Intramolecular Fischer Indole Synthesis for the Direct Synthesis of 3,4-Fused Tricyclic Indole and Application to the Total Synthesis of (-)-Aurantioclavine

Article abstract of DOI:10.1021/acs.orglett.6b02541

Aryl hydrazides with a ketone or aldehyde containing side chains linked to the meta-position of the aromatic ring undergo acid-promoted intramolecular Fischer indole synthesis to generate 3,4-fused tricyclic indoles. The preparative utility of this concep

Full text of DOI:10.1021/acs.orglett.6b02541

Letter
pubs.acs.org/OrgLett
Intramolecular Fischer Indole Synthesis for the Direct Synthesis of
3
,4-Fused Tricyclic Indole and Application to the Total Synthesis of
(
−)-Aurantioclavine
Jun Park, Dong-Hyun Kim, Tapas Das, and Cheon-Gyu Cho*
Center for New Directions in Organic Synthesis, Department of Chemistry, Hanyang University, 222 Wangshimni-ro, Seongdong-gu,
Seoul 04763, Korea
*
S Supporting Information
ABSTRACT: Aryl hydrazides with a ketone or aldehyde
containing side chains linked to the meta-position of the
aromatic ring undergo acid-promoted intramolecular Fischer
indole synthesis to generate 3,4-fused tricyclic indoles. The
preparative utility of this conceptually new synthetic approach,
which does not require prefunctionalization of the indole ring,
was demonstrated by its application to a concise total synthesis
of (−)-aurantioclavine.
ecently, tricyclic indole alkaloids bearing 3,4-fused rings
Scheme 1. Intramolecular Fischer Indole Synthesis
R
have attracted much attention because of their interesting
molecular architectures and important biological activities. This
interest is witnessed by the large number of efforts targeted at the
1
total syntheses of communesin F and welwitindolinone C
isothiocyanate and related indole alkaloids (Figure 1). A
2
linked to the para-position, underwent intramolecular Fischer
indolization reaction to form 3,5-fused tricyclic indoles 5a−5c.
This was a surprising result due to the expectation that the latter
process would encounter larger enthalpic and entropic barriers
Figure 1. Selected 3,4-fused tricyclic indole alkaloids.
continuous influx of new synthetic methods and strategies has
(
eq 2, Scheme 1).
The failure of the IMFIS of the meta-tethered aryl hydrazides
facilitated the synthesis of these complex polycyclic indole
3
alkaloids. Nonetheless, formidable synthetic challenges in this
1a−1c was initially attributed to the high strain energy barrier for
area still exist primarily because of difficulties with the
construction of medium-sized ring bridges between the C3 and
C4 indole positions.
In a previous study, we explored a new approach to the
synthesis of 3,4-fused tricyclic indoles (3a−3c, eq 1, Scheme 1).
The process involves intramolecular Fischer indole synthesis
conversion of the hydrazone intermediates to the indoles.
However, the results of a simple molecular modeling study and
comparisons to other intramolecular indole-forming reactions
indicated that the ring strain was likely not the cause of the
failure. Observations made in control experiments showed that
the problem with these processes is actually a consequence of the
instability of the tricyclic indole products 3a−3c under the
reaction conditions and not of strain of the transition state. To
explore this strategy further, we conducted studies with other aryl
hydrazides with a carbonyl group containing side chains linked to
(
IMFIS) of aryl hydrazides 1a−1c, which bear a carbonyl group
containing a side chain linked to the meta-position of the
aromatic ring. In contrast to expectation, we observed that aq
4
HCl promoted reactions of these substrates, regardless of their
side chain lengths, and all produced the corresponding cyclic
hydrazones. Attempts to drive these processes to completion did
not result in formation of the target indoles. On the contrary, aryl
hydrazides 4a−4c, with the carbonyl containing side chains
Received: August 24, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02541
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the meta-position of the aromatic ring. The results of this effort
show that, as originally anticipated, several substrates in this
group undergo IMFIS to form the corresponding 3,4-fused
tricyclic indoles efficiently. Herein, we report the details of the
IMFIS of meta-tethered aryl hydrazides and the application to the
total synthesis of (−)-aurantioclavine.
Aryl hydrazide 6b, having a N-Ts benzylamine containing
meta-side chain, was chosen as the first substrate for this re-
investigation. Interestingly, when treated with aq HCl in nPrOH
at 100 °C, 6b underwent IMFIS to form the corresponding 3,4-
fused tricyclic indole 7b in 71% yield (entry 1, Table 1). Reaction
49% yield. Furthermore, the aryl hydrazides 6f and 6g, with
aldehyde acetal containing meta-side chains, reacted under the
optimized conditions to produce the respective indoles 7f (15%)
and 7g (26%). Interestingly, the same products are generated in
much higher yields (60 and 68%, respectively) when reactions of
6f and 6g were conducted at 110 °C.
Next, IMFIS of aryl hydrazides 8a−8d, with benzamide
containing tethers, was investigated as a prelude to potential
applications to the syntheses of the naturally occurring 3,4-fused
tricyclic indole alkaloids (Scheme 3). When subjected to the
Scheme 3. IMFIS of Aryl Hydrazides 8a−8d
Table 1. IMFIS of 6b under Various Conditions
entry
conditions
results
1
2
3
4
5
6
7
8
9
n-PrOH, HCl (aq), 100 °C, 12 h
EtOH, HCl (aq), 80 °C, 12 h
71%
73%
53%
trace
78%
trace
trace
55%
trace
optimized conditions, 8b and 8c reacted to form the
corresponding tricyclic indoles 9b and 9c in 53 and 78% isolated
yields, respectively. In a manner that is similar to that of 6d,
IMFIS of 8d (n = 3) is much less efficient at forming 9d in a 39%
yield. Again, 8a (n = 0) does not undergo IMFIS.
In an effort to further probe the substrate scope, aryl
hydrazides 10 and 12 were subjected to IMFIS (Scheme 4).
EtOH, p-TsOH·H O (8.6 equiv), 80 °C, 12 h
2
EtOH, p-TsOH·H O (0.1 equiv), 80 °C, 60 h
2
n-PrOH, 4 M HCl in dioxane, 100 °C, 12 h
PhMe, p-TsOH·H O (8.6 equiv), 100 °C, 12 h
2
AcOH, 100 °C, 24 h
t-amyl alcohol, AcCl, 100 °C, 24 h
CF CH OH, AcCl, 80 °C, 12 h
3
2
Scheme 4. IMFIS of Aryl Hydrazides 10 and 12
of 6b in EtOH under reflux gave a slightly higher yield (entry 2),
while replacement of aq HCl by p-TsOH resulted in no beneficial
effect (entries 3 and 4). In addition, variations of the acid, solvent,
and temperature did not lead to higher yields (entries 6−9).
Finally, a maximum yield of 78% was obtained when the reaction
was conducted in nPrOH at 100 °C, premixed with a solution of
anhydrous HCl in 1,4-dioxane (entry 5).
Encouraged by these observations, we explored IMFIS of aryl
hydrazides 6a, 6c, and 6d with different chain lengths to see if
tricyclic indoles with other 3,4-fused ring sizes could be
generated (Scheme 2). Reaction of the one carbon shortened
(
n = 0) substrate was not found to produce even a trace of the
IMFIS product 7a. However, aryl hydrazide 6c with a one carbon
longer tether (n = 2) reacted efficiently to form the
corresponding tricyclic indole 7c containing an eight-membered
ring fusing the C3 and C4 positions. IMFIS of 6d with a one
carbon extended tether (n = 3) was less efficient, affording 7d in
Under the optimized conditions, aryl hydrazide 10 reacted to
produce the corresponding 3,4-fused tricyclic indole 11 in 50%
yield. The aryl hydrazide 12 with a benzyl ether tether also
underwent IMFIS to give indole 13 in 33% yield, along with the
ring-opened product 14 in 42% yield. The latter substance is
likely formed by acid-mediated trans-etherification of 13. When
heated in toluene with catalytic p-TsOH, 14 underwent
cyclization to generate 13 in 65% yield (see Supporting
Information for details).
Scheme 2. IMFIS of Aryl Hydrazides 6a−6g
To demonstrate the preparative utility of the new IMFIS5
strategy, it was applied to the synthesis of (−)-aurantioclavine,
an ergot alkaloid isolated from Penicillium aurantiovirens. This
small 3,4-fused tricyclic indole natural product could serve as a
key synthetic intermediate in routes to members of the highly
6
complex polycyclic communesin family of alkaloids. Despite its
small size, (−)-aurantioclavine is a deceptively elusive target
because of the sensitive nature of its benzylic and allylic C−N
bond. In our first attempt at the synthesis of this target, the fully
decorated IMFIS precursor 15 was prepared and subjected to the
a
The yield is for the reaction conducted at 100 °C in a sealed tube.
B
DOI: 10.1021/acs.orglett.6b02541
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Organic Letters
Letter
standard IMFIS conditions. However, the reaction did not form
the anticipated tricyclic indole 16, but rather diene 17 was
generated presumably by proton loss from the stable
intermediate carbocation 18 (Scheme 5). To circumvent the
synthesis of polycyclic indole alkaloids. This proposal has been
demonstrated by the application of the approach to a concise
synthesis of (−)-aurantioclavine. Further applications of this
method to structurally complex polycyclic indole natural
products with a 3,4-fused tricyclic indole core are now being
studied.
Scheme 5. Synthesis of (−)-Aurantioclavine
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02541.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: ccho@hanyang.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the grants from the National
Research Foundation of Korea (2014R1A5A1011165).
■
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DOI: 10.1021/acs.orglett.6b02541
Org. Lett. XXXX, XXX, XXX−XXX