Dearomatization of tryptophols via a vanadium-catalyzed asymmetric epoxidation and ring-opening cascade

Article abstract of DOI:10.1039/c3cc47921h

An enantioselective epoxidation of tryptophols followed by an intramolecular epoxide opening reaction was realized by chiral vanadium catalysts derived from C₂ symmetric bis-hydroxamic acid (BHA) ligands. 3a-Hydroxyfuroindoline derivatives with up to 89% yield and 90% ee were obtained under mild reaction conditions.

Full text of DOI:10.1039/c3cc47921h

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Dearomatization of tryptophols via a
vanadium-catalyzed asymmetric epoxidation
and ring-opening cascade†
Long Han,ab Chuan Liu,b Wei Zhang,*b Xiao-Xin Shia and Shu-Li You*ab
Cite this: Chem. Commun., 2014,
50, 1231
Received 15th October 2013,
Accepted 24th November 2013
DOI: 10.1039/c3cc47921h
www.rsc.org/chemcomm
An enantioselective epoxidation of tryptophols followed by an intra-
molecular epoxide opening reaction was realized by chiral vanadium
catalysts derived from C2 symmetric bis-hydroxamic acid (BHA)
ligands. 3a-Hydroxyfuroindoline derivatives with up to 89% yield
and 90% ee were obtained under mild reaction conditions.
As very useful tools in the total synthesis of natural products,
dearomatization reactions have recently undergone their renais-
sance with the intention of developing new dearomative protocols
and efficient stereoselective control of the processes.1 In this area,
oxidative dearomatization approaches are undoubtedly of great
potential since large amounts of aromatic rings are electron-rich
chemical entities, which are reactive under oxidative conditions.2
In fact, oxidative dearomatization reactions have a long history in
the total synthesis of natural products, and recent studies have
contributed many valuable methodologies in an enantioselective
manner.3 However, the current developments in asymmetric oxidative
Fig. 1 Representative natural products with 3a-hydroxyfuroindoline scaffold.
Scheme 1 Enantioselective synthesis of 3a-hydroxyfuroindolines via the
Sharpless asymmetric epoxidation reaction.
dearomatization reactions should be pointed out: (1) the substrates cyclization to build this valuable scaffold (Scheme 1).5–8 How-
are focused on phenols, and the vast majority of other aromatic rings ever, due to the inherent limitation of the Sharpless asymmetric
have been relatively less explored; (2) the existing strategies of epoxidation reaction, a stoichiometric amount of the chiral Ti
enantioselective control mainly rely on chiral oxidants or complex was required, and the experimental operation was very
stepped reactions combining the oxidative dearomatization strict in order to achieve the best result. In contrast, several
and the subsequent asymmetric desymmetrization;4 (3) many asymmetric catalytic systems have been demonstrated to be
well-established enantioselective oxidative conditions have not efficient for the epoxidation of electron-rich olefins.9 Among
been fully taken into consideration for application to asymmetric them, the chiral vanadium complexes derived from the C2
dearomatization reactions, and thus relative utilization in the symmetric bis-hydroxamic acid (BHA) ligands designed by
total synthesis is rare.
Yamamoto and co-workers proved to be ideal catalysts for the
3a-Hydroxyfuroindoline represents a preliminary structure enantioselective epoxidation of allylic as well as homoallylic
in numerous natural products (Fig. 1).5–7 In 2000, Omura and alcohols.10 Given our continuous research interest in asymmetric
¯
co-workers reported a pioneering study using the Sharpless asym- dearomatization reactions to construct polycyclic compounds with
metric epoxidation reaction and a subsequent intramolecular multiple chiral centers,11 we envisaged that an enantioselective
catalytic epoxidation of tryptophols followed by an epoxide opening
a School of Pharmacy, East China University of Science and Technology,
could yield the 3a-hydroxyfuroindoline derivatives conveniently.
Herein, we report such a catalytically enantioselective cascade
oxidative dearomatization reaction.
Firstly, tryptophol (1a) was selected as the model substrate
to test the feasibility of our hypothesis. To our great delight, the
initial testing with the catalyst derived from VO(acac)2 and BHA
130 Mei-Long Road, Shanghai 200237, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
China. E-mail: zhangwei@sioc.ac.cn, slyou@sioc.ac.cn; Fax: +86 21-54925087
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc47921h
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Table 1 Optimization of the reaction conditions – protecting groupsa
Table 2 Optimization of the reaction conditions – chiral ligands and
temperaturea
Entry
1, R
Time (h)
Yield of 2b (%)
eec (%)
1
2
3
4
5
6
1a, H
1b, Me
1c, Bn
1d, 1-naphthyl
1e, 9-anthryl
1f, Boc
14
12
12
18
18
18
2a 63
2b 66
2c 62
2d 79
2e 56
2f trace
61
43
82
80
10
N.A.
a
Reaction conditions: 0.5 mmol 1, 2.0 mol% VO(acac)2, 2.4 mol%
ligand 3a and 0.75 mmol tBuOOH (70 wt% aqueous solution) in toluene
(1.0 mL) at 0 1C. Isolated yield. Determined by HPLC analysis
b
c
Entry
Ligand
T (1C)
Time (h)
Yield of 2cb (%)
eec (%)
(Chiralpak AD-H).
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3a
3a
0
0
0
0
0
12
24
24
24
24
24
36
62
22
26
50
43
70
49
82
62
66
60
67
87
87
ligand 3a provided the desired epoxide opening product 2a in
63% yield and 61% ee (entry 1, Table 1). By comparing the sign
of the optical rotation with that of the known compound
reported in the literature, the absolute configuration of 2a
was assigned as (3aR,8aS).6b,12 Several commonly used solvents
were tested for this transformation, and toluene was found to
be the optimal one.12 Considering the possibility that the free N–H
of indoles brings negative effects to the epoxidation transforma-
tion, various protecting groups were investigated.12 As shown in
Table 1, electron-donating and bulky groups (Bn and 1-naphthyl)
on the indole N led to improved enantioselectivity (entries 3 and 4,
Table 1). However, when the 9-anthryl group was introduced, the
enantioselectivity dropped significantly, which might be due to
the fact that this extremely bulky group was not suitable for the
chiral environment provided by the vanadium complex during
the epoxidation step (entry 5, Table 1). The Boc group was also
tested, and the sluggish transformation revealed that electron-
deficient substrates were not suitable for this reaction (entry 6,
Table 1). Finally, Bn was selected as the protecting group.
Several BHA ligands with diverse chiral environments have
been examined in the cascade reaction of 1c, and ligand 3a
remained to be the optimal one in terms of the enantioselective
control (entries 1–5, Table 2). Next, with 2.0 mol% of VO(acac)2
and 2.4 mol% of ligand 3a, the effect of the reaction tempera-
ture was further investigated. Lowering the reaction tempera-
ture to À10 1C led to a prolonged reaction time but an improved
enantioselectivity (87% ee, entry 6, Table 2). However, further
decreasing the reaction temperature to À30 1C could not
improve the enantioselectivity any more (entry 7, Table 2).
With the optimal reaction conditions in hand, the scope of
the reaction was then explored. The results are summarized in
À10
À30
a
Reaction conditions: 0.5 mmol 1c, 2.0 mol% VO(acac)2, 2.4 mol%
ligand 3 and 0.75 mmol tBuOOH (70 wt% aqueous solution) in toluene
b
c
(1.0 mL) at T 1C. Isolated yield. Determined by HPLC analysis
(Chiralpak AD-H).
Scheme 2 Substrate scope.12
Scheme 2. For the N-Bn substrates with various substituents on decomposed to some extent during the reaction, and only
the phenyl moiety of indoles, a good and parallel level of reasonable yields could be obtained (43% to 70%, 2g to 2n,
enantioselectivity could be provided, irrespective of the posi- Scheme 2). Substrates with substituents at the 2-position of
tions or the electronic natures of these substituents (83% to indoles were also explored. The substrate with the 2-methyl
90% ee, 2g to 2n, Scheme 2). Due to the moderate activity of all group provided the corresponding product with only moderate
substrates during this transformation, prolonging the reaction enantioselectivity (71% yield, 47% ee, 2o, Scheme 2). However,
time was anticipated to deliver their corresponding products in the substrates with the 2-phenyl group were transformed
good yields. However, all the 3a-hydroxyfuroindoline derivatives to their corresponding products with relatively better results
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Scheme 3 Epoxidation of 1a and 1c with ligand 3f.12
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the results from those substrates without 2-substituents, the
N-protecting group was not necessary for this type of substrates
to obtain good enantioselectivity. A gram-scale reaction was
carried out for 1c, and the desired product could be obtained in
66% yield and 87% ee, which were comparable with those of
the 0.5 mmol scale reaction (entry 6, Table 2).12
Inspired by the results obtained for 2p and 2q, we envisaged
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provide good levels of enantioselectivity with an optimal chiral
ligand. To our delight, the preliminary results indicated that a very
simple BHA ligand 3f could provide similar reasonable results for
substrates 1a and 1c (Scheme 3). These results indicated that with a
suitable chiral ligand, the tryptophol derivatives with or without the
substituted group on indole N could all be suitable substrates for
this cascade reaction to deliver the 3a-hydroxyfuroindoline deriva-
tives with good enantioselectivity. It should also be mentioned that
due to the inherent stability of the chiral vanadium catalyst to
moisture and air, the reaction could be operated in air with a readily
available aqueous oxidant (70 wt% aqueous solution of
tBuOOH for the present reaction).
In summary, we have developed an enantioselective epoxidative
dearomatization of tryptophols followed by an intramolecular
epoxide opening reaction to construct the framework of enantio-
enriched 3a-hydroxyfuroindoline derivatives in moderate yields and
good levels of enantioselectivity. Further extension of the reaction
scope and the synthetic application of this methodology are
currently underway in our laboratory.
We thank the National Basic Research Program of China
(973 Program 2010CB833300) and the National Natural Science
Foundation of China (21025209, 21121062, 21272252, 21332009)
for generous financial support and Professor Hisashi Yamamoto
for helpful discussions.
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Chem. Commun., 2014, 50, 1231--1233 | 1233