34_Carbocations_2

Chem 206D. A. Evans Carbocations: Stability, Structure, & Rearrangements Problem 185: Final Exam, 1999. During Corey's synthesis of Aspidophytine (JACS, 1999, 121, 6771), the pivotal intermediate 3 was assembled by the union of 1 and 2 under the specified conditions. Provide a mechanism for this single-pot transformation. N OMe MeO Me NH2 OHC CHO Me3Si CO2R + 1) mix at room temp, 5 min 2) 2 equiv. TFAA, 0 °C N Rc Rd Ra Rb 3) excess NaBH3CN N N MeO MeO Me H CO2R 1 2 3 Problem 56: Here is a typical carbonium ion question that you should be able to handle by the end of the course. Write out a mechanism for the following transformation. Me Me Me O A. Srikrishna, Chem Commun 1994, 2259 BF3•OEt2 CH2Cl2 60% yield H Me Me Me CH2 O Holton & Co-workers, JACS, 110, 6558 (1988). Problem 79: In a synthesis of taxusin, the pivotal reaction(s) which generated the bicyclo [5.3.1.] undecane ring system charactertistic of this family of terpenoids are illustrated below. Given the illustrated transformation, what specific reagents would you employ to carry out this process. HO Me OH HO Me R Me Me H Me Me OH O OH HO Me R Me H ? D. A. Evans Wednesday December 14 , 2005 http://www.courses.fas.harvard.edu/~chem206/ Reading Assignment for this Lecture: Other Relevant Background Reading Carey & Sundberg, Advanced Organic Chemistry, 4th Ed. Part A Chapter 5, "Nucleophilic Substitution", 263-350 . Saunders, M. and H. A. Jimenez-Vazquez (1991). “Recent studies of carbocations.” Chem. Rev. 91: 375. Chemistry 206 Advanced Organic Chemistry Lecture Number 34 Introduction to Carbonium Ions–2 ! Allyl- & Vinylsilanes: The !-Silicon Effect ! Carbonium Ion Rearrangements Walling, C. (1983). “An Innocent Bystander Looks at the 2-Norbornyl Cation.” Acc. Chem. Res. 16: 448. (handout) Birladeanu (2000). “The Story of the Wagner-Meerwein Rearrangement.” J. Chem. Ed. 77: 858. (handout) Lambert, (1999). “The ! effect of silicon and related manifestations of " conjugation.” Acc. Chem. Res. 32, 183-190. (handout) Chem 206Carbocation Rearrangements-1M. Shair, D. Evans 2-electron Huckel transition state B A C D B A C D 1,2 Sigmatropic shifts are the most commonly encountered cationic rearrangements. When either an alkyl substituent or a hydride is involved, the term Wagner-Meerwein shift is employed to identify this class of rearrangments. Stereoelectronic requirement for migration.... B A C D bridging T.S. retention of stereochemistry Birladeanu (2000). “The Story of the Wagner-Meerwein Rearrangement.” J. Chem. Ed. 77: 858. (handout) Carbocation [1,2] Sigmatropic Rearrangements OH MsO OH TBSO H RO H O OH H H CH2Cl2, -78˚C S. L. Schreiber et al Tetrahedron Lett. 1989, 30, 3765. If migration accompanies ionization, the migration terminus will be inverted. Overlap between the ! C-C (migration origin) and the !* C-X (migration terminus) will be maximized in an antiperiplanar arrangement. RO H OH OH H H Et2AlCl OH OH O Pinacol rearrangement (vicinal diol): Driving force is the gen. of C=O CH2NH2 Deamination " NO+ " CH2 OH Demjanov-rearrangement (Driving force: relief of ring strain) H+ Me MeMe Me H Me Me H HMe OH Me Me H H Me Me Me HO H Wagner-Meerwein Rearrangements: Application in Total Synthesis !-caryophyllene alcohol E. J. Corey JACS 1964, 86, 1652 (handout). OH H Me Me Me Meequiv to A Preparation of A: Me Me H H Me O Me Me Me O H h" A MeMgBr [2+2] H2SO4 Chem 206Carbocation Rearrangements-2M. Shair, D. Evans Synthesis of (±)-Isocomene: Pirrung, JACS 1979, 7130; 1981, 82. Me Me Me Me (±)-Isocumene Me Me Me Me Me Me Me H+ Me Me Me Me Carbocations: Neighboring Group Participation R R X: R R Y R R R R X R R X: R R Nuc Nuc: Groups with accessable electron density (heteroatoms, arenes) and the correct stereoelectronic orientation (anti-periplanar) can "assist" in the ionization of a leaving group. OTs O Me O OTs O Me O HOAc HOAc OAc O Me Okrel = 1 krel = 10 +3 O O Me Y- OTs H non-classical carbonium ion OTs HOAc OTs krel = 95 krel = 1 R. G. Lawton, JACS 1961, 2399 OTs MeH Ph MeH The Cram Phenonium Ion Experiments: Cram, JACS 1949, 71, 3865 L-Threo Me Me HH OAc MeH Ph MeH Ph MeH H Me AcO L-Threo D-Threo 98% chemical fidelity TsO– OTs HMe Ph MeH L-Erythro Me H MeH OAc HMe Ph MeH Ph HMe H Me AcO 98% chemical fidelity TsO– L-Erythro L-Erythro Chem 206Allyl- & Vinylsilanes: The !-Silicon EffectM. Shair, D. Evans Allyl– & Vinylsilanes react with electrophiles References: Lambert Acc. Chem. Res. 1999, 32, 183-190 Lambert, JACS 1990, 112, 8120; 1996, 118, 7867. Fleming, Organic Reactions 1989, 37, 54. Fleming, Chem. Rev., 1997, 2063. R3Si E E SiMe3 E E "R3Si +" "R3Si +" (trapped by solution Nu) Mechanism - the simple picture: !-Silicon stabilizes carbocation R3Si E R3Si E Nu E SiMe3 E H2C SiMe3 E Nu E Fleming, Organic Reactions 1989, 37, 54. !-Silicon Effect: the origin of regioselectivity Si "Si–C # pz empty "SiC pz E"occ pz H3Si H H CH2 versus H3C H H CH2 Calculation: A more stable than B by 38 kcal/mol. Jorgensen JACS 1985, 107, 1496. A B Magnitude of the !-Silicon Effect Me3C H SiMe3 OCOCF3 H H 1 Me3C H Me OCOCF3 H H 2 Solvolysis (CF3CH2OH) k1 k2 = 2.4 x 10+12 Me3C H H OCOCF3 SiMe3H 3 Me3C H H OCOCF3 Me H 4 Solvolysis (CF3CH2OH) k3 k4 = 4 x 10+4 "These figures established the !-effect as one of the kinetically strongest in organic chemistry": J. Lambert Data provide no distinction between open and bridged intermediates In all instances, the solvolysis product is 1-tert-butylcyclohexene Proof for a stepwise mechanism provided the following protodesilylation experiment: Me3Si SiMe2Ph Me3Si SiMe2Ph Me3Si SiMe2Ph Me3Si SiMe2Ph both silanes yield the same product mixture. Hence, the reaction proceeds most likely via a common intermediate, a carbeniumion H Chem 206Allyl- & Vinylsilanes: The !-Silicon Effect-2M. Shair, D. Evans Allylsilanes are more nucleophilic than alkenes HOMO is higher in energy due to negative hyperconjugation ! (!*) !C–Si Houk, JACS 1982, 104, 7162. !Si–C E ! !* !Si–C ! Electrophile Addition - Stereoelectronics R3 R2 R1 H R Si R3 R2 H R Si !CSi E E major (trans) + Nu - NuSiMe3 anti addition observed A1,3-strain minimized !C–Si H R R3 E R1 R2 R3 R2 R1 Si H R R3 Si H R E R H R3 + Nu - NuSiMe3 E R1 R2 E R1 R2 !C–Si minor (cis) anti addition observed The stereochemical consequences for the major product are: Examples: Me Ph Me3Si H CH2Cl2 Ph t-Bu H Me t-BuCl, TiCl4 JACS 1982, 104, 4962.But R Ph HMe3Si HF Protodesilylation R Ph E:Z 88:12! ! trans-alkene: ! anti-addition of E+ with respect to SiR3 Carbonyl Addition of Allylsilanes: Open Transition States Me3Si – is not sufficiently Lewis acidic to activate C=O through pre-association; however (RO)2MeSi – is Lewis acidic enough to activate C=O through pre-association. These allylsilanes add to RCHO througl closed transition states R2R1 O H R SiMe3 XnM R2R1 R O H SiMe3 XnM ORAntiperiplanar TS Synclinal TS Calculations by Houk et al. show that the relative energy differences between the antiperiplanar and and synclinal transition states are negligible. Both the antiperiplanar and synclinal models predict a syn selectivity for the newly formed stereogenic centers. R O Me3Si Me TiCl4 CH2Cl2 + R Me OH > 95:5 syn R O Me3Si TiCl4 CH2Cl2 + R Me OH Me R Me OH ca. 65 : 35 syn Hayashi, TL 1983, 2865. H H Catalytic Enantioselective Addition of Allylic Organometallic Reagents to Aldehydes and Ketones, Denmark and Jiping Fu, Chem. Rev. 2003, 103, 2763-2793 (handout) Chem 206Allylsilanes: Reactions with ElectrophilesB. Breit, D. Evans Allylsilanes add to aldehydes and acetals under Lewis acid promotion regioselectivity: Allyl inversion Me3Si Ph O Me TiCl4 OH n-C3H7 Ph Me3Si O Me Ph + + TiCl4 OH n-C3H7 Ph H H Acetals can be used as well Me3Si Me Me Me3Si Me Me OCH3 H3CO n-C4H9 + + OCH3 H3CO n-C4H9 TiCl4 TiCl4 n-C4H9 OCH3 Me Me n-C4H9 OCH3 Me Me (80%) (83%) The Sakurai Reaction (Enone Conjugate Addition) Me O Me3Si TiCl4 CH2Cl2 Me OTiCl4 SiMe3 Me O Me O Me3Si 75% 17% Fleming, Org. Reactions 1989, 37, 127-133 Me O EtAlCl2 CH2Cl2 Me O SiMe3 Majetich, Tetrahedron 1987, 43, 5621 78% Reactions Proceedilng through Silicon-Migration Me O (Pri)3Si TiCl4 CH2Cl2 Me OTiCl4 Si(iPr)3 Me OTiCl4 Si(iPr)3 Me O (Pri)3Si A. I. Meyers, J. Org. Chem. 1998, 63, 5517 diastereoselection: 97:3 85% yield Si migration may be promoted by using hindered Si substituents MeO2C CO2Me Ar ZrCl4 CH2Cl2 (Pri)3Si Ph(Pri)2Si CO2Me Ar MeO OZrCl4 – SiR3 CO2Me Ar MeO OZrCl4 – SiR3 Ar MeO2C MeO2C SiR3diastereoselection: 96:4 68-70% yield CO2Me Me PhMe2Si Me H O CO2Me CHO Me PhMe2Si Me BF3°OEt2 rt 8 h diastereoselection: >30:1 93% yield Panek, J. Org. Chem. 1993, 58, 2345 Can you work out the mechanism?? Chem 206Vinylsilanes: Reactions with ElectrophilesB. Breit, D. Evans Stereochemistry of Electrophile Addition to Vinylsilanes R1 R2 H SiMe3 R1 R2 H I RETENTIONN O O I Vinyl/Allylsilanes in Organic Synthesis - Selected Examples Fleming, Org. Reactions 1989, 37, 54. El R1 R2 Me3Si H R1 R2 El SiMe3 H R2R1 SiMe3H El ! R2R1 ElH + Nu- - NuSiMe3 SiMe3 • Rotation in direction a favored (avoidance of eclipsing interactions, • Principle of least motion a El a OH H R MeMe SiMe3 H R O Me Me TiCl4 Fleming p 289 SiMe3 Et Et ClCH(OMe)2+ TiCl4 - 78 °C Et Et OMe (73%) OMe N H N Me N H NH Me SiMe3 (CH2O)n TsOH Fleming p 148 Summary Statements 1. Me3C+ is more stable than Me3Si+ in spite of the fact that Si is less electronegative than C. Si C Me Me H H H Si C Me Me H H H C C Me Me H H H C CMe Me H H H C–Si bond length: 1.87 Å C–C bond length: 1.54 Å C–Si hyperconjugation is less pronounced than the anaologous C–C hyperconjugation do to the impact of the longer C–Si bond lengths. 2. Carbonium ions ! to Si are less stabilized than carbonium ions " to Si. Si C Me Me H H Me Si C Me Me H H Me C Me3Si C H H H H C Me3Si C H H H H C(+) ! to silicon C(+) " to silicon C–Si hyperconjugation is less pronounced than the anaologous C–C hyperconjugation do to the impact of the longer C–Si bond lengths. 3. According to Lambert, silicon has a propensity to stabilize ! carbonium ion via hyperconjugation (vertical stabilization) rather than bridging (nonvertical stabilization. C Me3Si C H H H H C Me3Si C H H H HC(+) ! to silicon hyperconjugation more important than bridging C Me3Si C H H H H 4. Silicon has a lower propensity to undergo Wagner–Meerwein like rearrangements than carbon. Chem 206M. Shair, D. Evans Stabilized Cations: Iminium-Ions 1 N R1 R2 R4 R3 R1 R2 O N R4 R3 H N R1 R2 R4 R3 N OR2 R1 N R1 Iminium Ions Common Methods of Generation: H+, -H2O H+, -ROH or Lewis Acid or Lewis Acid X- N Me N Me Hg H H X– X N Me H Hg(0) HX X– rds Oxidation of Amines HgX2 N N H H MeO2C OH H N N H H MeO2C OH H H Stereoelectronic Effects on Nu Addition to Iminium Ions Hg(OAc)2/EDTA one diastereomer Stork et al. JACS 1972, 94, 5109. N H H CO2Me OH H R Nu (favored) C=N Stereoelectronic Effects: Lecture 20 H H NaBH4 NMe3Si Ph N Ph Me3Si N H Ph H N H Ph SiMe3 H H TFA (E) (Z) Overman et al. TL 1984, 25, 5739. Only in the case of the (Z) vinylsilane is the emerging p orbital coplanar with C-Si bond. Full stabilization of the empty orbital cannot occur with the (E) vinylsilane.....hence the rate difference. rel rates: 7000/1 TFA (Z) vinylsilane) N H Ph H H SiMe3 (E) vinylsilane) N O H TMS R Me Me N H Me RMe TMS N H Me RMe OH OH PPTS, MeOH 80˚C 71 % one double bond isomer Overman et al. JOC 1989, 54, 2591. pumiliotoxin A "Least Motion Argument" steps The Aza-Cope RearrangementD. A. Evans, M. Calter Chem 206 Review: Heimgartner, H. In "Iminium Salts in Organic Chemistry"; Bohme, H., Viehe, H., Eds.; Wiley: New York, 1979; Part 2, pp 655-732. The 3-aza-Cope Rearrangement: [3,3] Exothermic as written by ~7-10kcal/mole. 1 2 3 1 2 3 Neutral Variant: N N RR Ammonium Variant: [3,3] Even more exothermic than the neutral version, since enamine lacks resonance and iminium salt has stronger p-Bond than imine does. NN R R R R 2-aza-Cope Rearrangement: 3 2 1 [3,3] 1 2 In the simplest case, degenerate. Steric effects, conjugation, or selective trapping of a particular isomer, will drive equilibrium. As with the 3-aza-Cope, the cationic version proceeds under much milder conditions. N R N R 1-aza-Cope Rearrangement: 3 2 1 3 2 1 [3,3] The 3-aza-Cope rearrangement can be driven in reverse by judicious choice of substrates(i.e., incorporating the imine into a strained ring or by making R an acyl group). N R N R The 3-aza-Cope Rearrangement First Neutral Case: Hill TL 1967, 1421. 250oC, 1 hr "Practically quantitative", no real yields given. First Cationic Case: Elkik Compt. Rend. 1968, 267, 623. 80 oC, 2-3 hr + + No yields given. N Me Me Me N Me Me Me Me N Me Me N Me Me Me Me Me Me OHC Me H2O Good way to allylate aldehydes: Opitz Angew. Chem. 1960, 72, 169. + + OHC R' R N HR'' R'' R R' N R'' R'' X N R'' R'' R' RR R' R''' R'''R''' O H N R'' R'' R' R R'''[3,3] ! H2O -H2O 2-aza-Cope Equilibrium between A and B driven towards B by conjugation of iminium double bond to the aromatic ring in B. + HCHO HCOOH 100oC, 2hr. First Reported Case: Horowitz JACS 1950, 72, 1518. The 2-aza-Cope Rearrangement Chem 206D. A. Evans, M. Calter The Aza-Cope Rearrangement NH2Ph Ph N H N H Ph H2N BA H2O PhCHO Yohimbane 15-Methoxy-isoyohimbane HCHO, MeOH, Cat. H+, 85% Yohimbine Application to Yohimbine Analog Synthesis: Winterfeldt Chem. ber. 1968, 101, 2938. H N N H H NH O N H N NH H N N H H OMe H N N H OH CO2Me H POCl3 NaBH4 N NH H NaBH4 2-aza-Cope, driven by conjugation HCHO, H+, -H2O Mechanism for Yohimbane Analog Formation: .. N NH H N N H N N H N N H H OMe MeOH N-Acyliminium Ion Rearrangements: Hart JOC 1985, 50, 235. Hart observed an unusual product while trapping the intermediates of N-acyliminium olefin cyclizations. TFA N OH O C3H7 C3H7 O N N O C3H7 CF3CO2 C3H7 O N Et3SiH C3H7 O N C3H7 O N 40:60 ratio 2-Aza Cope rearrangements add to complexity of cyclization process Chem 206 M. Shair, D. Evans Stabilized Cations: AcylIminium-Ions N-Acyliminium Ion Rearrangements Synthesis of (-)-hastanecine: Hart JOC 1985, 50, 235. + 81% NaBH4, MeOH, 83% Me BnO NH2 O Me O O AcO NMe OMe O BnO OAcOAc BnO OH Me O NMe N Me Me OBn O OAc HCO2H OAc OMe Me N OBn H [3,3] (-)-hastancine N OAc O Me Me HO Me Me O OH NN OH BnO BnOHO N OAc O Me Me HCO2 BnO HCO2H HCO2H N O Me OH SiMe3 TFA N O Me SiMe3 N O CH2 Me H N O CH2 Me H 67% 29% Gelas-Mailhe, Tet. Lett, 1992, 33, 73 N O Me SiMe3 H [3,3] ???The origin of the modest diastereoselection has not been attributed to 2- aza-Cope process. Homo-chiral Mannich Pinacol : cyclization 1.5 hr, 79% O N Me Me Ph Ph N Ph Me Ph OH Me Me OH Ph N Me Ph NMe Me Ph Ph O Me OH Ph N Me Ph CSA, 60oC, [3,3] Competing 2-Aza-Cope and Pinacol Rearrangements: Which Dominates?? racemic product 2-aza-Cope rearrangements afford a low-barrier to competing processes Chem 206M. Shair, D. Evans Stabilized Cations: Iminium-Ions 2 N OR HO NR2 N OR HO NR2 2-Aza-Cope-Mannich sequence: (CH2O)n, Na2SO4 MeCN, 80˚C [3,3] N OR HO NR2 N O NR2 OR 98 %!! Axial Attack equivalent to N N OO H H H strychnine Overman et al. JACS 1995, 117, 5776. steps Mannich Rxn N O ROH2C H NR2 Overman et al. JOC 1991, 56, 5005 Another aza-Cope-Mannich sequence: HO O O NHBn Ar N O Bn OH N Bn Ar N Ar HO Bn N O Bn H H [3,3] [3,3] Mannich O O N O H H H2/Pd-C CH2O/HCl O H H N O O OO CH2O/HCl 97% 67% H N O O HO HO Pancracine steps Pictet-Spengler cyclization BF3 Chem 206D. Evans, E. Shaughnessy The Prins-Pinacol Reaction References Prins reaction: Adams, D.R.; Bhaynagar, S. D. Synthesis 1977, 661 Prins & carbonyl ene reactions: Snider, Comprehensive Organic Synthesis, 1991, Vol. 2 O R1 H R2 R1 R2 OH OO R1 R2 R2 R1 R2 OH - H+ HX R1 R2 OH X The Prins Process: O R1 H H R2 X– R1CHO The Prins-Pinacol Variant: O OMe Ph Me Me Me O Me Me Ph Me Cl4Sn–O Me O Me Me Ph Me Cl4Sn–O Me O Me Me Me Ph O Me Lewis Acid SnCl4 >95% ee Prins + – – H H Pinacol SnCl4 O OMe Ph Me Me Me O Me Me Ph Me O Me Evidence for Prins-Pinacol Mechanism >95% ee SnCl4, CH2Cl2 O O Me Me Ph Me - Cl4SnO Me O Me Me Ph Me - Cl4SnO Me Ph Me Me Me - Cl4SnO Me O Me MeMe PhO Me If a [3,3] rearrangement were intervening, the product would be racemic. Overman, JACS 2000, 122, 8672 Overman, Org Lett 2001, 3, 1225 + + enantiopure racemic Prins [3,3] Aldol (fast) pinacol H >95% ee Me MeHO OH OMe O Me O OMe Me Me Me OMe Me Me O Me Ph 7:1 anti:syn BF3•OEt2 (E)-CH=CHPhCHO CH2Cl2, -55 °C 97% SnCl4, CH2Cl2 -70 ! -23 °C 82% syn Examples of Stereoselective THF Formation Chem 206D. Evans, E. Shaughnessy The Prins-Pinacol Reaction O O Me Me Ph Me - Cl4SnO Me O Me Me Ph Me - Cl4SnO Me Ph Me Me Me – Cl4SnO Me O Me MeMe PhO Me Prins-Pinacol Mechanism >95% ee enantiopure Prins Aldol pinacol H SnCl4 [3,3] O O Me Me Ph Me Me CH2Cl2 Homo-chrial Prins cyclization faster than [3,3] rearrngement Homo-chiral Mannich Pinacol : cyclization 1.5 hr, 79% 2-aza-Cope vs. Pinacol: O N Me Me Ph Ph N Ph Me Ph OH Me Me OH Ph N Me Ph NMe Me Ph Ph O Me OH Ph N Me Ph CSA, 60oC, [3,3] racemic product [3,3] rearrngement faster than Mannich cyclization Overman: Magellanine Synthesis JACS, 1993, 115, 2992 TESO CH(OMe)2 O OMe H N O OMe H CHPh2 Me N O Me OH H (-)-Magellanine Me N O Me OH H (-)-Magellanine 57% Steps The pivotal transformation 1. OsO4, HIO4 2. Ph2CHNH3Cl NaBH3CN SnCl4 TESO O Me TESO CH(OMe)2 O OMe R H O OMe H ! ! ! mixture of diastereomers SnCl4 Chem 206D. Evans, E. Shaughnessy The Prins Reaction-3 Overman Synthesis of a Eunicellin Diterpene Overman & MacMillan JACS, 1995, 117, 10391 O Me Me Me HH Me AcOHO (-)-7-Deacetoxy-alcyoninacetate Me Me Me TMS OH OH ds = 9:1 OHC OTIPS Me OHC TMSO OMe Me Me Me Me Me I single stereoisomer 6 steps, 39% yield from (S)-carvone t-BuLi, THF, -78 °C PPTS, MeOH 64% Me Me Me TMS OH O R BF3•OEt2 (3 equiv.) CH2Cl2, -55! -20 °C 79% Me Me Me TMS OH O R Me2HC Me TMSO CHO [3,3] Me OTIPS Felkin Control (Lecture 20) Overman: Synthesis of trans-Kumausyne JACS, 1991, 113, 5378 O AcO Et Br trans-Kumausyne OH OH O H H O OBn BnOCH2CHO RSO3H, rt 69% O OH OBn [3,3] O OH OBn O H H OBn O O m-CPBA 72% 4:1 regioselectivity 1. H2, Pd-C, 88% 2. Swern, 100% O H H O O Et TMS BF3•OEt2 -78 °C ! rt 73% 1. 2. TBSCl O H H O O Et OTBS O HO Et OTBS H O DIBAL -78 °C 97% CHO Felkin Control (Lecture 20) Chem 206D. A. Evans The Prins Reaction-4 Mukaiyama Aldol–Prins Cascade Rychnovsky JACS, 2001, 123, 8420 The Basic Process OR El