Mechanistic Insights into the Origin of Stereoselectivity in an Asymmetric Chlorolactonization Catalyzed by (DHQD)2PHAL

Article abstract of DOI:10.1021/jacs.0c01830

Electrophilic halofunctionalization reactions have undergone a resurgence sparked by recent discoveries in the field of catalytic asymmetric halocyclizations. To build mechanistic understanding of these asymmetric transformations, a toolbox of analytical methods has been deployed, addressing the roles of catalyst, electrophile (halenium donor), and nucleophile in determining rates and stereopreferences. The test reaction, (DHQD)₂PHAL-catalyzed chlorocyclization of 4-arylpent-4-enoic acid with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), is revealed to be first order in catalyst and chlorenium ion donor and zero order in alkenoic acid substrate under synthetically relevant conditions. The simplest interpretation is that rapid substrate-catalyst binding precedes rate-limiting chlorenium attack, controlling the face selectivity of both chlorine attack and lactone closure. ROESY and DFT studies, aided by crystal structures of carboxylic acids bound by the catalyst, point to a plausible resting state of the catalyst-substrate complex predisposed for asymmetric chlorolactonization. As revealed by our earlier labeling studies, these findings suggest modes of binding in the (DHQD)₂PHAL chiral pocket that explain the system's remarkable control over rate- A nd enantioselection-determining events. Though a comprehensive modeling analysis is beyond the scope of the present work, quantum chemical analysis of the fragments' interactions and candidate reaction paths point to a one-step concerted process, with the nucleophile playing a critical role in activating the olefin for concomitant electrophilic attack.

Full text of DOI:10.1021/jacs.0c01830

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Article
Mechanistic Insights into the Origin of Stereoselectivity in an
2
Asymmetric Chlorolactonization Catalyzed by (DHQD)PHAL
Roozbeh Yousefi, Aritra Sarkar, Kumar Ashtekar, Daniel C. Whitehead, Tayeb
Kakeshpour, Daniel Holmes, Paul Reed, James E. Jackson, and Babak Borhan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c01830 • Publication Date (Web): 21 Mar 2020
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Mechanistic Insights into the Origin of Stereoselectivity in an Asym-
metric Chlorolactonization Catalyzed by (DHQD)2PHAL
Roozbeh Yousefi,† Aritra Sarkar,† Kumar Dilip Ashtekar,† Daniel C. Whitehead,‡ Tayeb Kakeshpour, Daniel
Holmes, Paul Reed, James E. Jackson* and Babak Borhan*
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Department of Chemistry, Michigan State University, East Lansing, Michigan, 48824, United States
KEYWORDS (Word Style “BG_Keywords”). If you are submitting your paper to a journal that requires keywords, provide significant
keywords to aid the reader in literature retrieval.
ABSTRACT:
Electrophilic halofunctionalization reactions have undergone a resurgence sparked by recent discoveries in the field of catalytic
asymmetric halocyclizations. To build mechanistic understanding of these asymmetric transformations, a toolbox of analytical methods has
been deployed, addressing the roles of catalyst, electrophile (halenium donor), and nucleophile in determining rates and stereopreferences.
The test reaction, (DHQD)2PHAL-catalyzed chlorocyclization of 4-aryl-4-pentenoic acids with 1,3-dichloro-5,5-dimethylhydantoin
(DCDMH), is revealed to be first order in catalyst and chlorenium ion donor and zero order in alkenoic acid substrate under synthetically
relevant conditions. The simplest interpretation is that rapid substrate-catalyst binding precedes rate-limiting chlorenium attack, controlling
the face selectivity of both chlorine attack and lactone closure. ROESY and DFT studies, aided by crystal structures of carboxylic acids bound
by the catalyst, point to a plausible resting state of the catalyst-substrate complex predisposed for asymmetric chlorolactonization,. As revealed
by our earlier labeling studies, these findings suggest modes of binding in the (DHQD)2PHAL chiral pocket that explain the system’s remark-
able control over rate- and enantioselection-determining events. Though a comprehensive modeling analysis is beyond the scope of the present
work, quantum chemical analysis of the fragments’ interactions and candidate reaction paths point to a one-step concerted process with the
nucleophile playing a critical role in activating the olefin for concomitant electrophilic attack.
by a factor of >10:1. The net result is predominant syn Cl, O
1 D
- , obviating the po-
Introduction
addition across the olefinic π-bond in
tential intermediacy of a 3-membered cyclic chloronium ion
(Figure 1c).
Electrophilic olefin halocyclizations (Figure 1a) are long-known
workhorse organic transformations,1 now returning to prominence
as their catalytic asymmetric variants offer a powerful strategy for en-
larging the chiral pool.2-50 In early work on 4-aryl-4-pentenoic acids,
we found Sharpless’s ligand, (DHQD)2PHAL, to be an efficient me-
diator for asymmetric chlorolactonization (Figure 1b).40,51 Since
then, reports from our own and other labs have confirmed the effi-
cacy of cinchona alkaloid dimers in a range of asymmetric halofunc-
tionalizations.17,19,22,41-43,52-55 With the growing list of examples, mech-
anistic insight into the catalytic activation and stereoinduction in
these processes is necessary to support the design of new reactions
and catalyst scaffolds. Taking (DHQD)2PHAL-catalyzed asymmet-
ric chlorolactonization of 4-aryl-4-propenoic acid as a test reaction,
we present here kinetic, spectroscopic, structural, and computa-
tional studies leading to a mechanistic model.
2. In principle, the two new bonds in the major product stereoi-
2 D
somer - could be formed stepwise, via a carbocation inter-
mediate, or concertedly (Figure 1c).
3. In either mechanistic case, the catalyst templates the ring clo-
sure. Catalyst binding, mainly via hydrogen bonding and van
der Waals interactions, presumably limits the conformational
1
choices of substrate , guiding the enantioselective cycliza-
tion.
4. As depicted in Figure 2, we have probed the effects of tuning
the chlorenium source in our asymmetric chlorolactonization
protocol. By preparing and studying a series of previously un-
known N-aroylated N-chlorohydantoins, we have shown that
N1 substituents inductively activate delivery of the N3 chlo-
rine to the substrate during the course of the chlorolactoniza-
tion. The reaction rates of these electronically perturbed chlo-
rinating agents vary as predicted by their HalA values (hale-
nium affinity).58 The linearity and low slope of the ∆∆G‡
[=RTln(kAr/kPh)] vs HalA plot suggests an early transition
state for chlorine transfer. Furthermore, chiral chlorohydan-
toins in these reactions display classic match-mismatch behav-
iors.57 These results indicate direct involvement of the
Our recent labeling and spectroscopic analyses56-57 revealed the
absolute and relative face selectivities of Cl (electrophile) and O
1
(nucleophile) addition across the double bond in (Figure 1c) as
well as the rate and stereochemical effects of varying the chlorohy-
dantoins (chlorenium ion donors).56-57 The cumulative findings of
this work led to the following conclusions:
1
1. Catalyst templated addition across the olefin shows both a
strong pro-R preference (>20:1) for chlorenium ion attach-
ment at C-6, and closure favoring the 5R over the 5S lactone
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1
chlorohydantoins in the rate and stereoselectivity-determin-
ing events in the asymmetric chlorocyclization.
In the original optimized reaction, 4-phenyl-4-pentenoic acid
1
2
3
4
5
6
at 0.051 M concentration was cyclized in the presence of 0.056 M
1,3-dichloro-5,5-diphenylhydantoin (DCDPH) as the chlorine
source, along with 10 mol% (DHQD)2PHAL as the chiral catalyst.
The highest enantioinduction was observed in a 1:1 chloroform:hex-
ane mixture as solvent with benzoic acid as an additive at 0.051 M
(Figure 1b).40
These preliminary mechanistic findings call for a full investiga-
tion of the reaction mechanism to identify the modes of interaction
among the participants, and to map out the catalytic cycle of this
(DHQD)2PHAL catalyzed asymmetric chlorolactonization.
a. Generalized Halofunctionalization Reaction
7
8
9
To follow the kinetics of this reaction, NMR analysis proved op-
timal as the reagent and products displayed well-resolved peaks un-
der the reaction conditions. The following modifications to the
standard protocol were introduced to simplify the mixture for ki-
netic studies: (i) deuterated chloroform was employed instead of 1:1
chloroform:hexane; (ii) 4 mol% of the catalyst was used to slow the
reaction, enabling capture of the important early data points. This
approach allowed time for temperature equilibration in the probe
and shimming, while retaining ≥85% of the starting material at the
initial point of measurement; (iii) 1,3-dichloro-5,5-dimethylhydan-
toin (DCDMH) was employed since the originally used DCDPH
results in the insoluble byproduct 1-chloro-5,5-diphenylhydantoin,
adversely affecting the spectra of the evolving reaction mixture. (iv)
to reduce the complexity of the initial kinetic studies, benzoic acid
was omitted, although, as described in the SI, and later in the manu-
script, including benzoic acid was illuminating with respect to the or-
der of the substrate. These adjustments for the kinetic studies led to
only a 5% drop in ee and presumably do not qualitatively change the
reaction mechanism.
R2
R2
R3
R1
X
R1
R3
R2
X
R1
X
Y
Y
donor
and/or
YH
R3
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b. Halocyclization using Model Substrate 1
(DHQD)2PHAL (10 mol%)
DCDPH (1.1 equiv)
Cl
Ph
O
OH
O
Ph
benzoic acid (1 equiv)
CHCl3:hexane (1:1), -40 °C
O
1
2, 86%. 89% ee
N
O
Me
N
Ph
Ph
O
H
O
O
H
N
N
N
Cl
H
N
H
Cl
O
N
Me
O
1,3-dichloro-5,5-diphenylhydantoin
(DCDPH)
N
(DHQD)2PHAL
c. Stereochemical Outcomes of the Chlorolactonization of 1-D
A detailed RPKA analysis of the chlorolactonization reaction re-
vealed the following results (see SI for detailed experimental analysis
and a brief theoretical description of RPKA in the context of asym-
metric halogenation):
92:8 (R:S)
97:3 (R:S)
H
D
(DHQD)2PHAL (10 mol%)
DCDPH (1.1 equiv)
Cl
O
O
D
6
OH
5
Ph
H
benzoic acid (1 equiv)
CHCl3:hexane (1:1), -40 °C
syn:anti 89:11
Ph
O
1-D
2-D
(a) The asymmetric chlorolactonization is zero order in alkene
1
carboxylic acid
.
O
B
Cl
A-Cl
H
D
A
H
δ+
-
O
O
δ
(DHQD)2PHAL (10 mol%)
chlorohydantoin (1.1 equiv)
Cl
or
Ph
A
H
B
Cl
Ph
O
D
OH
O
O
Ph
H
benzoic acid (1 equiv)
CHCl3:hexane (1:1), -40 °C
O
stepwise addition
concerted addition
1
2
HalA (Cl)a
%yield
Figure 1. a. Generalized depiction of halocyclization reactions; b. Catalytic
asymmetric chlorolactonization of 4-aryl-4-pentenoic acid mediated by
(DHQD)2PHAL; c. Summary of observed stereoselectivities with deuterated
substrate analog 1-D, highlighting the syn addition as the major product of the
catalytic reaction.
Ar
%ee
kAr (s-1)
chlorohydantoin
1
kcal/mol
O
Ph
4-Me-C6H4
C6H5
274.3
273.8
272.4
266.3
265.2
86
78
67
78
71
88
88
88
84
86
1.6 x 10-6
2.1 x 10-6
2.4 x 10-6
5.6 x 10-6
7.4 x 10-6
Ph
N
Cl
N
O
2-F-C6H4
4-CN-C6H4
4-NO2-C6H4
O
Ar
Results and Discussion
1. Kinetic Studies
aCalculated at the B3LYP/6-31G*/SM8 (CHCl3) level of theory.
Kinetic investigation of multistep organic reactions can provide
key insights into reaction mechanisms by revealing the order of indi-
vidual components in the rate-determining step (RDS). As articu-
lated in recent years by Blackmond and co-workers,59-62 Reaction
Progress Kinetic Analysis (RPKA) exploits modern reaction moni-
toring methods and easily accessible fitting and graphing software to
improve the ease and accuracy of analyses over classical approxima-
tion methods. A great advantage of RPKA is that it can probe practi-
cal reactions such as halofunctionalization under their native condi-
tions, unlike classical kinetic treatments that require e.g. the unbal-
anced concentrations used in pseudo first order studies. In this work,
RPKA results place critical boundary conditions on the mechanisms
proposed for this asymmetric chlorolactonization.
4-NO2-C6H4
4-CN-C6H4
C6H5
4-Me-C6H4
slope = -0.071
R2 = 0.985
2-F-C6H4
Figure 2. Electronic perturbation at the N1 substituent of chlorohydantoins
affecting the rate of chlorolactonization. The plot represents the linear varia-
tion of ∆∆G‡ = -RTln(kAr/kPh), relating the experimentally determined rate con-
stants (kAr) with the theoretically calculated absolute HalA (Cl) values.
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1
(b) The reaction shows first order dependence with respect to
the catalyst (DHQD)2PHAL and the chlorenium ion do-
nor-DCDMH.
catalyst. However, addition of completely reverses this complexa-
tion, returning the hydantoin spectrum to that of uncomplexed rea-
gent.40
1
2
3
4
5
6
7
8
9
10
resting state
Collision of suitable conformations of the
complex
(c) The reaction does not suffer from any catalyst deactivation
or product inhibition, as demonstrated by ‘the same excess’
experiments.
1
(DHQD)2PHAL- with DCDMH results in chlorenium transfer to
the alkene in a rate determining step (RDS, see SI for the detailed
kinetic model that leads to the rate law and proposed catalytic cycle).
This process may follow either of two paths: (a) formation of a b-
(Path A, Figure 3), or
, to directly access the
products (Path B, Figure 3). This latter AdE3-type process is an ex-
ample of nucleophile assisted alkene activation (NAAA).63
(d) Addition of an external carboxylic acid such as benzoic acid
or an inert alkenoic acid, that can potentially compete with
the substrate’s binding to the catalyst’s active site, retards
the overall rate of the reaction.
intermediate A
chloromethyl carbenium ion
transition state B
(b) a concerted addition via
The above observations can be summarized as follows:
ꢀꢁꢂꢃ = ꢄ [ ꢅꢆꢇꢅ ꢈꢉꢆꢊꢋ]ꢌ[ꢅꢍꢅꢎꢆ]ꢌ[ꢏ]ꢐ
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(
)
In the absence of (DHQD)2PHAL or quinuclidine catalysts, the
DCDMH and alkene are essentially unreactive at -40 ˚C. There-
fore, apart from controlling the enantioselectivity by providing a chi-
ral pocket, the catalyst must also activate the alkene or the DCDMH
intermediate
(or both). To promote the stepwise pathway leading to
1
The fact that the reaction is zeroth order in substrate (4-phe-
nylpent-4-enoic acid) suggests that the catalyst is saturated, binding
1
1
rapidly to the basic quinuclidine moiety to form the strongly hy-
drogen-bonded acid-base adduct. As detailed further below, this
resting state 1.
species is a 1:2 complex of (DHQD)2PHAL and
A
, the catalyst must activate the DCDMH to form the proposed
Quantum chemical modeling of the reaction components and
their interactions finds that quinuclidine has a substantially stronger
1
affinity for alkenoic acid (-15.8 kcal/mol) than for DCDMH (-10.6
kcal/mol; see inset Table in Figure 3). It is thus not surprising that
chlorocarbenium ion intermediate. The potential viability of form-
intermediate A
ing the ionic species depicted in
is supported by
NMR evidence that quinuclidine can deprotonate 3-chloro-5,5-di-
methyl hydantoin (MCDMH) (shaded box in Figure 3). Rapid cy-
clization, guided by the catalyst, would then afford the product. On
1
alkene outcompetes DCDMH for binding to the catalyst. NMR
evidence further supports this conclusion: 1,3-dichlorohydantoin
with (DHQD)2PHAL shows splitting of the CH2 hydrogens into a
diastereotopic pair, implying a complex formed with the chiral
N
transition state B
the other hand, the concerted pathway via
Me
O
N
O
H
O
H
N
N
H
H
O
O
O
Cl
Cl
N
Me
O
O
O
O
+
+
N
H
N H
N
N
N
(DHQD)2PHAL
Ph
Ph
Cl
Cl
O
O
3
2
3
2
Step 3
O
Ph
HO
1
H
H
O
O
Cl
H
Cl
Cl
H
Cl
N
N
N
N
Ph
Ph
N
N
O
O
O
O
Step 1
O
Me
O
Me
N
H
N
H
O
H
O
H
O
O
H
O
O
H
N
N
N
N
H
H
H
H
O
O
N
N
Me
Me
1.48 ppm
O
N
N
Intermediate A
Transition state B
N
N
H
Pairwise Association Energies
Step 2’
(concerted addition)
Step 2
(stepwise addition)
N
ΔH (kcal/mol)
Cl
2.83 ppm
O
δ-
O
slow step, RDS
slow step, RDS
Ph
O
O
quinuclidine---1
-15.8
-10.6
H
N
CDCl3
1.35 ppm
quinuclidine---DCDMH
O
N
Cl
N
Cl
N
Me
N
N
δ+
Cl
Cl
O
O
H
DCDMH---1
(interaction at CO2H)
O
O
O
O
H
-7.3
-4.0
N
N
H
DCDMH
DCDMH
H
H
N
N
Path B
Path A
O
N
N
DCDMH---1
(interaction at alkene)
Me
Resting State
Cl
O
3.01 ppm
N
Figure 3. Putative catalytic cycle for (DHQD)2PHAL catalyzed chlorolactonization of alkenoic acid 1 (in the absence of benzoic acid additive). Path A depicts a
stepwise addition via a carbocationic intermediate A. The shaded box on the right confirms the possibility of generating the ion-pair depicted in intermediate A
(1H NMR studies show that quinuclidine deprotonates 3-chloro-5,5-dimethyl hydantoin in CDCl3). Path B depicts a possible one step concerted addition to the
alkene 1. NMR studies and computational modeling of the proposed intermediates and transition states are detailed in the following section. The left table insert
displays calculated binding enthalpies of alkene 1, DCDMH and quinuclidine (a truncated model for the catalyst). These pairwise association energies argue for
the validity of the resting state. For clarity, only one alkenoic acid is shown bound to the catalyst, although experimental results indicate two molecules are
bound at one time (vida infra).
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Page 4 of 11
(DHQD)2PHAL (10 mol%)
DCDMH (1.1 equiv)
Cl
Ph
OH
O
O
1
2
3
4
activation of the chlorenium source.
O
benzoic acid (1 equiv)
CHCl3:hexane (1:1), -40 °C
additive (1 equiv)
1
1.0 equiv
In the case of stepwise cyclization, the cation closure (step three
in Figure 3) could not be rate limiting as this would predict a buildup
of cation intermediate, which is not observed. Also, reversible for-
mation of the carbocation should scramble the stereochemistry of
2
additives
5
6
OH
1-D
the alkene =CHD site in deuterium labeled substrate
(see
7
8
Scheme 1), a process ruled out by the finding that recovered starting
materials retain their stereochemical integrity.4a In the alternative
O
CF3
3
9
transition state B
event of a concerted addition via NAAA (
), the con-
OH
certed chlorenium ion attack and ring closure would directly form
the chlorolactone product. In either case (Path A or B), the chlo-
renium ion delivery to the olefin (step 2 or 2’) must be part of the
rate-determining step.
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O
4
NO2
The kinetic studies also helped clarify the role of the benzoic acid
additive, which marginally increases the enantioselectivity. We sur-
mise that its presence aids in maintaining the rigidity of the C2-sym-
metric (DHQD)2PHAL catalyst (see next section for validation of
this hypothesis by NMR and X-ray studies), and perhaps also aids in
shuttling the protons required to neutralize the byproduct hydan-
toin anions, especially toward the end of the reaction when the con-
Figure 4. Rate of formation of product 2 in presence of alkenoic acids 3 and
4. The reduced rates imply 3 and 4 are competitive inhibitors of the catalyst,
presumably binding to the active site and retarding the binding of substrate 1.
earlier (Figure 2), the N3 chlorine is activated when the N1 substit-
uent of DCDMH is an electron withdrawing group (EWG). As
quantified by the HalA values, stronger EWGs on N1 accelerate the
1
reaction, consistent with chlorine delivery to in the RDS. A related
1
centration of is low. Consistent with this idea, benzoic acid addi-
result is that chiral chlorohydantoins show match/mismatch effects
in reaction, pointing to direct involvement of the chlorenium deliv-
ery reagent in the chlorocyclizations.57
tion at an equimolar ratio to substrate lowers the rate of chlorolac-
tonization (see SI for experimental details); presumably benzoic
1
acid competes with 4-phenylpent-4-enoic acid for binding in the
catalyst’s active site (vida infra). This interpretation gained support
from RPKA studies with benzoic acid added, which raised the meas-
ured order of the alkene from zero to 0.5 in the rate equation. This
To probe the involvement of the carboxylic acid moiety in the
rate determining step, chlorocyclization of the deuterated 4-phe-
1-OD
nylpent-4-enoic acid
(RCO2D) was studied and compared to
1
change is expected due to the fact that alkene has to compete with
1
the same reaction with unlabeled substrate . An inverse isotope ef-
fect (kH/kD = 0.82, see SI) was measured, suggesting that the carbox-
ylate plays a direct role in the reaction. Considering Path A, the
change from H to D should not lead to the observed KIE, as the elec-
trophilic transfer of the chlorenium ion is ostensibly insensitive to
the nature of the hydrogen-bonded nucleophile. On the other hand,
would presumably be ac-
celerated by the H to D change, as the carboxylate oxygen’s, and
therefore the alkene’s nucleophilicity is more activated as a conse-
the benzoic acid for binding in the catalyst, making its concentration
relevant with respect to the rate. The following is the observed rate
law in presence of benzoic acid:
ꢀꢁꢂꢃ = ꢄ [ ꢅꢆꢇꢅ ꢈꢉꢆꢊꢋ]ꢌ[ꢅꢍꢅꢎꢆ]ꢌ[ꢏ]ꢐ.ꢑ
(
)
To further explore the proposed catalytic cycle, we resorted to
competition studies (Figure 4). Prior analysis of the catalytic asym-
metric chlorolactonization methodology revealed that 4-(4-(trifluo-
transition state B
the concerted Path B via
3
1 40
romethyl)phenyl)pent-4-enoic acid is one tenth as reactive as
.
1 OD 1-OH
vs .
quence of the increased acidity of
-
Nonetheless, the trifluoromethyl substituent should not interfere
with binding, as other sterically comparable substrates behaved well
Overall, reaction progress kinetic analysis (RPKA), competition,
reagent, and isotope studies find that (a) rate is first order in catalyst
and in DCDMH, but zero order in substrate; (b) chlorenium donor
ability and asymmetry characteristics affect reaction rates; and (c)
the carboxylic acid’s hydrogen isotope also modulates reaction rate.
The implication is that the rate-determining step involves chlo-
renium transfer and the carboxylic acid’s degree of deprotonation.
3
under the same reaction conditions. If substrate binds to the cata-
resting state
serve as a competitive inhibitor, decreasing the concentration of the
lyst to form an unreactive analogue of the
, it should
1
reactive complex with substrate . Indeed, as shown in Figure 4, the
chlorolactonization of was slowed dramatically (decreased by
1
3
58%) upon addition of one equivalent of to a 1:1 mixture of and
DCDMH with 1.5 mol% catalyst.
1
2. Resting state of the catalytic cycle
A similar competition study was performed between 4-phe-
1
nylpent-4-enoic acid and 4-(3-nitrophenyl)pent-4-enoic acid
known to be a slow substrate. With a 1:1:1 mixture of substrates
With the elementary steps of the catalytic cycle deduced from
the kinetic findings, we undertook NMR and computational studies
to gain structural insight into intermediates and transition states
4
,
1 4
,
and DCDMH under 1.5 mol% catalyst loading, the rate of the
rest-
along the reaction paths. Our first target in this process was the
ing state
1
chlorolactonization of was decreased by 71% (Figure 4). At a 1:1
ratio of inhibitor to substrate , a 50% decrease in rate would sug-
(catalyst-substrate complex) of the catalytic cycle.
4
1
A comprehensive conformational search of the free catalyst us-
ing molecular mechanics and density functional simulations re-
vealed three low energy conformational orientations for the two
sidechains on the phthalazine (see SI for computational details).
These showed HaCCHb dihedral angles of roughly 80° and 170°,
consistent with prior NMR and theoretical work.64-66 Figure 5 (left)
4
1
gest similar binding affinity of and with (DHQD)2PHAL; the
larger observed inhibition suggests a stronger complexation with
4
,
consistent with the formation of a putatively stronger p-acid-base
complex.
Further evidence supporting the idea that chlorine delivery from
1
the hydantoin to is rate-determining may be found in the effects of
structural variations in the hydantoin chlorenium donors. As noted
shows
a DFT-B3LYP/6-31G* (gas) minimized structure of
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9 Hz dd
2.8 Hz d
minimized structure of
(DHQD)2PHAL bound to 1
1
2
3
minimized structure of
free (DHQD)2PHAL
bound
(DHQD)2PHAL
6:1
4:1
2:1
1:1
0:1
4
5
6
7
8
9
10
11
12
Hb
Ha
Hb
Binding Free Energies
ΔG (kcal/mol)
Ha
(DHQD)2PHAL/1
-14.6
-27.9
-20.3
-24.3
9 Hz ddd
(DHQD)2PHAL/12
free (DHQD)2PHAL
Hb
(DHQD)2PHAL/1/DCDMH
(DHQD)2PHAL/12/DCDMH
3.5
3.4
ppm
Figure 5. Conformational changes observed upon binding of 1 to (DHQD)2PHAL. The left model represents the minimized structure of free (DHQD)2PHAL with
HaCCHb dihedral angle ~170°, supported by the 9 Hz coupling of Hb with Ha. H NMR titration induces a change in the Hb/Ha coupling from 9 to <3 Hz with the
addition of the alkenoic acid 1. The model on the right depicts a minimized structure of the catalyst bound to two alkenoic acid 1, where the two HaCCHb dihedral
angle are 73.8° and 80.7°. The dihedral angles of the bound catalyst fit well with the observed smaller coupling constant for Ha/Hb. Computed binding free energies
for complexation of the first and second alkenoic acids 1, and for DCDMH with (DHQD)2PHAL are shown in the shaded box.
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(DHQD)2PHAL with a HaCCHb dihedral of 169.4°. This is con-
sistent with the NMR of free (DHQD)2PHAL, where the Hb reso-
nance exhibits a ddd with three equivalent 9 Hz coupling constants.
Dihedral angles between Hb and the methylene protons in the qui-
nuclidine ring lead to the anticipated 9 Hz coupling. Thus, the third
9 Hz coupling of Hb is ascribed to its interaction with Ha, resulting
from the anti orientation of the two protons.
substantially outcompete the -5.7 kcal/mol binding free energy of a
resting
molecule of DCDMH. Interacting with the doubly occupied
state
, the association of DCDMH is even weaker, as shown by the
free energy values in Figure 5.
resting state
tained from NMR studies of a 2:1 mixture of 4-(4-fluoro-
Further structural data on the
complex were ob-
5
phenyl)pent-4-enoic acid and (DHQD)2PHAL in CDCl3 carried
5
1
out at -40 °C. Carboxylic acid was used as a substitute for since
its aromatic protons (ortho to fluorine) do not overlap with the aro-
matic protons of the catalyst. Table 1 compares the 1H NMR chem-
ical shifts of the substrate with and without (DHQD)2PHAL pre-
sent. It is notable that the vinylic protons and also two methylene
Table 1. 1H NMR analysis of alkenoic acid 5 and its complexes with
(DHQD)2PHAL and quinuclidine at -40 ºC in CDCl3.
Dd with
(DHQD)2PHAL
Dd with
quin.
d
(ppm)
Hm
Ht
Hl
proton
Ht
Hr
Hm
Hl
2.52
2.80
5.06
5.25
7.36
7.01
-0.52
-0.43
-0.46
-0.54
-0.23
-0.29
-0.19
-0.06
-0.04
-0.04
+0.04
-0.06
CO2H
5
groups of the alkenoic acid are shielded by ~0.5 ppm upon com-
Hr
F
Hj
plexation with catalyst. We interpret this shielding as a combination
of two effects: (a) deprotonation of the carboxylic acid and (b) bind-
ing in the cleft of the catalyst. To distinguish these contributions, 1H
5
Hk
quinuclidine
(quin.)
Hj
N
5
NMR spectra of were taken with quinuclidine in CDCl3. There, it
Hk
was the methylene group adjacent to the carboxylate moiety that
showed the highest upfield shift (0.19 ppm). The other protons’
shifts showed at most slight changes (~0.04 ppm). Thus, acid-base
complex formation does not account fully for the large shielding
seen with the catalyst–bound substrate.
1
Titration of (DHQD)2PHAL with substrate lowers the cata-
lyst’s Ha-Hb coupling constant from 9 to <3 Hz, suggesting a confor-
mation with an averaged HaCCHb dihedral angle close to 90°. This
geometry, as depicted in Figure 5, also orients the quinuclidine N
toward the chiral cleft of the catalyst. Furthermore, the 1:1 catalyst
complex exhibits broad peaks which sharpen on addition of another
To further probe the interactions between the substrate and the
catalyst, ROESY experiments using the methods described by Bo-
denhausen et al.67-69 found correlations between protons of and
5
resting state
equivalent of alkenoic acid suggesting that in the
, the
(DHQD)2PHAL offering further insights into binding. As depicted
in Figure 6, ROESY correlations, leading to average distances are
grouped into intramolecular and intermolecular correlations. The
ROESY Correlations of (DHQD)2PHAL + 5
catalyst binds two alkenes. Finally, conformational searching using
the MMFF94 force field, followed up by B3LYP-D3/6-
31G*/postSMD(CHCl3) structural optimization of the
(DHQD)2PHAL bound with two alkenoic acids found calculated
Intramolecular
Intermolecular
1
binding free energies for the first and second molecules of in
F
F
Hd…Hh 3.1 Å
Hn…Ht 3.0 Å
(DHQD)2PHAL of -14.6 and -13.3 kcal/mol, respectively. Among
the lowest energy complex minima, the structure shown at right in
Hd…Hv 2.6 Å
Hd…Hy 3.4 Å
Hn…Hr 3.2 Å
Hn…Hk 3.8 Å
Hk
Hn
N
N
resting state
Figure 5 is used here as the
catalyst model; this structure
Me
Ht
δ-
Hr
has HaCCHb dihedral angles of 73.8° and 80.7°, consistent with the
<3 Hz coupling of Ha with Hb in the NMR of the fully saturated com-
plex.
δ-
O
O
Hh
Ha
O
O
O
Ha
Hb
Hb
O
O
N
N
N
N
O
O
H
δ+
O
H
N
N
δ+
Hd
Hv
Hy
Given the desymmetrization observed in the NMR of dichloro-
hydantoin interacting with the catalyst, one might expect that
DCDMH binding would compete for the catalyst active site. How-
ever, for both the empty and singly occupied forms of the catalyst,
the -14.6 and -13.3 kcal/mol binding energies of an additional acid
Figure 6. Intramolecular and intermolecular ROESY correlations of 5 bound to
(DHQD)2PHAL. The intramolecular correlations place the ethyl group near the
phthalazine ring, while the methoxy shows close intermolecular relations with
the substrate methylene units. These interactions are present in the lowest
energy conformation of (DHQD)2PHAL (see Figure 5, bound structure).
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Results from prior study:
1
Kinetic Isotopic Studies
HalA (Cl) values (CHCl3) in kcal/mol
2
3
4
5
6
7
181.1
O
~173
1; R = H
1-D2; R = D
kH/kD = 1.0
O
169.4
no carbocation
intermediate
OH
HO
158.8
HO
Ph
N
O
R
R
N
O
R
O
O
O
HX
N
6; R = H
6-D2; R = D
kH/kD = 1.2
N
Me
carbocation
intermediate
OH
Me
1
Cl
6
Cl
4-MeO-C6H4
Me
Me
MeO
R
O
Chlorenium affinity HalA(Cl) of hydantoin anion in comparison to 1 and 6
8
9
O
O
O
1.7 Å
HO
HO
O
173.6
Cl
HO
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H
1.4 Å
173.3
DCDMH
DCDMH
O
stepwise
addition
2.3 Å
2.0 Å
concerted
addition
2.5 Å
1.9 Å
3.2 Å
2.5 Å
MeO
MeO
6
NAAA
conformation
1
TS-I
TS-II
TS in presence of quinuclidine
This work:
mimic for (DHQD)2PHAL
OH
O
Ph
O
O
1
N
O
N
1.5 Å
2.4 Å
H
O
quinuclidine
DCDMH, CHCl3
H
H
H
N
N
1.5 Å
2.4 Å
2.1 Å
2.1 Å
O
Cl
Cl
O
Cl
2.1 Å
anti-approach
syn-approach
O
H
H
N
transition states for concerted addition
ΔΔG‡ = 0.7 kcal/mol favoring anti-TS
experimental observation 5:1 anti:syn
2.1 Å
N
O
Cl
anti-TS
syn-TS
Figure 7. a. Prior work illustrating experimental evidences that support concerted addition to an alkene b. Transition states leading to syn and anti-addition for
quinuclidine catalyzed chloro-lactonization. Calculated using density functionals B3LYP-D3/6-31G* SM8 (CHCl3)
distances derived for the intramolecular interactions fit well with the
minimized structure of the catalyst, illustrated in Figure 5. Probing
intermolecular interactions, the OMe sidechains of the quinoline
group (Hn) showed contacts with the substrate’s methylene (Hr and
Ht) and phenyl protons (Hk). This also matches well with the calcu-
model, depicted in Figure 5, where the calculated
distances fall well within the ROESY measured values (Hn/Ht 2.6 Å
calc’d, 3.0 Å expt, Hn/Hr 2.5 calc’d, 3.2 Å expt, Hn/Hk 2.9 Å calc’d,
To further explore the stoichiometry of complexation,
(DHQD)2PHAL was treated with two equivalents of a 1:1 mixture
of alkenoic acids and . This NMR experiment showed shielding
behavior for both and similar to that seen in 2:1 substrate:catalyst
mixtures with the individual substrates. If catalyst had only a single
binding site, such mixtures should show more shielding of reso-
nances of the more tightly bound alkenoic acid. Since the same de-
gree of chemical shift is observed in the above case with the spectra
being well-resolved, it appears that the catalyst binds both substrates
in a 1:1:1 complex without competition. This 2:1 binding model is
1
4
1
4
resting state
lated
resting state
3.8 Å expt). The ROESY verified model for the
shown
in Figure 5 illustrates carboxylate binding to the protonated quinu-
clidine moiety, positioning the vinylic protons in the shielding re-
gions of the quinoline rings, which leads to their observed upfield
shifts.
1 3 4
, , and previously
in accord with the reactivity results involving
shown in Figure 4, and with the calculated binding energetics in Fig-
ure 5. As discussed further below, the 2:1 complex may undergo at-
tack by the chlorenium ion donor on either of the two essentially in-
dependently bound substrate molecules; it is thus the substrate for
attack by the chlorenium ion donor.
As a C2 symmetric cinchona alkaloid, (DHQD)2PHAL can po-
tentially bind to two substrates at the same time (as depicted in Fig-
ure 5). Consistent with this idea, when (DHQD)2PHAL is treated
1
An alternative scenario might involve dissociation to an active
1:1 complex, with the catalytically incompetent 2:1 complex serving
simply as an off-cycle reservoir. In this scenario, however, the initial
rate would not be the same for two reactions with different starting
concentrations, such as the different excess experiments carried out
in this study. We would anticipate the reaction with a higher
concentration of the starting alkene to have a smaller initial rate. This
behavior is not observed (see Figure S1 and the description of
kinetic models in the SI).
1
with only one equivalent of the alkenoic acid , the H NMR peak
broadening at room temperature clearly suggests loss of structural
symmetry due to partial occupancy of the substrate. The spectra
1
sharpen up in the presence of two equivalents of . These results sup-
port a picture in which (DHQD)2PHAL requires two substrates (or
other carboxylic acids) to maintain its conformational rigidity in the
C2-symmetric anti-open form. On the other hand, addition of four
equivalents of alkenoic acid to (DHQD)2PHAL resulted in an aver-
aged spectrum for the substrates, indicating fast equilibrium (on the
NMR time scale) between bound and free forms of the alkenoic acid,
while the catalyst’s spectra remained sharp. Similar behavior is seen
with benzoic acid (see SI for NMRs of (DHQD)2PHAL with ben-
zoic acid).
resting state
Although we were unable to obtain crystals of the
itself, we were able to co-crystallize the catalyst (DHQD)2PHAL
with benzoic acid. This crystal structure displayed essentially the
conformation deduced from the NMR studies (see SI for crystal
structure), with the two HaCCHb dihedral angle being 73.7° and
77.6°.
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moiety. This close proximity of the nucleophile sharply enhances the
3. Structural insights into transition state B
To understand the asymmetric induction achieved in the
1
2
3
4
5
6
7
8
alkene halenium affinity, enabling capture of the chlorenium ion
from its donor, as the nucleophile approach now stabilizes for the
developing charge in the alkene sp2 carbon. This view is verified fur-
ther by the contrasting isotope effects seen in the uncatalyzed reac-
1
(DHQD)2PHAL-catalyzed chlorocyclization of with DCDMH, a
rest-
model of the interaction of the chlorenium ion donor with the
ing state
is needed, which must entail both activation and asymmet-
1
6
tions of DCDMH with alkenes and (Figure 7, dashed box). Here,
1
1
ric specificity. The combination of substrate with DCDMH alone
is essentially unreactive (at -30 °C); a basic catalyst, such as quinu-
clidine or (DHQD)2PHAL is needed to promote the reaction. Also,
as noted earlier, both rate and stereoselectivity are affected by elec-
tronic and stereochemical variations in the dichlorohydantoins
used. Thus, the ring-forming reaction involves both the state of car-
boxylate deprotonation, and the identity of the chlorine donor.
in , replacement of the protons vicinal to the putative carbenium
site with deuterium showed no observable kinetic isotopic effect
(kH/kD = 1.0).63 As depicted in Figure 7, TS- illustrates the con-
I
certed transition state with bond distances that indicate a one-step,
asynchronous addition of the chlorenium and the carboxylate to the
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6
1
olefin. In the case of , the 4-methoxy analog of , the alkene’s nucle-
ophilicity is inherently enhanced enough that the nucleophile-as-
One path that might be envisioned is indirect chlorine transfer
to substrate via a chlorinated (DHQD)2PHAL. This can be ruled out
as it predicts that the enantioselectivity should be independent of the
chlorenium ion source (hydantoin) as the N-chloroquinuclidinium
form of (DHQD)2PHAL would now serve as the active in situ gen-
erated halogenating reagent. Also, as assessed in terms of HalA (Cl)
values, chlorenium ion transfer to the quinuclidine nitrogen in the
6
sisted pathway is unimportant; uncatalyzed reaction of with
1
DCDMH is much faster as compared to . However, as expected for
a stepwise pathway via a carbocationic intermediate, reaction of al-
kene displayed a significant secondary kinetic isotopic effect
(kH/kD = 1.2). In contrast to the concerted addition calculated for
alkene , TS- depicts the attack to form the carbocation in the step-
6
wise addition of the chlorenium ion to substrate . The HalA (Cl)
values of and (158.8 and 169.4 kcal/mol) differ by >10 kcal/mol,
supporting the formation of a carbocation intermediate. The HalA
(Cl) value of closely matches that of the hydrogen-bonded
MCDMH anion (~173 kcal/mol), consistent with unassisted chlo-
6
renium capture by to form the carbocation, an action too endo-
thermic for olefin without further activation.
6
1
II
catalyst would be strongly endothermic (DHalA (Cl) 24.0 kcal/mol
in CHCl3), even when the stabilizing effects of tight ion pairing and
solvation are included in the calculation.
1
6
6
Evidence for concerted addition (NAAA) pathway
Without assistance, chlorenium transfer from DCDMH to the
alkene would be unfavorable (DHalA (Cl) = 22.3 kcal/mol in
CHCl3) (see HalA values in Figure 7). Despite its low HalA, alkene
1
1
3
The m-NO2 analogue of , alkene , is intrinsically deactivated
and unreactive towards DCDMH, hinting that NAAA can only offer
so much activation if there are strong inherent factors retarding the
intrinsic nucleophilicity of the alkene. Though it appears quite gen-
eral for otherwise nonpolarized alkenes, the concerted NAAA mech-
anism evidently strikes a fine balance. With the experimental evi-
dence firmly indicating concerted addition to the alkene , transition
states with quinuclidine as well as (DHQD)2PHAL as a catalyst were
computationally modeled and analyzed in the following section.
1
greatly in the presence of a basic catalyst such as quinuclidine. This
does slowly react with DCDMH. However, the rate is accelerated
1
strongly suggests that the catalyzed halocyclization of proceeds via
a nucleophilic activated alkene addition (NAAA) mechanism. Pre-
vious reports on chlorolactonization (summarized in Figure 7,
dashed box) have noted that a low energy barrier pathway via con-
certed addition can be triggered when the substrate adopts confor-
mations with the anionic carboxylate oxygen atom near the alkene
1
a
b
O
H
O
R1
Cl
Ar
Cl
H
O
N
(DHQD)2PHAL (10 mol%)
Cl
Ph
O
R2
Cl
OH
N
N
Cl
Ar
+
N
benzoic acid (1 equiv)
CHCl3:hexane (1:1), -40 °C
N
O
O
O
9
O
O
5
8
(1.1 equiv)
Me
N
H
O
H
Ar = 4-F-C6H4
O
O
H
N
N
H
R1 R2
% yield % ee
H
O
N
(S)-8
(R)-8
i-Pr
H
H
i-Pr
78
44
83
69
Me
H
O
N
O
ΔΔG‡ = 0.5 kcal/mol
favoring (DHQD)2PHAL/1/(S)-8
Ph
2.1 Å
2.4 Å
2.1 Å
1.5 Å
Ha
Hb
θ(Ha:Hb)
61.7º
TS for (DHQD)2PHAL/1/(S)-8
match case
TS for (DHQD)2PHAL/1/(R)-8
mismatch case
TS for (DHQD)2PHAL/1/DCDMH
Figure 8. Transition states for (DHQD)2PHAL catalyzed chloro-lactonization using DCDMH and the chiral chlorenium reagent. The non-degeneracy of the two
transition states conforms with the previously reported matched-mismatched selectivity. Structures were calculated using the dispersion-corrected density functional
method B3LYP-D3, with all optimizations carried out in SMD simulated CHCl3. This scheme is denoted B3LYP-D3/6-31G*/SMD(CHCl3).
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Quinuclidine-catalyzed TS for syn and anti chlorocyclization
8
1
enantiomers of the chiral hydantoin and alkene . Consistent with
1
2
3
4
5
6
7
8
8
the experimental findings, the TS calculated with the (R)- (mis-
For the quinuclidine catalyzed reaction, transition structures for
the lowest energy syn and anti concerted addition pathways were
identified and optimized. (Figure 7, bottom). In search of optimized
structures, conformational analyses using the MMFF94 force field
provided poses, which were further refined via B3LYP-D3/6-
31G*/postSMD (CHCl3) calculations. Though the developing neg-
ative charge on the hydantoin ring in the syn TS benefits from prox-
imity to the partially positive protonated quinuclidine, that ad-
vantage is outweighed by the steric freedom of approach from the far
side (anti approach). In the CHCl3 “solvent” as represented by the
SMD dielectric continuum simulation, the anti-addition pathway is
found to be 0.7 kcal/mol lower in energy than its syn partner, a result
consistent with experimental findings. Both structures show similar
parameters, with the developing C-Cl and C-O bond lengths slightly
longer in the anti (2.2, 2.6 Å) than in the syn case (2.1, 2.4 Å). All
match) shows steric crowding of the isopropyl group with the qui-
nuclidine moiety of (DHQD)2PHAL, presumably magnified as the
resting state
hydantoin is approaching the
prior to reaching the TS.
The (S)-congener (match), however, has a more relaxed approach,
having the isopropyl group pointed in the opposite direction. This is
also represented in the activation energies for each transition state,
with the match TS having a slightly lower barrier (DDG‡ = 0.5
kcal/mol). Owing to less steric conflict with the catalyst, the ap-
8
9
proach of (S)- to the olefin is also more linear, avoiding the
DCDMH distortion seen in the TS from the (R) isomer.
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Summary
Reaction progress kinetic analysis (RPKA) and competition
studies revealed the delivery of chlorenium ion to the olefin as a key
feature of the rate determining step (RDS). These kinetic studies
also define the order of each reagent and consequently the rate equa-
tion of this catalytic reaction both in the presence and absence of the
benzoic acid: rate = k[(DHQD)2PHAL][DCDMH]. Moreover,
these studies were conducted at concentrations relevant to the opti-
mized standard protocol, obviating the need for extrapolations out-
side the range studied. The observed inverse isotope effect (acid ca-
talysis) suggests that the alkene-COOD is more activated for
1
attempts to initiate chlorenium atom transfer from DCDMH to
were monotonically endothermic in conformations that did not
place the nucleophilic carboxylate moiety nearby (Figure 7, bot-
tom). This implies that a stable b-chloromethyl carbenium ion in-
termediate is not a minimum along the reaction coordinate as would
be expected for the stepwise mechanism.
The experimentally observed syn:anti ratio for quinuclidine cat-
1 D
alyzed chlorocyclization of
-
is 1:5.56 This agrees with the discus-
transition state B
DCDMH attack in
the kinetic results, ROESY NMR studies, X-ray structures, and DFT
resting state
than alkene-COOH. Between
sion above, and also with the calculated difference in activation en-
ergies computed for the syn and anti TS structures shown in Figure
7 (DDG‡ = 0.7 kcal/mol).
analysis, we propose a
model in which two molecules of
1
substrate occupy the binding pockets of (DHQD)2PHAL. In the
proposed catalytic cycle (Figure 3), the alkene face that is ultimately
chlorinated is exposed to solution, allowing collision with DCDMH.
Ring closure is achieved when the backbone chain achieves a confor-
mation placing C-4 near the partially negatively charged carboxylate
oxygen, activating the olefin for the concerted NAAA closure. The
syn preference reflects the electrostatic attraction between the devel-
oping negative charge on the hydantoin and the positively charged
quinuclidinium ion. These mechanistic investigations, coupled with
our previously reported labeling studies, suggest that the rate-deter-
mining and enantioselectivity-determining events occur together in
the predominant pathway. Taken together, the experimental results
were combined with an initial DFT analysis that provided structural
Modeling of the syn-addition TS for (DHQD)2PHAL catalyzed re-
actions
Having identified the lowest energy TS structures for quinu-
1
clidine-catalyzed chlorocyclization of , we proceeded to model the
syn structure into the optimized geometry of (DHQD)2PHAL, re-
optimizing at the B3LYP-D3/6-31G* level of theory. The reader is
1 D
reminded that the asymmetric catalyzed chlorolactonization of
(syn:anti ratio ~9:1).56 The energy of ac-
2 D
-
-
favors the syn adduct
tivation (10.5 kcal/mol) and partial bond lengths (2.4 Å for C-O and
2.1 Å for C-Cl) for the lowest energy (DHQD)2PHAL catalyzed
transition state were comparable to the quinuclidine catalyzed addi-
tion (Figure 8a). The acute HaCCHb dihedral angle of 61.7° in the
TS effectively oriented the quinuclidine towards the center of the
catalyst allowing for the alkenoic acid to sit inside the chiral pocket
as it further enjoys π-π-stacking with the phthalazine linker. This di-
hedral angle also fits well with the NMR studies depicted in Figure 5
resting state
. Overall, using the asymmetric chlorolactonization of as a
transition
1
insight into the
state B
model and the corresponding
proof of principle, a toolbox of analytical techniques has been suc-
cessfully optimized and applied to probe the nuances underlying the
(DHQD)2PHAL catalyzed halofunctionalization of olefins. These
mechanistic studies have established an optimal range of alkene
HalA values over which concerted reactions dominate, firmly defin-
ing both relative and absolute stereochemical relationships. This
conceptual framework and set of tools for reaction assessment will
serve as a guide, in a broad sense, to the emerging field of catalytic
stereoselective halofunctionalizations of olefins. More specifically,
the localized interactions identified in exploring these chlorolactoni-
zation reaction paths point the way to key features needed in the de-
sign of simplified organocatalysts.
1
for (DHQD)2PHAL bound to . As illustrated in Figure 8a, the Re
face of the alkene is now readily accessible by both the chlorenium
ion donor and the quinuclidine-activated carboxylate nucleophile,
the simultaneous addition of which leads to the experimentally ob-
served major syn enantiomer. Computational searches for NAAA-
type TS structures leading to the minor products were much less suc-
cessful; those products may well arise via more complex stepwise
paths, and further studies in this direction are deferred to a future
detailed computational analysis.
Prior studies have demonstrated that chlorolactonization using
chiral chlorohydantoins exhibits matched-mismatched behavior
when used with (DHQD)2PHAL (Figure 8b, table in dashed box).
This provides further support for the hydantoin’s direct involvement
in the rate determining step as the chlorenium source. To connect
our computational results to these experimental findings, we reopti-
mized the (DHQD)2PHAL catalyzed transition state with the two
ASSOCIATED CONTENT
Supporting Information
. Experimental details, HalA calcula-
tions, characterization data, DFT computational data and MS
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(12) Fang, C.; Paull, D. H.; Hethcox, J. C.; Shugrue, C. R.; Martin, S. F.
Enantioselective Iodolactonization of Disubstituted Olefinic Acids Using a
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halolactonizations. Dihydroquinidine-halogen complexes as chiral sources
of positive halogen ion. Can. J. Chem. 1998, 76, 1233.
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experimental and computational approach to new chiral electrophiles.
Chem. Eur. J. 2005, 11, 5777.
(16) Haas, J.; Piguel, S.; Wirth, T. Reagent-controlled stereoselective
iodolactonizations. Org. Lett. 2002, 4, 297.
office excel template for RPKA analysis. This material is available
free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
*Corresponding Authors
babak@chemistry.msu.edu
jackson@chemistry.msu.edu
Author Contributions
9
†These authors contributed equally.
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(17) Ikeuchi, K.; Ido, S.; Yoshimura, S.; Asakawa, T.; Inai, M.; Hamashima, Y.;
Kan, T. Catalytic Desymmetrization of Cyclohexadienes by Asymmetric
Bromolactonization. Org. Lett. 2012, 14, 6016.
(18) Jaganathan, A.; Garzan, A.; Whitehead, D. C.; Staples, R. J.; Borhan, B. A
Catalytic Asymmetric Chlorocyclization of Unsaturated Amides. Angew.
Chem. Int. Ed. 2011, 50, 2593.
ORCID
Babak Borhan: 0000-0002-3193-0732
Notes
The authors declare no competing financial interest.
(19) Jaganathan, A.; Staples, R. J.; Borhan, B. Kinetic Resolution of Unsaturated
Amides in
a Chlorocyclization Reaction: Concomitant Enantiomer
Differentiation and Face Selective Alkene Chlorination by
Catalyst. J. Am. Chem. Soc. 2013, 135, 14806.
ACKNOWLEDGMENT
a Single
Generous support was provided in part by the NIH
(GM110525) and the NSF (CHE-1362812). The authors thank
Dr. Richard Staples for the X-ray structure of (DHQD)2PHAL
complexed with benzoic acid. The authors acknowledge the
work of undergraduates Melissa Mu, Christopher Rahn, Eduord
Toma, and Lindsey Kiilsika for their contributions to this work.
(20) Kitagawa, O.; Hanano, T.; Tanabe, K.; Shiro, M.; Taguchi, T.
Enantioselective halocyclization reaction using a chiral titanium complex.
J. Chem. Soc.-Chem. Commun. 1992, 1005.
(21) Lee, H. J.; Kim, D. Y. Catalytic enantioselective bromolactonization of
alkenoic acids in the presence of palladium complexes. Tetrahedron Lett.
2012, 53, 6984.
(22) Li, L.; Su, C.; Liu, X.; Tian, H.; Shi, Y. Catalytic Asymmetric Intermolecular
Bromoesterification of Unfunctionalized Olefins. Org. Lett. 2014, 16,
3728.
(23) Lozano, O.; Blessley, G.; del Campo, T. M.; Thompson, A. L.; Giuffredi, G.
T.; Bettati, M.; Walker, M.; Borman, R.; Gouverneur, V. Organocatalyzed
Enantioselective Fluorocyclizations. Angew. Chem. Int. Ed. 2011, 50,
8105.
(24) Mizar, P.; Burrelli, A.; Gunther, E.; Softje, M.; Farooq, U.; Wirth, T.
Organocatalytic Stereoselective Iodoamination of Alkenes. Chem. Eur. J.
2014, 20, 13113.
(25) Moyano, A.; Rios, R. Asymmetric Organocatalytic Cyclization and
Cycloaddition Reactions. Chem. Rev. 2011, 111, 4703.
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halocyclization. Heterocycles 2013, 87, 763.
(27) Murai, K.; Matsushita, T.; Nakamura, A.; Fukushima, S.; Shimura, M.;
Present Address
‡Department of Chemistry, Clemson University, Clemson,
South Carolina, 29634, United States.
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Cl
Ph
(DHQD)2PHAL (cat.)
chlorohydantoin
O
O
OH
Ph
O
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rate = k[(DHQD)2PHAL]1[chlorohydantoin]1[1]0
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