哈佛大学：《高等有机化学》（英文版）Lecture 27 Advanced Organic Chemistry

D.A. Evans Ambiphilic Functional Groups-2: Sulfur-Based Activating Groups Chem 206 http://www.courses.fasharvardedu/-chem206/ Relevant Background Reading N.s. Sulphones in Organic Synthesis Pergamon Press, New York, 1993 Chemistry 206 General: Magnus, P D. Tetrahedron 1977, 33, 2019 Advanced Organic chemist Julia: Kocienski, P.J. Chem. Ind. London)1981, 548 Electrophilic Properties: Trost, B M. Bull. Chem. Soc. Jpn. 1988, 61, 107. Lecture number 27 So2 Extrusion: Vogtle, F. Rossa, L. ACIEE 1979, 18, 515 Ambiphilic Functional Groups-2 Ramberg-Backlund Rxn: Paquette, L.A. Org. Reactions 1977, 25, 1 Sulfur-Based Activating Groups Triflones: Hendrickson, J B. Org. Prep. Proc. Int. 1977, 175 ■ Sulfur - Ylides Sulfoximides: Johnson C.R. Tetrahedron 1984. 40. 122 Sulfur -Stabilized carbanions: Structure ve construction of trans olefins through carbanion-mediated tion processes has still not been rendered general. One Sulfone-Based Transformations transformation that sed in certain circumstances is the one-step"Julia transformation illustr Provide a mechanism for this transformation Pummerer rearrangement so Rs ARA RACHO Reading Assignment for this Week: H78t025℃ Carey& Sundberg: Part A; Chapter 7 carbanions& Other Nucleophilic Carbon Species Carey Sundberg: Part B: Chapter 2 The cruel mechanistic problems that you should be prepared for in Chem 206 Reactions of Carbon Nucleophiles with Carbonyl Compounds Chemical Chameleons: Organosulfones as Synthetic Building Blocks AC2O/HOAC B M. Trost, Bull. chem. Soc. Japan, 1988, 61, 107-124(handout Meo Meo Matthew d shair Meo November 20. 2002 Padwa et al. Joc 1996. 61. 48

http://www.courses.fas.harvard.edu/~chem206/ N S S O O H RS RACHO MeO MeO N O O S O Et CO2Me RS RA RS RA N CO2Me O O MeO MeO N H S O D. A. Evans Chem 206 Matthew D. Shair Wednesday, November 20, 2002 Reading Assignment for this Week: Ambiphilic Functional Groups–2: Sulfur-Based Activating Groups Chemistry 206 Advanced Organic Chemistry Lecture Number 27 Ambiphilic Functional Groups–2 Sulfur-Based Activating Groups ■ Sulfur-Ylides ■ Sulfur-Stabilized Carbanions: Structure ■ Sulfone-Based Transformations ■ Pummerer Rearrangement Relevant Background Reading General: General: Julia: Electrophilic Properties: SO2 Extrusion: Ramberg-Bäcklund Rxn: Triflones: Sulfoximides: Simpkins, N.S. Sulphones in Organic Synthesis, Pergamon Press, New York, 1993. Magnus, P.D. Tetrahedron 1977, 33, 2019. Kocienski, P.J. Chem. Ind.(London) 1981, 548. Trost, B.M. Bull.Chem. Soc. Jpn. 1988, 61, 107. Vogtle, F.; Rossa, L. ACIEE 1979, 18, 515. Paquette, L.A. Org. Reactions 1977, 25, 1. Hendrickson, J.B. Org. Prep. Proc. Int. 1977, 175. Johnson, C.R. Tetrahedron 1984, 40, 1225 Cume Question, 1998: The stereoselective construction of trans olefins through carbanion-mediated condensation processes has still not been rendered general. One transformation that may be used in certain circumstances is the "one-step" Julia transformation illustrated below. Provide a mechanism for this transformation. 1 LiN(iPr)2 THF -78 to 25 °C + + + SO2 "Chemical Chameleons: Organosulfones as Synthetic Building Blocks" B. M. Trost, Bull. chem. Soc. Japan, 1988, 61, 107-124 (handout) Ac2O/HOAc 70% The cruel mechanistic problems that you should be prepared for in Chem 206 Padwa et al. JOC 1996, 61, 4888 Carey & Sundberg: Part A; Chapter 7 Carbanions & Other Nucleophilic Carbon Species Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds

D.A. Evans Sulfur-Based Functional Groups-1 Chem 206 Relevant Background Reading Reactions of sulfonium ylids m, Prs, New rer k 193. ic Synthesis General: Magnus, P D. Tetrahedron 1977, 33, 2019. Sulfonium Salt: pKa- 18 Julia: Kocienskl, P.J. Chem Ind. London)1981, 548. Electrophilic Properties: Trost, B M. Bul. Chem. Soc. Jpn. 1988, 61, 107. SO2 Extrusion: Vogtle, F Rossa, L. ACIEE 1979, 18, 515 Ramberg- Backlund Rxn: Paquette, LA Org. Reactions 1977, 25, 1 o-P=0 Triflones: Hendrickson, J B. Org. Prep. Proc. Int. 1977, 175. OH OH Sulfoximides: Johnson. C.R. Tetrahedron 1984. 40. 1225 S-Adenosylmethionine Acidities of Sulfur-based Functional Groups a Deprotonation: S-CH2+ Na-H H-H pKa (DMso H4 pKa-18 pKa (-56 H3 Leaving Group Potential: R2S--C(+ Sulfoxide 35pKa(-41) L L-S-CH3 Nu +Me-№u pKa 31 Excellent LG Sulfonium salt Bordwell, F. G. Zhang X.-M. Acc Chem. Res. 1993, 26, 510-17 Good lG

S CH3 CH3 CH3 S CH3 R R S R R S CH3 R R O N N N N NH2 OH OH S HO Me NH2 O S CH2 R R S CH3 R R S R R + + + + + + Me I CH3 S CH3 CH3 S CH3 O S O CH3 CH3 O Na H O NH2 S Me HO OH OH NH2 N N N N O O P R O – O O S O R CH3 O S CH3 L L L R2S C(+) CH4 NH3 HOH SN2 S O O – R L S: L L Me Nu Me Nu H H Me Nu D. A. Evans Chem 206 Relevant Background Reading pKa (~56) pKa 31 pKa (~41) Sulfide Sulfoxide Sulfone Sulfonium Salt pKa (DMSO) ~ 18 ~ 31 (45) ~35 Sulfonium Salt: pKa ~ 18 Reactions of Sulfonium Ylids ■ Synthesis: ●● SN2 + I – S-Adenosylmethionine SN2 + ●● ■ Deprotonation: – pKa ~ 38 pKa ~ 18 Sulfur-Based Functional Groups-1 Bordwell, F. G.; Zhang, X.-M. Acc. Chem. Res. 1993, 26, 510-17. Good LG Excellent LG ●● ●● SN2 + Nu: + + Nu: + SN2 + (+) + Nu: ■ Leaving Group Potential: Acidities of Sulfur-based Functional Groups General: General: Julia: Electrophilic Properties: SO2 Extrusion: Ramberg-Bäcklund Rxn: Triflones: Sulfoximides: Simpkins, N.S. Sulphones in Organic Synthesis, Pergamon Press, New York, 1993. Magnus, P.D. Tetrahedron 1977, 33, 2019. Kocienski, P.J. Chem. Ind.(London) 1981, 548. Trost, B.M. Bull.Chem. Soc. Jpn. 1988, 61, 107. Vogtle, F.; Rossa, L. ACIEE 1979, 18, 515. Paquette, L.A. Org. Reactions 1977, 25, 1. Hendrickson, J.B. Org. Prep. Proc. Int. 1977, 175. Johnson, C.R. Tetrahedron 1984, 40, 1225

D. A. Evans. K. Scheidt X-ray Structures of Metallated Sulfones Sulfoxides Chem 206 Sulfone& Sulfoxide based carbanions. Structure o Me Boche, etal. Angew. Chem. Int Ed 1986, 25, 1101 Sulfone-and sulfoxide-stabilized carbanions are extremely useful carbon nucleophiles in organic synthesis TMEDA A-s—cH E+) Ar-S—cH E(+) However, until recently little information was available on the solid state The Structure of Lithium Coumpounds of Sulfones, Sulfoximides, Sulfoxides, Thioethers, 1, 3 Dithianes, Nitriles, Nitro Compounds, and Hydrazones Boche, G. Angew. Chem., Int. Ed Engl. 1989, 28, 277 Here are several examples taken from the Boche review. CH2-LHTMEDA w. Chem. Int Ed. 1 The Li counterions are not associated with the charged carbon The carbanions are largely trigonal

Ar S O CH3 Ar S O O CH3 S O O CH2–Li–[TMEDA] Ar S O CH2–Li Ar S O O CH2–Li Li Li Ar S O CH2 El Ar S O O CH2 El S O C–Li Me Li Li Li Chem 206 Sulfone- & Sulfoxide Based Carbanions: Structure X-ray Structures of Metallated Sulfones & Sulfoxides LDA El(+) ■ Sulfone- and sulfoxide-stabilized carbanions are extremely useful carbon nucleophiles in organic synthesis. However, until recently little information was available on the solid state structures of these species: LDA El(+) "The Structure of Lithium Coumpounds of Sulfones, Sulfoximides, Sulfoxides, Thioethers, 1,3 Dithianes, Nitriles, Nitro Compounds, and Hydrazones." Boche, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 277. Here are several examples taken from the Boche review: Gais, etal. Angew. Chem. Int. Ed. 1985, 24, 859 Boche, etal. Angew. Chem. Int. Ed. 1986, 25, 1101 + TMEDA ■ The Li counterions are not associated with the charged carbon. ■ The carbanions are largely trigonal. D. A. Evans, K. Scheidt

D. A Evans. K scheidt X-ray Structures of Phenylsulfinyl Carbanions Chem 206 TMEDA TMEDA Boche, etal. Angew. Chem. Int. Ed. 1986, 25, 1101 Boche, etal. Angew. Chem. Int. Ed. 1985, 24, 573

S O C–Li Me Li Li Li S O O CH–Li Li Li D. A. Evans, K. Scheidt X-ray Structures of Phenylsulfinyl Carbanions Chem 206 Boche, etal. Angew. Chem. Int. Ed. 1986, 25, 1101 Boche, etal. Angew. Chem. Int. Ed. 1985, 24, 573 + TMEDA + TMEDA

D A. Evans Sulfur-Based Functional Groups-2 Chem 206 Reactions with ketones (王) Reactions of sulfones R2s--C Reactivity Pattern: Nonaltemate Synthesis: 0 H2O2 R2S R2S Good review article: Magnus, Tetrahedron 1977, 33, 2019-2045. Twenty-five Years of Dimethylsulfoxonium Methylide(Corey's Reagent) Gololobov, Y. G. Lysenko, V P ; Boldeskul, L. E. Tetrahedron 1987, 43, 2609 Reactions of sulfone Reactions of Sulfonium Ylids: Conjugate Addition more nucleophilic (-) R2SO2--C S-CH3 R2s- Cn pogue tang R2SO2-C Nonaltemate reactivity pattem revealed in (+) consecutive reactions R2S--C ? 1, 2-vS 1.4-addition ? Will function as lG ?

CH2 O – S Me Me S Me Me CH2 O – C H H S Me Me C H H S Me Me S Me Me O – S Me Me S Me Me O – S CH2 Me Me S CH2 R R S CH3 R R + + + + – + + + + + O O R2S C CH2 O R2S C Me Br Me Me Me Br :S Ph O O – H2O2 S Ph Me Me O O Me Me S Ph O CH2 R2S C O O R2S C R2S C Li O S Ph Me Me O O S O O Me Me Ph Li S O O Me Me Ph S Ph Me Me O O R2SO2 C BuLi H2O2 HIO4 R2SO2 C S Ph Me Me O O S Me Me O Ph D. A. Evans Sulfur-Based Functional Groups-2 Chem 206 – (+) (–) Reactivity Pattern: Nonalternate ■ Reactions with ketones: (±) "Twenty-five Years of Dimethylsulfoxonium Methylide (Corey's Reagent).", Gololobov, Y. G.; Lysenko, V. P.; Boldeskul, I. E. Tetrahedron 1987, 43, 2609. Nonalternate reactivity pattern revealed in consecutive reactions (+) (+) (–) Reactions of Sulfonium Ylids: Conjugate Addition ●● – Sulfinate ester not observed (Sulfinate anion) PhS: – Synthesis: Reactions of Sulfones Good review article: Magnus, Tetrahedron 1977, 33, 2019-2045. Will function as LG ?? 1,2- vs 1,4-addition ?? ?? (+) poorer leaving group than: ●● – more nucleophilic than: pKa ~ 25 Reactions of Sulfones (+) (+) (–) +

D. A. Evans. P. Carter Sulfur-Based Functional Groups-3 Chem 206 e SopH The Sulfone group may also be readily removed reductively BuLi 1.2-addition R2SO2--C Fragment Coupling with Sulfonyl Carbanions Alkoxide not sufficiently nucleophilic to MEMO displace Phso2 anion Heathcock, C.H.; et al. Not observed Jorg.chem.19853,1922 However!! Me ( soph SO2Ph 2 eq bUlI THF/HMPA. OTBS hen add iodide ndustrial synthesis developed by M. Julia OTBS MEMO 65-85%yed (-) R2so2-C R2so2--C trans chrysanthemic acid THFARMPALOA X 3 Me 50% yield Synthesis of Vitamin A: Julia& Co-workers, Bull. Soc. Chim. Fr. 1985. 130 H Me TBDPSO. SOpH Me Me( sO2Ph TBDPSO. CO2R 6 PMBO SO2 Ph Me CO2R mith. AB ll et al KOH/MeOH Tet. Lett.1989,30,6963 PMBO Reso 77% yield TFAA, DMSO:NEt TBDPSO. TBDPSO CH2CL, 78C Al-Hg, aq. THF CO2H R2SO2-C 90% yield PMBO

R2SO2 C Li S Ph Me Me O O S O O Me Me Ph Li Li Me SO2Ph Me Me Me R2SO2 C Me CO2R Br Me Me OEt O O R2SO2 C Me Me Me Me SO2Ph CO2R Me H Me Me OLi OEt Me Me SO2Ph O Me Me SO2Ph Me Me –O Me CO2Et Me H H Me Me R SO2Ph MeO TBDPSO PhO2S Me OH Me MEMO MEMO Me SO2Ph Me BuLi Me X Me MEMO OTBS Me Me H O S S Me PMBO R SO2Ph El R2SO2 C Me CO2H Me Me Me Me R2SO2 C TBDPSO MeO O S S Me PMBO H MeOH Na(Hg) TBDPSO MeO O S S SO2Ph Me PMBO TBDPSO MeO HO S S SO2Ph Me PMBO Me OTBS I Me El R H D. A. Evans, P. Carter Sulfur-Based Functional Groups-3 Chem 206 Industrial synthesis developed by M. Julia trans chrysanthemic acid However!! Not observed –PhSO2 – 1,2-addition (+) (+) Alkoxide not sufficiently nucleophilic to displace PhSO2 – anion. (–) (–) (+) El(+) The Sulfone group may also be readily removed reductively: Synthesis of Vitamin A: Julia & Co-workers, Bull. Soc. Chim. Fr. 1985, 130 (–) KOH/MeOH (+) (+) 1. MsCl, TEA 2. PhSLi, THF, RT 3. mCPBA Fragment Coupling with Sulfonyl Carbanions X= SO2Ph X = H Li wire, Na2HPO4 THF/HMPA/tBuOH 50% yield 2 eq. nBuLi THF/HMPA; then add iodide 65 - 85% yield Heathcock, C.H.; et al. J.Org.Chem. 1988, 53, 1922. TFAA, DMSO; NEt3 CH2Cl2, -78 oC Smith, A.B. III; et al. Tet.Lett. 1989, 30, 6963. 77% yield Al-Hg, aq. THF Reflux 90% yield

D A Evans.T. Dunn Sulfur-Based Functional Groups-4 Chem 206 Functionalization of cyclic Ethers Total synthesis of Okadaic Acid E(+) n-BuLi DMPU THF,-78°C PhO2s O Pho2s O SOpH (-) Reso SO2Ph Lewis acid 1 )Addition of 8° C to rt ROH 2 )CSA, MeOH R2SO2—C H COOH Ley et al, Synlett, 1992, 395: Ley et. al, Tetrahedron, 1992, 48, 7899 Total Synthesis of Routiennocin(CP-61, 405) Ley et al J. Chem. Soc., Perkin Trans. 1, 1998, 3907 Total synthesis of Bryostatin 2 DMPU OTBDMS Pho2S“0 HTHF.-78°0 C Ring OTBDMS 87% yield 1 )Addition of iodide, 78°c→RT OTBDMS 2)H’,H2O NHPh ° TBDMS Routiennocin Evans et ai,JACs.1999121,7540-7552 O COmE

Me Me HO OH O Me Me OH MeO2C CO2Me OH Me OH O O O O O n-Pr O H BuLi PhO2S O PhO2S O PhO2S O O O I Me Me O SO2Ph O SO2Ph El –SO2Ph R2SO2 C ROH El O El O OR O O O O O COOH O O Me H OH H H Me OH Me H Me H Me OH OH H R2SO2 C O O Me HO H Me n-BuLi, DMPU PhO2S O OBn H O SO2Ph R H O O I Me Me O OTf OTBDMS C Ring H H O SO2Ph N–iPh O H Me Me OPMB OTBDMS Li O NHPh O H Me Me OPMB O OTBDMS OTBDMS C Ring H H OH O O Me Me H N H O H N O HOOC HO O OBn O Me HO Me H H C D. A. Evans, T. Dunn Sulfur-Based Functional Groups-4 Chem 206 Functionalization of cyclic Ethers – El(+) Lewis acid + (–) (+) Ley et al, Synlett, 1992, 395; Ley et. al, Tetrahedron, 1992, 48, 7899 Total Synthesis of Routiennocin (CP-61,405) Routiennocin 68% yield 1.) Addition of iodide, -78o C ® RT 2.) H+ , H2O – + Total synthesis of Okadaic Acid n-BuLi, DMPU THF, -78o C Ley et al, J. Chem. Soc., Perkin Trans. 1, 1998, 3907. 90% yield 1.) Addition of iodide, -78o C to RT 2.) CSA, MeOH + Evans et al, JACS. 1999, 121, 7540-7552. 87% yield Bryostatin 2 Total synthesis of Bryostatin 2 THF, -78oC

D. A. Evans. P. Carter Sulfur-Based Functional Groups-5: Julia Olefin Synthesis Chem 206 Julia Trans Olefin Synthesis Julia Olefination - lonomycin 1. add RCHO. -780C. add Ac2O,-78° C to RT Elimination is stepwise; PhO2S、L 2Na/Hg, EtoAc/MeoH30°c SOpH mechanism of reduction step 86: 14 olefin mixture OTBS OTBS Good sulfone review. Trost, Bull Chem. Soc. Japan, 1988, 61, 107-124 Review: Kocienski etal. Phosphorus& Sulfur 1985, 24, 97-127 Evans. et al JAcs1990,112,5290 The reduction step is not stereosecific Cytovaricin Synthesis: JACS 1990, 112, 7001 PZOcH2OCH2CCl TESO sO2R TBSO SOaR TESO, 2 LiNEt2, THF Ac2O, pyr Phso2 Reactions accomplish So,Ar DEI OTES C21 OH deprotection Free acid must be used to prevent Kochenski. J. Chem. Soc Perkin Trans/. 1978. 834 loss of C4 OH in 2nd step TESO verall yield, 66%

OPMB OTES H H H O OTES Me MeO O HO H Me DEIPSO H O O H Me H H OH Me H TBSO Me H O OTES Me O O Me TESO Si t-Bu Me t-Bu 21 3 1 R SO2Ph BuLi SO2Ph R R' OH OAc R' R SO2Ph Ac2O Na(Hg) R2 R1 SO2R X X R1 R2 SO2Ar OAc OAc SO2Ar OAc MeOH R2 R1 R R' R1 R2 R' R PhO2S Li OTBDPS Me Me Me Me O O Me Me CHO H Me H Me OTBS Me O O H Me OCH2OCH2CCl3 O H Me H O H DEIPSO H Me Me CHO TBSO OPMB TESO Me Si O O OTES H O Me OTES H MeO H H O t-Bu t-Bu Me PhSO2 Me TESO O HO Me Me O O Me Me H Me H Me OTBS Me O O OTBDPS Me Me D. A. Evans, P. Carter Sulfur-Based Functional Groups-5: Julia Olefin Synthesis Chem 206 Problem: Work out the mechanism of reduction step. Good sulfone review: Trost, Bull Chem. Soc. Japan, 1988, 61, 107-124. Elimination is stepwise; therefore, not stereospecific major R'CHO Julia Trans Olefin Synthesis: Julia Olefination - Ionomycin 1. add RCHO, -78oC; add Ac2O, -78oC to R.T. 2. Na/Hg, EtOAc/MeOH, -30oC 70% yield 86:14 olefin mixture Evans, et al. JACS 1990, 112, 5290. Review: Kocienski etal. Phosphorus & Sulfur 1985, 24, 97-127 Kochenski, J. Chem. Soc Perkin Trans I, 1978, 834 Na(Hg) • or – ✻ + + e- • + e￾The reduction step is not stereosecific Cytovaricin Synthesis: JACS 1990, 112, 7001 Free acid must be used to prevent loss of C4 OH in 2nd step C21 OH deprotection 21 C=C construction Reactions accomplished: overall yield, 66% Ac2O, pyr 6% Na(Hg) -40 °C 2 LiNEt2, THF +

D. A. Evans. P. Carter Sulfur-Based Functional Groups- 5: Julia Olefin Synthesis-2 Chem 206 The Mechanism Phorboxazole B Synthesis H Meg 。Na is.. CH3 disconnection Olefin stereochemistry could be Evans Smith. Fitch. Cee established in the formation of a AcS2000,122,10033-10046 C3g-C46 Synthon Julia construction Recent Modifications of the julia process Kocienski, SynLett 2000, 3, 365-366 KHMDs C4Hg N:260℃n EZ:99:1(75%) 75% NaHMDS H3 RCHO KHMDS OMe O-NEa 60°Ct OHC-CgH19 R=Ph:Ez:29:71(70%) ≈oCH Ph Mechanism?? R=tBu:Ez:<1:99(95%) KHMDS -60%Ct E201(e Metternich, JOC 1999. 54. 9632

C39–C46 Synthon Me Br MeO O H H O O N O Me H H H HO H CH2 Me O MeO OH H N O H H O O H HO H Me 46 38 33 19 1 4 9 13 Br OMe S S N O O Br OMe CH3 I NaHMDS CH3 I O H Br OMe CH3 I O–Na S O S O N NaHMDS RCHO SO2 S N NaO Br OMe CH3 I Br OMe CH3 I A C O2 N S N N N Ph R CH3 I O–Na S O O N S R C O2 S Ph N N N N R C O2 S C4H9 N N N N Ph H R' O Me OR KHMDS KHMDS OHC OHC C9H19 KHMDS –60 °C®rt –60 °C®rt –60 °C®rt CH3 I O S O O S N R C4H9 C9H19 Ph R' Me OR R S N NaO SO2 CH3 I O S O O S N R R CH3 I D. A. Evans, P. Carter Sulfur-Based Functional Groups-5: Julia Olefin Synthesis-2 Chem 206 Phorboxazole B Synthesis THF, -78˚C - rt 75% E/Z = >95:5 Evans, Smith, Fitch, Cee JACS 2000, 122, 10033-10046. disconnection Julia Construction Mechanism?? The Mechanism: Olefin stereochemistry could be established in the formation of A. Recent Modifications of the Julia Process: Kocienski, SynLett 2000, 3, 365-366. E/Z: 99:1 (75%) R = Ph: E/Z: 29:71 (70%) R = tBu: E/Z: 10:1 (64%) Metternich, JOC 1999, 54, 9632

D A Evans, N Finne Sulfur-Based Functional Groups-5 Chem 206 Carbonyl Anions: A useful Reversed Polarity Equivalent The overall set of reactions which establishes the equivalency of the hypothetical carbonyl anion 1 and its equivalent synthon 2 is shown below. Consider the two possible polar disconnections of the C-R, bond of the ketone shown below Construction Ster 团 R2O (-)c-G T2 ⊙ R2④ +)c Carbonyl anions are not normally accessible via aldehyde deprotonation RI-C: O T2 E not feasible ! Rr-C-MgCI Why?? Nitronate Anions are also useful Carbonyl Anions Operational equivalents to the carbonyl anion are useful in synthesis 0 R nitronate anion highly stablized Construction 1,3-Dithianes as Carbonyl Anion Equivalents ()c-G 0 Reactivity Patterns: (RS)2-C(+) T Dithianes anions highly nucleophilic(indiscriminate) Nitonate anions higly discriminating

(RS) (RS)2 C(+) 2 C(–) (–) C–G (+) C–E (–) C–G (+) C–E O C R El El R S S C El R O2N O C R El + N – O – O R R T2 T2 + N R R O – O H C: – O R + N H R – O – O S S R Li C: O R1 Li R S S C: O R1 R–Li R1 C O MgCl R1 C O C O R1 S S R H T2 T1 +H2O –H2O C Cl O R1 RCHO R1 C O R2 SH SH Sulfur-Based Functional Groups-5 Chem 206 Operational equivalents to the carbonyl anion are useful in synthesis Carbonyl anions are not normally accessible via aldehyde deprotonation carbonyl anion not feasible !! Why?? Mg0 + R2 : R2 + : Consider the two possible polar disconnections of the C–R2 bond of the ketone shown below: Carbonyl Anions: A useful Reversed Polarity Equivalent pKa ~ 39 Construction Step Reactivity Patterns: Equivalent Synthons El H3O + El 1,3-Dithianes as Carbonyl Anion Equivalents The overall set of reactions which establishes the equivalency of the hypothetical carbonyl anion 1 and its equivalent synthon 2 is shown below: Dithianes anions highly nucleophilic (indiscriminate): Nitonate anions higly discriminating pKa 18 Nitronate Anions are also useful Carbonyl Anions Equivalent Synthons Construction Step HO – nitronate anion highly stablized (–) (±) Nef Reaction 1 2 D. A. Evans, N. Finney + + + El + El