D.A. Evans Enolates Metalloenamines-2 Chem 206 Assigned Journal Articles http:/www.courses.fasharvardedu/-chem206/ Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Chemistry 206 Afforded by Complex Structures D Seebach Angew. Chem. Int Ed Engl, 27, 1624(1983).(handout) Advanced organic Chemistry Stereoselective Alkylation Reactions of Chiral Metal Enolates D A. Evans Asymmetric Synthesis, 3, 1(1984).(handout) Lecture Number 23 Other Useful references Advances in Asymmetric Enolate Methodology"Arya, Qin, Tetrahedron 2000 Enolates metalloenamines-2 56.917-94 Recent Advances in Dianion Chemistry". C M. Thompson and D L C. Green Tetrahedron,47,4223(1991) The reactions of dianions of carbo tragnani and M. Yonashiro Synth thesis, 21 1982). ter Generation of Simple Enols in Solution". Capon, Guo, Kwok, Siddhanta, and Introduction and General trends Zucco Acc. Chem. Res 21, 121(1988) Enolate Alkylation: Electronic& Steric Control Elements Enolate Alkylation: Unusual Cases Keto-Enol Equilibrium Constants of Simple Monofunctional Aldehydes and Ketones in Aqueous Solution". Keeffe, Kresge, and Schepp JACS, 112, 4862 Chiral amide enolate (1990) Chiral Ester enolates Chiral Imide enolates pKa and Keto-Enol Equilibrium Constant of Acetone in Aqueous Solution Chiral metalloenamines Chiang, Kresge, and Tang JACS 106, 460(1984) a Reading Assignment for this Week Carey& Sundberg: Part A; Chapter 7 Carbanions Other Nucleophilic Carbon Species Explain why A is favored for X =O while B is favored for X= NNHR Carey Sundberg: Part B; Chapter 2 ase Reactions of Carbon Nucleophiles with Carbonyl Compounds Matthew d shair Monday, November 11. 2002
http://www.courses.fas.harvard.edu/~chem206/ R R O M R R N M R X Me Me A X Me Me B D. A. Evans Chem 206 Matthew D. Shair Monday, November 11, 2002 ■ Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7 Carbanions & Other Nucleophilic Carbon Species Enolates & Metalloenamines-2 Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds ■ Assigned Journal Articles Chemistry 206 Advanced Organic Chemistry Lecture Number 23 Enolates & Metalloenamines-2 "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) ■ Other Useful References "Advances in Asymmetric Enolate Methodology" Arya, Qin, Tetrahedron 2000, 56, 917-947 (pdf) "Recent Advances in Dianion Chemistry". C. M. Thompson and D. L. C. Green Tetrahedron, 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 and Ketones 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). ■ Introduction and General Trends ■ Enolate Alkylation: Electronic & Steric Control Elements ■ Enolate Alkylation: Unusual Cases ■ Chiral Amide Enolates ■ Chiral Ester Enolates ■ Chiral Imide Enolates ■ Chiral Metalloenamines Explain why A is favored for X = O while B is favored for X = NNHR base
D.A. Evans Enols, Enolates, Enamines Metalloenamines: Reactivity Hierarchy Chem 206 ■ Metalloenamines Decreasing Nucleophilicity Imines may be transformed into their conjugate bases(enolate counterparts) with strong bases: Metal R pKa-2933 Li-NR R-MgX The usual bases employed are either mides(LDA) or Grignard eagents. Note that grignard reagents do not add to the c=n pi-bond due to H3O the reduced dipole. With this functional group, deprotonation is observed to be the preferred reaction I When to use a metalloenamine -C-Cl Metalloenam antly more nucleophilic than ketone or ald when less reactive electrophiles are R-C-H o Me C no reaction However: relationship Meta、R ood yie ./R-C-OR+ Metalloenamines are reactive enough to open epoxides in good yield Ketone enolates are only marginally reactive enough for this family of electrophiles Me2CH--I R-C Nature uses enamines. " stabilized"enolates, and enol derivatives in C-C bond constructions extensively
X Decreasing Nucleophilicity Decreasing Electrophilicity C C OMe C C NR2 C C O C C NR N R R-MgX R C O Cl C H O R R C O R Me I C OR O R O H2C CH2 Me2CH I R C O NR2 O Me Me Me Me N R N OH R H3O + R O N Metal R N CH2 Li I Me Me Li-NR2 Li-NR2 OLi N Metal R N R N Me D. A. Evans Enols, Enolates, Enamines & Metalloenamines: Reactivity Hierarchy Chem 206 Nucleophile Electrophile Br2 , O3 + + + + + + + + + + + + + + + + + + + + + + – – ■ Metalloenamines: Imines may be transformed into their conjugate bases (enolate counterparts) with strong bases: The usual bases employed are either lithium amides (LDA) or Grignard reagents. Note that Grignard reagents do not add to the C=N pi-bond due to the reduced dipole. With this functional group, deprotonation is observed to be the preferred reaction. ■ When to use a metalloenamine: Metalloenamines are significantly more nucleophilic than ketone or aldehyde enolates. They are used when less reactive electrophiles are under consideration. For example: no reaction However: good yield Metalloenamines are reactive enough to open epoxides in good yield. Ketone enolates are only marginally reactive enough for this family of electrophiles. ■ Nature uses enamines, "stabilized" enolates, and enol derivatives in C–C bond constructions extensively. pKa~ 29-33 syn relationship
D.A. Evans C versus O Enolate Reactivity the Hammond Postulate Chem 206 Question: Why do we generally show enolates reacting with electrophiles The Hammond Postulate is also relevant to this issue and is broadly at carbon as opposed to oxygen ? Let's begin the the discussion with an used to make qualitative statements about transition state structure I"As electrophile reactivity increases, the percentage of reaction at the Hammond. JACS 1955.77 334 more reactive acetyl chloride extreme reactions, one which is strongly endothermic and one which is strongly exothermic El(+)C/O Rxn Ratio Strongly Exothermic Reactio E(+) AH >20 kcal/mol A a The very reactive acid chloride gives almost exclusively the O-acylation Rxn Coordinate roduct while the less reactive methyl iodide affords the alternate C-alkylation product Hammond Postulate These results may be understood in the context of qualitative statements "For strongly exothermic reactions, the transition state T made by Hammond(The Hammond Postulate)and Hine(The Principle of Least Motion) ooks like reactant(s)e.g.B LAs applied to the enolate-electrophile reaction, for very exothermic reactions, e.g. the reaction with acetyl chloride, the transition state for the "As reactions become more exothermic, the favored reaction becomes. instance the electrophile heads for the site of highest electron dens The Principle of Least Motion: process will involve little enolate structural reorganization. Hence in that path which results in the least structural (electronic)reorganization. Carey& Sundberg: Part A; Chapter 4, pp217-220 for discussion of hammonds Postulate See Hine in Advances in Phys. Org. Chem. 1977, 15, 1-61 Based upon the above discussion draw a detailed mechanism for the protonation of cyclohexanone enolate Since the X-ray data clearly support the picture that resonance structure 1 best represents the enolate structure, highly reactive electrophiles will favor o-attack according to Hine s generalization
Energy Rxn Coordinate O – O O–El O El Me C O Cl B Me I A O – B O A Carey & Sundberg: Part A; Chapter 4, pp217-220 for discussion of Hammond's Postulate H + Based upon the above discussion draw a detailed mechanism for the protonation of cyclohexanone enolate. ■ As applied to the enolate-electrophile reaction, for very exothermic reactions, e.g. the reaction with acetyl chloride, the transition state for the process will involve little enolate structural reorganization. Hence in this instance the electrophile heads for the site of highest electron density Hammond Postulate "For strongly exothermic reactions, the transition state T‡ looks like reactant(s) e.g. B." Strongly Exothermic Reactions DH ° > 20 kcal/mol T ‡ ■ In attempting to grasp the Hammond Postulate, let's consider two extreme reactions, one which is strongly endothermic and one which is strongly exothermic. The Hammond Postulate is also relevant to this issue and is broadly used to make qualitative statements about transition state structure. Since the X-ray data clearly support the picture that resonance structure 1 best represents the enolate structure, highly reactive electrophiles will favor O-attack according to Hine's generalization. 2 1 The Principle of Least Motion: "As reactions become more exothermic, the favored reaction becomes that path which results in the least structural (electronic) reorganization." ■ The very reactive acid chloride gives almost exclusively the O-acylation product while the less reactive methyl iodide affords the alternate C-alkylation product. These results may be understood in the context of qualitative statements made by Hammond (The Hammond Postulate) and Hine (The Principle of Least Motion) >> 1 << 1 El(+) C/O Rxn Ratio El(+) : – ■ "As electrophile reactivity increases, the percentage of reaction at the enolate oxygen increases." For example, consider the reactions of cyclohexanone enolate with the two electrophiles, methyl iodide and the much more reactive acetyl chloride: Question: Why do we generally show enolates reacting with electrophiles at carbon as opposed to oxygen ?? Let's begin the the discussion with an observation: D. A. Evans C versus O Enolate Reactivity & the Hammond Postulate Chem 206 Hammond, JACS 1955, 77, 334 See Hine in Advances in Phys. Org. Chem. 1977, 15, 1-61
D.A. Evans Enolate Alkylation: Stereoelectronic Control Elements Chem 206 Review Evans, D. A. Stereoselective Alkylation Reactions of Chiral/ Metal Enolates; Morrison, J D, Ed. AP: New York, 1984: Vol 3, pp 1-110 Examples where stereoelectronic factors are dominant Stereoelectronic Issues I Enolization: Breaking C-H bond must overlap with *C-O in TS# Alkylation: Forming C-El bond must overlap with T*C-O in TS+ LDA o NMe R-x 0 Bn-Br >99 Issue: Degree of rehybridization ood illustration of the impact of allylic strain in TS+? 日 BOC-N- R R-x a Cyclohexanone Enolate The C19 Angular Methyl Group in the steroid nucleus path A e3C LI/NH3 chair conformation Me- pathE Me3C R twistboat conformation Metal R-substituent Electrophile Ratio. a:e CD3l 70:30 83:17 Chair vs boat geometries not stongly reflected in diastereomeric TS*s.The The enolate(Chem 3D) transition states is early and enolate-like
N Boc O Me C C O R H R M H M O C H R C R El H Me3C R O C C O R R H M El C C O R El R M H Me3C H R O El El O Me3C H R C C R OLi H Me3C N O H H Me H O RO O Me OH H H Me O O Li CO2Me Me-I Li Me CD3I R–X Me-I N C C LiO H Me H Boc R–X N Boc O Me R R–X Allyl–Br Bn–Br LiO Me OH H H R H O Me OH H H R H Me N O H R Me H O RO Me-I path A ■ Cyclohexanone Enolate: Chair vs boat geometries not stongly reflected in diastereomeric TS‡s. The transition states is early and enolate-like. 83:17 Metal 70:30 R-substituent Electrophile Ratio, a:e twist boat conformation chair conformation ‡ e El(+) e El(+) Issue: Degree of rehybridization in TS‡? ■ Alkylation: Forming C–El bond must overlap with p* C–O in TS‡ ■ Enolization: Breaking C–H bond must overlap with p* C–O in TS‡ El(+) base Stereoelectronic Issues D. A. Evans Enolate Alkylation: Stereoelectronic Control Elements Chem 206 a Evans, D. A. Stereoselective Alkylation Reactions of Chiral Metal Enolates.; Morrison, J. D., Ed.; AP: New York, 1984; Vol. 3, pp 1-110. Review path E LDA ratio >99:1 93:7 Pilli, Tetrahedron, 1999, 55, 13321 Examples where stereoelectronic factors are dominant good illustration of the impact of allylic strain Li/NH3 (90%) one isomer The C19 Angular Methyl Group in the steroid nucleus The enolate (Chem 3D) LDA favored disfavored
D. A. Evans Enolate Alkylation: Steric Control Elements Chem 206 Steric Effects In this case, both e and a paths are stereoelectronically equivalent. Diastereoselectivity is now determined by the differential steric effects encountered in the two Tsts Cases with Opposed steric& electronic effects E(+) a oMe Me3C El Me3C H 8° E Me3C LI/NH Electrophile Ratio, E: A 95: 05 stereoelectronic n-Bu-Br 87 83:17 Representative cases 07:93 stent -Me Et- >595 COmE Me. CO2 Me Me comE Raio,80:20 Mel The enolate r= Me CO2Me Me CO 2 Me (Chem 3D LDA Rato.90:10 Based on above data, this case is reasonable gH5 Rat0.>97:3 Ph3 COCH2 ally+-Br PhaCOCH2 )>90:10 diastereoselectivity depends stongly on O-protecting group OTHP LDA Mel ≥0Rato>97:3 (67%)93:7
Me CO2Me OLi OMe Me3C H Me CO2Me Ph3COCH2 O O H Me H H O O MeI MeI MeI Me Me CO2Me CO2Me Me Me H Me3C CO2Me El Me O O H H Me H O Ph O 3COCH2 C3H5 Me Me CO2Me Me CO2Me Me Me-I n-Bu-Br CO2Me El Me3C H A Li R Me LiO H O Me R Me CN O H H O CO2Me Me OTHP –H –H R NaH Me-I Me-I LiNH2 R H El Me O Et-I Et-I CD3I CD3 I NC H O Me Me OTHP Me CO2Me O H Me O Me El H R D. A. Evans Enolate Alkylation: Steric Control Elements Chem 206 El(+) Ratio 95:05 83:17 07:93 >5:95 Cases with Opposed steric & electronic effects + Li/NH3 El(+) –Me –Me The enolate R = Me (Chem 3D) Dominant Control element stereoelectronic stereoelectronic steric steric Based on above data, this case is reasonable: (58%) >90 : 10 (67%) 93 : 7 However diastereoselectivity depends stongly on O-protecting group LDA Ratio, >97 : 3 Ratio, >97 : 3 allyl-Br LDA LDA Ratio, 90 : 10 Ratio, 80 : 20 LDA Representative cases -78 °C Electrophile Ratio, E:A 84:16 87:13 In this case, both e and a paths are stereoelectronically equivalent. Diastereoselectivity is now determined by the differential steric effects encountered in the two TS‡s. a e El(+) El(+) Steric Effects E
D. A. Evans Enolate Alkylation: Unusual Cases Chem 206 Cases which do not appear to give the expected product based on sterically Expected Results: the analysis of steric effects \COmE LDA OMe BnBr 97% ds +-Bur COmE 8%ds COmE R= Me, Et, CO2Me ≥88:12 eebach. He/y. chim. Acta 1987. 70. 1194 Contrasteric relatives Seebach, Angew. Chem. Int Ed 1981, 20, 1030 Ladner, Angew. Chem. Int. Ed 1982, 21, 449 ■ However: Me(0、O2Me -Bu MeOD >95%ds COS-t-Bu Moc BnBr 60%ds acetone 95%ds Seebach. He/. Chim. Acta 1987. 70. 1194 HMe Me rati,80:20 OMe cO2Me70:30 The enolate(MM-2) >95:5 Here is another example of a contrasteric alkylation HO2C LDA, conditions Ladner,chem.Ber.1983.116,3413-3426. (+)-menthyl-O2C CO2R Those factors defining olefin face selection are currently being defined: Would you have predicted the outcome of the following conditions reaction? R-CI THF,23℃80:20 +H-menthol R-Br THF-HMPA 0298 >94:6 78+20°C CMe2 K Yamada, Organic Synthesis Past Present, and Future, p 52 Danishefsky J. Org. Chem. 1991, 56, 387
Cases which do not appear to give the expected product based on the analysis of steric effects R Me CO2Me Me O O O O R C3H5 H CO2Me Me Me O N t-Bu O H OLi OMe O Me O CO2Me Me CO2Me Me Me H CO2Me O CO2Me O OH Me Me Me MeO2C Me O O O O MeMe H HO2C (+)-menthyl–O2C Me X HO2C Me CO2R CO2R Me HO2C OH Me CMe2 S-t-Bu OLi t-Bu O O O t-Bu O OLi OMe Me Me OMe OLi t-Bu O O Me O OSiR3 R3SiO EtO Li R-Br R-Cl X THF-HMPA -78®-20 °C MeI MeI BnBr MeI BzCl HgI2 OSiR3 OSiR3 EtO2C Me Me O O t-Bu CO2Me Me Me CO2Me Me t-Bu O O R CO2Me O H N t-Bu O R O O t-Bu COS-t-Bu Here is another example of a contrasteric alkylation K. Yamada, Organic Synthesis Past Present, and Future, p 525 (+)-menthol 02:98 THF, 23 °C 80:20 conditions Ratio LDA, conditions ratio, 80 : 20 acetone LDA ■ However: Ladner, Angew. Chem. Int. Ed 1982, 21, 449 LDA R = Me, Et, CO2Me Seebach, Angew. Chem. Int. Ed 1981, 20, 1030 allyl-Br 88 : 12 D. A. Evans Enolate Alkylation: Unusual Cases Chem 206 The enolate (MM-2) Ladner, Chem. Ber. 1983, 116, 3413-3426. Seebach, Helv. Chim. Acta 1987, 70, 1194. Seebach, Helv. Chim. Acta 1987, 70, 1194. >95 : 5 70 : 30 >95%ds 60% ds 95%ds MeOD BnBr acetone 97% ds >98% ds >95% ds Sterically Expected Results: Contrasteric relatives: Danishefsky J. Org. Chem. 1991, 56, 387 >94 : 6 Those factors defining olefin face selection are currently being defined: Would you have predicted the outcome of the following reaction?
D. A. Evans Chiral Enolate Enolate Alkylation Circa 1978 Chem 206 Chiral Enolate Design Requirements Circa 1978 a Enolization selectivity: Amide-based controllers Xc limited by enolization selectivity(Lecture 22 Overall enantioselection will be the sum total of the defects introduced through LM-N Enolization Enolate-electrophile face selectivity a Racemization attendant with Xc removal H Base Ratio, (E(2 disfavored favored r enolization S-BuLi(THF) 25: 75 Amide based chiral auxiliaries Li E+) 0 CH2OH M-0 0 CH2OH hydrolysi E With Takacs Tetrahedron Lett. 1980. 4233 diastereoselection Ca 95 Allylic Strain controls Enolate Geometry Enolization selectivity: Ester-based chiral controllers Xc limited by enolization selectivity (Lecture 22) ongly OCH: R strongly LM-NR2 RX H Allylic Strain Prevents Product Enolization: Base R-Substituent Ratio, (E): 2) 95:5 LDA (THF) -S-t-Bu strongly O-CHNAIR strongly favored R r disfavored
N R R H H N Li MeO Et Et N R R H Me N Li O H Et Et O O O O C El Me H C H Me H N R R N R R C H El Me C H H Me N R R N R R RX O Me XC R O RO R O El -S-t-Bu OLi RX Me XC R OM XC R O El RX Me OLi s-BuLi (THF) N O Et Me Et Me N O CH2OH 2 LiNR2 O N M O Me Li OLi N Me Et Et N Me OLi Et Et Me N O CH2OH El D. A. Evans Chiral Enolate Enolate Alkylation Circa 1978 Chem 206 Chiral Enolate Design Requirements Circa 1978 El(+) enolization hydrolysis ■ Enolization selectivity ■ Enolate-electrophile face selectivity ■ Racemization attendant with Xc removal Overall enantioselection will be the sum total of the defects introduced through: ■ Enolization selectivity: Ester-based chiral controllers XC limited by enolization selectivity (Lecture 22) 25 : 75 LDA (THF) 0 : 100 Base Ratio, (E):(Z) (E) (Z) + LDA (THF) 95 : 5 LDA (THF) Base -OMe, O-t-Bu 95 : 5 R-Substituent Ratio, (E):(Z) LM–NR2 (E) (Z) + ■ Enolization selectivity: Amide-based controllers XC limited by enolization selectivity (Lecture 22) LM–NR2 ‡ ‡ disfavored favored El(+) With Takacs,Tetrahedron Lett. 1980, 4233 diastereoselection Ca 95 % ■ Amide Based Chiral Auxiliaries Allylic Strain Prevents Product Enolization: strongly favored strongly disfavored Allylic Strain controls Enolate Geometry: strongly favored strongly disfavored
D. A. Evans Enolate Alkylation: Chiral Amide Enolates Chem 206 hiral amide enolates Amide Hydrolysis HOH,c O M-NR2 R-X Evans. Takacs intramoleclar general base catalysis Tet.Lett1980,21,42334236 Br964(98%) Me Br98:2(84%) Applications in lonomycin synthesis Chem 3D model lonomycin Calcium Complex Meho Mel JAcS1990,112,52905313 OH Me?HC 84% The nature of enolate chelation is ambiguous. Nitrogen chelation is a real possibility Me?Hc PhCH=CHCH2 Br diastereoselection 99: 1 o CH2OH OH Me 83% Myers, JACS 1997, 119, 6496 diastereoselection 97: 3
Ph Me I Ph N O Me Me CH2OH Me R O H2N O Me2HC O O N O Me Li Me N O O O Me2HC + 14 12 14 HOH2C O Me N M-NR2 O M Me N Li O R–X R–X Br Br Me Me Li N Me OH Me Me O R–X R HOH2C O Me N R N Me HOH2C O Li Li Me R OH O O CH2OH N R Me H + PhCH=CHCH2Br N O C O H H H R O H O N R HO H2O H Me H Me OH Me O O Me Me Me O Me OH OH Me O Me O O Me Ca Ph Me N O O O Me2HC O HN O R Me Me N Li O O K 14 14 JACS 1990, 112, 5290-5313 Applications in Ionomycin synthesis HCO3 - H2O, 5 min Amide Hydrolysis intramoleclar general base catalysis 1 9 17 Ionomycin Calcium Complex 14 12 83% 84% 14 LDA diastereoselection 97:3 diastereoselection 99:1 Chiral Amide Enolates Evans, Takacs, Tet. Lett. 1980, 21, 4233-4236 Chem 3D model 98:2 (84%) (minor) (major) 96:4 (98%) D. A. Evans Enolate Alkylation: Chiral Amide Enolates Chem 206 The nature of enolate chelation is ambiguous. Nitrogen chelation is a real possibility. Myers, JACS 1997, 119, 6496
D.A. Evans Enolate Alkylation: Chiral Imide Enolates Chem 206 灿xpe0- Enolate amination TrisVl-N ACS1987,109,6881 HOAC JACs1990,112,40124030 or NaNTM diastereoselection 91-99+% enolization selectivity >100:1 M=Lil BocN=NBoc JAcS1986,108,3695 CHMe 2 Tet1988,44,552540 Alkyl Halide BocHNNBoc 50-120 O-2N3 selection 97-99*% M=Li,THF≤0°C CH2C=CHCH2 Br (Trisyl-N3) CHMe2 M=Na,TH-78to0°C 50:1 CH3I 13:1Enolate Hydroxylation Enolate Acylation JAcS.1982.104.1737 00 00 PhHC—NSO2F Na-N(TMS 0JAcs1984106.1154 Imide( r) RatioYield Diastereoselection -97:3 Na enolate is required PhCH2- 94:686% CH2=CHCH 95 91% MeO2 CCH2 CH2 CH2 96:468% 90:1077% New stereocenter not lost 194% through enolization JACS X-ray structure For all indicated rxns, as the R on the enolate grp increases in size enolate-El face selectivity increases. Explain
Me N O O O Me2CH R1 R2 R O N O O M O O N O R Me Ph Me2CH R O N O O M N O O O Me2CH Et Me O CH3I CH3CH2I ArCH2Br ArCH2OCH2Br CH2C=CHCH2Br R XC O El El O XC R SO2N3 CHMe2 CHMe2 Me2HC R N O O O Me Ph N O R O O Bn M BocN=NBoc O PhHC NSO2Ph N O R O O Bn BocHNNBoc N3 Bn O O R N O R Cl O Me3CMeO2CCH2CH2CH2- PhCH2- Na-N(TMS)2 CH2=CHCH2- Li–NR2 Me Ph O N O O R OH For all indicated rxns, as the R on the enolate grp increases in size enolate-El face selectivity increases. Explain. D. A. Evans Enolate Alkylation: Chiral Imide Enolates Chem 206 El(+) Alkyl Halide 50-120 : 1 Ratio 50 : 1 50 : 1 25 : 1 13 : 1 M = Li, THF 100:1 Alkali Metal enolates: marginal reaction Enolate Hydroxylation 94 : 6 Enolate Amination Yield Imide (R) Ratio * PhJACS. 1985,107, 4346. 86 % 91 % 68 % 77 % 94 % 95 : 5 96 : 4 90 : 10 >99 : 1 Na enolate is required. Why? Trisyl-N3 JACS 1987,109, 6881. HOAc diastereoselection 91-99+ % diastereoselection 97-99+ % JACS 1986,108, 3695. M = K M = Li JACS 1990,112, 4012-4030 (Trisyl-N3 ) Tet. 1988, 44, 5525-40 Diastereoselection ~ 97 : 3 JACS 1984, 106, 1154. Enolate Acylation New stereocenter not lost through enolization authentic X-ray structure
D. A. Evans Enolate Alkylation: Chiral Ester Enolates Chem 206 Chiral Ester Enolates Helmchen, Angew. Chem. Int Ed. 1981, 20, 207-208 Chiral B-Keto Ester Enolates CO2t-Bu LICHIP ( LICHIPA) THF. HMPA Me?HC NH o Me? N o OMe SOpH toluene Me?HC HMPT H Lio Me the steacie tea eto e of pe c (El-enolate (z-enolate El(+) addend Yield RatIo(A: B) Me- THF 63% 96: 04 Me、Meso2Ph Me so,Ph Koga,JACS1984.10627182719 Me- HMPT57%0199 THF 48%99:01 HMPT 77%15:85 Chiral B-Keto Ester Dienolates 旧nC14H2g98515 (4) n-C14H29- 06 94 enolate contamination Helmchen, Angew. Chem. Int Ed. 1984, 23, 60-61 Me Me ou En,CN Major diastereomer Helmchen Tet. Lett. 1983. 24. 1235-1238 Helmchen Tet. Lett. 1983. 24. 3213-3216 t-BuLi E什+)=Me-,E+,BnBr SOpH Me. Me so PhH astereoselection 98% △ Rationalize the stereochemical outcome of reaction Rato,93:7(74%) Helmchen. Tet. Lett. 1985. 26. 3319-3322 Schlessinger, Tet. Lett. 1988, 29, 1489-1492
Li N Me Me (LiCHIPA) THF N H SO2Ph O LiO Me Me Me Me Me H Me SO2Ph N O O Me Me Me Me Me R H LiCHIPA O Me Me Me Me Me LiO Me N SO2Ph H H El SO2Ph N X O O Me Me Me Me H H O Me Me Me Me Me O N SO2Ph Br NH OMe Me2HC O CO2t-Bu H El O Me Me Me O N X SO2Ph Me KO-t-Bu Me2HC N O OMe Li O RO H O Me Me Me O N X SO2Ph H H THF CO2t-Bu Me2HC N O OMe El HMPT Me–I Me–I OLi Me Me Me N O A El N OMe Me2HC O CO2t-Bu Bn-Br THF Bn-Br HMPT t-BuLi THF B O N Me Me Me O HMPT O Me Me Me N O Me D. A. Evans Enolate Alkylation: Chiral Ester Enolates Chem 206 Koga, JACS 1984, 106, 2718-2719 Chiral Ester Enolates THF, HMPA 4:1 Helmchen, Angew. Chem. Int.Ed. 1981, 20, 207-208 (E)-enolate (Z)-enolate (E) enolate El(+) Ratio n-C14H29–I 98.5:1.5 (Z) n-C14H29–I 06:94 enolate contamination Helmchen, Angew. Chem. Int.Ed. 1984, 23, 60-61 Helmchen,Tet. Lett. 1983, 24, 1235-1238 Helmchen,Tet. Lett. 1983, 24, 3213-3216 Helmchen,Tet. Lett. 1985, 26, 3319-3322 Ratio, 93:7 (74%) Chiral b-Keto Ester Enolates LDA toluene 01:99 El(+) Yield Ratio (A:B) 63% addend 57% 96:04 99:01 77% 48% 15:85 Rationalize the effect of HMPA on the stereochemical outcome of reaction. Chiral b-Keto Ester Dienolates Major diastereomer El(+) El(+) El(+) E(+) = Me–I, Et–I, Bn–Br diastereoselection 98% Rationalize the stereochemical outcome of reaction. Schlessinger,Tet. Lett. 1988, 29, 1489-1492
