; Ruppel, J V.; Zhang, X P J Am Chem Soc 2007, 129, 12074–12075 David W Lin Myers • At low temperatures, rhodium(III) catalysts are compatible with higher !-alkyl-!-diazoesters, which otherwise often undergo undesired "-hydride elimination upon metal carbene formation: O Ph Chem 115 Cyclopropanation n-Bu EtO Rh2[(S)-PTTL]4 (0.5 mol%) hexane, –78 N2 • !-nitro-!-diazo aryl ketones give cis cyclopropanes selectively: O EtO2C oC 93%, 96% ee dr = 99:1 (trans:cis) n-Bu O O Rh O Ph Cl O2N Ph3C O Rh O N2 N OCH3 O Rh2[(S)-TCPTTL]4 (0.1 mol%) Et2O, –50 t-Bu Cl O O2N Cl O oC OCH3 Rh O 68%, 94% ee dr = 96:4 Rh2[(S)-PTTL]3TPA Cl N Rh O O t-Bu CF3 CF3 Rh2[(S)-TCPTTL]4 Boruta, D T.; Dmitrenko, O.; Yap, G P A.; Fox, J M Chem Sci 2012, 3, 1589–1593 • Diazo Substrates with Two Electron-Withdrawing Groups Lindsay, V N G.; Lin, W.; Charette, A B J Am Chem Soc 2009, 131, 16383–16385 • While symmetrical diazomalonates give poor selectivities, unsymmetrical diazomalonates are excellent substrates: O O N OCH3 N2 Ph Rh2[(S)-NTTL]4 (1 mol %) O N DCE, 23 ºC CO2CH3 Ph 79%, 96% ee dr > 30:1 (cis:trans) O Rh O H3CO2C Ph R N2 Ph CH2Cl2, 23 ºC O R NO2 H3C CH3 H3CO2C Ph in situ generated carbene precursor Ph trans (favored for R = OEt, n-Bu) Charette, A B.; Wurz, R P.; Ollevier, T Helv Chim Acta 2002, 85, 4468–4484 O O N N Ph Ph 82%, 91% ee dr = 94:6 (trans:cis) Cu+ SbF6 Ph – V • Alternatively, !-nitro-!-diazo acetates give cis cyclopropanes with cobalt(II)-porphyrin catalysts: O O NO2 NO2 Moreau, B.; Charette, A B J Am Chem Soc 2005, 127, 18014–18015 • For !-nitro-!-diazo carbonyls, the diastereoselectivity is sensitive to the nature of the carbonyl substituent: Rh2(OAc)4 V (2 mol%) Na2CO3 C6H6, 23 ºC t-Bu Marcoux, D.; Charette, A B Angew Chem Int Ed 2008, 47, 10155–10158 NO2 O H3CO2C I O Rh O I NO2 N Rh2[(S)-NTTL]4 O • !-nitro-!-diazo esters give trans cyclopropanes selectively In the example below, the oxidant iodosobenzene can be used to form the carbene precursor from !-nitro esters in situ: R NO2 Ph cis (favored for R = Ph, t-Bu) NO2 O O2N OEt IV (5 mol%) DMAP (50 mol%) hexanes, # 23 ºC 81%, 95% ee dr = 93:7 O2N OEt NO2 N2 Zhu, S.; Perman, J A.; Zhang, X P Angew Chem Int Ed 2008, 47, 8460–8463 David W Lin Myers Chem 115 Cyclopropanation • Diazo Substrates with One Electron-Withdrawing Group and One Electron-Donating Group • Metal carbenes with adjacent electron-donating and electron-withdrawing groups ("push-pull" systems) are relatively stable and reactive • A wide range of electron-withdrawing groups within the diazo substrate are tolerated: O H3CO P H3CO • Rhodium(II) complexes using chiral ligands derived from proline have often been employed: Rh2[(S)-PTAD]4 (2 mol%) Ph N2 Ph t-Bu CO2CH3 N2 Rh2[(S)-TBSP]4 (1 mol%) Ph Ph Ph 83%, 87% ee Rh O F3C CO2CH3 Ph N O Rh O Rh2[(S)-PTAD]4 (1 mol%) Ph N2 Ph Rh2[(S)-TBSP]4 Rh2[(S)-TBSP]4 (1 mol%) H O Rh O Rh2[(S)-PTAD]4 O S O Rh O N Ph Ph Reddy, R P.; Lee, G H.; Davies, H M L Org Lett 2006, 8, 3437–3440 CO2CH3 pentane, 23 ºC PhCF3, 23 ºC 94%, >98% ee dr > 20:1 O H3CO P H3CO CO2CH3 F3C Ph H Ph 2,2-dimethylbutane 50 ºC, 86% 99% ee, dr > 30:1 Denton, J R.; Sukumaran, D.; Davies, H M L Org Lett 2007, 9, 2625–2628 pentane, 23 ºC N2 OCH3 82%, 88% ee dr = 98 : H NC H3CO N2 Doyle, M P.; Zhou, Q.-L.; Charnsangavej, C.; Longoria, M A.; McKervey, M A.; GarcÌa, C F Tetrahedron Lett 1996, 37, 4129–4132 Davies, H M L.; Bruzinski, P R.; Fall, M J Tetrahedron Lett 1996, 37, 4133–4136 • Styrenes can also be considered as electron-donating groups on the diazo substrate: CO2Me N2 Et CO2Me pentane, 23 ºC 65%, >95% ee Et Ph toluene, –78 ºC 86%, 90% ee dr = 97:3 NC Ph H Ph Denton, J R.; Cheng, K.; Davies, H M L Chem Commun 2008, 1238–1240 • N-sulfonyl-1,2,3-triazoles serve as alternatives to diazo compounds as carbene precursors: H3CO2S N N N Rh2[(S)-TBSP]4 (1 mol%) Rh2[(S)-PTAD]4 (2 mol%) Ph H Ph Ph Rh2[(S)-NTTL]4 (0.5 mol%) DCE, 65 ºC K2CO3, MeOH H [Rh] H3CO2S N O H 67%, 98% ee dr > 20:1 O Rh O N Rh O t-Bu O Rh2[(S)-NTTL]4 R H Davies, H M L.; Bruzinski, P R.; Lake, D H.; Kong, N.; Fall, M J J Am Chem Soc 1996, 118, 6897–6907 Chuprakov, S.; Kwok, S W.; Zhang, L.; Lercher, L.; Fokin, V V J Am Chem Soc 2009, 131, 18034 David W Lin Grimster, N.; Zhang, L.; Fokin, V V J Am Chem Soc 2010, 132, 2510 10 Myers Chem 115 Cyclopropanation Selected Transformations of Cyclopropanes Selected Industrial Examples • Cyclopropanes can undergo direct C-H functionalization enantioselectively by Pd(II) complexes with chiral amino acid ligands • A copper-catalyzed diazo decomposition led to the asymmetric cyclopropanation of 2,5-dimethyl2,4-hexadiene in good yield and high enantioselectivities: • A special directing group is required on the cyclopropane substrate to coordinate the Pd(II) complex and direct insertion into the adjacent cis C-H bond H3C • The directing group is readily available and can be hydrolyzed to give the corresponding acid: H3C F OBn O F N H F CuCl (0.2 mol%) Ligand (0.22 mol%) Ph3CPF6 (0.22 mol%) EtOAc, ºC, 92% Ot-Bu n-Bu F OBn O Ag2CO3, NaHCO3 t-Amyl-OH, 40 ºC 62%, 92% ee F CH3 (3.86 g) O F CH3 O CH3 Ph B CH3 O CH3 Pd(OAc)2 (10 mol%) CN ligand (20 mol%) CH3 F N H Ph CN O Cl3C n-Bu O N H F CO2H N2 Ot-Bu H3C H3C H3C H3C H3C F O O N N Ot-Bu H3C 88:12 CH3 71% ee chrysanthemic acid t-butyl ester (a key intermediate to pyrethroid insecticides) H3C CH3 ligand O H3C CH3 96% ee (1.41 g) Ligand F H3C O CH3 CH3 Wasa, Y.; Engle, K M.; Lin, D W.; Yoo, E.-J.; Yu, J.-Q J Am Chem Soc 2011, 133, 19598–19601 Itagaki, M.; Masumoto, K.; Suenobu, K.; Yamamoto, Y Org Proc Res Dev 2006, 10, 245–250 • Cyclopropanes can undergo vinylcyclopropane-cyclopentene rearrangements: • Cinchona alkaloids were applied to the synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid ethyl esters in good yield and modest ee's H TBSO H3C N2 O t-Bu N O Cu O N t-Bu toluene, 110 ºC, 84% H O TBSO H3C O • H O O Br2, CCl4 Et2O, ºC DBU, DMF 50 ºC, 48% TBSO H3C • O • • O Ph N OEt TBSO H3C Corey, E J.; Myers, A G J Am Chem Soc 1985, 107, 5574–5576 Corey, E J.; Myers, A G Tetrahedron Lett 1984, 25, 3559–3562 H O O Br (16.74 g) Ph N CO2Et H2O, ºC Crude yield: A key intermediate in the 78%, 77% ee preparation of many After Chromatography: hepatitis C inhibitors 55%, >99% ee Catalyst Br– HO • Cat (3 mol %) NaOH, toluene Br (11.3 g) Et2AlCl, CH2Cl2 ºC, 80% + N N CF3 F3C Belyk, K M.; Xiang, B.; Bulger, P G.; Leonard, W R.; Balsells, J.; Yin, J.; chen, C.-y Org Proc Res Dev 2010, 14, 692–700 James Mousseau, David W Lin, Fan Liu 11 ... J Am Chem Soc 2007, 129, 13410–13411 David W Lin, Fan Liu Myers Chem 115 Cyclopropanation Asymmetric Cyclopropanation using Metal Carbenes • Transition metals catalyze the cyclopropanation of... 97% H H 130 • Many zinc reagents for cyclopropanation have been developed: : Charette, A B.; Lebel, H J Org Chem 1995, 60, 296 6–1967 • Diastereoselectrive cyclopropanation has been used in tandem... 6447–6458 Charette, A B.; Jolicoeur, E.; Bydlinkski, G A S Org Lett 2001, 3, 3293 – 3295 James Mousseau, Fan Liu Myers Chem 115 Cyclopropanation • The dioxaborolane promoter can be used to prepare 1,2,3-trisubstituted