A cation-directed two-component cascade approach to enantioenriched pyrroloindolines

Article abstract of DOI:10.1039/c4cc06683a

A cascade approach to complex pyrroloindolines bearing all-carbon quaternary stereocentres has been developed. This two-component process uses a chiral ammonium salt to control diastereo- and enantioselectivity in the addition of isocyanides to functionalized alkenes to afford pyrroloindolines with up to three stereocentres. A mechanistic proposal involving intramolecular hydrogen bond activation of the isocyanide is described.

Full text of DOI:10.1039/c4cc06683a

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A cation-directed two-component cascade
approach to enantioenriched pyrroloindolines†
Cite this: Chem. Commun., 2014,
50, 13585
Jamie R. Wolstenhulme, Alex Cavell, Matija Gredicak, Russell W. Driver and
ˇ
Martin D. Smith*
Received 25th August 2014,
Accepted 15th September 2014
DOI: 10.1039/c4cc06683a
www.rsc.org/chemcomm
A cascade approach to complex pyrroloindolines bearing all-carbon
In both of these processes, a chiral ammonium salt controls the
quaternary stereocentres has been developed. This two-component topicity of the cyclization, with concomitant activation of the
process uses a chiral ammonium salt to control diastereo- and isocyanide though hydrogen bonding (either via the substrate or
enantioselectivity in the addition of isocyanides to functionalized the catalyst).4 This approach is complementary to existing methods
alkenes to afford pyrroloindolines with up to three stereocentres. such as C-3 arylation5 or synthesis from the chiral pool, which have
A mechanistic proposal involving intramolecular hydrogen bond been demonstrated to be effective in the synthesis of complex
activation of the isocyanide is described.
pyrroloindoline-containing natural products.6 Here we report an
enantioselective two-component cascade to form pyrroloindolines
New methods for the rapid and stereoselective construction of containing three stereocentres, two of which are quaternary. We
complex organic frameworks from simple starting materials are reasoned that an isocyanide component could be deprotonated
valuable for target-oriented synthesis and the discovery of under basic conditions in the presence of a chiral ammonium salt
bioactive entities. As part of an on-going programme into the to form an ion pair, which could undergo an asymmetric Michael
development of new asymmetric phase transfer catalysed reactions, addition to an a,b-unsaturated ester.7 The enolate thus generated
we recently reported the synthesis of indolenines using the could subsequently cyclize onto the isocyanide to form an
intramolecular cyclization of a cyanocarbanion onto an isocyanide,1 intermediate pyrroline that can then be trapped by the adjacent
and subsequently extended this method to encompass the cascade N-protected aniline to form a pyrroloindoline. This approach
synthesis of pyrroloindolines bearing all-carbon quaternary stereo- has the potential to assemble the entire pyrroloindoline ring
centres (Fig. 1).2,3
system from simple and readily available precursors in a single
operation.
We began to explore the potential of this proposal by examining
the 1,4-addition of disubstituted symmetrical isocyanides 2 (Table 1).
Our preliminary investigations revealed that a,a-diaryl isocyanides
readily underwent the cascade in the presence of tetra n-butyl
ammonium bromide (TBAB) and potassium carbonate to afford a
single cis-fused diastereoisomer (as exemplified by 3), presumably
due to the ring strain associated with the alternative trans 5,5-ring
junction. The poor reactivity observed in the formation of 5
(22% isolated yield and 30% conversion of isocyanide)8 confirmed
our speculation that the acidity of the isocyanide component
could be important in the reaction, with relatively electron-poor
isocyanides delivering pyrroloindolines such as 4, 6 and 7 in
reasonable to good isolated yields.9
Fig. 1 Strategy for cascade assembly of pyrroloindolines.
The relationship between isocyanide acidity and overall conver-
sion observed in these preliminary investigations indicated that ease
of deprotonation could be a key consideration in the development
of a cascade that involved non-symmetric isocyanide components.
We were also interested to probe the effect of altering the aniline
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford,
OX1 3TA, UK. E-mail: martin.smith@chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Full experimental details,
1H and 13C NMR spectra and X-ray data. CCDC 1020472–1020476. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc06683a N-substituent and its ability to function as a hydrogen bond donor.
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Table 1 Preliminary cascade development. Conditions: 1 (1.0 eq.), 2
(1.0 eq.), TBAB (10 mol%), PhMe, K2CO3 (5.0 eq.), r.t., 16 h. Yields are for
isolated material
Treatment of a 1 : 1 mixture of isocyanide and a,b-unsaturated
ester in the presence of TBAB and potassium carbonate in toluene
afforded 11 and 12 in good yield, but in both cases as a 1 : 1
mixture of diastereoisomers. Gratifyingly, replacing the alkyl sub-
stituent with an aryl group was rewarded with a dramatic increase
in diastereoselectivity. Pyrroloindolines 13 and 14, featuring
2-nitro-5-fluoro and 2-nitro-5-methyl aromatic substituents respec-
tively were isolated in good yields as a single diastereoisomer
1
(420 : 1 by H NMR spectroscopy). We were able to confirm the
relative stereochemistry of 13 and 14 through X-ray crystallographic
analysis,10 which demonstrated that the methyl ester group occu-
pied the concave side of the pyrroloindoline scaffold, opposite to the
isopropyl ester group.11 The selectivity observed for this substrate
was consistent with other aryl-substituted isocyanides; this allowed
the synthesis of pyrroloindolines 17–21 as a single diastereoisomer.
Substitution on the Michael acceptor aryl ring was well-
tolerated, yielding 15 and 18 in 61% and 48% yields respectively
and with the same diastereoselectivity as previously observed.
Pleasingly, the nitro group in 16 could be replaced by a CF3 group (to
afford 20) or an electron donating OMe group (to give 17). Changing
the aniline N-substituent from a carbamate to an amide (as in 19) or
a urea (as in 21) was also successful, generating pyrroloindoline
products with three stereocentres as a single diastereoisomer. With
conditions for the diastereoselective cascade in hand, we decided to
a
Reaction time was 3 days.
Initially, we employed alkyl-substituted isocyanides derived from
valine and phenylalanine (R = isopropyl and benzyl respectively)
to evaluate their efficiency in our proposed cascade (Table 2).
Table
2
Diastereoselective synthesis of pyrroloindolines. Conditions:
Michael acceptor 8 (1.0 eq.), isocyanide 9 (1.0 eq.), TBAB (10 mol%), PhMe,
K2CO3 (5.0 eq.), r.t., 2–24 h. d.r. determined by 1H NMR spectroscopy
Table 3 Enantioselective reaction optimization. Conditions: 22 (1.0 eq.),
23 (1.1 eq.), catalyst (10 mol%), r.t., 24 h. d.r. determined by 1H NMR
spectroscopy. e.r. determined by chiral stationary phase HPLC
Entry
Catalyst
Base (eq.)
Solvent
e.r.
1
2
3
4
5
6
7
8
24
24
24
24
24
30
25
31
26
28
27
29
29
K2CO3 (5)
K2CO3 (5)
Na2CO3 (5)
Cs2CO3 (5)
K2CO3 (10)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
Toluene
80 : 20
82 : 18
n.r.
m-Xylene
m-Xylene
m-Xylene
m-Xylene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
65 : 35
82 : 18
25 : 75
81 : 19
23 : 77
57 : 43
23 : 77
68 : 32
87 : 13
91 : 9
9
10
11
12
13a
Toluene
Tol./CHCl3/H2Ob
a
a
b
KOH (25% w/w, aq.) was used as base.
Reaction was performed at À20 1C. Solvent ratio 15: 4: 1 respectively.
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examine the potential for an enantioselective catalytic trans- satisfactory results (as in 33). It may be that the extra acidity
formation. Preliminary studies revealed that a urea was the that an o-nitroaryl substituent imparts is necessary for reac-
most effective N-substituent for the cyclization and hence we tions involving cinchona alkaloid derived ammonium salts;
used substrate 22 and isocyanide 23 in our search (Table 3).
these are generally considered to exhibit poorer reactivity in
A survey of solvent and base combinations identified non-polar base-mediated reactions than simple alkylammonium salts.12
aromatic solvents and solid potassium carbonate as optimum The scalability of the reaction was demonstrated by the gram
(entry 1), together with cinchona-derived ammonium salts. Probing scale synthesis of 34, which was formed as a single diastereo-
the effect of different catalyst N-alkyl groups (entries 6–13) demon- isomer in 76% yield and 92 : 8 e.r.
strated that electron-poor benzylic groups on a quinidinium
During these asymmetric cascade processes we also observed
scaffold were most enantioselective, yielding 21 in 91 : 9 e.r. The the formation of another compound in trace amounts, particularly
addition of chloroform as a co-solvent was advantageous, likely with longer reaction times (Scheme 1).
aiding solubility of the urea substrate.
This was subsequently identified by X-ray crystallography as
With optimum conditions for the preparation of 21 estab- spirocyclic pyrroline 39. This material was isolated with the
lished, the scope of the enantioselective reaction was explored same d.r. and e.r. as the pyrroloindoline 21,13 and hence we
using a range of a-aryl substituted isocyanides (Table 4). In speculated that it might arise from a subsequent transformation
general the reaction is very effective, furnishing pyrroloindolines of the pyrroloindoline itself (Scheme 1). Consequently, we treated
in good yield and generally good to excellent diastereoselectivity 21 with TBAB and observed smooth conversion to 39 over 48 h,
as well as high enantioselectivity. The reaction is tolerant of once again without change in d.r. or e.r. With this information
different ester groups on the isocyanide; changing from Me to Bn we are able to propose a plausible mechanism for the cascade
i
to Pr esters led to pyrroloindolines 21, 32 and 34 respectively, reaction (Scheme 2). Initial enantiodetermining Michael addition
all as a single diastereoisomer and with high levels of enantio- of isocyanocarbanion 40 onto the a,b-unsaturated ester 41 is
control (e.r. up to 93 : 7). A limitation of the enantioselective effectively irreversible when mediated with cinchona alkaloids.
transformation is that an ortho-nitro group is required for The resultant intermediate ester enolate 42 can then undergo
a diastereoselective 5-endo-dig cyclization onto the isocyanide,
which is activated through intramolecular hydrogen bonding
Table 4 Enantioselective pyrroloindoline formation. Conditions: Michael
from the acylated aniline as in 43. This preferentially orientates
acceptor (1.0 eq.), isocyanide (1.1 eq.), catalyst 29 (10 mol%), PhMe : CHCl3 :
H2O 15 : 4 : 1, K2CO3 (5.0 eq.), À20 1C, 48 h. d.r. determined by 1H NMR
spectroscopy. e.r. determined by chiral stationary phase HPLC. e.r.
reported for the major diastereoisomer
Scheme 1 Unanticipated rearrangement. Conditions: TBAB (20 mol%),
PhMe, K2CO3 (5.0 eq.), r.t., 48 h.
a
b
Reaction was performed at 0 1C. Reaction was performed on a
1 g scale.
Scheme 2 Proposed mechanistic pathway.
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4 For phase transfer catalysts bearing Brønsted acidic groups see:
the smaller (ester) group on the more hindered concave face of
the nascent bicycle rather than the larger aryl substituent. It is
interesting to speculate whether the chiral cation is influential
in the diastereoselective pyrroline-forming reaction or whether
this is directed exclusively by the existing stereocentre. Once the
pyrroline has been formed in 44, ring closure to form the
pyrroloindoline skeleton inevitably leads to the cis-fused bicycle
45 due to the increased strain associated with the alternative
trans-isomer. The spirocycle 46 is likely formed through rever-
sible ring closing and ring opening of the indoline ring,
with subsequent trapping of the aniline nitrogen onto the
benzylic ester, giving rise to the amide as the thermodynamic
product.
´
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7 For organocatalytic reactions involving 1,4 addition of isocyanides see:
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In conclusion, we have developed an enantioselective two-
component approach to the synthesis of pyrroloindolines. This
cascade process, which exploits the remarkable reactivity profile
of the isocyanide functional group, offers a rapid and stereo-
selective approach to highly functionalized scaffolds that may
find application as natural product analogues and frameworks
for the discovery of bioactive compounds.
The European Research Council has provided financial
support (FP7/2007-2013)/ERC grant agreement no. 259056. This
work was supported by EPSRC and NSF (CHE-1026826), and the
Croatian Science Foundation (to M.G., grant no. 02.03./158).
We gratefully acknowledge the Diamond Light Source for an
award of instrument time on I19 (MT7768). We are grateful to
Keishi Kohara for helpful preliminary studies.
8 Complete consumption of the Michael acceptor was observed in this
reaction.
9 It is likely that the acidity of isonitriles affects the concentration of
reactive isocyanocarbanion in the organic phase (which ultimately
affects the rate of 1,4-addition). For the fluorenyl and di(chloroaryl)
isocyanides, complete consumption of isocyanide was observed but
a byproduct (likely carbene-derived) was also isolated in 34% and
25% yields respectively; see ESI† for full details.
10 X-ray crystal data for 13, 14 and 39 (CCDC 1020472, 1020473 and
1020474 respectively). Crystal data for two diastereoisomeric spiro-
cycles analogous to 39 is also included (CCDC 1020475 and 1020476
respectively).
11 The relative stereochemistry of other examples was assigned by
analogy to the X-ray structures of 13 and 14. We also observed a
diagnostic chemical shift of the 5,5-ring junction proton in 1H NMR
spectra which was used as further confirmation of stereochemical
outcome. See ESI† for further details.
12 M. Rabinovitz, Y. Cohen and M. Halpern, Angew. Chem., Int. Ed. Engl.,
1986, 25, 960.
Notes and references
1 (a) E. E. Maciver, P. C. Knipe, A. P. Cridland, A. L. Thompson and
M. D. Smith, Chem. Sci., 2012, 3, 537; (b) M. Li, P. A. Woods and
M. D. Smith, Chem. Sci., 2013, 4, 2907.
ˇ
2 P. C. Knipe, M. Gredicak, A. Cernijenko, R. S. Paton and M. D. Smith,
Chem. – Eur. J., 2014, 20, 3005.
3 For a review of catalytic methods for the synthesis of pyrroloindolines
see: L. M. Repka and S. E. Reisman, J. Org. Chem., 2013, 78, 12314.
13 In a control reaction we found that subjecting enantioenriched 21
(87 : 13 e.r.) to the reaction conditions using TBAB (r.t.) resulted in
only a small erosion of e.r. (to 85 : 15) in recovered 21.
13588 | Chem. Commun., 2014, 50, 13585--13588
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