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Song Lin and Eric N. Jacobsen*. Thiourea-catalysed ring opening of episulfonium ions with indole derivatives by means of stabilizing non-covalent interactions. Anne-Catherine Bédard Charette/Collins Meeting – November 27 th 2012. Nature Chem. 2012 , 4 , 817-824. Discovery .

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Song Lin and Eric N. Jacobsen*

Thiourea-catalysed ring opening of episulfoniumions with indolederivatives by means of stabilizingnon-covalent interactions

Anne-Catherine Bédard

Charette/Collins Meeting – November 27th 2012

Nature Chem.2012, 4, 817-824


  • Urea were originally designed as chiral ligand for Lewis acidic metal

  • The observation of enatioselectivity in the absence of the metal was unanticipated !

M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901-4902.

M.S. Sigman, P. Vachal, E.N. Jacobsen, Angew. Chem. Int. Ed.2000, 39, 1279 – 1281

Taylor, M. S., Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520-1543.

Lewis vs br nsted acid catalysis
Lewis vs Brønsted Acid Catalysis

“Why did the report of Yates and Eaton, and not that of Wasserman, capture the imagination of the early practitioners of asymmetric catalysis, leading to the current situation where chiral Lewis acid catalysis, rather than chiral Brønsted acid catalysis, is the dominant strategy for the promotion of enantioselective additions to electrophiles ?”

  • Taylor, M. S. and Jacobsen, E. N.

Yates, P., Eaton, P. J. Am. Chem. Soc.1960, 82, 4436-4437.

Wassermann, A. J. Chem. Soc. 1942, 618-621.

Taylor, M. S., Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520-1543.

H bonding catalysis in enzymes
H-Bonding Catalysis in Enzymes

  • Lewis vsBronsted Acid

  • Non-covalent catalysis via H-Bonding

  • Mimic the mode of action of enzymes by

    design of small molecule

    • Ex : Serine protease

    • 16 to 30 kDa

Zhang, Z. G., Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187–1198.

Enzyme vs small molecule catalysis
Enzyme vs Small Molecule Catalysis

  • Enzymes :

    • Accelerate reactions and impart selectivity as they stabilize specific transition structures through networks of cooperative interactions

  • Chiral small-molecule :

    • Catalysts is rationalized typically by the steric destabilization of all but one dominant pathway.

    • However, stabilizing effects also play an important role in small-molecule catalysis (rare mechanistic characterization)

Lin, S., Jacobsen, E. N. Nature Chem.2012, 4, 817-824


  • Thiourea : suitable host for an episulfonium ion formed in situ through interactions with the chiral counteranion

  • Friedel–Crafts-type indole alkylation reaction

Search for the episulfonium ion
Search for the Episulfonium Ion

  • Non-nucleophilic leaving group was required to achieve the desired reactivity

  • Otherwise major product is addition of chlorine atom.

Hamilton, G. L., Kanai, T. & Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984–14986.

Optimization acid
Optimization - Acid

Need a non-nucleophillic anion for the acid (entry 1 major product is Cl addition)

Sulfonate group work better/strong counterion effect

Optimization catalyst
Optimization – Catalyst

No direct correlation between size of the aromatic

group and e.e. (best = phenantryl)

No direct interaction of the thiourea sulfur atom

(Lewis based catalysis)

Scope leaving group
Scope – Leaving Group

Choice of leaving group doesn’t have an

effect on the enantioselectivity

1st step is protonation of trichloroacetamide

Substrate scope mecanism insight
Substrate Scope – Mecanism Insight

Benzyl is better than phenyl and alkyl


DFT : Benzylic protons in S-Benzyl episulfonium ions

partial positive charge

enhance attractive interactions with the catalyst

Substrate scope indole substitution
Substrate Scope – Indole Substitution

Indole N-H motif may be involved

in a key interaction during

e.e.-determining transition state

Substate scope episulfonium substitution
Substate Scope - Episulfonium Substitution

Para substitution decreases the enantioselectivity

Interaction of the C-H with thiourea-bond


Proposed mechanism
Proposed Mechanism

  • Protonation of trichloroacetamide

  • Formation of episulfonium ion

  • (endothermic ionisation)

  • 3. Nucleophillic attack

  • 4. Rearomatisation

Kinetic studies in situ ir
Kinetic Studies - in situ IR

  • Rate accelerated by chiral thiourea vs 4-NBSA alone

    • 2.0±0.1 kcal/mol

  • 0th order in substrate and 1st order in 4-NBSA

    • Quantitative protonation before rds

    • pKa 4-NBSA ≈ -7 and pKa substrate ≈ 2

  • 1st order in indole (present at rds)

  • Episulfonium-4-NBSA (covalent adduct) is the resting state of the substrate

Denmark, S. E.; Vogler, T. Chem. Eur. J. 2009, 15, 11737-11745.

Proposed mechanism1
Proposed Mechanism

  • Protonation of trichloroacetamide

  • Formation of episulfonium ion

  • (endothermic ionisation)

  • 3. Nucleophillic attack

  • 4. Rearomatisation

Aromatisation is rds?

Addition is rds?

5 substituted indole rate comparison
5-Substituted Indole : Rate Comparison

Catalysedby 4-NBSA and thiourea

Catalysedby 4-NBSA

  • Better nucleophile = faster rate

  • Consistent with addition being rds!

  • No KIE when 3-D-indole is used (0.93±0.12); if rearomatisation was rds kH/kD >2.5

  • Proposed mechanism2
    Proposed Mechanism

    • Protonation of trichloroacetamide

    • Formation of episulfonium ion

    • (endothermic ionisation)

    • 3. Nucleophillic attack

    • 4. Rearomatisation

    Rate and Enantiodetermining

    Catalyst substrate interactions nmr studies
    Catalyst-Substrate InteractionsNMR Studies

    NMR showed attractive interactions between the aromatic group in 3e and a-protons in 5

    Shift (downfield) observed for the 2 N-H in thiourea : consistent with H-Bond

    Kelly, T. R.; Kim, M. H. J. Am. Chem. Soc. 1994, 116, 7072-7080.

    Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science2010, 327, 986-990.

    Indole structure
    Indole Structure

    N-H is important for high yield and e.e.

    pKaindole rate 

    Rate is correlated with nucleophilicity and H-bond donor properties

    Aromatic group on thiourea
    Aromatic Group on Thiourea

    The arene affect may be caused by

    (1) acceleration of the major pathway through transition-state stabilization

    (2) inhibition of pathways that lead to the minor enantiomer through destabilizing interactions.

    Enantioselectivity increases

    because variations of the aryl

    component of the catalyst 3

    are, indeed, tied to stabilization

    of the major transition structure

    Uyeda, C. & Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 5062–5075

    Proposed model for enantioselection
    Proposed Model for Enantioselection


    • Enantioselective reaction : addition of indole to the episulfonium ion

    • Rate acceleration/enantioselectivity by thiourea catalyst

      • attractive non-covalent interactions in TS

      • stabilized by anion binding of the thiourea to the sulfonate

      • general base activation of the indole via a catalyst amide–indole N–H interaction

      • cation-p interaction between the arene of the catalyst and the benzylic protons of the episulfonium ion

    • “We anticipate that characterization of these enzyme-like non-covalent stabilizing elements with small-molecule catalysts such as 3e may enable the future design and application of such biomimetic strategies in organic asymmetric synthesis.”

    Lin, S.; Jacobsen, E. N. Nature Chem.2012, 4, 817-824

    Enzyme like non covalent stabilizing elements new concept
    Enzyme-Like Non-Covalent Stabilizing Elements : New Concept ?

    Xu, H., Zuend, S. J., Woll, M. G., Tao, Y. & Jacobsen, E. N. Science2010, 327, 986–990.

    Uyeda, C. & Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 5062–5075.

    What s a good h bond donor
    What ?’s a Good H-Bond Donor ?

    Connon, S. J. Chem. Eur. J. 2006, 12, 5418-5427.

    Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2006 , 45, 1520-1543.

    Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007 , 107 , 5713-5743.

    Akiyama, T. Chem. Rev. 2007 , 107 , 5744-5758.