Achiral counterion control of enantioselectivity in a Bronsted acid-catalyzed lactonization

Article abstract of DOI:10.1021/ja301858r

Highly enantioselective halolactonizations have been developed that employ a chiral proton catalyst-N-iodosuccinimide (NIS) reagent system in which the Bronsted acid is used at catalyst loadings as low as 1 mol %. An approach that modulates the achiral counterion (equimolar to the neutral chiral ligand-proton complex present at low catalyst loadings) to optimize the enantioselection is documented for the first time in this transformation. In this way, unsaturated carboxylic acids are converted to γ-lactones in high yields (up to 98% ee) using commercially available NIS.

Full text of DOI:10.1021/ja301858r

Communication
pubs.acs.org/JACS
Achiral Counterion Control of Enantioselectivity in a Brønsted Acid-
Catalyzed Iodolactonization
Mark C. Dobish and Jeffrey N. Johnston*
Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United
States
S
* Supporting Information
tion.12 Other approaches have also been investigated: phase-
transfer catalysis13 for iodolactonization; thiocarbamate/amine-
ABSTRACT: Highly enantioselective halolactonizations
catalyzed bromolactonization14 and aminobromination;15 chiral
amine-catalyzed chlorolactonization,16 bromolactonization,17
iodolactonization,18,19 chloroamination,20 and fluoroetherifica-
tion;21 and other transformations based on enantioselective
alkene halogenation.22−24
have been developed that employ a chiral proton catalyst−
N-iodosuccinimide (NIS) reagent system in which the
Brønsted acid is used at catalyst loadings as low as 1 mol
%. An approach that modulates the achiral counterion
(equimolar to the neutral chiral ligand−proton complex
present at low catalyst loadings) to optimize the
enantioselection is documented for the first time in this
transformation. In this way, unsaturated carboxylic acids
are converted to γ-lactones in high yields (up to 98% ee)
using commercially available NIS.
Success with enantioselective iodolactonization has been
limited to transformations with low enantioselection and/or
regioselection.8,13 The highest levels of enantioselection have
been achieved using cryogens (−80 °C) and a noncommercial
halogen source.19 Our interest resided in a strategy of direct
Brønsted acid halonium activation. Furthermore, the use of a
polar ionic hydrogen-bond catalyst, if effective, might be
optimized by manipulation of the achiral counterion rather than
restructuring the chiral ligand to optimize the reactivity and
enantioselectivity.25 Bis(amidine) (BAM)-based protic acid
complexes have been used extensively as bifunctional catalysts
for nitroalkane addition reactions but not elsewhere.26 The
polar ionic hydrogen bond (BAM−H+) formed from the
neutral ligand provides an achiral counterion that can be used
to modify the catalyst’s reactivity directly (Figure 2).27 We
report the discovery of highly enantioselective, chiral proton-
catalyzed iodolactonizations that illustrate the unique and
helpful role of an achiral counterion. Furthermore, a new
stilbenediamine-derived BAM provided a significant increase in
enantioselection relative to the use of a cyclohexanediamine
backbone.
he alkene halocarboxylation reaction was resistant to the
T
application of proven approaches to enantioselective
catalysis since its early realization, a shortcoming both
unfortunate and notorious considering the practical value of
the ester/lactone products.1 Sporadic indications that enantio-
selective halogenative addition reactions (e.g., the alkene
iodoacyloxylation outlined in Figure 1) are possible surfaced
Initial attempts to effect the transformation focused on δ-
unsaturated acid 3 and investigated both the free base (1) and
the triflic acid salt (1·HOTf) of the selected BAM catalyst (eq 1
in Figure 2). Low levels of enantioselection were observed with
the free base (19% ee), while slightly higher levels were
observed using the triflic acid salt (46% ee). Evidence of ligand
iodination at the 3 and 3′ positions was observed, as expected,
but control reactions with this derivative revealed essentially
identical behavior as the protocol implemented here, which
employs the des(iodo) ligand as the reagent for operational
convenience. Therefore, all of the reactions were prepared with
an excess of N-iodosuccinimide (NIS) equivalent to the catalyst
loading to account for bis(iodination) of the ligand.
Figure 1. Overview of alkene haloacetoxylation using electrophilic
halogen and the catalyst design used in this work.
in 2010, while careful mechanistic studies2−4 outlined obstacles
to significant, if not practically meaningful, enantioselectiv-
ity.5−7 Within the broader topic of alkene halofunctionalization,
the earliest strategies centered on Lewis base-promoted
halogenation strategies, such as chiral amine8,9 and phosphor-
amidite10 methods for halolactonization and polyene cycliza-
tion, respectively. A strategically complementary strategy
involves Lewis acid activation of the halogen donor:
haloamination of a chalcone alkene11 and enolsilane chlorina-
The effect of the counterion on the reactivity and selectivity
was examined by the use of different achiral Brønsted acid
sources, focusing on those providing a range of steric and
Received: December 15, 2011
Published: March 30, 2012
© 2012 American Chemical Society
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Communication
form.28−30 This effect was not entirely additive, as the
nonafluoric sulfonic acid salt behaved similarly to triflic acid
(Table 1, entry 6). We also considered that the carboxylic acid
substrate may be a more competitive counterion for the BAM
catalyst (resulting in a less selective catalyst) when less acidic
sulfonates are employed, a hypothesis advanced by others as an
interaction critical to high enantioselection.14,15
Triflylamine counterions, expected to have similar electronic
character but larger size relative to triflate, were next evaluated.
The triflamide counterion provided an active but less selective
catalyst (24% ee; Table 1, entry 7). Although relatively
dissociated, the counterion may still be critical in defining the
size and shape of the substrate binding pocket. Indeed,
triflimidic acid provided a substantial increase in enantiose-
lection to 84% ee (Table 1, entry 8). Use of a fluorinated cyclic
triflimide provided similar results (82% ee; Table 1, entry 9).
The response of enantioselection to counterions with varying
electronic and steric character suggests that the role of the
achiral counterion, despite its presence down to 1 mol % (see
below), is not simply to provide a resting state for the catalyst
but instead to affect the catalyst reactivity and structure directly
as it interacts with the substrate.31 Encouraged by these results,
we sought further increases in selectivity by examining other
reaction parameters (Table 2).
Decreasing the catalyst loading from 10 to 5 mol % (Table 2,
entry 2) did not dramatically influence the enantioselection, but
increased selectivity with a longer reaction time was observed
when the reaction mixture was diluted (Table 2, entry 3).
Among a range of ligands surveyed, increased reactivity and
selectivity were achieved when a stilbenediamine backbone
(StilbPBAM, 5) was used instead of the cyclohexanediamine
backbone to support the aminoquinoline donors (Table 2,
entries 4−6), while the counterion trend seen for PBAM (1)
was maintained. In a direct comparison, the StilbPBAM·HNTf2
catalyst delivered the adduct in 89% yield with 95% ee after
only 2.5 h (Table 2, entry 6). This increased selectivity may be
due to the smaller dihedral angle characteristic of the
stilbenediamine backbone32 relative to the cyclohexanediamine,
leading to a smaller cavity for presentation of the polar ionic
hydrogen bond. Furthermore, diluting the reaction to 0.05 M
(Table 2, entry 7) and lowering the catalyst loading to 5 mol %
(Table 2, entry 8) gave the adduct in 96 and 97% ee,
respectively. With longer reaction times, we were able to
decrease the catalyst loading to 2 mol % (Table 2, entry 9) and
1 mol % (Table 2, entry 10) with minimal effect on the yield, a
trend not observed with the initial BAM ligand, PBAM.33
A combination of 5 mol % catalyst loading and 24 h was
defined as the most general set of reaction parameters with
which to examine a variety of unsaturated carboxylic acids
(Table 3). The sterically demanding 2-naphthalene analogue
gave the desired lactone (Table 3, 4b) with 96% ee in 99%
yield. Substrates with p- and m-methyl substitution gave the
adducts with 96% ee (Table 3, 4c) and 97% ee (Table 3, 4d),
respectively, while maintaining high levels of conversion and
yield. Unfortunately, an o-methyl group (Table 3, 4e) stymied
the reaction, leading to less than 10% yield of the desired
adduct. It is interesting to note that this rate difference was not
observed when 4-dimethylaminopyridine was used to prepare
rac-4e, a reaction that was complete within 40 min at room
temperature. Aryl rings with halogen substitutions also
performed well in the reaction for both the p-fluoro (98% ee,
96% yield; Table 3, 4f) and p-chloro (97% ee, 91% yield; Table
3, 4h) analogues. Moving the halogens to the meta position did
Figure 2. Enantioselective iodolactonization: initial experiments to
explore the relationship between catalyst composition and stereo-
selection.
electronic variation (Table 1). Sulfonic acids generally
increased the enantioselection with acid strength (Table 1,
entries 1−5). The enantiomers of camphorsulfonate provided
essentially identical outcomes (29% ee; Table 1, entries 2 and
3). The selectivity trend may illustrate the need for a more
dissociated counterion, favoring a more electrophilic catalyst
Table 1. Iodolactonization Catalyzed by a Chiral Proton
Complex: Effect of the Achiral Counterion on the
a
Enantioselectivity
a
All reactions were performed on a 0.10 mmol scale (0.1 M) using 1
equiv of the carboxylic acid and a standard 22 h reaction time. The
absolute configuration of 4 has been assigned (see ref 19).
b
Enantiomeric ratios were measured using HPLC with a chiral
stationary phase. See the Supporting Information (SI) for details.
c
d
e


=
Isolated yields. RSO3 = (−)-camphorsulfonate. RSO3
(+)-camphorsulfonate.
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Communication
Table 2. Optimization (Ligand, Catalyst Loading,
Concentration) of the Chiral Proton-Catalyzed
Iodolactonization
Table 3. Preliminary Scope of the Chiral Proton-Catalyzed
Enantioselective Iodolactonization Reaction
a
a
a
All reactions were performed on a 0.10 mmol scale using 1 equiv of
the carboxylic acid, 5 mol % catalyst, and 1.1 equiv of NIS in toluene
b
a
(0.05 M) at −20 °C for 24 h, unless otherwise noted. Isolated yields.
All reactions were performed on a 0.10 mmol scale (0.1 M) using 1
c
Enantiomeric ratios were measured using HPLC with a chiral
equiv of the carboxylic acid and a standard 22 h reaction time.
d
b
c
stationary phase. See the SI for details. DIH (0.06 mmol) was used
instead of NIS. See the SI for details. The pentenoic acid (which
Isolated yields. Enantiomeric ratios were measured using HPLC with
e
a chiral stationary phase. See the SI for details.
forms a γ-lactone) was used rather than hexenoic acid substrate 4a.
not influence the selectivity (4g and 4i), but a significant effect
on conversion was observed, even with an extended reaction
time (48 h; Table 3, entries 8 and 11). A further increase in the
electron deficiency of the aryl ring using a p-trifluoromethyl
group (Table 3, 4j) led to a drop in reactivity while maintaining
the catalyst’s high selectivity. The electron rich p-methoxy
group (Table 3, 4k) gave lower levels of enantioselection than
expected when NIS was used (74% ee), but changing to 1,3-
diiodo-5,5-dimethylhydantoin (DIH) gave the adduct in 85%
ee after only 2 h of stirring. The nor-homologue (Table 3, 4l)
was more reactive than its parent compound, leading to the
desired lactone in high yield but with lower enantioselection
(67% ee). 1,1-Dialkylalkenes also performed well under these
conditions. The n-butyl derivative (Table 3, 4m) was isolated in
95% yield with 89% ee, while the more sterically demanding
isopropyl derivative (Table 3, 4n) was isolated in 86% yield
with 81% ee. Unfortunately, 6-hexenoic acid was significantly
less selective, affording the desired lactone (Table 3, 4o) with
only 33% ee.
the observed trends of reactivity and selectivity, we note the
following distinct behaviors. The electronic nature of the
aromatic ring in 4a−k had a significantly smaller effect on the
enantioselection, as described elsewhere.14a,16a,19 Moreover,
unlike the system described here, added acid either has no
effect or lowers the enantioselectivity.8,16,27 Our current
mechanistic hypothesis invokes a bifunctional role for the
catalyst: Brønsted acid activation of the NIS and Brønsted base
activation of the carboxylic acid.
In summary, a distinctive hydrogen-bond-catalyzed enantio-
selective iodolactonization using chiral proton catalysis was
discovered. The achiral counterion of the polar ionic hydrogen
bond can be used to optimize the enantioselection, offering an
innovative tool for the study of electrophilic halonium ion-
initiated reactions. To the best of our knowledge, there is no
precedent for this effect, and its observation here suggests that
the triflimide counterion is not exchanged for other potential
counterions present in larger amounts, particularly carboxylate
and succinimide. A trans-stilbenediamine-derived bis(amidine)
ligand was identified to achieve levels of enantioselection up to
98% ee. The success of this approach contributes to the small
but growing number of methods that form boundaries for
This scope improves upon the existing selection of
enantioselective iodolactonization protocols and utilizes
commercially available NIS without additives to achieve this.
While it is premature to advance a discrete model to rationalize
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Journal of the American Chemical Society
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ASSOCIATED CONTENT
* Supporting Information
■
S
Complete preparatory and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jeffrey.n.johnston@vanderbilt.edu
■
(27) An interesting complementary strategy using substoichiometric
achiral neutral Brønsted base and chiral (Brønsted acid) counterion as
cocatalysts for enantioselective bromoetherification just appeared. See:
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(b) Akiyama, T. Chem. Rev. 2007, 107, 5744. (c) Christ, P.; Lindsay, A.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Institutes of Health (GM
084333) for support of this work.
■
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