Chemistry 206 Advanced Organic Chemistry Handout-32B The Aza-Cope Rearrangement. Background and Application to Alkaloid Synthesis Mike calter Evans group seminar March 26. 1991 Review. Heimgartner, H. In"Iminium Salts in Organic Chemistry Bohme, H, Viehe, H, Eds. Wiley: New York, 1979; Part 2, pp655-732 Matthew d. shair Monday December 9. 2002
Chemistry 206 Advanced Organic Chemistry Handout–32B The Aza-Cope Rearrangement. Background and Application to Alkaloid Synthesis Matthew D. Shair Monday , December 9, 2002 Review: Heimgartner, H. In "Iminium Salts in Organic Chemistry"; Bohme, H., Viehe, H., Eds.; Wiley: New York, 1979; Part 2, pp 655-732. Mike Calter Evans Group Seminar March 26, 1991
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 Review The 3-aza-Cope Rearrangement Heimgartner, H In"Iminium Salts in Organic Chemistry". Bohme, H, Viehe, H, Eds. Wiley: New York, 1979; Part 2 pp655-732 First Neutral Case: Hill TL 1967. 1421 The 3-aza-Cope Rearrangement ■ Neutral variant M、入Me250°,Me Practically quantitative", no real 2 y Me 1hr Exothermic as written by -7-10kcal/mole First Cationic Case: Elkik Compt Rend. 1968, 267, 623 ■ Ammonium variant 80 No yields given Even more exothermic than the neutral version has st inium salt tronger p-Bond than imine does 2-aza- Cope Rearrangement OHC. In the simplest case, degenerate. Sterics or con- ing f a particul omer, will drive equilibrium to one side. As with Good way to allylate aldehydes: Opitz Angew. Chem. 1960, 72, 169 H20 a 1-aza-Cope Rearrangement u e incorporating the imine into a strained ring or OHC. R R"\ 32B-0111/2493924AM
D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 115 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. Sterics or conjugation, or selective trapping of a particular isomer, will drive equilibrium to one side. As with the 3-aza-Cope, the cationic version goes 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. 80oC, 2-3 hr + + H2O No yields given. Good way to allylate aldehydes: Opitz Angew. Chem. 1960, 72, 169. ∆ + H2O + + + -H2O 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 R''' N R'' R'' R' R R''' R''' R OHC R''' R' N R'' R R' R'' 32B-01 11/24/93 9:24 AM
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 N-Acyliminium lon Rearrangements: Hart JOC 1985, 50, 235 N-Acyliminium lon Rearrangements Synthesis of (-)-hastanecine: Hart JOC 1985, 50, 235 erved an unusual product while trapping mediates of N-acyliminium olefin 1)MeC(OEt)3. CF3CO2s TF Et3 SiH, Me' well-precedented reaction, 74%6 yield C3H, HCO2H NaBH4 C3H7 Expected product of nexpected, must be product iminium salt reduction. of 2-aza-Cope, followed by 3 and 4 substitution favors the rearrangement H2O,89% 1)BU3SnH 85%H0 astancine 2 is the sole product in 91% yield 32B-1011/24/9310:26AM
N-Acyliminium Ion Rearrangements Synthesis of (-)-hastanecine: Hart JOC 1985, 50, 235. 1)MeC(OEt)3, H+, 145oC 2)OH- 3)SO2Cl 4)Curtius 5)TFA 52% + 81% NaBH4, MeOH, 83% + HCO2H + MeOH, H2O, 89% overall 1)H2, Pd/C 2)AcCl 90% HgO,I2 85% 1)Bu3SnH 2)LiAlH4 82% (-)-hastancine 2 is the sole product in 91% yield. N-Acyliminium Ion Rearrangements: Hart JOC 1985, 50, 235. Hart observed an unusual product while trapping the intermediates of N-acyliminium olefin cyclizations. TFA + No Et3SiH, normal, well-precedented reaction, 74% yield Et3SiH, 73% Expected product of iminium salt reduction. 3 : 5 + Unexpected, must be product of 2-aza-Cope, followed by reduction. 3 and 4 substitution favors the rearrangement. HCO2H + 3 4 cycln. + + 2-aza-Cope 1 2 D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 115 N OH O C3H7 C3H7 O N N O C3H7 CF3CO2 N O C3H7 C3H7 O N Me O N N O H O Me Me O Me N O A N O Me O Me Me HCO2 N Me Me Me Me OBn BnO Me OH NH2 O O O AcO N O O BnO OAc OAc BnO OH O N N OAc OBn O OAc O OBn N N OAc O Me Me HCO2 HO Me Me O OH N N OAc O Me Me HO N I O OAc N OH BnO BnO AcO AcO HO 32B-10 11/24/93 10:26 AM
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 The 1-aza-Cope Rearrangement The 1-aza-Cope Rearrangement Fowler Joc1988,53,963: Fowler Joc1988,53,5998 Application to Aspidospermine Precursor The Basic Reaction 33] bomyl, the amide resonance energy should act s to favor the enamine product. 500°C, MeDco CO Me yield of l-aza-Cope product CO-Me 61% As you can see, not the greatest reaction, but it has been used to make an aspidospermine precursor aspidospermine 32B-1111/24/9310:30AM
4)ClCO2Me 33% The 1-aza-Cope Rearrangement aspidospermine t-BuOK 72% H2, Rh/C 81% 1-azaCope Application to Aspidospermine Precursor + MeAlCl2, 47% 1)NH2OH 2)BH3 3) FVT, 31% H+ As you can see, not the greatest reaction, but it has been used to make an aspidospermine precursor. Me OMe 61% Me CO2Me 33% Me Me 46% Me H 5% H H 0% R R' yield of 1-aza-Cope product The 1-aza-Cope Rearrangement Fowler JOC 1988, 53, 963; Fowler JOC 1988, 53, 5998 [3,3] The Basic Reaction In order to reverse the 3-aza-Cope rearrangement, Fowler put an acyl group on the imine nitrogen. Since the imine has negligible interaction with the carbonyl, the amide resonance energy should act to favor the enamine product. 500oC, FVT D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 115 O R O N N N MeO2CO CO2Me N MeO2CO CO2Me R' R R' R R N R' CO2Me N CO2Me R R' Et OMe O H Et MeOCHO N Cl O Cl MeO Et N OCO2Me O Cl Cl N O Et MeO OMe Et Cl O Cl O N Et O N O Et O Cl O N Et O N O Et O N Et N Ac MeO 32B-11 11/24/93 10:30 AM
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 The 2-aza-Cope Rearrangement I First Reported Case: Horowitz JACS 1950, 72, 1518 Mechanism for Yohimbane Analog Formation C 2-aza-Cope Equilibrium between a and B driven towards b by conjugation of iminium double bond in B Application to Yohimbine Analog Synthesis: Winterfeldt Chem. ber. 1968. 101, 2938 2-aza-Cope, driven by Yohimbine Yohimbine Meoh HCHO. MeOH 个 32B-0211/2493927AM
+ 2-aza-Cope, driven by conjugation + HCHO, H+, -H2O Mechanism for Yohimbane Analog Formation: + MeOH .. 2-aza-Cope Yohimbane 15-Methoxy-isoyohimbane HCHO, MeOH, Cat. H+, 85% 1) POCl3 2)NaBH4, 20% Equilibrium between A and B driven towards B by conjugation of iminium double bond to the aromatic ring in B. B A H2O Yohimbine Application to Yohimbine Analog Synthesis: Winterfeldt Chem. ber. 1968, 101, 2938. + PhCHO + + 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 115 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 N H N N H H O N H H Me H H MeO N N H N N H H OMe 32B-02 11/24/93 9:27 AM
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 Winterfeldt's Attempt at the Proper Oxidation Pattern for Yohimbine The Tandem Cationic aza-Cope Rearrangement/Mannich Cyclization Winterfeldt Chem. ber 1968. 101 2938. Benzene 80°c.24hr R"O Mannich HCHO 8497% 2-aza-Cope H’, The product of path b)is the only product observed, in 64% 32B-0311/24/939:30AM
The Tandem Cationic aza-Cope Rearrangement/Mannich Cyclization: Overman JACS 1979, 101, 1310. + RCHO + Benzene, 80oC, 24hr. 2-aza-Cope + .. Other Subtrates: + H+, Ag+, or Cu+ + + H+ 84-97% + H+ Mannich Winterfeldt Chem. ber. 1968, 101, 2938. Winterfeldt's Attempt at the Proper Oxidation Pattern for Yohimbine ? + + a) b) a) b) MeOH HCHO, MeOH, H+ 2-aza-Cope The product of path b) is the only product observed, in 64% yield. D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 115 N NH H OMe OMe N N H H OMe N OMe N H OMe NH N H N N H OMe N N H OMe H OMe N N H H H H O Me O H N H H N H R'' NH2R' R'''O N R R' R'' R'''O N R' R R'' O N O Me R R HO N Me H H R R N R R' R'' R'''O O Me N R H R MeO NH Me OMe Me N MeO OH N Me CN Ph Ph N Me OH N Me O Ph OMe N Me O 32B-03 11/24/93 9:30 AM
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 Mechanism and Stereochemistry. 2-aza-Cope vs Pinacol Overman JACS 1988. 110 4329: Overman JOC 1988. 53. 685 Mechanism: 1.5hr,79% Mannich Homo-chrial Pinacol Pinacol Mannich Mannich reaction is slow compared to these bond rotations(activation energy for bond rotation -3-5 kcal mol), then the compound will racemize before cyclization and the product will be racemic. Since the intermediates in the Pinacol mechanism are all chiral, the product should be chiral if it is formed by that mechanism. The product formed was racemic, so this is further evidence for the 2-aza-Cope/Mannich mechanism Path C discarded because no fragmentation products ever found in the rxn mixtures To test for a)vs. b), substrates 1-5 were prepared and subjected to the rn conditions. AgNO,, EtOH, Me 64% 1 hr.. rt Et37% 5 sO_Ph 20% The fact that 3 and 5 rearranged under the same conditions, even though ther djacent positive charge, argues strongly against mechanism b(assuming that the cyclization step is rate limiting) 32B0411/2493937AM
Homo-chrial achiral The iminium-enol derived from the 2-aza-Cope is an achiral compound in a chiral conformation. It can be racemized by two rotations around single bonds. If the Mannich reaction is slow compared to these bond rotations(activation energy for bond rotation ~3-5 kcal/mol), then the compound will racemize before cyclization and the product will be racemic. Since the intermediates in the Pinacol mechanism are all chiral, the product should be chiral if it is formed by that mechanism. The product formed was racemic, so this is further evidence for the 2-aza-Cope/Mannich mechanism. + Mannich Pinacol chiral + : 2-aza-Cope cyclization + CSA, 60oC, 1.5 hr, 79% ■ 2-aza-Cope vs. Pinacol: The fact that 3 and 5 rearranged under the same conditions, even though there is an approximately seventeen orders of magnitude difference in their ability to stabilize an adjacent positive charge, argues strongly against mechanism b(assuming that the cyclization step is rate limiting). 4 OEt 37% 5 SO2Ph 20% 3 SPh 76% 2 H 64% 1 Me 78% Compound R Yield AgNO3, EtOH, 1 hr., rt Path C discarded because no fragmentation products ever found in the rxn mixtures. To test for a) vs. b), substrates 1-5 were prepared and subjected to the rxn conditions. c) b) a) [3 + 2] Pinacol Mannich frgmt. cycln. [3,3] + + - + + + Mechanism: Overman JACS 1988, 110, 4329; Overman JOC 1988, 53, 685. Mechanism and Stereochemistry: D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 115 N R R' HO R'' R R'' HO N R' N R' HO R'' R R R'' HO N R' N R' OHC R R'' N HO H R Me CN O N H Me R O N Me Me Ph Ph N Ph Me Ph OH Me Me OH Ph N Me Ph Me N Me Ph N Me OH Ph Ph Ph O Me OH Ph N Me Ph Ph OH Me N Ph Me Me 32B-04 11/24/93 9:37 AM
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 Stereochemistry: Overman JOC 1988, 53, 685 Fused Pyrrolidines Overman TL 1982. 23 2733 and 2737 What does the transition state look like? Overman JOC 1983. 48 3393 Overman JOC 1985. 50. 2403 -Me H*/(cH2) (CH2)n Works for n=2 to 4 (CH2)n Chair Product Boat Product The reaction gives a 90% yield of a 93 7 mix of the Chair Product to the Boat Product. Normal Preparation of Amino Alcohol Substrates Chair cHo <h This nxn gives a 77% yield of a 74: 26 mixture of the Chair Product to the Boat he chair tranistion state for the z-olefin is destabilized relative to the chair tra ate for the E-olefin by a syn-pentane interaction between the Me and the ring n to lower chair selectivity Addition of vinyllithium usually occurs from side opposite nitrogen group in good Rearrangement of trans-aminoalcohol is less selective than that of cis developing syn-pentane 32B0511/2493948AM
Addition of vinyllithium usually occurs from side opposite nitrogen group in good yields. Rearrangement of trans-aminoalcohol is less selective than that of cis. (CH2) (CH n 2) (CH n 2)n Normal Preparation of Amino Alcohol Substrates: Works for n=2 to 4 (CH2)n + (CH2)n (CH2)n + + (CH2)n R'CHO, H+ (CH2)n Overman TL 1982, 23, 2733 and 2737. Overman JOC 1983, 48, 3393. Overman JOC 1985, 50, 2403. Stereochemistry: Overman JOC 1988, 53, 685. Fused Pyrrolidines: ■ What does the transition state look like? HCl, 65o C + chair boat + + + + Chair Product Boat Product The reaction gives a 90% yield of a 93:7 mix of the Chair Product to the Boat Product. + Chair Boat This rxn gives a 77% yield of a 74:26 mixture of the Chair Product to the Boat Product. The chair tranistion state for the Z-olefin is destabilized relative to the chair transition state for the E-olefin by a syn-pentane interaction between the Me and the ring, leading to lower chair selectivity. + developing syn-pentane D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 115 Me N OH NH OMe OMe OH N Me HO Me HO Me N OH N H Me N H Me CHO CHO HO N Me H N HO N Me Me N CHO Me H N H Me CHO HO Me N H H NH R' H R HO HO N R H R' N R' H R HO HO N R H R' N R R'' R'' R'' R'' O H R' HO Li R' NR2 O H R' NR2 NH R' H R HO 32B-05 11/24/93 9:48 AM
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 Fused Pyrrolidines: Stereochemical Issues (*)-Gephyrotoxin: Overman JACS 1980, 102, 1454 T1982.23 d2737 The rearrangement procedes through a chair giving the expected stereochemistry 1)Ph3 P=C(H)CHO 2)MeOH, H NHCbz 45% overall OMe When an aliphatic aldehyde is used instead of formaldehyde, the R group ends u syn to the newly expanded rin TsOH aminoalcohols give the same products as the cis, although This can be rationalized by the fact that the trans compound can on state. However, the amount of slippage into the boat transition 79%,32 diastereomers 32B-0611/2493954AM
6 steps, 11% overall + 2-aza-Cope 79%, 3:2 ratio of diastereomers + TsOH , NaBH4, 92% 1:1 1)Ph3P=C(H)CHO 2)MeOH, H+ 3)H2, Pd/C 45% overall (±)-Gephyrotoxin: Overman JACS 1980, 102, 1454. (± )-Perhdrogephyrotoxin Fused Pyrrolidines: Stereochemical Issues Overman TL 1982, 23, 2733 and 2737. Overman JOC 1983, 48, 3393. Overman JOC 1985, 50, 2403. The rearrangement procedes through a chair giving the expected stereochemistry. + + + When an aliphatic aldehyde is used instead of formaldehyde, the R group ends up syn to the newly expanded ring. + + + The trans aminoalcohols give the same products as the cis, although usually in lower selectivity. This can be rationalized by the fact that the trans compound can access the boat transition state. However, the amount of slippage into the boat transition state is usually small. + + + + + Boat Chair D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 115 N R' H HO R OH N O H R OH N R R' N R R' R' N R HO H R' R'' N OH R' R R'' OH R'' N R R' R' H N R O R'' N R'' R' H HO R N R' HO R H N R HO R' H R'' R'' R'' N R HO R' H R'' N R HO R' H R'' N O H R R' R' H N R O R'' CHO NHCbz BnO BnO NH2 OMe OMe OMe OMe NH2 BnO Me OMe OHC Me OMe Me OMe N BnO N BnO Me OMe N BnO O N C5H11 HO 32B-06 11/24/93 9:54 AM
D. A. Evans. M. Calter The Aza-Cope Rearrangement Chem 115 tabersonine: Overman JOC 1983, 48, 2685 ()-Crinine: Overman Helv. Chim. Acta 1985, 68, 745 COgMe OTMS ZnBr2 1: 1 mixture of diastereomers 45% yield of( 1R, 2R)after (1s,2S) 0c 6hr,90% AgNO3. 80% rality due to ring filips, so product with R=Bn give the same result (*] -16-methoxytabersonine 21% overall 32B-0711/24/9310:01AM
D. A. Evans, M. Calter The Aza-Cope Rearrangement Chem 115 (±)-16-methoxytabersonine 1)LDA 2)MeOCOCl 31% 110oC, 6 hr, 90% 1)Ph3P=CH2, 2)40% KOH, 93% 80% + 1)MCPBA 2)CaCO3, 44% 1)NaI 2)NH3 3)MeOCOCl, 68% ZnBr2, 84% + (±)-16-methoxytabersonine: Overman JOC 1983, 48, 2685. This iminium-enol intermediate undergoes the intermolecular Mannich reaction before losing chirality due to ring flips, so product is enantiomerically pure. Experiments with R=Bn give the same results. 5 steps, 21% overall Pd/C, Cyclohexene, 80% + + 2-aza-Cope Mannich AgNO3, 80% 91% + Swern, 95% HCHO, KCN92% 1:1 mixture of diastereomers, 45% yield of (1R,2R) after seperation (1R,2R) (1S,2S) + + (-)-Crinine: Overman Helv. Chim. Acta 1985, 68, 745. OTMS Et SPh SPh Cl Cl O Et Cl N CO2Me Et N SPh CO2Me Et O H OMe NBOC Li TMSO CN Li N Et O O O NHBOC OMe OMe NH2 HO O Et HN N Et N Et N MeO NH2 MeO MeO N Et N CO2Me H O N Me Ph Me2Al H OH NH Me Ph NH Me Ph OH N Me Ph OH CN O O N CN O Me Ph N Me Ph CN HO Li O O N OH Ar R N R Ar H OH Ar N Bn O H N H O O O O O HO H N 32B-07 11/24/93 10:01 AM