Cooperative activation with chiral nucleophilic catalysts and n-haloimides: Enantioselective iodolactonization of 4-arylmethyl-4-pentenoic acids

Article abstract of DOI:10.1002/anie.201400946

Chiral triaryl phosphates promote the enantioselective iodolactonization of 4-substituted 4-pentenoic acids to give the corresponding iodolactones in high yields with high enantioselectivity. N-Chlorophthalimide (NCP) is employed as a Lewis acidic activat

Full text of DOI:10.1002/anie.201400946

Angewandte
Chemie
DOI: 10.1002/anie.201400946
Asymmetric Catalysis
Cooperative Activation with Chiral Nucleophilic Catalysts and N-
Haloimides: Enantioselective Iodolactonization of 4-Arylmethyl-4-
pentenoic Acids**
Hidefumi Nakatsuji, Yasuhiro Sawamura, Akira Sakakura,* and Kazuaki Ishihara*
Abstract: Chiral triaryl phosphates promote the enantioselec-
tive iodolactonization of 4-substituted 4-pentenoic acids to give
the corresponding iodolactones in high yields with high
enantioselectivity. N-Chlorophthalimide (NCP) is employed
as a Lewis acidic activator and oxidant of I2 for the present
iodolactonization. In combination with 1.5 equivalents of
NCP, only 0.5 equivalents of I2 are sufficient to generate the
iodinating reagent.
dite under the reaction conditions and the deactivation of the
phosphoramidite with the generated acidic succinimide. The
development of a catalytic system for enantioselective
iodocyclization based on acid-base chemistry[10] is an impor-
tant issue. We report herein cooperative activation with chiral
phosphate catalysts and N-haloimides for the enantioselective
iodolactonization of 4-arylmethyl-4-pentenoic acids.
To obtain fundamental information of nucleophilic-base-
catalyzed iodolactonization of unsaturated carboxylic acids,
we began our study with examination of the catalytic activities
of various achiral phosphorous bases, which might nucleo-
philically activate the iodinating reagent. The reaction of
4-benzylpent-4-enoic acid (1a) was conducted with NIS
(1.1 equiv) in the presence of a base catalyst (30 mol%) in
E
lectrophilic olefin halocyclizations are powerful tools for
stereoselective functionalization of alkenes, the products of
which are useful chiral building blocks for the synthesis of
biologically relevant molecules.[1] Several recent studies have
successfully provided catalytic enantioselective halolactoni-
zations,[2–4] haloetherifications,[5] haloaminocyclizations,[6] and
related reactions.[7] Although these methods give the corre-
sponding chiral products with high enantioselectivities, reac-
tivities are not so high and require long reaction times in some
cases.
toluene at À408C for 4 hours (Table 1). As
a result,
Table 1: Catalytic activities of achiral Lewis bases.[a]
We previously reported a chiral Lewis base promoted
enantioselective iodocyclization of isoprenoids.[8] The chiral
nucleophilic phosphoramidite acts as a monofunctional Lewis
base[8a–e,9] and reacts with N-iodosuccinimide (NIS) to gen-
erate the corresponding phosphonium salt as an active
species. Although this method gives polycyclic 3-iodoterpe-
noids with high enantioselectivity, stoichiometric use of the
phosphoramidite is required for successful promotion of the
reaction and arises from the instability of the phosphorami-
Entry
Catalyst
Yield [%][b]
1
2
3
4
5
6
P(OPh)3
P(OiPr)3
PPh3
60 (81)[c] (0)[d]
55 (85)[c]
63 (80)[c]
O P(OPh)3
0 (100)[c] (18)[d]
3 (100)[c]
=
=
S P(OPh)3
no catalyst
1 (37)[c] (2)[d]
[a] The reaction of 1a (0.1 mmol) was conducted with NIS (1.1 equiv) in
the presence of a catalyst (30 mol%) in toluene (1 mL) at À408C for 4 h.
1
[*] Dr. H. Nakatsuji, Y. Sawamura, Prof. Dr. K. Ishihara
Graduate School of Engineering, Nagoya University
Furo-cho, Chikusa, Nagoya 464-8603 (Japan)
E-mail: ishihara@cc.nagoya-u.ac.jp
[b] Determined by H NMR analysis. [c] Yield when the reaction was
conducted with I2 (1.1 equiv) and NIS (1.1 equiv) for 1 h. [d] Yield when
the reaction was conducted with I2 (1.1 equiv) for 4 h.
Homepage: http://www.ishihara-lab.net
Prof. Dr. A. Sakakura
Graduate School of Natural Science and Technology
Okayama University
3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530 (Japan)
E-mail: sakakura@okayama-u.ac.jp
phosphorus(III) compounds such as triphenyl phosphite,
tri(isopropyl)phosphite, and triphenylphosphine showed
good catalytic activities (entries 1–3).[11,12] In sharp contrast,
pentavalent triphenyl phosphate and thiophosphate[13] were
almost inert (entries 4 and 5). However, very surprisingly,
when the triphenylphosphate- and triphenylthiophosphate-
catalyzed reactions were conducted in the presence of I2 and
NIS (1.1 equiv each)[2a,d,f] as iodinating agents, the reactivities
were remarkably increased to give 2a in almost quantitative
yield within 1 hour (entries 4 and 5). The combined use of I2
and NIS was also somewhat effective for trivalent phosphine
catalysts (entries 1–3). A highly active iodinating reagent
might be generated from I2 and NIS,[14] since the combined
use of I2 and NIS gave 2a in 37% yield in the absence of any
Prof. Dr. K. Ishihara
JST, CREST
Furo-cho, Chikusa, Nagoya 464-8603 (Japan)
[**] Financial support for this project was partially provided by
JSPS.KAKENHI (23350039), the Society of Iodine Science, and the
Program for Leading Graduate Schools “Integrative Graduate
Education and Research in Green Natural Sciences”, MEXT (Japan).
H.N. also acknowledges a JSPS research fellowship for young
scientists.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400946.
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Table 2: Enantioselective iodolactonization of 1a using 3 or 4.[a]
4b (R = Bu) or 4c (R = iBu) gave especially high enantiose-
lectivities (Table 2, entries 7 and 8).
Further investigation revealed that when either N-chloro-
succinimide (NCS)[18,19] or N-chlorophthalimide (NCP),
which are more stable and inexpensive than NIS, was used
instead of NIS, the reaction successfully proceeded to give 2a
in quantitative yields with excellent enantioselectivity
(Table 2, entries 9 and 10).[20] Very interestingly, in the
presence of 1.5 equivalents of NCP, the use of only 0.5 equiv-
alents of I2 successfully promoted the reaction to give 2a in
high yield with high enantioselectivity (entry 11). These
results indicated that NCP worked as not only the activator
but also the oxidant of I2 (0.5 equiv) to generate one
equivalent of the iodonium ion (I+). The fact that NCS and
NCP were consumed during the reaction to generate succi-
nimide or phthalimide also supported this consideration.
Under the optimized reaction conditions, only 1 mol% of 4a
successfully promoted a 5 mmol scale reaction to give 2a in
95% yield (1.5 gram) with 93% ee (entry 12). Since I2 and
NCP are much cheaper than other iodinating reagents such as
NIS, the present asymmetric iodolactonization should be
highly practical.
Entry
“I+” (equiv)
3 or 4
(mol%)
T [8C]
Yield
[%][b]
ee [%]
1
2
NIS (1.1)
I2 (1.1)
I2 (1.1), NIS (1.1)
NIS (1.1)
I2 (1.1)
I2 (1.1), NIS (1.1)
I2 (1.1), NIS (1.1)
I2 (1.1), NIS (1.1)
I2 (1.1), NCS (1.1)
I2 (1.1), NCP (1.1)
I2 (0.5), NCP (1.5)
I2 (0.5), NCP (1.5)
3 (30)
3 (30)
3 (30)
4a (30)
4a (30)
4a (5)
4b (5)
4c (5)
4c (5)
4c (5)
4c (5)
4c (1)
À40
À40
À78
À40
À40
À78
À78
À78
À78
À78
À78
À78
17
19
55
18
36
98
99
99
99
99
95
95[f]
40
19
50
38
38
50
86
88
88
92
93
93
3[c]
4
5
6[d]
7[d]
8[d]
9[d]
10[d]
11[d]
12[d,e]
We propose here a mechanism for the present enantiose-
lective iodolactonization of 1a. Lewis-acidic NCP might
activate I2 through halogen-bonding interactions in toluene
at À408C to form the active iodinating species 5 (X = I;
Figure 1a). The generation of 5 is supported by Raman
[a] The reaction of 1a (0.1 mmol) was conducted with “I+” in the
presence of either 3 or 4 in toluene (1 mL) for 15 h. [b] Determined by
1H NMR analysis. [c] I2, NIS, and 3 were stirred in toluene at À408C for
1 h prior to adding 1a at À788C. [d] I2 and NIS (or NCS, NCP) were
stirred in toluene at À408C for 1 h prior to adding 4 and 1a at À788C.
[e] On 5 mmol scale for 24 h. [f] Yield of isolated product.
catalysts, and the reaction with NIS or I2 was very low yielding
(entry 6).
Based on these results, we next investigated enantiose-
lective iodolactonization of 1a using either the chiral
phosphite 3 or phosphate 4a (R = H) as the catalyst
(Table 2). When the 3- or 4a-catalyzed reaction was con-
ducted with either NIS or I2 in toluene at À408C, moderate
enantioselectivity was induced, and the yield of 2a was low
(entries 1, 2, 4, and 5). Since the combined use of I2 and NIS
(1.1 equiv each) significantly increases reactivity, the reaction
could be conducted at À788C to improve the enantioselec-
tivity (entries 3 and 6). In particular, 4a showed much higher
catalytic activity than 3, and only 5 mol% of 4a was sufficient
to promote the reaction, but the enantioselectivity induced by
4a was almost same as that obtained with 3 (entry 6). The
absolute stereochemistry of the major enantiomer of 2a was
determined to be R.[15]
Figure 1. Proposed mechanism.
When I2 and NIS were stirred in toluene at À408C for
1 hour prior to adding 1a and 4a at À788C, the 4a-catalyzed
reaction showed higher reactivity than the reaction without
the premixing protocol.[16] In contrast, for the 3-catalyzed
reaction, the pretreatment of I2, NIS, and 3 in toluene at
À408C for 1 hour was required for the successful promotion
of the reaction at À788C.[14] These experimental results
suggested that a complex of I2 with NIS might be generated
as the active iodinating species at À408C,[14] and that 3 might
be oxidized to 4a during the pretreatment.[17] The introduc-
tion of alkyl groups at the 2,6-position of the phenoxy group
of 4 successfully increased the enantioselectivity. The use of
spectra of a mixture of NCP and I2 in toluene (observed at
114 cmÀ1).[15] When the phosphite 3 is used as a precatalyst, 5
could oxidize 3 in situ to give the phosphate 4 as an active
catalyst. The catalytic cycle would involve the reaction of 5
with 4 to give the chiral iodoxyphosphonium ion 6 as an active
species (Figure 1b).[21] Since this step generates ICl (X = I),
which could also act as an iodinating reagent through the
activation by NCP,[22,23] the use of 0.5 equivalents of I2 was
sufficient to complete the iodolactonization. Electrophilic
iodination of the double bond of 1a followed by cyclization
gives the desired (R)-2a and phthalimide.
2
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Table 3: Enantioselective iodolactonization of 1.[a]
Entry
1 (R’)
Yield [%][b]
ee [%]
1
2
3
4
5
6
7
8
1b (4-FC6H4CH2)
1c (2-FC6H4CH2)
1d (4-ClC6H4CH2)
1e (4-(MeO)C6H4CH2)
1 f (4-MeC6H4CH2)
1g (3-furylCH2)
1h (2-naphthylCH2)
1i (c-C6H12CH2)
1j (iBu)
95
99
92
97
90
97
99
95
95
72
63
93
2
94
92
92
92
90
90
80
10
22
Scheme 1. Transformations of the chiral iodolactones 2. DMAP=4-
(N,N-dimethylamino)pyridine, DIC=diisopropylcarbodiimide,
PDC=pyridinium dichromate, PPTS=pyridinium p-toluenesulfonate,
TMS=trimethylsilyl.
9
10
11
1k (Ph)
1l (n-C8H15)
In conclusion, we have demonstrated that the chiral triaryl
phosphate 4c and NCP cooperatively promote the enantio-
selective iodolactonization of 4-substituted 4-pentenoic acids
(1) to give the corresponding iodolactones 2 in high yields
with high enantioselectivity within a short reaction time. The
stable but less nucleophilic phosphate 4c shows better
catalytic activities than the phosphite 3 in the presence of
NCP as a Lewis acid. NCP is an effective activator and
oxidant of I2 for the present enantioselective iodolactoniza-
tion. Since I2 and NCP are much less expensive than other
iodinating reagents such as NIS, the present iodolactonization
should be highly practical. The present method was success-
fully applied to 4-alkyl-substituted 4-pentenoic acids (1) with
high enantioselectivities, while most previous methods are
applicable to only 4-aryl-substituted substrates.
[a] The reaction of 1 (0.1 mmol) was conducted with I2 (0.5 equiv) and
NCP (1.5 equiv) in the presence of 3d (5 mol%) in toluene (1 mL) at
À788C. [b] Yield of isolated product.
With the optimized catalyst and reaction conditions in
hand, we next examined the enantioselective iodolactoniza-
tion of 4-pentenoic acids (1) bearing various substituents at
the 4-position. As shown in Table 3, the present method could
be applied to a variety of 4-(arylmethyl)pent-4-enoic acids to
give the corresponding iodolactones with high enantioselec-
tivities within a short reaction time. For example, the 4c-
catalyzed reaction of 4-benzylpent-4-enoic acids bearing an
electron-withdrawing fluoro and chloro substituent, and
electron-donating methoxy and methyl substituents on the
phenyl group gave the corresponding iodolactones 2b and
2d–f with respective enantiomeric excesses between 92% and
94% within 6 hours (entries 1, and 3–5). The high enantiose-
lectivities were also observed in the reaction of the 3-
furylmethyl-substituted 1g and 2-naphthylmethyl-substituted
1h (entries 6 and 7). In addition to the 4-(arylmethyl)-
substituted substrates, the 4-(cyclohexylmethyl)-substituted
1i, and 4-isobutyl-substituted 1j were successfully converted
into 2i and 2j, respectively, with high enantioselectivities
(entries 8 and 9). In contrast, the introduction of a fluoro
substituent at the 2-position significantly decreased the
enantioselectivity (entry 2). In addition, the reaction of
phenyl- and n-octyl-substituted substrates showed poor
enantioselectivity, albeit with good reactivity (entries 10 and
11).
The synthetic applications of 2a were demonstrated by
the several transformations shown in Scheme 1. A four-step
sequence of reduction with LiAlH4, acid treatment, oxidation
with PDC, and methyl ester formation converted 2a into the
ester 9 in 82% yield without any loss of enantiomeric excess.
The compound 9 has the same carbon skeleton as PPAR
agonists.[24] Alkaline hydrolysis of 2a and subsequent acid-
catalyzed cyclization gave the hydroxylactone 10 in quanti-
tative yield. The compound 10 is a key intermediate for the
synthesis of nucleoside analogues, therapeutic agents against
AIDS and cancer.[25] The three-step transformation of 10 gave
the corresponding ester 11 in 91% yield.
Received: January 28, 2014
Revised: March 25, 2014
Published online: && &&, &&&&
Keywords: asymmetric catalysis · cyclization · iodine · lactones ·
.
organocatalysis
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1
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4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Asymmetric Catalysis
Active duty: Chiral triaryl phosphates
promote the enantioselective iodolacto-
nization of 4-substituted 4-pentenoic
acids to give the corresponding iodolac-
tones in high yields with high enantiose-
lectivity (see scheme). N-Chlorophthali-
mide (NCP) is employed as a Lewis acidic
activator and oxidant of I2 for the present
iodolactonization. In combination with
1.5 equivalents of NCP, only 0.5 equiva-
lents of I2 are sufficient for generating the
iodinating reagent.
H. Nakatsuji, Y. Sawamura, A. Sakakura,*
K. Ishihara*
&&&& — &&&&
Cooperative Activation with Chiral
Nucleophilic Catalysts and N-
Haloimides: Enantioselective
Iodolactonization of 4-Arylmethyl-4-
pentenoic Acids
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!