http://www.courses.fas.harvard.edu/~chem206/ R R OM R R NM R NR BuLi A NR Li NR El NLi R B N R El Chem 206D. A. Evans Matthew D. Shair Friday, November 8, 2002 a73 Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7Carbanions & Other Nucleophilic Carbon Species Enolates & Metalloenamines-1 Carey & Sundberg: Part B; Chapter 2Reactions of Carbon Nucleophiles with Carbonyl Compounds a73 Assigned Journal Articles a73 Rationalize why metalloenamine B is more stable than A. Chemistry 206 Advanced Organic Chemistry Lecture Number 22 Enolates & Metalloenamines-1 a73 Tautomerism in C=O and C=NR Systems a73 C=O Enolization with Metal Amide Bases a73 C=O Enolization: Kinetic Acidities a73 Mild Methods for Enolate Generation a73 Enolate Structure: A Survey of X-ray Structures a73 Metallo-Enamine X-ray Structures "Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures". D. Seebach Angew. Chem. Int. Ed. Engl., 27, 1624 (1983). (handout) "Stereoselective Alkylation Reactions of Chiral Metal Enolates". D. A. Evans Asymmetric Synthesis, 3, 1 (1984). (handout) a73 Other Useful References "Recent Advances in Dianion Chemistry". C. M. Thompson and D. L. C. GreenTetrahedron, 47, 4223 (1991). The Reactions of Dianions of Carboxylic Acids and Ester Enolates". N. Petragnani and M. Yonashiro Synthesis, 521 (1982). "Generation of Simple Enols in Solution". Capon, Guo, Kwok, Siddhanta, and Zucco Acc. Chem. Res. 21, 121 (1988). "Keto-Enol Equilibrium Constants of Simple Monofunctional Aldehydes andKetones in Aqueous Solution". Keeffe, Kresge, and Schepp JACS, 112, 4862 (1990). "pKa and Keto-Enol Equilibrium Constant of Acetone in Aqueous Solution". Chiang, Kresge, and Tang JACS 106, 460 (1984). more stable pKa (DMSO)~30 (El+) minor (<5%) major (<95%) Chem 206Enolates & Metalloenamines: IntroductionD. A. Evans "Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures". D. Seebach Angew. Chem. Int. Ed. Engl., 27, 1624 (1983). "Stereoselective Alkylation Reactions of Chiral Metal Enolates". D. A. Evans Asymmetric Synthesis, 3, 1 (1984). "Generation of Simple Enols in Solution". B. Capon, B.-Z. Guo, F. C. Kwok, A. K. Siddhanta, and C. Zucco Acc. Chem. Res. 21, 121 (1988). "pKa and Keto-Enol Equilibrium Constant of Acetone in Aqueous Solution". Y. Chiang, A. J. Kresge, and Y. S. Tang J. Am. Chem. Soc. 106, 460 (1984). Important References Ra O Rb Ra OH Rb Ra O– Rb El(+) El(+) Ra O Rb El Enols & Enolates are the most important nucleophiles in organic & biological chemistry. H+ base Ra N Rb El(+) El(+) H+ base Enamines & metalloenamines, their nitrogen counterparts, are equally important. R Ra N Rb R M Ra N Rb R H Ra N Rb R El Tautomers: Structural isomers generated as a consequence of the 1,3-shift of a proton adjacent to a X=Y bond. for example: + H + pK = 19.16 (calculated) pK = 10.94 (measured)+ H + pK = 8.22 (measured) Acidity of Keto and Enol Tautomers: Consider Acetone: + H +– H + – H ++ H + Keto-Enol Tautomers: Tautomerism may be catalyzed by either acids or bases: acid catalysis: + base catalysis: R CH3 O O – R H H HR OH R OH R H HCH3 O H H Z O CH3R X Y XZ Y H H C O CH3H3C C OH CH3C H H C H HH 3C C O – C H HH 3C C OH H3C C CH3 O C O – CH3C H H Kresge, JACS 1984, 106, 460 On the origin of the acidity of enols: Wiberg, JACS 1996, 118, 8291-8299 enamine metalloenamine N R R H H R Li OMe N R R H Me R Li OH O OH R O Me N Me N Me H MeNH2 –H2O R O Me OLi R Me R Me OLi O MeR Hc Hb Ha C OR HbHc R O – s-BuLi (THF) Li–N(SiMe2Ph)2 Li–N(SiEt3)2 Li–N(SiMe3)2 Li–N(i-Pr)2 LiNR2 -OMe -OMe -NEt2 -NEt2 -S-t-Bu -CMe3 -CHMe2 -C6H5 Me R OLi OLi R Me OLi MeR R Me OLi Chem 206Enolization with Metal Amides basesD. A. Evans Tautomeric Equilibria: Ketones vs. Imines Keq ~ 10–3 Keq > 10 The enamine content in an analogous imine is invariably higher than its carbonyl counterpart. In the case above, ring conjugation now stabilizes the enamine tautomer as the major tautomer in solution. Enolization: Amide Bases LM–NR2 ? (E) Geometry (Z) Geometry The Ireland Model (J. Am. Chem. Soc. 1976, 98, 2868)Narula, Tetrahedron Lett. 1981, 22, 4119 more recent study: Ireland, JOC 1991, 56, 650For the latest word on this subject see: Xie, JOC 1997, 62, 7516-9 R-Substituent Ratio, (E):(Z) 95 : 5 Base LDA (THF) LDA (THF, HMPA) 16 : 84 a73 Solvent 25 : 75 95 : 5LDA (THF) 0 : 100LDA (THF) LDA (THF) 0 : 100 0 : 100LDA (THF) LDA (THF) 40 : 60 -Et 77 : 23LDA (THF) LDA (THF) Base 95 : 5-OMe, O-t-Bu Ratio, (E):(Z)R-Substituent LM–NR2 (E) (Z) + 39 : 61 15 : 85 4 : 96 0 : 100 R = Cy, (E):(Z) 0 : 100 1 : 99 30 : 70 THF, -78 °C R = Et, (E):(Z) 70 : 30 Base a73 Base Structure Masamune (J. Am. Chem. Soc. 1982, 104, 5526) + (Z) Geometry(E) Geometry at equilibrium 16 : 84 Stereoelectronic Requirements: The α-C-H bond must be able to overlap with pi? C–O – Ha+ base a73 Stereochemistry pi? C–O Can you rationalize these differences? Et Me O LiNR 2 O MeEt NLi Me Me Me Me LiNR2 Li–N(i-Pr)2 OLi Et Me Me Et OLi LiTMP Me MeMe Me Me3C Me NLi Et Me OLi OLi MeEt KO Me O Ph K–H Na–H O Me Ph3C–Li Ph3C–Li LiN(i-Pr)2 LiN(SiMe3)2 t-BuOH O Ph O Me A A A OLi Ph OLi Me LiN(i-Pr)2 B B B OLi Ph OLi Me LiO Me Chem 206D. A. Evans Ratio, (E):(Z) LiTMP, 10% LiBr 98 : 2 86 : 14 THF, -78 °C + Collum (J. Am. Chem. Soc. 1991, 113, 5053) Collum (J. Am. Chem. Soc. 1991, 113, 9575) Lithium Halide Effects Collum (J. Am. Chem. Soc. 1991, 113, 9572) (LOBA) 98 : 2(LiTMP) 86 : 14 (LDA) 77 : 23 (E) Geometry (Z) Geometry + Base Structure Corey & Co-workers, Tetrahedron Lett. 1984, 25, 491, 495 THF, -78 °C M–base + Base temp Ratio (A:B)control kinetic–78 ° 99:1 kinetic–78 ° 95:5 kinetic–78 ° 90:10 thermoheat 10:90 thermoheat 26:74 thermoheat 38:62 Regioselective Enolization A: Alkyl groups stabilize metal enolate A: As M–O bond becomes more ionic A is attenuated M–base + Kinetic Selection sensitive to structure ratio: 99:1 estimatedpKa's (Bordwell) (25) (18) Unsaturated Ketones kinetic enolate KOt–Bu thermodynamicenolate see kinetic acidity handout for an extensive compilation of cases. Enolization with Metal Amides bases pKeq est: 7 (10+7) For the latest in the series of Column papers see: JACS 2000, 122, 2452-2458 Me Me O Me Me O Me Ph Me O Ph O O Me N O Et MeO O MeO OLi N OLi Et OLi Me Ph OLi Me CH 2 OLi Me Ph CH 2 OLi Me CH 2 OLi MeO OLi N OLi Et OLi Me Ph OLi Me Me OLi Me Ph Me OLi Me Me OLi O Me Me O OMe O O Me O Me MeMe OLi Me Me LiO OLi Me OLiMe O OLi Me MeMe Chem 206D. A. Evans Enolization with Metal Amides bases Kinetic Selection sensitive to structure LDA 71:29 LDA 99:1 LDA 14:86 LDA 99:1 LDA ~90:10 LDA ~83:17 LDA 85:15 LDA only enolate LDA only enolate LDA only enolate LDA only enolate LDA only enolate Kinetic Selection in Enolization of Unsaturated Ketones Choose Lewis Acid (LA) which can reversibly associate with amine base (B:). This system has the potential to enolize carbonyl functional groups: R CH2–H O LA O LA CH2R Useful Lewis Acid Pairs All of the above systems will enolize simple ketones to some extent. +O CH3R LA B B: B: LA B NMe Me B–H O OEt(EtO)2P O O OEt(EtO)2P O NHCbz CHO Me R CH3 O O CH3RS PhO CH3 O O CH3EtO R2N CH3 O Me NHCbz OEt O R OEt O OEt O Me Me Lithium Enolates Rathke, Nowak J. Org. Chem. 1985, 50, 2624-2626. MgBr2, 1.2 equiv Et3N, 1.1 equiv 1 equiv R= i-Pr, 40% yield R= n-C6H13, 100% yield Conventional methods of deprotonation (NaH) resulted in epimerization (Overman JACS 1978, 5179). 85% + 10% recovered aldehyde Above conditionsusing DIPEA 24 h, rt Base = DBU, 5 min, 99%, >50:1 E:ZBase = DIPEA, 7 h, 97%, >50:1 E:Z Horner-Wadsworth-Emmons Reaction. 1.2 equiv LiCl, 1.2 equivBase, 1.0 equiv i-PrCHO, 1 equivMeCN rt pKa 19.2 (DMSO), K+ counterion pKa 12.2 (Diglyme), Li+ counterion D.A. Evans Chem 206Design of Soft Enolization Systems Strategy LA + (–) (+) LA+ + + (+) (+)(–) Complexation MgBr2 + NEt3 Reversible ReversibleLi–X + NR3 Sn(OTf)2 + NR3 Reversible (Et3N, EtNi-Pr2) -OTf = - OSO2CF3 Reversible (Et3N, EtNi-Pr2)R2B-OTf + NR3 R2BCl + NR3 Reversible (Et3N, EtNi-Pr2) Reversible (Et3N, EtNi-Pr2)PhBCl2 + NR3 TiCl4 + NR3 Irreversible (Et3N, EtNi-Pr2) i-PrOTiCl3 + NR3 Reversible (Et3N, EtNi-Pr2) Reversible (Et3N, EtNi-Pr2)(i-PrO)2TiCl2 + NR3 (i-PrO)3TiCl + NR3 Reversible (Et3N, EtNi-Pr2) 100% enolization for B, Sn, Ti partial enolization for Li, Mg RCHO, 1 equivTHF, rt Roush & Masamune, Tet. Lett. 1984, 25, 2183-2186 O O EtO O OEt O O N Bn O Me O CO2Me O MeN O Bn O Mg Brn Et3N–H Me O Cl O O O Mg EtOH -CO2 MVK O COOH O Me N O Bn O CO2Me OEt O EtO O O Me O Me O O MePh TiCl4 NO2 O S OH O EtO OEt O Ph Me O Ph H O PhCHO Et Et O CHO Ph Me O Ph Ph O Me OH S O NO2 OH O HPh TiCl4 O OEtEtO O EtEt ++ ++ The Early Literature 10-15:1 Z/E TiCl4 DIPEA THF -40° C Brocchini, Eberle, Lawton J. Am. Chem. Soc. 1988, 110, 5211-5212. 91% yield95:5 syn/anti TiCl4 Et3N CH2Cl2, 0° C 30 min + Ketone and aldehyde combined followedby sequential addn of TiCl 4 and then amine Harrison, C. R. Tetrahedron Lett. 1987, 28, 4135-4138. 75% yield TiCl4 Pyridine THF Lehnert, W. Tetrahedron Lett. 1970, 4723-4724. + Michael reaction Rathke Evans, Bilodeau unpublished results. 73% yield, 93:7 diastereomer ratio Magnesium Enolates Deuterium quench indicates 25% enolization of N-propionyloxazolidinone MgBr2?OEt2 Et3N CH2Cl2, 0° C 75% yield MgCl2, 2 equiv Et3N, 4 equiv +CO2 MeCN rt 70 % yield MgCl2, 2 equiv NaI, 2 equiv Et3N, 4 equiv Ketone Carboxylation 85% yield MgCl2, 1 equiv Et3N, 2 equiv MeCN, rt Diethylmalonate acylations J. Org. Chem. 1985, 50, 2622-2624.J. Org. Chem. 1985, 50, 4877-4879. Syn. Comm. 1986, 16, 1133-1139. A Survey of 'Soft' Enolization TechniquesD.A. Evans Chem 206 Titanium Enolates CO2, MeCN rt R3N R3N O MeN O Bn O R O Me TiCl4 i-PrOTiCl3 TiCl4?2THF (i-PrO)3TiCl (i-PrO)2TiCl2 TiCl4 i-PrOTiCl3 O t-Bu Me TiCl4 Mei-Pr O O N Bn O Me OTiCl Cl Cl Cl R3N-TiCl4 TiCl4 i-PrOTiCl3 R3N (i-PrO)2TiCl2 MeO OMe O Me O Me Me O MeN O Bn O Ti Cl4 PhS Me O Xp (CH2)2COEt O Me Bn O N O O Me O Me OMe O Me O Xp Me O CH(OMe)2X p HC(OMe)3 Et O BOMCl Xp CH2OBn O Me Xp CH2OH O Me O MeN O Bn O Ti Cln O O O MeO O Me O R Me O PhSCH2Cl ClCH2NHCOPh MeOCH2NHCbz Me O O N O O Bn Me Me OH Me Me O CH2SPhX p Me O CH2NHCBzX p Xp CH2NHCOPh O Me 86% yield, >99:1 Evans, Clark, Metternich, Novack, Sheppard J. Am. Chem. Soc. 1990, 112, 866. 1. TiCl4 DIPEA 2. i-PrCHO 99%, >99:1 93%, 97:3 89%, 97:3 91%, 96:4 93%, 99:1 99%, >99:1 88%, >99:1 78%, 98:2 H2C=CHCO2Me J. Am. Chem. Soc. 1990, 112, 8215-8216.; J. Org. Chem. 1991, 56, 5750-5752. Reactions with Representative Electrophiles self condensationself condensation 1 50 80 100 % EnolizationLewis Acid Ethylisopropylketone 80 ~10 70 100 100 % EnolizationLewis Acid N-Propionyloxazolidone (1) Reversible ComplexationR3N-TiCl3(OiPr)+ -+ a73 Order of addition of reagents is not important for i-PrOTiCl3 or (i-PrO)2TiCl2. a73 Enolization process not responsive to tertiary amine structure a73 DIPEA, Et3N, N-Ethylpiperidine all suitable bases. a73 DBU and tetramethylguanidine do not provide enolate. a73 CH2Cl2 is the only suitable solvent for these enolizations. a73 Order of addition of reagents is important for TiCl4. + + - Irreversible Complexation Titanium Enolates a73 Enolizable substrates: a73 Substrates Which present problems: R=Ar, R<i-Pr Chem 206M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques RR -X– -X– MeH H O BL2OTf +X– H Me H +X– O BL 2XO MeMe Me Me Me O BR2 Me TfOB Me Me Me O BR2 Me Mr BOTfMe Me MeR OBX R R Me Me O OBL2 R Me O B R R Me R O BR2 MeMe B R Me R O R R OBL2 Me Mr Me O BR2 Me R O B X RR R2BOTf-ketone complex may deprotonate through charged complex with (Z) preference charged Cy2BCl-ketone complex may deprotonate through syn complex ++ syn ++ anti The Ketone-Boron Complexes as enolate precursors: ratio ~97: 3Bu2B-OTf, Et3N 9-BBN-OTf, Et3N ratio ~97: 3 R2B-X, R3N ratio 21:79Cy2B-Cl, Et3N Brown, J. Org. Chem. 1993, 58, 147-153 Cy2B-Cl, Et3N ratio ~ 3: 97 R2B-X, R3N ratio ~ 88: 12 Enolization Model: Paterson, Tetrahedron Lett. 1992, 33, 7223. Goodman, Tetrahedron Lett. 1992, 33, 7219. A Survey of 'Soft' Enolization Techniques: Boron Enolates-1 Borane and lutidine or DIPEA form 1:1 complex with L2B-OTf. Complexation reversible as enolization will occur upon addition of ketone. Less hindered nitrogen bases - pyridine, Dabco, DBU, irreversibly complex with L2B-OTf. 9-BBN-OTf, Et3N Evans, Nelson, Vogel, Taber J. Am. Chem. Soc. 1981, 103, 3099-3111. + -+ - NR'3 NR'3 (-)-(Ipc)2BOTf Chiral dialkylboron triflates Masamune, S. et. al. Tetrahedron Lett. 1979, 2225, 2229, 3937.Masamune, S. et. al. J. Am Chem. Soc. 1981, 103, 1566-1568. Diastereoselective Aldol Reactions of Boron Enolates. Di-n-butylboron triflate Evans, Vogel, Nelson J. Am. Chem. Soc. 1979, 101, 6120.Evans, Nelson, Vogel, Taber J. Am. Chem. Soc. 1981, 103, 3099-3111. Evans, Bartroli, Shih J. Am. Chem. Soc. 1981, 103, 2127. Dialkylboron Triflates Enolizes ketones with 2,6-lutidine or DIPEA in ethereal solvents. Mukaiyama, Inoue Chem. Lett. 1976, 559-562.Bull. Chem. Soc. Jpn. 1980, 53, 174-178. Masamune, Sato, Kim, Wollmann J. Am. Chem. Soc. 1986, 108, 8279-8281. Tetrahedron 1990, 46, 4663-4684.Tetrahedron Lett. 1989, 30, 997-1000. Tetrahedron Lett. 1986, 27, 4787-4790. D.A. Evans Chem 206 Enolate Stereochemistry Paterson, I. et. al. anti syn Mg N O Li Li O M HMe H O R M R R R O O Li HR H Br Mg OEt2 O Me CMe3 H H R H O Me M ORMRO O O RM M Me O O CMe3 H Li NMe 2 Me2N Mg Br MM M O M OR R O RR O M RR O R M R R O M OR M a71 a71 1.35 ? 1.34 ? + In solution and in the solid state metal enolates have a strong tendency to aggregate into dimers and tetramers to satisfy metal solvation requirements. Crystallized as the dimer Crystallized as the dimer Seebach & co-workers, J. Am. Chem. Soc. 1985,107, 5403. For certain metal enolates from heavy metals such as M = Hg+2 the C-metal tautomer is sometimes favored. The prediction stated above does hold, but the net change in the C–C bond length is < 2 % ! 1.36 ? 1.32 ? One would predict that as the relative importance of the C– structure increases, the C–O bond would shorten and the C–C bond would lengthen. Since enolates usually function as carbon nucleophiles, it is therefore of some interest to assess the relative importance of the illustrated contributing polar resonance structures. Within the last decade good X-ray crystal structures of a number of metal enolates have been obtained. C – resonance structure O– resonance structure For alkali metal enolates (M = Li, Na, K etc.) the O-metal tautomer is strongly favored. This generalization holds for most alkaline earth enolates (Mg+2) as well. These are the generally useful enolate nucleophiles Metal Tautomerism Resonance Structures D. A. Evans Chem 206Enolate Structures from X-ray Diffraction δ– Ab initio calculations (Spartan) indicate that the partial negatilve charge on the alpha carbon is ~ – 0.22 for the Li enolate M = HM = Li – 0.19– 0.22 O Me SiO CMe 3 Me Me Me Me O LiLi OLi OO O Li O Li Li O Li O LiLi O O Li Li O Li O N Li Li O O Li LiN O Si Li Li Li Li LiLi LiN Li O O Li SiMe Me Me O Me CMe3 H2C O Li Williard, P. G.; Hintze, M. J. J. Am. Chem. Soc. 1987, 109, 5539-5541. LDA Si Williard, P. G.; Carpenter, G. B. J. Am. Chem. Soc. 1986, 108, 462-468. Enolate Structures: Lithiun Enolates Chem 206D. A. Evans Li Enolates Me3C O Br O O O Zn O Zn Br O CMe3Br Me3C Zn Br C Zn Br O C O O ZnBr OMe3C Me3C O O ZnBr OO Zn O Zn THF THF Br O CMe3 Br Me3C Br Zn Zn Br O Enolate Structures: The Reformatsky Reagent Chem 206D. A. Evans Dekker, J.; Boersma, J.; van der Kerk, G. J. M. J. Chem. Soc. Chem. Commun. 1983, 553. Dekker, J.; Budzelaar, J.; Boersma, J.; van der Kerk, G. J. M. Organometallics 1984, 3, 1403. 2.0? Zn(0) Zn Enolates 2.0? The THF Complex O CHOO Br O Me C6H13 OH O O OH O Br CHO R O O R Br O CHOO N O Me O BnNBn O Me Br OZnBr N Br O Br Me O Bn O C 6H13 CHOMe O Br R Me Br O O Me O CHO O BrO O Me O OBr MeR Ph Br Me O O Me Ph Ph OH OH PhPh Me O PhCHO O O R OH O O OH O O OH R OHR Me O Et O O Et O Me R OH O O R H Sm Et O R(H) (R)H Summary of SmI2 chemistry: Sonderquist, Aldrichimica Acta 1991, 24, 15Review: Comprehensive Organic Synthesis, 1991; Vol 2, Chapter 1.8, pp 277-299 The "Classical" Reformatsky Process The Samarium(II) Variant Both cyclic and acyclic cases studied (11 cases). H. Nozaki & Co-workers, J. Am. Chem. Soc. 197, 99, 7705 48% yield Zn, Et2AlCl -20 °C 78% yield 25 °C C. H. Heathcock & Co-workers, J. Org. Chem. 1987, 52, 5745. Zn/THF 2 SmI2/THF -20 °C 8: 1 diastereoselection97% yield one isomer? 86% yield -78 °C 2 SmI2/THF G. A. Molander & Co-workers, J. Am. Chem. Soc. 1987, 109, 6556. Proposed Transition structure Rxns carried out in water with either activated Zn or Sn.19 cases reported. T. H. Chan & Co-workers, Chem. Commun. 1990, 505. diastereoselection 60:4087% yield Zn in HOH 25 °C Based on the Nozaki recipe JACS 1977, 99, 7705T. Nishida & Co-workers, Tetrahedron 1991, 47, 6623. diastereoselection 10:155% yieldZn, Et2AlCl Good entry into prior literature 82% yieldSmI2/0 °C R = H: 76% yield R = Me: 82% yieldaldol diastereoselection 62:38 no config assignment SmI2/0 °C R = Me: 82% yieldaldol diastereoselection 70:30 no config assignment R = H: 85% yieldSmI2/0 °C Chem 206 T. Tabushi & Co-workers, Tetrahedron Lett. 1986, 27, 3889. The Reformatsky ReactionD. A. Evans O LiN PhH OTMS O X O t-Bu Ph NLi Ph Me Me O NMe N NLi t-Bu Ph H OTMS O t-Bu OTMS t-Bu NMe N NLi Ph H O R N Me N NLi t-Bu Ph H (R) O R OTMS t-Bu (S) OTMS R t-Bu (1.0)Ph (0.8) i-Pr (0.8) R (equiv base) Koga, et al J. Am. Chem. Soc . 1986, 108 , 543-545. 51% yield (97% ee) 1 equiv HMPA10 equiv TMSCl -105 °C With an in situ quench: Koga, et al Heterocycles 1990, 30 , 307-318. 73% yield (96% ee) TMSCl (5 equiv)HMPA (1 eq) 1) Simpkins, J. Chem. Soc., Chem. Commun. 1986, 88-90. X = Br or OH70% ee NBS or MCPBA 2) TMSCl, THF Asymmetric Deprotonation of Meso Ketones Chem 206Chiral Amide Bases: Deprotonation of KetonesD.M. Barnes, D. A. Evans The Effects of Additives on Induction THF, -78 °c Conditions ee(%) Internal quench with TMSCl External quench of TMSCl Reaction run with 0.5 equiv of LiCl(rel. to amide), then quenched with TMSCl 69 23 83 Does a change in aggregation state inhibit racemization of the initial Li enolate? Simpkins and Cousins, Tetrahedron Lett . 1989, 30 , 7241-7244Simpkins and Bunn, J. Org. Chem . 1993, 58 , 533-534.(1) Kinetic Resolution of Ketones HMPA, TMSCl, THF-105 °C 45% (90% ee)66% (30% ee) 78% (18% ee) 51% (94% ee)33% (98% ee) 22% (94% ee) Koga, et al Tetrahedron Lett . 1989, 30, 6537-6540. Me TMSO H Me TMSO H HTMSO Me HTMSO Me MeN O O O NMe N NLi t-Bu Ph H OCOPhMeN CO2Me O OO O Ph NLi Ph Me Me MeN OTMS OTMS O OTMS OO O C8H17Me Me O H C8H17Me Me O H NMe N NLi t-Bu t-Bu H cocaine more stable more stable Simpkins, et al Tetrahedron 1993, 49 , 207-218. 88% (85% ee) 79% (88% ee) 5 equiv TMSClTHF, -95 °C (R) - 1 Other cyclic ketones can be used as substrates.See: Cox and Simpkins, Tetrahedron: Asymmetry 1991, 2, 1-26. Momose, et. al Chem. Pharm. Bull . 1990, 38 , 2072-2074 Chem 206Chiral Amide Bases: Other Ketonic SubstratesD.M. Barnes, D. A. Evans a73 Regioselective Deprotonation of Unsymmetrical Ketones Conditions Ratio (TMS)2NH, TMSILDA (R) - 1(S) - 1 9078 2>98 1022 98<2 9384 4>98 716 96<2 (TMS)2NH, TMSI LDA(R) - 1 (S) - 1 RatioConditions ThermodynamicKinetic KineticKinetic ThermodynamicKinetic KineticKinetic Koga, et al Tetrahedron: Asymmetry 1990, 1 , 295-298. TMSCl, HMPA -100° 80% yield90% ee O Me Me Ph NLi Ph Me Me NLi NH H LiN NEt OTBS O O OH OTBS OH 62 (R) 92 (S) 31 (R) 78 (R) Me Ph O CMe3 CO2H MeO Ph NKO Me Me Me CH2CO2HBr CMe3 CMe3 Cl CH2CO2H O Ph Me Me OH CH2 OH CMe3 HOOC OH HPh HOOC CMe3 Duhamel, et al, Chem Commun. 1993, 116-117 90% yield84% ee THF, -70 °C this number has been challenged Aggregation pheremoneof the Douglas Fir Beetle 358THF, HMPA, 0°+ 3 3 2 1 Ref. Kinetic Resolution of Racemic Epoxides 92% yield (90% ee - rotation) - Asami, Tetrahedron Lett . 1985, 26 , 5803-5806.73% yield (76% ee -Mosher) - Hendrie and Leonard, Tetrahedron 1987, 43 , 3289-3294. 2 / PhH 3 2 1 1 Whitesell and Felman, J. Org. Chem . 1980, 45, 755-756. 2 Asami, Chem. Lett . 1984, 289-832. 3 Asami and Kirihara, Chem. Lett . 1987, 389-392. 80THF, HMPA, 0° 77 65 THF, 0° THF, reflux ee(%)Yield (%)Conditions Ring opening of meso epoxides Chem 206Chiral Amide Bases: Epoxide Opening and EliminationsD.M. Barnes, D. A. Evans 2, THF -78° - RT 26% yield~ 80% ee 26% yield + Mori, Tetrahedron 1987, 43 , 2249-2254. (+) (+) 2, DBU, THF Equivalents 2 Yield (ee) Yield (ee) 0.750.33 31 (>95) 67 (30) 60 (33)21 (72) Asami and Kanemaki, Tetrahedron Lett . 1989, 30, 2125-2128. Asymmetric Eliminations HCl, Et2O 1, THF / hexane 96% yield74% eeDuhamel, et al Tetrahedron Lett . 1987, 28 , 5517-5520.(+) Reviews: Cox and Simpkins, Tetrahedron: Asymmetry 1991, 2, 1-26. Simpkins, Pure Appl. Chem. 1996, 68, 691-694.Simpkins, In Advanced Asymmetric Synthesis; Stephenson, G. R., Ed.; Chapman & Hall: London, U.K., 1996; pp 111-125.