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 NH S O Chem 206D. A. Evans 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 a73 Sulfur-Ylides a73 Sulfur-Stabilized Carbanions: Structure a73 Sulfone-Based Transformations a73 Pummerer Rearrangement Relevant Background Reading General: General: Julia: Electrophilic Properties: SO2 Extrusion: Ramberg-B?cklund 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 throughcarbanion-mediated condensation processes has still not been rendered general. One transformation that may be used in certain circumstances is the "one-step" Juliatransformation 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 7Carbanions & Other Nucleophilic Carbon Species Carey & Sundberg: Part B; Chapter 2Reactions of Carbon Nucleophiles with Carbonyl Compounds S CH3 CH3 CH3 S CH3 R R S R R CH3S R R O N N N N NH2 OHOH SHO Me NH2 O S CH2 R R S CH3 R R S R R+ + + + + + Me I S CH3CH3 SCH3 CH3 O S O CH3CH3 O Na H O NH2 S Me HO OH OH NH2 N NN N O O P RO 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 a73 Synthesis: SN2a71a71 + I – S-Adenosylmethionine SN2 + a71 a71a73 Deprotonation: – pKa ~ 38pKa ~ 18 Sulfur-Based Functional Groups-1 Bordwell, F. G.; Zhang, X.-M. Acc. Chem. Res. 1993, 26, 510-17. Good LG Excellent LG a71a71 a71a71 SN2 +Nu:+ + Nu: +SN2 +(+) Nu:+ a73 Leaving Group Potential: Acidities of Sulfur-based Functional Groups General: General: Julia: Electrophilic Properties: SO2 Extrusion: Ramberg-B?cklund 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 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(+) a73 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 a73 The Li counterions are not associated with the charged carbon. a73 The carbanions are largely trigonal. D. A. Evans, K. Scheidt S O C–Li Me Li Li Li S O O CH–Li Li Li D. A. Evans, K. Scheidt Chem 206X-ray Structures of Phenylsulfinyl Carbanions Boche, etal. Angew. Chem. Int. Ed. 1986, 25, 1101 Boche, etal. Angew. Chem. Int. Ed. 1985, 24, 573 + TMEDA+ TMEDA 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 –SMe 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 BrMe Ph:S O O – H2O2 S PhMe Me O O Me SMe Ph O CH2 R2S C O O R2S C R2S C OLi S PhMe Me O O S OO Me Me Ph Li S OO Me Me Ph S PhMe Me O O R2SO2 C BuLi H2O2 HIO4 R2SO2 C S PhMe Me O O SMe Me O Ph D. A. Evans Chem 206Sulfur-Based Functional Groups-2 – (+) (–) Reactivity Pattern: Nonalternate (± )a73 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 a71 a71 – Sulfinate esternot 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: a71 a71 –more nucleophilic than: pKa ~ 25 Reactions of Sulfones (+) (+) (–) + R2SO2 C Li S PhMe Me O O S O O Me Me Ph Li Li SO2PhMe Me MeMe R2SO2 C Me CO2R Br Me OEtMe O O R2SO2 C Me Me Me Me SO2Ph CO2R Me H Me Me OLi OEt Me Me SO2Ph OMe Me SO2Ph Me Me –O CO2EtMe 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 SO2PhR El R2SO2 C Me CO2H Me Me MeMe 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 MeI El R H D. A. Evans, P. Carter Chem 206Sulfur-Based Functional Groups-3 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, TEA2. PhSLi, THF, RT 3. mCPBA Fragment Coupling with Sulfonyl Carbanions X= SO2Ph X = H Li wire, Na2HPO4 THF/HMPA/tBuOH 50% yield 2 eq. nBuLiTHF/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. THFReflux 90% yield Me MeHO OH O MeMe OHMeO 2C CO2Me OH OHMe O O O OO On-Pr H BuLi OPhO2S OPhO2S OPhO2S O O I MeMe OSO 2Ph O SO2Ph El –SO2PhR 2SO2 C ROH OElOEl OR O O O O O COOH OO Me H OHH H Me OH Me H Me H OHMe OH H R2SO2 C O O Me HO H Me n-BuLi, DMPU OPhO2S OBn H OSO2Ph RH O O I MeMe O OTf OTBDMS C Ring HH O SO2Ph N–iPh O H MeMe OPMB OTBDMS Li O NHPh O H Me Me OPMB OTBDMSO OTBDMS C Ring HH OH O O Me MeH N H O H N O HOOC HO O OBnO Me HO MeH H C D. A. Evans, T. Dunn Chem 206Sulfur-Based Functional Groups-4 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 OPMB OTES H H H O OTESMeMeOO HO H Me DEIPSO H O O H Me H H OH MeH TBSO Me H O OTES Me O OMeTESO Si t-Bu Me t-Bu 21 3 1 SO2PhR BuLi SO2Ph R R' OH OAc R'R SO2Ph Ac2O Na(Hg) R2 R1 SO2RX 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 OMe Me CHO H Me H MeOTBS MeOO H Me OCH2OCH2CCl3 O H Me H OH HDEIPSO Me CHOMe TBSO OPMB TESO Me Si O O OTES H O MeOTES HMeO H H O t-Bu t-Bu Me PhSO2 Me TESO O HO Me Me O OMe Me H Me H MeOTBS MeOO OTBDPS Me Me D. A. Evans, P. Carter Chem 206Sulfur-Based Functional Groups-5: Julia Olefin Synthesis 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% yield86:14 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 – a54 ++ e-?+ e- The reduction step is not stereosecific Cytovaricin Synthesis: JACS 1990, 112, 7001 Free acid must be used to prevent loss of C 4 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 + C39–C46 Synthon Me Br MeO O HH O O N O Me HH H HO H CH2 Me O MeO OHH N O H H O O H HO H Me 46 38 33 19 1 4 9 13 Br OMe S S N OO Br OMe CH3 I NaHMDS CH3 I O H Br OMe CH3 I O–Na S O O S N NaHMDSRCHO SO2 S NNaO Br OMe CH3 I Br OMe CH3 I A C O2SN N N N Ph R CH3 I O–Na S O O SN R C O2S Ph NN N N R C O2S C4H9 NN N N Ph H R' O Me OR KHMDS KHMDS OHC C9H19OHC KHMDS –60 °C→rt –60 °C→rt –60 °C→rt CH3 I O S O O S N R C4H9 C9H19Ph R' Me OR R S NNaO SO2 CH3 I O S O O S N R R CH3 I D. A. Evans, P. Carter Chem 206Sulfur-Based Functional Groups-5: Julia Olefin Synthesis-2 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: <1:99 (95%) E/Z: >10:1 (64%) Metternich, JOC 1999, 54, 9632 (RS)2 C(–)(RS)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 Chem 206Sulfur-Based Functional Groups-5 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+ Ar S R O Ar S R O TFAA H+ Ar S R OH H Ar S R OTFA H –H2O –TFAOH Ar S R H Ar S R H +TFAO– –ArSH +H2O O R H Ar S R OTFA N S O O RHN CO2Bn S Ar O O N N O S H Et R Ph O TsOH ? TFAA R N R O R H+ –H2O O R H +H2O –R2NHR N R OH R H R N RR H MeO MeO N O O S O Et CO2Me S Ar O N N O S H Et R Ph N S O RHN CO2Bn OAc N N O H Et R PhS N CO2Me O O MeO MeO S Ar O Chem 206The Pummerer Rearrangement Basic Transformation: D. A. Evans De Lucchi, Miotti, et al. (1991). “The Pummerer reaction of sulfinyl compounds.” Organic Reactions 1991, 40: 157. Grierson, and Husson (1991). Polonovski- and Pummerer-type Reactions and the Nef Reaction. Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon Press. 6: 909. Padwa, A., D. E. Gunn, et al. “Application of the Pummerer reaction toward the synthesis of complex carbocycles and heterocycles.” Synthesis 1997 1353-1377. Carreno, “Applications of sulfoxides to asymmetric synthesis of biologically active compounds.” Chem. Reviews 1995 95, 1717-1760. The Pummerer Rearrangement facilitates the transformation of a sulfinyl → aldehyde transformation. The rearrangement may be initiated by either a Bronsted acid or an anhydride such as trifluoroacetic anhydride (TFAA). With the latter reagent, the transformation occurs at room temperature. Leading References The Related Polonovski Reaction: Regioselectivfity: Depends on the relative kinetic acidy of the protons Transformations Mediated by the Pummer Rearrangement 86% 81% P. Magnus et al. Accts Chem Res. 1984, 17, 35 Ac2O/HOAc >80% Ac2O/HOAc 70% The cruel mechanistic problems that you should be prepared for in Chem 206 Padwa et al. JOC 1996, 61, 4888 Kita, Y. and N. Shibata (1996). “Asymmetric pummerer-type reactions induced by O-silylated ketene acetals.” Synlett(4): 289-296. MeO MeO N O O S O Et CO2Me N CO2Me O O MeO MeO NMe H N S Et OO Me S EtO O N O CO2MeMeO OMe Ac H S Et O N O CO2MeMeO OMe N O CO2MeMeO OMe O SEtH N O CO2MeMeO OMe O SEt O SEt COOCH3N OMe OMe O N O COOCH3 O MeO MeO NMe H N S Et OO Me H N N Et O SMe H HMe OAc OAc NMe N Et O SMe H N H N S Et OMe Me NMe H N S Et OMe Chem 206The Pummerer RearrangementD. A. Evans Ac2O/HOAc 70% Padwa et al. JOC 1996, 61, 4888 Endo [4+2] Pummerer Endo [4+2] Product Pummerer Mechanism?? TsOH, THF 78 % Exam 3, 2000: Question 5 (11 points). An interesting rearrangement which also results in the construction of this same ring system (Question 4) has been reported by Langlois & coworkers ( J.Org. Chem. 1985 , 50 , 961). This rearrangement is illustrated below. Provide a mechanism for this transformation. Pummerer Pummerer Product