Iridium-Catalyzed Intramolecular Asymmetric Allylic Dearomatization Reaction of Pyridines, Pyrazines, Quinolines, and Isoquinolines

Article abstract of DOI:10.1021/jacs.5b10440

The first Ir-catalyzed intramolecular asymmetric allylic dearomatization reaction of pyridines, pyrazines, quinolines, and isoquinolines has been developed. Enabled by in situ formed chiral Ir-catalyst, the dearomatized products were isolated in high levels of yield (up to 99% yield) and enantioselectivity (up to 99% ee). It is worth noting that the Me-THQphos ligand is much more efficient than other tested ligands for the dearomatization of pyrazines and certain quinolines. Mechanistic studies of the dearomatization reaction were carried out, and the results suggest the feasibility of an alternative process which features the formation of a quinolinium as the key intermediate. The mechanistic findings render this reaction a yet unknown type in the chemistry of Reissert-type reactions. In addition, the utility of this method was showcased by a large-scale reaction and formal synthesis of (+)-gephyrotoxin.

Full text of DOI:10.1021/jacs.5b10440

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Article
Iridium-Catalyzed Intramolecular Asymmetric Allylic Dearomatization
Reaction of Pyridines, Pyrazines, Quinolines and Isoquinolines
Ze-Peng Yang, Qing-Feng Wu, Wen Shao, and Shu-Li You
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b10440 • Publication Date (Web): 25 Nov 2015
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Journal of the American Chemical Society
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Iridium-Catalyzed Intramolecular Asymmetric Allylic
Dearomatization Reaction of Pyridines, Pyrazines, Quinolines
and Isoquinolines
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Ze-Peng Yang, Qing-Feng Wu, Wen Shao and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, China; Collaborative Innovation Center of Chemical Science and Engi-
neering (Tianjin).
ABSTRACT: The first Ir-catalyzed intramolecular asymmetric allylic dearomatization reaction of pyridines, pyrazines,
quinolines and isoquinolines has been developed. Enabled by in situ formed chiral Ir-catalyst, the dearomatized products
were isolated in high levels of yield (up to 99% yield) and enantioselectivity (up to 99% ee). It is worth noting that Me-
THQphos ligand is much more efficient than other tested ligands for the dearomatization of pyrazines and certain quino-
lines. Mechanistic studies of the dearomatization reaction were carried out, and the results suggest the feasibility of an
alternative process which features the formation of a quinolinium as the key intermediate. The mechanistic findings ren-
der this reaction a yet unknown type in the chemistry of Reissert-type reaction. In addition, the utility of this method was
showcased by large-scale reaction and formal synthesis of (+)-Gephyrotoxin.
dihydroindolizines
a]pyrazines were easily synthesized in high levels of yield
and
6,7-dihydropyrrolo[1,2-
INTRODUCTION
Aromatic compounds are important structural motif and
widely distributed in nature. Among them, heterocyclic
aromatics, especially those containing one or more nitro-
gen atoms, occupy a privileged position as they are found
in numerous biologically active compounds and pharma-
ceuticals.1 Functionalization of these compounds has wit-
nessed significant progresses for a long time. Dearomati-
zation reaction represents a special class of transfor-
mations, in which planar aromatics are directly converted
to complex three-dimensional molecules.2 In particular,
catalytic asymmetric dearomatization (CADA) reaction
has attracted enormous attention because of its potential
impact on synthetic organic chemistry.3 Over the past
decade, transition-metal-catalyzed allylic dearomatization
reaction4 has emerged as an innovative and powerful type
of CADA reactions.5 However, successful cases are limited
and enantioselectivity.
This dearomatization process was originally proposed
to proceed according to the mechanism shown in Scheme
1. It was speculated that the reaction is initiated by the
well established iridium mediated oxidative addition of
allylic carbonate.12 Then the acidic H is deprotonated by
the liberated methoxy anion, forming a relatively stable
carbon anion. The conjugation effect compels the N-
attack to be achieved, and the corresponding dearoma-
tized product is thus obtained.
to electron-rich aromatics, such as indoles5b,5d,5g,5j,5k,5m,5n
,
pyrroles5e,5h,5i, phenols5c,5l and naphthols5f, while electron-
poor aromatics, such as pyridines, pyrazines, quinolines
and isoquinolines are less studied.
Direct addition of nucleophiles to pre-activated elec-
trophilic pyridinium intermediate, known as the Reissert-
type reaction, is a valuable strategy for asymmetric
dearomatization of pyridines.6 Other viable methods in-
clude hydrogenation7, transfer-hydrogenation8, hydrosi-
lylation9 and hydroboration10 reactions. As a step toward
the dearomatization of N-heteroaromatics, we recently
developed an iridium-catalyzed intramolecular asymmet-
ric allylic dearomatization reaction of pyridines and pyra-
zines.11 By employing this method, a series of 2,3-
Scheme 1. Originally proposed mechanism of the
dearomatization reaction of pyridine.
In this full article, we sought to further study the scope
and detailed reaction mechanism. Our research along
these lines led to an alternative catalytic cycle. In addition,
we exploited the synthetic utility of this method as the
core structure of the dearomatized products is found in
many biologically active natural products (Chart 1).13,14
Herein, we present a full account of our recent work on
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Page 2 of 10
the Ir-catalyzed intramolecular asymmetric allylic ee (Table 1, entry 3). Further screening of temperature
1
2
3
4
5
6
7
8
dearomatization reaction of N-heteroaromatics, which
mainly addresses these following aspects: 1) exploration of
broader substrate scope for dearomatization reaction of
pyrazines; 2) asymmetric dearomatization reaction of
quinolines and isoquinolines; 3) mechanistic studies of
the dearomatization reaction; and 4) formal synthesis of
(+)-Gephyrotoxin.
and solvents (Table 1, entries 9-12) led to the optimal con-
ditions: 2 mol % of [Ir(cod)Cl]2, 4 mol % of L3 in THF un-
der room temperature, and 4a was obtained in 99% yield
and 97% ee. Under these conditions, various 2-pyrazinyl
allylic carbonates were examined.
Table 1. Optimization of the reaction conditions for
the dearomatization of pyrazinesa.
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Chart 1. Selected biologically active piperidine con-
taining natural products.
SUBSTRATE SCOPE AND MECHANISTIC
STUDIES
Iridium-catalyzed intramolecular asymmetric allylic
dearomatization reaction of pyridines. First, the
dearomatization of pyridines was investigated by using in
situ formed chiral Ir-complex as the catalyst. Under very
mild conditions, 15 examples of intramolecular dearoma-
tization were successfully explored (Scheme 2), and the
dearomatized structure was further confirmed by X-ray
analysis.11 The corresponding 2,3-dihydroindolizines 2
were obtained in excellent yields and enantioselectivity.
entry
ligand T (°C)
solvent
conv.
(%)b
ee
(%)c
1
L1
50
50
50
50
50
50
50
50
25
THF
THF
THF
THF
THF
THF
THF
THF
THF
45
25
>95
85
33
85
93
93
94
80
93
-77
-
2
3
4
5
6
7
8
9
L2
L3
L4
L5
L6
L7
L8
L3
65
80
8
Scheme 2. Ir-catalyzed intramolecular asymmetric
allylic dearomatization reaction of pyridines.
Iridium-catalyzed intramolecular asymmetric allylic
dearomatization reaction of pyrazines. Dearomatiza-
tion of pyrazines very important as provides a rapid ac-
cess to a variety of 6,7-dihydropyrrolo[1,2-a]pyrazines,
which could lead to valuable piperazines after simple
transformations.
>95
97
(99)d
10
11
L3
L3
25
25
CH2Cl2
>95
>95
94
95
1,4-
dioxane
Our efforts to develop the dearomatization of pyrazines
began by evaluating the reaction of 3a as the model sub-
strate. Exposure of 3a to chiral Ir-complex, derived from
[Ir(cod)Cl]2 and the Feringa ligand L1, in THF afforded
the dearomatized product 4a in 45% conversion and 85%
ee (Table 1, entry 1). The low conversion might be caused
by the attenuated nucleophilicity of the pyrazine core.
Next, several chiral ligands were examined (Table 1, en-
tries 2-8). To our delight, it was found that Me-THQphos
L3, developed by our group, was effective in this reaction.
Substrate 3a was consumed completely, giving 4a in 93%
12
L3
25
toluene
>95
95
a
Reaction conditions: 2 mol % of [Ir(cod)Cl]2, 4 mol % of lig-
and, 0.2 mmol of 3a in solvent (2.0 mL). Catalyst was prepared
n
1
via PrNH2 activation.12i b Determined by H NMR of the crude
c
d
reaction mixture. Determined by HPLC analysis. Isolated
yield of 4a in parenthesis.
As shown in Table 2, the reaction proceeded well with a
range of substrates, encompassing N-atom as terminating
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Journal of the American Chemical Society
nucleophile and delivering a range of heterocyclic ring
7
8
9
3g (Ar = 4-ClC6H4) 12 4g
3h (Ar = 4-BrC6H4) 48 4h
3i (Ar = 4-MeC6H4) 12 4i
63
68
77
98
96
98
1
2
3
4
5
6
7
8
systems. A series of 2-pyrazinyl allylic carbonates bearing
different electron-withdrawing substituents (Table 2, en-
tries 1-9) all underwent dearomatization in good to excel-
lent yields and enantioselectivity. For the ester group, the
yield and enantioselectivity of the reaction decreased with
the increase of the steric hindrance (68-99% yields, 92-97%
ee; Table 2, entries 1-3). Notably, switching the ester
group to cyano led to the detriment of enantioselectivity
(78% yield, 61% ee; Table 2, entry 4). To our delight, aryl
carbonyl substituted allylic carbonates were suitable in
this reaction, affording the dearomatized products in
good to excellent yields and excellent stereocontrol (63-95%
yields, 96-98% ee; Table 2, entries 5-9).
10
11
3j (R = 4-FC6H4)
36 4j
75
75
82
95
96
97
96
98
9
10
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3k (R = 4-ClC6H4) 40 4k
3l (R = 4-MeC6H4) 36 4l
12
13
3m (R = 4-
MeOC6H4)
21 4m
40 4n
36 4o
To further test the potential of this Ir-catalyzed
dearomatization reaction, we turned our attention toward
the exploration of substrates bearing various substituents
on the pyrazine core. Good to excellent yields and excel-
lent ee values were obtained for the cyclization of 3j-3n,
varying aryl substituents on the 5-position of the pyrazine
in the substrates (75-95% yields, 96-98% ee; Table 2, en-
tries 10-14). It was worth noting that phenylmercapto
group was also tolerated (82% yield, 99% ee; Table 2, en-
try 15). Furthermore, 5- or 6-methyl substituted pyrazine
derivatives proved to be good substrates for the dearoma-
tization reaction (64-71% yields, 86-91% ee; Table 2, en-
tries 16-17). Finally, formation of the six-membered ring
also proceeded smoothly starting from substrate 3r (91%
yield, 92% ee; Table 2, entry 18).
14
15
3n (R = 2-
naphthyl)
94
82
98
99
3o (R = PhS)
16
17
3p
3q
1.5 4p
40 4q
64
71
91
86
Table 2. The reaction substrate scope of pyrazine de-
rivativesa.
18
3r
36 4r
91
92
a
Reaction conditions: 2 mol % of [Ir(cod)Cl]2, 4 mol % of L3,
0.2 mmol of 3 in THF (2.0 mL) at 25 °C. Catalyst was prepared
via PrNH2 activation. Isolated yield. Determined by HPLC
analysis.
entry 3
t (h)
4
yield ee
(%)b (%)c
n
b
c
Iridium-catalyzed intramolecular asymmetric allylic
dearomatization reaction of quinolines and isoquino-
lines. To broaden the scope of this Ir-catalyzed dearomati-
zation reaction, we next examined the reactions of quino-
lines and isoquinolines. Careful investigations of ligands
revealed that Feringa ligand L1, Alexakis ligand L2, Me-
THQphos L3 and BHPphos L6 were all effective in this reac-
tion, affording 6d in good to excellent yields and excellent
enantioselectivity (Table 3, entries 1-4). Especially, the
Alexakis ligand L2 and Me-THQphos L3 offered superior
results. Altering the temperature and solvents influenced
the reaction considerably (Table 3, entries 6-9). Reducing
the catalyst loading gave slightly decreased yield in a pro-
longed time (Table 3, entry 10).
1
3a (R = Me)
24 4a
18 4b
17 4c
99
88
68
97
94
92
2
3
3b (R = Et)
3c (R = tBu)
4
3d
11
4d
78
61
Table 3. Optimization of the reaction conditions for
the dearomatization of quinolinesa.
5
3e (Ar = Ph)
12 4e
95
66
97
97
6
3f (Ar = 4-FC6H4) 40 4f
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the benzo[f]quinoline derivative 5q (95% yield, 99% ee;
1
Table 4, entry 17). Gratifyingly, this Ir-catalyzed dearoma-
tization protocol was also suitable for substrate bearing
an N-linker, efficiently delivering the cyclized product 6r
(99% yield, 91% ee; Table 4, entry 18). Notably, this em-
bedded substructure bearing an N-linker is found as a
basic framework in nucleophilic acyl transfer catalysts
introduced by the Deng group.16 Finally, when isoquino-
line 5s was used in the reaction, the dearomatized prod-
uct was obtained smoothly, displaying excellent efficiency
and enantiocontrol (99% yield, 96% ee; Table 4, entry 19).
The structure and stereochemistry of the products were
confirmed unambiguously by X-ray crystallographic anal-
ysis of a crystal of enantiopure 6h. The absolute configu-
ration was determined to be R and this stereocontrol is in
accord with the general rule for the Ir-catalytic sys-
tem.12c,12d
2
3
4
5
6
7
8
9
entry ligand
T
(°C)
t (h) solvent
yield
(%)b
ee
(%)c
1
L1
50
50
50
50
50
25
25
25
7
THF
THF
THF
THF
THF
THF
CH2Cl2
85
97
91
94
98
97
98
-87
99
78
98
2
3
4
5
6
7
8
L2
L3
L6
L7
L2
L2
L2
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
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34
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
7
78
68
93
99
87
7
12
12
12
Table 4. The reaction substrate scope of quinoline
and isoquinoline derivatives.
1,4-
dioxane
9
L2
L2
25
25
12
toluene
THF
93
88
99
99
10d
24
entry
5
con t
ds. (h
)
6
yield ee
(%)a (%
b
)
a
Reaction conditions: 4 mol % of [Ir(cod)Cl]2, 8 mol % of lig-
and, 0.2 mmol of 5d in solvent (2.0 mL). b Isolated yield of 6d. c
d
Determined by HPLC analysis. 2 mol % of [Ir(cod)Cl]2 and 4
mol % of L2 were used.
1c
2c
3c
4
5a (R = OMe)
5b (R = OEt)
5c (R = OnPr)
5d (R = Ph)
A
A
A
A
4
4
4
6a
6b
6c
87
94
99
93
98
98
98
99
During the exploration of the substrate scope, it was
found that Me-THQphos L3 could provide a better out-
come for certain substrates. We attributed this fact to the
delicate spatial arrangement and characteristic C(sp2)-H
bond activation of L3 during the formation of active iridi-
um catalyst.15 This is also consistent with previous find-
ings that L3 is appropriate for reactions with bulky sub-
strates.15b Hence, two conditions were employed here to
investigate the substrate scope (conditions A: 4 mol % of
[Ir(cod)Cl]2, 8 mol % of L2 in THF under room tempera-
ture; conditions B: 4 mol % of [Ir(cod)Cl]2, 8 mol % of L3
in THF at 50 °C) and the results are summarized in Table
4. When ester substituted carbonates were employed, 20
mol % of DABCO were requisite to maintain the excellent
enantioselectivity (87-99% yields, 98% ee; Table 4, entries
1-3). Substituents on 4-, 5-, 6- or 7-position of the quino-
line core have little influence on yield and enantioselctivi-
ty and a number of methyl or methoxy-substituted (5e,
5h, 5i and 5j) and halogenated (5f, 5g, 5k, 5l, 5m and 5n)
aromatics all furnished dearomatized products in excel-
lent yields and enantioselectivity (81-99% yields, 96-99%
ee; Table 4, entries 5-14). Allylic carbonates incorporating
8-halogenated arenes were found to be highly dependent
on the steric effect. Switching the substituent from fluo-
rine to chlorine resulted in a dramatic decrease in both
yield and enantioselectivity (53-94% yields, 57-94% ee;
Table 4, entries 15-16). The tolerance of complicated sub-
strate was demonstrated in the successful conversion of
12 6d
5
6
7
5e (R = OMe)
5f (R = Cl)
B
B
B
5
4
4
6e
6f
91
96
98
96
90
87
5g (R = Br)
6g
8
9
5h
B
4
4
6h
6i
81
98
99
5i (R = Me)
A
88
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5j (R = OMe)
5k (R = F)
A
A
B
4
4
5
6j
98
82
89
99
98
97
1
2
3
4
11
6k
6l
12
5l (R = Br)
5
6
7
8
9
13
14
5m (R = F)
5n (R = Cl)
A
A
4
4
6m
6n
99
99
98
98
10
11
12
13
14
15
16
17
18
19
20
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22
23
24
25
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Scheme 3. Ir-catalyzed intramolecular asymmetric
allylic dearomatization reaction of 1o and pKa
(DMSO) values17 of corresponding compounds.
15
16
5o (R = F)
5p (R = Cl)
B
B
2
6o
94
53
94
57
Another plausible mechanism for the dearomatization
of quinolines is proposed in Scheme 4 (path b). First, oxi-
dative addition yields the -allyl intermediate I. Subse-
quent nucleophilic substitution by the N-atom of quino-
line generates the quinolinium IIb, which would be
deprotonated by base to afford the dearomatized product
6a finally. With the formation of quinolinium intermedi-
ate, the acidity of H would increase dramatically. To
some degree, the dearomatization reaction of 1o supports
the existence of path b. In addition, the fact that dimin-
ished yields and ee are observed when the steric bulkiness
of the ester group increases in 3a-3c (Table 2, entries 1-3)
also supports the existence of N-allylated intermediate
(pyrazinium). The bulky ester group will cause the slow
deprotonation process, and therefore lead to possible C-N
cleavage and other side reactions.
24 6p
17
18
5q
5r
B
B
10 6q
95
99
99
91
1
6r
6s
19
5s
B
7
99
96
a
b
c
Isolated yield. Determined by HPLC analysis. 20 mol % of
DABCO was used as the additive.
Mechanistic studies of the Ir-catalyzed intramolecu-
lar asymmetric allylic dearomatization reaction. Dur-
ing the exploration of substrate scope of the pyridine
dearomatization reaction, we tested the reaction of 1o
without electron-withdrawing substituent at the -
position under the standard conditions. As shown in
Scheme 3 (top), cyclized product 2o was obtained in ex-
cellent yield and enantioselectivity after subsequent hy-
drogenation reaction.11 The previously proposed reaction
mechanism (Scheme 1) could not account for the experi-
mental observations. According to the proposed mecha-
nism, the H is deprotonated firstly by the liberated
methoxy anion. However, it seems that the basicity of
methoxy anion might not be enough to cleave the C-H
bond (Scheme 3, bottom). These results challenged the
proposed catalytic cycle and prompted us to conduct de-
tailed mechanistic studies on this reaction.
Scheme 4. Plausible mechanism of dearomatization
reaction.
To further shed light on the mechanism, we synthe-
sized substrate 5t bearing a phosphate leaving group. Un-
der the standard conditions, the dearomatized product 6a
was obtained in 67% yield and 42% ee (Scheme 5, top).
Apparently, the observation of dearomatization of phos-
phate substrate 5t seems to support the existence of path
b as the base in this system (according to the pKa values,
dearomatized product 6a might be the strongest base in
the system) is not strong enough to deprotonate H in the
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Journal of the American Chemical Society
substrate (Scheme 5, bottom, 5.06 vs >11). The poor enan-
tiocontrol might arise from the effect of the reversible C-
N bond formation due to the slow deprotonation of quin-
olinium intermediate.
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Scheme 6. Capture and in situ transformation of
quinolinium species.
Scheme 5. Dearomatization of phosphate substrate 5t
and pKa (DMSO) values17 of corresponding com-
pounds.
The absence of Thorpe-Ingold effect in substrate 5u
might cause the failure of its transformation under Ir-
catalysis. Based on these information, it was envisaged
that switching the leaving group in 1o from carbonate to
chloride will provide a chance to characterize the corre-
sponding pyridinium intermediate with iridium complex
as the catalyst. As expected, the pyridinium intermediate
2p was obtained starting from allylic chloride substrate 1p
(Scheme 7). Subsequent hydrogenation produced 20 with
poor enantioselectivity, which was attributed to the re-
versible C-N bond formation. Therefore, it is strongly in-
dicated that path b (Scheme 4) is a feasible process, albeit
path a can not be ruled out.
These findings encouraged us to examine whether we
could observe or separate the quinolinium intermediate.
However, this intermediate was difficult to be observed
1
by in situ IR or H NMR experiments. Thus, we prepared
substrate 5u without an electron-withdrawing group. The
N-alkylation reaction could not take place under Ir-
catalysis. Surprisingly, compound 6u was obtained by
employing [Pd(PPh3)4] as the catalyst, implying the feasi-
bility of N-attack directly (Scheme 6, top).
During our investigation, preliminary results showed
that the reaction of allylic carbonate with a methylene
linker could not afford quinolinium product, only a small
amount of hydrolysis product was obtained. At this stage,
further attention was paid to the in situ transformation of
the proposed quinolinium intermediate. Gratifyingly, the
proposed quinolinium species can be captured by hydro-
genation reaction, giving cyclized product 6v by employ-
ing allylic carbonate 5v as the starting material (Scheme 6,
bottom). Pd-catalyzed reversible C-N cleavage during
hydrogenation might account for the low ee value (27%
ee).18
Scheme 7. Dearomatization of allylic chloride sub-
strate 1punder Ir-catalysis.
SYNTHETIC APPLICATION
Large-scale reaction. The robustness and practicality of
current methodology could further be demonstrated by
large-scale synthesis. The reaction of 3e, 3r and 5h on a
gram-scale delivered the corresponding products in good
yields and excellent enantioselectivity (Scheme 8).
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Scheme 9. Formal synthesis of (+)-Gephyrotoxin.
CONCLUSION
In summary, we have developed the first Ir-catalyzed in-
tramolecular asymmetric allylic dearomatization reaction
of pyridines, pyrazines, quinolines and isoquinolines.
These reactions are enabled by in situ formed chiral Ir-
catalyst. For pyrazines and certain quinolines, Me-
THQphos ligand is required to obtain the best outcome.
Initial mechanistic studies resulted in the discovery of an
alternative reaction pathway. The new catalytic cycle fea-
tures the formation of quinolinium as the key intermedi-
ate. However, the previously proposed mechanism involv-
ing the deprotonation of acidic H as the first step can not
be excluded. The mechanistic findings render this reac-
tion a yet unknown type in the chemistry of Reissert-type
reaction, which is realized by an intramolecular -H elim-
ination protocol. Meanwhile, it is the first time to realize
Ir-catalyzed allylic substitution reaction by employing
pyridines, pyrazines, quinolines and isoquinolines as the
N-nucleophiles. The robustness and practicality of this
method was demonstrated by large-scale reactions. The
utility of this method was further illustrated by formal
synthesis of (+)-Gephyrotoxin.
Scheme 8. Large-scale reaction.
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Formal synthesis of (+)-Gephyrotoxin. Gephyrotoxin is
one member of a family of alkaloids isolated from the skin
extracts of the Columbian frog, Dendrobates histrioni-
cus.19 Different from other dendrobatid alkaloids, Gephy-
rotoxin is relatively nontoxic and possesses mild musca-
rinic activity and interesting neurological activities.20 The
interesting biological characteristics of Gephyrotoxin
have stimulated synthetic activity in many groups.21 In
1983, Ito and co-workers synthesized hexahydro-
pyrrolo[1,2-a]quinoline 12 and converted it to Gephy-
rotoxin.21i To further demonstrate the synthetic utility of
this new method, efforts have been taken towards the
preparation of Ito’s intermediate 12.
As shown in Scheme 9, the synthesis commenced with
the selective hydroboration/oxidation of terminal olefin
in 6h and subsequent hydrogenation furnished 8 as a sin-
gle diastereoisomer in 48% yield and 92% ee. Protection
of the hydroxyl group with MOMCl yielded 9 in a quanti-
tative conversion and its relative configuration was de-
termined by NOE experiments.22 Hydrolysis of the methyl
ester was achieved by stirring with LiOH·H2O, affording a
carboxylic acid, which, after removal of aqueous MeOH,
was decarboxylated smoothly under modified Barton de-
carboxylation conditions23 in 64% yield over two steps.
Final deprotection of the MOM group produced Ito’s in-
termediate 12. It is noteworthy that this route is the first
asymmetric synthesis of Gephyrotoxin by a catalytic
method.
ASSOCIATED CONTENT
Experimental procedures and spectral data. Single crystal X-
ray diffraction data for compound 6h. This material is availa-
ble free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
slyou@sioc.ac.cn
ACKNOWLEDGMENT
We thank the National Basic Research Program of China (973
Program 2015CB856600), NSFC (21332009, 21421091), and the
Chinese Academy of Sciences for generous financial support.
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