Enantioselective Halo-oxy- and Halo-azacyclizations Induced by Chiral Amidophosphate Catalysts and Halo-Lewis Acids

Article abstract of DOI:10.1021/jacs.8b02607

Catalytic enantioselective halocyclization of 2-alkenylphenols and enamides have been achieved through the use of chiral amidophosphate catalysts and halo-Lewis acids. Density functional theory calculations suggested that the Lewis basicity of the catalyst played an important role in the reactivity and enantioselectivity. The resulting chiral halogenated chromans can be transformed to α-Tocopherol, α-Tocotrienol, Daedalin A and Englitazone in short steps. Furthermore, a halogenated product with an unsaturated side chain may provide polycyclic adducts under radical cyclization conditions.

Full text of DOI:10.1021/jacs.8b02607

Subscriber access provided by UNIV OF TEXAS ARLINGTON
Communication
Enantioselective Halo-oxy- and Halo-azacyclizations Induced
by Chiral Amidophosphate Catalysts and Halo-Lewis Acids
Yanhui Lu, Hidefumi Nakatsuji, Yukimasa Okumura, Lu Yao, and Kazuaki Ishihara
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02607 • Publication Date (Web): 30 Apr 2018
Downloaded from http://pubs.acs.org on April 30, 2018
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 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 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.
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 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Enantioselective Halo-oxy- and Halo-azacyclizations Induced by
Chiral Amidophosphate Catalysts and Halo-Lewis Acids
Yanhui Lu,† Hidefumi Nakatsuji,†,‡ Yukimasa Okumura, Lu Yao, and Kazuaki Ishihara*
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
Graduate School of Engineering, Nagoya University, B2-3(611), Furo-cho, Chikusa, Nagoya 464-8603, Japan
Supporting Information Placeholder
nium ions can form haliranium ions with alkenes, their
stabilities and reactivities are quite different,18 and thus
the same nucleophilic catalysts do not work equally well
in different halogenations.9b,10j,n,11a,b We have previous-
ly reported the cooperative activation system of I2 using
chiral phosphate catalysts and halo-Lewis acids for the
enantioselective iodolactonization.9f However, the sub-
strate scope is limited to 4-arylmethyl-4-pentenoic acids.
Here, we describe an efficient, enantioselective, and site-
selective (in the presence of multiple olefins) iodo- and
bromocycloetherification of 7 to construct chiral chro-
mans using chiral Lewis basic amidophosphate catalysts
9 (Lb*) and halo-Lewis acids (X–L). Moreover, the
broad applicability of this catalytic system for not only
halo-oxycyclization but also halo-azacyclization is
demonstrated.
ABSTRACT: Catalytic enantioselective halocyclization
of 2-alkenylphenols and enamides have been achieved
through the use of chiral amidophosphate catalysts and
halo-Lewis acids. DFT calculations suggested that the
Lewis basicity of the catalyst played an important role in
the reactivity and enantioselectivity. The resulting chiral
halogenated chromans can be transformed to α-
tocopherol, α-tocotrienol, Daedalin A and Englitazone
in short steps. Furthermore, a halogenated product with
an unsaturated side chain may provide polycyclic ad-
ducts under radical cyclization conditions.
Biologically active compounds with a chiral chroman
skeleton are abundant in nature and synthetic analogues
(Figure 1a).1 In addition to the well-known Vitamin E
family (12, 23), small synthetic chiral chromans have
also been shown to be effective against hyperpigmenta-
tion (34), metabolic disorders (45, 56) and cancers (67).
Asymmetric catalysis has recently emerged as a power-
ful method for building the chiral chroman skeleton.8 In
constructing chiral chromans, it is important to control
the stereoselectivity at position 2. We proposed that
enantioselective halocyclizations of certain 2-
alkenylphenols 7 could deliver chiral centers at position
2 (Figure 1b). Enantioselective alkene halogenation has
been a subject of intense investigation over the past dec-
ade.9–13 Although enantioselective halolactonizations
have been well-documented, enantioselective cycliza-
tions of 7 are still limited to some polyene systems.10l,m
One major issue in the development of catalytic asym-
metric alkene halogenations is the rapid racemization of
chiral haliranium ions through olefin-to-olefin halirani-
um transfer.14 Chiral nucleophilic base-catalyzed halo-
functionalizations have been shown to be effective over
the past decade because of the coordination effect.15
However, there are important differences between io-
donium and bromonium ions: 1) The ionic radius of io-
donium ion is much longer than that of bromonium
ion;16 2) Iodonium ion forms a stronger halogen bond
with Lewis bases;17 3) While both iodonium and bromo-
(a)
R =
HO
HO
OH
1, α-Tocopherol (Antioxidant)
2, α-Tocotrienol (Antioxidant)
O
O
R
3, Daedalin A
(Tyrosinase Inhibitor)
OH
O
OH
O
N
HN
NC
OH
OH
S
HO
O
O
Bn
O
O
OH
4, Englitazone
(Hypoglycemic reagent)
5, Cromakalim
(Antihypertensive)
6, Catechin
(Antitumor)
(b)
enantioselective manner
Lb*+
cat. Lb*: (9)
R1
X
2
L–
X
*
R1
*
I–I/X-L or Br-L
O
O
8-X
OH
R1
7
10
H
X = I, Br
R1
R
7
For iodocyclization
X–L
I–I
Lb*
+
Iδ •••I–Xδ –L
–
R1
X+
R1
R
X+
(I+ source)
X–L (halo-Lewis acid; X = I, Br, Cl)
L–
L–
R
O
R1
H
For bromocyclization
Br–L (Lewis acidic Br+ source)
racemization
through olefin-to-olefin haliranium transfer
Figure 1. (a) Natural products or synthetic analogues con-
taining chiral chromans. (b) Strategies for constructing
chiral
chromans
through
enantioselective
halo-
oxycyclization using chiral Lewis base catalysts and halo
Lewis acids.
ACS Paragon Plus Environment

Journal of the American Chemical Society
We initiated enantioselective halo-oxycyclization of 2-
alkenylphenol 7a. For the iodo-oxycyclization, I2 was
used as the iodine source in the presence of BINOL-
derived phosphoric acid derivative 9 as a catalyst and
Lewis acidic N-chlorosuccinimide (NCS).19 For the
Page 2 of 5
addition of iodonium ion preferentially occurred on the
si-face of 7a to avoid steric repulsion between 7a and 9d,
as shown in Figure 2. On the other hand, the addition of
iodonium ion on the re-face of 7a was sterically disfa-
vored. Although the para-substituent effect of the N-
phenyl moiety of 9e for enantioselective bromocycliza-
tion is not clear, the bulkiness and electron-donating
ability might stabilize the transition state close to that
shown in Figure 2.
1
2
3
4
5
6
7
8
bromo-oxycyclization,
1,3-dibromo-5,5-
dimethylhydantoin (DBH) was used as the Lewis acidic
bromine source in the absence of any other halo-Lewis
acidic additives because of high reactivity of DBH (Ta-
ble 1). The previous chiral phosphate triester catalyst 9a
promoted iodocyclization in 85% ee (entry 1).9f On the
other hand, the electron-donating substituents of triesters
9b and 9c contributed to increase the ee values (entries 2
and 3). Interestingly, the amidophosphate 9d catalyzed
the iodocyclization more efficiently than triesters 9a–c
to provide chroman 8a-I with 97% ee (entry 4). DFT
calculations suggested that amidophosphates are more
electron-rich than phosphate triesters, and electron-
donating substituents increased the electron density.
The stronger Lewis base catalyst 9 should form a more
stable intermediate 10 that may help to suppress olefin-
to-olefin racemization. Moreover, the N–H protons in
amidophosphates were found to be relatively electron-
poor.20 Other approaches, including converting the
amine moieties to more bulky (9f) or smaller (9i) sub-
stituents, as well as changing the P=O to P=S (9g, 9j) or
P=Se (9h) gave lower yields and ee values. As in iodo-
cyclization, chiral amidophosphate catalyst was more
efficient in enantioselective bromocyclizations. Howev-
er, the best catalyst 9d for iodocyclization did not provi-
de the desired ee in bromocyclization. Surprisingly, the
introduction of a bulky group at the para-position of the
N-phenyl moiety in 9d, dramatically increased the ee
(entry 5).
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
narrow space
open
space
HO
R
9d
X
H
7a
H
halogen reagents
very narrow space
favored si-face iodination with 9d
Figure 2. Proposed stereoselective process for halocycliza-
tions using 9d based on its crystal structure.
BINOL-derived amidophosphates are easily modifiable
by replacing the 3,3’-substituents and amino moieties.
Through the optimization of catalysts, we found that this
system was suitable for both halo-O-cyclization and ha-
lo-N-cyclization. Representative examples are listed in
Tables 2 and 3. Generally, excellent yields (89–99%)
and enantioselectivities (91–98% ee) were observed for
iodocycloetherification of 2-alkenylphenols with alkyl
side chains that varied from methyl to cyclohexyl groups
(Table 2, 7a–f) in the presence of catalyst 9d.22 In par-
ticular, chiral chroman 8a-I was obtained on a 10-gram
scale in the presence of only 0.50 mol% of 9d. Moreo-
ver, 8d-I was obtained as a single product, and exhibited
excellent chemoselectivity for terminal over internal
olefins. The para-substituted phenols 7g~7i were also
suitable for use in this reaction. However, when 7j (R1
= H) was used as a substrate, the reactivity dropped (the
reaction occurred only at temperatures higher than –
60 °C), and catalyst 9e was effective for achieving high
enantioselectivity. As stated in Table 1, 9e was effective
for bromocyclization to give chiral chromans 8a-Br, 8i-
Br, and 8b-Br in high yields and ee values. On the oth-
er hand, for the enantioselective iodocyclization of steri-
Table 1. Halocycloetherification of 2-Alkenylphenol 7a
Catalyzed by Nucleophilic Phosphoric Acid Derivativesa
SiPh3
cat. 9 (5.0 mol%)
X+ reagent (1.1 equiv)
O
O
Z
P
R
O
toluene (0.1 M)
–78 °C
Y
OH
X
8a-X (X =I or Br)
7a
9
SiPh3
yield (%),d ee (%)e of 8a-X
8a-Ib
85, 85
85, 89
95, 92
99, 97
98, 96
84, 89
27, 13
54, 33
99, 9
8a-Brc
80, 71
77, 81
66, 82
90, 85
93, 94
44, 58
15, 4
entry cat. 9 [P(=Z)YR]
1
2
3
4
5
6
7
8
9
9a [P(=O)OC6H3-2,6-Me2]
9b [P(=O)OC6H2-2,4,6-Me3]
9c [P(=O)OC6H2-4-MeO-2,6-Me2]
9d [P(=O)NHC6H3-2,6-Me2]
9e [P(=O)NHC6H2-4-t-Bu-2,6-Me2]
9f [P(=O)NHC6H3-2,6-i-Pr2]
9g [P(=S)NHC6H3-2,6-Me2]
9h [P(=Se)NHC6H3-2,6-Me2]
9i [P(=O)NHTf]
cally
bulky
2-alkenylphenol
7k,
3,3’-di(9-
anthryl)BINOL-derived catalyst 9k was effective. Inter-
estingly, the inverted asymmetric induction was ob-
served due to the steric bulkiness of 7k.21
26, 7
90, 14
10, 25
10
9j [P(=S)NHTf]
87, 17
Furthermore, catalyst 9k worked very well in the iodo-
cyclization of unsaturated amides 7l~7p to give enanti-
oenriched pyrrolidines 8l-I~8p-I in high yields and en-
antioselectivities.22 Both alkyl and aryl side chains were
acceptable.9h,10b Although both Ts and Ns protective
groups were useful in the iodocyclization, the more elec-
tron-deficient Ns group was necessary for the high enan-
aReactions were carried out with 7a (0.10 mmol), 9 (0.0050 mmol), and X+
reagent (0.11 mmol) in toluene (1 mL) at –78 °C. bA mixture of I2 (0.11 mmol)
and NCS (0.11 mmol) was used as I+ reagent. cDBH (0.11 mmol) was used as
Br+ reagent. dIsolated yield. eEe values were determined by HPLC analysis.
Based on the X-ray diffraction analysis of 9d and the
absolute configuration of 8-X,21 it was assumed that the
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
tioselectivity in bromocyclization to 8p-Br.10b Moreo-
ver, catalyst 9k was modified to 9l, which possesses a
10-aryl-substituent on the 9-anthryl group for bromocy-
clization. We proposed that steric repulsion between the
10-aryl group and the amine moiety might change the
angles of 3,3-substituents, which would increase the
steric effect around the phosphine oxide.
arylallyl)phenols 11g~11k under the same conditions as
in Table 2. When a bromo-Lewis acid such as DBH or
NBS was used in place of NCS, desired chiral chromans
12g-I~12k-I were obtained in high yields with high en-
antio- and anti-selectivities. Interestingly, asymmetric
induction in the cyclization of 11g~11k was opposite to
that of 11a~11f.21
1
2
3
4
5
6
7
8
Table 2. Asymmetric Halocyclization of 2-Alkenylphenols
Table 3. Asymmetric Halocycloetherification of 11
and Unsaturated Amides 7a
9 (5.0 mol%)
R2
NCS (1.1 equiv), I2 (0.50 equiv) for X = I
DBH (1.1 equiv) for X = Br
9 (5.0 mol%)
NCS (1.1 equiv), I2 (0.50 equiv) for X =I
9
X
( )n
R1
X
( )n
A
R3
R3
R2
R2
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
R1
AH
R1
R2
toluene, –78 °C
R1
O
12-X
OH
11
DBH or NBS for X = Br
toluene
7
8-X
yield,b eec
yield,b eec
I
I
Cl
I
MeO
I
I
I
O
O
O
O
MeO2C
O
O
12a-I
O
O
Et
( )6
8a-I
97% (10 g),d 95% ee
[9d, –78 °C, 2 h]
8b-I
99%, 96% ee
[9d, –78 °C, 2 h]
8c-I
99%, 98% ee
[9d, –78 °C, 10 h]
8d-I
95%, 95% ee
[9d, –78 °C, 11 h]e
I
I
12b-I
88%, 94% ee
(9k, 5 h)
12c-I
97%, 96% ee
(9k, 5 h)
12d-I
74%, 96% ee
(9k, 5 h)
92%, 96% ee
(9k, 5 h)
I
Br
Cl
Br
MeO
I
I
O
O
O
12a-Br
O
O
O
O
8e-I
95%, 93% ee
c-C6H11
i-Pr
12b-Br
91%, 90% ee
(9l, 10 h)
12e-I
75%, 83% ee
(9k, 5 h)d
I
8f-I
92%, 92% ee
8g-I
93%, 94% ee
8h-I
95%, 96% ee
[9d, –78 °C, 8 h]
I
81%, 95% ee
(9l, 10 h)
[9d, –78 °C, 10 h]e [9d, –78 °C, 10 h]e [9d, –78 °C, 6 h]
I
I
MeO
I
F
F
O
O
Ph
O
Ph
O
O
O
O
H
12f-I
84%, 78% ee
(9k, 5 h)d
12g-I
95%, 94% ee
12h-I
94%, 91% ee
(9f, 3 h)e
I
I
Br
Br
8i-I
89%, 97% ee
[9d, –78 °C, 5 h]
8j-I
89%, 90% ee
[9e, –60 °C, 12 h] [9e, –78 °C, 5 h]f
8a-Br
93%, 94% ee
8i-Br
83%, 96% ee
[9e, –78 °C, 12 h]
(9f, 3 h)e
I
I
I
BnO
I
I
Br
OMe
O
O
O
c-C6H11
O
O
( )7
Br
N
N
Ts
12i-I
97%, 97% ee
(9f, 6 h)e
12j-I
83%, 92% ee
(9f, 6 h)e
12k-I
95%, 84% ee
(9f, 12 h)f
Et
Br
Ts
8l-I
92%, 90% ee
I
8b-Br
94%, 96% ee
[9e, –78 °C, 8 h]f
8k-I
92% (1.3 g), 90% ee
8m-I
95%, 99% ee
[9k, –78 °C, 12 h]
[9k, –78 °C, 12 h] [9k, –78 °C, 12 h]
aUnless otherwise stated, reactions were carried out with substrate 7 (0.10
mmol) and 9 (0.0050 mmol) in toluene (1 mL). bIsolated yield. cEe values
were determined by HPLC analysis. dNIS was used in place of NCS. eDBH
was used in place of NCS. fNBS was used in place of NCS.
I
I
I
Br
c-C6H11
c-C6H11
( )7
N
Ns
N
N
Ns
N
Ns
Ph
Ns
8o-I
96%, 96% ee
8n-I
98%, 90% ee
[9k, –60°C, 15 h]
8p-I
90%, 98% ee
[9k, –60°C, 15 h]
8p-Br
94%, 92% ee
[9l, –20°C, 48 h]g
[9k, –60°C, 15 h]
Based on the results of an NMR study, we confirmed
that IBr and NIS were generated from the mixture of
molecular iodine and NBS at ambient temperature.23
Indeed, 0.2 equiv. of IBr and 1.1 equiv. of NIS with cat-
alyst 9f (5 mol%) efficiently promoted the iodocycliza-
tion of 11g in high yield with high enantioselectivity.24
These results suggest that a highly reactive species 14
was generated from 9f, IBr and NIS (Scheme 1). First,
the dual activation of I2 with 9f and NBS/DBH or the
dual activation of in situ-generated IBr with 9f and NIS
provided iodonium species 13,23,24 which has been previ-
aUnless otherwise stated, reactions were carried out with substrate 7 (0.10
mmol) and 9 (0.0050 mmol) in toluene (1 mL). bIsolated yield. cEe values
were determined by HPLC analysis. d0.50 mol% of 9d was used. eNIS was
used in place of NCS. fDBH was used. gNBS was used.
Ar
O
O
Ph
9k: Ar = 9-anthryl
P
9l: Ar = 10-(4-t-Bu-C6H4)-9-anthryl
O
N
H
Ph
Ar
Table 3 presents the scope of internal olefins 11 that
undergo endo-cyclization to give chiral halogenated
chromans 12-X. Catalysts 9k and 9l were effective for
the iodo- and bromocyclization of 2-(3,3’-
dialkylallyl)phenols 11, respectively.22 Neither electron-
deficient nor electron-rich substituents at the para- or
meta-positions on the hydroxyphenyl group of 11 influ-
enced the high enantioselectivities (12a-X~12d-X).21 In
the case of polyenylphenols such as 11e and 11f, the
carbon–carbon double bond closest to phenols selective-
ly reacted to give chiral chromans with unsaturated side
chains in good yields and enantioselectivities. However,
Scheme 1. Proposed New Active Species 14 from 13
O
O
NIS
N
Br
O
O
N
O
2 δ–
X
+
O
O
I
Br
O
I
δ+
fast
fast
X1
O
O
O
O
O
I
I
P
*
δ– δ+
P
P
NHR
*
*
NHR
NHR
[X1 = I, X2 = Br] or [X1 = Br, X2 = I]
139m
14 (more reactive)
ously reported.9f However, 13 would be immediately
transformed to species 14 because the succinimide anion
preferred to react with IBr to give NIS. Thus, the enan-
iodocyclization
did
not
proceed
for
2-(3-
ACS Paragon Plus Environment

Journal of the American Chemical Society
rial is available free of charge via the Internet at
Page 4 of 5
tioselective iodocyclization of 11g proceeded via species
14, which was more electrophilic than 13.25
1
2
http://pubs.acs.org.
Halogenated chiral chromans and halopyrrolidines are
useful building blocks and synthetic intermediates
(Scheme 2). Compound 8h-I could be transformed to
Daedalin A 3 through a 3-step process. Key intermedi-
ates in the synthesis of Vitamin E (126 and 227) and
Englitazone 428 could be obtained from 8k-I and 8j-I.
In addition, a bicyclic adduct 15 was obtained from 8a-I
through DDQ oxidation. In particular, 12f-I underwent
radical cyclization to give a tricyclic adduct 16 with high
diastereoselectivity. Although further improvement of
the enantioselectivity is needed, we believe that this
method is an efficient alternative approach for obtaining
polycyclic compounds. Finally, halopyrrolidine 8n-I
could be transformed to chiral aziridine 17 through a
known method.10b
AUTHOR INFORMATION
Corresponding Author
3
4
5
6
7
8
9
ishihara@cc.nagoya-u.ac.jp
Author Contributions
†Y.L. and H.N. contributed equally.
‡The current affiliation of H.N. is Kwansei Gakuin Univer-
sity.
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
ACKNOWLEDGMENT
This work was financially supported by JSPS KAKENHI
Grant Numbers JP15H05755 and JP15H05810 for Precise-
ly Designed Catalysts with Customized Scaffolding, and
the Program for Leading Graduate Schools: IGER Program
in Green Natural Sciences (MEXT). We thank Mr. Katsu-
ya Yamakawa for experimental assistance.
Scheme 2. Synthetic Transformation of Optically
Active Halocyclic Products
MeO
HO
1. CsOAc (97%)
2. DDQ (99%)
REFERENCES
Isolated yield
is shown
in parentheses.
O
O
1. Shen, H. C. Tetrahedron 2009, 65, 3931 and references therein.
2. Farrell, P. M.; In Vitamin E. A Comprehensive Treatise, ed. L. J.
Machlin. Marcel Dekker, New York, 1980.
3. (a) Chen, Z. -Y.; Ma, K. Y.; Liang, Y.; Peng, C.; Zuo, Y. J. Funct.
Foods 2011, 3, 61. (b) Aggarwal, B. B.; Sundaram, C.; Prasad, S.;
Kannappan, R. Biochem. Pharmacol. 2010, 80, 1613.
4. Sekimoto, M.; Hattori, Y.; Morimura, K.; Hirota, M.; Makabe, H.
Biol. Med. Chem. Lett. 2010, 20, 1063.
5. Valsamakis, G.; Kumar, S. Exp. Opin, Pharmacother. 2000, 1,
1413 and references therein.
3. NaH/EtSH (65%)
1. CsOAc
/LiOH
I
3
OH
8h-I
1. CsOAc
/LiOH
(98%)
HO
BnO
HO
(98%)
2. ref. 26
2. Tf2O
(92%)
3. ref. 27
O
O
O
R
I
R
1
8k-I
2
1. CsOAc
/LiOH
(90%)
1. CsOAc
/LiOH
(98%)
R
O
6. De Cree, J.; Geukens, H.; Leempoels, J.; Verhaegen, H. Drug Dev.
Res. 1986, 8, 109. (b) Van de Water, A.; Janssen, W.; Van Nueten,
J.; Xhonneux, R.; De Cree, J.; Verhaegen, H.; Reneman, R. S.;
Janssen, P. A. J. J. Cardiovasc. Pharmacol. 1988, 11, 552.
7. Weyant, M. J.; Carothers, A. M.; Dannenberg, A. J.; Bertagnolli,
M. M. Cancer Res. 2001, 61, 118.
8. (a) Tanaka, S.; Seki, T.; Kitamura, M. Angew. Chem. Int. Ed. 2009,
48, 8948. (b) Tokunou, S.; Nakanishi, W.; Kagawa, N.; Kumamo-
to, T.; Ishikawa, T. Heterocycles 2012, 84, 1045. (c) Uyanik, M.;
Hayashi, H.; Ishihara, K. Nature 2014, 345, 291.
9. For asymmetric iodofunctionalizations, see: (a) Sakakura, A.; Ukai,
A.; Ishihara, K. Nature 2007, 445, 900. (b) Veitch, G. E.; Jacob-
sen, E. N. Angew. Chem. Int. Ed. 2010, 49, 7332. (c) Dobish, M.
C.; Johnston, J. N. J. Am. Chem. Soc. 2012, 134, 6068. (d) Fang,
C.; Paull, D. H.; Hethcox, J. C.; Shugrue, C. R.; Martin, S. F. Org.
Lett. 2012, 14, 6290. (e) Brucks, A. P.; Treitler, D. S.; Liu, S. -A.;
Synder, S. A. Synthesis 2013, 45, 1886. (f) Nakatsuji, H.;
Sawamura, Y.; Sakakura, A.; Ishihara, K. Angew. Chem. Int. Ed.
2014, 53, 6974. (g) Arai, T.; Sugiyama, N.; Masu, H.; Kado, S.;
Yabe, S.; Yamanaka, M. Chem. Comm. 2014, 42, 8287. (h) Mizar,
P.; Burrelli, A.; Gunther, E.; Softje, M.; Farooq, U.; Wirth, T.
Chem. -Eur. J. 2014, 20, 13113. (i) Arai, T.; Watanabe, O.; Yabe,
S.; Yamanaka, M. Angew. Chem. Int. Ed. 2015, 54, 12767.
10.For asymmetric bromofunctionalizations, see: (a) Murai, K.;
Matsushita, T.; Nakamura, A.; Fukushima, A.; Shimura, M.; Fuji-
oka, H. Angew. Chem. Int. Ed. 2010, 49, 9174. (b) Zhou, L.; Chen,
J.; Tan C. K.; Yeung, Y. -Y. J. Am. Chem. Soc. 2011, 133, 9164.
(c) Murai, K.; Nakamura, A.; Matsushita, T.; Shimura, M.; Fujioka,
H. Chem. Eur. J. 2012, 18, 8448. (d) Paull, D. H.; Fang, C.; Don-
ald, J. R.; Pansick, A. D.; Martin, S. F. J. Am. Chem. Soc. 2012,
134, 11128. (e) Wilking, M.; Muck-Lichtenfeld, C.; Daniliuc, C.
G.; Hennecke, U. J. Am. Chem. Soc. 2013, 135, 8133. (f) Xie, W.;
Jiang, G.; Liu, H.; Hu, J.; Pan, X.; Zhang, H.; Wan, X.; Lai, Y.;
Ma, D. Angew. Chem. Int. Ed. 2013, 52, 12924. (g) Ke, Z.; Tan, C.
2. ref. 28
2. DDQ
(95%)
O
O
Bn
H
O
O
15
8j-I
8a-I
I
4
I
i-Pr
AIBN
Bu3SnH
PhSH
LiOH
I
Ph
Ph
N
Ns
N
(88%)
I
(68%)
O
O
16 (90:10 dr)
12f-I
8n-I
17
In conclusion, we have developed an efficient enanti-
oselective iodo- and bromocyclization for the construc-
tion of chiral chromans and pyrrolidines using chiral
amidophosphate catalysts based on the same strategy.
Several natural products and key synthetic intermediates
could be obtained through the easy transformation of
halocyclic products. Experimental results and DFT cal-
culations suggested that the nucleophilicity of the cata-
lysts plays an important role in the enantioselectivity.
Based on the results of NMR studies and control exper-
iments, we proposed a new highly reactive species from
catalyst, I2 and NBS. Apparently, a deeper chiral cavity
around the halonium ion is required to induce high enan-
tioselectivity in bromocyclization compared to iodocy-
clization. Further studies will be needed to fully eluci-
date the reaction mechanism.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, spec-
troscopic data, and crystallographic data (CIF). This mate-
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
-K.; Chen, F.; Yeung, Y. -Y. J. Am. Chem. Soc. 2014, 136, 5627.
17.(a) Beale, T. M.; Chudzinski, M. G.; Sarwar, M. G.; Sarwar, M.
G.; Taylor, M. S. Chem. Soc. Rev. 2013, 42, 1667. (b) Bulfield,
D.; Huber, S. M. Chem. Eur. J. 2016, 22, 14434.
18.Brown, B. S.; Nagorski, R. W.; Bennet, A. J.; MuClung, R. E. D.;
Aarts, G. H. M.; Klobukowski, M.; McDonald, R.; Santarsiero, B.
D. J. Am. Chem. Soc. 1994, 116, 2448.
(h) Toda, Y.; Pink, M.; Johnston, J. N. J. Am. Chem. Soc. 2014,
136, 14734. (i) Cheng, Y. A.; Yu, W. Z.; Yeung, Y. -Y. Angew.
Chem. Int. Ed. 2015, 54, 12102. (j) Jiang, X.; Tan, C. K. Zhou, L.
Yeung, Y. -Y.; Angew. Chem. Int. Ed. 2015, 51, 7771. (k) Kawato,
Y.; Ono, H.; Kubota, A.; Nagao, Y.; Morita, N.; Egami, H.; Ha-
mashima, Y. Chem. Eur. J. 2016, 22, 2127. (l) Pan, H.; Huang,
H.; Liu, W.; Tian, H.; Shi, Y. Org. Lett. 2016, 18, 896. (m)
Sawamura, Y.; Ogura, Y.; Nakatsuji, H.; Sakakura, A.; Ishihara, K.
Chem. Commun., 2016, 52, 6068. (n) Samanta, R. C.; Yamamoto,
H. J. Am. Chem. Soc. 2017, 139, 1460. (o) Yu, S. -N.; Li, Y. -L.;
Deng, J. Adv. Synth. Catal. 2017, 359, 2499.
1
2
3
4
5
6
7
8
19.We previously reported that a halo-Lewis acid activated molecular
iodine to promote iodocyclization. See reference 9f.
The
screening of halo-Lewis acids is described in SI (Section 1, Tables
S1~4).
20.See details of DFT calculations in SI (Section 2, Table S5).
21.For the determination of the absolute configuration of 8h-I, 8j-I,
8k-I, 8n-I, 12b-I, and 12g-I and the proposed models for the
asymmetric induction, SI (Section 4).
22.Iodocyclization of unsaturated aliphatic alcohol and aromatic am-
ides gave the corresponding cyclic products with moderate ee val-
ues. Bromocyclization of 7a, 7h, and 11i did not proceed success-
fully. For detail, see SI (Schemes S2 and S3).
23.IBr might be initially generated from I2, 9f and NBS/DBH at –
78 °C under the optimized conditions of iodocyclization.
24.NIS does not directly react with 9f to give 13 under the reaction
conditions, because the 9f-catalyzed cyclization of 7a with NIS
did not occur at all without I2 in toluene at –78 °C. Thus, the pos-
sibility that 9f attacks NIS directly to generate 13 is excluded.
25.See details in SI (Section 3, Table S6) for the screening of halo-
Lewis acids and reactions using IBr. Although the iodocyclization
of 11g proceeded quite quickly with IBr even in the absence of
catalyst, 0.20 equiv. of IBr was used for the enantioselective iodo-
cyclization catalyzed by 9f.
9
11.For asymmetric chloro- and fluorofunctionalizations, see: (a)
Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am.
Chem. Soc. 2010, 132, 3298. (b) Jaganathan, A.; Garzan, A.;
Whitehead, D. C.; Staples, R. J.; Borhan, B. Angew. Chem. Int. Ed.
2011, 50, 2593. (c) Yin, Q.; You, S. L. Org. Lett. 2014, 16, 2426.
(d) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura,
S.; Toru, T.; Shiro, M. Angew. Chem. Int. Ed. 2008, 47, 4157. (e)
Egami, H.; Niwa, T.; Sato, H.; Hotta, R.; Rouno, D.; Kawato, Y.;
Hamashima, Y.; J. Am. Chem. Soc. 2018, 140, 2785.
12.For asymmetric multiple halogenations, see: (a) Wang, Y.-M.; Wu,
J.; Hoong, C.; Rauniyar, V.; Toste, F. D. J. Am. Chem. Soc. 2012,
134, 12928. (b) Soltanzadeh, B.; Jaganathan, A.; Staples, R. J.;
Borhan, B. Angew. Chem. Int. Ed. 2015, 54, 9517. (c) Zhou, P.;
Lin, L.; Chen, L.; Zhong, X.; Liu, X.; Feng, X. J. Am. Chem. Soc.
2017, 139, 13414. (d) Stoltanzadeh, B.; Jaganathan, A.; Yi, Y.; Yi,
H.; Staples, R. J.; Borhan, B. J. Am. Chem. Soc. 2017, 139, 2132.
13.For reviews of catalytic asymmetric halofunctionalizations, see:
(a) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem. Int.
Ed. 2012, 51, 10938. (b) Tan, C. K.; Yu, W. Z.; Yeung, Y. -Y.
Chirality 2014, 26, 328. (c) Chen, J.; Zhou, L. Synthesis 2014, 46,
586. (d) Mizar, P.; Wirth, T. Synthesis 2016, 49, 981.
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
26.Rein, C.; Demel, P.; Outten, R. A.; Netscher, T.; Breit, B. Angew.
Chem. Int. Ed. 2007, 46, 8670.
27.(a) Chênevert, R.; Courchesne, G.; Pelchat, N. Bioorg. Med. Chem.
2006, 14, 5389. (b) Couladouros, E. A.; Moutsos, V. I.; Lam-
propoulou, M.; Little, J. L.; Hyatt, J. A. J. Org. Chem. 2007, 72,
6735.
14.Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc.
2010, 132, 1232.
15.Cui, X-L.; Brown, R. S. J. Org. Chem. 2000, 65, 5653. (b) Den-
mark, S. E.; Burk, M. T. Org. Lett. 2012, 14, 256.
16.Marcus, Y. Chem. Rev. 1988, 88, 1475.
28.Urban, F. J.; Moore, B. S. J. Heterocyclic Chem. 1992, 29, 431.
TOC (Table of Contents)
O
N
Xδ–
O
O
δ–N
Br
N Br
I
R4
R4
I
δ+O
δ+O
O
R5
R5
O
O
P
N
P
N
H
H
O
O
R4
R4
ACS Paragon Plus Environment