Chiral Br?nsted Acid Catalyzed Enantioselective Dehydrative Nazarov-Type Electrocyclization of Aryl and 2-Thienyl Vinyl Alcohols

Article abstract of DOI:10.1021/jacs.8b02339

An efficient chiral Br?nsted acid-catalyzed enantioselective dehydrative Nazarov-type electrocyclization (DNE) of electron-rich aryl- and 2-thienyl-β-amino-2-en-1-ols is described. The 4π conrotatory electrocyclization reaction affords access to a wide variety of the corresponding 1H-indenes and 4H-cyclopenta[b]thiophenes in excellent yields of up to 99% and enantiomeric excess (ee) values of up to 99%. Experimental and computational studies based on a proposed intimate contact ion-pair species that is further assisted by hydrogen bonding between the amino group of the substrate cation and chiral catalyst anion provide insight into the observed product enantioselectivities.

Full text of DOI:10.1021/jacs.8b02339

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Chiral Brønsted Acid Catalyzed Enantioselective Dehydrative
Nazarov-type Electrocyclization of Aryl and 2-Thienyl Vinyl Alcohols
Jianwen Jin, Yichao Zhao, Ali Gouranourimi, Alireza Ariafard, and Philip Wai Hong Chan
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 09 Apr 2018
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Journal of the American Chemical Society
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Chiral Brønsted Acid Catalyzed Enantioselective Dehydrative Naza-
rov-type Electrocyclization of Aryl and 2-Thienyl Vinyl Alcohols
†
†
§
§,
†,‡,
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Jianwen Jin, Yichao Zhao, Ali Gouranourimi, Alireza Ariafard, * and Philip Wai Hong Chan *
†
School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
‡
Department of Chemistry, University of Warwick, Coventry, CV4 7AL, United Kingdom
§
School of Physical Sciences–Chemistry, University of Tasmania, Hobart, Tasmania 7001, Australia
Supporting Information Placeholder
ABSTRACT: An efficient chiral Brønsted acid-catalyzed enantioselective dehydrative Nazarov-type electrocyclization (DNE) of
electron-rich aryl- and 2-thienyl-b-amino-2-en-1-ols is described. The 4p conrotatory electrocyclization reaction affords access to a
wide variety of the corresponding 1H-indenes and 4H-cyclopenta[b]thiophenes in excellent yields of up to 99% and enantiomeric
excess (ee) values of up to 99%. Experimental and computational studies based on a proposed intimate contact ion-pair species that
is further assisted by hydrogen bonding between the amino group of the substrate cation and chiral catalyst anion provide insight
into the observed product enantioselectivities.
(
Scheme 1a). This is followed by elimination of a molecule of
INTRODUCTION
water to give the substrate cation, with one or more of the
remaining pendant electron-rich (hetero)aryl or vinyl groups
facilitating the dehydration step by stabilizing the putative
carbocationic species. Subsequent 4p conrotatory electrocy-
clization would then deliver the cyclopenta-1,3-dienyl ring
system with product enantioselectivity believed to be deter-
mined by this latter step. However, this has often been thought
to be challenging due to the limited stereoelectronic interac-
tions creating a poorly-defined stereochemical environment in
The Nazarov cyclization of divinyl and (hetero)aryl vinyl ke-
tones mediated by a Brønsted or Lewis acid is among one of
the most powerful and efficient methods for the synthesis of
cyclopentenone derivatives (Scheme 1). A reflection of this
is its frequent use in synthetic strategies to natural and synthet-
ic compounds of current biological and materials interest con-
taining the structural motif or as a building block. This func-
tional group transformation has also inspired the development
of new 4p electrocyclization processes that has included the
DNE of electron-rich divinyl and (hetero)aryl vinyl alcohols to
cyclopenta-1,3-dienes (Scheme 1a).
cyclization, an asymmetric variant of the DNE reaction, either
by using a chiral auxiliary or catalyst, by contrast, has so far
remained a challenge (Scheme 1a).
1
–6
2
,3
4
i
the proposed acyclic precursor I shown in Scheme 1a. In this
context, we were drawn to the potential enantioselective DNE
chemistry of this compound class with a pendant amino group
4–6
Unlike the Nazarov
1,6
catalyzed by a chiral Brønsted acid (BAH*, Scheme 1b). We
reasoned this would provide the corresponding intimate ion-
pair species II in which the amino group of the associated
cation of the substrate and anion of the chiral catalyst can ad-
ditionally participate in hydrogen bonding interactions. With
the chiral Brønsted acid anion now occupying one face of the
substrate cation as a result, this might then allow asymmetric
induction in the ensuing pericyclic reaction step to be accom-
plished to give the pentacyclic product in an enantioselective
manner. Herein, we report the details of this study that offers
an expedient route to these two potentially useful members of
the 1H-indene and 4H-cyclopenta[b]thiophene compound
3
,5
Scheme 1. The Nazarov Cyclization and DNE of Divinyl
and (Hetero)aryl Vinyl Ketones and Alcohols
(a) previous works:
Nazarov
cyclization
O
*
X
DNE
Het/
Ar
Het/
Ar
R
Het/
Ar
Het/
Ar
Brønsted
or
R
Brønsted
or
R
R
2
Lewis acid 1, X = O
3, X = OH
Lewis acid
I
4
√
many elegant
× asymmetric DNE remains a challenge
enantioselective examples
(b) this work, proposed strategy to induce chirality:
7
BA*
HO R1
R1
family in excellent yields and enantioselectivities. A density
functional theory (DFT) calculation on the origin of the ob-
served product enantioselectivities is also presented.
R1
H
N
NHR2
Ar2
BAH*
NHR2
Ar2
BA*
Het/
Ar1
Het/
Ar1
R2
–HOH
Het/
Ar1
Ar2
3
I
II
R
R1 BA*
1
RESULTS AND DISCUSSION
4
π-electro-
cyclization
NHR2
Het/
–BAH* Ar1
NHR2
Het/
Ar1
We began our studies by examining the chiral Brønsted acid-
mediated enantioselective DNE of 3a to establish the optimum
reaction conditions (Table 1). This initially revealed subjecting
the substrate to 5 mol % of chiral N-triflyl phosphoramide (S)-
A, 4 Å molecular sieves (MS) in toluene at 25 °C for 1 h gave
4a in 95% yield and an ee value of 63% (entry 1). The struc-
ture and absolute stereochemistry of the carbocyclic adduct
*
Ar2
H
Ar
2
III
4
From a mechanistic viewpoint, the Brønsted acid-mediated
DNE reaction is thought to involve initial protonation of the
alcohol motif in the electron-rich substrate by the catalyst
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Journal of the American Chemical Society
Page 2 of 8
was determined by NMR measurements and X-ray crystallo-
graphic analysis of two closely related products vide infra. An
examination of other chiral Brønsted acid catalysts showed the
performance of (S)-B, (S)-C, (S)-D, (S)-E, (S)-F, (S)-G and
and the substrate was recovered in near quantitative yield (en-
try 14).
With the reaction conditions established, we next sought to
evaluate the generality of the present procedure using a series
of electron-rich aryl-b-amino-2-en-1-ols 3b–w (Table 2).
Overall, the (S)-C-catalyzed reaction conditions were shown
to be broad, providing a family of 1H-indenes 4b–w contain-
ing a variety of substitution patterns in excellent yields and ee
values from the corresponding substrates. Reactions of starting
8
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
S)-H for 1–12 h gave product yields of 74–99% along with ee
values of 30–73% (entries 2, 3, and 9–13). Likewise, the anal-
ogous control reactions mediated by (S)-C in which toluene
was replaced by dichloromethane or 1,2-dichloroethane as the
solvent were found to give product yields of 92 and 94% along
with ee values of 40 and 45%, respectively (entries 4 and 5).
Our subsequent studies found that repeating the (S)-C-
catalyzed reaction in toluene as the solvent at –60 °C for 36 h
gave the best result, providing the 1H-indene product in 95%
yield and 95% ee (entry 7). However, increasing the reaction
temperature to –40 °C for 24 h or decreasing it to –78 °C for
materials with
a
pendant para-substituted electron-
withdrawing phenyl (3b,c), ptolyl (3d), or 2-naphthyl (3e)
group at the alkenyl carbon center were found to react well,
giving 4b–e in 93–99% yield and 94.5–95% ee. Likewise,
electron-rich substrates containing an acetylenic motif with a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Enantioselective DNE of Aryl-
b
-amino-2-en-1-ols
4
8 h was found to lead to slightly lower product yields of 94
a
3
b–w Catalyzed by (S)-C
and 82% and ee values of 91 and 82%, respectively (entries 6
and 8). In a final control experiment with the less acidic chiral
phosphoric acid (S)-I as the catalyst, no reaction was detected
R1
HO R1
(S)-C (5 mol %)
R2
Ar
NHTs
R2
4
Å MS, toluene, 0.05 M
NHTs
3b–w
Table 1. Optimization of the Reaction Conditions for the
25 or –60 °C, 0.5 or 36 h
Ar
4b–w
a
Chiral Brønsted Acid-Mediated Asymmetric DNE of 3a
OMe
NHTs
R
OMe
OMe
OMe
Bn
catalyst (5 mol %)
HO
4
Å MS, toluene
.05 M, T, t
NHTs
Ph
NHTs
0
MeO
MeO
NHTs
NHTs
MeO
MeO
MeO
Ph
Ph
3
a
4a
A, Ar = Ph, X = NTf
B, Ar = 4-tBuC H , X = NTf
C, Ar = 4-biphenyl, X = NTf
D, Ar = 3,5-(CF , X = NTf
E, Ar = 2,4,6-(iPr) , X = NTf
F, Ar = 1-naphthyl, X = NTf
G, Ar = 9-phenanthryl, X = NTf
H, Ar = 1-pyrenyl, X = NTf
Ar
4b, R = F (93%, 94.5% ee)
c, R = Br (99%, 95% ee)
4d, R = Me (99%, 94.5% ee)
4e, (99%, 94.5% ee)
4f, (99%, 92% ee)
b
6
4
4
R
3 2 6 3
) C H
C H
3 6 2
O
O
O
( )n
P
XH
Ar
3 6 2
I, Ar = 2,4,6-(iPr) C H , X = O
NHTs
NHTs
b
c
entry catalyst T (°C)
t (h)
1
yield (%)
95
ee (%)
63
35
73
40
45
91
95
82
30
58
66
60
54
-
MeO
Me
O
NHTs
Ph
Ph
Me
O
1
2
3
(S)-A
(S)-B
(S)-C
(S)-C
(S)-C
(S)-C
(S)-C
(S)-C
(S)-D
(S)-E
(S)-F
(S)-G
(S)-H
(S)-I
25
25
Ph
b
4
g, (99%, 92% ee)b
4h, n = 1 (89%, 90% ee)b
i, n = 4 (99%, 95% ee)b
4j, R = H (99%, 99% ee)
1
95
4k, R = Me (95%, 94% ee)b
4
(95%, 94% ee)b
25
1
99
4l, R = CF
3
S
Ph
Ph
d
4
5
25
1
92
R2
e
25
1
94
R1
NHTs
NHTs
6
–40
–60
–78
25
24
36
48
1
94
NHTs
R
Me
O
7
8
95
Me
O
Ph
Ph
Ph
4m, (95%, 86% ee)b
4n, R = F (99%, 92% ee)b
o, R = Cl (99%, 92.5% ee)b
4p, R = OBn (99%, 99% ee)
4q, R1 = F, R2 = H
82
4
(99%, 89% ee)b
9
93
b
4r,
R
1
= Cl, R
2
= H
(99%, 91.5% ee)b
Ph
Ph
10
25
12
1
97
s, R1 = H, R2 = F
4
(94%, 96.5% ee)b
1
1
1
1
2
3
4
25
74
25
1
99
NHTs
NHTs
Me
O
Me
O
25
1
97
f
NHTs
1
a
25
24
-
Me
O
All reactions were performed at the 0.1 mmol scale with
mol % of catalyst, 4 Å MS (100 mg) in toluene (2 mL) at
given temperature and time. Isolated yield. Ee values were
determined using an AD-H chiral column (eluent: nhex-
R
Ph
b
R
=
M
e
(
9
9
%
,
9
3
.
5
%
e
e
)
4v, (76%, 94% ee)b
4w, (95%, 0% ee)
4
4
t
,
5
(96%, 96% ee)b
u, R = CF
3
b
c
a
All reactions were performed at the 0.1 mmol scale with 5
d
mol % of (S)-C, 4 Å MS (100 mg) in toluene (2 mL) at –60 °C
for 36 h. Values in parentheses denote isolated product yields
and ee values determined using an AD-H chiral column (elu-
ane:iPrOH = 9:1). Reaction conducted with CH
2
2
Cl as the
as the solvent.
1
e
solvent. Reaction conducted with (CH
2
Cl)
2
f
No reaction detected by TLC analysis and H NMR meas-
b
ent: nhexane:iPrOH = 9:1). Reaction conducted at 25 °C for
urements with recovery of 3a in 99% yield.
0
.5 h.
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phenethyl (3f), vinyl (3g), cycloalkyl (3h,i), aryl (3j–l), or 2-
thienyl (3m) substituent in place of an anisyl group were
found to have minimal influence on the outcome of the reac-
tion. In these experiments, which could be conducted at 25 °C,
the corresponding 1H-indene products 4f–m were afforded in
gave 4
ues of 91 and 89%. The reactions of substrates containing a 2-
benzothienyl (3 ) or N-methyl indolyl (3 ) group in place of
the 2-thienyl moiety at the carbinol carbon center were ob-
served to be the only exception. In these experiments, the cor-
and 4 in respective yields of 88 and 84% and ee val-
b g
1
2
3
4
5
6
7
8
9
d
e
8
9–99% yield and 86–99% ee with the (8R) absolute configu-
responding tricyclic adducts 4
and 4 were afforded as a
d e
8
ration of 4j established by X-ray crystallography. Added to
this, starting 1,4-enynols containing an aryl motif with elec-
tron-donating and/or -withdrawing substituent at various posi-
tons of the ring at the carbinol or alkynyl carbon center, as in
racemate in respective yields of 76 and 62%. On the other
hand, in all the above experiments, no other cyclic adducts that
could be formed from competitive arylation of the aryl vinyl
group of the substrate or product isomerization was detected
1
3
n–v, gave the corresponding carbocycles 4n–v in 76–99%
by H NMR analysis of the crude mixtures.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
yield and 89–99% ee. The reaction of 3w containing a cyclo-
hexyl motif at the carbinol carbon center was the only instance
to give the corresponding 1H-indene adduct 4w as a racemate
in 95% yield.
A tentative mechanistic rationale for the origin of the prod-
uct enantioselectivities obtained in the present chiral Brønsted
acid-catalyzed asymmetric DNE reactions is presented in Fig-
ure 1. Using 3j as a representative example, this might initially
involve protonation of the substrate by the chiral Brønsted
acid to give the carbocationic species Ij and Ij' and the cata-
lyst anion (S)-C' on release of a molecule of water. Building
on the premise put forward in Scheme 1b that chiral induction
might then be achieved in the ion-pair species forming step,
this would give the four possible conformers IIj , IIj , IIj'
Having established the generality of the reaction conditions
that gave 1H-indenes, we next examined the scope of the
methodology for the enantioselective synthesis of 4H-
cyclopenta[b]-fused heterocycles (Table 3). With this in mind,
the (S)-C-mediated enantioselective DNE of electron-rich 2-
thienyl-substituted 1,4-enynols 3x–
tif contained an aryl group were first examined. This led us to
find that the corresponding S-heterocycles 4x– could be fur-
a
in which the alkyne mo-
a
b
a
and IIj' . In all four cases, we surmise that the amino motif
b
a
hydrogen atom in the ion-pair species acts as a directing group
through its ability to hydrogen bond with the catalyst anion,
thereby determining whether it sits on the re or si face of the
nished in 82–91% yield and 83–88% ee. Under similar condi-
tions, the reaction of substrates with a pendant 7-methoxy-2-
naphthyl (3
b
) or 2-thienyl (3
g
) on the acetylenic carbon center
Ph
Table 3. Enantioselective DNE of 2-Heteroaryl-
b
-amino-2-
HO
a
en-1-ols 3x–
e
Catalyzed by (S)-C
Ph
NHTs
R
MeO
R
3j
(
S)-C −H O
2
HO
X
(S)-C (5 mol %)
(
a)
(b)
H
X
Ph
4
Å MS, toluene, 0.05 M
25 °C, 0.5 h
NHTs
Ph
H
Ph
Ph
Ts
NHTs
Ts
N
N
Ph
Ph
3
x–ε
4x–ε
MeO
OMe
MeO
R2
Ij
Ij'
(
S)-C'
(S)-C'
R1
*
*
*
*
O
O
O
O
P
O
O
O
O
OMe
MeO
P
OMe
P
MeO
P
NTf
O NTf
TfN
O
TfN
O
S
O
H
H
H
H
HH
Ph
H
H
S
NHTs
Ph
Ph
Ph
Ph
NHTs
H
H
N
H
N
N
H
N
Ph
Ph
Ph
Ph
x, R1 = R2 = H (91%, 83% ee)
Ts
IIjb
Ts
IIja
Ts
Ts
Ph
IIj'b
IIj'a
4β, (88%, 91% ee)
4
4y, R1 = H, R2 = Me (91%, 87% ee)
counterclockwise
clockwise
counterclockwise
O
clockwise
4
4
z, R1 = H, R2 = F (82%, 83.5% ee)
α, R1 = Me, R2 = OMe (90%, 88% ee)
*
*
*
*
O
P
O
O
O
O
O
P
O
S
Ph
P
P
O
Ph
Ph
O
O
Ph
Ph
O
NTf
TfN
H
NTf
Ts
Ts
TfN
Ts
Ts
H
H
H
N
N
H
N
N
X
H
S
NHTs
H
Ph
H
Ph
Ph
Ph
H
NHTs
H
H
H
IIIj
Ph
OMe
MeO
OMe
MeO
Ph
IIIj
b
IIIj
a
IIIj'
b
'
a
4
γ, (84%, 89% ee)
4δ, X = S (76%, 0% ee)
4ε, X = NMe (62%, 0% ee)
a
All reactions were performed at the 0.1 mmol scale with 5
(
S)-4j
(R)-4j
(S)-4j
(R)-4j
mol % of (S)-C, 4 Å MS (100 mg) in toluene (2 mL) at 25 °C
for 36 h. Values in parentheses denote isolated product yields
and ee values, determined using an AD-H chiral column (elu-
ent: nhexane:iPrOH = 9:1).
Figure 1. Proposed mechanistic rationale for the product en-
antioselectivities obtained for the (S)-C-catalyzed asymmetric
DNE of electron-rich aryl- and 2-thienyl-b-amino-2-en-1-ols
represented by 3j.
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Journal of the American Chemical Society
Page 4 of 8
substrate cation. For IIj
clization of the ion-pair species would lead to IIIj
a
, clockwise 4p conrotatory electrocy-
being
sistent with this are our findings in a control reaction with the
N,N-disubstituted substrate 3 under the (S)-C-catalyzed con-
ditions described in Scheme 2, which gave 4 in 99% yield
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
z
formed with the resulting acidic aryl proton (labeled red in
Figure 1a) and chiral Brønsted acid anion positioned on the
same face of the cyclic adduct. This is important as we reason
it would permit the facile deprotonation and re-aromatization
of the Wheland-type intermediate IIIj
acid anion to deliver the product (R)-4j. Conversely, the
counterclockwise pericyclic reaction of IIj would give IIIj
whereby the acidic aryl proton and chiral Brønsted acid anion
are now situated on the opposite faces of the carbocyclic cati-
on. As a consequence, this might prevent the deprotonation
step from occurring and the formation of this cyclic carbo-
cation is anticipated to lead to a dead end unless it undergoes
the reverse reaction. A second possibility is that intermediate
z
and 0% ee. The posited involvement of the ion-pair species II
would explain the marked differences in product ee values
obtained for the reactions of 3a in toluene, dichloromethane
and 1,2-dichloroethane detailed in Table 1, entries 3–5. It
might be expected that is an increase in interactions between
the substrate cation and catalyst anion with the reaction medi-
um as the solvent dielectric constant (e) increases on going
from toluene (e = 2.4, 290 K) to dichloromethane (e = 9.2, 288
a
by the chiral Brønsted
9
b
b
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10
K) and 1,2-dichloroethane (e = 11.0, 288 K). As a conse-
quence, this may disrupt the ability of the substrate cation and
catalyst anion to form a tight ion-pair species, resulting in a
decrease in product ee values. We reason a similar rationale
IIIj
ity of which is dependent on the size of the water cluster
O) involved in the process. However, this was thought to
b
could be deprotonated if water serves as a base, the abil-
could be in play in the reactions of 3w, 3 and 3 that led to
d e
the corresponding products being obtained as a racemate. The
presence of a bulky cyclohexyl or benzofused ring in these
substrates might provide sufficient unfavorable steric interac-
tions to prevent the substrate cation and catalyst anion forming
the requisite intimate ion-pair species II.
(
H
2
n
be less likely based on our experience predicting such depro-
tonations to require an activation energy of ca 17 kcal/mol,
which is higher than that required for the conversion of IIj
IIIj vide infra. As illustrated in Figure 1b for the path-
ways involving IIj' and IIj' , a similar rationale would ac-
a
®
a
Scheme 2. Control Experiment with 3
z
a
b
Ph
count for the preferential outcome of the enantiomer (S)-4j. In
this regard, our hypothesis predicts that product formation can
Ph
(
S)-C (5 mol %)
HO
only come from pathways involving the ion-pair species IIIj
and IIIj' with the dominant ion-pair species in solution being
a
Me
N
Ts
Ph 4 Å MS, toluene, 0.05 M
25 °C, 0.5 h
b
N
MeO
the former in view of a product ee value of 99%. It also im-
plies that the catalyst anion may not preferentially occupy one
face of the substrate cation in an ion-pair species containing a
tertiary amino substituent. In the absence of the directing
group, this might subsequently allow both the clockwise and
counterclockwise pericyclic reaction pathways to be operative
MeO
Ts
3ζ
Me
Ph
4ζ, 99% yield, 0% ee
To verify the proposed mechanistic rationale for the ob-
served product enantioselectivities outlined in Figure 1, we
performed a series of DFT calculations. As summarized in
Figure 2, a number of transition states and intermediates were
in equal measure and give the product as a racemate. Con-
*
O
O
Ph
H
H
Ph
Ts
Ts
P
N
N
TfN
O
Ph
*
H
Ph
Ph
O
O
P
*
N
2.6 (2.4)
Ts
Ph
H H
O
Ph
Ij'
Ij
OMe
O
O
MeO
NTf
Ph
H
P
0
.0 (0.0)
N
Ts TfN
O
*
*
Ts
Ph
N
H
O
O
O
O
H
H
MeO
-
H
H
TSIIj'
8.9 (-25.4)
b
-IIIj'b
P
P
Ph
TfN
O
TfN
O
TSIIja-IIIja
OMe
-15.5 (-32.5)
(
S)-C'
(S)-C'
OMe
TSIIIja-(R)-4j
Ph
-20.3 (-33.4)
TsHN
Ph
11.3
-23.3 (-42.2)
*
-26.7 (-41.5)
-26.8 (-42.6)
*
*
O
O
P
(R)-4j OMe
O
O
O
*
OH
NTf
*
+
*
O
P
O
O
P
NHTf
O
Ph
O
P
O
O
P
O
NTf
(S)-4j
(S)-C
MeO
H
O
O
H
(S)-C''
TfN
P
OMe
-45.3 (-47.2)
O
OMe
-45.5 (-46.2)
N
S
CF3
H
O
NTf
O
N
(R)-4j
Ph
Ts
O
O
H
1.807 A
Ph
H
H
H
H
H
-48.7 (-48.9)
Ph
N
Ph
O
O
O
P
H
Ph
*
Ts
H
N
H
N
NHTf
Ph
O
Ph
IIj'
b
1.751 A
(S)-C
Ts
IIj
Ts
OMe
IVj
a
a
IIIj
a
pathway b
pathway a
Figure 2. Energy profile of pathways a and b for the (S)-C-catalyzed enantioselective DNE of 3j to (R)-4j and (S)-4j, respectively.
Structures IIj and IVj show short P=O···HN and S=O···HN interactions (1.751, 1.807 Å) that indicate hydrogen bonding. The rela-
tive Gibbs and potential energies (in parentheses) obtained from M06-CPCM/6-31+G(d,p)//B3LYP-CPCM/6-31G(d) calculations
are given in kcal/mol and bond lengths in Å.
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produced in the two possible reaction pathways a and b from
3a in the absence of the Brønsted acid revealed the pericyclic
reaction step required an activation energy of 13.7 kcal/mol
(Figure 3b). This implied that 3a was intrinsically more reac-
tive than 3j toward carbocyclic ring formation and is in good
agreement with the need for lower experimental temperatures
of –60 °C to achieve chiral induction in such diaryl-substituted
substrates. The source of this greater reactivity was attributed
to the steric demand of the aryl ring limiting its ability to stabi-
lize the cationic charge by p-conjugation in Ia, as corroborated
by the much longer C1–C2 bond distance in the carbocation
species than in Ij (cf. Figures 3a and 3b). As with 3j, the ex-
perimentally observed product enantioselectivity obtained
from 3a was found to be a result of conformer Ia being 2.4
kcal/mol more stable than that of conformer Ia'.
1
2
3
4
5
6
7
8
9
Ij and Ij' to the corresponding (R) and (S) enantiomers of 4j.
On the basis of these calculations, pathway a was revealed to
be favored with rotation from Ij to Ij' shown to be endergonic
by 2.6 kcal/mol. Accordingly, the latter conformer was found
to be sparsely populated, which is in good agreement with our
experimental findings showing (R)-4j being afforded in 99%
ee. This was followed by the interaction of the substrate cation
with (S)-C', which lowers the energy of the carbocationic spe-
cies by >26 kcal/mol. As such, the ensuing ion-pair species
a
IIj functioned as a thermodynamic sink that prevented inter-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
conversion between the two substrate cation conformers. In the
ion-pair species, the chiral Brønsted acid anion was found to
be located on the re face of the substrate cation due to hydro-
gen bonding interactions between the former and the latter, as
evidenced by a P=O···HN bond distance of 1.751 Å. The ion-
In a final set of calculations, the Gibbs energy on forming
IVj
kcal/mol
CPCM/6-31G(d)
31+G(d,p)//B3LYP-CPCM/6-31G(d)
While the analogous calculations could not be accomplished
for the formation of IIj , these findings nonetheless indicated
a
from Ij and (S)-C' was determined to be –13.3 and –30.8
at the B3LYP-CPCM/6-31+G(d,p)//B3LYP-
and B3LYP-D3-CPCM/6-
level, respectively.
a
pair species IVj depicted in Figure 2, the most stable among
other possible interactions, was also considered. However, this
latter hydrogen bonded ion-pair species was thought to be less
likely as it was found to be 5.4 kcal/mol less stable and had a
slightly longer S=O···HN bond distance of 1.807 Å. Our cal-
culations further suggested clockwise 4p conrotatory electro-
a
that the dispersive interactions implied in Scheme 1b are oper-
ative and play a key role in the stability of the ion-pair species.
cyclization of IIj
energy barrier of 11.3 kcal/mol. For the reaction steps after the
formation of the Wheland-type intermediate IIIj , the Brønsted
a a
to IIIj occurred through TSIIja–IIIja with an
Interestingly, our DFT studies also revealed that if the stere-
oelectronic nature of the amino substituent in the substrate was
changed by replacing the N-Ts motif with a N-Boc group, as in
a
acid anion was found to play a crucial role in the deprotonation
of the adduct. By accepting the aryl proton sitting on the same
face of the catalyst anion, this provided the product (R)-4j and
3 shown in Scheme 3 and Figure S1 in the Supporting Infor-
h
mation (SI), a switch in the stereochemical outcome of the
reaction should be observed. Calculations for the substrate in
the absence of (S)-C at the M06-CPCM/6-31+G(d,p)//B3LYP-
CPCM/6-31G(d) and B3LYP-CPCM/6-311+G(d,p)//B3LYP-
(
S)-C'' via TSIIIja–(R)-4j with an energy barrier of 3.0 kcal/mol.
This implied that the re-aromatization process was more facile
than the preceding carbocyclic ring forming step. Regeneration
of the chiral Brønsted acid catalyst was readily achieved
through tautomerization of (S)-C'', which was found to be
exergonic by 3.2 kcal/mol.
CPCM/6-31G(d) level found I ' to be more stable than I by
h h
0.5 and 1.9 kcal/mol, respectively, which implied the (S)-
enantiomer would be afforded as the major product. Pleasing-
ly, this was supported by our subsequent findings in experi-
In a second set of calculations in the absence of (S)-C, the
activation energy required for the 4p electrocyclization step
was demonstrated to increase by 6.1 kcal/mol, as shown in
Figure 3a. This suggested that the interaction between the cati-
on of the substrate and the anion of the catalyst in TSIIja–IIIja
ments with 3
lyzed by (S)-C under the conditions described in Scheme 3. In
these test reactions, the corresponding 1H-indene adducts 4
and 4 were furnished in respective yields of 95 and 85% and
and its 2-naphthyl substituted analogue 3 cata-
h q
h
q
was stronger than that in IIj
a
. Repeating these calculations for
ee values of 80 and 87% with the (8S) absolute configuration
(a)
Ph
(b)
8
of the former ascertained by X-ray crystallography.
Ts
H
OMe
N
Scheme 3. (S)-C-Catalyzed Asymmetric DNE of 3
h
and 3
q
Ts
H
OMe
H
H
N
OMe
Ph
TSIj-Vj
a
OMe
MeO
H
(
S)-C (5 mol %)
Ph
H
17.4 (16.8)
H
Ts
H
Ph
HO
Ts
TSIa-Va
N
a
N
OMe
4 Å MS, toluene, 0.05 M
60 °C, 36 h
1
3.7 (13.3)
Ar
NHBoc
NHBoc
–
Ph
Ph
MeO
MeO
Ar
MeO
Ij'
MeO
Ia'
3
η, Ar = Ph
4η, 95% yield, 80% ee
4θ, 85% yield, 87% ee
4.9 (3.3)
Ph
3θ, Ar = 2-naphthyl
2
.6 (2.4)
2.4 (2.5)
0.0 (0.0)
3
.9 (2.0)
OMe
Ts
H
0
.0 (0.0)
Ph
CONCLUSIONS
N
OMe
Ts
Ts
Ts
H
H
H
H
In summary, we have developed a chiral Brønsted acid-
catalyzed method for the asymmetric synthesis of 1H-indenes
and 4H-cyclopenta[b]thiophenes from the respective electron-
rich aryl- and 2-thienyl-b-amino-2-en-1-ols. The excellent
product ee values were achieved by realizing the first example
of an enantioselective DNE from a posited chiral ion-pair spe-
cies to asymmetrically assemble the bicyclic ring system. Our
studies suggest the origin of the observed product enantiose-
lectivity was initially due to the more stable conformation of
the substrate cation. The ensuing ion-pair species then acted as
H
Ph
N
N
1
N
1
1
.394 A
1.450 A
H
2
2
Ph
Ph
H
Ph
Vja
OMe
Ij
OMe
Ia
OMe
Vaa
OMe
Figure 3. Energy profiles for the 4p conrotary electrocycliza-
tion step of (a) 3j and (b) 3a in the absence of (S)-C. The rela-
tive Gibbs and potential energies (in parentheses) obtained
from
M06-CPCM/6-31+G(d,p)//B3LYP-CPCM/6-31G(d)
calculations are given in kcal/mol and bond lengths in Å.
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a thermodynamic sink to prevent interconversion between
Page 6 of 8
material is available free of charge via the Internet at
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
these two conformers. Also instrumental was the role of the
amino group in the substrate cation in directing the chiral cata-
lyst anion to preferentially sit on one face of the adduct and the
ability of the latter to efficiently facilitate re-aromatization to
give the product. We envision that the present synthetic meth-
od will encourage the further development of asymmetric
strategies in reactions where there is such intrinsic low direc-
tionality through the installation of a directing group.
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*
phil.chan@monash.edu; p.w.h.chan@warwick.ac.uk (P.W.H.C.)
alireza.ariafard@utas.edu.au (A.A.)
Notes
EXPERIMENTAL SECTION
The authors declare no competing financial interests.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Considerations. All reactions were performed in
oven-dried glassware under a nitrogen atmosphere. Unless
specified, all reagents and starting materials were purchased
from commercial sources and used as received. The chalcones
used in the synthesis of substrates 3 and chiral Brønsted acids
ACKNOWLEDGMENT
This work was supported by
(DP160101682) from the Australian Research Council.
a Discovery Project Grant
1
1,12
REFERENCES
A-I were prepared following literature procedures.
Toluene
was freshly distilled from sodium/benzophenone. Analytical
thin layer chromatography (TLC) was performed using pre-
coated silica gel plate. Visualization was achieved by UV light
(1) Selected reviews on Nazarov and Nazarov-type cyclizations: (a)
Simeonov, S. P.; Nunes, J. P. M.; Guerra, K.; Kurteva, V. B.;
Afonso, C. A. M. Chem. Rev. 2016, 116, 5744. (b) Di Grandi,
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J. ChemCatChem 2011, 3, 1531. (h) Grant, T. N.; Rieder, C. J.;
West, F. G. Chem. Commun. 2009, 5676. (i) Nakanishi, W.;
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(2) Selected recent examples: (a) Krieger, J.; Smeilus, T.;
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Tang, M. L.; Peng, P.; Liu, Z. Y.; Zhang, J.; Yu, J. M.; Sun, X.
Chem. Eur. J. 2016, 22, 14535. (c) Rao, W.; Boyle, J. W.; Chan,
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C.-H.; Chan, P. W. H. Chem. Eur. J. 2015, 21, 9111. (i) Rao,
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(
254 nm). Flash chromatography was performed using silica
gel and gradient solvent system (nhexane:EtOAc as the elu-
1
13
ent). H and C NMR spectra were recorded on 300 and 400
MHz spectrometers. Chemical shifts (ppm) were recorded with
tetramethylsilane (TMS) as the internal reference standard.
Multiplicities are given as: s (singlet), br s (broad singlet), d
(
doublet), t (triplet), dd (doublet of doublets) or m (multiplet).
The number of protons (n) for a given resonance is indicated
by nH and coupling constants are reported as a J value in Hz.
Infrared spectra were taken on a IR spectrometer. High resolu-
tion mass spectra (HRMS) were obtained on a LC/HRMS TOF
spectrometer using simultaneous electrospray (ESI). Ee values
were determined by high performance liquid chromatography
(
HPLC) analysis using a AD-H column. Optical rotations were
measured in CHCl on a polarimeter with a sodium vapor lamp
3
at 589 nm and 10 cm cell (c given in g/100 mL).
General Procedure for (S)-C-Catalyzed Asymmetric DNE
h q
of Aryl Vinyl Alcohols 3a–3e, 3 , 3 and 3w. To a round-
bottom flask was charged the substrate (0.1 mmol), chiral
Brønsted acid (S)-C (3.9 mg, 0.005 mmol, 5 mol %) and 4 Å
MS (100 mg) followed by the addition of toluene (2 mL) at –
6
0 °C. The reaction mixture was stirred at this temperature for
36 h. On completion, the reaction mixture was quenched with
NaHCO (8.4 mg, 0.1 mmol). After warming to room tempera-
2
015, 137, 6350. (j) Wu, Y. K.; Dunbar, C. R.; McDonald, R.;
Ferguson, M. J.; West, F. G. J. Am. Chem. Soc. 2014, 136,
4903. (k) Vaidya, T.; Cheng, R.; Carlsen, P. N.; Frontier, A. J.
3
ture, the reaction mixture was directly passed through a silica
gel column (eluent: nhexane/EtOAc = 8:1) to give the title
compound.
1
Eisenberg, R. Org. Lett. 2014, 16, 800. (l) Rao, W.; Koh, M. J.;
Li, D.; Hirao, H.; Chan, P. W. H. J. Am. Chem. Soc. 2013, 135,
7
926.
General Procedure for (S)-C-Catalyzed Asymmetric DNE
z
of Aryl Vinyl Alcohols 3f–3v and 3x–3 . To a round-bottom
flask was charged the substrate (0.1 mmol), chiral Brønsted
acid (S)-C (3.9 mg, 0.005 mmol, 5 mol %) and 4 Å MS (100
mg) followed by the addition of toluene (2 mL) at 25 °C. The
reaction mixture was allowed to stir at room temperature for
(
3) Selected examples of asymmetric Nazarov cyclizations: (a)
Wang, C.-S.; Wu, J.-L.; Li, C.; Li, L.-Z.; Mei, G.-J.; Shi, F. Adv.
Synth. Catal. 2018, 360, 846. (b) Wang, G.-P.; Chen, M.-O.;
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M.; Cai, P.-J.; Tu, Y.-Q.; Yu, Z.-X.; Chen, Z.-M.; Wang, S.-H.;
Wang, S.-H.; Zhang, F.-M. J. Am. Chem. Soc. 2015, 137, 8344.
(
d) Kitamura, K.; Shimada, N.; Stewart, C.; Atesin, A. C.;
3
0 min. Upon completion, the reaction mixture was directly
passed through a silica gel column (eluent: nhexane/EtOAc =
:1) to give the title compound.
Atesin, T. A.; Tius, M. A. Angew. Chem. Int. Ed. 2015, 54,
6288. (e) Takeda, T.; Harada, S.; Nishida, A. Org. Lett. 2015,
8
1
2
7, 5184. (f) Zi, W.; Wu, H. Toste, F. D. J. Am. Chem. Soc.
015, 137, 3225. (g) Raja, S.; Nakajima, M.; Rueping, M. An-
ASSOCIATED CONTENT
gew. Chem. Int. Ed. 2015, 54, 2762. (h) William, R.; Wang, S.;
Ding, F.; Arviana, E. N.; Liu, X.-W. Angew. Chem. Int. Ed.
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1
Detailed experimental procedures, characterization data and
H
1
3
and C NMR spectra for all starting materials and products, raw
DFT data, XYZ coordinates, and the CIF files for 4j and 4 . This
h
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Journal of the American Chemical Society
9
156. (k) Hutson, G. E.; Turkmen, Y. E.; Rawal, V. H. J. Am.
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Lalli, C.; Bernadat, G.; Maury, J.; Masson, G. Chem. Eur. J.
2018, 24, 3925. (b) James, T.; van Gemmeren, M.; List, B.
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TOC
(
S)–C =
Ph
1
HO
R
1
R
NHR2
(S)–C (5 mol %)
Ar1
S-Het
O
O
O
P
Ar
1
/
/
NHR
2
+ HOH
NHTf
S-Het
4 Å MS, toluene
0.05 M, 25 °C for 0.5 h
or –60 °C for 36 h
*
Ar
2
Ar2
30 examples
up to 99% yield
and 99% ee
Ph
0
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