Chiral Iodine-Catalyzed Dearomatizative Spirocyclization for the Enantioselective Construction of an All-Carbon Stereogenic Center

Article abstract of DOI:10.1002/chem.201501583

The first enantioselective dearomatizative spirocyclization of 1-hydroxy-N-aryl-2-naphthamide derivatives has been accomplished by chiral organoiodine catalysis to stereoselectively create an all-carbon stereogenic center, providing a straightforward approach to access spirooxindole derivatives in good yields and with high to excellent levels of enantioselectivity. Chiral hypervalent phenyl-λ³-iodanes generated in situ from the oxidation of the chiral phenyl iodine actually participate in the asymmetric oxidative dearomatizative spirocyclization reaction.

Full text of DOI:10.1002/chem.201501583

DOI: 10.1002/chem.201501583
Communication
&
Organocatalysis
Chiral Iodine-Catalyzed Dearomatizative Spirocyclization for the
Enantioselective Construction of an All-Carbon Stereogenic Center
Dong-Yang Zhang,[a] Lue Xu,[a] Hua Wu,[a] and Liu-Zhu Gong*[a, b]
Abstract: The first enantioselective dearomatizative spiro-
cyclization of 1-hydroxy-N-aryl-2-naphthamide derivatives
has been accomplished by chiral organoiodine catalysis to
stereoselectively create an all-carbon stereogenic center,
providing a straightforward approach to access spirooxin-
dole derivatives in good yields and with high to excellent
levels of enantioselectivity. Chiral hypervalent phenyl-l3-io-
danes generated in situ from the oxidation of the chiral
phenyl iodine actually participate in the asymmetric oxida-
tive dearomatizative spirocyclization reaction.
The enantioselective dearomatization of phenols and structur-
ally relevant electronically rich aromatic molecules has
Scheme 1. Previously reported phenol dearomatization reactions with hyper-
emerged as a valuable platform for the construction of densely
valent iodines: A) Asymmetric dearomatization of phenols catalyzed by
functionalized cyclic skeletons that hold great potential in the
chiral hypervalent iodine;[7] B) oxidative coupling via hypervalent iodine-
synthesis of structurally complicated molecules and has hence
received increasing research interest.[1,2] Chiral hypervalent
iodine compounds have been frequently exploited, either as
reagents or catalysts, for the oxidative enantioselective func-
tionalization and other transformations, owing to their privi-
leged characteristics including their low toxicity, mild reaction
conditions, and environmentally benign nature.[3–6] In particu-
lar, chiral hypervalent iodine species have been highly efficient
organocatalysts for the enantioselective dearomatization of
phenols, leading to various transformations that are otherwise
hard to accomplish, benefiting from the fundamental contribu-
tions given by the groups of Kita, Ishihara, and others.[7] Specif-
ically, notable progress has been made in asymmetric oxidative
spirolactonization [Scheme 1A, Eq. (1)] and hydroxylative
phenol dearomatization [Scheme 1A, Eq. (2)] catalyzed by
chiral organoiodines. Very recently, Du, Zhao, and co-workers
described a unique intramolecular metal-free oxidative aryl–
aryl coupling, which was considered to proceed via a sequential
hypervalent iodine-mediated phenol dearomatization and
Lewis acid-catalyzed rearrangement (Scheme 1B).[8]
mediated dearomatization. PIFA=phenyliodine(III) bis(trifluoroacetate).[8]
However, enantioselective construction of an all-carbon
spiro-stereogenic center has long been considered a daunting
challenge for organic synthesis[9] and, therefore, the creation of
new efficient and green protocols to ultimately get this goal
will be of great synthetic value. The asymmetric dearomatiza-
tion of phenol derivatives of type 1 to generate all-carbon
spiro-stereogenic center (Scheme 2), however, has, to our
Scheme 2. Asymmetric oxidative spirocyclization: Enantioselective genera-
tion of all-carbon spiro-stereogenic center (reported herein).
[a] D.-Y. Zhang, L. Xu, H. Wu, Prof. Dr. L.-Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale and
Department of Chemistry
knowledge, not been documented to date. Herein, we report
the first enantioselective dearomatizative spirocyclization of 1-
hydroxy-N-aryl-2-naphthamide derivatives enabled by chiral or-
ganoiodine catalysis, to directly generate spirooxindole deriva-
tives in good yields and with high enantioselectivity.
University of Science and Technology of China
Hefei 230026 (P. R. China)
[b] Prof. Dr. L.-Z. Gong
Collaborative Innovation Center of Chemical Science and Engineering
Tianjin 300072 (P. R. China)
The initial studies commenced with an oxidative spirocycli-
zation of 1-hydroxy-N-methyl-N-(2-naphthalenyl)-2-naphtha-
mide (1a) catalyzed by 3a in the presence of 3-chloroperoxy-
E-mail: gonglz@ustc.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501583.
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tries 5–7). Under the preliminarily optimized conditions, a seri-
ous of chiral iodoarenes were next evaluated. The N-aryl sub-
stituents of the catalyst 3 evidently had considerable impact
on either the chemical yield or enantioselectivity. The presence
of electron-deficient N-aryl groups turned out to be deleterious
to the stereoselectivity (Table 1, entries 9 and 10). In contrast,
the installation of electronically rich N-aryl substituents to the
catalysts 3 was seemingly beneficial to the stereochemical con-
trol (Table 1, entries 4 and 11 vs. 8–10). Although the catalyst
3e was able to provide the highest levels of enantioselectivity
(51% ee), a much lower yield was obtained in comparison with
other relatively promising chiral iodine catalysts (Table 1,
entry 11 vs. 4 and 8). The tertiary amide-based chiral iodine
catalyst 3 f, which was found to be superior to secondary
amide-derived ones in controlling the enantioselectivity of
direct CÀH/CÀH oxidative coupling reaction of N1,N3-diphenyl-
malonamides,[4c] gave a slightly diminished yield and enantio-
selectivity in comparison with the reaction catalyzed by 3a
(Table 1, entry 12 vs. 4).
Table 1. Optimization of reaction conditions.
Entry
3
Oxidant
Additive (equiv)
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3a
mCPBA
mCPBA
mCPBA
mCPBA
CH3CO3H
TBHP
TFA (2)
–
64
30
47
48
–
–
10
42
44
50
–
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3 f
HFIP (50)
TFE (50)
TFE (50)
TFE (50)
TFE (50)
TFE (50)
TFE (50)
TFE (50)
TFE (50)
TFE (50)
TFE (50)
TFE (50)
[d]
[d]
–
–
With the optimal chiral iodoarene catalyst 3a in hand, we
then investigated other reaction parameters to further opti-
mize the conditions. In fact, the enantioselectivity is highly sen-
sitive to the reaction temperature. For instance, a much dimin-
ished enantiomeric excess was obtained when the reaction
was conducted at room temperature (Table 1, entry 13) where-
as a significantly improved enantioselectivity was obtained
upon carrying out the reaction at À308C (entry 14). The
groups of Ochiai and Harned both found that the presence of
water was able to improve the yields of some oxidative cou-
pling reactions catalyzed by organoiodines.[10] Inspired by
these findings, we systematically investigated whether water
exerts an effect on the reaction performance (see the Support-
ing Information for details). Interestingly, the presence of water
(10 equiv) not only resulted in a much higher yield, but also
a dramatically improved enantioselectivity (Table 1, entry 15).
Furthermore, increasing the catalyst loading to 15 mol% led to
[d]
BPO
–
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
34
39
41
24
46
44
51
41
À5
15
51
47
31
71
84
87
9
10
11
12
13[e]
14[f]
15[f]
16[g]
3a
3a
3a
3a
TFE (50)+H2O (10) 74
TFE (50)+H2O (10) 72
[a] Unless indicated otherwise, the reaction was carried out on
a 0.1 mmol scale (1a); [b] yield of the isolated product; [c] ee values de-
termined by HPLC analysis; [d] no target product; [e] at room tempera-
ture; [f] T=À308C; [g] 15 mol% of 3a was used, T=À308C. mCPBA=3-
chloroperoxybenzoic acid; TFA =trifluoroacetic acid; HFIP=1,1,1,3,3,3-
hexafluoro-2-propanol; TFE=trifluoroethanol; TBHP=tert-butyl hydrogen
peroxide; BPO=benzoyl peroxide.
benzoic acid (mCPBA, 1.3 equiv) and trifluoroacetic acid
(2.0 equiv) in CH3NO2 at 08C (Table 1). As anticipated, the reac-
tion proceeded smoothly to generate the desired product, (S)-
3-methyl-1’H-spiro[benzo[e]indole-1,2’-naphthalene]-1’,2(3H)-
dione (2a) in a good yield of 64%, but with a rather poor
enantioselectivity of 10% ee (Table 1, entry 1). Previously, Ishi-
hara and co-workers indicated that the presence of alcohol ad-
ditives was able to significantly enhance the enantioselectivity
of the chiral organoiodine-catalyzed dearomatization reac-
tions.[7e] Thus, we also investigated the effect of alcohol addi-
tives on the reaction performance and identified that the pres-
ence of 50 equivalents of trifluoroethanol (TFE) permitted the
reaction to give the best results in terms of both chemical
yield and enantiomeric excess under the otherwise identical
conditions (Table 1, entries 3 and 4). Since external oxidants ex-
erted a notable effect on the reactions of this type,[4c] a variety
of organic oxidants were subsequently investigated. Indeed,
the oxidants played a dominant role in the reactivity in this
case. For instance, other common oxidants, including
CH3CO3H, tBuOOH, and benzoyl peroxide (BPO), failed to oxi-
dize the substrate 1a into the desired product 2a (Table 1, en-
a
slightly greater enantioselectivity (entry 16, 72% yield,
87% ee).
Under the optimized conditions, the generality of the asym-
metric oxidative spirocyclization reaction for different sub-
strates was explored (Scheme 3). All N-methyl-N-(2-naphthyl)-2-
naphthamide substrates 1b–e underwent clean oxidative spi-
rocyclization reactions to generate 2b–e in high yields ranging
from 73% to 80% and with good levels of enantioselectivity
(82–84% ee). Steric features and the substitution pattern of the
substituents on the N-(2-naphthyl) moiety had little effect on
the reaction performance. In contrast, for N-methyl-N-(phenyl)-
2-naphthamide substrates 1 f–j, both the reaction conversion
and stereoselectivity were highly sensitive to substituents on
the N-phenyl group. In general, higher levels of enantioselec-
tivity but diminished yields were provided by these substrates
in comparison with the N-methyl, N-(2-naphthyl)-2-naphtha-
mide substrates (2b–e vs 2 f–j). In particular, excellent enantio-
selectivities of 91 and 92% ee were observed for 2 f and 2h,
respectively. Additionally, changing N-methyl to either N-ethyl
or N-phenyl was also tolerated to give the desired products in
good to moderate yields and with high enantioselectivities, as
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Scheme 4. Proposed reaction mechanism.
termediate IV could also be possibly generated from II
(Scheme 4, Pathway B), leading to the generation of racemic
2a. Because 2,2,2-trifluoroethoxy and hydroxy are both less
active leaving groups than carboxylate, the presence of large
excess amounts of TFE and water would facilitate the favorable
formation of III and thereby inhibit the generation of IV to
result in better stereochemical control.
Since the Re face of the naphthamide moiety in either inter-
mediate IIIa or IIIa’ was blocked by one of the bulky N-phenyl
amides, the Si face was open for the nucleophilic attack of
the N-naphthyl moiety in a syn-addition–elimination manner,
to therefore allow for the favorable generation of (S)-2a
(Scheme 5).
Scheme 3. Substrate scope of the asymmetric spirocyclization reaction.
[a] 5 equivalents of H2O were used.
exemplified by 2k and 2l. The installation of a substituent at
the 4-position of the naphthamide moiety was well tolerated
to undergo the desired reaction in a fairly good yield and with
high stereoselectivity, as shown for 2m. The absolute configu-
ration of 2a was assigned to be S by X-ray crystallographic
analysis of the single crystal. The configurations of the other
products were assigned by analogy.[11]
As reported previously,[4,10] the chiral aryl iodine 3 was pro-
posed to be oxidized into a hypervalent phenyl-l3-iodane I by
mCPBA (see proposed mechanism, Scheme 4). Subsequent
substitution of I with the hydroxy group of 1a then yields
a chiral iodo-enol type intermediate II. Based on Ishihara’s hy-
pothesis,[7e] the intermediate II would be able to undergo
a ligand exchange with trifluoroethanol or water to generate
an associative intermediate III or III’ (Scheme 4, Pathway A),
either of which would undergo an intramolecular SN2’-like Frie-
del–Crafts substitution[4c,7a–c,e] to give the product and to re-
lease the chiral iodobenzene 3. Alternatively, a dissociative in-
Scheme 5. The intermediate to explain the stereochemistry.
In conclusion, we have established the first highly enantiose-
lective dearomatizative spirocyclization of 1-hydroxy-N-aryl-2-
naphthamide derivatives by virtue of chiral iodine catalysis, en-
abling the direct synthesis of optically spirooxindoles and their
analogues through intramolecular SN2’-like Friedel–Crafts sub-
stitution. Chiral hypervalent phenyl-l3-iodanes generated in
situ from the oxidation of the chiral phenyl iodine species
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Acknowledgements
We are grateful for financial support from MOST (973 project
2015CB856600), NSFC (21232007), and the Ministry of Educa-
tion.
Keywords: asymmetric
hypervalent iodine · organocatalysis · spirooxindoles
catalysis
·
dearomatization
·
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Received: April 22, 2015
Published online on June 10, 2015
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