哈佛大学：《高等有机化学》（英文版）Lecture 23 A Enolate Acylation

Chemistry 206 Advanced Organic Chemistry Handout-23A Enolate Acylation Matthew d. shair Monday November 11. 2002

Chemistry 206 Advanced Organic Chemistry Handout–23A Enolate Acylation Matthew D. Shair Monday , November 11, 2002

D. A. Evans Enolate Acylation Acylation Carboxylation Chem 206 The Reaction: OM Deacylation: When an acyl residue is employed in the one of the illustrated bond constructions, it may then be removed by R nucleophilic deacylation: Several examples are provided R2 Deformylation Carboalkoxylation Situations where the reaction is employ i competitive ring cleavage not a problem due to more electrophilic formyl C=O a Acyl moiety is a constituent of the target structure Decarboxylation Alkyl-Oxygen Cleavage: tert-butyl esters R R2 CO2--Bu R-Br R OR3 R2 R2 L Acyl moiety employed in assisting bond construction but not part of the target structure ion in this system is a sigmatropic rearrangement involving +R-x presentative procedure: Henderson, Synthesis 1983, 996 a Alkyl-Oxygen Cleavage: Methyl esters → R COz-Me Co2-CO2 R=H leading references Tet let1990.31.14014 H23-01-Acylation Intro 11/5/008: 20 PM

Tet Let. 1990, 31, 1401-4 JOC. 1991, 56, 5301-7 D. A. Evans Enolate Acylation Acylation & Carboxylation Chem 206 The Reaction: Acylation + Carboalkoxylation + Situations where the reaction is employed: ■ Acyl moiety is a constituent of the target structure: + + (–) (+) (–) (+) ■ Acyl moiety employed in assisting bond construction but not part of the target structure: + R–X Deacylation: When an acyl residue is employed in the one of the illustrated bond constructions, it may then be removed by nucleophilic deacylation: Several examples are provided. Deformylation: HCO3 – competitive ring cleavage not a problem due to more electrophilic formyl C=O Decarboxylation in this system is a sigmatropic rearrangement involving C=O participation Decarboxylation: ■ Alkyl-Oxygen Cleavage: tert-butyl esters NaH, DMF R–Br CF3CO2H ∆ –CO2 representative procedure: Henderson, Synthesis 1983, 996 ■ Alkyl-Oxygen Cleavage: Methyl esters Li–I/H2O ∆ H3O+ CO2 R = H HO– Acylketene intermediate leading references OM R1 R2 X R3 O R2 R1 O R3 O O OR3 O R1 R2 O X OR3 R2 R1 OM R2 R1 OH OR3 O O OR3 O R1 R2 R2 R1 O X OR3 O O O OR3 O H R2 R1 X O R R H O O O O Me CO2Me CO2Me Me O Me R2 CO2Me R1 O OR3 O O Me Me Me Me O O Me CO2Me Me O CHO O Me Me Me Me O O CO2-t-Bu CO2-t-Bu O R R O O O O H H O R O CO2-Me Me N Me CO2 – O R O R O O– OR C O O H23-01-Acylation Intro 11/5/00 8:20 PM

D. A. Evans Claisen Condensation Related Processes Chem 206 Claisen Condensation: Condensation of 2 esters I Analysis of the two processes i Conventional Carbomethoxylation: Equilibrium achieved between all species oR+ COmE Intramolecular Variant: Dieckmann Condensation CO,Me RO Keg -10 MeoH COmE Me2CO3 ly speaking, the Claisen and Dieckmann condensations are defined as condensations discussion, we choose to liberalize the classifcation to include ketone enolates as well. I a Reaction Thermodynamics: Overall Keq -1 with aromatic ring disrupting the required planarity of the delo by peri-interaction Critical issue: Product enolate a is significantly destabi eater stability of B dictates the product. RO I Final enolization Step: Keq -10 COmE L This type of control is general rOH 2Et pKa 12 pKa 16 HCO2Et Me Me Reaction Control Elements: These reactions can be manipulated to give Meyers, JOC 1976, 41, 1976 either kinetic or thermodynamic control HCO2Et kinetic product Piers. Tet. Let 1968. 583 HCODEt hermodynamic MeO OM H23-02-Claisen Condensation 11/5/00 8: 17 PM

LDA D. A. Evans Claisen Condensation & Related Processes Chem 206 ■ Claisen Condensation: Condensation of 2 esters + RO– H3O+ ■ Intramolecular Variant: Dieckmann Condensation H3O+ RO– Strictly speaking, the Claisen and Dieckmann condensations are defined as condensations between ester enolates & ester electrophiles. In this discussion, we choose to liberalize the classifcation to include ketone enolates as well. ■ Reaction Thermodynamics: Overall Keq ~ 1 RO– + 2 + RO + – + ROH ■ Final enolization Step: Keq ~ 10+4 Contrary to popular belief, final enolization step does not render the process irreversible pKa 12 pKa 16 Reaction Control Elements: NaH kinetic product Thermodynamic product -78 °C 0 °C ■ Analysis of the two processes: Conventional Carbomethoxylation: Equilibrium achieved between all species Me2CO3 + MeO– + MeOH Keq ~ 10-2 Keq ~ 10+4 Me2CO3 Keq > 10+4 Critical issue: Product enolate A is significantly destabilized by peri-interaction with aromatic ring disrupting the required planarity of the delocalized enolate. Hence, the greater stability of B dictates the product. A B Keq >> 1 A B ■ This type of control is general: HCO2Et KOtBu Meyers, JOC 1976, 41, 1976 Piers, Tet. Let 1968, 583 MeO– HCO2Et benzene benzene HCO2Et MeO– JACS 1965, 87, 5728 These reactions can be manipulated to give either kinetic or thermodynamic control: CO2Me R Me CO2Me OR O O OR R O OR O R R O Me CO2Me R R O OR O R R O OR R O OR O O OR O– R R O NC OMe O O CO2Me O MeO OMe CO2Me O Me CO2Et O OH Me Me OH O CO2Et Me O– O CO2Me CO2Me O– O– CO2Me O O– CO2Me O– MeO O H CO2Me O– O Me O Me Me O Me O Me Me OH RO– H23-02-Claisen Condensation 11/5/00 8:17 PM

D. A. Evans Kinetic Enolate Acylation: The Mander Reagent Chem 206 a Kinetic Acylation: Methyl Cyanoformate (1): a The Tetrahedral Intermediate 2; Why is it so stable? 78°c Me 2 LCN Enolate acylation with 1 is fast Intermediate 2 breaks down to product Consider this in the broader context of elimination reactions more slowly than the acylation step of the elcb classification where Under these conditions, proton transfer ither c or some heteroatom from product to enolate does not occur X might ous leaving groups such as CN, OR etc. OMe slow +X les: o Co, Me 84% I Data is available for the case where x= CN, or&Y= carbanion Stirling, Chem. Commun. 1975. 940-941 CO2 Me 65% FG base CFG 一 FG COmE leaving grp pKa log OTMS Mander Tet. Lett. 1983. 24. 5425 Me-Li H CO,Me CMe Mander, SynLett. 1990, 169 Above data makes the point that CN is a poor LG but it also leads one to the faulty conclusion that 2 should partition to acyl cyanide rather than methyl ester! R2Cu(CN Hashimoto, chem Lett. 1989. 1063 R2 LICN H23-03-Mander Reagent 11/5/00 8: 21 PM

-78 °C fast D. A. Evans Kinetic Enolate Acylation: The Mander Reagent Chem 206 ■ Kinetic Acylation: Methyl Cyanoformate (1): + slow + LiCN 1 Enolate acylation with 1 is fast Intermediate 2 breaks down to product more slowly than the acylation step 2 Under these conditions, proton transfer from product to enolate does not occur. Mander Tet. Lett. 1983, 24, 5425 ■ Examples: LDA 1 84% 1 LDA 65% 75% LDA 1 1 Me-Li + isomer 7% Mander, SynLett. 1990, 169 1 R2Cu(CN)2Li2 82% Hashimoto, Chem. Lett. 1989, 1063 ■ The Tetrahedral Intermediate 2; Why is it so stable? 2 slow + LiCN Consider this process in the broader context of elimination reactions of the E1cb classification where: Y might be either C or some heteroatom X might be various leaving groups such as CN, OR etc. base – slow + X– + X slow – – base Data is available for the case where X = CN, OR & Y = carbanion: Stirling, Chem. Commun. 1975, 940-941 leaving grp (X) pKa H–X log kX kOPh –OPh 10 1 –CN 9.5 <-7 –C(Me)2-NO2 ~10 <-9 –OMe 16 -3.9 + LiOMe 2 + LiCN Above data makes the point that CN is a poor LG but it also leads one to the faulty conclusion that 2 should partition to acyl cyanide rather than methyl ester! O Li O CN R1 OMe R2 R2 O R1 OMe O X FG H R FG X FG X Y Y R Y H X R R R2 R R O R1 OMe O CN Li O R1 OMe O R R2 2 O R1 CN O O O NC OMe O R2 O R1 OMe O CN Li CO2Me Me OTMS Me CMe3 Me3C H R1 OLi R2 O R1 OMe O R2 Me O Me CO2Me O Me O CO2Me O Me Me O Me CO2Me O OTBS O CO2Me H23-03-Mander Reagent 11/5/00 8:21 PM

J. L Leighton, D. A. Evans Carbon Acylation with N-Methoxy-N-methylamides Chem 206 Acylating agents can be desiged where the tetrahedral intermediate exhibits exceptional stability (OMe)2 人人 THF/Et2O o-MeHgo OMe-110°cto0°C esen and c. Heathcock R凵 d or R-MgBr H3O Bn OMe THF,0°c M. Angelastro, N. Peet and P Be R= Me, n-Bu, or Ph; yields >90% Jorg.chem1989,54,3913 Weinreb Tet. Lett 1981. 22. 3815 Nucleophiles: Me R1-M RyMe-R制 H3O R1 R2 OMe Acceptable Unacceptable R-Li, R-Mgx R--Li(MgX) R-ZnX& other colalent metal alkyls Enolates and Metalloenamines J. Org. Chem.1991,56.2911-2 choli other colalent metal enolates THF,-78°c DIBAL LiAIH4 LiB(R)3H Weak hydride reagents: NaBH 47% In excellent review on all aspects of Weinreb amide chem THF.-78°ctoR.T M. Sibi, Organic Preparations and Procedures Int, 1993, 25(1), 15-40 J. Org. Chem.198954,4229 i Hydride Reductions Representative Organometals OMe OMe OMe TBSO OTBS OTBS N OMe DIBAl-H LOMe THF,7895% MeMgBr e OMe THF,0°C OMe OMe OMe TBsO Several other examples reported. Prasad and L Liebeskind Evans and s. mill g. Chem1993,58471 Me oMe MeMe Me H23-04 Weinreb Amides-1 11/5/008: 22 PM

Acylating agents can be desiged where the tetrahedral intermediate exhibits exceptional stability: Chem 206 D. Evans and S. Miller J. Org. Chem. 1993, 58, 471. 95% THF, -78 °C DIBAl-H M. Angelastro, N. Peet and P. Bey J. Org. Chem. 1989, 54, 3913. THF, -78 °C 73% P. Thiesen and C. Heathcock J. Org. Chem. 1988, 53, 2374. THF/Et2O -110 °C to -80 °C 62% Several other examples reported. J. Prasad and L. Liebeskind Tetrahedron Lett. 1987, 28, 1857. THF, 0 °C 99% MeMgBr R-Li or R-MgBr THF, 0 °C R = Me, n-Bu, or Ph; yields > 90% J. L. Leighton, D. A. Evans Carbon Acylation with N-Methoxy￾N-methylamides Nu(-) H3O+ Weinreb Tet. Lett. 1981, 22, 3815. Nucleophiles: R–Li, R–MgX Acceptable DIBAL LiAlH4 LiB(R)3H Weak hydride reagents: NaBH4 Unacceptable R–ZnX & other colalent metal alkyls other colalent metal enolates An excellent review on all aspects of Weinreb amide chemistry: M. Sibi, Organic Preparations and Procedures Int., 1993, 25 (1), 15-40. Representative Organometals: H3O+ Hydride Reductions: R1–M H3O+ H3O+ R2–M W. Wipple, H. Reich J. Org. Chem. 1991, 56, 2911-2. THF, -78 °C THF, -78 °C to R. T. J. Org. Chem. 1989, 54, 4229. Enolates and Metalloenamines: 83% 47% R Li(MgX) RO OLi R' N O Me OMe LiN R Li Ar S O R' R O O CH2Li BrMg OEt N OMe O N MeO Me OLi R Me N OMe O N O Li Nu R N O Me OMe R Me Me R Nu O N O Me OTBS N O OMe Me Ar N O Me OTBS Me O O R1 Ar MeO2C N Me OR O OMe MeO2C P(OMe)2 OR O O Li P(OMe)2 O CbzHN N Me Bn O OMe CbzHN OEt Bn O Me N OMe Me OMe Me TBSO Me O2N OMe OMe Me O OMe OMe Me H OMe Me OMe Me TBSO Me O2N OMe OMe Me O OMe O t-Bu OLi O O t-Bu O R1 R2 O N O Me OMe OLi Me O O Me H23-04 Weinreb Amides-1 11/5/00 8:22 PM

JLLeghonD.AEvansCarbonAcyatonwithNMethoxy-Nmethyamides-2 Chem 206 The Rutamycin B Synthesis, H Ng, Ph D. Thesis, Harvard University, 1993 / NMe2 C1-C16 Subunit C17-C37 Subunit Problem is to control C=O reactivity on central D-fragment TESO OMOP 0 ESO Me Ho eCN-H2080% Et The Solution E2,78℃c PMBC Me CH2 MOP C-OMe Evans, Rieger, Jones, Kaldor, JOC, 1990, 55, 6260-6268 tetrahedral intel stable for h The X-206 Synthesis, S. L. Bender, Ph. D. Thesis, Harvard University, 1986 0A0°c 人人人 Evans, Bender, Moms J Am. Chem. Soc. 1988, 110, 2506 H23-05-Weinreb Amides-2 11/5/00 8: 25 PM

tetrahedral intermediate stable for hours at 0°C Problem is to control C=O reactivity on central D-fragment 35 21 28 30 F D 29 21 D F 17 28 Evans, Rieger, Jones, Kaldor, JOC, 1990, 55, 6260-6268 C28–C29 C20–C21 29 29 29 The Rutamycin B Synthesis, H. Ng, Ph. D. Thesis, Harvard University, 1993 Evans, Bender, Morris J. Am. Chem. Soc. 1988, 110, 2506. The Solution: Et2O, -78 °C LDA, 0 °C 83% The X-206 Synthesis, S. L. Bender, Ph. D. Thesis, Harvard University, 1986 MOP = 1 A 7 + 16 17 21 C1-C16 Subunit C17-C37 Subunit A B C D E F 1 7 15 21 27 35 A D F 35 27 F D E 12 15 21 27 30 35 7 11 11 1 J. L. Leighton, D. A. Evans Carbon Acylation with N-Methoxy￾N-methylamides-2 Chem 206 several steps 25 5 1 8 17 12 33 20 HF MeCN-H2O 80% 23 26 32 20 LDA 23 20 26 32 97% 26 20 26 32 80% 32 Me N Li NMe2 Me H Me Me Me OMOP Me O O O O X O Me OBn H Me Me N O NMe2 Me O H Et O H M Me O OH Me OH Me Me Me Et PMBO Me TESO O N Et OMe Me Et PMBO N H NMe2 Me Me O O Me O O H O Me OH O O Me OH Me TESO Me O O O O O O Me OH Me Me Me HO Et Me OH Me OH OH Me Me OH Me Me O OH Me Me OMe Me H Me OH Et O O O O OH OR O Me OR Me Me OR Me Me O H O O Me Me O OO O OH Me Me Me OH Me Me O Me OH OH OH O O Et OH Me H OH Me Me H Me H Li O Me Me H H Me H O Me HO Me OH Me HO Me Et H Me Et PMBO Me O H Me I Me O Me O Me Me O O H H Me Me Me CH2 N Me O O N Me NMe2 MeO OMOP H Me H Me Me Me CH2 O Li O O N Me NMe2 MeN OMOP H Me H Me Me Me CH2 O O O OMOP O H Me Et Me H Me Me NH OBn NMe2 O Et Me H OBn Me O Me C Me Me OMe Me HO Me O Me O O H O H23-05-Weinreb Amides-2 11/5/00 8:25 PM

D. H. Ripin, D A. Evans The Eschenmoser Coupling Reaction Chem 20 Key Bond Construction Needed for the B12 Synthesis: cH2)2CO 2 M (CH2l2 M E. Knott J. Chem. Soc. 916(1955) () The General Reaction: Acylation of an Amide C=O (CH2)2CO2Me (CH2)2CO2 Me Base, Thiophile Review. Trost Comp. Org. Synth. Vol. 2, Ch 3.7(1991) Me Meo2CCH H The Thioamide component R" Reagents p-MeOP -PhOMe A Eschenmoser Science 196, 1410(1977) JoC463558(1981). Synthesis149(1973) Lawesson ' s R Bull. Chim. Soc. Belg. 87, 229& 293(1978) lan J. Chem., Sect. B 14, 999, (1976) JAcs102,2392(1980) RCS2R'+ R2NH Imidate +H2s 一 Thioamidehem. Ind (London)803(1974) H23-06-Eschenmoser-1 11/5/008: 27 PM

E. Knott J. Chem. Soc. 916 (1955) The Thioamide component: Reagents P4S10 JOC 46, 3558 (1981), Synthesis 149 (1973) Lawesson's Reagent Bull. Chim. Soc. Belg. 87, 229 & 293 (1978) P4S10, Et3N or NaHCO3 Indian J. Chem., Sect. B 14, 999, (1976) JACS 102, 2392 (1980) RCS2R' + R2NH Thioamide Imidate +H2S Thioamide Chem. Ind. (London) 803 (1974) Angew. Chem. 79, 865 (1967) R R3P=S 3P The Solution: ? (+) (–) The Problem: ?? (–) (+) (–) (+) (–) (+) ?? A. Eschenmoser Science 196, 1410 (1977) Key Bond Construction Needed for the B12 Synthesis: ? Key papers: Review: Trost Comp. Org. Synth. Vol. 2, Ch. 3.7 (1991) A. Eschenmoser Helv. Chim. Acta. 54, 710 (1971) A. Eschenmoser Angew. Chem., Int. Ed. Engl. 6, 866 (1967) A. Eschenmoser Angew. Chem., Int. Ed. Engl. 8, 343 (1969) Base, Thiophile The General Reaction: Acylation of an Amide C=O D. H. Ripin, D. A. Evans The Eschenmoser Coupling Reaction Chem 206 R N X R3 S R’ R” O N R” R’ R R3 O N N H N O O Me Me (CH2)2CO2Me O Me N H N H O N H (CH2)2CO2Me Me Me O O N H O R N O R’ R” N R” R’ S (CH2)2CO2Me R P S P Me Me O N Me H (CH2)2CO2Me (CH2)2CO2Me Me Me O N R Me Me O N O H N H N O O Me Me R3 Me Me R3 Me R2 Me R3 O R2 Me R2 N NH N H O N N H N H N N H S NH N Me MeO2CCH2 Me MeO2CCH2 O (CH2)2CO2Me Me MeO2CCH2 C S N Me N H N S N X S S S p-MeOPh PhOMe H H23-06-Eschenmoser-1 11/5/00 8:27 PM

D A Evans and P H. Carter Intramolecular Enolate Acylation-Dieckmann Condensation Chem 206 The Dieckmann Condensation Regioselectivity Reviews: Schaefer, Bloomfield, Organic Reactions 1967, 15, 1 Eto2C、A∠CO2Eac6 CO2Et Davis& Garratt, Comprehensive Organic Synthesis 1991, 2, 806-829 Kinetic Control? CO2RCO2R NaoEt/EtOH √ EtO2C\CH2CO2Et Eto2C CO2Et Thermodynamic Accesible Ring Sizes CO2Et ONa CO2R CO2R NaOT/EtOH Eto2C、 COrI ot observed CO2R Explanation B2 not viable excellent excellent acceptable situation dependent i Enolization at (A)preferred on basis of inductive effects. Hence Path a preferred in kinetically controlled situatie The individual steps Enolates(B1)and(B2) both more stable than enolate(A) Enolization: Under equilibrating conditions(B1) appears to be preferred over(B2) The effect of beta heteroatoms: classical kinetic vs thermodynamic contr of bases may be considered for the enolization step hilic base such as nah are comn Choice of base can be important(Vide infra) KOtBu /PhH CO2Et Ring Closure Keq(enoliz N、co2Et oEt CO2Et CO2Et R.H. Schlessinger, et al. Heterocycles 1987, 25, 315. CO2Et Statements claiming that the final enolization step renders the process irreversible are simply incorrect H23-07 Dieckmann-1115/008:29PM

Under equilibrating conditions (B1) appears to be preferred over (B2) Not observed Enolates (B1) and (B2) both more stable than enolate (A) Enolization at (A) preferred on basis of inductive effects. Hence, Path A preferred in kinetically controlled situation Explanation: Thermodynamic Control? Kinetic Control? B B2 NaOEt/EtOH NaOEt/EtOH A NaH/C6H6 Davis & Garratt, Comprehensive Organic Synthesis 1991, 2, 806-829 A B1 ( )n Reviews: The Dieckmann Condensation Regioselectivity: D. A. Evans and P.H. Carter Intramolecular Enolate Acylation–Dieckmann Condensation Chem 206 Schaefer, Bloomfield, Organic Reactions 1967, 15, 1. ( )n not viable excellent excellent acceptable situation dependent high dilution required Accesible Ring Sizes The individual steps: + EtO– Enolization: + base + base-H A variety of bases may be considered for the enolization step. Either alkoxide or a non-nucleophilic base such as NaH are commonly used. Choice of base can be important (Vide infra). Ring Closure: + EtOH Keq (enoliz) Keq (cycliz) ~ 1 Keq (enoliz) ~ 10+4 Statements claiming that the final enolization step renders the process irreversible are simply incorrect. NaOEt EtOH ∆ KOtBu / PhH R.H. Schlessinger, et al. Heterocycles 1987, 25, 315. NaOEt / EtOH The effect of beta heteroatoms: classical kinetic vs. thermodynamic control ∆ ∆ EtO2C CH2CO2Et ONa N ONa CO2Et MeO MeO CO2Et CO2Et N CO2Et OH N OH CO2Et EtO O – OEt O O OEt O – EtO O – O CO2R O CO2R O CO2R O CO2R O CO2R CO2R O CO2RCO2R CO2Et EtO2C CO2Et CO2Et ONa CO2Et CO2Et EtO2C O OEt O EtO2C EtO CO2Et O CO2Et CO2Et H23-07-Dieckmann-1 11/5/00 8:29 PM

D. H. Ripin, D. A. Evans The Eschenmoser Coupling Reaction-2 Chem 206 Reagents for the Reaction MHCO MOH MH. MOR Organic: R3N, N-methylmorpholine, buffered solutions Thiophiles: Ar3P, R3P, (RO)3P - BuO2C H Rapoport. Org. Chem. 46, 3230(1981) IMe2 PhP 此Em8m6:gn A Eschenmoser Science 196, 1410(1977) NaH Meo CH2)2CO2Me Eto2C a)1.05 eqiv(PhcoO) Me T Kametani J. Chem. Soc, Perkin Trans. 11607 (1980) 84%0 ( CH2)22 Me CO2t-Bu △RaN,68% R2 Me S Danishefsky R2 Tet Lett. 30. 362 (CH2)2CO2Me (CH2)2CO2Me R364% carbenes Thioethers s-Ylids H23-08-Eschenmoser-2 11/5/008: 27 PM

carbenes Thioethers S-Ylids : + – + Rh(OAc)2 ∆ Ra-Ni, 68% + ii NaOH S. Danishefsky Tet. Lett. 30, 3625 (1989) 99% * 79% DBU NaH CuBr T. Kametani J. Chem. Soc., Perkin Trans. I 1607 (1980) mix Et3N, PPh3 H. Rapoport J. Org. Chem. 46, 3230 (1981) 64% t-BuOK t-BuOH, 25 °C P(CH2CH2CN)3, TFA, sulfolane A. Eschenmoser Science 196, 1410 (1977) This center readily epimerizes to a 2:1 mix of diaster. in favor of the shown. b) P(OEt)3, Xylene, ∆ a) 1.05 eqiv. (PhCOO)2 84% (+) H. Rapoport J. Org. Chem. 46, 3230 (1981) A. Eschenmoser Helv. Chim. Acta. 54, 710 (1971) Bases: Inorganic: MHCO3, MOH, MH, MOR Organic: R3N, N-methylmorpholine, buffered solutions Thiophiles: Ar3P, R3P, (RO)3P Combination: 2 2 D. H. Ripin, D. A. Evans The Eschenmoser Coupling Reaction-2 Chem 206 Reagents for the Reaction: PhP NMe2 PhP N O N Bn t-BuO2C S TfO Me CO2Bn O O t-BuO2C N Bn Me O O CO2Bn N H MeN OAc S Br CO2Me Ar CO2Et MeN CO2Et OAc N H CO2MeBr OMe Me N MeO Me CO2Me OAc NMe EtO2C N2 HN O S CO2t-Bu N CO2t-Bu O CO2t-Bu N S O N2 S N –O CO2t-Bu O CO2t-Bu N S S R S R N H N O O Me Me (CH2)2CO2Me O Me (CH2)2CO2Me Me Me O S N H O (CH2)2CO2Me Me Me O N Me H (CH2)2CO2Me (CH2)2CO2Me Me Me S N R Me O N O H N H N O O Me Me R3 Me Me R3 Me R2 Me R3 O R2 Me R2 N NH NH N MeO2CCH2 Me MeO2CCH2 O (CH2)2CO2Me Me MeO2CCH2 Me Br R R R C R R R H23-08-Eschenmoser-2 11/5/00 8:27 PM

D A Evans and P H. Carter Intramolecular Enolate Acylation-Dieckmann Condensation Chem 206 Miscellaneous dieckmann reactions of potential Interest Intramolecular Ketone Acylation NaH CO2Et R Danieli, J. Org. Chem. 1983, 48, 123 H -J. Liu and Co-workers Tet Left. 1982. 23. 295 N,∠CO2Et (tBOC)HN OTMS tOc 8: 1 mixture CO2Et KH.THE sHN TsHN J.L. Adams, J.Org. Chem. 1985. 50, 2730 T M. Harris and Co-workers, J.Org. Chem. 1984, 49, 3681 BUOK/PI CO2Et THF,-78° When X= NR2, this is a good reaction, but when X= OR, it is a poor reaction Deduce the mechanism of this multistep process S. Brandawge and Co-workers, Tet. Lett 1992, 33, 3025 Naot Cl0 Me CO2Et 22Et 78°C G. Stork and Co-workers. JAm. chem. Soc. 1960. 82 4315. Kocienski and Co-workers. Tet. 1990. 46. 1716 H23-09 Dieckmann-211/5/00830PM

Kocienski and Co-workers, Tet. 1990, 46, 1716 -78 °C LDA D. A. Evans and P.H. Carter Intramolecular Enolate Acylation–Dieckmann Condensation Chem 206 8:1 mixture Peterset, Recl.Trav.Chim.Pays-Bas 1977, 96, 219. R.Danieli, J.Org.Chem. 1983, 48, 123. J.L. Adams, J.Org.Chem. 1985, 50, 2730. tBuOK / PhH LDA NaH DMSO Miscellaneous Dieckmann Reactions of Potential Interest G.Stork and Co-workers, J.Am.Chem.Soc. 1960, 82, 4315. NaOEt Et2O Deduce the mechanism of this multistep process. T.M. Harris and Co-workers, J.Org.Chem. 1984, 49, 3681. no loss of stereochemical integrity H.-J. Liu and Co-workers, Tet.Lett. 1982, 23, 295. KH, THF NaH Intramolecular Ketone Acylation S.Brandawge and Co-workers, Tet.Lett. 1992, 33, 3025. When X = NR2, this is a good reaction, but when X = OR, it is a poor reaction. (TMS)2NLi THF, -78oC EtO2C R CO2Et SEt O R EtS CO2Et CO2Et S CO2Et N TMS tBOC S OTMS OEt (tBOC)HN CO2Et X X Me CO2Et CO2Et Me Cl O CO2Et Me O CO2Et H Me O CO2Et O Me Me Me CO2Et O Me O Me Me Me O O H N O Me TsHN CO2Et H H N TsHN O O R Cl O O Me O Me O Me O X O Me Me O HO O Me Me O Me O O OMe OMe H23-09-Dieckmann-2 11/5/00 8:30 PM