Regioselective Direct C-4 Functionalization of Indole: Total Syntheses of (-)-Agroclavine and (-)-Elymoclavine

Article abstract of DOI:10.1021/acs.orglett.7b01681

An efficient rhodium-catalyzed method for direct C-H functionalization at the C4 position of unprotected indoles has been developed. The utility of this method is demonstrated by the concise total syntheses of agroclavine and elymoclavine in a divergent manner. These syntheses feature a Pd-catalyzed asymmetric allylic alkylation reaction to assemble the triyclic indole moiety, and a ring-closing metathesis reaction to form the D ring.

Full text of DOI:10.1021/acs.orglett.7b01681

Letter
pubs.acs.org/OrgLett
Regioselective Direct C‑4 Functionalization of Indole: Total Syntheses
of (−)-Agroclavine and (−)-Elymoclavine
Jianbo Lv,† Bin Wang,† Kuo Yuan, Yuan Wang, and Yanxing Jia*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road,
Beijing 100191, China
S
* Supporting Information
ABSTRACT: An efficient rhodium-catalyzed method for direct C−H
functionalization at the C4 position of unprotected indoles has been
developed. The utility of this method is demonstrated by the concise
total syntheses of agroclavine and elymoclavine in a divergent manner.
These syntheses feature a Pd-catalyzed asymmetric allylic alkylation
reaction to assemble the triyclic indole moiety, and a ring-closing
metathesis reaction to form the D ring.
he 4-substituted indole frameworks are found in a wide
variety of bioactive natural products and pharmaceuticals
(Figure 1), which include the medicinally important ergot
breakthroughs have been achieved recently in transition-metal-
catalyzed direct C−H functionalization at the C4 and C5−C7
positions of indoles.12−15 In connection with our work on the
total synthesis of 3,4-indole alkaloids,16 we have reported the first
site-selective Pd-catalyzed method for the direct olefination of
tryptophans at the 4-position (Scheme 1, eq 1).12a Shortly after
T
Scheme 1. Direct C-4 Functionalization of Indoles
Figure 1. Natural products and drug derived from 4-substituted indoles.
alkaloids (1−4),1−3 ambiguine H,4 and dragmacidin D.5 As a
result, there is continuing interest in the development of efficient
methods for the synthesis of 4-substituted indoles,6,7 and most of
them are based on heteroannulation of substituted aromatic
derivatives in a multistep scheme or utilize the expensive 4-
haloindoles as starting materials.2−7
The most desirable method undoubtedly is the direct C4
functionalization of simple indole derivatives. However, selective
functionalization of C−H bonds at C4 positions of indoles is
extremely difficult due to its inherently poor nucleophilic
reactivity and high nucleophilic reactivity of the pyrrole moiety.
Despite two successful approaches already reported, direct C4
functionalization is rarely used because of the toxic thallium
reagent and harsh reaction conditions.8,9 Transition-metal-
catalyzed C−H bond functionalization can directly construct
C−C and C−X bonds in a single step without prefunctionaliza-
tion. It is a powerful strategy in organic synthesis,10,11 and major
our work, Prabhu and co-workers described a Ru-catalyzed direct
C4-functionalization of 1-benzyl-indole-3-carboxaldehydes by
employing an aldehyde functional group as the directing group
(Scheme 1, eq 2).12b However, the nitrogen of indole was
protected in all reported methods. Until now, direct C−H
functionalization at the C4 position, even at C5−C7 positions, of
unprotected indoles has not been reported. We speculated that
unprotected indoles could be employed as the starting material
while an aldehyde is present at the C3 position as a directing
Received: June 4, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01681
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Organic Letters
Letter
group.12b,c,17 Herein, we report a method for direct C4-
functionalization of unprotected indoles, which offer a
strategically distinct approach to 4-substituted indoles in a
straightforward manner (Scheme 1, eq 3). The utility of this
method was demonstrated by the first catalytic asymmetric total
syntheses of (−)-agroclavine (1) and (−)-elymoclavine (3).
Initially, 1-H-indole-3-carboxaldehyde (5a) and n-butyl
acrylate (6a) were employed as model substrates and subjected
to Prabhu’s reaction conditions (Table 1, entry 1). The desired 4-
a
Scheme 2. Substrate Scope of 4-Substituted Indoles
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
mol %
solvent
yield (%)
1
2
3
4
5
6
7
8
9
[Ru(p-cymene)Cl2]2
[RhCp*(MeCN)3]SbF6
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
2.5 mol %
1.25 mol %
DCE
32(55)
trace
61
DCE
DCE
toluene
THF
18
51
dioxane
t-AmOH
DCE
53
55
60
DCE
45
a
Reaction conditions: 5a (0.3 mmol), 6a (1.2 mmol), AgSbF6 (4 equiv
b
of catalyst), Cu(OAc)2 (0.6 mmol), solvent (1.0 mL). Isolated yield,
based on recovered starting materials in parentheses.
olefination product 7a was obtained in 32% yield. Although the
yield of 7a was low, this result showed our proposal was correct.
Encouraged by this initial result, we first attempted to improve
the yield of 7a using [Ru(p-cymene)Cl2]2 as the catalyst.
However, even after a variety of reaction conditions (various
oxidants, solvents, and temperatures) were screened, no
improvement was obtained. We then shifted to investigate the
metal catalysts and found that they had remarkable influence on
the reaction yield (Table 1, entries 1−3). [RhCp*(MeCN)3]-
SbF6 provided 7a in a trace amount (Table 1, entry 2). Gratefully,
[RhCp*Cl2]2 delivered 7a in 61% yield (Table 1, entry 3). The
effects of solvents were further examined, and DCE gave the best
result (Table 1, entries 3−7). To our delight, we also found that
the catalytic loading could be reduced to 2.5 mol % without a
decrease of the yield (Table 1, entries 8 and 9). It is worthy to
note that the reaction must be stopped when 5a was close to
completely consumed. Otherwise, a small amount of 2,4-
diolefination product could be produced. The amount of 2,4-
diolefination product increased with the prolonging of the
reaction time.
Having optimized the reaction conditions, we next explored
the scope of the reaction with respect to the alkene coupling
partner and the indole-3-carboxaldehyde derivatives (Scheme 2).
The substrate scope was quite general. A variety of acrylates and
indole-3-carboxaldehyde derivatives could be used as reaction
partners and gave the desired products in moderate to high
yields. Particularly, 7p was obtained in a remarkable yield of 95%.
In addition, substrates with electron-rich groups on the phenyl
moiety gave the desired products in higher yield (Scheme 2, 7s
and 7t).
a
Reaction conditions: 5 (0.3 mmol), 6 (1.2 mmol), [RhCp*Cl2]2 (2.5
mol %), AgSbF6 (10 mol %), and Cu(OAc)2 (0.6 mmol) in DCE (1.0
mL) at 110 °C for 4 h.
turned our attention to the total synthesis of 3,4-substituted
indole alkaloids. Agroclavine (1)18 and elymoclavine (3)19 were
selected as the targets since 1 could be easily converted to
festuclavine, costaclavine, setoclavine, and isosetoclavine,20 and
most importantly, 3 could be easily converted to lysergic acid (4)
and drug pergolide.21 In addition, the catalytic asymmetric total
synthesis of 1 and the enantioselective synthesis of 3 have not yet
been reported. Retrosynthetically, we envisioned 1 and 3 could
be generated by late-stage manipulation of 8a and 8b,
respectively (Scheme 3). The D-ring of both 8a and 8b could
be formed via ring-closing metathesis (RCM) of 9a and 9b. The
cyclization precursors 9a and 9b could be accessed from the
common intermediate 10. The key chiral 10 could be prepared
from 11 by a Pd-catalyzed asymmetric allylic alkylation (AAA).22
In turn, 11 could be readily obtained from 7b.
Our synthesis commenced with 7b (Scheme 4). During the
preparation of 7b, we found that the reaction can be scaled up to
20 g with only 0.5 mol % of catalyst to provide the product 7b in
higher yield (68%) than that run at small scale (see Table 1). Boc
protection of the indole nitrogen gave aldehyde 12 in 85% yield.
Condensation of aldehyde 12 with nitromethane provided the
vinyl nitro compound 13. Reduction of ester with DIBAL
Having established the method for direct functionalization at
the C4 position of 1-H-indole-3-carboxaldehyde derivatives, we
B
DOI: 10.1021/acs.orglett.7b01681
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Letter
total synthesis of 1, which required only 11 steps from
commercially available 5a. Since agroclavine has already been
converted to festuclavine, costaclavine, seto-clavine, and
isosetoclavine, formal synthesis of these alkaloids was also
achieved.20
Scheme 3. Retrosynthetic Analysis for (−)-Agroclavine and
(−)-Elymoclavine
Having successfully completed the total synthesis of 3 from
intermediate 7b, we then conducted the transformation of 10
into 3 following the same sequence as described for 1 (Scheme
5). Reduction of nitro 10 followed by alkylation of amine with
Scheme 5. Synthesis of (−)-Elymoclavine
Scheme 4. Synthesis of (−)-Agroclavine
allylic bromide 16 and protection of the resulting secondary
amine with ClCO2Me gave diene 9b. RCM of 9b followed by
reduction with LiAlH4 gave 17. Finally, removal of the TBS
group with PPTS gave (−)-elymoclavine (3).19
In summary, we have developed a highly efficient method for
the synthesis of 4-substituted indole via a rhodium-catalyzed
direct functionalization of a wide range of unprotected indoles at
the C4 position. This protocol featured mild reaction conditions,
a low catalyst loading, and compatibility with diverse functional
groups and provided a straightforward strategy for the
preparation of 4-substituted indole derivatives. The utility of
this method was further demonstrated by the first asymmetric
total syntheses of (−)-agroclavine and (−)-elymoclavine. The
total syntheses of agroclavine and elymoclavine were achieved in
a divergent manner. We expect that this protocol will find broad
use in chemical synthesis.
followed by reduction of olefin with NaBH4 afforded allylic
alcohol 14. Acetylation of alcohol furnished the allylic acetate 11.
The intramolecular Pd-catalyzed AAA of the nitroacetate 11
employing (S)-(−)-BINAP as the ligand gave 10 and its C5
diastereoisomer in 73% yield (dr = 3.5:1), which could not be
separated by flash column chromatography. The enantioselec-
tivity of 10 was determined to be 95% by chiral HPLC analysis of
the downstream product (see Supporting Information).
Reduction of nitro with zinc provided the corresponding
amine, which was alkylated with 15. Subsequent protection of
the resulting secondary amine with ClCO2Me gave carbamate 9a.
With diene 9a available, the key RCM was examined. However,
reaction of 9a with Grubbs I and II catalysts as well as Hoveyda’s
catalyst at a variety of solvents and temperatures gave no desired
cyclization product. To our delight, Zhan catalyst 1-B proved
more powerful to promote the RCM reaction to deliver 8a
smoothly, which was not stable and immediately reduced with
LiAlH4 to give (−)-agroclavine (1). The physical data of our
synthesized products 1 are identical to those reported in the
literature.18 Thus, we have achieved the first catalytic asymmetric
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01681.
■
S
Full experimental procedures, and H and 13C NMR
spectra of compounds 1, 3, 7−14, and 17 (PDF)
1
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yxjia@bjmu.edu.cn.
ORCID
Yanxing Jia: 0000-0002-9508-6622
Author Contributions
†J.L. and B.W. contributed equally.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b01681
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Letter
activation/cyclization of indolyl aldehydes, see: (f) Liu, X.; Li, G.; Song,
F.; You, J. Nat. Commun. 2014, 5, 5030.
(13) For C5 selective C−H bond functionalization of indoles, see ref
12d.
ACKNOWLEDGMENTS
■
This research was supported by the National Natural Science
Foundation of China (Nos. 21372017, 21402003, and
21290183).
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