Copper-catalyzed radical cyclization to access 3-hydroxypyrroloindoline: Biomimetic synthesis of protubonine A

Article abstract of DOI:10.1021/ol501287x

An unprecedented copper-catalyzed intramolecular radical cyclization was developed for the synthesis of 3-hydroxypyrroloindoline skeletons in excellent yields. The 3-hydroxyl group was introduced by trapping the radical intermediate with molecular oxygen or TEMPO. This process represents a unique radical oxidation pathway for tryptamine/tryptophan derivatives and allows a rapid biomimetic synthesis of natural product protubonine A.

Full text of DOI:10.1021/ol501287x

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Radical Cyclization To Access
3‑Hydroxypyrroloindoline: Biomimetic Synthesis of Protubonine A
Xu Deng,†,§ Kangjiang Liang,†,‡,§ Xiaogang Tong,†,‡ Ming Ding,†,‡ Dashan Li,†,‡ and Chengfeng Xia*,†
†State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of
Sciences, Kunming 650201, Yunnan, China
‡University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: An unprecedented copper-catalyzed intramolecular
radical cyclization was developed for the synthesis of 3-
hydroxypyrroloindoline skeletons in excellent yields. The 3-hydroxyl
group was introduced by trapping the radical intermediate with
molecular oxygen or TEMPO. This process represents a unique
radical oxidation pathway for tryptamine/tryptophan derivatives and
allows a rapid biomimetic synthesis of natural product protubonine
A.
ince first described in the late 1930s, the 3-hydroxypyrro-
loindoline alkaloids, as a large family of natural products,
have received substantial attention among the scientific
community for their diverse molecular architecture and wide
range of biological profiles. Gypsetin (Figure 1), isolated from
development of new drugs,5 biological probes,6 and chiral
catalysts.7
S
As an important precursor for these natural alkaloids, the
development of C-3-functionalization/cyclization reaction of
tryptamine or tryptophan derivatives has attracted extensive
interest from synthetic chemists. Some remarkable efforts have
been directed to the synthesis of 3-hydroxypyrroloindoline,
including Nishiyama’s and our group’s previously reported
iodine(III)-mediated intramolecular annulation,8 selenocycliza-
tion/oxidative deselenation sequence,9 Danishefsky’s DMDO
oxidation,10 and photosensitized oxygenation.11 All of these
methods included a three-member onium salt as a key
intermediate followed by intramolecular amide nucleophilic
ring-opening reaction. However, most of these strategies are
carried out in multistep procedures, with extensive use of
protecting groups or with poor yield and unwanted side
reactions. At the same time, enzymatic oxidation of indole is
well-recognized as a key step in indole alkaloid biosynthesis,12
rendering oxidative synthetic approaches inherently biomime-
tic.2b,13 As part of our ongoing interest in developing new
strategies for the synthesis of pyrroloindoline alkaloids, we
herein report the first radical-mediated annulation/hydroxyla-
tion to access 3-hydoxypyrroloindoline.
Figure 1. Representative 3-hydroxypyrroloindoline natural products.
fungal source Nannizzia gypsea var. incurvata IFO9228,1 has
evoked interest as the competitive inhibitor of acyl-CoA:ch-
olesterol acyltransferase (ACAT) with a Ki value of 5.5 μM.2
NW-G01 exhibited strong antibacterial activity against Gram-
positive bacteria Bacillus subtilis, Bacillus cereus, Staphylococcus
aureus, and methicillin-resistant S. aureus. Their MIC values
were 3.90, 3.90, 7.81, and 7.81 μg/mL, respectively.3 Recently,
voatinggine, which is characterized by an unprecedented
pentacyclic indole skeleton, was isolated from a Malayan
Tabernaemontana species.4 Moreover, unnatural 3-hydroxypyr-
roloindoline derivatives are important building blocks for the
Our initial investigation commenced with the copper-
catalyzed aerobic reaction of readily available benzenesulfon-
yl-protected tryptamine 1. By treating tryptamine 1 with a
catalytic amount of cupric chloride in the presence of 3 equiv of
DBU under 1 atm of oxygen in CH3CN, the 3-hydroxypyrro-
loindoline 2 was delivered in moderate yield (Table 1, entry 1).
Cupric bromide and cupric acetate also could catalyze this
annulation/hydroxylation, albeit in lower yield. The relative
Received: May 6, 2014
© XXXX American Chemical Society
A
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Letter
TEMPO, the reaction went smoothly, giving the desired
product 4 in excellent yield (Scheme 1). The tetramethylpiper-
idine (TMP) part was easily removed by reduction with zinc in
acetic acid to afford the 3-hydroxypyrroloindoline 5.
Table 1. Screening of Conditions for the Metal-Catalyzed
Aerobic Radical Cyclization/Hydroxylation of Tryptamine
Derivatives
Scheme 1. Optimized Cyclization Conditions with TEMPO
as a Radical Scavenger
a
entry
catalyst
CuCl2
equiv
convn (%)
yield (%)
1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
100
100
68
40
26
0
2
CuBr2
b
3
Cu(OAc)2
FeCl3
90
4
0
0
Given the reaction intermediate could be trapped by both
molecular oxygen and TEMPO, a radical mechanism was
proposed. To confirm whether the radical annulation originates
from N1 of the indole moiety or Nb of the amide group, two
analogues were prepared by masking the nitrogen of the indole
moiety with a methyl or sulfonyl group (Scheme 2). When
these two substrates were subjected to cupric chloride and
TEMPO conditions, no reaction occurred, indicating that the
radical originates on the N1 of the indole moiety.
5
K3Fe(CN)6
NiBr2
0
b
6
62
b
50
82
91
72
61
74
7
Mn(OAc)2
CoCl2
100
8
100
b
9
Co(ClO4)2·6H2O
Co(BF4)2·6H2O
CoC2O4·2H2O
85
b
10
11
73
b
80
a
b
Isolated yields by chromatography. Incomplete conversion of
starting materials.
Scheme 2. Masking N1 of the Indole Moiety with Methyl or
Sulfonyl Group Inhibited the Cyclization
stereochemistry of 3-hydroxypyrroloindoline 2 was confirmed
by X-ray crystallography, indicating that the newly generated
pyrrolo ring fuses with the indoline moiety in a cis manner. To
improve the reaction yield, we then surveyed a series of one-
electron oxidants as the catalyst with oxygen as the co-oxidant
and DBU as the base. As indicated in Table 1, iron catalysts,
such as ferric chloride and potassium hexacyanoferrate, failed to
give any desired product, whereas manganese acetate catalyzed
the annulation/hydroxylation in much better yield, and nickel
bromide also promoted the reaction with only partial
conversion. To our delight, we observed an excellent yield of
annulation/hydroxylation product when cobalt chloride was
utilized as a catalyst (Table 1, entry 8). Comparison of a series
of cobalt salt, such as cobalt perchlorate and cobalt oxalate,
revealed that cobalt chloride exerts significant effects on the
conversion and the yield (Table 1, entries 9−11).
Encouraged by the cobalt chloride catalyzed annulation/
hydroxylation, we extended the scope of the reaction to other
substrates by changing the protecting groups of tryptamine. It is
surprising that when acetyl tryptamine 3 was served as a
reactant, very few products were detected after 48 h. Screening
the solvents (THF, DMSO, and 1,4-dioxane) or varying the
base (Et3N, DABCO, NaH, and t-BuOK) did not make any
improvements. Although other catalysts, such as cupric
chloride, could catalyze acetyl tryptamine 3 to afford the
desired 3-hydroxypyrroloindoline product 5, only around 30%
yield was achieved. We proposed that the lifetime of the radical
intermediate was very short and the low concentration of
oxygen in the solvent could not efficiently trap the radical
intermediate. To circumvent this problem, 2,2,6,6-tetramethyl-
piperidine-1-oxyl (TEMPO) was used as the radical trapping
reagent and the oxidant to recycle the catalyst.14 However, few
products were observed when cobalt chloride was used as
catalyst and TEMPO as oxidant. To our delight, when the
catalyst was switched to cupric chloride in the presence of
On the basis of the above results, a plausible mechanism was
outlined as in Scheme 3. Cupric salt oxidizes the indole N1 to
generate the radical in the presence of base, which transfers to
C3 by forming an imine. Subsequently, the imine may be
involved in two potential pathways. In pathway A, the imine
undergoes a 5-exo-trig cyclization process first and the C3
Scheme 3. Proposed Copper-Catalyzed Radical Cyclization
Mechanism
B
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radical is quenched by TEMPO to give the annulation product.
Alternatively, the imine radical may be trapped by TEMPO first
and the cyclization occurs afterward as shown in pathway B. We
speculate that pathway A is favored for sulfonamide 1, while
pathway B is favored for acetyl protected tryptamine 3, as the
former is more nucleophilic than the latter.
Scheme 5. Controlling the Cyclization Stereochemistry by
Changing the Nb-Protecting Groups
We then examined a number of different tryptamine
derivatives for the oxidative annulation reaction under the
optimized reaction conditions (Scheme 4). It was found that
Scheme 4. Scope of Copper-Catalyzed Oxidative Cyclization
proposed that the reactions involve in pathway A as depicted in
Scheme 3, during which the steric hindrance and the stability of
the radical intermediate are the dominate controlling factors for
the exo selectivity.15 However, when Nb was protected by a
benzenesulfonyl, methylsulfonyl, or benzoyl group, the reaction
furnished the anti-cis products 20, 22 and 23, whose absolute
stereochemistry was unambiguously assigned by NMR with the
upfield shift of the ester methyl group15 and also by the X-ray
crystallography of the reductive derivative 24. We reasoned that
the lower pKa value and higher nucleophilicity of these amide
are the main driving forces behind the endo selectivity.15,16
Unlike most of the previously reported methods that provide
only the anti-cis products,15,17 both anti-cis and syn-cis products
could be simply assembled by changing the Nb protecting
groups.
To highlight the utility and efficiency of this direct 3-
hydroxylation method for the synthesis of pyrroloindoline
natural products, we sought to complete the total synthesis of
protubonine A. Protubonine A was isolated from the cultured
marine-derived fungus Aspergillus sp. SF-5044.18 Its C-11
absolute configuration was originally assigned as (R) config-
uration. Very recently, de Lera revised this configuration by
total synthesis of two C-11 epimers. They found that the
synthetic (11S) epimer’s spectroscopic data were in full
agreement with those reported for the natural product.19
Tryptophan-derived diketopiperazines 25 was prepared on a
gram-scale from L-tryptophan methyl ester hydrochloride and
N-(tert-butoxycarbonyl)-L-leucine according to literature meth-
ods (Scheme 6).20 When diketopiperazines 25 was subjected to
the copper-catalyzed annulation under aerobic conditions,
product 26 was obtained in excellent regioselectivity with the
five-membered pyrroloindoline but not the six-membered
pyridoindole structure. However, no diastereoselectivity of
this annulation was observed. When TEMPO was employed as
the radical scavenger instead, the desired product 27 was
generated in excellent yield and with acceptable diastereose-
lectivity (dr value 4:1). These two epimers could be easily
separated by chromatography. Clearly, the steric hindrance of
the radical trapping reagents was important for the observed
diastereoselectivity. After acetylation of the N1 position and
the aryl substitution pattern exerted a significant effect on the
yield. Electron-withdrawing substituents could be tolerated,
providing the 3-hydroxypyrroloindoline in good to excellent
yield (8−10). Electron-donating substituents (11) gave us
moderate yield. This may be due to the low electrophilicity of
the imine intermediate. Variation at the amide part could be
tolerated (12, 13, and 15). In addition to the amide and
sulfonamide nucleophiles, it is also noteworthy that alcohol
could also serve as the nucleophile for cyclization by using
DBU instead of t-BuOK as a base (14), which further validated
the proposal that the radical originates from N1 of the indole
moiety. Moreover, tryptophan derivatives were also suitable
substrates, providing 3-functionized products in moderate to
good yield (16−18). Thus, a wide range of substrates are
tolerated in this copper-catalyzed oxidative annulation reaction.
In an effort to investigate the diastereoselectivity of the
annulation/hydroxylation reaction, a series of trptophan
derivatives with different protecting groups were subjected to
the standard reaction condition. All of these substrates
underwent highly diastereoselective cyclization. Interestingly,
when Nb was protected by an acetyl group or methyl formate
group, the reaction provided syn-cis products 19 and 20, whose
stereochemistry were assigned by diagnostic chemical shift of
the ester methyl group because of the absence of shielding by
the aromatic ring current (Scheme 5).15 In this setting, we
C
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Scheme 6. Total Synthesis of Protubonine A with Copper-
Catalyzed Cyclization
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reductive removal of the TMP, protubonine A was obtained in
good yield. The spectroscopic data of the synthetic one was in
full agreement with those reported for the natural product.18,19
In summary, we have developed a novel and efficient
synthetic method for the synthesis of 3-hydroxy pyrroloindoline
through a copper-catalyzed radical annulation process from
readily available tryptamine derivatives. Importantly, the
reported conditions were suitable for a wide range of
tryptamine/tryptophan derivatives and will be applicable for
the preparation of 3-hydroxypyrroloindoline natural products
and drugs. Both the syn-cis and anti-cis 3-hydroxypyrroloindo-
line skeletons exist in nature. The previously reported methods
could not furnish both of these two skeletons. This method can
furnish both of the isomers simply by changing the Nb
protecting groups. The efficiency and utility of the method was
further demonstrated by the total synthesis of indole alkaloid
protubonine A.
ASSOCIATED CONTENT
* Supporting Information
■
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11953−11963. (b) Crich, D.; Huang, X. J. Org. Chem. 1999, 64, 7218−
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41−63.
S
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) Lee, S. U.; Asami, Y.; Lee, D.; Jang, J.-H.; Ahn, J. S.; Oh, H. J.
Nat. Prod. 2011, 74, 1284−1287.
AUTHOR INFORMATION
Corresponding Author
■
(19) Lorenzo, P.; Alvarez, R.; de Lera, A. R. Eur. J. Org. Chem. 2014,
12, 2557−2564.
*E-mail: xiachengfeng@mail.kib.ac.cn.
Author Contributions
§These authors contributed equally to this work.
Notes
(20) Kieffer, M. E.; Chuang, K. V.; Reisman, S. E. J. Am. Chem. Soc.
2013, 135, 5557−5560.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Natural Science
Foundation of China (21272242 and 21302193), Yunnan
High-End Technology Professionals Introduction Program
(2010CI117), and National Basic Research Program of China
(2011CB915500).
D
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