http://www.courses.fas.harvard.edu/~chem206/ R R OM R R NM R X Me Me A X Me Me B Chem 206D. A. Evans Matthew D. Shair Monday, November 11, 2002 a73 Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7Carbanions & Other Nucleophilic Carbon Species Enolates & Metalloenamines-2 Carey & Sundberg: Part B; Chapter 2Reactions of Carbon Nucleophiles with Carbonyl Compounds a73 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) a73 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. 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). a73 Introduction and General Trends a73 Enolate Alkylation: Electronic & Steric Control Elements a73 Enolate Alkylation: Unusual Cases a73 Chiral Amide Enolates a73 Chiral Ester Enolates a73 Chiral Imide Enolates a73 Chiral Metalloenamines Explain why A is favored for X = O while B is favored for X = NNHR base X Decreasing Nucleophilicity De cre asi ng El ect rop hil icit y C C OMe C C NR2 C C O C C NR NR 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 RMetal CH2N Li I Me Me Li-NR2 Li-NR2 OLi N RMetal NR N Me Enols, Enolates, Enamines & Metalloenamines: Reactivity Hierarchy Chem 206D. A. Evans Nucleophile Electrophile Br2, O3 + + + + +++ + + + +++ + + ++ + + + + + – – a73 Metalloenamines: Imines may be transformed into their conjugate bases (enolate counterparts) with strong bases: The usual bases employed are either lithium amides (LDA) or Grignardreagents. 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. a73 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. a73 Nature uses enamines, "stabilized" enolates, and enol derivatives in C–C bond constructions extensively. pKa~ 29-33 syn relationship En erg y Rxn Coordinate O– O O–El O El Me C O Cl BMe I A O– B O A Carey & Sundberg: Part A; Chapter 4, pp217-220for discussion of Hammond's Postulate H + Based upon the above discussion draw a detailed mechanism for the protonation of cyclohexanone enolate. a73 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 ?H° > 20 kcal/mol T? a73 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." a73 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 C/O Rxn RatioEl(+) El(+) :– a73 "As electrophile reactivity increases, the percentage of reaction at the enolate oxygen increases." For example, consider the reactions of cyclo- hexanone 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: C versus O Enolate Reactivity & the Hammond Postulate Chem 206D. A. Evans Hammond, JACS 1955, 77, 334 See Hine in Advances in Phys. Org. Chem. 1977, 15, 1-61 N Boc O Me C COR H R HM OM C H RC R ElHMe 3C OR C COR RHM El C COR El R HM Me3C H R O El El O Me3C H R C C OLiR H Me3C NO H H Me H O RO O MeOH H H Me OO Li CO2Me Me-I Li Me CD3I R–X Me-I N C C HLiO Me HBoc R–X N Boc O Me R R–X Allyl–Br Bn–Br LiO MeOH H HR H O MeOH H HR H Me NO H R Me H O RO Me-I path A a73 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 Ratio, a:eElectrophileR-substituent twist boat conformation chair conformation ? e eEl(+) El(+) Issue: Degree of rehybridization in TS?? a73 Alkylation: Forming C–El bond must overlap with pi? C–O in TS? a73 Enolization: Breaking C–H bond must overlap with pi? 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 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 HMe H O OPh3COCH2 C3H5 Me Me CO2Me CO2MeMe Me Me-I n-Bu-Br CO2Me El Me3C H A Li R Me LiO H O Me R Me CN O H HO CO 2Me MeOTHP –H –H R NaH Me-I Me-I LiNH2 R HEl MeO Et-I Et-I CD3I CD3I NC H O Me Me OTHPMe CO2Me O H Me O ElMe H R Chem 206Enolate Alkylation: Steric Control ElementsD. A. Evans 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) DominantControl 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 : 3allyl-BrLDA LDA Ratio, 90 : 10 Ratio, 80 : 20LDA 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 Cases which do not appear to give the expected product based on the analysis of steric effects RMe CO2MeMe O O O O R C3H5 H CO2Me Me Me O Nt-Bu O H OLi OMe O OMe 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 CO 2R CO2R Me HO2C OH Me CMe2 S-t-Bu OLi t-Bu O O O Ot-Bu 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 BnBrMeI BzCl HgI2 OSiR3 OSiR3 EtO2C Me Me O Ot-Bu CO2Me Me CO2MeMe Me t-Bu O O R CO2Me HO Nt-Bu O R O Ot-Bu COS-t-Bu Here is another example of a contrasteric alkylation K. Yamada, Organic Synthesis Past Present, and Future, p 525 (+)-menthol 02:9880:20 THF, 23 °C Ratioconditions LDA, conditions ratio, 80 : 20 acetone LDA a73 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 Chem 206Enolate Alkylation: Unusual CasesD. A. Evans 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%ds60% ds 95%ds MeODBnBr 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? NR R H H N Li OMe Et Et NR R H Me N Li O H Et Et O O O O C El Me H C H Me H N RR N RR C H El Me C H H Me N RR N RR 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 MeEt Et Me N O CH2OH 2 LiNR 2 O N OM Me Li OLi N Me Et Et N Me OLi Et Et Me N O CH2OH El Chem 206Chiral Enolate Enolate Alkylation Circa 1978D. A. Evans Chiral Enolate Design Requirements Circa 1978 El(+) enolization hydrolysis a73 Enolization selectivity a73 Enolate-electrophile face selectivity a73 Racemization attendant with Xc removal Overall enantioselection will be the sum total of the defects introduced through: a73 Enolization selectivity: Ester-based chiral controllers XC limited by enolization selectivity (Lecture 22) 25 : 75 0 : 100LDA (THF) Base Ratio, (E):(Z) (E) (Z) + 95 : 5LDA (THF) LDA (THF) Base 95 : 5-OMe, O-t-Bu Ratio, (E):(Z)R-Substituent LM–NR2 (E) (Z) + a73 Enolization selectivity: Amide-based controllers XC limited by enolization selectivity (Lecture 22) LM–NR2 ? ? favoreddisfavored El(+) With Takacs,Tetrahedron Lett. 1980, 4233 diastereoselection Ca 95 % a73 Amide Based Chiral Auxiliaries Allylic Strain Prevents Product Enolization: strongly favored strongly disfavored Allylic Strain controls Enolate Geometry: strongly favored strongly disfavored Ph Me IPh N O MeMe CH2OH Me R O H2N O Me2HC OO N OMe Li Me N O O O Me2HC + 14 12 14 HOH2C O Me N M-NR2 O M MeN Li O R–X R–X Br BrMe Me Li N Me OH Me Me O R–X R HOH2C O MeN R N Me OHOH2C Li Li Me R OH O CH2OHO NR Me H+ PhCH=CHCH2Br N OC O H H H R OH O N R HO H2O H Me H MeOH MeOO MeMeMe O Me OH OHMe O Me O O Me Ca Ph Me N O O O Me2HC O HN OR Me Me N OLiO 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 1214 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%) Chem 206Enolate Alkylation: Chiral Amide EnolatesD. A. Evans The nature of enolate chelation is ambiguous. Nitrogen chelation is a real possibility. Myers, JACS 1997, 119, 6496 Me N O O O Me2CH R1 R2 R O N O O MO O N OR PhMe Me2CH R O N O O M N O OO Me2CH Et Me O CH3I CH3CH2I ArCH2Br ArCH2OCH2Br CH2C=CHCH2Br R X C O El El O XCR SO2N3 CHMe2 CHMe2 Me2HC R N O O O Me Ph N OR O O Bn M BocN=NBoc O PhHC NSO2Ph N OR O O BnNBocBocHN N3 Bn OO R N O R Cl O Me3C- MeO2CCH2CH2CH2- PhCH2- Na-N(TMS)2 CH2=CHCH2- Li–NR2 PhMe 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. Chem 206Enolate Alkylation: Chiral Imide EnolatesD. A. Evans El(+) Alkyl Halide 50-120 : 1 Ratio 50 : 1 50 : 1 25 : 1 13 : 1 M = Li, THF < 0 °C M = Na, THF -78 to 0 °C JACS. 1982,104, 1737. El(+) LDA or NaNTMS2 enolization selectivity >100:1 Alkali Metal enolates: marginal reaction Enolate Hydroxylation 94 : 6 Enolate Amination Yield *RatioImide (R) Ph- JACS. 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 authenticX-ray structure 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 OMe2HC CO2t-Bu H El O Me Me Me O N X SO2Ph Me KO-t-Bu Me2HC N O OMe Li ORO 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 ElN OMe OMe2HC CO2t-Bu Bn-Br THF Bn-Br HMPT t-BuLi THF B ON MeMe 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, HMPA4:1 Helmchen, Angew. Chem. Int.Ed. 1981, 20, 207-208 (E)-enolate (Z)-enolate (E) enolate El(+) Ratio 98.5:1.5n-C14H29–I n-C14H29–I 06:94(Z) 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 β-Keto Ester Enolates LDA toluene 01:99 Ratio (A:B)El(+) Yield 63% addend 57% 96:04 99:01 77% 48% 15:85 Rationalize the effect of HMPA on the stereochemical outcome of reaction. Chiral β-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 CO2Me Me RO2C O O H EtO Me O n-C4H9 OTs H EtO O n-C4H9 H Br LiNR2 LiNR2 MeI LiNR2 Hn-C4H9 O Me EtO EtO MeO n-C4H9 H H O O RO2C Me CO2Me H NN Me O Bn S Boc S Me3Si OBn Ph O OMPh OMeMe3Si R LiNR2 Sn(OTf)2 Me–CHO O OMeMe OLi O-t-BuR CO2Et I H CH2 TBSOCH2 Me CO2Me CO2Me Me TBSOCH2 H CH2 H Me Me PhMe2Si OEt R OOMR OEtPhMe2Si (MeS)3C–Li KOt-Bu Me–I R–CHO MeI LiNR2 MeI NH4Cl OMe OMe MeSMeS MeMeS OPh OBnMe3Si Me H OH H H CO 2Et CO2-t-Bu R S N Boc N SBn OMe OHR H R Me3Si OMe Ph O Allylic Strain & Enolate Diastereoface SelectionD. A. Evans Chem 206 Y. Yamaguchi & Co-workers, Tetrahedron Letters 1985, 26,1723. R = Me: > 15 :1 R = H: one isomer THF -78 °C diastereoselection 90:10 at C3 one isomer at C2 71% yield I. Fleming & Co-workers, Chem. Commun. 1986, 1198. 86% diastereoselection 99:1 K. Koga & Co-workers, Tetrahedron Letters 1985, 26, 3031. T. Mukaiyama & Co-workers, Chem. Letters 1986, 637 diastereoselection >95% 91-95% Y. Yamamoto & Co-workers, Chem. Commun. 1984, 904. major diastereomer opposite to that shown40:60 80:20 87:13 R = CHMe2 R = Et R = Me R-substituent diastereoselection I. Fleming & Co-workers, Chem. Commun. 1985, 318. R = Ph: diastereoselection 97:3 R = Me: diastereoselection 99:1 I. Fleming & Co-workers, Chem. Commun. 1984, 28. D. Kim & Co-workers, Tetrahedron Lett. 1986, 27, 943. diastereoselection 98:2 G. Stork & Co-workers, Tetrahedron Lett. 1987, 28, 2088. "one isomer" 95% yield "one isomer" T. Money & Co-workers, Chem. Commun. 1986, 288. diastereoselection 89:11 N R Me N Et–MgCl N R Me N CMe3 N RM NR M N R El El NR Me N R Me Me N R N Me Bn–Br Et–MgCl ? H3O+ Et–MgCl n-Bu–Br Me2CH–I H3O+ H3O+ H3O+ H3O+ Me Me N Me –NMe2 R R Bu O Bn Me O Me Me O Me H O Me Me s-BuLi s-BuLi s-BuLi s-BuLi H3O+ O MeBu Bn Me O Me Me O MeMe + 1 equiv HMPA 100:0–cyclohexyl ratio –cyclohexyl 74:26 base base 100:0 base 10:90–cyclohexyl ratio +Me–I base a73 Nature of N-substituent, base, and solvent additive can play a role in deprotonation regioselectivity: Hosomi, JACS, 1982, 104, 2081-2082 Stork & Dowd, JACS, 1963, 85, 2178-2180 Me–I 83% overall 60% overall 60% overallconditions: base + R-X in refluxing THF a73 Representative Reactions: nonbonding N-lone pair may be stabilized by delocalizatin into antibonding orbital of C=C. Remember, (Z) geometry also favored for enol ethers a73 Geometry Rationalization: a73 Seminal Paper: Stork & Dowd, JACS, 1963, 85, 2178-2180 Enders in Asymmetric Synthesis, 1984; Vol 3, Chapter 4, pp 275-339 a203 Anion geometry is (Z)a203 For M = Li, anion is delocalized rather than localized as pictured Collum, JACS 1993, 115, 789-790Collum, JACS 1986, 108, 3415-3422 Collum, JACS 1985, 107, 2078-2082 X-ray structure reveals the following: Collum, JACS 1984, 106, 4865-4869 a73 Solid State & Solution Structure: a73 Generation & Structure: Fraser, Chem. Commun. 1979, 47 Fraser, JACS 1978, 100, 7999Kinetic product geometry strongly favors the syn isomer (>99%) (Fraser) (E) anion (Z) anion El(+) anti product syn productEl(+) The base: R–Li; RMgX; R 2N–Li base Bregbreiter in Asymmetric Synthesis, 1983; Vol 2, Chapter 9, pp 243-273 Whitesell Synthesis, 1983, 517-535 Martin in Comprehensive Organic Synthesis, 1991; Vol 2, Chapter 1.16, pp 475-502 a73 Reviews: D. A. Evans Metalloenamines-1 Chem 206 Acidity Measurements: (Streitwiser, JOC 1991, 56, 1989; Fraser, ibid. 1985, 50, 3234): pKa~ 29-33 N Bn CMe3 H NBn Me3C H Me MeI CMe3 N BnLi MeI MeHMe 3C XH Me H MeHMe 3C XH Me H H X Me3C H Me HHMe 3C XMe N R1 O R2 N N CH2OMe MeO BnN CMe3 NNMe2 CN CN NNMe2Me H Me H Me3C H Me NC NNMe2 MeMe 3C H NNMe2 Me H NNMe2Me H Me Me H Me NNMe2 H MeI X MeI R–X O R2 R1N M H3O+ Et–I Me–I R–X n-Pr–I CH2OMe NN R El O N R El Enders in Asymmetric Synthesis, 1984; Vol 3, Chapter 4, pp 275-339 LDA Chiral Metallated Hydrazones Meyers, J. Am. Chem. Soc 1981, 103, 3081 LDA El(+) full papers: Meyers, J. Am. Chem. Soc 1981, 103, 3088 Meyers, J. Am. Chem. Soc 1981, 103, 3081 Meyers, J. Org. Chem 1978, 43, 892 Meyers, J. Am. Chem. Soc 1976, 98, 3032 Whitesell, J. Org. Chem. 1978, 42, 377-378early papers: Major Product El(+) Ratio, 90:10 LDA Chem 206Metalloenamines-2D. A. Evans Chiral Metalloenamines: base The base: R–Li; RMgX; R 2N–Li Stereoelectronic Issues: LDA Ratio, 97:3 Fraser, JACS 1978, 100, 7999 Tendency for axial-chair alkylation is significantly greater that for ketones LDA Ratio 94:06X = N-Bn X = O 60:40 Fraser, JACS 1978, 100, 7999 87 ee 94 99Collum, JACS 1984, 106, 4865-4869 LDA N H Li N Me Me N H Li D. A. Evans, K. Scheidt Chem 206Metalloenamine X-ray Structures Collum & Clardy, JACS 1984, 106, 4865 LI LI LI LI LI LILi N N CH2OMe N RN Li RH O Me A (Enders) N NLi OMe R–X N RN Li RH O Me B NN R MeO Li Li D. A. Evans Chem 206SAMP-Metalloenamine X-ray Structure For a review of this methodology see Enders, D. in Asymmetric Synthesis.; Morrison, J. D., Ed.; AP: New York, 1984; Vol. 3, p 275-339. diastereotopic face attacked by El(+) LDA Chiral Metallated Hydrazones THF deleted Which of the reactive chelate conformations are we to begin our analysis from? diastereotopic face attacked by El(+)