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 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 OO O NH O Me MeO Me O O Me MeO H Me HOH 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 R HCCl 3 Base + R Cl Cl Dihalocarbene O O O O H N 2 R + O O H N 2 R R CO 2 R H Cu(I), Rh(II) .... Metal Carbenoids X-ZnCH 2 Y Simmons - Smith Reaction (Carbenoid) O S H 2 C O O Ylides + First Reports R 4 R 2 R 1 R 3 CH 2 I 2 + Zn(Cu) R 4 R 2 R 1 R 3 Et 2 O 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-CH 2 I 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 R 1 R 4 R 2 R 3 R 1 R 4 R 2 R 3 ? 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 Et 2 O R R ZnI I R R ZnI I R R Zn(Cu) ZnI I CH 2 I 2 + "I-Zn-CH 2 I" A + A + O Zn I CH 3 reflux, 48 h + Simmons, H.; Smith, R. J. Am. Chem. Soc., 1959, 81, 4256 A filter Cu A (Cu free) H 2 O CH 3 I I 2 CH 2 I 2 R 1 R 4 R 2 R 3 R 1 R 4 R 2 R 3 Zn(Cu) "I-Zn-CH 2 I" A First Mechanistic Investigations Zn Cl I Zn Cl I Zn Cl I Y Zn X Zn Y X Zn X CH 2 I 2 + + A Et 2 O 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 ZnI 2 shortens the induction period slightly. ? Use of ICH 2 Cl instead of CH 2 I 2 gives an active cyclopropanating reagent that releases CH 3 I upon addition of H 2 O and only sparing amounts of CH 3 Cl. CH 2 Cl 2 and CH 2 Br 2 do not form active cyclopropanation reagents. I-Zn-CH 2 I Zn(CH 2 I) 2 + ZnI 2 09B-03 3/29/98 12:21 PM Improvements on Reaction Logistics Furukawa, J.; Kawabata, C.; Nishimura, N. Tet. Lett., 1966, 28, 3353 Reproducibility of Zn reagent: Zn - Ag couple CH 2 I 2 ? More reactive towards CH 2 I 2 ? Higher yielding Denis, J.; Girard, C.; Conia, J. Synthesis, 1972, 549 Reaction Accelerators: Zn - Cu couple CH 2 Br 2 , additive ? TiCl 4 , acetyl chloride, and TMSCl accelerate cyclopropanation dramatically (1 - 2 mol%) Friedrich, E. et al.; J. Org. Chem., 1990, 2491 New Zinc Source: CH 2 N 2 , ZnI 2 Wittig, et al.; Angew. Chem., 1959, 71, 652 R 2 Zn CH 2 I 2 Furukawa's Breakthrough Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron, 1968, 24, 53 O O O Cl Et 2 Zn, CH 2 I 2 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 Et 2 Zn, PhCHI 2 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 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 Zn I Product Selectivity X Y Favored Poulter, C. D.; Friedrich, E. C.; Winstein, S. J. Am. Chem. Soc., 1969, 91, 6892 Disfavored SYN Zn(Cu) CH 2 I 2 1.54 ± 0.1 OH OCH 3 OH OH OH OH OH OH OH O Zn Solvent I I ZnI 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 k rel 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 Ph CH 3 Ph O O OH OBn Ph O O na 100 (70) CO 2 i-Pr 99 (>99.5) CO 2 i-Pr 78 (> 99.5) 94 (12) 92 (88) 100 (85) 89 (41) 64 (98) Denmark: Studies of Zn(CH 2 Cl) 2 and Zn(CH 2 I) 2 + Zn(CH 2 X) 2 (2 equiv) 82 (91) na na Substrate Yield X = Cl (X = I) d.e. X = Cl (X = I) ? (ClCH 2 ) 2 Zn 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 ICH 2 Cl + Et 2 Zn Zn(CH 2 Cl) 2 2 CH 2 I 2 + Et 2 Zn Zn(CH 2 I) 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 Et 2 Zn (equiv) ICH 2 X (equiv) solvent X = I (4) ClCH 2 CH 2 Cl 2 X = Cl (4) " 2 X = I (4) toluene Et 2 Zn (equiv) ICH 2 X (equiv) solvent 10 X = I (10) toluene 1 : >25 2 X = Cl (2) toluene 6 : 1 2 X = Cl (4) ClCH 2 CH 2 Cl 1 : >25 2 X = I (4) 2 X = I (4) Zn(CH 2 I) 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 Arai, I; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 8254 R 1 O O CO 2 R 2 CO 2 R 2 R 1 O O CO 2 R 2 CO 2 R 2 O O CO 2 i-Pr CO 2 i-Pr O O Et 2 Zn, CH 2 I 2 hexane, -20 °C to 0 °C CO 2 Et CO 2 Et ? 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) R 1 = Me R 2 = i- Pr R 1 = n- Pr R 2 = i - Pr R 1 = Ph R 2 = 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. MeO 2 C Yield n=1 n=2 n=3 O O Zn-Cu, CH 2 I 2 Et 2 O, 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 R X RO 2 C R 1 O O CO 2 R 2 CO 2 R 2 R 1 O O CO 2 R 2 CO 2 R 2 O O H R RO 2 C Zn I I Zn I RO 2 C O O H R RO 2 C O O CO 2 R CO 2 R H Zn I I Zn I MAJOR O O Possible Explanation for Yamamoto's Results CO 2 R CO 2 R Et 2 Zn, CH 2 I 2 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 R X RO 2 C O O H RO 2 C Zn I I Zn I RO 2 C O O H R RO 2 C MINOR ? Sterically favored conformation but stereoelectronically misaligned for cyclopropanation O O CO 2 R CO 2 R H R Zn I I Zn O O CO 2 R CO 2 R H R ? Disfavored due to steric interactions with the ester group MINOR O O O O OBn OBn OBn OBn MINOR O O O CH 2 OBn n Bn n Zn I I Zn-Cu, CH 2 I 2 Et 2 O, reflux O O O CH 2 OBn ? 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-CH 2 group and stereoelectronically aligned: π ? σ? C-I and σ C-Zn - π? 09B-08 3/29/98 12:30 PM OO PhPh O O nn Ph Ph Zn-Cu, CH 2 I 2 Et 2 O, reflux n = 1 n = 2 n = 3 OO Ph Ph 66 90 77 62 Diastereomer ratio 13:1 19:1 15:1 16:1 yieldSubstrate ? 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 nn Et 2 Zn, CH 2 I 2 Et 2 O, 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 Yield d.e.Susbstrate OH 1. PCC 2. K 2 CO 3 , 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-Bu 3 Al. ? Diastereoselectivity improved with higher temperatures; ZnI 2 generally slowed the reaction and had variable effects on d.e. 09B-09 3/29/98 12:31 PM OHC CO 2 Me CO 2 Me O O i-PrO 2 C i-PrO 2 C CO 2 Me O Bu 3 Sn OEt Chiral Acetals in Synthesis 1. HC(OEt) 3 NH 4 NO 3 2. L-DIPT, TsOH pyr. 78% 1. CH 2 I 2 , Et 2 Zn 2. TsOH, MeOH, H 2 O CO 2 Me 1. BuLi, OHC 2. TsOH, THF-H 2 O Ph 3 P 94% 74% 41% 4 I BuLi, HMPA 2. NaOH, MeOH-THF-H 2 O CO 2 H 1. 24% yield 5,6-methanoleukotriene A 4 H Mori, A.; Arai, I.; Yamamoto, H. Tetrahedron, 1986, 42, 6447 X= R B O O COX COX R B O O COX COX R OH Zn(Cu), CH 2 I 2 Et 2 O, reflux O O B H 2 O 2 , KHCO 3 THF Chiral Auxiliary Methods: Boronic Esters n- Butyl " " Benzyl " Phenyl " O X O X O-Me O-i Pr N(Me) 2 O- i Pr N(Me) 2 O- i Pr N(Me) 2 41 44 48 57 61 60 46 73 86 93 81 89 73 91 R= R Yield(%) Zn %ee of ROH R I Imai, T.; Mineta, H.; Nishida, S. J. Org. Chem.. 1990, 55, 4996 Proposed Model of Stereochemical Induction 09B-10 3/29/98 12:33 PM I OR HN O Ph OR HN O Ph X c HN O Ph X c HN O Ph O NH O Ph Zn Et Zn I O Ph O NH O TIPS R = H 16-62% y Zn X R = TIPS 24 to 56% y 99 : 1 99 : 1 Ph Camphor Derived Auxiliaries Et 2 Zn, CH 2 I 2 CH 2 Cl 2 , rt Tanaka, K.; et al.; Tet. Asymm. 1994, 5, 1175 ? Addition of (0.5 equiv) of L(-), D(+) or meso-diethyl tartrate to the reaction improved the yield in both substrates without compromising selectivity. H N R O Ph H N R R = H R = TIPS Davies' Iron Acyl Complexes as Chiral Auxiliaries Ambler, P.; Davies, S. Tet. Lett. 1988, 29, 6979 CO Fe OR Cp Ph 3 P CO Fe OR Cp Ph 3 P ZnCl 2 (4 equiv), R n M (1.5 equiv) CH 2 I 2 (4 equiv), toluene, r.t. Me n-Pr n-Bu i-Pr 9 : 1 14 : 1 16 : 1 24 : 1 91 91 95 93 R= selectivity Yield(%) Using Et 2 Zn, CH 2 I 2 Using Et 3 Al, CH 2 I 2 Me n-Pr n-Bu i-Pr 16 : 1 18 : 1 19 : 1 24 : 1 74 86 62 49 R= selectivity Yield(%) 09B-11 3/29/98 12:34 PM Ambler, P.; Davies, S. Tet. Lett. 1988, 29, 6979 CO Fe OR 1 Cp Ph 3 P CO Fe Ph 2 P O Fe Ph 2 P O Cp CO Fe Ph 2 P O Cp CO Davies' Rationale for Selectivity "CH 2 " R 2 R 1 = H R 2 = Me 63 1.3 : 1 11 1 : 1 R 1 = Me R 2 = Me 89 11 : 1 80 30 : 1 Yield(%) selectivity Yield(%) selectivity "X-Zn-CH 2 I" Et 3 Al, CH 2 I 2 ? Lewis acid complexation to the carbonyl introduces severe non-bonding interactions with the cis-methyl group ? The "methylene" approaches the olefin away from CO and Ph 3 P appendages L.A. LA Charette's Chiral Auxilary O OBn BnO BnO OH O R 1 R 2 R 3 O OBn BnO BnO OH O R 1 R 2 R 3 Sugar-O Pr Sugar-O Me Sugar-O Ph Sugar-O Me Sugar-O Pr Sugar-O Sugar-O Et 2 Zn (10 equiv) CH 2 I 2 (10 equiv) toluene, >97% y Me Charette, A.; C?té, B.; Marcoux, J. J. Am. Chem. Soc. 1991, 113, 8166 -35 to 0 -35 to 0 -35 to 0 -35 to 0 -50 to -20 -20 to 0 -35 to 0 124 : 1 >50 : 1 130 : 1 111 : 1 114 : 1 >50 : 1 100 : 1 Substrate Temp (°C) Diastereoselectivity ? Auxiliary is derived from DMDO epoxidation of tri -O- benzyl-D-glucal followed by reaction with the desired allylic alcohol ? Enantiomeric cyclopropanes can be formed using L-rhamnose as the chiral auxiliary with virtually the same selectivities OTBS 09B-12 3/29/98 12:35 PM O O O OH OR RO HO RO HO O OH BnOH 2 C BnO BnO O R 1 R 3 R 2 O OH BnOH 2 C BnO BnO O R 1 R 3 R 2 Me Pr Me Ph β?D-series α?D-series (readily available) Me β?L-glucopyranoside series (expensive) Et 2 Zn, CH 2 I 2 t-BuOMe, 0°C 93 83 95 93 16.5 : 1 12.3 : 1 11.0 : 1 15.0 : 1 Substrate Yield (%) Selectivity α?D-Glucopyranosides: A Cheaper Alternative to L-Rhamnose Charette, A.; Turcotte, N.; Marcoux, J. Tet. Lett. 1994,35, 513 Sugar-O Sugar-O Sugar-O Sugar-O O O BnO BnO R 1 R 3 R 2 O Zn I O O O OBn OBn OBnR 1 R 2 R 3 Zn I R R O O BnO BnO R 1 R 3 R 2 O Zn Zn I Et ? Free hydroxyl group reacts immediately to form Zn-alkoxide. This intermediate complexes RZn(CH 2 I), the active reagent. ? O-ZnEt may serve to activate the (CH 2 I)ZnR moeity, not only enhancing the electrophilicity of the methylene, but rigidifying the chelate structure as well R ? Unfavorable bonding interations with α-series might explain slower reaction and lower selectivites. EtZn ZnEt Stereochemical Rationale for Charette Auxiliary Charette, A.; Marcoux, J. Synlett 1995, 1197 BnO BnO 09B-13 3/29/98 12:37 PM O AcO BnO BnO O O OH BnO BnO O R 1 R 3 R 2 O OH BnO BnO R 1 R 3 R 2 NH CCl 3 O O OH BnO BnO O R 1 R 3 R 2 O OH BnO BnO R 1 R 3 R 2 O R 1 R 3 R 2 HO O CHO BnO BnO 1. BF 3 ?OEt 2 (1 equiv), ROH 2. TiCl 4 (1 equiv) 3. MeONa, MeOH O 1. BF 3 ?OEt 2 (cat), ROH 2. MeONa, MeOH BnO BnO BnO 1. Tf 2 O, pyr 2. DMF, pyr, H 2 O, ? or and 70-80% 1. SmI 2 , THF, EtOH 2. Ms 2 O, ? 67% Installation and Removal of Charette's Auxiliary Charette, A.; Marcoux, J. Synlett 1995, 1197 BnO BnO BnO BnO BnO BnO OX OR OX OR -O Pr Pr-O -O Ph -O Me Me -O Ph -O ICH 2 Cl, Et 2 Zn toluene -20 °C Me " " " " 3 5 5 5 5 3 3 3 3 3 -OH -OH -OMe -OAc -OTBS -OH -OH -OH -OH -OH >97 88 97 85 >95 97 97 98 90 95 >20 : 1 > 15 : 1 1.6 : 1 5.3 : 1 1.3 : 1 24 : 1 24 : 1 23 : 1 15 : 1 > 20 : 1 Substrate Et 2 Zn, ClCH 2 I (equiv) OX = Yield(%) d.s. ? Both enantiomers of the cyclohexane diol are available through enzymatic resolution Charette, A.; Marcoux, J. Tet. Lett. 1993, 34, 7157. Charette: Simplifying the Auxiliary OP OH 1. RBr 2. deprotect OH OR OP OR 1. Tf 2 O, Bu 4 NI 2. BuLi ROH (92-97%) (ca 80%) Installation: Removal: OTIPS 09B-14 3/29/98 12:38 PM CO 2 H H 2 N Et Et OH O OMe Et CO 2 Me O-p-NO 2 Bz Et CO 2 Me OH Et CO 2 Me OH O AcO BnO BnO OCNHCCl 3 O OH BnO BnO O TIPSO Et H O OH BnO BnO O TIPSO H Et O OH BnO BnO O TIPSO Et H O OH BnO BnO O TIPSO H Et O OH BnO BnO K 2 CO 3 MeOH 87% Charette, A.; C?té. B. J. Am. Chem. Soc. 1995,117, 12721 Charette: Synthesis of Coronamic Acids Ph 3 P, DEAD, THF p-NO 2 C 6 H 4 CO 2 H 85% yield O TIPSO Et H A 1. A, BF 3 ?OEt 2. DIBAL-H 3. TIPSOTf 1. TIPSOTf 2. DIBAL-H 3. A, BF 3 ?OEt 4. K 2 CO 3 , MeOH O OH BnO BnO 73% y O TIPSO H Et 78% y Et 2 Zn (7 equiv) CH 2 I 2 (5 equiv) CH 2 Cl 2 , -30 °C Et 2 Zn (4 equiv) ClCH 2 I (4 equiv) CH 2 Cl 2 , -60 °C 93% yield > 99 : 1 98 % yield > 66 : 1 BnO BnO BnO BnO BnO BnO BnO Charette: Synthesis of Coronamic Acids HO TIPSO Et H HO TIPSO H Et 75% from auxiliary removal 80% from auxiliary removal RuCl 3 , NaIO 4 (83%) HO 2 C TIPSO Et H Charette, A.; C?té. B. J. Am. Chem. Soc. 1995,117, 12721 BOCNH CO 2 H Et A RuCl 3 , NaIO 4 (91%) HO 2 C TIPSO H Et B t-BuO 2 C NHBOC Et BOCNH CO 2 H Et t-BuO 2 C NHBOC Et N-BOC-(-)-allo- Coronamic acid N-BOC-(+)-Coronamic Acid N-BOC-(-)-Coronamic acid t-Bu ester N-BOC-(+)-allo- Coronamic acid t-Bu ester 82% Yield 42% Yield 64% Yield 41% Yield 5 steps 5 steps 5 steps 5 steps 09B-15 3/29/98 12:39 PM N CH 3 OH H 3 C H 3 C Ph Et 2 Zn N Zn O H 3 C H 3 C Ph H 3 C n Et Ph CH 2 OH Zn(CH 2 I) 2 Ph CH 2 OH Et 2 Zn (equiv) CH 2 I 2 (equiv) A (equiv) A Yield (%) %eeSolvent toluene THF toluene THF DME toluene DME 2 2 2 2 2 1 1 2 2 2 2 2 2 2 4 4 2 2 4 4 4 82 81 nd nd 85 63 54 18 -11 nd nd 23 15 19 ? The chiral controller A was shown to dramatically decelerate the reaction. Denmark: Ephedrine-Derived Chiral Controller Denmark, S.; Edwards, J. Synlett 1992, 229 nd = not determined R 2 R 1 OH 1. Et 2 Zn 2. XOC COX HO OH 3. Et 2 Zn, CH 2 I 2 R 2 R 1 OH OEt OEt OMe OMe Oi-Pr On-Bu OEt OEt Ph OH Ph CH 2 OH Ph(H 2 C) 3 CH 2 OH " " " " " CH 2 Cl 2 Cl(CH 2 ) 2 Cl* CH 2 Cl 2 Cl(CH 2 ) 2 Cl CH 2 Cl 2 CH 2 Cl 2 CH 2 Cl 2 CH 2 Cl 2 22 54 12 52 24 17 60 46 50 79 64 23 27 58 70 81 Substrate X = Solvent Yield(%) %ee ? Reactions are very slow, even at rt. ? Reaction work-up is plagued by difficult purification ? All enantiomeric excesses were determined by rotation. *Reaction performed at -12 °C 0 °C to rt Ukaji, Y.; Nishimura, M.; Fujisawa, T. Chem. Lett. 1992, 61 Fujisawa: Tartrate-Controlled Cyclopropanation 09B-16 3/29/98 12:40 PM R 1 R 3 Si OH 1. Et 2 Zn 2. (+)-DET, 0 °C 3. Et 2 Zn, CH 2 I 2 R 1 R 3 Si OH PhMe 2 Si OH 42 Substrate Yield(%) %ee ? Silyl substrates react much faster than the all-alkyl substrates (4 - 20 h). Ukaji, Y.; Sada, M.; Inomata, K. Chem. Lett. 1993, 1227 Ukaji: Tartrate-Controlled Cyclopropanation of Silated Olefins PhMe 2 Si OH Me Me 3 Si OH Me Ph 3 Si OH Me PhMe 2 Si OH Bu Me OH SiMe 3 Ph OH SiMe 3 88 53 82 84 50 84 -22 -30 -30 0 -30 0 0 Temp (°C) 77 92 87 90 87 46 80 OHPh O O B Me 2 NOC CONMe 2 Bu (1.1 equiv)1. 2. Zn(CH 2 I) 2 , rt, 2 h OHPh OMPh Li Na K MgBr ZnEt H H H H H M = Zn(CH 2 I) 2 (equiv) Solvent enantioselectivity (%ee) 5 5 5 5 5 5 5 5 2.2 1 * CH 2 Cl 2 CH 2 Cl 2 CH 2 Cl 2 CH 2 Cl 2 CH 2 Cl 2 CH 2 Cl 2 toluene DME CH 2 Cl 2 CH 2 Cl 2 (89) (58) (91) (33) (85) (93) (93) (81) (93) (93) 17.1 : 1 3.8 : 1 22 : 1 2 : 1 12 : 1 26 : 1 26 : 1 9.7 : 1 29 : 1 29 : 1 ? Cyclopropanation of the methyl or TIPS ether of cinnamyl alcohol afforded racemic material O O B O R O NMe 2 O NMe 2Zn I X Proposed Transition State Charette: Chiral Dioxaborolane Chiral Controller Charette, A.; Juteau, H. J. Am. Chem. Soc. 1994,116, 2651 <95% Yield * 85% yield 09B-17 3/29/98 12:41 PM OH R 3 R 2 R 1 O O B Me 2 NOC CONMe 2 Bu (1.1 equiv)1. 2. Zn(CH 2 I) 2 , rt, 2 h OH R 3 R 2 R 1 Charette: Chiral Dioxaborolane Chiral Controler Charette, A.; Juteau, H. J. Am. Chem. Soc. 1994,116, 2651 Ph OH Pr OH OH Me OH OH Et Me TBDPSO >98 80 90 85 80 29 : 1 (93) 27 : 1 (93) 29 : 1 (93) 32 : 1 (94) 21 : 1 (91) Substrate Yield (%) enantioselectivity (%ee) ? Reaction tends to become less selective or explodes upon scale-up due to uncontrolled exotherms. Charette, A.; Prescott, S.; Brochu, C. J. Org. Chem. 1995,60, 1081 OHPh O O B Me 2 NOC CONMe 2 Bu (1.1 equiv) Zn(MeCHI) 2 , CH 2 Cl 2 OHPh Charette: 1,2,3-Trisubstituted Cyclopropanes Charette, A.; Lemay, J. Angew. Chem. Int. Ed. Eng. 1997,36, 1090 Me >50 : 1 d.s. > 95% ee OHPh OHPh OHBnO OH Et OH OHPr >50 : 1 14 : 1 >50 : 1 20 : 1 15 : 1 10 : 1 98 90 94 90 94 93 96 83 80 84 87 93 Substrate d.s. %ee %Yield A A OHPh Zn(CHICH 2 CH 2 OTIPS) 2 (2.2 equiv) A (1.1 equiv) OHPh TIPSO > 95% ee > 95 : 5 d.s. OH Zn(CHICH 2 CH 2 OTIPS) 2 (2.2 equiv) A (1.1 equiv) OH TIPSO > 95% ee > 95 : 5 d.s. ? Relative stereochemistry of the cyclopropanation was the alkyl group (derived from the Zn reagent) is anti to the hydroxymethyl group ? Lower diastereoselectivity observed in the absence of the chiral promoter 09B-18 3/29/98 12:43 PM Kitajima, H.; Aoki, Y.; Ito, K.; Katsuki, T. Chem. Lett. 1995, 1113 BINOL-Derived Chiral Promoters OH OH CONR 2 CONR 2 A Et 2 Zn, CH 2 I 2 , (3 equiv) CH 2 Cl 2 , 0 °C, 15 h Ph OHPh OH A (1 equiv) Chiral Auxilary (R =) Et 2 Zn (equiv) Yield (%) %ee Me Me Me Me Et Et n-Pr n-Pr n-Bu 2 4 6 6 + ZnI 2 (1 equiv) 6 6 + ZnI 2 (1 equiv) 6 6 + ZnI 2 (1 equiv) 6 -14 26 67 75 94 90 85 79 89 7 85 90 87 55 87 51 88 58 ? Chiral controller is derived from the BINOL nucleus in three steps (Me = 37%, Et = 33%, n-Pr = 16%, n-Bu = 30%) Kitajima, H.; Ito, K.; Aoki, Y.; Katsuki, T. Bull. Chem. Soc. Jpn. 1997, 207 OH OH CONEt 2 CONEt 2 A Et 2 Zn (6 equiv), CH 2 I 2 , (3 equiv) CH 2 Cl 2 , 0 °C R 1 OHR 1 OH A (1 equiv) Yield (%) %ee R 2 R 2 Ph OH p -MeO-Ph OH p -Cl-Ph OH OHPh OH TBDPSO OH TrO OHTrO 44 78 59 65 59 64 34 92 94 90 89 87 88 65 Substrate O O Zn O NEt 2 O NEt 2 Zn Zn I O Zn Et Et Et Author's Proposed Transition State BINOL-Derived Chiral Promoters 09B-19 3/29/98 12:43 PM OH 1. Zn(CH 2 I) 2 (-78 °C to -20 °C) 2. L.A. Ph OHPh OHPh OHPr OHMe OH " " " " " " " none BBr 3 TiCl 4 ZnI 2 Zn(OTf) 2 Et 2 AlCl SnCl 4 TiCl 2 (O-i-Pr) TiCl 4 " " Me TBDPSO <5 90 90 14 18 87 55 80 85 90 85 Substrate Lewis Acid Yield (%) ? NMR studies indicate that allyl alcohol and Zn(CH 2 I) 2 react at -78 °C to form the (allyloxy)-Zn(CH 2 I) complex and CH 3 I. ? This complex does not react to form cyclopropane for at least four hours at -20 °C. ? Upon addition of a Lewis acid, cyclopropanation was complete within 2 hours at -20 °C. Charette: Lewis Acid-Catalyzed Cyclopropanation of Allylic Alcohols Charette, A.; Brochu, C. J. Am. Chem. Soc. 1995, 117, 11367 OH 1. Zn(CH 2 I) 2 (-78 °C to 0 °C) 2. A (25 mol%), 1.5 h Ph OHPh Charette: Lewis Acid-Catalyzed Allylic Cyclopropanation Charette, A.; Brochu, C. J. Am. Chem. Soc. 1995, 117, 11367 OO Ti Ph Ph Ph Ph OO i-Pr-O O-i-Pr A OH 1. Zn(CH 2 I) 2 (-78 °C to 0 °C) 2. A (25 mol%), 1.5 h Me Me OHMe Me 80% yield 90% ee 90% yield 60%ee OH Zn(CH 2 I) 2 (1 equiv) OZnCH 2 I CH 3 I+ O ZnCH 2 I LA O ZnI LA OZnI LA 09B-20 3/29/98 12:45 PM R 1 OH R 2 H NHSO 2 Ar NHSO 2 Ar R 1 OH R 2 H Ph OH OHPh OHPh ? Reaction proceeds to approximately 20% in the absence of the ligand under the reaction conditions ? Cinnamyl methyl ether reacted under similar conditions as cinnamyl alcohol, yet afforded racemic material OH CH 2 I 2 TrO Et 2 Zn (2.0 equiv) (3.0 equiv) (0.12 equiv) bissulfonamide (Ar = ) Substrate yield (%) %ee OHBnO C 6 H 5 o-NO 2 -C 6 H 4 m-NO 2 -C 6 H 4 p-NO 2 -C 6 H 4 " " " " " " OH 68 75 33 76 75 82 36 80 13 66 75 92 72 82 71 quant. 70 86 36 79 OH BnO TrO CH 2 Cl 2 , -23 °C, 5 h Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S. Tet. Lett. 1992, 2575 Kobayashi: First Catalytic Asymmetric Simmons-Smith Reaction " " SO 2 R N N SO 2 R " Zn R 1 OH R 2 H SO 2 Ar N N SO 2 Ar Al-R R 1 OH R 2 H Ph OH OHPh OH Me Me Et i-Bu " " " " Ph (2 equiv) Et 2 Zn CH 2 I 2 bissulfonamide (Ar = ) OH (3 equiv) yield (%) TrO (0.1 equiv) " " " " Substrate %ee CF 3 p-NO 2 -C 6 H 4 p-NO 2 -C 6 H 4 p-NO 2 -C 6 H 4 p-CF 3 -C 6 H 4 C 6 H 5 " " quant " " " " " " 92 14 70 66 71 66 76 73 78 CH 2 Cl 2 , -20 °C Imai, N.; Takahashi, H.; Kobayashi, S. Chem. Lett. 1994, 177 Kobayashi: Aluminum-Catalyzed Asymmetric Simmons-Smith Reaction R 09B-21 3/29/98 12:46 PM R 1 OH R 2 H NHSO 2 -C 6 H 4 -p-NO 2 NHSO 2 C 6 H 4 -p-NO 2 SO 2 R N N SO 2 R Zn R 1 OH R 2 H (2.0 equiv) Et 2 Zn CH 2 I 2 (3.0 equiv) (0.1 equiv) CH 2 Cl 2 , -20 °C Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S. Tet. Lett., 1992, 33, 2575 Chiral Silyl and Stannyl Cyclopropylmethanols PhMe 2 Si OH Bu 3 Sn OH OHPhMe 2 Si OHBu 3 Sn 75 67 94 83 81 86 59 66 Substrate Yield(%) %ee Ph OH R 2 O 2 SHN NHSO 2 R 3 R 1 Et 2 Zn, CH 2 I 2 , CH 2 Cl 2 -23 °C, 20 h Ph OH Ph Me Ph Me Me Me Me Me Me Ph Me Ph Me CF 3 p-MeC 6 H 4 p-NO 2 C 6 H 4 Me Me Me 3 C Me 3 C PhCH 2 PhCH 2 PhCH 2 PhCH 2 quant " " " " " 93 quant 58 61 42 46 74 34 82 85 R 1 R 2 R 3 Yield (%) %ee ? Other substrates were examined, but gave lower selectivites (ca. 60% ee). (2 equiv)(3 equiv) Imai, N.; Sakamoto, K.; Maeda, M.; Kouge, K.; Yoshizane, K.; Nokami, J. Tet. Lett. 1997, 38, 1423 Chiral Sulfonamide Promoters Derived from Amino Acids (10 mol%) 09B-22 3/29/98 12:47 PM Ph OH NHSO 2 R NHSO 2 R Ph OH CH 2 I 2 Et 2 Zn (1.0 equiv) (2.0 equiv) (0.1 equiv) CH 2 Cl 2 , -23 °C Denmark, S.; Christenson, B.; O'Connor, S. Tet. Lett. 1995, 2219 Denmark: Optimization of Reaction Protocols SO 2 R N N SO 2 R Zn Et 2 Zn (1.1 equiv) Bissulfonamide (R = ) t 1/2 (min) %ee CH 3 CH 3 CH 2 i-Pr C 6 H 5 1-naphthyl 4-NO 2 -C 6 H 4 4-CH 3 OC 6 H 4 C 6 F 5 50 130 140 70 50 70 60 100 80 67 49 77 48 76 74 29 ? There is a clear linear relationship between the promoter %ee and the enantioselectivity of the reaction. ? There is a marked induction period early in reaction that disappears upon addition of ZnI 2 (t 1/2 = 3 min). Enantioselectivities improved from 80% to 86% with ZnI 2 Denmark, S.; Christenson, B.; Coe, D.; O'Connor, S. Tet. Lett. 1995, 2215 Ph OH Ph OH CH 2 I 2 Et 2 Zn (1.0 equiv) (2.0 equiv) (0.1 equiv) CH 2 Cl 2 , -23 °C, 5 h Denmark: Optimization of Chiral Promoter Et 2 Zn (1.1 equiv) NHSO 2 CH 3 NHSO 2 CH 3 Ph Ph NHSO 2 CH 3 NHSO 2 CH 3 H 3 C Ph OCH 3 NHSO 2 CH 3 H3C Ph OH NHSO 2 CH 3 NHSO 2 CH 3 NHSO 2 CH 3 Promoter NH S O 2 NHSO 2 CH 3 NHSO 2 CH 3 NHSO 2 CH 3 NHSO 2 CH 3 (80 min, 20% ee) (110 min, 14% ee) (150 min, rac) (180 min, 29% ee) (80 min, 5% ee) (90 min, 79% ee) (>240 min, nd) (50 min, 80% ee) (T 1/2 , %ee) Denmark, S.; Christenson, B.; O'Connor, S. Tet. Lett. 1995, 2219 09B-23 3/29/98 12:48 PM Ph OH NHSO 2 CH 3 NHSO 2 CH 3 Et 2 Zn (1.1 equiv) MX n (1.0 equiv) Ph OH (0.1 equiv) CH 2 I 2 (2.0 equiv) Et 2 Zn (1.0 equiv) none ZnI 2 ZnBr 2 ZnCl 2 ZnF 2 Zn(OAc) 2 CdCl 2 CdI 2 MgI 2 PbI 2 MnI 2 HgI 2 GaI 3 8 >3 >3 4 10 10 11 11 50 8 12 15 decomp. 80 86 80 76 72 45 83 75 26 72 35 39 n.d. additive t 1/2 (min) %ee ? Using higher chiral ligand loadings resulted in slower conversions and lower enantioselectivity ? Use of in situ prepared ZnI 2 (Et 2 Zn + 2 I 2 ) reproducibly give 92% yield and 89% ee with cinnamyl alcohol. 1 5 10 25 50 100 50% 80% 80% 64% 41% 16% mol% %ee Denmark: Role of ZnI 2 ? Denmark, S.; O'Connor, S. J. Org. Chem. 1997, 62, 3390 Zn(CH 2 I) 2 + ZnI 2 2 IZn(CH 2 I) Ph OH NHSO 2 CH 3 NHSO 2 CH 3 Et 2 Zn (1.1 equiv) Ph OH Et 2 Zn + 2CH 2 I 2 A Denmark: Role of ZnI 2 ? Denmark, S.; O'Connor, S. J. Org. Chem. 1997, 62, 3390 ? NMR studies indicate for A and D clear formation of bis-iodomethylzinc species. ? Route B also showed formation of a single species from I 2 and appears to form ICH 2 -Zn-I upon CH 2 I 2 addition. ? C forms multiple species postulated to be Et-Zn-CH 2 I, Zn(CH 2 I) 2 and Et 2 Zn indicating another Schlenk equilibrium. ? Route D formed ICH 2 ZnI, but contaminated with another Zn species as yet unidentified "I-CH 2 -Zn-I" (0.1 equiv) ZnI 2 2 ICH 2 -Zn-I Et 2 Zn + I 2 Et-Zn-I CH 2 I 2 ICH 2 -Zn-I Et 2 Zn + CH 2 I 2 Et-Zn-CH 2 I I 2 ICH 2 -Zn-I Et 2 Zn + 2CH 2 I 2 Zn(CH 2 I) 2 I 2 ICH 2 -Zn-I Zn(CH 2 I) 2 B C D A B C D >3 3 10 20 86 86 73 23 method t 1/2 (min) %ee Zn(CH 2 I) 2 + ZnI 2 I-CH 2 -ZnI ? Author's conclude that the Schlenk equilibrium: lies on the side of ICH 2 -ZnI. This was independently confirmed by Charette: (Charette, A.; et al. J. Am. Chem. Soc. 1996, 118, 4539). 09B-24 3/29/98 12:48 PM OCH 3 OCH 3 O O Zn I I + Zn(CH 2 I) 2 Zn(1) - O(1) 2.103(10) Zn(1) - O(2) 2.20(1) Zn(1) - C(13) 1.92(2) Zn(1) - C(14) 1.98(2) I(1) - C(13) 2.21(2) I(2) - C(14) 2.16(2) I(1) -C(13) - Zn(1) 116.4(9) I(2) -C(14) - Zn(1) 107.9(8) Zn(1) - I(2) 3.513(2) Zn(1) - I(1) 3.350(3) Zn(1) - I(4) 3.929(2) Bond Lengths (?) Bond Angles (deg) Non-Bonded Distances (?) ? Two molecules in unit cell are virtually identical with respect to bond distances and angles. They are related by a pseudo-rotational center about the Zn atom. ? Distance between Zn(1) and I(2) is within the sum of their van der Waals radii. ? The endo iodomethylene unit bisects the O-Zn-O angle, possibly due to a stereoelectronic stablization: σ C-Zn donation into σ* C-I. Denmark: X-Ray Structure of a Bis-Iodomethyl Zinc Complex Denmark. S.; Edwards, J.; Wilson, S. J. Am. Chem. Soc. 1991. 113, 723 Denmark: Substrate Generality Denmark, S.; O'Connor, S. J. Org. Chem. 1997, 62, 584 R 2 OH NHSO 2 CH 3 NHSO 2 CH 3 R 2 OH Et 2 Zn (1.1 equiv) R 1 R 3 R 1 R 3 ZnI 2 (1.0 equiv) (0.1 equiv) CH 2 I 2 (2.0 equiv) Et 2 Zn (1.0 equiv) Ph H Ph(CH 2 ) 2 H Ph CH 3 Ph H Ph(CH 2 ) 2 H Ph CH 3 H Ph H Ph(CH 2 ) 2 CH 3 Ph H Ph H Ph(CH 2 ) 2 CH 3 Ph H " " " " " CH 3 " " " " " 7 <3 5 <3 <3 <3 40 18 9 5 25 45 91 81 89 89 91 88 90 97 98 90 85 85 80 81 81 72 73 81 5 10 26 50 43 16 R 1 R 2 R 3 t 1/2 (min) Yield(%) %ee ? Cinnamyl alcohol has been cyclopropanated by this group previously in 89% ee using distilled Et 2 Zn and I 2 to generate ZnI 2 . 09B-25 3/29/98 12:50 PM I N N Zn S H 3 C O O O I Zn Zn Et I PhH H X N N Zn S O R O S O RO O Zn I R 3 R 2 R 1 Denmark: Working Transition State Hypothesis R 1 OH NHSO 2 CH 3 NHSO 2 CH 3 Et 2 Zn (1.1 equiv) ZnI 2 (1.0 equiv) R 1 OH (0.1 equiv) CH 2 I 2 (2.0 equiv) Et 2 Zn (1.0 equiv) R 2 R 3 R 2 R 3 ? Substitution alpha to the CH 2 OH group experiences unfavorable steric interactions with the "spectator" sulfonamide group. ? Activation of I-CH 2 -ZnI moiety occurs by I coordination to the chiral promoter-Zn complex. Denmark, S.; O'Connor, S. J. Org. Chem. 1997, 62, 584. Zn Et Summary What we know: ? Activated zinc metal reacts with CH 2 I 2 to form an active cyclopropanation reagent that shows remarkable directing effects with Lewis basic sites on molecules. The Furukawa reagent (Et 2 Zn, CH 2 I 2 ) also shows the same reactivity trends. ? Zinc alkoxides are necessary appendages to most chiral auxiliary-based methods and all enantio- selective methods in order to achieve any selectivity. ? Lewis acids accelerate cyclopropanation of allylic alcohols. ? Various auxiliary methods exist for cyclopropanation of both cyclic and acyclic ketones and aldehydes. ? Glucose-derived auxiliaries give excellent induction in the cyclopropanation of allylic alcohols. ? Several methods for enantioselective cyclopropanation exist; however, most are stoichiometric in chiral reagent. ? So far only the bissulfonamide promoted Simmons-Smith reaction gives high induction in several cases. ? Mechanism of cyclopropanation and the exact nature of the reagents involved is unclear at present. 09B-26 3/29/98 12:50 PM