THIOUREA-CATALYSED RING
OPENING OF EPISULFONIUM
IONS WITH INDOLE DERIVATIVES
BY MEANS OF STABILIZING
NON-COVALENT INTERACTIONS
Song Lin and Eric N. Jacobsen*
Anne-Catherine Bédard
Charette/Collins Meeting – November 27th 2012
Nature Chem. 2012, 4, 817-824
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 – 1281
Taylor, 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.
H-Bonding Catalysis in Enzymes
4

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

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
6


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
7
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
8
Entry
Acid
Yield (%) e.e. (%)
1
HCl
10
5
2
HOTf
73
32
3
FSO3H
78
19
4
2,4-diNBSA
79
63
5
4-NBSA
72
73
6
4-NBSA (w/o cat.)
7
n/a
Need a non-nucleophillic anion for the acid (entry 1 major product is Cl addition)
Sulfonate group work better/strong counterion effect
Optimization – Catalyst
9
Entry
Catalyst
Yield (%)
e.e. (%)
1
A (Ar = H)
16
12
2
B
72
73
3
C
84
84
4
D
80
85
5
E
93
93
6
F
91
91
7
G
97
88
8
4E (urea)
98
92
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
10
Entry Leaving group Yield (%) e.e. (%)
1
2
3
87
91
85
87
85
85
Choice of leaving group doesn’t have an
effect on the enantioselectivity
1st step is protonation of trichloroacetamide
Substrate Scope – Mecanism Insight
11
Entry
R group
Yield (%) e.e. (%)
1
Bn
99
93
2
Ph
84
80
3
4-F-C6H4
73
81
4
4-Me-C6H4
76
87
5
2-naphtyl
90
88
6
PMB
>99
94
7
Me
72
84
8
tBu
89
87
Benzyl is better than phenyl and alkyl
Rational
12
DFT : Benzylic protons in S-Benzyl episulfonium ions
partial positive charge
enhance attractive interactions with the catalyst
Substrate Scope – Indole Substitution
13
Entry
Substituant
Yield (%) e.e. (%)
1
5-Me
97
91
2
5-OMe
93
93
3
5-Br
83
92
4
5-F
88
95
5
6-F
92
85
6
4-OMe
83
91
7
2-Me
95
79
8
N-Me
54
3
9
Benzotriazole
92
80
Indole N-H motif may be involved
in a key interaction during
e.e.-determining transition state
Substate Scope - Episulfonium Substitution
14
Entry
Substitution
Yield (%)
e.e. (%)
1
3-MeO-C6H4
85
93
2
3-F-C6H4
97
95
3
3-Me-C6H4
95
93
4
2-Me-C6H4
99
79
5
4-F-C6H4
91
45
6
4-Me-C6H4
89
60
7
4-MeO-C6H4
67
6
8
4-CF3-C6H4
18
5
9
-(CH2)4-
16
9
10
-
87
87
Para substitution decreases the enantioselectivity
Interaction of the C-H with thiourea-bond
sulfonate?
Proposed Mechanism
15
1. Protonation of trichloroacetamide
2. Formation of episulfonium ion
(endothermic ionisation)
3. Nucleophillic attack
4. Rearomatisation
Kinetic Studies - in situ IR
16

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 Mechanism
17
1. Protonation of trichloroacetamide
2. Formation of episulfonium ion
(endothermic ionisation)
3. Nucleophillic attack
4. Rearomatisation
5-Substituted Indole : Rate Comparison
18
Catalysed by 4-NBSA
Catalysed by 4-NBSA and thiourea
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 Mechanism
19
1. Protonation of trichloroacetamide
2. Formation of episulfonium ion
(endothermic ionisation)
3. Nucleophillic attack
4. Rearomatisation
Catalyst-Substrate Interactions
NMR Studies
20
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. 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 Thiourea
22
Aromatic Group on Thiourea
23
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
24
Conclusion
25

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 noncovalent 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 Synthesis
27
Different Types of H-Bonding
Interactions
28
What’s a Good H-Bond Donor ?
29
pKa
propency to dimerize mode of activation
urea
26
high
Double H-Bond
thiourea
20
low
Double H-Bond
bisphenol
18
low
Double H-Bond
guanidinium
15
low
Double H-Bond
diol
20
-
Single H-Bond
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 Synthesis
30
Catalyst Investigation
31
pKa Corrected
32
Catalyst Investigation
33
Use of a Chiral Phosphoric Acid
34