Development and mechanism of an enantioselective bromocycloetherification reaction via Lewis base/chiral Bronsted acid cooperative catalysis

Article abstract of DOI:10.1002/chir.22259

The development of a binary catalyst system for bromocycloetherification, consisting of an achiral Lewis base and a chiral Bronsted acid, is described in detail. The results of preliminary kinetic studies are also presented. Chirality 26:343-354, 2013.

Full text of DOI:10.1002/chir.22259

CHIRALITY 26:344–355 (2014)
Development and Mechanism of an Enantioselective
Bromocycloetherification Reaction via Lewis Base/
Chiral Brønsted Acid Cooperative Catalysis
1
2
*
SCOTT E. DENMARK, AND MATTHEW T. BURK
1Department of Chemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA
2Department of Chemistry, Yale University, New Haven, CT, USA
ABSTRACT
The development of a binary catalyst system for bromocycloetherification,
consisting of an achiral Lewis base and a chiral Brønsted acid, is described in detail. The results of
preliminary kinetic studies are also presented. Chirality 26:344–355, 2014. © 2013 Wiley Periodicals, Inc.
KEY WORDS: enantioselective; halofunctionalization; Lewis base; cooperative catalysis
INTRODUCTION AND BACKGROUND
greatly accelerated by the addition of a stoichiometric
Bromocycloetherification of olefins1–4 is an interesting and
useful synthetic transformation, with proven application to the
synthesis of biologically relevant molecules.5–13 The bromo
ether products can be valuable synthetic intermediates,11 or
natural product targets themselves.9,10,12,13 Surprisingly,
methods for the enantioselective synthesis of bromo ethers
have only recently been reported.14–16 The development of
such methods presents a particular challenge, due in part to
the propensity of the intermediate bromiranium ions to
racemize by transfer between alkenes at rates competitive with
nucleophilic capture.17,18 Previous efforts in this laboratory19
dealt with one potential strategy to overcome the racemization
of haliranium ion intermediate. Specifically, these studies
revealed a dramatic dependence of constitutional site selectiv-
ity (γ vs. δ-lactone) on the structure of the Lewis base in
bromolactonization reactions. This behavior implied the
continued association of the intermediate haliranium ion with
the Lewis base catalyst. Thus, if the catalyst were chiral, this
association would provide a mechanism for enantioselection
via equilibrating diastereomeric bromiranium ions. As will be
detailed below preliminary attempts to develop an enantioselective
bromolactonization reaction were not promising. In view of
successful, asymmetric bromolactonizations reported contempo-
raneously from other laboratories,20–24 our attention shifted to
the bromoetherification reactions. However, because the
previous studies failed to provide evidence for association
of the Lewis base in bromoetherifications, a different
approach was sought, namely the ion pairing of the
bromiranium ion with a chiral counterion.21,22 Ion pairing of
this type should in principle provide the same opportunity
for stereocontrol that an associated chiral Lewis base does,
except with the added advantage that the association of the
haliranium ion with its counterion is guaranteed in nonpolar
media by the principle of electroneutrality25 and the force of
Coulombic attraction.26 Consequently, a chiral counterion
should have the opportunity to influence the stereochemical
course of every step of the reaction, regardless of any known
or unknown racemization pathways. Such a chiral ion pair
should arise as a natural consequence of catalysis by a
sufficiently strong, chiral Brønsted acid or the combination of a
chiral Brønsted acid and a Lewis base because the acid should
protonate and replace the succinimide counterion (Scheme 1).
Related studies in these laboratories had demonstrated that Lewis
base catalyzed seleno,27 thio28 and bromocycloetherification19 are
amount of an achiral Brønsted acid. The pKa and gen-
eral applicability of chiral phosphoric acids made them
attractive candidates for the development of an
enantioselective bromocycloetherification process using
a catalytic amount of a chiral Brønsted acid, potentially
in conjunction with a Lewis base co-catalyst.29–34 This
line of research led to the development of an enantioselective
bromocycloetherification reaction of 5-arylpentenols (1a, 1d-m)
cooperatively catalyzed by the combination of the versatile chi-
ral phosphoric acid TRIP35,36 (2a) and the achiral Lewis base
Ph3P=S, producing chiral tetrahydrofurans (3a, 3d-m) and
tetrahydropyrans (4a, 4d-m) (Fig. 1).15,19 The development
of this bromocycloetherification will be discussed here in
full detail.
Furthermore, our attempts to develop an enantioselective
bromolactonization of 5-aryl-4-pentenoic acids (5a-b), catalyzed
by chiral Lewis basic sulfides (6a-f), and producing regrettably
racemic bromolactones (7a, 8a-b), will be discussed in
abbreviated detail.
Following the development of the chiral Brønsted acid/
achiral Lewis base cooperatively catalyzed enantioselective
bromocycloetherification reaction, the novelty of the
proposed mechanism made further investigation impera-
tive. Additionally, the early results obtained in the ab-
sence of Ph3P=S, the reactivity of unconjugated olefins
in the absence of Ph3P=S and the independent results
from the Shi laboratory16 raised questions about the
true role of Ph3P=S in this system. Therefore, after
having demonstrated the scope of the cooperatively
catalyzed bromocycloetherification reaction it was
deemed necessary to explore the mechanism of the
reaction. The determination of the kinetic equation
for the reaction was judged to be an appropriate means
of doing so.
Contract grant sponsor: National Institutes of Health; Contract grant number:
GM R01-85235.
*Correspondence to: Scott E. Denmark, Department of Chemistry, University
of Illinois, Urbana-Champaign, 245 Roger Adams Laboratory, 600 S. Mathews
Avenue, Urbana, IL 61801, USA. E-mail: sdenmark@illinois.edu
Received for publication 31 July 2013; Accepted 13 September 2013
DOI: 10.1002/chir.22259
Published online 7 November 2013 in Wiley Online Library
(wileyonlinelibrary.com).
© 2013 Wiley Periodicals, Inc.

ENANTIOSELECTIVE BROMOCYCLOETHERIFICATION
345
N-bromosuccinimide
LB: (Lewis base)
HY* (chiral Brønsted acid)
3Å molecular sieves. N-Bromosuccinimide (NBS) was recrystallized twice
from hot water,37 dried under vacuum at room temperature, stored at
ꢀ20 °C, and protected from light. Phosphoric acid 2a used in preparative
experiments was prepared according to the procedure of Gong,38 and was
recrystallized from MeCN according to the procedure of List35 whereas
2a used for kinetic experiments was prepared by the procedure of List.35
Other chiral acids were prepared by literature procedures (2b-l)36,39–45
and were acid-washed according to the procedure of Ishihara,46 or
prepared without chromatography. The preparations of 1a-m, 3a-m,
and 4a-m (Table 4) were previously reported.15 Procedures for the
preparation of 6e-f and 2h are given in the Supporting Information.
Kinetic data was acquired by 19F NMR using a Varian Unity Inova 600
NB spectrometer in a mixture of toluene and toluene-d8. Spectra were
manually phased, zero filled, Gaussian apodized, baseline corrected and
integrated in MestReNova 7. Integral regions covered 42 Hz on either
side of the peak centers. Concentrations were computed by integration
relative to a fluorobenzene internal standard using an initial time point
Br
R
OH
R
O
Y*
HY*
H
O
LB+ Br + Y*–
R
LB Br N
Br+
OH
succinimide
Y*–
LB: +
LB:
Br Y*
O
Scheme 1. Hypothesized mechanism of Lewis base/Chiral Brønsted acid
cooperative catalysis.
MATERIALS AND METHODS
General Experimental
All undeuterated reaction solvents were dried by percolation through
neutral alumina in a solvent dispensing system. Toluene-d8 was dried over
R
OH
1a-m
Aryl
iPr
iPr
O
O
O
P
iPr
Aryl=
OH
Aryl
2a
Br
O
2
2
6
R
R
O
O
Br
4a-m
3a-m
Ph
OH
5a
O
Br
2
O
2
6
R
O
R
O
Br
8a
7a
O
O
OH
Ph
Ph
O
Br
5b
Fig. 1. Compound numbering scheme.
8b
Chirality DOI 10.1002/chir

346
DENMARK AND BURK
prior to catalyst addition to correct for the effects of incomplete relaxation
and the volatility of the internal standard.
added, and the resulting biphasic mixture was transferred to a 60-
mL separatory funnel where it was extracted with CH2Cl2 (2 × 2 mL).
The combined organic extracts were washed with NaHCO3
(2 × 2 mL), dried over MgSO4, filtered and concentrated in vacuo
(23 °C, 10 mmHg). The residue was purified by column chromatogra-
phy (silica gel (1 g), Pasteur pipet, hexane/EtOAc, 4:1), to provide
26 mg (99%) of 8b. The spectroscopic data were in accordance with
those described in the literature.21
Preparative Procedures
Bromolactonization of 5a in the presence of 6a. Preparation of
rel-(5R,6S)-5-bromotetrahydro-6-phenyl-2H-pyran-2-one (7a)19
(Table 1, Entry 1). A 5-mL, flame-dried Schlenk flask, fitted with a
septum and a magnetic stir bar, was charged with N-bromosuccinimide
(21mg, 0.12 mmol, 1.2 equiv). The flask was wrapped in Al-foil and then
was evacuated and filled with argon. Dichloromethane (0.3 mL) was added
via syringe. A solution of 5a (17.6 mg in 0.4 mL, 0.1mmol, 1.0 equiv) was
added via a short cannula. A solution of 6a in CH2Cl2 (0.9mg in 50μL,
0.1M, 0.05 equiv, 0.005 mmol) was added rapidly via syringe, and the
resulting solution was stirred for at room temperature for 5 min. Aq.
Na2S2O3 solution (1 mL) was added, and the resulting biphasic mixture
was transferred to a 60-mL separatory funnel where it was diluted
with sat. aq. NaHCO3 solution (5 mL) and was extracted with EtOAc
(5 mL, 2 x 2.5 mL). The combined organic extracts were dried over
Na2SO4, decanted and concentrated in vacuo (23 °C, 10 mmHg). A
7.3:1 mixture of 7a and 8a was observed by 1H NMR spectroscopy.
The residue was purified by column chromatography (silica gel (1 g),
Pasteur pipet., CH2Cl2), to provide 19.9 mg (78%) of a mixture of 7a
and 8a.
Data for 8b: SFC: (S)/(R)-8b, tR 4.38 min (49.9%); (S)/(R)-8b, tR
4.90 min (50.1%); (Chiralpak AD, 125 bar, 3 mL/min, 5% MeOH in CO2).
Optimization of the bromocycloetherification of 1b in the absence of
Ph3=S. bromocycloetherification of 1b in the presence of 2a
(Table 6, Entry 1). A 10-mL, oven-dried Schlenk flask, fitted with a
septum and a magnetic stir bar, wrapped in Al-foil, under Ar, was charged
with N-bromosuccinimide (22 mg, 0.12 mmol, 1.2 equiv). The flask was then
evacuated and filled with argon. Toluene (3.2 mL) was added via syringe
and then the flask was cooled to 0 °C (thermostated H2O/ethylene glycol
bath). A solution of 1b (16.0 mg, 0.1 mmol, 1.0 equiv) in toluene (0.6mL)
was added via short cannula. A solution of 2a (7.5 mg, 0.01 mmol, 0.1 equiv)
in toluene (0.2 mL) was added via syringe. The reaction mixture was stirred
at 0 °C for 39h. Chilled (ca. 0 °C) aq. Na2S2O3 solution (1 mL) was added,
followed by chilled sat. aq. NaHCO3 solution (1mL). The resulting biphasic
mixture was stirred at 0 °C for 10min, after which it was allowed to warm to
room temperature while stirring vigorously. The colorless biphasic mixture
was transferred to a 60-mL separatory funnel where it was diluted with
H2O (5 mL) and was extracted with Et2O (3 × 5 mL). The combined
organic extracts were dried over MgSO4, filtered, and concentrated in vacuo
(23 °C, 6 mmHg). The residue was purified by column chromatography
(silica gel (4.5 g), 1 cm diam., 10cm length, hexane/EtOAc, 19:1) to provide
23.9 mg (89%) of 3b. Spectral data matched those previously reported.19
SFC: (2S,6R)-3b, tR 6.7 min (15.5%); (2R,6S)-3b, tR 7.8 min (84.5%)
(Chiralcel OD, 200 bar, 1.5mL/min, 2% MeOH in CO2)
Data for 7a/8a: SFC: (5R,6S)/(5S,6R)-7a, tR 5.0 min (38.1%);
(5S,6R)/(5R,6S)-7a, tR 5.5 min (38.7%); (5R,6S)/(5S,6R)-8a, tR 6.3 min
(11.7%); (5S,6R)/(5R,6S)-8a, tR 7.2min (11.4%) (Chiralpak OJ, 125 bar,
3 mL/min, 5% MeOH in CO2).
Bromolactonization of 5b in the presence of 6e. Preparation of
5-(bromomethyl)dihydro-5-phenyl-2(3H)-furanone (8b) (Table 2,
Entry 1)21
and
.
A 5-mL, flame-dried Schlenk flask, fitted with a septum
a
magnetic stir bar, was charged with N-bromosuccinimide
(21 mg, 0.12 mmol, 1.2 equiv). The flask was wrapped in Al-foil and
then was evacuated and filled with argon. Dichloromethane (3 mL)
was added via syringe. A solution of 5b (17.7 mg, 0.1 mmol, 1.0
equiv) and 6e (2.5 mg, 0.05 equiv, 0.005 mmol) in CH2Cl2 (1.0 mL)
was added via a short cannula, and the resulting solution was stirred
for at room temperature for 5 min. Aq. Na2S2O3 solution (2 mL) was
General Procedure for Kinetic Studies
Determination of the partial order in 1l for bromocyclization of 1l by
19F NMR. (0.025 M, replicate 1). An oven-dried, 5-mm NMR tube,
fitted with a septum and wrapped in Al foil was charged with NBS
TABLE 1. Attempted Enantioselective Bromolactonization of 5a
O
Br
H
NBS (1.2 equiv)
catalyst (0.05 equiv)
O
O
Ph
+
Ph
OH
23 oC, CH2Cl2
O
Ph
O
Br
5a
7a
8a
Me Me
H
H
Me
N
P
N
Me
Me
N
P
S
Se
N
P
P
N
Me
Me
N
S
S
N
N
Me
S
6a
6b
6c
6d
entry
catalyst
7a:8a
er (7a)b
er (8a)b
yield, %a
1
2
3
4
6a
6b
6c
6d
7.3:1
20:1
4.9:1
7.5:1
50:50
50:50
50:50
51:49
51:49
53:47
50:50
53:47
78
73
82
66
aDetermined by CSP-HPLC analysis.
bYield of chromatographically homogenous material.
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE BROMOCYCLOETHERIFICATION
347
TABLE 2. Attempted Enantioselective Bromolactonization of 5b
S
O
Ph
Ph
6e R=
6f R=
P
NBS (1.2 equiv)
O
OH
N
Ph
S
P
Ph
O
N(Me)2
N(Me)2
O
Br
R
N
5b
8b
entry
catalyst
mol %
solvent
CH2Cl2
toluene/CHCl3 2:1
CH2Cl2
T, °C
era
yield, %b
1
2
3
4
6e
6e
6f
5
10
5
23
ꢀ75
23
ꢀ75
50:50
50:50
51:49
54:46
98
4
88
91
6f
10
toluene/CHCl3 2:1
aDetermined by CSP-HPLC analysis.
bYield of chromatographically homogenous material.
(3.72 mg, 0.021 mmol). The septum was removed and tube was then
brought in to an Ar filled glove box, where the septum was replaced.
The tube removed from the glove box and was charged with toluene-
d8 (0.1 mL), a stock solution of 1l and fluorobenzene in dry toluene
(1:1 molar ratio, 216.6 M, 81 μL, 0.017 mmol) and toluene (494 μL).
The tube was agitated in a vortex mixer until homogenous by visual
inspection. The tube was inserted into the NMR spectrometer and
shimmed. An initial time point was acquired (64 scans, at=1,
pw=8.25, d1=2.77). The tube was ejected from the spectrometer. A
stock solution of Ph3P=S and 2a (8.76 mM, 25 μL, 0.000219 mmol)
was added. The tube was rapidly inverted three times and was
reinserted into the spectrometer. An arrayed acquisition was begun
(nt=8, d1=2.77, at=1, pad=array of zeroes).
Chiral Phosphoric Acid Catalysis
On the basis of the broad applicability of 2a, the potential of
2b to act as a Lewis base, and general knowledge of the chiral
Brønsted acid catalysis literature, catalysts 2a-c seemed to
provide the best chances for inducing enantioselectivity.
Gratifyingly, 2a-c (Table 3, entries 1–3) catalyzed the
enantioselective bromocycloetherification of 1a to provide
the exo cyclization product 3a with moderate to high
enantioselectivity and the endo cyclization product 4a with
low enantioselectivity. With achiral Lewis bases, 3a is a
minor product in the cyclization of 1a.19 It is therefore fortu-
nate that 2a-b substantially increase the proportion of 3a
formed, albeit to only ca. 1:1 mixtures. Contrary to what had
been hypothesized based on its potential to provide
an internal Lewis base to assist in activation of the NBS, 2a
(entry 1) catalyzed the cyclization in higher yield and selectiv-
ity than the thio analog 2b (entry 2). Triflimide 2c (entry 3)
catalyzed the cyclization in higher conversion, however the
site and enantioselectivity was again lower and the absolute
sense of enantioselectivity was inverted (entry 3). Lower
enantio- and site selectivities were also observed when the re-
action was run at higher concentrations (entries 4–5) or when
the cyclizations were run in CHCl3 (entry 6), PhCF3 (entry 7),
Et2O (entry 8), hexane (entry 9), or MeCN (entry 10). From
this initial survey, it appeared that a Lewis base was not
required for this transformation.
RESULTS
Initial Efforts with Chiral Lewis Bases
In view of the foregoing studies from these laboratories on
halocyclization,19 the initial efforts toward the development of
enantioselective bromocyclization reactions were focused on
the use of chiral Lewis bases. In particular, these efforts were
directed toward bromolactonization, as our previous work dem-
onstrated the involvement of achiral sulfur-containing Lewis ba-
ses in the cyclization step of bromolactonization, implying that
these classes of compound were suitable for the development
of enantioselective catalysts. Thioureas, phosphine sulfides,
thiophosphoramides, and selenophosphoramides showed a
promising ability to effect the ratio of endo to exo cyclization in
the bromolactonization of 5a. Accordingly, the sulfide catalysts
6a-d were tested under the conditions established in the
previous study (Table 1).19 Although catalysts 6a and 6c-d
were able to alter the ratio of 7a to 8a, no enantioselectivity
was observed. Catalysts 6c-d were previously optimized for
analogous thio-28 and seleno-27 cycloetherifications, so their
failure in this transformation was particularly disappointing.
Inspired by the pioneering work of Yeung on
bromolactonization,21,22,47 catalysts 6e-f were prepared and
tested in a series of bromolactonization reactions (Table 2).
No significant enantioselectivity was observed in any case.
The absence of enantioselectivity observed with these cata-
lysts suggested that a different approach would be required,
although the recent development of a bromoaminocyclization
catalyzed by a monofunctional chiral selenide48 shows that
the general approach may be viable, albeit quite difficult
to implement
Chiral Brønsted Acid/Achiral Lewis Base
Cooperative Catalysis
Unfortunately, a serious problem was encountered while
attempting to extend the results described above. Subse-
quent batches of 2a catalyzed the cyclization of 1a in substan-
tially lower conversion and site selectivity and slightly lower
enantioselectivity. The cause of this discrepancy was not
firmly established because unfortunately the original batch
had been expended before the problem was noticed. Multiple
batches of 2a prepared from different batches of the diol
precursor exhibited similar behavior, so the new, inferior
result appeared to be the reproducible one. It was hypothe-
sized that the original material contained some co-catalytic
impurity, possibly some sort of Lewis base. It was found that
the addition of catalytic amounts of Ph3P=S restored catalyst
Chirality DOI 10.1002/chir

348
DENMARK AND BURK
TABLE 3. Optimization of Chiral Phosphoric Acid Catalyzed Bromocycloetherification
NBS (1.2 equiv)
Chiral acid (0.1 equiv)
Br
O
2
2
Ph
OH
6
+
Ph
Ph
0 oC
O
Br
1a
3a
4a
Aryl
i-Pr
2a X=O Y=OH
2b X=S Y=OH
2c X=O Y=NHSO2CF3
O
X
Aryl =
P
Y
O
i-Pr
i-Pr
Aryl
entry
catalyst
solvent
conc., M
time, h
4a:3aa
er (4a)b
er (3a)b
yield, %c
1
2
3
4
5
6
7
8
9
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
toluene
toluene
toluene
toluene
toluene
CHCl3
PhCF3
hexane
Et2O
0.025
0.025
0.025
0.05
24
24
13
24
24
24
24
24
25
1
48:52
56:44
87:13
61:39
72:28
89:11
73:27
80:20
98:2
62:38
59:41
48:52
58:42
55:45
51:49
52:48
51:49
50:50
50:50
95:5
94:6
28:72
92:8
88:12
86:14
74:26
81:19
51:49
51:49
64
40
78
39
48
59
82
37
57
75
0.1
0.025
0.025
0.025
0.025
0.025
10
MeCN
98:2
aDetermined by integration of 1H NMR signals for HC(6).
bDetermined by CSP-SFC analysis.
cYield of chromatographically homogenous material.
activity and site selectivity (Table 4). The optimal conditions
(entry 1) gave higher conversion than the original conditions
in shorter reaction times using only half as much 2a.
of a substrate with a strongly electron donating substituent
(4-CH3O) on the phenyl ring resulted in a 5-exo product that
was too unstable to isolate or characterize (data not shown).
The cyclization of substrates containing (Z)-configured olefins
occurred with uniformly high exo selectivity (entries 4–10).
These cyclizations proceeded with only slightly lower
enantioselectivity than those of (E)-configured olefins (entries
1 and 4, 2 and 8), and minimal differences were seen among
substrates with varied steric demands (entries 5–8). Lower
enantio-selectivity was again observed in the cyclizations of
electron-poor substrates (entries 9–10).
The enantioselectivities observed in the cyclization
of unconjugated olefins 1b-c were significantly lower
(Table 6, entry 1). This outcome is partially due to the higher
intrinsic reactivity of 1b-c, which leads to a substantial rate of
cyclization in the absence of acid. When Ph3P=S was omitted,
enantioselectivity improved (entries 2–3), although not to the
level observed with conjugated olefins. This modification
came at the cost of greatly extended reaction times and, in
the case of 1c, low conversion. Several additional catalysts
were prepared and tested in the cyclization of 1b-c. Cycliza-
tion of 1c proceeded in modestly higher enantioselectivity
when catalyzed by 2g than when catalyzed by 2a (entry 5),
however no difference was observed in the cyclization of
1b (entry 4).
Several additional catalysts were prepared, and the effects
of solvent, concentration and catalyst were evaluated under
the new conditions (Table 4). In all cases, furan 3a was
formed with higher enantioselectivity than pyran 4a.
Phosphoric acid 2a continued to be the optimal catalyst
(entry 1). Substantially lower enantio- and site selectivities
were observed when catalysts with alternative acidic groups
(entries 2–3), alternative 3,3-aryl groups (entries 4–5) and
an alternative chiral scaffold (entry 6) were used. Curiously,
the absolute sense of enantioselectivity induced by 2c was
inverted compared to the previous result (entry 3 vs. Table 3
entry 3), making it the same as that observed with 2a-b and
2d-f. Increasing the reaction concentration (entry 7) or using
solvents other than toluene (entries 8–9) gave inferior
enantioselectivity.
A series of substrates, exhibiting variations in olefin config-
uration as well as sterically and electronically diverse aryl
groups, were prepared and subjected to the cyclization
conditions in order to obtain a better understanding of the
selectivity of this cyclization and explore its potential utility
(Table 5). Altering the electronic properties of the aryl group
strongly affected the selectivity of the cyclization, particularly
among (E)-configured substrates. Inclusion of a moderately
electron donating group (CH3) in the 4-position of the phenyl
ring unsurprisingly reduced the proportion of 5-exo cycliza-
tion (entry 2), although enantioselectivity increased. Con-
versely, the introduction of an electron-withdrawing group
(CF3) increased the proportion of exo cyclized product
3f but with lower enantioselectivity (entry 3). Cyclization
Single crystal, X-ray diffraction analysis of 3h established the
absolute configuration of the (Z)-olefin derived products. The
absolute configurations of (E) and (Z)-olefin derived products
were correlated by reductive dehalogenation of 3a and 3g.
The 2-benzyltetrahydrofuran samples produced were judged
to be of identical configuration by optical rotation ([α]2D4 -1.9
and ꢀ5.5) and CSP-SFC analysis (tR 3.707 and 3.714 min)
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE BROMOCYCLOETHERIFICATION
349
TABLE 4. Optimization of Chiral Bronsted Acid/Achiral Lewis Base Cooperatively Catalyzed Bromocycloetherification
NBS (1.2 equiv)
Chiral acid (0.05 equiv)
Br
O
2
2
Ph
OH
6
+
Ph
Ph
Ph3P=S (0.05 equiv)
0 oC
O
Br
1a
3a
4a
i-Pr
2a X=O Y=OH
2b X=S Y=OH
Aryl =
2c X=O Y=NHSO2CF3
i-Pr
i-Pr
Aryl
O
O
Aryl =
Aryl =
2d X=O Y=OH
X
P
2-Naphthyl
Y
O
O
Ph
Ph
P
i-Pr
Aryl
OH
O
2e X=O Y=OH
9-Anthryl
i-Pr
2f
entry
cat.
solvent
conc., M
t, h
3a:4a
er (3a)
er (4a)
yield, %b
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2a
2a
2a
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Et2O
0.025
0.025
0.025
0.025
0.025
0.025
0.1
9
12
12
12
35
12
12
12
12
48:52
13:87
12:88
15:85
26:74
19:81
39:61
17:83
3:97
93:7
57:43
50:50
49:51
50:50
49:51
48:52
54:46
50:50
51:49
83
65
85
95
31
86
84
87
90
72:28
75:25
63:37
77:23
68:31
90:10
88:12
56:44
0.025
0.025
CHCl3
aDetermined by 1H NMR integration of signals for HC(6) of 3a against HC(2) of 4a.
bYield after chromatography, all reactions run on 0.1 mmol substrate.
(Scheme 2). The configurations of 4a–m were assigned on the
soluble component (acid 2a, Ph3P=S, and olefin 1l) five
concentrations per component were chosen such that the
data points spanned an order of magnitude, were evenly
spaced on a logarithmic scale, and were centered around
the baseline conditions (25 mM 1l, 30 mM NBS, 0.31mM
Ph3P=S, 0.31 mM 2a). Because of the limited solubility of
NBS in toluene, five concentrations were chosen such that
they were evenly spaced on a logarithmic scale and spanned
an order of magnitude from the baseline concentration
(30 mM NBS) to 1/10th of the baseline concentration
(3 mM NBS). Triplicate experiments were run for each
concentration. Additional replicates were run as needed.
On the basis of the collected data (Fig. 2), the rate equation
for the reaction was:
basis of this information.
Kinetic Studies
The kinetic behavior of the cooperatively-catalyzed
bromocycloetherification reaction was studied using the
method of initial rates. In situ monitoring of the
bromocycloetherification of 1l using 19F NMR spectroscopic
analysis was chosen because this method provides good
sensitivity, and a high sampling rate (Fig. 1). This method
is also applicable to a substrate (1l) that was known to react
productively and selectively. The solubility of NBS in toluene
required that the reactions be carried out at 23 °C* and the
concentrations of Ph3P=S and 2a were reduced by a factor
of 4 to 0.31 mM (1.25 mol% at 25 mM 1l) to allow a sufficient
number of data points to be collected. Otherwise the
conditions developed for the preparative reaction were used.
To determine the partial order of the reaction in each readily
1:07
0:82
1:47
1:02
R ¼ kobs½NBSꢁ ½1lꢁ ½Ph3PSꢁ
where kobs ¼ k½2aꢁ
The two well-behaved components, NBS and 2a, displayed
clean first order behavior with respect to the concentrations
of (1.07
0.08 and 1.021
0.005 respectively). However,
*
TetramethylNBS was explored as an alternative, more soluble reagent,
fractional partial orders were obtained for Ph3PS and 1l. Such
fractional orders in the kinetic data greatly complicate
analysis of the reaction mechanism. The observed order of
0.82 in substrate could arise from a systematic error, partial
Chirality DOI 10.1002/chir
however the reaction rate was much lower and there was an induction pe-
riod of ca. 8.5 min. The use of this reagent was judged to be a substantial
alteration that was likely to affect the outcome of the study and was there-
fore not pursued further.

350
DENMARK AND BURK
TABLE 5. Scope of Bromocycloetherification
NBS (1.2 equiv)
Br
O
2
2a (0.05 equiv)
2
R
OH
+
6
3
R
Ph3P=S (0.05 equiv)
PhMe, 0 oC 12-14 h
R
O
Br
1a, 1e-m
3a, 3e-m
4a, 4e-m
entry
R
products
3:4b
er (3)c
yield (3), %d
er (4)
yield (4), %
1
2
3
4
5
6
7
8
9
10
(E)-C6H5
3a, 4a
3e, 4e
3f, 4f
3g
3h, 4h
3i, 4i
3j
3k, 4k
3l, 4l
3m, 4m
45:55
37:63
86:14
>95:5
95:5
93:7
97:3
85:15
91:9
92:8
94:6
92:8
94:6
90:10
84:16
77f
28
43
77
58:42
65:35
65:35
n/d
n/d
89:11
n/d
65:35
60:40
n/d
(E)-4-CH3C6H4
(E)-4-CF3C6H4
(Z)-C6H5
(Z)-2-naphthyl
(Z)-2-CH3C6H4
(Z)-3-CH3C6H4
(Z)-4-CH3C6H4
(Z)-4-FC6H4
67
12e
73
94:6
86f
86
>95:5
90:10
95:5
64
9
78f
77f,g
(Z)-4-CF3OC6H4
98:2
aAll reactions run at 0.025 M on 1.0 mmol substrate.
bDetermined by 1H NMR integration of signals for HC(6) of 3 against HC(2) of 4.
cDetermined by CSP-SFC analysis.
dYields of analytically pure material.
eRun at 23 °C for full conversion, selectivity at 0 °C was unchanged.
fYield of both isomers.
gYield of chromatographically homogenous material.
(ca. 40% at 25 mM 1l) contribution of a mechanism with an
order of ½ or the beginning of a slow transition to a saturation
kinetic regime. Attempts to determine whether saturation
could be reached were stymied by the onset of radical E/Z
isomerization at high olefin concentration.†
acquired time point. Acquiring data with higher time resolution
may allow mechanistic information to be extracted from this
phase of the reaction, however this will require an entirely
different method of reaction monitoring.
Under the conditions of this study, all reactions stalled at low
conversion (typically ca. 30%) due to catalyst deactivation. As
discussed above, at low Ph3P=S concentration the reactions
stalled before reaching 10% conversion. It is therefore likely
that Ph3P=S is the component of the catalyst system that is
deactivated. The severity of catalyst deactivation is unfortunate
because it makes numerical modeling of the reaction time
course to resolve the origin of the observed fractional orders
quite difficult.
The origin of the fractional order (1.47) in Ph3P=S is
unclear however it may be due to experimental difficulties.‡
At the lowest concentration of Ph3P=S, 0.0988 mM, the
reactions stalled before reaching 10% conversion, making it
impossible to process the data in a manner consistent with
the rest of the study. To construct the plot in Figure 2, the
initial rate for that point was calculated from the first 5% con-
version. The time/concentration plots for the low [Ph3P=S]
still show some curvature that is not present in the other data
series which should increase the apparent order. At the highest
concentration of Ph3P=S examined (0.988 mM) only two data
points could be acquired below 10% conversion because of the
high reaction rate.
Several noteworthy phenomena were encountered in the
analysis of this data. The first is that the reaction exhibits a
transient phase or induction period. The length of this period
depends on the reagent concentrations and is therefore
unlikely to be due to incomplete mixing or other experimental
artifacts. The most likely explanation is that it takes time for the
concentrations of reactive intermediates to reach a steady state.
The transient phase has been removed from the plotted data by
basing the initial rate on the interval from 1 to 10% conversion,
or in the case of the order in (E)-1l, by removing the first
DISCUSSION
The development and subsequent mechanistic study of the
enantioselective Lewis base/chiral Brønsted acid cooperatively
catalyzed bromocycloetherification has provided insights in to
the mechanism of this unique process and synthetically useful
levels of enantioselectivity. These advances, their implications
for future work in the field, and key unanswered questions will
be discussed.
Optimization
Apart from the poor reproducibility of the results in Table 3,
the trends observed during the optimization of the coopera-
tively catalyzed bromoetherification reaction (Table 4) are
strikingly similar to those observed in the absence of Ph3P=S
(Table 3) with an intriguing difference. In both cases, phos-
phoric acid 2a was the optimal catalyst. However, while all
BINOL-derived catalysts surveyed in the presence of Ph3P=S
provided the same sense of enantioselectivity, suggesting
that they exhibit a similar mechanism of enantioselection,
the BINOL-derived triflimide 2c provided the opposite sense
of enantioselectivity when run in the absence of Ph3P=S
†The inclusion of 0.5 mol % of 2,6-di-tert-butyl-4-methoxyphenol as a radi-
cal inhibitor greatly reduced isomerization, however the resulting data
was still not satisfactory.
‡The fractional order in Ph3PS is not due to random error, multiple ap-
proaches to data analysis including nonlinear regression place an order
of 1.0 outside of the 99% confidence limit.
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE BROMOCYCLOETHERIFICATION
351
TABLE 6. Catalyst Survey for Bromocycloetherification of Unconjugated Olefins
R
Ph Br
Ph
OH
NBS (1.2 equiv)
Chiral acid (0.05 equiv)
O
O
2
P
6
OH
Lewis base (0.05 equiv)
0 oC, PhMe, 0.025 M
O
R
O
(E) 1b
(Z) 1c
3b, 3c
2a, 2g-l
entry
cat.
R
Lewis base
substrate
t, h
era
yield, %b
1
2
3
4
5
6
7
8
2a
2a
2a
2g
2g
2h
2h
2i
2,4,6-i-Pr3(C6H2)
2,4,6-i-Pr3(C6H2)
2,4,6-i-Pr3(C6H2)
2,4,6-Cy3(C6H2)
2,4,6-Cy3(C6H2)
2,4,6-Ph3(C6H2)
2,4,6-Ph3(C6H2)
2,4,6-Me3(C6H2)
2,4,6-Me3(C6H2)
4-CF3C6H4
Ph3P=S
1b
1b
1c
1b
1c
1b
1c
1b
1c
1b
1c
1b
1c
1b
1c
12
39
40
40
40
40
15
40
40
40
40
40
40
12
40
65:35
85:15
82:18
85:15
86:14
53:47
56:44
68:32
80:20
61:39
70:30
63:37
64:36
72:28
72:28
n/d
89
50
83
79
30
75
65
76
59
64
82
75
87
74
-
-
-
-
-
-
-
-
-
-
-
-
-
-
9
2i
10
11
12
13
14
15
2j
2j
4-CF3C6H4
2k
2k
2l
3,5-(CF3)2C6H4
3,5-(CF3)2C6H4
9-anthryl
2l
9-anthryl
aDetermined by CSP-SFC analysis.
bYield after chromatography, all reactions run on 0.1 mmol substrate.
Br
5-arylpentenols. (Table 5) The reaction is tolerant of a variety
of substituted aryl groups, although strongly electron
withdrawing substituents led to reduced enantioselectivity.
Very high site selectivity favoring the tetrahydrofuran isomer
(3g-m) was observed in the cyclization of Z-configured
olefins 1g-m.
n-Bu3SnH
AIBN
benzene
2
1g (Z )
O
3g
2
O
Br
n-Bu3SnH
AIBN
benzene
2
The bromocyclizations of E and Z unconjugated olefins 1b-c
(Table 6) highlight a limitation of achiral Lewis base/chiral
Brønsted acid cooperative catalysis, that is the rate of reaction
catalyzed purely by the achiral Lewis base must be negligible.
Unfortunately, the unconjugated olefins 1b-c do not satisfy this
criterion; they cyclize in the presence of only Ph3P=S and NBS,
resulting in greatly reduced enantioselectivity in cooperatively
catalyzed reactions. (Table 6, entry 1) Olefins 1b-c also display
elevated reactivity in the presence of only NBS and acid 2a and
under such conditions improved enantioselectivity is observed
at the cost of longer reaction times and lower conversion.
(Table 6, entries 2–3) A survey of additional catalysts identified
2g as a more selective catalyst for the cyclization of Z olefin 1c
(Table 6, entry 5), although the enantioselectivity observed in
the cyclization of 1b-c remains lower that that obtained in the
cooperatively catalyzed cyclizations of all but the most
electron-poor conjugated olefins.
1a (E )
O
3a
Scheme 2. Correlation of the absolute configuration of E and Z olefin
derived bromotetrahydrofurans.
(Table 3, entry 3 vs. Table 4, entry 3). This reversal of
selectivity suggests that Ph3P=S free reactions catalyzed by
2c are in some way mechanistically different than those
catalyzed by 2a-b as well as those catalyzed by 2c in the
presence of Ph3P=S.
The catalyst survey undertaken for the bromocyclizations
of E and Z unconjugated olefins 1b-c (Table 6) highlights
several salient points. First, there is no consistent relationship
between reaction rate and any other parameter, such as olefin
geometry, catalyst identity, or enantioselectivity. Second, the
relationship between catalyst structure and enantioselectivity
is sufficiently different between cyclizations of E and Z olefins
to justify screening them separately in the future.
Site Selectivity
The ratio of constitutional isomers produced in the reaction
provides additional information about the reaction
mechanism. Most clearly, the effect of electron-donating and
withdrawing groups on site selectivity (Table 5, entries 2–3)
is consistent with altering the degree of charge stabilization
Chirality DOI 10.1002/chir
Scope
The scope of the cooperatively catalyzed bromocycloetherification
includes a range of E (1a, 1e-f) and Z (1g-m) substituted

352
DENMARK AND BURK
NBS, Ph3PS, 2a
Br
toluene/toluene-d8
OH
F
rt, 19F NMR
fluorobenzene (int. std.)
O
F
1l
3l
Fig. 2. Determination of partial orders in reaction components.
at the benzylic carbon of a bromiranium ion intermediate.
The greater proportion of 5-exo cyclization observed in the
presence of 2a (Table 4, entry 1) indicates that the chiral acid
must be present in the final cyclization step rather than
simply providing stereocontrol in an initial, irreversible
bromirenium ion delivery. This finding is consistent with
the major enantiomer undergoes both cyclization modes.
Furthermore, as all cyclizations of 1a in the absence of chiral
acids were highly endo selective, any background reaction
would also produce mostly 4a in racemic form.
The racemization of bromiranium ions, or more precisely
stereomutation of bromiranium phosphate ion pairs, by
olefin-to-olefin transfer does occur in this catalyst system,
however its contribution to the product composition at the
optimal concentration (0.025 M) is small. A four-fold increase
in reaction concentration led to a small decrease in the
enantiomeric composition of 3a (93:7 to 90:10) and a modest
decrease in the proportion of exo cyclization (3a:4a 48:52 to
39:61). This result demonstrates that either olefin-to-olefin
transfer is slower than but competitive with cyclization at
0.1 M, or the equilibrium ratio of bromiranium ions is
favorably high.¶ Under the optimal conditions of 0.025 M 1a,
associative transfer should be 16 times slower,∥ and therefore
the erosion of enantioselectivity should be negligible. A some-
what greater erosion of enantioselectivity was observed when
Lewis base-free cyclizations were run at 0.1 M (95:5 to 88:12).
the hypothesized intermediacy of
a chiral ion pair.
Conversely, the presence or absence of Ph3P=S in 2a
catalyzed cyclizations had negligible influence on the ratio
of 5-exo to 6-endo cyclized products. Although it is tempting
to suggest that Ph3P=S dissociates from the bromiranium
ion prior to the cyclization step, a negative result is not
conclusive in this case.
The exo and endo products 3a and 4a are produced with
strikingly different levels of enantioselectivity, regardless of
changes in catalyst structure or the presence or absence of
Ph3P=S. The available data is insufficient to distinguish all
possible hypotheses; however the asymmetric environment
produced by the chiral counterions renders all four product-
generating transition states nonequivalent and therefore
potentially unequal in energy. Therefore, the enantiomeric
compositions of 3 and 4 are, in principle, expected to differ
(Scheme 3). For example, if kRe–endo/kRe–exo > kSi–endo/kSi–exo
then an asymmetric transformation would occur, increasing
the er of 3a at the expense of lower er of 4a and a lower ratio
of 3a:4a.§ In other words, the minor enantiomer of the
bromiranium ion undergoes mostly endo cyclization, while
Origin of Enantioselectivity
The absolute configurations of the (E)- and (Z)-olefin de-
rived products hold an important clue about the origin of
¶In principle, the equilibrium ratio could be estimated by greatly increas-
ing the reaction concentration. However, as discussed below, very high
olefin concentrations promote radical processes that would likely compli-
cate such an experiment.
§This situation is analogous to the divergence of enantioselectivity for cis
and trans epoxides seen in the Jacobsen epoxidation of (Z) alkenes.
∥This analysis makes the reasonable assumption that the associative bi-
molecular transfer is second order in olefin.
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE BROMOCYCLOETHERIFICATION
353
Br
kSi-exo
Br
Ph
O
Ph
3a
Ph
Br
O
O
kSi
kSi-endo
Higher
OH
OH
Faster
Ph
4a
Ph
O
P
O
Br
O-
OH
O
Br
O
Ph
Br
1a
kRe
kRe-exo
Ph
ent-3a
O
O
kRe-endo
Ph
Ph
Faster
ent-4a
Br
Lower
Br
Scheme 3. Hidden asymmetric transformation of bromiranium ion intermediates
enantioselection. First, it is a critical point that the Si and Re
designations for prochiral faces are defined with respect to a
single trigonal carbon atom. Thus, an olefin with two
prochiral, trigonal carbon atoms requires two such designa-
tions per face. Just as a molecule with two (R)-configured
stereocenters is designated (R,R), the two trigonal carbons
that constitute the (Z) olefin faces are (Si, Si) and (Re, Re)
whereas the (E) olefin faces are (Si, Re) and (Re, Si). There-
fore, the cyclization of (E) and (Z) isomers can be said to have
the same (or opposite) sense of enantioselection only if one
focuses on one trigonal carbon. This is not a consequence
of nomenclature; rather the nomenclature is a consequence
of the nature of the system. This catalyst system consistently
delivers the bromirenium ion to the C(4)-Si face, regardless
of whether that face is also C(5)-Si or C(5)-Re (Fig. 3). This
outcome likely reflects which substituent on the double bond
dominates the enantioface selection and that since the config-
uration of the tetrahydrofuran is conserved (Scheme 2, C(4)
of 1, C(2) of 3), the dominant recognition feature is the
tethered hydroxyl group. This sense of recognition is
tentatively hypothesized to result from hydrogen bonding to
the phosphate group, analogous to what is proposed in
certain Mannich reactions (Fig. 3).49,50
Kinetic Studies
The authors are keenly aware of the incomplete nature of
the kinetic data presented here, however we believe that
some conclusions may be drawn from this data despite its
flaws. Furthermore, the nature of certain experimental
difficulties provides additional insight into the behavior of
the catalyst system.
Most importantly, the reaction displayed clean first order
dependence on NBS and phosphoric acid 2a. This behavior
is consistent with the mechanism proposed in Scheme 1.
Despite the lack of a definitive interpretation of the observed
fractional orders in Ph3P=S and 1l the existence of non-zero
orders in Ph3P=S and 1l is significant. The non-zero order
in Ph3P=S demonstrates the intimate involvement of the
phosphine sulfide in the catalytic cycle and supports the hy-
pothesis that the two catalysts act cooperatively. The non-zero
order in olefin 1l excludes the possibility that the activation of
NBS, or any step involving only the Ph3P=S, NBS, and 2a, is
rate-determining. Rather, the rate determining step must be
the formation of the bromiranium ion, nucleophilic opening
of the bromiranium ion, or the subsequent proton transfer.
All of these possibilities imply that one or more intermediates
may be observable under appropriate conditions.
CONCLUSIONS
In conclusion, an enantioselective bromocycloetherification
of 5-aryl-4-pentenols has been developed using a chiral
Brønsted acid and an achiral Lewis base to provide good yield
and enantioselectivity. High site selectivity was achieved by a
combination of substrate and catalyst control. Cooperative
catalysis was not applicable to more reactive, unconjugated
5-alkylpentenols due to the intervention of a purely Lewis
base catalyzed pathway. However, 5-alkyl-4-pentenols could
be cyclized productively in the absence of achiral Lewis
bases, albeit with lower enantioselectivity.
The mechanism of enantioselective bromocycloetherification
and the nature of the observed cooperative catalysis were
explored by a 19F NMR kinetic study. This study constitutes
the first published attempt at a comprehensive kinetic analysis
of an enantioselective bromocycloetherification reaction. The
complete mechanism could not be elucidated due to the limita-
tions of the experimental method chosen. Nevertheless, the
Chirality DOI 10.1002/chir
Br
4Si, 5Re
Br
4Si, 5Si
5
Ph
4
Ph
OH
5
4
OH
4Re, 5Si
4Re, 5Re
H
O
O
Ar
O
O
Ar
P
O
Br
R
Fig. 3. Observed sense of enantioselectivity and postulated substrate-
catalyst interaction

354
DENMARK AND BURK
18. Denmark SE, Burk MT, Hoover AJ. On the absolute configurational
intimate involvement of Ph3P=S in the catalytic cycle was
clearly demonstrated. Furthermore, no step prior to the
entry of olefin 1l into the catalytic cycle can be rate
determining. More definite conclusions will require
reinvestigation of the system at lower temperature or
the observation of a reactive intermediate.
stability of bromonium and chloronium ions.
J Am Chem Soc
2010;132:1232–1233.
19. Denmark SE, Burk MT. Lewis base catalysis of bromo- and
iodolactonization, and cycloetherification. Proc Natl Acad Sci U S A
2010;107:20655–20660.
20. Chen J, Zhou L, Tan CK, Yeung Y-Y. An Enantioselective Approach
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21. Zhou L, Tan CK, Jiang X, Chen F, Yeung Y-Y. Asymmetric
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ACKNOWLEDGMENT
We are grateful to the National Institutes of Health
(R01 GM82535)) for financial support, and to Dr. D. Kalyani
for assistance and helpful discussions. M.T.B. thanks the Uni-
versity of Illinois for a Seemon H. Pines Graduate Fellowship.
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SUPPORTING INFORMATION
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Enantioselective bromolactonization of conjugated (Z)-enynes. J Am
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