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