D. A. Evans Iminium lons and their transformations Chem 206 http:/www.courses.fasharvardedu/-chem206/ )mix at room Chemistry 206 Or Meo Advanced Organic Chemistry Lecture number 32 o reversible? Introduction to carbonium lons-3 a Stabilized Carbocations: Iminium Ions(C-=nR2(+) i Meo I Stabilized Carbocations: Oxo-Carbenium lons( C=OR(+)) Meo Me t Meo a Stabilized Carbocations: Addition Rearrangements Reading Assignment for this Lecture Carey Sundberg, Advanced Organic Chemistry, 4th Ed CO2R Part A Chapter 5, "Nucleophilic Substitution, 263-350 12, 7) he pava a ie mediate was ssem sed by the nios of anydnzunders.:Meo- the specified conditions. Provide a mechanism for this single-pot transformation CHO at room Ra Rb 3)excess temp, 5 min NaBH3CN The product-determining step could be step A NabH3CN Rc R Meo Me Matthew d shair December 9. 2002
D. A. Evans Chem 206 Matthew D. Shair Monday, December 9 , 2002 http://www.courses.fas.harvard.edu/~chem206/ Reading Assignment for this Lecture: Iminium Ions and Their Transformations Carey & Sundberg, Advanced Organic Chemistry, 4th Ed. Part A Chapter 5, "Nucleophilic Substitution", 263-350 . Question 13. Final Exam, 1999. During Corey's recent 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 Chemistry 206 Advanced Organic Chemistry Lecture Number 32 Introduction to Carbonium Ions–3 ■ Stabilized Carbocations: Iminium Ions (C=NR2 (+)) ■ Stabilized Carbocations: Oxo–Carbenium Ions (C=OR(+)) ■ Stabilized Carbocations: Addition & Rearrangements OHC CHO Me3Si CO2R + 1) mix at room temp, 5 min 1 2 N OR O TMS N OMe MeO Me OR RO N OR O TMS N OMe MeO Me OR N OR O TMS N MeO MeO Me N N MeO MeO Me H CO2R N N MeO MeO Me H CO2R H N N MeO MeO Me H CO2R NaBH3CN TFA reversible? A The product-determining step could be step A
M. Shair D. Evans Stabilized cations: Iminium-lons 1 Chem 206 TEA Me si Common Methods of generation rel rates: 7000/1 月3H,+20 0 H-N R or Lewis Acid ROR Overman et al. TL 1984. 25. 5739 N-R, orlewis Add L, Oxidation of amines Hg(0) X (4 vinylsilane) (E)vinylsilane) HgX2 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 Related to polonovski Pummerer Reactions: Lecture 27 Stereoelectronic Effects on Nu Addition to Iminium lons PPTS MeOH Hg(OAch/EDTA MeO,C OH 71% one diastereomer Least Motion Argument Stork et aL. JACS 1972. 94. 5105 Overman et al. JOC 1989. 54. 2591 C=N Stereoelectronic Effects: Lecture 19
M. Shair, D. Evans Chem 206 N R1 R2 R4 R3 R1 R2 O N R4 R3 H N R1 R2 R4 R3 N OR2 R1 N R1 N N H H MeO2C OH Iminium Ions Common Methods of Generation: H N N H H MeO2C OH Stabilized Cations: Iminium-Ions 1 H + , -H2O H + , -ROH or Lewis Acid H or Lewis Acid H Stereoelectronic Effects on Nu Addition to Iminium Ions Hg(OAc)2 /EDTA one diastereomer Stork et al. JACS 1972, 94, 5109. N Me N Me Hg H H X – X N Me H Hg(0) HX X – rds Oxidation of Amines N H H CO2Me OH H R Nu (favored) N Me3Si 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 CSi 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 Me R TMS N H Me Me R OH OH PPTS, MeOH 80˚C 71 % one double bond isomer Overman et al. JOC 1989, 54, 2591. pumiliotoxin A "Least Motion Argument" steps C=N Stereoelectronic Effects: Lecture 19 H H Related to Polonovski & Pummerer Reactions: Lecture 27 NaBH4 HgX2 X -
D.A. Evans. M. Calter The Aza-Cope Rearrangement Chem 206 Review. The 3-aza-Cope Rearrangement Heimgartner, H In"Iminium Salts in Organic Chemistry"; ohme, H, Viehe, H, Eds. Wiley. New York, 1979; Part 2, First Neutral Case: Hill TL 1967. 1421 The 3-aza-Cope Rearrangement Neutral variant. 地2,MN Practically quantitative, no real 33] Exothermic as written by -7-10kcal/mole First Cationic Case: Elkik Compt. Rend. 1968, 267, 623 Ammonium Variant: Me80℃,Me、 133 Even more exothermic than the 2-3h version since enamine lacks and iminium salt has stronger H mine does 2-aza-Cope Re R In the simplest case, degenerate. Steric 3,3] effects, conjugation, or selective trapping of a particular isomer, will drive equilibriun As with the 3-aza-Cope, the cationic Good way to allylate aldehydes: Opitz Angew. Chem. 1960, 72, 169 version proceeds under much milder OHC 1-aza-Cope Rearrangement: The 3-aza-Cope rearrangement can be driven in reverse by judicious choice substrates(i.e, incorporating the imine into a strained ring or by making R an acyl group
D. A. Evans, M. Calter The Aza-Cope Rearrangement 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. 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. 1 2 3 1 2 3 Neutral Variant: 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. 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). 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. Good way to allylate aldehydes: Opitz Angew. Chem. 1960, 72, 169. + + N N R R N N R R R R N R N R N R N R N Me Me Me N Me Me Me Me N Me Me N Me Me Me Me Me OHC R' Me R OHC Me N R'' H R'' R R' N R'' R'' X N R'' R'' R' R R R' R''' R''' R''' O H N R'' R'' R' R R''' [3,3] H2O D H2O -H2O
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 206 The 2-aza-Cope Rearrangement Mechanism for Yohimbane Analog Formation First Reported Case: Horowitz JACS 1950, 72, 1518 HCHO a-Cope HcHO 2-aza-Cope, driven by A librium between A and B driven towards B by conjugation of iminium double bond N-Acyliminium lon Rearrangements: Hart JOC 1985, 50, 235 art observed an unusual product while trapping the intermediates of N-acyliminium Yohimbine Yohimbine C3H7 HCHO, MeOH Cat. H*. 85% 2-Aza Cope rearrangements add to 15-Methoxy-isoyohimbane complexity of cyclization proce H
2-aza-Cope, driven by conjugation HCHO, H + , -H2O Mechanism for Yohimbane Analog Formation: .. 2-aza-Cope Yohimbane 15-Methoxy-isoyohimbane HCHO, MeOH, Cat. H+ , 85% Equilibrium between A and B driven towards B by conjugation of iminium double bond to the aromatic ring in B. Yohimbine Application to Yohimbine Analog Synthesis: Winterfeldt Chem. ber. 1968, 101, 2938. + HCHO HCOOH 100oC, 2hr. First Reported Case: Horowitz JACS 1950, 72, 1518. The 2-aza-Cope Rearrangement D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 206 Ph NH2 Ph N H N H Ph H N N H H NH O H2N N H N NH H N N H H OMe H N N H OH CO2Me H N NH H N N H N N H N N H H OMe 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 POCl3 NaBH4 C3H7 O N Et3SiH C3H7 O N C3H7 O N 40:60 ratio 2-Aza Cope rearrangements add to complexity of cyclization process MeOH A B H2O PhCHO
M. Shair. D. evans Stabilized Cations: AcylIminium-lons Chem 206 N-Acyliminium lon Rearrangements SiMe3 Synthesis of (-)-hastanecine: Hart JOC 1985, 50, 235 SiMe3 TFA Meme The orgin of the modest 3]?2 been attributed to 2-aza 29% HCOH Gelas-Mailhe, Tet Lett, 1992, 33, 73 Competing 2-Aza-Cope and Pinacol Rearrangement Which Dominates?? 33] BnO- o OBn 2H CSA, 6 cyclization HCO2 [33] Pinacol Homo-chiral ()-hastancine Mannich P racemic product Conclusion: 2-aza-Cope rearrangements afford a low-barrier to competing processes
M. Shair, D. Evans Stabilized Cations: AcylIminium-Ions Chem 206 N-Acyliminium Ion Rearrangements Synthesis of (-)-hastanecine: Hart JOC 1985, 50, 235. + 81% NaBH4 , MeOH, 83% (-)-hastancine Me BnO NH2 O Me O O AcO Me N Me O O BnO OAc OAc BnO OH Me O Me N N OAc Me Me OBn O OAc Me O Me N N OAc O Me Me HO Me Me O OH N N OH BnO HO BnO OBn H [3,3] N OAc O Me Me HCO2 BnO 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 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 Me N Me Ph Ph O Me OH Ph N Me Ph CSA, 60oC, [3,3] racemic product N O Me SiMe3 H [3,3] ??? Conclusion: 2-aza-Cope rearrangements afford a low-barrier to competing processes The origin of the modest diastereoselection has not been attributed to 2-azaCope process. Competing 2-Aza-Cope and Pinacol Rearrangements: Which Dominates?? HCO2H HCO2H
M. Shair. D. evans Stabilized cations: Iminium-Ions 2 Chem 206 2-Aza-Cope-Mannich sequence Another aza-Cope-Mannich sequence ,3] MecN,80℃C A CHOIR 33] Axial Attack 98%Mannich H2/Pd-C ROHC 97% equivalent to 0 Overman et al. JACS 1995. 117 5776 veman et al JOC 1991. 56. 5005 Pancracine nine
M. Shair, D. Evans Stabilized Cations: Iminium-Ions 2 Chem 206 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 O O H H H strychnine Overman et al. JACS 1995, 117, 5776. steps Mannich Rxn 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 O O CH2O/HCl 97% 67% H N O O HO HO Pancracine steps Pictet-Spengler cyclization N O ROH2C H NR2 BF3
D. Evans, E. Shaughnessy The Prins-Pinacol reaction Chem 206 References Evidence for Prins-Pinacol Mechanism Prins reaction: Adams, D.R.; Bhayr S thesis1977,661 Prins& carbonyl ene reactions: Snider, Comprehensive Organic Synthesis, 1991, Vol. 2 The Prins process >95%ee R2 X Pri CLSno AlSo R, CHO pinacol enantiopure Aldol (fast) The Prins-Pinacol variant >95%ee If a[ 3, 3 rearrangement were t would be racemic Overman Examples of Stereoselective THF Formation Pinacol 0→-23%C CLSn-o BF3.0Et2 2,-55°C
D. Evans, E. Shaughnessy The Prins-Pinacol Reaction Chem 206 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 O O R1 R2 R2 R1 R2 OH - H+ HX R1 R2 OH X The Prins Process: O R1 H H R2 X – The Prins-Pinacol Variant: O Me O 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 Me O Ph Me Me Me O Me Me Ph Me O Me O O Me Me Ph Me - Cl4SnO Me O Me Me Ph Me - Cl4SnO Me Ph Me Me Me - Cl4SnO Me O Me Me Me Ph O Me Evidence for Prins-Pinacol Mechanism If a [3,3] rearrangement were intervening, the product would be racemic. Overman, JACS 2000, 122, 8672 Overman, Org Lett 2001, 3, 1225 + + >95% ee enantiopure racemic Prins [3,3] Aldol (fast) pinacol H SnCl4 , CH2Cl2 Me HO Me OH Me O O Me O Me O Me Me Me Me O 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 >95% ee R1CHO
D. Evans, E. Shaughnessy The Prins-Pinacol Reaction Chem 206 Prins-Pinacol Mechanism anine Synthesis JACs,1993,1152992 )-Magellanine H Me prins 33] The pivotal transformation pinacol enantiopure TESO H SncE >OMe 1. 2. Ph2 CHNH3CI Nabhacn Prins cyclization faster than [3, 3] rearrngement ()-Magellanine 2-aza-Cope vs Pinacol: cSA,60°C, TESO ESO 33] Pinacol Homo-chiral Mannich P [3, 3] rearrngement faster than Mannich cyclization E mixture of diastereomers
D. Evans, E. Shaughnessy The Prins-Pinacol Reaction Chem 206 O O Me Me Ph Me - Cl4SnO Me O Me Me Ph Me - Cl4SnO Me Ph Me Me Me – Cl4SnO Me O Me Me Me Ph O Me Prins-Pinacol Mechanism >95% ee enantiopure Prins Aldol pinacol H SnCl4 [3,3] 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 Me N Me Ph Ph O Me OH Ph N Me Ph O O Me Me Ph Me Me CH2Cl2 Homo-chrial CSA, 60oC, [3,3] racemic product 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% TESO O Me Steps The pivotal transformation TESO CH(OMe)2 O OMe R H O OMe H 1. OsO4 , HIO4 2. Ph2CHNH3Cl NaBH3CN ✻ ✻ ✻ mixture of diastereomers Prins cyclization faster than [3,3] rearrngement [3,3] rearrngement faster than Mannich cyclization SnCl4 SnCl4
D. Evans, E. Shaughnessy The prins reaction -3 Chem 206 Overman Synthesis of a Eunicellin Diterpene Overman: Synthesis of trans-Kumausyne verman& MacMillan JACS. 1995. 117.10391 Aco ()-7-Deacetoxy-alcyoninacetate M JAcs,191,113.5378 trans-Kumaus Felkin Control ( Lecture 20) CHO 33] t-BuLi THF PPts, MeOH 69% TMS OBn Me TMS OTIPS m-CPBA ctivity 1.H2,PdC,88% Felkin Control ( Lecture 20 78℃→t CHO TMS ds=9:1 2. TBSCl OTIPS 6 steps, 39% yield from(S)-carvone
D. Evans, E. Shaughnessy The Prins Reaction-3 Chem 206 Overman Synthesis of a Eunicellin Diterpene Overman & MacMillan JACS, 1995, 117, 10391 O Me Me Me H H Me HO AcO (-)-7-Deacetoxy-alcyoninacetate Me Me Me TMS OH OH ds = 9:1 OHC OTIPS Me OHC O TMS 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 O TMS CHO [3,3] Me OTIPS Overman: Synthesis of trans-Kumausyne JACS, 1991, 113, 5378 O AcO Et Br trans-Kumausyne OH OH O H H O OBn O H H OBn O O BnOCH2CHO RSO3H, rt 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 69% O OH OBn [3,3] O OH OBn Felkin Control (Lecture 20) Felkin Control (Lecture 20)
D.A. Evans The prins reaction -4 Chem 206 Mukaiyama Aldok-Prins Cascade Application to Leucasandrolide Rychnovsky JACS, 2001, 123, 8420 The Basic Process OMe o 5.5: 1 ratio The Pivotal Ste SiMe TBSO base. 78% Control of hydroxyl center. see Lecture 20 Let El(*)=Lewis acid activated RCHO BF3. OEt2 lo(little) control over anti selec ths(米) stereocenter RCHO TMS Evans et al. JACS 1996. 116 4322 Aldehyde Synthesis Chiral enolate alkylation: see Lecture 23 IBALH 0 Prins oTBs diastereoselection >20:1 Bno. SiMe Myers,Acs1997,119,6496 o CH2 CMe cyclic oXo-carbenium ion addition: see Lecture 19
D. A. Evans The Prins Reaction-4 Chem 206 Mukaiyama Aldol–Prins Cascade Rychnovsky JACS, 2001, 123, 8420 The Basic Process R O El R O SiMe3 R O SiMe3 El El El R O SiMe3 El Let El(+) = Lewis acid activated RCHO R O R O SiMe3 BF3 •OEt2 R OH No (little) control over this (❋) stereocenter ❋ R O SiMe3 H R O F3B R O BF3 aldol Prins Prins R O R OX ❋ SiMe3 –TMSX Application to Leucasandrolide O OMe O Me OH Me Me O O O OMe O Me OH Me Me O HO The seco acid OH The Pivotal Step: O O Me OBn H O SiMe3 TBSO base base = Me3C N CMe3 O OH O Me OBn OTBS BF3 •OEt2 base, 78% 5.5:1 ratio Control of hydroxyl center: see Lecture 20 BnO R O H BF3 •OEt2 BnO R OH R O Evans et al., JACS 1996, 116, 4322 R O TMS anti selection: ~5–8:1 Aldehyde Synthesis O N Me OTBS BnO Me Myers, JACS 1997, 119, 6496 Ph OH Me Chiral enolate alkylation: see Lecture 23 O N Me OTBS BnO Me Ph OH Me I LDA diastereoselection >20:1 H + O O Me OBn 77% O OAc Me OBn DIBALH SiMe3 BF3 •OEt O 2 CH2 Me OBn H cyclic oxo-carbenium ion addition: see Lecture 19 H RCHO Ac2O