Toward Catalytic, Enantioselective Chlorolactonization of 1,2-Disubstituted Styrenyl Carboxylic Acids

Article abstract of DOI:10.1021/acs.joc.6b01455

An investigation into the use of Lewis base catalysis for the enantioselective chlorolactonization of 1,2-disubstituted alkenoic acids is described. Two mechanistically distinct reaction pathways for catalytic chlorolactonization have been identified. Mec

Full text of DOI:10.1021/acs.joc.6b01455

Article
pubs.acs.org/joc
Toward Catalytic, Enantioselective Chlorolactonization of 1,2-
Disubstituted Styrenyl Carboxylic Acids
,†
Scott E. Denmark,* Pavel Ryabchuk, Matthew T. Burk, and Bradley B. Gilbert
Department of Chemistry University of Illinois 600 South Mathews Avenue Urbana, Illinois 61801, United States
*
S Supporting Information
ABSTRACT: An investigation into the use of Lewis base
catalysis for the enantioselective chlorolactonization of 1,2-
disubstituted alkenoic acids is described. Two mechanistically
distinct reaction pathways for catalytic chlorolactonization
have been identified. Mechanistic investigation revealed that
tertiary amines predominately operate as Brønsted rather than
Lewis bases. Two potential modes of activation have been
identified that involve donation of electron density of the carboxylate to the CC bond as well hydrogen bonding to the
chlorinating agent. Sulfur- and selenium-based additives operate under Lewis base catalysis; however, due to the instability of the
intermediate benzylic chloriranium ion, chlorolactonization suffers from low chemo-, diastereo-, and enantioselectivities.
Independent generation of the benzylic chloriranium ion shows that it is in equilibrium with an open cation, which leads to low
specificities in the nucleophilic capture of the intermediate.
INTRODUCTION
BACKGROUND
■
■
The lactone function is an important structural motif that is
found in a variety of natural products and pharmaceutical
Current Methods for Enantioselective Chlorolactoni-
zation. The first halolactonization reactions were reported by
Frost in the Fittig School in Strassbourg in 1884, followed by
1
1
1
agents. It is also frequently used as a versatile building block en
more detailed studies by Stobbe around the turn of the 20th
route to other oxygen-containing heterocycles and carboxylic
12
2
century. Since then, it has been widely used in organic
synthesis. However, for quite some time, the only way to obtain
enantiopure lactones was by starting from chiral alkenoic acids
acid derivatives. Among the many methods of forming
3
common-ring lactones, halogen-initiated cyclization of un-
saturated carboxylic acids remains an attractive and direct
approach to the synthesis of functionalized lactones, providing
a heterocycle with up to two stereogenic centers and a useful
13
containing a stereogenic element. Reagent-controlled,
enantioselective halocyclizations started to appear only
relatively recently. In 1992, Taguchi and co-workers reported
the first enantioselective halolactonization, promoted by
stoichiometric amounts of chiral titanium complex, affording
4
functional group.
Among the common halogens, halolactonization initiated by
chlorine (or other electrophilic chlorine equivalents) is much
less common, particularly for enantioselective variants, than the
corresponding transformations with bromine and iodine. This
deficiency is particularly striking when one considers the greater
abundance of chlorine and the large number of chlorine-
containing natural products. Several important reasons for this
discrepancy exist; the low stability of the intermediate
chloriranium ions often leads to lower yielding reactions, and
chlorides are less useful for further manipulation than are
14
enantioenriched iodo lactones in 65% ee. A number of other
methods employing stoichiometric reagents such as chiral
15
16
17
5
amines, pyridines, and dimeric iodonium salts have been
reported.
6
Remarkably, methods for catalytic halolactonization were
absent until 2004 when Tunge and co-workers reported
chlorolactonization catalyzed by phenylselenyl chloride using
N-chlorosuccinimide as a chlorine source; in the same report,
catalytic bromolactonization under similar conditions is
7
18
disclosed (Scheme 1).
The first catalytic, highly enantioselective chlorolactonization
8
bromides or iodides, for example. Of these, the latter is
balanced by the need to prepare chlorinated products. Recent
interest in the synthesis of chlorinated natural products has
further highlighted the need for additional methods for the
was disclosed by Borhan and co-workers in 2010 using a
dimeric cinchona alkaloid based catalyst (Scheme 2, eq 1).
Chlorolactonization of 1,1-disubstituted alkene 1 with 1,3-
dichlorodiphenylhydantoin (DCDPH) as a source of chlorine
19
9
stereoselective installation of chlorine into complex molecules.
The results reported herein are an account of our work in this
10
Special Issue: Heterocycles
Received: June 18, 2016
area to use Lewis base catalysis as a means to catalyze and
control the enantioselectivity of chlorolactonization of 1,2-
disubstituted alkenoic acids.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1
halogenating reagent by hydrogen bonding with the catalyst.
Unfortunately, this catalyst promotes the chlorolactonization
on only a very limited number of substrates, mainly 4-arylpent-
4
-enoic acids. Extension of the substrate scope to homologue 6
was not successful; lactone 7 is obtained as a racemic mixture in
low yield (Scheme 3, eq 2). Finally, isomeric 1,2-disubstituted
styrenyl carboxylic acid 8 was fully converted into correspond-
ing lactone 9; however, the product was also racemic (Scheme
3
, eq 3).
The most recent report of enantioselective chlorolactoniza-
tion by Zhou and co-workers involves vinylbenzoic acids using
a C -symmetric, cinchonine-squaramide catalyst 10 (Scheme
3
2
2
could be successfully catalyzed by (DHQD) PHAL in the
4). With catalyst 10 in the presence of an excess of 4-
nitrobenzenesulfonamide and DCDMH, α-methylstyrene de-
rivative 11 is converted to γ-lactone 12 in good yield and
enantioselectivity. Although the role of the additive is not clear,
the reaction presumably is operating through hydrogen bond
activation of halogenating agent. Under identical reaction
conditions, isomer 13 affords isochromanone 14 in highly
2
presence of a stoichiometric amount of benzoic acid.
Butyrolactone 2 was obtained in synthetically useful yield and
enantioselectivity; lower selectivity was observed when
electron-rich styrenes and 1,1-disubstituted aliphatic alkenes
were used as substrates. A series of experiments were
conducted to shed light on the origin of enantioselectivity of
this transformation. In a low temperature experiment using
stoichiometric amounts of reactants, close association of
23
enantiopure form. To our knowledge, this example represents
the only case of enantioselective chlorolactonization of 1,2-
disubstituted alkenoic acids.
chlorinating agent 3 with (DHQD) PHAL was observed by
2
1
H NMR spectroscopy (Scheme 2, eq 2). On the basis of the
A recent mechanistic investigation by Borhan and co-workers
performed on deuterium-labeled substrates established that
chlorolactonization of 1,1-disubstituted alkenoic acids occurs
predominantly as a syn addition of chlorenium and the
nucleophile across the double bond, which precludes the
observed splitting of the HC(5) signal, two different complexes
were proposed: 4a invoking a hydrogen bond association
between the protonated catalyst and the chlorenium source and
complex 4b involving a tight ion pair between a chlorinated
quinuclidine and the conjugate base of monochlorohydantoin.
Given the need for a stoichiometric amount of benzoic acid, the
authors conclude that 4a is a relevant intermediate but
recognize that they cannot unambiguously exclude the
involvement of 4b since the reaction also proceeds in the
absence of benzoic acid, albeit with lower selectivity. Further
studies using a series of modified, N-chlorinated hydantoins
24
formation of chloriranium ion as an intermediate. It was
concluded that the reaction operates via an open tertiary
carbocation intermediate which then undergoes ring closing
under the stereocontrol of the catalyst. This mechanism of
operation explains the lack of selectivity for 1,2-disubstituted
olefinic acids in the chlorolactonization with cinchona-based
catalysts; these substrates should form less stable secondary
carbocations and would be more prone to be captured as
chloriranium ions or tight ion pairs in an anti addition process.
Objectives. The primary objective of this study was to
develop a catalytic, enantioselective chlorolactonization of 1,2-
disubstituted styrenyl carboxylic acids. Halolactonizations of
this class of substrates are particularly attractive since the
resulting lactones contain two consecutive stereogenic centers.
Enantioselective halolactonization of 1,2-disubstituted alkenoic
(
both chiral and achiral) supported the hypothesis of
participation of complex between the chlorenium source and
(
20
DHQD) PHAL in the enantiodetermining step.
2
Enantioselective chlorolactonization of 1,1-disubstituted
styrenyl carboxylic acids has also been reported by Tang and
21
co-workers who used a cinchona-derived urea catalyst 5.
Substrate 1 undergoes highly selective chlorolactonization at
room temperature with only 5 mol % catalyst loading using 1,3-
dichlorodimethylhydantoin (DCDMH) as a chlorenium source
25
(Scheme 3, eq 1). The authors propose an activation of
acids remains rare.
Scheme 2
B
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3
Scheme 4
As a part of our ongoing program on enantioselective Lewis
RESULTS AND DISCUSSION
■
26
base catalyzed difunctionalization of alkenes, we sought to
identify a chiral Lewis base that could induce the formation of
an enantioenriched chloriranium ion which could be further
captured by a carboxylic acid to afford an anti-configured
lactone (Scheme 5). A previous study from these laboratories
demonstrated that chloriranium ions are configurationally
stable and do not undergo racemization by olefin-to-olefin
Survey of Achiral Lewis Bases. An initial survey of
chlorolactonization conditions using unsaturated acid 8 as a
representative substrate was carried out in deuterated chloro-
1
form and monitored by H NMR spectroscopy. The survey of
suitable chlorinating agents is summarized in Table 1. No
background reaction was observed with N-chlorosuccinimide
NCS) and N-chlorophthalimide (NCP), whereas DCDMH
(
2
7
transfer. Thus, chlorofunctionalization reactions may be more
gave a very slow reaction; 11% of lactone 9 was formed after 20
h (entries 1−3). The most reactive reagent, 1-chlorobenzo-
triazole (1-CBT), gave a higher rate of uncatalyzed reaction,
resulting in a 25% yield of 9 after 20 h (entry 4).
The next stage of the optimization involved the evaluation of
various Lewis bases to activate NCS for chlorolactonization.
Recent work on the activation of NCS with phosphine sulfides
for electrophilic halogenation of arenes suggested the use of
various sulfur-containing Lewis bases. Hexamethylthiophos-
phoramide, triphenyl- and tributylphosphine sulfide, and
thiourea derivatives showed moderate activity as catalysts;
however, they were more active in catalyzing the unproductive
consumption of 8 than in catalyzing the formation of 9 (entries
2
6a−c
amenable to enantioselective catalysis than, e.g., bromo-
or
26d
selenofunctionalization. On the basis of this hypothesis, the
following goals were set for this investigation: (1) identify a
chlorinating agent that would have a slow background
(
uncatalyzed) reaction, (2) identify a Lewis base that would
activate it and promote chlorolactonization, and (3) evaluate
chiral, nonracemic Lewis basic catalysts that afford high
enantioselectivities with a range of alkenes.
28
Scheme 5
5
−9). Selenium-based donors such as hexamethylselenophos-
phoramide and tricyclohexylphosphine selenide were also
inefficient catalysts for chlorolactonization (entries 10 and
C
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 1. Optimization of Chlorolactonization Conditions
a
Reactions were performed at rt by the addition of 0.2 mmol of 8, 0.24 mmol of chlorinating agent, and 1.0 mL of CDCl in a 5 mm NMR tube,
3
b
1
followed by the addition of 0.02 mmol of catalyst. Determined by integration of H NMR signals against tetramethylsilane internal standard.
1
1
1). Selenoethers were unreactive with NCS (entries 12 and
3), and thioethers gave complex mixtures of products without
Scheme 6
full consumption of the starting material (entries 14 and 15).
A recent report from Yamamoto describes the aniline-
promoted, catalytic chlorination of electron-rich aromatic
compounds and stimulated a survey of nitrogen-containing
2
9
catalysts. 2,4,6-Trimethylaniline, tosylamide, and diphenyl
phosphoramide were tested; however, they were completely
unreactive with NCS (entries 16−18). Remarkably, however,
quinuclidine catalyzed the chlorolactonization; even though full
conversion was not achieved, the reaction was clean and did not
show any observable side products (entry 19). Other
chlorinating agents were tested with quinuclidine, and to our
delight, DCDMH resulted in a very fast and clean reaction. 1-
Chlorobenzotriazole also gave good conversions, but side
products were observed (entries 20−22). Notably, Yamamoto
reports that arylamines generate an N-chloroarylamine
intermediate that acts as a highly reactive but selective
electrophilic halogen source. Moreover, N-chloroammonium
salts (including quinuclidinium salts) have been used for
toluene for 12 h followed by addition of 0.5 equiv of
tetrabutylammonium iodide (TBAI) and further heating at
1
15 °C for 6 h. Presumably, the iodide displaces the bromide
30
selective chlorination of electron-rich aromatic compounds.
ion from the less reactive diastereomer of 17 to produce an
intermediate benzyl iodide of the correct configuration that
undergoes ring closure to the desired quinuclidine 15.
According to the original report, benzyl bromides 17 gave
exclusively 15 in 76% yield; however, in our hands, a minor
product of the isomeric quinuclidine 19 was obtained (Scheme
6). The outcome of the reaction did not change with or without
the added TBAI. Fortunately, the diastereomeric quinuclidines
were separable by silica gel column chromatography, thus
providing the opportunity to explore the use of 19 for
enantioselective chlorofunctionalization reactions as well. In
previous work, Corey also described a synthesis and resolution
of diphenyl quinuclidine 20, which was also prepared and was
Thus, it appeared plausible that under the optimized reaction
conditions N-chloroquinuclidine is formed catalytically.
Synthesis of Chiral Quinuclidines. The third stage of the
method development involved the synthesis of chiral, non-
racemic quinuclidines for enantioselective chlorolactonization.
The first structure targeted was the C -symmetric triphenyl
3
quinuclidine 15 reported several years ago by Corey and co-
3
1
workers. Quinuclidine 15 was synthesized from N-(tert-
butoxycarbonyl)-4-pyridone 16 according to the route
developed by Corey (Scheme 6).
The last step in the reaction sequence is the cyclization of
diastereomeric mixture of bromides 17. In this two-step
protocol, 17 was exposed to sodium bicarbonate in refluxing
32
tested for enantioselective chlorolactonization.
D
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Synthesis of N-Chloroquinuclidines. Attempts to pre-
pare N-chloroquinuclidinium salts from 15 and 19 failed with
chlorinating agents such as iodosobenzene dichloride, NCS,
and DCDMH. The targeted species were not formed even
when molecular chlorine was used! Quinuclidines 15 and 19
were resistant to the action of 1 equiv of chlorine at 25 °C;
however, upon exposure to an excess of chlorine, the
quinuclidines decomposed (Scheme 7). The low reactivity of
Scheme 8
15 and 19 can be attributed to the inductive electron-
withdrawing effect and the steric congestion caused by the
phenyl groups around nitrogen atom. Fortunately, diphenyl
quinuclidine 20 did react with chlorine to form a new species,
2
1. All three proton signals adjacent to the nitrogen center were
ingly, the best catalyst, (DHQD) PHAL, provided 9 in only
2
broadened and shifted downfield (Figure 1).
4
5:55 er. Previously, (DHQD) PHAL had been shown to
2
catalyze the chlorolactonization of 1 with high enantioselectiv-
ity using DCDPH as a chlorine source.
Scheme 7
19
To demonstrate that enantioselective cyclizations are
possible using 1-CBT as a chlorine source, alkene 1 was
subjected to chlorination with (DHQD) PHAL as the catalyst,
2
which afforded 2 in moderate yield and enantioselectiveity
(
Scheme 10). Thus, although this combination of reagents is
less selective than the optimized procedure developed by
Borhan, the failure to effect enantioselective cyclization of 8
clearly shows the extreme substrate dependence of this process.
Mechanistic Experiments. Lewis vs Brønsted Base
Catalysis. The working hypothesis for this reaction proposes
that the chlorinating agent transfers a chlorenium ion to the
nitrogen atom of a chiral quinuclidine. The generated N-
chloroquinuclidinium salt reacts with an alkene to generate a
chloriranium ion, which is then opened with the carboxylate
(
formed by deprotonation by the conjugate base of the
Survey of Enantiomerically Enriched Lewis Bases.
Chiral quinuclidines 15 and 19 were tested in the reaction of
interest with DCDMH as a chlorinating agent (Scheme 8). Not
surprisingly, both amines only slightly accelerated the rate of
the reaction, providing lactone 9 in 50:50 er. The inability of
triaryl-substituted quinuclidines to promote chlorolactonization
can clearly be attributed to the decreased nucleophilicity of the
nitrogen atom, thus inhibiting formation of the chlorinating
reagent. In support of this hypothesis, the more electron-rich
quinuclidine 20 efficiently promoted chlorolactonization of 8 to
afford 9 in 75% yield in 90 min; however, the resulting product
was still racemic. Other chlorinating agents such as NCS or
NCP did not improve the enantioselectivity.
chlorinating agent). The only observed product was the trans-
configured lactone, thus supporting the hypothesis of anti-
addition via chloriranium ion formation.
To further probe the validity of this hypothesis, additional
experiments were performed to test some of the assumptions
implicit in the proposed mechanism. To test the involvement of
the carboxylate ion, substrate 22 (the TBDMS ester of 8) was
prepared and subjected to the reaction conditions with and
without quinuclidine as the catalyst. Compound 22 was
unreactive under both conditions, suggesting that formation
of the chloriranium ion, if involved, requires the free
carboxylate (Scheme 11).
To test the involvement of a carboxylate salt in the
chlorolactonization, substrate 23, the tetrabutylammonium
salt of 8 was prepared and tested for its competence under
A survey of other chiral tertiary amines was carried out using
a stronger chlorinating agent 1-CBT (Scheme 9). Disappoint-
1
Figure 1. H NMR spectrum of 22.
E
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 9
Scheme 10
Table 2. Chlorolactonization of Tetrabutylammonium
a
Carboxylate 23.
different reaction conditions. Remarkably, in the presence of
DCDMH alone (i.e., no catalyst), 23 reacted with a significant
background rate to afford a mixture of δ- and γ-lactone
products, 9 and 24, respectively (Table 2, entry 1). Addition of
a
10 mol % of 20 to the reaction mixture had no effect (Table 2,
Reactions were performed at rt by the addition of 0.2 mmol of 23,
entry 2). During the course of the reaction, N-chloroquinucli-
dinium salt, 21, was not observed by H NMR analysis; in fact,
the chemical shifts of the catalyst 20 did not change. However,
with 10 mol % of quinuclidine itself, cyclization was complete
in 20 min (Table 2, entry 3).
0.02 mmol of catalyst, and 1.0 mL of CDCl into a 5 mm NMR tube,
3
1
b
followed by the addition of 0.24 mmol of DCDMH. Determined by
1
integration of H NMR signals against tetramethylsilane internal
c
standard. After 20 min.
The striking difference in reactivity between 22 and 23
implies a critical role for the carboxylate ion in the reaction
mechanism. Several interpretations can be considered, includ-
ing activation of the chlorinating reagent or activation of the
substrate. Activation of the chlorinating agent could involve the
carboxylate anion acting as a Lewis base, ultimately resulting in
the formation of an acyl hypochlorite by chlorenium ion
transfer to the carboxylate oxygen. From there, either intra- or
intramolecular chlorenium ion transfer to the alkene could
produce a chloriranium ion that suffers opening by the
carboxylate.
Scheme 11
F
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
Figure 2. H NMR spectra of the olefinic region: (A) 8, (B) 23; (C) 23 + DCDMH.
Activation of the substrate could involve electronic polar-
ization of the alkene by the pendant carboxylate to enhance
nucleophilicity. Although not widely known, the rate of
electrophilic addition reactions of alkenes is dependent on
lactone 9, the product of anti addition, potentially bypassing the
intermediacy of a chloriranium ion.
Although the influence of the carboxylate on the electronic
properties of the alkene present a compelling explanation of the
dramatic rate of chlorolactonization of 23, this influence may
not be relevant in the presence of a chlorinating agent. Thus, a
spectroscopic analysis of a 1:1 mixture of 23 and DCDMH was
undertaken. Inspection of the 1H NMR spectrum of the
reaction mixture corresponding to entry 1, Table 2, revealed a
number of important features. First, after only 10 min, ca. 20%
of 23 was converted to a mixture of 9 and 24. Second, the
olefinic protons of 23 returned to a normal splitting pattern
33
the nucleophile (Ad 2 reactions). In the late 1960s, Shilov
E
demonstrated that the rate of iodoetherification of allylphenols
is dependent on the electron density at the oxygen (through
34
ring substituents). Indeed, the entire spectrum of Ad type
reactions from Ad 2 to Ad 2 (electrophile initiated, nucleo-
E
N
phile initiated, and of course, synchronous in between) is
treated in many advanced textbooks on physical organic
3
5,36
chemistry.
Spectroscopic Evidence for Activation of Alkene vs
with signals centered at 6.277 ppm for H
, indicating that the interaction of the alkene with the
carboxylate had diminished though still with a significant
upfield shift of H (Figure 2C). Third, the methylene protons
a
and 6.204 ppm for
Activation of DCDMH. Insight into these possibilities was
H
b
1
provided by inspection of the H NMR spectra of 23 as well as
of reaction mixtures involving 23. The chemical shifts of the
a
olefinic protons in free acid 8 appear at 6.455 ppm for H and
next to the carboxylate group moved downfield by ca. 0.07
ppm, while those next to the olefin remained unchanged. Taken
together, these spectral clues suggest that the carboxylate is
engaged in an equilibrium interaction with the chlorinating
agent. However, on the basis of the change in chemical shift for
the methylene protons next to the carboxylate, it does not
appear that an acyl hypochlorite has been formed in
a
6
.217 ppm for H (Figure 2A). However, carboxylate salt 23
b
shows a significant change such that these two protons appear
as a merged multiplet centered at 6.270 ppm (Figure 2B).
Clearly, H was shifted upfield, while H was shifted downfield.
a
b
The dramatic changes in the chemical shifts for 23 cannot be
explained by the inductive effect of the carboxylate functional
group, which is too remote to have such a pronounced effect.
Alternatively, the change in chemical shifts could arise from an
interaction of carboxylate ion with the alkene such that it causes
a redistribution of the electron density in the π-system (Scheme
37
spectroscopically detectable amounts. Rather, the observed
changes are more consistent with a halogen-bonding
38
interaction with the carboxylate which results in enhanced
electrophilic character of the chlorine (i.e., Lewis base
10,39
activation of Lewis acidity, Scheme 13).
At this point, is
12). The electronically activated alkene thus reacts readily with
not possible to deconstruct the overall rate enhancement to
a weak chlorinating agent, such as DCDMH, to afford chloro
Scheme 13
Scheme 12
G
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
Figure 3. H NMR spectra of the olefinic region: (A) 8; (B) 8 + quinuclidine; (C) 8 + quinuclidine + DCDMH.
Scheme 14
identify the relative contributions of these two factors, olefin
activation vs electrophile activation.
both components in the reaction. This difference in reactivity of
the alkene is also manifest in the relative rates of
chlorolactonization of 8 and 23 in the presence of quinuclidine.
With 10 mol % of the catalyst, 8 is completely consumed in 20
h compared to full conversion of 23 in 20 min. The reasons for
the different rates in the presence of quinuclidine are more
subtle. Considering the Brønsted basicity of quinuclidines (and
the other tertiary amines tested), we suspect that these amines
are fully protonated by the carboxylic acid under catalytic
conditions. Thus, whereas the Lewis basicity of the amines is
now quenched and unable to generate an activated chlorinating
agent, the carboxylate (ion paired with the quinuclidinium ion)
can provide electron density to activate the alkene as described
above. Moreover, it is also possible that the quinuclidinium ion
can provide electrophilic activation of DCDMH (Scheme 14).
Thus, what was initially interpreted as Lewis base catalysis is, in
fact, Brønsted base/Brønsted acid catalysis. The final aspect of
the rate differences involves the effect of quinuclidine on the
rate of chlorolactonization of 23 (cf. Table 2, entries 1 and 3).
The significant increase in rate induced by 10 mol % of
quinuclidine cannot be ascribed to its function as a Brønsted
base as the carboxylate is already fully deprotonated. Thus, the
Lewis basic character of the quinuclidine can now be expressed
in the formation of an active chlorinating agent from DCDMH
Finally, and perhaps most importantly, it was essential to
establish if these interactions are spectroscopically detectable
under more relevant chlorocyclization reaction conditions.
1
Thus, H NMR spectra of the combination of 8 with 1.0 equiv
of quinuclidine and with 1.0 equiv of DCDMH were collected,
Figure 3. On the basis of pK , it is expected that the carboxylate
a
would be stoichiometrically deprotonated (quinuclidine pKbH
1
2.1), and accordingly, the olefinic region shows a modest
contraction of the chemical shifts compared to 8 with signals
centered at 6.400 ppm for H and 6.218 ppm for H (Figure
a
b
3B). Clearly, though detectable, the polarization of the alkene
electron density is significantly attenuated compared to 23.
Interestingly, upon addition of DCDMH, no change in the
olefinic region of the salt is detectable (Figure 3C).
Catalysis of Chlorolactonization of 23. Two interesting
differences in the behavior of 8 and 23 in the presence of
DCDMH with and without quinuclidine merit comment. The
first concerns the rate of chlorolactonization. Under identical
conditions in the absence of quinuclidine, the rates are
dramatically different; acid 8 undergoes 12% conversion in 20
h whereas 23 undergoes 64% conversion in only 2.5 h. As
detailed above, the carboxylate provides activation of either or
H
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
and thereby further accelerate the functionalization of the
double bond (Scheme 14).
Table 3. Solvolytic Substitution with 25
The second difference concerns the constitutional site
selectivity of the chlorolactonization of the two substrates
under catalysis by quinuclidine. Reaction of free acid 8 affords
exclusively trans chloro lactone 9, whereas ammonium
carboxylate 23 affords a 4:1 mixture of δ- and γ-lactones, 9
and 24, respectively. The clean anti addition in a Markovnikov
sense is the generally expected outcome of these kinds of Ad
reactions characterized by an unsymmetrical buildup of positive
a
a
entry
X
conv (%)
time
anti/syn
1
2
3
4
5
1
100
100
100
76
15 min
17 min
70 min
48 h
62:38
60:40
62:38
62:38
2
5
33
10
20
charge next to the phenyl group in the transition state.
0
48 h
NA
However, the formation of both constitutional isomers from
Markovnikov and anti-Markovnikov addition with 23 is
unusual. The rate enhancement observed by forming the
tetrabutylammonium salt suggests that the electronic activation
of either the alkene or the chlorinating agent shifts the
transition state to an earlier position on the reaction coordinate,
thus requiring less interaction with the chlorenium ion source
and a correspondingly lower difference in the accumulation of
positive charge.
a
1
Determined by integration of H NMR signals against tetramethylsi-
lane internal standard.
addition of acetate to a benzylic carbocation. Moreover, syn-26
may also arise from an open carbocation or by direct S 2-type
N
displacement of mesylate 24. The formation of syn-26 by direct
displacement was excluded by demonstrating that the
diastereomeric ratio of the products remained unchanged as
the amount of the nucleophile was increased (Table 3, entries
−4). Interestingly, the rate of the reaction decreased with
larger quantities of n-Bu NOAc, ultimately leading to complete
loss of reactivity with 20 equiv of n-Bu NOAc (Table 3, entry
5). On the basis of these experiments, it can be concluded
that the benzylic chloriranium ion, if formed, is in equilibrium
with an open benzylic carbocation, giving rise to poorly
selective nucleophilic capture and formation of unwanted
elimination products.
Ground-State Conformation of Chlorolactone 9. Although
it is mentioned in the literature, chloro lactone 9 has never
21
been fully described. As part of the spectroscopic character-
ization, we noted that the vicinal coupling constant between the
hydrogens on the two stereogenic centers was unexpectedly
2
3
4
small ( J = 5.9 Hz), suggesting that the hydrogens are both
equatorial and that the chlorine atom and phenyl group are in
axial positions. This surprising observation was confirmed by
straightforward calculations of the ground-state energies of the
two limiting chair conformations using semiempirical methods
to obtain geometries and DFT calculations (B3LYP//6-31G*)
for their energies (Scheme 15). The modest preference for the
diaxial conformation likely results from energetic gains arising
4
41
40
from favorable σ → σ* overlap (gauche effect) which are not
offset by unfavorable steric interactions because of the lack of
axial substituents at O(1) and C(2).
CONCLUSIONS
■
In summary, depending on the catalyst, two modes of operation
for catalytic chlorolactonization of 1,2-disubstituted styrenyl
carboxylic acids have been identified. In the first scenario,
catalysts with Brønsted basic character (i.e., quinuclidines)
promote chlorolactonization by deprotonation of the carboxylic
acid. The resulting carboxylate activates either or both the
alkene and the chlorinating agent by donation of electron
density into the olefinic π-system and potentially by hydrogen
bonding to the hydantoin. In the second scenario, catalysts act
as Lewis bases which transfer the chlorenium ion from the
source to the substrate. However, a chloriranium ion, if formed,
is unstable and leads to various side products. The greatest
challenge in developing an enantioselective chlorolactonization
is capturing the chloriranium ion faster than it can decompose
or open to a free carbocation. Other challenges include
designing catalysts that are stable under reaction conditions and
avoiding unproductive side reactions between the chlorine
electrophile and other functionality in the substrate.
Scheme 15
Solvolysis Experiments. The results in Table 1 show that the
more Lewis basic but less Brønsted basic sulfur- and selenium-
containing catalysts were not efficient for chlorolactonization of
8. One possible explanation is that various side products arose
because of the instability of intermediate chloriranium ion. To
test this hypothesis, the solvolytic substitution of a
disubstituted, benzylic chloriranium ion was examined. The
ion was generated by solvolytic substitution of configurationally
defined β-chloro mesylate 25 with tetrabutylammonium acetate
in strongly ionizing media (Table 3). In a previous study on
stability of haliranium ions, it was found that acetolysis of
dialkyl-substituted chloriranium ions proceeds with high
Despite the recent progress the area of enantioselective
halolactonization reactions, enantioselective chlorolactonization
is still limited to 1,1-substituted aryl alkenoic acids. The study
reported herein highlights main challenges associated with the
development of catalytic asymmetric chlorolactonization and
provides insights for further development of this important
class of reactions.
8
diastereospecificity, giving exclusively the anti-chloro acetate.
Acetolysis of 25 in a 1:1 mixture of HFIP/DCM with 1 equiv
of tetrabutylammonium acetate afforded an anti/syn mixture of
chloro acetates in a 62:38 ratio along with various products of
elimination (Table 3, entry 1). Acetate product anti-26 can be
formed by the opening of a chloriranium ion or by direct
I
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
■ EXPERIMENTAL SECTION
Article
dried NMR tube equipped with a septum was charged with 1-CBT (10
mg, 0.078 mmol, 1.2 equiv) and 1,2,4,5-C H Cl (10.2 mg). The tube
was then purged with Ar through a needle. Deuterochloroform (600
μL) was added via syringe, and then the tube was agitated with a
vortex mixer. Acid 8 (12.1 mg, 0.066 mmol) was added as a solid, and
then the tube was agitated with a vortex mixer. A solution of
6
2
4
(
DHQD) PHAL (5.0 mg in 50 μL of CDCl 0.0065 mmol, 0.1 equiv)
2
3
,
was added via syringe, and then the tube was agitated with a vortex
mixer. The reaction mixture was analyzed by H NMR spectroscopy
after 1 and 24 h. After 24 h, a solution of butyl vinyl ether in ethanol
Chlorolactonization of 8 with DCDMH in the Presence of 1
equiv of Quinuclidine. Preparation of rel-(5R,6S)-5-Chlorote-
trahydro-6-phenyl-2H-pyran-2-one (9). A flame-dried 50 mL
Schlenk flask was charged with quinuclidine (333 mg, 3.00 mmol, 1.00
equiv) and chloroform (15.0 mL, 0.200 M) at room temperature. (E)-
1
(15 vol %, 100 μL) was added to quench the reaction. The resulting
solution was concentrated in vacuo (23 °C, 6 mmHg). The residue
was purified by column chromatography (silica gel, 1 g, 1 cm diam,
CH Cl /hexane, 4:1) to afford 8.8 mg (66%) of 9 as a colorless oil.
5-Phenyl-4-pentenoic acid 8 (529 mg, 3.0 mmol) was added to the
2
2
solution, followed by DCDMH (709 mg, 3.6 mmol, 1.20 equiv), and
the resulting mixture was stirred at room temperature for 3 h. The
reaction was quenched by the addition of a solution of butyl vinyl
ether (388 μL, 300 mg, 3.0 mmol, 1.0 equiv) in ethanol (4.0 mL,
approximately 10% v/v solution). After being stirred for 10 min, the
solution was poured into a separatory funnel, washed with water (2 ×
CSP-SFC: (5R,6S)/(5S,6R)-9, t 7.0 min (45.0%); (5S,6R)/(5R,6S)-9,
R
tR 11.5 min (55.0%) (Chirapak AD, 125 bar, 3 mL/min, 5% MeOH in
CO2).
10 mL) and brine (1 × 10 mL), dried over sodium sulfate (4 g),
filtered, and concentrated in vacuo (30 °C, 10 mmHg) to form a thick,
1
yellow oil. Integration of the crude H NMR indicated a mixture of 9
and 24 in a ca. 100:17 ratio. Filtration through a silica plug (4 cm ⌀ ×
10 cm) eluting with dichloromethane provided a white solid that was
subsequently recrystallized from tert-butyl methyl ether to provide 9 as
white needles (398 mg, 63%). Residual TBME incorporated into the
crystalline product can be removed by sublimation of the needles at 60
Preparation of 2,6,7-Triphenylquinuclidines (15 and 19). A
flame-dried, 100 mL, single-neck, round-bottomed flask fitted with a
magnetic stir bar, reflux condenser, and Ar inlet was charged with
bromoamine 18 (879 mg, 2.09 mmol, 1.0 equiv) and dissolved in
toluene (30 mL). To the obtained solution was added sodium
bicarbonate (176 mg, 4.18 mmol, 2.0 equiv), and the reaction mixture
was heated at 115 °C for 12 h. Then the reaction mixture was cooled
to room temperature and quenched with 30 mL of distilled water. The
mixture was transferred to a 125 mL separatory flask, and the aqueous
layer was extracted with dichloromethane (3 × 60 mL). The combined
organic layer was washed with saturated brine solution (1 × 50 mL),
°
C/0.1 mmHg. Purification of the mother liquor by radial silica gel
chromatography (4 mm, 9:1 hexanes/ethyl acetate) provided the
minor isomer 24 as a clear, colorless oil (95.0 mg, 15%). Data for 9:
1
mp (sublim) 99−100 °C; H NMR (500 MHz, CDCl ) δ 7.48−7.34
3
(
m, 3 H, HC(9 and 10)), 7.35−7.29 (m, 2 H, HC(8)), 5.49 (d, J = 5.9
Hz, 1 H, HC(6)), 4.32 (ddd, J = 6.2, 5.9, 4.2 Hz, 1 H, HC(5)), 2.96
ddd, J = 18.2, 9.0, 7.1 Hz, 1 H, HaC(3)), 2.71 (ddd, J = 18.2, 6.5, 5.5
(
Hz, 1 H, HbC(3)), 2.35 (dddd, J = 14.1, 8.9, 6.5, 4.2 Hz, 1 H,
HaC(4)), 2.20 (dddd, J = 14.1, 7.2, 6.3, 5.5, 0.89 Hz, 1 H, HbC(4));
1
3
1
dried over MgSO , and concentrated by rotary evaporation to give the
C{ H} NMR (126 MHz, CDCl ) δ 169.2 (C(2)), 137.1 (C(7)),
4
3
crude mixture of quinuclidines as yellow oil. Purification by flash
1
2
29.2 (C(10)), 129.0 (C(9)), 126.4 (C(8)), 85.4 (C(6)), 56.4 (C(5)),
7.3 (C(3)), 26.8 (C(4)); IR (neat, cm ): 3445 (w), 2963 (w), 1724
−1
chromatography (SiO , 200 mm × 25 mm, 10 mL fractions, hexanes/
2
CH Cl , 4:1 then hexane/EtOAc, 19:1) yielded C -symmetric
(
(
s, CO), 1495 (w), 1458 (w), 1382 (w), 1221 (s), 1066 (m), 1031
2
2
3
+
quinuclidine 15 as a white solid (349 mg, 49%) and C -symmetric
s), 949 (m), 920 (m), 756 (m), 697 (s), 648 (m), 515 (m); MS (EI ,
1
+
37
+
35
quinuclidine 19 as a colorless oil (183 mg, 26%, R 0.39 (hexane/
TOF, 70 eV) 212.1 (22, M , Cl), 210.1 (66, M , Cl), 148.1 (18),
38.0 (10), 120.1 (10), 105.1 (74), 104.0 (100), 91.1 (9), 76.0 (41);
f
1
EtOAc, 19:1) [UV, I ]). The H NMR spectroscopic data matched
those from an alternative preparation. Data for 15: H NMR (500
MHz, CDCl ) δ 7.66 (d, J = 8.2 Hz, 6 H, HC(2)), 7.37 (t, J = 7.7 Hz,
1
2
3
1
1
+
HRMS (EI , TOF) m/z calcd for C H O Cl 210.0448, found
11
11
2
2
10.0446; TLC R 0.24 (hexanes/EtOAc 3:1) [UV, KMnO ]. Anal.
3
f
4
6
H, HC(3)), 7.25 (t, J = 7.7 Hz, 3 H, HC(4)), 4.18 (t, J = 8.8 Hz, 3
Calcd for C H O Cl (210.66): C, 62.72; H, 5.26; Cl, 16.83. Found:
11
11
2
H, HC(5, 9, 10)), 2.35−2.25 (m, 4 H, HC(6, 7, 8, 11)), 1.76 (t, J =
C, 62.37; H, 5.28; Cl, 16.91.
1
10.8 Hz, 3 H, HC(6′, 8′, 11′)); TLC R 0.48 (hexane/EtOAc, 19:1)
Data for 24: H NMR (500 MHz, CDCl ) δ 7.52−7.30 (m, 5 H,
f
3
[
UV, I ].
HC(aryl)), 5.05 (d, J = 5.7 Hz, 1 H, HC(6)), 4.85 (td, J = 7.1, 5.8 Hz,
2
Data for (2R,6R,7S)-2,6,7-triphenylquinuclidine (19): 1H NMR
1
H, HC(5)), 2.60−2.44 (m, 2 H, H C(3)), 2.42−2.21 (m, 2 H,
2
13 1
(400 MHz, CDCl ) δ 7.76 (d, J = 7.5 Hz, 2 H, HC(aryl)), 7.39 (t, J =
H C(4)); C{ H} NMR (126 MHz, CDCl ) δ 176.3 (C(2)), 136.5
3
2
3
7
.5 Hz, 2 H), 7.25 (t, J = 8.5 Hz, 3 H, HC(aryl)), 7.01 (d, J = 7.1 Hz, 2
(
(
(
C(7)), 129.2 (C(10)), 128.9 (C(9)), 128.0 (C(8)), 82.1 (C(5)), 64.2
C(6)), 28.4 (C(3)), 24.3 (C(4)); IR (neat, cm ) 3546 (w), 2928
−1
H, HC(aryl)), 6.96−6.74 (m, 6 H, HC(aryl)), 4.44 (dd, J = 10.8, 4.4
Hz, 1 H, HC(9/10)), 4.37 (t, J = 8.7 Hz, 1 H, HC(9/10)), 3.88 (t, J =
w), 1776 (s, γ-lactone CO stretch), 1495 (w), 1454 (m), 1419 (w),
9
.6 Hz, 1 H, HC(5)), 2.38 (s, 1 H, HC(7)), 2.30 (m, 2 H, HC(8, 11)),
1
5
331 (w), 1173 (s), 1027 (m), 910 (m), 838 (w), 750 (w), 700 (m),
13
1
+
+
37
+
1.98 (m, 9.6 Hz, 4 H, HC(6, 8′, 11′)); C{ H} NMR (126 MHz,
33 (w); MS (EI , Quad, 70 eV) 212.1 (4, M , Cl), 210.1 (10, M ,
3
5
+
CDCl ) δ 144.3 (C(1)), 143.7 (C(1′)), 142.1 C(1″), 129.6, 128.2,
Cl), 125.0 (17), 114.9 (9), 85.1 (100); HRMS (ES , TOF) m/z
3
1
27.3, 127.2, 126.8, 126.7, 126.6 (C(2/3/4)), 126.3 (C(4′)), 124.8
calcd for C H O Cl, 211.0526, found 211.0532; TLC R 0.22
11
12
2
f
(
3
3
C(4″)), 63.1 (C(9/10)), 62.4 (C(9/10)), 51.7 (C(5)), 32.6 (C(6)),
(
hexanes/EtOAc 3:1) [UV, KMnO4].
1.4 (C(8/11)), 29.5 (C(8/11)), 24.4 (C(7)); IR (neat) 3058 (w),
026 (w), 2929 (w), 2865 (w), 1684 (w), 1601 (w), 1493 (w), 1466
(w), 1447 (w), 1337 (m), 1299 (w), 1202 (w), 1179 (w), 1074 (w),
1
043 (w), 984 (m), 908 (w), 841 (w), 825 (w), 805 (w), 788 (w), 741
+
(s), 692 (s), 649 (w), 612 (w), 592 (w), 550 (w); LR MS (EI , 70 eV)
+
+
3
40.2.; HR MS (EI , [M + H] ) m/z calcd for C H N 340.2065,
25 26
found 340.2065. CSP-HPLC: (R,R,S)-19, t 9.71 min (99%); (S,S,R)-
R
1
9, tR 12.24 min (1%) (NP-HPLC, CHIRALPAK OJH, 98.0:2.0
General Procedure: Chlorolactonization of 8 with 1-CBT in
the Presence of (DHQD) PHAL. Preparation of rel-(5R,6S)-5-
hexane/i-PrOH, 0.5 mL/min, 210 nm, 22 °C); [α] −90.25 (22 °C, c
= 1.3, THF).
D
2
Chlorotetrahydro-6-phenyl-2H-pyran-2-one (9). A 5 mm, oven-
J
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mmol, 1.0 equiv) was added dropwise by syringe at a rate in which the
internal temperature was maintained below −70 °C to give a light
yellow homogeneous solution. The reaction mixture was stirred for 20
min at −70 °C and quenched with 40 mL of satd aq NH Cl solution.
4
The mixture was allowed to warm to room temperature and then was
transferred to 250 mL separatory funnel and was diluted with diethyl
ether (100 mL). The aqueous layer was extracted with diethyl ether (3
Preparation of tert-Butyldimethylsilyl (E)-5-Phenylpent-4-
enoate (22). A flame-dried, 25 mL, single-neck, round-bottomed flask
fitted with a magnetic stir bar and Ar inlet was charged with (E)-5-
phenylpent-4-enoic acid (176 mg, 1.0 mmol, 1.0 equiv) and dissolved
in DMF (3 mL). tert-Butyldimethylsilyl chloride (226 mg, 1.5 mmol,
×
50 mL); the combined organic layers were washed with brine (1 ×
1
00 mL), dried over MgSO , and concentrated by rotary evaporation
4
to give the crude product as yellow oil. Purification by flash
1
.5 equiv) and 1H-imidazole (136 mg, 2.0 mmol, 2.0 equiv) were
added successively. The solution was heated to 40 °C in an oil bath for
h and then cooled to room temperature and stirred overnight. The
chromatography (SiO , 200 mm × 25 mm, 10 mL fractions,
2
hexane/EtOAc, 19:1 increased to hexane/EtOAc, 9:1) yielded anti-
7
2
-chloro-1-phenyloctan-1-ol (94:6 mixture of anti/syn diastereomers as
mixture was transferred to a 125 mL separatory flask, diluted with 50
mL of ethyl acetate, and washed with saturated brine solution (5 × 50
1
determined my H NMR spectroscopy) as a colorless oil (1.35 g,
4%). An analytical sample was obtained by Kugelrohr distillation (air
4
mL). The organic layer was dried over MgSO and concentrated by
4
bath = 170 °C, 1.0 mmHg). Data for anti-2-chloro-1-phenyloctan-1-ol:
rotary evaporation to give the product as a clear, colorless oil (253 mg,
1
H NMR (500 MHz, CDCl ) δ 7.41−7.29 (m, 5 H, HC(2, 3, 4)), 4.94
3
8
7%). The silyl ester was used immediately for further reactions
1
(d, J = 4.1 Hz, 1 H, HC(5)), 4.18 (dt, J = 8.6, 4.3 Hz, 1 H, HC(6)),
without purification. Data for 22: H NMR (400 MHz, CDCl ) δ 7.31
3
2
.57 (s, 1 H, HO(13)), 1.76−1.62 (m, 2 H, HC(7)), 1.62−1.43 (m, 2
(
dt, J = 15.2, 7.6 Hz, 4 H, HC(10 and 11)), 7.21 (t, J = 7.2 Hz, 1 H,
H, HC(8)), 1.38−1.14 (m, 6 H, HC(9, 10, 11)), 0.87 (t, J = 7.0 Hz, 3
HC(12)), 6.44 (d, J = 15.8 Hz, 1 H, HC(8)), 6.30−6.16 (m, 1 H,
H, HC(12)); 13C{ H} NMR (126 MHz, CDCl ) δ 140.0 (C(4)),
1
HC(7)), 2.52 (s, 4 H, HC(5 and 6)), 0.95 (s, 9H, HC(1)), 0.28 (s, 6
3
H, HC(3)); 13C{ H} NMR (126 MHz, CDCl ) δ 173.5 (C(4)), 137.5
1
128.5 (C(2)), 128.1 (C(4)), 126.7 (C(3)), 77.16 (C(5)), 68.6 (C(6)),
3
3
1
2
1.7 (C(7)), 31.5 (C(8)), 28.8 (C(9)), 26.7 (C(10)), 22.7 (C(11)),
4.2 (C(12)); IR (neat) 3420 (w), 3031 (w), 2954 (w), 2857 (w),
926 (w), 2857 (w), 1495 (w), 1453 (w), 1378 (w), 1189 (w), 1123
(
1
−
1
C(9)), 130.9 (C(8)), 128.7 (C(12)), 128.6 (C(11)), 127.2 (C(7)),
26.1 (C(12)), 35.8 (C(6)), 28.6 (C(5)), 25.7 (C(1)), 17.73 (C(2),
4.65 (C(3)); IR (neat) 3027 (w), 2955 (w), 2930 (w), 2858 (w),
717 (s), 1599 (w), 1495 (w), 1472 (w), 1463 (w), 1447 (w), 1413
w), 1363 (w), 1252 (s), 1177 (m), 1077 (w), 1029 (w), 1006 (w),
(w), 1028 (w), 915 (w), 800 (w), 727 (w), 761 (m), 699 (s), 602 (w),
+
5
7
18 (w); TLC R 0.30 (hexane/EtOAc, 9:1) [KMnO ]; LR MS (EI ,
(
f
4
+
+
0 eV) 240.1; HR MS (EI , [M] ) m/z calcd for C H ClO 240.1281,
9
6
62 (m), 938 (m), 892 (w), 840 (s), 813 (s), 788 (s), 741 (s), 691 (s),
09 (w); LR MS (EI+, 70 eV) 291.2; HR MS (EI , [M + H] ) m/z
14 21
+
+
found 240.1283. Anal. Calcd for C H ClO (240.77): C, 69.84; H,
14 21
8
.79. Found: C, 69.75; H, 8.65.
calcd for C H O Si 291.1775, found 291.1780.
17
27
2
Preparation of Tetrabutylammonium (E)-5-Phenylpent-4-
enoate (23). To a 20 mL scintillation vial equipped with a plastic
screw cap and a magnetic stir bar was added (E)-5-phenylpent-4-enoic
acid (176 mg, 1.0 mmol) followed by the addition of 40% aqueous
solution of tetrabutylammonium hydroxide solution (8.0 mL, 12.0
mmol, 12 equiv). The resulting homogeneous reaction mixture was
stirred for 30 min and then was transferred to a 50 mL separatory
funnel and extracted with chloroform (3 × 50 mL). The combined
organic layers were washed with water (3 × 20 mL) and brine (1 × 50
Preparation of rel-(1R,2S)-2-Chloro-1-phenyloctyl Methane-
sulfonate (25). A flame-dried, 25 mL, two-neck, round-bottomed
flask fitted with a magnetic stir bar, and Ar inlet, and a rubber septum
was charged with anti-2-chloro-1-phenyloctan-1-ol (197 mg, 0.82
mmol) and dissolved in dichloromethane (5 mL). Triethylamine (228
μL, 1.64 mmol, 2.0 equiv) was added, and the reaction mixture was
cooled in an ice bath (internal temperature 3 °C). Methanesulfonyl
chloride (95 μL, 1.23 mmol, 1.5 equiv) was added in one portion by
syringe, and the reaction mixture was allowed to warm to room
temperature and was stirred overnight. The reaction was quenched by
mL), dried over MgSO , and concentrated by rotary evaporation to
4
1
give the product as a pale yellow oil (374 mg, 90%). Data for 23: H
NMR (400 MHz, CDCl ) δ 7.31 (d, J = 8.0 Hz, 2 H, HC(7)), 7.24 (t,
3
the addition of satd aq NH Cl solution (3 mL) with vigorous stirring.
4
J = 7.6 Hz, 2 H, HC(8)), 7.14 (t, J = 7.1 Hz, 1 H, HC(9)), 6.37 (d, J =
The biphasic layer was poured into a 25 mL separatory funnel
containing 10 mL of dichloromethane, and the organic layer was
washed with distilled water (1 × 10 mL), satd aq sodium bicarbonate
solution (1 × 10 mL), and brine (1 × 10 mL). The organic layer was
3
(
8
.6 Hz, 2 H, HC(4 and 5)), 3.41−3.24 (m, 8H, HC(1′)), 2.70−2.47
m, 2 H, HC(3)), 2.41−2.28 (m, 2 H, HC(2)), 1.61 (p, J = 7.6 Hz,
H, HC(2′)), 1.41 (h, J = 7.3 Hz, 8H, HC(3′)), 0.98 (t, J = 7.3 Hz, 12
13
1
H, HC(4′)); C{ H} NMR (126 MHz, CDCl ) δ 177.8 (C(1)),
3
dried over MgSO and concentrated by rotary evaporation to give the
4
1
38.5 (C(6)), 132.7 (C(5)), 128.7 (C(9)), 128.6 (C(8)), 126.4
crude product as colorless oil. The crude product was passed through a
short silica plug (1 cm) in a Pasteur pipet with a 1:1 mixture of
EtOAc/hexane (10 mL), and concentrated by rotary evaporation to
give the 25 (94:6 mixture of anti/syn diastereomers as determined by
(
C(4)), 125.9 (C(7)), 58.8 (C(1′)), 38.6 (C(3)), 30.9 (C(2)), 24.2
(
C(2′)), 19.9 (C(3′)), 13.8 (C(4′)); IR (neat) 2960 (m), 2874 (m),
1
717 (w), 1649 (w), 1579 (s), 1489 (m), 1462 (m), 1378 (s), 1275
(
(
m), 1151 (w), 1106 (w), 1069 (w), 1027 (w), 963 (m), 882 (m), 802
m), 742 (s), 694 (s), 491 (m); HR MS (EI , [M] ) m/z calcd for
1
+
−
H NMR spectroscopy) as a colorless oil (226 mg, 87%). Data for 25:
1
H NMR (500 MHz, CDCl ) δ 7.42 (s, 5 H, HC(2, 3, 4)), 5.61 (d, J =
C H O 175.0759, found 175.0752.
3
11
11
2
6
.1 Hz, 1 H, HC(5)), 4.20 (ddd, J = 9.7, 6.1, 2.8 Hz, 1 H, HC(6)),
2
.77 (s, 3 H, HC(13)), 2.03−1.86 (m, 1 H, HC(7)), 1.78−1.49 (m, 2
H, HC(7′, 8)), 1.45−1.16 (m, 7 H, HC(8′, 9, 10, 11)), 0.87 (t, J = 6.9
Hz, 3 H, HC(12)); 13C{ H} NMR (126 MHz, CDCl ) δ 135.5
1
3
(
C(1)), 129.6 (C(4)), 128.9 (C(2/3)), 127.6 (C(2/3)), 85.7 (C(5)),
Preparation of rel-(1R,2S)-2-Chloro-1-phenyloctan-1-ol. A
flame-dried, 100 mL Schlenk flask fitted with a magnetic stir bar and
rubber septum under argon was charged with 2-chlorooctanal (486
mg, 3.0 mmol) and dissolved in THF (60 mL). The reaction mixture
was then cooled in a dry ice/2-propanol bath (internal temperature
63.9 (C(6)), 39.3 (C(13)), 33.0 (C(7)), 31.7 (C(9/10/11)), 28.7
(C(9/10/11)), 26.1 (C(8)), 22.6 (C(9/10/11)), 14.2 (C(12)); IR
(neat) 2927 (m), 2857 (w), 1746 (s), 1455 (s), 1371 (w), 1227 (s),
1029 (w), 761 (w), 701 (m); TLC R 0.19 (hexane/EtOAc, 9:1) [UV];
LR MS (EI+, 70 eV) 318.1; HR MS (EI , [M] ) m/z calcd for
4
2
f
+
+
−73 °C), and 1.9 M phenyllithium in dibutyl ether (1.58 mL, 3.0
C H O ClS 318.1056, found 318.1048.
15
23
3
K
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(3) Maier, M. In Science of Synthesis; Carreira, E. M., Panek, J. S., Eds.;
Thieme: Stuttgart, 2010; Vol. 20; pp 1421−1551.
4) Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.; Jayaraman,
N. Tetrahedron 2004, 60, 5273−5308.
5) (a) Zheng, S.; Schienebeck, C. M.; Zhang, W.; Wang, H.-Y.;
(
(
Tang, W. Asian J. Org. Chem. 2014, 3, 366−376. (b) Tan, C. K.; Yu, W.
Z.; Yeung, Y.-Y. Chirality 2014, 26, 328−343. (c) Fujioka, H.; Murai,
K. Heterocycles 2013, 87, 763−805. (d) Mendoza, A.; Fananas, F. J.;
Rodriguez, F. Curr. Org. Synth. 2013, 10, 384−393. (e) Tan, C. K.;
Yeung, Y.-Y. Chem. Commun. 2013, 49, 7985−7996. (f) Denmark, S.
E.; Kuester, W. E.; Burk, M. T. Angew. Chem., Int. Ed. 2012, 51,
Preparation of rel-(1R,2S)-2-Chloro-1-phenyloctyl Acetate
(
anti-26). To a 1 dram glass vial equipped with a plastic screw cap and
a Teflon coated stir bar were added anti-2-chloro-1-phenyloctan-1-ol
12 mg, 0.05 mmol), pyridine (12 μL, 0.15 mmol, 3.0 equiv), and
dichloromethane (1 mL). The reaction mixture was stirred at room
temperature for 5 min, and acetic anhydride (9.5 μL, 0.10 mmol, 2.0
equiv) was added in one portion via syringe. After being stirred at
room temperature for 12 h, the reaction mixture was transferred to a
(
1
0938−10953. (g) Hennecke, U. Chem. - Asian J. 2012, 7, 456−465.
(
5
h) Castellanos, A.; Fletcher, S. P. Chem. - Eur. J. 2011, 17, 5766−
776. (i) Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Synlett 2011, 1335−1339.
2
5 mL separatory funnel and was diluted with dichloromethane 10
(
6) Suess, H. E.; Urey, H. C. Rev. Mod. Phys. 1956, 28, 53−74.
7) (a) Gribble, G. W. Environ. Chem. 2015, 12, 396−405.
mL. The organic layer was washed with 2 M HCl solution (2 × 10
(
mL), distilled water (1 × 10 mL), satd aq sodium bicarbonate solution
(b) Gribble, G. W. Progress in the Chemistry of Organic Natural
(
1 × 10 mL), and brine (1 × 10 mL). The organic layers were dried
Products 2009, 91, 1−613. (c) Gribble, G. W. Chemosphere 2003, 52,
over MgSO and concentrated by rotary evaporation to give the crude
4
2
89−297. (d) Gribble, G. W. Acc. Chem. Res. 1998, 31, 141−152.
product as colorless oil. The crude product was passed through a short
silica plug (1 cm) in a Pasteur pipet with hexane/EtOAc, 9:1 (10 mL)
and was concentrated by rotary evaporation to give anti-26 (94:6
(e) Gribble, G. W. Progress in the Chemistry of Organic Natural Products
1996, 68, 1−498.
1
mixture of anti/syn diastereomers as determined by H NMR
(8) (a) Olah, G. A.; Bollinger, J. M. J. Am. Chem. Soc. 1967, 89,
4744−4752. (b) Olah, G. A.; Bollinger, J. M. J. Am. Chem. Soc. 1968,
90, 947−953. (c) Olah, G. A.; Bollinger, J. M.; Brinich, J. J. Am. Chem.
Soc. 1968, 90, 2587−2594.
1
spectroscopy) as a colorless oil (8 mg, 56%). Data for anti-26: H
NMR (500 MHz, CDCl ) δ 7.43−7.31 (m, 5 H, HC(2, 3, 4)), 5.93 (d,
3
J = 5.4 Hz, 1 H, HC(5)), 4.18 (dq, J = 9.5, 3.1 Hz, 1 H, HC(6)), 2.14
(
s, 3 H, HC(14)), 1.87−1.71 (m, 1 H, HC(7)), 1.67−1.51 (m, 2 H,
(9) (a) Chung, W.-j.; Vanderwal, C. D. Angew. Chem., Int. Ed. 2016,
55, 4396−4434. (b) Chung, W.-j.; Vanderwal, C. D. Acc. Chem. Res.
2014, 47, 718−728. (c) Nilewski, C.; Carreira, E. M. Eur. J. Org. Chem.
HC(7′, 8)), 1.41−1.09 (m, 7 H, HC(8′, 9, 10, 11)), 0.87 (t, J = 6.9 Hz,
1
3
1
(
(
2
(
H, HC(12)); 13C{ H} NMR (126 MHz, CDCl ) δ 136.9 (C(1)),
3
28.6 (C(4)), 128.4 (C(2/3)), 127.6 (C(2/3)), 77.8 (C(5)), 64.36
C(6)), 33.2 (C(7)) 31.8 (C(9/10/11)), 28.8 (C(9/10/11)), 26.4
C(8)), 22.7 (C(9/10/11)), 21.2 (C(14)), 14.2 (C(12)); IR (neat)
2
(
1
(
012, 1685−1698.
10) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
560−1638.
11) Frost, B. Liebigs Ann. Chem. 1884, 226, 363−376.
(12) (a) Stobbe, H.; Strigel, A.; Meyer, C. Justus Liebigs Ann. Chem.
927 (m), 2857 (w), 1746 (s), 1455 (s), 1371 (w), 1227 (s), 1029
w), 761 (w), 701 (m); TLC R 0.48 (hexane/EtOAc, 9:1) [UV]; LR
f
+
+
+
MS (EI , 70 eV) 246.1; HR MS (EI , [M − HCl] ) m/z calcd for
C H O 246.1620, found 246.1621.
1
902, 321, 105−126. (b) Stobbe, H. Liebigs Ann. Chem. 1894, 282,
1
6
22
2
2
(
80−319.
13) Bartlett, P. A.; Myerson, J. J. Am. Chem. Soc. 1978, 100, 3950−
ASSOCIATED CONTENT
Supporting Information
3
(
952.
14) Kitagawa, O.; Hanano, T.; Tanabe, K.; Shiro, M.; Taguchi, T. J.
■
*
S
Chem. Soc., Chem. Commun. 1992, 1005−1007.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01455.
(
(
15) Haas, J.; Piguel, S.; Wirth, T. Org. Lett. 2002, 4, 297−300.
16) Cui, X. L.; Brown, R. S. J. Org. Chem. 2000, 65, 5653−5658.
Optimization studies, and H and 13C spectra of all
1
(17) Garnier, J. M.; Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2007,
007, 3281−3291.
2
described compounds (PDF)
(18) Mellegaard, S. R.; Tunge, J. A. J. Org. Chem. 2004, 69, 8979−
8
981.
(19) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am.
Chem. Soc. 2010, 132, 3298−3300.
20) Yousefi, R.; Whitehead, D. C.; Mueller, J. M.; Staples, R. J.;
Borhan, B. Org. Lett. 2011, 13, 608−611.
21) Zhang, W.; Liu, N.; Schienebeck, C. M.; Decloux, K.; Zheng, S.;
AUTHOR INFORMATION
■
Corresponding Author
Tel: (217) 333-0066. Fax: (217) 333-3984. E-mail:
(
*
sdenmark@illinois.edu.
(
Notes
Werness, J. B.; Tang, W. Chem. - Eur. J. 2012, 18, 7296−7305.
(22) Han, X.; Dong, C.; Zhou, H.-B. Adv. Synth. Catal. 2014, 356,
1275−1280.
The authors declare no competing financial interest.
ISHC member.
†
(23) Relative and absolute configurations of the products were not
assigned.
ACKNOWLEDGMENTS
■
0
(24) Yousefi, R.; Ashtekar, K. D.; Whitehead, D. C.; Jackson, J. E.;
We are grateful to the National Institutes of Health (GM R01-
85235) for generous financial support.
Borhan, B. J. Am. Chem. Soc. 2013, 135, 14524−14527.
(25) For an example of enantioselective bromolactonization of 1,2-
disubstituted alkenes, see: Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Org. Lett.
2011, 13, 2738−2741.
REFERENCES
■
(
26) Bromination: (a) Denmark, S. E.; Burk, M. T. Chirality 2014,
(
1) (a) Collins, I. J. Chem. Soc., Perkin Trans. 1 1998, 1869−1888.
b) Donnelly, D. M. X.; Meegan, M. J. Comprehensive Heterocyclic
2
6, 344−355. Selenylation: (b) Denmark, S. E.; Kalyani, D.; Collins,
(
W. R. J. Am. Chem. Soc. 2010, 132, 15752−15765. Sulfenylation:
(c) Denmark, S. E.; Kornfilt, D. J. P.; Vogler, T. J. Am. Chem. Soc.
2011, 133, 15308−15311. (d) Denmark, S. E.; Jaunet, A. J. Org. Chem.
2014, 79, 140−171. (e) Denmark, S. E.; Chi, H.-M. J. Am. Chem. Soc.
2014, 136, 8915−8918. (f) Denmark, S. E.; Rossi, S.; Webster, M. P.;
Wang, H. J. Am. Chem. Soc. 2014, 136, 13016−13028. (g) Denmark, S.
Chemistry; Katritzky, A. R., Ed.; Pergamon: New York, 1984; Vol. 4, pp
57−712. (c) Devon, T. K.; Scott, A. I. In Handbook of Naturally
Occurring Compounds; Academic Press: New York, 1975; Vol. 1, p 249.
d) Martin, S. F.; Guinn, D. E. Synthesis 1991, 245−262.
2) (a) Rashid, S.; Bhat, B. A.; Mehta, G. Org. Lett. 2015, 17, 3604−
607. (b) Cao, J.; Perlmutter, P. Org. Lett. 2013, 15, 4327−4329.
6
(
(
3
L
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
E.; Hartmann, E.; Kornfilt, D. J. P.; Wang, H. Nat. Chem. 2014, 6,
1
(
2
(
056−1064.
27) Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc.
010, 132, 1232−1233.
28) Maddox, S. M.; Nalbandian, C. J.; Smith, D. E.; Gustafson, J. L.
Org. Lett. 2015, 17, 1042−1045.
29) Samanta, R. C.; Yamamoto, H. Chem. - Eur. J. 2015, 21, 11976−
1979.
30) (a) Smith, J. R. L.; McKeer, L. C.; Taylor, J. M. J. Chem. Soc.,
(
1
(
Perkin Trans. 2 1987, 1533−1537. (b) Smith, J. R. L.; McKeer, L. C.;
Taylor, J. M. J. Chem. Soc., Perkin Trans. 2 1988, 385−391. (c) Smith,
J. R. L.; McKeer, L. C.; Taylor, J. M. J. Chem. Soc., Perkin Trans. 2
1
989, 1529−1536.
31) Gao, X.; Singh, R. P.; Corey, E. J. Org. Lett. 2010, 12, 1812−
814.
32) Corey, E. J.; Yuen, P.-W. Tetrahedron Lett. 1989, 30, 5825−
828.
33) For a thorough treatment of the stereochemistry and
mechanism of Ad reactions, see: (a) Kocovskí, P. Addition Reactions:
(
1
(
5
(
̌
E
Polar Addition. In Organic Reaction Mechanisms; Knipe, A. C., Ed.;
Wiley: Chichester, 2007. (b) De la Mare, P. B. D.; Bolton, R.
Electrophilic Additions to Unsaturated Systems, 2nd ed.; Elsevier: New
York, 1982; pp 136−197. (c) Vʼyunov, K. A.; Ginak, A. I. Russ. Chem.
Rev. 1981, 50, 151−163. (d) Schmid, G. H.; Garratt, D. G In The
Chemistry of Doubly Bonded Functional Groups; Patai, S., Ed.; Wiley-
Interscience: New York, 1977; Supplement A, Part 2, Chapter 9.
(
e) Freeman, F. Chem. Rev. 1975, 75, 439−490. (f) Fahey, R. C. In
Topics in Stereochemistry; Eliel, E. L., Allinger, N. L., Eds.; Wiley: New
York, 1968; Vol. 3, pp 237−342.
(
34) (a) Staninets, V. I.; Shilov, E. A. Ukrain. Khim. Zh. 1968, 34,
3
72. (b) Staninets, V. I.; Shilov, E. A. Russ. Chem. Rev. 1971, 40, 272−
283.
(
35) (a) Isaacs, N. S. Physical Organic Chemistry; Longman Scientific
&
Technical: London, 1987; Chapter 12. (b) Lowry, T. H.;
Richardson, K. S. Mechanism and Theory in Organic Chemistry, 2nd
ed.; Harper and Row: New York, 1981; pp 506−526.
(
36) During the course of our studies, we became aware of a
comprehensive investigation of the role of carboxylate ions in the
activation of chlorolactonization reactions by Borhan, Jackson, and co-
workers. We are grateful to Prof. Borhan for sharing the results of
those studies. Ashtekar, A. D.; Vetticatt, M.; Yousefi, R.; Jackson, J. E.;
Borhan, B. J. Am. Chem. Soc. 2016, 138, 8114−8119.
(
37) The chemical shifts for acetic acid and acetyl hypochlorite (in
CCl ) are 2.10 and 2.24 ppm, respectively. Evans, J. C.; Lo, G. Y-S.;
4
Chang, Y.-L. Spectrochim. Acta 1965, 21, 973−979.
(
38) (a) Metrangolo, P., Resnati, G., Eds. Halogen Bonding I. In
Topics in Current Chemistry; Springer: Heidelberg, 2015; Vol. 358. (b)
Metrangolo, P.; Resnati, G., Eds. Halogen Bonding. In Topics in
Current Chemistry; Springer: Heidelberg, 2008; Vol. 126.
(
39) Weinhold, F.; Landis, C. Valency and Bonding: A Natural Bond
Orbital Donor−Acceptor Perspective; Cambridge University Press:
Cambridge, 2005; pp 275−306.
(
(
40) Wolfe, S. Acc. Chem. Res. 1972, 5, 102−111.
41) Because HFIP possesses extremely high ionizing power and low
nucleophilicity, it primarily functions by stabilizing the leaving group
(
mesylate). The attenuation of solvolysis in the presence of a large
excess of tetrabutylammonium acetate might arise from a buffering
effect on the hydrogen bonding ability of the solvent. Schadt, F. L.;
Schleyer, P. v. R.; Bentley, T. W. Tetrahedron Lett. 1974, 15, 2335−
2338.
(
42) Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2009, 48, 5121−5124.
M
DOI: 10.1021/acs.joc.6b01455
J. Org. Chem. XXXX, XXX, XXX−XXX