One-Pot Transformation of Simple Furans into Octahydroindole Scaffolds

Article abstract of DOI:10.1002/anie.201700620

A highly efficient and general singlet-oxygen-initiated one-pot transformation of readily accessible furans into octahydroindole scaffolds has been developed.

Full text of DOI:10.1002/anie.201700620

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201700620
German Edition: DOI: 10.1002/ange.201700620
Alkaloid Synthesis
One-Pot Transformation of Simple Furans into Octahydroindole
Scaffolds
Dimitris Kalaitzakis, Myron Triantafyllakis, Georgios I. Ioannou, and
Georgios Vassilikogiannakis*
Abstract: A highly efficient and general singlet-oxygen-
initiated one-pot transformation of readily accessible furans
into octahydroindole scaffolds has been developed.
I
ncreasing the molecular complexity of a simple precursor in
a minimum number of synthetic operations is one of the
foremost goals of synthetic chemists today. One-pot reaction
sequences[1] not only usually increase molecular complexity
substantially and reduce the steps of a synthetic sequence
(step economy),[2] but also demonstrate synthetic elegance
and creativity.[3] Furthermore, the avoidance of protecting
groups, nonstrategic redox manipulations, and other func-
tional group interconversions is also very important in order
to shorten synthetic approaches.[4] The quality of a new
method may be correlated to the number of constructive
bonds generated in a single synthetic operation.[5]
With these criteria in mind, carbo-[3+3] annulations seem
to be packed with potential because they generate multiple
bonds simultaneously with excellent stereochemical control.[6]
The most common products of these reactions are bicyclo-
[3.3.1] adducts[7] or cyclohexane derivatives.[8] Even though
the diversity of the structures that can be assembled is
potentially huge, to the best of our knowledge, these reactions
have never been investigated for the construction of fused 1-
azabicyclic systems.
The 1-azabicyclic [4.3.0] system is the core structural unit
of a wide range of biologically active natural products and is
usually referred to as an octahydroindole (OHI, Scheme 1).[9]
The ubiquity of the scaffold has prompted the development of
several efficient methodologies for the synthesis of octahy-
droindoles.[10] Nevertheless, various complexities associated
with accessing these OHI scaffolds rendered the development
of more versatile and sustainable synthetic approaches
starting from readily accessible precursors highly imperative.
Herein, we introduce an innovative methodology for the
synthesis of a wide variety of OHI motifs. The key synthetic
intermediate is the 2-pyrrolidinone of type 3 derived from the
reaction of singlet oxygen with simple furans 1[11] followed by
treatment with Me2S and primary amines 2 (Scheme 2).[12]
Specifically, we had envisioned that 2-pyrrolidinone 3 could
Scheme 1. General structures of naturally occurring alkaloids contain-
ing the octahydroindole scaffold.[9]
.
serve as an electron-rich dienophile, and, consequently,
participate in an inverse-electron-demand hetero-Diels–
Alder reaction[13] with electron-poor a,b-unsaturated carbon-
yl partner compounds 4.[14] Although the expected tetrahy-
dropyranopyrrolone (THPP) product 5 (Scheme 2) is itself an
important structural unit,[15] investigation of the potential
rearrangement of 5 to the desired OHI scaffolds of type 6
through the intermediates 5i and 5ii was our primary
intention. The transformation of 2-pyrrolidinone 3 into the
[*] Dr. D. Kalaitzakis, M. Triantafyllakis, G. I. Ioannou,
Prof. Dr. G. Vassilikogiannakis
Department of Chemistry, University of Crete
Vasilika Vouton, 71003, Iraklion, Crete (Greece)
E-mail: vasil@chemistry.uoc.gr
Homepage: http://www.chemistry.uoc.gr/vassilikogiannakis
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201700620.
Scheme 2. Envisioned scenario for the synthesis of octahydroindole
scaffolds from furans. RB=rose bengal.
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final product 6 (Scheme 2) can be considered to be a [3+3]-
annulation.
reaction sequence (products 5 f–5i, 51–65% yield). More-
over, the presence of reactive functional groups in the side
chain of the furan (1c, 1e, and 1 f) did not in anyway diminish
the efficiency of the reaction (products 5j, 5l, and 5m, 54–
62% yield). Only in case of furan 1d did the reaction
sequence proceed with a compromised 43% yield for 5k.
It is notable that in all cases the reaction exclusively
afforded the cis-fused diastereoisomer of the THPPs, a result
that is consistent with a concerted [4+2] cycloaddition.[13b,c]
The proposal that the addition is concerted is also supported
by the absence of byproducts. If a stepwise mechanism were in
operation, the reaction would proceed via the intermediate 5i
(Scheme 2), which would be expected to lead to the concom-
itant formation of isomeric analogues.[13b] For instance, during
the formation of THPP 5d (Scheme 3), the ester moiety could
trigger double bond migration to the exocyclic position, while
in case of 5i and 5j the hydroxyl groups at R2 and R1 would be
expected to trap the intermediate 5i forming a fused or a spiro
product, respectively (vide infra). Another feature of note is
that the Diels–Alder reaction takes place even at room
temperature (conditions c, Scheme 3) without the use of any
catalyst. This is most likely the outcome of an inverse-
electron-demand Diels–Alder cycloaddition driven by relief
of ring strain (strained 2-pyrrolidinone 3).[16]
Having looked into the Diels–Alder reaction, we pro-
ceeded to investigate the rearrangement step for the prepa-
ration of OHI motifs. We believed that subjecting THPPs of
type 5 to acidic conditions might trigger the formation of
intermediates of type 5i and 5ii (Scheme 2), and, conse-
quently, facilitate progression to the desired OHI scaffold.
Intriguingly, addition of just 0.2 equiv of AlCl3 to compound
5a in CH2Cl2 at room temperature afforded exclusively the
dihydroindolone (DHI) 8a after only 30 min (62% yield,
conditions A, Scheme 4). Exactly the same conditions were
applied to compounds 5k and 5m and in each case the
corresponding DHIs were produced (8b and 8c, 61% and
65% yield, respectively). Apparently, the intermediate bicy-
cle of type 6 was dehydrated to iminium 7 (Scheme 4) which
led to the final DHI 8. It was possible to engage electrophilic
intermediate 7 in additional cyclizations with the pendant
olefinic nucleophile when starting from 5m. Thus, use of
AlCl3 (0.2 equiv) in refluxing DCM led to the more complex
tricyclic product 8d (d.r. = 3:1, 64% yield).
Initially, we studied the first part of the proposed trans-
formation (1!5). In particular, we investigated the progress
of the Diels–Alder reaction of 2-pyrrolidinone 3a [derived
from 2-methylfuran (1a) and benzylamine (2a) using our
standard singlet-oxygen protocol][12] with acrolein (4a) in
different solvents (Scheme 3). The reaction proved to be
unsuccessful at room temperature in methanol (< 10%
conversion), but at 408C the cycloaddition proceeded to
afford the desired THPP 5a albeit with poor 66% conversion
(31% overall yield). Under these conditions the methanol-
trapped analogue of 3 formed concurrently, thus causing the
reaction to stall. The Diels–Alder reaction was more success-
ful in CH2Cl2 at room temperature (75% conv., 50% overall
yield), and, was further improved, at reflux where complete
consumption of the starting material was observed and the
final product was isolated in 72% overall yield starting from
furan 1a (Scheme 3). Different furans, amines, and a,b-
unsaturated carbonyl compounds were then used in order to
probe the scope and limitations of the reaction. Specifically,
reaction of a,b-unsaturated carbonyl compounds 4b, 4c, and
4d with 2-pyrrolidinone 3a afforded the desired products 5b–
5d (55–65% overall yield). Starting from 2-hexylfuran (1b),
the reaction also proceeded smoothly to give THPP 5e (70%
overall yield). Application of ammonia (2b) or ethanolamine
(2c) as nitrogen sources did not influence the course of the
The rearrangement (5!8) was also catalyzed by Brønsted
acids. Treatment of 5d with trifluoroacetic acid (TFA;
0.5 equiv) at room temperature furnished 8e (81% yield).
However, when THPP 5j was treated with TFA (1.0 equiv),
the reaction clearly led to the kinetic spiro product 8 f (d.r. =
5.5:1). This compound proved to be very stable at room
temperature, even when larger quantities of TFA (3 equiv)
were used. The facile formation of this stable spirocyclic
compound at this point, which had not occurred during the
preparation of the THPP in the previous step, is a further
strong indication that the preceding Diels–Alder reaction had
occurred in a concerted manner (vide supra).
In an attempt to expand the versatility of the new method,
we combined the acid-catalyzed rearrangement with the
addition of a reducing agent in order to end up with the fully
saturated products of type 9. Starting from THPPs of type 5
Scheme 3. One-pot synthesis of THPP derivatives of type 5 from
furans. [a] 1.8 equiv of a,b-unsaturated carbonyl compound was used.
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of substituted furans into DHIs of type 8 or OHI scaffolds of
type 9. Specifically, we applied the photooxygenation con-
ditions to furan 1a and 1 f, followed by addition of Me2S,
benzyl amine (2a), and acrolein (4a), securing the formation
of the corresponding THPPs 5a and 5m (Scheme 3). The
subsequent addition of AlCl3 without isolation of the
compounds of type 5 terminated this reaction sequence
affording 8a and 8c in 55% and 48% overall yield,
respectively (Scheme 5, conditions D). Alternatively, addi-
Scheme 5. One-pot synthesis of DHIs 8 and OHI scaffolds 9 starting
from simple furans.
tion of BF3·OEt2 and Et3SiH to the crude mixture containing
THPP 5b, or TFA and Et3SiH to the crude mixture containing
THPP 5e, provided the OHI scaffolds 9b and 9e in 62% and
60% overall yield, respectively (Scheme 5, conditions E and
F, respectively). The yields of the one-pot operations were
better than the overall yield of two individual synthetic
operations (when compounds of type 5 were isolated). The
yields of the one-pot transformations (1!8 or 9) are
remarkably good considering the degree by which molecular
complexity has been increased.
In summary, a general and versatile method for the
synthesis of a diverse array of important tetrahydropyrano-
pyrrolones 5, dihydroindolones 8, and hexahydroindolones 9
has been introduced. The target molecules are constructed
using a highly efficient one-pot reaction sequence which starts
with the photooxygenation of simple and readily accessible
furan substrates. The dramatic increase in molecular com-
plexity and the high atom economy achieved in a single
synthetic operation render this novel method an important
addition to the alkaloid synthesis toolbox.
Scheme 4. Acid-catalyzed rearrangement of THPPs 5 to DHIs 8 and
OHI scaffolds 9. [a] Conditions A: AlCl3 (0.2 equiv), RT, 30 min.
[b] Conditions B: Et3SiH (6 equiv), BF3·OEt2 (1 equiv), RT, 18 h. [c] Con-
ditions C: Et3SiH (6 equiv), TFA (5 equiv), RT, 18 h.
(where R1 = H), we found that the optimal conditions for the
desired transformation were a combination of BF3·OEt2 with
Et3SiH (conditions B, Scheme 4). In every case, the reaction
efficiently furnished the cis-fused OHI scaffolds (9a–9d, 62–
73% yield) as single diastereomers. In all the other examples
(where R1 ¼ H), the optimum reductive conditions were TFA
with Et3SiH (conditions C), and, once again, the final
saturated products were formed with high diastereoselectivity
(9e, 9 f, 9h, 67–72% yield). Only in case of product 9g was
a 1:1 mixture of separable diastereomers formed (72%
combined yield for both isomers). Reaction of the THPP 5k
functionalized with an ester group under conditions C
afforded the tricyclic compound 9i as a single diastereomer.
This result illustrates the extent of the molecular complexity
that can be achieved using such reaction sequences (see the
Supporting Information for a detailed mechanism). We
1
observed (by tlc analysis and from crude H NMR spectra
of the reaction 5!9) that the rearrangement reaction
proceeds rapidly (within roughly 1 h), while the reduction of
the intermediate iminium 7 by Et3SiH is responsible for
retarding the reaction (18 h).
To further underscore the synthetic utility of the current
methodology, we next focused on the one-pot transformation
Acknowledgements
The research leading to these results received funding from
the European Research Council under the European Unionꢀs
Seventh Framework Programme (FP7/2007-2013)/ERC grant
agreement no. 277588 as well as from the European Unionꢀs
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Keywords: 2-pyrrolidinones · annulation · Diels–Alder reaction ·
octahydroindoles · singlet oxygen
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Manuscript received: January 18, 2017
Final Article published: && &&, &&&&
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Communications
Alkaloid Synthesis
D. Kalaitzakis, M. Triantafyllakis,
G. I. Ioannou,
G. Vassilikogiannakis*
&&&& — &&&&
Generating complexity: A diverse array of
important hydroindole scaffolds has been
synthesized via a one-pot reaction
sequence starting with the photooxyge-
nation of simple furans (see figure).
One-Pot Transformation of Simple Furans
into Octahydroindole Scaffolds
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