Myers Cyclopropanation Chem 115 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 (") eA (") • Applications of Cyclopropanes in Synthesis 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 HH H H H • via carbenes generated by decomposition of diazo compounds H H H H H H RCHN2 • Cyclopropanes are stable but highly strained compounds (ring strain ~29 kcal/mol). R • via Michael addition and ring closure • 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 RCH–LG have higher s character compared to normal sp3 bonds. EWG EWG EWG LG R • Because of their inherent strain, the reactivity of cyclopropanes is more closely analogous to that of alkenes than that of alkanes. RCH2 R 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 1 Myers Cyclopropanation Chem 115 Simmons-Smith Reaction –– Zinc Reagents in Cyclopropanation • Diastereoselective cyclopropanation is possible in the presence of directing groups: • Original Report: OH OH OCH3 CH3O H H CH2I2, Zn(Cu) CH2I2, Zn(Cu) H CH I , Zn(Cu) Et O, 35 ºC Et O, 35 ºC 2 2 2 H 2 H (±) 63% (±) (±) ~60% (±) Et2O, 35 ºC 48% 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: OZnR' OZnR' OZnR' H H Zn I H R1 "ZnCH I" CH R H 2 2 1 OBn OBn OBn R1 H R H R R2 2 2 Zinc Reagent dr yield Zn(CH I) (1 equiv) >25:1 >95% Butterfly transition state 2 2 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 CH • Zinc cyclopropanating reagents can be generated in various ways. Both Zn metal and ZnEt can be Et2Zn, CH2I2 3 2 CH3 CH3 used. CH Cl , –10 °C H 2 2 H 97% : • Many zinc reagents for cyclopropanation have been developed: 130 1 Charette, A. B.; Lebel, H. J. Org. Chem. 1995, 60, 2966–1967. • Diastereoselectrive cyclopropanation has been used in tandem asymmetric organozinc additions: O O I Zn I I EtO Zn Zn F C P I 3 Zn Zn 1. HBEt , PhCH , 23 ºC I H3C EtO 2 3 I I OH Simmons 2. Et2Zn, i-PrCHO ZnEt2, CH2I2 OH and Smith Denmark Furukawa Shi Charette CH3 H3C CH3 Ph CH Cl , 23 ºC CH3 Ph 2 2 Ph O CH3 N H CH3 Highly reactive OH carbenoid for Highly stable carbenoid 75%, 99% ee H3C (4 mol%) General applicability unreactive alkenes dr >20:1 –78 ! –10 ºC 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 2 Myers Cyclopropanation Chem 115 • 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 OBn Et Zn, CH I O 2 2 2 O A (1.1 equiv) BnO O Ph BnO O Ph BnO BnO H OH toluene, –35 ! 0 ºC OH Zn(CH2I)2, DME, CH2Cl2 98%, dr >50:1 OH OH 0 ! 23 ºC 1. Tf O, C H N >98%, 93% ee 2 5 5 then 30% aq H O 2. 2 2 via OBn DMF, H2O, C5H5N Me 160 ºC, 90% O Et BnO O OBn via O BnO Me O O H3C O HO Ph N(CH ) EtZn Zn O N(CH ) O 3 2 C + BnO (H3C)2N 3 2 B H I BnO 2 CHO O O O O H B Zn O N(CH3)2 A I Charette, A. B.; Côté, B.; Marcoux, J.-F. J. Am. Chem. Soc. 1991, 113, 8166–8167. n-Bu Ph H • Allylic amines: Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc. 1998, 120, 11943–11952. Ph OH Ph OH • Allylic alcohols are cyclopropanated selectively: Et2Zn, CH2I2 H3C N Ph H3C N Ph CH2Cl2, 0 °C CH3 CH3 ent-A (1.1 equiv) 95%, dr = 98:2 CH3 CH3 CH3 H3C Zn(CH2I)2, DME, CH2Cl2 H3C H H3C Aggarwal, V. K.; Fang, G. Y.; Meek, G. Org. Lett. 2003, 5, 4417–4420. then 30% aq H O OH 2 2 80%, 95% ee OH • ",#-Unsaturated carbonyls: 1. (EtO)3CH, NH4NO3 (cat.) H C EtOH, 23 ºC 3 O Nicolaou, K. C.; Sasmal, P. K.; Rassais, G.; Reddy, M. V.; Altmann, K. H.; Wartmann, M.; O'Brate, H3C H CO2i-Pr O A.; Giannakakou, P. Angew. Chem. Int. Ed. 2003, 42, 3515–3520. O 2. OH CO2i-Pr CO2i-Pr • The cyclopropanation of allenic alcohols affords spiropentane derivatives: i-PrO2C OH Et2Zn, CH2I2 C5H5NH•OTs, C6H6 hexanes, –20 °C OH 80 ºC, 79% A (1.1 equiv) MO Et OH Et Zn(CH2I)2, DME, CH2Cl2 C Et H H3C O H pTSA, THF Et H –10 ! 23 ºC Et H C CO2i-Pr Et 3 H O then 10% aq NaOH H O, 65 ºC 70%, 97% ee O 2 yield not provided CO2i-Pr 90%, dr = 97:3 Mash, E. A.; Nelson, K. A. J. Am. Chem. Soc. 1985, 107, 8256–8258. Charette, A. B.; Jolicoeur, E.; Bydlinkski, G. A. S. Org. Lett. 2001, 3, 3293–3295 Mori, A.; Arai, I.; Yamamoto, H. Tetrahedron 1986, 42, 6447–6458. James Mousseau, Fan Liu 3 Myers Cyclopropanation Chem 115 • The dioxaborolane promoter can be used to prepare 1,2,3-trisubstituted cyclopropanes. • Unfunctionalized alkenes can undergo asymmetric Simmons–Smith cyclopropanation in presence of • In the example shown, the intermediate borinate was used directly for Suzuki coupling: a valine/proline dipeptide. • Selectivity is higher for trisubstituted alkenes than for disubstituted alkenes. O O (H3C)2N N(CH3)2 Ph C (1.25 equiv) Ph O CO2CH3 BocHN 1. Et2Zn 2. A (1.2 equiv) O O Et2Zn, CH2I2 N Ph OH Ph OZnEt B n-Bu CH2Cl2, 0 ºC Ph O 0 ºC, CH2Cl2 H3C CH3 ZnEt 83%, 90% ee absolute stereochemistry C not reported O O n-Bu 3. EtZnI•OEt , CHI H (H C) N N(CH ) 2 3 H B 3 2 3 2 B-Zn Exchange CH2Cl2, –78 ! –40 ºC Long, J.; Yuan, Y.; Shi, Y. J. Am. Chem. Soc. 2003, 125, 13632–13633. O ZnI Ph O O H B Ph O n-Bu • Catalytic Enantioselective Simmons-Smith Cyclopropanation Reactions ZnEt • Chiral bis-sulfonamides have been used to direct asymmetric Simmons–Smith reactions of allylic 4. Pd(PPh3)4 alcohols: (5 mol%) Ph PhI, KOH Ph OH D (10 mol %) THF, 65 ºC 59%, 92% ee, >20:1 dr Et Zn, ZnI , Zn(CH I) 2 2 2 2 NHSO2CH3 OH OH CH2Cl2, 0 ºC Zimmer, L. E.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 15624–15626. NHSO CH 92%, 89% ee 2 3 • Homoallylic ethers can be cyclopropanated using a zinc phosphate, prepared in situ from a chiral D phosphoric acid: B (1.2 equiv) OBn Et2Zn, CH2I2 OBn Denmark, S. E.; O'Connor, S. P. J. Org. Chem. 1997, 62, 584–594. CH2Cl2, 0 ºC 85%, 93% ee • "Taddolates" can also be used: E Et Et B via E (25 mol %) O O Ar Ar = Ar Zn(CH I) , 4Å MS Ph Ph OH 2 2 OH O O O O Ph Ph P P CH2Cl2, 0 ºC O O O OH O OZnCH I Ti 2 85%, 92% ee i-PrO Oi-Pr Ar Ar 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 4 Myers Cyclopropanation Chem 115 • A bifunctional Al-complex is an effective cyclopropanation catalyst and is believed to bind both the • Telluronium ylides can also be used: Zn and the allylic alcohol: ligand (10 mol%) Et2AlCl (10 mol%) H3C TBDPSO TBDPSO 1. LiTMP, HMPA CO2Et OH + Et Zn, CH I OH Te TMS 2 2 2 THF, toluene, –95 ºC CH Cl , 23 ºC 2 2 CH TMS 3 2. CO Et 99%, 90% ee 2 O ligand O 81%, 97% ee NH N via O OH HO I Ph Ph N N Zn Al Liao, W.-W.; Li, K.