BINOL-derived bifunctional sulfide catalysts for asymmetric synthesis of 3,3-disubstituted phthalides via bromolactonization

Article abstract of DOI:10.1039/C9OB00417C

An efficient enantioselective synthesis of 3,3-disubstituted phthalides possessing a chiral quaternary carbon center was achieved via catalytic asymmetric bromolactonization that utilized BINOL-derived bifunctional sulfide catalysts. Transformations of th

Full text of DOI:10.1039/C9OB00417C

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Takeharu Haino et al.
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BINOL-derived bifunctional sulfide catalysts for asymmetric
synthesis of 3,3-disubstituted phthalides via bromolactonization
Megumi Okada,a Kazuma Kaneko,b Masahiro Yamanakab and Seiji Shirakawa*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Efficient enantioselective synthesis of 3,3-disubstituted phthalides to enantioselectively synthesize 3,3-disubstituted phthalides 2
possessing a chiral quaternary carbon center was achieved via using chiral bifunctional sulfide catalysts. Transformations of
catalytic asymmetric bromolactonization that utilized BINOL- the bromo group in optically active phthalide products 2 were
derived bifunctional sulfide catalysts. Transformations of the also performed to demonstrate the potential utility of the
bromo group in optically active phthalide products were also present synthetic protocol.
performed to demonstrate the utility of this novel synthetic
R'
R
protocol.
core structure of important natural products
integral part of biologically active compounds
O
The phthalide structure appears in many important natural
O
products and biologically active compounds, which is why
MeO2C
chiral phthalide
Ph
phthalides are recognized as some of the most important
lactones (Scheme 1).1 There have been numerous attempts to
build this structural motif, which includes the asymmetric
synthesis of chiral phthalides.2 A catalytic asymmetric synthesis
of 3,3-disubstituted phthalides possessing a chiral quaternary
carbon center ranks among the most important challenges in
modern organic synthesis. Catalytic enantioselective fluoro-
n-C7H15
O
OMe OH
Me
O
HN
O
O
O
N
O
O
H2N
Me
OH
paecilocin A
eleutherol
dermacozine D
and chlorolactonizations of substrate
1 were recently
Br
Y
R
developed as effective methods to produce 3,3-disubstituted
phthalides.3,4 Unfortunately, a catalytic asymmetric method for
the bromolactonization of 1 has remained elusive, despite great
expectations for the synthetic utility of the resultant bromo-
substituted phthalides 2 for use in further transformations.5 In
the course of our recent study into the development of chiral
bifunctional sulfide catalysts (S)-3 for bromolactonization to
produce chiral 3,4-dihydroisocoumarins,6 we became
interested in the construction of 3,3-disubstituted chiral
phthalides via the asymmetric bromolactonization of 1 with our
sulfide catalysts (Scheme 1).7,8 Our previously developed
bifunctional sulfide (S)-3 possesses a urea moiety, but has
shown poor selectivity for the present reaction. However,
redesigned sulfide catalysts (S)-4 bearing a hydroxy group
improved the enantioselectivity. Herein, we report our efforts
R
chiral sulfide
R
O
catalyst
O
CO2H
O
asymmetric
bromolactonization
further
transformation
O
1
2
previously developed catalyst
new bifunctional catalyst
SR
SR
OH
H
H
N
N
redesign
Ar
O
(S)-3
not effective
(S)-4
effective
Scheme 1 Important chiral phthalides and our synthetic
approach.
a. Department of Environmental Science, Graduate School of Fisheries and
Environmental Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-
8521, Japan. E-mail: seijishirakawa@nagasaki-u.ac.jp
Our initial aim was to find an effective catalyst for the
asymmetric bromolactonization of 1 (Table 1). An attempted
reaction of 1a with N-bromophthalimide (NBP) in toluene-
CH2Cl2 under the influence of a urea-type bifunctional sulfide
catalyst (S)-3a,9 which is an effective catalyst for different
enantioselective bromolactonizations,6 at –78 °C for 24 h
b. Department of Chemistry and Research Center for Smart Molecules, Faculty of
Science, Rikkyo University, 3-34-1, Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501,
Japan
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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afforded the target phthalide product 2a in a high yield, but with
poor enantioselectivity (53:47 er, entry 1). This result prompted
us to examine different types of chiral sulfide catalysts. To our
9
10
(S)-6c
99
98
8V6ie:1w4Article Online
(50:50)
nonee
DOI: 10.1039/C9OB00417C
a
Reaction conditions: 1a (0.10 mmol), NBP (0.12 mmol),
delight, the reaction with a relatively simple bifunctional sulfide catalyst (10 mol %, 0.010 mmol), toluene (1.5 mL)-CH2Cl2 (0.5
b
c
(S)-4a possessing a hydroxy group gave product 2a with good mL), –78 °C, 24 h. Yield of isolated product 2a. Determined
enantioselectivity (88:12 er, entry 2). To clarify the role of the by HPLC analysis on a chiral stationary phase. d Reaction time =
hydroxy group in bifunctional catalysts (S)-4, we also examined 6 h. e The reaction was performed without a catalyst.
a reaction with hydroxy-protected mono-functional catalyst (S)-
5a. As expected, the reaction with mono-functional catalyst (S)-
5a produced 2a in a low level of enantioselectivity with opposite gain
Next, we examined the effects of brominating reagents to
mechanistic information of the present
configuration of the major isomer (43:57 er, entry 3). These bromolactonization with bifunctional catalyst (S)-4b (Scheme 2).
results suggested that the bifunctional design of sulfide The enantioselectivity of product 2a significantly depends on
catalysts (S)-4 bearing a hydroxy group is essential in order to the structure of the brominating reagents. Reactions with
obtain a high level of enantioselectivity. Encouraged by these brominating reagents possessing 5-membered ring structures
results, a fine-tuning of the sulfide moiety on the catalyst (S)-4 gave product 2a with high levels of enantioselectivity (88:12–
was performed to improve the enantioselectivity. The higher 94:6 er). The reaction with dibromoisocyanuric acid (DBI)
enantioselectivities of product 2a were observed in the reaction possessing a 6-membered ring structure provided 2a with a
using catalysts (S)-4b (R = i-Pr, 94:6 er, entry 4) and 4c (R = t-Bu, moderate level of enantioselectivity (71:29 er). On the other
93:7 er, entry 5), which possess a more bulky alkyl group on the hand, acyclic brominating reagent, such as
a
N-
sulfur. Although we generally performed the reaction for 24 h, bromoacetamide (NBA), produced 2a with a low level of
the actual reaction was almost completed within 6 h (entry 6). enantioselectivity (66:34 er). Additionally, the reaction with
The introduction of substituents at the 3-position of a bromine (Br2) provided 2a as a racemate.10 These results
binaphthyl unit on the catalyst did not improve the suggest that the corresponding imide anions generated from
enantioselectivity (catalysts (S)-6a–c, entries 7–9). It should be brominating reagents are involved in the stereo-determining
noted that the present reaction efficiently proceeded even steps in the present reaction system.
Br
without a catalyst (entry 10).
Ph
Ph
(S)-4b
(10 mol %)
+
Br-X
Table 1 Catalyst optimizationa
O
toluene-CH2Cl2
–78 °C, 24 h
Br
Br
(1.2 equiv)
CO2H
Ph
Ph
catalyst
(10 mol %)
O
N
O
O
1a
2a
+
O
5-membered ring
toluene-CH2Cl2
–78 °C, 24 h
Br
CO2H
Br
N
O
Br
N
O
O
1a
2a
O
O
NBP
N
O
O
(1.2 equiv)
N
Br
Sn-Bu
SR
NBP
NBS
DBH
98%, 94: 6 er
85%, 88:12 er
94%, 92: 8 er
H
H
N
N
OH
Ph
6-membered ring
acyclic
(S)-4a: R = n-Bu
(S)-4b: R = i-Pr
(S)-4c: R = t-Bu
Br
O
Br
O
N
O
(S)-3a
(S)-4
Br2
O
N
H
N
N
Br
H
Si-Pr
Sn-Bu
OMe
O
DBI
56%, 71:29 er
NBA
OH
99%, 66:34 er
99%, 50:50 er
(S)-6a: X = Br
(S)-6b: X = Ph
(S)-6c: X = 3,5-Ph2-C6H3
Scheme 2 Effect of brominating reagents.
X
(S)-5a
(S)-6
The assumed catalytic cycle for the present attempts at
bromolactonization using bifunctional sulfide catalyst (S)-4b
appear in Scheme 3. In that scheme, when the chiral sulfide
catalyst (S)-4b is mixed with NBP, bromosulfonium phthalimide
is formed (A in Scheme 3). The position of the phthalimide anion
is fixed by the hydrogen-bonding interaction with a hydroxy
group of the catalyst. The alkene portion of substrate 1 is then
activated by the bromosulfonium moiety to form a cyclic
bromonium ion intermediate (B in Scheme 3). Simultaneously,
Entry
Catalyst
Yieldb (%)
erc
1
2
3
4
5
6d
7
8
(S)-3a
(S)-4a
(S)-5a
(S)-4b
(S)-4c
(S)-4b
(S)-6a
(S)-6b
99
92
97
98
95
92
90
92
53:47
88:12
43:57
94: 6
93: 7
95: 5
85:15
94: 6
2 | J. Name., 2012, 00, 1-3
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a carboxylic acid moiety of 1 is also activated by the phthalimide of 1 to produce various 3,3-disubstituted phthalidVeiesw2Ar(tSicclehOenmlinee
anion, which serves as a Brønsted base, to provide a well- 4). In general, good to high levels of eDnOanI:t1i0o.1s0e3le9/cCti9vOitBy00w4e17rCe
organized transition-state (TS). Highly enantioselective observed in the synthesis of 3-arylphthalides (2a–h).
lactonization then occurs to provide target product 2 with the Unfortunately, 3-alkylphthalides such as 3-methylphthalide 2i
regeneration of catalyst (S)-4b. Based on our previously and 3-butylphthalide 2j were obtained with only low levels of
reported associative TS model involving succinimide anion as enantioselectivity. 3-Arylphthalides possessing substituents on
the stereo-determining cyclization step,6 a plausible TS model the aromatic ring at the phthalide core could also be obtained
for the (S)-4c-catalyzed bromolactonization with N- with good to high levels of enantioselectivity (2k–n).12
Br
bromosuccinimide (NBS) was proposed via DFT-computed
molecular modeling (B’ in Scheme 3).11 The sulfide and naphthol
moieties of (S)-4c capably arrange the positions of the
bromonium ion generated from carboxylic acid 1 and the
succinimide anion via sulfide/bromonium interaction and the
exhaustive hydrogen bonding network, respectively. The
proposed TS model thoroughly explains the crucial role of the
naphthol moiety of (S)-4, which was revealed in the control
experiments (entries 1–3 in Table 1).
Br
R
R
O
(S)-4b
(10 mol %)
N
O
O
+
X
X
toluene-CH2Cl2
–78 °C, 24 h
CO2H
O
1
NBP
(1.2 equiv)
2
Me
Cl
Br
Br
Br
Ph
O
O
O
O
O
2b
O
2c
2a
99%, 96: 4 erb
97%, 90:10 erc
98%, 91: 9 erc
F
OMe
OCF3
Br
Br
Br
O
O
O
O
2d
O
2e
O
2f
90%, 93: 7 er
91%, 82:18 er
88%, 96: 4 er
Ph
Br
Br
Br
F
Me
O
O
O
O
2g
O
2h
O
2i
83%, 88:12 er
91%, 93: 7 er
94%, 53:47 er
Br
Br
Br
n-Bu
Ph
Ph
F
Cl
O
O
O
Cl
O
O
O
2j
2k
88%, 91: 9 er
2l
91%, 52:48 er
80%, 82:18 erc
Br
Br
Ph
Ph
O
Me
Me
O
O
O
2m
99%, 90:10 er
2n
95%, 88:12 erc
Scheme 4 Scope and limitation. a a Reaction conditions: 1 (0.10
mmol), NBP (0.12 mmol), (S)-4b (10 mol %, 0.010 mmol),
b
toluene (1.5 mL)-CH2Cl2 (0.5 mL), –78
°
C, 24 h. The reaction
Scheme
3 Proposed catalytic cycle and transition-state
was conducted on a 10-fold scale (1a: 1.0 mmol). c The reactions
with 1b, 1c, 1l, and 1n were performed using catalyst (S)-4c.
structure.
With the effective bifunctional sulfide catalysts (S)-4 in hand,
we studied the substrate generality of the bromolactonization
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This work was supported by JSPS KAKENHI GrVainewt ArNticulemObnelinres
JP16K05780 (for S.S.), JP18H04660 (HybridDCOaI:ta10ly.1s0is39fo/Cr9MOB.Y0.0),41t7hCe
Cooperative Research Program of "Network Joint Research Center
for Materials and Devices" (20181268 for S.S.), and Shorai
Foundation for Science and Technology (for S.S.).
To show additional utility of the present method for the
asymmetric synthesis of 3,3-disubstituted phthalides, we
examined transformations of the bromo groups in optically
active bromolactonization products 2 to form other functional
groups (Scheme 5). The bromo group of 2a was removed via
reduction with tributyltin hydride under radical conditions to
provide 7. Allylation with allyltributyltin was also performed to
obtain 8. Introductions of heteroatom substituents were also
possible via nucleophilic substitutions, and product 9 possessing
a thiophenyl group was synthesized via a reaction with
thiophenol. It is noteworthy that these reactions proceeded
with no loss of enantioselectivity.
Notes and references
1
For reviews on phthalides, see: (a) J. J. Beck and S.-C. Chou, J.
Nat. Prod., 2007, 70, 891; (b) R. Karmakar, P. Pahari and D.
Mal, Chem. Rev., 2014, 114, 6213.
2
For examples of catalytic asymmetric synthesis of chiral
phthalides, see: (a) M. Kitamura, T. Ohkuma, S. Inoue, N. Sayo,
H. Kumobayashi, S. Akutagawa, T. Ohta, H. Takaya and R.
Noyori, J. Am. Chem. Soc., 1988, 110, 629; (b) K. Everaere, J.-
L. Scheffler, A. Mortreux and J.-F. Carpentier, Tetrahedron
Lett., 2001, 42, 1899; (c) J.-G. Lei, R. Hong, S.-G. Yuan and G.-
Q. Lin, Synlett 2002, 927; (d) K. Tanaka, G. Nishida, A. Wada
and K. Noguchi, Angew. Chem., Int. Ed., 2004, 43, 6510; (e) H.-
T. Chang, M. Jeganmohan and C.-H. Cheng, Chem. – Eur. J.,
2007, 13, 4356; (f) K. Tanaka, T. Osaka, K. Noguchi and M.
Hirano, Org. Lett., 2007, 9, 1307; (g) J. Luo, H. Wang, F. Zhong,
J. Kwiatkowski, L.-W. Xu and Y. Lu, Chem. Commun., 2012, 48,
4707; (h) F. Zhong, J. Luo, G.-Y. Chen, X. Dou and Y. Lu, J. Am.
Chem. Soc., 2012, 134, 10222; (i) J. Luo, C. Jiang, H. Wang, L.-
W. Xu and Y. Lu, Tetrahedron Lett., 2013, 54, 5261; (j) J. Luo,
H. Wang, F. Zhong, J. Kwiatkowski, L.-W. Xu and Y. Lu, Chem.
Commun., 2013, 49, 5775; (k) R. Liu, R. Jin, J. An, Q. Zhao, T.
Cheng and G. Liu, Chem. – Asian J., 2014, 9, 1388; (l) L. Kong,
J. Zhao, T. Cheng, J. Lin and G. Liu, ACS Catal., 2016, 6, 2244;
(m) W. Liu, Z.-P. Hu, Y. Yan and W.-W. Liao, Tetrahedron Lett.,
2018, 59, 3132; (n) J. M. Cabrera, J. Tauber and M. J. Krische,
Angew. Chem., Int. Ed., 2018, 57, 1390.
Me
Ph
n-Bu3SnH
AIBN
O
toluene
100 °C, 24 h
O
7
56% (96: 4 er)
Br
Ph
n-Bu3Sn
Ph
O
AIBN
O
benzene
80 °C, 24 h
O
2a
(96: 4 er)
O
8
63% (96: 4 er)
PhS
Ph
PhSH
K2CO3
O
CH3CN
75 °C, 24 h
O
9
3
4
(a) X. Han, C. Dong and H.-B. Zhou, Adv. Synth. Catal., 2014,
356, 1275; (b) D. Parmar, M. S. Maji and M. Rueping, Chem. –
Eur. J., 2014, 20, 83; (c) H. Egami, J. Asada, K. Sato, D.
Hashizume, Y. Kawato and Y. Hamashima, J. Am. Chem. Soc.,
2015, 137, 10132.
94% (96: 4 er)
Scheme 5 Conversions of product 2a.
For examples of synthesis of phthalides via intramolecular
lactonization of alkenes, see: (a) J. Chen, L. Zhou, C. K. Tan and
Y.-Y. Yeung, J. Org. Chem., 2012, 77, 999; (b) S. Hajra, S. M. S.
Akhtar and S. M. Aziz, Chem. Commun., 2014, 50, 6913; (c) S.
Song, X. Li, X. Sun, Y. Yuan and N. Jiao, Green Chem., 2015, 17,
3285; (d) F. Gelat, M. Coffinet, S. Lebrun, F. Agbossou-
Niedercorn, C. Michon and E. Deniau, Tetrahedron:
Asymmetry, 2016, 27, 980; (e) B. N. Hemric, K. Shen and Q.
Wang, J. Am. Chem. Soc., 2016, 138, 5813; (f) E. M. Woerly, S.
M. Banik and E. N. Jacobsen, J. Am. Chem. Soc., 2016, 138,
13858; (g) F. Gelat, S. Lebrun, N. Henry, F. Agbossou-
Niedercorn, C. Michon and E. Deniau, Synlett, 2017, 28, 225.
For reviews on catalytic asymmetric halolactonization, see: (a)
G. Chen and S. Ma, Angew. Chem., Int. Ed., 2010, 49, 8306; (b)
C. K. Tan, L. Zhou and Y.-Y. Yeung, Synlett, 2011, 1335; (c) A.
Castellanos and S. P. Fletcher, Chem. – Eur. J., 2011, 17, 5766;
(d) S. E. Denmark, W. E. Kuester and M. T. Burk, Angew. Chem.,
Int. Ed., 2012, 51, 10938; (e) U. Hennecke, Chem. – Asian J.,
2012, 7, 456; (f) C. K. Tan and Y.-Y. Yeung, Chem. Commun.,
2013, 49, 7985; (g) K. Murai and H. Fujioka, Heterocycles, 2013,
87, 763; (h) C. K. Tan, W. Z. Yu and Y.-Y. Yeung, Chirality, 2014,
26, 328; (i) S. Zheng, C. M. Schienebeck, W. Zhang, H.-Y. Wang
and W. Tang, Asian J. Org. Chem., 2014, 3, 366; (j) Y. A. Cheng,
W. Z. Yu and Y.-Y. Yeung, Org. Biomol. Chem., 2014, 12, 2333;
(k) C. B. Tripathi and S. Mukherjee, Synlett, 2014, 25, 163; (l)
A. Sakakura and K. Ishihara, Chem. Rec., 2015, 15, 728; (m) M.
H. Gieuw, Z. Ke and Y.-Y. Yeung, Chem. Rec., 2017, 17, 287; (n)
Y. Kawato and Y. Hamashima, Synlett, 2018, 29, 1257.
Conclusions
In summary, we have successfully achieved the highly
enantioselective synthesis of 3,3-disubstituted phthalides
possessing a chiral quaternary carbon center via catalytic
asymmetric
bromolactonization
using
BINOL-derived
bifunctional sulfide catalysts. The importance of the hydroxy
group on the chiral sulfide catalysts to recognize the imide anion
generated from brominating reagents was clarified based on
the results of control experiments. The great utility of the
present synthetic protocol was demonstrated in
transformations of the bromo group in optically active
phthalide products. Further applications of bifunctional sulfide
catalysts to other asymmetric reactions are currently under way
by our research group.
5
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
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6
7
R. Nishiyori, A. Tsuchihashi, A. Mochizuki, K. Kaneko, M.
View Article Online
DOI: 10.1039/C9OB00417C
Yamanaka and S. Shirakawa, Chem. – Eur. J., 2018, 24, 16747.
For reviews on chiral sulfide catalysts, see: (a) V. K. Aggarwal,
Synlett, 1998, 329; (b) V. K. Aggarwal and C. L. Winn, Acc.
Chem. Res., 2004, 37, 611; (c) E. M. McGarrigle, E. L. Myers, O.
Illa, M. A. Shaw, S. L. Riches and V. K. Aggarwal, Chem. Rev.,
2007, 107, 5841; (d) R. Gómez Arrayás and J. C. Carretero,
Chem. Commun., 2011, 47, 2207; (e) J. Luo, X. Liu and X. Zhao,
Synlett, 2017, 28, 397.
8
For recent examples of chiral sulfide catalysts, see: (a) Z. Ke,
C. K. Tan, F. Chen and Y.-Y. Yeung, J. Am. Chem. Soc., 2014,
136, 5627; (b) Z. Ke, C. K. Tan, Y. Liu, K. G. Z. Lee and Y.-Y.
Yeung, Tetrahedron, 2016, 72, 2683; (c) X. Liu, R. An, X. Zhang,
J. Luo and X. Zhao, Angew. Chem., Int. Ed., 2016, 55, 5846; (d)
Q.-Z. Li, X. Zhang, R. Zeng, Q.-S. Dai, Y. Liu, X.-D. Shen, H.-J.
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Cao, J. Luo and X. Zhao, Angew. Chem., Int. Ed., 2019, 58, 1315.
For optimization of the reaction solvents, see Table S1 in
Supplementary Information.
9
10 The reaction with bromine (Br2) may proceed via non-
catalyzed reaction pathway (background reaction pathway).
11 The transition structure was partially optimized (the reaction
center was frozen) at the B3LYP/6-31LAN (LANL2DZ for Br and
6-31G* for the rest) level. For detail, see Supplementary
Information.
12 See also, Scheme S1 in Supplementary Information.
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Graphical Abstract
Br
N-bromophthalimide
bifunctional sulfide
Ph
Ph
(10 mol %)
99%
O
96: 4 er
CO2H
O
Si-Pr
PhS
Ph
Ph
OH
O
O
bifunctional sulfide
96: 4 er
O
O
Efficient enantioselective synthesis of 3,3-disubstituted
phthalides possessing a chiral quaternary carbon center was
achieved via catalytic asymmetric bromolactonization using
BINOL-derived bifunctional sulfide catalysts.
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