Chiral ion-pair organocatalyst promotes highly enantioselective 3-exo iodo-cycloetherification of allyl alcohols

Article abstract of DOI:10.1039/c5sc02485d

By designing a novel chiral ion-pair organocatalyst composed of chiral phosphate and DABCO-derived quaternary ammonium, highly enantioselective 3-exo iodo-cycloetherification of allyl alcohols was achieved using NIS as a halogen source. Based on this reaction, one-pot asymmetric 3-exo iodo-cycloetherification/Wagner-Meerwein rearrangement of allyl alcohols en route to enantioenriched 2-iodomethyl-2-aryl cycloalkanones was subsequently developed. Due to the participation of adjacent iodine, the Wagner-Meerwein rearrangement of 2-iodomethyl-2-aryl epoxide proceeds with unusual retention of stereoconfiguration.

Full text of DOI:10.1039/c5sc02485d

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Chiral Ion-Pair Organocatalyst Promotes Highly Enantioselective
3-exo Iodo-cycloetherification of Allyl Alcohols
Zhigao Shen,a,b,† Xixian Panc,† Yisheng Lai,b,† Jiadong Hu,b Xiaolong Wan,d Xiaoge Li,d Hui Zhang,e
and Weiqing Xiea
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
By designing a novel chiral ion-pair organocatalyst composed of enantioenriched more strained three-membered rings via
chiral phosphate and DABCO-derived quaternary ammonium, catalytic asymmetric halocyclization remains elusive. In this
highly enantioselective 3-exo iodo-cycloetherification of allyl regard, although 3-exo halo-cycloetherification of allyl alcohol
alcohols was achieved using NIS as halogen source. Based on this has been long known,10 reactive halogenating reagents or
reaction,
one-pot
asymmetric
3-exo
iodo- harsh reaction conditions are needed to effect the
cycloetherification/Wagner-Meerwein rearrangement reaction of energetically disfavored 3-exo halocyclization, which impede
allyl alcohols en route to enantioenriched 2-iodomethyl-2-aryl the development of asymmetric version of this reaction.
cycloalkanones was subsequently developed. Due to the
a) bifunctional ion-pair organocatalyst designing:
participation
of
adjacent
iodine,
Wagner-Meerwein
rearrangement of 2-iodomethyl-2-aryl epoxide proceeds with
unusual retention of stereoconfiguration.
Chiral Pocket
for inter acting
with substrate
& Br nsted Base
φ
Ar
R
Halogenative functionalization of olefin is one of the most
important transformations in organic synthesis as this reaction
not only provides a versatile handle for further derivatization,
but also delivers highly diastereoselective ring closure when
nucleophile and alkene are tethered together.1 Even though
applications of halogenation reaction in total synthesis are well
documented,2 catalytic enantioselective halogenation remains
a big challenge due to the rapid interexchange of halonium
complex between olefins, which leads to rapid racemization of
enantiopure halonium intermediate.3 Therefore limited
success has been achieved despite of enormous efforts that
are devoted to asymmetric halogenation reactions.4 Very
recently, this field experienced impressive progress after the
♦ unprecedented bifunctional
catalyst;
♦ quick catalsyt screening via
combinational aprroaches;
O
O
O
O
N
P
N
unique catalytic activity;
♦
Ar
Ion-pair Catalyst
for stablizing
halonium
Lewis Base
b) enantioselective 3-exo iodo-cycloetherification:
I
ion-pair
OH or ganocatalyst
O
R
R
NIS
up to 98% ee
2
1
5d
landmark reports of Bohan,5a Tang,5b Fujioka,5c Jacobsen,
Fig. 1 Ion-pair organocatalyst designing for enantioselective 3-
and Yeung5e in 2010 by taking advantage of organocatalysts to
effect asymmetric halo-lactonizaton.5 Organocatalyzed
enantioselective halocyclization of olefinic amines, alcohols
and other substrates subsequently emerged.6-9 However,
asymmetric halocyclization reactions are currently limited to
formation of four- to six-membered rings.5-9 The generation of
exo iodo-cycloetherification of allyl alcohol.
With the advent and booming of organocatalyst,11a-c ion-
pairing of organocatalysts has emerged as a powerful strategy
for designing new efficient organocatalysts.11d
By
cooperatively activating reactive partners, ion-pair catalyst has
catalyzed enantioselective reactions that are otherwise
difficult to be achieved by other organocatalysts. In addition,
ion-pairing strategy also enables catalyst screening via
combinational approaches, which greatly accelerates catalyst
screening process. Inspiration from recent Toste’s work8b-8f
and our work on enantioselective halogenation reactions using
chiral anionic phase transfer catalyst,12 we postulated that ion-
pair catalyst would facilitate enantioselective halogenation
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reaction by cooperative and synergistic activation of both enantioselective 3-exo iodo-cycloetherification of allyl alcohols
reactants (Fig. 1), which is responsible for the success of using commercially available NIS as halogen source.
previous catalysts.5-9 To this end, chiral phosphate was Additionally, this protocol also gives direct access to
judiciously chosen as counter anion for its fine-tunable chiral enantiopure 2-iodomethyl epoxides,14 which are tediously
pocket as well as its Brønsted basicity for interacting with prepared from allyl alcohols previously via asymmetric
substrate.8 On the other hand, DABCO-derived quaternary Sharpless epoxidation/hydroxyl transformation procedure.15
ammonium would serve as an excellent candidate for the
To validate our hypothesis, enantioselective 3-exo-
cation moiety since its tertiary amine moiety could act as Lewis iodocyclization of allyl alcohol 1a was explored using ion-pair
base for stabilizing halonium, which had been utilized for organocatalyst generated in situ by combining silver
synthesis of the well-known Selectfluor13 and other phosphate with DABCO-derived quaternary ammonium salt for
halogenating reagents8d,9c,10b
convenience of catalyst screening (Table 1). Initially, various
ammonium salts were evaluated by using 8H-R-TRIP-OAg L1 as
Table 1. Reaction condition optimization of enantioselective 3- chiral counter-anion source. After extensive screening, A3 was
exo-Iodocyclization of allyl alcohol 1a a
.
determined to be the privileged scaffold, affording epoxide 2a
in 77% ee with marginal yield (entries 1-3, and Supporting
Information). In contrast, ammonium salt A2 derived from
quinuclidine provided lower enantioselectivity, showing that
tertiary amine moiety of A1 played a pivotal role in the
reaction (entries 1 and 2). Further structural modification of
ammonium salt A3 revealed that A8 was the optimal cation
fragment for the ion-pair organocatalyst, furnishing epoxide 2a
in 92% ee (entries 3-9). As for the anion fragment, 8H-R-TRIP-
OAg provided better result than any other evaluated chiral
silver phosphate (see Supporting Information). Importantly,
both cationic and anionic fragments were indispensable for
the reaction as indicated by control experiment (entries 10-
12). It should be pointed out that other organocatalysts (e.g.
chiral phosphoric acid and quinine-derived catalysts) were also
surveyed under identical reaction conditions, which gave no
desired cyclization product with starting material being fully
recovered (Table S2, Supporting Information).
I
O
NIS, CH2Cl2
OH
conditions
1a
2a
R
Ar
O
O
Ar
O
O
N
N
P
Y
Br
O
O
OAg
O
P
A3: Y = H
A4: Y = 4-CN
A5: Y = 4-OMe
A6: Y = 3-OMe
A7: Y = 4-OC4H9
O
O
Ar
N
N
L1
Ar
Ar = 2,4,6-triisopropylphenyl
A1: X= N
A2: X = CH
C1
X
N
Bu
A8: Y = 4-OC6H13 R = 4-OC6H13
A9: Y = 4-OC8H16 Ar = 2,4,6-triisopropylphenyl
Br
entr
y
cat.
additive
(equiv)
T
t
(h)
Yieldb
(%)
eec
(%)
(equiv)
L1 (0.1)
L1 (0.1)
L1 (0.1)
L1 (0.1)
L1 (0.1)
L1 (0.1)
L1 (0.1)
L1 (0.1)
L1 (0.1)
--
(oC)
1
2
A1 (0.12)
A2 (0.12)
A3 (0.12)
A4 (0.12)
A5 (0.12)
A6 (0.12)
A7 (0.12)
A8 (0.12)
A9 (0.12)
--
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
20
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
107
16
18
44
16
69
47
65
60
50
ND
ND
ND
42
82
63
62
31
99
30
19
77
69
86
80
91
92
91
--
3
4
With anionic and cationic moiety of the catalyst being
identified, ion-pair organocatalyst C1 was directly synthesized
from 8H-R-TRIP and ammonium A8 (see Supporting
Information) and examined under the otherwise identical
reaction conditions. To our surprise, 2a was obtained only in
moderate enantioselectivity (83% ee, entry 13). As slightly
excess amount of A8 was used in the in-situ procedure, we
reasoned that A8 might be an effective promoter for this
reaction. Indeed, comparable enantioselectivity (92% ee, entry
14) was obtained by adding catalytic amount of A8 into the
reaction. It’s postulated that A8 might act as Lewis base for
stabilizing iodonium intermediate8d and facilitates the transfer
of iodine from NIS to the DABCO moiety of the ion-pair
5
6
7
8
9
10
11
12
13
14
15
16d
17e
18
L1 (0.1)
--
--
--
A8 (0.12)
--
--
C1 (0.1)
C1 (0.1)
83
92
90
69
67
94
A8 (0.1)
C1 (0.1) S=PPh3 (0.1)
C1 (0.1)
C1 (0.1)
C1 (0.1)
A8 (0.1)
A8 (0.1)
A8 (0.1)
organocatalyst, which led to accelerating reaction rate and
7c,e
increased enantioselectivity. Employment of S=PPh3
as
a
To a mixture of silver salt L1 (0.01 mmol), ammonium salt A
additive also gave comparable result, verifying the positive
effect of Lewis base as co-catalyst on this reaction (entry 15).
With the suitable catalyst in hand, other reaction variations
were subsequently evaluated. Other halogenating reagents
such as NCS and NBS gave inferior results, leading to no
reaction or sharp drop in enantioselectivities (see Supporting
Information). CH2Cl2 was determined to be the optimal solvent
(entries 16, 17 and Supporting Information) and lowing
(0.012 mmol) and NIS (0.12 mmol) was added CH2Cl2 (1 mL) then
the reaction mixture was cooled to 0 oC. Allyl alcohol 1a (0.1
mmol) in 0.5 mL CH2Cl2 was then added dropwise and the
b
c
reaction was quenched at indicated time. Isolated yield.
d
Determined by HPLC using Chiralpak AD column. CHCl3 as
solvent. e EtOAc as solvent. ND = not detected.
Herein, we would like to report the success of
implementation of ion-paring strategy, which leads to the
o
reaction temperature to -20 C was beneficial to the reaction
discovery of
unprecedented
a
novel ion-pair organocatalyst. This
organocatalyst enables the first
(entry 18).
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good yields with partial loss of enantioselectivities (93% ee vs
97% ee for epoxide 2c). Surprisingly, absolute configuration of
3c was established to be S by X-ray crystallographic analysis of
hydrozone
4 , which indicated retention of
derived from 3c 16
stereoconfiguration in the Wagner-Meerwein rearrangement.
This could be ascribed to the opening of epoxide by the
adjacent iodine to generate iodonium TS2, which was
rearranged to ketone 3c with double inversion of
configuration. Furthermore, derivatizations of 3c were also
performed to display its synthetic utilities. Substitution of
iodide with NaN3 smoothly provided azide ketone
could also be converted to alcohol
formyloxylation/hydrolysis19 to give hydroxyl ketone
5 and iodide
via
in
6
satisfactory yield. It’s noteworthy that no erosion of
enantiopurity was detected in all these reactions.
Scheme 1 Substrate variation of enantioselective 3-exo iodo-
cycloetherification of allyl alcohols.
Scheme 2 Transformations of spiro-epoxide 2c
.
After establishing the optimal reaction conditions, the
substrate scope of this reaction was examined (Scheme 1).
Both electron-withdrawing groups (2aa-2af, and 2ce-2cf) and
electron-donating groups (2ag-2ah and 2ca-2ch) on phenyl
moiety were well tolerated, affording corresponding epoxides
in good to excellent enantioselectivities (87% ee-99% ee).
Gem-substituents were crucial for the reaction as 2f lacking
gem-substituents was obtained only in 41% yield and 63% ee.
Epoxides with cyclic gem-substituents were obtained in higher
enantioselectivities (2c-2ch and Supporting Information) than
those with acyclic gem-substituents (2a and 2b). 2-Alkyl
substituted allyl alcohol was also smoothly converted to
epoxide 2g albeit in low enantioselectivity (37% ee).
Furthermore, gram syntheses of epoxide 2a, 2c-2e were also
smoothly realized by using 5 mol% C1 without affecting
enantioselectivities and catalyst loading could even be reduced
to 1 mol% to afford comparable results (Scheme 1 and
Supporting Information). The absolute configuration of
Scheme
cycloetherification/Wagner-Meerwein rearrangement reaction.
3
One-pot
asymmetric
3-exo
iodo-
To simplify the operation, one-pot asymmetric 3-exo iodo-
cycloetherification/Wagner-Meerwein rearrangement was also
epoxide
crystallographic analysis of epoxide 2ac 16
confirmed by vibrational circular dichroism (VCD) studies of
2
was determined to be
R
based on X-ray
,
which was
implemented
(Scheme
2).
Fortunately,
when
iodo-
cycloetherification reaction was completed, addition of BF3•OEt2 to
the reaction mixture smoothly provided desired cyclohexanone 3c
without reducing enantioselectivity even on 2.7 mmol scale (92%
ee). Different substituents on phenyl were found to be compatible
with the one-pot process, affording corresponding cyclohexanones
3c-3f in satisfactory enantiopurities. Furthermore, seven-membered
cycloketone 3g could also be obtained via this one-pot cascade
epoxide 2c 17
.
Next, Wagner-Meerwein rearrangement18 of epoxide 2c
was explored for construction of 2-iodomethyl-2-aryl
cyclohexanone with chiral quaternary carbon center (Scheme
1). BF3•Et2O was determined to be the most efficient promoter
(see Supporting Information), delivering cyclohexanone 3c in
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,
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Conclusions
In conclusion, a novel ion-pair organocatalyst comprised of
chiral phosphate and DABCO-derived quaternary ammonium
was designed, which enabled the first asymmetric 3-exo iodo-
cycloetherification of allyl alcohols using NIS as halogenating
reagent. By employing this novel catalyst,
a variety of
6
7
For reviews: (a) A. Castellanos and S. P. Fletcher，Chem.-Eur.
enantiopure 2-iodomethyl-2-aryl epoxides were successively
prepared in good to excellent enantioselectivities even on
gram scale. Subsequently, one-pot asymmetric 3-exo iodo-
cycloetherification/Wagner-Meerwein rearrangement of 2-
aryl-2-propen-3-ol was explored, which provided direct access
to chiral 2-iodomethyl-2-aryl cycloalkanones in good
enantioselectivities. Unusual retention of configuration owing
to the assistance of the adjacent iodide was also observed in
the Wagner-Meerwein rearrangement.
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Acknowledgement
We are grateful for financial support from the National Natural
Science Foundation of China (grand No. 21372239, 21202187)
and the Scientific Research Foundation of Northwest A&F
University (grand No. Z111021501).
8
Notes and references
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(a) F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry,
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Snyder, Z.-Y. Tang and R. J. Gupta, Am. Chem. Soc., 2009
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For enantioselective halo-lactonization reactions, see: (a) D.
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4 | J. Name., 2012, 00, 1-3
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11 For selected reviews: (a) New Frontiers in Asymmetric
Catalysis, vol (Eds.: K. Mikami, M. Lautens), Wiley-
Interscience, Hoboken, NJ, 2007 (b) Enantioselective
3
;
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15 For selected examples: (a) T. Ichige, Y. Okano, N. Kanoh and
M. Nakata, J. Am. Chem. Soc., 2007, 129, 9862; (b) A. R. Van
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16 CCDC 1023013 and 1028455 contains the supplementary
crystallographic data for compound 2ac and
These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
4 respectively.
www.ccdc.cam.ac.uk/data_request/cif. For the rationale for
the observed stereoselectivity, see Supporting Information.
17 See Supporting Information for detailed experiment data.
18 Selected examples: (a) Y. Kita, K. Higuchi, Y. Yoshida, K. Iio, S.
Kitagaki, K. Ueda, S. Akai and H. Fujioka, J. Am. Chem. Soc.,
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19 A, Abad, C. Agulló, A. C. Cuñat and I. Navarro, Synthesis,
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