Oxazaborolidine Catalysts for Asymmetric DielsAlder Reactions

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Oxazaborolidine Catalysts for Asymmetric
Diels-Alder Reactions

• Nicole Mancey
• 4th June 2008

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In the beginning
Syn. Lett, 1990, 194
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In the beginning
Syn. Lett, 1990, 197
Tet. Asymmetry, 1991, 2, 639
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Coreys Initial Experiments
J. Am. Chem. Soc. 1991, 113, 8966
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A Variety of Dienes
Tet. Lett. 1993, 34, 3979 J. Am. Chem. Soc.
1994, 116, 3611
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Catalyst Synthesis
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An alternative transition state
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Stereoselective coordination of dienophile

• NOE show aldehyde-catalyst complex fairly rigid
• Bright orange-red colour due to formation of
  charge-transfer complex
• Indole ring is crucial to enantioselectivity

J. Am. Chem. Soc. 1992, 114, 8290
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Dienophile conformation S-cis vs S-Trans
S-cis and s-trans conformers lead to enantiomeric
products Complexes of both are in rapid
equilibrium
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Formyl C-H ... O/F hydrogen bonding
Tet. Lett. 1997, 38, 33 Tet. Lett. 1997, 38, 33
Chem. Comm. 2001, 1321 Wong, M. W. J. Org. Chem.
2005, 70, 5487.
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Pistols at Dawn?!
Tet. Lett. 1993, 34, 2669
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Catalyst Enantiomer
J. Am. Chem. Soc. 1992, 114, 8290
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Applications to natural productsmore complex
dienes
J. Am. Chem. Soc. 1994, 116, 3611
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First enantioselective synthesis of gibberellic
acid
J. Am. Chem. Soc. 1994, 116, 3611
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Even more challenging
J. Am. Chem. Soc. 2001, 123, 1872
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The next stepcationic Lewis acids
J. Am. Chem. Soc. 1996, 118, 5502
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Less reacive dienes
a) -94 oC, 1 h, 10 mol catalyst B b) -94 oC, 2
h, 10 mol catalyst B
J. Am. Chem. Soc. 1996, 118, 5502
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Transition State
Oriented for optimal H bonding S-trans as no
steric clashes
J. Am. Chem. Soc. 1996, 118, 5502
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The next generation of oxazaborolidine catalyst
J. Am. Chem. Soc. 2002, 124, 3808
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The next generation of catalyst
J. Am. Chem. Soc. 2002, 124, 3808
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Extending the range of dienophiles
J. Am. Chem. Soc. 2002, 124, 9992
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Extending the range of dienophiles
J. Am. Chem. Soc. 2002, 124, 9992
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Quinone monoketals
J. Am. Chem. Soc. 2002, 124, 9992
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Explaining the different enantioselectivity
Substrate dependent can use transition state
models to predict your product
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Changing the counterion Triflimide activation
J. Am. Chem. Soc. 2003, 125, 6388
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Changing the counterion Triflimide activation
J. Am. Chem. Soc. 2003, 125, 6388
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Unsymmetrical dienes and dienophiles the next
challenge
J. Am. Chem. Soc. 2003, 125, 6388
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Unsymmetrical dienes and quinones the next
challenge
J. Am. Chem. Soc. 2003, 125, 6388
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Acyclic intramolecular Diels-Alders
Org. Lett. 2003, 5, 3979
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Predictive Selection Rules

• The catalyst will coordinate to the least
  sterically hindered oxygen lone pair
• The catalyst will coordinate to the most Lewis
  basic of the two 1,4-quinone oxygens
• An unsubstituted quinone double bond is more
  reactive than substituted ones
• The Diels-Alder reaction will occur at the CC
  bond syn to the coordinated lone pair
• The most nucleophilic carbon of an unsymmetrical
  diene will attack the most electrophilic carbon
  on the quinone - the carbon b to the coordinated
  carbonyl
• The transition state leads to an endo arrangement
  of diene and coordinated quinone

Order of decreasing importance
J. Am. Chem. Soc. 2004, 126, 4800
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Predictive Selection Rules An example
J. Am. Chem. Soc. 2004, 126, 4800
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Lewis Acid activation
Lewis acid activation. Requires only 1 eq
AlBr3 More efficient catalyst generally only 4
mol used Excellent stereo, regio and
enantiocontrol
J. Am. Chem. Soc. 2007, 129, 1498
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Application to furans
a ) 4 mol catalyst, b) 8 mol catalyst
J. Am. Chem. Soc. 2007, 129, 1498
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Application to 22 Cycloaddition reactions
10 mol catalyst, DCM, -78 oC
J. Am. Chem. Soc. 2007, 129, 12686
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Yamamotos alternative Lewis Acid activation
Angew. Chem. Int. Ed. 2005, 44, 1484
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..Bronsted Acid activation
J. Am. Chem. Soc. 2007, 129, 9536
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Regio and stereoselective reactions with
2-cyclopentadienes
J. Am. Chem. Soc. 2007, 129, 9536
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.. And 1-substituted cyclopentadienes
J. Am. Chem. Soc. 2007, 129, 9536
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Transition States
J. Am. Chem. Soc. 2007, 129, 9536 Application to
natural product 9534
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Haradas catalyst Ketone dienophiles
J. Org. Chem. 2006, 71, 3433
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Application to ketone dienophiles
Coreys OTf catalyst
Eur. J. Org. Chem. 2005, 3433
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Less reactive dienes
J. Org. Chem. 2008, 73, 212
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And finally furans
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Transition States
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Questions for you to practice