http://www.courses.fas.harvard.edu/~chem206/ Me Me MeSMe S PPh3 S=PPh3 Me Me MeS Me Chem 206D. A. Evans Matthew D. Shair Wednesday, October 16, 2002 a73 Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11Concerted Pericyclic Reactions Pericyclic Reactions: Part–3 Chemistry 206 Advanced Organic Chemistry Lecture Number 13 Pericyclic Reactions–3 a73 Introduction to Sigmatropic Rearrangements a73 [2,3] Sigmatropic Rearrangements a73 Other Reading Material: Fleming: Chapter 4Thermal Pericyclic Reactions a73 Problems of the Day: [2,3] Sigmatropic Rearrangements Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 6, Chapter 4.6: Nakai, T.; Mikami, K. Org. React. (N.Y.) 1994, 46, 105-209. Hoffmann, Angew. Chem. Int. Ed. 1979, 18, 563-572 (Stereochemistry of) Nakai, Chem. Rev. 1986, 86, 885-902 (Wittig Rearrangement) Evans, Accts. Chem. Res. 1974, 7, 147-55 (Sulfoxide Rearrangement) Vedejs, Accts. Chem. Res. 1984, 17, 358-364 (Sulfur Ylilde Rearrangements) [3,3] Sigmatropic Rearrangements Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope) Chapter 7.2, Claisen S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen) S. R. Wilson, Organic Reactions 1993, 43, 93 (oxy-Cope) T. S. Ho, Tandem Organic Reactions 1992, Chapter 12 (Cope, Claisen) Paquette, L. A. (1990). “Stereocontrolled construction of complex cyclic ketones by oxy-Cope rearrangement.” Angew. Chem., Int. Ed. Engl. 29: 609. For study on this [2,3] rxn See Baldwin JACS 1971, 93, 6307 heat Provide a mechanism for this transformation. Evans, et al. Acc. Chem. Res. 1974, 7, 149-155. X H H C XH R C RHX C Me H 1 3 R X Y:– X R X X H ? ? ? ? YHX H X H Y H X Y X Y ? R Y–:X H X X X R X H Y MeH HX H Y D Y CH3 X ? ? YHX H Y H3C X Me H Y CH3 X D Sigmatropic Rearrangements-1 Chem 206D. A. Evans Bridging distance too great for antarafacial migration. Antarafacial GeometrySuprafacial Geometry bonding Ψ2 (allyl HOMO) antibondingbonding bonding a73 Construct TS by uniting an allyl and H radical: Consider the orbitals needed to contructthe transition state (TS). ? consider the 1,3-migration of H a73 [1,3] Sigmatropic Rearrangements (H migration) [3,3] Sigmatropic rearrangement [2,3] Sigmatropic rearrangement [1,3] Sigmatropic rearrangement [1,5] Sigmatropic rearrangement Sigmatropic rearrangements are those reactions in which a sigma bond(& associated substituent) interchanges termini on a conjugated pi system a73 Examples: Sychronous bonding to both termini is possible from this geometry a203 The stereochemical constraints on the suprafacial migration of carbonwith inversion of configuration is highly disfavored on the basis of strain. bonding bonding Inversion at carbon Suprafacial on allyl fragment Retention at carbon Sychronous bonding to both termini cannot be achieved from this geometry bonding a73 [1,3] Sigmatropic Rearrangements (C migration) consider the 1,3-migration of Carbon ?Consider the orbitals needed to contruct the transition state (TS). a203 Construct TS by uniting an allyl and Me radicals: antibonding Suprafacial on allyl fragment ? 1 3 These rearrangements are only seen in systems that are highly strained,an attribute that lowers the activation for rearrangement. 120 °C 3 1 no observed scrambling of labels a54a54 [1,3]-Sigmatropic rearrangements are not common R R R RR H H R R R H H Me Me H H R H H H H R Me Me H H H R H H R HH Me Me Sigmatropic Rearrangements-2 Chem 206D. A. Evans a73 [1,5] Sigmatropic Rearrangements (C migration) [1s,5s] alkyl shift ? RETENTION SIGMATROPIC REACTIONS - FMO-Analysis 1 2 3 ?/hν R = H, CR3 4 5 1 2 3 4 5 [1a,5a] alkyl shift ? INVERSIONa73 [1,5] Sigmatropic Rearrangements (H migration) disfavored a73 [1,5] (C migration): Stereochemical Evaluation 230-280°C RETENTION [1,5s]H- shift[1,5s]C- shift nonbonding thermal hν photochemical the transiton structure View as cycloadditon between following species: pentadienyl radical + either, or suprafacial preferred Dewar–Zimmerman Analysis: Retention 0 phase inversions ? Huckel toplogy 6 electrons therefore, allowed thermally 13 5 1 5 a71 a71 a71 R R R R R R R R O R C O O R R H BuLi O R Li O Li C O OLi R R H O Li R Sigmatropic Rearrangements: An Overview Chem 206D. A. Evans [1,2] Sigmatropic Rearrangements: Carbon + + consider as cycloaddition transition state a71 a71 olefin radical cation a71 + [1,2]-Sigmatropic rearrangements to cationic centers allowed.Wagner-Meerwein Rearrangement [1,2]-Sigmatropic rearr to carbanionic centers not observed consider as cycloaddition a71a71 a71a71stepwise a71 olefin radical anion a71a71 a71 a71a71 a71 antibonding transition state The Wittig Rearrangement [1,2] "[2,3]-Wittig Sigmatropic Rearrangements in Organic Synthesis.", Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885. Marshall, J. A. The Wittig Rearrangement.; Trost, B. M. and Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, pp 975. a71 Ra71This 1,2-sigmatropic rearrangement is non-concerted The Wittig Rearrangement [2,3] Allyl radical ketyl radical a71a71 a71a71 Ea ~16 Kcal/mol The G? between concerted and non-concerted pathways can be quite small a71a71 concerted transition state FMO analysis FMO analysis FMO analysis N MeCN Me R2 R3R1 – + X Y: R2 R3R Me O Ph Me Ph O R BuLi BuLi R O Ph Li+ Me Ph O Me Li+ R2 R3R :X Y Ph O H Li R? Me PhLiO Me Y:X R R3 R2 Li O R Ph N Me Me Me N R1 R3 R2 Me CNMe O MeMe Me Me S S BuLi BuLi BuLi BuLi N CH2 MeMe O MeMe Me Me S S Li+ NMe2CH2 H OH MeMe MeMe Me2N R1 R3 R2 CN S S OH MeMe Me Me NMe2Me important extension lacking CN FG; Sato, JACS 1990, 112, 1999 Mander, JOC 1973, 38, 2915 Buchi, JACS 1974, 96, 7573 + a73 X - N, Y = C; Ammonium Ylide Rearrangement: – a73 X - S, Y = C; Sulfonium Ylide Rearrangement: Lythgoe, Chem Commum 1972, 757 Chem 206D. A. Evans [2,3]-Sigmatropic Rearrangements: An Introduction – a203 Sommelet-Hauser: [2,3] a203 Modern versions of Stevens: Review, Pines, Org. Rxns 1970, 18, 416 [2,3] [2,3] [2,3] Sigmatropic Rearrangements a54a54 a73 General Reviews: a73 Representative X-Y Pairs: ? An important early paper: Baldwin, J. Chem. Soc., Chem. Comm. 1970, 576 S–P, S–N, S–O (sulfoxides) O–P (phosphites) N–N, Cl+–C (haloium ylids) P–C, C–C (homoallylic anions). Attributes: Stereoselective olefin construction & chirality transfer a73 The basic process: X & Y = permutations of C, N, O, S, Se, P; however X is usually a heteroatom Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 6, Chapter 4.6: Nakai, T.; Mikami, K. Org. React. (N.Y.) 1994, 46, 105-209. Hoffmann, Angew. Chem. Int. Ed. 1979, 18, 563-572 (Stereochemistry of) Nakai, Chem. Rev. 1986, 86, 885-902 (Wittig Rearrangement)Evans, Accts. Chem. Res. 1974, 7, 147-55 (sulfoxide Rearrangement) Vedejs, Accts. Chem. Res. 1984, 17, 358-364 (Sulfur Ylilde Rearrangements) N–O (amine oxides) S–C (sulfur ylids) O–C (Wittig rearrangement) N–C (nitrogen ylids) S–S (disulfides) Baldwin, JACS 1971, 93, 3556 – a73 X - O, Y = C; Wittig Rearrangement: [2,3] – [1,2] ? Garst, JACS 1976, 98, 1526 base temp –25 °C ~70% ~30%Rautenstrauch, Chem Commun. 1979, 1970 N Me Me O R2 R3R1 + – R2 R3R1 OH R1 R3 R2 N N O H OMe OMe NMe2 –N2 Cu(I) C NMe2 O R2 R3R1 O R1 R3 R2 C NMe2 O H R2 R3R1 CO R1 R3 R2 O R2 R3R1 NMe2 R2 R3R1 OR O ROH R2 R3R1 SeAr N Ts S OAr R1 R3 R2 S TsO Ph Ts–N–Cl Na+ Se Ar N R2 R3R1 Ts R1 R3 R2 OS Ar S Ph TsO NTs BuLi PhSCl R1 R3 R2 ONMe Me N Ts R1 R3 R2 OH NTsO Ts SPh N Ts TsO R2 R3R1 OH NH–Ts R1 R3 R2 (MeO)3P NaOH keq < 1 note that the product contains the retrons for the enolate Claisen rearrangement Smith, Chem. Commun. 1974, 695; Smith, JOC 1977, 42, 3165 a73 X - O, Y = C; An all-carbon Rearrangement : Chem 206D. A. Evans [2,3]-Sigmatropic Rearrangements: Introduction-2 In thinking about this rearrangement, also consider the carbenoid resonance form as well: – + 140 °C a73 X - O, Y = C; Wittig-like Rearrangements Buchi, JACS 1974, 96, 5563 – Hopkins, Tet Let. 1984, 25, 15 Hopkins, JOC 1984, 49, 3647 a54a54 a73 X - S, Y = N; Related Rearrangement + a54 selenophile Evans, Accts. Chem. Res. 1974, 7, 147 thiophilea54 – + a73 X - S, Y = O; Sulfoxide Rearrangement a54 a54 Hopkins, JOC 1985, 50, 417 a73 X - N, Y = O; Meisenheimer Rearrangement Zn/HOAc Tanabe, Tet Let. 1975, 3005 a73 X - Se, Y = N; Related Rearrangement – [2,3] –85% yield overall Dolle, Tet Let. 1989, 30, 4723 Me O Ph RLi Y:X Ra Rb X Y: RbRa X Y Rb H H Ra H X Y HRb Ra Rb Ra:X Y Ra Y X HH Rb Y:XRa Rb H Ra Rb X Y H X Ra RbY: RbRa :X Y CO2H O Me R1 S OAr R2 R2 SAr O R Me O SnBu3 R MeOBu3Sn R1–XRLi n-BuLi n-BuLi OS R1 Ar R2 HO Me Ph CO2H Me HO R Me OH Me OHR MeOH (MeO)3P R2R1 OH R OH Me a74 Product olefin geometry will be (E) from (Z) starting material Houk JOC 1990, 55, 1421 (Wittig transition states) Houk JOC 1991, 56, 5657 (Sulfur ylide transition states) Several theoretical studies have been published: Good reading only (E) isomer (91%)-78 °C a74 However, Cis selectivity is dependent on starting olefin geometry -78 °C ratio, 65:35 The preceeding transition state models do not explain some of the results: Evans, Accts. Chem. Res. 1974, 7, 147-55 (E) selectivity: >95% Nakai, Tet. Lett 1981, 22, 69 (E) selectivity: 75%2 LDA-75 to -50 °C -75 to -50 °C (E) selectivity: "only isomer" a74 Product olefin geometry can be either (E) or (Z) from (E) starting material a74 (Z) Olefin rearrangements might exhibit higher levels of 1,3 induction a74 Olefin geometry dictates sense of asymmetric induction in rearrangement Conclusions ? favored ?highly disfavored a74 Cis selectivity has been observed: Still JACS 1978, 100, 1927. Starting olefin: Trans Ra & Rb prefer to orient in pseudo-equatorial positions during rearrangement;nevertheless, this is a delicately balanced situation ? ? [2,3]-Sigmatropic Rearrangements: Olefin GeometryD. A. Evans Chem 206 a73 1,2-Disubstitution: Good Trans Olefin Selectivity Starting olefin: Cis favored disfavored N + Me MeMe Me N + Me Me CH2–TMS Me X R1 R2Y: Me X Y: R2R1 Me X Y R2 H H R1 Me R1 Y X HH R2 Me H R1 R2 X Y H Me H X Y HR2 R1 Me Y:X R1 R2 Me R2R1 :X Y Me R2 R1:X Y Me Y:XR1 R2 Me Me O n-Bu CH2–Li SnBu3O Me n-Bu n-Bu Me O Li n-BuLi KH MeH O H2C HH Li C4H9 Me H C4H9 H O H2C H Li n-Bu Me OH n-Bu Me OH Me NMe2 Me NMe2 halogen SnBu3 Me n-Bu LiO CH2 Me CH2LiOR1 a74 Olefin geometry dictates sense of asymmetric induction in rearrangement a74 (Z) Olefin rearrangements might exhibit higher levels of 1,3 induction a74 Product olefin geometry can be either (E) or (Z) from (E) starting material a74 Product olefin geometry will be (E) from (Z) starting material a73 Starting olefin: (Z) Chem 206D. A. Evans [2,3]-Sigmatropic Rearrangements: Olefin Geometry ? ? R1–Me interaction can destabilize the (E) transition state while (Z) TS might be destabilized by R 1 interactions with both X-Y and allyl moiety. a73 Starting olefin: (E) Trisubstituted highlydisfavored ? favored ? Conclusions (E)-path (Z)-path -78 °C a73 (Z) selectivity has been observed: Still JACS 1978, 100, 1927. 95%, >96% (Z) Still says that the TS is early, so that the 1,2 interactions in the TS are most important. (Z)-path (E)-path ? ? destabilizing a73 (Z) selectivity has also been observed by others: Sato JACS 1990, 112, 1999. -70 °C LHMDS, NH3 76%, (Z):(E) 95:5 X - X - 61%, (E):(Z) 100:0 Cs–F in HMPA 25 °C Me SN N Me S O R1 Me Ar n-BuLi N Me N S Me Li H PhS O H H R1 Me H R1 O S HH Me Ph Br Me Me OH Me Me Me N Me N S Me Me OHH Me SN N Me Me Me O Me Me N Me N S Me OS R1 Me Ph RCO3H R1 S O Me Ph Bu SPh Me Me O C5H11 CO2H CO2Me Me O Me N2 C(COOMe)2 S R R CuSO4 :CR2 Me SPh Bu CO2Me CO2Me C5H11 HO CO2H Me S R R C R R Me CO2MeHO Me C R R S R R H Me S Bu PhCO2Me CO2Me Trisubstituted olefins via [2,3]-rearrangement of sulfoxides: However, this reaction is not general: LDA (E):(Z) 31:69 Nakai, Tet Let 1986, 27, 4511 Nakai, Tet Let 1981, 22, 69 (E):(Z) > 95:5 (74%)2 LDA a73 Trisubstituted olefins via Wittig [2,3]-rearrangement: pKa ~ 18 (DMSO base +–++ A general procedure for the direct synthesis of sulfur ylides: Grieco, JOC 1973, 38, 2572 (E):(Z) > 90:10 (70%) a73 Trisubstituted olefins via [2,3]-rearrangement of sulfonium ylides: –+100 °C (–)is operationally equivalent to:(–) Accts. Chem. Res. 1974, 7, 147-55 [2,3] α α/γ = 90:10 (95%) γ α (E):(Z) > 97:3 (80-85%) 25 °C Et2NH, MeOH – (Z)-path (E)-path ? ? [2,3]-Sigmatropic Rearrangements: Olefin GeometryD. A. Evans Chem 206 favored disfavored Me Me Me Me MeMeMe Me Me Me Me Me Me MeMe Me SPh X Y: RMR L Me Me Me OH S MeMe Me Me Me H OMe OMe NMe2 n-BuLi H X Y RM H RL H RL Y X RMH O MeMe Me C: NMe2 Me Me Me Me S Me Li Me Me Me Me Me SLi O Me Me NMe 2 Me RM RL :X Y Y :X RL RM SMe Me Me Me Ph MeMeMeMe Me Me Me Me Me Me S Me Me S MeMeMe Me MeS MeMeMe S Me Me Me MeS Me Me Me Me F MgBr This rxn is probably not as stereoselective as advertised poorly selective 140 °C Buchi, JACS 1974, 96, 5563 Rautenstrauch, Helv. Chim Acta 1971, 54, 739 (E):(Z) = 3:2 For related [2,3] rxns See Baldwin JACS 1968, 90, 4758 Baldwin JACS 1969, 91, 3646 For study on this [2,3] rxn See Baldwin JACS 1971, 93, 6307 Squalene Li/NH3 "gave one major product in high yield" [2,3] – + benzyne heat PPh3 → S=PPh3 An elegant squalene synthesis Ollis, Chem. Commun 1969, 99 [2,3] (RL = large) a73 Trisubstituted olefins via [2,3]-rearrangement: One might project that the (E) path will be moderately favored with selectivity depending on size difference between RL & RM (Z)-path (E)-path ? ? [2,3]-Sigmatropic Rearrangements: Olefin GeometryD. A. Evans Chem 206 CO2H NH2 Me Me S + O – O Me Me Me S + Me Me Me O O CO2H SH Me Me S O O Me Me Me HBF4CH 2Cl2 N2 S Me Me Me O O CO2H S Me Me Me S O O Me Me Me C3H7 O MeBu3Sn Me OBOMMe ROCH2 CH2OR NO O Me O O N CH2OR ROCH2 BuLi BuLi OBOM MeBu3Sn O Me C3H7 MeS + Me Me O O – Me Me Me Me O O S Me Me Me O O S Me HO O XC XC O HO OH OBOM MeMe Me C3H7 C3H7 MeMe Me OBOMOH See these papers for other applications Kallmerten SynLet 1992, 845. Kallmerten TL 1993, 34, 749. Kallmerten TL 1993, 34, 753. n-BuLi, THF, -78 °C Kallmerten TL 1988, 29, 6901. diastereoselection > 100:1 (64%) diastereoselection > 100:1 (57%) n-BuLi, THF, -78 °C Internal Relay of Stereochemistry in C–C Constructions Cp2ZrCl2 97% syn; 96% de (43%) 96% de (61%) Katsuki, Tet Lett 1986, 27, 4577 Chiral Auxiliaries can also be used in the Wittig Rearrangement 64%, 4:93 steps steps DBU, -78 °C Allylation [2,3] Sulfur Ylide Rearrangement Using a Chiral Auxiliary Kurth JOC 1990, 55, 2286 and TL 1991, 32, 335 66%, 94:4 BF4 - [2,3]-Sigmatropic Rearrangements: Chirality TransferD. A. Evans Chem 206 SO Ph NMe O OMe HO MeO NMe O CO2Et H H C5H11 ? SPh C5H11 CO2Et O HO NMe NMeS O Ph O MeTBSO TMS O O Me O Me SnBu3 n-BuLi OH C5H11 O CO2H O CO2Et C5H11 OH –SPh O O CH C OH2C Me HO MeO O Me TMS TBSO OH Me TMS TBSO OH O O Me HO Me Can you rationalize the stereochemical outcome of this reaction? Allylic Ethers to Make Three Contiguous Stereocenters Nakai TL, 1988, 29, 4587. n-BuLi, -78 °C 94% 4% Bruckner, Angew. Chem. Int. Ed. 1988, 27, 278 A Felkin analysis predicts the major product – ratio 79 : 6 Cases where the chirality is exocyclic to the rearrangement 15 15 15 steps Kondo Tet. Lett. 1978, 3927. 1) MCPBA 2) P(OMe)3 HSPh, KOt-Bu Taber J. Am. Chem. Soc. 1977, 99, 3513. cepharamine Tandem [ 4+2 ] & [ 2,3 ] Process: Evans, Bryan, Sims J. Am. Chem. Soc. 1972, 2891. Na2S, MeOH + Internal Relay of Stereochemistry in C–O Constructions [2,3]-Sigmatropic Rearrangements: Chirality TransferD. A. Evans Chem 206 C N S R3 SMe NHTs R3 OH H Me Me H O CH2 O H OMe OMe NMe2 C NMe2 O R3 HO Me O H MeMe H O R3 NMe2 H Me Me HC O Me HO S Ph O CMe3 S Ph CMe3 H Me3C X :Y H N2=CHCO2Et N NHTs C SMe–S H MeMe N NHTs Me S C SMe S R3 C SMe SMe R3 S O CMe3 OEt MeMe O H HHO MeMeMe Me MgBr Me Br MeMe H H Me Me H S Me MeS CMe3 N CH CN CMe3 O (MeO)3PMeOH H2SeO3 NaH NaH H Me3C OSPh S Ph CMe3 CH CO 2Et NMe 3C H CN Me3C H OH O OEt H Me3C Y X:Me3C H CO2EtH Me3C SPh OHMe3C H Cu(I) catalysis Mander, JOC, 1973, 38, 2915 selectivity: 90:10– -10 °C 25 °C selectivity: 75:25 selectivity: 52:48 selectivity: 92:8 Evans, JACS, 1972, 94, 3672 House, JOC 1975, 40, 86 a73 The comparison of analogous [2,3] & [3,3] rearrangements: selectivity: 91:9 – + 25 °C favored heat heat [2,3] Sigmatropic rearrangements respond to subtile steric effects Note that rearrangement is not required to proceed via the carbenoid. propose altenate mechanism Bakkenolide-A HgCl2, HOH 65% (no other isomer) 65 °C a73 The synthesis: 65 °C Baldwin, Chem Comm 1972, 354 : a73 Candidate processes: : Buchi, JACS 1974, 96, 5563 140 °C : The Synthesis of Bakkenolide-A (Evans JACS 1977, 99, 5453) Chem 206D. A. Evans [2,3]-Sigmatropic Rearrangements: Chirality Transfer + S Cu(O) N2 CO2Et S Et O Me O Me Me OH HO Me O NMe Me NaNH2 KOt-Bu S N Me CH2 S CO2Et DBU TfO CO2Et N Me S EtO2C S CO2Et N MeH NMe Me Me O Me Me Br Ph O R2N–Li Ph N Ph Me Li Me N Ph O Me Me Me Me N MeMe O Ph Me O Me MeO– MeO– MeOH MeOH Me Ph N Me Me Me O N OMe Me Me Ph Me Me HO Me Me O Me O salts readily separated nonselective N-alkylation Stevenson, Tet. Lett 1990, 31, 4351 A ring contraction using the Stevens Rearrangement Both rearrangements afford a single isomer 78% 54% + + Marshall, JACS 1988, 110, 2925 A ring contraction using the Wittig Rearrangement Aristolactone 82%, 69% eeWith chiral amidebases induction is observed! – 83% liq NH3 Hauser, JACS 1957, 79, 4449 + – + An early ring expansion using the Sommelet-Hauser Rearrangement Vedejs, JACS 1989, 111, 8430 Methynolide has been synthesized by Vedejsusing this ring-expansion methodology 72% 72% + 50%–+ Methods based on sulfur ylides: (review) Vedejs, Accts. Chem. Res. 1984, 17, 358 Ring expansion reactions have been investigated Chem 206D. A. Evans [2,3]-Sigmatropic Rearrangements: Ring Expansion & Contraction