Enantioselective Bromolactonization of Trisubstituted Olefinic Acids Catalyzed by Chiral Pyridyl Phosphoramides

Article abstract of DOI:10.1002/chem.201804630

Enantioselective bromolactonization of trisubstituted olefinic acids producing synthetically useful chiral lactones with two contiguous asymmetric centers has remained mainly unexplored except for the 6-exo cyclization mode. In this work, the 5-exo- and 6

Full text of DOI:10.1002/chem.201804630

A Journal of
Accepted Article
Title: Enantioselective Bromolactonization of Trisubstituted Olefinic
Acids Catalyzed by Chiral Pyridyl Phosphoramides
Authors: Yasuhiro Nishikawa, Yuhta Hamamoto, Rika Satoh, Naho
Akada, Shuhei Kajita, Marina Nomoto, Megumi Miyata,
Madoka Nakamura, Chinatsu Matsubara, and Osamu Hara
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To be cited as: Chem. Eur. J. 10.1002/chem.201804630
Link to VoR: http://dx.doi.org/10.1002/chem.201804630
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COMMUNICATION
Enantioselective Bromolactonization of Trisubstituted Olefinic
Acids Catalyzed by Chiral Pyridyl Phosphoramides
Yasuhiro Nishikawa*, Yuhta Hamamoto, Rika Satoh, Naho Akada, Shuhei Kajita, Marina Nomoto,
Megumi Miyata, Madoka Nakamura, Chinatsu Matsubara, and Osamu Hara*
Abstract: Enantioselective bromolactonization of trisubstituted
olefinic acids producing synthetically useful chiral lactones with two
contiguous asymmetric centers has remained mainly unexplored
except for the 6-exo cyclization mode. In this work, the 5-exo- and 6-
endo modes of bromocyclization of trisubstituted olefinic acids were
enabled for the first time using N-bromosuccinimide and pyridyl
phosphoramide catalyst. The utility of the resulting bromolactones
was demonstrated by transformations harnessing reactive alkyl
bromide moieties without losing stereochemical information.
Optimization studies and control experiments revealed that the
basicity of pyridine moieties and presence of N-H protons in
phosphoramide species strongly affected both the reactivity and
enantioselectivity parameters.
developed yet, although a few examples of 5-exo-cyclization
with moderate stereoselectivity were reported (Scheme 1, Eq.
(2) and (3)).[14] In this study, enantioselective bromolactonization
reactions with two distinct modes of cyclization enabled using
pyridyl phosphoramide as a single catalyst are described.
6-exo-cyclization: H. Fujioka et al. (2012)[11]
O
Trisimidazoline
R2
R1
Br
O
catalyst
O
(eq 1)
R2
Br+ source
R1
up to 90% ee
OH
5-exo-cyclization: Several entries in Ref.[13] This work
Enantioselective halocyclization of olefins is an important
organic transformation utilized for the construction of chiral
heterocyclic compounds containing carbon-halogen bonds.[1] In
2010, the first successful application of organocatalysis in the
asymmetric halolactonization of disubstituted olefins was
reported by several groups.[2] These pioneering works triggered
the development of various types of halocyclization reactions
involving amides,[3] carbamates,[4] alcohols,[5] and tosylamides[6].
Among various heterocyclic products synthesized by these
methods, chiral halolactones have attracted much attention
because lactone derivatives include biologically active
compounds and synthetically useful intermediates.[7] Numerous
attempts to enlarge the scope of enantioselective
halolactonization have been dedicated to achieving the 5-exo, 6-
endo, and 6-exo modes of cyclization using 1,1-disubstituted or
1,2-disubstituted derivatives of olefinic acid.[2,8-11] On the other
hand, the halolactonization process conducted using
trisubstituted olefinic acids remains underdeveloped despite its
ability to produce various types of lactones containing two
contiguous stereocenters with tetrasubstituted carbons. The sole
example of a highly enantioselective halolactonization reaction
was reported by Fujioka and co-workers, in which 6-exo-
cyclization was performed using chiral trisimidazoline catalysts
(Scheme 1, Eq. (1)).[12,13] In contrast, a general method for the 5-
exo- and 6-endo-cyclization of trisubstituted olefins via a highly
enantioselective bromolactonization reaction has not been
Organo
catalysts
O
O
Br
O
(eq 2)
R2
R2
OH
Br+ source
R1
R1
moderate ee
6-endo-cyclization: unexplored, This work
O
R2
O
O
R2
(eq 3)
R1
OH
Br+ source
R1
Br
Scheme 1. Several modes of the cyclization reaction enabled via the
bromolactonization of trisubstituted olefinic acids.
From the results of our previous study on pyridinium
phosphoramide, we predicted that Brønsted acid catalysts could
be utilized for the enantioselective bromolactonization of olefinic
acids.[15] Contrary to our expectations, pyridyl phosphoramide 1
exhibited much higher reactivity in the preliminary
bromolactonization of 1,1-disubstituted alkenoic acid than that of
pyridinium phosphoramide 1•TfOH; hence, several pyridyl
phosphoramides were screened in this work (Table 1).[16] As a
result, 1a demonstrated the best catalytic performance in the
bromolactonization of (Z)-trisubstituted olefinic acid 2a with N-
bromosuccinimide (NBS) characterized by good yield and
excellent enantioselectivity (entry 1). The E/Z ratio of the starting
compound 2a reflected the diastereomeric ratio of the resulting
bromolactone 3a, indicating that the reaction proceeded in a
highly diastereoselective manner. The effect of the Lewis
Dr. Y. Nishikawa, Y. Hamamoto, R. Sato, N. Akada, S. Kajita, M.
Nomoto, M. Miyata, M. Nakamura, C. Matsubara, Prof. Dr. O. Hara
Faculty of Pharmacy
Meijo University
150 Yagotoyama, Tempaku-ku, Nagoya, Aichi 468-8503, Japan
E-mail: yasuhiro@meijo-u.ac.jp; oshara@meijo-u.ac.jp
basicity of the catalyst was evaluated using catalyst 1a
−
c with a
substituted pyridine ring. The obtained results suggest that the
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201804630
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Table 2. Substrates for the 5-exo mode of bromolactonization.[a]
Table 1. Optimization of the reaction conditions.[a]
Standard condition
Standard condition
1a (10 mol %)
NBS (1.2 equiv)
O
1a (10 mol %)
NBS (1.2 equiv)
O
Br
O
O
Br
O
O
R1
R1
OH
toluene (0.025 M)
-50 °C, 18 h
Me
Me
OH
R2
toluene (0.025 M)
R2
2a-n
Ph
Ph
-50 °C, 18 h
3a-n
2a (E : Z = 7 : 93)
3a
(E : Z = 1: >99 ~ 8 : 92)
Ar
R
Ar
O
O
O
O
Br
Br
Br
Br
O
O
O
O
O
O
O
P
O
O
Me
Me
Me
Cl
Me
P
O
N
N
O
N
H
Ar
Ar
Br
F
3a (dr 4 : 96)
95%, 92% ee
3b (dr 9 : 91)
98%, 89% ee
3c (dr 9 : 91)
97%, 95% ee
3d (dr 7 : 93)
95%, 95% ee
Ar = 4-biphenyl
1a (R = NMe2)
1b (R = OMe)
1c (R = H)
Ar = 4-biphenyl
1d
O
O
O
O
Br
Br
Br
O
Br
O
O
O
Me
Me
Me
Me
Me
Entry
1
Varietion from standard conditions
Standard[a]
3a: Yield [%][b]
ee [%][c]
92
87
85
5
95
94
6
MeO
Me
OMe
2
1b (R = OMe) instead of 1a
1c (R = H) instead of 1a
1d instead of 1a
3e (dr 7 : 93)
91%, 92% ee
3f (dr 34 : 66)[c]
52%, 45% ee
3g (dr 9 : 91)
94%, 94% ee
3h (dr 7 : 93)
89%, 92% ee
3
4
13
73
8
O
O
O
O
Br
S
Br
O
Br
O
5
CH2Cl2 instead of toluene
THF instead of toluene
Toluene (0.05 M)
69
−
Me
Me
Me
6
Me
7
95
98
86
84
4
90
86
88
87
94
88
8
Toluene (0.1 M)
3i (dr 1 : <99)
17%[b], ND
3j (dr 1 : <99)
86%, 92% ee
3k (dr 11 : 89)[d]
84%, 81% ee
9
DBDMH instead of NBS
−30 °C
O
O
O
10
11
12
Br
Br
O
Br
O
O
−70 °C
Me
Et
5 mol% of 1a
87
[a] Reactions were performed by dissolving 0.1 mmol of 2a, 0.01 mmol of
1a, and 0.12 mmol of NBS in toluene (4 mL) at −50 °C. See Supporting
Information for details. [b] Isolated yields of diastereomer mixtures (dr = 96 :
4). [c] Determined by chiral HPLC.
3l (dr 1 : <99)
99%, 72% ee
3m (dr 4 : 96)
97%, 40% ee
3n (dr 8 : 92)
91%, 47% ee
[a] Reactions were performed by dissolving 0.1 mmol of 2, 0.01 mmol of 1a,
and 0.12 mmol of NBS in toluene (4 mL) at −50 °C. See Supporting
Information for details. The isolated yields of the diastereomer mixtures are
listed. [b] 1H-NMR yield. [c] The E/Z ratio of 2f was 7/93. [d] The E/Z ratio of
2k was 8/92.
strong Lewis basicity of the pyridine catalyst is essential for
achieving high
reactivity (entries 1−3). Notably, pyridyl phosphoric ester 1d
without phosphoramide N-H groups showed almost no
enantioselectivity (entry 4). These results clearly suggest that
those of relatively polar solvents (entries 5 and 6). In addition,
more diluted toluene solutions exhibited higher reaction
enantioselectivity values (entries 7 and 8). The use of 1,3-
the presence of N-H protons in phosphoramide 1a c was a
−
critical factor affecting the enantioselectivity of the reaction. The
screening of the reaction solvents revealed that toluene
produced higher yield and enantioselectivity as compared to
dibromo-5,5-dimethylhydantoin (DBDMH) as
a brominating
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probably because the Lewis basic olefins activated by these
groups were prone to producing racemic bromonium ion
intermediates with NBS prior to the interactions with the chiral
catalyst 1a (product 3f).[17] On the other hand, the meta-
substituted phenyl groups containing both methyl and methoxy
Table 3. Substrates for the 6-endo mode of bromolactonization.[a]
O
1a (10 mol %)
NBS (1.2 equiv)
R2
O
O
R2
R1
moieties
resulted
in
good
yields
and
excellent
R1
OH
enantioselectivities (products 3g and 3h). The bulky
environment of the olefin-containing reaction sites inhibited the
bromolactonization reaction, as was shown for the case of ortho-
substituted derivative 2i (product 3i). Subsequently, the
substrates having 2-naphthyl, 3-thienyl, or 3-indenyl groups (in
addition to phenyl groups) were investigated as well; the
resulting bromolactones demonstrated moderate and good
toluene (0.025 M)
Br
-20 °C, 18 h
4
5
(E : Z = >99 : 1)
(single diastereomer)
O
O
O
O
O
O
O
O
Me
Me
Me
Me
enantioselectivities (products 3j
−
l). Unfortunately, 2m containing
a
cyclohexyl group reacted smoothly, but with low
Br
Br
Br
Br
Cl
F
Me
enantioselectivity. For 2i, the 4-heptenoic acid derivative 2n
having a bulky functional group near the olefin structure
produced a low value of ee (product 3n).
5a
5b
5c
5d
85%, 95% ee
100%, 96% ee
93%, 92% ee
83%, 98% ee
O
O
O
O
After achieving these results, the 6-endo mode of the
enantioselective bromolactonization of (E)-trisubstituted olefinic
acids was realized. To our delight, the standard conditions for 5-
exo-cyclization could be applied for the reaction of 5-phenyl-4-
heptenoic acid 4a by changing the reaction temperature to
−20 °C, producing 5a as a single diastereomer with good yield
and excellent enantioselectivity. Both electron withdrawing and
donating moieties attached to the para positions of phenyl
groups (such as halogens and methyl groups) produced no
negative effects, leading to the formation of the cyclized
O
O
Me
Me
Me
MeO
Me
Br
Br
Br
MeO
5e
5f
5g
71%, 47% ee
98%, 94% ee
72%, 85% ee
O
O
O
O
O
O
O
O
Me
Et
Me
Me
Br
Me
products 5b d with high ee values. Moderate enantioselectivity
−
Br
Me
Br
Br
Me
was observed when the substrate 5e with a p-methoxy group
was used, probably for the reason suggested for the reaction of
2f. In contrast, m-methoxy derivative 4f was a good substrate for
this system (product 5f). While the use of m-tolyl derivative 4g
5h
47%, 4% ee
5i
47%, 49% ee
5j
5k
17%, 44% ee
44%, 7% ee
O
H
[a] Reactions were performed by dissolving 0.1 mmol of 2a, 0.01 mmol of 1a,
and 0.12 mmol of NBS in toluene (4 mL) at −20 °C. See Supporting
Information for details. The isolated yields of the obtained products are listed.
O
Bu3SnH
AIBN
Me
Ph
3ab
51%, 90% ee
benzene
reflux
O
H
O
O
Br
O
Cs2CO3
H3C
OMe
Me
MeOH
rt
Ph
O
N3
O
NaN3
3a
92% ee
dr 7 : 93
reagent instead of NBS produced a comparable yield with lower
selectivity (entry 9). The optimal reaction temperature was equal
to −50 °C (for comparison, the reactions conducted at −30 °C
and 70 °C demonstrated high enantioselectivities and lower
yields; see entries 10 and 11). Finally, the catalyst loading could
be reduced to 5 mol.% without significant decreases in the yield
and selectivity (entry 12).
DMSO
80 °C
Me
Ph
3aa
96%, 90% ee
3ac
61%, >92%ee
dr 5 : 95
dr 7 : 93
O
O
Me
Bu3SnH
AIBN
Ph
After
bromolactonization of 2a, we tested the applicability of our
method to various trisubstituted alkenoic acids 2b n (Table 2).
performing
the
stereoselective
5-exo-dig
O
H
5ab
63%, 95% ee
benzene
reflux
CH3
O
O
Me
Cs2CO3
−
OMe
Ph
O
H
MeOH
rt
The bromolactonization of (Z)-4-aryl-4-hexenoic acids containing
various electron withdrawing halogen moieties on their phenyl
groups proceeded smoothly with relatively high yields and
Br
O
DBU
5aa
5a
O
Me
81%, 95% ee
DMF
40 °C
96% ee
Ph
5ac
97%, 96%ee
excellent enantioselectivities (products 3b d). The presence of
−
electron donating groups (such as methyl ones) was also
tolerated (product 3e). However, electron-rich groups including
Scheme 2. Derivatization of bromolactones 3a and 5a.
the methoxy species of p-methoxyphenyl groups had
a
deleterious effect on both the yield and stereoselectivity,
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resulted in a slightly lower enantioselectivity, o-tolyl derivative 4h
produced almost racemic compound 5h with a moderate yield.
Likewise, the substrate 5i containing a bulky ethyl group with a
double bond exhibited inferior reactivity and selectivity as
compared to those of the methyl derivative 5a. When R1
substituent consisted of a methyl, not aromatic group, no control
of cyclization regioselectivity was observed, producing a mixture
of the 6-membered lactone 5j and 5-membered lactone 5k with
low to moderate yields and enantioselectivities.
The utility of chiral bromolactones was demonstrated as
shown in Scheme 2. Upon the methanolysis of the lactone
moieties of 3a and 5a by the treatment with Cs2CO3 in methanol,
the corresponding methyl esters with tertiary alcohols were
generated and simultaneously cyclized to produce epoxide 3aa
and 5aa while retaining the stereochemical information.[17] In
turn, the carbon-halogen bonds of 3a and 5a can be reduced
selectively under a radical condition, forming the products 3ab
and 5ab with intact lactone moieties.[18] Furthermore, the
substitution reaction of the neopentyl bromide group in 3a with
1a, the reactivity of 1a was compared with that of PPh3 Lewis
base during a short reaction time.[19] While PPh3 reacted better
in THF than in toluene, 1a produced lactone 2a with higher yield
in toluene, indicating that the reaction pathway catalyzed by 1a
was different from that catalyzed by PPh3. In addition, an
important structural element in 1a was elucidated by conducting
control experiments involving 4-dimethylaminopyridine (DMAP).
To our surprise, the reactions with DMAP in toluene and THF
were very slow, suggesting that the simultaneous presence of
DMAP and N-H species in phosphoramide moieties was also
essential for good reactivity (entries 1, 2, 5, and 6). Furthermore,
1H-NMR analysis of 2a with or without one equivalent of 1a was
performed. While the methylene protons in 2a were observed to
be magnetically equivalent as two triplet signals (Figure 1,
above), the same protons appeared upfield and magnetically
non-equivalent in the presence of 1a (Figure 1, below). These
results indicate that the methylene protons of 2a become
diastereotopic in the chiral environment caused by the
complexation of 2a and chiral pyridylphosphoramide 1a.
HB HB
CO2H
Me
Table 4. Description of the control experiments.
HA HA
Ph
HA (2.14, t)
2a
(600 MHz, toluene-d8)
catalyst (10 mol %)
NBS (1.2 equiv)
O
O
Br
O
HB (2.55, t)
Me
Me
OH
solvent (0.025 M)
Ph
Ph
2a
-50 °C, 2 h
3a
NMe2
HB HB
Entry[a]
Catalyst
1a
Solvent
Toluene
THF
Yield [%][b]
ee [%][c]
CO2H
O
P
Me
HA (2.01, m)
+
O
O
HA HA
Ph
2a
(600 MHz, toluene-d8)
N
H
N
1
2
3
4
5
6
94
8
90
-
1a
1a
HB (2.39, m)
PPh3
PPh3
DMAP
DMAP
Toluene
THF
33
90
15
15
-
-
-
Toluene
THF
Figure 1. 1H-NMR analysis of the complex of carboxylic acid 2a and catalyst
1a.
-
[a] Reactions were performed by dissolving 0.1 mmol of 2a (E/Z = 4/96),
0.01 mmol of 1a, and 0.12 mmol of NBS in toluene (4 mL) at −50 °C. See
Supporting Information for details. [b] 1H-NMR yields as diastereomer
mixtures. [c] Determined by chiral HPLC.
Based on these data, we proposed a plausible mechanism
for the bromolactonization reaction (Scheme 3). We predicted
that 1a might first react with carboxylic acid 2 as a Brønsted
base catalyst to form the pyridinium salt A through double
hydrogen bonding interactions.[8c,20] The initial pyridinium cation
in A is transformed to the dimethylammonium cation first and
then interact ionically with the carboxylate anion.[21] The resulting
two acidic N-H moieties activate the carbonyl group of NBS in a
bidentate manner, arranging 2 and NBS in a proximal position
(intermediate B). It should be noted that the phosphoramide N-H
group strongly affected not only the reactivity, but also the
enantiodiscriminating step as intermediate B (Table 1, entry 4
and Table 4, entry 5). Polar solvents (such as THF) can disturb
the ionic and hydrogen bonding interactions in B (Table 4, entry
sodium azide at the bulky position can be performed to produce
the corresponding azide 3ac in the diastereomerically pure form.
Interestingly, the same reaction condition for 5a resulted in the
formation of cyclopropane 5ac with a relatively low yield;
therefore, we deliberately synthesized 5ac with a good yield by
the treatment of DBU in DMF.
To gain mechanistic insights into the bromolactonization
reaction catalyzed by the chiral pyridyl phosphoramide 1a,
several control experiments were performed (Table 4). To
evaluate the possibility of the Lewis basic activation of NBS with
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10.1002/chem.201804630
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[2]
a) D. C. Whitehead, R. Yousefi, A. Jaganathan, B. Borhan, J. Am.
Chem. Soc. 2010, 132, 3298; b) W. Zhang, S. Zheng, N. Liu, J. B.
Werness, I. A. Guzei, W. Tang, J. Am. Chem. Soc. 2010, 132, 3664; c)
L. Zhou, C. K. Tan, X. Jiang, F. Chen, Y.-Y. Yeung, J. Am. Chem. Soc.
2010, 132, 15474; d) G. E. Veitch, E. N. Jacobsen, Angew. Chem. Int.
Ed. 2010, 49, 7332; Angew. Chem. 2010, 122, 7490; e) K. Murai, T.
Matsushita, A. Nakamura, S. Fukushima, M. Shimura, H. Fujioka,
Angew. Chem. Int. Ed. 2010, 49, 9174; Angew. Chem. 2010, 122, 9360.
For recent examples, see a) H. Egami, T. Niwa, H. Sato, R. Hotta, D.
Rouno, Y. Kawato, Y. Hamashima, J. Am. Chem. Soc. 2018, 140, 2785;
b) N. Salehi Marzijarani, R. Yousefi, A. Jaganathan, K. D. Ashtekar, J.
E. Jackson, B. Borhan, Chem. Sci. 2018, 9, 2898. c) Y. Kawato, H.
Ono, A. Kubota, Y. Nagao, N. Morita, H. Egami, Y. Hamashima, Chem.
Eur. J. 2016, 22, 2127; d) Q. Yin, S.-L. You, Org. Lett. 2014, 16, 2426;
e) A. Jaganathan, R. J. Staples, B. Borhan, J. Am. Chem. Soc. 2013,
135, 14806; f) Y.-M. Wang, J. Wu, C. Hoong, V. Rauniyar, F. D. Toste, J.
Am. Chem. Soc. 2012, 134, 12928; g) V. Rauniyar, A. D. Lackner, G. L.
Hamilton, F. D. Toste, Science 2011, 334, 1681.
2). Furthermore, the different enantioselectivities obtained using
NBS and DBDMH suggest that the brominating reagents are
parts of the transition state. Intermediate
B undergoes
bromocyclization to produce 3 and C, which release succinimide
and catalyst 1a, thus completing the catalytic cycle.
Ar
NMe2
N
[3]
O
P
O
OH
O
O
O
N
H
NH
O
Ar
R
1a
Me
Ar
2
Ar
O
NMe2
NMe2
O
O
O
O
P
P
O
N
H
N
H
N
H
O
N
H
O
[4]
[5]
For recent examples, see a) H. Pan, H. Huang, W. Liu, H. Tian, Y. Shi,
Org. Lett. 2016, 18, 896; b) C.-L. Zhu, J.-S. Tian, Z.-Y. Gu, G.-W. Xing,
H. Xu, Chem. Sci. 2015, 6, 3044; c) A. Garzan, A. Jaganathan, N. S.
Marzijarani, R. Yousefi, D. C. Whitehead, J. E. Jackson, B. Borhan,
Chem. Eur. J. 2013, 19, 9015; d) D. Huang, X. Liu, L. Li, Y. Cai, W. Liu,
Y. Shi, J. Am. Chem. Soc. 2013, 135, 8101.
O
Ar
Ar
N
O
C
A
Me
Me
Ar
N
R
O
Me
Br
O
O
P
O
For recent examples, see a) Y. Lu, H. Nakatsuji, Y. Okumura, L. Yao, K.
Ishihara, J. Am. Chem. Soc. 2018, 140, 6039; b) R. C. Samanta, H.
Yamamoto, J. Am. Chem. Soc. 2017, 139, 1460; c) Z. Shen, X. Pan, Y.
Lai, J. Hu, X. Wan, X. Li, H. Zhang, W. Xie, Chem. Sci. 2015, 6, 6986;
d) S. E. Denmark, M. T. Burk, Chirality 2014, 26, 344; e) Z. Ke, C. K.
Tan, F. Chen, Y.-Y. Yeung, J. Am. Chem. Soc. 2014, 136, 5627; f) S. E.
Denmark, M. T. Burk, Org. Lett. 2012, 14, 256; g) D. Huang, H. Wang,
F. Xue, H. Guan, L. Li, X. Peng, Y. Shi, Org. Lett. 2011, 13, 6350; h) U.
Hennecke, C. H. Müller, R. Fröhlich, Org. Lett. 2011, 13, 860.
O
O
O
Br
R
N
N
H
O
N
H
Me
Ar
O
R
Me
N
O
3
Br
B
O
Scheme 3. A plausible mechanism of the bromolactonization reaction.
[6]
[7]
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In conclusion, the catalytic enantioselective bromocyclization
of trisubstituted olefinic acids in both the 5-exo and 6-endo
cyclization modes was performed for the first time. In this
system, pyridyl phosphoramide 1a promotes two different modes
of cyclization, producing a variety of bromolactones, which can
be further transformed to useful derivatives. The results of
optimization and mechanistic studies revealed that 1a might
potentially serve as a dual catalyst activating both carboxylic
acid and the brominating reagent simultaneously through ionic
and hydrogen bonding interactions. The findings of this study
may help to develop a new strategy of catalyst design for
promoting asymmetric transformations.
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Acknowledgements
Y. Nishikawa thanks Meijo University for financial support.
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Keywords: asymmetric catalysis • cyclization • halogenation •
lactones • organocatalysis
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10.1002/chem.201804630
Chemistry - A European Journal
COMMUNICATION
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10.1002/chem.201804630
Chemistry - A European Journal
COMMUNICATION
Layout 2:
COMMUNICATION
Dr. Y. Nishikawa*, Y. Hamamoto, R.
catalyst
(10 mol %)
NBS
O
catalyst
(10 mol %)
NBS
Ar
NMe2
N
O
R2
O
O
Satoh, N. Akada, S. Kajita, M. Nomoto,
M. Miyata, M. Nakamura, C. Matsubara
and Dr. O. Hara*
Br
O
P
O
O
R2
R1
O
R1
OH
R1
N
H
R1 = Ar
R2 = H
R3 = Ar
5-exo mode
R3 = H
R3
R3
Br
6-endo mode
Ar
trisubstuted
olefinic acids
up to 98% ee
up to 95% ee
catalyst
Page No. – Page No.
Enantioselective Bromolactonization
of Trisubstituted Olefinic Acids
Catalyzed by Chiral Pyridyl
Phosphoramides
Enantioselevtive bromolactonization of trisubstituted olefinic acids producing
synthetically useful chiral lactones with two contiguous asymmetric centers was
performed. The use of pyridyl phosphoramide as a Brønsted base catalyst enabled
the 5-exo and 6-endo modes of bromolactonization leading to the formation of a
variety of chiral lactones, which can be transformed to synthetically useful
compounds.
This article is protected by copyright. All rights reserved.