Design of AcidBase Catalysis for the Asymmetric Direct Aldol Reaction

1
Design of Acid-Base Catalysis for the Asymmetric
Direct Aldol Reaction

• Susumu Saito and Hisashi Yamamoto
• Acc. Chem. Res. 2004, 37, 570-579
• Ana Stankovic
• 05/09/05

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Polyene macrolide antibiotics containing complex
b-hydroxy carbonyl and 1,3-diol units
Rychnovsky, S.D. Chem Rev. 1995, 95, 2021-2040
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Utility of the Aldol Reaction

• Concise method for preparing the b-hydroxy
  carbonyl and 1,3-diol units
• Rapid development of enantioselective aldol
  reactions
• The discovery of the versatile catalytic nature
  of proline occurring via enamine intermediates
  has undoubtedly been the biggest breakthrough in
  this field of research.

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Initial Idea for Acid-Base Catalysis - Proline

• Enamine catalysis
• Aldol
• Mannich
• Michael
• a -Amination
• a -Oxidation

a -Sulfenylation a -Chlorination a-Alkylation IED
A
Yamamoto, H., Saito, S. Acc. Chem. Res. 2004, 37,
570-579
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Approach to Designing the Amine-Acid Catalyst

• Fundamental nature of the amine-acid catalyst
• Multiple step acid-base catalysis is thought to
  be involved in the formation and reaction of
  enamine intermediates
• Acidic part of amine-acid catalyst systems seems
  to be largely responsible for rapidly promoting
  the steps of enamine and cacrbon-carbon bond
  formation

Yamamoto, H. , Saito, S. Acc. Chem.
Res. 2004, 37, 570
6
Approach to Designing the Amine-Acid Catalyst

• How does the acidic function participate in aldol
  catalysis? ? Tune the acidic function
• Create a complex but more cooperatively arranged
  hydrogen-bond network system that would stabilize
  a transition state

Structural and electronic tuning would therefore
be effective in promoting new reactivity and
better selectivity
Yamamoto, H. , Saito, S. Acc. Chem. Res. 2004,
37, 570
7
Approach to Designing the Amine-Acid Catalyst

• Unique acidic functions instead of H...(OH)R
  type acids
• A diamine-acid catalyst (R3N.....H)X- and,
• An amine-acid catalyst R2Nd--Hd
• Amine-acid catalyst would also provide for an
  additional proton binding site and consequently
  more arranged hydrogen-bond networks stabilizing
  the TS

pKa12 in DMSO
pKa10 in DMSO
pKa8 in DMSO
Yamamoto, H. , Saito, S. Acc. Chem. Res. 2004,
37, 570
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Background for Catalyst Design
Hine, J., Acc. Chem. Res. 1978, 11, 1
Barbas, C.F. III J. Am. Chem.. Soc. 2000, 122,
2395
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Background for Catalyst Design
81 yield
Janda, K.D., J. Am. Chem.. Soc. 2002, 124, 3220

• Orr, R.K. Tetrahedron Lett. 2003, 44, 5699

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Acid-Base Catalysts Derived from a Lewis Acid
and Diamine

• (S)-()-1-(2-pyrrolidinemethyl)pyrrolidine and
  lanthanide Lewis acid
• Identification of essential features of catalysis
  indicated that TfOH may catalyze the reaction
  instead of the triflate salt Gd(OTF)3

Yamamoto, H. Synlett 2001, 1245
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Acid-Base Catalysts Derived from a Bronsted Acid
and Diamine

• Diamine-diBronsted acid complex 5 did not work
• A mixture of 11 of 5 and 2 did promote the
  reaction ? suggests that a 11 mixture of 2 and
  TfOH (catalyst 7 or presumably 6) is the real
  active species

Yamamoto, H. , Saito, S. Acc. Chem. Res. 2004,
37, 570
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Acid-Base Catalysts Derived from a Bronsted Acid
and Diamine Further Evaluations

• 2. Solvent Effects

1. Protonic acid variations
Reactions were performed using diamine 4 (3 mol)
and acid (3 mol) in acetone (27 eq) at 40 C for
2h under air in a closed system.
Yamamoto, H. Synlett 2001, 1245
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Acid-Base Catalysts Derived from a Bronsted Acid
and Diamine Further Evaluations
3. Various diamines (L-Proline and D-Phenyl
alanine derivatives)
Yamamoto, H. Synlett 2001, 1245
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Diamine-Bronsted Acid Catalysts
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Diamine-Bronsted Acid Catalysts
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Diamine-Bronsted Acid Catalysts for Catalytic
Asymmetric Aldol Reaction
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Diamine-Bronsted Acid Catalysts for Catalytic
Asymmetric Aldol ReactionSome of the Optimal
Results
Secondary-tertiary diamine 11 best ee values
overall 11 with 1b and 1c extensive elimination
Primary-tertiary diamine Avoided formation of
dehydration products
Secondary-primary diamine 16 was totaly
ineffective regarding both productivity and
efficiency
Secondary-secondary diamine 20 gave the most
optimal results, but was followed by considerable
dehydration
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Proposed Plausible Mechanism of Diamine-Acid
Catalysis
Yamamoto, H. Synlett 2001, 1245
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Advanced Acid-Base Catalyst with a Tetrazole
Functionality

• Must posses both acidic and basic functions
• Acidic function superior to that of proline
• Basic function capable of binding the Bronsted
  acid of the reaction substrate

Pyrrole Imidazole
Pyrrazole 1,2,4-Triazole 1,2,3-Triazole
Tetrazole
pKa16.5 14.5 14.0
10.0 9.4
4.9
Elguero, J.. Bull. Soc. Chim. Fran. 1985, I-30
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Advanced Acid-Base Catalyst with a Tetrazole
Functionality
Yamamoto, H. Synlett 2001, 1245 Yamamoto, H.
Tetrahedron 2002, 58, 8167
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Advanced Acid-Base Catalyst with a Tetrazole
Functionality
Yamamoto, H. Synlett 2001, 1245 Yamamoto, H.
Tetrahedron 2002, 58, 8167
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Advanced Acid-Base Catalyst with a Tetrazole
Functionality Extension to Aldehydes Having a
High Affinity for Water
Yamamoto, H. Synlett 2001, 1245 Yamamoto, H.
Tetrahedron 2002, 58, 8167
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Effects of Water on the Mechanism of Tetrazole
Catalysis

• No 1HNMR peaks corresponding to the imminium ion
  or aminal identified
• Does water affect this shift by formation of the
  hydrated form of chloral?
• Catalytic amount of water (0.2 --gt 0.5eq)
  disables the catalytic cycle (remaining chloral
  poisons the catalyst s activity)
• By contrast, 1.0eq of water improves the
  catalysis markedly

Yamamoto, H. , Saito, S. Acc. Chem. Res. 2004,
37, 570
24
Possibility of Hydrogen-Bond Networks in the
Transition Structure Model System

• Implication of the importance of hydrogen-bonding
  between nitrogen and the hydroxy group
• Hydrogen-bond networks spread over complex
  aggregates of multiple monohydates

Yamamoto, H. , Saito, S. Acc. Chem. Res. 2004,
37, 570
25
Possibility of Hydrogen-Bond Networks in the
Transition Structure
Proposed hydrogen-bond networks created by
interactions between catalyst and chloral hydrate

• Assumption of the existence of effective
  hydrogen-bond networks (which would create a
  structurally arranged TS) in agreement with
  obtained ee values for tetrazole containing
  amine-acid catalyst

Yamamoto, H. , Saito, S. Acc. Chem. Res. 2004,
37, 570
26
5-Pyrrolidin-2-yltetrazole as a Catalyst for
Enantioselective O-nitroso Aldol Reactions
Zhong, G. Anew. Chem. Int. Ed. Engl. 2003, 42,
4247
Hayashi, Y. Tetrahedron Lett. 2003, 44, 8293
MacMillan, D.W.C. J. Am. Chem. Soc. 2003, 125,
10808
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5-Pyrrolidin-2-yltetrazole as a Catalyst for
Enantioselective O-nitroso Aldol Reactions
Yamamoto, H. Proc. Natl. Acad. Sci. 2004,
101, 5374
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5-Pyrrolidin-2-yltetrazole as a Catalyst for
Enantioselective O-nitroso Aldol Reactions Scope
Yamamoto, H. Proc. Natl. Acad. Sci. 2004,
101, 5374
29
5-Pyrrolidin-2-yltetrazole as a Catalyst for
Enantioselective O-nitroso Aldol Reactions
Proposed Transition State

• Reaction may proceed from the same side of
  tetrazole by either activation of nitrosobenzene
  by an acidic proton (10a) or an indirect route
  via amine-nitrosobenzene complexation (10a)

Yamamoto, H. Proc. Natl. Acad. Sci. 2004,
101, 5374
30
5-Pyrrolidin-2-yltetrazole as a Catalyst for
Asymmetric Mannich-type Reactions

• Tetrazole more soluble than proline in
  conventional solvents
• Enantioselectivity not affected, though lower
  yields observed due to hydrolysis of imine
• Generally reactions faster with tetrazole (by TLC)

Ley, S. Synlett 2004, 558
Barbas, C.F. III J. Am. Chem. Soc 2002, 124,
1842
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5-Pyrrolidin-2-yltetrazole as a Catalyst for
Asymmetric Mannich-type Reactions
TS of the tetrazole organocatalyzed Manncih
reaction. The PMP group on the imine sits axially
to avoid clash with the terazole thereby forcing
the E-amine (preferred) to form the syn product.
Ley, S. Synlett 2004, 558
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Results and Future Perspectives

• lllustration of the importance and power of
  molecular design of acid-base catalysts for the
  asymmetric aldol reaction
• Tetrazole matched or exceeded the results derived
  from proline
• Water participates positively in the reaction
• Effective hydrogen-bond networks that stabilize
  the transition state
• Each reaction course is strongly dependent on
• the acidic-basic nature of the catalyst
• the structure of the catalyst
• The correct adjustment of reaction conditions
  (solvent)
• Improving reactivity as to take us beyond the
  catalytic function of metal-based catalysis in
  the asymmetric aldol reaction
• Design of acid-base catalysis requires and will
  benefit from further molecular manipulations
• Acid-base catalysis has been successfully
  employed in the o-nitroso aldol as well as
  Mannich-type reactions

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Tetrazole synthesis