1Enantioselective MSPV Reduction ofEnantioselective MSPV Reduction ofKetimines Using 2-Propanol and (Ketimines Using 2-Propanol and (BINOL)AlBINOL)AlIIIIIIC.R. Graves, K.A. C.R. Graves, K.A. ScheidtScheidt, and S.T. Nguyen, and S.T. NguyenNorthwestern UniversityNorthwestern UniversityOrganic LettersOrganic Letters, ASAP, 2/24/2006, ASAP, 2/24/2006Sarah RussickSarah RussickChemistry 2320Chemistry 23203/20/20063/20/2006OUTLINEOUTLINE• Key Point• Background• Enantioselective MSPV Reduction of Ketimines• Origin of Enantioselectivity• Summary• Future WorkS. Russick - Chem 232013/20/20062KEY POINTKEY POINTUtilization of Al, BINOL, and 2-propanol in the asymmetric reductionof acyclic aliphatic ketimines to form chiral secondary amines• High yields• Exceptional enantioselectivities• Mild, inexpensive reaction conditionsCurrently the only method to afford this transformation and meet above criteriaOOAlOHR R1NP(O)Ph2R R1NP(O)Ph2HH(BINOL)AlIIIKetimineChiral 2° Aminetoluene, 60ºCOOAlBACKGROUND:BACKGROUND: CHIRAL SECONDARY AMINES CHIRAL SECONDARY AMINESR1HN(O)CHOCH(OH)CH2NHR2Ph enethanolamines-!-adrenergic blockersJ.M ed.Chem . 1982, 670-679CNOHNCH2PhMeOChiral !-amino acidsTetrahedron, 1994, 50, 1539-1650OHNH2Betti base and derivatives- Chiral base for asymmetric synthesisTetrahedron: Asymmetry 1998, 9, 3667-3665- Prevalent in natural products, pharmaceuticals, and fine chemicals- Enantioselective reduction of prochiral ketimines chiral 2° amines-Few practical/high-yielding/selective processes currently existJ. Am. Chem. Soc. 2003, 125, 6864-6865Phomopsin A- Antimitotic agentS. Russick - Chem 232023/20/20063BACKGROUND:BACKGROUND: RuRu-CATALYZED KETIMINE REDUCTION-CATALYZED KETIMINE REDUCTION• Noyori’s “state of the art” asymmetric reduction of ketiminesConditions: chiral Ru(II) complex and formic acid-triethyl amine mixtureJ. Am. Chem. Soc. 1996, 118, 4916-4917Highlights:• Catalytic• High yields (>90%)• High ee’s (>95%)• Proceeds at 28ºC• Works well for cyclic N-benzylic imines Limitations:• Poor selectivity for exocyclic and acylic ketimines• Conditions cleave many N-protecting groupsRu(II) catalystsModel ReactionBACKGROUND:BACKGROUND: MSPV REDUCTION MSPV REDUCTIONR2R1OR4R3HOHR2R1HO HR4R3Ocar bon ylsim ple alc ohol re du ce d c arb onyloxidiz e d alc ohol++A l(OR )3R2R1OR4R3HOAlORRO• Independently discovered by Meerwein and Schmidt, Ponndorf, and Verley in mid-1920’s• Al catalyzed hydride reduction of a carbonyl• Hydride donated by alcohol component• Mild, inexpensive, environmentally friendly• Occurs via concerted 6- member T.S.Drawbacks:• Excess Al(OR)3 required; High aggregation state of Al alkoxidesS. Russick - Chem 232033/20/20064BACKGROUND:BACKGROUND: ENANTIOSELECTIVE MSPV REDUCTION ENANTIOSELECTIVE MSPV REDUCTIONAngew. Chem. Int. Ed. 2002, 41, 1020-1022 • First reported Al-catalyzed asymmetric MSPV reduction of carbonyls using an achiral hydrogen source• Yields and ee’s ≥ 80% Model Reaction Proposed Transition StateRelated Work: •Noyori’s and Evans’ asymmetric MSPV reductions utilized achiral hydrogen sources and chiral transition metal catalysts • Neutral reaction conditionsENANTIOSELECTIVE MSPV REDUCTION OF KETIMINESENANTIOSELECTIVE MSPV REDUCTION OF KETIMINESI. Reaction OptimizationModel Reaction:N-phosphinoyl ketiminesReaction Notes:• Does not proceed at RT - Optimal Temp is 60°C• AlMe3: BINOL ratio is 1:1• Optimal AlMe3/BINOL: Substrate ratio is 1.2:1 - Indicates single turnover eventS. Russick - Chem 232043/20/20065ENANTIOSELECTIVE MSPV REDUCTION OF KETIMINESENANTIOSELECTIVE MSPV REDUCTION OF KETIMINESII. Reaction ScopeAryl/alkyl ketiminesα,β-unsaturated ketiminesDoubly aliphatic ketimines• Wider scope than Noyori reduction• Excellent yields and ee’s maintainedAsymmetric environment evendistinguishes between primaryalkyl groupsENANTIOSELECTIVE MSPV REDUCTION OF KETIMINESENANTIOSELECTIVE MSPV REDUCTION OF KETIMINESIII. Preparation of Deuterated Secondary AminesPh MeNP(O)Ph2OHD+1.2 equiv AlMe31.2 equiv (S)-BINOLtoluene, 60oCPh MeNP(O)Ph2HD(R)Yield = 75%ee = 96%• Isotope labeling• Kinetic studiesS. Russick - Chem 232053/20/20066ENANTIOSELECTIVE MSPV REDUCTION OF KETIMINESENANTIOSELECTIVE MSPV REDUCTION OF KETIMINESIV. Ligand RecyclingOHOH(S)-BINOL• Inexpensive in bulk- ~$1.86/g on kg scale• Acid/base extraction/ recovery procedure- ~93% recoveryHOOH(R)-BINOLORIGIN OF ENANTIOSELECTIVITYORIGIN OF ENANTIOSELECTIVITYHighly organized metal-substrate complex:• 4-member chelation of Al by iminophosphinoyl• 5th coordination to Al by phosphinoyl oxygen - (27Al NMR indicates pentacoordinate Al)• Hydride transferred via concerted 6-member T.S.• RL of ketimine is pseudo-axial and RS is pseudo-equitorialS. Russick - Chem 232063/20/20067ORIGIN OF ENANTIOSELECTIVITYORIGIN OF ENANTIOSELECTIVITYPredictability of absolute configuration:For ketimine 1:(S)-BINOL (R)-amide(R)-BINOL (S)-amide• 1:1 AlMe3 : BINOL is optimal - increasing ligand ratio decreases yieldSUMMARYSUMMARY• High yielding and highly enantioselective MSPV reduction of ketimines to form secondary amines• Mild, neutral reaction conditions• 1:1 ratio of AlMe3:BINOL and excess propanol used as reagents• Reagents must be used stoichiometrically• Inexpensive and environmentally friendly process• Wide range of ketimines can be reducedS. Russick - Chem 232073/20/20068FUTURE WORKFUTURE WORK• Examine further application of reagents on different substrates•Is N-phosphinoyl group necessary for selectivity?• Develop conditions for catalytic amounts of Al/BINOL reagents• Necessary if reagents are inexpensive and recyclable?• Explore full mechanistic detailsWORKS CITEDWORKS CITED1. Graves, C.R.; Scheidt, K.A.; Nguyen, S.T. Org. Lett. 2006, ASAP.2. Clifton, J.E. et. al; J. Med. Chem. 1982, 25, 670-679.3. Duthaler, R.O. Tetrahedron 1994, 50, 1539-1650.4. Cardellicchio, C.; et. Al. Tetrahedron: Asymmetry 1998, 9, 3667-3675.5. Noyori, R.; et. al. J. Am. Chem. Soc. 1996, 118, 4916-4917.6. Campbell, E.J.; Zhou, H.; Nguyen, S.T. Angew. Chem. Int. Ed. 2002, 41, 1020-1022 7. Cohen, R.; Graves, C.R.; Nguyen, S.T.; Martin, J.M.L.; Ratner, M.A. J. Am. Chem. Soc. 2004, 126, 14796- 148038. Mattson, A.E.; Scheidt, K.A. Org. Lett. 2004, 6, 4363-4366.9. “Strategic Applications of Named Reactions in Organic Synthesis.” Kurti, L.; Czako, B.; Elsevier, St.
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