Thioureas as highly active catalysts for biomimetic bromocyclization of geranyl derivatives

Article abstract of DOI:10.1021/acs.orglett.9b00352

Thioureas bearing electron-deficient aryl groups show high catalytic activity in the biomimetic bromocyclization of geranyl derivatives. The reaction of geranyl derivatives with N-bromosuccinimide (NBS) proceeds rapidly in CH₂Cl₂ to

Full text of DOI:10.1021/acs.orglett.9b00352

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Thioureas as Highly Active Catalysts for Biomimetic
Bromocyclization of Geranyl Derivatives
Miyuki Terazaki, Kei-ichi Shiomoto, Haruki Mizoguchi, and Akira Sakakura*
Graduate School of Natural Science and Technology, Okayama University, 3-1-1, Tsushima-naka, Kita-ku, Okayama, Japan
S
* Supporting Information
ABSTRACT: Thioureas bearing electron-deficient aryl
groups show high catalytic activity in the biomimetic
bromocyclization of geranyl derivatives. The reaction of
geranyl derivatives with N-bromosuccinimide (NBS) proceeds
rapidly in CH2Cl2 to give the corresponding bromocyclization
products in high yields as a ca. 1:1 mixture of endo- and exo-
isomers. The reactivity of geranyl derivatives highly depends
on the terminal substituent: electron-donating substituents
increase the reactivity, while electron-withdrawing substituents decrease the reactivity.
rominated polycyclic terpenoids, which have a 1-bromo-
2,2-dimethylcyclohexane core, are an important class of
of geranyl derivatives.11 Burns and colleagues reported
enantioselective dihalogenation followed by solvolytic cycliza-
tion for the synthesis of enantioenriched 1-bromo-2,2-
dimethylcyclohexane natural products.12 Ishihara and Sakaku-
ra’s group also developed phosphite−urea cooperative catalysts
for the bromocyclization of geranyl derivatives.13−15 Sterically
hindered electron-deficient phosphites bearing a urea moiety
successfully catalyze bromocyclization to give the corresponding
products in high yields (Scheme 1). The phosphite moiety of
these catalysts nucleophilically activates NBS to generate active
B
natural products.1 Some of these compounds show unique
biological activities such as anticancer and antiviral activities.
The biosynthesis of the 1-bromo-2,2-dimethylcyclohexane core
of these polycyclic terpenoids appears to involve an electrophilic
bromination of acyclic isoprenoids induced by enzymes such as
vanadium bromoperoxidase (V-BPO), followed by diastereose-
lective cyclization.2,3 For the chemical synthesis of these
bromine-containing polycyclic compounds, bromonium ion-
induced biomimetic bromocyclization is the most desirable
approach. Thus, considerable effort has been devoted to the
development of efficient methods for the bromocyclization of
acyclic isoprenoids.4−6 For example, in 2009, Snyder and
colleagues reported Et2SBr·SbCl5Br (BDSB) as a highly reactive
electrophilic brominating reagent.7,8 Although this method gave
the corresponding bromocyclization products in high yields, a
stoichiometric amount of BDSB, a rather expensive brominating
agent, was required. In addition, the reaction conditions are
highly acidic, and side reactions might also proceed in some
cases. In 2018, Gulder and colleagues reported the halocycliza-
tion of geranyl derivatives with N-halosuccinimides in the
presence of a stoichiometric amount of morpholine-HFIP salt in
HFIP.9
Scheme 1. Phosphite−Urea Catalyst for the
Bromocyclization of 4-Homogeranyltoluene13
As a practical method for the biomimetic bromocyclization of
acyclic isoprenoids, the use of an inexpensive and easily available
brominating agent is desirable. N-Bromosuccinimide (NBS) is
one of these desirable brominating agents, although its reactivity
is low. A catalyst can be used to activate less reactive brominating
agents and promote bromocyclization under mild conditions.
Some catalysts that promote the bromocyclization of geranyl
derivatives have recently been reported. For example, Chan and
McErlean’s group reported an N-heterocycle-flanked phosphor-
amidite catalyst that promoted the diastereoselective bromocyc-
lization of a chiral geraniol derivative.10 In 2017, Yamamoto and
Samanta reported a chiral BINOL-derived thiophosphoramide
catalyst that enantioselectively promoted the bromocyclization
Received: January 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00352
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
species in situ. The urea moiety of the catalysts catches a
succinimide anion via hydrogen bonding to promote generation
of the active species. Although these catalysts show quite high
activities, their structures are large and highly complex, and they
require many steps to be synthesized. We report here a new
method for the bromocyclization of geranyl derivatives. In this
study, we focus on the development of structurally simple
catalysts that can activate NBS and promote bromocyclization
under weakly acidic or basic conditions at a low reaction
temperature.
the presence of a catalyst (10 mol %) in toluene at −78 °C. As
reported previously,13 the combined use of electron-deficient
phosphite 4 and urea 5a (1:1 molar ratio) showed better
catalytic activity than the use of either 4 or 5a alone, and the
corresponding bromocyclization products 2a were obtained in
64% yield as a ca. 1:1 mixture of endo- and exo-isomers (entries
2−4). Both endo- and exo-2a were generated as single
diastereomers. When the reaction of 1a was conducted in the
absence of a catalyst, desired product 2a was not obtained, and a
small amount (10%) of bromohydrin 3a was generated.
To improve the catalytic activity, more acidic thiourea 5b was
used instead of urea 5a. However, the combined use of 4 and 5b
(1:1 molar ratio) slightly decreased the yield of 2a (58%, entry
5). Very interestingly, we found that when the reaction was
conducted in the presence of only thiourea 5b as a catalyst,
bromocyclization product 2a was obtained in quantitative yield
(entry 6). Since thiourea 5b showed high catalytic activity, we
next examined the activities of structurally related compounds
5−8. In contrast to the high activity of electron-deficient 5b,
thiourea 5c without electron-withdrawing substituents and 5d
bearing electron-donating methoxy groups showed poor
catalytic activity (entries 7 and 8). Thiocarbamate 6, which
has only one acidic proton, also gave poor results (entry 9).
These results indicated that not only a nucleophilic sulfur atom
but also rather acidic protons of 5b were important for high
catalytic activity. Indeed, thiophosphoric triamide 7 also showed
good activity (entry 10), while triphenylphosphine sulfide (8)16
was almost inert (entry 11).
Our study commenced with an examination of catalytic
activities in the bromocyclization of geranyl TBS ether 1a (Table
1). The reaction of 1a with NBS (1.2 equiv) was conducted in
a
Table 1. Catalytic Activities in the Bromocyclization of 1a
The reactivity of the bromocyclization of 1a highly depended
on the solvents. When dichloromethane was used as a solvent,
the reaction completed within an hour to give 2a in 95% yield
(entry 13), while the reaction did not proceed in the absence of
5b in CH2Cl2 (entry 12). The reactivity in nitroethane was
moderate, and endo-2a was obtained as a major product (entry
15). Highly polar nitroethane might stabilize a carbocation
intermediate to generate a thermodynamically stable endo-
isomer preferentially. The use of propionitrile and THF gave
poor results, and a significant amount of 3a was generated
(entries 16 and 17). The reaction of 1a (1 mmol) under the
optimized conditions also gave 2a in 88% yield (entry 14).
Here we propose the active species generated from 5b and
NBS (Scheme 2). Based on previous reports11,17,18 and our
endo-2a/
b
b
entry catalyst
solvent time (h) yield of 2a (%)
exo-2a
c
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
EtNO2
EtCN
19
19
19
19
19
19
19
19
19
19
19
1
1
2
19
19
19
0
53
0
2
3
4
5
6
7
8
9
4
5a
4 + 5a
4 + 5b
5b
5c
5d
6
1.6:1
c
64
58
99
21
23
23
69
7
1.1:1
1.1:1
1:1.3
1:2.7
1:1.6
1:2.2
1.4:1
1.2:1
Scheme 2. Proposed Active Species 9 and 10
c
10
11
12
13
14
15
16
17
7
8
0
5b
5b
5b
5b
5b
95
88
48
2
1.4:1
1.3:1
4.3:1
1:1
d
c
c
THF
0
experimental results that the use of thioureas 5b−d gave 2a
while urea 5a was inert under the same reaction conditions,19 it
is conceivable that the sulfur atom of 5b acted as a nucleophilic
catalyst to generate cationic active species 9 or its neutral variant
10. In active species 9, succinimide anion would interact with the
acidic protons of the thiourea moiety via hydrogen bonding.
Active species 9 or 10 selectively reacted with the Δ6,7-double
a
The reaction of 1a (0.1 mmol) with NBS (1.2 equiv) was conducted
in the presence of a catalyst (10 mol %) in a solvent (1.5 mL) at −78
b
1
°C. Evaluated by H NMR analysis using trichloroethylene as an
c
internal standard. Bromohydrin 3a was obtained in 10% (entries 1
and 3), 11% (entry 9), 42% (entry 15), and 22% yield (entry 16).
d
Compound 1a (1 mmol) was used as a substrate. endo- and exo-2a
was obtained in respective isolated yields of 42 and 29%.
B
DOI: 10.1021/acs.orglett.9b00352
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bond of 1a to promote cyclization and give 2a along with
succinimide. Since electron-deficient thiourea 5b showed higher
activity than electron-rich 5d, the rate-determining step would
not be the formation of active species 9 or 10, but rather
bromination of the Δ6,7-double bond of 1a.
The reactivity of geraniol derivatives 1 was also affected by the
protecting group of the hydroxy group. For example, the
reaction of geranyl acetate (1b) under the optimized conditions
did not give any product, and 1b was recovered quantitatively
(Scheme 3). In contrast to the poor reactivity of 1b, the
bromocyclization of farnesyl acetate (11) gave the correspond-
ing product 12 in 59% yield under the same reaction conditions.
ranylanisole (13b), which have an electron-donating methyl or
methoxy group on the aryl group, proceeded rapidly to give the
corresponding products in respective yields of 100% and 92%
(entries 1 and 2). However, 4-homogeranylfluorobenzene (13c)
bearing an electron-withdrawing fluoro group required a rather
long time for the reaction to complete under the same
conditions (6 h, 93% yield, entry 4).
The experimental results shown in Table 1 and Scheme 3
indicated that the reactivity of 1 highly depended on the electron
density of the Δ2,3-double bond. It was conceivable that
cyclization would proceed via a concerted pathway and that
electron-donating interaction of the Δ2,3-double bond with the
Δ6,7-double bond would be important for efficient promotion
of the bromocyclization of 1 (Scheme 4). In the bromocycliza-
Scheme 3. 5b-Catalyzed Bromocyclization of Geranyl Acetate
(1b) and Farnesyl Acetate (11)
Scheme 4. Proposed Mechanism of the Bromocyclization of
Geranyl Derivatives 1 and 13
The optimized reaction conditions could also be applied to
the bromocyclization of homogeranylarenes 1313a (Table 2).
tion of geranyl TBS ether (1a), the electron-donating
interaction of the Δ2,3-double bond with the Δ6,7-double
bond would stabilize the transition state to promote
bromination of the Δ6,7-double bond. However, the electron-
donating interaction of the Δ2,3-double bond would be quite
weak in the reaction of geranyl acetate (1b) due to the electron-
withdrawing acetoxy group. This could explain why 1b was inert
under the present reaction conditions. In contrast to 1b, the
Δ6,7-double bond of farnesyl acetate (11) had a high enough
electron density to stabilize the transition state to promote the
bromocyclization.
Table 2. 5b-Catalyzed Bromocyclization of
a
Homogeranylarenes 13
The reactivities of homogeranylarenes 13 depended on the
electron density of the aryl group (Table 2). These results
implied that the electron-donating interaction of not only the
Δ3,4-double bond with the Δ7,8-double bond but also that of
the aryl group with the Δ3,4-double bond stabilized the
transition state to promote the bromocyclization of 13, even in
the case of the formation of monocyclization products 14
(Scheme 4).
time
(h)
yield of 14 and 15
endo-14/
b
b
b
entry
13
(%)
14/15
exo-14
c
1
13a
13a
13b
13c
6
0
2
3
4
0.7
0.7
6
100
92
93
58:42
55:45
73:27
1:1.4
1:1.4
1:1.8
a
The reaction of 13 (0.1 mmol) with NBS (1.2 equiv) was conducted
We next examined the bromocyclization of 2-geranylphenols
1613b,c (Scheme 5). The reaction of 2-geranylphenol (16a)
proceeded rapidly to give the corresponding products 17a and
18a in 84% yield. Since the nucleophilicity of the phenol group
was high, biscyclization product 18a was obtained as a major
product (17a/18a = 19:81). Finally, the present bromocycliza-
tion was applied to the synthesis of 4-isocymobarbatol (18b).
Since the aryl group of 16b was highly electron-rich and
susceptible to electrophilic bromination, NBS was added in
eight portions. As a result, 18b was obtained in 41% isolated
yield along with a mixture of bromination products of the aryl
group of 16b (ca. 20%).
in the presence of 5b (10 mol %) in CH2Cl2 (1.5 mL) at −78 °C.
b
Evaluated by 1H NMR analysis using trichloroethylene as an internal
c
standard. The reaction was conducted in the absence of 5b.
When the reaction of 13 with NBS (1.2 equiv) was conducted in
the presence of 5b (10 mol %), a mixture of endo- and exo-14 was
obtained along with biscyclization product 15. Each product was
obtained as a single diastereomer. Since endo-, exo-14 could be
quantitatively converted to 15 by treatment with SnCl4 and
trifluoroacetic acid,13a the combined yield of 14 and 15 was
evaluated by 1H NMR analysis of the crude product. As a result,
the reaction of 4-homogeranyltoluene (13a) and 4-homoge-
C
DOI: 10.1021/acs.orglett.9b00352
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In conclusion, we found that electron-deficient thiourea 5b
showed high catalytic activity in the biomimetic bromocycliza-
tion of geranyl derivatives. The reaction with NBS proceeded
rapidly in CH2Cl2 even at −78 °C to give the corresponding
products in high yields. The reactivity of the present
bromocyclization highly depends on the terminal substituents
of the substrates: geranyl TBS ether (1a) was rapidly converted
to the corresponding product 2a, while geranyl acetate (1b) was
inert under the same conditions. The reactivities of 4-
homogeranylarenes 13 depended on the electron density of
their aryl groups. The present bromocyclization could be
successfully applied to a synthesis of 4-isocymobarbatol (18b).
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ASSOCIATED CONTENT
* Supporting Information
■
Am. Chem. Soc. 2017, 139, 13562−13569.
S
(13) (a) Sawamura, Y.; Nakatsuji, H.; Sakakura, A.; Ishihara, K. Chem.
Sci. 2013, 4, 4181−4186. (b) Sawamura, Y.; Nakatsuji, H.; Akakura, M.;
Sakakura, A.; Ishihara, K. Chirality 2014, 26, 356−360. (c) Sawamura,
Y.; Ogura, Y.; Nakatsuji, H.; Sakakura, A.; Ishihara, K. Chem. Commun.
2016, 52, 6068−6071.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00352.
Experimental procedures and characterization data for all
new compounds (PDF)
(14) For reports on iodocyclization catalyzed by phosphorus(III)
compounds, see: (a) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007,
445, 900−903. (b) Sakakura, A.; Ishihara, K. Chim. Oggi 2007, 25, 9−
12. (c) Sakakura, A.; Shomi, G.; Ukai, A.; Ishihara, K. Heterocycles 2010,
82, 249−255. (d) Nakatsuji, H.; Sawamura, Y.; Sakakura, A.; Ishihara,
K. Angew. Chem., Int. Ed. 2014, 53, 6974−6977.
(15) For reports on protocyclization catalyzed by Lewis bases, see:
(a) Sakakura, A.; Sakuma, M.; Ishihara, K. Org. Lett. 2011, 13, 3130−
3133. (b) Sakuma, M.; Sakakura, A.; Ishihara, K. Org. Lett. 2013, 15,
2838−2841.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sakakura@okayama-u.ac.jp.
ORCID
Akira Sakakura: 0000-0002-2995-1251
Notes
(16) (a) Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U. S. A.
2010, 107, 20655−20660. (b) Denmark, S. E.; Burk, M. T. Org. Lett.
2012, 14, 256−259. (c) Denmark, S. E.; Burk, M. T. Chirality 2014, 26,
344−355.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully thank the Division of Instrumental
Analysis, Department of Instrumental Analysis & Cryogenics,
Advanced Science Research Center, Okayama University for the
NMR and HRMS measurements.
(17) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y.-Y. J. Am.
Chem. Soc. 2010, 132, 15474−15476.
(18) (a) Tripathi, C. B.; Mukherjee, S. J. Org. Chem. 2012, 77, 1592−
1598. (b) Jakab, G.; Hosseini, A.; Hausmann, H.; Schreiner, P. R.
Synthesis 2013, 45, 1635−1640.
(19) pKa value of thiourea 5c is almost the same as that of urea 5a.
Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.; Schreiner, P. R. Org.
Lett. 2012, 14, 1724−1727.
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DOI: 10.1021/acs.orglett.9b00352
Org. Lett. XXXX, XXX, XXX−XXX