thiourea-catalysed ring opening of episulfonium ions with indole derivatives by means of stabilizing...
TRANSCRIPT
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
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
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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-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. 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
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
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.
What’s a Good H-Bond Donor ?
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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.