Stereoselective synthesis of spirocyclic oxindoles based on a one-pot Ullmann coupling/Claisen rearrangement and its application to the synthesis of a hexahydropyrrolo[2,3-b]indole alkaloid

Article abstract of DOI:10.1016/j.tet.2013.08.057

An efficient and convenient approach to the synthesis of spirocyclic oxindoles from iodoindoles has been developed. The most striking feature of this approach is that the sequential intramolecular Ullmann coupling and Claisen rearrangement proceeds in a one-pot manner to afford 3-spiro-2-oxindoles in good yield with excellent diastereoselectivity. Application of this one-pot reaction to chiral non-racemic tertiary alcohol substrates resulted in complete chirality transfer to the spirocyclic quaternary carbon. Using this method, asymmetric total synthesis of (-)-debromoflustramine B was accomplished.

Full text of DOI:10.1016/j.tet.2013.08.057

Tetrahedron 69 (2013) 9481e9493
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of spirocyclic oxindoles based on a one-pot
Ullmann coupling/Claisen rearrangement and its application to the
synthesis of a hexahydropyrrolo[2,3-b]indole alkaloid
y
*
Hiroshi Miyamoto , Tomohiro Hirano, Yoichiro Okawa, Atsuo Nakazaki ,
*
Susumu Kobayashi
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 August 2013
Received in revised form 19 August 2013
Accepted 21 August 2013
Available online 27 August 2013
An efficient and convenient approach to the synthesis of spirocyclic oxindoles from iodoindoles has been
developed. The most striking feature of this approach is that the sequential intramolecular Ullmann
coupling and Claisen rearrangement proceeds in a one-pot manner to afford 3-spiro-2-oxindoles in good
yield with excellent diastereoselectivity. Application of this one-pot reaction to chiral non-racemic ter-
tiary alcohol substrates resulted in complete chirality transfer to the spirocyclic quaternary carbon. Using
this method, asymmetric total synthesis of (ꢀ)-debromoflustramine B was accomplished.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Spiro compounds
Sigmatropic rearrangement
Nitrogen heterocycles
Domino reactions
Total synthesis
1. Introduction
Oxindoles that incorporate a quaternary stereogenic center at
C3 are attractive targets in organic synthesis because of their sig-
nificant biological activity as well as wide-ranging utility as syn-
thetic intermediates for alkaloids, drug candidates, and clinical
pharmaceuticals (Fig. 1).1 As such, a number of synthetic methods
have been developed in pursuit of this structure, including in-
termolecular alkylations,2 transition-metal-mediated reactions,1g,3
cycloadditions,4 and sigmatropic rearrangements.5 During the
course of our studies of the synthesis of spirocyclic terpenes, we
developed a stereoselective Claisen rearrangement using bicyclic
dihydropyran A as the rearrangement substrate to provide multi-
functionalized spiro[4.5]decane B (Scheme 1).6,7 On the basis of
this result, we envisioned that a Claisen rearrangement of pyr-
anoindole
D would produce spirocyclic oxindole (3-spiro-2-
oxindole) E in a stereoselective manner.8 The pyranoindole D
starting material for this transformation can be generated from 2-
haloindole
C via an intramolecular Ullmann coupling (IUC)
(Scheme 2).
* Corresponding authors. E-mail addresses: nakazaki@agr.nagoya-u.ac.jp (A. Na-
kazaki), kobayash@rs.noda.tus.ac.jp (S. Kobayashi).
y
Present address: Process Technology Research Laboratories, Daiichi Sankyo Co.,
Fig. 1. Alkaloids and clinical pharmaceuticals having a quaternary stereogenic center at
Ltd, 1-12-1 Shinomiya, Hiratsuka-shi, Kanagawa 254-0014, Japan.
C3 position of oxindole or related scaffold.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.057

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H. Miyamoto et al. / Tetrahedron 69 (2013) 9481e9493
of chiral non-racemic spirocyclic oxindoles by asymmetric trans-
mission is newly described. Moreover, this one-pot procedure is
applied to the asymmetric synthesis of (ꢀ)-debromoflustramine B
(1) based on our previously reported strategy.12
2. Results and discussion
Scheme 1. Synthesis of spiro[4.5]decane B through Claisen rearrangement of bicyclic
dihydropyran A.
2.1. Synthesis of 2-haloindoles as one-pot cyclization
precursors
In order to define the scope of this rearrangement process, we
began with the development of a general route for assembling cy-
clization precursors via two different approaches: method A starting
from 2-iodoindole H (Scheme 4, a), and method B involving a Larock
indole synthesis (Larock heteroannulation)13 as the key reaction
(Scheme 4, b). Method A involves a Michael addition of 2-iodoindole
H and nucleophilic addition of an alkenyl metal species, such as
alkenyl aluminate or a Grignard reagent to prevent reduction of the
2-iodo group. Although this method is the shorter of the reaction
sequences, it is not suitable for the synthesis of enantioenriched
products. In contrast, method B involves the Larock indole synthesis
of readily available silylalkyne L with a stereochemically defined
allylic alcohol moiety and 2-iodoaniline K. The Larock indole syn-
thesis is among the most reliable processes for the synthesis of in-
dole frameworks in terms of substitution and functionality; and it is
ideally suited to the construction of the chiral non-racemic 2-
haloindole J0 because the annulation of K and L proceeds with ex-
cellent regioselectivity to give 2-silylindoles, which can be readily
converted to the 2-iodoindoles J0 by iododesilylation followed by
deprotection of the hydroxy group. This method is advantageous for
the introduction of substituents to the aromatic ring, as well as in
the preparation of enantioenriched precursors.
Scheme 2. Key transformations in this report.
Stereoselectively synthesized spirocyclic oxindole F is expected
to be potentially useful because it can be converted directly into
a biologically active spirocyclic oxindole alkaloid (Scheme 3). In
addition, after cleavage of the internal double bond of the cyclo-
hexene ring in F, a stereochemically defined oxindole G having
a quaternary chiral center results, and oxindole G is also considered
to be a useful chiral building block for the synthesis of biologically
active compounds including hexahydropyrrolo[2,3-b]indole alka-
loids,9 such as debromoflustramine B,9b flustramine B9c,d and
pseudophrynaminol.9e
Scheme 3. Two approaches to the synthesis of indole alkaloids using a stereochemi-
cally defined spirocyclic oxindole.
We reported a one-pot synthesis involving a sequential IUC of 2-
haloindole C followed by a Claisen rearrangement of the in situ
generated 2-(alkenyl)pyranoindole D affording spirocyclic oxindole
E in good yield with excellent diastereoselectivity (Scheme 2),10,11
and we also demonstrated total synthesis of hexahydropyrrolo
[2,3-b]indole alkaloids.12 Reported herein are the full details of our
development of a highly stereoselective method for the synthesis of
spirocyclic oxindole derivatives. Utilizing our procedure, synthesis
Scheme 4. General schemes for preparation of 2-iodoindole.
Initial efforts focused on preparation of the racemic cyclization
precursors of the one-pot reaction using Method A. In order to
synthesize the aldehydes or ketones needed for nucleophilic

H. Miyamoto et al. / Tetrahedron 69 (2013) 9481e9493
9483
addition to the alkenyl metal, a Michael addition of N-protected
indoles to -unsaturated carbonyl compounds was performed
reductive amination of benzaldehyde and the corresponding
iodoanilines with NaBH3CN and ZnCl2 in MeOH (Scheme 7).19
Starting materials 30aec are commercially available or were syn-
thesized via literature methods.20
The synthesis of 7-(trimethylsilyl)hept-1-en-6-yn-3-ol 35 and
enantioenriched (R)-35 is illustrated in Scheme 8. The synthesis
began with commercially available 5-(trimethylsilyl)pent-4-yn-1-
ol 32, which was oxidized using DMSO/(COCl)2 to the aldehyde
33, and this compound was converted to the allylic alcohol 34 by
addition of vinyllithium. The racemic alcohol 34 was subjected to
Sharpless kinetic resolution conditions using t-BuOOH, Ti(Oi-Pr)4,
a,b
(Scheme 5). N-Methylindole, a commercially available substance,
can be conveniently converted to the desired 2-iodoindole 2a (n-
BuLi in Et2O at reflux, followed by quenching with iodine).14 Elec-
trophilic alkylation of 2a at the C3 position with acrolein using
trifluoroacetic acid and N-methylaniline provides the aldehyde
4a.15 Other indole derivatives 4bed, 5a, and 5b containing N-pro-
tecting groups, such as TBS, MOM, and Bn, as well as a bromine
functionality were synthesized in a similar manner.
and (þ)-diisopropyl
L
-tartrate (DIPT) in CH2Cl2 at ꢀ20 ꢁC to give (R)-
34 (>98% ee) in 41% yield.21 Finally, protection of the hydroxy group
with chlorotriethylsilane furnished (R)-35 in 97% yield through
resolution, or racemic 35 in 97% yield if the resolution step is
omitted.
With the required coupling partners now in hand, the next task
was to synthesize the indole nucleus. The crucial, palladium-
catalyzed Larock indole synthesis was accomplished using
Walsh’s conditions (Scheme 9).22 Reaction of 35 or (R)-35 and
31aec in DMF at 100 ꢁC using Pd(OAc)2 (5 mol %) and PPh3 (5 mol %)
in the presence of 1 equiv of LiCl and 2.5 equiv of K2CO3 afforded the
2-silylindoles 36aec in 39e71% yields. Iododesilylation of 36aec
using ICl in CH2Cl2 at ꢀ78 ꢁC followed by a standard silyl depro-
tection provided racemic 37aec in 30e72% yield from 2-silylindole
and enantioenriched (R)-37a and (R)-37b with high optical purity
(>99% ee). In the iododesilylation step, the allylic alcohol double
bond of 36aec was iodinated easily in a side reaction. For 36a and
(R)-36a, this side reaction was suppressed by cooling the reaction to
ꢀ78 ꢁC. However, the side reaction was not suppressed for 36b, (R)-
36b, and 36c, and the yields of 37b, (R)-37b, and 37c were di-
minished. These results presumably reflect the difference in re-
activity toward ICl derived from the substituents on the indole ring.
It was possible to synthesize the tertiary allylic alcohol (R)-42,
a more complex compound, via the same Larock protocol (Scheme
10). The two building blocks for synthesis, compounds 31a and 40,
are both readily available. With respect to the chiral, non-racemic
silylalkyne 40, a facile and short synthesis was achieved com-
mencing with ozonolysis of (R)-(ꢀ)-linalool (>98% ee). Employing
a known procedure, oxidative cleavage of the more electron-rich
double bond of (R)-(ꢀ)-linalool with ozone in CH2Cl2/pyridine at
ꢀ78 ꢁC afforded lactol 38 as a mixture of diastereomers in 66%
yield.23 It is important that the reaction be carried out to only about
60e70% completion to minimize overoxidation. Treatment of the
resulting lactol with OhiraeBestmann reagent gave the corre-
sponding propargylic alcohol 39,24 on, which the terminal acety-
lene and hydroxyl groups were simultaneously silylated with
chlorotrimethylsilane using n-BuLi as a base to furnish the desired
40 in 93% yield. Subjection of 40 to a palladium-catalyzed coupling
reaction with 31a in the same manner as described in Scheme 9
gave the 2-silylindole 41 in 82% yield. Iododesilylation with ICl,
followed by removal of the TMS group with tetra-n-butylammo-
nium fluoride provided (R)-42 with 97% ee in 58% yield from 41.
Scheme 5. Preparation of 2-haloindoles. aYield from indole.
The ketone 8 was prepared via InCl3-catalyzed conjugate addi-
tion16 of 617 with methyl vinyl ketone followed by N-alkylation
(Scheme 5). However, alkenylation of the aldehyde and ketone in
the next step was somewhat troublesome. Initial attempts at
alkenylation of the aldehyde 4a using isopropenylmagnesium
bromide 12 resulted in low yields of 20d due to the competing
unfavorable deiodination by an alkenylmetal species. It was found,
however that use of excess alkenyl Grignard reagents and rapid
quenching after the disappearance of starting material afforded
20d in good yield (Table 1, entry 4). Similarly, addition of alke-
nyllithium in the presence of AlMe3 was effective in avoiding the
deiodination (Table 1, entries 1e3, 6, 8, and 9).18 However, since this
reaction was often accompanied by addition of a methyl group
(derived from AlMe3) to the aldehyde, the Grignard method is
considered more advantageous.
According to the similar manner, the cyclization precursor 29 for
the synthesis of five-membered ring system was prepared as
shown in Scheme 6. Methyl N-methylindoleacetate 26, prepared
from commercially available 3-indoleacetic acid in two steps, was
treated with LiAlH4 to provide primary alcohol 27. And lithiation
and subsequent iodination of the C2 position, followed by oxidation
of the primary hydroxy group by DesseMartin periodinane, led to
the corresponding aldehyde 28. Addition of vinylmagnesium bro-
mide to this aldehyde provided the precursor 29 in good overall
yield.
2.2. Optimization of reaction conditions
At the outset of this project, the plan was to examine the syn-
thesis of 2-(alkenyl)pyranoindole O as a precursor for Claisen rear-
rangement from indole M having no halogen substituent at the C2
position (Scheme 11). To our knowledge, few general procedures are
available for the preparation of the pyranoindole scaffold and/or
related structures. In 1978, Nakagawa and co-workers reported that
oxidative cyclization of 3-indolepropanol and 3-indolepropanethiol
with N-bromosuccinimide in CH2Cl2 gave the corresponding pyr-
anoindole and thiopyranoindole, respectively, in good yields.25
Likewise, Rainier and co-workers also reported the formation of
Multisubstituted and/or chiral non-racemic 2-iodoindoles 37
and (R)-42 were prepared efficiently via Method B (Scheme 4),
a palladium-catalyzed Larock indole synthesis from N-benzyl or-
tho-iodoaniline 31 and silylalkyne 35 or 40 (Schemes 9 and 10,
respectively). N-Benzyl ortho-iodoanilines 31aec were prepared by

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H. Miyamoto et al. / Tetrahedron 69 (2013) 9481e9493
Table 1
Synthesis of 2-haloindoles
Entry
Formyl or ketoindole
Alkenyl metal
Product
Yield [%]a (EIZ)b
1
4a
4a
4a
61
2
3
82 (>95% E)
42 (>95% Z)
4
4a
71
5
8
72
6
4a
4a
4a
4a
4a
82 (>95% E)
7
85
8
44 (>95% E)
73 (>95% E)
14 (>95% E)
9
10

H. Miyamoto et al. / Tetrahedron 69 (2013) 9481e9493
9485
Table 1 (continued )
Entry
Formyl or ketoindole
Alkenyl metal
Product
Yield [%]a (EIZ)b
11
12
13
14
4b
65 (>95% E)
75 (>95% E)
73 (>95% E)
70 (>95% E)
4c
4d
5a
19
19
10
15
5b
19
79 (>95% E)
a
Yield of isolated product.
b
Determined by 1H NMR spectroscopic analysis.
Scheme 8. Synthesis of silylalkynes 35 and (R)-35. aEnantiomeric excess was de-
termined by chiral HPLC analysis.
Scheme 6. Preparation of 2-iodoindole 29.
substituted thiopyranoindoles from the corresponding thiols by
oxidative cyclization using iodine.26
Following these precedents, we initially attempted oxidative
cyclization of the corresponding indole 43 containing
a 3-
hydroxynon-4-enyl side chain at the C3 position with N-bromo-
succinimide, iodine or other oxidants. However, the reactions led to
no desired product 45; undesired spirocyclic products were ob-
served together with a mixture of polymerization products of 43
(Scheme 12). For example, when 43 was treated with iodine in
Scheme 7. Preparation of N-benzyl-2-iodoanilines 31aec.

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H. Miyamoto et al. / Tetrahedron 69 (2013) 9481e9493
Scheme 11. Synthetic plans of 2-(alkenyl)pyranoindole O.
failures suggest that both 43 and 45 are more sensitive to electro-
philes, including a proton, than the compounds used in the litera-
ture. Since careful control to prevent side reactions is required in
the oxidative cyclization method, much milder conditions were
required.
Scheme 9. Synthesis of N-benzyl-2-iodoindoles. aYield for the two steps; bEnantio-
meric excess was determined by chiral HPLC analysis.
Scheme 12. Attempted oxidative cyclization of 43.
It was decided that the next step would be to examine the
transition-metal-catalyzed intramolecular CeO coupling of 2-
haloindole, which is usually carried out under basic conditions
(from 2-iodoindole N to pyranoindole O in Scheme 11). For CeO
bond formation, a copper-mediated Ullmann-type reaction was
chosen for its ease and low cost.28 Although several recent syntheses
have involved IUC, these examples are much rarer than in-
termolecular versions. As a preliminary survey, several known
procedures using two 2-iodoindoles 20a and 20b as model sub-
strates were compared. The methods of Buchwald (CuI/1,10-
phenanthroline, Cs2CO3),29 Song (CuCl/2,2,6,6-tetramethylheptane-
3,5-dione, Cs2CO3),30 and Zhu (CuCl, NaH)31 all gave poor results in
our system; either a large amount of starting material remained
unchanged or reductive dehalogenation of starting material
was observed. In contrast, the Hauptman protocol (CuCl/2-
aminopyridine, NaOMe)32 was found to be effective, proceeding in
moderate yield (up to 60%). However, direct application of the
Hauptman method to our indole substrates suffered from poor re-
producibility. After many trials, this problem was overcomed by
employing two minor modifications: (1) addition of a small amount
of MeOH (approx. 2% v/v); and (2) an increase in the amount of base
Scheme 10. Synthesis of (R)-42. aEnantiomeric excess was determined by chiral HPLC
analysis.
CH2Cl2, a diastereomeric mixture of the spirocyclic indolenine 44
was obtained in 30% yield. The formation of 44 probably proceeds
via initial activation of the hydroxyl group of 43 by a proton, fol-
lowed by cyclization of the resulting allylic cation intermediate,
giving rise to a more thermodynamically favorable six-membered
ring. While making use of pyridine as an acid scavenger under
the same reaction conditions, the undesired spirocyclic oxindole 46
resulted in 28% yield with low diastereoselectivity. This oxindole
product presumably is formed via an iodination at the C3 position
of the desired pyranoindole 45, followed by the addition of H2O at
the C2 position, with concomitant skeletal rearrangement.27 These

H. Miyamoto et al. / Tetrahedron 69 (2013) 9481e9493
9487
(NaOMe). (Using 2.0 equiv of commercial NaOMe in MeOH solution
(25 wt %) gave the best results, with good reproducibility.) Under the
optimized conditions, the IUC of 20a proceeded rapidly (completed
within 10 min) to give pyranoindole 49a in 91% yield (Scheme 13).
Interestingly, neither the dehalogenated product 47 nor the
methoxylated product 48 was obtained. Finally, 49a underwent
Claisen rearrangement to afford the desired oxindole 50a by heating
in 1,2-dimethoxyethane (DME) at 150 ꢁC.
reaction time was required for the latter case (Table 2, entries 2 and
5). Increasing the concentration of 20a to 0.10 mol/L resulted in
a slight decrease in yield due to side reactions during the IUC step
(Table 2, entry 6). In the absence of CuCl and 2-aminopyridine the
IUC was sluggish, and the yield of 50a dropped to 6% with 74% of
20a recovered (Table 2, entry 7), suggesting that CuCl and 2-
aminopyridine efficiently catalyze the IUC.
2.3. Scope and limitation
To study the effect of substituents on the Claisen rearrangement,
compound 20a with a variety of substituents on the allylic alcohol
unit were investigated next. The results are summarized in Table 3.
It is noteworthy that all of the indoles with trans-oriented sub-
stituents on the allylic double bond afforded the corresponding
oxindoles as a single diastereomer, irrespective of the substituent
(Table 3, entries 1, 2, 6e11). The relative stereochemistry was
assigned based on an X-ray crystal structure of oxindole 50h,33 and
NOE experiments (Fig. 2).
The stereochemistry of these products indicates that the Claisen
rearrangement proceeds through a boat-like transition state anal-
ogous to previous results (Scheme 14).34 In contrast, the reaction of
the cis-isomer 20c did not give the desired product; instead, de-
composition of the corresponding pyranoindole 49c initially
formed was observed (Table 3, entry 3). This result can be ratio-
nalized by considering the unfavorable transition state, which
would result from steric repulsion between the cis-oriented methyl
group and the hydrogen atoms of the dihydropyran ring (Scheme
14). The rate of Claisen rearrangement is strongly dependent on
the presence of substituents on the allylic double bond. The re-
action of substrates with an alkyl or aryl substituent on the allylic
double bond is fast (Table 3, entries 1, 6, 8e10).35 In contrast,
substrates with no substituent on the allylic double bond react
slowly (Table 2, entry 2).7a For bromoindole 24, although the re-
activity in the IUC is apparently lower than that of iodide 20b, the
reaction did proceed to afford oxindole 50b in 55% yield (Table 3,
entry 2). Notably, sterically hindered substrates, such as 20e (ter-
tiary alcohol) and 20g (trisubstituted olefin) gave the desired 50e
and 50g, respectively, in good yield (Table 3, entries 5 and 7). It was
possible to accelerate the slow reaction of 20g by raising the re-
action temperature, without any side reactions. The fact that diol
20i gave 50i exclusively, in 93% yield, indicates that the allylic hy-
droxyl group reacts selectively and that the IUC is tolerant of un-
protected hydroxy groups (Table 3, entry 9). The low yield observed
for silyl-bearing 20k is due to the formation of the desilylated
product 50a and its double bonded isomer (Table 3, entry 11).
In contrast, five-membered ring closure using precursor 29 was
found to provide neither desired furanoindole 51 nor the corre-
sponding spirocyclic oxindole 52; 2-methoxyindole 53a and the
dehalogenated product 53b were obtained (Scheme 15). This result
indicates that intramolecular CeO bond formation would be retard
by some unfavorable conformation in the transition state to form
five-membered cyclic ether.
Scheme 13. Synthesis of spirocyclic oxindole 50a through IUC and Claisen
rearrangement.
As noted above, pyranoindole 49a is relatively unstable, espe-
cially under acidic conditions; and thus, significant decomposition
of 49a was observed during purification by silica gel column
chromatography. Therefore, in the next phase of the reaction op-
timization, a one-pot synthesis of 50a was attempted (Table 2). A
mixture of 20a, CuCl, 2-aminopyridine, and NaOMe/MeOH in DME
was heated to 100 ꢁC for 24 h, and 50a was obtained in 53% yield
with 22% of 49a also recovered (Table 2, entry 1). Upon raising the
reaction temperature to 150 ꢁC after complete formation of 49a (at
100 ꢁC for 10 min; judged by HPLC), the rearrangement of 49a
proceeded more efficiently to afford 50a in 84% yield (Table 2, entry
2). Using CH3CN or toluene as the solvent led to a considerable
decrease in yield (Table 2, entries 3 and 4). Catalyst and ligand
loadings of 10 mol % and 5 mol % gave similar results, but a longer
Table 2
One-pot synthesis of spirocyclic oxindole 50aa
Entry CuCl
2-NH2Py Solvent [20a]
[mol Lꢀ1
Conditions
Yield [%]b
[mol %] [mol %]
]
49a 50a
1
2
10
10
10
10
DME
DME
0.05
0.05
100 ꢁC, 24 h
100 ꢁC, 10 min
150 ꢁC, 12 h
100 ꢁC, 24 h
100 ꢁC, 1 h
22
0
53
84
The synthetic utility of N-methylated oxindoles is rather limited
due to difficulty in deprotecting the N-methyl group. However, the
direct conversion of unprotected N-free iodoindoles to the corre-
sponding N-free oxindoles is difficult because of the unstable na-
ture of unprotected iodoindoles. Thus, in order to eliminate these
limitations, a suitable N-protecting group for the iodoindole, which
does not alter the reactivity of the indole nucleus and can be re-
moved under facile conditions was examined next (Table 4). N-tert-
Butyldimethylsilyl (TBS) indole 21 afforded deprotected oxindole
54b in 57% yield (Table 4, entry 1). In this reaction, all of 21 was
initially converted to an N-free iodoindole 21 upon heating to
100 ꢁC, as monitored by HPLC analysis. However, the subsequent
IUC of 21 was rather slow, and the reaction temperature had to be
3
4
10
10
10
10
CH3CN
Toluene 0.05
0.05
26
0
36
41
150 ꢁC, 12 h
100 ꢁC, 3 h
5
6
5
10
0
5
10
0
DME
DME
DME
0.05
0.10
0.05
0
0
80
72
6c
150 ꢁC, 12 h
100 ꢁC, 10 min
150 ꢁC, 12 h
100 ꢁC, 24 h
7
10
a
Reaction conditions: indole 20a (0.50 mmol), NaOMe/MeOH (25 wt %;
2.0 equiv), Ar, sealed tube.
b
Yield of isolated product.
20a was recovered in 74% yield.
c

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H. Miyamoto et al. / Tetrahedron 69 (2013) 9481e9493
Table 3
Synthesis of N-methyl spirocyclic oxindolesa
Entry
Substrate
Product
Conditions
Yieldb (% dec)
1
100 ꢁC, 0.5 h
150 ꢁC, 1 h
89 (>95)
2
3
50b
100 ꢁC, 24 h
55d (>95)
NDe
100 ꢁC, 1.5 h
150 ꢁC, 6h
d
4
5
6
7
100 ꢁC, 4 h
150 ꢁC, 1 h
80
130 ꢁC, 21 h
150 ꢁC, 1 h
84
100 ꢁC, 1 h
150 ꢁC, 1 h
92 (>95)
100 ꢁC, 22 h
120 ꢁC, 11 h
89 (>95)
90 (>95)
8
9
100 ꢁC, 1 h
84 (>95)
93 (>95)
100 ꢁC, 0.5 h
150 ꢁC, 1 h
10
100 ꢁC, 1 h
150 ꢁC, 0.7 h
66f (>95)

H. Miyamoto et al. / Tetrahedron 69 (2013) 9481e9493
9489
Table 3 (continued )
Entry
Substrate
Product
Conditions
Yieldb (% dec)
11
100 ꢁC, 5 h
150 ꢁC, 2 h
20g (>95)
a
Reaction conditions: substrate (0.50 mmol), CuCl (10 mol %), 2-aminopyridine (10 mol %), DME (0.05 M), NaOMe/MeOH (25 wt %; 2.0 equiv), Ar, sealed tube, Reaction time
and temperature were not optimized for each substrate.
b
Yield of isolated product.
c
Determined by 1H NMR spectroscopic analysis.
d
24 was recovered (31%).
Complex mixture was obtained.
50i was isolated in 25% yield (>95% de).
50a and its regioisomer were isolated in 47% yield (50a/isomer¼2:1).
e
f
g
Scheme 15. Attempted one-pot sequence to provide furanoindole 51.
Fig. 2. NOE experiments to determine the stereochemistry of spirocyclic oxindoles.
An attempt using the benzenesulfonyl group failed cleavage of
the protecting group followed by methylation of the resulting N-
free indole occurred.37 In an effort to enhance the practicality of
these transformations, the reaction of 23 at atmospheric pressure
was carried out using diglyme as a solvent. Interestingly, acceler-
ation of the IUC step was observed, and oxindole 56b was obtained
in almost same yield as in DME (Table 4, entry 3). This result sug-
gests that Claisen rearrangement of pyranoindole can be readily
accomplished without carrying out the reaction in a sealed tube.
Exposure of 37b to the standard reaction conditions using DME
provided an oxindole product 57 in 87% yield (Table 4, entry 5). In
this case, the complete conversion of 37b to the pyranoindole in-
termediate was observed following heating at 100 ꢁC for 1 h, and
the subsequent rearrangement to 57 was achieved by heating at
150 ꢁC for 6 h. At this point, no trace of the methoxy-substituted
product was detected. This result suggests that the present cata-
lytic system could be applied to bromo-functionalized substrates,
which are generally reactive to copper-mediated alkoxydehaloge-
nations or reductive dehalogenations. In contrast to the bromo
derivative 37b, the methoxy-substituted iodoindole 37c was ap-
parently less reactive in the IUC (Table 4, entry 6). Although 76%
yield of oxindole 58 was obtained, starting material 37c was re-
covered in 10% yield, even after a prolonged reaction time (120 ꢁC,
13 h).
Encouraged by the results with diglyme, the accelerating effect
of other ethereal solvents was next investigated (Table 5). Reactions
were carried out at 150 ꢁC using bromoindole 25, which was found
to be sluggish in the IUC. Under the standard reaction conditions
using DME, the IUC of 25 did not complete even after 45 h, and
debrominated 59 was isolated in 4% yield as a side product (Table 5,
Scheme 14. Possible transition states of Claisen rearrangement.
elevated to 150 ꢁC to achieve complete consumption of 21. In
contrast, the methoxymethyl (MOM) and benzyl groups were
found to be suitable N-protecting groups for the present trans-
formation. The IUC of 22 and Claisen rearrangement of the resulting
pyranoindole occurred smoothly to give 55b in 92% yield as a single
isomer (Table 4, entry 2). Similarly, the reaction of N-benzylindole
23 proceeded in high yield with high diastereoselectivity to
give 56b (Table 4, entry 3). Deprotection of the MOM group was
readily achieved in 81% yield utilizing the Fukuyama procedure
(Scheme 16).36

9490
H. Miyamoto et al. / Tetrahedron 69 (2013) 9481e9493
Table 4
Table 5
Synthesis of spirocyclic oxindolesa
Accelerating effect of ethereal solventsa
Entry
Substrate
Product
Conditions
Yieldb
(% dec)
1
100 ꢁC, 1 h 57 (>95)
150 ꢁC, 24 h
Entry
Solvent
Time
Yield [%]b
25
56b
59
2
3
100 ꢁC, 1 h 92 (>95)
1
2
3
DME
Diglyme
Triyglyme
45 h
2 h
1 h
4
0
75
79
82
4
150 ꢁC, 0.5 h
Trace
0
Trace
a
Reaction conditions: substrate (0.5 mmol), CuCl (10 mol %), 2-aminopyridine
(10 mol %), solvent (0.05 M), NaOMe/MeOH (25 wt %; 2.0 equiv), Ar, sealed tube.
Diastereomeric excess was determined by 1H NMR spectroscopic analysis.
100 ꢁC, 1 h 89 (>95)
150 ꢁC, 0.5 h
b
Isolated yield.
100 ꢁC, 0.5 h 83d (>95)
150 ꢁC, 0.5 h
IUC are not clear at present, however, we speculate that higher
polarity and an increase in oxygen lone pairs from the diglyme or
triglyme prompt the IUC reaction.32,38
A one-pot IUC/Claisen rearrangement of chiral non-racemic
precursors was also examined (Table 6). A sequential reaction of
the secondary alcohol (R)-37a (>99% ee) was carried out under the
same conditions as for the racemic alcohol. Contrary to expecta-
tions, the desired spirocyclic oxindole (S)-56a was isolated in 74%
yield with a decrease in the enantiomeric excess, regardless of the
4
100 ꢁC, 0.5 h 71
150 ꢁC, 4 h
120 ꢁC, 6 h 72d
5
100 ꢁC, 1 h 87
150 ꢁC, 6 h
Table 6
Synthesis of chiral non-racemic spirocyclic oxindolesa
6
100 ꢁC, 4 h 76e
120 ꢁC, 13 h
150 ꢁC, 3 h
a
Reaction conditions: substrate (0.50 mmol in entries 1e5, 0.27 mmol in entry 6),
CuCl (10 mol %), 2-aminopyridine (10 mol %), DME (0.05 M), NaOMe/MeOH
(25 wt %; 2.0 equiv), Ar, sealed tube, Reaction time and temperature were not op-
timized for each substrate.
Entry Substrate
Methodb Conditions
Yield [%]c % eed Product
100 ꢁC, 1 h 74
86
(S)-56a
b
1
(R)-37a (>99% ee)
A
Yield of isolated product.
150 ꢁC, 4 h
c
Determined by 1H NMR spectroscopic analysis.
2
3
B
A
120 ꢁC, 10 h 73
100 ꢁC, 1 h 83
150 ꢁC, 5 h
120 ꢁC, 7 h 84
120 ꢁC, 5 h 85
88
90
(S)-56a
(S)-57
d
Reaction was performed in diglyme as a solvent in an open vessel.
e
(R)-37b (>99% ee)
37c was recovered in 10% yield.
4
5
B
B
91
97
(S)-57
(S)-60
(R)-42 (97% ee)
a
Reaction scale: substrate (0.50 mmol in entries 1,2. 0.3 mmol in entries 3e5).
Method A: solvent¼DME (0.05 M), sealed tube. Method B: solvent¼diglyme
b
(0.05 M), open vessel.
c
Yield of isolated product.
Enantiomeric excess was determined by chiral HPLC analysis.
d
Scheme 16. Removal of MOM group of spirocyclic oxindole 55b.
reaction conditions (Table 6, entries 1 and 2). In addition, reactions
using 6-bromoindole (R)-37b (>99% ee) resulted in the formation
of (S)-57 at the same level of enantiomeric excess (Table 6, entries 3
and 4). In sharp contrast, the sequential reaction gave the corre-
sponding oxindole (S)-60 with perfect asymmetric transmission
(97% ee) when the tertiary alcohol (R)-42 (97% ee) was used (Table
6, entry 5). The details of the racemization of spirocyclic oxindoles
in the secondary alcohol system are obscure at this time. However,
the racemization would be expected to take place during the IUC
process or after the formation of the pyranoindole intermediate39
entry 1). In contrast, the use of diglyme as a solvent dramatically
improved the reaction rate, and the desired 56b was obtained as
a single isomer in 79% yield, without 59 (Table 5, entry 2). Fur-
thermore, surprisingly, the use of triglyme was found to be ex-
tremely effective and led to a substantially higher reaction rate than
diglyme (Table 5, entry 3). Since the use of triglyme as a solvent for
the Ullmann reaction is not common, its accelerating effect is
noteworthy. The factors responsible for the increase in rate of the

H. Miyamoto et al. / Tetrahedron 69 (2013) 9481e9493
9491
based on the control experiment shown in Scheme 17; no race-
mization was observed when (S)-56a was subjected to the IUC
conditions. Racemization mechanism in the IUC process could be
rationalized by the thermal decomposition of copper(I) alkoxide
intermediate leading to enone and copper(I) hydride and sub-
sequent reduction of the resulting enone by copper(I) hydride.40
Scheme 17. Control experiment for racemization of the spirocyclic oxindole. aE-
nantiomeric excess was determined by chiral HPLC analysis.
2.4. Total synthesis of (L)-debromoflustramine B
Flustramines are the simplest members of hexahydropyrrolo
[2,3-b]indole alkaloids, which display significant biological activ-
ity.41 (ꢀ)-Debromoflustramine B (1) and the related (ꢀ)-flustr-
amine B were first isolated from the marine byrozoan Flustra
foliacea.9c,d (ꢀ)-Flustramine B has been found to exhibit muscle
relaxant activity, affecting both skeletal and smooth muscles.42 The
hexahydropyrrolo[2,3-b]indole having a quaternary carbon preny-
lated at C-3a is the defining structural feature of these alkaloids and
therefore many efficient methods have been developed for their
synthesis.5h,43
To demonstrate the potential usefulness of our methodology for
natural product synthesis, the total synthesis of (ꢀ)-debromo-
flustramine B (1) was performed based on the previously reported
our strategy using racemic 2-iodoindole 42 with a slight mod-
ification.12a For preparing (S)-60, the IUC and Claisen rearrange-
ment procedure of chiral non-racemic iodoindole (R)-42 (97% ee),
prepared from (R)-(ꢀ)-linalool shown in Scheme 10, was readily
carried out on a multigram scale (Scheme 18). Oxidative cleavage of
the carbonecarbon double bond of (S)-60 with OsO4eNaIO4 gave
aldehyde 61, which was subsequently converted to exo-methylene
62 via NaClO2 oxidation followed by a Wittig olefination of the
resulting keto-carboxylic acid with the ylide generated from
methyltriphenylphosphonium bromide and n-BuLi in 73% yield
from (S)-60. Exposure of 62 to concentrated H2SO4-dioxane in the
presence of MgSO4 resulted in isomerization to an internal olefin,
providing the requisite carboxylic acid as a 20:1 mixture with 62.
The carboxylic acid was then transformed to the amide 63 via the
mixed anhydride method using ethyl chloroformate and MeNH2 in
90% yield from 62.43c The overall yield of 63 was improved when
the reaction temperature of the amidation of mixed anhydride was
elevated to rt (cf. 65% overall yield from 62 at ꢀ60 ꢁC). Minor exo-
isomer derived from 62 was separated at this stage by silica gel
chromatography. Amide 63 containing a prenyl side chain was
transformed to the hexahydropyrrolo[2,3-b]indole derivative 65
using Kawasaki’s protocol43a involving reductive cyclization of 63
with an excess of AlH3$NEtMe2 at ꢀ15 ꢁC to produce 2-
oxopyrroloindoline 64 in 81% yield, followed by an additional
alane reduction at room temperature to afford 65 in 86% yield.44
Finally, reductive debenzylation of 65 with sodium in liquid am-
monia and quenching of the resulting amide anion with prenyl
bromide completed the total synthesis of (ꢀ)-debromoflustramine
Scheme 18. Total synthesis of (ꢀ)-debromoflustramine B (1).
3. Conclusions
We have developed a convenient and efficient method for the
preparation of spirocyclic oxindoles, with vicinal stereogenic cen-
ters, from the corresponding 2-haloindoles via a one-pot IUC and
Claisen rearrangement. IUC is a simple and low cost method for the
preparation of the rearrangement precursors, alkenyl pyr-
anoindoles. The Claisen rearrangement of the pyranoindoles pro-
ceeds smoothly to give the desired 3-spiro-2-oxindoles in good
yield and with high diastereoselectivity. In addition, a remarkable
acceleration of the IUC/Claisen sequence using diglyme or triglyme
was observed. Since the Claisen rearrangement is stereospecific in
the tertiary alcohol system, this methodology would also be ap-
plicable to the enantioselective synthesis of spirocyclic oxindoles.
The application of this reaction to the asymmetric total synthesis of
a hexahydropyrrolo[2,3-b]indole alkaloid has been demonstrated.
4. Experimental section
4.1. Synthesis of alkenyl pyranoindole 49a by intramolecular
Ullmann coupling (Scheme 13)
A screw cap test tube (PyrexÒ, 61 mL) was charged with CuCl
(5 mg, 0.05 mmol), 2-aminopyridine (5 mg, 0.05 mmol) and a small
amount of DME. The tube was evacuated and backfilled with argon.
The substrate 20a (0.50 mmol) in DME (10 mL) was added. After
bubbling with argon for 3 min, NaOMe solution in MeOH (25 wt %,
0.23 mL, 1.00 mmol) was added. The test tube was sealed with
screw cap and stirred vigorously at 100 ꢁC for 10 min until all 20a
B (1), [
a
]
D
25 ꢀ95.5 (c 1.29, CHCl3) (lit.9b
[
a]
20 ꢀ98.2 (c 0.02, CHCl3)), in
D
93% yield.43b The 1H and 13C NMR spectra of the synthetic
(ꢀ)-debromoflustramine B are identical to those of reported
data.43i

9492
H. Miyamoto et al. / Tetrahedron 69 (2013) 9481e9493
was consumed as judged by TLC and HPLC analysis. After cooling to
rt, the reaction mixture was quenched with satd aq NH4Cl (3 mL)
and H2O (10 mL), and extracted with AcOEt (3ꢂ20 mL). The organic
layers were combined, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash chromatography (alumina,
benzene) to afford 49a (97 mg, 91% yield) as a white solid. Mp
63e64 ꢁC; Rf 0.36 (hexane/AcOEt¼10:1); 1H NMR (400 MHz, CDCl3)
Sports, Science and Technology of Japan, NOVARTIS Foundation
(Japan) for the Promotion of Science, and Chugai Pharmaceutical
Co., Ltd. (A.N.). We thank Prof. Dr. Takao Ikariya and Prof. Dr. Shigeki
Kuwata (Tokyo institute of technology) for the X-ray analysis. We
also thank Takasago International Corporation for a generous gift of
(R)-(ꢀ)-linalool.
Supplementary data
d
7.35e7.32 (m, 1H), 7.18e7.13 (m, 1H), 7.09e7.04 (m, 2H), 6.05
(dddd, J¼17.3, 10.5, 5.6, 1.4 Hz, 1H), 5.41 (dd, J¼17.3, 1.4 Hz, 1H), 5.27
(dd, J¼10.5, 1.4 Hz, 1H), 4.76e4.72 (m, 1H), 3.56 (s, 3H), 2.75e2.69
(m, 2H), 2.18e2.10 (m, 1H), 1.98e1.86 (m, 1H); 13C NMR (100 MHz,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.08.057.
CDCl3)
d 148.5, 136.7, 132.1, 126.4, 119.2, 118.7, 116.5, 116.2, 108.0,
References and notes
85.9, 79.3, 28.4, 27.3, 17.3; IR (KBr, cmꢀ1) 2924, 1627, 1580, 1473,
1323, 739; HRMS (EI) calcd for C14H15NO: 213.1153, found:
213.1153; HPLC Analytical Condition: L-column ODS (4.6ꢂ250 mm),
1. (a) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org. Biomol. Chem. 2012, 10, 5165;
(b) Dalpozzo, R.; Bartolib, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247; (c)
Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381; (d) Trost, B. M.;
Brennan, M. K. Synthesis 2009, 3003; (e) Marti, C.; Carreira, E. M. Eur. J. Org.
Chem. 2003, 2209; (f) Toyota, M.; Ihara, M. Nat. Prod. Rep. 1998, 327; (g) Dounay,
A. B.; Hatanaka, K.; Kodanko, J. J.; Oestreich, M.; Overman, L. E.; Pfeifer, L. A.;
Weiss, M. M. J. Am. Chem. Soc. 2003, 125, 6261 and references therein.
2. For examples, see: (a) Huang, A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc.
2004, 126, 14043; (b) Bagul, T. D.; Lakshmaiah, G.; Kawabata, T.; Fuji, K. Org. Lett.
2002, 4, 249.
CH3CN/0.02
M
AcONH4 water¼80/20, flow rate¼1.0 mL/min,
Detection¼UV at 220 nm, Temperature¼40 ꢁC.
4.2. Synthesis of spirocyclic oxindole 50a by Claisen re-
arrangement (Scheme 13)
To a screw cap test tube (PyrexÒ, 61 mL) substrate 49a (94 mg,
0.44 mmol) in DME (10 mL) was added. The test tube was sealed
with screw cap and stirred vigorously at 150 ꢁC for 8 h until all 49a
was consumed as judged by TLC and HPLC analysis. After cooling to
rt, the reaction was quenched with H2O (10 mL) and extracted with
AcOEt (3ꢂ20 mL). The organic layers were combined, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
flash chromatography (silica gel, hexane/AcOEt¼9:1) to afford 50a
(79 mg, 84% yield) as a white solid. Mp 69e70 ꢁC; Rf 0.37 (hexane/
3. For a review, see: Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org. Chem. 2011, 6821.
4. For examples, see: (a) Voituriez, A.; Pinto, N.; Neel, M.; Retailleau, P.; Marinetti,
A. Chem.dEur. J. 2010, 16, 12541; (b) Yong, S. R.; Williams, M. C.; Pyne, S. G.;
Ung, A. T.; Skelton, B. W.; White, A. H.; Turner, P. Tetrahedron 2005, 61, 8120; (c)
Beccalli, E. M.; Clerici, F.; Gelmi, M. L. Tetrahedron 2003, 59, 4615.
5. For examples, see: (a) Cao, T.; Linton, E. C.; Deitch, J.; Berritt, S.; Kozlowski, M. C.
J. Org. Chem. 2012, 77, 11034; (b) Ignatenko, V. A.; Zhang, P.; Viswanathan, R.
Tetrahedron Lett. 2011, 52, 1269; (c) Linton, E. C.; Kozlowski, M. C. J. Am. Chem.
Soc. 2008, 130, 16162; (d) Duguet, N.; Slawin, A. M. Z.; Smith, A. D. Org. Lett.
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Sekiguchi, H.; Sakaguchi, K.; Sakamoto, M. J. Org. Chem. 2005, 70, 2957; (f) Mao,
Z.; Baldwin, S. W. Org. Lett. 2004, 6, 2425; (g) Booker-Milburn, K. I.; Fedouloff,
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2000, 41, 4657; (h) Somei, M.; Yamada, F.; Izumi, T.; Nakajou, M. Heterocycles
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6. For reviews, see: (a) Nakazaki, A.; Kobayashi, S. Synlett 2012, 1427; (b) Nakazaki,
A.; Kobayashi, S. J. Synth. Org. Chem. Jpn 2008, 66, 124; (c) Tamura, K.; Nakazaki,
A.; Kobayashi, S. Synlett 2009, 2449; (d) Nakazaki, A.; Kobayashi, S. Synlett
2009, 1605; (e) Nakazaki, A.; Era, T.; Kobayashi, S. Chem. Lett. 2008, 37, 770; (f)
Nakazaki, A.; Era, T.; Kobayashi, S. Chem. Pharm. Bull. 2007, 55, 1606; (g) Na-
kazaki, A.; Kobayashi, S. Chem. Lett. 2007, 36, 42; (h) Nakazaki, A.; Era, T.; Nu-
mada, Y.; Kobayashi, S. Tetrahedron 2006, 62, 6264; (i) Nakazaki, A.; Miyamoto,
H.; Henmi, K.; Kobayashi, S. Synlett 2005, 1417.
AcOEt¼2:1); 1H NMR (400 MHz, CDCl3)
7.33 (dd, J¼7.6,1.0 Hz,1H),
d
7.28 (td, J¼7.6, 1.0 Hz, 1H), 7.02 (td, J¼7.6, 1.0 Hz, 1H), 6.87 (br d,
J¼7.6 Hz, 1H), 5.97e5.84 (m, 2H), 3.23 (s, 3H), 2.70e2.61 (m, 1H),
2.37e2.29 (m, 2H), 2.07 (ddd, J¼13.2, 9.5, 7.8 Hz, 1H), 1.95 (ddt,
J¼17.8, 4.9, 1.7 Hz, 1H), 1.56e1.48 (m, 1H); 13C NMR (100 MHz,
CDCl3)
d 180.6, 142.7, 134.4, 127.5, 126.6, 124.8, 123.8, 122.2, 107.8,
45.8, 31.6, 28.9, 26.2, 21.7; IR (KBr, cmꢀ1) 2912, 1703, 1610, 1470,
767; HRMS (EI) calcd for C14H15NO: 213.1153, found: 213.1153;
HPLC Analytical Condition: L-column ODS (4.6ꢂ250 mm), CH3CN/
0.02 M AcONH4 water¼80/20, flow rate¼1.0 mL/min, Detec-
tion¼UV at 220 nm, Temperature¼40 ꢁC.
7. For reviews on Claisen rearrangement, see: (a) Castro, A. M. M. Chem. Rev. 2004,
104, 2939; (b) Chai, Y.; Hong, S.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C.
Tetrahedron 2002, 58, 2905.
8. For the related example of Claisen rearrangement in 2-(allyloxy)indole systems,
the excellent results have been reported by Kawasaki’s group, see Ref. 5e.
9. For review on hexahydropyrro[2,3-b]indole, see: (a) Ruiz-Sanchis, P.; Savina, S.
4.3. One-pot synthesis of oxindoles in DME (Tables 2e4)
ꢀ
A.; Albericio, F.; Alvarez, M. Chem.dEur. J. 2011, 17, 1388 For debromoflustr-
amine B, see: (b) Holst, P. B.; Anthoni, U.; Christophersen, C.; Nielsen, P. H. J. Nat.
The preparation of oxindole 50a is representative. A screw cap test
tube (PyrexÒ, 61 mL) was charged with CuCl (5 mg, 0.05 mmol), 2-
aminopyridine (5 mg, 0.05 mmol) and a small amount of DME. The
tube was evacuated and backfilled with argon. The substrate 20a
(0.50 mmol) in DME (10 mL) wasadded. After bubbling with argon for
3 min, NaOMe solution in MeOH (25 wt %, 0.23 mL, 1.00 mmol) was
added. The test tube was sealed with screw cap and stirred vigorously
at 100 ꢁC for 10 min until all 20a was consumed as judged by TLC and
HPLC analysis, and then at 150 ꢁC for 12 h until the resultant 49a was
consumed. After cooling to rt, the reactionwas quenched with satd aq
NH4Cl (3 mL) and H2O (10 mL), extracted with AcOEt (3ꢂ20 mL). The
organic layers were combined, dried over MgSO4, and concentrated
invacuo. The residuewaspurified by flash chromatography (silica gel,
hexane/AcOEt¼10:1) to afford 50a (89 mg, 84% yield) as a white solid.
HPLC Analytical Condition: L-column ODS (4.6ꢂ250 mm), CH3CN/
0.02 M AcONH4 water¼80/20, flow rate¼1.0 mL/min, Detection¼UV
at 220 nm, Temperature¼40 ꢁC.
ꢀ
Prod. 1994, 57, 997 For flustramine B, see; (c) Carle, J. S.; Christophersen, C. J. Am.
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Chem. Soc. 1979, 101, 4012; (d) Carle, J. S.; Christophersen, C. J. Org. Chem. 1980,
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Kobayashi, S. Heterocycles 2009, 79, 805.
13. (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689; (b) Larock, R. C.;
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Acknowledgements
This work was supported by a Grant-Aid for Young Scientists (B)
(KAKENHI 19790026) from the Ministry of Education, Culture,

H. Miyamoto et al. / Tetrahedron 69 (2013) 9481e9493
9493
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39. Enantiomeric excess of pyranoindole was not checked because of its unstable
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~
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yield).