Enantioselective bromocyclization of 2-geranylphenols induced by chiral phosphite-urea bifunctional catalysts

Article abstract of DOI:10.1039/c6cc00229c

Chiral phosphite-urea bifunctional catalysts have been developed for the enantioselective bromocyclization of 2-geranylphenols with N-bromophthalimide (NBP) for the first time. The chiral triaryl phosphite moiety activates NBP to generate a bromophosphonium ion. On the other hand, the urea moiety interacts with a hydroxyl group of the substrate through hydrogen bonding interactions. Enantioselectivity is effectively induced through two-point attractive interactions between the catalyst and the substrate.

Full text of DOI:10.1039/c6cc00229c

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Enantioselective Bromocyclization of 2-Gernaylphenols Induced
by Chiral Phosphite–Urea Bifunctional Catalysts†
Yasuhiro Sawamura,a Yoshihiro Ogura,a Hidefumi Nakatsuji,ab Akira Sakakura*c and Kazuaki
Ishihara*a
AReceived 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Chiral phosphite–urea bifunctional catalysts have been developed
for the first enantioselective bromocyclization of 2-geranylphenols phosphorous(III) catalysts bearing protic functional groups,
with N-bromophthalimide (NBP). The chiral triaryl phosphite and
, for the halocyclization of polyprenoids (Scheme 1).7–14
moiety activates NBP to generate a bromophosphonium ion. On Catalysts and activate N-halosuccinimides (X = I and Br) to
Since 2007, we have also developed nucleophilic
3
4
3
4
the other hand, the urea moiety interacts with a hydroxyl group of generate active halophosphonium salt species in situ (Scheme
the substrate through hydrogen bonding interactions. 2). This activation step proceeds smoothly via a mechanism
Enantioselectivity is effectively induced through two-point that involves catching a succinimide anion with protons of the
attractive interactions between the catalyst and substrate.
catalysts under equilibrium.15 A halophosphonium salt then
reacts with polyprenoids at the terminal olefin of
1
to mainly
Optically active bromine-containing natural products isolated
from marine organisms have been shown to possess several
bioactivities such as anticancer and antiviral activities.1 These
natural products are biosynthesized by enantioselective
bromocyclization induced by enzymes such as vanadium
bromoperoxidase (V-BPO).2 For example, in the biosynthesis
of isoaplysin-20, the bromonium ion generated in the active
site of V-BPO reacts with the terminal olefin of geranylgeraniol
give halogenated trans-fused AB-ring product
2. Chiral
phosphoramidite
enantioselectivity.8a However, a stoichiometric amount of
was required to give (X = I) in sufficient yield due to strong
acid–base affinity between and succinimide. In contrast, low
enantioselectivity was observed in the bromocyclization of
using
under the same conditions.8a More recently, we
succeeded in the highly efficient site- and diastereoselective
3 gave iodinated product 2 (X = I) with high
3
2
3
1
3
site- and enantioselectively. Subsequent diastereoselective
cation cyclization gives isoaplysin-20.3
π-
While the
diastereoselective bromocyclization of linear polyprenoids has
been studied for about 50 years,4,5 there have been few
reports on the enantioselective bromocyclization of
polyprenoids induced by chiral catalysts.6 In 2010, Snyder and
colleagues demonstrated enantioselective bromocyclization
with stoichiometric amounts of
a
Hg(OTf)2–chiral
bis(oxazoline) complex.6a In 2013, Braddock and colleagues
reported that enantiospecific polyene cyclization was initiated
by the formation of an enantiopure bromiranium ion.6b
However, these methods require stoichiometric amounts of
promoters or multiple reaction steps.
Scheme 1 Halocyclization of 1 with nucleophilic phosphorous catalysts (Our previous
results).
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mol % of 8b was also effective, and both 6a and 7a were
obtained without any loss of enantioselectivity (entry 10).
Catalyst 8c was examined because in our previous studies
chiral 3,3’-bis(triphenylsilyl)-1,1’-binphthol-derived catalysts
were effective for inducing high enantioselectivity, such as in
the iodo- and protocyclization of polyprenoids8,9 and
iodolactonization.11c
enantioselectivity (entry 11). The use of 8a was much more
effective than the use of 8d or 8d 10 (entries 12 and 13).
However, 8c did not induce high
–
Some phosphites [P(III)] are readily oxidized to the
corresponding phosphates [P(V)] in the presence of
halogenating reagents and moisture or air. Although the
Scheme 2 Proposed mechanism (Our previous results).
reaction was examined using phosphate
9 as a catalyst or
bromocyclization of
achiral triaryl phosphite–urea cooperative catalyst
brominated product (X
Br) in excellent yield.8c,d
Nevertheless, we still have not achieved catalytic
enantioselective halocyclization of
1
with the use of a catalytic amount of
without catalysts just in case, 5a was almost recovered (entries
14 and 15). The absolute configuration of 6a and 7a was
determined to be (2R,4aR,9aR) by derivatization to known
4
to give
2
=
a
1.
Table 1 Enantioselective bromocyclization of 5a with 8aa
One reason why enantioselective bromocyclization is
difficult is that the three-membered cyclic bromiranium ion
rapidly transfers to other olefins.16
In the course of
bromiranium ion–olefin transfer, the enantioenriched
bromiranium ion is racemized. We envisioned that
bromiranium ion–olefin transfer might be suppressed by
second non-covalent bonding interaction between a substrate
and a catalyst. Here we describe the rational design of chiral
phosphite–urea bifunctional catalysts for the enantioselective
bromocyclization of 2-geranylphenols.
We first examined the bromocyclization of 2-geranylphenol
5a with chiral phosphite–urea bifunctional catalysts
8 (Table
1). The reaction was conducted with 1.1 equivalents of N-
bromosuccinimide (NBS) as the brominating reagent in the
presence of 10 mol % of 8a in toluene at –40 °C for 6 h. As a
result, trans-fused brominated AB-ring product 6a was
obtained in 30% yield with 18% ee together with endo- and
exo-isomeric A-ring products 7a in 56% yield with 39% ee
(entry 1).17,18 A-ring products 7a could be converted to a
diastereomeric mixture of trans- and cis-fused AB-ring
products 6a (trans : cis = 3 : 1) by treatment with TfOH, and
the enantioselectivity was determined at this stage.19
Interestingly, 7a were obtained with higher enantioselectivity
6a
7a
Entry
Cat.
Br–L
Solvent
Yield
(%)b
30
18
31
29
35
22
25
21
21
19
21
8
Ee
(%)
18
13
21
21
4
Yield
(%)b
56
32
55
57
40
47
54
63
66
60
34
16
26
5
Ee
(%)c
39
33
44
43
19
36
51
65
61
65
–21
–
1
2
8a
8a
8a
8a
8a
8a
8b
8b
8b
8b
8c
NBS
NBA
TBCO
NBP
NBP
NBP
NBP
NBP
NBP
NBP
NBP
NBP
NBP
NBP
NBP
PhMe
PhMe
3
PhMe
4
PhMe
than 6a
.
Next, we examined the use of other brominating
Both the reactivity and
5
PhCl
reagents in place of NBS.
6
1,3,5-Me3C6H3
PhMe
24
16
19
13
19
–16
–
enantioselectivity were decreased with N-bromoacetamide
(NBA) (entry 2). In contrast, the use of 2,4,4,6-tetrabromo-2,5-
cyclohexadienone (TBCO) and N-bromophthalimide (NBP)
slightly increased the enantioselectivity (entries 3 and 4).
Thus, we chose NBP because it was less expensive than TBCO.
Next, we examined the solvent effect. The enantioselectivity
was decreased with chlorobenzene (entry 5) and the reactivity
was decreased with mesitylene (entry 6). The use of 8b gave
7
8d
9d,e
10d,f
11
12
13g
14
15
PhMe
PhMe
PhMe
PhMe
8d
8d/10
9
PhMe
PhMe
29
4
–
–
PhMe
–
–
–
PnMe
0
–
0
–
especially high enantioselectivity for 7a
,
while the
a Unless otherwise noted, the reaction of 5a (0.1 mmol) was conducted with Br–L
enantioselectivity of 6a was decreased (entry 7). Moreover,
when the concentration was lowered to 0.02 M, the
enantioselectivity was increased to 65% (entry 8). The
enantioselectivity was rather decreased when the reaction was
cooled to –60 °C (entry 9). This result suggests that catalysts
may aggregate under these reaction conditions. The use of 2
b
(1.1 equiv) in the presence of 8 (10 mol %) in toluene (1 mL) at –40 °C for 6 h.
Determined by 1H NMR analysis using tetrachloroethane as an internal standard.
c Determined after treatment with TfOH (4 equiv) in i-PrNO2 (0.6 mL) at –78 °C for
d
e
24 h.
The reaction was conducted in toluene (5 mL).
The reaction was
conducted at –60 °C. f 2 mol % of 8b was used for 12 h. g Each 10 mol % of 8d
and 10 was used.
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Scheme 3 Determination of the absolute configuration of 6a and 7a.
optically active compound 11a (Scheme 3).19
The substrate scope and limitations were investigated
under the optimized conditions (Table 2). The results showed
that 4- or 5-substituted 2-geranylphenols were suitable as
substrates. A-ring products
with good enantioselectivities (65 ~ 71% ee). In contrast, AB-
ring products were obtained in low yields with low
enantioselectivities (13 ~ 29% ee).17 Products
and were
easily separated by column chromatography on silica gel.
7 were obtained in good yields
6
6
7
Our proposed mechanism is shown in Scheme 4. First,
bromophosphonium ion intermediate 12 should be generated
from 8b and NBP in situ. The geometry of 12 is also shown by
the Newman projection viewed along the P–Br bond. The
terminal alkenyl moiety of substrate 5a reacted with the
bromonium ion of 12, which probably minimized steric
hindrance for each other. The approach of the bromonium ion
to the si-face of 5a might be disfavored because of steric
repulsion between the 3-[3,5-bis(pentafluorosulfanyl)phenyl]
group and the dimethylmethylene group of 5a, as shown in 14
.
Therefore, the re-face approach via 13 might be favored to
give (2R)-6a and (2R)-7a enantioselectively.
Next, we considered why A-ring products 7a were obtained
with higher enantioselectivity than AB-ring product 6a (Table 1
and Scheme 4). The cyclization step to form the A-ring should
be different in the reaction pathways to 6a and 7a because
both enantioselectivities were not identical. The double-
cyclization reaction should concertedly occur via a transition
state (TS) 15, since 6a was obtained as only a trans-fused
diastereomer. If 6a is formed by a stepwise mechanism, cis-
fused product 6a should also be generated as a minor
diastereomer. The ee value of 6a was quite low, probably due
to rapid racemization of a chiral cyclic bromiranium ion
intermediate16 or low enantioface discrimination of the
terminal alkenyl moiety of 5a with 8b. In contrast, A-ring
Table 2 Enantioselective bromocyclization of 5 with NBP catalysed by 8ba
Scheme 4 Proposed mechanism for the enantioselective bromocyclization of 5a
with NBP catalysed by 8b.
products 7a were obtained as major products with good
enantioselectivity. The deprotonation of a tertiary carbocation
intermediate to give 7a predominantly occurred in place of a
second cyclization to give 6a. Hydrogen bonding interactions
between the 2-hydroxyl group of 5a and the urea moiety of 8b
might dually suppress the second cyclization by decreasing
nucleophilicity of the 2-hydroxy group and controlling its
conformation. Furthermore, these interactions might play a
role in stabilizing TS-16 to give 7a with high
enantioselectivity.20
Yield
(%)b
23
Ee
(%)
29
21
20
19
13
Yield
(%)b
60
Ee
(%)c
66
Entry
5 (X)
6
7
1
2
3
4
5
5b (4-CF3)
5c (4-Br)
6b
6c
6d
6e
6f
7b
7c
7d
7e
7f
18
61
71
5d (4-OMe)
5e (4-Me)
5f (5-Ph)
19
68
67
16
56
67
28
63
65
a
The reaction of 5 (0.1 mmol) was conducted with NBP (1.1 equiv) in the
presence of 8b (10 mol %) in toluene (5 mL) at –40 °C for 6 h. b Determined by 1H
NMR analysis using tetrachloroethane as an internal standard. c Determined after
treatment with TfOH (4 equiv) in i-PrNO2 (0.6 mL) at –78 °C for 24 h.
To ascertain the significance of the hydrogen bonding in
the present catalysis, we examined the bromocyclization of
geranylbenzene 17 and O-protected substrate 19 under the
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10 For halocyclization of alkenes catalyzed by Lewis bases, see:
(a) A. Sakakura and K. Ishihara, Chim. Oggi Chem. Today,
2007, 25, 9; (b) S. E. Denmark and M. T. Burk, Proc. Natl.
Acad. Sci. U.S.A., 2010, 107, 20655; (c) Y.-C. Wong, Z. Ke and
Y.-Y. Yeung, Org. Lett., 2015, 17, 4944.
11 For recent examples on catalytic asymmetric iodocyclization
of alkenes, see: (a) C. B. Tripathi, S. Mukherjee, Org. Lett.,
2014, 16, 3368; (b) D. W. Tay, G. Y. C. Leung and Y.-Y. Yeung,
Angew. Chem. Int. Ed., 2014, 53, 5161; (c) H. Nakatsuji, Y.
Sawamura, A. Sakakura and K. Ishihara, Angew. Chem. Int.
Ed., 2014, 53, 6974; (d) T. Arai, N. Sugiyama, H. Masu, S.
Scheme 5 Bromocyclization of 17 and 19 with NBP catalysed by 8a.
Kudo, S. Yabe and M. Yamanaka, Chem. Commun., 2014, 50
,
8287; (e) P. Mizar, A. Burrelli, A. Günther, M. Söftje, U.
Farooq and T. Wirth, Chem. Eur. J., 2014, 20, 13113; (f) Y.
Toda, M. Pink and J. N. Johnston, J. Am. Chem. Soc., 2014,
136, 14734; (g) Z. Shen, X. Pan, Y. Lai, J. Hu, X. Wan, X. Li, H.
Zhang and W. Xie, Chem. Sci., 2015, 6, 6986; (h) T. Arai, O.
Watanabe, S. Yabe and M. Yamanaka, Angew. Chem. Int. Ed.,
2015, 54, 12767.
same conditions (Scheme 5). In both cases, the corresponding
brominated products were obtained in good yield with very
low enantioselectivity. These results suggest that a hydroxyl
group plays a crucial role in asymmetric control.
In conclusion, we designed chiral phosphite–urea
bifunctional
bromocyclization of 2-geranylphenols
ring products
Subsequent treatment of
products as major diastereomers. Hydrogen bonding
catalysts
for
the
enantioselective
12 For
recent
examples
on
catalytic
asymmetric
5.
Catalyst 8b gave A-
bromocyclization of alkenes, see: (a) Z. Ke, C. K. Tan, F. Chen
and Y.-Y. Yeung, J. Am. Chem. Soc., 2014, 136, 5627; (b) Y.
Kawato, A. Kubota, H. Ono, H. Egami, Y. Hamashima, Org.
Lett., 2015, 17, 1244; (c) H. Huang, H. Pan, Y. Cai, M. Liu, H.
Tian and Y. Shi, Org. Biomol. Chem., 2015, 13, 3566; (d) Y. A.
Cheng, W. Z. Yu and Y.-Y. Yeung, Angew. Chem. Int. Ed.,
2015, 127, 12102.
7
in good yield with good enantioselectivity.
with TfOH gave trans-fused AB-ring
6
6
interactions between the urea moiety of 8b and 2-hydroxyl
group of the substrate strongly supported the enantioselective
bromocyclization. Further studies on the catalyst to improve
enantioselectivity and catalytic activity and investigation of the
detailed reaction mechanism are underway.
13 For
recent
examples
on
catalytic
asymmetric
chlorocyclization of alkenes, see: (a) Q. Yin and S. L. You, Org.
Lett., 2014, 16, 2426; (b) A. Jaganathan and B. Borhan, Org.
Lett., 2014, 16, 3616; (c) C.-L. Zhu, Z.-Y. Tian, Z.-Y. Gu, G.-W.
Financial support was provided in part by JSPS KAKENHI
Grant Number 15H05755 and Program for Leading Graduate
Schools “IGER program in Green Natural Sciences”, MEXT,
Japan. Y.O. is grateful for a JSPS Research Fellowship for
Young Scientists.
Xing and H. Xu, Chem. Sci., 2015,
14 For recent examples on
fluorocyclization of alkenes, see: (a) V. Rauniyar, A. D.
Lackner, G. L. Hamilton and F. D. Toste, Science, 2011, 334
1681; (b) H. Egami, J. Asada, K. Sato, D. Hashizume, Y.
6, 3044.
catalytic
asymmetric
,
Kawato and Y. Hamashima, J. Am. Chem. Soc., 2015, 137
10132.
,
Notes and references
15 (a) A. Sakakura, R. Kondo, Y. Matsumura, M. Akakura and K.
Ishihara, J. Am. Chem. Soc., 2009, 131 17762; (b) Y.
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For a review, see: A. Butler and M. Sandy, Nature, 2009, 460
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,
Matsumura, T. Suzuki, A. Sakakura and K. Ishihara, Angew.
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,
,
16 (a) R. S. Brown, R. W. Nagorski, A. J. Bennet, R. E. D.
McClung, G. H. M. Aarts, M. Klobukowski, R. McDonald and
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4
5
6
For a review, see: S. A. Snyder, D. S. Treitler and A. P. Brucks,
Aldrichim. Acta , 2011, 44, 27.
C. Recsei, B. Chan and C. S. P. McErlean, J. Org. Chem. 2014,
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17 B-ring product (ca. 5~10% yield) and dibrominated product
(ca. 0~5% yield) were obtained as byproducts in all cases.
7
8
For recent reviews of catalytic asymmetric functionalization
of alkenes, see: (a) S. E. Denmark, W. E. Kuester and M. T.
Burk, Angew. Chem. Int. Ed., 2012, 51, 10938; (b) Y. A.
Cheng, W. Z. Yu and Y.-Y. Yeung, Org. Biomol. Chem., 2014,
12, 2333.
18 The para-substituted N-[3,5-bis(trifluoromethyl)phenyl]urea
moieties of 8a as well as 4 were crucial (Scheme 2): The use
of meta-isomer of 8a reduced not only catalytic activity but
also enantioselectivity. See also refs. 8c and 8d.
19 The same optical purity was observed for trans- and cis-
fused 11a. See ESI (page S16) for details.
20 We cannot exclude the possibility of an anion exchange
reaction between the phthalimide anion (L–) and 8b or 5a. In
this case, good enantioselectivity might be induced through
alternative hydrogen bonding interactions between the
(a) A. Sakakura, A. Ukai and K. Ishihara, Nature, 2007, 445
,
900; (b) A. Sakakura, G. Shomi, A. Ukai and K. Ishihara,
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oxyanion of 5a and the urea moiety of 8b
.
21
9
For reports of polyene protocyclization with chiral Brønsted
bases, see: (a) A. Sakakura, M. Sakuma and K. Ishihara, Org.
Lett., 2011, 13, 3130; (b) M. Sakuma, A. Sakakura and K.
Ishihara, Org. Lett., 2013, 15, 2838.
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