Catalytic asymmetric bromocyclization of polyenes

Article abstract of DOI:10.1021/jacs.6b13193

The first catalytic asymmetric bromonium ion-induced polyene cyclization has been achieved by using a chiral BINOL-derived thiophosphoramide catalyst and 1,3-dibromo-5,5-dimethylhydantoin as an electrophilic bromine source. Bromocyclization products are o

Full text of DOI:10.1021/jacs.6b13193

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Communication
Catalytic Asymmetric Bromocyclization of Polyenes
Ramesh C. Samanta, and Hisashi Yamamoto
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 06 Jan 2017
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Catalytic Asymmetric Bromocyclization of Polyenes
Ramesh C. Samanta* and Hisashi Yamamoto*
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Molecular Catalyst Research Center, Chubu University, 1200 Matsumotoꢀcho, Kasugai, Aichi, 487ꢀ8501, Japan
Supporting Information Placeholder
Scheme 1. Asymmetric bromocyclization
ABSTRACT: The first catalytic asymmetric bromonium
ionꢀinduced polyene cyclization has been achieved by
using a chiral BINOLꢀderived thiophosphoramide cataꢀ
lyst and 1,3ꢀdibromoꢀ5,5ꢀdimethylhydantoin (DBDMH)
as an electrophilic bromine source. Bromocyclization
products are obtained in high yields, with good enantioꢀ
meric ratios and high diastereoselectivity, and are abunꢀ
dantly found as scaffolds in natural products.
Thousands of polycyclic natural products containing
halogen atoms have been isolated from marine sources
with a particularly high abundance of bromine atoms.1ꢀ4
Carbocycles containing a halogen atom with gemꢀ
disubstituents are ubiquitous in terpenoid natural prodꢀ
ucts (Scheme 1A). Nature makes such molecules by a
mechanism that is initiated by an electrophilic halogenaꢀ
tion onto a double bond. Being enzymes, haloperoxidasꢀ
es produce electrophilic halogens, which trigger the
formation of halogenated polycyclic terpenoids in an
enantioselective manner.5 Bromonium ionꢀinduced cyꢀ
clization of polyenes and cationꢀπ cyclization of preꢀ
formed bromohydrine were developed in the 1970s to
mimic the biosynthesis of halogenated terpenoids in raꢀ
cemic form, though in low yields.6ꢀ9 Vanadium
haloperoxidase has also been used for bromocyclization
of geraniol and nerol.10 Development of new reagents,
such as IPy2BF4 by Barluenga et al.11,12 and
Et2SBrꢀSbCl5Br and its iodo and chloro variant by
Snyder et al.13ꢀ15, has improved the yield of halocyclizaꢀ
tion reactions. While the racemic variant is well develꢀ
oped, asymmetric electrophilic halocyclization of polyꢀ
enes to synthesize halogenated polycyclic terpenoids in
optically active form in the laboratory is highly demandꢀ
ing.
g a twoꢀstep method (Scheme 1Bb): enantioselective
mercuration using 1.2 equiv of chiral ligand 2 and broꢀ
moꢀdemercuration.15 In contrast to these two stoichioꢀ
metric methods, development of a catalytic method for
asymmetric electrophilic halocyclization of polyenes has
great potential.20 Numerous catalysts have been develꢀ
oped for halofunctionalization of olefins with both the
internal and external nucleophiles. In all cases, they are
The first asymmetric iodocyclization (Scheme 1Ba)
was reported by Ishihara et al.16 A stoichiometric amount
of chiral phosphoramidites (1a, 1b) was used as a chiral
promoter and the attempt at bromocyclization was unꢀ
successful (75% yield, 68:32 er).17ꢀ20 Snyder et al. have
achieved the bromocyclization of polyenes by usinꢀ
heteroatoms
(haloetherification,
halolactonization,
haloamination, etc.)21ꢀ42 and the olefins are activated by
nucleophiles that has recently been studied by Borhan et
al.43 We have developed a catalytic asymmetric method
for bromonium ionꢀinduced polyene cyclization by using
a chiral thiophosphoramide catalyst.
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The initial experiment was started with homogeranyl 3d were reacted to give the products 5aꢀ5d in good
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toluene 3a as the standard substrate for polyene cyclizaꢀ
tion, using phosphoric acids or phosphoric acid derivaꢀ
tives as a catalyst and Nꢀbromosuccinimide (NBS) as an
electrophilic bromine source, and the results are summaꢀ
rized in Scheme 2. Under reaction conditions, the comꢀ
pletely cyclized product 5a was formed together with
partially cyclized products 4a and 4b (4a:4b:5a =
5.1:1.0:5.3). The crude reaction mixture was treated with
chlorosulfonic acid (ClSO3H) to promote the fully cyꢀ
clized product 5a. Chiral thiophosphoramides that have
been developed and exploited as strong Brønsted acids
in numerous reactions by our group44,45 worked excelꢀ
lently in bromocyclization reactions. BINOLꢀderived
yields and with high er values (up to 91:9 er). Substituꢀ
tion at the 3,5ꢀpositions of the arene ring with methyl
groups 3e had a negligible effect, while substitution with
methoxy groups 3f gave a bromocyclization product
having additional bromination in aromatic ring 5f with
slightly increased enantioselectivity (92.5:7.5 er). Introꢀ
duction of one additional methoxy group, 3,4,5ꢀ
trimethoxy homogeranyl benzene 3g, gave the bromocyꢀ
clization product 5g in a high yield and with very high
enantioselectivity (97:3 er).
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Table 1. Scope of bromocyclization for different ho-
mogeranylbenzenes
chiral
thiophosphoramide
8a
with
2,4,6ꢀ
triisopropylphenyl (TRIP) substituents at the 3,3’ꢀ
position delivered the desired product 5a in a 68% yield
with a low enantiomeric ratio (65:35). In spite of having
similar acidity, phosphoramide46,47 7 delivered the broꢀ
mocyclization product 5a in a low yield (20%) and with
no selectivity (50:50 er). Therefore, we believe that the
Lewis basicity of sulfur plays an important role, together
with the Brønsted acidity of thiophosphoramide
(Scheme 1C). Screening of various BINOLꢀderived chiꢀ
ral thiophosphoramide catalysts, solvents, reaction temꢀ
peratures and electrophilic bromine sources was extenꢀ
sively carried out. Using catalyst 8b, having 2,6ꢀ
diisopropylꢀ4ꢀ(9ꢀanthracenyl)phenyl substituents at the
3,3’ꢀposition, toluene/CH2Cl2 (10:1) as a solvent, 1,3ꢀ
dibromoꢀ5,5ꢀdimethylhydantoin (DBDMH) 9 as an elecꢀ
trophilic bromine source at −90oC with an 18 h reaction
time and an additional 12 h for treatment with ClSO3H
i
in PrNO2 delivered the product 5a in a 69% yield with
an 89:11er. The yield was improved by performing two
steps in one pot (87% yield and 89.5:10.5 er) (see supꢀ
porting information for detailed optimization studies).
Scheme 2. Optimization of bromocyclization reac-
tions
All the reactions were performed in 0.1 mmol scale unless
otherwise specified. Step 1: 3 (0.1 mmol), 8b (0.005
mmol), 9 (0.105 mmol), toluene/CH2Cl2 (10:1, 4 mL) at –
o
i
90 C for 18 to 24 h. Step 2: PrNO2 (2.0 mL), ClSO3H
o
(0.75 mmol) at –78 C for 12 h. Yields of the isolated
products are given. Enantiomeric ratios (er) were deterꢀ
mined by chiral HPLC. For compound 5a, 5b, 5c and 5d
minor diastereomer was formed in >10:1 ratio; determined
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a
by H NMR of crude reaction mixture. One pot two step
process; after first step ClSO3H (0.75 mmol) was added to
o
the same reaction mixture and continued stirring at –78 C
for 12 h. b Performed at 0.05 mmol scale. 5g was isolated
and characterized after first step.
Geranylphenol derivatives are another class of highly
important but challenging substrates for bromonium ionꢀ
induced cyclization reactions resulting in low diastereoꢀ
and enantioselectivity.20 2ꢀGeranylphenol 10a was cyꢀ
clized under optimized bromocyclization conditions to a
Having the optimized conditions, several homogeraꢀ
nyl benzene derivatives were examined. Both electronꢀ
withdrawing and ꢀdonating substituents on aromatic ring
(paraꢀsubstituted) as well as unsubstituted benzene 3aꢀ
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single diastereomer 11a in an 84% yield and with 89:11 enantiomeric ratio of 5a could be improved to 98.5:1.5
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er; additional treatment by ClSO3H was not required.
er after single recrystallization.
Table 2. Bromocyclization of geranylphenols
Scheme 3. Bromocyclization of geranylbenzene and
determination of absolute configuration
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Intriguingly, when geranyl benzene 12 was subjected
to bromocyclization conditions, compound 13a was
formed in a 65% yield and with 93:7 er, together with
the formation of compound 13b in a 17% yield and with
low enantioselectivity (63:37 er). This clearly shows
that a common bromonium ion intermediate cannot
be involved, but a much more likely the chiral thioꢀ
phosphoramide remains bound to the bromonium
ion and the two diastereomeric complexes lead to
different amounts of the product isomers.48 These
pathways, responsible for the formation of the partial
cyclization products competing for the formation of the
fully cyclized product resulted in low enantioselectivity
after treatment with ClSO3H to promote the completed
cyclization product. For substrates having highly elecꢀ
tronꢀrich arenes, the formation of partially cyclized
products is minimized, which is consistent with the inꢀ
creased er obtained for highly activated arenes both in
the case of homogeranyl benzene derivatives (97:3 er)
and geranylphenols (99:1 er).
All the reactions were performed in 0.1 mmol scale. 10 (0.1
mmol), 8b (0.005 mmol), 9 (0.105 mmol), toluene/CH2Cl2
(10:1/ 4 mL) at –90 oC for 16 to 24 h. Yields of the isolated
products are given. Enantiomeric ratios (er) were deterꢀ
mined by chiral HPLC.
Likewise, 4ꢀsubstituted geranylphenols 10bꢀ10d delivꢀ
ered the bromocyclization products 11bꢀ11d as a single
diastereomer with high yields and enantioselectivities
(up to 93.5:6.5 er). 1ꢀGeranylꢀ2ꢀnaphthol 10e was cyꢀ
clized to give 11e as a single diastereomer in a 58%
yield and with 94:6 er. Surprisingly, 6ꢀgeranylꢀ2,4ꢀ
dimethoxy phenol 10f underwent cyclization via aroꢀ
matic substitution to produce a [6,5,6]ꢀfused ring prodꢀ
uct 11f as a single diastereomer in 91% yield and with
excellent enantioselectivity (99:1 er).
Table 3. Scale-up experiments
Compound 5a was converted to a known compound (–
)ꢀ14 and, by comparing its specific rotation value, the
absolute configuration of 5a was determined.49 The abꢀ
solute configurations of 11a-11d were determined by
comparing the specific rotation value known in the literꢀ
ature.20 Other compounds were assigned in analogy.
In conclusion, we have developed the first catalytic
asymmetric halocyclization method for bromonium ionꢀ
induced polyene cyclization. A wide variety of hoꢀ
mogeranyl benzene derivatives were cyclized with very
high enantioselectivities (up to 97:3 er). Geranylphenols
delivered the bromocyclization products as single diaꢀ
stereomers in good yields and with high enantioselecꢀ
tivities (up to 99:1 er). Detailed mechanistic studies and
applications of this method to natural product synthesis
are currently ongoing in our laboratory and theoretical
calculation is on our agenda.
When this bromocyclization reaction was conducted in 1
mmol scale the products 5b and 11d were obtained with
identical enantioselectivities but with slight lower yields
(Table 3). An increased yield and slight lower enantioseꢀ
lectivity was obtained for product 5a. Gratifyingly, the
ASSOCIATED CONTENT
Supporting Information.
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Sawamura, Y.; Ogura, Y.; Nakatsuji, H.; Sakakura, A.; Ishiꢀ
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Supporting information PDF file
AUTHOR INFORMATION
Corresponding Author
*rsamanta@isc.chubu.ac.jp
*hyamamoto@isc.chubu.ac.jp
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by ACTꢀC. We thank JSPS for
Postdoctoral Fellowship to RCS. The authors thank to Dr.
Y. Shimoda and Dr. M. Sai for helpful discussions.
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Catalytic Asymmetric Bromocyclization of Polyenes
Ramesh C. Samanta* and Hisashi Yamamoto*
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