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 The Aza-Cope Rearrangement D. A. Evans, M. Calter 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. a73 Ammonium Variant: [3,3] + + Even more exothermic than the neutral version,since enamine lacks resonance and iminium salthas stronger p-Bond than imine does. 1 2 3 1 2 3 a73 Neutral Variant: a73 2-aza-Cope Rearrangement: 3 2 1 + [3,3] + 1 2 In the simplest case, degenerate. Sterics or con-jugation, or selective trapping of a particularisomer, will drive equilibrium to one side. As withthe 3-aza-Cope, the cationic version goes undermuch milder conditions. a73 1-aza-Cope Rearrangement: 3 2 1 3 2 1 [3,3] The 3-aza-Cope rearrangement can be drivenin reverse by judicious choice of substrates(i.e., incorporating the imine into a strained ring orby making R an acyl group). The 3-aza-Cope Rearrangement First Neutral Case: Hill TL 1967 , 1421. 250 o C, 1 hr "Practically quantitative", no realyields given. First Cationic Case: Elkik Compt. Rend. 1968 , 267 , 623. 80 o C, 2-3 hr + + H 2 O No yields given. Good way to allylate aldehydes: Opitz Angew. Chem. 1960 , 72 , 169. ? + H 2 O + + + -H 2 O NN 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 H R' ' 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 N-Acyliminium Ion Rearrangements Synthesis of (-)-hastanecine: Hart JOC 1985 , 50, 235. 1)MeC(OEt) 3 , H + , 145 o C 2)OH - 3)SO 2 Cl 4)Curtius5)TFA 52% + 81% NaBH 4 , MeOH,83% HCO 2 H ++ MeOH,H 2 O, 89% overall 1)H 2 , Pd/C 2)AcCl 90% HgO,I 2 85% 1)Bu 3 SnH 2)LiAlH 4 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 Et 3 SiH, normal,well-precedentedreaction, 74% yield Et 3 SiH, 73% Expected product of iminium salt reduction. 3 : 5 + Unexpected, must be productof 2-aza-Cope, followed byreduction. 3 and 4 substitution favors the rearrangement. HCO 2 H + 3 4 cycln. + + 2-aza-Cope 1 2 The Aza-Cope Rearrangement D. A. Evans, M. Calter Chem 115 N OH O C 3 H 7 C 3 H 7 O N N O C 3 H 7 CF 3 CO 2 N O C 3 H 7 C 3 H 7 O N Me O N N O O H Me Me O Me N O A N O Me O Me Me HCO 2 N Me Me Me Me OBn BnO Me OH NH 2 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 HCO 2 HO MeMe O OH N N OAcO Me Me HO N I O OAc N OH BnO BnOAcO AcO HO 32B-10 11/24/93 10:26 AM 4)ClCO 2 Me 33% The 1-aza-Cope Rearrangement aspidospermine t-BuOK72% H 2 , Rh/C 81% 1-aza-Cope Application to Aspidospermine Precursor + MeAlCl 2 , 47% 1)NH 2 OH 2)BH 3 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 CO 2 Me 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 thecarbonyl, the amide resonance energy should actto favor the enamine product. 500 o C, FVT The Aza-Cope Rearrangement D. A. Evans, M. Calter Chem 115 O R O NN N MeO 2 CO CO 2 Me N CO 2 Me MeO 2 CO R' R R' R R N R'CO 2 Me NCO 2 Me R R' EtOMe O H Et MeO CHO N Cl O Cl MeO Et NOCO 2 Me O Cl Cl O N Et MeO OMe Et Cl O Cl O N Et O NO Et O Cl O N Et O N O Et O N Et N Ac MeO 32B-11 11/24/93 10:30 AM + 2-aza-Cope, driven byconjugation + HCHO,H + , -H 2 O Mechanism for Yohimbane Analog Formation: + MeOH .. 2-aza-Cope Yohimbane 15-Methoxy-isoyohimbane HCHO, MeOH,Cat. H + , 85% 1) POCl 3 2)NaBH 4, 20% Equilibrium between A and B driven towards B by conjugation of iminium double bond to the aromatic ring in B . B A H 2 O Yohimbine Application to Yohimbine Analog Synthesis: Winterfeldt Chem. ber. 1968 , 101 , 2938. + PhCHO + + HCHOHCOOH100 o C, 2hr. a73 First Reported Case: Horowitz JACS 1950 , 72 , 1518. The 2-aza-Cope Rearrangement Chem 115 D. A. Evans, M. Calter The Aza-Cope Rearrangement NH 2 Ph Ph N H N H Ph H N N H H NH O H 2 N N H N NH H N N H HO M e H N N H OH CO 2 Me 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 HO M e 32B-02 11/24/93 9:27 AM The Tandem Cationic aza-Cope Rearrangement/Mannich Cyclization: Overman JACS 1979 , 101 , 1310. RCHO + + Benzene,80 o C, 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. Chem 115 D. A. Evans, M. Calter The Aza-Cope Rearrangement N NH H OMe OMe N N H HO M e N OMe N H OMe NH N H N N H OMe N N H OMe HO M e N N H H H H O Me O H N H H N H R'' NH 2 R' R'''O R N R' R'' R'''O N R' R R' ' O N O Me R R HO N Me H H R R R N R' R'' R'''O O Me R N 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 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, 60 o C, 1.5 hr, 79% a73 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 SO 2 Ph 20% 3 SPh 76% 2 H 64% 1 Me 78% Compound R Yield AgNO 3 , 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: Chem 115 D. A. Evans, M. Calter The Aza-Cope Rearrangement N R R' HOR' ' R R' ' HO NR'NR' HOR' ' R R R' ' HO NR' NR' OHC R R' ' N HO H RMe CN O N Me H R ON Me Me Ph Ph N PhMe Ph OH Me Me OH Ph NMe Ph N Me Me Ph N Me OH Ph Ph Ph O Me OH Ph NMe Ph Ph OH Me N Ph Me Me 32B-04 11/24/93 9:37 AM Addition of vinyllithium usually occurs from side opposite nitrogen group in good yields. Rearrangement of trans-aminoalcohol is less selective than that of cis. (CH 2 ) n (CH 2 ) n (CH 2 ) n Normal Preparation of Amino Alcohol Substrates: Works for n=2 to 4 (CH 2 ) n + (CH 2 ) n (CH 2 ) n + + (CH 2 ) n R'CHO,H + (CH 2 ) n Overman TL 1982 , 23 , 2733 and 2737. Overman JOC 1983 , 48 , 3393. Overman JOC 1985 , 50 , 2403. Fused Pyrrolidines: Stereochemistry: Overman JOC 1988 , 53, 685. a73 What does the transition state look like? HCl, 65 o 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 Chem 115 D. A. Evans, M. Calter The Aza-Cope Rearrangement Me N OH NH OMe OMe OH N Me Me HO HO Me N OH N H Me N H Me CHO CHO N HO Me HN HO N Me Me N CHO Me HN H Me CHO HO Me N H H NH R' H R HO HO NR H R' N R' H R HO HO NR H R' NR R'' R'' R'' R'' O H R' HO Li R' NR 2 O H R'NR 2 NH R' H R HO 32B-05 11/24/93 9:48 AM 6 steps,11% overall + 2-aza-Cope 79%, 3:2 ratio of diastereomers + TsOH , NaBH 4 , 92% 1:1 1)Ph 3 P=C(H)CHO 2)MeOH, H + 3)H 2 , 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 Chem 115 D. A. Evans, M. Calter The Aza-Cope Rearrangement N R' H HO R OH N O R H OH N R R' N R R' R' NR HO H R' R'' N OH R' R R'' R'' OH N R R' R' H N R O R'' R'' N 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 R H R' R' H N R O R'' CHONHCbz BnO BnO NH 2 OMe OMe OMe OMe NH 2 BnO Me OMe OHC Me OMe OMe Me N BnO N BnO Me OMe N BnO O N C 5 H 11 HO 32B-06 11/24/93 9:54 AM The Aza-Cope Rearrangement D. A. Evans, M. Calter Chem 115 (±)-16-methoxytabersonine 1)LDA2)MeOCOCl 31% 110 o C, 6 hr, 90% 1)Ph 3 P=CH 2 , 2)40% KOH, 93% 80% + 1)MCPBA2)CaCO 3 , 44% 1)NaI2)NH 3 3)MeOCOCl,68% ZnBr 2 , 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% + + Mannich 2-aza-Cope AgNO 3 , 80% 91% + Swern,95% HCHO,KCN92% 1:1 mixture of diastereomers,45% yield of (1R,2R) afterseperation (1R,2R) (1S,2S) + + (-)-Crinine: Overman Helv. Chim. Acta 1985 , 68, 745. OTMSEt SPh SPh Cl Cl O Et Cl N CO 2 Me Et NSPh CO 2 Me Et O H OMe NBOC Li TMSO CN Li N Et O O O NHBOC OMe OMe NH 2 HO O Et HN N Et N Et N MeO NH 2 MeO MeO N Et NCO 2 Me H O N Me Ph Me 2 Al H OHNH Ph Me NH Me Ph OH N Me Ph OH CN O O CN N O Ph Me 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 (±)-Crinine Overman JACS 1981 , 103, 5579. 62% NaCNBH 3 , 88% HCHO, H + , DMSO + 65% Pd/C,cyclohexene,95% Intermediate A HCHO,H + , 79% 4 steps,26% overall (±)-crinine Alternative Routes to Intermediate A: + 72% 74% AgNO 3 , 93% ++ + + Mannich 2-aza-Cope Pd/C,Cyclohexene,95% Intermediate A Chem 115 D. A. Evans, M. Calter The Aza-Cope Rearrangement ON N HO Ph Ph Ph Ph O O O O Li H H O O NHC(H)Ph 2 HO HO NC(H)Ph 2 O O H N Ar HO R H N R HO Ar H N Ar O R H N O C(H)Ph 2 O O H H O O N H O N H O O O O O HO H N OTMSOTMS N H Bn CN NBn CN O Li O O HO NBn O O H CN N OH Ar R N R Ar H OH Ar N Bn O N O H ArH 32B-08 11/24/93 10:00 AM D C B A E D C B A Akuammicine E-ring willnot close(manysubstratestried) CSA,110 o C, 20 min., 100% 1)HCHO2)TBSCl 95% 1)Ph 3 P=CH 2 , 2)40% KOH, 95% 70% + Swern,87% 1)DIBAL-H2)TIPSCl3)BnN(AlMe 2 )H 4)PhOCOCl 47% MCPBA,92% The last two steps tie into Danishefsky'ssynthesis of (±)-6a-epipretazettine.Danishefsky JACS 1982 , 104 , 7591. 1)HC(OMe) 3 , H + 2)H 3 O + 73% 1)MCPBA2)Ms 2 O,MeOH 3)TBAF 15% 1)TMSOTf2)DIBAL-H3)PhSeCl 60% H 2 O 2 , KF, 76% + + Cu(OTf) 2 94% 41% + (±)-6a-epipretazettine: Overman JACS 1979 , 101, 1310. Akuammicine: Overman JOC 1985 , 50, 4021. D-ring has to assume boat conformation inorder for E-ring to close. The Aza-Cope Rearrangement D. A. Evans, M. Calter Chem 115 CO 2 Et Me Me CO 2 Et O HO N PhO 2 C Me OTIPS Bn N Bn OTIPS Me PhO 2 C HO N NBOC Li TMSO CN Li Me OTIPS O Bn O O BOCHN H 2 N HO N HN Bn OH Me Me TBSO BnO H 2 N N N TBSO Bn NCO 2 Me N H N NR X Me H O N O O Cl 2 Ce SiMe 2 Ph Me CN SiMe 2 Ph O O N HO Me NC N Me O H O O SiMe 2 Ph N Ar SiMe 2 Ph OH OH SiMe 2 Ph Ar N Me Me N OH Me HO O O SiMe 2 Ph N H Ar O N Me Me HO ArH OTMS PhSe HO OH H Ar N Me HO N Me H O O O OH 32B-09 11/24/93 10:21 AM