Chem 206D. A. Evans 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 OMeMeO Me NH2 OHC CHO Me3Si CO2R + 1) mix at roomtemp, 5 min 2) 2 equiv.TFAA, 0 °C NRc Rd Ra Rb+ 3) excess NaBH3CN N N MeOMeO Me H CO2R 1 2 3 Chemistry 206 Advanced Organic Chemistry Lecture Number 32 Introduction to Carbonium Ions–3 a73 Stabilized Carbocations: Iminium Ions (C=NR2(+))a73 Stabilized Carbocations: Oxo–Carbenium Ions (C=OR(+)) a73 Stabilized Carbocations: Addition & Rearrangements OHC CHO Me3Si CO2R + 1) mix at roomtemp, 5 min1 2 N OR O TMS N OMeMeO Me OR RO N OR O TMS N OMeMeO Me ORN OR O TMS NMeOMeO Me N N MeOMeO Me H CO2R N N MeOMeO Me H CO2R H N N MeOMeO Me H CO2R NaBH3CN TFA reversible? A The product-determining step could be step A. Chem 206M. Shair, D. Evans NR1R 2 R4 R3 R1 R2 O N R4 R3H NR1 R2 R4 R3 N OR2 R1 N R1 N N H HMeO 2C OH Iminium Ions Common Methods of Generation: H N N H HMeO 2C 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 HX– X N Me H Hg(0) HX X– rds Oxidation of Amines N H H CO2Me OHH R Nu (favored) NMe3Si Ph N Ph Me3Si NH Ph H N H Ph SiMe3H 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 HH SiMe3 (E) vinylsilane) N O H TMS R Me Me N H Me RMeTMS 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 C=N Stereoelectronic Effects: Lecture 19 H H Related to Polonovski & Pummerer Reactions: Lecture 27 NaBH4 HgX2 X- 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. 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. 123 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: 321 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 realyields 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 NRR NN R R R R N R N R NR NR N MeMeMe NMe MeMe MeN MeMeNMe Me MeMe Me OHC R' Me R OHC Me N HR'' R'' R R'NR'' R'' X NR''R'' R'RRR' R''' R'''R''' O H NR''R'' R'R R'''[3,3] H2O ?H2O -H2O 2-aza-Cope, driven byconjugation 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 HCOOH100oC, 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 NH NHPh HN N H H NH O H2N N H N NH H N N HH OMe H N N H OHCO2MeH N NH H N N H N N H N N HH 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 OC3H7 C3H7 O N N OC3H7 CF3CO2POCl3NaBH4 C3H7 O N Et3SiH C3H7 O N C3H7 O N 40:60 ratio 2-Aza Cope rearrangements add to complexity of cyclization process MeOH BA H2O PhCHO Chem 206M. Shair, D. Evans Stabilized Cations: AcylIminium-Ions N-Acyliminium Ion Rearrangements Synthesis of (-)-hastanecine: Hart JOC 1985, 50, 235. + 81% NaBH4, MeOH,83% (-)-hastancine MeBnO NH 2 O Me O O AcO NMe OMe O BnO OAcOAcBnO OH Me ON MeN OAc Me Me OBn O OAc OMe Me N N OAc OMe Me HOMeMe O OH NN OH BnO BnOHO OBn H [3,3] N OAc OMe MeHCO 2 BnO N O Me OH SiMe 3TFA 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 MeMe Ph Ph N Ph Me Ph OH Me Me OHPh NMe Ph NMe Me PhPh O Me OH Ph N Me Ph CSA, 60oC, [3,3] racemic product N O Me SiMe3H[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-aza-Cope process. Competing 2-Aza-Cope and Pinacol Rearrangements: Which Dominates?? HCO2H HCO2H Chem 206M. Shair, D. Evans Stabilized Cations: Iminium-Ions 2 N OR HO NR 2 N OR HO NR 2 2-Aza-Cope-Mannich sequence: (CH2O)n, Na2SO4 MeCN, 80?C [3,3] N OR HO NR2 N ONR 2 OR 98 %!! Axial Attack equivalent to N N OO H H Hstrychnine Overman et al. JACS 1995, 117, 5776. steps MannichRxn Overman et al. JOC 1991, 56, 5005 Another aza-Cope-Mannich sequence: HO O O NHBn Ar N O Bn OH NBn Ar N ArHO BnN O Bn H H [3,3] [3,3] Mannich O O N O H H H2/Pd-CCH 2O/HCl O H H N O O OO CH2O/HCl 97% 67% H N O O HO HO Pancracine steps Pictet-Spenglercyclization N O ROH2C H NR2 BF3 Chem 206D. Evans, E. Shaughnessy The Prins-Pinacol Reaction References Prins reaction: Adams, D.R.; Bhaynagar, S. D. Synthesis 1977, 661Prins & 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– 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 MeMe PhO Me Lewis AcidSnCl4 >95% ee Prins +– – H H PinacolSnCl4 O OMe Ph Me Me Me O MeMe Ph Me O Me O O Me Me Ph Me - Cl4SnO Me O Me Me Ph Me - Cl4SnO Me Ph Me MeMe- Cl4SnO Me O Me MeMe PhO 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 MeMeHO OH OMe O Me O OMe Me Me Me OMe Me Me OMe Ph7:1 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 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 MeMe– Cl4SnO Me O Me MeMe PhO 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 MeMe Ph Ph N Ph Me Ph OH Me Me OHPh N Me Ph NMe Me PhPh O Me OH Ph N Me Ph O O Me Me PhMe 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 MeN O Me OH H(-)-Magellanine MeN 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, HIO42. Ph2CHNH3Cl NaBH3CN a54 a54 a54 mixture of diastereomers Prins cyclization faster than [3,3] rearrngement [3,3] rearrngement faster than Mannich cyclization SnCl4 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 MeHHMe AcOHO(-)-7-Deacetoxy-alcyoninacetate Me Me Me TMS OH OH ds = 9:1 OHC OTIPS Me OHC TMSO OMeMe 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.)CH 2Cl2, -55→ -20 °C 79% Me Me Me TMS OH O R Me2HC Me TMSO CHO [3,3] Me OTIPS Overman: Synthesis of trans-Kumausyne JACS, 1991, 113, 5378 OAcO Et Brtrans-Kumausyne OH OH O H H O OBn O H H OBnO O BnOCH2CHORSO 3H, rt m-CPBA 72%4:1 regioselectivity 1. H2, Pd-C, 88%2. Swern, 100% O H H OOEt TMS BF3?OEt2-78 °C → rt 73% 1. 2. TBSClO H H OO EtOTBS O HO EtOTBS H O DIBAL-78 °C 97% CHO 69% O OH OBn [3,3] O OH OBn Felkin Control (Lecture 20) Felkin Control (Lecture 20) Chem 206D. A. Evans The Prins Reaction-4 Mukaiyama Aldol–Prins CascadeRychnovsky JACS, 2001, 123, 8420 The Basic Process OR ElOR SiMe3 OR SiMe3 El El El OR SiMe3 El Let El(+) = Lewis acid activated RCHO OROR SiMe3 BF3?OEt2 ROH No (little) control over this (a70) stereocenter a70 OR SiMe3 H R OF3B R O BF3 aldol Prins Prins OR R OX a70 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 = NMe 3C 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 OTMS anti selection:~5–8:1 Aldehyde Synthesis O NMe OTBS BnO Me Myers, JACS 1997, 119, 6496 Ph OH Me Chiral enolate alkylation: see Lecture 23 O NMe OTBS BnO Me Ph OH Me I LDA diastereoselection >20:1 H+ O O Me OBn 77% O OAcMe OBn DIBALH SiMe3 BF3?OEt2O CH2 Me OBn H cyclic oxo-carbenium ion addition: see Lecture 19 H RCHO Ac2O