Thiourea-catalysed ring opening of episulfonium

ions with indole derivatives by means of stabilizing

non-covalent interactions

Nature Chem. 2012, 4, 817-824

Song Lin and Eric N. Jacobsen*

Anne-Catherine BédardCharette/Collins Meeting – November 27th 2012

Discovery 2

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 – 1281Taylor, M. S., Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520-1543.

Lewis vs Brønsted Acid Catalysis

3

“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.

Lewis vs Bronsted 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

H-Bonding Catalysis in Enzymes

4

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

Enzyme vs Small Molecule Catalysis

5

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

Proposal Thiourea : suitable host for an

episulfonium ion formed in situ through interactions with the chiral counteranion

Friedel–Crafts-type indole alkylation reaction

6

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.

7

Optimization - Acid

Need a non-nucleophillic anion for the acid (entry 1 major product is Cl addition)Sulfonate group work better/strong counterion effect

8

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)

9

Scope – Leaving Group10

Choice of leaving group doesn’t have an effect on the enantioselectivity

1st step is protonation of trichloroacetamide

Substrate Scope – Mecanism Insight

11

Benzyl is better than phenyl and alkyl

Rational DFT : Benzylic protons in S-Benzyl episulfonium ions

partial positive chargeenhance attractive interactions with the catalyst

12

Substrate Scope – Indole Substitution

13

Indole N-H motif may be involved

in a key interaction during e.e.-determining transition

state

Substate Scope - Episulfonium Substitution

14

Para substitution decreases the enantioselectivity

Interaction of the C-H with thiourea-bond sulfonate?

Proposed Mechanism15

1. Protonation of trichloroacetamide2. Formation of episulfonium ion (endothermic ionisation)3. Nucleophillic attack4. Rearomatisation

Kinetic Studies - in situ IR16

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 Mechanism17

1. Protonation of trichloroacetamide2. Formation of episulfonium ion (endothermic ionisation)3. Nucleophillic attack4. Rearomatisation

5-Substituted Indole : Rate Comparison

18

Catalysed by 4-NBSA Catalysed by 4-NBSA and thiourea

Better nucleophile = faster rateConsistent 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 Mechanism19

1. Protonation of trichloroacetamide2. Formation of episulfonium ion (endothermic ionisation)3. Nucleophillic attack4. Rearomatisation

Catalyst-Substrate InteractionsNMR Studies

20

NMR showed attractive interactions between the aromatic group in 3e and a-protons in 5Shift (downfield) observed for the 2 N-H in thiourea : consistent with H-BondKelly, 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. Science 2010, 327, 986-990.

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

pKa indole rate Rate is correlated with nucleophilicity and

H-bond donor properties

H-Bonding with Thiourea22

Aromatic Group on Thiourea23

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.

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

Enantioselectivity increases because variations of the aryl component of the catalyst 3 are, indeed, tied to stabilizationof the major transition structure

Proposed Model for Enantioselection

24

Conclusion25

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 ?26

Xu, H., Zuend, S. J., Woll, M. G., Tao, Y. & Jacobsen, E. N. Science 2010, 327, 986–990.Uyeda, C. & Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 5062–5075.

Thiourea Synthesis27

Different Types of H-Bonding Interactions

28

What’s a Good H-Bond Donor ?

29

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.

Substrate Synthesis30

Catalyst Investigation31

pKa Corrected 32

Catalyst Investigation33

Use of a Chiral Phosphoric Acid

34