Chemistry 206 Advanced Organic Chemistry Handout-09B Simmons-Smith reaction: Enantioselective Variants For a recent general review of the Simmons-Smith reaction see Charette& beauchemin, Organic Reactions, 58, 1-415(2001) Jason s Tedrow Evans Group Seminar, February 13, 1998 Matthew d. shair Monday October 7. 2002
Chemistry 206 Advanced Organic Chemistry Handout–09B Simmons-Smith Reaction: Enantioselective Variants Matthew D. Shair Monday, October 7, 2002 Jason S. Tedrow Evans Group Seminar, February 13, 1998 For a recent general review of the Simmons-Smith reaction see: Charette & Beauchemin, Organic Reactions, 58, 1-415 (2001)
The Simmons-Smith Reaction Enantioselective Variants Jason s. tedrow Evans group Friday seminar, February 13, 1998 I. Discovery and Mechanistic Insights l. Chiral auxiliaries Ill. Chiral Promoters MV. Catalytic Enantioselective Variants Leading Reference Charette, A ; Marcoux, J. Synlett 1995, 1197 Some Cyclopropane Containing Natural Products FR·900848 Yoshida, et al. J. Antibiotics. 1990. 43. 748 Barrett et al. J. Chem. Soc. Chem. Commun. 1995. 649 Meo 09B-0112/17/9912:18PM
The Simmons-Smith Reaction: Enantioselective Variants Jason S. Tedrow Evans group Friday seminar, February 13, 1998 I. Discovery and Mechanistic Insights II. Chiral Auxiliaries III. Chiral Promoters IV. Catalytic Enantioselective Variants Leading Reference Charette, A.; Marcoux, J. Synlett 1995, 1197 Some Cyclopropane Containing Natural Products O H N O HO OH H N O O FR - 900848 O O O NH O Me MeO Me O O Me MeO H Me H OH O H Cl Callipeltoside Minale, et al, J. Am. Chem. Soc. 1996, 118, 6202 Yoshida, et al. J. Antibiotics, 1990, 43, 748 Barrett, et al. J. Chem. Soc. Chem. Commun., 1995, 649 09B-01 12/17/99 12:18 PM
Methods of Olefin Cyclopropanation Hcc Dihalocarbene X-ZnCH2Y First Reports reflux. 48 h Authors believe that 1-Zn-CH2l is present in solution △ Simmons, H; Smith, R J. Am. Chem. Soc., 1958, 80, 5323 09B-023/299812:20PM
Methods of Olefin Cyclopropanation R HCCl3 Base + R Cl Cl Dihalocarbene O O O O H N2 R + O O H N2 R R CO2R H Cu(I), Rh(II) .... Metal Carbenoids X-ZnCH2Y Simmons - Smith Reaction (Carbenoid) O S H2C O O Ylides + First Reports R4 R1 R2 R3 CH2I2 + Zn(Cu) R4 R1 R2 R3 Et2O reflux, 48 h Ph Ph Ph Ph 48 29 49 32 27 35 31 Olefin Product Yield OAc • Cyclopropanation is highly stereoselective : cis-3-hexene gives only cis cyclopropane • Authors believe that I-Zn-CH2I is present in solution and is the active reagent or a precursor to a low- energy carbene Simmons, H.; Smith, R. J. Am. Chem. Soc., 1958, 80, 5323. OAc + 09B-02 3/29/98 12:20 PM
First Mechanistic Investigatio Et2O A (Cu free In all CH2l2 Electron-rich olefins give higher yields O-methoxystyrene gave a higher yield of Simmons. H. Smith R. J. Am. Chem. Soc. 1959. 81 4256 First Mechanistic Investigations CH22+ Zn(cu "1-Zn-CH2l reflux. 48h e formation show marked induction dition of Znl2 shorten se of ICH2Cl instead of CH2lz gives an active d CH2Br2 do not form active cyclopropanation reagents Simmons, H; Smith, R. J Am. Chem. Soc., 1964, 86, 1337 09B-033/299812:21PM
R1 R4 R2 R3 R1 R4 R2 R3 • In all cases investigated, cyclopropanation is completely stereoselective. • Electron-rich olefins give higher yields than electron-deficient ones. • O-methoxystyrene gave a higher yield of cyclopropane than m- or p-methoxystyrene. First Mechanistic Investigations Et2O R R ZnI I R R ZnI I R R Zn(Cu) ZnI I CH2I2 + "I-Zn-CH2I" A + A + O Zn I CH3 reflux, 48 h + Simmons, H.; Smith, R. J. Am. Chem. Soc., 1959, 81, 4256 A filter Cu A (Cu free) H2O CH3I I2 CH2I2 R1 R4 R2 R3 R1 R4 R2 R3 Zn(Cu) "I-Zn-CH2I" A First Mechanistic Investigations Zn Cl I Zn Cl I Zn Cl I Y Zn X Zn Y X Zn X CH2I2 + + A Et2O reflux, 48h Y Simmons, H; Smith, R. J. Am. Chem. Soc., 1964, 86, 1337 • No carbene insertion products. • Both ethylene production (olefin absent) and cyclopropane formation show marked induction period. Addition of ZnI2 shortens the induction period slightly. • Use of ICH2Cl instead of CH2I2 gives an active cyclopropanating reagent that releases CH3I upon addition of H2O and only sparing amounts of CH3Cl. CH2Cl2 and CH2Br2 do not form active cyclopropanation reagents. I-Zn-CH2I Zn(CH2I)2 + ZnI2 09B-03 3/29/98 12:21 PM
Improvements on Reaction Logistics Reproducibility of Zn reagent More reactive towards CH2l2 Zn-Ag coup Denis, J. Girard, C; Conia, J. Synthesis, 1972, n-Cu couple TiCl4, acetyl chloride, and TMSCl accele CH2 Br2, additive Friedrich, E et al. J. Org. Chem, 1990, 2491 CH2N2, Znl Wittig, et al.: Angew. Chem., 1959, 71, 652 Rzn CH2l2 N.Tet.Lett.1966,28.3353 Furukawa's Breakthrough t2Zn, CH2l2 Solvent Time(h) Yield (%) benzene benzene 11 te retention of olefin geometry: ye cis-cyclopropanes and trans-olefins benzene Et2Zn, PhCHI2 benzene Furukawa, J ; Kawabata, N; Nishimura, J. Tetrahedron, 1968, 24, 53 Furukawa, J. Kawabata, N; Fujita, T. Tetrahedron, 1970, 26, 243 09B-043/299812:22PM
Improvements on Reaction Logistics Furukawa, J.; Kawabata, C.; Nishimura, N. Tet. Lett., 1966, 28, 3353 Reproducibility of Zn reagent: Zn - Ag couple CH2I2 • More reactive towards CH2I2 • Higher yielding Denis, J.; Girard, C.; Conia, J. Synthesis, 1972, 549 Reaction Accelerators: Zn - Cu couple CH2Br2, additive • TiCl4, acetyl chloride, and TMSCl accelerate cyclopropanation dramatically (1 - 2 mol%) Friedrich, E. et al.; J. Org. Chem., 1990, 2491 New Zinc Source: CH2N2, ZnI2 Wittig, et al.; Angew. Chem., 1959, 71, 652 R2Zn CH2I2 Furukawa's Breakthrough Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron, 1968, 24, 53 O O O Cl Et2Zn, CH2I2 Solvent benzene benzene benzene benzene benzene ether 11 11 10 3 15 26 79 76 60 92 80 42 Substrate Solvent Time (h) Yield (%) • Electron-rich olefins react much faster than electron- poor ones. • Complete retention of olefin geometry: cis-olefins give cis-cyclopropanes and trans-olefins produce trans products. Ph Et2Zn, PhCHI2 ether, rt 69% syn : anti 94 : 6 Furukawa, J.; Kawabata, N.; Fujita, T. Tetrahedron, 1970, 26, 243 09B-04 3/29/98 12:22 PM
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
Mash: New Ketals For Directed Cyclopropanation Zn-Cu, CH2l2 Et2O, reflux Substrate Diastereo ratio 13 Ketalization of starting enones proceed in good yields(48-87%) n=2 hp时ge ketal products are 15:1 No mention of stereochemical rationale ash, E; Torok, D J. Org. Chem. 1989, 54, 250 Chiral enol ethers Et2Zn, CH2l2 Et2O, rt Substrates are derived from the appropriate ketals by treatment with FBu3Al n=1 temperatures, Znlz generally slowed the reaction and had variable effects on de 2. K2CO3, MeOH 60% Sugimura, T; Yoshikawa, M; Futugawa, T: Tai, A Tetrahedron 1990, 46, 5955 09B-093/299812:31PM
O O Ph Ph O O n n Ph Ph Zn-Cu, CH2I2 Et2O, reflux n = 1 n = 2 n = 3 O O Ph Ph 66 90 77 62 Diastereomer ratio 13:1 19:1 15:1 16:1 Substrate yield • Ketalization of starting enones proceed in good yields (48 - 87%) • Most cyclopropane ketal products are highly crystalline • No mention of stereochemical rationale Mash, E.; Torok, D. J. Org. Chem. 1989, 54, 250 Mash: New Ketals For Directed Cyclopropanation O OH O OH OR OR n n Et2Zn, CH2I2 Et2O, rt n = 0 n = 1 n = 2 n = 3 81 86 77 58 80 57 >99 >99 >99 >99 O >99 i-Pr OH >99 i-Pr Susbstrate Yield d.e. OH 1. PCC 2. K2CO3, MeOH 60% Sugimura, T.; Yoshikawa, M.; Futugawa, T.; Tai, A. Tetrahedron 1990, 46, 5955 Chiral Enol Ethers • Substrates are derived from the appropriate ketals by treatment with i-Bu3Al. • Diastereoselectivity improved with higher temperatures; ZnI2 generally slowed the reaction and had variable effects on d.e. 09B-09 3/29/98 12:31 PM
