Domino Ring Expansion: Regioselective Access to 9-Membered Lactones with a Fused Indole Unit from 2-Nitrophenyl-1,3-cyclohexanediones

Article abstract of DOI:10.1002/chem.201705645

The domino anionic fragmentation of 2-nitrophenyl-1,3-cyclohexanediones containing an electrophilic appendage such as aldehyde and epoxide is disclosed. This reaction, initiated by a series of nucleophiles, involves the generation of an intermediate hydroxylate followed by the regioselective formation and fragmentation of an intermediate lactolate into enolate. This strategy, devoid of any protecting group, enlarges the initial ring and provides an original access to decorated 9-membered lactones with a fused indole unit.

Full text of DOI:10.1002/chem.201705645

A Journal of
Accepted Article
Title: Domino Ring Expansion: Regioselective Access to 9-Membered
Lactones with a Fused Indole Unit from 2-Nitrophenyl-1,3-
cyclohexanediones
Authors: Michael De Paolis, David Reyes Loya, Alexandre Jean,
Morgan Cormier, Catherine Fressigné, Stefano Nejrotti,
Jérôme Blanchet, and Jacques Maddaluno
This manuscript has been accepted after peer review and appears as an
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using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Chem. Eur. J. 10.1002/chem.201705645
Link to VoR: http://dx.doi.org/10.1002/chem.201705645
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10.1002/chem.201705645
Chemistry - A European Journal
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Synthetic
methodology
Domino Ring Expansion: Regioselective Access to 9-Membered Lactones
with a Fused Indole Unit from 2-Nitrophenyl-1,3-cyclohexanediones
David Reyes Loya,a Alexandre Jean,a Morgan Cormier,a Catherine Fressigné,a Stefano Nejrotti,a
Jérôme Blanchet,b Jacques Maddaluno,a and Michaël De Paolis*,a
In memory of István E. Markó
Abstract: The domino anionic fragmentation of 2-nitrophenyl-1,3-
cyclohexanediones containing an electrophilic appendage such as
aldehyde and epoxide is disclosed. This reaction, initiated by a
series of nucleophiles, involves the generation of an intermediate
hydroxylate followed by the regioselective formation and
fragmentation of an intermediate lactolate into enolate. This
strategy, devoid of any protecting group, enlarges the initial ring
and provides an original access to decorated 9-membered lactones
with a fused indole unit.
With the ability to bind to proteins with a large and rigid structure,
macrocycles offering multisite interactions, such as medium-sized
lactones, are pertinent in medicinal chemistry.[1] While the usual
disconnection of lactones involves the intramolecular reaction of
carboxylic acid with alcohol, this strategy is delicate when directed
toward medium-sized lactones due to the risk of intermolecular
reaction. Alternatives, such as the ring closing metathesis of alkenes
and alkynes or C‒H oxidation of linear alkenoic acids, emerged for
the elegant synthesis of large-sized lactones.[2] Another way to
prepare a lactone without a lactonisation step is based on the ring
Scheme 1. A) Known anionic fragmentation of diketones and B,C)
applications to the regio- and diastereoselective ring expansion of 2-
nitrophenyl-1,3-diketone scaffold.
expansion of activated ketones by internal hydroxylate triggering a
fragmentation (Scheme 1A).[3] Still today, the strategy inspires
creative access to 10-membered (and more) lactones or lactams by
employing aza-nucleophiles.[4] We noted though that despite an
During a program of total synthesis, we observed that
early report from Mahajan with dimedone derivatives[5] and the
treatment of aldehyde 1 with lithium trimethylsilylacetylide led
directly to 9-membered lactone 2a in 46% yield, dr = 2:1 (Scheme
1B). This result could be explained by an unprecedented domino
contribution of Rodriguez in the field, anionic fragmentations
producing strained 9-membered lactones remained scarce.[6]
ring expansion fostered by an anionic fragmentation that was
initiated by internal hydroxylate.[9] So far, aldehyde 1 had been
brilliantly employed by Bonjoch and Bosch to access highly
substituted pyrrolidines en route to complex natural products, a
reductive amination step with chiral amines warranting the
desymmetrization of 1.[10] Distinct from this strategy, the domino
fragmentation of 1 opened different routes to be harnessed, as
illustrated with lactone 2a in which C-C and C-O bonds were
created. Incorporating the carbon nucleophile that induced the
fragmentation, lactone 2a also contained a versatile nitroaryl
substituent which facilitates the whole process and provides an entry
to elaborated scaffold once converted into indole. Hence, a route
toward substituted and strained lactones embedding the indole motif
IV was developed (Scheme 1C) and applied to several derivatives of
The indole and indoline cores are found in numerous natural
products and biomolecules. Owing to the inherent and competitive
C‒ and N‒nucleophilicity of indole, regio- and chemoselective
functionalization at C2/C3 can be tedious without resorting to
protecting groups, as well as their incorporation into lactones.[7,8] If
natural products combining medium-sized lactone and indole motifs
are rather uncommon, the combination of two classic
pharmacophores is expected to afford new platforms of interest in
molecular biosciences.
[]
D. Reyes Loya, Dr. A. Jean, Dr. M. Cormier, S. Nejrotti, Dr.
J. Blanchet, Dr. J. Maddaluno, Dr. M. De Paolis
Normandie Université, UNIROUEN, INSA de Rouen,
CNRS, Laboratoire COBRA (UMR 6014 & FR 3038),
76000 Rouen, France.
2-nitrophenyl-1,3-cyclohexanedione
I demonstrating interesting
[a]
levels of regio- and diastereoselectivity. Proceeding through
transient lactolate intermediates II, the methodology encompassed
the grafting of nucleophiles into the resulting 9-membered ring III
by reaction with the corresponding aldehydes and epoxides.
Screening of conditions revealed that the preformation of the
organocerium reagent of lithium trimethylsilylacetylenide enhanced
the yield of 2a to 55% (dr = 2:1) from 1 while lactone 2b was
produced in 30% yield (dr = 4:1) with lithium phenylacetylenide as
E-mail: michael.depaolis@univ-rouen.fr
[b]
LCMT, ENSICAEN et Université de Caen, CNRS; 6 bd du
Maréchal Juin, 14050 - Caen, France
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the
author.
1
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10.1002/chem.201705645
Chemistry - A European Journal
nucleophile (Scheme 2). Explaining the low yield in 2b,
deprotonation of the hindered aldehyde 1 and side reactions of the
nucleophile with ketone and nitroaryl moieties are likely to occur.
For the same reasons, C(sp2) and C(sp3) nucleophiles (vinyl-,
allylmagnesium bromide or nBuLi) were found poorly compatible
formation of an amount of the isomeric lactol intermediate 8b along
with 8a, the privileged isomer due to the high electrophilic character
at C(2). But these two isomers could well be in thermodynamic
equilibrium, as well as the enolates lactones 8c and 8d resulting
from their respective fragmentations. And a shift of these equilibria
leading to the regioselective production of isomer 8c is conceivable
under the assumption that the steric hindrance of the quaternary
carbon acts as an impediment to the transannular Dieckmann
reaction of the enolate with the lactone moiety in 8c. In any case, the
exquisite selectivity of the whole process is worth underlining: a
single regio- and diastereoisomer was observed where four were
expected.
With a less congested substrate however, such as cis-10, the
regioselectivity of the intramolecular nucleophilic attack was
minored (Scheme 3C). Hence, lactones 11/11’ were produced in a
ratio of 3:1 (50 % yield). Incidentally, the fragmentation of the
intermediates occurred spontaneously without the need of
subsequent basic treatment. Respectively functionalized with ester
and nitrile appendage, the cis/trans aldehydes 12 and 14 were
converted into the lactones 13 and 15 (Scheme 3D) in 70 % and
58% yields (2-step including the ozonolysis of the olefin not shown)
with regioselectivity but modest diastereoselectivity in both
cases.[16,17]
with 1.[11] This drawback was overcome by resorting to
a
combination of an allyl pronucleophile (nBu3SnAll) and a mild
Lewis acid (SnCl4) that converted aldehyde 1 into lactone 2c (67%
yield, dr = 5:1), a scaffold ready for various synthetic manipulations.
On the other hand, reduction of 1 with NaBH4 furnished directly
lactone 2d in 70% yield or lactone 2e in 84% yield by reaction with
aldehyde 3, derived from dimedone. Applied to -substituted
aldehyde 4, the reduction warranted a stereoselective access to cis-
lactone 5 in 60% yield (2 steps, dr > 20:1) owing to an anti
stereoselective protonation step of the enolate intermediate.
Scheme 2. Ring expansion of 1,
3 and 4 by reaction with
nucleophiles (Ar = 2-NO2Ph). Conditions: a) TMSCCLi or PhCCLi,
CeCl3, THF, ‒78 °C; b) nBu3SnAll, SnCl4, CH2Cl2, ‒78 °C; c) NaBH4,
iPrOH/CH2Cl2 or MeOH, 0 °C
To examine the regioselectivity of the fragmentation, non-
symmetrical 1,3-cyclohexanediones were prepared by a known
sequence of domino double Michael-cyclization that allows the
installation of various substituents to the scaffold which, once
assembled, could be arylated and allylated in position 2 (see SI for
details).[12] As the reaction of the aldehydes with NaBH4 could
deliver two regioisomers, we were curious to analyse the outcome of
the fragmentation (Scheme 3). A case in point, the isomerically pure
trans-6[13] led to lactone 7 (X-ray) in 40% yield (Scheme 3A), as a
single regio- and diastereoisomer. In this case, the process required a
basic treatment (K2CO3, THF, 80 °C) to complete the fragmentation
and convert the various intermediates of the reaction into 7. Whether
this treatment could also promote the epimerization of dia-7 into 7
in the event of its formation could not be determined. At any rate, a
mixture of cis/trans-6 (dr = 1:1) solely led to isomerically pure 7 in
50% yield (3-step) upon reductive and basic treatment (Eq. 2).[14]
To investigate the regioselectivity of the process, we looked at
the electrophilic character of C(2) and C(6) in sodium alcoholate 8,
the starting point of the process. DFT calculations (M06-2X
continuum MeOH) and NBO analysis revealed that the most
hindered carbonyl ‒ flanked by two quaternary carbons ‒ is more
electropositive (C(2) = +0.703 e) than the less hindered one (C(6) =
+0.658 e). In an attempt to discern the role of the nitro substituent,
DFT calculations were also performed on a similar substrate
deprived of the nitro moiety (Ar = Ph). They still indicate a disparity
of electropositivity between C(2) (+0.684 e) and C(6) (+0.657 e) but
the difference was ebbed.[15] These calculations suggest therefore a
significant electronic effect of NO2-substituent that could emphasise
the regioselectivity of the attack by increasing the electropositivity
of C(2). Yet, it is very likely that electronic guise only partially
explain the observed regioselectivity. Hence steric hindrance of the
quaternary carbon combined to considerations regarding the Bürgi-
Dunitz angle of the alkoxide trajectory could indeed induce the
Scheme 3. Fragmentation of aldehydes 8, 10, 12 and 14 (Ar = 2-
NO2Ph), dr determined by 1H NMR spectroscopy (300 MHz).
Conditions: a) NaBH4, iPrOH/CH2Cl2, 0 °C; b) K2CO3, THF, 80 °C; c)
O3, CH2Cl2, ‒78 °C.
Encouraged by the stereoselective formation of 7 by reduction
of aldehyde 6 (see above), we examined the diastereoselectivity of
the process with carbon nucleophiles. The domino reaction would
produce lactones with three stereocenters but we inferred that a level
of stereocontrol could be observed. Pleasingly, allylation of
cis/trans-6 (dr = 1:1) afforded after basic treatment, lactones trans-
16 and cis-16 (42% yield, 3 steps from 9), two diastereoisomers out
of four possible (Scheme 4). Considering the regioselectivity issue,
the result is even more interesting since only two isomeric lactones
were formed out of eight possible. It is especially noteworthy the
secondary hydroxylate still reacted, in spite of its own hindrance, at
the most hindered ketone. In the next case, straightforward
hydroalkynylation of aldehyde trans-12 gave lactone 17 in good
2
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10.1002/chem.201705645
Chemistry - A European Journal
yield (50% yield, 2-step) with ester and alkyne appendages. A
complex isomeric mixture was however observed which was not
surprising given the results obtained with hydride (Scheme 3D). Yet,
subsequent reduction of the nitro group gave indole 18 in 70% yield
with modest stereoselectivity (dr = 3:2) but with complete
regioselectivity.[16]
with a level of stereoselectivity (dr = 10:1:2.5:1), the major isomer
being identified by 2D NMR spectroscopy.
In addition to the highly substituted lactone 18, various
lactones 22a-q were generated upon reductive treatment of the
corresponding nitroaryl lactones with alkyl, alkyne, alkene, ester,
nitrile and amino appendages that are described in Figure 1.
Circumventing the need for protecting groups, an access to
functionalized lactones with a fused indole was thus established. To
complement the study and illustrate the versatility of the scaffold,
synthetic manipulations were carried out. To that end, the
diastereoselective oxidation of indole 22m was achieved with
mCPBA in THF, this solvent being crucial for the stereoselectivity
of the transformation (Scheme 6). Embedded into the 9-membered
lactone, hydroxyindolenine 25 was obtained in 80% yield.[20]
Furthermore, trans esterification of 25 provided furoindoline 26
(78% yield) while exposure of 25 to LiHMDS afforded
pyridoindolinic lactone 27 in excellent yield (90%).[21]
Scheme 4. Conditions (Ar = 2-NO2Ph): a) nBu3SnAll, SnCl4, CH2Cl2,
‒78 °C; b) TMSCCLi, CeCl3, THF, ‒78 °C; c) K2CO3, THF, 80 °C; d)
Zn, AcOH, 40 °C.
Moreover, we wondered if the epoxide 19a could be included
in the panoply of electrophiles undergoing the domino process
(Scheme 5). Gratifyingly, mild nucleophiles such as NaN3 reacted
efficiently with 19a in the presence of CeCl3 providing azido lactone
20a in excellent yield (94%, dr = 1:2, cis/trans).[18] Alternatively,
ring opening of the epoxide 19a was effected with MgBr2●OEt2
leading to bromo lactone 21 in 77% yield (dr = 2:1).[19] When
exposed to NaN3/CeCl3, the more sensitive epoxide 19b gave azido
lactone 20b and hydrogenation in the presence of Boc2O was
conducted yielding amino indole 22n (47%). Concisely, the route
leads to a scaffold containing strained and substituted lactone with a
fused indole and amine appendage.
Scheme 6. Conditions: a) mCPBA, THF, 0 °C; b) MeONa, MeOH,
80 °C; c) LiHMDS, THF, ‒78 °C. mCPBA = 3-chloroperbenzoic acid,
LiHMDS = lithium hexamethyldisilazide.
In summary, an unprecedented domino process in the field of
anionic fragmentation was illustrated from substituted 2-nitroaryl-
1,3-cyclohexanediones bearing aldehyde and epoxide electrophilic
appendages. Mild nucleophiles were best suited to initiate the
fragmentation process, forging various bonds and leading to 9-
membered lactones with the nucleophile incorporated into the
scaffold. The counter-intuitive regioselectivity of the attack opened
a route to functionalized lactones. Investigated by DFT calculations,
the origin of the regioselectivity could initially rely on the higher
electrophilic character of the most hindered ketone subtlety
emphasised by the electronic effect of the nitro moiety. The
stereoselectivity issues were also explored with promising results for
a future asymmetric access to this class of rigid lactones. Once
converted into lactones with a fused indole unit, appendages are
available for functionalization or interactions with biological hosts.
Alternatively, they were easily converted into elaborated
hydroxyindolenine, furoindoline and pyridoindoline.
Scheme 5. Ring expansion of epoxides 19a,b and 23 (Ar = 2-NO2Ph),
conditions: a) NaN3, CeCl3.7H2O, CH3CN/H2O, 80 °C; b) MgBr2●OEt2,
THF, 70 °C; c) H2, Pd/C, Boc2O, MeOH. brsm = based on recovered
starting material.
Acknowledgements
With the hindered epoxide 23 (dr = 10:2), the domino
sequence produced azido lactone 24 in 61% yield (72% conversion)
Figure 1. Preparation of lactones 22a-q from the corresponding nitroaryl precursors, conditions: a) Zn, AcOH, 40 °C; b) H2, Pd/C, MeOH, rt; c)
H2, Pd/C, Ac2O, THF/tBuOH, rt; d) H2, Pd/C, Boc2O, MeOH, rt.
3
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Chemistry - A European Journal
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We gratefully acknowledge the CRUNCh network for a grant
(D.R.L.), ISCE-CHEM (Interreg IV, European Program), Labex
SynOrg (ANR-11-LABX-0029) and ANR (GPYRONE, 14-CE06-
0016-01) for financial support. We thank Erasmus for a fellowship
(S.N.), Brice Kauffmann (IECB, Pessac, France) and Prof. Paul
Williard (Brown University, USA) for X-ray analysis, Masahiro
Abe (Normandie Université) for further experiments. Calculations
were run at CRIANN supercomputing facilities, supported by
Région Normandie, France and the European Union.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: domino · regioselectivity · medium-sized lactones · ring
expansion
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4
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10.1002/chem.201705645
Chemistry - A European Journal
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it was difficult to prevent the degradation of the ozonide arising from
the most reactive olefin. This could explain the fair yield (50%)
obtained from this 3-step sequence. From the 1H and 13C NMR
analysis of the crude, no other regioisomer could be detected.
[15] In agreement with these calculations, we noted during a previous
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dialkylcyclohexane-1,3-dione: R. B. Devi, M. Henrot, M. De Paolis, J.
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chromatography.
[18] When treated with organomagnesium, organocerium or organolithium
alkynyl reagents in the presence of Lewis acids, only degradation of
the starting materials occurred. The combination of both reagents
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[19] This result provided an alternative to the strategy of
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electropositive bromide. See for example: Y. A. Cheng, T. Chen, C. K.
Tan, J. J. Heng, Y.-Y. Yeung, J. Am. Chem. Soc. 2012, 134,
16492−16495.
[20] CCDC 1532416, 1532415 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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[22] The relative configuration of 25 was deduced from the analysis of the
product 27 by 2D NMR spectroscopy.
[17] As a current limitation of the methodology, aldehydes derived from 1
with one of the ketone -substituted with phenyl or heteroatoms (F,
OAc) were decomposed upon treatment with NaBH4. Additionally,
aldehyde 4 failed to react with organocerium alkynyl reagent.
5
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10.1002/chem.201705645
Chemistry - A European Journal
Synthetic methodology
David Reyes Loya, Alexandre Jean,
Morgan Cormier, Stefano Nejrotti,
Jérôme Blanchet, Jacques Maddaluno,
Michaël De Paolis*______ Page – Page
Domino Ring Expansion:
Regioselective Access to 9-
Membered Lactones with a Fused
Indole Unit from 2-Nitrophenyl-1,3-
cyclohexanediones
Continuity with change: The domino ring expansion of 2-nitrophenyl-1,3-
cyclohexanediones connected to an electrophilic appendage – aldehyde and
epoxide – into 9-membered lactones was developed. Regio- and stereoselectivity
were observed upon treatment with carbon, aza, bromide and hydride nucleophiles,
opening access to highly substituted lactones.
6
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