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. Tang, Y. J. Am. Chem. Soc. 2003, 125, 13030–13031. O O Cl ZnEt

• Camphor-derived sulfur ylides can be employed for stereoselective cyclopropanations of Michael- Shitama, H.; Katsuki, T. Angew. Chem. Int. Ed. 2008, 47, 2450–2453. acceptor olefins:

Cyclopropanation via Michael Addition and Ring Closure –– Asymmetric Cyclopropanation Through Chiral Ylides

• In an early report, optically enriched oxosulfonium F was prepared in 3 steps, which CH CO2CH3 H3C 3 H C CH3 Ph stereoselectively cyclopropanates Michael-acceptors: CH3 3 CO Me Br Ph CH3 2 S S Ph t-BuOK OH acetone OH H C THF, –78 ºC Ph Ph 3 –20 ºC, 92% H3C 1. p-tolSO N , Cu 3. Me OBF – 2 3 3 4 O BF4 O O 77%, 99% ee CH3OH, 65 ºC H Na2CO3 S S N(CH3)2 dr > 99:1 S N H3C H3C p-tol 2. H SO H C p-tol 2 4 3 p-tol 71% F

O F, NaH H O CH CH H3C 3 H3C 3 COPh Ph COPh Ph Ph Ph Ph DMSO, 23 ºC Br Ph t-BuOK H CH2 94%, 35% ee S acetone S Ph Ph Ph H3C CH3 H3C THF, –78 ºC OH –20 ºC, 92% OH 78%, 96% ee – O BF4 dr > 99:1 H S N(CH ) Ph 3 2 p-tol H O OH 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. Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1968, 90, 6852–6854. James Mousseau, Fan Liu

5 Myers Cyclopropanation Chem 115

• Catalytic Enantioselective Ylide Cyclopropanations • Chiral sulfoxonium intermediates can be generated in situ by trapping of a rhodium carbenoid: • Cinchona alkaloids have been employed to generate chiral ammonium ylides, which stereoselectively cyclopropanates Michael-acceptors: Rh2(OAc)4 (10 mol%) G (20 mol%) O CO Et Ph N Ts J (20 mol%) Ph 2 O O O N + Cs2CO3 N N Br + O O Ph H + O BnEt N+Cl- (20 mol%) Et2N Ph Et2N Na 3 CH3CN, 80 ºC CO Et o O 2 1,4-dioxane, 40 C 94%, 97% ee 91% ee, dr = 88:12

NR3 catalyst J Rh2(OAc)4 " Cs CO O O O 2 3 S – O NR3Br Et2N Ph Et2N O RhII R* NR + Ph CH 3 Ph S N O 3 R* O Ph H CH3 H CO2Et J OCH3 N O H (20 mol%) O H Cl Na2CO3, NaBr O O OCH3 Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem. Int. N Ed. 2001, 40, 1433–1436. CH3CN, 80 ºC G: R = H 79%, 95% ee H R H: R = CH3

• 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 CO2H H • Lanthanum complexes were also found to be effective: H O O CH3 O (20 mol%) + S n-Pr Ph Li n-Pr H H C Ph CHCl , –10 ºC 3 3 H * O O * 85%, 95% ee, dr = 30:1 O O OH 1. La(O-i-Pr)3 O La O H O OH THF, 0 ºC ! 23 ºC 2. MeLi, THF Li O O Li 0 ºC ! 23 ºC * I Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240–3241.

I (10 mol%) O O NaI (10 mol%) O + CH CH H C S Ph 3 Ph 3 3 CH2 THF, toluene H3C CH3 4Å MS, –55 ºC CH3 73%, 94% ee

Kakei, H.; Sone, T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 13410–13411. David W. Lin, Fan Liu

6 Myers Cyclopropanation Chem 115

Asymmetric Cyclopropanation using Metal Carbenes • Since the initial report, extensive research has been done to develop other C2-symmetric Cu(I) and • Transition metals catalyze the cyclopropanation of electron-rich olefins via carbenoids formed from Ru(II) oxazoline complexes. electron-deficient diazo compounds. various linker • The catalytic cycle proceeds via a Fischer-type (electrophilic) metal carbene formed from diazo groups precursors: used here R1 various N2 O O R2 groups R1 R2 R3 R2 ML* used here N N R1 3 t-Bu t-Bu MLn R H H H catalyst

MLn 3 N2 R transition R1 R2 state • Many alkenes can be used, with styrenes and enol ethers being the most common.

Fischer-type (electrophilic) electron-rich • The reaction proceeds with retention of the olefin geometry: metal carbene alkene

O CO2R'' catalyst R' • This methodology is most effective for three classes of diazo substrates: R' + OR'' R • Diazo substrates with one electron-withdrawing group 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: t-Bu t-BuO2C CO2t-Bu F O CH F I (1 mol%) N 3 H O Cu CuOTf (1 mol%) Ph Ph N Ph H CH3 + + O Ph OEt O 93% ee Ph CO Et t-Bu CHCl3, 23 ºC CO2Et 2 F CuOTf•I N2 + trans-cyclopropane 77% 99% ee 97% ee Ot-Bu (major) Ph favored N 56% trans:cis = 81:19 2 dr = 81:19 t-Bu t-BuO2C CO2t-Bu Ph O CH Ph N 3 H Cu CH I (0.12 mol%) H C CH F N F 3 O 3 3 H CH3 CuOTf (0.1 mol%) H3C CO Et O + 2 O O H3C OEt t-Bu 89% ee CHCl3, 0 ºC H3C N N cis-cyclopropane N2 disfavored 91%, >99% ee (minor) t-Bu t-Bu I Haufe, G.; Rosen, T. C.; Meyer, O. G. J.; Fröhlich, R.; Rissanen, K. J. Fluorine Chem. 2002, 114, Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726–728. 189–198. David W. Lin, Fan Liu

7 Myers Cyclopropanation Chem 115

• Examples of Cu(I)- and Ru(II)-catalyzed enantioselective cyclopropanations: • Chiral Ir(III)-salen complexes afford cis-1,2-cyclopropanes with high enantioselectivities:

I (2.5 mol%) O H O CuOTf (2 mol%) Ot-Bu EtO2C PhNHNH2 (2 mol%) OEt N2 CO CH O 2 3 CO2Me III (1 mol%) N CH2Cl2, 0 ! 20 ºC H O N N 2 p-CF C H 91% ee (crude) 3 6 4 Ir THF, –78 ºC CO2t-Bu F3C O O after recrystallization: 73%, 97% ee X 53%, >99% ee dr = 97:3 Ph Ph

O Böhm, C.; Reiser, O. Org. Lett. 2001, 3, 1315–1318. III (1 mol%) Ot-Bu BzO BzO III, X = p-Tol • Intramolecular reactions can also proceed with high enantioselectivities: N2 THF, –78 ºC 87%, 94% ee CO2t-Bu dr = 96:4

CH I (0.12 mol%) O 3 [Cu(MeCN) ]PF (1 mol%) CH3 Suematsu, H.; Kanchiku, S.; Uchida, T.; Katsuki, T. J. Am. Chem. Soc. 2008, 130, 10327–10337. 4 6 O CH Cl , 23 ºC O O 2 2 82%, 90% ee H N2 O • Co(II)-porphyrin complexes can cyclopropanate electron-deficient alkenes enantioselectively: O

Doyle, M. P.; Peterson, C. S.; Parker Jr., D. L. Angew. Chem. Int. Ed. 1996, 35, 1334–1336.. IV (1 mol%) CH3 H3C DMAP (50 mol%) H3C CH3 EtO C 2 CO2t-Bu 3,5-di-t-BuPh PhCH3, 23 ºC EtO C 2 O O 92%, 91% ee O II (0.5 mol%) NH HN CO2t-Bu dr = 99:1 Ot-Bu N N O F C CH2Cl2, 0 ! 20 ºC Co 3 N2 85%, 99% ee F3C Ot-Bu N N dr = 96:4 NH HN N 2 O O 3,5-di-t-BuPh H3C CH3 IV (1 mol%) DMAP (50 mol%) H C CH H2N H N CO t-Bu 3 3 O O 2 2 CH3 IV H3C Ph Ph PhCH , 23 ºC N Ru N O 3 O 77%, 97% ee Ph H2O Cl CO Ph dr = 99:1 II

Chen, Y.; Ruppel, J. V.; Zhang, X. P. J. Am. Chem. Soc. 2007, 129, 12074–12075. Ito, J.-i.; Ujiie, S.; Nishiyama, H., Chem.–Eur. J. 2010, 16, 4986–4990. David W. Lin

8 Myers Cyclopropanation Chem 115

• At low temperatures, rhodium(III) catalysts are compatible with higher !-alkyl-!-diazoesters, which • !-nitro-!-diazo aryl ketones give cis cyclopropanes selectively: otherwise often undergo undesired "-hydride elimination upon metal carbene formation:

O Rh [(S)-PTTL] O 2 4 O N Cl (0.5 mol%) 2 n-Bu EtO2C n-Bu Cl Cl EtO O Rh2[(S)-TCPTTL]4 O N2 Ph hexane, –78 oC OCH N2 O Rh O N 3 (0.1 mol%) O2N Ph O Cl 93%, 96% ee Ph3C o O Et2O, –50 C dr = 99:1 (trans:cis) O Rh O t-Bu Rh O N OCH3 O 3 68%, 94% ee dr = 96:4 Rh O t-Bu Rh2[(S)-PTTL]3TPA CF 3 4 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

• While symmetrical diazomalonates give poor selectivities, unsymmetrical diazomalonates are Lindsay, V. N. G.; Lin, W.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 16383–16385. excellent substrates: • !-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:

O O Rh [(S)-NTTL] 2 4 O (1 mol %) H3C CH3 H CO C NO I N OCH3 CO2CH3 3 2 2 H3CO2C NO2 H3CO2C NO2 O O N O O Ph N2 DCE, 23 ºC Rh O N I N N Ph O Ph Ph V (2 mol%) + Rh O t-Bu Ph Cu Ph 79%, 96% ee Na2CO3 Ph in situ generated 82%, 91% ee SbF – dr > 30:1 (cis:trans) C6H6, 23 ºC 6 4 carbene precursor dr = 94:6 (trans:cis) Rh2[(S)-NTTL]4 V

Marcoux, D.; Charette, A. B. Angew. Chem. Int. Ed. 2008, 47, 10155–10158. 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 • Alternatively, !-nitro-!-diazo acetates give cis cyclopropanes with cobalt(II)-porphyrin catalysts: substituent:

O O O O Rh2(OAc)4 O N NO NO2 NO2 IV (5 mol%) 2 R 2 R R OEt CH Cl , 23 ºC NO2 DMAP (50 mol%) Ph 2 2 N2 Ph Ph hexanes, 0 # 23 ºC trans cis O 81%, 95% ee (favored for (favored for O2N dr = 93:7 NO R = OEt, n-Bu) R = Ph, t-Bu) OEt 2 N2

Charette, A. B.; Wurz, R. P.; Ollevier, T. Helv. Chim. Acta 2002, 85, 4468–4484. Zhu, S.; Perman, J. A.; Zhang, X. P. Angew. Chem. Int. Ed. 2008, 47, 8460–8463. David W. Lin

9 Myers Cyclopropanation Chem 115

• Diazo Substrates with One Electron-Withdrawing Group and One Electron-Donating Group • A wide range of electron-withdrawing groups within the diazo substrate are tolerated: • Metal carbenes with adjacent electron-donating and electron-withdrawing groups ("push-pull" systems) are relatively stable and reactive. O Rh2[(S)-PTAD]4 O • Rhodium(II) complexes using chiral ligands derived from proline have often been employed: P Ph (2 mol%) H3CO H CO P Ph H CO 3 O 3 PhCF3, 23 ºC H3CO N2 Ph 94%, >98% ee Rh O N H Ph O t-Bu dr > 20:1 Rh O

Rh2[(S)-TBSP]4 CO2CH3 Ph CO CH Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8, 3437–3440. (1 mol%) 2 3 4 Rh [(S)-PTAD] N2 Ph O S O 2 4 pentane, 23 ºC Ph Ph Rh O N Rh2[(S)-PTAD]4 F C Ph 83%, 87% ee 3 (1 mol%) F3C Ph Rh O 4 N 2 Ph 2,2-dimethylbutane H Ph 50 ºC, 86% Rh [(S)-TBSP] 2 4 99% ee, dr > 30:1

Rh2[(S)-TBSP]4 (1 mol%) CO CH CO2CH3 2 3 Denton, J. R.; Sukumaran, D.; Davies, H. M. L. Org. Lett. 2007, 9, 2625–2628. pentane, 23 ºC N2 H 82%, 88% ee Rh2[(S)-PTAD]4 NC Ph OCH3 (2 mol%) NC Ph dr = 98 : 2 H3CO N2 Ph toluene, –78 ºC H Ph 86%, 90% ee Doyle, M. P.; Zhou, Q.-L.; Charnsangavej, C.; Longoria, M. A.; McKervey, M. A.; GarcÌa, C. F. dr = 97:3 Tetrahedron Lett. 1996, 37, 4129–4132. Davies, H. M. L.; Bruzinski, P. R.; Fall, M. J. Tetrahedron Lett. 1996, 37, 4133–4136. 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: • Styrenes can also be considered as electron-donating groups on the diazo substrate:

H O H CO S N 3 2 N N Ph Ph H

1. Rh2[(S)-NTTL]4 Rh2[(S)-TBSP]4 (0.5 mol%) O (1 mol%) Rh N CO2Me DCE, 65 ºC 67%, 98% ee O CO2Me O pentane, 23 ºC 2. K2CO3, MeOH dr > 20:1 N2 Et Rh O t-Bu 65%, >95% ee Et H [Rh] 4 Rh [(S)-NTTL] N 2 4 H3CO2S R H

Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J. J. Am. Chem. Soc. 1996, Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin, V. V. J. Am. Chem. Soc. 2009, 118, 6897–6907. 131, 18034. Grimster, N.; Zhang, L.; Fokin, V. V. J. Am. Chem. Soc. 2010, 132, 2510. David W. Lin

10 Myers Cyclopropanation Chem 115

Selected Transformations of Cyclopropanes Selected Industrial Examples • Cyclopropanes can undergo direct C-H functionalization enantioselectively by Pd(II) complexes • A copper-catalyzed diazo decomposition led to the asymmetric cyclopropanation of 2,5-dimethyl- with chiral amino acid ligands. 2,4-hexadiene in good yield and high enantioselectivities:

• A special directing group is required on the cyclopropane substrate to coordinate the Pd(II) CH3 complex and direct insertion into the adjacent cis C-H bond. H3C CH3 • The directing group is readily available and can be hydrolyzed to give the corresponding acid: CuCl (0.2 mol%) O H3C O H3C (3.86 g) Ligand (0.22 mol%) Ot-Bu Ot-Bu H C Ph3CPF6 (0.22 mol%) H3C 3 F O H C CH H3C CH3 EtOAc, 0 ºC, 92% H3C 3 3 CH Ot-Bu O 3 88:12 CH3 n-Bu O Ph B N2 96% ee 71% ee F (1.41 g) CH3 O Cl C O N chrysanthemic acid CH F 3 CO2H 3 n-Bu H t-butyl ester F Pd(OAc)2 (10 mol%) F CN OBn O Ligand (a key intermediate F CN ligand (20 mol%) OBn O H3C CH3 to pyrethroid N F ligand H H C O O CH insecticides) N F Ag2CO3, NaHCO3 F 3 3 H Ph F t-Amyl-OH, 40 ºC H3C N N CH3 62%, 92% ee

Wasa, Y.; Engle, K. M.; Lin, D. W.; Yoo, E.-J.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19598–19601.

• Cyclopropanes can undergo vinylcyclopropane-cyclopentene rearrangements: Itagaki, M.; Masumoto, K.; Suenobu, K.; Yamamoto, Y. Org. Proc. Res. Dev. 2006, 10, 245–250. • 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 t-Bu N H O Cu O O Cat (3 mol %) N + NaOH, toluene Ph N CO Et TBSO t-Bu • H Ph N Br 2 TBSO OEt Br H3C O N2 H3C H2O, 0 ºC toluene, 110 ºC, 84% O O (11.3 g) (16.74 g) O Crude yield: 1. Br2, CCl4 78%, 77% ee A key intermediate in the Et O, 0 ºC 2 Catalyst After Chromatography: preparation of many 2. DBU, DMF 55%, >99% ee hepatitis C inhibitors 50 ºC, 48% Br– N Et2AlCl, CH2Cl2 HO • • CF3 TBSO • H C • 3 0 ºC, 80% TBSO H N O O F C H3C 3 O O

Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107, 5574–5576. Belyk, K. M.; Xiang, B.; Bulger, P. G.; Leonard, W. R.; Balsells, J.; Yin, J.; chen, C.-y. Org. Proc. Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559–3562. Res. Dev. 2010, 14, 692–700. James Mousseau, David W. Lin, Fan Liu

11