Catalytic Enantioselective [2,3]-Rearrangements of Allylic Ammonium Ylides: A Mechanistic and Computational Study

Article abstract of DOI:10.1021/jacs.6b11851

A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using ¹⁹F NMR and density functional theory computations have elucidated a reaction profile

Full text of DOI:10.1021/jacs.6b11851

Subscriber access provided by UB + Fachbibliothek Chemie | (FU-Bibliothekssystem)
Article
Catalytic Enantioselective [2,3]-Rearrangements of Allylic
Ammonium Ylides: A Mechanistic and Computational Study
Thomas H. West, Daniel M. Walden, James E Taylor, Alexander C. Brueckner,
Ryne C. Johnston, Paul H.-Y. Cheong, Guy C. Lloyd-Jones, and Andrew D. Smith
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 23 Feb 2017
Downloaded from http://pubs.acs.org on February 23, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Catalytic Enantioselective [2,3]-Rearrangements of Allylic Ammonium Ylides: A
Mechanistic and Computational Study
Thomas H. West,a Daniel M. Walden,b James E. Taylor,a Alexander C. Brueckner,b
Ryne C. Johnston,b Paul Ha-Yeon Cheong,*b Guy C. Lloyd-Jones*c and Andrew D. Smith*a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aEaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK
bDepartment of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, Oregon, 97333, USA
cEaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh,
EH9 3FJ, UK
ABSTRACT: A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium
ylides is described. Reaction kinetic analyses using 19F NMR and density functional theory computations have elucidated a
reaction profile and allowed identification of the catalyst resting state and turnover-rate limiting step. A catalytically-
relevant catalyst-substrate adduct has been observed, and its constitution elucidated unambiguously by C and N iso-
topic labelling. Isotopic entrainment has shown the observed catalyst-substrate adduct to be a genuine intermediate on
the productive cycle towards catalysis. The influence of HOBt as an additive upon the reaction, catalyst resting state and
turnover-rate limiting step has been examined. Crossover experiments have probed the reversibility of each of the pro-
posed steps of the catalytic cycle. Computations were also used to elucidate the origins of stereocontrol, with a 1,5-S•••O
interaction and the catalyst stereodirecting group providing transition structure rigidification and enantioselectivity,
while preference for cation-π interactions over C-H•••π is responsible for diastereoselectivity.
13
15
have
reported
a
tandem
INTRODUCTION
The [2,3]-rearrangement of allylic ammonium ylides is a
direct and elegant method towards the synthesis of α-
amino acid derivatives containing multiple stereocenters.1
The mechanism of this process, and that of the competi-
tive [1,2]-Stevens rearrangement, has been much dis-
cussed and disputed within the literature. A concerted
thermally allowed sigmatropic process is thought to be
operative in the [2,3]-rearrangement, while a radical
mechanism involving bond cleavage and recombination is
usually favored for [1,2]-rearrangement (Scheme 1A).2
Scheme 1. Rearrangements of allylic ammonium
ylides
To date, few mechanistic analyses of [2,3]-
rearrangements of allylic ammonium ylides have been
conducted, although Jacobsen and co-workers have re-
cently reported a detailed mechanistic investigation into
the related thiourea-catalyzed [2,3]-Wittig rearrange-
ment.3 The elegant experimental and computational work
of Singleton and co-workers concerning the competitive
[2,3]- and [1,2]-rearrangements of allylic ammonium
ylides promoted by DBU represents the current state-of-
the-art (Scheme 1B). Through 13C kinetic isotope effects,
crossover experiments and computation, these studies
demonstrate that the origin of competitive [1,2]- and [2,3]-
rearrangement is the common loose transition state lead-
ing to dynamic bond cleavage.4 The development of both
catalytic and stereoselective variants of the [2,3]-
rearrangement of allylic ammonium ylides has been a
significant synthetic challenge. Tambar and co-workers
ammonium salt formation and diastereoselective [2,3]-
rearrangement process, exploiting Pd-catalyzed allylic
substitution to form the reactive ammonium salt in situ,
giving (±)-anti-α-amino acid derivatives with excellent
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 13
diastereocontrol via proposed transition state 13 (Scheme
2A).5
The
allylic ammonium ylides (Scheme 1C). In situ NMR analy-
sis has allowed a reaction profile to be elucidated, while
isotopic-labelling studies have unambiguously identified a
1
2
3
4
5
6
genuine productive catalytic intermediate. Kinetic analy-
sis
Scheme 2. Stereochemical models for [2,3]-
rearrangements
Scheme
3.
Catalytic
enantioselective
[2,3]-
rearrangement
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
observed diastereoselectivity of this [2,3]-rearrangement
process, and indeed most [2,3]-rearrangements, can be
rationalized through the exo- or endo- transition states 15
and 17 initially described by Houk and Marshall for the
related [2,3]-Wittig rearrangement (Scheme 2B).6
Prior to our studies within this area, only limited meth-
ods capable of imparting enantiocontrol in the [2,3]-
rearrangement of allylic ammonium ylides had been de-
veloped. Sweeney first demonstrated a chiral auxiliary
approach to allow access to enantiomerically enriched α-
amino acid derivatives,7 while the use of a super-
stoichiometric chiral Lewis acid promoter was subse-
quently reported by Somfai.8 Catalytic enantioselective
variants were unknown until 2014, when our laboratory
reported an isothiourea-catalyzed9 [2,3]-rearrangement of
allylic quaternary ammonium salts to give syn-α-amino
acid derivatives with excellent levels of diastereo- and
enantiocontrol (Scheme 3).10 Treatment of quaternary
ammonium salts 19 bearing an activated p-nitrophenol
ester, either isolated or generated in situ, with catalytic
(+)-benzotetramisole ((+)-BTM) 20, co-catalytic hy-
droxybenzotriazole (HOBt) and iPr2NH gave stereoselec-
tive [2,3]-rearrangement into syn-α-amino acid derivatives
with excellent levels of stereocontrol. This process can be
performed in the absence of HOBt, however its addition
provides a subtle enhancement in both diastereo- and
enantioselectivity. We tentatively proposed a Lewis base
catalytic cycle, initiated by nucleophilic addition of (+)-
BTM 20 into the activated ester substrate to form an acyl
ammonium intermediate prior to the formation of am-
monium ylide 22. However, alternative mechanistic
pathways using either Lewis or Brønsted base catalysis
proceeding via different intermediates can be envisaged
(Scheme 3). For example, assuming Lewis base catalysis is
operative, the reaction could proceed through initial for-
mation of a ketene intermediate 23 en route to acyl am-
monium ylide 22. Furthermore, the origin of the observed
diastereo- and enantiocontrol in the rearrangement pro-
cess is currently unknown.
has given insight into the overall process and crossover
studies have provided information about the reversibility
of each step. Kinetic isotope analysis has also been used
to probe the stereodetermining [2,3]-rearrangement step
of the process. Computational reaction coordinate model-
ling provides deeper insight into the catalytic cycle and
transition state modelling reveals the origins of stereo-
chemical control.
RESULTS AND DISCUSSION
Mechanistic Studies.
(i) Temporal concentration profiles. Initial studies
aimed to establish the kinetics of the [2,3]-rearrangement
and identify any reaction intermediate(s) or catalyst rest-
ing-states. Ammonium salt 25a (34 mM) rearranges to 26a
in d3-MeCN/d6-DMSO (9:1) at −20 °C, catalyzed by (+)-
BTM 20 (20 mol %) (Scheme 4). The presence of various
salts in the reaction medium causes extensive line-
1
broadening in the H NMR spectrum, making it unsuita-
ble for in situ analysis of the [2,3]-rearrangement. Howev-
er, the 19F{1H} and 13C{1H} NMR spectra were tractable, and
the 4-fluoro substituent in 25a allows quantitative moni-
toring of the process by in situ 19F{1H} NMR (δF = −113.1
ppm), with PhCF3 as an internal standard.11 After an initial
burst-phase (<1000 s) ammonium salt 25a is converted
into 26a (>80 % 26a, δF = −117.6 ppm) with pseudo-first
order kinetics, vide infra, over a period of 4 hours. During
the reaction evolution, a transient species (δF = −117.0
ppm) was detected, accumulating to a maximum concen-
tration of ~5.2 m
depleting
M
in the early stages of catalysis and then
as
Scheme 4. System chosen for in situ 19F NMR study.
Herein we report experimental and computational in-
vestigations into the mechanism and origins of stereocon-
trol in the isothiourea-catalyzed [2,3]-rearrangement of
ACS Paragon Plus Environment

Page 3 of 13
Journal of the American Chemical Society
F
1
2
3
4
5
6
7
8
9
F
O
(+)-BTM20 (20mol %)
HOBt (20 mol %)
O
Br
PNPO
Me
PNPO
iPr2NH (1.4 equiv.)
d3-MeCN:d6-DMSO
(9:1), −20 °C, 4 h
N
N
Me
Me
Me
δ
F = −117.6 ppm
δF = −113.1 ppm
26a
25a
With HOBt >95:5 dr, >99% ee
Without HOBt 88:12 dr, 92% ee
PNP= 4-NO C6H4
2
substrate 25a was consumed. Rearrangement in the ab-
sence of HOBt resulted in a similar reaction profile, but
afforded higher concentrations of the same species (δF =
−117.0 ppm), over a longer period, assisting in its analysis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(ii) Identification of an on-cycle catalytic interme-
diate.
(a) Catalyst speciation. To determine if the transient
species (δF = −117.0 ppm) involves the catalyst, a fluorinat-
ed variant,12 (+)-F-BTM 27, was prepared.11 In situ moni-
toring of the [2,3]-rearrangement of 25a, catalyzed by 27
(Figure 1), confirmed conversion of free (+)-F-BTM 27 (δF
= −123.3 ppm) into a catalyst-derived species (δF = −113.4
ppm), which was also transient, reaching a maximum
Figure 1. Temporal concentration data for [2,3]-
a
rearrangement of 25a using (+)-F-BTM 27, conditions: 25a
(29.5 mM), (+)-F-BTM 27 (6.8 mM), iPr2NH (47 mM), d3-
MeCN/d6-DMSO (9:1), −20 °C. Inset: monitoring of catalyst-
derived species.
A) Isotopically-labelledsubstratesused (
=
13C)
•
concentration of 4.6 m
M at ~2500 s, and decaying as the
O
O
O
Br
Br
Br
Ar
Ar
Ph
reaction proceeds to completion (see inset graph to Fig-
ure 1). The comparable temporal intensities of the two
signals (δF = −117.0 ppm and −113.4 ppm) strongly suggest
they arise from a single transient intermediate containing
both 25a and 27 in a formal 1:1 combination. Based on
reference to isothiouronium salt 28 (δF = −113.3 ppm), the
19F chemical shift of the catalyst-derived component in
transient species 29 suggested it to be an N-acylated
isothiourea.
PNPO
Me
PNPO
Me
PNPO
Me
N
N
N
Me
1-[13C1]-25a
Me
Me
1,2-[13C2]-25a
1,2,3'-[13C3]-25b
Ar = 4-FC H4
Ar = 4-FC H4
6
6
B)
F
N
Ph
15N
O
Ar
S
O
( )-[15N1]-27(20 mol %)
±
1,2-[13C2]-
R315N
25a
PNPO
iPr2NH (0.7 equiv.)
N
(b) Atom connectivity: C/15N labelling. Isotopically-
13
Me
Me
[
15N1,13C2]-
29a
1,2-[13C2]-26a
labelled substrates and catalyst (1-[13C1]-25a, 1,2-[13C2]-25a,
1,2,3’-[13C3]-25b (Figure 2A) and (±)-[15N1]-27) were pre-
pared11 to deduce connectivity between various atoms in
the intermediate and probe for reversibility in its genera-
Observed by 15N-13
coupling in13C NMR
C
C) 13C=O region of 13C{1H} NMR
F
tion. Rearrangement of 1,2-[13C2]-25a (34 m
M
) catalyzed by
S
1JCC = 51.9 Hz
O
15N
N
F
F
1JCN = 5.2 Hz, 2JCN = 7.0 Hz
1,2-[13C2]-26a
N
[
15N1,13C2]-29a Ph
Ph
N
S
F
O
27
(δF = −123.3 ppm)
O
(+)-F-BTM(20 mol %)
iPr2NH (1.4 equiv.)
d3-MeCN:d6-DMSO
(9:1), −20 °C, 4 h
Br
PNPO
Me
PNPO
N
N
Me
Me
Me
173.6 173.3 173.0 172.7 172.4
δC (ppm)
25a (δF = −113.1 ppm)
PNP= 4-NO2C6H4
26b (δF = −117.6 ppm)
92:8 dr, 97% ee
anti-1,2-[13C2]-26a
175
174
173
172
171
170
169
168
167
166
165
164
163
162
δC (ppm)
Figure 2. A)Isotopically-labelled substrates. B) Generation of
[15N1, 13C2]-labelled intermediate 29a. C) 13C{1H} NMR sub-
spectrum (101 MHz, d3-MeCN/d6-DMSO (9:1), 273K) of the
13C=O region. Conditions, 1,2-[13C2]-25a (34 m ), (±)-15N-F-
M
BTM [15N1-27] (6.8 m
(±)-[15N1]-27 (6.8 m
NMR (Figure 2B). Reducing the iPr2NH concentration to
M
), iPr2NH (23.8 m
M).
M
, 20 mol %) was monitored by 13C{1H}
23.8 m prolonged the lifetime of the intermediate,
M
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 13
[15N1,13C2]-29a, allowing detailed analysis of the 13C=O re-
employing 1-[13C1]-25a (17 m
1-[13C1]-29a had reached its maximum concentration (~5
). A further 1.0 equivalent (17 m ) of a differently la-
M), was allowed to evolve until
gion, Figure 2C. The characteristic doublets (1JCC = 52 Hz)
1
2
3
4
5
6
7
8
13
arising from the adjacent C labels, C(1)-C(2), in the sub-
mM
M
strate (1,2-[13C2]-25a) and the product (1,2-[13C2]-26a) are
belled substrate, 1,2-[13C2]-25a, was then rapidly added,
resulting in an isotopic perturbation of the system. At the
point that 1,2-[13C2]-25a is added, there has been 32% net
conversion of 25a ([13C1]- and [13C2]-). However, neither of
the [2,3]-rearrangement products (29a and 26a) yet con-
tain any of the [13C2]-label: all of this resides in unreacted
[13C1,2]-25a, which comprises 0.28 [13C1] / 0.72 [13C2]. The
key features are the changes in 13C2-populations in the
substrate 25a, intermediate 29a and product 26a, as the
reaction evolves. Irrespective of the pathway (A-D) the
population in the final product (26a) must ultimately rise
from 0 to 50%, as dictated by the equal proportions of 1-
[13C1]-25a and 1,2-[13C2]-25a added overall. For case A,
where 29a is not productive, the isotope population in
29a will depend only on that of the final product (26a;
max 50% 13C2) and at all stages will be lower or equal to it.
For case B, where the intermediate is productive, but is in
equilibrium with 25a, the 13C2-population in 25a will be
reduced, in the limit from 72% to 55%. For cases C and D,
where the [2,3]-rearrangement to 29a is irreversible, the
13
replaced by a double-doublet in [15N1, C2]-29a, (δC = 173.1
ppm).13 The magnitude of the C-C coupling (1JCC = 52 Hz)
confirms that C(2) remains sp3-hybridized. The magni-
tude of the additional coupling constant (1JCN = 5.2 Hz)13
indicates that C(1) is directly bound to the 15N-labelled
atom in the catalyst, confirming 29a to be an N-acylated
isothiourea (Figure 2).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Attempts to identitify the atom adjacent to C(2) in [15N1,
13
13C2]-29a from its 1H-coupled C NMR signal were thwart-
ed by line broadening.13 Instead, the 13C{1H} NMR spec-
trum of intermediate 1,2,3-[13C3]-29b, generated from
1,2,3’-[13C3]-25b, was analysed, (Figure 3). The C(2) signal
of the resulting [2,3]-rearrangement product 1,2,3-[13C3]-
26b (δC = 70.5 ppm) displayed the expected double-
doublet coupling arising from C(2)-C(3) bond formation.
However, this coupling pattern was also evident in inter-
1
1
mediate 1,2,3-[13C3]-29b (δC = 68.0 ppm, JCC 51.4 Hz, JCC
35.8 Hz) with the magnitude of the C(2)-C(3) coupling
indicative of sp3-hybdrization at both centres.13 Overall
the data confirms that the intermediate (29) is a catalyst-
bound, post [2,3]-rearrangement, acyl ammonium salt
(Figure 3).
13
isotope population in 25a is constant (72% C2-) and the
13C2-content in 29a rises from 0 % to a maximum of 72 %
as it is repopulated from 25a.14 However, for case C, equil-
bration of 29a with product 26a will attenuate the rise in
13C2-population in 29a, in the limit to 50%. Only for case
13
D will the C2 isotope population in 29a rise, in advance
of 26a, to reach a maximum 72% 13C2.14 Comparison of the
predicted and experimentally determined 13C2-populations
as a function of net conversion (Figure 4) confirms that 26
arises from two irreversible sequential first-order inter-
conversions (25→29→26) where 29 is the productive cata-
lytic intermediate (case D).14 Kinetic modelling confirms
that the impact of heavy-atom (12C/13C) KIEs on the iso-
tope-entrainment are negligible.11
Figure 3. Catalyst-bound [2,3]-rearrangement product,
13C{1H} NMR sub-spectrum (101 MHz, d3-MeCN/d6-DMSO
(9:1), 293K) of the 13C(2)-H region. Conditions: 1,2,3’-[13C3]-
25b (34 mM), (+)-F-BTM 27 (6.8 mM), iPr2NH (23.8 mM).
(c) Productivity of the intermediate. The data present-
ed so far does not discriminate between the N-acylated
isothiourea species (29) being peripheral to the produc-
tive catalytic cycle (Figure 4, case A) or an integral part of
it (cases B-D). The following isotopic entrainment test
distinguishes these four possibilities. A catalytic reaction
ACS Paragon Plus Environment

Page 5 of 13
Journal of the American Chemical Society
32 % conversion
35
F
1-[13C1] (28%)
1,2-[13C2] (72%)
25a
1-[13C1] (100%)
1,2-[13C2] (0%)
29a
1-[13C1] (100%)
1,2-[13C2] (0%)
1
2
3
HOBt
Added
30
25
20
15
10
5
26a
O
HOBt Ester 30
117.2 ppm
N
CAT
CAT
=
F
N
4
5
6
N
O
PROD
26
SUB
25
PROD
26
SUB
25
N
A
B
Me
Me
7
8
INT
29
INT
29
CAT
CAT
9
PROD
26
SUB
25
PROD
26
SUB
25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
C
D
INT
29
INT
29
0
0
5000
25a (δF = -113.1 ppm)
10000
15000
time (s)
Intermediate 29 (δF = -117.0 ppm)
80
80
70
60
50
40
30
20
10
0
Total Product
25
70
60
50
40
30
20
10
0
Figure 5. Addition of stoichiometric HOBt at t = 3920 s.
Conditions, 25a (34 m
), d3-MeCN/d6-DMSO (9:1), HOBt (34 m
refers to both HOBt ester 30 and 26a.
M
), (+)-BTM (6.8 m
M
), iPr2NH (47.6
m
M
M
). Total Product
29
The (+)-BTM-catalyzed rearrangement of 25a in the pres-
ence of stoichiometric HOBt (34 m ) was studied by
26
M
19F{1H} NMR. The presence of HOBt strongly suppressed
accumulation of acyl ammonium intermediate 29c ((+)-
BTM replaces (+)-F-BTM) and resulted in the formation
of the corresponding HOBt ester 30 (δF = −117.2 ppm, con-
firmed by comparison with an authentic sample),11 in ad-
dition to the PNPO ester product 26a. Addition of HOBt
once the acyl ammonium intermediate 29c reached the
0
20
40
60
80
100
Conversion (%)
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. 13C2 Entrainment into the catalytic cycle. Condi-
tions, 1-[13C1]-25a (17 m
), (+)-BTM (6.8 m ), iPr2NH (47.6
), d3-MeCN/d6-DMSO (9:1), with 1,2-[13C2]-25a (17 m
M
M
pseudo-steady state (5 mM, t = 3920 s, Figure 5) resulted
m
M
M)
in immediate formation of HOBt ester 30, and consump-
tion of acyl ammonium intermediate 29c. HOBt thus
shifts the catalyst speciation to be strongly dominated by
free (+)-BTM, (Figure 5). The background iPr2NH-
mediated reaction that converts 25 into racemic (±)-26
presumably involves the generation of ylide intermediate
24. Interception of this species by free (+)-BTM would
also generate intermediate 29, thus leading to non-
racemic 26. The higher the concentration of free BTM, the
more effective this interception.
added at 32% net conversion of 25a. Open circles: experi-
mental (13C{1H} NMR) data for 13C2-incorporation (%) versus
net conversion (%). Dashed lines: kinetic simulation where
29 is a productive intermediate in two irreversible sequential
pseudo-first-order interconversions (25→29→26, Case D;
with rate-ratio 0.407).14
(iii) HOBt cleavage of acyl ammonium intermedi-
ate. HOBt provides optimal diastereo- and enantiocon-
trol (Scheme 4), however its role within the catalytic cycle
is unclear. To probe if the HOBt enhances stereocontrol
via suppression of the base-mediated background reac-
tion, the iPr2NH-mediated rearrangement of 25a was ex-
Scheme 5. Effect of HOBt on overall catalytic cycle
amined. Reaction of 25a with iPr2NH (47 mM) in the ab-
sence of the BTM catalyst resulted in slow formation of
racemic 26a with low diastereocontrol (79:21 dr) and a kobs
of 2.74 × 10-5 s-1. The addition of a catalytic amount of
HOBt (6.8 mM) resulted in no change in rate (kobs 2.70 ×
10-5 s-1). This rules out the role of HOBt as improving ste-
reocontrol through direct suppression of the rate of the
background reaction.
Overall, the beneficial effect of HOBt on the selectivity
may arise from both a change in catalyst speciation to
favour free BTM and by diversion of the background reac-
tion onto the enantioselective pathway (Scheme 5).
(iv) Reaction kinetics, and impact of additives.
13
Having identified, by 19F{1H} and C{1H} NMR, the major
reactant-derived and catalyst-derived components pre-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 13
F
sent in the reaction mixture, the empirical rate-equation
was established by analysis of the decay in substrate 25a
during the pseudo-steady-state phase of the catalysis
F
1
2
3
4
5
6
O
D
O
kH/kD = 1.031
D
PNPO
3
(Scheme 6).15 The standard conditions [25a (34 m
M
), (+)-
)],
N
PNPO
2
Br
Me
Me 1
N
BTM (6.8 m
M
), HOBt (6.8 m
M
) and iPr2NH (47 m
M
(+)-BTM (20 mol %)
Me
Me
afforded a pseudo-first order rate constant, kobs = 1.37 × 10-
iPr2NH (1.4 equiv.)
aryl-D0-C(3)-D1-26a
aryl-D0-C(3)-D1-25a
4 s-1.
+
F
d3-MeCN/d6-DMSO
(9:1), –20 °C
+
F
7
Scheme 6. Empirical rate equationa
O
D
(aryl-kH/kD = 1.044)
O
8
9
H
H
PNPO
Br
D
3
PNPO
N
2
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
Me 1
Me
Me
aryl-D1-C(3)-D0-25a
aryl-D1-C(3)-D0-26a
F = 0.28 ppm
F = 0.29 ppm
The SKIE was measured by competition using aryl-D1-
C(3)-D0-25a and aryl-D0-C(3)-D1-25a, and a double-
labelling method,16 in which the C(3)-D / C(3)-H ratio as a
function of fractional conversion is detemined by 19F NMR
(ꢀδF = 0.28 ppm; aryl-D0 / aryl-D1). After correction for
the effect of aryl deuteration,17,18 a value of kH/kD = 1.031
was obtained. The presence of a small positive SKIE is
a
Conditions: 25a (17 – 68 m
), iPr2NH (23.8 – 95.2 m
DMSO (9:1), 253 K, 4 h.
M
), (+)-BTM (1.7 – 13.6 m
M),
HOBt (0 – 34 m
M
M
), d3-MeCN/d6-
There was a linear relationship between the enantiopurity
of (+)-BTM and product 26a, consistent with predomi-
nant or exclusive speciation of the catalyst in an active,
monomeric, form.11 Systematic variation of the concentra-
tion of the reaction components afforded first-order de-
consistent
with
a
product-determining
[2,3]-
rearrangement transition state (Scheme 7). A linear free
energy relationship analysis of a range of C(3)-aryl sub-
strates, against standard Hammett sigma values, showed
the C(3) position to be insensitive to electronic substitu-
ent effects.11
pendencies on (+)-BTM (1.7-13.6 m
mine (23.8-95.2 m ), and with no rate-impact from the
HOBt (0-34 m ). Addition of n-Bu4N 4-nitrophenoxide
(27.2 m
M) and diisopropyla-
M
M
M
) in the absence of HOBt resulted in a large in-
crease in rate (kobs = 2.42 × 10-4 s-1) and reduced the accu-
(vi) Crossover and reversibility studies. We have
previously demonstrated the [2,3]-rearrangement step to
be intramolecular and irreversible.10 To distinguish which
steps prior to the [2,3]-rearrangement are reversible, a
crossover reaction between ammonium salts 25a and 31
(1:1) bearing two distinct activated ester groups (4-
NO2C6H4 and 3,5-(CF3)2C6H3) and two distinct C(3)-aryl
units (4-FC6H4 and 3-FC6H4) was monitored in situ under
catalytic conditions (Scheme 8A). Complete equilibration
with ammonium salts 32 and 33 was observed,11 consistent
with reversible generation of non-rearranged (+)-BTM
acyl ammonium intermediates. To examine reversibility
at the deprotonation step, the [2,3]-rearrangement of α-
dideuterio ammonium salt α-[D2]-25 (75% D2) was moni-
tored in situ. The product was obtained with significantly
lower deuterium incorporation (29% D), consistent with a
reversible deprotonation step (Scheme 8B).19 Reaction of
ammonium salt 33 in the presence of rearrangement
product 26b (Scheme 8C) bearing distinct C(3)-aryl units
and activated esters demonstrated no crossover, con-
sistent with catalyst turnover being irreversible, confirm-
ing the conclusions deduced from isotopic entrainment.
mulation of the [2,3]-rearrangement acyl ammonium in-
termediate 29c (≤2 m
Bu4NBr (27.2 m ) resulted in a similar rate enhancement
(kobs = 2.35 × 10-4 s-1) but did not suppress the accumula-
tion of 29c (5 m ). The observed increase in kobs may be
rationalized by an increase in ionic strength of the medi-
um.11 The n-Bu4N 4-nitrophenoxide thus promotes cata-
lyst turnover of acyl ammonium 29c into product 26a and
M). Control studies showed that n-
M
M
(+)-BTM. Addition of 4-nitrophenol (0-34 mM) resulted in
a decrease in rate, with a negative first-order dependency.
Overall, this suggests that 4-nitrophenoxide or benzotria-
zololate are required for efficient turnover of acyl ammo-
nium 29c into products 26a / 30 and (+)-BTM.
(v) Secondary Kinetic Isotope Effect (SKIE). Alt-
hough it is clear that the [2,3]-rearrangement to generate
29 is irreversible, it is not evident whether this is the
product-determining step, i.e. the first irreversible step in
the cycle. During the [2,3]-rearrangement step, the carbon
that becomes C(3)-H in 29 undergoes rehybridization
from sp2 to sp3. The process to generate a C(3)-D isotopo-
2
logue of 29 would be thus expected to exhibit a H-SKIE.
Computational Studies.
Alternatively, if deprotonation at C(2)-H to generate an
allylic ammonium ylide (Scheme 3) was the product-
determining step, there would not be any significant
SKIE, as C(3)-D is remote.
i) Computed catalytic cycle. We computed all inter-
mediates, transitions structures (TSs), and possible salt
complexes involved in the mechanisms shown in Scheme
9. Exhaustive searches were performed to locate all perti-
nent conformations. Geometries and thermodynamic
corrections were computed at the M06-2X20/6-31G(d)21
level of theory.22 Vibrational frequencies and thermal cor-
rections to the Gibbs free energy were calculated at –20 °C
and 1 atm
Scheme 7. C(3) SKIE competition experiment
ACS Paragon Plus Environment

Page 7 of 13
Scheme 8. Crossover studiesa
Journal of the American Chemical Society
meta-GGA functional M06-2X is generally more robust
1
2
3
4
5
6
7
8
than B3LYP at accounting for dispersion and non-bonding
interactions routinely found in organocatalytic reac-
tions.25 Kinetic isotope effects were calculated using the
theory of Bigeleisen and Mayer26 along with the rigid-
rotor harmonic oscillator approach (∆H∆S).27 Quantum
mechanical tunnelling effects were also calculated for
both methods using the one-dimensional parabolic ap-
proximation.28 The calculation of the KIE was automated
by use of the Onyx isotope effect program.29 While both
rigid-rotor and Bigeleisen-Mayer methods agree qualita-
tively, the latter was consistently in better agreement with
experiments, and is reported herein as the computed KIE.
The catalytic cycle and the computed reaction coordinate
are summarised in Scheme 9.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Direct acylation begins with BTM attack on allylic am-
monium activated substrate (TS-II, ∆G‡ = 14.8 kcal·mol–1)
to form tetrahedral intermediate III. Release of PNPO−
(TS-IV, ∆G‡ = 12.0 kcal·mol–1) gives dication V. Indirect
acylation
a
i) (+)-BTM (20 mol %), iPr2NH (1.4 equiv.), 25a (0.5
equiv.), 31 (0.5 equiv.), d3-MeCN/d6-DMSO (9:1), 253 K, 4
h. ii) (+)-BTM (20 mol %), HOBt (20 mol %), iPr2NH (1.4
equiv.), 26b (0.5 equiv.), 33 (0.5 equiv.), MeCN, 253 K
to match the experimental conditions. Further energy
refinements
were
completed
using
M06-2X/6-
311++G(2df,p).23 Implicit solvation corrections were ap-
plied using the polarized continuum model (PCM)24 with
UFF radii for acetonitrile in both the geometry optimiza-
tions and the single-point energy refinements. The hybrid
Scheme 9. Proposed catalytic cycle and computed reaction coordinate
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 13
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
through formation of the ammonium ketene III' was
ruled an unlikely reactive intermediate based on its high
thermodynamic barrier for formation (∆G‡
22.0
the absence of HOBt, this step is highly competitive with
rearrangement as turnover-rate limiting.
=
(ii) The effect of counterions on the theoretical
KIE. The presence of counterions posed a challenge to
the accuracy of DFT, and significantly increased the com-
plexity of the conformational search and the number of
relevant structures to consider.32 Almost all species pre-
sent in the catalytic cycle prior to catalyst turnover bear a
positive charge, with intermediate V being dicationic.
Species indicated to include a counterion in Scheme 8
were optimized with the explicit ion shown. Given the
charged nature of the species present, the identification
of the structures that compose the free-energy span33 re-
sulted from considering all possible counterion coordina-
tion combinations for all conformations of each charged
species in the catalytic cycle. This exhaustive process led
to the identification of acyl substrate I and TS-VIII as the
most stable intermediate and turnover-rate limiting step,
respectively. Rearrangment is computed as the first irre-
versible step of the mechanism, thereby allowing kinetic
kcal·mol–1).The small endergonicity of dication V (∆G‡ =
3.3 kcal·mol–1) confirms the observed reversibility of cata-
lyst acylation. Dication V is in equilibrium with ylide VII
(∆G = 1.6 kcal·mol–1) through deprotonation of the α-
proton of V by PNPO– (∆G‡ = 11.4 kcal·mol–1), also in
agreement with the experimentally-observed reversibility
of the deprotonation step.30,31
NBO analyses reveal significant enolate character of
ylide intermediate VII. Intermediate VII subsequently
undergoes stereoselective and turnover-rate limiting
[2,3]-rearrangement (TS-VIII-(2S,3S)-Major, ∆G‡ = 17.3
kcal·mol–1) to yield enantio- and diastereoenriched acyl
ammonium product-catalyst complex IX. Catalyst turno-
ver is computed as stepwise and begins with PNPO− at-
tack (TS-X) and ends with catalyst and product release
(TS-XII). The barrier for PNPO− attack as calculated from
intermediate IX (∆G‡ = 16.9 kcal·mol–1) indicates that, in
ACS Paragon Plus Environment

Page 9 of 13
Journal of the American Chemical Society
isotopic fractionation to occur. The computed KIE de-
pends on the vibrational frequencies of I and TS VIII. The
computed KIE could then be utilized to corroborate the
computed thermodynamics and barriers of this energy
span.34
1
2
3
4
5
6
7
8
In a multistep reaction with highly charged and zwit-
terionic species, leveraging KIE prescribes a means to not
only identify the structures that compose the free-energy
span,33 but also which ions coordinate, the specific bind-
ing site of the counterion,35 and the conformation.27b,36 We
sought to identify the coordination state of TS-VIII by
leveraging both the KIE and computed barriers for TS-
VIII-F; i.e. bearing the 4-fluoro substituent used for KIE
determination (Scheme 7). Coordination to TS-VIII-F,
formation of byproduct salt complexes, and confor-
mations all affect the barrier in going from I-F to TS-VIII-
F. Two possible counterions, PNPO– and Br–, were con-
sidered as TS counterions, while iPr2NH2+ was evaluated
as a component of the possible remaining complexes
(Figure 6). No coordination to the TS (Figure 6, left)
leaves H-bond complex PNPOH•••iPr2NH as the lowest-
energy remaining complex, giving an overall ∆G‡ = 18.3
kcal·mol–1. Bromide ion binding to the TS (TS-VIII-F-
(2S,3S)•••Br, Figure 7, middle) also leaves complex
PNPOH•••iPr2NH (∆G‡ = 18.7 kcal·mol–1). PNPO– binding
and the complexation of iPr2NH2+ and Br– gives the high-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 6. Computed TSs, ions, complexes, and KIEs involv-
ing the 4-fluoro substituted substrate I-F. The computed KIE
depends on the coordination state of substrate I-F and TS-
VIII-F. The violet highlighted atom is the isotopic proton
(H/D).37 All energies in kcal·mol–1. Shaded grey lines repre-
sent forming/breaking bonds. Green lines represent C–H
electrostatic interactions and hydrogen bonds.
est barrier (TS-VIII-F-(2S,3S)•••PNPO, ∆G‡
=
22.8
kcal·mol–1). With no counterion coordination to the TS
(TS-VIII-F-(2S,3S)-Major), the KIEcomp of 1.028 matches
well with experiment (KIEexp = 1.031). Bromide complexa-
tion, which is computed as 0.4 kcal·mol–1 higher, also
matches fairly closely, giving KIEcomp of 1.041.38 PNPO–
complexation leads to an erroneously large magnitude of
rate difference between kH/kD, yielding KIEcomp of 1.050.
E, as shown in the model system Z/E-35 where the Z is
favored by >16 kcal·mol–1. All stable [2,3]-rearrangement
transition structures feature the Z-enolate.
iii) Stereocontrol model. The computed diastereo-
meric [2,3]-rearrangement TSs are shown in Figure 8. All
TSs feature concerted C-C bond formation and ammoni-
um N-C bond cleavage.4,6 The four main elements that
control the stereochemical outcome of the reaction are
(Figure 8):
B) Anti vs. syn Scatalyst to Osubstrate orientation: In all the
lowest energy conformations of the ylide-VII and rear-
rangement TS-VIII, the S–O relationship is syn. The syn
distances (~2.7-2.8 Å) are significantly below the sum of
the Van der Waals radii (3.4 Å), indicating close-contact
S•••O interactions (Figures 7 and 8, orange lines).40 Com-
puted model systems show >4 kcal·mol–1 preference for
the conformation which contains the 1,5-S•••O interaction
(anti/syn-38, Figure 8). All [2,3]-rearrangement TSs that
do not bear the S•••O interaction are higher by >6
kcal·mol–1.11 The conformational bias towards the S–O syn
arrangement is proposed to result from nO to σ*C–S delo-
calization coupled with electrostatic attraction of the par-
tially-positive sulfur atom and partially-negative oxygen
atom.41
A) E vs. Z configuration of the enolate in ylide VII: NBO
analysis indicates that both ylide VII and TS-VIII-(2S,3S)-
Major have significant enolate character.39 Ylide VII dis-
plays a C-O bond-order of 1.39 and a C-C bond-order of
1.52 (Figure 8, bottom left inset), while TS-VIII-(2S,3S)-
Major displays a C-O bond-order of 1.54 and a C-C bond-
order of 1.21.11 The computed bond order of 1.52 for ylide
VII suggests partial C-C double bond character leading to
distinct isomeric E and Z enolate configurations prior to
rearrangementm with the configuration set in place by
the deprotonation step. The Z-configuration is heavily
favored over the
C) Facial selectivity of rearrangement: The S•••O inter-
action significantly rigidifies the ylide-VII structure, leav-
ing conformational freedom only to the substrate cin-
namyl group. With rearrangement possible from either
face of the planar isothiourea catalyst, the facial selectivi-
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 13
ty is controlled by the catalyst Ph stereodirecting group.
The most
analysis by 19F NMR has allowed reaction profiles to be
established and has identified an intermediate species.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 8. Computed model systems (all energies in kcal·mol–
and distances in Å). (A) Preference for Z over E enolate.
1
Figure 7. Stereodeterming [2,3]-rearrangement TSs.34 All
energies in kcal·mol–1 and distances in Å. Shaded grey lines
represent forming/breaking bonds. Solid orange lines repre-
sent non-bonding S•••O interactions. Dashed blue lines rep-
resent aromatic interactions.
Enolate-like character indicated by bond orders (B. O.) esti-
mated from the Wiberg bond indices (bottom left inset). (B)
Effect of S•••O interaction on acylated catalyst conformation.
(C) With the acylated catalyst conformation held rigid
(S•••O), the BTM stereodirecting Ph sterically biases open
enolate face. (D) Endo rearrangement is favored. In the major
TS, this preference is reinforced by a π-cation interaction
(bottom right inset).
favorable [2,3]-TSs favor approach opposite to this
group (TS-VIII-(2S,3S)-Major and TS-VIII-(2S,3R), Fig-
ure 7). Approach on the same side as the stereodirecting
Ph is disfavored by >6 kcal·mol–1 (TS-VIII-(2R,3R) and
TS-VIII-(2R,3S)).
Isotopic labelling of catalyst (15N) and substrate (13C)
has confirmed the constitution of the catalytic intermedi-
ate as 29/IX by 13C NMR. Isotopic entrainment has shown
29/IX to be an irreversibly-generated intermediate that is
productive towards catalysis. A series of crossover exper-
iments have provided detailed information regarding the
reversibility of each individual step of the catalytic cycle.
The turnover-rate limiting step of the process varies be-
tween product release and [2,3]-rearrangement, depend-
ing on substrate conversion, Figure 1. The effect of excess
HOBt upon the reaction is to accelerate product release,
thus generating a greater proportion of the free BTM cata-
lyst, Figure 5. This may then result in more effective in-
terception of the background racemic reaction, and thus
greater diversion onto the enantioselective pathway,
Scheme 5. Computational analysis has provided finer de-
tail for the fundamental steps in the catalytic cycle as well
as the key interactions that control the stereochemical
outcome of the process. The insight gained into this pro-
cess will have implications in a wider context, especially
in the use of activated esters in Lewis base catalysis,
which is currently under investigation in our laborato-
ries.44
D) Endo vs. exo [2,3]–TS: Rearrangement can occur ei-
ther endo or exo with repect to the substrate C=O (Figure
9). In the simple allyl model TS, the endo/exo preference
is ~1 kcal·mol–1. This preference is ~2 kcal·mol–1 between
TS-VIII-(2S,3S)-Major and TS-VIII-(2S,3R), and addi-
tional interactions contribute to the diastereoselectivity.
In major TS there is a π-cation interaction,42 which is fa-
vored over the π-C–H interaction found in the minor.43
Truncated fully optimized model systems probing the
difference in energy between these interactions in the
context of cationic BTM reveal ~1 kcal•mol-1 preference for
38 π-cation over 38 π-C–H (Figure 8, bottom right in-
set).11 These two factors contribute to the computed 2
kcal·mol–1 preference for TS-VIII-(2S,3S)-Major over TS-
VIII-(2S,3R), in good agreement with the experimental
selectivity of 1.5 kcal·mol–1.
CONCLUSIONS
The experimental and computational investigation re-
ported herein has provided mechanistic and stereochemi-
cal insight into the enantioselective isothiourea-catalyzed
[2,3]-rearrangement of allylic ammonium ylides. Kinetic
ASSOCIATED CONTENT
10
ACS Paragon Plus Environment

Page 11 of 13
Journal of the American Chemical Society
inal report, see: Birman, V. B.; Guo, L. Org. Lett. 2006, 8,
Additional discussion, kinetic data, experimental procedures,
1
2
3
4
5
6
7
8
4859-4861. For reviews on isothiourea catalysis, see: (a) Tay-
lor, J. E.; Bull, S. D.; Williams, J. M. J. Chem. Soc. Rev. 2012,
41, 2109-2121. (b) Merad, J.; Pons, J.-M.; Chuzel, O.; Bressy,
C. Eur. J. Org. Chem. 2016, 2016, 5589-5610.
characterization data, NMR spectra and HPLC chromato-
grams, computed geometries, energies, and vibrational fre-
quencies. This data is available free of charge via the internet.
(10) West, T. H.; Daniels, D. S. B.; Slawin, A. M. Z.; Smith, A. D.
J. Am. Chem. Soc. 2014, 136, 4476-4479.
(11) See the supporting information for details.
(12) (+)-F-BTM 27 (20 mol %), HOBt (20 mol %) gave compara-
ble reactivity and stereocontrol (68% yield, 92:8 dr, 97% ee)
to the reaction using (+)-BTM 20 under the same condi-
tions.
AUTHOR INFORMATION
Corresponding Authors
paulc@science.oregonstate.edu
guy.lloyd-jones@ed.ac.uk
ads10@st-andrews.ac.uk
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Notes
(13) Typical range for one bond carbon-carbon coupling con-
stants: sp2-sp2 1JCC 75 – 80 Hz, sp2-sp3 1JCC 35 – 60 Hz, sp3-sp3
1JCC 25-55 Hz, Hansen, P. E.; Wray, V. Org. Magn. Resonance
Authors declare no competing financial interests
1
2
1981, 15, 102-103. The magnitude of observed JCN and JCN
coupling constants are consistent with the literature; Frey-
er, V. W. Z. Chem. 1981, 21, 47-58; see supporting infor-
ACKNOWLEDGMENTS
We thank Dr. Carl Poree, Dr Lorna Murray, Mr Juraj Bella, Dr
Dušan Uhrín (all Edinburgh), Mrs. Melanja Smith and Dr.
Tomas Lebel (both St Andrews) for assistance with NMR
experiments. The research leading to these results (T. H. W.,
J. E. T., G. C. L.-J. and A.D.S) has received funding from the
ERC under the European Union's Seventh Framework Pro-
gramme (FP7/2007-2013) / E.R.C. grant agreements n° 279850
and n° 340163. A.D.S. thanks the Royal Society for a Wolfson
Research Merit Award. We also thank the EPSRC UK Nation-
al Mass Spectrometry Facility at Swansea University. P.H.-
Y.C. is the Bert and Emelyn Christensen Professor and grate-
fully acknowledges financial support from the Stone Family
of OSU. Financial support from the National Science Foun-
dation (NSF) (CHE-1352663) is acknowledged. D.M.W.
acknowledges the Bruce Graham and Johnson Fellowships of
OSU. A.C.B. acknowledges the Johnson Fellowship of OSU.
D.M.W., A.C.B., and R.C.J. and P.H.-Y.C. also acknowledge
computing infrastructure in part provided by the NSF Phase-
2 CCI, Center for Sustainable Materials Chemistry (CHE-
1102637).
2
mation for select examples. A JCH value of ~1-2 Hz would be
expected for coupling between C(2) and C(3)H in the in-
termediate if the [2,3]-rearrangement has taken place. The
presence or absence of this coupling could not be unambig-
uously established.
(14) The maximum 13C2 population attainable in the intermedi-
ate is dictated by the relative rate of build-up and decay of
the intermediate. The simulation used in Figure 4 employs a
rate ratio for step 1 vs step 2 (k1/k2) of 0.407 leading to a
maximum 6 mM concentration of the intermediate, analo-
gous to that found experimentally under catalytic condi-
tions.
(15) An initial drop in substrate concentration is observed and
after ~3000 s 25a decays with good pseudo-first order kinet-
ics.
1
(16) Direct competition experiment analysed by H NMR was
not possible due to siginifcant line broadening. To allow 19
F
NMR to be used, a double-labeling experiment was em-
ployed.
(17) Gonzalez, J. A.; Ogba, O. M.; Morehouse, G. F.; Rosson, N.;
Houk, K. N.; Leach, A. G.; Cheong, P. H. Y.; Burke, M. D.;
Lloyd-Jones, G. C. Nat. Chem. 2016, 8, 1067-1075.
(18) (a) Perrin, C. L.; Dong, Y. J. Am. Chem. Soc. 2007, 129, 4490-
4497. (b) Pehk, T.; Kiirend, E.; Lippmaa, E.; Ragnarrsson, U.;
Grehn, L. J. Chem. Soc. Perk., Trans 2 1997, 445-450.
(19) Re-treatment of the PNP ester products under the reaction
conditions resulted in no epimerization of the products.
(20) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215−241
(21) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972,
56, 2257–2261.
REFERENCES
(1) (a) Sweeney, J. B. Chem. Soc. Rev. 2009, 38, 1027-1038. (b)
West, T. H.; Spoehrle, S. S. M.; Kasten, K.; Taylor, J. E.;
Smith, A. D. ACS Catal. 2015, 5, 7446-7479.
(2) Clark, J. S. Nitrogen, Oxygen, and Sulfur Ylide Chemistry: A
Practical Approach in Chemistry; Oxford University Press:
New York, 2002.
(3) Kennedy, C. R.; Guidera, J. A.; Jacobsen, E. N. ACS Cent. Sci.
2016, 2, 416-423.
(4) Biswas, B.; Collins, S. C.; Singleton, D. A. J. Am. Chem. Soc.
2014, 136, 3740-3743.
(5) (a) Soheili, A.; Tambar, U. K. J. Am. Chem. Soc. 2011, 133,
12956-12959. (b) Nash, A.; Soheili, A.; Tambar, U. K. Org.
Lett. 2013, 15, 4770-4773. (c) Soheili, A.; Tambar, U. K. Org.
Lett. 2013, 15, 5138-5141.
(6) Wu, Y. D.; Houk, K. N.; Marshall, J. A. J. Org. Chem. 1990,
55, 1421-1423.
(7) Workman, J. A.; Garrido, N. P.; Sançon, J.; Roberts, E.; Wes-
sel, H. P.; Sweeney, J. B. J. Am. Chem. Soc. 2005, 127, 1066-
1067.
(8) (a) Blid, J.; Panknin, O.; Somfai, P. J. Am. Chem. Soc. 2005,
127, 9352-9353. (b) Blid, J.; Panknin, O.; Tuzina, P.; Somfai,
P. J. Org. Chem. 2007, 72, 1294-1300.
(22) Frisch, M. J. et al. Gaussian 09 (Gaussian, Inc., Wallingford
CT, 2009). See supporting information for full citation.
(23) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213–
222.
(24) Miertus,̌ S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55,
117−129.
(25) (a) Wheeler, S. E.; Seguin, T. J.; Guan, Y.; Doney, A. C. Acc.
Chem. Res. 2016, 49, 1061–1069. (b) Sunoj, R. B. Acc. Chem.
Res. 2016, 49, 1019–1028. (c) Walden, D. M.; Ogba, O. M.;
Johnston, R. C.; Cheong, P. H.-Y. Acc. Chem. Res. 2016, 49,
1279–1291. (d) Gould, E.; Walden, D. M.; Kasten, K.; John-
ston, R. C.; Wu, J.; Slawin, A. M. Z.; Mustard, T. J. L.; John-
ston, B.; Davies, T.; Cheong, P. H.-Y. and Smith, A. D. Chem.
Sci., 2014, 5, 3651–3658.
(26) Bigeleisen, J.; Mayer, M. G. J. Chem. Phys. 1947, 15, 261–267.
(9) Isothioureas have been widely explored as Lewis base cata-
lysts across a range of organocatalytic processes. For a sem-
11
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 13
(27) (a) Fong, A.; Meyer, M. P.; O’Leary, D. J. Molecules 2013, 18,
energetic accessibility of conformers and complexes indi-
1
2
3
4
5
6
7
8
2281–2296. (b) O’Leary, D. J.; Rablen, P. R.; Meyer, M. P.
Angew. Chem. Int. Ed. 2011, 50, 2564–2567.
(28) (a) Northrop, D. B. J. Am. Chem. Soc. 1999, 121, 3521–3524.
(b) Bell, R. P. The Tunnel Effect in Chemistry. New York:
Chapman and Hall; 1980. (c) Bell, R. P. Chem. Soc. Rev.
1974, 4, 513–544.
(29) Kinetic isotope effects calculated using the Onyx program:
Brueckner, A. C.; Cevallos, S. L.; Ogba, O. M.; Walden, D.
M.; Meyer, M. P.; O’Leary, D. J. ; Cheong, P. H.-Y. Onyx, ver-
sion 1.0; Oregon State University: Corvallis, OR, USA, 2016.
(30) Deprotonation by iPr2NH was also computed, but gave a
much higher barrier of 20.5 kcal·mol–1. See supporting in-
formation for structural details.
(31) The presence of an ylide intermediate has been confirmed
in the closely related [1,2]-Stevens rearrangement of ammo-
nium acetophenones: Capobianco, A.; Caruso, T.; Palombi,
L.; Peluso, A. Electrochim. Acta 2013, 92, 446–451.
(32) Bedin, M.; Karim, A.; Reitti, M.; Carlsson, A-C. C.; Topić, F.;
Cetina, M.; Pan, F.; Havel, V.; Al-Ameri, F.; Sindelar, V.; Ris-
sanen, K.; Gräfenstein, J.; Erdélyi, M. Chem. Sci. 2015, 6,
3746–3756.
(33) Free energy span is the energetic counterpart of turnover
frequency: (a) Rohmann, K.; Hölscher, M.; Leitner, W. J.
Am. Chem. Soc. 2016, 138, 433–443. (b) Yu, Z.-X.; Cheong, P.
H.-Y.; Liu, P.; Legault, C. Y.; Wender, P. A.; Houk, K. N. J.
Am. Chem. Soc. 2008, 130,2378–2379. (c) Kozuch, S.; Shaik,
S. J. Am. Chem. Soc. 2006, 128, 3355–3365.
(34) Plata, R. E.; Singleton, D. A. J. Am. Chem. Soc. 2015, 137,
3811–3826.
(35) Świderek, K.; Paneth, P. Chem. Rev. 2013, 113, 7851–7879.
(36) Hirschi, J. S.; Takeya, T.; Hang, C.; Singleton, D. A. J. Am.
Chem. Soc. 2009, 131, 2397–2403.
cates that explicit solvation and dynamics also play a role.
(39) Computed bond orders using NBO analysis indicated eno-
late character for ylide VII. TS-VIII lies in between dication
V and ylide VII in terms of enolate-like character. See SI for
details.
(40) For S•••O interactions as control elements in isothiourea
catalysis, see: (a) Robinson, E. R. T.; Walden, D. M.; Fallan,
C.; Greenhalgh, M. D.; Cheong, P. H.-Y.; Smith, A. D. Chem.
Sci. 2016, 7, 6919-6927. (b) Abbasov, M. E.; Hudson, B. M.;
Tantillo, D. J.; Romo, D. J. Am. Chem. Soc. 2014, 136, 4492–
4495. (c) Liu, P.; Yang, X.; Birman, V. B.; Houk, K. N. Org.
Lett. 2012, 14, 3288–3291. (d) Birman, V. B.; Li, X.; Han, Z.
Org. Lett. 2007, 9, 37–40. For an alternative use of non-
bonded S•••O interactions in asymmetric synthesis see Na-
gao, Y.: Miyamote, S.; Miyamoto, M.; Takeshige, H.;
Hayashi, K.; Sano, S.; Shiro, M.; Yamaguchi, K.; Sei, Y. J. Am.
Chem. Soc. 2006, 128, 9722-9729.
(41) NBO calculation by Romo and Tantillo suggest a number of
orbital interactions responsible for the conformational pref-
erence. See 35b. For additional discussions on the origin of
the S•••O interaction, see: (a) Beno, B. R.; Yeung, K.-S.;
Bartberger, M. D.; Pennington, L. D.; Meanwell, N. A. J.
Med. Chem. 2015, 58, 4383–4438. (b) Zhang, X.; Gong, Z.; Li,
J.; Lu, T. J. Chem. Inf. Model. 2015, 55, 2138–2153. Fairlie has
suggested electrostatic attraction and dipole minimization.
See: (c) Reid, R. C.; Yau, M.-K.; Singh, R.; Lim, J.; Fairlie, D.
P. J. Am. Chem. Soc. 2014, 136, 11914–11917.
(42) (a) Wheeler, S. E.; Bloom, J. W. G. J. Phys. Chem. A 2014, 118,
6133–6147. (b) Yang, X.; Liu, P.; Houk, K. N.; Birman, V. B.
Angew. Chem. Int. Ed. 2012, 51, 9638–9642. (c) Yang, X.;
Bumbu, V. D.; Birman, V. B. Org. Lett. 2011, 13, 4755–4757.
(d) Yamada, S.; Fossey, J. S. Org. Biomol. Chem. 2011. 9,
7275–7281. (e) Wheeler, S. E.; Houk, K. N. J. Am. Chem. Soc.
2009, 131, 3126–3127. (f) Zhao, Y.; Cotelle, Y.; Sakai, N.; Ma-
tile, S. J. Am. Chem. Soc. 2016, 138, 4270-4277. (g) Kennedy,
C. R.; Lin, S.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2016, 55,
12596-12624.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(37) Structure images generated using the CylView molecular
visualization program: Legault, C. Y. CYLview, version 1.0b;
Université de Sherbrooke: Quebec, Canada, 2009;
http://www.cylview.org.
(38) Bromide coordination to the TS is likely weak, as evidenced
by the minor difference in energy between bromide coordi-
nated TS and uncoordinated TS (0.4 kcal·mol–1 favoring no
counterion, Figure 6). This suggests a Boltzmann-weighted
distribution of KIEs contributes to the experimentally ober-
served KIE. The Boltzmann averaged KIE from the static
TSs matches the observed KIE. However, the flexibility and
(43) Krenske, E. H.; Houk, K. N. Acc. Chem. Res. 2013, 46, 979–
989.
(44) The research data underpinning this publication can be
found at DOI: http://dx.doi.org/10.17630/0dbeff98-db91-
4051-803c-24e46c073f22.
12
ACS Paragon Plus Environment

Page 13 of 13
Journal of the American Chemical Society
TOC Graphic
1
2
3
4
5
6
O
N
O
Ph
endo
Ph
Br
Ph
(S)
cation
PNPO
Me
S
N
PNPO
(S)
H/D
S•••O
N
(+)-BTM (20 mol%)
N
Me
Me
Me
7
8
9
• Kinetic analysis • Isotopic labelling • Computations
Competition KIEs • Onyx KIE program • Additive effects
O
Ph
Sigmatropic [2,3]
KIEexp = 1.031
KIEcomp =1.028
(S)
Productive BTM-substrate intermediate
identified by 15N and 13C labelling
R3N
(S)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
Me
Me
13
ACS Paragon Plus Environment