Enantioselective thiourea-catalyzed cationic polycyclizations

Article abstract of DOI:10.1021/ja101256v

A new thiourea catalyst is reported for the enantioselective cationic polycyclization of hydroxylactams. Both the yield and enantioselectivity of this transformation were found to vary strongly with the identity of a single aromatic residue on a common ca

Full text of DOI:10.1021/ja101256v

Published on Web 04/07/2010
Enantioselective Thiourea-Catalyzed Cationic Polycyclizations
Robert R. Knowles, Song Lin, and Eric N. Jacobsen*
Department of Chemistry & Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received February 16, 2010; E-mail: jacobsen@chemistry.harvard.edu
Scheme 1. Proposal for Enantioselective Polycyclization
Advances in cyclase enzymology have provided strong
evidence that cation-π interactions play an essential catalytic
role in biosynthetic polyene cyclizations.1,2 Structural, kinetic,
and site-directed mutagenesis studies all suggest that the cationic
intermediates and transition states accessed in these transforma-
tions are stabilized through a series of attractive interactions with
aromatic residues that line the cyclase active site.3 This
mechanistic insight suggests the intriguing possibility that
analogous stabilizing cation-π interactions might also be
engineered into selective small-molecule catalysts.4
We became interested in developing an asymmetric polycy-
clization jointly predicated on this biosynthetic model and our
recent work in anion binding thiourea catalysis.5,6 The ability
of arenes to stabilize cations offers a logical complement to the
anion binding properties of thioureas.7 As such, an appropriate
bifunctional catalyst would be capable of electrostatically
stabilizing both poles of a reactive ion pair in a spatially resolved
manner, increasing the probability of strong binding to the
enantioselectivity-determining transition state structure (Scheme
1).8 Herein, we report the development of a new thiourea catalyst
for the enantioselective bicyclization of hydroxylactams, together
with evidence that stabilizing cation-π interactions play a
principal role in asymmetric induction.
c
-
Table 1. Catalyst Optimizationa
Our efforts focused on developing an enantioselective variant
of a polycyclization originally reported by Speckamp that
proceeds through an N-acyliminium ion intermediate (Table 1).9
In accord with our previous reports on asymmetric transforma-
tions utilizing these electrophiles, we envisioned that treatment
of a hydroxylactam substrate with hydrochloric acid would result
in dehydrative formation of a chlorolactam intermediate.6c
Hydrogen bond-mediated ionization of this chlorolactam by the
thiourea would generate a catalyst-bound iminium•chloride ion
pair that would in turn undergo cyclization enantioselectively.
In evaluating the bicyclization of hydroxylactam 1, a preliminary
survey of thioureas and solvents produced a lead result with
thiourea 3, with tetracycle 2 generated in 10% yield and 9% ee
upon treatment with 25 mol% of HCl in TBME containing 4 Å
molecular sieves at -30 °C (Table 1). Catalyst 4, a conforma-
tionally constrained analogue of 3 bearing a 2-phenylpyrrolidine
ring, afforded a modest increase in enantioselectivity.10 Modi-
fication of the electronic properties of the aromatic group of 4
by introduction of simple substituents had little effect on catalyst
performance. In contrast, 2-arylpyrrolidine catalysts bearing
larger aromatic groups proved substantially more reactive and
enantioselective. The naphthyl-substituted catalysts 5 and 6 both
provided 2 in greater than 60% ee, while 9-phenanthryl-derived
catalyst 7 furnished product 2 in 52% yield and 87% ee. Spurred
by the apparent correlation between the expanse of the pyrro-
lidine arene and catalytic performance, we prepared and evalu-
ated 4-pyrenyl-substituted thiourea derivative 8. This proved to
be the optimal catalyst, providing 2 in 78% yield and 95% ee.11
Under the action of all the catalysts described in Table 1,
a Yields determined by GC analysis relative to an internal standard.
b Enantiomeric excess determined by SFC analysis on commercial chiral
columns. c Optimization reactions performed on 0.033 mmol scale.
tetracycle 2 was formed as a single detectable diastereomer, the
relative stereochemistry of which was secured by X-ray crystal-
lography (Supporting Information).12,13 Notably, reactions per-
formed in the absence of a thiourea catalyst provided none of
the desired bicyclization product.14
Having identified a selective catalyst and suitable reaction
conditions, we evaluated the substrate scope of this bicyclization
protocol. A variety of aromatic groups were found to be efficient
and selective terminating nucleophiles (Table 2). In addition to
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10.1021/ja101256v  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Eyring Analysis of Enantioselectivity
Table 2. Substrate Scopeg
entry
catalyst
∆∆H‡ (kcal/mol)
∆∆S‡ (cal/mol·K)
1
2
3
6
7
8
-1.12 ( 0.07
-1.87 ( 0.08
-3.95 ( 0.17
-2.0 ( 0.3
-2.8 ( 0.3
-8.9 ( 0.7
enthalpy increased markedly as the catalyst arene increased in
size. In fact, this term roughly doubles in magnitude with the
addition of each new aromatic ring, reaching nearly four kcal/
mol for the optimal catalyst 8. The effect of this increase was
attenuated slightly by a compensating increase in the differential
entropy terms across the series.
The energetic benefits of increasing the strength of a nonco-
valent binding interaction are typically manifested enthalpi-
cally.18 As such, the increasing magnitude of the differential
enthalpy in catalysts with more extended arenes is consistent in
principle with a progressively more stabilizing cation-π interac-
tion in the dominant transition state structure and with the fact
polycyclic aromatic hydrocarbons are known to bind cations
more strongly as they increase in size.19 However, these data
do not rule out the possibility that increasing the expanse of the
arene energetically destabilizes the minor transition state as-
sembly, presumably through steric interactions.20 To ascertain
whether the extended aromatic system is stabilizing the transition
state leading to the major enantiomer or destabilizing the minor
pathway, we investigated whether correlations existed between
the degree of observed enantioinduction and the physical
properties that underlie cation-π interactions. The strength with
which a given arene interacts with a positive charge in a
transition state is primarily a function of electrostatic and
dispersion forces.21,22 As such, if the strength of a cation-π
interaction is a determinant in enantioselectivity, there may be
a correlation between the degree of asymmetric induction
observed and the quadrupole moment and polarizability of the
arene involved. Conversely, if the effect was largely steric and
repulsive in origin, no significant correlation with these physical
properties would be expected. The enantioselectivity observed
with catalysts 4, 6, 7, and 8 under standard conditions was found
to correlate strongly with both the polarizability and the
quadrupole moment of the arenes found in each catalyst (R2 )
0.99, 0.97 respectively, see Supporting Information).23,24 Taken
altogether, these data provide compelling evidence for a mech-
anism incorporating a selectivity-determining cation-π interaction.
In conclusion, the enantioselective cationic polycyclization
reactions catalyzed by 8 appear to engage stabilizing cation-π
interactions as a principal element of enantioselectivity. In this
respect, these findings emulate the particularly striking role
cation-π interactions play in the catalysis of biosynthetic
polyene cyclizations and provides clear support for the notion
that these interactions can dictate stereocontrol in small-molecule
catalysis contexts as well. Moreover, this work further advances
the view that stabilization of the dominant transition state
a Isolated yields after chromatography on silica gel. b Enantiomeric
excess determined by SFC analysis on commercial chiral columns.
c Reaction run with 2.0 equivalents of TMSCl. d Reaction run with 50
mol% HCl. e Reaction run at -10 °C. f The structure and absolute
configuration of 20 was established by X-ray crystallography and the
stereochemistry of all other products was assigned by analogy.
g Reactions performed on 0.25 mmol scale.
the model substrate 1, the unsubstituted phenyl substrate 9 (entry
1), a number of para-substituted phenyl derivatives (entries
2-5), an extended naphthyl-containing substrate 17 (entry 6),
and a chlorinated thiophene 19 (entry 7) all underwent cyclization
with high enantioselectivity under the action of catalyst 8.15
Furthermore, in each case the bicyclization products were formed
as single diastereomers, as judged by NMR analysis.16 The use
of more electron-rich arene nucleophiles or alteration of the
non-aromatic portions of the substrate led to significant losses
in either reactivity or enantioselectivity.17
The fact that the enantioselectivity observed in these poly-
cyclizations is highly dependent upon the expanse of the catalyst
arene, taken together with the cationic nature of the reaction,
raises the possibility that stabilizing cation-π interactions may
play a key role in asymmetric induction. To evaluate this
hypothesis, an Eyring analysis of enantioselectivity was con-
ducted for catalysts 6, 7, and 8 in the bicyclization of substrate
1. All three catalysts displayed linear correlations between ln(er)
and reciprocal temperature over a 70 °C range (Table 3).
Evaluation of the differential activation parameters derived from
these plots revealed that enantioselectivity was enthalpically
controlled in all cases and that the magnitude of the differential
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C O M M U N I C A T I O N S
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structure through noncovalent interactions is a viable means of
achieving high levels of enantioselectivity in counterion catalysis.
Acknowledgment. This work was supported by the NIGMS
(PO1 GM-69721 and RO1 GM-43214) and by a postdoctoral
fellowship to R.R.K. from the NIH. We thank Dr. Shao-Liang
Zheng for crystal structure determinations and Dr. Kristine Nolin
for the synthesis and use of catalysts.
Supporting Information Available: Full experimental procedures,
syntheses of substrates and catalysts, characterization data for all
new compounds, NMR spectra for bicyclization products, SFC traces
for scalemic bicyclization products, data sets for Eyring analysis
and correlations with arene properties, and crystallographic informa-
tion for compounds 2, 18, and 20. This material is available free of
charge via the Internet at http://pubs.acs.org.
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(14) In the absence of the thiourea catalyst, an HCl-catalyzed process forms a
monocyclized byproduct.
(15) Higher yields and faster reactions are observed using increasing amounts
of HCl, though with diminished enantioselectivities.
(16) In all cases, the only detectable byproduct is a monocyclized and eliminated
product formed with low enantioselectivity.
(17) Enantioselectivity is strongly correlated with the electronic properties of
the arene nucleophile, with electron-deficient arenes proving optimal.
Results for less enantioselective substrates are included in the Supporting
Information.
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