Simmons-Smith Directed Cyclopropanations Winstein S CH2l2 150: 1 cis: trans 75% yield J. Am. Chem. Soc., 1961, 91, Authors note that the reaction with cyclopentenol is much faster than with the cor ding acetate or cyclopentadiene Substrate Selectivity ANT Favored SYN C. D E.C. Winstein S. J. Am. chem. Soc. 1969. 91 6892 Simmons-Smith Directed Cyclopropanations Substrate 0.50±0.05 1.54±0.1 046±0.05 Author's Proposal electronic effects: I-o*(C-O)thus reducing the 0.091±0.012 nucleophilicity of the olefin (Hoveyda, A Evans, D A; Fu, G: Chem. Rev. 1993, 93, 1307) All substrates give exclusively Rickbom B. Chan JJ. Am. chem. Soc. 1968. 90. 6406 09B-053/299812:23PM
ANTI OH OH OH OH OH OH OH OH O H Zn I X Y 150:1 cis : trans 75% yield Winstein, S.; Sonnenberg, J. J. Am. Chem. Soc., 1961, 91, 3235 • Authors note that the reaction with cyclopentenol is much faster than with the corresponding acetate or cyclopentadiene > 99 : 1 9 : 1 > 99 : 1 O H Simmons-Smith Directed Cyclopropanations Substrate I Zn Product Selectivity X Y Favored Poulter, C. D.; Friedrich, E. C.; Winstein, S. J. Am. Chem. Soc., 1969, 91, 6892 Disfavored SYN Zn(Cu) CH2I2 1.54 ± 0.1 OH OCH3 OH OH OH OH OH OH OH O Zn Solvent I I I Zn I 1.00 0.46 ± 0.05 0.50 ± 0.05 H Simmons-Smith Directed Cyclopropanations 0.091 ± 0.012 • All substrates give exclusively cis cyclopropane adducts Substrate krel Rickborn, B.; Chan, J. J. Am. Chem. Soc., 1968, 90, 6406 Author's Proposal • Stereoelectronic effects: π − σ∗ (C-O) thus reducing the nucleophilicity of the olefin (Hoveyda, A.; Evans, D. A.; Fu, G.; Chem. Rev. 1993, 93, 1307) 09B-05 3/29/98 12:23 PM
Denmark: Studies of Zn(CH2Ci)2 and zn(CH2)2 Zn(CH2X)2(2 equiv) DCE Substrate Yield x= cl de x= CI (=D 2 ICH2Cl Et2Zn Zn(CH2 CI)2 100(85) H2)2Zn reactions in benzene were plagued by rous side products resulting from reaction with 89(41) 99(995) (>99.5) 100(70) 82(91) Denmark, S; Edwards, J.J. Org. Chem. 1991, 56, 6974 Charette: Selective Cyclopropanation Conditions ICH2X (equiv) (equiv nt syn: anti (4) 9:1 2 X=1(4) toluene CH2x solvent X=1(10) X=C|(2) toluene X=1(4) toluene(0.35M)1:>25 toluene(0.05M) Zn(CH2I2.DME(2 toluene >25:1 Charette, A; Marcoux, J. Synlett, 1995, 1197 09B063/299812:25PM
Ph CH3 Ph O O OH OBn Ph O O na 100 (70) CO2i-Pr 99 (>99.5) CO2i-Pr 78 (> 99.5) 94 (12) 92 (88) 100 (85) 89 (41) 64 (98) Denmark: Studies of Zn(CH2Cl)2 and Zn(CH2I)2 + Zn(CH2X)2 (2 equiv) 82 (91) na na Substrate Yield X = Cl (X = I) d.e. X = Cl (X = I) • (ClCH2)2Zn reactions in benzene were plagued by numerous side products resulting from reaction with solvent Denmark, S.; Edwards, J. J. Org. Chem. 1991, 56, 6974 2 ICH2Cl + Et2Zn Zn(CH2Cl)2 2 CH2I2 + Et2Zn Zn(CH2I)2 DCE OBn OBn OBn 2 OH OBn >99 :1 OH 9 : 1 OH 1 : 1 OBn OBn syn:anti syn:anti Charette, A.; Marcoux, J. Synlett, 1995, 1197 Charette: Selective Cyclopropanation Conditions Syn Anti Et2Zn (equiv) ICH2X (equiv) solvent X = I (4) ClCH2CH2Cl 2 X = Cl (4) " 2 X = I (4) toluene Et2Zn (equiv) ICH2X (equiv) solvent 10 X = I (10) toluene 1 : >25 2 X = Cl (2) toluene 6 : 1 2 X = Cl (4) ClCH2CH2Cl 1 : >25 2 X = I (4) 2 X = I (4) Zn(CH2I)2•DME (2 equiv) toluene (0.35M) toluene (0.05M) toluene 1 : >25 1 : 2 >25 : 1 09B-06 3/29/98 12:25 PM
Chiral Auxiliary Methods: Acetals Et2zn, CH2l2 eaR220o0° CO2R2 Acetal Yield (% d e (%) R1=Me R2= fPr R2=i-Pr (Mori, A; Arai, I; Yamamoto, H. Tetrahedron, 1986, 42, 6458) Arai. I: Mon. A. Yamamoto. H. J. Am. chem. Soc. 1985. 107. 8254 Mash: Ketals for Cyclic Olefins Zn-Cu, CH2l2 OBn Et20, reflux Substrate de Ketones ingood yields e-99 No mention of stereochemical 0 Mash. E: Nelson K. J. Am. Chem. Soc. 1985. 107. 8256 09B-073/299812:26PM
Chiral Auxiliary Methods: Acetals Arai, I; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 8254 R1 O O CO2R2 CO2R2 R1 O O CO2R2 CO2R2 O O CO2i-Pr CO2i-Pr O O Et2Zn, CH2I2 hexane, -20 °C to 0 °C CO2Et CO2Et • There was no mention of stereochemical rationale. However, later publications state that the mechanism of induction is unclear. (Mori, A; Arai, I; Yamamoto, H. Tetrahedron, 1986, 42, 6458) R1 = Me R2 = i- Pr R1 = n- Pr R2 = i - Pr R1 = Ph R2 = i- Pr 90 91 92 94 91 91 81 61 89 88 Acetal Yield (%) d.e. (%) O O O O OBn OBn OBn OBn O O O O Substrate n O O n d.e. MeO2C Yield n=1 n=2 n=3 O O Zn-Cu, CH2I2 Et2O, reflux 3 80 80 77 90 33 86 0 98 72 90 99 88 88 62 • Ketals formed from corresponding ketones in good yields (43-93%) • No mention of stereochemical rationale Mash, E.; Nelson, K. J. Am. Chem. Soc. 1985, 107, 8256 Mash: Ketals for Cyclic Olefins 09B-07 3/29/98 12:26 PM
Possible Explanation for Yamamoto's Results CO2R CO2R CO2R RO2C RO2C RO2C MINOR MAJOR red conformation but tercel H CO2R CO2R disfavored and stereoelectronical due to steric interactions with the -Cu, CH2I2 Possible Explanation for Mash's Ketals.0 Eto, reflux OBn Bno Bno ated away from BnO-CH and chronically aligned:π-σ*C-landσCZn-π 09B-08329/9812:30PM
R X RO2C R1 O O CO2R2 CO2R2 R1 O O CO2R2 CO2R2 O O H R RO2C Zn I I Zn I RO2C O O H R RO2C O O CO2R H CO2R Zn I I Zn I MAJOR O O Possible Explanation for Yamamoto's Results CO2R CO2R Et2Zn, CH2I2 hexane, -20°C to 0°C H R • Sterically favored conformation and stereoelectronically alligned: π − σ∗ C-I and σ C-Zn - π∗ • Sterically disfavored and stereoelectronically misaligned MAJOR X R RO2C O O H RO2C Zn I I Zn I RO2C O O H R RO2C MINOR • Sterically favored conformation but stereoelectronically misaligned for cyclopropanation O O CO2R H CO2R R Zn I I Zn O O CO2R H CO2R R • Disfavored due to steric interactions with the ester group MINOR O O O O OBn OBn OBn OBn MINOR O O O CH2OBn n Bn n Zn I I Zn-Cu, CH2I2 Et2O, reflux O O O CH2OBn • Chelation reduces the electrophilicity of the Zn reagent enough to slow cyclopropanation from this face of the olefin Bn Possible Explanation for Mash's Ketals X O O Zn I I Zn I BnO BnO O O BnO BnO MAJOR • Coordinated away from BnO-CH2 group and stereoelectronically aligned: π − σ∗ C-I and σ C-Zn - π∗ 09B-08 3/29/98 12:30 PM